CDC Clinical Practice Guideline for Prescribing Opioids for Pain

Morbidity and Mortality Weekly Report

Recommendations and Reports / Vol. 71 / No. 3 November 4, 2022

U.S. Department of Health and Human Services

Centers for Disease Control and Prevention

CDC Clinical Practice Guideline for Prescribing

Opioids for Pain — United States, 2022

The MMWR series of publications is published by the Center for Surveillance, Epidemiology, and Laboratory Services, Centers for Disease Control and Prevention (CDC),

U.S. Department of Health and Human Services, Atlanta, GA 30329-4027.

Suggested citation: [Author names; first three, then et al., if more than six.] [Title]. MMWR Recomm Rep 2022;71(No. RR-#):[inclusive page numbers].

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Recommendations and Reports

CONTENTS

Introduction ............................................................................................................1

Clinical Practice Guideline Development Methods

..................................9

Recommendations

............................................................................................. 15

Determining Whether or Not to

Initiate Opioids for Pain

................................................................................. 17

Recommendation 1

.......................................................................................... 17

Recommendation 2

.......................................................................................... 21

Selecting Opioids and Determining

Opioid Dosages

................................................................................................ 28

Recommendation 3

........................................................................................... 28

Recommendation 4

........................................................................................... 30

Recommendation 5

........................................................................................... 32

Deciding Duration of Initial Opioid Prescription and Conducting

Follow-Up

........................................................................................................... 38

CONTENTS (Continued)

Recommendation 6 ........................................................................................... 38

Recommendation 7

........................................................................................... 40

Assessing Risk and Addressing Potential Harms of Opioid Use

........ 43

Recommendation 8

........................................................................................... 43

Recommendation 9

........................................................................................... 48

Recommendation 10

........................................................................................ 50

Recommendation 11

........................................................................................ 52

Recommendation 12

........................................................................................ 54

Conclusion and Future Directions

................................................................ 59

References

............................................................................................................. 62

Appendix: Primary Clinical Questions, Detailed Methods, and

Findings for the Systematic and Contextual Evidence Reviews

..... 77

References

............................................................................................................. 88

MMWR / November 4, 2022 / Vol. 71 / No. 3 1

US Department of Health and Human Services/Centers for Disease Control and Prevention

CDC Clinical Practice Guideline for Prescribing Opioids for Pain —

United States, 2022

Deborah Dowell, MD

; Kathleen R. Ragan, MSPH

; Christopher M. Jones, PharmD, DrPH

; Grant T. Baldwin, PhD

; Roger Chou, MD

Division of Overdose Prevention, National Center for Injury Prevention and Control, CDC;

Office of the Director, National Center for Injury Prevention and Control, CDC;

Pacific Northwest Evidence-based Practice Center and Oregon Health & Science University, Portland, Oregon

Summary

This guideline provides recommendations for clinicians providing pain care, including those prescribing opioids, for outpatients

aged ≥18 years. It updates the CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016 (MMWR

Recomm Rep 2016;65[No. RR-1]:1–49) and includes recommendations for managing acute (duration of <1 month), subacute

(duration of 1–3 months), and chronic (duration of >3 months) pain. The recommendations do not apply to pain related to

sickle cell disease or cancer or to patients receiving palliative or end-of-life care. The guideline addresses the following four areas:

1) determining whether or not to initiate opioids for pain, 2) selecting opioids and determining opioid dosages, 3) deciding

duration of initial opioid prescription and conducting follow-up, and 4) assessing risk and addressing potential harms of opioid

use. CDC developed the guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE)

framework. Recommendations are based on systematic reviews of the scientific evidence and reflect considerations of benefits and

harms, patient and clinician values and preferences, and resource allocation. CDC obtained input from the Board of Scientific

Counselors of the National Center for Injury Prevention and Control (a federally chartered advisory committee), the public, and

peer reviewers. CDC recommends that persons with pain receive appropriate pain treatment, with careful consideration of the

benefits and risks of all treatment options in the context of the patient’s circumstances. Recommendations should not be applied

as inflexible standards of care across patient populations. This clinical practice guideline is intended to improve communication

between clinicians and patients about the benefits and risks of pain treatments, including opioid therapy; improve the effectiveness

and safety of pain treatment; mitigate pain; improve function and quality of life for patients with pain; and reduce risks associated

with opioid pain therapy, including opioid use disorder, overdose, and death.

Introduction

Background

Pain is one of the most common reasons adults seek medical

care in the United States (1). Acute pain, a nearly universal

experience, is a physiologic response to noxious stimuli that

can become pathologic. Acute pain is usually sudden in onset

and time limited (defined in this clinical practice guideline

as having a duration of <1 month) and often is caused by

injury, trauma, or medical treatments such as surgery (2,3).

Unresolved acute pain or subacute pain (defined in this clinical

practice guideline as pain that has been present for 1–3 months)

can evolve into chronic pain (4). Chronic pain typically lasts

>3 months (4) and can be the result of an underlying medical

disease or condition, injury, medical treatment, inflammation,

or unknown cause (2). Approximately one in five U.S. adults

had chronic pain in 2019 and approximately one in 14 adults

Corresponding author: Division of Overdose Prevention, National Center

for Injury Prevention and Control, CDC. Email: [email protected].

experienced “high-impact” chronic pain, defined as having pain

on most days or every day during the past 3 months that limited

life or work activities (5). Pain, especially chronic pain, can

affect almost every aspect of a person’s life, leading to impaired

physical functioning, poor mental health, and reduced quality

of life, and contributes to substantial morbidity each year (6).

In 2011, the economic costs of chronic pain were estimated

to range from $560 to $635 billion in annual direct medical

costs, lost productivity, and disability (2).

Pain is a complex phenomenon influenced by multiple

factors, including biologic, psychological, and social factors

(7). This complexity means substantial heterogeneity exists

in the effectiveness of various pain treatments, depending

on the type of underlying pain or condition being treated

(7–11). Patients might experience persistent pain that is

not well controlled (6). Chronic pain often co-occurs with

behavioral health conditions, including mental and substance

use disorders (12,13). Patients with chronic pain also are at

increased risk for suicidal ideation and behaviors (14,15).

Data from death investigations in 18 states during 2003–2014

indicate that approximately 9% of suicide decedents had

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evidence of having chronic pain at the time of death; however,

this is likely an underestimate because of the limitations of the

underlying data sources used in the study (16). These factors

and potentially harmful outcomes associated with chronic pain

for some persons add to the clinical complexity and underscore

the importance of adequately treating and providing care

to persons with pain. Thus, prevention, assessment, and

treatment of pain is a persistent challenge for clinicians. Pain

might go unrecognized, and some persons (e.g., members of

marginalized racial and ethnic groups; women; older persons;

persons with cognitive impairment; persons with mental and

substance use disorders, sickle cell disease, or cancer-related

pain; and persons at the end of life) can be at risk for inadequate

pain treatment (2,6,17–23).

Although substantial opportunity exists for improved pain

management broadly across the United States, data underscore

opportunities for addressing specific, long-standing health

disparities (24–26) in the treatment of pain. For example,

patients who identify as Black or African American (Black),

Hispanic or Latino (Hispanic), and Asian receive fewer

postpartum pain assessments relative to White patients (27).

Black (28,29) and Hispanic (29) patients are less likely than

White patients to receive analgesia for acute pain. Among

Black and White patients receiving opioids for pain, Black

patients are less likely to be referred to a pain specialist, and

Black patients receive prescription opioids at lower dosages

than White patients (24,30). Racial and ethnic differences

remain even after adjusting for access-related factors, the

needs and preferences of patients, and the appropriateness of

the intervention (25). These disparities appear to be further

magnified for Black and Hispanic patients who live in

socioeconomically disadvantaged neighborhoods (26). Women

might be at higher risk for inadequate pain management

(31), although they have higher opioid prescription fill rates

(32) than men at a population level. Geographic disparities

contribute to increased use of opioids for conditions for which

nonopioid treatment options might be preferred but are less

available. For example, adults living in rural areas are more

likely to be prescribed opioids for chronic nonmalignant

pain than adults living in nonrural areas (33). Although not

Hispanic or Latino (non-Hispanic) American Indian or Alaska

Native and non-Hispanic White populations have experienced

much higher rates of prescription opioid–related overdose

deaths than non-Hispanic Black, Hispanic, or non-Hispanic

Asian or Pacific Islander populations (34), application of

safeguards in opioid prescribing are disproportionately applied

to Black patients. In one study, Black patients were more likely

than White patients to receive regular office visits and have

restricted early refills (35). In another study, clinicians were

substantially more likely to discontinue opioids if there was

evidence of misuse for Black patients compared with White

patients (36). Differentially untreated or undertreated pain

as a result of clinician biases persists and demands immediate

and sustained attention and action (37–40).

Because of the clinical, psychological, and social consequences

associated with pain, including limitations in activities, lost

work productivity, reduced quality of life, and pervasive stigma,

it is essential that clinicians have the training, education,

guidance, and resources to provide appropriate, holistic, and

compassionate care for patients with pain (2,6). An important

aim of pain management is the provision of person-centered

care built on trust between patients and clinicians. Such care

includes appropriate evaluation to identify potentially reversible

causes of pain and establish a diagnosis and measurable

treatment outcomes that focus on optimizing function and

quality of life (6). To achieve this aim, it is important that

clinicians consider the full range of pharmacologic and

nonpharmacologic treatments for pain care, and that health

systems, payers, and governmental programs and entities make

the full spectrum of evidence-based treatments accessible to

patients with pain and their treating clinicians.

The range of therapeutic options has historically been

inaccessible to many patients because of factors such as

inadequate clinician education, training, and guidance;

unconscious bias; a shortage of pain management specialists;

insufficient access to treatment modalities such as behavioral

therapy; siloed health systems; insurance coverage and

reimbursement policies; and lack of clarity about the evidence

supporting different pain treatments (6,17

,41–46). Partly

because of these factors affecting access to a wide range of

treatment modalities, for many years medications such as

prescription opioids have been the mainstay to treat pain,

despite very limited evidence to support their long-term

(>1 year) benefits; most placebo-controlled trials have been

<6 weeks in duration (2,6,47,48).

Opioids can be essential medications for the management

of pain; however, they carry considerable potential risk.

A systematic review published in 2014 by the Agency for

Healthcare Research and Quality (AHRQ) found insufficient

evidence to demonstrate long-term benefits of prescription

opioid treatment for chronic pain, and long-term prescription

opioid use was found to be associated with increased risk for

overdose and opioid misuse, among other risks (47). Some

risks, such as overdose, were dose dependent (47). In 2014, on

the basis of accumulating evidence of potential risks to patients,

the Food and Drug Administration (FDA) required new safety

labeling changes for extended-release and long-acting opioids.

Changes included a boxed warning on the “risks of addiction,

abuse, and misuse, which can lead to overdose and death”

and, for patients receiving opioids during pregnancy, the risk

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for neonatal abstinence syndrome (a group of conditions that

can occur when newborns withdraw from certain substances

including opioids; withdrawal caused by in utero exposure to

opioids also is called neonatal opioid withdrawal syndrome)

(49). In 2016, these warnings were added to the labels for

immediate-release opioids (50).

In addition to the potential risks to patients, prescribed

opioids have the potential for diversion and nonmedical

use among persons to whom they were not prescribed (51).

In the United States, opioid prescribing increased fourfold

during 1999–2010; this increase was paralleled by an

approximately fourfold increase in overdose deaths involving

prescription opioids during the same period (52) and increases

in prescription opioid use disorder (53). In addition to the

increased overall volume of opioid prescriptions during this

period, how opioids were prescribed also changed; opioids

increasingly were prescribed at higher dosages and for longer

durations, prescribing behaviors associated with opioid use

disorder and overdose (54,55). The limited evidence of long-

term effectiveness of opioids for chronic pain, coupled with

risks to patients and to persons using prescription opioids that

were not prescribed to them, underscored the importance of

reducing inappropriate opioid prescribing while advancing

evidence-based pain care to improve the lives of persons living

with pain.

CDC recognized the need for a national guideline on pain

management that could improve appropriate opioid prescribing

while minimizing opioid-related risks and released the CDC

Guideline for Prescribing Opioids for Chronic Pain — United

States, 2016 (referred to as the 2016 CDC Opioid Prescribing

Guideline hereafter). The 2016 CDC Opioid Prescribing

Guideline included 12 recommendations for the prescribing

of opioids for chronic pain by primary care clinicians in

outpatient settings, excluding active cancer treatment, palliative

care, and end-of-life care (56). The recommendations in the

2016 CDC Opioid Prescribing Guideline were based on a

systematic review of the best-available evidence at the time,

along with input from experts and the public and review and

deliberation by the Board of Scientific Counselors (BSC)

of the National Center for Injury Prevention and Control

(NCIPC) (a federally chartered advisory committee). The

goals of the guideline were to 1) ensure that clinicians and

patients considered safer and more effective pain treatment;

2) improve patient outcomes, such as reduced pain and

improved function; and 3) reduce the number of persons

who developed opioid use disorder, experienced overdose,

or experienced other prescription opioid–related adverse

events (56). To facilitate uptake and implementation of the

2016 CDC Opioid Prescribing Guideline in clinical practice,

CDC used a broad-reaching strategy that included clinician

education and training, partnerships with health systems and

payers, and multiple clinical tools and fact sheets (57).

The number of overall opioid prescriptions in the United

States declined after 2012, and further declines have been

observed after the release of the 2016 CDC Opioid Prescribing

Guideline (58). The timing of this release was associated

with accelerated decreases in overall opioid prescribing and

declines in potentially high-risk prescribing (e.g., high-dosage

opioid prescribing and concurrent prescribing of opioid

pain medication and benzodiazepines) (58,59). The release

of the 2016 CDC Opioid Prescribing Guideline also was

temporally associated with modest increases in the prescribing

of nonopioid pain medication (60). Although not the intent

of the 2016 CDC Opioid Prescribing Guideline, design and

implementation of new laws, regulations, and policies also

appeared to reflect its recommendations. For example, since

2016, consistent with SUPPORT Act requirements (61), some

state Medicaid programs have used the guideline and other

resources to promote nonopioid options for chronic pain

management (62). Approximately half of all states have passed

legislation limiting initial opioid prescriptions for acute pain

to a ≤7-day supply (63), and many insurers, pharmacy benefit

managers, and pharmacies have enacted similar policies (64).

At least 17 states have passed laws requiring or recommending

the coprescription of naloxone in the presence of overdose risk

factors, such as high dosages of opioids or concomitant opioid

pain medications and benzodiazepines (65).

Although some laws, regulations, and policies that appear

to support recommendations in the 2016 CDC Opioid

Prescribing Guideline might have had positive results for

some patients, they are inconsistent with a central tenet of

the guideline: that the recommendations are voluntary and

intended to be flexible to support, not supplant, individualized,

patient-centered care. Of particular concern, some policies

purportedly drawn from the 2016 CDC Opioid Prescribing

Guideline have been notably inconsistent with it and have

gone well beyond its clinical recommendations (6,66,67). Such

misapplication includes extension to patient populations not

covered in the 2016 CDC Opioid Prescribing Guideline (e.g.,

cancer and palliative care patients), rapid opioid tapers and

abrupt discontinuation without collaboration with patients,

rigid application of opioid dosage thresholds, application of

the guideline’s recommendations for opioid use for pain to

medications for opioid use disorder treatment (previously

referred to as medication assisted treatment), duration

limits by insurers and pharmacies, and patient dismissal and

abandonment (66–68). These actions are not consistent

with the 2016 CDC Opioid Prescribing Guideline and

have contributed to patient harm, including untreated and

undertreated pain, serious withdrawal symptoms, worsening

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pain outcomes, psychological distress, overdose, and suicidal

ideation and behavior (66–71).

Rationale

Since release of the 2016 CDC Opioid Prescribing

Guideline, new evidence has emerged on the benefits and

risks of prescription opioids for both acute and chronic

pain, comparisons with nonopioid pain treatments, dosing

strategies, opioid dose-dependent effects, risk mitigation

strategies, and opioid tapering and discontinuation (7–11).

This evidence includes studies on misapplication of the 2016

CDC Opioid Prescribing Guideline (66), benefits and risks

of different tapering strategies and rapid tapering associated

with patient harm (68,71–73), challenges in patient access to

opioids (6), patient abandonment and abrupt discontinuation

of opioids (71), a seminal randomized clinical trial comparing

prescription opioids to nonopioid medications on long-term

pain outcomes (74), the association of characteristics of initial

opioid prescriptions with subsequent likelihood for long-term

opioid use (75,76), and the small proportion of opioids used

by patients compared with the amount prescribed to them for

postoperative pain (77–79).

Opioid medications remain a common treatment for pain

despite declines in the number of opioid prescriptions after

2012 (58). During 2015–2018, approximately 6% of U.S.

adults reported use of one or more prescription opioids during

the past 30 days (80), and in 2020, approximately 143 million

opioid prescriptions were dispensed from pharmacies in the

United States (81). Rates of opioid prescribing continue to vary

across states, medical specialties, patient demographics, and pain

conditions in ways that cannot be explained by the underlying

health status of the population, and often are discordant with

the 2016 CDC Opioid Prescribing Guideline recommendations

(25,77,82–84). The prevalence of prescription opioid misuse

and prescription opioid use disorder also has declined in recent

years. In 2019, among persons aged ≥12 years in the United

States, 9.7 million reported misuse of prescription opioids

during the past year (a decrease from 12.5 million in 2015), and

1.4 million met criteria for a past-year prescription opioid use

disorder (a decrease from 2.0 million in 2015) (85). However,

in 2020, prescription opioids remained the most commonly

misused prescription drug in the United States (51). Also in

2020, among those reporting misuse during the past year, 64.6%

reported the main reason for their most recent misuse was to

“relieve physical pain” compared with 11.3% to “feel good or get

high” and 2.3% “because I am hooked or have to have it” (51).

Taken together, these factors underscore the need for an updated

clinical practice guideline on appropriate opioid prescribing for

pain and pain management.

This clinical practice guideline expands and updates

the 2016 CDC Opioid Prescribing Guideline to provide

evidence-based recommendations for prescribing opioid

pain medication for acute, subacute, and chronic pain for

outpatients aged ≥18 years, excluding pain management

related to sickle cell disease, cancer-related pain treatment,

palliative care, and end-of-life care (Boxes 1 and 2). Lessons

learned from the development of the 2016 CDC Opioid

Prescribing Guideline informed the process used to generate

this update. This update leverages new data to expand content

on prescription opioids for acute and subacute pain throughout

the recommendations. Importantly, the update also aims to

clearly delineate recommendations that apply to patients who

are being considered for initial treatment with prescription

opioids and patients who have been receiving opioids as part

of their ongoing pain management.

CDC developed a draft clinical practice guideline on

the basis of five systematic reviews of the best-available

evidence on the benefits and risks of prescription opioids,

nonopioid pharmacologic treatments, and nonpharmacologic

treatments. The draft clinical practice guideline was reviewed

by an independent federal advisory committee (the Board

of Scientific Counselors of the National Center for Injury

Prevention and Control), peer reviewers, and the public and

was revised after feedback from these reviews. Additional

insights from patients, caregivers, and clinicians shared during

virtual conversations held in 2020 were incorporated in the

update. Importantly, to discourage the misapplication of opioid

pain medication dosage thresholds as inflexible standards,

revised recommendation statement language emphasizes

principles such as avoiding increasing dosage above levels

likely to yield diminishing returns in benefits relative to risks

to patients. More-specific considerations related to dosage

have been moved to implementation considerations that

follow each recommendation statement, where more nuance is

offered to inform clinical decision-making and individualized

patient care.

This clinical practice guideline provides recommendations

but does not replace clinical judgment and individualized,

patient-centered decision-making. The recommendations are

based on emerging evidence, including observational studies or

randomized clinical trials with notable limitations; thus, they

should be considered in the context of the clinician-patient

relationship built on shared understanding and a whole-person

approach that considers such factors as the patient’s physical

and psychological functioning, support needs, expected

health outcomes and well-being, home environment, and

home and work responsibilities. Flexibility for clinicians and

patients is paramount when making patient-centered clinical

treatment decisions. The recommendations aim to improve

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BOX 1. Executive summary of the CDC Clinical Practice Guideline for Prescribing Opioids for Pain — United States, 2022

This clinical practice guideline updates and expands

the CDC Guideline for Prescribing Opioids for Chronic

Pain — United States, 2016 (MMWR Recomm Rep

2016;65[No. RR-1]:1–49]) and provides evidence-based

recommendations for primary care and other clinicians

(including physicians, nurse practitioners and other

advanced practice registered nurses, physician assistants,

and oral health practitioners) providing pain care, including

those prescribing opioids, for outpatients aged ≥18 years

with acute (duration of <1 month) pain, subacute (duration

of 1–3 months) pain, or chronic (duration of >3 months)

pain. Recommendations on use of opioids for acute pain

and on tapering opioids for patients already receiving

opioid therapy have been substantially expanded in this

update. These recommendations do not apply to patients

experiencing pain associated with the following conditions

or settings: pain management related to sickle cell disease,

cancer-related pain treatment, palliative care, and end-of-life

care. Applicable outpatient settings include clinician offices,

clinics, and urgent care centers. The recommendations do

not apply to providing care to patients who are hospitalized

or in an emergency department or other observational

setting from which they might be admitted to inpatient care.

These recommendations do apply to prescribing for pain

management when patients are discharged from hospitals,

emergency departments, or other facilities.

This clinical practice guideline addresses the following areas:

1. Determining whether or not to initiate opioids

for pain

2. Selecting opioids and determining opioid dosages

3. Deciding duration of initial opioid prescription and

conducting follow-up

4. Assessing risk and addressing potential harms of

opioid use

CDC developed this clinical practice guideline using the

Grading of Recommendations Assessment, Development,

and Evaluation (GRADE) framework, and recommendations

are made based on a systematic review of the available

scientific evidence while considering benefits and harms;

values and preferences of patients, caregivers, and clinicians;

and resource allocation (e.g., costs to patients or health

systems, including clinician time). CDC obtained input

on this clinical practice guideline through individual

conversations with patients, caregivers, and clinicians and

public comment opportunities available via Federal Register

notices. CDC also sought input from the Board of Scientific

Counselors of the National Center for Injury Prevention

and Control (BSC/NCIPC) (a federally chartered advisory

committee), federal partners, and peer reviewers with

scientific and clinical expertise.

The clinical evidence reviews found that a number of

nonpharmacologic treatments and a number of nonopioid

medications are associated with improvements in pain,

function, or both, that appear comparable to improvements

associated with opioid use. Multiple noninvasive

nonpharmacologic interventions (e.g., exercise and

psychological therapies) are associated with improvements

in pain, function, or both, that are sustained after treatment

and are not associated with serious harms. Nonopioid drugs,

including serotonin and norepinephrine reuptake inhibitor

(SNRI) antidepressants, pregabalin and gabapentin, and

nonsteroidal anti-inflammatory drugs (NSAIDs), are

associated with small to moderate improvements in chronic

pain and function for certain chronic pain conditions.

Nonopioid drug class–specific adverse events include serious

cardiovascular, gastrointestinal, or renal effects with NSAIDs

and sedation with anticonvulsants. Opioid therapy is

associated with similar or decreased effectiveness for pain and

function versus NSAIDs across several acute pain conditions

and with small improvements in short-term (1 to <6 months)

pain and function compared with placebo; evidence was

found of attenuated pain reduction over time with opioids

(between 3 and 6 months versus between 1 and 3 months).

Opioid therapy is associated with increased risk for serious

harms (including opioid use disorder and overdose) that

appears to increase with increase in opioid dosage, without

a clear threshold below which there is no risk. No validated,

reliable way exists to predict which patients will suffer serious

harm from opioid therapy. Evidence was sparse for long-

term improvement of pain or function for any treatment

for chronic pain. Some evidence indicated that beneficial

effects of some nonpharmacologic therapies persist for

up to 12 months after the end of a course of a treatment.

Among 154 trials of nonopioid medications rated as good

or fair quality, eight were long term (≥1 year). A single

trial evaluated outcomes at 1 year for opioid medications

(compared with nonopioid medications).

Continued on the next page.

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BOX 1. (Continued) Executive summary of the CDC Clinical Practice Guideline for Prescribing Opioids for Pain — United States, 2022

CDC invited input on the draft clinical practice guideline

and received approximately 5,500 public comments. Many of

these comments were related to experiences with pain or with

the aftermath of a family member’s, friend’s, or significant

person’s overdose; barriers to and access to pain care and

evidence-based treatment; concerns about the level of

specificity of recommendations; and overall communication

and implementation of the clinical practice guideline. Some

respondents expressed concerns that insufficient specificity of

recommendations might leave clinicians without sufficient

practical advice or context, whereas others were concerned

that inclusion of more-specific recommendations or

information in the guideline could facilitate misapplication

through adaption of the clinical practice guideline or

components of the guideline into rigid policies and laws.

CDC incorporated insights from public comments into the

clinical practice guideline, including special considerations

for each recommendation. To help prevent misapplication

of recommendations as inflexible rules and enable clinicians

to account for individualized, person-centered clinical

considerations, specific prescription dosages and durations

are generally not included in the summary recommendation

statements, which highlight general principles. Greater

specificity is provided in implementation considerations and

supporting rationales, which can offer more flexibility to help

clinicians weigh benefits and risks of different therapeutic

courses for specific patients.

Recommendation statements emphasize that opioids

should be used only when benefits for pain and function

are expected to outweigh risks. Before initiating opioid

therapy for patients with pain, clinicians should discuss

with patients the realistic benefits and known risks of opioid

therapy. Before starting ongoing opioid therapy for patients

with subacute or chronic pain, clinicians should work with

patients to establish treatment goals for pain and function

and consider how opioid therapy will be discontinued if

benefits do not outweigh risks. When opioids are initiated,

clinicians should prescribe the lowest effective dosage of

immediate-release opioids for no longer than needed for the

expected duration of pain severe enough to require opioids.

During ongoing opioid therapy, clinicians should collaborate

with patients to evaluate and carefully weigh benefits and

risks of continuing opioid therapy and exercise care when

increasing, continuing, or reducing opioid dosage. Before

starting and periodically during continuation of opioid

therapy, clinicians should evaluate risk for opioid-related

harms and should work with patients to incorporate relevant

strategies to mitigate risk, including offering naloxone and

reviewing potential interactions with any other prescribed

medications or substances used. Clinicians should offer or

arrange treatment with evidence-based medications to treat

patients with opioid use disorder.

CDC recommends that persons with pain receive

appropriate pain treatment with careful consideration of the

benefits and risks of all treatment options in the context of the

patient’s circumstances. Clinicians should collaborate with

patients when making treatment decisions and designing a

treatment plan, including when initiating or changing pain

management strategies and particularly when considering

initiating, increasing, tapering, or discontinuing opioids.

Clinicians should avoid abrupt discontinuation of opioids,

especially for patients receiving high dosages of opioids,

should avoid dismissing patients from care, and should

ensure (provide or arrange) appropriate care for patients

with pain and patients with complications from opioid use

(e.g., opioid use disorder). Quality and equitable care across

sociodemographic groups requires attention to mitigation

of potential barriers to care, such as through linguistically

tailored care and cost-assistance programs to ensure access

to appropriate pharmacotherapy, psychological support, and

physical therapy as needed.

This voluntary clinical practice guideline provides

recommendations only and is intended to support, not

supplant, clinical judgment and individualized, person-

centered decision-making. This clinical practice guideline

should not be applied as inflexible standards of care across

patient populations by health care professionals; health

systems; pharmacies; third-party payers; or state, local,

or federal organizations or entities. This clinical practice

guideline is intended to improve communication between

clinicians and patients about the benefits and risks of pain

treatment, including opioid therapy for pain; improve the

safety and effectiveness of pain treatment; mitigate pain;

improve function and quality of life for patients with

pain; and reduce risks associated with opioid pain therapy,

including opioid use disorder, overdose, and death.

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BOX 2. Intended use of CDC’s Clinical Practice Guideline for

Prescribing Opioids for Pain — United States, 2022

This clinical practice guideline is

• a clinical tool to improve communication between

clinicians and patients and empower them to make

informed, person-centered decisions related to pain

care together;

• intended for primary care clinicians and other

clinicians providing pain care for outpatients aged

≥18 years with



acute pain (duration of <1 month),



subacute pain (duration of 1–3 months), or



chronic pain (duration of >3 months); and

• intended to be flexible to enable person-centered

decision-making, taking into account a patient’s

expected health outcomes and well-being.

This clinical practice guideline is not

• a replacement for clinical judgment or individualized,

person-centered care;

• intended to be applied as inflexible standards of care

across patients or patient populations by health care

professionals, health systems, pharmacies, third-party

payers, or governmental jurisdictions or to lead to the

rapid tapering or abrupt discontinuation of opioids

for patients;

• a law, regulation, or policy that dictates clinical

practice or as a substitute for Food and Drug

Administration–approved labeling;

• applicable to



management of pain related to sickle cell disease,



management of cancer-related pain, or



palliative care or end-of-life care; or

• focused on opioids prescribed for opioid use disorder.

communication between clinicians and patients about the

benefits and risks of prescription opioids and other pain

treatment strategies; improve the safety and effectiveness of

pain treatment; improve pain, function, and quality of life for

persons with pain; and reduce the risks associated with opioid

pain treatment (including opioid use disorder, overdose, and

death) and with other pain treatment.

This clinical practice guideline provides voluntary clinical

practice recommendations for clinicians that should not be

used as inflexible standards of care. The recommendations are

not intended to be implemented as absolute limits for policy

or practice across populations by organizations, health care

systems, or government entities.

Scope and Audience

This clinical practice guideline is intended for clinicians who

are treating outpatients aged ≥18 years with acute (duration

of <1 month), subacute (duration of 1–3 months), or chronic

(duration of >3 months) pain, and excludes pain management

related to sickle cell disease, cancer-related pain treatment,

palliative care, and end-of-life care. The recommendations are

most relevant to clinicians whose scope of practice includes

prescribing opioids (e.g., physicians, nurse practitioners and

other advanced-practice registered nurses, physician assistants,

and oral health practitioners). Because clinicians might work

within team-based care, this clinical practice guideline also refers

to and promotes integrated pain management and collaborative

working relationships among clinicians (e.g., behavioral

health specialists such as social workers or psychologists,

pharmacists, and registered nurses). This guideline update

includes recommendations for primary care clinicians (e.g.,

internists and family physicians) and other clinicians managing

pain in outpatient settings (e.g., surgeons, emergency medicine

clinicians, occupational medicine clinicians, physical medicine

and rehabilitation clinicians, and neurologists). Applicable

settings include clinician offices, clinics, and urgent care

centers. The recommendations do not apply to care provided

to patients who are hospitalized or in an emergency department

or other observational setting from which they might be

admitted to inpatient care. These recommendations do apply

to prescribing for pain management for patients when they

are discharged from hospitals, emergency departments, or

other facilities.

In addition to updating recommendations on the basis of new

evidence regarding management of chronic pain, this clinical

practice guideline is intended to assist clinicians in weighing

benefits and risks of prescribing opioid pain medication for

painful acute conditions (e.g., low back pain, neck pain, other

musculoskeletal pain, neuropathic pain, dental pain, kidney

stone pain, and acute episodic migraine) and pain related to

procedures (e.g., postoperative pain and pain from oral surgery).

In 2020, several of these indications were prioritized by an ad hoc

committee of the National Academies of Sciences, Engineering,

and Medicine (86) as those for which evidence-based clinical

practice guidelines would help inform prescribing practices, with

the greatest potential effect on public health. This update includes

content on management of subacute painful conditions, when

duration falls between that typically considered acute (defined as

lasting <1 month) and chronic (defined as lasting >3 months).

The durations used to define acute, subacute, and chronic pain

might imply more specificity than is found in real-life patient

experience, when pain often gradually transitions from acute

to chronic. These time-bound definitions are not meant to be

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absolute but rather to be approximate guides to facilitate the

consideration and practical use of the recommendations by

clinicians and patients.

The 2016 CDC Opioid Prescribing Guideline focused on

recommendations for primary care physicians. This clinical

practice guideline expands the scope to additional clinicians.

Although primary care physicians prescribe approximately

37% of all opioid prescriptions, other clinicians, including

pain medicine clinicians (8.9%) and dentists (8.6%), account

for considerable proportions of prescriptions. Pain medicine

and physical medicine and rehabilitation clinicians prescribe

opioids at the highest rates, followed by orthopedic and

family medicine clinicians (83). Thus, expanding the scope

to outpatient opioid prescribing can provide evidence-based

advice for many additional clinicians, including dentists and

other oral health providers, clinicians managing postoperative

pain in outpatients, and clinicians providing pain management

for patients being discharged from emergency departments.

Many principles of pain management are similar whether

or not the treating clinician is a pain management specialist,

and many of the recommendations might be relevant for pain

management specialists. Many pain management specialists

already follow principles outlined in this clinical practice

guideline; however, use by pain management specialists is not

the focus of this clinical practice guideline. Pain management

specialists often have extensive training and expertise in pain

management modalities that other clinicians do not, and

they might treat patients with clinical situations that are

more complex, less prevalent, and not well addressed by the

available evidence; therefore, the balance of benefits and risks

to patients might differ when the treating clinician is a pain

management specialist.

The recommendations address the use of opioid pain

medication in certain special populations (e.g., older adults

and pregnant persons) and in populations with conditions

posing special risks (e.g., a history of a substance use disorder).

The recommendations do not address the use of opioid pain

medication in children or adolescents aged <18 years. The

available evidence concerning the benefits and risks of long-

term opioid therapy in children and adolescents remains

limited, and few opioid medications provide information in

their labeling regarding safety and effectiveness in pediatric

patients. Guidelines and recommendations are available for

pain management in children with sickle cell disease (87), for

children undergoing surgical procedures (88), and for palliative

care in adolescent and young adult patients with cancer (89).

Although some principles in this clinical practice guideline

might be helpful in the management of pain related to sickle

cell disease, cancer-related pain treatment, palliative care, and

end-of-life care, some recommendations might not be relevant

for pain management in these contexts. Other guidelines

more specifically address pain management in these situations

(87,89–93); therefore, this clinical practice guideline does

not apply to patients experiencing pain associated with these

conditions or types of care. This does not imply that any other

types of pain are more or less worthy of effective treatment,

only that clinicians are referred to existing clinical guidelines

that more specifically address unique considerations for

management of pain related to sickle cell disease, cancer-related

pain treatment, palliative care, and end-of-life care.

This clinical practice guideline follows the Institute of

Medicine’s definition of palliative care as care that provides

relief from pain and other symptoms, supports quality of life,

and is focused on patients with serious advanced illness (94).

Palliative care can begin early in the course of treatment for any

serious illness that requires advanced management of pain or

other distressing symptoms (94). In this guideline, end-of-life

care refers to care for persons in hospice care and others with a

terminal illness or at high risk for dying in the near future in

hospitals, receiving long-term services and supports (including

institutional care and home- and community-based services),

or at home. This clinical practice guideline does not apply to

patients undergoing cancer-related pain treatment, palliative

care, or end-of-life care because of the unique therapeutic goals,

ethical considerations, opportunities for medical supervision,

and balance of benefits and risks with opioid therapy in such

care. For example, for many persons at the end of life, serious

potential long-term opioid-related harms such as opioid use

disorder might not be relevant.

Recommendations on pain management for patients with

cancer and patients who have survived cancer are available

in the National Comprehensive Cancer Network (NCCN)

Clinical Practice Guidelines in Oncology: Adult Cancer

Pain (90), NCCN Clinical Practice Guidelines in Oncology:

Survivorship (91), and Management of Chronic Pain in

Survivors of Adult Cancers: American Society of Clinical

Oncology (ASCO) Clinical Practice Guideline (92). Because

of unique considerations in management of pain related to

sickle cell disease, which can change the balance of benefits

and risks of the use of opioids, clinicians should refer to the

American Society of Hematology (ASH) 2020 Guidelines for

Sickle Cell Disease: Management of Acute and Chronic Pain

(87). In 2018, NCCN and ASCO convened and led a meeting

including representatives and guideline authors from NCNN,

ASCO, ASH, and CDC to review existing pain management

guidelines and guidelines then in development from these

organizations (56,87,90–92). Meeting participants noted

that these guidelines applied to different patient populations

and target audiences but found no disagreement among

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recommendations when applied to the appropriate patient

and clinical situation (95).

Although this update includes content on pain management

for patients with opioid use disorder and one recommendation

on management of opioid use disorder as a complication of

opioid use, recommendations on opioids used specifically as

medications for opioid use disorder are not the focus of this

clinical practice guideline. More detailed recommendations on

management of patients with opioid use disorder are available

in the American Society of Addiction Medicine (ASAM)

National Practice Guideline for the Treatment of Opioid Use

Disorder: 2020 Focused Update (96).

Clinical Practice Guideline

Development Methods

Systematic Reviews and Evidence Sources

The 2016 CDC Opioid Prescribing Guideline was based on a

systematic clinical evidence review sponsored by AHRQ on the

effectiveness and risks of long-term opioid therapy for chronic

pain (47,97), a CDC update to the AHRQ-sponsored review,

and additional contextual questions (56,98). The systematic

review addressed the effectiveness of long-term opioid therapy

for outcomes related to pain, function, and quality of life; the

comparative effectiveness of different methods for initiating and

titrating opioids; the harms and adverse events associated with

opioids; and the accuracy of risk prediction instruments and

effectiveness of risk mitigation strategies on outcomes related to

overdose, opioid use disorder, illicit drug use, and prescription

opioid misuse. The CDC update to the AHRQ-sponsored

review included literature published during or after 2015 and an

additional question on the association between opioid therapy

for acute pain and long-term use. The contextual evidence review

addressed effectiveness of nonpharmacologic and nonopioid

pharmacologic treatments, clinician and patient values and

preferences, and information about resource allocation.

For this update to the 2016 CDC Opioid Prescribing

Guideline, CDC funded AHRQ in 2018 and 2019 to conduct

five systematic reviews (7–11). AHRQ’s Evidence-based

Practice Centers completed these reviews, which included new

evidence related to the treatment of chronic and acute pain.

The AHRQ review of opioids for chronic pain updated and

expanded the evidence for the 2016 CDC review; studies were

included on short-term (1 to <6 months), intermediate-term

(6 to <12 months) and long-term (≥12 months) outcomes of

therapy involving opioids, effects of opioid plus nonopioid

combination therapy, effects of tramadol, effects of naloxone

coprescription, risks of coprescribed benzodiazepines, risks of

coprescribed gabapentinoids, and effects of concurrent use

of cannabis (7). The systematic clinical evidence review on

opioids for chronic pain (7) also included contextual questions

on clinician and patient values and preferences, costs and cost-

effectiveness of opioid therapy, and risk mitigation strategies.

CDC considered four new complementary AHRQ reviews

on the benefits and harms of nonpharmacologic treatments

for chronic pain (9), nonopioid pharmacologic treatments for

chronic pain (8), treatments for acute episodic migraine (11),

and treatments for acute (nonmigraine) pain (10). A question

on management of acute pain in the systematic clinical evidence

review for the 2016 CDC Opioid Prescribing Guideline was

included in the new review on therapies for acute pain (10).

CDC also reviewed AHRQ-sponsored surveillance reports

conducted in follow-up to the five systematic reviews for any

new evidence that could potentially change systematic review

conclusions. To supplement the clinical evidence reviews, CDC

sponsored a contextual evidence review on clinician and patient

values and preferences and resource allocation (costs) for the

areas addressed in the four new reviews (8–11).

AHRQ Method for Evaluating

Quality of Evidence

The reviews used the AHRQ approach to synthesize and grade

the strength of evidence (99). The AHRQ approach is based

on a systematic review of the evidence and provides an overall

strength of evidence indicating the level of certainty (high,

moderate, low, or insufficient); similar factors are considered

in the Advisory Committee on Immunization Practices (ACIP)

adapted (100,101) Grading of Recommendations Assessment,

Development, and Evaluation (GRADE) (102) method. These

factors include study limitations and risk for bias, consistency,

directness, precision, and reporting bias. Large strength of

association, dose response, and plausible confounders can

strengthen observed findings. The primary clinical questions,

detailed methods, and findings for the systematic and

contextual evidence reviews are presented (Appendix).

ACIP Adapted GRADE Method for

Evaluating Quality of Evidence

The GRADE method is predicated on a systematic

review of scientific evidence and provides a transparent

framework for grading the quality of evidence and strength

of recommendations. GRADE has been adapted by ACIP

(100,101), and CDC used the ACIP adaptation in this clinical

practice guideline. Under the ACIP GRADE framework, each

body of evidence is initially categorized using a hierarchy that

reflects the degree of confidence in the effect of a clinical action

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on health outcomes. The categories in the hierarchy are type 1

evidence (randomized clinical trials or overwhelming evidence

from observational studies), type 2 evidence (randomized

clinical trials with important limitations, or exceptionally

strong evidence from observational studies), type 3 evidence

(observational studies or randomized clinical trials with notable

limitations), and type 4 evidence (clinical experience and

observations, observational studies with important limitations,

or randomized clinical trials with several major limitations)

(Box 3). The evidence is downgraded if issues are identified

with regard to risk for bias, inconsistency, indirectness,

imprecision, or publication bias. Observational studies might

be upgraded in certain situations (large strength of association,

presence of dose response, or plausible effects of confounding

would strengthen findings; that is, if confounding would likely

provide results opposite to the observed findings, it strengthens

the confidence that the observed association is present). A final

evidence type is assigned based on these considerations. Type 1

evidence indicates high confidence that the true effect is close to

the estimate of the effect; type 2 evidence means that the true

effect is likely to be close to the estimate of the effect, but there

is some uncertainty; type 3 evidence means that confidence

in the effect estimate is limited (moderate uncertainty), and

the true effect could differ substantially from the estimate of

the effect; and type 4 evidence indicates very little confidence

in the effect estimate (high uncertainty), and the likelihood is

high that the true effect differs from the estimate of the effect

(100,103). When no studies are available or the evidence is too

limited to estimate effects, evidence is considered insufficient.

Categorizing the Evidence

The AHRQ approach uses a different method and

terminology (high, moderate, low, or insufficient) to grade the

strength of evidence from the ACIP adapted GRADE method

(evidence types 1, 2, 3, or 4) (99). However, the underlying

principles are similar, enabling translation from AHRQ to

CDC grades. A methodologist translated the AHRQ strength

of evidence grades to CDC evidence types according to the

information provided in the summary of evidence tables in

the AHRQ reviews. Tables with GRADE clinical evidence

review ratings of the evidence for the key clinical questions

are available (https://stacks.cdc.gov/view/cdc/121663).

Evidence was categorized into the following types: type 1

(randomized clinical trials or overwhelming evidence from

observational studies; equivalent to AHRQ high strength of

evidence), type 2 (randomized clinical trials with important

limitations, or exceptionally strong evidence from observational

studies; equivalent to AHRQ moderate strength of evidence),

type 3 (observational studies, or randomized clinical trials

with notable limitations; equivalent to most AHRQ low

strength of evidence ratings), or type 4 (clinical experience and

observations, observational studies with important limitations,

or randomized clinical trials with several major limitations;

equivalent to AHRQ low strength of evidence with serious

limitations). When no studies were available or the evidence

was too limited to estimate effects, evidence was assessed as

insufficient. Results from meta-analyses conducted for the

AHRQ reviews were reported when available; otherwise, the

evidence was synthesized qualitatively.

Recommendation Development

CDC developed this clinical practice guideline using the

method developed by the GRADE working group (https://

www.gradeworkinggroup.org). Recommendations are based

on the reviewed evidence. In the ACIP adapted GRADE

framework, recommendations are assigned one of two

categories (category A or B). Four major factors determine the

category of the recommendation: 1) the quality of evidence,

2) the balance between desirable and undesirable effects,

3) values and preferences, and 4) resource allocation (e.g.,

costs to patients or health systems) (104). Other considerations

include feasibility and acceptability and effect on equity

(105). Recommendations are more likely to be category A

when the evidence is higher quality, a balance of desirable

relative to undesirable effects is greater, resources and costs are

lower, and recommendations are less sensitive to differences

in values and preferences. Category A recommendations

typically apply to all persons in the group addressed in the

recommendation and indicate a course of action that can be

followed in most circumstances. Category B recommendations

indicate that the recommendation might not apply to all

persons in the group addressed in the recommendation;

therefore, different choices will be appropriate for different

patients, and decisions should be made based on the patient’s

circumstances. For category B recommendations, clinicians

must help patients arrive at a decision consistent with patient

values and preferences and specific clinical situations (shared

decision-making) (106). In the GRADE method, a particular

quality of evidence does not necessarily result in a particular

strength of recommendation (102–104). Although it is

desirable for category A recommendations to be based on

type 1 or type 2 evidence, category A recommendations can

be based on type 3 or type 4 evidence when the advantages of

a clinical action clearly outweigh the disadvantages in terms

of benefits and harms, values and preferences, and costs,

despite uncertainty in effect estimates (104). The GRADE

working group has presented several paradigmatic situations

in which strong (category A) recommendations might be

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BOX 3. Recommendations for prescribing opioids for outpatients with pain, excluding pain management related to sickle cell disease, cancer-

related pain treatment, palliative care, and end-of-life care; recommendation categories; and evidence types — CDC Clinical Practice Guideline

for Prescribing Opioids for Pain — United States, 2022

Determining Whether or Not to Initiate Opioids for

Pain (Recommendations 1 and 2)

1. Nonopioid therapies are at least as effective as opioids

for many common types of acute pain. Clinicians

should maximize use of nonpharmacologic and

nonopioid pharmacologic therapies as appropriate for

the specific condition and patient and only consider

opioid therapy for acute pain if benefits are anticipated

to outweigh risks to the patient. Before prescribing

opioid therapy for acute pain, clinicians should discuss

with patients the realistic benefits and known risks of

opioid therapy (recommendation category: B; evidence

type: 3).

2. Nonopioid therapies are preferred for subacute and

chronic pain. Clinicians should maximize use of

nonpharmacologic and nonopioid pharmacologic

therapies as appropriate for the specific condition and

patient and only consider initiating opioid therapy if

expected benefits for pain and function are anticipated

to outweigh risks to the patient. Before starting opioid

therapy for subacute or chronic pain, clinicians should

discuss with patients the realistic benefits and known

risks of opioid therapy, should work with patients to

establish treatment goals for pain and function, and

should consider how opioid therapy will be discontinued

if benefits do not outweigh risks (recommendation

category: A; evidence type: 2).

Selecting Opioids and Determining Opioid Dosages

(Recommendations 3, 4, and 5)

3. When starting opioid therapy for acute, subacute, or

chronic pain, clinicians should prescribe immediate-

release opioids instead of extended-release and long-

acting (ER/LA) opioids (recommendation category: A;

evidence type: 4).

4. When opioids are initiated for opioid-naïve patients

with acute, subacute, or chronic pain, clinicians should

prescribe the lowest effective dosage. If opioids are

continued for subacute or chronic pain, clinicians

should use caution when prescribing opioids at any

dosage, should carefully evaluate individual benefits and

risks when considering increasing dosage, and should

avoid increasing dosage above levels likely to yield

diminishing returns in benefits relative to risks to patients

(recommendation category: A; evidence type: 3).

5. For patients already receiving opioid therapy, clinicians

should carefully weigh benefits and risks and exercise

care when changing opioid dosage. If benefits outweigh

risks of continued opioid therapy, clinicians should

work closely with patients to optimize nonopioid

therapies while continuing opioid therapy. If benefits

do not outweigh risks of continued opioid therapy,

clinicians should optimize other therapies and work

closely with patients to gradually taper to lower dosages

or, if warranted based on the individual circumstances

of the patient, appropriately taper and discontinue

opioids. Unless there are indications of a life-

threatening issue such as warning signs of impending

overdose (e.g., confusion, sedation, or slurred speech),

opioid therapy should not be discontinued abruptly,

and clinicians should not rapidly reduce opioid dosages

from higher dosages (recommendation category: B;

evidence type: 4).

Deciding Duration of Initial Opioid Prescription and

Conducting Follow-Up (Recommendations 6 and 7)

6. When opioids are needed for acute pain, clinicians

should prescribe no greater quantity than needed for

the expected duration of pain severe enough to require

opioids (recommendation category: A; evidence type: 4).

7. Clinicians should evaluate benefits and risks with

patients within 1–4 weeks of starting opioid therapy

for subacute or chronic pain or of dosage escalation.

Clinicians should regularly reevaluate benefits and

risks of continued opioid therapy with patients

(recommendation category: A; evidence type: 4).

Continued on the next page.

justified despite low-quality evidence (e.g., when high-quality

evidence suggests equivalence of two alternatives and low-

quality evidence suggests harm in one alternative, or when

high-quality evidence suggests modest benefits and low- or

very low–quality evidence suggests possibility of catastrophic

harm) (104). Category B recommendations are made when

the advantages and disadvantages of a clinical action are more

balanced or when more uncertainty exists with regard to

whether benefits clearly outweigh harms.

In accordance with the ACIP adapted GRADE method,

CDC drafted evidence-based recommendations focused

on determining whether or not to initiate opioids for pain,

selecting opioids and determining opioid dosages, deciding

duration of initial opioid prescription and conducting

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BOX 3. (Continued) Recommendations for prescribing opioids for outpatients with pain, excluding pain management related to sickle cell

disease, cancer-related pain treatment, palliative care, and end-of-life care; recommendation categories; and evidence types — CDC Clinical

Practice Guideline for Prescribing Opioids for Pain — United States, 2022

Assessing Risk and Addressing Potential Harms of Opioid

Use (Recommendations 8, 9, 10, 11, and 12)

8. Before starting and periodically during continuation of

opioid therapy, clinicians should evaluate risk for opioid-

related harms and discuss risk with patients. Clinicians

should work with patients to incorporate into the

management plan strategies to mitigate risk, including

offering naloxone (recommendation category: A;

evidence type: 4).

9. When prescribing initial opioid therapy for acute,

subacute, or chronic pain, and periodically during

opioid therapy for chronic pain, clinicians should

review the patient’s history of controlled substance

prescriptions using state prescription drug monitoring

program (PDMP) data to determine whether the patient

is receiving opioid dosages or combinations that put

the patient at high risk for overdose (recommendation

category: B; evidence type: 4).

10. When prescribing opioids for subacute or chronic pain,

clinicians should consider the benefits and risks of

toxicology testing to assess for prescribed medications

as well as other prescribed and nonprescribed controlled

substances (recommendation category: B; evidence

type: 4).

11. Clinicians should use particular caution when

prescribing opioid pain medication and benzodiazepines

concurrently and consider whether benefits outweigh

risks of concurrent prescribing of opioids and other

central nervous system depressants (recommendation

category: B; evidence type: 3).

12. Clinicians should offer or arrange treatment with

evidence-based medications to treat patients with

opioid use disorder. Detoxification on its own, without

medications for opioid use disorder, is not recommended

for opioid use disorder because of increased risks for

resuming drug use, overdose, and overdose death

(recommendation category: A; evidence type: 1).

Recommendation categories (on basis of evidence type,

balance between desirable and undesirable effects, values

and preferences, and resource allocation [cost]).

• Category A recommendation: Applies to all persons;

most patients should receive the recommended course

of action.

• Category B recommendation: Individual decision-

making needed; different choices will be appropriate for

different patients. Clinicians help patients arrive at a

decision consistent with patient values and preferences

and specific clinical situations.

Evidence types (on basis of study design and as a

function of limitations in study design or implementation,

imprecision of estimates, variability in findings,

indirectness of evidence, publication bias, magnitude

of treatment effects, dose-response gradient, and

constellation of plausible biases that could change effects).

• Type 1 evidence: Randomized clinical trials or

overwhelming evidence from observational studies.

• Type 2 evidence: Randomized clinical trials with

important limitations, or exceptionally strong evidence

from observational studies.

• Type 3 evidence: Observational studies or randomized

clinical trials with notable limitations.

• Type 4 evidence: Clinical experience and observations,

observational studies with important limitations, or

randomized clinical trials with several major limitations.

follow-up, and assessing risk and addressing potential harms

of opioid use. To help assure the draft guideline’s integrity

and credibility, CDC then began a multistep review process.

Federal Advisory Committee

Review and Recommendation

CDC sought recommendations on the draft clinical practice

guideline from one of its federal advisory committees, the Board

of Scientific Counselors of the National Center for Injury

Prevention and Control (BSC/NCIPC). BSC/NCIPC advises

the U.S. Department of Health and Human Services (HHS)

Secretary, the CDC Director, and the NCIPC Director and

makes recommendations regarding scientific, programmatic,

and research policies, strategies, objectives, projects, and

priorities. BSC/NCIPC also reviews progress toward injury

and violence prevention. BSC/NCIPC members are special

government employees appointed by the HHS Secretary or

their designee as CDC advisory committee members. Members

are required to complete the Office of Government Ethics

Form 450 annually to disclose relevant interests and report on

their disclosures during meetings. Disclosures for BSC/NCIPC

are reported in this clinical practice guideline. Meeting minutes

and documents for public BSC/NCIPC meetings are available

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on the BSC/NCIPC website (https://www.cdc.gov/injury/bsc/

meetings.html).

On December 4–5, 2019, CDC held a public meeting of

BSC/NCIPC (announced via Federal Register 84 FR 57021;

84 FR 65159) and provided a presentation on the background

for updating the clinical practice guideline. CDC then requested

the formation of an Opioid Workgroup (OWG), under the

parent BSC, whose primary purpose would be to review a

draft clinical practice guideline and to develop a report of their

observations for BSC/NCIPC (107). After considering CDC’s

presentations, the proposed OWG Terms of Reference, and

public comments, BSC/NCIPC voted unanimously to establish

an OWG that reports to BSC/NCIPC. CDC then held a public

nomination process for prospective OWG members (107).

To provide background to BSC/NCIPC for informing

the creation of OWG with a balance of perspectives, CDC

identified audiences that would be 1) directly affected by

the clinical practice guideline, 2) directly involved with

implementing or integrating recommendations into current

practice, and 3) qualified to represent a specific discipline

or expertise in alignment with the tasks of the workgroup

for consideration by BSC/NCIPC. Identified groups with

perspectives that would support the workgroup’s capacity

included, but were not limited to, patients with pain,

family members and caregivers, clinicians, public health

practitioners, and research scientists. CDC announced the call

for nominations at the December 4–5, 2019, public meeting

and heard recommendations from the public during the

public comment opportunities, as well as from BSC/NCIPC

members, regarding recommendations for nominations.

Persons interested in being considered for the workgroup were

encouraged to submit self-nominations from December 4,

2019, through February 4, 2020. CDC’s BSC/NCIPC received

255 nominations for OWG.

After reviewing clinical expertise, professional credentials,

and diversity in perspectives of all nominees (including

diversity of gender, race and ethnicity, geographic region,

institutional affiliations, and personal experiences relevant to

pain management and providing care to patients with pain),

OWG’s Designated Federal Officer (DFO) created a list of

prospective workgroup members and sent them invitations

to participate, along with conflict of interest disclosure forms.

OWG’s DFO and BSC/NCIPC’s DFO reviewed conflict of

interest disclosure forms. CDC’s Strategic Business Initiatives

Unit (SBIU), which oversees the Federal Advisory Committee

Act program, also reviewed the OWG Terms of Reference,

prospective OWG roster, curricula vitae, and conflict of interest

disclosure forms and determined all reported financial or other

conflicts of interest were not present or nonsignificant before

finalizing selection.* OWG members disclosed any potential

topical conflicts of interest related to OWG meeting agenda

items before each meeting. Disclosures of OWG are reported

in the clinical practice guideline.

OWG had 23 members (108) including four ex officio

members representing federal partner agencies (see Federal

Partner Engagement). In accordance with CDC guidance

(109,110) that at least two BSC/NCIPC members must serve

on OWG and one of the two members must serve as the

workgroup chair, OWG included a total of three BSC/NCIPC

members, with one BSC/NCIPC member serving as the OWG

chair. An NCIPC subject matter expert served as OWG’s DFO.

OWG members included patients with pain, caregivers, and

family members of patients with pain. OWG also comprised

clinicians and subject matter experts, with the following

perspectives represented: primary care, pain medicine, public

health, behavioral health, pharmacy, emergency medicine,

medical toxicology, obstetrics/gynecology, bioethics, orthopedic

surgery, plastic surgery, dentistry, sickle cell disease, substance

use disorder treatment, and research. OWG members were

diverse in regard to gender, race and ethnicity, geographic

region, institutional affiliation, subject matter expertise, and

personal experiences. The CDC NCIPC OWG DFO presented

the OWG roster and reviewed the Terms of Reference at the

publicly held BSC/NCIPC meeting on July 22, 2020 (Federal

OWG had 11 meetings from October 2020 through

June 2021. Before receiving the draft clinical practice

guideline, OWG held meetings to review and discuss the

2016 CDC Opioid Prescribing Guideline; CDC’s community

engagement activities with patients, caregivers, and clinicians;

and GRADE methodology. CDC NCIPC staff provided OWG

with evidence reviews, public comments from BSC/NCIPC

meetings, and summaries of community engagements for

review before providing OWG with the draft clinical practice

guideline in March 2021. OWG held seven meetings to

review and discuss the draft clinical practice guideline and

develop a report summarizing their expert observations

and findings for BSC/NCIPC. The OWG report provided

overall observations on overarching themes and draft clinical

practice guideline recommendations (111). In addition, many

members of OWG developed a document entitled OWG

Guiding Principles that was included as an appendix in the

OWG report; this document outlines the “general process and

* Financial conflict of interest means a significant financial interest that could

directly and significantly affect the design, conduct, or reporting of Public

Health Service-funded research (42 CFR 50.603). Although certain members

reported receiving research support totaling or equivalent to more than $10,000,

SBIU determined these activities did not constitute a substantial conflict of

interest pertaining to the content of this clinical practice guideline.

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principles by which OWG approached their assigned tasks.”

These Guiding Principles included minimizing bias, ensuring

scientific integrity, enhancing inclusivity, being patient and

clinician centered, and considering historical context.

The OWG chair presented the OWG report at a public

BSC/NCIPC meeting on July 16, 2021 (Federal Register

86 FR 30048). After hearing additional CDC presentations on

the process and progress of the draft clinical practice guideline,

discussion of the OWG report, and a 2-hour public comment

period, BSC/NCIPC voted unanimously that CDC adopt the

OWG report, while considering ideas and suggestions raised

by BSC/NCIPC and the public during the meeting, and

that OWG’s work be considered complete and that OWG be

sunsetted. BSC/NCIPC provided their recommendations to

HHS and CDC on July 20, 2021. CDC considered OWG’s

observations, BSC/NCIPC recommendations, and public

comments during BSC/NCIPC meetings when revising

the draft clinical practice guideline (112,113). A list of

BSC/NCIPC and of OWG members appears at the end of

this report. The recommendations and all statements included

in this guideline are those of CDC and do not necessarily

represent the official position of any persons or organizations

providing comments on this guideline.

Federal Partner Engagement

BSC/NCIPC invited federal partners to serve as ex officio

members of OWG, including representatives from the National

Institute on Drug Abuse (NIDA) at the National Institutes

of Health (NIH), the Substance Abuse and Mental Health

Services Administration (SAMHSA), FDA, and the Indian

Health Service (IHS). BSC/NCIPC included ex officio

members from the Administration for Children and Families;

the Administration on Aging in the Administration for

Community Living; the National Institute for Occupational

Safety and Health and the National Center for Health Statistics

at CDC; the Health Resources and Services Administration;

IHS; SAMHSA; and the National Institute on Aging, the

National Institute of Child Health and Human Development,

NIDA, and the National Institute of Mental Health at NIH.

Additional federal partners were engaged throughout the

clinical practice guideline update process. Federal partners

reviewed the full draft clinical practice guideline as part of

CDC’s agency clearance process.

Public Comment and

Community Engagement

CDC sought input through Federal Register notices to better

understand community members’ experiences and perspectives

related to pain and pain management options before drafting

the clinical practice guideline (113). Through the Federal

through June 16, 2020, CDC invited input specifically on

topics focused on using or prescribing opioid pain medications,

nonopioid medications, or nonpharmacologic treatments

and received 5,392 public comments. Public comments were

synthesized into common themes, using a CDC-funded

analysis contract, and reviewed by CDC.

In addition, the Lab at the U.S. Office of Personnel

Management (OPM) (https://lab.opm.gov) worked with

CDC to design and implement community engagement

opportunities. These opportunities were designed to gain

additional insight into the values and preferences of groups

including patients with acute or chronic pain, patients’ family

members or caregivers, and clinicians who care for patients

with pain or conditions that can complicate pain management

(e.g., opioid use disorder or overdose).

CDC planned to have in-person individual conversations

with patients, caregivers, and clinicians but pivoted to holding

conversations with persons in a virtual format because of the

COVID-19 pandemic. CDC posted a companion Federal

August 21, 2020, to solicit input from patients, caregivers,

and clinicians interested in participating in individual

conversations. After the Federal Register notice closed, CDC

and OPM randomly selected participants within each group

(i.e., patients, caregivers, and clinicians) from 973 respondents.

CDC and OPM also developed a randomly selected waiting

list of participants to fill conversation appointments that were

missed or canceled by participants. The community engagement

was authorized under the Generic Clearance for the Collection

of Qualitative Feedback on Agency Service Delivery (OMB

Control Number 0920–1050) approval for the Paperwork

Reduction Act. CDC and OPM conducted telephone and

video conversations throughout September 2020 and spoke

with 106 persons, including 42 patients, 21 caregivers, and

43 clinicians. Participants lived and worked all over the United

States and had diverse experiences with opioids. Participants

provided verbal consent for their conversations to be recorded.

A transcription service reviewed the conversation recordings to

develop anonymized transcripts. CDC and OPM reviewed the

anonymized transcripts to develop thematic summaries.

CDC and OPM also held two human-centered codesign

workshops with staff from CDC and the Centers for Medicare

& Medicaid Services. Workshop topics included framing priority

needs for public input; objectives for individual conversations;

and synthesizing engagement strategies on the basis of insights

from public comments and conversations with patients,

caregivers, and clinicians. Workshop participants included HHS

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staff who were themselves patients, caregivers, clinicians, clinical

practice guideline authors, and other subject matter experts.

CDC also gathered input through oral and written public

comment opportunities at and in conjunction with public

BSC/NCIPC meetings. These public comment opportunities

were announced through Federal Register notices (Federal Register

84 FR 57021; 84 FR 65159; 85 FR 30709; 85 FR 40290;

86 FR 1502; 86 FR 30048) and NCIPC newsletters.

CDC reviewed thematic summaries of public comments,

individual conversations, and workshops to learn more about

values and preferences of patients, caregivers, clinicians, and

experts before drafting the clinical practice guideline (113).

After incorporating observations and comments on the draft

clinical practice guideline from BSC/NCIPC and the agency

clearance process, CDC posted the revised full draft clinical

practice guideline and supporting materials in the Federal

public comment period was open for 60 days (February 10–

April 11, 2022). The Federal Docket received approximately

5,500 unique comments (including one comment submitted

with 28,322 additional signatories) from the public, including

patients with acute and chronic pain, caregivers, and clinicians,

and organizational perspectives from medical associations,

professional organizations, academic institutions, state and

local governments, and advocacy and industry groups. CDC

reviewed and considered all public comments when revising

the clinical practice guideline.

Peer Review

This clinical practice guideline provides influential scientific

information that could have a clear and substantial effect on

public- and private-sector decisions. Therefore, peer review of

the draft clinical practice guideline was required per the final

information quality bulletin for peer review (https://www.

whitehouse.gov/wp-content/uploads/2019/04/M-19-15.pdf).

CDC identified peer reviewers on the basis of multiple

factors, including scientific and subject matter expertise, racial

and ethnic diversity, gender diversity, diversity of experiences

and perspectives, independence from the clinical practice

guideline development process, and consideration of conflicts

of interest. Specific effort was made to identify subject matter

experts with knowledge and experience in topics such as

chronic and acute pain management, clinical practice, health

equity, mental health and well-being, opioids and opioid

therapies, opioid tapering, opioid use disorder treatment,

pharmacologic and nonpharmacologic pain management, and

surgical pain management. CDC assessed potential conflicts

of interest before finalizing selection of peer reviewers. The

NCIPC Associate Director for Science reviewed conflict

of interest disclosure forms and determined no conflicts of

interest were present. After the peer reviews were completed,

CDC posted the names of peer reviewers on the NCIPC and

CDC/ATSDR Peer Review Agenda websites, which provide

information about the peer review of influential government

scientific documents (114,115). Peer reviewers independently

reviewed the draft clinical practice guideline and evaluated its

scientific merit and practical implementation considerations,

with the goal of maintaining high-quality science and providing

evidence-based recommendations to guide clinical practice and

decision-making to help prevent opioid-related harms. CDC

reviewed and considered peer review comments when revising

the clinical practice guideline.

Recommendations

This clinical practice guideline includes 12 recommendations

for clinicians who are prescribing opioids for outpatients

aged ≥18 years with acute (duration of <1 month), subacute

(duration of 1–3 months), or chronic (duration of >3 months)

pain, excluding pain management related to sickle cell disease,

cancer-related pain treatment, palliative care, and end-of-

life care (Box 3). The recommendations are not intended

to be implemented as absolute limits of policy or practice

across populations by organizations, health care systems, or

government entities. In accordance with the ACIP adapted

GRADE method, CDC based the recommendations on

consideration of clinical evidence, contextual evidence (e.g.,

benefits and harms, values and preferences, and resource

allocation), and expert opinion. Expert input is reflected within

the recommendation rationales. For each recommendation

statement, CDC notes the recommendation category (A or B)

and the type of evidence (1, 2, 3, or 4) supporting the statement

(Box 3).

Category A recommendations indicate that most

patients should receive the recommended course of action;

category B recommendations indicate that different choices

will be appropriate for different patients, requiring clinicians to

help patients arrive at a decision consistent with patient values

and preferences and specific clinical situations. Consistent with

the ACIP (106,116) and GRADE method (103), category A

recommendations were made, even with type 3 and 4 evidence,

when there was broad agreement that the advantages of

a clinical action greatly outweighed the disadvantages.

Category B recommendations were made when there was broad

agreement that the advantages and disadvantages of a clinical

action were more balanced, but advantages were significant

enough to warrant a recommendation. Recommendations were

associated with a range of evidence types, from type 1 to type 4.

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In summary, the categorization of recommendations was

based on the following assessment:

• A number of nonpharmacologic treatments and nonopioid

medications are associated with improvements in pain,

function, or both that are reportedly comparable to

improvements associated with opioid use (7–11).

• Evidence exists that multiple noninvasive nonpharmacologic

interventions improve chronic pain and function, with small

to moderate effects in specific pain conditions, and are not

associated with serious harms. Compared with medication

treatment, for which benefits are anticipated while patients

are taking the medication but are not usually expected to

persist after patients stop taking the medication, multiple

noninvasive nonpharmacologic interventions are associated

with improvements in pain, function, or both that are

sustained after completion of treatment (9).

• Nonopioid drugs, including serotonin and norepinephrine

reuptake inhibitor (SNRI) antidepressants, pregabalin or

gabapentin, and nonsteroidal anti-inflammatory drugs

(NSAIDs), are associated with small to moderate

improvements in chronic pain and function. Drug class–

specific adverse events include serious cardiovascular,

gastrointestinal, or renal effects with NSAIDs and sedation

with anticonvulsants (8).

• Opioid therapy is associated with similar or decreased

effectiveness for pain and function versus NSAIDs across

multiple common acute pain conditions (10). Opioid

therapy is associated with small improvements in short-

term (duration of 1 to <6 months) pain and function

compared with placebo, with increased short-term harms

compared with placebo, and with evidence of attenuated

pain reduction over time (between 3 and 6 months versus

between 1 and 3 months) (10). Evidence exists from

observational studies of an association between opioid use

for acute pain and long-term opioid use (10). Evidence

on long-term effectiveness of opioids remains very limited

(7); a long-term (12 months) randomized trial of stepped

therapy for chronic musculoskeletal pain found no

difference in function and higher pain intensity after

starting with opioid therapy compared with starting with

nonopioid therapy (74). Evidence exists of increased risk

for serious harms (including opioid use disorder and

overdose) with long-term opioid therapy that appears to

rise with increase in opioid dosage, without a clear

threshold below which there is no risk (7).

• No validated, reliable way exists to predict which patients

will experience serious harm from opioid therapy and

which patients will benefit from opioid therapy (7).

• Discontinuing opioids after extended periods of

continuous opioid use can be challenging for clinicians

and patients. Tapering or discontinuing opioids in patients

who have taken them long term can be associated with

clinically significant risks (68), particularly if opioids are

tapered rapidly or patients do not receive effective support.

• Patients, caregivers, and clinicians responded to CDC with

invited input about their experiences and perspectives

related to pain and pain management options. Themes

included strained patient-clinician relationships and the

need for patients and clinicians to make shared decisions,

the effects of misapplication of the 2016 CDC Opioid

Prescribing Guideline, inconsistent access to effective pain

management solutions, and achieving reduced prescription

opioid use through diverse approaches.

• Members of the public responded to CDC with invited

comments. Themes included experiences with pain or

experiences in the aftermath of the overdose of a friend,

family member, or significant other; barriers and access to

pain care and to evidence-based treatment; concerns about

the level of specificity of recommendations; and overall

communication and implementation of the clinical

practice guideline.

Each of the 12 recommendation statements is followed

by considerations for implementation and a rationale for

the recommendation. The implementation considerations

offer practical insights, context, and specific examples meant

to further inform clinician-patient decision-making for the

respective recommendation and are not meant to be rigidly

or inflexibly followed.

The recommendations are grouped into four areas:

1. Determining whether or not to initiate opioids for pain

2. Selecting opioids and determining dosages

3. Deciding duration of initial opioid prescription and

conducting follow-up

4. Assessing risk and addressing potential harms of opioid use

In addition, these five guiding principles should broadly

inform implementation across recommendations (Box 4):

1. Acute, subacute, and chronic pain needs to be appropriately

assessed and treated independent of whether opioids are

part of a treatment regimen.

2. Recommendations are voluntary and are intended to

support, not supplant, individualized, person-centered

care. Flexibility to meet the care needs and the clinical

circumstances of a specific patient is paramount.

3. A multimodal and multidisciplinary approach to pain

management attending to the physical health, behavioral

health, long-term services and supports, and expected

health outcomes and well-being of each person is critical.

4. Special attention should be given to avoid misapplying

this clinical practice guideline beyond its intended use

or implementing policies purportedly derived from it

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BOX 4. Guiding principles for implementation of the CDC Clinical

Practice Guideline for Prescribing Opioids for Pain — United States,

2022 recommendations

1. Acute, subacute, and chronic pain needs to be

appropriately assessed and treated independent of

whether opioids are part of a treatment regimen.

2. Recommendations are voluntary and are intended

to support, not supplant, individualized, person-

centered care. Flexibility to meet the care needs

and the clinical circumstances of a specific patient

is paramount.

3. A multimodal and multidisciplinary approach to

pain management attending to the physical health,

behavioral health, long-term services and supports,

and expected health outcomes and well-being of

each person is critical.

4. Special attention should be given to avoid misapplying

this clinical practice guideline beyond its intended

use or implementing policies purportedly derived

from it that might lead to unintended and potentially

harmful consequences for patients.

5. Clinicians, practices, health systems, and payers should

vigilantly attend to health inequities; provide culturally

and linguistically appropriate communication,

including communication that is accessible to

persons with disabilities; and ensure access to an

appropriate, affordable, diversified, coordinated, and

effective nonpharmacologic and pharmacologic pain

management regimen for all persons.

that might lead to unintended and potentially harmful

consequences for patients.

5. Clinicians, practices, health systems, and payers should

vigilantly attend to health inequities; provide culturally and

linguistically appropriate communication (117), including

communication that is accessible to persons with disabilities;

and ensure access to an appropriate, affordable, diversified,

coordinated, and effective nonpharmacologic and

pharmacologic pain management regimen for all persons.

Determining Whether or Not to

Initiate Opioids for Pain

All patients with pain should receive treatment that provides

the greatest benefits relative to risks. (See Recommendation 1

for determining whether or not to initiate opioids for acute

pain [i.e., pain lasting <1 month] and Recommendation 2 for

determining whether or not to initiate opioids for subacute

pain [i.e., pain lasting 1–3 months] or chronic pain [i.e., pain

lasting >3 months].)

Recommendation 1

Nonopioid therapies are at least as effective as opioids for

many common types of acute pain. Clinicians should maximize

use of nonpharmacologic and nonopioid pharmacologic

therapies as appropriate for the specific condition and patient

and only consider opioid therapy for acute pain if benefits are

anticipated to outweigh risks to the patient. Before prescribing

opioid therapy for acute pain, clinicians should discuss with

patients the realistic benefits and known risks of opioid

therapy (recommendation category: B; evidence type: 3).

Implementation Considerations

• Nonopioid therapies are at least as effective as opioids for

many common acute pain conditions, including low back

pain, neck pain, pain related to other musculoskeletal

injuries (e.g., sprains, strains, tendonitis, and bursitis),

pain related to minor surgeries typically associated with

minimal tissue injury and mild postoperative pain (e.g.,

simple dental extraction), dental pain, kidney stone pain,

and headaches including episodic migraine.

• Clinicians should maximize use of nonopioid pharmacologic

(e.g., topical or oral NSAIDs, acetaminophen) and

nonpharmacologic (e.g., ice, heat, elevation, rest,

immobilization, or exercise) therapies as appropriate for the

specific condition.

• Opioid therapy has an important role for acute pain related

to severe traumatic injuries (including crush injuries and

burns), invasive surgeries typically associated with

moderate to severe postoperative pain, and other severe

acute pain when NSAIDs and other therapies are

contraindicated or likely to be ineffective.

• When diagnosis and severity of acute pain warrant the use

of opioids, clinicians should prescribe immediate-release

opioids (see Recommendation 3) at the lowest effective

dose (see Recommendation 4) and for no longer than the

expected duration of pain severe enough to require opioids

(see Recommendation 6).

• Clinicians should prescribe and advise opioid use only as

needed (e.g., hydrocodone 5 mg/acetaminophen 325 mg,

one tablet not more frequently than every 4 hours as

needed for moderate to severe pain) rather than on a

scheduled basis (e.g., one tablet every 4 hours) and

encourage and recommend an opioid taper if opioids are

taken around the clock for more than a few days (see

Recommendation 6).

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• If patients already receiving opioids long term require

additional medication for acute pain, nonopioid

medications should be used when possible and, if

additional opioids are required (e.g., for superimposed

severe acute pain), they should be continued only for the

duration of pain severe enough to require additional

opioids, returning to the patient’s baseline opioid dosage

as soon as possible, including a taper to baseline dosage if

additional opioids were used around the clock for more

than a few days (see Recommendation 6).

• Clinicians should ensure that patients are aware of

expected benefits of, common risks of, serious risks of, and

alternatives to opioids before starting or continuing opioid

therapy and should involve patients meaningfully in

decisions about whether to start opioid therapy.

Supporting Rationale

Evaluation of the patient is critical to appropriate management.

Evaluation can identify reversible causes of pain and underlying

etiologies with potentially serious sequelae that require urgent

action. To guide patient-specific selection of therapy, clinicians

should evaluate patients and establish or confirm the diagnosis.

Diagnosis can help identify interventions to reverse, ameliorate,

or prevent worsening of pain and improve function (e.g.,

surgical intervention to repair structure and function after

certain traumatic injuries, bracing to prevent recurrence of acute

ankle sprain, fracture immobilization, ice or elevation to reduce

swelling, and early mobilization to maintain function) (118).

Noninvasive Nonpharmacologic Approaches to

Acute Pain

Noninvasive nonpharmacologic approaches to acute pain

have the potential to improve pain and function without risk

for serious harms (10). Clinical evidence reviews found that

some nonpharmacologic treatments were likely effective for

acute pain, such as heat therapy for acute low back pain; several

others might be effective for specific acute pain conditions, such

as spinal manipulation for acute back pain with radiculopathy, a

cervical collar or exercise for acute neck pain with radiculopathy,

acupressure for acute musculoskeletal pain, massage for

postoperative pain (10), and remote electrical neuromodulation

for acute pain related to episodic migraine (11).

The American College of Physicians (ACP) recommends

nonpharmacologic treatment with superficial heat, massage,

acupuncture, or spinal manipulation as a cornerstone of

treatment for acute low back pain (119). ACP and the

American Academy of Family Physicians (AAFP) suggest

acupressure to improve pain and function and transcutaneous

electrical nerve stimulation to reduce pain in patients with

acute musculoskeletal injuries (120).

Despite evidence supporting their use, noninvasive

nonpharmacologic therapies are not always or fully covered

by insurance (43), and access and cost can be barriers,

particularly for persons who are uninsured, have limited

income, have transportation challenges, or live in rural areas

where treatments are not available (121). Experts from OWG

expressed concern about limited access to nonopioid pain

management modalities, in part because of lack of availability

or lack of coverage by payers, and emphasized improving access

to nonopioid pain management modalities as a priority. Health

insurers and health systems can contribute to improved pain

management and reduced medication use by increasing access

to noninvasive nonpharmacologic therapies with evidence

of effectiveness (9,43). Noninvasive nonpharmacologic

approaches should be used as appropriate to alleviate acute

pain, including ice and elevation to reduce swelling and

discomfort from musculoskeletal injuries, heat to alleviate

low back pain, and other modalities depending on the cause

of the acute pain.

Nonopioid Medications for Acute Pain

Many acute pain conditions often can be managed most

effectively with nonopioid medications (10,122). A systematic

review found that for musculoskeletal injuries such as sprains,

whiplash, and muscle strains, topical NSAIDs provided the

greatest benefit-harm ratio, followed by oral NSAIDs or

acetaminophen with or without diclofenac (122). NSAIDs

have been found to be more effective than opioids for surgical

dental pain and kidney stone pain and similarly effective

to opioids for low back pain (10). Evidence is limited on

comparative effectiveness of therapies for acute neuropathic

pain, neck pain, and postoperative pain (10). For episodic

migraine, triptans, NSAIDs, antiemetics, dihydroergotamine,

calcitonin gene-related peptide antagonists (gepants), and

lasmiditan are associated with improved pain and function

with usually mild and transient adverse events (11).

ACP recommends NSAIDs or skeletal muscle relaxants if

pharmacologic treatment is desired to treat low back pain (119).

For acute musculoskeletal injuries other than low back pain,

ACP and AAFP recommend topical NSAIDs with or without

menthol gel as first-line therapy and suggest oral NSAIDs to

relieve pain or improve function or oral acetaminophen to

reduce pain (120). The American Dental Association (ADA)

recommends NSAIDs as first-line treatment for acute dental

pain management (123). For acute kidney stone pain, NSAIDs

are at least as effective as opioids (124–127), can decrease the

ureteral smooth muscle tone and ureteral spasm (128) causing

kidney stone pain, and are preferred for kidney stone pain if not

contraindicated. Triptans, NSAIDs, combined triptans with

NSAIDs, antiemetics, dihydroergotamine, and acetaminophen

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are established acute treatments for migraine (11). Lasmiditan,

an 5-HT1F receptor agonist, and ubrogepant, a gepant, were

approved by FDA in 2019 for the treatment of migraine

(129); another gepant, rimegepant, was approved in 2020.

Lasmiditan and the gepants were more effective than placebo in

providing pain relief at 2 hours, 1 day, and 1 week (11). Adverse

events related to these newer medications require further

study; however, their mechanisms of action are believed to be

nonvasoconstrictive (130) and potentially carry lower risks

than vasoactive medications in patients with cardiovascular

risk factors (11).

When not contraindicated, NSAIDs should be used for

low back pain, painful musculoskeletal injuries (including

minor pain related to fractures), dental pain, postoperative

pain, and kidney stone pain; triptans, NSAIDs, or their

combinations should be used along with antiemetics as

needed for acute pain related to episodic migraine. NSAID

use has been associated with serious gastrointestinal events

and major coronary events (8), particularly in patients with

cardiovascular or gastrointestinal comorbidities, and clinicians

should weigh risks and benefits of use, dose, and duration of

NSAIDs when treating older adults as well as patients with

hypertension, renal insufficiency, heart failure, or those with

risk for peptic ulcer disease or cardiovascular disease. Vasoactive

effects of triptans and ergot alkaloids might preclude their use

in patients with migraine who also have cardiovascular risk

factors (11,131,132). Clinicians should review FDA-approved

labeling, including boxed warnings, before initiating treatment

with any pharmacologic therapy.

Pain Management for Pregnant and

Postpartum Persons

For pain management in the postpartum period, the

American College of Obstetricians and Gynecologists

(ACOG) recommends stepwise, multimodal, shared decision-

making, incorporating pharmacologic treatments that might

include opioids. After vaginal delivery, ACOG recommends

acetaminophen or NSAIDs, and if needed, adding an opioid.

After cesarean delivery, ACOG recommends standard oral and

parenteral medications such as acetaminophen, NSAIDs, or low-

dose, low-potency, short-acting opioids with duration of opioid

use limited to the shortest reasonable course expected for treating

acute pain (133). ACOG recommends counseling persons who

are prescribed opioids about the risk for central nervous system

depression in the postpartum person and in the breastfed infant

(133), noting that if a codeine-containing medication is selected,

duration of therapy and neonatal signs of toxicity should be

reviewed with patients and their families (133).

Opioid Medication for Acute Pain

A systematic review found that for musculoskeletal injuries

such as sprains, whiplash, and muscle strains, no opioid

provided better benefit than NSAIDs, and opioid use caused

the most harms (122). The evidence review (10) found that

opioids might not be more effective than nonopioid therapies

for some acute pain conditions (134–138), and use of opioids

might negatively affect recovery and function (139,140).

The review found that opioids were probably less effective

than NSAIDs for surgical dental pain and kidney stone pain,

less effective than acetaminophen for kidney stone pain,

and similarly effective as NSAIDs for low back pain (10).

For postoperative pain, effects of opioids on pain intensity

were inconsistent, and opioids were associated with increased

likelihood of repeat or rescue analgesic use (10). Evidence was

insufficient for opioids in treatment of episodic migraine (11).

Compared with NSAIDs or acetaminophen, opioids were

associated with increased risk for short-term adverse events,

including any adverse event, nausea, dizziness, and somnolence

(10). Observational studies found that opioid use for acute low

back pain or postoperative pain was associated with increased

likelihood of long-term opioid use (10). Proportions of adults

with new long-term opioid use at follow-up after initiation for

short-term use for postoperative pain have ranged from <1%

to 13% (141–146). Odds of long-term opioid use at follow-up

after initiation for short-term use for acute pain might be greater

with higher dosage and longer initial duration of exposure.

For example, one study found that, compared with no early

opioid use for acute low back pain, the adjusted odds ratio was

2.08 (95% CI: 1.55–2.78) for an early prescription totaling

1–140 MME and increased to 6.14 (95% CI: 4.92–7.66) for

an early prescription totaling ≥450 MME (140). In episodic

migraine, opioids as well as butalbital-containing medications

were associated with a twofold higher risk for development of

medication overuse headache compared with simple analgesics

and triptans (11,147). Serious adverse events were uncommon

for opioids and other medications; however, studies were not

designed to assess risk for overdose, opioid use disorder, or

long-term harms (10).

For acute low back pain, ACP found insufficient evidence

for effectiveness of opioids and recommends nonopioid

medications (see Nonopioid Medications for Acute Pain) if

choosing pharmacologic treatment (119). ACP and AAFP

suggest against treating patients with acute pain from

musculoskeletal injuries with opioids, including tramadol

(120). ADA recommends NSAIDs as the first-line therapy

for acute pain management (see Nonopioid Medications

for Acute Pain) (123). Multiple guidelines that address

prescribing for postoperative pain include both nonopioid and

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opioid treatment options and have emphasized multimodal

analgesia, incorporating around-the-clock nonopioid

analgesics and nonpharmacologic therapies and noting that

systemic opioids often are needed postoperatively but are not

required in all patients (148–151). The American Headache

Society recommends against prescribing opioid or butalbital-

containing medications as first-line treatment for recurrent

headache disorders (152), and the American Academy of

Neurology also recommends against use of both of these

classes of medications for treatment of migraine, except as a

last resort (153).

Because of equivalent or lesser effectiveness for pain relief

compared with NSAIDs and risks for long-term opioid use after

using opioids for acute pain, opioids are not recommended as

first-line therapy for many common acute pain conditions,

including low back pain, neck pain, pain related to other

musculoskeletal injuries (e.g., sprains, strains, tendonitis, and

bursitis), pain related to minor surgeries typically associated

with minimal tissue injury and only mild postoperative pain

(e.g., simple dental extraction), dental pain, kidney stone pain,

and headaches including episodic migraine. Opioid therapy

has an important role for acute pain related to severe traumatic

injuries (including crush injuries and burns), invasive surgeries

typically associated with moderate to severe postoperative pain,

and other severe acute pain when NSAIDs and other therapies

are contraindicated or likely to be ineffective.

When diagnosis and severity of acute pain warrant the

use of opioids, clinicians should prescribe immediate-release

opioids (see Recommendation 3) at the lowest effective

dose (see Recommendation 4) and for no longer than the

expected duration of pain severe enough to require opioids

(see Recommendation 6) to minimize unintentional initiation

of long-term opioid use. Clinicians should maximize use of

nonopioid pharmacologic (e.g., NSAIDs, acetaminophen, or

both) and nonpharmacologic (e.g., ice, heat, elevation, rest,

immobilization, or exercise) therapies as appropriate for the

specific condition and continue these therapies as needed after

opioids are discontinued. Clinicians should work with patients

to prevent prolonged opioid use, prescribe and advise opioid

use only as needed (e.g., hydrocodone 5 mg/acetaminophen

325 mg, one tablet not more frequently than every 4 hours as

needed for moderate to severe pain) rather than on a scheduled

basis (e.g., one tablet every 4 hours), and encourage and include

an opioid taper if opioids will be taken around the clock for

more than a few days (see Recommendation 6). Clinicians

should consider concurrent medical conditions, including

sleep apnea, pregnancy, renal or hepatic insufficiency, mental

health conditions, and substance use disorders, in assessing

risks of opioid therapy (see Recommendation 8); offer

naloxone, particularly if the patient or a household member

has risk factors for opioid overdose (see Recommendation 8);

use particular caution when prescribing benzodiazepines

or other sedating medications with opioid pain medication

(see Recommendation 11); and check the prescription drug

monitoring program (PDMP) database to ensure a new opioid

prescription will not contribute to cumulative opioid dosages

or medication combinations that put the patient at risk for

overdose (see Recommendation 9). If signs of opioid use

disorder are present, clinicians should address concerns with the

patient, offer or arrange medication treatment for patients who

meet criteria for opioid use disorder, and use nonpharmacologic

and pharmacologic treatments as appropriate to manage

the patient’s pain (see Recommendation 12 and the ASAM

National Practice Guideline for the Treatment of Opioid Use

Disorder: 2020 Focused Update) (96).

Although findings regarding risks for new long-term opioid

use after use for acute pain (10) relate specifically to patients

who were previously opioid naïve, risks also might be associated

with dosage escalation (see Recommendation 4) if patients

already treated with long-term opioids are prescribed additional

opioid medication for new acute pain superimposed on chronic

pain. Therefore, strategies that minimize opioid use should be

implemented for both opioid-naïve and opioid-tolerant patients

with acute pain when possible. If patients receiving long-term

opioid therapy require additional medication for acute pain,

nonopioid medications should be used when possible. If

additional opioids are required (e.g., for superimposed severe

acute pain), they should be continued only for the duration

of pain severe enough to require additional opioids, returning

to the patient’s baseline opioid dosage as soon as possible,

including an appropriate taper to baseline dosage if additional

opioids were used around the clock for more than a few days

(see Recommendation 6).

Patient education and discussion before starting outpatient

opioid therapy are critical so that patient preferences and

values can be understood and used to inform clinical decisions.

Clinicians should ensure that patients are aware of expected

benefits of, common risks of, serious risks of, and alternatives

to opioids before starting or continuing opioid therapy and

should involve patients in decisions about whether to start

opioid therapy. Essential elements for communication and

discussion with patients before prescribing outpatient opioid

therapy for acute pain include the following:

• Advise patients that short-term opioid use can lead to

unintended long-term opioid use and of the importance

of working toward planned discontinuation of opioid use

as soon as feasible, including a plan to appropriately taper

opioids as pain resolves if opioids have been used around

the clock for more than a few days (see Recommendation 6).

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• Review communication mechanisms and protocols patients

can use to tell clinicians of severe or uncontrolled pain and

to arrange for timely reassessment and management.

• Advise patients about serious adverse effects of opioids,

including potentially fatal respiratory depression and

development of a potentially serious opioid use disorder

(see Recommendation 12) that can cause distress and

inability to fulfill major role obligations at work, school,

or home.

• Advise patients about common effects of opioids, such as

constipation, dry mouth, nausea, vomiting, drowsiness,

confusion, tolerance, physical dependence, and withdrawal

symptoms when stopping opioids. To prevent constipation

associated with opioid use, advise patients to increase

hydration and fiber intake and to maintain or increase

physical activity as they are able. Prophylactic pharmacologic

therapy (e.g., a stimulant laxative such as senna, with or

without a stool softener) might be needed to ensure regular

bowel movements if opioids are used for more than a few

days. Stool softeners or fiber laxatives without another

laxative should be avoided. To minimize withdrawal

symptoms, clinicians should provide and discuss an opioid

tapering plan when opioids will be used around the clock

for more than a few days (see Recommendation 6).

Limiting opioid use to the minimum needed to manage

pain (e.g., taking the opioid only when needed if needed

less frequently than every 4 hours and the prescription is

written for every 4 hours as needed for pain) can help limit

development of tolerance and therefore withdrawal after

opioids are discontinued.

• If formulations are prescribed that combine opioids with

acetaminophen, advise patients of the risks of taking additional

over-the-counter products containing acetaminophen.

• To help patients assess when a dose of opioids is needed,

explain that the goal is to reduce pain to make it

manageable rather than to eliminate pain.

• Discuss effects that opioids might have on a person’s ability

to safely operate a vehicle or other machinery, particularly

when opioids are initiated or when other central nervous

system depressants (e.g., benzodiazepines or alcohol) are

used concurrently.

• Discuss the potential for workplace toxicology testing

programs to detect therapeutic opioid use.

• Discuss increased risks for opioid use disorder, respiratory

depression, and death at higher dosages, along with the

importance of taking only the amount of opioids

prescribed (i.e., not taking more opioids than prescribed

or taking them more often).

• Review increased risks for respiratory depression when

opioids are taken with benzodiazepines, other sedatives,

alcohol, nonprescribed or illicit drugs (e.g., heroin), or

other opioids (see Recommendations 8 and 11).

• Discuss risks to household members and other persons if

opioids are intentionally or unintentionally shared with others

for whom they are not prescribed, including the possibility

that others might experience overdose at the same or lower

dosage than prescribed for the patient and that young children

and pets are susceptible to unintentional ingestion. Discuss

storage of opioids in a secure and preferably locked location,

options for safe disposal of unused opioids (154), and the

value of having naloxone available.

• Discuss planned use of precautions to reduce risks, including

naloxone for overdose reversal (see Recommendation 8) and

clinician use of PDMP information (see Recommendation 9).

Recommendation 2

Nonopioid therapies are preferred for subacute and chronic

pain. Clinicians should maximize use of nonpharmacologic

and nonopioid pharmacologic therapies as appropriate

for the specific condition and patient and only consider

initiating opioid therapy if expected benefits for pain and

function are anticipated to outweigh risks to the patient.

Before starting opioid therapy for subacute or chronic pain,

clinicians should discuss with patients the realistic benefits

and known risks of opioid therapy, should work with patients

to establish treatment goals for pain and function, and

should consider how opioid therapy will be discontinued if

benefits do not outweigh risks (recommendation category: A;

evidence type: 2).

Implementation Considerations

• To guide patient-specific selection of therapy, clinicians should

evaluate patients and establish or confirm the diagnosis.

• Clinicians should recommend appropriate noninvasive

nonpharmacologic approaches to help manage chronic

pain, such as exercise (e.g., aerobic, aquatic, or resistance

exercises) or exercise therapy (a prominent modality in

physical therapy) for back pain, fibromyalgia, and hip or

knee osteoarthritis; weight loss for knee osteoarthritis;

manual therapies for hip osteoarthritis; psychological

therapy, spinal manipulation, low-level laser therapy,

massage, mindfulness-based stress reduction, yoga,

acupuncture, and multidisciplinary rehabilitation for low

back pain; mind-body practices (e.g., yoga, tai chi, or

qigong), massage, and acupuncture for neck pain;

cognitive behavioral therapy, myofascial release massage,

mindfulness practices, tai chi, qigong, acupuncture, and

multidisciplinary rehabilitation for fibromyalgia; and

spinal manipulation for tension headache.

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• Low-cost options to integrate exercise include walking in

public spaces or use of public recreation facilities for group

exercise. Physical therapy can be helpful, particularly for

patients who have limited access to safe public spaces or

public recreation facilities for exercise or whose pain has

not improved with low-intensity physical exercise.

• Health insurers and health systems can improve pain

management and reduce medication use and associated

risks by increasing reimbursement for and access to

noninvasive nonpharmacologic therapies with evidence

for effectiveness.

• Clinicians should review FDA-approved labeling, including

boxed warnings, and weigh benefits and risks before

initiating treatment with any pharmacologic therapy.

• When patients affected by osteoarthritis have an

insufficient response to nonpharmacologic interventions

such as exercise for arthritis pain, topical NSAIDs can be

used in patients with pain in a single or few joints near

the surface of the skin (e.g., knee). For patients with

osteoarthritis pain in multiple joints or incompletely

controlled with topical NSAIDs, duloxetine or systemic

NSAIDs can be considered.

• NSAIDs should be used at the lowest effective dose and

shortest duration needed and should be used with caution,

particularly in older adults and in patients with

cardiovascular comorbidities, chronic renal failure, or

previous gastrointestinal bleeding.

• When patients with chronic low back pain have had an

insufficient response to nonpharmacologic approaches

such as exercise, clinicians can consider NSAIDs or

duloxetine for patients without contraindications.

• Tricyclic, tetracyclic, and SNRI antidepressants; selected

anticonvulsants (e.g., pregabalin, gabapentin enacarbil,

oxcarbazepine); and capsaicin and lidocaine patches can

be considered for neuropathic pain. In older adults,

decisions to use tricyclic antidepressants should be made

judiciously on a case-by-case basis because of risks for

confusion and falls.

• Duloxetine and pregabalin are FDA-approved for the

treatment of diabetic peripheral neuropathy, and

pregabalin and gabapentin are FDA-approved for

treatment of postherpetic neuralgia.

• In patients with fibromyalgia, tricyclic (e.g., amitriptyline)

and SNRI antidepressants (e.g., duloxetine, milnacipran),

NSAIDs (e.g., topical diclofenac), and specific

anticonvulsants (i.e., pregabalin and gabapentin) are used

to improve pain, function, and quality of life. Duloxetine,

milnacipran, and pregabalin are FDA-approved for the

treatment of fibromyalgia. In older adults, decisions to use

tricyclic antidepressants should be made judiciously on a

case-by-case basis because of risks for confusion and falls.

• Patients with co-occurring pain and depression might be

especially likely to benefit from antidepressant medication

(see Recommendation 8).

• Opioids should not be considered first-line or routine

therapy for subacute or chronic pain. This does not mean

that patients should be required to sequentially fail

nonpharmacologic and nonopioid pharmacologic therapy

or be required to use any specific treatment before

proceeding to opioid therapy. Rather, expected benefits

specific to the clinical context should be weighed against

risks before initiating therapy. In some clinical contexts

(e.g., serious illness in a patient with poor prognosis for

return to previous level of function, contraindications to

other therapies, and clinician and patient agreement that

the overriding goal is patient comfort), opioids might be

appropriate regardless of previous therapies used. In other

situations (e.g., headache or fibromyalgia), expected

benefits of initiating opioids are unlikely to outweigh risks

regardless of previous nonpharmacologic and nonopioid

pharmacologic therapies used.

• Opioid therapy should not be initiated without

consideration by the clinician and patient of an exit

strategy to be used if opioid therapy is unsuccessful.

• Before opioid therapy is initiated for subacute or chronic

pain, clinicians should determine jointly with patients how

functional benefit will be evaluated and establish specific,

measurable treatment goals.

• For patients with subacute pain who started opioid therapy

for acute pain and have been treated with opioid therapy

for ≥30 days, clinicians should ensure that potentially

reversible causes of chronic pain are addressed and that

opioid prescribing for acute pain does not unintentionally

become long-term opioid therapy simply because

medications are continued without reassessment.

Continuation of opioid therapy at this point might

represent initiation of long-term opioid therapy, which

should occur only as an intentional decision that benefits

are likely to outweigh risks after informed discussion

between the clinician and patient and as part of a

comprehensive pain management approach.

• Clinicians seeing new patients already receiving opioids

should establish treatment goals, including functional

goals, for continued opioid therapy. Clinicians should

avoid rapid tapering or abrupt discontinuation of opioids

(see Recommendation 5).

• Patient education and discussion before starting opioid

therapy are critical so that patient preferences and values

can be understood and used to inform clinical decisions.

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• Clinicians should review available low-cost options for

pain management for all patients and particularly for

patients who have low incomes, do not have health

insurance, or have inadequate insurance.

• Clinicians should ensure that patients are aware of

expected benefits of, common risks of, serious risks of, and

alternatives to opioids before starting or continuing opioid

therapy and should involve patients in decisions about

whether to start opioid therapy.

Supporting Rationale

To guide patient-specific selection of therapy, clinicians

should evaluate patients and establish or confirm the diagnosis

(155). Detailed recommendations on diagnosis are provided

in other guidelines (156–159). Evaluation should include a

focused history, including history and characteristics of pain

and potential contributing factors (e.g., function, work history

and current work demands, psychosocial stressors, and sleep),

and physical examination, with imaging or other diagnostic

testing only if indicated (e.g., if severe or progressive neurologic

deficits are present or if serious underlying conditions

are suspected) (158,159). For complex pain syndromes,

consultation with a pain specialist can be considered to assist

with diagnosis and management.

Diagnosis can help identify disease-specific interventions

to reverse, ameliorate, or prevent worsening of pain and

improve function (e.g., improving glucose control to prevent

progression of diabetic neuropathy; immune-modulating

agents for rheumatoid arthritis; physical or occupational

therapy to address posture, muscle weakness, or repetitive

occupational motions that contribute to musculoskeletal

pain; or surgical intervention to relieve severe mechanical

or compressive pain) (159). The underlying mechanism

for most pain syndromes has traditionally been categorized

as neuropathic (e.g., diabetic neuropathy and postherpetic

neuralgia) or nociceptive (e.g., osteoarthritis and muscular

back pain). More recently, nociplastic pain has been suggested

as a third, distinct category of pain with augmented central

nervous system pain and sensory processing and altered pain

modulation as experienced in conditions such as fibromyalgia

(160). The diagnosis and pathophysiologic mechanism of

pain have implications for symptomatic pain treatment with

medication. For example, evidence is limited for improved

pain or function, or evidence exists of worse outcomes, with

long-term use of opioids for several chronic pain conditions for

which opioids are commonly prescribed, such as osteoarthritis

(161), nonspecific low back pain (119,162), headache (152),

and fibromyalgia (163,164). For moderate to severe chronic

back pain or hip or knee osteoarthritis pain, a nonopioid

strategy starting with acetaminophen or NSAIDs results in

improved pain intensity with fewer side effects compared with

a strategy starting with opioids (74). Tricyclic antidepressants,

SNRI antidepressants, selected anticonvulsants, or transdermal

lidocaine are recommended for neuropathic pain syndromes

(e.g., diabetic neuropathy or postherpetic neuralgia) (156).

Review of the patient’s history and context beyond the

presenting pain syndrome is helpful in selection of pain

treatments. In particular, medications should be used only after

assessment and determination that expected benefits outweigh

risks, considering patient-specific factors. For example,

clinicians should consider fall risk when selecting and dosing

potentially sedating medications (e.g., tricyclic antidepressants,

anticonvulsants, and opioids) and should weigh benefits

and risks of use, dosage, and duration of NSAIDs when

treating older adults and patients with hypertension, renal

insufficiency, heart failure, or those with risk for peptic ulcer

disease or cardiovascular disease. NSAIDs are potentially

inappropriate for use in older adults with chronic pain because

of higher risk for adverse effects with prolonged use (165).

Some guidelines recommend topical NSAIDs for localized

osteoarthritis (e.g., knee osteoarthritis) over oral NSAIDs in

patients aged ≥75 years to minimize systemic effects (166). (See

Recommendation 8 for additional considerations for assessing

risks of opioid therapy.)

Noninvasive Nonpharmacologic Approaches to

Subacute and Chronic Pain

Many noninvasive nonpharmacologic approaches, including

physical therapy, weight loss for knee osteoarthritis, and

behavioral therapies (e.g., cognitive behavioral therapy and

mindfulness-based stress reduction), can improve pain and

function without risk for serious harms (9). High-quality

evidence exists that exercise therapy (a prominent modality in

physical therapy) for back pain, fibromyalgia, and hip or knee

osteoarthritis reduces pain and improves function immediately

after treatment and that the improvements are sustained for

at least 2–6 months (9,167–170). Previous guidelines have

recommended aerobic, aquatic, or resistance exercises for

persons with chronic pain, including osteoarthritis of the knee

or hip, back pain, and fibromyalgia (119,156,166,171). Other

noninvasive nonpharmacologic therapies that improve pain,

function, or both for at least 1 month after delivery without

apparent risk for serious harm include cognitive behavioral

therapy for knee osteoarthritis; manual therapies for hip

osteoarthritis; psychological therapy, spinal manipulation, low-

level laser therapy, massage, mindfulness-based stress reduction,

yoga, acupuncture, and multidisciplinary rehabilitation for low

back pain; mind-body practices (e.g., yoga, tai chi, and qigong),

massage, and acupuncture for neck pain; cognitive behavioral

therapy, myofascial release massage, mindfulness practices, tai

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chi, qigong, acupuncture, and multidisciplinary rehabilitation

for fibromyalgia; and spinal manipulation for tension headache

(9). For temporomandibular disorder pain, patient education

and self-care can be effective, as can occlusal splints for some

patients and biobehavioral therapy for prevention of disabling

symptoms (172,173). Exercise, mind-body interventions, and

behavioral treatments (including cognitive behavioral therapy

and mindfulness practices) can encourage active patient

participation in the care plan and help address the effects of

pain in the patient’s life; these active therapies have somewhat

more robust evidence for sustained improvements in pain

and function than more passive treatments (e.g., massage),

particularly at longer-term follow-up (9). In addition,

physical activity can provide additional health benefits, such

as preventing or reducing symptoms of depression (174).

Active approaches that engage the patient should be used

when possible, with a supplementary role for more passive

approaches, to reduce pain and improve function.

Despite their favorable benefit-to-risk profile, noninvasive

nonpharmacologic therapies are not always covered or fully

covered by insurance (43). Access and cost can be barriers

for patients, particularly persons who have low incomes, do

not have health insurance or have inadequate insurance, have

transportation challenges, or live in rural areas where services

might not be available (121). Health insurers and health

systems can improve pain management and reduce medication

use and associated risks by increasing reimbursement for

and access to noninvasive nonpharmacologic therapies with

evidence for effectiveness (9,43). In addition, for many

patients, aspects of these approaches can be used even when

access to specialty care is limited. For example, previous

guidelines have strongly recommended aerobic, aquatic, or

resistance exercises for patients with osteoarthritis of the knee

or hip (166) and maintenance of physical activity, including

normal daily activities, for patients with low back pain (158).

A randomized trial found no difference in reduced chronic low

back pain intensity, frequency, or disability between patients

assigned to relatively low-cost group aerobics and those

assigned to individual physiotherapy or muscle reconditioning

sessions (175). Low-cost options to integrate exercise include

walking in public spaces or use of public recreation facilities

for group exercise. Physical therapy can be helpful, particularly

for patients who have limited access to safe public spaces or

public recreation facilities for exercise or whose pain has not

improved with low-intensity physical exercise. A randomized

trial found a stepped exercise program, in which patients

were initially offered an Internet-based exercise program and

progressively advanced to biweekly coaching calls and then

to in-person physical therapy if not improved at previous

steps, successfully improved symptomatic knee osteoarthritis,

with 35% of patients ultimately requiring in-person physical

therapy (176). In addition, primary care clinicians can integrate

elements of psychosocial therapies such as cognitive behavioral

therapy, which addresses psychosocial contributors to pain and

improves function (177), by encouraging patients to take an

active role in the care plan, supporting patients in engaging

in activities such as exercise that are typically beneficial but

that might initially be associated with fear of exacerbating

pain (159), or providing education in relaxation techniques

and coping strategies. In many locations, free or low-cost

patient support, self-help, and educational community-based

or employer-sponsored programs are available that can provide

stress reduction and other mental health benefits. Clinicians

should become familiar with such options within their

communities so they can refer patients to low-cost services.

Patients with higher levels of anxiety or fear related to pain or

other clinically significant psychological distress can be referred

for treatment with a mental health specialist (e.g., psychologist,

psychiatrist, or clinical social worker).

Nonopioid Medications for Subacute and

Chronic Pain

Several nonopioid pharmacologic therapies (including

acetaminophen, NSAIDs, and selected antidepressants and

anticonvulsants) are used for painful symptoms in chronic pain

conditions. Nonopioid pharmacologic therapies are associated

with risks, particularly in older adults, pregnant patients, and

patients with certain comorbidities such as cardiovascular,

renal, gastrointestinal, and liver disease. For example, NSAID

use has been associated with serious gastrointestinal events and

major coronary events (8). Increases in nonserious adverse

events have been found with anticonvulsants pregabalin

(blurred vision, cognitive effects, sedation, weight gain,

dizziness, and peripheral edema) and gabapentin (blurred

vision, cognitive effects, sedation, and weight gain), cannabis

(nausea and dizziness), and SNRI antidepressants duloxetine

(nausea and sedation) and milnacipran (nausea); dosage

reductions reduced the risk for some adverse events with SNRI

antidepressants (8). Clinicians should review FDA-approved

labeling, including boxed warnings, before initiating treatment

with any pharmacologic therapy.

For osteoarthritis, NSAIDs including topical NSAIDs

and SNRI antidepressant duloxetine have small to moderate

benefits for pain and function at short-term assessment

(3–6 months), with intermediate-term (6–12 months) evidence

for certain medications (celecoxib and duloxetine) and evidence

that duloxetine is more effective in older (>65 years) than

younger patients and in patients with knee osteoarthritis (8).

Acetaminophen has limited evidence for effectiveness (8) and

is no longer considered a first-line treatment for osteoarthritis

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(161). When patients have an insufficient response to

nonpharmacologic interventions (e.g., exercise for arthritis

pain), and if a single or a few joints near the surface of the

skin (e.g., knee) are affected by osteoarthritis, use of topical

NSAIDs is recommended (161). In patients with osteoarthritis

pain in multiple joints or incompletely controlled pain with

topical NSAIDs, systemic NSAIDs or duloxetine can be used.

However, systemic NSAIDs should be used at the lowest

effective dosage and shortest duration needed because risks

might increase with longer use and at higher dosages (178).

Oral NSAIDs should be used with caution, particularly in

older persons and in patients with cardiovascular comorbidities,

chronic renal failure, or previous gastrointestinal bleeding. In

patients with gastrointestinal comorbidities but without current

or previous gastrointestinal bleeding, cyclooxygenase-2 inhibitors

or NSAIDs with proton pump inhibitors can be used to minimize

risk compared with risk with use of NSAIDs alone (161).

Moderate-quality evidence demonstrates small improvements

in chronic low back pain with NSAIDs (119) and with

duloxetine (8). When patients with low back pain have had an

insufficient response to nonpharmacologic approaches such as

exercise, clinicians can consider NSAIDs or duloxetine (119)

for patients without contraindications.

For temporomandibular disorder pain that is not sufficiently

improved with nonpharmacologic interventions, NSAIDs

can be effective (179,180). Tricyclic, tetracyclic, and SNRI

antidepressants; selected anticonvulsants; and capsaicin and

lidocaine patches are recommended for neuropathic pain (156).

However, evidence on topical lidocaine and capsaicin is limited

(8). SNRI antidepressant duloxetine and anticonvulsants

pregabalin, gabapentin, enacarbil, and oxcarbazepine are

associated with small improvements in neuropathic pain

(mainly diabetic neuropathy and postherpetic neuralgia) (8).

Duloxetine and pregabalin are FDA-approved for the treatment

of diabetic neuropathy, and pregabalin and gabapentin are

FDA-approved for treatment of postherpetic neuralgia.

In patients with fibromyalgia, multiple medications are

associated with small to moderate improvements in pain,

function, and quality of life, including SNRI antidepressants

(duloxetine and milnacipran), NSAIDs (topical diclofenac),

and specific anticonvulsants (pregabalin and gabapentin) (8).

Tricyclic and SNRI antidepressants also can relieve fibromyalgia

symptoms. Duloxetine, milnacipran, and pregabalin are FDA-

approved for and are recommended for the treatment of

fibromyalgia (156). Tricyclic antidepressant amitriptyline often

is used and recommended for patients with fibromyalgia (156),

although evidence for its effectiveness is limited (8). Because

patients with chronic pain might experience concurrent

depression (181) and depression can exacerbate physical

symptoms including pain (182), patients with co-occurring

pain and depression might be especially likely to benefit from

antidepressant medication (see Recommendation 8).

Tricyclic antidepressants are potentially inappropriate for

older adults (aged ≥65 years) because of their anticholinergic

effects (165). Evidence on effectiveness of cannabis for painful

conditions is limited and inconsistent across studies, and some

studies have reported adverse events such as dizziness, nausea,

and sedation (8,183).

Opioid Medication for Subacute and Chronic Pain

Clinical evidence reviews found insufficient evidence to

determine long-term benefits of opioid therapy for chronic

pain and found an increased risk for serious harms related to

long-term opioid therapy that appears to be dose dependent

(7). Compared with no opioid use, opioid use was associated

with increased risk for opioid use disorder, overdose, all-cause

deaths, fractures, falls, and myocardial infarction (7). Opioids

also were associated with increased risk for discontinuation

because of gastrointestinal adverse events, somnolence,

dizziness, and pruritus (7). Compared with placebo, at short-

term follow-up (1 to <6 months), opioids were associated with

small mean improvements in pain intensity (mean difference:

−0.79 on a 0–10 scale; 95% CI: −0.93 to −0.67; I

: 71%) and

function (7). Some evidence indicates that improvement in

pain is reduced with longer duration of opioid therapy, from

a mean improvement of 1 on a 0–10 scale at 1–3 months to

approximately 0.5 at 3–6 months (7). No placebo-controlled

trial evaluated effectiveness of opioids at intermediate

(6 to <12 months) or long-term (≥12 months) follow-up (7).

Compared with nonopioid treatments at short-term follow-up,

there were no differences in mean pain improvement (mean

difference: −0.29 on a 0–10 scale; 95% CI: −0.61 to 0.03)

or functional improvement. No trials were identified that

compared opioids with nonopioid therapies at intermediate-

or long-term follow-up, with the exception of one trial that

found stepped therapy starting with opioids to be associated

with higher pain intensity than stepped therapy starting

with nonopioids (4.0 versus 3.5; mean difference: 0.5;

95% CI: 0–1.0) at 12 months (7,74).

Clinical evidence reviews identified an observational study

(54) finding long-term (>90 days’ supply) opioid prescription

to be associated with considerably increased risk for a new

opioid use disorder diagnosis for all dosages of long-term

(>90 days’ supply) opioids prescribed compared with no

opioids prescribed, with adjusted odds ratios of 15, 29, and 122

at low (1–36 MME/day), medium (36–120 MME/day), and

high (≥120 MME/day) opioid dosages, respectively. Compared

with no opioid use, opioid use was associated with increased

risk for opioid use disorder, overdose, all-cause deaths, fractures,

falls, and myocardial infarction (7).

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Multiple experts from OWG stated that they appreciated this

recommendation because of the importance of highlighting

both pain and function, sharing realistic expectations with

patients before initiating treatment, and paying attention to

tapering and exit strategies. Although some experts reasoned

the recommendation statement could state nonopioid

therapies “may be preferred” or “may be effective” for chronic

pain, others agreed with language that nonopioid therapies

“are preferred” for chronic pain because opioid therapies are

associated with small short-term benefits compared with

placebo, comparable or reduced short-term benefits compared

with nonopioid therapies, uncertain long-term benefits, and

potential for serious harms.

Opioids should not be considered first-line or routine therapy

for subacute or chronic pain. Although evidence on long-term

benefits of nonopioid therapies also is limited, these therapies

also are associated with short-term benefits, no evidence exists

for attenuated benefit over time or difficulty stopping therapy

when benefits do not outweigh risks, and risks for serious

harms are usually lower. This does not mean that patients

should be required to sequentially fail nonpharmacologic and

nonopioid pharmacologic therapy or be required to use any

specific treatment before proceeding to opioid therapy. Rather,

expected benefits specific to the clinical context should be

weighed against risks before initiating therapy. In some clinical

contexts (e.g., serious illness in a patient with poor prognosis

for return to previous level of function, contraindications

to other therapies, and clinician and patient agreement that

the overriding goal is patient comfort), opioids might be

appropriate regardless of previous therapies used. In other

situations (e.g., headache or fibromyalgia), expected benefits

of initiating opioids are unlikely to outweigh risks regardless

of previous nonpharmacologic and nonopioid pharmacologic

therapies used.

Clinical evidence reviews found no instrument with high

accuracy for predicting opioid-related harms, such as overdose

or opioid use disorder (7). For clinicians, predicting whether

benefits of opioids for chronic pain will outweigh risks of

ongoing opioid treatment for individual patients can be

challenging. Therefore, opioid therapy should only be initiated

with consideration by the clinician and patient of an exit

strategy that could be used if opioid therapy is unsuccessful

in improving pain and pain-related function.

Before opioid therapy is initiated for subacute or chronic

pain, clinicians should determine with patients how functional

benefit will be evaluated and establish treatment goals.

Some patients have reported treatment goals are effective

in increasing motivation and functioning (7). Goals ideally

include improvement in function (including social, emotional,

and physical dimensions), pain, and quality of life. Goals can

be tailored to specific patient and clinical circumstances. For

example, for some patients with diseases typically associated

with progressive functional impairment or catastrophic

injuries such as spinal cord trauma, reductions in pain

without improvement in physical function might be more

realistic. Clinicians can assess and then follow function, pain

severity, and quality of life using tools such as the three-item

PEG (Pain average, interference with Enjoyment of life, and

interference with General activity) assessment scale (184) (see

Recommendation 7). Clinically meaningful improvement

has been defined as a 30% improvement in scores for both

pain and function (185). Clinicians can ask patients about

functional goals that have meaning for them (e.g., walking

the dog or walking around the block, returning to part-time

work, and attending family events or recreational activities),

and then use these goals in assessing benefits of opioid therapy

and weighing benefits against risks of continued opioid therapy

for individual patients (see Recommendation 7).

Patients with subacute pain might be at a particularly

critical point, both for potential transition to chronic pain and

potential transition to long-term opioid therapy. Clinicians

should reevaluate patients with subacute pain and their

treatment course, ensure that potentially reversible causes of

ongoing pain are addressed, and optimize pain management

as needed. For patients with subacute pain who started opioid

therapy for acute pain and have been treated with opioid

therapy for ≥30 days, clinicians should ensure that opioid

prescribing for acute pain does not unintentionally become

long-term opioid prescribing simply because medications

are continued without reassessment. Continuation of opioid

therapy at this point might represent initiation of long-term

opioid therapy, which should occur only as an intentional

decision that benefits are likely to outweigh risks after informed

discussion between the clinician and patient and as part of a

comprehensive pain management approach.

Clinicians seeing new patients already using opioid

medication should establish treatment goals, including

functional goals, for continued opioid therapy. Clinicians

should avoid rapid tapering or abrupt discontinuation of

opioids (see Recommendation 5). Although the clinical

evidence reviews did not find studies evaluating the

effectiveness of written agreements or treatment plans (7),

clinicians and patients who clearly document a treatment plan

including specific functional goals in advance of prescribing

will clarify expectations about how opioids will be prescribed

and monitored with an aim to improve patient safety, health,

and well-being.

Patient education and discussion before starting opioid

therapy are critical so that patient preferences and values can

be understood and used to inform clinical decisions. Clinicians

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should ensure that patients are aware of expected benefits of,

common risks of, serious risks of, and alternatives to opioids

before starting or continuing opioid therapy and should

involve patients in decisions about whether to start opioid

therapy. Many patients rank pain relief, nausea, vomiting, and

constipation as important effects (7). The following elements

are essential for communication and discussion with patients

before starting opioid therapy:

• Review available low-cost options for pain management

for all patients, and particularly for patients who have low

incomes, do not have health insurance, or have inadequate

insurance. Review considerations related to access to care

because of the clinical oversight needed to initiate and

continue opioid therapy and other treatments for pain.

• Be explicit and realistic about expected benefits of opioids,

explaining that there is not robust evidence that opioids

improve pain or function with long-term use and that

complete elimination of pain is unlikely.

• Emphasize improvement in function as a primary goal and

that function can improve even when pain is not eliminated.

• Advise patients about serious adverse effects of opioids,

including potentially fatal respiratory depression and

development of a potentially serious opioid use disorder

that can cause distress and inability to fulfill major

obligations at work, school, or home.

• Advise patients about common effects of opioids, such as

constipation, dry mouth, nausea, vomiting, drowsiness,

confusion, tolerance, physical dependence, and withdrawal

symptoms when stopping opioids. To prevent constipation

associated with opioid use, advise patients to increase

hydration and fiber intake and to maintain or increase

physical activity. Prophylactic pharmacologic therapy (e.g.,

a stimulant laxative such as senna, with or without a stool

softener) is usually needed to ensure regular bowel

movements if opioids are taken regularly. Stool softeners or

fiber laxatives without another laxative should be avoided.

• If formulations are prescribed that combine opioids with

acetaminophen, advise patients of the risks for taking additional

over-the-counter products containing acetaminophen.

• Discuss effects that opioids might have on ability to safely

operate a vehicle or other machinery, particularly when opioids

are initiated, when dosages are increased, or when other central

nervous system depressants, such as benzodiazepines or alcohol,

are used concurrently.

• Discuss the potential for workplace toxicology testing

programs to detect therapeutic opioid use.

• Discuss increased risks for opioid use disorder, respiratory

depression, and death at higher dosages, along with the

importance of taking only the amount of opioids

prescribed (i.e., not taking more opioids than prescribed

or taking them more often).

• Review increased risks for respiratory depression when opioids

are taken with benzodiazepines, other sedatives, alcohol,

nonprescribed drugs such as heroin, or other opioids.

• Discuss risks for household members and other persons if

opioids are intentionally or unintentionally shared with others

for whom they are not prescribed, including the possibility

that others might experience overdose at the same or at lower

dosage than prescribed for the patient and that young children

are susceptible to unintentional ingestion. Discuss storage of

opioids in a secure, preferably locked location and options

for safe disposal of unused opioids (154).

• Discuss the importance of periodic reassessment to ensure

that opioids are helping to meet patient goals and, if opioids

are not effective or are harmful, to allow opportunities for

consideration of opioid tapering and dosage reduction or

discontinuation and of additional nonpharmacologic or

nonopioid pharmacologic treatment options.

• Discuss expectations for clinician and patient responsibilities

to mitigate risks of opioid therapy and planned use of

precautions to reduce risks, including naloxone for

overdose reversal (see Recommendation 8) and clinician

use of PDMP information (see Recommendation 9) and

toxicology screening (see Recommendation 10).

• Consider whether cognitive status might interfere with

management of opioid therapy and, if so, determine whether

a caregiver can responsibly comanage medication therapy.

Discuss the importance of reassessing medication use over

time with both the patient and caregiver, as appropriate.

Because of the possibility that benefits of opioid therapy might

diminish or that risks might become more prominent over time,

clinicians should elicit patients’ experiences and preferences and

review expected benefits and risks of continued opioid therapy

with patients periodically (see Recommendation 7).

Interventional Approaches to Subacute and

Chronic Pain

Office-based interventional approaches, such as arthrocentesis

and intra-articular glucocorticoid injection for pain associated

with rheumatoid arthritis (186) or osteoarthritis (187) and

subacromial corticosteroid injection for rotator cuff disease

(188), can provide short-term improvement in pain and

function to supplement or facilitate exercise, physical therapy,

and other conservative approaches. Evidence is insufficient to

determine the extent to which repeated glucocorticoid injection

increases potential risks such as articular cartilage changes (in

osteoarthritis) and sepsis (187).

Interventional pain management specialists offer additional

interventions that can alleviate pain as part of a comprehensive

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pain management approach (6) for patients with indications

including back pain, persistent pain after spinal surgery,

neuropathic pain, and complex regional pain syndrome.

Certain more common procedures include epidural steroid

injections (for lumbar radiculopathy with herniated disc), nerve

ablation procedures (e.g., radiofrequency denervation for low

back pain), and neurostimulation procedures (e.g., peripheral

nerve stimulation and spinal cord stimulation). Descriptions

of common interventional procedures are available (6). Level

of evidence for effectiveness and risks varies by procedure,

and additional research is needed to establish the clinical

benefits as well as risks of specific interventional procedures

for specific pain conditions (6,189) compared with risks of

opioid pain medications and other pharmacologic therapies.

Rare, serious adverse events have been reported with epidural

injection (190). Interventional procedures should be performed

by properly trained clinicians following meticulous infection

control protocols. Clinicians can consult with a qualified pain

management specialist who is well versed in benefits and risks

of diagnostic and therapeutic options to determine potential

appropriateness of specific interventional procedures for their

patients’ indications and clinical circumstances.

Multimodal Therapy for Subacute and

Chronic Pain

Integrated pain management requires coordination of

medical, psychological, and social aspects of health care and

includes primary care, mental and behavioral health care, and

specialist services when needed (191). Multimodal therapies

and multidisciplinary biopsychosocial rehabilitation (e.g.,

combining psychological therapies with exercise) can reduce

long-term pain and disability compared with usual care and

compared with physical treatments (e.g., exercise) alone.

Nonpharmacologic therapies also can provide synergistic

benefits when nonopioid or opioid pain medications are used

(6). When needed, medications should ideally be combined

with nonpharmacologic therapy to provide greater benefits to

patients in improving pain and function. Multimodal therapies

are not always available or reimbursed by insurance and can

be time consuming and costly for patients, and disparities

in abilities to access multimodal care exist (6). Evidence

exists that less-intensive multidisciplinary rehabilitation can

be similarly effective to high-intensity multidisciplinary

rehabilitation (9). Multimodal therapies should be considered

for patients not responding to single-modality therapy, and

combinations should be tailored depending on patient needs,

cost, convenience, and other individual factors.

Depending on patient comorbidities and benefit-to-risk ratios

in individual patients, combinations of medications (e.g., two

nonopioid medications with different mechanisms of action or a

nonopioid with an opioid medication) also might be used. In some

cases, medication combinations might provide complementary

or synergistic benefits and facilitate lower dosing of individual

medications, as has been demonstrated in trials of patients with

neuropathic pain (7). However, this approach should be used with

caution to avoid synergistic risks of medications. For example,

combinations of medications that depress the central nervous

system and cause sedation (see Recommendation 11), such as an

opioid with gabapentin, have been associated with increased risk

for overdose compared with either medication alone (7).

Selecting Opioids and Determining

Opioid Dosages

Recommendation 3

When starting opioid therapy for acute, subacute, or

chronic pain, clinicians should prescribe immediate-release

opioids instead of extended-release and long-acting (ER/LA)

opioids (recommendation category: A; evidence type: 4).

Implementation Considerations

• Clinicians should not treat acute pain with ER/LA opioids

or initiate opioid treatment for subacute or chronic pain

with ER/LA opioids, and clinicians should not prescribe

ER/LA opioids for intermittent or as-needed use.

• ER/LA opioids should be reserved for severe, continuous pain.

FDA has noted that some ER/LA opioids should be considered

only for patients who have received certain dosages of opioids

of immediate-release opioids daily for at least 1 week.

• When changing to an ER/LA opioid for a patient previously

receiving a different immediate-release opioid, clinicians

should consult product labeling and reduce total daily

dosage to account for incomplete opioid cross-tolerance.

• Clinicians should use additional caution with ER/LA

opioids and consider a longer dosing interval when

prescribing to patients with renal or hepatic dysfunction

because decreased clearance of medications among these

patients can lead to accumulation of drugs to toxic levels

and persistence in the body for longer durations.

• Methadone should not be the first choice for an ER/LA

opioid. Only clinicians who are familiar with methadone’s

unique risk profile and who are prepared to educate and

closely monitor their patients, including assessing risk for QT

prolongation and considering electrocardiographic

monitoring, should consider prescribing methadone for pain.

• Only clinicians who are familiar with the dosing and

absorption properties of the ER/LA opioid transdermal

fentanyl and are prepared to educate their patients about

its use should consider prescribing it.

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Supporting Rationale

ER/LA opioids include methadone, transdermal fentanyl,

and extended-release versions of opioids such as oxycodone,

hydromorphone, hydrocodone, and morphine. Clinical

evidence reviews found that effects of opioids on short-term

pain and function were generally consistent across duration of

action (short- or long-acting) and opioid type (opioid agonist,

partial agonist, or mixed mechanism [with mixed opioid and

nonopioid mechanisms of action] agent), although five trials

directly comparing different types of opioids found a mixed

mechanism agent associated with greater pain relief versus a

pure opioid agonist, with fewer nonserious adverse events (7).

A fair-quality study demonstrated a higher risk for overdose

among patients treated with ER/LA opioids than among those

treated with immediate-release opioids, especially within the

first 2 weeks of therapy, with relative risk decreasing with

longer duration of exposure (7,192). Clinical evidence reviews

did not find evidence that continuous, time-scheduled use of

ER/LA opioids is more effective or safer than intermittent

use of immediate-release opioids or that time-scheduled use

of ER/ LA opioids reduces risk for opioid use disorder (7).

In 2014, FDA modified the labeling for ER/LA opioid pain

medications, noting serious risks and recommending that

ER/LA opioids be reserved for management of pain severe

enough to require daily, around-the-clock, long-term opioid

treatment when alternative treatment options (e.g., nonopioid

analgesics or immediate-release opioids) are ineffective,

not tolerated, or would be otherwise inadequate to provide

sufficient management of pain and not used as as-needed

pain relievers (49). FDA also noted that some ER/LA opioids

are only appropriate for opioid-tolerant patients, defined as

patients who have received certain dosages of opioids (e.g.,

60 mg daily of oral morphine, 30 mg daily of oral oxycodone,

or equianalgesic dosages of other opioids) for at least 1 week

(193). Time-scheduled opioid use can be associated with

greater total average daily opioid dosage compared with

intermittent, as-needed opioid use (194). Technologies

have been used to prevent manipulation intended to defeat

extended-release properties of ER/LA opioids and to prevent

opioid use by unintended routes of administration, such

as intravenous injection of oral opioids. FDA guidance for

industry on evaluation and labeling of these “abuse-deterrent”

opioids (195) indicates that these technologies, although they

are expected to make manipulation of opioids more difficult

or reduce the potent effects of manipulation, do not prevent

opioid misuse or overdose through oral intake (the most

common route of opioid misuse) and can still be misused by

nonoral routes. The “abuse-deterrent” label does not indicate

that there is no risk for misuse or opioid use disorder. No

studies were found in the clinical evidence reviews assessing

the effectiveness of “abuse-deterrent” technologies as a risk

mitigation strategy for deterring or preventing opioid misuse,

opioid use disorder, or overdose (7). Experts from OWG

agreed with the recommendation for clinicians to initiate

opioid treatment with immediate-release opioids instead of

with ER/LA opioids and said they appreciated discussion of

the lack of evidence for “abuse-deterrent” formulations.

In comparing different ER/LA formulations, clinical

evidence reviews found inconsistent results for overdose risk

with methadone versus other ER/LA opioids used for chronic

pain, with two cohort studies of Medicaid beneficiaries finding

methadone associated with increased risk for overdose or all-

cause deaths versus morphine and one cohort study of U.S.

Department of Veterans Affairs patients finding methadone

to be associated with decreased risk (7). Methadone has

been associated with disproportionate numbers of overdose

deaths relative to the frequency with which it is prescribed

for pain (196). In addition, methadone is associated with

cardiac arrhythmias along with QT prolongation on the

electrocardiogram, and it has complicated pharmacokinetics

and pharmacodynamics, including a long and variable half-

life and peak respiratory depressant effect occurring later

and lasting longer than peak analgesic effect (197–199). In

regard to other ER/LA opioid formulations, the absorption

and pharmacodynamics of transdermal fentanyl are complex,

with gradually increasing serum concentration during the first

part of the 72-hour dosing interval, and variable absorption

affected by factors such as external heat. In addition, the dosing

of transdermal fentanyl is in mcg/hour, which is not typical

for a drug used by outpatients and can be confusing. These

complexities might increase the risk for fatal overdose when

methadone or transdermal fentanyl is prescribed.

Clinicians should not treat acute pain with ER/LA opioids

or initiate opioid treatment for subacute or chronic pain with

ER/LA opioids, and clinicians should not prescribe ER/LA

opioids for intermittent use. Because of the longer half-life

and longer duration of effects (e.g., respiratory depression)

of ER/LA opioids (e.g., methadone, fentanyl patches, or

extended-release versions of oxycodone, hydromorphone,

hydrocodone, or morphine), clinicians should not prescribe

ER/LA opioids for the treatment of acute pain. ER/LA opioids

should be reserved for severe, continuous pain and should be

considered only for patients who have received certain dosages

of immediate-release opioids daily (e.g., 60 mg daily of oral

morphine, 30 mg daily of oral oxycodone, or equianalgesic

dosages of other opioids) for at least 1 week (193). When

changing to an ER/LA opioid for a patient previously receiving

a different immediate-release opioid, clinicians should consult

product labeling and reduce total daily dosage to account

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for incomplete opioid cross-tolerance. Clinicians should use

additional caution with ER/LA opioids and consider a longer

dosing interval when prescribing to patients with renal or

hepatic dysfunction because decreased clearance of medications

among these patients can lead to accumulation of medications

to toxic levels and persistence in the body for longer durations.

Although in certain situations clinicians might need to

prescribe immediate-release and ER/LA opioids together (e.g.,

when transitioning patients from ER/LA opioids to immediate-

release opioids by temporarily using lower dosages of both, for

temporary postoperative use of short-term opioids in a patient

already receiving ER/LA opioids, or in patients with opioid

use disorder treated and stabilized on methadone who need

short-acting opioids for acute pain), clinicians should consider

the potential for increased overdose risk and use caution when

prescribing immediate-release opioids in combination with

ER/LA opioids.

When an ER/LA opioid is prescribed, using one with

predictable pharmacokinetics and pharmacodynamics

is preferred to minimize unintentional overdose risk. In

particular, unique characteristics of methadone and transdermal

fentanyl make safe prescribing of these medications for pain

especially challenging. Methadone should not be the first

choice for an ER/LA opioid. Only clinicians who are familiar

with methadone’s unique risk profile and who are prepared

to educate and closely monitor their patients, including

risk assessment for QT prolongation and consideration of

electrocardiographic monitoring, should consider prescribing

methadone for pain. A clinical practice guideline regarding

methadone prescribing for pain has been published previously

(200). Because dosing effects of transdermal fentanyl often are

misunderstood by both clinicians and patients, only clinicians

who are familiar with its dosing and absorption properties of

and are prepared to educate their patients about its use should

consider prescribing transdermal fentanyl.

Recommendation 4

When opioids are initiated for opioid-naïve patients with

acute, subacute, or chronic pain, clinicians should prescribe

the lowest effective dosage. If opioids are continued for

subacute or chronic pain, clinicians should use caution when

prescribing opioids at any dosage, should carefully evaluate

individual benefits and risks when considering increasing

dosage, and should avoid increasing dosage above levels likely

to yield diminishing returns in benefits relative to risks to

patients (recommendation category: A; evidence type: 3).

Implementation Considerations

• The recommendations related to opioid dosages are not

intended to be used as an inflexible, rigid standard of care;

rather, they are intended to be guideposts to help inform

clinician-patient decision-making. Risks of opioid use,

including risk for overdose and overdose death, increase

continuously with dosage, and there is no single dosage

threshold below which risks are eliminated. Therefore, the

recommendation language emphasizes that clinicians

should avoid increasing dosage above levels likely to yield

diminishing returns in benefits relative to risks to patients

rather than emphasizing a single specific numeric

threshold. Further, these recommendations apply

specifically to starting opioids or to increasing opioid

dosages, and a different set of benefits and risks applies to

reducing opioid dosages (see Recommendation 5).

• When opioids are initiated for opioid-naïve patients with

acute, subacute, or chronic pain, clinicians should

prescribe the lowest effective dosage.

• For patients not already taking opioids, the lowest effective

dose can be determined using product labeling as a starting

point with calibration as needed based on the severity of

pain and other clinical factors such as renal or hepatic

insufficiency (see Recommendation 8).

• The lowest starting dose for opioid-naïve patients is often

equivalent to a single dose of approximately 5–10 MME

or a daily dosage of 20–30 MME/day. A listing of common

opioid medications and their doses in MME equivalents

is provided (Table).

• If opioids are continued for subacute or chronic pain,

clinicians should use caution when prescribing opioids at

any dosage and should generally avoid dosage increases

when possible.

• Many patients do not experience benefit in pain or

function from increasing opioid dosages to ≥50 MME/day

but are exposed to progressive increases in risk as dosage

increases. Therefore, before increasing total opioid dosage

to ≥50 MME/day, clinicians should pause and carefully

reassess evidence of individual benefits and risks. If a

decision is made to increase dosage, clinicians should use

caution and increase dosage by the smallest practical

amount. The recommendations related to opioid dosages

are not intended to be used as an inflexible, rigid standard

of care; rather, they are intended to be guideposts to help

inform clinician-patient decision-making.

• Additional dosage increases beyond 50 MME/day are

progressively more likely to yield diminishing returns in

benefits for pain and function relative to risks to patients as

dosage increases further. Clinicians should carefully evaluate

a decision to further increase dosage on the basis of

individualized assessment of benefits and risks and weighing

factors such as diagnosis, incremental benefits for pain and

function relative to risks with previous dosage increases,

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TABLE. Morphine milligram equivalent doses for commonly

prescribed opioids for pain management

Opioid Conversion factor*

Codeine 0.15

Fentanyl transdermal (in mcg/hr) 2.4

Hydrocodone 1.0

Hydromorphone 5.0

Methadone 4.7

Morphine 1.0

Oxycodone 1.5

Oxymorphone 3.0

Tapentadol

†

0.4

Tramadol

0.2

Sources: Adapted from Von Korff M, Saunders K, Ray GT, et al. Clin J Pain

2008;24:521–7 and Nielsen S, Degenhardt L, Hoban B, Gisev N. Pharmacoepidemiol

Drug Saf 2016;25:733–7.

Abbreviations: mcg/hr = microgram per hour; mg = milligram; MME = morphine

milligram equivalent.

* Multiply the dose for each opioid by the conversion factor to determine the

dose in MMEs. For example, tablets containing hydrocodone 5 mg and

acetaminophen 325 mg taken four times a day would contain a total of 20 mg

of hydrocodone daily, equivalent to 20 MME daily; extended-release tablets

containing oxycodone 10 mg and taken twice a day would contain a total of

20 mg of oxycodone daily, equivalent to 30 MME daily. The following cautions

should be noted: 1) All doses are in mg/day except for fentanyl, which is

mcg/hr. 2) Equianalgesic dose conversions are only estimates and cannot

account for individual variability in genetics and pharmacokinetics. 3) Do not

use the calculated dose in MMEs to determine the doses to use when

converting one opioid to another; when converting opioids, the new opioid

is typically dosed at a substantially lower dose than the calculated MME dose

to avoid overdose because of incomplete cross-tolerance and individual

variability in opioid pharmacokinetics. 4) Use particular caution with

methadone dose conversions because methadone has a long and variable

half-life, and peak respiratory depressant effect occurs later and lasts longer

than peak analgesic effect. 5) Use particular caution with transdermal fentanyl

because it is dosed in mcg/hr instead of mg/day, and its absorption is affected

by heat and other factors. 6) Buprenorphine products approved for the

treatment of pain are not included in the table because of their partial

µ-receptor agonist activity and resultant ceiling effects compared with full

µ-receptor agonists. 7) These conversion factors should not be applied to

dosage decisions related to the management of opioid use disorder.

†

Tapentadol is a µ-receptor agonist and norepinephrine reuptake inhibitor. MMEs

are based on degree of µ-receptor agonist activity; however, it is unknown

whether tapentadol is associated with overdose in the same dose-dependent

manner as observed with medications that are solely µ-receptor agonists.

Tramadol is a µ-receptor agonist and norepinephrine and serotonin reuptake

inhibitor. MMEs are based on degree of µ-receptor agonist activity; however, it is

unknown whether tramadol is associated with overdose in the same dose-

dependent manner as observed with medications that are solely µ-receptor agonists.

other treatments and effectiveness, and patient values and

preferences. The recommendations related to opioid dosages

are not intended to be used as an inflexible, rigid standard

of care; rather, they are intended to be guideposts to help

inform clinician-patient decision-making.

Supporting Rationale

Benefits of high-dose opioids for pain are not well established.

Few trials evaluated opioid dosages of ≥90 MME/day (7). Opioid

dosages of 50–90 MME/day were associated with a minimally

greater (below the threshold for small) improvement in mean

pain intensity compared with dosages of <50 MME/day (mean

difference: −0.26; 95% CI: −0.57 to −0.02); there was no

difference in mean improvement in function (7). Analyses of

placebo-controlled trials also found some evidence of a plateauing

effect at ≥50 mg MME/day (7). One trial of more liberal dose

escalation compared with maintenance of current dosage found

no difference in outcomes related to pain or function (7).

At the same time, risks for serious harms related to opioid

therapy, including opioid misuse, overdose, and death, increase

at higher opioid dosage, without a single point below which there

is no risk (201). One cohort study from the clinical evidence

reviews found higher dosages of opioids were associated with

increased risk for all-cause deaths; one cohort study found

modest associations between higher dose of long-term opioid

and increased risk for falls and major trauma; one case-control

study found opioid dosages of >20 MME/day were associated

with increased odds of road trauma injury when the analysis

was restricted to drivers, with no dose-dependent association at

dosages of >20 MME/day; and cohort studies found association

between higher opioid dose and risk for various endocrinological

adverse events (7). Patients on higher doses reported reliance on

opioids despite ambivalence about their benefits (7).

Four observational studies identified in the clinical evidence

reviews consistently found an association between higher doses

of long-term opioids and risk for overdose or overdose death

(7). Opioid dosages for chronic pain of 50 to <100 MME/day

in observational studies have been associated with increased

risks for opioid overdose by factors of 1.9–4.6 compared with

dosages of 1 to <20 MME/day, and dosages of ≥100 MME/day

were found to be associated with increased risks for overdose

2.0–8.9 times the risk at 1 to <20 MME/day, after adjusting

for confounders on the basis of demographics, comorbidities,

concomitant medications, and other factors (55,202,203).

When opioids are prescribed for acute pain, similar associations

have been found, with dosages of 50 to <100 MME/day

associated with 4.73 times the risk for overdose and dosages of

≥100 MME/day associated with 6.64 times the risk, compared

with dosages of 1 to <20 MME/day (55). The MME cut points

in these studies (e.g., 20 MME, 50 MME, and 100 MME) were

selected by the authors for research purposes, and whereas their

findings are consistent with progressive increases in overdose

risk being associated with increases in prescribed opioid

dosages, they do not demonstrate a specific dosage threshold

below which opioids are never associated with overdose. In a

national sample of Veterans Health Administration patients

with chronic pain who were prescribed opioids, mean

prescribed daily opioid dosage among patients who died from

opioid overdose was 98 MME (median: 60 MME), compared

with mean prescribed daily opioid dosage of 48 MME (median:

25 MME) among patients not experiencing fatal overdose

(204). A narrative review conducted by FDA staff concluded

that, although there is not a single dosage threshold below

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which overdose risk is eliminated (201), the studies included

in the review indicated an increasing risk for serious adverse

health outcomes, including misuse, overdose, and death

associated with increasing opioid dose. These studies examined

dose-response risk for overdose for full agonist opioids and

not for partial agonist opioids such as buprenorphine, which

is unlikely to have the same continuous association between

dosage and overdose risk because respiratory depressant effects

of buprenorphine reach a plateau (205).

Multiple experts from OWG expressed concern that

including specific dosage thresholds in a main recommendation

statement would emphasize them as authoritative absolutes

and would lead to noncollaborative tapers or other potentially

harmful consequences. Experts also noted the lack of a single

standard formula for calculating MMEs (206). However,

experts agreed there is a need for thresholds as benchmarks

and suggested including them in the supporting text after the

main recommendation statement. Experts also agreed with

separating recommendations on dosage into a recommendation

applying to patients starting opioids and patients already

receiving opioids.

When opioids are used for acute, subacute, or chronic pain,

clinicians should start opioids at the lowest possible effective

dosage. For patients not already taking opioids, the lowest

effective dose can be determined using product labeling as a

starting point with calibration as needed on the basis of the

severity of pain and other clinical factors, such as renal or

hepatic insufficiency (see Recommendation 8). The lowest

starting dose for opioid-naïve patients is often equivalent to a

single dose of approximately 5–10 MME or a daily dosage of

20–30 MME/day. A listing of common opioid medications

and their doses in MME equivalents is provided (Table).

For example, a label for hydrocodone bitartrate (5 mg) and

acetaminophen (300 mg) (207) states that the usual adult

dosage is one or two tablets every 4–6 hours as needed for

pain, and the total daily dosage should not exceed eight tablets.

Clinicians should use additional caution when initiating opioids

for patients aged ≥65 years and patients with renal or hepatic

insufficiency because of a potentially smaller therapeutic window

between safe dosages and dosages associated with respiratory

depression and overdose (see Recommendation 8). Formulations

with lower opioid doses (e.g., hydrocodone bitartrate 2.5 mg/

acetaminophen 325 mg) are available and can facilitate dosing

when additional caution is needed. Product labeling regarding

tolerance includes guidance for patients already taking opioids.

In addition to opioids, clinicians should consider cumulative

dosages of other medications, such as acetaminophen, that are

combined with opioids in many formulations and for which

decreased clearance of medications might result in accumulation

of medications to toxic levels.

Clinicians should generally avoid unnecessary dosage

increases, use caution when increasing opioid dosages, and

increase dosage by the smallest practical amount because

overdose risk increases with increases in opioid dosage.

Although evidence to recommend specific intervals for dosage

titration is limited, rapid dosage increases put patients at greater

risk for sedation, respiratory depression, and overdose. For

opioid-naïve outpatients with acute pain treated with an opioid

for a few days or less, dosage increases are usually unnecessary

and should not be attempted without close monitoring because

of the risks for respiratory depression. In the context of long-

term opioid use, when dosage is increased, clinicians should

reevaluate patients after increasing dosage for changes in pain,

function, and risk for harm (see Recommendation 7).

Before increasing total opioid dosage to ≥50 MME/day,

clinicians should pause, considering that dosage increases to

>50 MME/day are unlikely to provide substantially improved

pain control for most patients while overdose risk increases with

dosage, and carefully reassess evidence of benefits and risks. If

a patient’s opioid dosage for all sources of opioids combined

reaches or exceeds 50 MME/day, clinicians should implement

additional precautions, including increased frequency of

follow-up (see Recommendation 7), and offer naloxone and

overdose prevention education to both the patient and the

patient’s household members (see Recommendation 8).

Additional dosage increases beyond 50 MME/day are

progressively more likely to yield diminishing returns in

benefits for pain and function relative to risks to patients.

Clinicians should carefully evaluate a decision to increase

dosage after an individualized assessment of benefits and risks

and weighing factors such as diagnosis, incremental benefits

for pain and function relative to risks with previous dosage

increases, other treatments and effectiveness, and patient values

and preferences.

Certain states require clinicians to implement clinical

protocols at specific dosage levels. For example, before

increasing long-term opioid therapy dosage to >120 MME/day,

clinicians in Washington state must obtain consultation from

a pain specialist who agrees that the increase is indicated and

appropriate (208). Clinicians should be aware of policies

related to MME thresholds and associated clinical protocols

established by their states.

Recommendation 5

For patients already receiving opioid therapy, clinicians

should carefully weigh benefits and risks and exercise care

when changing opioid dosage. If benefits outweigh risks of

continued opioid therapy, clinicians should work closely with

patients to optimize nonopioid therapies while continuing

opioid therapy. If benefits do not outweigh risks of continued

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opioid therapy, clinicians should optimize other therapies

and work closely with patients to gradually taper to lower

dosages or, if warranted based on the individual circumstances

of the patient, appropriately taper and discontinue opioids.

Unless there are indications of a life-threatening issue such

as warning signs of impending overdose (e.g., confusion,

sedation, or slurred speech), opioid therapy should not be

discontinued abruptly, and clinicians should not rapidly

reduce opioid dosages from higher dosages (recommendation

category: B; evidence type: 4).

Implementation Considerations

• Clinicians should carefully weigh both the benefits and

risks of continuing opioid medications and the benefits

and risks of tapering opioids.

• If benefits outweigh risks of continued opioid therapy,

clinicians should work closely with patients to optimize

nonopioid therapies while continuing opioid therapy.

• When benefits (including avoiding risks of tapering) do not

outweigh risks of continued opioid therapy, clinicians should

optimize other therapies and work closely with patients to

gradually taper to a reduced opioid dosage or, if warranted

based on the individual clinical circumstances of the patient,

appropriately taper and discontinue opioid therapy.

• In situations where benefits and risks of continuing opioids

are considered to be close or unclear, shared decision-

making with patients is particularly important.

• At times, clinicians and patients might not be able to agree

on whether or not tapering is necessary. When patients

and clinicians are unable to arrive at a consensus on the

assessment of benefits and risks, clinicians should

acknowledge this discordance, express empathy, and seek

to implement treatment changes in a patient-centered

manner while avoiding patient abandonment.

• Patient agreement and interest in tapering is likely to be

a key component of successful tapers.

• For patients agreeing to taper to lower opioid dosages and

for those remaining on higher opioid dosages, clinicians

should establish goals with the patient for continued

opioid therapy (see Recommendations 2 and 7) and

maximize pain treatment with nonpharmacologic and

nonopioid pharmacologic treatments as appropriate (see

Recommendation 2).

• Clinicians should collaborate with the patient on the

tapering plan, including patients in decisions such as how

quickly tapering will occur and when pauses in the taper

might be warranted.

• Clinicians should follow up frequently (at least monthly)

with patients engaging in opioid tapering. Team members

(e.g., nurses, pharmacists, and behavioral health professionals)

can support the clinician and patient during the ongoing

taper process through telephone contact, telehealth visits,

or face-to-face visits.

• When opioids are reduced or discontinued, a taper slow

enough to minimize symptoms and signs of opioid

withdrawal (e.g., anxiety, insomnia, abdominal pain,

vomiting, diarrhea, diaphoresis, mydriasis, tremor,

tachycardia, or piloerection) should be used.

• Longer duration of previous opioid therapy might require

a longer taper. For patients who have taken opioids long-

term (e.g., for ≥1 year), tapers can be completed over several

months to years depending on the opioid dosage and should

be individualized based on patient goals and concerns.

• When patients have been taking opioids for longer durations

(e.g., for ≥1 year), tapers of 10% per month or slower are

likely to be better tolerated than more rapid tapers.

• For patients struggling to tolerate a taper, clinicians should

maximize nonopioid treatments for pain and should

address behavioral distress.

• Clinically significant opioid withdrawal symptoms can

signal the need to further slow the taper rate.

• At times, tapers might have to be paused and restarted

again when the patient is ready and might have to be

slowed as patients reach low dosages.

• Before reversing a taper, clinicians should carefully assess

and discuss with the patient the benefits and risks of

increasing opioid dosage.

• Goals of the taper might vary (e.g., some patients might

achieve discontinuation whereas others might attain a

reduced dosage at which functional benefits outweigh

risks). If the clinician has determined with the patient that

the ultimate goal of tapering is discontinuing opioids, after

the smallest available dose is reached the interval between

doses can be extended and opioids can be stopped when

taken less frequently than once a day.

• Clinicians should access appropriate expertise if considering

tapering opioids during pregnancy because of possible

risks to the pregnant patient and the fetus if the patient

goes into withdrawal.

• Clinicians should advise patients of an increased risk for

overdose on abrupt return to a previously prescribed higher

dose because of loss of opioid tolerance, provide opioid

overdose education, and offer naloxone.

• Clinicians should remain alert to signs of and screen for

anxiety, depression, and opioid misuse or opioid use

disorder (see Recommendations 8 and 12) that might be

revealed by an opioid taper and provide treatment or

arrange for management of these comorbidities.

• Clinicians should closely monitor patients who are unable to

taper and who continue on high-dose or otherwise high-risk

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opioid regimens (e.g., opioids prescribed concurrently with

benzodiazepines) and should work with patients to mitigate

overdose risk (e.g., by providing overdose education and

naloxone) (see Recommendation 8).

• Clinicians can use periodic and strategic motivational

questions and statements to encourage movement toward

appropriate therapeutic changes and functional goals.

• Clinicians have a responsibility to provide or arrange for

coordinated management of patients’ pain and opioid-

related problems, including opioid use disorder.

• Payers, health systems, and state medical boards should

not use this clinical practice guideline to set rigid standards

or performance incentives related to dose or duration of

opioid therapy; should ensure that policies based on

cautionary dosage thresholds do not result in rapid tapers

or abrupt discontinuation of opioids; and should ensure

that policies do not penalize clinicians for accepting new

patients who are using prescribed opioids for chronic pain,

including those receiving high dosages of opioids, or for

refraining from rapidly tapering patients prescribed long-

term opioid medications.

• Although Recommendation 5 specifically refers to patients

using long-term opioid therapy for subacute or chronic

pain, many of the principles in these implementation

considerations and supporting rationale, including

communication with patients, pain management, behavioral

support, and slower taper rates, also are relevant when

discontinuing opioids in patients who have received them

for shorter durations (see Recommendations 6 and 7).

Supporting Rationale

Patients receiving long-term, high-dosage opioid therapy

for chronic pain are at increased risk for adverse events

including overdose death (55,72,202,203,209). However,

discontinuation of long-term, high-dosage opioid therapy has

been associated with adverse events including mental health

crisis, overdose events, and overdose death (71–73,210,211).

In addition, opioid tapering has been found to be associated

with subsequent termination of care (212). One study found

that whereas sustained opioid therapy discontinuation (i.e.,

opioid discontinuation for at least 3 months) was associated

with an approximately 50% reduction in risk for overdose,

dose variability was a risk factor for opioid overdose (213).

In another study, discontinuation of long-term, high-dosage

opioid therapy was associated with increased risk for suicide

but with reduced risk for overdose when compared with stable

or increasing dosage (211). Both starting and stopping opioids

were associated with overdose or suicide risk in another study;

risk associated with stopping opioids was increased when

patients had received opioids for longer durations. Death rates

for overdose or suicide in one study increased immediately

after starting or stopping treatment with opioids, with the

incidence decreasing over approximately 3–12 months (214)

in one study and persisting over 2 years in another study (215).

In observational studies evaluating outcomes related to heroin

use after discontinuation of prescription opioids, one study

found that heroin use was associated with discontinuation of

long-term opioid use (216); another study found that among

persons experiencing heroin overdose, prescription opioid use

in the past 12 months was common but discontinuation of

long-term opioid use was uncommon (217).

Discontinuation of opioids has been associated with greater

risks when it occurs over shorter periods. FDA has advised that

risks of rapid tapering or sudden discontinuation of opioids

in physically dependent patients include acute withdrawal

symptoms, exacerbation of pain, serious psychological

distress, and thoughts of suicide (68). One observational

study found that, among adults prescribed stable higher

opioid dosages (mean: ≥50 MME/day) long-term, increasing

maximum monthly dose reduction rate by 10% was associated

with an adjusted incidence rate ratio of 1.09 for overdose

(95% CI: 1.07–1.11) and 1.18 for mental health crisis

(95% CI: 1.14–1.21) (210). Another study of patients on

long-term, high-dosage (≥120 MME/day) opioid therapy

found that each additional week of tapering time before opioid

discontinuation was associated with a 7% relative reduction

in the risk for opioid-related emergency department visits or

hospitalizations (71). The clinical evidence reviews did not find

studies comparing different rates of opioid tapering; however,

a taper support intervention (psychiatric consultation, opioid

dosage tapering, and 18 weekly meetings with a physician

assistant to explore motivation for tapering and learn pain

self-management skills) was associated with better functional

outcomes (specifically, improvement in pain interference)

compared with usual care, with effects persisting at 34-week

follow-up (7). A systematic review (218) found that, among

studies rated as good or fair quality, when opioids were tapered

after discussion with patients who agreed to taper, opioid dose

reduction was associated with improved pain, function, and

quality of life. These results suggest that involving patients in

decisions regarding continuation or discontinuation of opioid

medications as well as practices including behavioral support,

integration of nonpharmacologic pain management, and

slower tapers might improve outcomes.

Experts from OWG said they appreciated the complexity of

managing patients already receiving higher dosages of opioids

long-term. Although some experts indicated there should be

more consideration of obtaining informed consent before

tapering opioids, others believed that informed discussion is

more appropriate than informed consent when considering

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tapering opioids because of clinicians’ overriding responsibility

to avoid providing treatment that harms patients. Some experts

were concerned that overemphasizing risks of tapering could

increase harm from continued high-dosage opioid use.

Determining Whether, When, and How to Taper

Opioids

The benefits and risks of opioid therapy change over time and

should be reevaluated periodically (see Recommendations 6

and 7). Opioid therapy should be limited to circumstances

where benefits of therapy outweigh risks. Because tapering

opioids can be harmful in some circumstances, benefits of

continuing opioids in patients who have already received

them long-term might include avoiding risks of tapering and

discontinuing opioids. In situations where benefits and risks

of continuing opioids are considered to be close or unclear,

shared decision-making with patients is particularly important.

At times, clinicians and patients might not be able to agree on

whether tapering is necessary. When patients and clinicians are

unable to arrive at a consensus on the assessment of benefits

and risks, clinicians should acknowledge this discordance,

express empathy, and seek to implement treatment changes in a

patient-centered manner while avoiding patient abandonment.

Unless there is a life-threatening issue such as warning signs

of an imminent overdose, the benefits of rapidly tapering

or abruptly discontinuing opioids are unlikely to outweigh

the substantial risks of these practices (71,219). However,

after slow, voluntary reduction of long-term opioid dosages,

patients might experience improvements in function, quality

of life, anxiety, and mood without worsening pain or with

decreased pain levels (218). Clinicians and patients should

consider whether opioids continue to meet treatment goals,

including functional goals; whether opioids are exposing

the patient to an increased risk for serious adverse events

or opioid use disorder; and whether benefits continue to

outweigh risks of opioids. Clinicians should not insist on

opioid tapering or discontinuation when opioid use might

be warranted (i.e., when benefits of opioids outweigh risks)

(66,219). Clinicians should access appropriate expertise if

considering tapering opioids during pregnancy because of

possible risk to the pregnant patient and the fetus if the patient

goes into withdrawal. For pregnant persons with opioid use

disorder, medications for opioid use disorder are preferred

over withdrawal management (i.e., discontinuation of opioids

through either short- or medium-term tapering) (220,221).

Some patients using more than one respiratory depressant

(e.g., benzodiazepines and opioids) might require tapering

one or more medications to reduce risk for respiratory

depression. Tapering decisions and plans should be coordinated

with prescribers of all respiratory depressant medications

(see Recommendation 11). Benzodiazepines should be tapered

gradually because of risks (anxiety, hallucinations, seizures,

delirium tremens, and, rarely, death) of benzodiazepine

withdrawal (222,223). Patients who are not taking prescribed

opioids (e.g., patients who are diverting all opioids they obtain)

do not require tapers.

Consistent with the HHS Guide for Clinicians on the

Appropriate Dosage Reduction or Discontinuation of

Long-Term Opioid Analgesics (219), clinicians should

consider tapering to a reduced opioid dosage or tapering and

discontinuing opioid therapy and discuss these approaches

with patients before initiating changes when

• the patient requests dosage reduction or discontinuation,

• pain improves and might indicate resolution of an

underlying cause,

• opioid therapy has not meaningfully reduced pain or

improved function,

• the patient has been treated with opioids for a prolonged

period (e.g., years) and the benefit-risk balance is unclear

(e.g., decreased positive effects because of tolerance and

symptoms such as reduced focus or memory that might

be due to opioids),

• the patient is receiving higher opioid dosages without

evidence of benefit from the higher dosage,

• the patient experiences side effects that diminish quality

of life or impair function,

• evidence of opioid misuse exists,

• the patient experiences an overdose or other serious event

(e.g., an event leading to hospitalization or injury) or has

warning signs for an impending event (e.g., confusion,

sedation, or slurred speech), or

• the patient is receiving medications (e.g., benzodiazepines) or

has medical conditions (e.g., sleep apnea, liver disease, kidney

disease, or fall risk) that increase risk for adverse outcomes.

For patients already taking opioids long term (both

established patients and patients transferring from other

clinicians), the possibility of opioid dosage reduction might

provoke substantial anxiety. In addition, tapering opioids after

years of taking them can be especially challenging because of

physical and psychological dependence. However, patients

should be offered the opportunity to reevaluate their continued

use of opioids. Clinicians should review benefits and risks of

continued opioid therapy with empathy.

Whenever possible, clinicians should collaborate with

patients and share decision-making about whether and how

to taper opioids. Clinicians should review benefits and risks of

opioid therapy with the patient and decide whether tapering

is appropriate for the patient. If the existing opioid regimen

does not put the patient at imminent risk for overdose or

other injury, tapering does not need to occur immediately,

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and clinicians can take time to reach agreement with patients

(224). For patients who agree to taper opioids to lower dosages,

clinicians should collaborate with the patient on a tapering

plan. Open discussion between the clinician and patient should

take place, whether the goal of the taper is stopping opioids

or reducing opioids to a point where benefits outweigh risks;

the goal will depend on the patient’s circumstances and an

individualized assessment of benefits and risks. Tapering is

more likely to be successful when patients collaborate in the

taper (224). Clinicians can discuss with patients the patient’s

perceptions of benefits, risks, and adverse effects of continued

opioid therapy; include patient concerns in taper planning; and

include patients in making decisions such as which medication

will be decreased first (e.g., in patients prescribed more than

one opioid) and how quickly tapering will occur.

Providing Advice to Patients Before Tapering

Clinicians should advise patients that overall, after

voluntary reduction of long-term opioid dosages, most

patients report stable or improved function, anxiety, and

mood without worsening pain or with decreased pain levels

(66,218,225–228). However, other patients report insomnia,

anxiety, depression, and increased pain, particularly in the short

term (66,225,227,229,230). Increased pain might be related

to hyperalgesia or opioid withdrawal and can be prolonged in

some patients (229). Patients can be counseled that worsening

of pain is a frequent symptom of opioid withdrawal that tends

to diminish over time (219). Clinicians should advise patients

about the increased risk for overdose with abrupt return to a

previously prescribed higher dosage because of loss of opioid

tolerance and warn of a risk for overdose if the patient returns

to their original dosage (219). Clinicians should provide opioid

overdose education and offer naloxone.

Pain Management During Tapering

Clinicians should commit to working with patients to

improve function and decrease pain, whether or not opioids are

tapered. Nonpharmacologic and nonopioid treatments should

be integrated into patients’ pain management plans after an

individualized assessment of benefits and risks that considers

the patient’s diagnosis, circumstances, and unique needs (see

Recommendation 2). Integrating behavioral and nonopioid pain

therapies before and during a taper can help manage pain (218)

and strengthen the therapeutic relationship between the clinician

and patient. Whether patients are agreeing to taper to lower opioid

dosages or remaining on higher opioid dosages, clinicians should

work with them to establish functional goals for continued opioid

therapy (see Recommendations 2 and 7) and maximize pain

treatment with nonpharmacologic and nonopioid pharmacologic

treatments as appropriate (see Recommendation 2).

Behavioral Health Support During Tapering

Integrating behavioral and nonopioid pain therapies and

treatment for comorbid mental health conditions before and

during a taper can help manage pain (218), strengthen the

therapeutic relationship between the clinician and patient, and

improve the likelihood of positive tapering outcomes (228).

Mental health comorbidities including depression and anxiety

are common in patients with painful conditions, especially those

receiving long-term opioid therapy (231). Depressive symptoms

predict taper dropout (225,226). Primary care clinicians should

collaborate with mental health specialists and with other specialty

clinicians as needed to optimize nonopioid pain management (see

Recommendation 2) and provide psychosocial support for patients

who have anxiety related to the taper. Clinicians should consider

arranging for consultation with a behavioral health specialist before

initiating a taper in patients with serious mental illness who are

at high risk for suicide or with suicidal ideation (219). Clinicians

should remain alert to signs of and screen for anxiety, depression,

and opioid misuse or opioid use disorder (see Recommendations

8 and 12) that might be revealed by an opioid taper and provide

treatment or arrange for management of these comorbidities.

Successful tapering studies have used at least weekly follow-up

(218), and clinicians should follow up frequently (at least monthly)

with patients engaging in opioid tapering. Team members (e.g.,

nurses, pharmacists, and behavioral health professionals) can

support the clinician and patient during the ongoing taper process

through telephone contact, telehealth visits, or face-to-face visits.

Clinicians can acknowledge patient fears about tapering (232), ask

how they can support the patient (232), and make sure patients

receive appropriate and accessible psychosocial support (228).

Many patients fear withdrawal symptoms, pain, or abandonment

(233), and clinicians can help patients by telling them what to

expect (e.g., the rate will be kept slow to minimize withdrawal

symptoms and pain might worsen at first but usually improves over

time) and that they will be supporting them through the process.

Tapering Rate

Evidence to support specific tapering rates is limited. The

rate of tapering should be individualized based on the patient’s

clinical situation. When opioids are reduced or discontinued,

a taper slow enough to minimize symptoms and signs of

opioid withdrawal (e.g., anxiety, insomnia, abdominal pain,

vomiting, diarrhea, diaphoresis, mydriasis, tremor, tachycardia,

or piloerection) should be used. Tapers can be completed over

several months to years depending on the opioid dosage and

should be individualized based on patient goals and concerns.

Longer durations of previous opioid therapy might require

longer tapers. Evidence on optimal taper rate is emerging. Tapers

of approximately 10% per month or slower are likely to be better

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tolerated than more rapid tapers when patients have been taking

opioids for longer durations (e.g., ≥1 year) (219). When patients

have taken opioids for shorter durations (e.g., weeks to months

rather than years), a decrease of 10% of the original dose per

week or slower (until approximately 30% of the original dose is

reached, followed by a weekly decrease of approximately 10% of

the remaining dose) is less likely to trigger withdrawal (225) and

can be successful for some patients. For patients struggling to

tolerate a taper, clinicians should maximize nonopioid treatments

for pain and should address behavioral distress (234). Clinically

significant opioid withdrawal symptoms can signal the need to

further slow the taper rate. At times, tapers might have to be

paused and restarted again when the patient is ready and might

have to be slowed as patients reach low dosages to allow gradual

accommodation to lower opioid dosages and development of

new skills for nonopioid management of pain and emotional

distress. Before reversing a taper, clinicians should carefully assess

and discuss with patients benefits and risks of increasing opioid

dosage. If the clinician and patient have determined that the

goal is discontinuing opioids, after the smallest available dose is

reached, the interval between doses can be extended and opioids

can be stopped when taken less frequently than once a day.

More rapid tapers might be needed for patient safety under

certain circumstances (e.g., for patients who have experienced

overdose on their current dosage) (219). However, unless there

are indications of a life-threatening issue, such as warning

signs of impending overdose, opioid therapy should not be

discontinued abruptly, and clinicians should not rapidly reduce

opioid dosages from higher dosages. Sudden discontinuation

might precipitate substantial opioid withdrawal (71). Rapid

tapering or sudden discontinuation of opioids in physically

dependent patients also can increase risks for psychological

distress and opioid-related emergency department visits and

hospitalizations (68,71). Ultrarapid detoxification under

anesthesia is associated with substantial risks, including death,

and should not be used (235).

Management of Opioid Withdrawal During

Tapering

The first approach to withdrawal symptoms and signs should

generally be consideration of slowing or pausing the taper rate.

If needed, short-term oral medications might also help manage

withdrawal symptoms (232). These include alpha-2 agonists

for the management of autonomic signs and symptoms (e.g.,

sweating and tachycardia). Alpha-2 agonists clonidine and

lofexidine are more effective than placebo in reducing severity

of withdrawal (236) from heroin or methadone in the context

of abrupt (not gradual) discontinuation. Similar research

could not be found on clonidine and lofexidine in patients

tapering from long-term opioid treatment for pain (225);

however, alpha-2 agonist tizanidine has been used to help

taper patients from long-term, high-dosage opioids for chronic

pain (230). Other medications addressing specific symptoms

(NSAIDs, acetaminophen, or topical menthol or methyl

salicylate for muscle aches; trazodone for sleep disturbance;

prochlorperazine, promethazine, or ondansetron for nausea;

dicyclomine for abdominal cramping; and loperamide or

bismuth subsalicylate for diarrhea) also have been used (232).

Challenges to Tapering

Some patients with unanticipated challenges to tapering,

such as inability to make progress in tapering despite opioid-

related harm, might have undiagnosed opioid use disorder.

Therefore, patients experiencing such challenges should be

assessed for opioid use disorder using Diagnostic and Statistical

Manual of Mental Disorders, Fifth Edition (DSM-5) criteria

and, if criteria for opioid use disorder are met, offered evidence-

based medication treatment (see Recommendation 12) and

naloxone for opioid overdose reversal (see Recommendation 8).

Emerging evidence suggests that patients for whom risks of

continued high-dose opioid use outweigh benefits but who

are unable to taper and who do not meet criteria for opioid

use disorder might benefit from transition to buprenorphine

(219,237,238). Buprenorphine is a partial agonist opioid

that can treat pain and opioid use disorder (239) and has

other properties that might be helpful (155), including less

respiratory depression (205) and overdose risk than other

opioids (155,237). Although overdose is less likely with

buprenorphine than with full agonist opioids, overdose is still

possible, particularly if buprenorphine is taken concurrently

with other respiratory depressants (e.g., full agonist opioids,

benzodiazepines, or alcohol) (240). A specialty clinic offering

opioid tapering services for patients receiving high-dosage

opioids (defined in this study as ≥90 MME/day) for chronic

pain found that 44.6% of patients referred for opioid taper

were able to successfully taper to <90 MME/day, and an

additional 18.8% who were unable to taper were able to

successfully transition to sublingual buprenorphine (

230).

Different buprenorphine products, available at different

formulations and doses, are approved for the treatment of

pain and for the treatment of opioid use disorder. Although

prescription of buprenorphine for treatment of opioid use

disorder requires the clinician to have a waiver from SAMHSA

(see Recommendation 12), prescription of buprenorphine for

treatment of chronic pain does not require a waiver (237).

To avoid precipitating withdrawal, transitioning any

patient taking full agonist opioids to buprenorphine requires

specific timing of the initial buprenorphine dose (219) (see

Recommendation 12 for application to patients with opioid use

disorder). Patients should be in mild to moderate withdrawal

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from full agonist opioids before the first buprenorphine dose

(219). To do this, experts have advised that clinicians and

patients should wait at least 8–12 hours after the last dose of

short-acting full agonist opioids and longer after the last dose

of long-acting full agonist opioids (e.g., at least 12–24 hours

after the last dose of an ER/LA full agonist opioid, and longer

for methadone) before the first dose of buprenorphine is

administered (229). As an alternative for patients not yet

in opioid withdrawal, certain studies have described low

dose initiation of buprenorphine to allow for initiation of

buprenorphine in patients receiving full agonist opioids for

acute or chronic pain (241). SAMHSA’s Providers Clinical

Support System (https://pcssnow.org) offers training, technical

assistance, and mentors to assist clinicians who are unfamiliar

with initiation of buprenorphine and have additional questions

about the diagnosis and treatment of opioid use disorder.

Because the duration of action for analgesia is shorter than

the duration of action for suppression of opioid withdrawal

and stabilization of opioid use disorder (242), dosing of

buprenorphine for pain is typically multiple times daily rather

than once-a-day dosing as done for the treatment of opioid

use disorder (229).

Continuing High-Dosage Opioids

Clinicians should closely monitor patients who are unable to

taper and who continue on high-dosage or otherwise high-risk

opioid regimens (e.g., opioids prescribed concurrently with

benzodiazepines) and should work with patients to mitigate

overdose risk (e.g., by providing overdose education and

naloxone) (see Recommendation 8). Clinicians can use periodic

and strategic motivational questions and statements to encourage

movement toward appropriate therapeutic changes (224).

Management of chronic pain with opioids can be

challenging, as can management of opioid discontinuation

(67). However, clinicians have a responsibility to provide or

arrange for coordinated management of patients’ pain and

opioid-related challenges. Payers and health systems should

not use this clinical practice guideline to set rigid standards

related to dosage or duration of opioid therapy and should

ensure that policies based on cautionary dosage thresholds

do not result in rapid tapers or abrupt discontinuation of

opioids, do not penalize clinicians for accepting new patients

who are receiving opioids for chronic pain, and do not

provide incentives to clinicians to implement rapid tapering.

Patients prescribed opioids but unable to access ongoing care

(243) might be at risk for abrupt opioid discontinuation and

might miss opportunities to receive life-saving interventions,

including monitoring for and management of mental health

and substance use comorbidities.

Deciding Duration of Initial Opioid

Prescription and Conducting Follow-Up

Recommendation 6

When opioids are needed for acute pain, clinicians

should prescribe no greater quantity than needed for the

expected duration of pain severe enough to require opioids

(recommendation category: A; evidence type: 4).

Implementation Considerations

• Nontraumatic, nonsurgical acute pain can often be

managed without opioids (see Recommendation 1).

• Opioids are sometimes needed for treatment of acute pain

(see Recommendation 1). When the diagnosis and severity

of acute pain warrant use of opioids, clinicians should

prescribe no greater quantity than needed for the expected

duration of pain severe enough to require opioids. For

many common causes of nontraumatic, nonsurgical pain,

when opioids are needed, a few days or less are often

sufficient, and shorter courses can minimize the need to

taper opioids to prevent withdrawal symptoms at the end

of a course of opioids. However, durations should be

individualized to the patient’s clinical circumstances.

• Clinicians should generally avoid prescribing additional opioids

to patients just in case pain continues longer than expected.

• For postoperative pain related to major surgery, procedure-

specific opioid prescribing recommendations are available

with ranges for amounts of opioids needed (on the basis

of actual use and refills and on consensus).

• To minimize unintended effects on patients, clinicians,

practices, and health systems should have mechanisms in

place for the subset of patients who experience severe acute

pain that continues longer than the expected duration. These

mechanisms should allow for timely reevaluation to confirm

or revise the initial diagnosis and adjust pain management

accordingly. Clinicians, practices, and health systems can help

minimize disparities in access to and affordability of care and

refills by ensuring all patients can obtain and afford additional

evaluation and treatment, as needed.

• Longer durations of opioid therapy are more likely to be

needed when the mechanism of injury is expected to result

in prolonged severe pain (e.g., severe traumatic injuries).

• Patients should be evaluated at least every 2 weeks if they

continue to receive opioids for acute pain.

• If opioids are continued for ≥1 month, clinicians should

ensure that potentially reversible causes of chronic pain

are addressed and that opioid prescribing for acute pain

does not unintentionally become long-term opioid therapy

simply because medications are continued without

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reassessment. Continuation of opioid therapy at this point

might represent initiation of long-term opioid therapy,

which should occur only as an intentional decision that

benefits are likely to outweigh risks after discussion

between the clinician and patient and as part of a

comprehensive pain management approach. Clinicians

should refer to recommendations on subacute and chronic

pain for initiation (Recommendation 2), follow-up

(Recommendation 7), and tapering (Recommendation 5)

of ongoing opioid therapy.

• If patients already receiving long-term opioid therapy

require additional opioids for superimposed severe acute

pain (e.g., major surgery), opioids should be continued

only for the duration of pain severe enough to require

additional opioids, returning to the patient’s baseline

opioid dosage as soon as possible, including a taper to

baseline dosage if additional opioids were used around the

clock for more than a few days.

• If opioids are used continuously (around the clock) for

more than a few days for acute pain, clinicians should

prescribe a brief taper to minimize withdrawal symptoms

on discontinuation of opioids.

• If a taper is needed, taper durations might need to be adjusted

depending on the duration of the initial opioid prescription

(see Supporting Rationale for this recommendation for

additional details).

• Tapering plans should be discussed with the patient before

hospital discharge and with clinicians coordinating the

patient’s care as an outpatient. (See Recommendation 5

for tapering considerations when patients have taken

opioids continuously for >1 month.)

Supporting Rationale

Data suggest that pain improves within days for many

patients with common types of acute pain in primary care

or emergency department settings. Analysis of nationwide

U.S. commercial insurance claims in 2014 found median

durations of initial opioid analgesic prescriptions for acute

pain indications in primary care settings were 4–7 days

(244), suggesting that in most cases, clinicians considered an

initial opioid prescription of 4–7 days’ duration sufficient.

Some patients (17.8%; range: 11.7%–30.0% depending on

the acute pain condition) obtained at least one refill within

30 days after their initial opioid prescription, suggesting that

although these durations might have been sufficient or more

than necessary for most patients, variation across diagnoses

and among patients in time to recovery is likely. In an older

study of the course of acute low back pain (not associated with

malignancies, infections, spondyloarthropathies, fractures, or

neurologic signs) in a primary care setting, a large decrease

in pain occurred until the fourth day after treatment with

paracetamol, with smaller decreases thereafter (245). A more

recent single-center survey of patients prescribed opioids for

acute pain on emergency department discharge (246) found

that patients taking opioids continued them for a median of

4 days (IQR: 2–7 days), including on the day of discharge,

with variation across patients and diagnoses. Median numbers

of days that patients continued taking prescribed opioids were

6 days (IQR: 4–8 days) for back pain and fractures, 2 days

(IQR: 1–5 days) for renal colic, 5.5 days (IQR: 4–7 days)

for musculoskeletal injury, and 3 days (IQR: 2–6) for other

diagnoses. Most patients (92.5%) reported having leftover

pills, with 52.2% of pills unused overall. A Canadian study

following patients for 14 days after discharge from the

emergency department with opioid prescriptions for acute

pain similarly found most (68%) total prescribed opioids were

unused, and the quantity of 5-mg morphine tablets to prescribe

to adequately supply 80% of the patients with the amount of

opioids they used was 20 tablets for musculoskeletal pain, 30

for fracture, 15 for renal colic or abdominal pain, and 20 for

other pain conditions (247).

Since 2017, multiple studies have found that many patients

do not use all prescribed opioids after surgery and that

prescribing a lower quantity of opioids postoperatively is

associated with less opioid use without increases in pain score or

in requests for refills of pain medication and without reductions

in satisfaction with pain management (77–79). One study

found that, after five common surgical procedures, median

opioid consumption was three 5-mg oxycodone pills or less,

and that following consensus recommendations intended to

reduce unnecessary postoperative opioid prescribing published

in 2018 and 2019 would still result in 47%–56% of pills

prescribed remaining unused (248). Evidence exists of variation

in opioid needs across patients undergoing the same procedures

attributable to factors including pain at discharge and previous

opioid use (249). One study found that, although a majority of

patients used no or few (>0 to <50 MME during their entire

postoperative course) opioids, some patients required opioids

for up to 15 days after surgery (250).

Clinical evidence reviews found observational evidence

that opioid use for acute pain is associated with long-term

opioid use and that a greater amount of early opioid exposure

is associated with greater likelihood of long-term use, noting

recent evidence for a dose- and duration-dependent effects

(63,75,141,244,251,252). Opioids prescribed for surgery and

other acute pain conditions that go unused are a potential

source for misuse and diversion (249,253–255). In addition,

sudden discontinuation of opioids might result in clinically

significant opioid withdrawal (71). Therefore, limiting duration

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of opioids prescribed can minimize the need for a taper to prevent

distressing or unpleasant withdrawal symptoms.

Many common causes of nonsurgical, nontraumatic

acute pain can often be managed without opioids (see

Recommendation 1). When the diagnosis and severity of acute

pain warrant the use of opioids, clinicians should prescribe

no greater quantity than needed for the expected duration of

pain severe enough to require opioids. A few days or less are

often sufficient when opioids are needed for many common

causes of nonsurgical acute pain, and limiting the duration

of opioid therapy can minimize the need to taper to prevent

withdrawal symptoms at the end of the course of opioids

and limit unused opioids. Certain circumstances (e.g., severe

traumatic injuries) might require use of opioids for durations

of >7 days. Durations should be individualized based on the

patient’s clinical circumstances.

When patients are discharged from the hospital after

surgery, the course and dosage of any opioid medications

administered during hospitalization and before discharge can

help predict ongoing pain management needs (150,256,257).

For postoperative pain, procedure-specific opioid prescribing

recommendations are available with ranges for amounts of

opioids needed (on the basis of use and refills and on consensus)

(149,151,250).

Clinicians should generally not prescribe additional opioids

to patients just in case pain continues longer than expected.

However, if pain continues longer than expected, some patients

might face challenges in successfully navigating the health care

system (e.g., clinician and pharmacy contact, transportation,

and need for assistance) to obtain additional medication as

needed, leading to potential disparities in treatment. Clinicians,

practices, and health systems should have mechanisms in

place for the subset of patients who experience severe acute

pain that continues longer than the expected duration. These

mechanisms should allow for timely reevaluation to confirm

or revise the initial diagnosis and adjust pain management

accordingly. In particular, clinicians, practices, and health

systems should ensure all patients can obtain and afford

additional evaluation and treatment as needed to minimize

disparities in access to and affordability of care and refills.

Patients should be evaluated at least every 2 weeks if

they continue to receive opioids for acute pain. If opioids

are continued for ≥1 month, clinicians should ensure that

potentially reversible causes of chronic pain are addressed and

that opioid prescribing for acute pain does not unintentionally

become long-term opioid therapy simply because medications

are continued without reassessment. Continuation of

opioid therapy at this point might represent initiation of

long-term opioid therapy, which should occur only as an

intentional decision that benefits are likely to outweigh

risks after discussion between the clinician and patient and

as part of a comprehensive pain management approach.

Clinicians should refer to recommendations on subacute and

chronic pain for initiation (Recommendation 2), follow-up

(Recommendation 7), and tapering (Recommendation 5) of

ongoing opioid therapy. If patients already receiving long-

term opioids require additional opioids for superimposed

severe acute pain (e.g., major surgery), opioids should be

continued only for the duration of pain severe enough to

require additional opioids, returning to the patient’s baseline

opioid dosage as soon as possible, including a taper to baseline

dosage if additional opioids were used around the clock for

more than a few days.

If opioids are used continuously (around the clock) for more

than a few days for acute pain, clinicians should prescribe a brief

taper to minimize withdrawal symptoms on discontinuation of

opioids. Taper durations might need to be adjusted depending

on the duration of the initial opioid prescription. For example,

if opioids are used continuously for >3 days but for <1 week,

clinicians can consider reducing the daily dosage to 50% for

2 days to ameliorate withdrawal symptoms when discontinuing

opioids. When patients have taken opioids continuously for

≥1 week but <1 month, clinicians might consider a slower taper

(e.g., reducing the daily dosage by approximately 20% every

2 days, a range consistent with tapering rates successfully used in

studies of postoperative opioid prescribing) (256,257). When

patients are discharged from the hospital after surgery, opioid

dosages needed during hospitalization and before discharge can

help predict tapering needs to prevent withdrawal symptoms

(150,256,257). Tapering plans should be discussed with the

patient before discharge and with clinicians coordinating the

patient’s care as an outpatient. (See Recommendation 5 for

tapering considerations when patients have taken opioids

continuously for >1 month.)

Recommendation 7

Clinicians should evaluate benefits and risks with patients

within 1–4 weeks of starting opioid therapy for subacute or

chronic pain or of dosage escalation. Clinicians should regularly

reevaluate benefits and risks of continued opioid therapy with

patients (recommendation category: A; evidence type: 4).

Implementation Considerations

• In addition to evaluating benefits and risks of opioids

before starting opioid therapy (see Recommendation 2),

clinicians should evaluate patients to assess benefits and

risks of opioids within 1–4 weeks of starting long-term

opioid therapy or of dosage escalation.

• Clinicians should consider follow-up intervals within the

lower end of this range when ER/LA opioids are started

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or increased, because of the increased risk for overdose

within the first 2 weeks of treatment, or when total daily

opioid dosage is ≥50 MME/day. (Overdose risk is doubled

across multiple studies for dosages of 50 to <100 MME/

day relative to <20 MME/day.) (See Recommendation 4.)

• Shorter follow-up intervals (every 2–3 days for the first

week) should be strongly considered when starting or

increasing the dosage of methadone, because of the variable

half-life of this drug (see Recommendation 3) and the

potential for drug accumulation during initiation and

during upward titration of dosage.

• An initial follow-up interval closer to 4 weeks can be

considered when starting immediate-release opioids at a

dosage of <50 MME/day.

• Clinicians should follow up with and evaluate patients

with subacute pain who started opioid therapy for acute

pain and have been treated with opioid therapy for 30 days

to reassess the patient’s pain, function, and treatment

course; ensure that potentially reversible causes of chronic

pain are addressed; and prevent unintentional initiation

of long-term opioid therapy. Continuation of opioid

therapy at this point might represent initiation of long-

term opioid therapy, which should occur only as an

intentional decision that benefits are likely to outweigh

risks after discussion between the clinician and patient and

as part of a comprehensive pain management approach

(see Recommendation 2).

• Clinicians should regularly reassess all patients receiving

long-term opioid therapy, including patients who are new

to the clinician but on long-term opioid therapy, with a

suggested interval of every 3 months or more frequently

for most patients.

• Clinicians seeing new patients already receiving opioids

should establish treatment goals, including functional goals,

for continued opioid therapy (see Recommendation 2).

• Clinicians should reevaluate patients who are at higher

risk for opioid use disorder or overdose (e.g., patients with

depression or other mental health conditions, a history of

substance use disorder, a history of overdose, taking

≥50 MME/day, or taking other central nervous system

depressants with opioids) more frequently than every

3 months. Clinicians should regularly screen all patients

for these conditions, which can change during the course

of treatment (see Recommendation 8).

• Clinicians, practices, and health systems can help minimize

unintended effects on patients by ensuring all patients can

access and afford follow-up evaluation.

• In practice contexts where virtual visits are part of standard

care (e.g., in remote areas where distance or other context

makes follow-up visits challenging), or for patients for

whom in-person follow-up visits are challenging (e.g., frail

patients), follow-up assessments that allow the clinician

to communicate with and observe the patient through

telehealth modalities might be conducted.

• At follow-up, clinicians should review patient perspectives

and goals, determine whether opioids continue to meet

treatment goals, including sustained improvement in pain

and function, and determine whether the patient has

experienced common or serious adverse events or early

warning signs of serious adverse events or has signs of

opioid use disorder.

• Clinicians should ensure that treatment for depression,

anxiety, or other psychological comorbidities is optimized.

• Clinicians should ask patients about their preferences for

continuing opioids, considering their effects on pain and

function relative to any adverse effects experienced. If risks

outweigh benefits of continued opioid therapy (e.g., if

patients do not experience meaningful, sustained

improvements in pain and function compared with before

initiation of opioid therapy; if patients are taking higher-

risk regimens [e.g., dosages of ≥50 MME/day or opioids

combined with benzodiazepines] without evidence of

benefit; if patients believe benefits no longer outweigh

risks; if patients request dosage reduction or discontinuation;

or if patients experience overdose or other serious adverse

events), clinicians should work with patients to taper and

reduce opioid dosage or taper and discontinue opioids

when possible (see from Recommendation 5).

• Clinicians should maximize pain treatment with

nonpharmacologic and nonopioid pharmacologic

treatments as appropriate (see Recommendation 2).

Supporting Rationale

Although clinical evidence reviews did not find studies

evaluating the effectiveness of more frequent monitoring

intervals (7), they identified an observational study (54)

that found risk for opioid use disorder was associated with

continuing opioid therapy for ≥3 months. The reviews also

identified a study that found risk for overdose associated with

ER/LA opioids might be particularly high during the first

2 weeks of treatment (192). Another study found the first

3 months after opioid initiation to be a period of higher risk

for opioid overdose (214). Patients who do not have pain

relief with opioids at 1 month are unlikely to experience pain

relief with opioids at 6 months (258). Although evidence

is insufficient to determine at what point within the first

3 months of opioid therapy the risks for opioid use disorder

increase, reassessment of pain and function within 1 month

of initiating opioids provides an opportunity to modify the

treatment plan to achieve pain treatment goals, including

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functional goals, and minimize risks of long-term opioid

use by tapering and discontinuing opioids among patients

not receiving a clear benefit from these medications. In

addition, evaluation within the first 3 months might provide

opportunities to identify and mitigate risks for opioid use

disorder and overdose.

Experts from OWG noted that although little evidence

exists for specific follow-up time frames, the recommendation

was reasonable and reflects common practice and therefore

supported the recommendation. Experts further noted that

social determinants of health affecting ability to return

frequently for care (e.g., role as unpaid caregiver or work at a

job with minimal paid time off) or payer issues (e.g., copays)

could have consequences when recommending frequent visits

and should be considered.

Clinicians should evaluate patients to assess benefits and

risks of opioids within 1–4 weeks of starting long-term opioid

therapy or of dosage escalation. Clinicians should consider

follow-up intervals within the lower end of this range when

ER/LA opioids are started or increased, because of the increased

risk for overdose within the first 2 weeks of treatment (192),

or when total daily opioid dosage is ≥50 MME/day, because

the overdose risk is doubled across multiple studies for

dosages of 50 to <100 MME/day relative to <20 MME/day

(see Recommendation 4). Shorter follow-up intervals (every

2–3 days for the first week) should be strongly considered when

starting or increasing the dosage of methadone because of the

variable half-life of this drug (see Recommendation 3) and the

potential for drug accumulation during initiation and during

upward titration of dosage. An initial follow-up interval closer

to 4 weeks can be considered when starting immediate-release

opioids at a dosage of <50 MME/day.

Patients who started opioid therapy for acute pain and are

continuing to receive opioids for subacute pain might be at

a particularly critical point for potential transition to chronic

pain and potential transition to long-term opioid therapy.

Clinicians should follow up with and evaluate patients with

subacute pain who have been treated with opioid therapy for

30 days. Clinicians should ensure that opioid prescribing for

acute pain does not unintentionally become long-term opioid

therapy simply because medications are continued without

reassessment, but only as an intentional decision that benefits

are likely to outweigh risks after discussion between the

clinician and patient. Clinicians should reassess the patient’s

pain, function, and treatment course; ensure that potentially

reversible causes of chronic pain are addressed; and optimize

pain management as needed (see Recommendation 2).

In analyses of placebo-controlled trials, the clinical evidence

reviews found that effects of opioids on mean improvement

in pain and in function were greater at 1–3 months than at

3–6 months (7). A cohort study found an association between

longer duration of therapy and increased risk for new-onset

depression (7). Because of potential changes in the balance

of benefits and risks of opioid therapy over time, clinicians

should regularly reassess all patients receiving long-term opioid

therapy, including patients who are new to the clinician but

on long-term opioid therapy, with a suggested interval of every

3 months or more frequently. Clinicians seeing new patients

already receiving opioids should establish treatment goals,

including functional goals, for continued opioid therapy (see

Recommendation 2). Clinicians should reevaluate patients

who are at greater risk for opioid use disorder or overdose (e.g.,

patients with depression or other mental health conditions,

a history of substance use disorder, a history of overdose,

taking ≥50 MME/day, or taking other central nervous system

depressants with opioids) more frequently than every 3 months.

Clinicians should regularly screen all patients for these

conditions, which can change during the course of treatment

(see Recommendation 8). Clinicians, practices, and health

systems can help minimize unintended effects on patients by

ensuring all patients can access and afford follow-up evaluation

(86). In addition, policymakers can consider evidence-based

methods of minimizing barriers to care (e.g., paid sick leave)

(259). In practice contexts where virtual visits are part of

standard care (e.g., in remote areas where distance or other

context makes follow-up visits challenging), or for patients

for whom in-person follow-up visits are challenging (e.g., frail

patients), follow-up assessments that allow the clinician to

communicate with and observe the patient through telehealth

modalities might be conducted when available.

At follow-up, clinicians should review patient perspectives

on progress and challenges in moving toward treatment goals;

determine whether opioids continue to meet treatment goals,

including sustained improvement in pain and function;

determine whether the patient has experienced common or

serious adverse events or early warning signs of serious adverse

events or has signs of opioid misuse or opioid use disorder (e.g.,

difficulty controlling use, cravings, work, and social or family

problems related to opioid use); determine whether benefits

of opioids continue to outweigh risks; and determine whether

there is a need for opioid dosage reduction or discontinuation.

Clinicians should assess benefits in function, pain control, and

quality of life by asking patients about progress toward person-

centered functional goals that have meaning for them (see

Recommendation 2) or by using tools such as the three-item

PEG assessment scale (184); clinically meaningful improvement

has been defined as a 30% improvement in scores for both pain

and function (185). Clinicians also should ask patients about

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common adverse effects such as constipation and drowsiness

(see Recommendation 2) and should ask about and assess

for effects that might be early warning signs for more serious

problems such as overdose (e.g., sedation or slurred speech) or

opioid use disorder (e.g., craving, wanting to take opioids in

greater quantities or more frequently than prescribed, difficulty

controlling use, or work, social, or family problems related to

opioid use). Clinicians can use validated screening tools such

as the Drug Abuse Screening Test (DAST) (260), the Tobacco,

Alcohol, Prescription medication, and other Substance use Tool

(TAPS) (261), and the three-question version of the Alcohol

Use Disorders Identification Test (AUDIT-C) (262,263) (see

Recommendations 8 and 12). Because depression, anxiety,

and other psychological comorbidities often coexist with

and can interfere with resolution of pain, clinicians should

use validated instruments to assess for these conditions (see

Recommendation 8) and ensure that treatment for these

conditions is optimized. Clinicians should ask patients about

their preferences for continuing opioids considering their effects

on pain and function relative to any adverse effects experienced.

If risks outweigh benefits of continued opioid therapy (e.g., if

patients do not experience meaningful, sustained improvements

in pain and function compared with before initiation of opioid

therapy; if patients are taking higher-risk regimens [e.g., dosages

of ≥50 MME/day or opioids combined with benzodiazepines]

without evidence of benefit; if patients believe benefits no

longer outweigh risks; if patients request dosage reduction or

discontinuation; or if patients experience overdose or other

serious adverse events), clinicians should work with patients

to taper and reduce opioid dosage or to taper and discontinue

opioids when possible (see Recommendation 5). Clinicians

should maximize pain treatment with nonpharmacologic

and nonopioid pharmacologic treatments as appropriate (see

Recommendation 2).

Assessing Risk and Addressing Potential

Harms of Opioid Use

Recommendation 8

Before starting and periodically during continuation of

opioid therapy, clinicians should evaluate risk for opioid-

related harms and discuss risk with patients. Clinicians should

work with patients to incorporate into the management

plan strategies to mitigate risk, including offering naloxone

(recommendation category: A; evidence type: 4).

Implementation Considerations

• Clinicians should ask patients about their drug and alcohol

use and use validated tools or consult with behavioral

specialists to screen for and assess mental health and

substance use disorders.

• When considering initiating long-term opioid therapy,

clinicians should ensure that treatment for depression and

other mental health conditions is optimized, consulting

with behavioral health specialists when needed.

• Clinicians should offer naloxone when prescribing

opioids, particularly to patients at increased risk for

overdose, including patients with a history of overdose,

patients with a history of substance use disorder, patients

with sleep-disordered breathing, patients taking higher

dosages of opioids (e.g., ≥50 MME/day), patients taking

benzodiazepines with opioids (see Recommendation 11),

and patients at risk for returning to a high dose to which

they have lost tolerance (e.g., patients undergoing tapering

or recently released from prison).

• Practices should educate patients on overdose prevention

and naloxone use and offer to provide education to

members of their households.

• Naloxone coprescribing can be facilitated by clinics or

practices with resources to provide naloxone training, by

collaborative practice models with pharmacists, or through

statewide protocols or standing orders for naloxone

at pharmacies.

• Resources for prescribing naloxone in primary care and

emergency department settings can be found through

Prescribe to Prevent at https://prescribetoprevent.org.

Additional resources are at https://www.samhsa.gov.

• In part because of concerns about cost of naloxone and

access for some patients and reports that purchasing of

naloxone has in some cases been required to fill opioid

prescriptions, including for patients without a way to afford

naloxone, this recommendation specifies that naloxone

should be offered to patients. To that end, clinicians, health

systems, and payers can work to ensure patients can obtain

naloxone, a potentially lifesaving treatment.

• Clinicians should avoid prescribing opioids to patients

with moderate or severe sleep-disordered breathing when

possible to minimize risk for respiratory depression.

• When making decisions about whether to initiate opioid

therapy for pain during pregnancy, clinicians and patients

together should carefully weigh benefits and risks. For

pregnant persons already receiving opioids, clinicians should

access appropriate expertise if tapering is being considered

because of possible risks to the pregnant patient and the fetus

if the patient goes into withdrawal (see Recommendation 5).

• For pregnant persons with opioid use disorder, medication

for opioid use disorder (buprenorphine or methadone) is

the recommended therapy and should be offered as early

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as possible in pregnancy to prevent harms to both the

patient and the fetus (see Recommendation 12).

• Clinicians should use additional caution and increased

monitoring (see Recommendation 7) to minimize risks of

opioids prescribed for patients with renal or hepatic

insufficiency and for patients aged ≥65 years. Clinicians

should implement interventions to mitigate common risks

of opioid therapy among older adults, such as exercise or

bowel regimens to prevent constipation, risk assessment

for falls, and patient monitoring for cognitive impairment.

• For patients with jobs that involve potentially hazardous

tasks and who are receiving opioids or other medications

that can negatively affect sleep, cognition, balance, or

coordination, clinicians should assess patients’ abilities to

safely perform the potentially hazardous tasks (e.g.,

driving, use of heavy equipment, climbing ladders,

working at heights or around moving machinery, or

working with high-voltage equipment).

• Clinicians should use PDMP data (see Recommendation 9)

and toxicology screening (see Recommendation 10) as

appropriate to assess for concurrent substance use that

might place patients at higher risk for opioid use disorder

and overdose.

• Clinicians should provide specific counseling on increased

risks for overdose when opioids are combined with

other drugs or alcohol (see Recommendation 2) and

ensure that patients are provided or receive effective

treatment for substance use disorders when needed (see

Recommendation 12).

• Although substance use disorders can alter the expected

benefits and risks of opioid therapy for pain, patients with

co-occurring pain and substance use disorder require

ongoing pain management that maximizes benefits relative

to risks. (See Recommendation 12, Pain Management for

Patients with Opioid Use Disorder for additional

considerations specific to these patients.)

• If clinicians consider opioid therapy for chronic pain for

patients with substance use disorder, they should discuss

increased risks for opioid use disorder and overdose with

patients, carefully consider whether benefits of opioids

outweigh increased risks, and incorporate strategies to

mitigate risk into the management plan (e.g., offering

naloxone [see Offering Naloxone to Patients] and increasing

frequency of monitoring [see Recommendation 7]).

• If patients experience nonfatal opioid overdose, clinicians

should evaluate for opioid use disorder and treat or arrange

treatment if needed. Clinicians should work with patients

to reduce opioid dosage and to discontinue opioids when

indicated (see Recommendation 5) and should ensure

continued close monitoring and support for patients

prescribed or not prescribed opioids.

• If clinicians continue opioid therapy in patients with

previous opioid overdose, they should discuss increased

risks for overdose with patients, carefully consider whether

benefits of opioids outweigh substantial risks, and

incorporate strategies to mitigate risk into the management

plan (e.g., offering naloxone and increasing frequency of

monitoring [see Recommendation 7]).

Supporting Rationale

The clinical evidence reviews found evidence too limited to

determine effects of patient demographics and comorbidities

on risk for opioid-related harms (7). However, on the basis

of observational studies (181,264–273) and expert opinion,

certain risk factors are likely to increase susceptibility to

opioid-related harms and warrant incorporation of additional

strategies into the management plan to mitigate risk. Clinicians

should assess these risk factors periodically, with frequency

individualized to patient comorbidities and other risk factors.

For example, factors that vary over time, such as alcohol

use, require more frequent assessment. Clinicians should

offer naloxone and reevaluate patients more frequently (see

Recommendation 7) when factors are present that increase

risk for harm, such as sleep-disordered breathing, history of

overdose, history of substance use disorder, higher dosages

of opioids (e.g., ≥50 MME/day), and concurrent use of

benzodiazepines with opioids. Experts from OWG had

concerns about the cost of purchasing naloxone for patients

with limited means and reported that purchasing of naloxone

has in some cases been required to fill opioid prescriptions. In

part because of these concerns and because in certain settings

naloxone is directly provided by a practice or health system to

patients, “offering” naloxone (which can be done by offering a

prescription or by offering naloxone directly) is recommended

rather than specifying “prescribing” naloxone. Clinicians,

health systems, and payers should work to ensure patients can

obtain naloxone, a potentially lifesaving treatment.

Patients with Sleep-Disordered Breathing,

Including Sleep Apnea

A case-control analysis among veterans prescribed opioids

found that sleep apnea was associated with increased risk for

life-threatening respiratory/central nervous system depression

or overdose (264). Careful monitoring and cautious dose

titration should be used if opioids are prescribed for patients

with mild sleep-disordered breathing. Clinicians should avoid

prescribing opioids to patients with moderate or severe sleep-

disordered breathing, whenever possible, to minimize risks for

respiratory depression.

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Pregnant Persons

Pregnant, postpartum, and parenting persons should

receive compassionate, evidence-based care for pain or opioid

use disorder. ACOG has noted that a cautious approach

to prescribing opioids should be balanced with the need to

address pain, and pregnancy should not be a reason to avoid

treating acute pain (274). At the same time, opioid use during

pregnancy might be associated with risks to both the pregnant

person and the fetus. Certain observational studies have shown

an association of opioid use in pregnancy with stillbirth,

poor fetal growth, and preterm delivery (265–268,275). In

some cases, opioid use during pregnancy leads to neonatal

abstinence syndrome/neonatal opioid withdrawal syndrome

(269). ACOG has emphasized that pregnancy should not

be a reason to avoid treating acute pain because of concern

for opioid misuse or neonatal abstinence syndrome and that

neonatal abstinence syndrome is an expected and treatable

condition that can follow prenatal exposure to opioid agonists.

Clinicians and patients together should carefully weigh

benefits and risks when making decisions about whether

to initiate opioid therapy for pain during pregnancy. In

addition, before initiating opioid therapy for persons

who can become pregnant, clinicians and patients should

discuss family planning and potential effects of long-

term opioid use on any future pregnancy. For all persons

with reproductive potential, discussing future pregnancy

intentions and engaging in shared decision-making regarding

contraception, if appropriate, is a core component of care. A

review of all prescription and nonprescription medications

is recommended during prepregnancy and interpregnancy

care (276,277). Intentional application of a patient-centered

reproductive justice framework and use of a shared decision-

making model is the recommended approach for providing

supportive contraceptive counseling and care to help patients

to achieve their reproductive goals (278). Counseling should

be noncoercive and include a discussion of all contraceptive

options (276–278). When opioids are needed for treatment

of acute pain in pregnant persons, the lowest effective dose

(see Recommendation 4) should be used for no longer than

the expected duration of pain severe enough to require

opioids (see Recommendation 6). For pregnant persons

with chronic pain, ACOG recommends that practice goals

include strategies to avoid or minimize the use of opioids for

pain management, highlighting alternative pain therapies

such as nonpharmacologic (e.g., exercise, physical therapy,

and behavioral approaches), and nonopioid pharmacologic

treatments (274). Pharmacokinetic and physiologic changes

occur during pregnancy, especially in the third trimester, and

these changes might require dose adjustments (274). For

pregnant persons already receiving opioids, clinicians should

access appropriate expertise if considering tapering opioids

because of possible risk to the pregnant patient and the fetus

if the patient goes into withdrawal (see Recommendation 5).

ACOG has noted that early universal screening, brief

intervention (e.g., engaging in a short conversation and

providing feedback and advice), and referral for treatment

of pregnant persons with opioid use disorder improve both

maternal and infant outcomes (274). For pregnant persons

with opioid use disorder, medication for opioid use disorder

(buprenorphine or methadone) is the recommended therapy,

has been associated with improved maternal outcomes,

and should be offered as early as possible in pregnancy to

prevent harms to both the patient and the fetus (274) (see

Recommendation 12). In contrast, criminalization or otherwise

punishing (e.g., through threatened loss of child custody) the

use of opioids, including for opioid use disorder, discourages

pregnant, postpartum, and parenting persons from seeking

care; nonpunitive public health approaches to treatment result

in better outcomes (274,279).

The American Academy of Pediatrics (AAP) has published

recommendations for the care of infants with neonatal opioid

withdrawal syndrome, including that pregnant persons with

opioid use disorder should receive antenatal counseling to

provide education on the clinical signs of withdrawal and

on postnatal treatment for neonatal opioid withdrawal

syndrome (e.g., nonpharmacologic treatment, including

breastfeeding, and pharmacotherapy) (280). In addition, all

infants with long-term opioid exposure should be observed

for at least 72 hours (4–7 days if exposed to buprenorphine

or ER/LA opioids and 5–7 days if exposed to methadone) to

monitor for the development of withdrawal (280). Clinicians

caring for pregnant persons receiving prescribed or using

nonprescribed opioids should arrange for delivery at a facility

prepared to monitor, evaluate for, and treat neonatal opioid

withdrawal syndrome. In instances when travel to such a

facility would present an undue burden on the pregnant

person, it is appropriate for the clinician to arrange delivery

locally, monitor and evaluate the newborn for neonatal opioid

withdrawal syndrome, and transfer the newborn for additional

treatment if needed. Previous consensus recommendations have

advised that if a codeine-containing medication is selected for

postpartum management, clinicians should review duration of

therapy and neonatal signs of toxicity with patients and their

families (133).

Patients with Renal or Hepatic Insufficiency

A case-control study of risk for life-threatening respiratory/

central nervous system depression or overdose among veterans

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prescribed opioids found that renal disease and moderate or

severe liver disease were associated with increased risk for these

events (264). Clinicians should use additional caution and

increased monitoring (see Recommendation 7) to minimize

risks of opioids prescribed for patients with renal or hepatic

insufficiency because of their decreased ability to process and

excrete medications, susceptibility to accumulation of opioids,

and reduced therapeutic window between safe dosages and

dosages associated with respiratory depression and overdose

(281) (see Recommendations 3, 4, and 7).

Patients Aged ≥65 Years

Older adults are a heterogenous group comprising a wide span

of ages and functional abilities, ranging from healthy, active

older adults to frail older adults. Frail older adults in particular

can be at risk for changes in function that might be exacerbated

by pain and contribute to deterioration in overall health and

independence. Functional assessment is especially important

in patients aged ≥65 years to better assess effects of pain on

function and independence. Persons aged ≥65 years can be at

risk for inadequate pain treatment (2,6,17,282). For certain

older adults (e.g., older adults with serious illness that requires

advanced management of pain or other distressing symptoms)

(94), palliative care, which is beyond the scope of this guideline

but addressed in other guidelines (93), is appropriate.

Pain management for older patients can be challenging

because of increased risks of both nonopioid pharmacologic

therapies (see Recommendation 2) and opioid therapy in this

population. Because of reduced renal function and medication

clearance even in the absence of renal disease, patients aged

≥65 years might have increased susceptibility to accumulation

of all medications, increased risk for drug-drug interactions,

and a smaller therapeutic window between safe dosages and

dosages associated with adverse effects. These adverse effects

include renal, cardiovascular, and gastrointestinal effects

with oral NSAIDs (see Recommendation 2) and respiratory

depression and overdose with opioids. A case-control analysis

among veterans prescribed opioids found that age ≥55 years was

associated with increased risk for life-threatening respiratory/

central nervous system depression or overdose (264). Some

older adults might have a cognitive impairment, such as

dementia, that can increase risk for medication errors and

make opioid-related confusion riskier. In addition, older adults

are more likely than younger adults to experience comorbid

medical conditions and are more likely to receive multiple

medications, some of which might interact with opioids.

Clinicians should review all current medications, over-

the-counter drugs, and natural remedies before prescribing

any new drugs. Clinicians should use additional caution and

increased monitoring (see Recommendation 7) for patients

aged ≥65 years to ensure pain is addressed and minimize risks

of opioids prescribed. Clinicians should educate older adults

receiving opioids to avoid medication-related behaviors that

increase risk, such as saving unused medications. Caregivers

can have an important role in management of opioid therapy

for older persons with cognitive impairment. Clinicians also

should implement interventions to mitigate common risks of

opioid therapy among older adults, such as monitoring for

cognitive impairment, risk assessment for falls, and exercise

and bowel regimens to prevent constipation.

Patients in Safety Critical Jobs

A safety critical job involves work or an occupational

environment where limitations in physical or mental

performance, or both, involve dangers to self, coworkers, or

the public. According to the American College Occupational

Environmental Medicine, for occupations with higher risks

(especially public transportation), prescription of an opioid

might be incompatible with continued employment in a

safety critical job (270,283). For patients with safety critical

jobs who are receiving opioids or other medications that can

negatively affect sleep, cognition, balance, or coordination,

clinicians should assess patients’ abilities to perform jobs that

involve driving, using heavy equipment, climbing ladders,

working at heights or around moving machinery, or working

with high-voltage equipment.

Patients with Mental Health Conditions

Psychological distress frequently interferes with improvement

of pain and function in patients with chronic pain; therefore,

using validated instruments such as the Generalized Anxiety

Disorder (GAD)-7 and the Patient Health Questionnaire

(PHQ-9 or PHQ-4) to support assessment for anxiety,

posttraumatic stress disorder (PTSD), and depression (284)

might help clinicians improve overall pain treatment outcomes.

Patients with mental health conditions including depression

might be at higher risk than other patients for opioid use

disorder (181,271) and drug overdose (272). Additional

caution and increased monitoring (see Recommendation 7)

might lessen the increased risk for overdose among patients

with depression (264,272). In addition, patients with anxiety

disorders and other mental health conditions are more likely to

receive benzodiazepines, which can exacerbate opioid-induced

respiratory depression and increase risk for overdose (see

Recommendation 11). Clinicians should ensure that treatment

for depression and other mental health conditions as well as

treatment for pain is optimized, consulting with behavioral

health specialists when needed. Treatment for depression can

improve pain symptoms and depression and might decrease

overdose risk (272). For treatment of chronic pain in patients

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with depression, clinicians should consider using tricyclic or

SNRI antidepressants for analgesic as well as antidepressant

effects if these medications are not otherwise contraindicated

(see Recommendation 2).

Patients with Substance Use Disorders

Patients with substance use disorders are likely to experience

greater risks for opioid use disorder and overdose (55,202,264)

than persons without these conditions. Despite increased risk

for opioid misuse and opioid use disorder when prescribed

opioid analgesics (271,285), patients with histories of substance

use disorders are more likely than other patients to receive

long-term opioid treatment for chronic pain (286). Previous

guidelines have recommended screening or risk assessment

tools to identify patients at higher risk for opioid misuse or

opioid use disorder. However, the clinical evidence reviews

found that available risk stratification tools (e.g., Opioid

Risk Tool, Screener and Opioid Assessment for Patients

with Pain [SOAPP] Version 1, SOAPP-R, and Brief Risk

Interview) demonstrate limited and variable accuracy for

classification of patients as at low or high risk for opioid use

disorder or misuse (7). If these tools are used, they should be

supplemented with other assessments, such as discussions with

patients, family, and caregivers; clinical records; PDMP data

(see Recommendation 9); and toxicology screening data (see

Recommendation 10). Clinicians should always use caution

when considering or prescribing opioids and should not

overestimate the ability of available risk stratification tools to

rule out risks of long-term opioid therapy.

Nonprescribed drugs (e.g., heroin, illicitly manufactured

fentanyl, cocaine, and methamphetamine) (287) and alcohol

(288) are listed as contributory factors on a substantial

proportion of death certificates for prescription opioid–

involved overdose deaths. Clinicians should ask patients about

their drug (289) and alcohol use. Single screening questions

can be used (290). For example, the question “How many

times in the past year have you used an illegal drug or used

a prescription medication for nonmedical reasons?” (with an

answer of one or more considered positive) was found in a

primary care setting to be 100% sensitive and 73.5% specific

for the detection of a drug use disorder compared with a

standardized diagnostic interview (291). Validated screening

tools, such as the Drug Abuse Screening Test (DAST) (260);

the Tobacco, Alcohol, Prescription medication, and other

Substance use Tool (TAPS) (261); and the three-question

version of the Alcohol Use Disorders Identification Test

(AUDIT-C) (262,263), also can be used. Clinicians should

use PDMP data (see Recommendation 9) and toxicology

screening (see Recommendation 10) as appropriate to assess

for concurrent substance use that might place patients at

higher risk for opioid use disorder and overdose. Clinicians

should also provide specific counseling on increased risks

for overdose when opioids are combined with other drugs

or alcohol (see Recommendation 2) and ensure that patients

receive effective treatment for substance use disorders when

needed (see Recommendation 12).

If clinicians consider prescribing opioid therapy for chronic

pain to patients with substance use disorders, they should

discuss increased risks for opioid use disorder and overdose

with patients; carefully consider whether benefits of opioids

outweigh increased risks; and incorporate strategies to mitigate

risk into the management plan, such as offering naloxone

(see Offering Naloxone to Patients) and increasing frequency

of monitoring (see Recommendation 7) when opioids are

prescribed. Clinicians should communicate with patients’

substance use disorder treatment providers if opioids are

prescribed. Although substance use disorders can alter the

expected benefits and risks of opioid therapy for pain, patients

with co-occurring pain and substance use disorder require

ongoing pain management that maximizes benefits relative to

risks. (See Recommendation 12, Pain Management for Patients

with Opioid Use Disorder for additional considerations.)

Patients with Previous Overdose

Previous opioid overdose is associated with substantially

increased risk for future nonfatal or fatal opioid overdose

(273). Yet, a cohort study of commercially insured patients

found that opioids were dispensed to 91% of patients who

had a previous overdose; a substantial percentage experienced

a repeated opioid overdose, with a cumulative incidence at

2 years of 17% among patients receiving ≥100 MME/day, 15%

among those prescribed 50–100 MME/day, 9% among those

prescribed <50 MME/day, and 8% among those prescribed

no opioids (273).

If patients experience nonfatal opioid overdose, clinicians

should evaluate them for opioid use disorder and provide or

arrange treatment if needed. Treatment with buprenorphine

or methadone for opioid use disorder after overdose is

associated with reduced all-cause and opioid-related deaths

(292). Clinicians should work with patients to reduce

opioid dosage and discontinue opioids when indicated (see

Recommendation 5) and should ensure continued close

monitoring and support for patients prescribed or not

prescribed opioids. If clinicians continue opioid therapy in

patients with previous opioid overdose, they should discuss

increased risks for overdose with patients; carefully consider

whether benefits of opioids outweigh substantial risks; and

incorporate strategies to mitigate risk into the management

plan, such as offering naloxone (see Offering Naloxone to

Patients), involving patient-identified trusted family members,

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and increasing frequency of monitoring combined with shorter

prescription durations (see Recommendation 7).

Offering Naloxone to Patients

Naloxone is an opioid antagonist that can reverse severe

respiratory depression; its administration by laypersons, such as

friends, family, and caregivers of persons who experience opioid

overdose, can save lives (293). Naloxone precipitates acute

withdrawal among patients physically dependent on opioids.

Serious adverse effects (e.g., pulmonary edema, cardiovascular

instability, and seizures) have been reported but are rare at

doses consistent with labeled use for opioid overdose (294).

The clinical evidence reviews identified one observational study

(295) that found provision of naloxone to patients prescribed

opioids in primary care clinics was associated with decreased

likelihood of opioid-related emergency department visits (7).

Clinicians should offer naloxone when prescribing opioids,

particularly to patients at increased risk for overdose, including

patients with a history of overdose, patients with a history of

substance use disorder, patients taking benzodiazepines with

opioids (see Recommendation 11), patients at risk for returning

to a high dose to which they have lost tolerance (e.g., patients

undergoing tapering or recently released from prison), and

patients taking higher dosages of opioids (≥50 MME/day).

Practices should provide education on overdose prevention

and naloxone use to patients receiving naloxone prescriptions

and members of their households. Naloxone coprescribing can

be facilitated by clinics or practices with resources to provide

naloxone training and by collaborative practice models with

pharmacists. Resources for prescribing naloxone in primary

care settings can be found through Prescribe to Prevent at

https://prescribetoprevent.org.

Recommendation 9

When prescribing initial opioid therapy for acute,

subacute, or chronic pain, and periodically during opioid

therapy for chronic pain, clinicians should review the

patient’s history of controlled substance prescriptions using

state prescription drug monitoring program (PDMP) data to

determine whether the patient is receiving opioid dosages or

combinations that put the patient at high risk for overdose

(recommendation category: B; evidence type: 4).

Implementation Considerations

• Ideally, PDMP data should be reviewed before every opioid

prescription for acute, subacute, or chronic pain. This

practice is recommended in all jurisdictions where PDMP

availability and access policies, as well as clinical practice

settings, make it practicable (e.g., clinician and delegate

access permitted).

• At a minimum, during long-term opioid therapy, PDMP

data should be reviewed before an initial opioid prescription

and then every 3 months or more frequently.

Recommendation category B acknowledges variation in

PDMP availability and circumstances. However, because

PDMP information can be most helpful when results are

unexpected and, to minimize bias in application, clinicians

should apply this recommendation when feasible to all

patients rather than differentially on the basis of assumptions

about what they will learn about specific patients.

• Clinicians should use specific PDMP information about

medications prescribed to their patient in the context of

other clinical information, including their patient’s history,

physical findings, and other relevant testing, to help them

communicate with and protect their patient.

• Clinicians should review PDMP data specifically for

prescription opioids and other controlled medications

patients have received from additional prescribers to

determine whether a patient is receiving total opioid

dosages or combinations (e.g., opioids combined with

benzodiazepines) that put the patient at risk for overdose.

• PDMP-generated risk scores have not been validated

against clinical outcomes such as overdose and should not

take the place of clinical judgment.

• Clinicians should not dismiss patients from their practice

on the basis of PDMP information. Doing so can adversely

affect patient safety and could result in missed opportunities

to provide potentially lifesaving information (e.g., about

risks of prescription opioids and about overdose prevention)

and interventions (e.g., safer prescriptions, nonopioid pain

treatment [see Recommendations 1 and 2], naloxone [see

Recommendation 8], and effective treatment for substance

use disorders [see Recommendations 8 and 12]).

• Clinicians should take actions to improve patient safety:



Discuss information from the PDMP with the patient and

confirm that the patient is aware of any additional

prescriptions. Because clinicians often work as part of

teams, prescriptions might appropriately be written by

more than one clinician coordinating the patient’s care.

Occasionally, PDMP information can be incorrect (e.g., if

the wrong name or birthdate has been entered, the patient

uses a nickname or maiden name, or another person has

used the patient’s identity to obtain prescriptions).



Discuss safety concerns, including increased risk for

respiratory depression and overdose, with patients found

to be receiving overlapping prescription opioids from

multiple clinicians who are not coordinating the patient’s

care or patients who are receiving medications that

increase risk when combined with opioids (e.g.,

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benzodiazepines) (see Recommendation 11), and offer

naloxone (see Recommendation 8).



Use particular caution when prescribing opioid pain

medication and benzodiazepines concurrently,

understanding that some patient circumstances warrant

prescribing of these medications concomitantly.

Clinicians should communicate with others managing

the patient to discuss the patient’s needs, prioritize

patient goals, weigh risks of concurrent benzodiazepine

and opioid exposure, and coordinate care (see

Recommendation 11).



Consider the total MME/day for concurrent opioid

prescriptions to help assess the patient’s overdose risk

(see Recommendation 4). Buprenorphine should not

be counted in the total MME/day in calculations because

of its partial agonist properties at opioid receptors that

confer a ceiling effect on respiratory depression. If a

patient is found to be receiving total daily dosages of

opioids that put them at risk for overdose, discuss safety

concerns with the patient, consider in collaboration with

the patient whether or not benefits of tapering outweigh

risks of tapering (see Recommendation 5), and offer

naloxone (see Recommendation 8).



Discuss safety concerns with other clinicians who are

prescribing controlled substances for the patient. Ideally,

clinicians should first discuss concerns with the patient

and inform them that they plan to coordinate care with

their other clinicians to improve the patient’s safety.



Screen for substance use and discuss concerns

with the patient in a nonjudgmental manner (see

Recommendations 8 and 12).



When diverting (sharing or selling prescription opioids

and not taking them) might be likely, consider toxicology

testing to assist in determining whether prescription

opioids can be discontinued without causing withdrawal

(see Recommendations 5 and 10). A negative toxicology

test for prescribed opioids might indicate the patient is

not taking prescribed opioids, although clinicians should

consider other possible reasons for this test result (e.g.,

false-negative results or misinterpretation of results) (see

Recommendation 10).

Supporting Rationale

PDMPs are databases overseen by states, territories, counties,

and the District of Columbia that collect information on

controlled prescription drugs dispensed by pharmacies and, in

selected jurisdictions, by dispensing clinicians. PDMPs do not

report nonprescribed opioid use. A clinical evidence review did

not find studies evaluating the effectiveness of PDMPs for risk

mitigation (7). However, among patients receiving concurrent

treatment with opioids and benzodiazepines, overdose risk is

further increased among patients receiving these treatments

from multiple prescribers rather than one prescriber, highlighting

potential room for improvement in care coordination (296).

PDMP data also can be helpful when patient medication history

is not otherwise available (e.g., when patients transition care to

a new clinician). A contextual evidence review (7) identified a

survey of physicians in Maryland (297) finding that although

barriers to PDMP review were noted (e.g., not knowing about

the program, registration difficulties, and difficulty accessing

data), most participants felt that PDMPs improved opioid

prescribing by decreasing opioid prescription amounts and

increasing comfort with prescribing opioids (7). Integration

of PDMPs with electronic health records (EHRs) can reduce

burden on clinicians compared with having to access a separate

system (298,299).

Special attention should be paid to ensure that PDMP

information is not used in a way that is harmful to patients.

For example, PDMP information has been used to dismiss

patients from clinician practices (300), which might adversely

affect patient safety and result in untreated or undertreated

pain. Many state laws require PDMP use under specific

circumstances (301). Experts from OWG had concerns about

PDMP risk scores or other algorithmic interpretations from

software platforms that can lead to distrust between clinicians

and patients and stigmatization, particularly for patients

with conditions such as opioid use disorder. Risk scores are

reportedly generated by applying proprietary algorithms that

are not publicly available to information from patient EHRs

and other sources such as court records and criminal and

sexual trauma histories; these algorithms might disparately

affect women, persons of color, and persons who live in

poverty (302). Importantly, whereas one PDMP-generated

risk measure has shown fair concurrence with the WHO

Alcohol, Smoking, and Substance Involvement Screening

Test (ASSIST), these scores have not been externally validated

against clinical outcomes (302,303). Such risk scores should

not take the place of clinical judgment. Rather, clinicians

should use specific PDMP information about medications

prescribed to their patient in the context of other clinical

information, including their patient’s history, physical findings,

and other relevant testing, to help them communicate with

and protect their patient.

Experts raised varying points regarding frequency of PDMP

use, with many agreeing that PDMPs should be consulted

before every opioid prescription, several agreeing that universal

application would mitigate bias in application to different

patients, and others believing it might not be warranted or

feasible to check the PDMP in all cases, particularly before

prescribing opioids for acute pain for a small number of days.

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Ideally, PDMP data should be reviewed before every opioid

prescription for acute, subacute, or chronic pain. This practice

is recommended in all jurisdictions where PDMP availability

and access policies make it practicable (e.g., clinician and

delegate access permitted). At a minimum, PDMP data

should be reviewed before initial opioid prescriptions for

subacute or chronic pain and then every 3 months or more

frequently during long-term opioid therapy. Recommendation

category B acknowledges variation in PDMP availability and

circumstances (e.g., a clinician might reasonably determine that

a patient with severe acute pain in the emergency department

during a PDMP system access failure would be adversely

affected by waiting hours for a prescription). However, because

PDMP information can be most helpful when results are

unexpected and, to minimize bias in application, clinicians

should apply this recommendation when feasible to all patients

rather than differentially on the basis of assumptions about

what they will learn about specific patients.

Clinicians should review PDMP data for prescription

opioids and other controlled medications patients might have

received from additional prescribers to determine the total

amount of MME prescribed and to assess if the total dosage or

combinations (e.g., opioids combined with benzodiazepines)

put the patient at high risk for overdose. If patients are found

to have total opioid dosages or combinations of medications

that might put them at risk for overdose, or multiple controlled

substance prescriptions written by different clinicians,

clinicians should take actions to improve patient safety (see

Recommendation 9, Implementation Considerations).

Recommendation 10

When prescribing opioids for subacute or chronic pain,

clinicians should consider the benefits and risks of toxicology

testing to assess for prescribed medications as well as

other prescribed and nonprescribed controlled substances

(recommendation category: B; evidence type: 4).

Implementation Considerations

• Toxicology testing should not be used in a punitive manner

but should be used in the context of other clinical

information to inform and improve patient care. Clinicians

should not dismiss patients from care on the basis of a

toxicology test result. Dismissal could have adverse

consequences for patient safety, potentially including the

patient obtaining opioids or other drugs from alternative

sources and the clinician missing opportunities to facilitate

treatment for substance use disorder.

• Before starting opioids and periodically (at least annually)

during opioid therapy, clinicians should consider the

benefits and risks of toxicology testing to assess for

prescribed opioids and other prescription and

nonprescription controlled substances that increase risk

for overdose when combined with opioids, including

nonprescribed and illicit opioids and benzodiazepines.

• Clinicians, practices, and health systems should aim to

minimize bias in testing and should not apply this

recommendation differentially on the basis of assumptions

about patients.

• Predicting risk is challenging, and available tools do not

allow clinicians to reliably identify patients who are at low

risk for substance use or substance use disorders. Clinicians

should consider toxicology screening results as potentially

useful data, in the context of other clinical information,

for all patients and consider toxicology screening whenever

its potential limitations can be addressed.

• Clinicians should explain to patients that toxicology

testing will not be used to dismiss patients from care and

is intended to improve their safety.

• Clinicians should explain expected results (e.g., presence

of prescribed medication and absence of drugs, including

nonprescribed controlled substances not reported by the

patient) and ask patients in a nonjudgmental manner

about use of prescribed and other drugs and whether there

might be unexpected results.

• Limited toxicology screening can be performed with a

relatively inexpensive presumptive immunoassay panel

that tests for opiates as a class, benzodiazepines as a class,

and several nonprescribed substances. Toxicology screening

for a class of drugs might not detect all drugs in that class.

For example, fentanyl testing is not included in widely

used toxicology assays that screen for opiates as a class.

• Clinicians should be familiar with the drugs included in

toxicology screening panels used in their practice and

should understand how to interpret results for these drugs.

For example, a positive opiates immunoassay detects

morphine, which might reflect patient use of morphine,

codeine, or heroin, but does not detect synthetic opioids

and might not detect semisynthetic opioids. In some cases,

positive results for specific opioids might reflect metabolites

from opioids the patient is taking and might not mean

the patient is taking the specific opioid that resulted in

the positive test.

• Confirmatory testing should be used when



toxicology results will inform decisions with major

clinical or nonclinical implications for the patient;



a need exists to detect specific opioids or other drugs

within a class, such as those that are being prescribed,

or those that cannot be identified on standard

immunoassays; or

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

a need exists to confirm unexpected screening toxicology

test results.

• Restricting confirmatory testing to situations and

substances for which results can reasonably be expected

to affect patient management can reduce costs of

toxicology testing.

• Clinicians might want to discuss unexpected results with

the local laboratory or toxicologist and should discuss

unexpected results with the patient.

• Clinicians should discuss unexpected results with patients

in a nonjudgmental manner, avoiding use of potentially

stigmatizing language (e.g., avoid describing a specimen

as testing “clean” or “dirty”).

• Discussion with patients before specific confirmatory

testing can sometimes yield a candid explanation of why

a particular substance is present or absent and remove the

need for confirmatory testing during that visit. For

example, a patient might explain that the test is negative

for prescribed opioids because they felt opioids were no

longer helping and discontinued them. If unexpected

results from toxicology screening are not explained, a

confirmatory test on the same sample using a method

selective enough to differentiate specific opioids and

metabolites (e.g., gas or liquid chromatography–mass

spectrometry) might be warranted.

• Clinicians should use unexpected results to improve

patient safety (e.g., optimize pain management

strategy [see Recommendation 2], carefully weigh

benefits and risks of reducing or continuing opioid

dosage [see Recommendation 5], reevaluate more

frequently [see Recommendation 7], offer naloxone [see

Recommendation 8], and offer treatment or refer the patient

for treatment with medications for opioid use disorder [see

Recommendation 12], all as appropriate).

Supporting Rationale

The clinical evidence reviews did not find studies evaluating

the effectiveness of toxicology screening for risk mitigation

during opioid prescribing for pain. However, concurrent use of

opioid pain medications with other opioid pain medications,

benzodiazepines, or heroin or other nonpharmaceutical opioids

can increase patients’ risk for overdose. Toxicology tests can

provide information about drug use that is not reported by

the patient. In addition, toxicology tests can assist clinicians

in identifying when patients are not taking opioids prescribed

for them, which might in certain cases indicate diversion or

other clinically important issues such as difficulties with adverse

effects. The most commonly drug-tested bodily specimen is

urine. Oral fluid (saliva) testing also is available (304), although

testing protocols using oral fluid are not as well established.

On October 25, 2019, SAMHSA published guidelines for

the inclusion of oral fluid specimens in toxicology testing

programs of federal executive branch agencies (305), effective

January 1, 2020. Toxicology testing results can be associated

with outcomes and practices that harm patients (e.g.,

stigmatization and inappropriate termination from care).

False positive and false negative presumptive results are not

uncommon, a problem that can be compounded because

clinicians commonly misinterpret results (306,307), leading

to inappropriate consequences for patients. Urine toxicology

tests do not provide accurate information about how much or

what doses of opioids or other drugs a patient took. Testing

for fentanyl is not available in widely used toxicology assays,

potentially leading to false assurance. Ideally, clinicians would

only test for substances for which results could affect patient

management. However, it can be challenging for clinicians

in many settings to tailor widely used toxicology panels

to include the specific substances most relevant to clinical

decisions for their patient. Toxicology testing costs are not

always covered fully by insurance and can be a burden for

patients, and clinician time is needed to interpret, confirm,

and communicate results.

Experts from OWG had concerns that biases and disparities

affecting which patients undergo toxicology testing could

have disproportionately negative consequences among Black

and Hispanic patients. In addition, testing costs would have

the greatest consequences for patients with the least ability to

pay. Because of these concerns, some experts said that grading

the recommendation as category A could potentially reduce

bias and disparities. However, others indicated that although

universal application could mitigate bias in who is tested, it

would not mitigate stigma associated with testing. In addition,

experts had concerns about accuracy, clinician interpretation,

testing costs, and potential for a delay in care while waiting

for test results.

Because of these concerns, the recommendation is rated

category B. However, clinicians, practices, and health systems

should aim to minimize bias in its application and should

not apply this recommendation differentially on the basis of

assumptions about what they will learn about specific patients.

Predicting risk is challenging, and available tools do not allow

clinicians to reliably identify patients who are at low risk for

substance use disorder (7). Rather, clinicians should consider

toxicology test results as potentially useful data, in the context

of other clinical information, for all patients and consider

toxicology testing whenever its potential problems can be

mitigated. For example, clinicians can become familiar with

the drugs included in toxicology testing panels used in their

practice and understand how to interpret results; practices

and health systems can ensure a laboratorian or toxicologist is

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available to discuss unexpected results, that costs to patients are

not burdensome, and that practice policies regarding testing

and frequency can minimize bias. For example, routine use

of testing with standardized policies at the practice or clinic

level might help destigmatize their use. Because truly random

testing might not be feasible in clinical practice, some clinics

obtain a specimen at every visit but only send it for testing on

a random schedule.

Before starting opioids and periodically (at least annually)

during opioid therapy, clinicians should consider benefits and

risks of toxicology testing to assess for prescribed opioids and

other prescription and nonprescribed substances that increase

risk for overdose when combined with opioids, including

nonprescribed and illicit opioids and benzodiazepines. Before

ordering toxicology testing, clinicians should have a plan for

responding to unexpected results. Clinicians should explain

to patients that toxicology testing will not be used punitively

(e.g., will not be used to dismiss patients from care) and is

intended to improve their safety. Clinicians should also explain

expected results (e.g., presence of prescribed medication and

absence of substances, including nonprescribed substances, not

reported by the patient). Clinicians should ask patients about

use of prescribed medications and other substances and ask

whether there might be unexpected results. This will provide an

opportunity for patients to provide information about changes

in their use of prescribed opioids or other drugs.

In most situations, initial toxicology testing can be performed

with a relatively inexpensive immunoassay panel that tests

for opiates and benzodiazepines as classes and for multiple

nonprescribed substances. Patients prescribed oxycodone

or nonmorphine-based opioids (e.g., buprenorphine or

methadone) require specific testing for those agents. The

use of confirmatory testing can add costs and should be

used when toxicology results will inform decisions with

major clinical or nonclinical implications for the patient, a

need exists to detect a specific opioid that is prescribed or

that cannot be identified on standard immunoassays, or to

confirm unexpected toxicology screening results for which

there is no other explanation. Clinicians and health systems

can work to minimize inequitable cost burdens for patients

and limit specific testing to situations when it is necessary.

Clinicians should be familiar with the compounds included

in toxicology testing panels used in their practice and should

understand how to interpret results. For example, a positive

opiate immunoassay test result detects morphine, which

might reflect patient use of morphine, codeine, or heroin,

but this immunoassay does not detect synthetic opioids (e.g.,

fentanyl or methadone) and might not detect semisynthetic

opioids (e.g., oxycodone or buprenorphine). Many laboratories

use an oxycodone immunoassay that detects oxycodone

and oxymorphone; however, these agents might need to be

ordered or identified separately in a toxicology testing panel.

In some cases, positive results for specific opioids might reflect

metabolites from opioids the patient is taking and might not

mean the patient is taking the specific opioid for which the test

was positive. For example, hydromorphone is a metabolite of

hydrocodone, and oxymorphone is a metabolite of oxycodone.

Detailed considerations for interpretation of urine toxicology

test results, including which tests to order and expected results,

drug detection time in urine, and drug metabolism, have been

published previously (308). A review including interpretation

of oral fluid sample toxicology test results is also available (304).

Restricting confirmatory testing to situations and substances

for which results can reasonably be expected to affect patient

management can reduce costs of toxicology testing.

Clinicians might want to discuss unexpected results with the

local laboratory or toxicologist and should discuss unexpected

results with the patient. Discussion with patients before specific

confirmatory testing can sometimes yield a candid explanation

of why a particular substance is present or absent and obviate

the need for confirmatory testing on that visit. For example,

a patient might explain that the test is negative for prescribed

opioids because they felt opioids were no longer helping and

discontinued them. If unexpected results are not explained,

a confirmatory test using a method selective enough to

differentiate specific opioids and metabolites (e.g., gas or liquid

chromatography–mass spectrometry) might be warranted to

clarify the situation.

Clinicians should use unexpected results to improve

patient safety (e.g., change pain management strategy [see

Recommendation 2], carefully weigh benefits and risks of

reducing or continuing opioid dosage [see Recommendation 5],

reevaluate more frequently [see Recommendation 7], offer

naloxone [see Recommendation 8], and offer or refer patients

for substance use disorder treatment [see Recommendation 12],

all as appropriate). If tests for prescribed opioids are repeatedly

negative, including confirmatory tests, and the clinician has

verified that the patient is not taking the prescribed opioid,

clinicians can discontinue the prescription without a taper

and discuss options for safe disposal of unused opioids (154).

Clinicians should not dismiss patients from care on the

basis of a toxicology test result. Dismissal could have adverse

consequences for patient safety, potentially including the

patient obtaining opioids from alternative sources and the

clinician missing opportunities to facilitate treatment for a

substance use disorder.

Recommendation 11

Clinicians should use particular caution when prescribing

opioid pain medication and benzodiazepines concurrently

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and consider whether benefits outweigh risks of concurrent

prescribing of opioids and other central nervous system

depressants (recommendation category: B; evidence type: 3).

Implementation Considerations

• Although in some circumstances it might be appropriate

to prescribe opioids to a patient who is also prescribed

benzodiazepines (e.g., severe acute pain in a patient taking

long-term, stable low-dose benzodiazepine therapy),

clinicians should use particular caution when prescribing

opioid pain medication and benzodiazepines concurrently.

In addition, clinicians should consider whether benefits

outweigh risks for concurrent use of opioids with other

central nervous system depressants (e.g., muscle relaxants,

nonbenzodiazepine sedative hypnotics, and potentially

sedating anticonvulsant medications such as gabapentin

and pregabalin).

• Buprenorphine or methadone for opioid use disorder should

not be withheld from patients taking benzodiazepines or

other medications that depress the central nervous system.

• Clinicians should check the PDMP for concurrent

controlled medications prescribed by other clinicians

(see Recommendation 9) and should consider involving

pharmacists as part of the management team when

opioids are coprescribed with other central nervous

system depressants.

• In patients receiving opioids and benzodiazepines long

term, clinicians should carefully weigh the benefits

and risks of continuing therapy with opioids and

benzodiazepines and discuss with patients and other

members of the patient’s care team.

• Risks of concurrent opioid and benzodiazepine use are

likely to be greater with unpredictable use of either

medication, with use of higher-dosage opioids and higher-

dosage benzodiazepines in combination, or with use with

other substances including alcohol (compared with long-

term, stable use of lower-dosage opioids and lower-dosage

benzodiazepines without other substances).

• In specific situations, benzodiazepines can be beneficial,

and stopping benzodiazepines can be destabilizing.

• Clinicians should taper benzodiazepines gradually before

discontinuation because abrupt withdrawal can be

associated with rebound anxiety, hallucinations, seizures,

delirium tremens, and, rarely, death. The rate of tapering

should be individualized.

• If benzodiazepines prescribed for anxiety are tapered or

discontinued, or if patients receiving opioids require

treatment for anxiety, evidence-based psychotherapies

(e.g., cognitive behavioral therapy), specific antidepressants

or other nonbenzodiazepine medications approved for

anxiety, or both, should be offered.

• Clinicians should communicate with other clinicians

managing the patient to discuss the patient’s needs,

prioritize patient goals, weigh risks of concurrent

benzodiazepine and opioid exposure, and coordinate care.

Supporting Rationale

Benzodiazepines and opioids both cause central nervous

system depression, and benzodiazepines can potentiate opioid-

induced decreases in respiratory drive. Epidemiologic studies

find concurrent benzodiazepine use in large proportions of

opioid-related overdose deaths (203,309,310). The clinical

evidence reviews identified three cohort studies that found an

association between concurrent use of benzodiazepines and

opioids versus opioids alone and increased risk for overdose

(7). A case-cohort study found concurrent benzodiazepine

prescription with opioid prescription to be associated with

a near-quadrupling of risk for overdose death compared

with opioid prescription alone (311). The clinical evidence

reviews did not find studies evaluating the effectiveness of

avoiding coprescribing of benzodiazepines and opioids on

risk for overdose (7). The clinical evidence reviews identified

three observational studies that found an association between

concurrent use of gabapentinoids and opioids versus opioids

alone and increased risk for overdose, with higher risks at

increased gabapentinoid doses (7).

Experts from OWG noted that rather than necessarily being

a direct cause of overdose, benzodiazepines might serve as a

marker of risk for overdose because of underlying conditions,

in specific situations benzodiazepines can be beneficial,

and that stopping benzodiazepines can be destabilizing. In

addition, experts noted that long-term, stable use might

be safer than erratic, unpredictable use. Because of these

considerations, multiple experts indicated that recommending

extreme caution with concurrent prescription of opioid pain

medications and benzodiazepines was more appropriate than a

recommendation to avoid prescribing opioid pain medication

and benzodiazepines concurrently and that category B would

be more appropriate than category A for this recommendation.

Although in certain circumstances it might be appropriate

to prescribe opioids to a patient receiving benzodiazepines

(e.g., severe acute pain in a patient taking long-term, stable

low-dosage benzodiazepine therapy), clinicians should use

particular caution when prescribing opioid pain medication

and benzodiazepines concurrently. In addition, because other

central nervous system depressants (e.g., muscle relaxants,

nonbenzodiazepine sedative hypnotics, and potentially sedating

anticonvulsant medications such as gabapentin and pregabalin)

(312) can potentiate respiratory depression associated with

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opioids, clinicians should consider whether benefits outweigh

risks of concurrent use of these medications. Clinicians

should check PDMPs for concurrent controlled medications

prescribed by other clinicians (see Recommendation 9)

and should consider involving pharmacists as part of the

management team when opioids are coprescribed with other

central nervous system depressants.

In patients receiving opioids and benzodiazepines long-

term, clinicians should carefully weigh the benefits and risks

of continuing therapy with opioids and benzodiazepines and

discuss with patients and other members of the patient’s care

team, as appropriate. In specific situations, benzodiazepines

can be beneficial, and stopping benzodiazepines can be

destabilizing. As emphasized in an FDA advisory (313),

buprenorphine or methadone for opioid use disorder should

not be withheld from patients taking benzodiazepines or other

medications that depress the central nervous system. Whereas

the combined use of these medications increases risks, the

harm caused by untreated opioid use disorder can outweigh

these risks.

If risks are determined to outweigh benefits of continuing

opioids for pain and benzodiazepine therapy at current dosages,

decisions about tapering medications (e.g., whether to taper

opioids first, taper benzodiazepines first, or consider carefully

transitioning from full agonist opioids to buprenorphine

before tapering benzodiazepines) should be individualized

and reevaluated over time. Considerations include patient

priorities, the patient’s clinical considerations, the patient’s

response to therapeutic changes, consultation with other

clinicians managing the patient’s care, and, consultation

with other specialists (e.g., an addiction specialist) if needed.

Clinicians should taper benzodiazepines gradually before

discontinuation because abrupt withdrawal can be associated

with rebound anxiety, hallucinations, seizures, delirium

tremens, and, rarely, death (222,223). Tapering rates should

be individualized. Examples of benzodiazepine tapers and tips

for managing benzodiazepine withdrawal are available (314).

Cognitive behavioral therapy increases tapering success rates

and might be particularly helpful for patients struggling with

a benzodiazepine taper (315). If benzodiazepines prescribed

for anxiety are tapered or discontinued, or if patients receiving

opioids require treatment for anxiety, evidence-based

psychotherapies (e.g., cognitive behavioral therapy), specific

antidepressants or other nonbenzodiazepine medications

approved for anxiety, or both, should be offered. Clinicians

should communicate with mental health professionals

managing the patient to discuss the patient’s needs, prioritize

patient goals, weigh risks of concurrent benzodiazepine and

opioid exposure, and coordinate care.

Recommendation 12

Clinicians should offer or arrange treatment with evidence-

based medications to treat patients with opioid use disorder.

Detoxification on its own, without medications for opioid use

disorder, is not recommended for opioid use disorder because

of increased risks for resuming drug use, overdose, and overdose

death (recommendation category: A; evidence type: 1).

Implementation Considerations

• Although stigma can reduce the willingness of persons

with opioid use disorder to seek treatment, opioid use

disorder is a chronic, treatable disease from which persons

can recover and continue to lead healthy lives.

• If clinicians suspect opioid use disorder, they should discuss

their concern with their patient in a nonjudgmental

manner and provide an opportunity for the patient to

disclose related concerns or problems.

• Clinicians should assess for the presence of opioid use

disorder using DSM-5 criteria.

• For patients meeting criteria for opioid use disorder,

particularly if moderate or severe, clinicians should offer

or arrange for patients to receive evidence-based treatment

with medications for opioid use disorder.

• Clinicians should not dismiss patients from their practice

because of opioid use disorder because this can adversely

affect patient safety.

• Medication treatment of opioid use disorder has been

associated with reduced risk for overdose and overall

deaths. Identification of opioid use disorder represents an

opportunity for a clinician to initiate potentially life-saving

interventions, and the clinician should collaborate with

the patient regarding their safety to increase the likelihood

of successful treatment.

• For pregnant persons with opioid use disorder, medication

for opioid use disorder (buprenorphine or methadone) is

the recommended therapy and should be offered as early

as possible in pregnancy to prevent harms to both the

patient and the fetus.

• Clinicians unable to provide treatment themselves should

arrange for patients with opioid use disorder to receive

care from a substance use disorder treatment specialist

(e.g., an office-based buprenorphine or naltrexone

treatment provider), or from an opioid treatment program

certified by SAMHSA to provide methadone or

buprenorphine for patients with opioid use disorder.

• All clinicians, and particularly clinicians prescribing

opioids in communities without sufficient treatment

capacity for opioid use disorder, should obtain a waiver to

prescribe buprenorphine for opioid use disorder.

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• Clinicians prescribing opioids should identify treatment

resources for opioid use disorder in the community,

establish a network of referral options that span the levels

of care that patients might need to enable rapid

collaboration and referral, when needed, and work

together to ensure sufficient treatment capacity for opioid

use disorder at the practice level.

• Although identification of an opioid use disorder can alter

the expected benefits and risks of opioid therapy for pain,

patients with co-occurring pain and opioid use disorder

require ongoing pain management that maximizes benefits

relative to risks.

Supporting Rationale

Opioid use disorder (previously known as opioid abuse or

opioid dependence in the Diagnostic and Statistical Manual of

Mental Disorders, Fourth Edition [DSM-IV]) (316) is defined

in DSM-5 as a problematic pattern of opioid use leading to

clinically significant impairment or distress (317). Treatment

with opioids for pain is associated with increased risk for opioid

use disorder, particularly if opioids are prescribed for >90 days

(54). A systematic review found the rate of opioid addiction

among patients with chronic pain averaged 8%–12% in studies

published during 2000–2013 (318). More recent studies

have found prevalence estimates of 23.9%–26.5% for any

prescription opioid use disorder and 5.2%–9.0% for moderate

to severe opioid use disorder (using DSM-5 diagnostic criteria)

among adults receiving long-term opioid therapy for pain,

with slightly lower prevalence (21.5% for any and 4.2% for

moderate to severe opioid use disorder) in clinics with more

consistent use of risk reduction practices (319,320).

Opioid use disorder is manifested by at least two of 11

defined criteria occurring within a year (317):

1. Opioids are often taken in larger amounts or over a longer

period than was intended.

2. There is a persistent desire or unsuccessful attempts to cut

down or control opioid use.

3. A great deal of time is spent in activities necessary to obtain

the opioid, use the opioid, or recover from its effects.

4. Craving, or a strong desire or urge to use opioids.

5. Recurrent opioid use resulting in a failure to fulfill major

role obligations at work, school, or home.

6. Continued opioid use despite having persistent or

recurrent social or interpersonal problems caused or

exacerbated by the effects of opioids.

7. Important social, occupational, or recreational activities

are given up or reduced because of opioid use.

8. Recurrent opioid use in situations in which it is physically

hazardous.

9. Continued opioid use despite knowledge of having a

persistent or recurrent physical or psychological problem that

is likely to have been caused or exacerbated by the substance.

10. Tolerance, as defined by either of the following:

a. a need for markedly increased amounts of opioids to

achieve intoxication or desired effect, or

b. a markedly diminished effect with continued use of the

same amount of an opioid.

11. Withdrawal, as manifested by either of the following:

a. the characteristic opioid withdrawal syndrome, or

b. opioids (or a closely related substance) are taken to

relieve or avoid withdrawal symptoms.

Criteria 10 and 11 are not considered to be met for those

persons taking opioids solely under appropriate medical

supervision (317). Severity is specified as mild (2–3 criteria),

moderate (4–5 criteria), or severe (≥6 criteria) (317).

FDA-approved medications indicated for the treatment of

opioid use disorder include buprenorphine (a partial agonist

opioid), methadone (a full agonist opioid), and naltrexone (an

opioid antagonist). Experts from OWG stated that partial agonist

opioid, full agonist opioid, and opioid antagonist treatment

should not be framed as equal options for opioid use disorder,

noting that partial and full agonist opioid treatments have

stronger evidence for better outcomes, do not require abstinence,

have less challenges with initiation, and are much more widely

used than opioid antagonist treatment. Clinical evidence reviews

found evidence on the effectiveness of interventions (e.g.,

medications and behavioral treatments) for opioid use disorder

related to prescription opioids to be limited (7). However,

moderate-quality evidence indicated buprenorphine (a partial

agonist opioid) and methadone (a full agonist opioid) to be

effective in preventing return to drug use among patients with

opioid use disorder involving heroin (321–323), although the

presence of pain among patients in these studies is generally

not described. In addition, a small number of studies have

evaluated buprenorphine for patients with prescription opioid

dependence (using DSM-IV criteria) (316) and found it to be

effective in preventing return to drug use (324,325). One study

found that among persons with opioid use disorder, previous

prescription opioid use predicts stabilization on buprenorphine

(326). Another trial that performed buprenorphine initiation

and then randomized patients to buprenorphine taper versus

maintenance was terminated early without reporting of planned

outcomes because all patients randomized to the taper arm

switched to maintenance or experienced a return to drug use;

five of six patients in the maintenance arm completed the trial

(327). In another trial identified by the clinical evidence reviews,

no difference was found between buprenorphine/naloxone and

methadone in likelihood of retention in the study and in pain,

function, or self-reported side effects (328). Buprenorphine

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and methadone treatment of opioid use disorder has been

associated with reduced overdose deaths (329) and reduced

all-cause deaths (330). Naltrexone (an opioid antagonist) also

can be used for opioid use disorder, particularly for highly

motivated persons (331,332). Naltrexone blocks the effects of

opioids if they are used. Naltrexone has not been evaluated in

persons with concomitant pain and opioid use disorder, and

opioid medications for pain generally cannot be used in patients

receiving naltrexone. Naltrexone requires adherence to monthly,

long-acting injections. The effectiveness of oral naltrexone can be

limited by poor medication adherence (332), and oral naltrexone

should not be used except under very limited circumstances (96)

(e.g., for patients who would be able to comply with observed

daily dosing to enhance adherence) (96,317). Naltrexone also

must be started after full withdrawal from opioids, which is a

challenge for some patients; however, for patients who have

completed or are able to complete withdrawal, naltrexone has

comparable effectiveness as buprenorphine in prevention of

return to drug use (333).

Certain studies suggest that using behavioral therapies

in combination with medications for opioid use disorder

can reduce opioid misuse and increase retention during

treatment (334,335). At the same time, a study of treatment

for prescription opioid dependence (using DSM-IV criteria)

(316) found buprenorphine treatment combined with

standard medical management (including basic counseling

recommending abstinence and self-help group participation)

as effective as buprenorphine combined with more intensive

opioid dependence counseling (i.e., addiction, recovery, and

prevention of return to drug use education with self-help and

lifestyle change recommendations, interactive exercises, and

take-home assignments delivered by trained substance use

treatment or mental health professionals in 45–60 minute

sessions using drug counseling manuals with demonstrated

efficacy); neither standard medical management nor opioid

dependence counseling alone, without buprenorphine,

was effective in preventing return to drug use (325).

Recommendations for treatment of opioid use disorder include

assessing the patient’s psychosocial needs and offering or

referring the patient to psychosocial treatment in collaboration

with qualified behavioral health care providers based on those

needs; however, a patient’s decision to decline psychosocial

treatment or the absence of available psychosocial treatment

should not preclude or delay medications for opioid use disorder

(96). Additional recommendations have been published on

goals, components of, and types of effective psychosocial

treatment to use in conjunction with pharmacologic treatment

of opioid use disorder (96).

If clinicians suspect opioid use disorder on the basis of

patient concerns or behaviors or on findings in PDMP data

(see Recommendation 9) or from toxicology testing (see

Recommendation 10), they should discuss their concern with

their patient and provide an opportunity for the patient to

disclose related concerns or problems. Clinicians should assess

for the presence of opioid use disorder using DSM-5 criteria

(317). Opioid use disorder can coexist with other substance use

disorders, and patients who are actively using substances during

opioid use disorder treatment might require greater support,

potentially including involvement of an addiction specialist (96).

Clinicians should ask about use of alcohol and other substances

(see Recommendation 8). Alternatively, clinicians can arrange

for a substance use disorder treatment specialist to assess for the

presence of opioid and other substance use disorders.

For patients meeting criteria for opioid use disorder,

particularly if moderate or severe, clinicians should offer or

arrange for patients to receive evidence-based treatment with

medications for opioid use disorder. Patients with opioid use

disorder might benefit from counseling and referrals to mutual

help groups such as Narcotics Anonymous (336), although

this should not take the place of treatment with medication.

Clinicians also should offer naloxone and training on proper

use for overdose reversal to patients with opioid use disorder

and to their household members and significant others (96) (see

Recommendation 8). Clinicians should not dismiss patients

from their practice because of opioid use disorder because this

can adversely affect patient safety. Identification of opioid use

disorder represents an opportunity for a clinician to initiate

potentially life-saving interventions, and it is important for the

clinician to collaborate with the patient regarding their safety to

increase the likelihood of successful treatment. Detoxification

on its own, without medications for opioid use disorder, is not

recommended for opioid use disorder because of increased

risks for return to drug use, overdose, and overdose death (96).

For pregnant persons with opioid use disorder, medications

for opioid use disorder (buprenorphine or methadone) have

been associated with improved maternal outcomes and should

be offered as early as possible in pregnancy to prevent harms

to both the patient and the fetus (see Recommendation 8)

(133,220). Previous recommendations have suggested that

transmucosal buprenorphine (without naloxone) is preferred

during pregnancy to avoid potential prenatal exposure to

naloxone, especially if injected, and evidence on the safety

of naloxone in pregnant persons remains limited (96,274).

However, combination buprenorphine/naloxone products are

frequently used, a systematic review did not find reports of

serious maternal or neonatal outcomes associated with maternal

buprenorphine/naloxone use (337), and experts have noted

that combination products are likely to be safe and effective for

pregnant persons when taken as prescribed (96,274). ACOG

also recommends that if a person is stable on naltrexone

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before pregnancy, the decision regarding whether to continue

naltrexone treatment during pregnancy should involve a careful

discussion between the clinician and the patient, weighing the

limited safety data on naltrexone with the potential risk for

return to drug use with discontinuation of treatment (274).

For persons receiving buprenorphine or methadone for opioid

use disorder and considering breastfeeding, AAP recommends

breastfeeding be supported if there has been no return to drug

use for ≥90 days and there are no other contraindications,

considered if there has been no return to drug use within

30–90 days, and discouraged if there is active substance use

or has been a return to drug use within the last 30 days (280).

In April 2021, to expand access to buprenorphine, the

Practice Guidelines for the Administration of Buprenorphine

for Treating Opioid Use Disorder (338) exempted eligible

physicians, physician assistants, nurse practitioners, clinical

nurse specialists, certified registered nurse anesthetists, and

certified nurse midwives from previous Controlled Substances

Act certification requirements related to training, counseling

and other ancillary services (i.e., psychosocial services). To

prescribe buprenorphine for opioid use disorder for up to

30 patients in an office-based setting, clinicians can forgo or

choose to undertake training but must still receive a waiver

from SAMHSA. Information about qualifications and the

process to obtain a waiver are available from SAMHSA (339).

Additional recommendations have been published on

initiation, use, and monitoring of buprenorphine treatment

for opioid use disorder (96,336). Buprenorphine for treatment

of opioid use disorder is usually combined with naloxone in a

sublingual or buccal film or tablet (e.g., Suboxone), to reduce

the potential for misuse of buprenorphine when injected.

Naloxone is poorly absorbed orally; however, if buprenorphine/

naloxone is manipulated and injected, naloxone can trigger

opioid withdrawal (340). In 2018, long-acting injectable

formulations of buprenorphine became available (341). As

a partial agonist, buprenorphine should generally not be

initiated until there are objective signs of withdrawal, to

avoid precipitating withdrawal. As an alternative for patients

not yet in opioid withdrawal, certain studies have described

a low-dose initiation approach (sometimes referred to as

microdosing) (342,343) to avoid precipitating withdrawal

when initiating buprenorphine, although evidence regarding

this approach is limited. Low-dose buprenorphine initiation

is a potential option for patients with opioid use disorder

who are taking opioid medications for pain. With this

dosing strategy, full agonist opioids can be continued while

buprenorphine is initiated, and the patient does not need to

experience opioid withdrawal symptoms. For standard (not

low-dose) buprenorphine initiation, after objective signs of

withdrawal are observed, buprenorphine should be initiated

(96) and titrated upward under supervision at approximately

2-hour intervals as needed to control withdrawal symptoms.

Protocols for initiating buprenorphine by patients at home after

an initial encounter with a clinician to establish the diagnosis

of opioid use disorder and discuss medication options are in

use by more experienced clinicians (344).

Importantly, opioid dosage thresholds for caution in the

treatment of pain are not applicable to opioid agonist treatment

of opioid use disorder (345) because recommended dosages of

methadone and buprenorphine for opioid use disorder (96)

differ from those for pain management. No recommended

duration limit exists for treatment of opioid use disorder

with buprenorphine or methadone, and discontinuation is

associated with risks for return to drug use and opioid overdose

(96). If discontinued, buprenorphine should be tapered very

gradually (over several months) (96).

Compared with buprenorphine, which can be prescribed

by clinicians with a waiver in any setting or dispensed from

a SAMHSA-certified opioid treatment program, ongoing

methadone treatment for opioid use disorder can only be

provided through an opioid treatment program. As short-term

exceptions, any clinician may administer (but not prescribe)

methadone or buprenorphine to treat acute opioid withdrawal

for up to 3 days, while working to refer the patient to opioid

use disorder treatment (346). Previously, up to a 1-day

supply could be administered per day for up to 3 days; in

December 2020, Congress directed the Drug Enforcement

Administration (DEA) to revise regulations to allow for a

3-day supply of medication to be dispensed at one time

(347); DEA subsequently advised practitioners how to request

exceptions to the 1-day supply limitation pending amendment

of 21 CFR 1306.07(b) (348). Patients already receiving

treatment for opioid use disorder and admitted for other

medical reasons may continue to directly receive methadone or

buprenorphine treatment in an emergency department or in a

hospital throughout inpatient hospitalization (336,346,349).

Naltrexone does not require a waiver and can be prescribed

in any setting. Additional recommendations have been

published previously on naltrexone treatment for opioid

use disorder (96). A minimum of 7–10 days free of opioids

is recommended before the first naltrexone dose to avoid

precipitation of severe opioid withdrawal (350). Extended-

release injectable naltrexone is typically administered every

4 weeks by deep intramuscular injection in the gluteal muscle

at 380 mg per injection (96), alternating buttocks for each

subsequent injection (350). Certain patients, including those

who metabolize naltrexone more rapidly, might benefit from

dosing as frequently as every 3 weeks (96). Oral naltrexone is

no longer recommended and should not be used except under

very limited circumstances (96). No recommended duration

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limit exists for treatment of opioid use disorder with naltrexone.

If discontinued, naltrexone can be stopped abruptly without

precipitating withdrawal symptoms (96). Clinicians should

warn patients who discontinue naltrexone of the risk for

potentially fatal opioid overdose if opioid use is resumed (96),

because of the loss of tolerance to the previous opioid dosage.

Clinicians are strongly encouraged to provide medication

treatment for their patients with opioid use disorder. Those

unable to provide treatment themselves should arrange for

patients with opioid use disorder to receive care from a

colleague who is able to provide treatment, from a substance

use disorder treatment specialist (e.g., an office-based

buprenorphine or naltrexone treatment clinician), or from an

opioid treatment program certified by SAMHSA to provide

methadone or buprenorphine for patients with opioid use

disorder. Resources to help clinicians arrange for treatment

include SAMHSA’s buprenorphine physician locator (https://

www.samhsa.gov/medication-assisted-treatment/find-

treatment/treatment-practitioner-locator) and SAMHSA’s

Opioid Treatment Program Directory (https://dpt2.samhsa.

gov/treatment/directory.aspx). Clinicians should assist

patients in finding qualified treatment specialists, should

arrange for patients to follow up with these specialists, and

should coordinate continuing care with these specialists.

Rapidly identifying appropriate care can be challenging.

Treatment need in a community is often not met by capacity

to provide buprenorphine or methadone therapy (351).

Clinicians prescribing opioids in communities without

sufficient treatment capacity for opioid use disorder should

obtain a waiver to prescribe buprenorphine. SAMHSA’s

Providers Clinical Support System (https://pcssnow.org/) offers

training, technical assistance, and mentors to assist clinicians

in assessment for and treatment of substance use disorders,

specifically opioid use disorder, and on the interface of pain and

opioid misuse. Clinicians prescribing opioids should identify

treatment resources for substance use disorders including

opioid use disorders in the community, establish a network of

referral options that span the levels of care that patients might

need to enable rapid collaboration and referral, when needed,

and work together to ensure sufficient treatment capacity at

the practice level.

Management of Opioid Misuse That Does Not

Meet Criteria for Opioid Use Disorder

Clinicians can have challenges distinguishing between

opioid misuse behaviors without opioid use disorder and

mild or moderate opioid use disorder (352). For patients

with opioid misuse that does not meet criteria for opioid

use disorder (e.g., taking opioids in larger amounts than

intended without meeting other criteria for opioid use

disorder), clinicians should reassess the patient’s pain, ensure

that therapies for pain management have been optimized

(see Recommendation 2), discuss with patients, and carefully

weigh benefits and risks of continuing opioids at the current

dosage (see Recommendation 5). For patients who choose

to but are unable to taper, clinicians can reassess for opioid

use disorder and offer buprenorphine treatment or refer for

buprenorphine or methadone treatment if criteria for opioid

use disorder are met. Even without a diagnosis of opioid

use disorder, transitioning to buprenorphine for pain also

can be considered because of reduced risk for overdose with

buprenorphine compared with risk associated with full agonist

opioids (see Recommendation 5).

Pain Management for Patients with Opioid Use

Disorder

Although identification of an opioid use disorder can alter

the expected benefits and risks of opioid therapy for pain,

patients with co-occurring pain and substance use disorder

require ongoing pain management that maximizes benefits

relative to risks. Clinicians should use nonpharmacologic

and nonopioid pharmacologic pain treatments as appropriate

(96) (see Recommendations 1 and 2) to provide optimal

pain management. For patients with pain who have an active

opioid use disorder but are not in treatment, clinicians should

consider buprenorphine or methadone treatment for opioid

use disorder, which also can help with concurrent management

of pain (96). For patients who are treated with buprenorphine

for opioid use disorder and experience acute pain, clinicians

can consider temporarily increasing the buprenorphine

dosing frequency (e.g., to twice per day) (96) to help manage

pain because the duration of effects of buprenorphine is

shorter for pain than for suppression of withdrawal (242).

For severe acute pain (e.g., from trauma or unplanned major

surgery) in patients receiving buprenorphine for opioid use

disorder, clinicians can consider additional as-needed doses

of buprenorphine. In supervised settings, adding a short-

acting full agonist opioid to the patient’s regular dosage of

buprenorphine can be considered without discontinuing the

patient’s regular buprenorphine dosage; however, if a decision

is made to discontinue buprenorphine to allow for more

µ-opioid receptor availability, patients should be monitored

closely because high doses of a full agonist opioid might be

required, potentially leading to oversedation and respiratory

depression as buprenorphine’s partial agonist effect lessens

(96). For patients receiving naltrexone for opioid use disorder,

short-term use of higher-potency nonopioid analgesics (e.g.,

NSAIDs) can be considered to manage severe acute pain (96).

Patients receiving methadone for opioid use disorder who

require additional opioids as treatment for severe acute pain

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management should be monitored carefully, and when feasible,

should optimally be treated by a clinician experienced in the

treatment of pain in consultation with their opioid treatment

program (96). The ASAM National Practice Guideline for the

Treatment of Opioid Use Disorder (2020 Focused Update)

provides additional recommendations (see Part 9) (96) for

the management of patients receiving medications for opioid

use disorder who have planned surgeries for which nonopioid

therapies are not anticipated to provide sufficient pain relief.

Conclusion and Future Directions

CDC indicated the intent to evaluate and reassess the 2016

CDC Opioid Prescribing Guideline as new evidence became

available and determine when sufficient new evidence would

prompt an update (56). CDC funded AHRQ to conduct

systematic reviews of the scientific evidence. The following

five areas were assessed: 1) noninvasive nonpharmacologic

treatments for chronic pain, 2) nonopioid pharmacologic

treatments for chronic pain, 3) opioid treatments for chronic

pain, 4) treatments for acute pain, and 5) acute treatments

for episodic migraine (7–11). An update to the 2016 CDC

Opioid Prescribing Guideline was warranted on the basis of

these reviews.

The new evidence reviews conducted by AHRQ’s Evidence-

based Practice Centers affirmed the appropriateness of the

recommendations in the 2016 CDC Opioid Prescribing

Guideline for using opioids to treat chronic pain. The

reviews also prompted CDC to modify the recommendations

to include acute and subacute pain more explicitly. This

updated clinical practice guideline also includes a new topline

recommendation for patients who are already receiving

ongoing opioid therapy for pain. Specifically, the clinical

practice guideline outlines how clinicians and patients should

work together in assessing the benefits and risks of continued

opioid use and if or when to taper opioids to a lower dosage

or discontinue opioids altogether in accordance with the HHS

Tapering Guide (219,353).

Four key areas are covered in this clinical practice guideline

for prescribing of opioid pain medication for patients aged

≥18 years for pain, excluding pain management related to sickle

cell disease, cancer-related pain treatment, palliative care, and

end-of-life care. These areas are 1) determining whether or not

to initiate opioids for pain; 2) selecting opioids and determining

opioid dosages; 3) deciding duration of initial opioid prescription

and conducting follow-up; and 4) assessing risk and addressing

potential harms of opioid use. In addition, five guiding

principles were identified to inform implementation across

recommendations. These guiding principles focus on 1) the

appropriate treatment of pain; 2) flexibility to meet the care

needs and clinical circumstances of each patient; 3) a multimodal

and multidisciplinary approach to pain management; 4) avoiding

misapplication of the clinical practice guideline beyond its

intended use; and 5) vigilance in attending to health inequities

and ensuring access to appropriate, affordable, diversified,

coordinated, and effective nonpharmacologic and pharmacologic

pain treatment for all persons.

A central tenet of this clinical practice guideline is that acute,

subacute, and chronic pain needs to be appropriately and

effectively treated regardless of whether opioids are part of a

treatment regimen. Clinicians should select nonpharmacologic

or pharmacologic treatment modalities, or both, that maximize

patient safety and optimize outcomes in pain, function, and

quality of life. A multimodal and multidisciplinary approach

to pain management that considers the biologic, psychological,

and social characteristics of each person is critical (6). The

care provided needs to be individualized and person centered

(6). Clinicians and patients should work together to identify

treatment goals, including functional goals, and tailor an

approach that considers both the benefits and risks of available

options (6). Progress should be monitored over time and

treatment protocols adjusted accordingly. Health systems and

payers can work to ensure multimodal treatment options are

available, accessible, and reimbursed for patients. Public and

private payers can support a broader array of nonpharmacologic

interventions such as exercise, multidisciplinary rehabilitation,

mind-body interventions, cognitive behavioral therapy, and

certain complementary and integrative medicine therapies

(e.g., acupuncture and spinal manipulation) that increasingly

are known to be effective (9). Reimbursement often is cited as

a principle barrier to why these nonpharmacologic treatments

are not more widely used (9).

An integral part of providing access to and delivery of high-

quality health care, including pain treatment, is understanding

how the social determinants of health influence the health

care provided and the differential outcomes observed (354).

Social, economic, educational, and neighborhood-level

factors might create and exacerbate health inequities that

certain persons experience throughout their lives (354). These

social determinants of health are borne out of historical and

contemporary injustices that advantage some and disadvantage

others in society, leading to the systemic marginalization or

oppression of some groups (355). These inequities affect

persons from some racial and ethnic groups, women, persons

living in rural areas, persons experiencing homelessness,

persons with disabilities, persons with substance use disorders,

justice-involved populations, persons with diverse sexual

orientation, identity, or gender, and non-U.S. born persons,

among others (356).

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Outcomes such as function and quality of life also are

influenced by the health care context (354). Differential access

to and coverage for high-quality, culturally and linguistically

appropriate, health-literate care might influence attitudes

toward health care and use of available services (354). Prejudice,

bias, discrimination, and stereotyping by clinicians, practices,

health systems, and payers serve to reinforce these health

disparities (355). Clinicians, practices, health systems, and

payers should attend to health inequities to protect patient

safety; guard against unnecessary risks; and ensure access

to appropriate, diversified, effective nonpharmacologic and

pharmacologic pain management options that are person

centered, affordable, accessible, and well coordinated.

This begins with raising awareness and acknowledging the

presence of these inequities, strengthening patient-clinician

communication, leveraging community health workers,

implementing multidisciplinary care teams, tracking and

monitoring performance measures, and integrating quality

improvement initiatives that support and invest in guideline-

concordant care for all persons (355).

To avoid unintended consequences for patients, this clinical

practice guideline should not be misapplied, or policies

derived from it, beyond its intended use (67). Examples of

misapplication or inappropriate policies include being inflexible

on opioid dosage and duration, discontinuing or dismissing

patients from a practice, rapidly and noncollaboratively

tapering patients who might be stable on a higher dosage,

and applying recommendations to populations that are not

a focus of the clinical practice guideline (e.g., patients with

cancer-related pain, patients with sickle cell disease, or patients

during end-of-life care) (67).

This clinical practice guideline provides overarching

voluntary recommendations on the use of opioids to manage

pain. To assist in the uptake and understanding of this new

clinical practice guideline, CDC will provide tools and

resources for clinicians, health systems, patients, and others on

the use of opioid and nonopioid pain treatments. The uptake

and widespread use of the 2016 CDC Opioid Prescribing

Guideline hinged on its successful dissemination, and CDC

supported its translation and integration in clinical practice.

CDC produced a checklist and mobile app so clinicians could

more readily apply guideline recommendations; developed fact

sheets, posters, and public service announcements to make

the guideline more accessible and understandable to clinicians

and patients; and developed a 14-module interactive, web-

based training with self-paced learning, case-based content,

knowledge checks, and integrated resources for clinicians (57).

Updated and new resources and tools will align with this new

clinical practice guideline and will support health equity.

CDC will work with public and private payers by sharing

evidence that can be used to inform decisions about coverage

for nonpharmacologic treatments, access to nonopioid pain

medication, support for patient counseling and coordination

of care, access to evidence-based treatments of opioid use

disorder, and availability of multidisciplinary and multimodal

care. Robust coverage and access (e.g., limited utilization

management and cost sharing for evidence-based treatments)

and decision support (e.g., adjustment of EHR prescribing

defaults) can be used to facilitate and encourage evidence-based

treatments as default treatments for pain (357,358).

This clinical practice guideline updates and expands the

recommendations in the 2016 CDC Opioid Prescribing

Guideline using the best available evidence as interpreted and

informed by expert opinion and attending to the values and

preferences expressed by patients, caregivers, and clinicians.

Although the strength of the evidence is sometimes low quality

and research gaps remain (Box 5), clinical scientific evidence

continues to advance and supports the recommendations in

this clinical practice guideline (6–11,359).

The principal aim of this clinical practice guideline is to

ensure persons have equitable access to safe and effective pain

management that improves their function and quality of life

while illuminating and reducing risks associated with prescription

opioids. CDC will evaluate this clinical practice guideline to

identify the effects of the recommendations on clinician and

patient outcomes and on health disparities, including intended

and unintended consequences. Communication between

clinicians and patients about the benefits and risks of opioids

should be central to treatment decisions for patients in pain.

This clinical practice guideline can help inform those decisions

and assist clinicians in meeting the unique needs of each person.

CDC will revisit this clinical practice guideline when remaining

evidence gaps have sufficiently been addressed and another

update is warranted.

Acknowledgments

The Board of Scientific Counselors of the National Center for

Injury Prevention and Control; the Board of Scientific Counselors

of the National Center for Injury Prevention and Control Opioid

Workgroup; peer reviewers; members of the public who provided

comments during meetings; members of the public who provided

comments through Federal Register opportunities; patients,

caregivers, and clinicians who participated in telephone or video

conversations; and participants of the codesign workshops.

Guidehouse: Marissa R. Kessler; Cara M. Klansek, MPH; Laura Riley,

MPH; Bintu Fofana, MPH; Truc Pham, MPH; Chamnan Po, MS;

Shelby Scott, PhD; Gillian Shulman, MPH; and Rachel Travis, MBA.

The Lab at the U.S. Office of Personnel Management: Benjamin P.

Winter, Sarah E. Hughes, Jennifer Gardner, and Katherine Fisher;

federal partners; CDC Office of the Director: Rochelle P. Walensky,

MMWR / November 4, 2022 / Vol. 71 / No. 3 61

US Department of Health and Human Services/Centers for Disease Control and Prevention

BOX 5. Areas for additional research to build the evidence base for

optimal pain management

• Efficacy of screening tools to assess risk for opioid

misuse and developing an opioid use disorder.

• Effective management of patients on high-dosage

opioids, the application of multidisciplinary and

multimodal models of pain treatment, and service

delivery modalities including telehealth.

• Long-term comparative effectiveness of pharmaco-

logic and nonpharmacologic therapies for chronic

pain, including effects of treatment combinations,

dosage variation, and comorbidities.

• Comparative effectiveness and comparative risks of

partial agonist opioids (e.g., buprenorphine) versus

full agonist opioids for pain.

• Comparative effectiveness and risks of interventional

procedures as part of a comprehensive pain manage-

ment plan.

• Effects of therapies on nonpain outcomes.

• Treatment outcomes for specific pain conditions

and how benefits and risks of therapies vary among

subpopulations.

• Adapting evidence-based opioid prescribing and

pain management strategies to meet the needs of

special populations, including persons from some

racial and ethnic groups, older adults, and persons

living in rural communities.

• Effectiveness of clinician and health system strate-

gies to promote equitable access to high-quality pain

management.

• Improved diagnostics in measuring pain.

• Enhanced clinician and patient education about

pain and the use of opioids, and the assessment of

practice-level strategies in health systems to improve

management and care coordination for patients on

opioid therapy.

• Transition from acute to chronic pain and how to

apply effective diagnostic, preventive, and therapeutic

approaches.

• Effects of stigma as a barrier for treating pain and

receiving treatment for an opioid use disorder, and

effective ways to counter the effects of stigma on

access to treatment for pain and opioid use disorder.

MD; Anne Schuchat, MD (Retired); Debra Houry, MD; and

Celeste Philip, MD. CDC National Center for Injury Prevention

and Control: Amy B. Peeples, MPA; Arlene I. Greenspan, DrPH;

Gwendolyn H. Cattledge, PhD (Retired); Elizabeth J. Solhtalab,

MPA; Kelly Holton; S. Kinzie Lee, MPH; Erica Reott, MPH;

C. Leah Chan, MPH; Valerie Godoshian, MPH; Tonia Lindley;

Victor Cabada, MPH; Board of Scientific Counselors of the National

Center for Injury Prevention and Control support staff; Jan L.

Losby, PhD, Division of Overdose Prevention; Melanie R. Ross,

MPH, Division of Overdose Prevention; Christine R. Curtis, MD,

Division of Overdose Prevention; Christina A. Mikosz, MD, Division

of Overdose Prevention; Amy Holmes-Chavez, MPH, Division of

Overdose Prevention; Michelle Putnam, MPH, Division of Overdose

Prevention; Parul Parikh, JD, Division of Overdose Prevention;

JinYoung Kim, MPH, Division of Overdose Prevention, LeShaundra

Cordier, MPH, Division of Overdose Prevention; Helen Kingery,

MPH, Division of Overdose Prevention; Loretta Jackson Brown,

PhD, Division of Overdose Prevention; Robin A. Rinker, MPH,

Division of Overdose Prevention; Takeydra Jones, MPH, Division

of Overdose Prevention; Kristin M. Holland, PhD, Division of

Overdose Prevention; Erin M. Parker, PhD, Division of Overdose

Prevention; Lara DePadilla, PhD, Division of Overdose Prevention;

Elizabeth Hazelwood, MPH, Division of Overdose Prevention; and

Terry W. Davis, EdD, Division of Overdose Prevention.

Conflicts of Interest and Disclosures of Relationship

All authors have completed and submitted the International

Committee of Medical Journal Editors form for disclosure of potential

conflicts of interest; no significant conflicts of interest were disclosed.

The National Center for Injury Prevention and Control (NCIPC)

Associate Director for Science reviewed peer reviewers’ conflict of

interest disclosure forms and determined no conflicts of interest

were present.

The Opioid Workgroup’s (OWG’s) Designated Federal

Officer (DFO); the Board of Scientific Counselors of NCIPC’s

(BSC/NCIPC’s) DFO; and CDC’s Strategic Business Initiatives

Unit (SBIU), which oversees the Federal Advisory Committee Act

program, reviewed OWG members’ conflict of interest disclosure

forms and determined all reported potential financial or other

conflicts of interest were not present or nonsignificant.

OWG members disclosed the following activities related to the

content of this clinical practice guideline: Anne L. Burns disclosed

that she is employed by the American Pharmacists Association, a

nonprofit 501c6 organization, where she is involved in advancing

pharmacists’ patient care services, including pain management

services, and she serves on the board of directors for the Pharmacy

Quality Alliance, a nonprofit organization that develops quality

measures, including opioid-related measures. Beth Darnall disclosed

that she consulted with AppliedVR, a virtual reality for chronic and

acute pain company. Neeraj Gandotra disclosed that he provided

expert testimony before the Senate Judiciary Committee on

December 17, 2019, on behalf of the Substance Abuse and Mental

Health Services Administration (SAMHSA) regarding the opioid

epidemic. Christine Goertz disclosed that she served as a consultant

to the American Chiropractic Association until September 30,

2019, and that she has received National Institutes of Health (NIH)

foundation funding to conduct research on nonpharmacologic

approaches to pain management. Jennifer Waljee disclosed that she

62 MMWR / November 4, 2022 / Vol. 71 / No. 3

US Department of Health and Human Services/Centers for Disease Control and Prevention

received research support funding from CDC, NIH, the Michigan

Department of Health and Human Services, and SAMHSA for

research examining the effect of opioid use before and after surgery

on postoperative outcomes.

SBIU reviewed BSC/NCIPC members’ Office of Government

Ethics Form 450 and determined all reported potential financial or

other conflicts of interest were not present or nonsignificant. Three

BSC/NCIPC members (Chinazo O. Cunningham, Frank Floyd,

and Elizabeth Habermann) served on OWG. Roger Chou is a BSC/

NCIPC member and coauthor of the clinical practice guideline and

AHRQ-sponsored systematic clinical evidence reviews. Dr. Chou

disclosed that he receives funding to conduct reviews on opioids and

recused himself from the July 16, 2021, BSC/NCIPC meeting and

discussion of the OWG report on the draft clinical practice guideline.

Wilson Compton disclosed that he has long-term stock holdings in

General Electric, Pfizer, and 3M Companies.

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Recommendations and Reports

Opioid Workgroup

Chair:

Chinazo O. Cunningham, MD.

Workgroup Members: Anne L. Burns; Beth Darnall, PhD; Frank Floyd, MD; Christine Goertz, DC, PhD; Elizabeth Habermann, PhD; Joseph Hsu, MD;

Marjorie Meyer, MD; Paul Moore, DMD, PhD; Aimee Moulin, MD; Kate Nicholson, JD; Tae Woo Park, MD; Jeanmarie Perrone, MD; Travis Rieder, PhD;

Roberto Salinas, MD; Doreleena Sammons-Hackett, SM; Wally R. Smith, MD; Jennifer Waljee, MD; Mark Wallace, MD.

Ex Officio Members: Wilson Compton, MD; Neeraj Gandotra, MD; Mallika Mundkur, MD; Stephen Rudd, MD.

Designated Federal Officer: Melanie R. Ross, MPH.

Peer Reviewers

Anika Alvanzo, MD, Pyramid Healthcare, Inc.; Michael Englesbe, MD, University of Michigan; Joseph Frank, MD, University of Colorado Hospital; Ajay D.

Wasan, MD, University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine.

Board of Scientific Counselors of the National Center for Injury Prevention and Control

Co-Chairs: Amy Bonomi, PhD (04/20/2021–08/31/2024); Chinazo O. Cunningham, MD (04/20/2021–12/01/2021); Victoria Frye, DrPH (07/17/2019–

02/28/2021); Daniel J. Whitaker, PhD (11/04/2019–02/28/2021).

Members: Donna H. Barnes, PhD (09/01/2018–02/28/2021); Amy Bonomi, PhD (04/20/2021–08/31/2024); Roger Chou, MD (09/01/2019–08/31/2023);

Phillip Coffin, MD (01/03/2017–02/28/2021); Kermit A. Crawford, PhD (01/31/2017–02/28/2021); Chinazo O. Cunningham, MD (09/01/2018–

12/01/2021); Wendy Ellis, DrPH (04/22/2021–08/31/2024); Frank Floyd, MD (09/01/2019–08/31/2022); Frank A. Franklin II, PhD, JD (09/01/2018–

08/31/2022); Victoria Frye, DrPH (01/27/2017–2/28/2021); Kevin M. Guskiewicz, PhD (09/01/2018–01/14/2020); Elizabeth Habermann, PhD

(09/01/2019–08/31/2023); James H. Hedlund, PhD (01/30/2017–02/28/2021); Todd Herrenkohl, PhD (09/01/2018–02/28/2021); Mark S. Kaplan, DrPH

(09/01/2018–08/31/2022); Karen D. Liller, PhD (09/01/2018–08/31/2022); Angela Lumber-Brown, MD (04/22/2021–08/31/2022); Jeffrey P. Michael, EdD

(04/20/2021–08/31/2023); Elizabeth Miller, MD, PhD (04/20/2021–08/31/2024); Steven J. Ondersma, PhD (04/21/2021–08/31/2024); Rosalie Liccardo

Pacula, PhD (04/20/2021–08/31/2023); Christina A. Porucznik, PhD (09/01/2019–08/31/2023); John Armand Rich, MD (04/22/2021–08/31/2024);

David C. Schwebel, PhD (02/03/2017–02/28/2021); Lyle Ungar, PhD (04/22/2021–08/31/2024); Daniel J. Whitaker, PhD (01/31/2017–02/28/2021).

Ex Officio Members: Melissa L. Brodowski, PhD; Dawn Castillo, MPH; Mindy J. D. Chai, PhD; Wilson Compton, MD; Jennifer Fan, PhD; Meredith A.

Fox, PhD; Holly Hedegaard, MD; John Howard, MD; Lyndon J. O. Joseph, PhD; Valerie Maholmes, PhD; Bethany D. Miller, MEd; Constantinos Miskis, JD;

Judy A. Staffa, PhD; Kelly M. Taylor, MS.

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Appendix: Primary Clinical

Questions, Detailed Methods, and

Findings for the Systematic and

Contextual Evidence Reviews

Primary Clinical Questions

Across reviews, the main outcomes were pain, function,

and quality of life. Harms varied depending on the therapy

evaluated but included serious adverse events when reported;

for opioids, key harms included overdose and harms related to

opioid use disorder. The reviews of therapies for chronic pain

assessed outcomes at short- (1 to <6 months), intermediate-

(6 to <12 months), and long-term follow-up (≥12 months).

The reviews of therapies for acute pain assessed outcomes at

<1 day, 1 day to <1 week, 1 week to <2 weeks, and 2–4 weeks;

the review of treatments for acute nonmigraine pain also

evaluated outcomes at ≥4 weeks. All reviews included key

questions (KQs) or subquestions on how benefits and harms

varied according to demographic (age, sex, race), clinical

(severity and duration of pain, medical and psychiatric

comorbidities, concomitant medications), and intervention

(dose, duration, intensity) characteristics.

The systematic clinical evidence reviews addressed questions

regarding the effectiveness and comparative effectiveness

of noninvasive nonpharmacologic treatments; nonopioid

pharmacologic treatments; and opioid treatments for chronic

pain, acute pain, and episodic migraine pain (details including

questions are available in the full AHRQ reports) (1–5).

Opioids for Chronic Pain

• The effectiveness and comparative effectiveness (benefits

[KQ 1] and harms [KQ 2]) of long-term opioid therapy

versus placebo, no opioid therapy, or nonopioid therapy.

• The comparative effectiveness of various opioid dosing

strategies (KQ3):



Different methods for initiating and titrating opioids



Short-acting versus long-acting and extended-release

opioids



Different long-acting opioids



Short- acting plus long-acting versus long-acting opioid

alone



Scheduled, continuous versus as-needed dosing



Opioid dose escalation versus dose maintenance or use

of dose thresholds



Opioid rotation versus maintenance



Different strategies for treating acute exacerbations of

chronic pain



Decreasing opioid doses or tapering off opioids versus

continuation of opioids



Different tapering protocols and strategies



Different opioid dosages and durations of therapy

• The accuracy of instruments for predicting risk for opioid

overdose, addiction, abuse, or misuse; the effectiveness of

risk prediction instruments; the effectiveness of various

risk mitigation strategies; and comparative effectiveness

of strategies for managing patients with opioid use disorder

(KQ 4). The following are risk mitigation strategies:



Opioid management plans



Patient education



Urine drug screening



Use of prescription drug monitoring program (PDMP)

data



Use of monitoring instruments in patients prescribed

opioids



More frequent monitoring intervals



Pill counts



Use of abuse-deterrent formulations



Consultation with mental health specialists when mental

health conditions are present or suspected



Avoidance of coprescribing of sedative hypnotics



Coprescribing of naloxone

Noninvasive Nonpharmacologic

Treatments for Chronic Pain

• The effectiveness and comparative effectiveness (benefits and

harms) of noninvasive nonpharmacologic treatments (exercise,

mind-body practices, psychological interventions,

multidisciplinary rehabilitation, mindfulness practices,

musculoskeletal manipulation, physical modalities, and

acupuncture) versus inactive treatments, usual care, no

treatment, pharmacologic therapy, or selected active treatments

(exercise [chronic pain conditions other than headache] or

biofeedback [headache]), for the following conditions:



Chronic low back pain (KQ 1)



Chronic neck pain (KQ 2)



Osteoarthritis (knee, hip, hand) (KQ 3)



Fibromyalgia (KQ 4)



Chronic tension headache (KQ 5)

Nonopioid Pharmacologic Treatments

for Chronic Pain

• Effectiveness and comparative effectiveness (benefits

[KQ 1] and harms [KQ 2]) of nonopioid pharmacologic

agents (nonsteroidal anti-inflammatory drugs [NSAIDs],

antidepressants, anticonvulsants, acetaminophen, muscle

relaxants, memantine, topical agents, and cannabis) versus

placebo or other nonopioid pharmacologic agents.

78 MMWR / November 4, 2022 / Vol. 71 / No. 3

US Department of Health and Human Services/Centers for Disease Control and Prevention

Treatments for Acute Pain

• Effectiveness and comparative effectiveness (benefits and

harms) of opioid therapy versus nonopioid pharmacologic

therapy (acetaminophen, NSAIDs, skeletal muscle relaxants,

benzodiazepines, antidepressants, anticonvulsants, and

cannabis) or nonpharmacologic therapy (exercise, cognitive

behavioral therapy, meditation, relaxation, music therapy,

virtual reality, acupuncture, massage, manipulation or

mobilization, and physical modalities); nonopioid

pharmacologic therapy versus other nonopioid

pharmacologic treatments or nonpharmacologic therapy;

and nonpharmacologic therapy versus inactive treatments

or usual care, for the following conditions:



Acute back pain (including back pain with radiculopathy)

(KQ 1)



Acute neck pain (including neck pain with radiculopathy)

(KQ 2)



Musculoskeletal pain not otherwise included in KQ 1

or KQ 2 (including fractures) (KQ 3)



Peripheral neuropathic pain (related to herpes zoster and

trigeminal neuralgia) (KQ 4)



Postoperative pain (excluding inpatient management of

pain following major surgical procedures (KQ 5)



Dental pain (KQ 6)



Kidney stones (including inpatient management) (KQ 7)



Sickle cell crisis (episodic pain) (KQ 8)

Treatments for Acute Episodic Migraine

• Effectiveness and comparative effectiveness (benefits and

harms) of the following:



Opioid therapy versus nonopioid pharmacologic therapy

(acetaminophen, NSAIDs, triptans, ergot alkaloids,

combination analgesics, muscle relaxants, antinausea

medications, cannabis, or others [e.g., gepants]) or

nonpharmacologic therapy (exercise, cognitive behavioral

therapy, acupuncture, or others) (KQ 1)



Nonopioid pharmacologic therapy versus a different

nonopioid pharmacologic therapy or nonpharmacologic

therapy (KQ 2)



Nonpharmacologic therapy versus inactive treatments,

usual care, or no treatment (KQ 3)

Search Protocols

Complete methods and data, including detailed search

protocols and inclusion and exclusion criteria, for the five

AHRQ reports summarized here have been published

(1–5). Study authors developed the search protocols using a

standardized process with input from experts and the public.

The review protocols were submitted for registration in the

PROSPERO database before conducting the reviews. For each

review, research librarians conducted searches on multiple

electronic databases. For all reviews, searches were conducted

on MEDLINE, Cochrane CENTRAL, and the Cochrane

Database of Systematic Reviews; other databases that were used

for one or more reviews (depending on the topic) were Embase

PsycINFO, CINAHL, Scopus, and others. The searches

were supplemented by a review of reference lists (including

previous AHRQ and CDC reviews on these topics) (6–8) and

gray literature sources. Searches were conducted in August or

September 2019 for the chronic pain reviews and in July or

August 2020 for the acute pain reviews.

Summarizing the Evidence

The reviews categorized magnitude of effects for pain and

function using the same system as previous AHRQ reviews

(6,9). A small effect was defined for pain as a mean between-

group difference after treatment of 0.5–1.0 points on a 0- to

10-point numeric rating scale (NRS) or visual analog scale

(VAS) and for function as a standardized mean difference

(SMD) of 0.2–0.5 or a mean difference of 5–10 points on

the 0- to 100-point Oswestry Disability Index (ODI) (10),

1–2 points on the 0- to 24-point Roland-Morris Disability

Questionnaire (RDQ) (11), or equivalent. A moderate effect

was defined for pain as a mean difference of 10–20 points on

a 0- to 100-point VAS (1–2 points on a 0- to 10-point NRS)

and for function as an SMD of 0.5–0.8, or a mean difference

of 10–20 points on the ODI, 2–5 points on the RDQ, or

equivalent (6,9). Large or substantial effects were defined as

greater than moderate. Similar thresholds were applied to other

outcomes measured. Small effects using this system might not

meet proposed thresholds for clinically meaningful effects (12).

However, estimated minimum clinically important differences

vary across studies, and the clinical relevance of effects

classified as small might vary for specific patients depending

on preferences, baseline symptom severity, harms, cost, and

other factors (13,14). The reviews also evaluated results on the

basis of dichotomous outcomes (e.g., likelihood of experiencing

clinically meaningful improvement in pain or function, often

defined as >30% or >50% improvement from baseline).

Summary of Findings for

Clinical Questions

Opioids for Chronic Pain

The AHRQ systematic clinical evidence review on opioids

for chronic pain (1) updated the 2014 AHRQ report (7)

and 2016 CDC update (8) and expanded on the previous

reviews by adding evidence from randomized trials reporting

short-term outcomes, including tramadol as an opioid

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intervention, addressing risks of coprescribing benzodiazepines

or gabapentin, and addressing effects of co-use of cannabis.

Effectiveness (Benefits and Harms)

For short-term (1 to <6 month) outcomes, based on over

70 placebo-controlled trials (evidence type 1), opioids were

associated with beneficial effects versus placebo but mean

differences were small: for pain, <1 point on a 0–10 scale and

for function, a SMD of 0.22 or <1 point on the 0- to 10-point

Brief Pain Inventory (15) interference scale and <1 point on

the 0- to 24-point RDQ. Opioids were associated with a

number of patients needed to treat (NNT) of approximately

6.7 to achieve one additional case of short-term pain relief

(e.g., ≥30% improvement in pain). Analyses based on a

combination of head-to-head (within study) comparisons

as well as a meta-regression of placebo-controlled trials

indicated an association between higher opioid dosage and

greater short-term effects on pain that appeared to plateau

at approximately 50 mg morphine equivalent dose (MME)/

day (evidence type 2). Evidence also indicated that effects of

opioids dissipate with longer duration of therapy. Opioids

were associated with a small mean improvement in short-term

sleep quality (evidence type 2) versus placebo and a small mean

short-term improvement in Short-Form 36-item (SF-36) (16)

mental health status (evidence type 1). Effects of opioids on

short-term outcomes were generally consistent across opioid

types (opioid agonist, partial agonist, or mixed medication

agent). Effects on pain were somewhat greater for neuropathic

than musculoskeletal pain (effects on pain approximately

0.5 point greater for neuropathic versus musculoskeletal pain

on a 0–10 scale). Use of a crossover or enriched enrollment

randomized withdrawal (EERW) design (a type of trial in

which potential participants receive the study drug for a period

in a prerandomization phase and only those who benefit from

the drug and can tolerate the side effects continue in the trial,

randomly assigned to continue on the study drug or placebo)

(17) was associated with greater effects on pain than parallel

group or non-EERW studies.

Opioids were associated with increased risk versus placebo

for discontinuation because of adverse events (number of

patients treated to cause one adverse event [number needed

to harm, NNH 10], and increased risk for gastrointestinal

events [NNH 7.1 for nausea, 14.3 for vomiting, and 7.1

for constipation], somnolence [NNH 11.1], dizziness

[NNH 12.5], and pruritus [NNH 14.3]) (evidence type 1).

Few serious adverse events and no difference between opioids

versus placebo in risk were reported in the short-term trials

(evidence type 2); however, serious adverse events were not

well defined by the trials, the trials excluded patients at higher

risk (e.g., those with a history of substance use disorder),

and the trials were not designed to assess serious but less

common harms such as overdose, opioid use disorder death,

cardiovascular events, and fractures. EERW studies tended

to report lower risk with opioids of discontinuation because

of adverse events and gastrointestinal adverse events than

non-EERW studies. Uncontrolled studies (studies without a

nonopioid control group) were not included in the AHRQ

review, although a recent systematic review with such studies

found that rates of misuse ranged from 21% to 29% (95% CI:

13%–38%) and rates of addiction ranged from 8% to 12%

(95% CI: 3%–17%), based on higher-quality observational

evidence (18).

As in the 2014 AHRQ report and 2016 CDC update, the

clinical evidence review identified no long-term (>1 year)

randomized controlled trials (RCTs) of opioid therapy versus

placebo. One new cohort study found long-term opioid

therapy was not associated with improved pain, function, or

other outcomes versus no opioids (19). New observational

studies included in the new AHRQ review were consistent

with the 2014 AHRQ report in finding an association between

use of prescription opioids and risk for addiction, overdose,

fractures, falls, and cardiovascular events (evidence type 3);

a new study also found an association between opioid use

and risk of all-cause deaths (20) (evidence type 4). New

observational studies also were consistent with the 2014

AHRQ report in finding associations between higher dosages of

opioids and risks for overdose, addiction, and endocrinological

adverse events; new studies also found an association between

higher dosage and increased risk for incident or refractory

depression (21,22). Observational studies also indicated an

association between coprescription of gabapentinoids (23–25)

or benzodiazepines (26–28) and increased risk for overdose,

with most pronounced risk occurring soon after initiation of

these medications (evidence type 3). All observational studies

were susceptible to residual confounding.

No differences were found across 16 trials between opioids

versus nonopioids (most commonly NSAIDs, gabapentinoids,

and nortriptyline) in short-term pain, function, health status or

quality of life, sleep quality, or mental health outcomes (evidence

type 1 for function; evidence type 2 for other outcomes),

although opioids were associated with increased risk for short-

term adverse effects (evidence type 1 or 2). Most trials were

<6 months; one trial of patients with chronic low back pain or

pain associated with osteoarthritis (mean pain intensity: 5.4 on

a 0–10 scale at baseline) evaluated outcomes at 1 year (29). The

trial found no differences between stepped therapy with opioids

versus stepped therapy starting with nonopioids in function,

sleep, or mental health outcomes; opioids were associated

with slightly worse effects (by approximately 0.5 point on a

0–10 scale) on pain (evidence type 2). Although tramadol was

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an option in step 3 of the nonopioid stepped therapy arm, only

11% received tramadol; mean opioid doses for stepped opioid

therapy and stepped therapy starting with nonopioids were 26

versus 1 MME/day, respectively, at 12 months.

Also, there were no differences between combination therapy

versus a nonopioid alone in short-term effectiveness but

increased risk for short-term adverse effects for combination

therapy, on the basis of six trials (evidence type 3). Combination

therapy was associated with a small (5–13 MME/day) opioid-

sparing effect versus opioid therapy alone, with little effect on

pain. All trials of combination therapy evaluated patients with

neuropathic pain and primarily evaluated gabapentinoids or

nortriptyline. Evidence on long-term effects of combination

therapy versus an opioid or nonopioid alone was lacking.

Opioid Dosing Strategies

Evidence on the effectiveness of different opioid dosing

strategies remains limited. One trial included in the 2014

AHRQ report found no differences between a more liberal

dosage escalation strategy versus maintenance of current

dosages in pain, function, or discontinuation because of opioid

misuse; however, the difference in opioid dosages between arms

was small (52 versus 40 mg MMD/day) (30) (evidence type 3).

No clear differences were found between short- versus long-

acting opioids (evidence type 3) or between different long-

acting opioids (evidence type 2) in pain or function; however,

in most trials, dosages were titrated to achieve adequate pain

control. Evidence on comparative risks of methadone versus

other opioids and risk for overdose remains limited and

inconsistent. Evidence on the benefits and harms of different

methods for initiating and titrating opioids, scheduled and

continuous versus as-needed dosing of opioids, use of opioid

rotation, and methods for titrating or discontinuing opioids

remains insufficient. The 2014 AHRQ report found buccal or

intranasal fentanyl more effective than placebo or oral opioids

for treatment of exacerbations of chronic pain, based on

immediate effects (up to 2 hours after administration). None

of the trials of buccal or intranasal fentanyl was designed to

assess longer-term benefits or harms, and no new trials were

identified for the 2020 systematic review. In 2007, the Food

and Drug Administration released a public health advisory

due to case reports of deaths and other life-threatening adverse

effects in patients prescribed buccal fentanyl (31).

Risk Mitigation Strategies

New evidence on the accuracy of risk prediction instruments

was consistent with the 2014 AHRQ report, which found highly

inconsistent estimates of diagnostic accuracy, methodological

limitations, and few studies of risk assessment instruments

other than the Opioid Risk Tool (32) and Screening and

Opioid Assessment for Patients with Pain-Revised instrument

(33) (evidence type 3). Evidence on the effectiveness of risk

mitigation strategies also remains limited. One new observational

study found that provision of naloxone to patients prescribed

opioids in primary care clinics was associated with decreased

likelihood of opioid-related emergency department visits;

there were too few opioid poisoning deaths to assess effects on

overdose mortality (evidence type 3) (34). Evidence on opioid

tapering was largely limited to a trial that found a taper support

intervention associated with better functional outcomes and a

trend toward lower opioid doses versus usual opioid care (35)

(evidence type 2). A cohort study found discontinuation of

opioid therapy was associated with increased risk for overdose

death versus continuation; however, there was no statistically

significant difference in risk for all-cause deaths (36). Findings

should be interpreted with caution because of potential

confounding related to the reason for discontinuation.

No trial compared different rates of opioid tapering,

although one observational study found an association between

longer time to opioid discontinuation in patients on long-term,

high-dosage opioid therapy and decreased risk of opioid-

related emergency department visit or hospitalization (37)

(evidence type 3). The review did not identify any study that

evaluated the effectiveness of risk mitigation strategies, such as

use of risk assessment instruments, opioid management plans,

patient education, urine drug screening, PDMP data review,

monitoring instruments in patients prescribed opioids, more

frequent monitoring intervals, pill counts, abuse-deterrent

formulations, or avoidance of coprescribing of benzodiazepines

on risk for overdose, addiction, abuse or misuse.

Evidence on the effectiveness of interventions for opioid use

disorder in patients with prescription opioid dependence or

opioid use disorder was limited by such factors as small sample

sizes, high attrition or crossover, and exclusion of patients with

chronic pain.

Noninvasive Nonpharmacologic

Treatment for Chronic Pain

The AHRQ systematic clinical evidence review (2) focused

on commonly encountered pain conditions and frequently

used interventions. Selection of conditions for review was

informed by stakeholder input.

Benefits

Chronic Low Back Pain. The review found psychological

therapies associated with small improvements versus usual

care or an attention control for function and pain at short-,

intermediate-, and long-term follow-up (evidence type 2).

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Exercise, low-level laser therapy, spinal manipulation, massage,

yoga, acupuncture, and multidisciplinary rehabilitation were

associated with improvements in function at short- and

intermediate-term follow-up versus usual care, placebo,

waiting list, or inactive therapies; effects on pain were small

for all therapies except yoga, for which benefits were moderate

(evidence type 2 at short term for exercise, massage, and yoga;

evidence type 3 for others). Massage, mindfulness-based stress

reduction, acupuncture, and multidisciplinary rehabilitation

were associated with small short-term improvement in pain

versus control (evidence type 2); exercise, low-level laser therapy,

and yoga also were associated with small to moderate short-term

improvement in pain, although evidence was not as strong

(evidence type 3). At intermediate term, spinal manipulation,

yoga, multidisciplinary rehabilitation (evidence type 2) and

exercise and mindfulness-based stress reduction (evidence type 3)

were associated with improved pain versus sham, usual care, or

attention control; effects were small for all therapies except for

yoga, for which effects were moderate. Compared with exercise,

multidisciplinary rehabilitation was associated with small

improvements in function and pain at short and intermediate

terms (evidence type 2).

Chronic Neck Pain. The AHRQ systematic clinical evidence

review found low-level laser therapy (evidence type 2) and

massage (evidence type 3) associated with improved short-term

function and pain for chronic neck pain. The magnitude of

effect was moderate for low-level laser therapy and small for

massage. Exercise was associated with small improvement in

long-term function versus attention control (evidence type 3)

and combination exercise was associated with improved short-

and long-term function and short-term pain versus waiting

list or attention control (evidence type 3). Acupuncture was

associated with small improvements in short- and intermediate-

term function versus sham, placebo, or usual care; however,

there were no differences in pain versus sham acupuncture,

an intervention meant to mimic acupuncture but without

acupuncture effects (e.g., needles in nonacupuncture point,

or nonpenetrating needles or pressure on acupuncture points)

(evidence type 3). Pilates was associated with improved short-

term function (small effect) and pain (large effect) versus

acetaminophen (evidence type 3).

Osteoarthritis Pain. The AHRQ systematic clinical

evidence review found that for knee osteoarthritis, exercise was

associated with small improvements in short- and long-term

function and pain versus usual care, no treatment, or sham

(evidence type 2 for short-term and type 3 for long-term)

and moderate improvement in intermediate-term pain and

function (evidence type 3). For hip osteoarthritis, exercise was

associated with small improvement in short-term function

and pain versus usual care (evidence type 3). Functional

improvement persisted at intermediate-term follow-up but

pain improvement did not (evidence type 3).

Fibromyalgia. The AHRQ systematic clinical evidence

review found exercise, mind-body practices, multidisciplinary

rehabilitation, and acupuncture associated with small

improvement in short-term function versus usual care or

inactive treatments for fibromyalgia (evidence type 2 for

acupuncture; evidence type 3 for others). At intermediate

term, exercise, acupuncture, cognitive behavioral therapy,

mindfulness-based stress reduction, myofascial release,

and multidisciplinary rehabilitation were associated with

improvements in function versus inactive treatments, usual care,

or waiting list (evidence type 2 for exercise and acupuncture;

evidence type 3 for others). Effects on intermediate-term

function were moderate for cognitive behavioral therapy and

small for the other therapies. At long term, multidisciplinary

rehabilitation was associated with persistent small improvement

in function versus usual care but not for pain (evidence type 3).

Tai chi was associated with small improvement in function

versus exercise at short- to intermediate-term follow-up

(evidence type 3). Therapies associated with improved pain

versus usual care, waiting list, no treatment, or inactive

treatments were exercise (small effect, short and intermediate

term; evidence type 2), cognitive behavioral therapy (small,

short term; evidence type 3), mindfulness practices (small,

intermediate term; evidence type 3), and multidisciplinary

rehabilitation (small, intermediate term; evidence type 3).

Chronic Tension Headache. The AHRQ systematic clinical

evidence review found spinal manipulation was associated

with moderate improvement in short-term pain and small

improvement in function versus usual care for chronic

tension headache (evidence type 3). For other interventions,

evidence was sparse, and the majority of trials had serious

methodological limitations.

Harms

Across conditions, data on harms of nonpharmacologic

therapies were limited but no evidence suggested serious

harms. Although reporting on harms was suboptimal, among

studies that reported data, nonserious treatment-related adverse

events (e.g., discomfort, soreness, bruising, increased pain,

and worsening of symptoms) were infrequently reported, few

withdrawals from nonpharmacologic therapies due to adverse

events were reported, and no differences were found between

comparison groups (either usual care or no nonpharmacologic

therapy or another therapy) in the frequency of intervention-

related adverse events or withdrawals (evidence type 2 or 3).

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Nonopioid Pharmacologic Treatments

for Chronic Pain

Benefits

For neuropathic pain, the AHRQ systematic clinical evidence

review (3) found anticonvulsants (gabapentin, pregabalin,

and oxcarbazepine) were associated with small short-term

improvement in pain versus placebo (evidence type 2), with

no difference between pregabalin versus gabapentin enacarbil

(evidence type 3). The antidepressant duloxetine was associated

with small improvements in short-term pain, function, and

quality of life versus placebo in patients with diabetic peripheral

neuropathy (evidence type 2 for pain and quality of life;

evidence type 3 for function). Tetrahydrocannabinol (THC)

and cannabidiol (CBD) oral spray had inconsistent effects

on pain in patients with multiple sclerosis or with allodynia

(evidence type 3). Topical capsaicin was not associated with

statistically significant effects on pain versus placebo, or effects

were below the threshold for a small effect (evidence type 2).

For fibromyalgia, serotonin and norepinephrine reuptake

inhibitor (SNRI) antidepressants milnacipran and duloxetine

were associated with small, short- and intermediate-term

improvements in pain and quality of life versus placebo; a small

beneficial effect on function was only observed at short-term

(evidence type 2). Anticonvulsants pregabalin and gabapentin

were associated with small short-term improvements in pain

and function versus placebo; there were no effects on quality of

life (evidence type 2). Memantine was associated with moderate

intermediate-term improvements in pain, function, and quality

of life versus placebo (evidence type 3).

For osteoarthritis, NSAIDs were associated with small short-

term improvement in pain (evidence type 2) and function

(evidence type 1). Topical diclofenac was associated with

small improvement in short-term pain (evidence type 2) and

function (evidence type 3) versus placebo. Duloxetine was

associated with small improvement in pain severity, function,

and quality of life and moderate improvement in likelihood

of a pain response (evidence type 1). Acetaminophen was not

associated with improvement in pain or function versus placebo

(evidence type 3).

For inflammatory arthritis, NSAIDs were associated with

small improvements in short-term pain and function versus

placebo (evidence type 2); effects on pain and function were

small at intermediate-term follow-up (evidence type 3). At

long-term follow-up, effects on pain were large, with no effects

on function (evidence type 3).

For low back pain, duloxetine was associated with a small

short-term improvement in pain intensity and likelihood of

a pain response versus placebo; however, improvements in

function and quality of life did not meet the threshold for

small improvement (evidence type 2).

Harms

Across all classes of nonopioid therapies, the AHRQ

systematic clinical evidence review found that the incidence

of serious adverse events was low; however, the trials were not

designed to assess serious adverse events, and there were few

serious adverse events (evidence type 3).

Antidepressants were associated with increased risk for

withdrawal due to adverse events (WAE) versus placebo. SNRI

antidepressants were associated with moderate to large increases

in risk for nausea and excessive sweating (evidence type 2

or 3). Duloxetine was associated with a large, dose-dependent

increase in sedation versus placebo (evidence type 2 or 3).

With regard to anticonvulsants, oxcarbazepine was

associated with a large increase in risk for WAEs versus placebo

(evidence type 2). Pregabalin and gabapentin were associated

with moderate increased risk for WAEs (evidence type 2),

with an association between higher dosages of pregabalin and

increased risk. Pregabalin and gabapentin were associated

with large increases in blurred vision, dizziness, weight gain,

and cognitive effects (e.g., confusion) (evidence type 2). In

addition, pregabalin was associated with large increases in risk

for peripheral edema and sedation (evidence type 2).

NSAIDs were associated with increased risk for WAEs versus

placebo; the magnitude was small for ibuprofen and diclofenac

and moderate for naproxen (evidence type 2). There was no

statistically significant increase in risk for any cardiovascular

event for NSAIDs as a group; however, diclofenac was

associated with a small increase in risk, particularly in the first

6 months, and with higher dosages (evidence type 2). Versus

placebo, the risk for major coronary events was elevated with

diclofenac and celecoxib (moderate effect) and with ibuprofen

(large effect). For every 3,000 patients treated with diclofenac

or celecoxib, there were an estimated three additional major

coronary events. No difference was found in cardiovascular

events between celecoxib versus nonselective NSAIDs in

the intermediate or long term (evidence type 2). The risk

for serious upper gastrointestinal events was increased with

diclofenac (moderate effect) and ibuprofen or naproxen

(large increase), particularly in the first 6 months of treatment

(evidence type 1–2). In the intermediate term, diclofenac and

naproxen were associated with large increase in risk for hepatic

harms (evidence type 1–2).

Acetaminophen was not associated with increased risk

for short- or intermediate-term WAEs versus placebo

(evidence type 3). Capsaicin was associated with a large increase

in risk for application site pain (evidence type 2) and a small

increased risk for erythema (evidence type 3). Cannabis as

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oral dronabinol solution was associated with a large increase

in risk for dizziness, and as THC or CBD was associated

with a large increase in risk for WAEs, dizziness, and nausea

(evidence type 3).

Treatments for Acute Pain

The AHRQ systematic clinical evidence review (4) found that

most trials of treatments for acute pain focused on effects on pain

at short-term (up to 1 week) follow-up. Evidence was somewhat

stronger for pharmacologic than nonpharmacologic therapies.

For acute surgical dental pain (evidence type 3) and kidney

stone pain (evidence type 2), the AHRQ systematic clinical

evidence review found that opioids were associated with small

to moderate increases in pain or need for rescue medication use

versus NSAIDs. Findings for postoperative pain were somewhat

inconsistent. Although opioids were associated with increased

likelihood of repeat or rescue medication use at 1 day to 1 week

(evidence type 3), evidence on pain intensity was insufficient

due to inconsistency. Results for postoperative pain were based

on a small number of trials and pain related to a limited set

of surgical procedures (most commonly cesarean section,

anterior cruciate ligament reconstruction, knee arthroplasty,

and cholecystectomy), limiting generalizability to other surgical

procedures. Opioids were associated with increased risk for

adverse events such as nausea, dizziness, and sedation versus

nonopioid pharmacologic therapies (evidence type 2 or 3).

The trials were not designed to assess serious adverse events,

and few such events were reported. Evidence on opioids

versus acetaminophen was somewhat mixed: for dental pain,

the systematic clinical evidence review found opioids were

associated with small improvement in pain outcomes on certain

measures (evidence type 2) but for kidney stone pain, opioids

were associated with a small increase in pain (evidence type 2).

Evidence on NSAIDs versus acetaminophen was also somewhat

mixed: for dental pain, evidence indicated that NSAIDs were

associated with moderate to large decrease in pain (evidence

type 2) but for kidney stone pain, evidence was insufficient.

Evidence on nonopioid pharmacologic therapies other than

NSAIDs or acetaminophen was very limited.

Evidence on nonpharmacologic therapies for acute pain

was limited. For low back pain, the AHRQ systematic clinical

evidence review found that heat therapy was associated with

a moderate decrease in pain versus usual care or placebo at

1 day to <1 week and at 2 to <4 weeks (evidence type 2–3).

For nonradicular low back pain, there might be no difference

between spinal manipulation versus inactive controls (evidence

type 2–3), although one trial of patients with radiculopathy

found manipulation was associated with increased likelihood

of improvement in pain at 2 to <4 weeks and at ≥4 weeks

(evidence type 3) (38). Acupuncture was associated with

moderate improvement in pain and function versus an NSAID

for low back pain; however, findings were based on one

trial that evaluated one session of acupuncture and a single

dose of an NSAID (evidence type 3) (39). For postoperative

pain, there was type 3 evidence that massage might have

some effectiveness, with likely no difference between cold

therapy versus no cold therapy, with the possible exception of

decreased pain medication use at <1 week. Evidence supporting

effectiveness of acupressure for acute musculoskeletal pain

was limited (evidence type 3). Reporting of harms for

nonpharmacologic therapies was suboptimal. However, the

noninvasive nonpharmacologic therapies evaluated in the

AHRQ systematic clinical evidence review were generally not

thought to be associated with serious harms, and harms were

few when reported.

Trials of opioid therapy for acute pain were not designed to

evaluate effects on long-term use of opioids or outcomes such as

misuse or development of opioid use disorder. Limited evidence

from observational studies found that being prescribed an

opioid for acute low back pain or after minor or elective

surgical procedures was associated with increased likelihood of

opioid use at longer term (e.g., 6 months or 1 year) follow-up

(evidence type 3). Evidence on factors associated with opioid

prescribing in patients with acute pain conditions was very

limited and suggested that legislation mandating use of PDMP

data before prescribing was not associated with decreases in

opioid prescribing for low back pain or postoperative pain.

No studies were identified that evaluated the accuracy or

effectiveness of risk assessment instruments to inform use of

opioids for acute pain.

Treatments for Acute Episodic Migraine

The AHRQ review on treatments for acute episodic migraine

(5) found limited evidence on the benefits and harms of

opioids. The review found that opioids might be associated

with decreased pain versus placebo but worse pain outcomes

versus nonopioid pharmacologic therapy (evidence type 3).

Most outcomes were assessed at short-term (2 hours or 1 day)

follow-up. Opioids were associated with increased risk for

adverse events, although evidence on serious adverse events was

lacking. No studies were found on instruments for predicting

opioid misuse, opioid use disorder, overdose, or risk mitigation

strategies in patients prescribed opioids for migraine.

The AHRQ review found stronger (type 1 or 2) evidence

supporting the effectiveness of multiple established nonopioid

pharmacologic therapies for improving pain resolution

in acute episodic migraine, including triptans, NSAIDs,

dihydroergotamine, and ergotamine plus caffeine. Evidence

also favored antiemetics versus placebo or no antiemetic

but was more limited (evidence type 3). Newer treatments

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(calcitonin gene-related peptide [CGRP] antagonists [gepants],

and lasmiditan [a 5-HT1F receptor agonist]) were associated

with reduced pain and improved function versus placebo

(evidence type 2 or 3). However, lasmiditan was associated

with increased risk for serious adverse events (most commonly,

dizziness; evidence type 3); evidence on serious adverse events

of CGRP antagonists was insufficient.

Evidence on nonpharmacologic therapy for acute episodic

migraine was sparse. Moderate evidence (evidence type 2)

supported remote electrical neuromodulation. More limited

evidence (evidence type 3) supported acupuncture, chamomile

oil, external trigeminal nerve stimulation, and eye movement

desensitization reprocessing. Evidence was insufficient to

determine risk for serious adverse events with nonpharmacologic

therapies for acute episodic migraine.

Contextual Evidence Review

Patient and Clinician Values and

Preferences

Opioids for Chronic Pain. The contextual evidence review

conducted for the 2016 CDC Opioid Prescribing Guideline

(8) found data indicating that physicians frequently lacked

confidence in their ability to safely prescribe opioids, predict

or identify prescription medication misuse or opioid use

disorder, or discuss these issues with their patients. Clinicians

reported favorable beliefs and attitudes about effects of opioids

on pain and quality of life; however, they also had concerns

about risk for opioid use disorder and overdose yet did not

consistently use risk mitigation strategies (e.g., use of PDMP

data, urine toxicology testing, or opioid treatment agreements).

Evidence on patient values and preferences was limited but

indicated unfamiliarity with certain terms (“opioids”), more

familiarity with the term “narcotics” but an association between

“narcotics” and “addiction” or “abuse,” and concerns about

addiction and abuse. Side effects such as nausea, constipation,

and somnolence (rather than pain relief) accounted for most

of the variation in patient preferences regarding use of opioids.

Patients prescribed high-dose opioids reported reliance on

opioids and ambivalence or uncertainty about benefits and

side effects.

The AHRQ review identified new information on

preferences and values. A survey of 961 clinicians found that

82% were reluctant to prescribe opioids and less than half

(47%) expressed confidence in caring for patients with chronic

noncancer pain (40). A total of 67% were aware of the 2016

CDC Opioid Prescribing Guideline and 55% were enrolled in

the state PDMP; 2% always or frequently prescribed naloxone

to patients on opioids, although results are difficult to interpret

because the study did not specify whether patients met 2016

CDC Opioid Prescribing Guideline criteria for naloxone.

Guideline awareness was associated with increased confidence

in caring for patients with chronic pain. Other surveys found

negative attitudes or concerns regarding prescription opioid

use disorder but beliefs in potential effectiveness of opioids for

treating pain and support for policies and guidelines aimed at

mitigating risks, with increased confidence when following

“best practices” (41–43).

Regarding patient preferences and values, a new systematic

review found that among various opioid-related outcomes

(effects), patients ranked pain relief, nausea, and vomiting as

most important, followed by constipation (44). “Addiction”

was only evaluated in two studies and rated as less important

than pain relief. An online (non–peer reviewed) survey of

approximately 3,000 patients 1 year after the release of the

2016 CDC Opioid Prescribing Guideline found that 84%

reported more pain and worse quality of life and 42% said

they had considered suicide; however, the survey did not

attempt to sample patients with chronic pain using a rigorous

methodological approach (45).

Noninvasive Nonpharmacologic Treatments for Chronic

Pain. The contextual evidence review found that evidence

on patient values and preferences related to noninvasive

nonpharmacologic treatments for chronic pain was limited.

A Gallup poll found that 78% of Americans preferred

nonpharmacologic therapies (e.g., physical therapy and

chiropractic care) to address pain over prescribed pain

medication (46). Another survey indicated frequent use of

complementary and integrative therapies for chronic pain (47).

Clinicians generally agreed with use of guideline-supported

therapies and therapies supported by evidence, including

nonpharmacologic therapies; clinicians also felt that treatments

should be credible and individualized to the patient (48,49).

Clinician concerns regarding nonpharmacologic treatments

included costs and safety (49). Surveys indicated high support

for use of exercise therapy, complementary medicine therapies,

and psychological therapies (50–52); clinicians also supported

chronic pain management informed by a biopsychosocial

framework or using a multidimensional approach (53). Barriers

to use of therapies included lack of knowledge or expertise

and uncertainty regarding potential benefits (48,50,52–55).

Nonopioid Pharmacologic Treatments for Chronic Pain.

The contextual evidence review found limited evidence on

clinician and patient values and preferences related to nonopioid

pharmacologic treatments. Evidence described variability

in patient preferences regarding nonopioid pharmacologic

treatments, interest in medical cannabis, cost as an important

consideration, high priority on pain reduction as well as side

effects and harms (including risk for opioid use disorder),

and high value for having alternatives to opioids (56–58). A

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survey of pharmacists in Canada found that 38% agreed that

nonprescription analgesics should be first line for chronic low

back pain and 79% agreed that tricyclic antidepressants are

effective for peripheral diabetic neuropathy (59).

Treatments for Acute Pain. The contextual evidence review

found limited evidence suggesting variability in patient values

and preferences regarding treatments for acute pain (60,61),

with some evidence of high satisfaction when postoperative

pain was managed using an opioid-sparing pathway (62). Also,

there was variability in clinician values and preferences regarding

acute pain treatments that were affected by clinical specialty,

knowledge regarding effectiveness, and costs; negative attitudes

toward acute pain conditions were associated with less likelihood

of using or redosing opioids (63–67). A systematic review

found inconsistent evidence that education increased clinician

adherence with acute low back pain guideline recommendations

in terms of referral rates to physiotherapy (67).

Treatments for Acute Episodic Migraine. The contextual

evidence review found very limited evidence on clinician

and patient values and preferences related to treatments for

acute episodic migraine. One survey found that patients with

headaches (primarily episodic or chronic migraine) prioritized

efficacy of treatment over the safety or route of administration

and preferred oral over parenteral medications (68). A survey

of Canadian pharmacists found that 42% agreed that migraine

patients should try nonprescription before prescription

medications and 53% agreed that triptans should be reserved

until failure of at least two other prescription medications (59).

Costs and Cost-Effectiveness

Opioid Therapy for Chronic Pain. The contextual evidence

review conducted for the 2016 CDC Opioid Prescribing

Guideline estimated (on the basis of studies published after

2010) yearly direct and indirect costs related to prescription

opioids at $53.4 billion for nonmedical use of prescription

opioids; $55.7 billion for abuse, dependence (i.e., opioid use

disorder), and misuse of prescription opioids; and $20.4 billion

for opioid-related overdoses (69–71). In 2012, total expenses

for outpatient prescription opioids were estimated at $9 billion,

an increase of 120% from 2002 (72). On the basis of a large

national sample of 2008 claims data, direct costs of opioids

in patients with osteoarthritis were estimated at $287.40

per patient; however, there was wide variability in estimates

(SD: $1,652.10) (73). One study estimated costs of urine

toxicology testing (including screening and confirmatory tests)

at $211–$363 per test (74).

The AHRQ report included data that estimated the total

economic burden of fatal overdose, abuse, and dependence of

prescription opioids in 2013 at $78.5 billion, with $28.9 billion

related to increased health care and substance use disorder

treatment costs (75). More recent data indicate that spending

on opioid prescriptions peaked at $1.6 billion in 2009, with

a decrease to $1.2 billion in 2016 (76). However, costs of

treatment for opioid use disorder and overdose increased

($646 million in 2009 and $2.6 billion in 2016). Data also

indicate that Medicaid spending on opioids has declined since

2014, although spending on buprenorphine (a partial opioid

agonist often used to treat opioid use disorder) has increased

(77), likely because of greater numbers of persons accessing

medication and treatment for opioid use disorder.

No study was identified that formally evaluated the cost-

effectiveness of opioid therapy versus no opioid therapy or

nonopioid pharmacologic therapy for noncancer pain. A

modeling study that estimated 80% of opioid overdose deaths

to be attributable to illicit opioids projected that interventions

targeting prescription opioid misuse (e.g., prescription

monitoring programs) would decrease the number of opioid

overdose deaths by 3.0%–5.3% (78). Also, there were no cost-

effectiveness analyses of risk mitigation strategies in persons

prescribed opioids for chronic pain. A systematic review

that included 43 economic evaluation studies of treatments

for opioid use disorder found evidence supporting the cost-

effectiveness of methadone therapy, with less evidence for other

opioid use disorder therapies (79). Additional analyses from

the United Kingdom and California also found treatment for

opioid use disorder to be cost-effective or cost-saving (80,81).

Noninvasive Nonpharmacologic Treatments for Chronic

Pain. The contextual evidence review found that for

nonpharmacologic treatments covered by commercial

insurers, out-of-pocket costs ranged from $25 to $60 per

visit ($150–$720 for a 6- to 12-visit course of therapy) (55).

Studies found that a number of nonpharmacologic therapies

were cost-effective for various chronic pain conditions.

For osteoarthritis, cost-effective interventions (relative to a

comparison such as no therapy or usual care) included exercise,

acupuncture, and transcutaneous electrical nerve stimulation

(

82–90). For low back pain, cost-effective interventions

included interdisciplinary rehabilitation, exercise, yoga,

acupuncture, spinal manipulation, cognitive behavioral

therapy, mindfulness-based stress reduction, biofeedback, and

multidisciplinary rehabilitation (91–99). For neck pain, cost-

effective interventions included manual therapy, physiotherapy,

acupuncture, exercise, and spinal manipulative therapy

(94,100–104). For fibromyalgia, cost-effectiveness analyses of

nonpharmacologic therapies were very limited (105); however,

certain evidence suggested that cognitive behavioral therapy

dominated (associated with cost savings and greater benefits)

pharmacologic therapy or usual care (106).

Nonopioid Pharmacologic Treatments for Chronic Pain.

The contextual evidence review found certain evidence indicating

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that nonopioid pharmacologic therapies are cost-effective for

chronic pain. For osteoarthritis and low back pain, there was

evidence that nonopioid pharmacologic therapies (NSAIDs

and duloxetine) are cost-effective versus opioids (107–109);

studies also found NSAIDs, duloxetine, and pregabalin to be

cost-effective versus usual care or no treatment (108,110–112).

For neuropathic pain, cost-effective treatments included tricyclic

antidepressants, duloxetine, pregabalin, and topical capsaicin or

lidocaine (113–126). For fibromyalgia, cost-effective treatments

included duloxetine, pregabalin, and amitriptyline, although

analyses of relative cost-effectiveness among these therapies were

inconsistent (127–134).

Treatments for Acute Pain. The contextual evidence review

found limited evidence that exercise was cost-effective for acute

low back pain and interdisciplinary rehabilitation cost-effective

for low back pain that was identified as high risk for becoming

chronic (102,135,136). Evidence that acetaminophen and

spinal manipulation were not cost-effective for acute low back

pain was limited (the acetaminophen analysis was based on a

randomized trial that found acetaminophen to be ineffective for

acute low back pain, and the spinal manipulation analysis was

based on a cohort study that found manipulation for acute low

back pain did not reduce follow-up visits or days of sick leave

for low back pain) (137,138). One cohort study of patients

with postsurgical pain found use of long-acting opioids within

30 days to be associated with greater costs of services ($11,900

versus $8,400; p<0.0001) (139).

Treatments for Acute Episodic Migraine. The contextual

evidence review found that studies on costs and cost-effectiveness

of treatments for acute episodic migraine focused almost

exclusively on triptans. Triptans were consistently found to be

associated with low costs per pain-free episode and other outcomes

(e.g., migraine-disability days averted) (140–148). Triptans

were dominant (more effective and less costly) over a fixed-dose

combination of ergotamine tartrate plus caffeine (149).

Summary of Surveillance Reports

Opioid Treatments for Chronic Pain

To identify new evidence on opioid treatments for chronic

pain that might have an impact on the conclusions or findings

of the original (2020) systematic review, a series of three

updates was conducted; searches for the final (third) update

were conducted on March 16, 2022 (150). New evidence

did not change the main findings of the original systematic

review. For opioids versus placebo, updated meta-analyses

that included three additional trials (151–153) reported a

small reduction in pain intensity (mean difference: −0.78:

95% CI: −0.91 to −0.65), increased likelihood of experiencing

>30% improvement in pain (RR: 1.33; 95% CI: 1.22–1.46),

and small improvement in function (standardized mean

difference: −0.21; 95% CI: −0.27 to −0.15), with estimates

very similar to the original review. Findings for increased risk

of opioids versus placebo of short-term harms (discontinuation

because of adverse events, constipation, nausea, vomiting,

dizziness, somnolence, and pruritus) also were unchanged.

One new randomized trial (154) found transcutaneous

electrical nerve stimulation to be associated with a small

improvement in short-term function versus opioids and with

decreased risk for any adverse event, nausea, constipation,

and dizziness (strength of evidence: low); no study evaluated

this comparison in the original review. No new randomized

trials of opioids versus other nonpharmacological therapies or

nonopioid medications were found. Two new cohort studies

(155,156) found opioid dosage reduction or discontinuation to

be associated with increased risk for mental health crisis events

or fatal or nonfatal suicide attempts; however, evidence on the

association between tapering or discontinuation and risk for

overdose was inconsistent. The studies were not designed to

evaluate the indication or circumstances for dosage reduction or

methods used to support dosage reductions or discontinuation

and had methodologic limitations, including potential for

confounding. New evidence on long-term benefits and harms,

risk mitigation strategies, dose-dependent risks of opioids, and

management of opioid use disorder was limited; for all of these

areas, findings with the addition of studies identified in the

updates were consistent with the original report.

Nonopioid Pharmacologic Treatments

for Chronic Pain

To identify new evidence on nonopioid pharmacologic

treatments for chronic pain that might have an impact on the

conclusions or findings of the original (2020) systematic review,

a series of three updates was conducted; searches for the final

(third) update were conducted on April 1, 2022 (157

). The

addition of evidence identified during the updates did not

change the main conclusions of the original review, which found

nonopioid drugs (mainly SNRI antidepressants, pregabalin

and gabapentin, and NSAIDs) to be associated with small

to moderate improvements in short-term pain and function

outcomes in patients with specific types of noncancer chronic

pain. Evidence on intermediate- and long-term outcomes of

nonopioid pharmacologic treatments for chronic pain remained

limited. Findings after the addition of new studies were also

consistent with the original review in finding nonopioid drugs

to be associated with increased risk for class-specific harms

(e.g., gastrointestinal events with NSAIDS), with certain

patients withdrawing because of adverse events. For neuropathic

pain, new evidence resulted in certain changes to strength

of evidence of magnitude of effects assessments, including a

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change to low strength of evidence for small increased likelihood

of experiencing a pain response with cannabis (RR: 1.30;

95% CI: 0.88–1.94; magnitude of reduction previously assessed

as moderate) and large risk for sedation with cannabis (RR: 5.84;

95% CI: 1.90–17.92; previously insufficient evidence), due

to the addition of one new randomized trial (158); strength

of evidence was changed to low for no difference between

gabapentin or pregabalin and duloxetine in pain intensity

(previously insufficient evidence), due to the addition of two

new randomized trials (159,160). An updated meta-analysis

found capsaicin to be associated with a large increased risk for

discontinuation because of adverse events (strength of evidence

moderate) compared with placebo (previously no increase in

risk), due to the addition of one new randomized trial (161),

although the absolute number of participants who withdrew

because of adverse events was small (<1%).

Noninvasive Nonpharmacologic

Treatments for Chronic Pain

To identify new evidence on noninvasive nonpharmacologic

treatment for chronic pain that that might have an impact on

the conclusions or findings of the original (2020) systematic

review, a series of three updates was conducted; searches for

the final (third) update were conducted in March 2022 (162).

The addition of evidence identified during the updates did

not change the main conclusions of the original review, which

found exercise, multidisciplinary rehabilitation, acupuncture,

cognitive behavioral therapy, mindfulness practices, massage,

and mind-body practices to be associated with improved

function, pain, or both, beyond the course of therapy for

specific chronic pain conditions. Updated meta-analyses

with the addition of new studies were conducted for low

back pain (exercise, psychological therapies, manual therapy,

mind-body practices, and acupuncture), neck pain (exercise),

knee osteoarthritis (exercise, physical modalities [low-level

laser therapy], ultrasound, and mind-body therapies), and

fibromyalgia (exercise, mindfulness practices, acupuncture,

and multidisciplinary rehabilitation). On the basis of the

updated meta-analyses, the strength of evidence for mind-

body therapies for knee osteoarthritis was upgraded to low

for moderate improvement in pain and small improvement in

function (previously insufficient evidence), due to the addition

of one new trial (163); the strength of evidence for low level

laser therapy for knee osteoarthritis was also upgraded to low

for no difference in pain improvement and small improvement

in function (previously insufficient evidence), due to the

addition of one new trial (164). Otherwise, findings were

unchanged from the original review. As in the original review,

harms were poorly reported across interventions, although

serious intervention-related adverse events were not identified.

Treatments for Acute Pain

To identify new evidence on noninvasive nonpharmacologic

treatment for chronic pain that might have an impact on the

conclusions or findings of the original (2020) systematic review,

a series of three updates was conducted; searches for the final

(third) update were conducted on May 6, 2022 (165). The

addition of evidence identified during the updates did not change

the main conclusions of the original review. Specifically, opioid

therapy was associated with decreased or similar effectiveness

for pain versus an NSAID for surgical dental pain, kidney

stone pain, and low back pain. New evidence was identified

for low back pain (acupuncture), musculoskeletal pain (opioid

versus acetaminophen, and topical ibuprofen versus capsaicin),

postoperative pain (opioid versus NSAID and opioid versus

acetaminophen; cold therapy; music therapy; abdominal binder;

and transcutaneous electrical nerve stimulation), and dental

pain (opioid versus NSAID, opioid versus acetaminophen,

and NSAID versus acetaminophen). As in the original review,

opioids and NSAIDs were more effective than acetaminophen

for surgical dental pain and acute musculoskeletal pain, but

opioids were less effective than acetaminophen for kidney stone

pain. Opioids were associated with increased risk for short-term

adverse events versus NSAIDs or acetaminophen, including

any adverse event, nausea, dizziness, and somnolence. Serious

adverse events were uncommon for all interventions; however,

studies were not designed to assess risk for overdose, opioid

use disorder, or long-term harms. Being prescribed an opioid

for acute low back pain or postoperative pain was associated

with increased likelihood of use of opioids at long-term follow

up versus not being prescribed, on the basis of observational

studies, although potential confounding could have had an

impact on findings. Evidence on nonpharmacologic therapies

for acute pain remained limited; however, heat therapy, spinal

manipulation, massage, acupuncture, acupressure, a cervical

collar, music therapy, transcutaneous electrical nerve stimulation,

and exercise were effective for specific acute pain conditions.

Evidence remained limited on the comparative effectiveness of

therapies for sickle cell pain, acute neuropathic pain, neck pain,

and management of postoperative pain after discharge; effects of

therapies for acute pain on nonpain outcomes; effects of therapies

on long-term outcomes, including long-term opioid use; and

variations of benefits and harms of therapies among subgroups. A

new finding from the updates was an association of preoperative

education with decreased opioid use with similar or reduced pain

intensity versus no preoperative education; this finding was based

on three new trials (166–168) (no previous trials).

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Treatments for Acute Episodic Migraine

To identify new evidence on treatments for acute episodic

migraine that might have an impact on the conclusions or

findings of the original (2020) systematic review, a series

of three surveillance reports was conducted; searches for

the final (third) update were conducted on March 21,

2022 (169). The addition of new evidence identified in the

updates did not change the main conclusions of the original

review regarding the effectiveness for improving short-term

(<1 day) pain and function of established pharmacological

treatments (e.g., triptans, NSAIDs, antiemetics, and ergot

alkaloids) and newer treatments (e.g., gepants and ditans);

pharmacological treatments were associated with mild

adverse events. Evidence on opioids for acute treatment of

episodic migraine remain remained low or insufficient, and

evidence on nonpharmacological treatments remained low,

except for remote electrical neuromodulation (strength of

evidence moderate). New evidence identified for the updates

supported effectiveness of the calcitonin gene-related peptide

eptinezumab (one new RCT) (170) and propofol (one new

RCT) (171), occipital and supraorbital nerve blocks (two new

RCTs) (172,173), transcranial stimulation (one new RCT)

(174), and inhaled oxygen (one new RCT) (175) in acute

treatment of episodic migraine (moderate strength of evidence

for eptinezumab; otherwise low strength of evidence).

A Note on Historically Used Terms

Historically, terms such as “abuse,” “drug abuse,” and “opioid

abuse” have been used in research and diagnostic terminology.

For example, opioid use disorder, defined in the Diagnostic and

Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)

as a problematic pattern of opioid use leading to clinically

significant impairment or distress (176), was previously referred

to as opioid abuse or opioid dependence in the Diagnostic

and Statistical Manual of Mental Disorders, Fourth Edition

(DSM-IV) (177,178). However, more recent research indicates

that use of terms such as “abuse” negatively affects perceptions

and judgments about persons with drug use and substance use

disorders (179–181). In the CDC Clinical Practice Guideline

for Prescribing Opioids for Pain — United States, 2022, “abuse”

is sometimes used to accurately reflect underlying sources

or to report findings from research conducted using this

terminology; however, terms such as “drug use” or “opioid

use” typically are used to describe behaviors, and terms such

as “substance use disorder” or “opioid use disorder” are used

when discussing relevant diagnoses (176).

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