Nonestrogen Treatments for Hot Flashes

Author: Sarah J. Winsor, PharmD, and Jennifer Cina, PharmD

More than 85% of menopausal American women experience hot flashes, and a majority of these Historically, hormone replacement therapy (HRT) has been advocated as the cure-all remedy for postmenopausal signs and symptoms and as a reliable method for reducing the risk of cardiovascular disease and osteoporosis. Although HRT appears to be the most effective option for reducing the incidence and severity of hot flashes, new evidence from the Women?s Health Initiative (WHI) supports skepticism about its long-term safety.(2)

The WHI has organized several studies designed to expand knowledge in the area of prevention of diseases in women as they age. A recent WHI study examined the positive and negative effects of the combination of estrogen and progestin HRT. More than 16,000 healthy menopausal women aged 50 to 79, who had not undergone a hysterectomy, were assigned to HRT (estrogen/prog-estin) or placebo. The Data Safety Monitoring Board (DSMB) reported this year that the incidence Table 1of breast cancer was significantly higher in the HRT group than in the placebo group and that there was also a greater incidence of coronary heart disease, stroke, and blood clots in the HRT group (Table 2). Although the incidence of hip fractures and colon cancers decreased, the National Heart, Lung, and Blood Institute stopped the trial on the recommendation of the DSMB, because the risks of this therapy appeared to outweigh the benefits. Originally designed to continue for 8.5 years, the trial was discontinued after 5.2 years of follow-up.(2)The early halt to the WHI trial and the subsequent media reports declaring HRT unsafe have led many women to seek alternative therapies to relieve their hot flashes and other menopausal symptoms. Readers should note that none of the medications discussed below are FDA approved for the treatment of hot flashes.

Nonhormonal Prescription Drug Therapy
Clonidine
The use of clonidine to treat hot flashes was investigated because of the effect of the agent on hypertension and its ability to reduce vascular reactivity. A study of oral clonidine versus placebo demonstrated that the average decrease in hot flashes was greater in the clonidine group than in the placebo group after 4 weeks of treatment (37% compared with 20%) and after 8 weeks (38% compared with 24%).(3)Clonidine did, however, cause dry mouth and sleepiness. Other side effects of clonidine that may be intolerable to some women and may limit its use include nausea, depression, headache, and fatigue.  Due to its minimal proven efficacy and the severity of its side effects, clonidine is not widely used or recommended for the treatment of hot flashes.

Megestrol
Megestrol acetate also was studied for use in the treatment of hot flashes. In 1 study, the drug showed an 80% reduction in hot flashes, compared with 20% with placebo.(4)Although the results of the study seemed favorable, they demonstrated that megestrol requires 2 to 3 weeks before reducing hot flashes, and these effects may persist for weeks after discontinuation of the drug. Long-term side effects were not reported in this study. Megestrol can, however, cause weight gain, thromboembolic disorders, edema, lipid changes, and cardiovascular morbidity, and it has a possible influence on bone structure and on hormone-dependent cancers.

Venlafaxine
Venlafaxine is a serotonin and nor-epinephrine reuptake inhibitor that was studied in clinical trials after anecdotal reports of its effects on hot flashes. A study examined hot flashes in placebo patients and in patients taking venlafaxine 37.5 mg, 75 mg, and 150 mg. It was reported that hot flashes decreased in the venlafaxine groups by 27%, 37%, and 61%, respectively, after 4 weeks.(5)The authors of the study concluded that the most appropriate dose of ven-lafaxine for hot flashes is 75 mg daily. That dosage was more effective than 37.5 mg daily and less toxic than 150 mg daily.(6)Side effects of venlafaxine were dry mouth, anorexia, and nausea, which were tolerated by most patients. It was noted that, in contrast with HRT, which may take weeks to show an effect, venlafaxine reduced hot flashes in a matter of days in some patients.

Fluoxetine
A study of fluoxetine revealed some improvements in hot flashes after therapy. Approximately 80 women were randomized to fluoxetine 20 mg/day or placebo, resulting in a decrease in hot flash score (frequency x average severity) of 50% in the flu-oxetine arm versus a 36% decrease in the placebo arm.(7)The authors concluded that, although the results were modest, fluoxetine was well tolerated, and future studies may yield more impressive results.

Paroxetine
A 6-week pilot study monitored the effects of paroxetine hydrochloride on hot flashes in 27 breast cancer survivors who were experiencing at least 2 hot flashes daily. The study showed that treatment with paroxetine (10 mg/day) for 1 week, followed by 20 mg/day for 4 weeks, reduced the average number of hot flashes by 67% and the average severity by 75%.(8)Few patients experienced side effects; however, some did develop somnolence.

Table 2

Nonhormonal Nonprescription Drug Therapy
Vitamin E
Vitamin E was shown to decrease the incidence of hot flashes by an average of 1 hot flash per day, which the authors attributed to a possible placebo effect.(9)Although this is not a significant reduction, vitamin E was not associated with any side effects in the study, and it is inexpensive.

Soy Phytoestrogens
On average, 25% of Japanese women (who traditionally have a diet high in soy) and 85% of North American women (whose diets are generally lower in soy) complain of hot flashes.(10)These figures correlate with those of studies examining the effects of soy in the reduction of hot flashes. In 1 study, 51 women received 60 g of isolated soy proteins and 76 mg of isoflavones (aglycone units), and 53 women received 60 g of casein (placebo) containing 40 g of proteins but no isoflavones. Women taking soy had a 45% reduction in the number of hot flashes at the end of 12 weeks, compared with a 30% reduction in those women who had taken placebo.(10)The rates of adverse effects were similar in the soy and placebo groups, with gastrointestinal side effects being the most common in both groups.

Black Cohosh
Many women have used black cohosh
(Cimicifuga racemosa) for the treatment of menopausal hot flashes. A study of 85 women that was conducted over 2 months, however, showed no difference in the intensity of hot flashes or in the number of hot flashes experienced between women assigned to a treatment group and to a placebo group.(12)Although the results of this study were unfavorable, the authors suggested that, if women used black cohosh for a longer duration, in higher doses, or in combination with other therapies, favorable outcomes might occur. Remifemin, a commercially available product, contains approximately 20 mg of black cohosh. The suggested regimen is 1 tablet twice daily.(13)According to the German Commission E, no safety data exist beyond 6 months.(13)Adverse effects that have been associated with the use of black cohosh include stomach upset, headache, and weight gain. At higher doses, seizures, visual disturbances, and decreased heart rate have been seen.

Discussion
To date, HRT appears to be the most effective treatment for menopause-associated hot flashes, reportedly reducing their incidence by as much as 70% to 80%.(14)Given recent data, there are limited therapeutic options available that are both safe and effective for the treatment of hot flashes. Herbal products, especially, must be used with caution due to their unregulated status, varying content, and questionable purity. Because of the recent focus on women?s health, studies are being conducted to evaluate the safety and efficacy of short-term use of HRT as well as alternative treatments.  Pharmacists should be vigilant for changes in prescription patterns as they relate to the treatment of this condition and should be prepared to answer questions and counsel patients appropriately.

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