Nonhormonal Therapies for Hot Flashes in Menopause

Nonhormonal Therapies for Hot Flashes

in Menopause

DANA G. CARROLL, PHARM.D., B.C.P.S., University of Oklahoma–Tulsa College of Medicine, Tulsa, Oklahoma

he results of the Women’s Health

Initiative (WHI) study

of hor-

mone therapy in postmenopausal

women, published in 2002, have

prompted many women and primary care

physicians to reconsider the use of estro-

gen and progesterone hormone therapy to

alleviate hot flashes. In the study,

16,608

healthy, postmenopausal women with an

intact uterus were randomized to receive

therapy with conjugated equine estrogens

plus medroxyprogesterone acetate, or pla-

cebo. The study was stopped early because

researchers found increased incidences of

breast cancer (number needed to harm

[NNH] = 1,250), coronary heart disease

(NNH = 1,428), stroke (NNH = 1,250), and

pulmonary embolism (NNH = 1,250) in

the treatment group when compared with

the placebo group.

Many women find the

risks associated with hormone therapy to

be unacceptable and are requesting non-

hormonal therapies to manage their hot

flash symptoms. There have been numerous

reports in the medical literature and gen-

eral media as to the effectiveness of various

over-the-counter and prescription agents in

reducing menopausal hot flash symptoms.

The following is a review of the published

data for several of these agents (Table 1). Key

recommendations for different regimens are

listed in the strength of recommendations

(SORT) table, with the study duration and

the dosages used. Study considerations and

limitations are listed in Table 2.

2-33

A poten-

tial confounder in most hot flash trials is the

placebo response rate, which in the studies

evaluated for this review was reported as

between 18 and 40 percent. This is similar to

Numerous reports in the medical literature and popular media have discussed the effectiveness

of various nonhormonal agents in reducing menopausal hot flash symptoms. Data for these

therapies are limited, and most of the studies have been conducted in women with a history of

breast cancer. Selective serotonin reuptake inhibitors and venlafaxine have been shown to reduce

hot flashes by 19 to 60 percent and were well tolerated by study participants. Soy isoflavones

reduced hot flashes by 9 to 40 percent in some trials, but most trials showed no difference com-

pared with placebo. Black cohosh and red clover also have had inconsistent results, with some

trials showing benefit and some no difference compared with placebo. Soy isoflavones, black

cohosh, and red clover were well tolerated in clinical trials. Other agents that have been used

to alleviate hot flashes include belladonna/ergotamine tartrate/phenobarbital combination,

dong quai, evening primrose oil, gabapentin, ginseng, mirtazapine, trazodone, vitamin E, and

wild yam, but few data regarding their effectiveness have been published. Further randomized

can Academy of Family Physicians.)



Patient information:

A handout on non-

hormonal options for

hot flashes is provided

on page 467.

TABLE 1

Nonhormonal Agents Used as Therapy for Hot Flashes

Prescription

Belladonna/ergotamine tartrate/

phenobarbital combination

(Bellergal,* Bellamine)

Clonidine (Catapres)

Fluoxetine (Prozac)

Gabapentin (Neurontin)

Mirtazapine (Remeron)

Paroxetine (Paxil)

Trazodone (Desyrel)

Venlafaxine (Effexor)

Nonprescription

Black cohosh

Dong quai

Evening primrose oil

Ginseng

Melatonin

Red clover isoflavones

Soy isoflavones

Vitamin E

Wild yam

*—Bellergal is no longer available commercially in the United States.

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458 American Family Physician www.aafp.org/afp Volume 73, Number 3

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Hot Flashes

rates found in studies of hormonal agents, but makes it

more difficult to ascertain the true effects of therapy on

hot flashes.

SSRIs and Venlafaxine

SUMMARY

Studies of selective serotonin reuptake inhibitors (SSRIs)

and venlafaxine (Effexor), a serotonin and norepineph-

rine reuptake inhibitor, have shown an absolute risk

reduction (ARR) in hot flashes of 19 to 60 percent with

these agents compared with placebo (number needed to

treat [NNT] = 2 to 5), primarily in women with a history

of breast cancer.

2-9

MECHANISM OF ACTION

The exact mechanism of action by which these medica-

tions alleviate hot flashes is unknown, although hot flashes

have been linked to an imbalance in serotonin.

2,6,34

STUDIES

Initial pilot studies

3,4,6

reported 50 to 67 percent decreases

in hot flashes among women with a history of breast

cancer; these results prompted larger studies. In a ran-

domized crossover

study

involving

87 women with a

history of breast

cancer who received

fluoxetine (Pro-

zac), patients expe-

rienced a median

19 percent decrease

in the frequency of

hot flashes (P = .01). In another randomized study,

researchers evaluated the effectiveness of venlafaxine at

three different dosages in reducing hot flashes among

228 women with a history of breast cancer. Forty-five

percent of patients receiving low-dosage venlafaxine

(37.5 mg daily) experienced at least a 50 percent reduc-

tion in hot flashes, compared with 63 percent of patients

receiving a moderate dosage (75 mg daily), 55 percent

of patients receiving a high dosage (150 mg daily), and

20 percent of patients receiving placebo.

All venlafaxine treatment groups had a significant

change in mean hot flashes compared with the pla-

cebo group (P < .0001). This trial

was continued as an

open-label study with 157 participants. The venlafaxine

dosages were titrated to desired effect or continued

at previous dosages if effective. Overall, hot flashes

were decreased by 60 percent compared with baseline.

Patients who previously received a high or moderate

dosage maintained their initial responses, and patients

who previously received a low dosage or placebo experi-

enced significant reductions in hot flashes.

Two studies

2,9

involved women who did not have

a history of breast cancer. In one study,

165 post-

menopausal women were randomized to receive con-

trolled-release paroxetine (Paxil CR) in a low or high

dosage or placebo. Participants experienced reductions

in hot flash scores of 37 percent in the placebo group,

62 percent in the low-dosage group, and 65 percent in

the high-dosage group (P < .001). However, the U.S.

Food and Drug Administration (FDA) withdrew Paxil

CR from the market in March 2005 because of concerns

regarding its manufacturing quality. In a study

80 postmenopausal women receiving extended-release

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation

Daily dosages

used in studies Study durations

Evidence

rating References

Black cohosh may be effective for short-term

treatment of hot flashes.

16 to 127 mg Eight weeks to

one year

B 29-33, 40

Clonidine (Catapres) is an effective option for

treating hot flashes.

0.1 mg Eight to 12 weeks B 10-12

Fluoxetine (Prozac) is an effective option for

treating hot flashes, based on limited evidence.

20 mg Nine weeks B 5

Paroxetine (Paxil) is an effective option for treating

hot flashes.

20 to 40 mg Four weeks B 3, 4

Soy and other isoflavones may be helpful in the

short-term treatment of hot flashes.

40 to 164 mg Seven to 12 weeks B 16, 19, 20, 28

Venlafaxine (Effexor) is an effective option for

treating hot flashes.

37.5 to 150 mg Four to 12 weeks B 7-9

NOTE: See Table 2 for study considerations and limitations. All dosages and durations listed are those used in the specific studies, not necessarily

the recommended dosage or duration of therapy.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-

oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 374 or http://

www.aafp.org/afpsort.xml.

When using a selective

serotonin reuptake inhibi-

tor or venlafaxine to treat

hot flashes, it is prudent to

initiate the medication at a

low dosage and titrate to

effect.

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Hot Flashes

venlafaxine (Effexor XR) or placebo for 12 weeks,

participants reported decreases in hot flash scores of

51 and 15 percent, respectively.

ADVERSE EFFECTS AND DOSAGE

Most of the studies reported transient, dose-related

adverse effects. The most common adverse effects

reported were insomnia or excitement, nausea, consti-

pation, and anorexia.

2,5,7

In the trials using venlafaxine

for hot flashes there were no reported increases in blood

pressure, which is a dose-related adverse effect com-

monly associated with this agent.

6,8

The dosage and duration of these medications most

appropriate in alleviating hot flashes is unknown; how-

ever, regimens using low to moderate dosages seem to

be as effective as those using high dosages and have

significantly fewer reported adverse effects. Therefore,

when using an SSRI or venlafaxine to treat hot flashes, it

is prudent to initiate the medication at a low dosage and

titrate to effect.

Clonidine

SUMMARY

Clonidine (Catapres) has been found to reduce hot flashes

by 15 to 20 percent (ARR) compared with placebo (NNT =

5 to 7) in women with a history of breast cancer.

10-12

MECHANISM OF ACTION

The exact mechanism of action is unknown, but it is

thought to relate to clonidine’s ability to reduce vascular

reactivity.

STUDIES

In one randomized, crossover study,

researchers com-

pared the effectiveness of a clonidine patch with placebo

in 110 women with a history of breast cancer. The patch

was found to decrease the frequency of hot flashes by

20 percent and the hot flash score by 27 percent com-

pared with placebo (P < .0001). Oral clonidine also has

been assessed. In 198 women with a history of breast

cancer who were randomized to receive oral clonidine at

TABLE 2

Considerations and Limitations of Studies of Nonhormonal Therapies for Hot Flashes in Menopause

Study considerations and limitations

Agent Durations Populations Other

SSRIs

2-5

and

venlafaxine

(Effexor)

6-9

Relatively short;

long-term efficacy

unknown

Primarily women with a history

of breast cancer receiving

tamoxifen (Nolvadex), and

predominantly white

Worsening hot flash symptoms could be

associated with a rapid decline in estrogen as

well as the adverse effects of chemotherapy,

radiation, and tamoxifen therapy.

Clonidine

(Catapres)

10-12

Relatively short;

long-term efficacy

unknown

Primarily women with a history

of breast cancer receiving

tamoxifen

Few studies have been performed.

Exclusion criteria were numerous and could

limit application to a larger population.

Soy

isoflavones

13-24

Relatively short;

long-term efficacy

unknown

Varied greatly, including women

who were perimenopausal,

women who were menopausal,

and women with a history of

breast cancer

Results were inconsistent.

Studies that reported significant positive

results with soy isoflavones compared with

placebo were conducted in women with

moderate to severe hot flashes.

Studies did not use consistent commercial,

standardized products and dosages.

Red clover

25-28

Relatively short;

long-term efficacy

unknown

Menopausal, predominantly

white women

Studies did not use consistent commercial,

standardized products and dosages.

Black cohosh

29-33

Most relatively short;

long-term efficacy

unknown

Varied greatly, including women

who were premenopausal,

women who were menopausal,

and women with a history of

breast cancer

Results were inconsistent.

Studies were weak in design.

Studies did not use consistent commercial,

standardized products and dosages.

SSRI = selective serotonin reuptake inhibitor.

Information from references 2 through 33.

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Hot Flashes

bedtime or placebo, hot flashes decreased by 38 percent

in the clonidine group and by 23 percent in the placebo

group (P < .006).

Another study,

in which clonidine

was administered transdermally in 30 postmenopausal

women, showed that clonidine decreased the number

and the severity and duration of hot flashes compared

with placebo.

ADVERSE EFFECTS AND DOSAGE

Adverse effects occurred more commonly with the cloni-

dine patch compared with placebo; the most commonly

reported side effects were dry mouth, constipation,

drowsiness, and application site irritation.

There was

little difference in adverse effects with oral clonidine

compared with placebo.

The most appropriate dosage and duration of cloni-

dine is unknown.

Soy Isoflavones

SUMMARY

Soy isoflavones may have a modest benefit for hot flashes,

but study results are inconclusive.

13-24

MECHANISM OF ACTION

Soy has been linked to reduced vasomotor symptoms

in Asian women who consume a soy-rich diet.

35,36

contains large quantities of phytoestrogens and is one

of the richest sources of isoflavones available. Isofla-

vones are similar to endogenous estrogen: they compete

with estrogen for the same receptors and exert estro-

genic and antiestrogenic effects. The agonist/antagonist

effects are determined largely by concentrations of

isoflavones and endogenous estrogen, as well as meno-

pausal status.

17,37,38

STUDIES

Researchers have evaluated the effectiveness of soy iso-

flavones as tablets, capsules, and liquids in more con-

trolled environments. A small pilot study

of the effects

of soy isoflavones in 39 menopausal women reported a

20 percent ARR in hot flashes weekly compared with pla-

cebo (P < .01). Other studies have shown no difference

in effectiveness between isoflavones and placebo. One

randomized study

involving 62 menopausal women

reported a 40 percent response rate in both groups;

another randomized study

involving 157 menopausal

women with a history of breast cancer showed a response

rate of 30 percent for both groups; a randomized study

involving 241 perimenopausal women showed no signif-

icant difference between the two groups (P = .10); and

a randomized, crossover study

involving 182 women

with a history of breast cancer also showed no difference

in soy isoflavones compared with placebo in reducing

hot flash symptoms (P = .78).

Positive results of soy isoflavone use also have been

reported. In a randomized study

involving 177 meno-

pausal women, soy isoflavones were found to be superior

to placebo in decreasing hot flash severity (27 percent

reduction versus 18 percent, respectively; P = .01), but

not hot flash frequency (P = .078). In a randomized

study

involving 75 menopausal women there was

a 61 percent decrease in hot flashes with isoflavones

compared with a 21 percent decrease with placebo

(P = .01), and 68 percent of patients in the isoflavone

group experienced a decrease in their hot flashes of more

than one half, compared with 32 percent in the placebo

group. Also, a randomized controlled trial

(RCT) of

82 postmenopausal women reported an improvement

in vasomotor symptoms on the Kupperman index (a

commonly used menopause symptom index) with the

use of soy isoflavones compared with baseline and with

placebo (P < .01).

In one RCT

conducted to evaluate the effects of soy

isoflavones and melatonin, participants were random-

ized to one of four different therapies: soy isoflavones

monotherapy, melatonin monotherapy, soy isoflavones

and melatonin combination therapy, or placebo. Results

showed no statistically or clinically significant differ-

ences in outcomes among the four groups. Three other

studies

22-24

of various isoflavone regimens did not show

any significant differences in outcomes between the

treatment and placebo groups.

The American College of Obstetricians and Gyne-

cologists (ACOG) states that soy and isoflavones may

be helpful in the short-term (i.e., two years or less)

treatment of vasomotor symptoms; however, given the

possibility of their interacting with estrogen, these

agents should not be considered free of potential harm

for women, particularly those who have an estrogen-

dependent cancer.

ADVERSE EFFECTS AND DOSAGE

Adverse effects were similar when comparing soy iso-

flavones and placebo.

14-19

The long-term effects of soy

isoflavones on estrogen-sensitive tissues is unknown.

However, in one study

there were no significant changes

in endometrial thickness from baseline in the soy-treated

patients.

Because a wide range of soy isoflavone dosages and

many different commercial products were used, it is dif-

ficult to recommend the most appropriate dosage and

product.

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Hot Flashes

Red Clover

SUMMARY

Red clover isoflavones do not appear to be more effective

than placebo in reducing hot flashes, based on limited

data from small clinical trials.

25-28

MECHANISM OF ACTION

Red clover, like soy, contains isoflavones, which act as

agonist/antagonists on estrogenic receptors.

STUDIES

In two small pilot studies,

25,26

researchers compared red

clover with placebo in postmenopausal women and found

no difference in effectiveness of reducing hot flashes.

In a randomized study

with 252 menopausal women,

researchers compared two different commercial red clover

products with placebo. All groups reported significant

declines in hot flashes compared with baseline (P < .0001),

but neither of the red clover products demonstrated superi-

ority over placebo (P > .20). In a smaller study

involving

30 menopausal women, however, those taking red clover

isoflavones experienced an additional 44 percent decrease

in hot flashes over the placebo group (P < 0.01).

ADVERSE EFFECTS AND DOSAGE

Researchers reported similar adverse effects in women

treated with red clover and those treated with placebo.

27,28

The long-term safety of red clover is unknown.

The best dosage and commercial product of red clover

isoflavones to use is not clear based on the limited data

available.

Black Cohosh

SUMMARY

Black cohosh shows promise for treatment of hot flashes,

but study results are inconsistent.

29-33,40

MECHANISM OF ACTION

The exact mechanism of action of black cohosh is

unknown. It was theorized that black cohosh competes

with estrogen for binding sites and exerts a positive

estrogenic effect, but newer data suggest it may act as a

selective estrogen receptor modifier, depending on the

tissue receptors,

and that it also may exert an agonistic

effect on serotonin receptors.

In addition, black cohosh

may decrease luteinizing hormone, leading to a reduc-

tion in hot flashes.

STUDIES

Black cohosh is the most studied and perhaps the most

popular herb for treatment of hot flashes. Typically, it is

not used on a long-term basis.

One randomized study

involving 84 women with a history of breast cancer

reported that black cohosh was similar to placebo in

alleviating hot flashes (P = .86). However, in a study

in which 80 menopausal women were randomized to

receive estrogen, black cohosh, or placebo, the women

receiving black cohosh had an 84 percent decrease in

their hot flash symptoms compared with a 40 percent

decrease in the estrogen and placebo groups (P < .001).

A study

in which 97 menopausal women were random-

ized to estrogen, black cohosh, or placebo showed black

cohosh to be as effective as estrogen and superior to pla-

cebo in decreasing hot flash symptoms (P = .046).

In an open-label, randomized study

involving

136 premenopausal women with a history of breast can-

cer who received black cohosh or placebo, researchers

found that, at the end of the study, 46 percent of women

receiving black cohosh were free of hot flashes (P < .01).

Twenty-nine percent of women receiving black cohosh

continued to have severe hot flashes, compared with

74 percent of those receiving placebo (P < .01). Results

of a study

involving 152 postmenopausal women

receiving a high or a low dosage of black cohosh showed

similar decreases in Kupperman index scores in the

two groups (from a median score of 35 at baseline to

a median score of 8 at 12 weeks), suggesting that the

higher dose was no more effective than the lower dose

(P = .73). ACOG states that black cohosh may be helpful

in the short-term (i.e., less than six months) treatment

of women with vasomotor symptoms.

ADVERSE EFFECTS AND DOSAGE

Black cohosh was reported to be well tolerated, and no

serious adverse events were linked to its use.

29-32

One

12-week study

reported no change in endometrial

thickness in women receiving black cohosh. The long-

term safety of black cohosh is unknown.

Because many different dosages and commercial prod-

ucts of black cohosh were used, it is difficult to recom-

mend one as the most appropriate.

Other Agents

Other agents also have been used for the treatment of hot

flash symptoms in menopause, including belladonna/

ergotamine tartrate/phenobarbital combination (Bel-

lergal [not available in the United States]; Bellamine),

dong quai,

evening primrose oil,

gabapentin (Neu-

rontin),

ginseng,

mirtazapine (Remeron),

trazodone

(Desyrel),

vitamin E,

and wild yam,

but there are

few published data on their effectiveness. Studies on

these agents are summarized in Table 3.

44-52

Belladonna/

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Hot Flashes

ergotamine tartrate/phenobarbital combination and

gabapentin were more effective than placebo in reduc-

ing hot flashes in two small clinical trials.

44,47

However,

larger clinical studies are needed to support these initial

findings.

Final Comment

Hot flash symptoms can significantly impact a woman’s

quality of life and should be addressed. Severity of the hot

flashes, medical history, and concomitant medications

should be considered in determining the best therapy for

each patient. As already mentioned, the placebo response

rate is a potential confounder in most trials, making it

difficult to determine the true success of therapy. Further

RCTs are needed to determine more clearly the most

effective therapy for alleviating hot flashes in menopausal

women for whom hormonal therapy is not appropriate

or by whom it is declined.

DATA SOURCES: English-language studies, as well as pertinent

references from these articles, were identified through a

search of PubMed (1966 to May 2005), the Cochrane

TABLE 3

Agents Used in the Treatment of Hot Flashes with Limited Supporting Evidence

Agent Study population Dosage Study duration Results Adverse effects*

Belladonna/

ergotamine

tartrate/

phenobarbital

combination

(Bellergal,†

Bellamine)

71 menopausal

women

1 tablet three

times per day

Eight weeks 75 percent decrease in hot

flashes with Bellergal versus

68 percent with placebo

(P < .001, NNT = 14)

Similar incidence

between groups

Dong quai

71 menopausal

women

4.5 g per day Six months No significant difference

compared with placebo

Similar incidence

between groups

Evening

primrose oil

56 menopausal

women

500 mg per day Six months No significant difference

compared with placebo

Similar incidence

between groups

Gabapentin

(Neurontin)

59 menopausal

women

300 mg three

times per day

12 weeks 45 percent decrease in hot

flashes with gabapentin

versus 29 percent with

placebo (P = .02, NNT = 6)

Somnolence;

dizziness

Ginseng

384 menopausal

women

200 mg per day Four months No significant difference

compared with placebo

Similar incidence

between groups

Mirtazapine

(Remeron)

Four menopausal

women

15 to 30 mg

per day

Varied by

patient

All four women experienced

a decline in frequency and

severity (40 to 80 percent)

of hot flashes while

receiving mirtazapine.

None reported

Trazodone

(Desyrel)

25 climacteric

women

75 mg per day Three months No significant difference

from baseline

Drowsiness

Vitamin E

125 women with

a history of

breast cancer

800 IU per day Nine weeks No significant difference

compared with placebo

Similar incidence

between

groups

Wild yam

50 menopausal

women

1 teaspoon

topically twice

per day

Six months

No significant difference

compared with placebo

None reported

NNT = number needed to treat.

*— Adverse effects listed are those reported in these trials, and may not be an accurate representation of the overall side-effect profile for each agent.

†—Bellergal is not available in the United States.

Information from references 44 through 52.

February 1, 2006

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Hot Flashes

Database, and the Natural Medicine Database. Key search

terms included climacteric, hot flash, hot flush, flushing,

menopause, postmenopause, therapy, isoflavones, sero-

tonin reuptake inhibitors, clonidine, belladonna, evening

primrose oil, ginseng, dong quai, wild yam, gabapentin,

vitamin E, and black cohosh.

Members of various family medicine departments develop articles for

“Practical Therapeutics.” This article is one in a series coordinated by the

Department of Family Medicine at the University of Oklahoma College of

Medicine, Tulsa, Okla. Coordinator of the series is John Tipton, M.D.

The Author

DANA G. CARROLL, PHARM.D., B.C.P.S., is adjunct assistant professor in

the Department of Family Medicine at the University of Oklahoma–Tulsa

College of Medicine, and assistant professor in the Department of

Pharmacy: Clinical and Administrative Sciences at the University of

Oklahoma College of Pharmacy, Tulsa. She received her degrees from

Auburn University School of Pharmacy, Auburn, Ala., and completed a

primary care residency at the University of Mississippi, Jackson.

Address correspondence to Dana G. Carroll, Pharm.D., B.C.P.S.,

at University of Oklahoma–Tulsa College of Medicine, College of

Pharmacy, 1111 S. St. Louis St., Tulsa, OK 74120 (e-mail: dana-carroll@

ouhsc.edu). Reprints are not available from the author.

Author disclosure: Nothing to disclose.

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