Nonhormonal therapies for hot flashes in menopause

American Family Physician,  Feb 1, 2006  by Dana G. Carroll

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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. (Am Fam Physician 2006;73:457-64, 467. Copyright [C] 2006 American Academy of Family Physicians.)

The results of the Women's Health Initiative (WHI) study (1) 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 nonhormonal 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. (2-33) 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.

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. (2-9)

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 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 randomized crossover study (5) 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 trial (7) 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)