Objective: Gabapentin is used to treat vasomotor symptoms (VMS) in postmenopausal women with contraindications to hormonal therapy or who prefer alternatives. We investigated the efficacy and tolerability of gabapentin for treating menopausal hot flushes via a meta-analysis.

Methods: We searched the PubMed, MEDLINE, EMBASE, and CENTRAL databases for English-language articles published until June, 2018. The following search terms were used: “menopause,” “hot flushes,” “vasomotor symptoms,” “gabapentin,” and “non-hormonal therapy.” Primary outcomes were frequency, duration, and composite score of hot flushes. Secondary outcomes were adverse effects and dropout rate. We estimated the standardized mean difference (SMD) and combined odds ratio (OR) using fixed or random-effects models, depending on study heterogeneity. Subgroup and meta-regression analyses of gabapentin dosage were performed.

Results: We included seven randomized controlled trials that compared single-agent gabapentin with placebo for treating hot flushes in the meta-analysis. Women who received gabapentin reported a significantly greater reduction in the frequency (SMD 2.99 [95% confidence interval 2.01–3.98], P < 0.001), duration (0.89 [0.49–1.30], P < 0.001), and composite score (2.31 [1.50–3.11], P < 0.001) of hot flushes. Adverse events were significantly more frequent among those taking gabapentin than among those taking the placebo (OR 1.58 [0.98–2.18], P < 0.001; and 1.19 [0.43–1.95], P = 0.002 for dizziness and unsteadiness, respectively).

Conclusions: Gabapentin could be used to treat VMS in postmenopausal women with contraindications to hormonal therapy. Future studies should investigate the lowest effective dose of gabapentin to minimize adverse effects.

Menopause is the permanent cessation of a woman’s menstrual cycle. Despite increasing life expectancy worldwide, the average age at the onset of menopause has remained at approximately 51 years. Considering that the average life expectancy of women in the United States is 81 years, women may be postmenopausal for more than one-third of their lives. Hot flushes and night sweats are the most common menopausal symptoms, and there is evidence these symptoms may last for 4 to 10 years, peaking in the year around the final menstrual period and with an average duration of 7 years in some studies.^[1,2] Around 25% of women experience problematic vasomotor symptoms (VMS) that reduce quality of life, requiring treatment in severe cases.^[3]

Estrogen has been used as a hormonal supplement in the treatment of menopausal symptoms for over 60 years, and estrogen therapy is the most effective treatment for VMS in postmenopausal women.^[4] However, more recently, randomized trials such as the Women’s Health Initiative (WHI),^[5] which included women who were mostly at a stage long after the onset of menopause, have shown no such benefit. Moreover, an increased risk of coronary heart disease (CHD) and breast cancer associated with hormone therapy (HT) has led to an abrupt decrease in the use of this treatment.^[6] Subsequent reanalysis of data from the WHI with age stratification, newer randomized and observational data, and several meta-analyses now consistently show that CHD and mortality are reduced when HT is initiated soon after menopause.^[7] Although these recent data show that women who are younger (aged <60 years) and generally healthy at the onset of menopause have a very favorable risk-benefit profile when using HT, there is still concern amongst general practitioners and women that the risks of HT far outweigh the benefits. Additionally, estrogen therapy is contraindicated for treatment of VMS in women with a history of breast cancer, CHD, previous venous thromboembolic events, transient ischemic attack, or stroke; unexplained vaginal bleeding; high-risk endometrial cancer; and active liver disease.^[8]

For this reason, nonhormonal approaches have been considered to treat VMS in postmenopausal women.

Nonhormonal prescription therapies including selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), gabapentin, and clonidine have been tested in randomized placebo-controlled trials, and shown to be effective.^[9] In 2015, The North American Menopause Society (NAMS) published recommendations based on their review of evidence regarding the nonhormonal management of menopause-associated VMS. They reported that cognitive behavioral therapy and clinical hypnosis may be effective nonprescription therapies for the reduction of VMS, and summarized that there is suggestive evidence for the efficacy of SSRIs, SNRIs, gabapentinoids, and clonidine as nonhormonal therapies for VMS.^[10] However, some SSRIs interfere with tamoxifen metabolism by inhibiting the CYP2D6 enzyme that metabolizes tamoxifen to its more potent metabolite, endoxifen.^[11] While paroxetine has been shown to have a strong interaction, venlafaxine and gabapentin are not known to interact with tamoxifen.^[12] Gabapentin could be used for the treatment of VMS in postmenopausal women with contraindications to HT, especially patients with breast cancer who are taking tamoxifen as endocrine therapy or for high-risk women who are taking tamoxifen to reduce their risk of breast cancer. To the best of our knowledge, only one meta-analysis^[13] has been conducted on this topic, which revealed that gabapentin reduced the frequency and severity of VMS.

In the present study, we conducted an updated meta-analysis including the latest evidence to evaluate the efficacy and tolerability of gabapentin for the treatment of menopausal hot flushes. Our investigation included subgroup, sensitivity, and meta-regression analyses.