Update on nonhormonal approaches to menopausal management

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As detailed in Table 1, studies of SSRIs have usually been only weeks in duration, have often been uncontrolled or retrospective in design, and have generally enrolled small numbers of patients, making it difficult to draw valid conclusions from their data.10–13 Overall, the results with SSRIs are mixed with respect to efficacy in reducing the incidence and severity of vasomotor symptoms.

Most studies of SSRIs for this indication have been performed with paroxetine, which has the highest affinity for the norepinephrine receptor among the SSRIs. Fluoxetine and paroxetine have each been studied in randomized controlled trials in menopausal women with vasomotor symptoms, and each has resulted in a reduction in the frequency and severity of those symptoms compared with placebo.11,12 The North American Menopause Society (NAMS), in its 2004 position statement on management of menopause-related vasomotor symptoms,5 and the National Institutes of Health2 have recognized fluoxetine and paroxetine as possible alternatives to HT for the treatment of vasomotor symptoms.

One cautionary note is required with SSRI use in this setting: because SSRIs are strong inhibitors of CYP2D6, an enzyme important in the metabolism of tamoxifen,14 the potential for interactions between SSRIs and tamoxifen must be recognized. In breast cancer patients with the CYP2D6 genotype, paroxetine reduced plasma levels of the active metabolite of tamoxifen.15


Studies of SNRIs have also enrolled few patients, with treatment durations of 4 to 52 weeks (Table 1).10,13

Venlafaxine has been the most widely studied of the SNRIs, but the longest follow-up in studies of venlafaxine has been only 12 weeks.10,13,16–18 It has been shown to reduce the frequency and severity of vasomotor symptoms in several studies, and two of its studies had randomized controlled designs.16,18 In its 2004 position statement, NAMS recognizes low-dose venlafaxine (37.5 to 75.0 mg) as a nonhormonal alternative for the treatment of vasomotor symptoms.5

Duloxetine has been assessed in a single published clinical trial for vasomotor symptoms, a small, 8week, open-label investigation that demonstrated a small reduction in the frequency of vasomotor symptoms with its use.19

Desvenlafaxine succinate, the active metabolite of venlafaxine, was approved by the US Food and Drug Administration (FDA) in February 2008 for the treatment of major depressive disorder. It is currently under FDA review for treatment of menopause-related vasomotor symptoms and is expected to be the first FDA-approved nonhormonal agent for the treatment of menopausal vasomotor symptoms. Among the centrally acting agents studied for treatment of vasomotor symptoms, desvenlafaxine has been assessed in the largest randomized controlled trials to date.

In a randomized trial of 541 menopausal women with hot flashes, both dosages of desvenlafaxine tested (100 and 150 mg/day) were associated with a sustained significant reduction in the incidence of moderate to severe vasomotor symptoms compared with placebo over the 12 to 26 weeks of treatment.20 Withdrawal of desvenlafaxine was associated with a recurrence of symptoms, which the study authors argue is proof that the drug was responsible for the reduced incidence of vasomotor symptoms, despite the large placebo effect observed in the study.

Another randomized trial compared four dosages of desvenlafaxine (50, 100, 150, or 200 mg/day) with placebo in 707 healthy postmenopausal women who experienced at least 50 moderate to severe hot flashes per week.21 Among the 620 evaluable women, the best results overall were seen with the 100-mg dose of desvenlafaxine, which was associated with a 64% reduction from baseline in the average daily number of hot flashes at week 12. Compared with the placebo group, significantly greater percentages of patients achieved a 75% or greater reduction in the number of hot flashes from baseline in the 100-, 150-, and 200­mg dose groups at week 4, and in the 100- and 200-mg dose groups at week 12.

The most common side effects associated with desvenlafaxine were nausea, dizziness, and insomnia. The most common symptoms that occurred upon discontinuation were dizziness, nausea, and headache.21 The rate of discontinuation with desvenlafaxine was lowest in the group assigned to 50 mg, which suggests a dose-related effect in terms of side effects. It should be noted that desvenlafaxine in this study was started at full dosage without titration and was discontinued abruptly, practices that are not typical with the use of venlafaxine and may account for the above-mentioned side effects.

SNRIs are weak inhibitors of CYP2D6 and therefore represent a good nonhormonal alternative for vasomotor symptoms in breast cancer patients being treated with tamoxifen.


Gabapentin is an anticonvulsant that has been assessed in several trials for the treatment of vasomotor symptoms, showing superior efficacy to placebo in all placebo-controlled trials (Table 1). Its mechanism of action against hot flashes is uncertain, but it has been theorized that gabapentin may modulate calcium currents.5

In addition to the placebo-controlled trials mentioned above, gabapentin has been assessed in comparison with estrogen22 and in combination with antidepressants.23 One study randomized 60 postmenopausal women with moderate to severe hot flashes to treatment with conjugated estrogens (0.625 mg/day), gabapentin (titrated to 2,400 mg/day), or placebo for 12 weeks.22 Gabapentin and estrogen were similarly effective in reducing the study’s primary outcome measure—hot flash composite score at 12 weeks—and each was significantly superior to placebo in this regard.

Another study assessed gabapentin in combination with antidepressants (mostly venlafaxine or paroxetine) in 118 women with inadequate hot flash control, 91 of whom were evaluable at 5 weeks.23 Three-fourths of the study population had a history of breast cancer, and two-thirds were taking tamoxifen or an aromatase inhibitor at entry. Women were randomized either to remain on their antidepressant and have gabapentin added or to be weaned off their antidepressant and switched to gabapentin monotherapy. Gabapentin alone was associated with a statistically significant 50% median reduction in hot flash frequency from baseline, with no additional efficacy induced by continuation of the antidepressant. Negative mood changes and nervousness by week 2 were noted in the women who discontinued their antidepressants, although there was no change in quality-of-life evaluations.

The most common side effects of gabapentin in this clinical setting have been somnolence, disorientation, and headache. Notably, the effective dosages of gabapentin studied in women with vasomotor symptoms were higher (900 to 2,700 mg/day) than is sometimes possible to achieve in real-world practice, so the clinical relevance of these studies may be somewhat limited. Nevertheless, the NAMS position statement recognizes gabapentin as an alternative to HT for treating vasomotor symptoms.5

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Case studies and clinical considerations in menopausal management

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