Nonhormonal Therapies for Hot Flashes in Menopause



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Am Fam Physician. 2006 Feb 1;73(3):457-464.

  Patient information: See related handout on nonhormonal options for hot flashes.

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 compared 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 controlled trials are needed.

The results of the Women’s Health Initiative (WHI) study1 of hormone therapy in postmenopausal women, published in 2002, have prompted many women and primary care physicians to reconsider the use of estrogen and progesterone hormone therapy to alleviate hot flashes. In the study,1 16,608 healthy, postmenopausal women with an intact uterus were randomized to receive therapy with conjugated equine estrogens plus medroxyprogesterone acetate, or placebo. 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.1  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 general 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 2.233 A potential 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 rates found in studies of hormonal agents, but makes it more difficult to ascertain the true effects of therapy on hot flashes.

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

2933,40

Clonidine (Catapres) is an effective option for treating hot flashes.

0.1 mg

Eight to 12 weeks

B

1012

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

79


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.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

View Table

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

2933,40

Clonidine (Catapres) is an effective option for treating hot flashes.

0.1 mg

Eight to 12 weeks

B

1012

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

79


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.

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.

TABLE 1   Nonhormonal Agents Used as Therapy for Hot Flashes

View Table

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.

TABLE 2

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

Agent Study considerations and limitations
Durations Populations Other

SSRIs25 and venlafaxine (Effexor)69

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)1012

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 isoflavones1324

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 clover2528

Relatively short; long-term efficacy unknown

Menopausal, predominantly white women

Studies did not use consistent commercial, standardized products and dosages.

Black cohosh2933

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.

TABLE 2   Considerations and Limitations of Studies of Nonhormonal Therapies for Hot Flashes in Menopause

View Table

TABLE 2

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

Agent Study considerations and limitations
Durations Populations Other

SSRIs25 and venlafaxine (Effexor)69

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)1012

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 isoflavones1324

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 clover2528

Relatively short; long-term efficacy unknown

Menopausal, predominantly white women

Studies did not use consistent commercial, standardized products and dosages.

Black cohosh2933

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.

SSRIs and Venlafaxine

SUMMARY

Studies of selective serotonin reuptake inhibitors (SSRIs) and venlafaxine (Effexor), a serotonin and norepinephrine 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.29

MECHANISM OF ACTION

The exact mechanism of action by which these medications alleviate hot flashes is unknown, although hot flashes have been linked to an imbalance in serotonin.2,6,34

STUDIES

Initial pilot studies3,4,6 reported 50 to 67 percent decreases in hot flashes among women with a history of breast cancer; these results prompted larger studies. In a randomized crossover study5 involving 87 women with a history of breast cancer who received fluoxetine (Prozac), patients experienced a median 19 percent decrease in the frequency of hot flashes (P = .01). In another randomized study,7 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 reduction 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 placebo group (P < .0001). This trial7 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 experienced significant reductions in hot flashes.8

Two studies2,9 involved women who did not have a history of breast cancer. In one study,2 165 post-menopausal women were randomized to receive controlled-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 study9 of 80 postmenopausal women receiving extended-release 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, constipation, 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 commonly associated with this agent.6,8

The dosage and duration of these medications most appropriate in alleviating hot flashes is unknown; however, 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.1012

MECHANISM OF ACTION

The exact mechanism of action is unknown, but it is thought to relate to clonidine’s ability to reduce vascular reactivity.10

STUDIES

In one randomized, crossover study,10 researchers compared 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 compared 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 bedtime or placebo, hot flashes decreased by 38 percent in the clonidine group and by 23 percent in the placebo group (P < .006).11 Another study,12 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 clonidine patch compared with placebo; the most commonly reported side effects were dry mouth, constipation, drowsiness, and application site irritation.10 There was little difference in adverse effects with oral clonidine compared with placebo.11

The most appropriate dosage and duration of clonidine is unknown.

Soy Isoflavones

SUMMARY

Soy isoflavones may have a modest benefit for hot flashes, but study results are inconclusive.1324

MECHANISM OF ACTION

Soy has been linked to reduced vasomotor symptoms in Asian women who consume a soy-rich diet.35,36 It contains large quantities of phytoestrogens and is one of the richest sources of isoflavones available. Isoflavones are similar to endogenous estrogen: they compete with estrogen for the same receptors and exert estrogenic and antiestrogenic effects. The agonist/antagonist effects are determined largely by concentrations of isoflavones and endogenous estrogen, as well as menopausal status.17,37,38

STUDIES

Researchers have evaluated the effectiveness of soy isoflavones as tablets, capsules, and liquids in more controlled environments. A small pilot study13 of the effects of soy isoflavones in 39 menopausal women reported a 20 percent ARR in hot flashes weekly compared with placebo (P < .01). Other studies have shown no difference in effectiveness between isoflavones and placebo. One randomized study14 involving 62 menopausal women reported a 40 percent response rate in both groups; another randomized study15 involving 157 menopausal women with a history of breast cancer showed a response rate of 30 percent for both groups; a randomized study16 involving 241 perimenopausal women showed no significant difference between the two groups (P = .10); and a randomized, crossover study17 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 study18 involving 177 menopausal 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 study19 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 trial20 (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 RCT21 conducted to evaluate the effects of soy isoflavones and melatonin, participants were randomized 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 differences in outcomes among the four groups. Three other studies2224 of various isoflavone regimens did not show any significant differences in outcomes between the treatment and placebo groups.

The American College of Obstetricians and Gynecologists (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.39

ADVERSE EFFECTS AND DOSAGE

Adverse effects were similar when comparing soy isoflavones and placebo.1419 The long-term effects of soy isoflavones on estrogen-sensitive tissues is unknown. However, in one study14 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 difficult to recommend the most appropriate dosage and product.

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.2528

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 study27 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 superiority over placebo (P > .20). In a smaller study28 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.2933,40

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,41 and that it also may exert an agonistic effect on serotonin receptors.42 In addition, black cohosh may decrease luteinizing hormone, leading to a reduction in hot flashes.43

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.40 One randomized study29 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 study30 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 study31 in which 97 menopausal women were randomized to estrogen, black cohosh, or placebo showed black cohosh to be as effective as estrogen and superior to placebo in decreasing hot flash symptoms (P = .046).

In an open-label, randomized study32 involving 136 premenopausal women with a history of breast cancer 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 study33 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.39

ADVERSE EFFECTS AND DOSAGE

Black cohosh was reported to be well tolerated, and no serious adverse events were linked to its use.2932 One 12-week study31 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 products of black cohosh were used, it is difficult to recommend 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 (Bellergal [not available in the United States]; Bellamine),44 dong quai,45 evening primrose oil,46 gabapentin (Neurontin),47 ginseng,48 mirtazapine (Remeron),49 trazodone (Desyrel),50 vitamin E,51 and wild yam,52  but there are few published data on their effectiveness. Studies on these agents are summarized in Table 3.4452 Belladonna/ergotamine tartrate/phenobarbital combination and gabapentin were more effective than placebo in reducing 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.

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)44

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 quai45

71 menopausal women

4.5 g per day

Six months

No significant difference compared with placebo

Similar incidence between groups

Evening primrose oil46

56 menopausal women

500 mg per day

Six months

No significant difference compared with placebo

Similar incidence between groups

Gabapentin (Neurontin)47

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

Ginseng48

384 menopausal women

200 mg per day

Four months

No significant difference compared with placebo

Similar incidence between groups

Mirtazapine (Remeron)49

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)50

25 climacteric women

75 mg per day

Three months

No significant difference from baseline

Drowsiness

Vitamin E51

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 yam52

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.

TABLE 3   Agents Used in the Treatment of Hot Flashes with Limited Supporting Evidence

View Table

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)44

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 quai45

71 menopausal women

4.5 g per day

Six months

No significant difference compared with placebo

Similar incidence between groups

Evening primrose oil46

56 menopausal women

500 mg per day

Six months

No significant difference compared with placebo

Similar incidence between groups

Gabapentin (Neurontin)47

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

Ginseng48

384 menopausal women

200 mg per day

Four months

No significant difference compared with placebo

Similar incidence between groups

Mirtazapine (Remeron)49

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)50

25 climacteric women

75 mg per day

Three months

No significant difference from baseline

Drowsiness

Vitamin E51

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 yam52

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.

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 Database, and the Natural Medicine Database. Key search terms included climacteric, hot flash, hot flush, flushing, menopause, postmenopause, therapy, isoflavones, serotonin reuptake inhibitors, clonidine, belladonna, evening primrose oil, ginseng, dong quai, wild yam, gabapentin, vitamin E, and black cohosh.

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.

REFERENCES

1. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy menopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288:321–33.

2. Stearns V, Beebe KL, Iyengar M, Dube E. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA. 2003;289:2827–34.

3. Weitzner MA, Moncello J, Jacobsen PB, Minton S. A pilot trial of paroxetine for the treatment of hot flashes and associated symptoms in women with breast cancer. J Pain Symptom Manage. 2002;23:337–45.

4. Stearns V, Isaacs C, Rowland J, Crawford J, Ellis MJ, Kramer R, et al. A pilot trial assessing the efficacy of paroxetine hydrochloride (Paxil) in controlling hot flashes in breast cancer survivors. Ann Oncol. 2000;11:17–22.

5. Loprinzi CL, Sloan JA, Perez EA, Quella SK, Stella PJ, Mailliard JA, et al. Phase III evaluation of fluoxetine for treatment of hot flashes. J Clin Oncol. 2002;20:1578–83.

6. Loprinzi CL, Pisansky TM, Fonseca R, Sloan JA, Zahasky KM, Quella SK, et al. Pilot evaluation of venlafaxine hydrochloride for the therapy of hot flashes in cancer survivors. J Clin Oncol. 1998;16:2377–81.

7. Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomized controlled trial. Lancet. 2000;356:2059–63.

8. Barton D, La VB, Loprinzi C, Novotny P, Wilwerding MB, Sloan J. Venlafaxine for the control of hot flashes: results of a longitudinal continuation study. Oncol Nurs Forum. 2002;29:33–40.

9. Evans ML, Pritts E, Vittinghoff E, McClish K, Morgan KS, Jaffe RB. Management of postmenopausal hot flushes with venlafaxine hydrochloride: a randomized, controlled trial. Obstet Gynecol. 2005;105:161–6.

10. Goldberg RM, Loprinzi CL, O’Fallon JR, Veeder MH, Miser AW, Mailliard JA, et al. Transdermal clonidine for ameliorating tamoxifen-induced hot flashes [published correction appears in J Clin Oncol 1996;14:2411]. J Clin Oncol. 1994;12:155–8.

11. Pandya KJ, Raubertas RF, Flynn PJ, Hynes HE, Rosenbluth RJ, Kirshner JJ, et al. Oral clonidine in postmenopausal patients with breast cancer experiencing tamoxifen-induced hot flashes: a University of Rochester Cancer Center Community Clinical Oncology Program study. Ann Intern Med. 2000;132:788–93.

12. Nagamani M, Kelver ME, Smith ER. Treatment of menopausal hot flashes with transdermal administration of clonidine. Am J Obstet Gynecol. 1987;156:561–5.

13. Scambia G, Mango D, Signorile PG, Anselmi Angeli RA, Palena C, Gallo D, et al. Clinical effects of a standardized soy extract in postmenopausal women: a pilot study. Menopause. 2000;7:105–11.

14. Penotti M, Fabio E, Modena AB, Rinaldi M, Omodei U, Vigano P. Effect of soy-derived isoflavones on hot flushes, endometrial thickness, and the pulsatility index of the uterine and cerebral arteries. Fertil Steril. 2003;79:1112–7.

15. Van Patten CL, Olivotto IA, Chambers GK, Gelmon KA, Hislop TG, Templeton E, et al. Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomized, controlled clinical trial. J Clin Oncol. 2002;20:1449–55.

16. Burke GL, Legault C, Anthony M, Bland DR, Morgan TM, Naughton MJ, et al. Soy protein and isoflavone effects on vasomotor symptoms in peri- and postmenopausal women: the Soy Estrogen Alternative Study. Menopause. 2003;10:147–53.

17. Quella SK, Loprinzi CL, Barton DL, Knost JA, Sloan JA, LaVasseur BI, et al. Evaluation of soy phytoestrogens for the treatment of hot flashes in breast cancer survivors: a North Central Cancer Center Treatment Group Trial. J Clin Oncol. 2000;18:1068–74.

18. Upmalis DH, Lobo R, Bradley L, Warren M, Cone FL, Lamia CA. Vasomotor symptom relief by soy isoflavone extract tablets in postmenopausal women: a multicenter, double-blind, randomized, placebo-controlled study [published correction appears in Menopause 2000;7:422]. Menopause. 2000;7:236–42.

19. Faure E, Chantre P, Mares P. Effects of a standardized soy extract on hot flushes: a multicenter, double-blind, randomized, placebo-controlled study. Menopause. 2002;9:329–34.

20. Han KK, Soares JM Jr, Haidar MA, de Lima GR, Baracat EC. Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstet Gynecol. 2002;99:389–94.

21. Secreto G, Chiechi LM, Amadori A, Miceli R, Venturelli E, Valerio T, et al. Soy isoflavones and melatonin for the relief of climacteric symptoms: a multicenter, double-blind, randomized study. Maturitas. 2004;47:11–20.

22. St Germain A, Peterson CT, Robinson JG, Alekel DL. Isoflavone-rich or isoflavone-poor soy protein does not reduce menopausal symptoms during 24 weeks of treatment. Menopause. 2001;8:17–26.

23. Kotsopoulos D, Dalais FS, Liang YL, McGrath BP, Teede HJ. The effects of soy protein containing phytoestrogens on menopausal symptoms in postmenopausal women. Climacteric. 2000;3:161–7.

24. Nikander E, Kilkkinen A, Metsa-Heikkila M, Adlercreutz H, Pietinen P, Tiitinen A, et al. A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Obstet Gynecol. 2003;101:1213–20.

25. Knight DC, Howes JB, Eden JA. The effect of Promensil, an isoflavone extract, on menopausal symptoms. Climacteric. 1999;2:79–84.

26. Baber RJ, Templeman C, Morton T, Kelly GE, West L. Randomized placebo-controlled trial of an isoflavone supplement and menopausal symptoms in women. Climacteric. 1999;2:85–92.

27. Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) study. JAMA. 2003;290:207–14.

28. van de Weijer PH, Barentsen R. Isoflavones from red clover (Promensil) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas. 2002;42:187–93.

29. Jacobson JS, Troxel AB, Evans J, Klaus L, Vahdat L, Kinne D, et al. Randomized trial of black cohosh for the treatment of hot flashes among women with a history of breast cancer. J Clin Oncol. 2001;19:2739–45.

30. Stoll W. Phytopharmacon influences atrophic vaginal epithelium: double blind study—cimicifuga vs estrogenic substances. Therapeuticon. 1987;1:23–31.

31. Wuttke W, Seidlova-Wuttke D, Gorkow C. The Cimicifuga preparation BNO 1055 vs. conjugated estrogens in a double-blind placebo-controlled study: effects on menopause symptoms and bone markers. Maturitas. 2003;44(suppl 1):S67–S77.

32. Hernandez Munoz G, Pluchino S. Cimicifuga racemosa for the treatment of hot flushes in women surviving breast cancer. Maturitas. 2003;44(suppl 1):S59–S65.

33. Liske E, Hanggi W, Henneickevon Zepelin HH, Boblitz N, Wustenberg P, Rahlfs VW. Physiological investigation of a unique extract of black cohosh (Cimicifugae racemosae rhizome): a 6-month clinical study demonstrates no systemic estrogenic effect. J Womens Health Gend Based Med. 2002;11:163–74.

34. Berendsen HH. The role of serotonin in hot flushes. Maturitas. 2000;36:155–64.

35. Boulet MJ, Oddens BJ, Lehert P, Vemer HM, Visser A. Climacteric and menopause in seven South-east Asian countries. Maturitas. 1994;19:157–76.

36. Tang GW. The climacteric of Chinese factory workers. Maturitas. 1994;19:177–82.

37. Albertazzi P, Purdie D. The nature and utility of the phytoestrogens: a review of the evidence. Maturitas. 2002;42:173–85.

38. Farrell E. Medical choices available for management of menopause. Best Pract Res Clin Endocrinol Metab. 2003;17:1–16.

39. American College of Obstetricians and Gynecologists Committee on Practice Bulletins. Use of botanicals for management of menopausal symptoms. Obstet Gynecol 2001;97(suppl 1–11). Accessed online August 15, 2005 at: http://www.acog.org/from_home/publications/misc/pb028.htm.

40. Kronenberg F, Fugh-Berman A. Complementary and alternative medicine for menopausal symptoms: a review of randomized, controlled trials. Ann Intern Med. 2002;137:805–13.

41. Bodinet C, Freudenstein J. Influence of marketed herbal menopause preparations on MCF-7 cell proliferation. Menopause. 2004;11:281–9.

42. Burdette JE, Liu J, Chen SN, Fabricant DS, Piersen CE, Barker EL, et al. Black cohosh acts as a mixed competitive ligand and partial agonist of the serotonin receptor. J Agric Food Chem. 2003;51:5661–70.

43. Borrelli F, Ernst E. Cimicifuga racemosa: a systematic review of its clinical efficacy. Eur J Clin Pharmacol. 2002;58:235–41.

44. Bergmans MG, Merkus JM, Corbey RS, Schellekens LA, Ubachs JM. Effect of Bellergal Retard on climacteric complaints: a double-blind, placebo-controlled study. Maturitas. 1987;9:227–34.

45. Hirata JD, Swiersz LM, Zell B, Small R, Ettinger B. Does dong quai have estrogenic effects in postmenopausal women? A double-blind, placebo-controlled trial. Fertil Steril. 1997;68:981–6.

46. Chenoy R, Hussain S, Tayob Y, O’Brien PM, Moss MY, Morse PF. Effect of oral gamolenic acid from evening primrose oil on menopausal flushing. BMJ. 1994;308:501–3.

47. Guttuso T Jr, Kurlan R, McDermott MP, Kieburtz K. Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol. 2003;101:337–45.

48. Wiklund IK, Mattsson LA, Lindgren R, Limoni C. Effects of standardized ginseng extract on quality of life and physiological parameters in symptomatic postmenopausal women: a double-blind, placebo-controlled trial. Swedish Alternative Medicine Group. Int J Clin Pharmacol Res. 1999;19:89–99.

49. Waldinger MD, Berendsen HH, Schweitzer DH. Treatment of hot flushes with mirtazapine: four case reports. Maturitas. 2000;36:165–8.

50. Pansini F, Albertazzi P, Bonaccorsi G, Zanotti L, Porto S, Dossi L, et al. Trazodone: a non-hormonal alternative for neurovegetative climacteric symptoms. Clin Exp Obstet Gynecol. 1995;22:341–4.

51. Barton DL, Loprinzi CL, Quella SK, Sloan JA, Veeder MH, Egner JR, et al. Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol. 1998;16:495–500.

52. Komesaroff PA, Black CV, Cable V, Sudhir K. Effects of wild yam extract on menopausal symptoms, lipids and sex hormones in healthy menopausal women. Climacteric. 2001;4:144–50.

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.


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