Gabapentin for the Treatment of Hot Flushes in Menopause

A Meta-analysis

Sang-Hee Yoon, MD, PhD; Ji Young Lee, MD, PhD; Chulmin Lee, MD, PhD; Hyojin Lee, MD; Soo-Nyung Kim, MD, PhD

Disclosures

Menopause. 2020;27(4):485-493. 

In This Article

Discussion

The present meta-analysis demonstrates that gabapentin reduces hot flush frequency, duration, and composite score in postmenopausal women. Subgroup analyses revealed the frequency, duration, and composite score of hot flushes reduced with all doses of gabapentin, and meta-regression analysis indicated gabapentin dose to be a significant predictor of frequency and composite score, but not duration, of hot flushes.

Although the mechanism underlying menopausal hot flushes is not fully understood, the thermoregulatory zone is narrowed during menopause; therefore, body temperature changes of as little as 0.1°C can trigger a hot flush.[39,40] Gabapentin possibly affects the thermoregulatory center in the hypothalamus, and may have nociceptive activities due to its high affinity for binding sites on calcium channels.[41] The drug binds to hypothalamic calcium channels, thereby widening the thermoregulatory zone and potentially decreasing the incidence of hot flushes.[32,34,42] Although gabapentin is structurally related to γ-aminobutyric acid (GABA), it does not appear to affect GABA synthesis or reuptake.[43] Based on the above mechanism and the results of this meta-regression analysis, the dose of gabapentin appears to decrease the frequency of hot flushes, but not the duration. The decrease in frequency of hot flushes was more significant than the decrease in duration.

Regarding adverse events, we found that gabapentin leads to increased incidence of dizziness and somnolence. However, there was no difference in the dropout rate. These results suggest that although gabapentin may be associated with adverse effects, they are not so severe that patients wish to discontinue treatment.

Gabapentin is a structural analog of the neuro-transmitter GABA, which is used in the treatment of epilepsy, neurogenic pain, restless legs syndrome, essential tremor, bipolar disorder, and migraine.[44] It is used for the treatment of neurogenic pain during chemotherapy and symptoms of persistent numbness after chemotherapy for gynecological cancers (cervical, endometrial, and ovarian cancer). Salpingo-oophorectomy is often employed in the case of ovarian and endometrial cancer for treatment and staging. This procedure can lead to iatrogenic menopause, which can lead to intractable menopausal symptoms. In this situation, gabapentin is preferred over HT for treatment of menopausal symptoms. Survivors of breast cancer—a representative female cancer—are often prescribed tamoxifen and sometimes complain of menopausal symptoms associated with the drug.[45,46] Tamoxifen and aromatase-inhibitor therapy do not alter efficacy of venlafaxine, citalopram, or paroxetine in terms of hot flush treatment.[11] However, some antidepressants may interfere with tamoxifen metabolism by inhibiting CYP2D6 which metabolizes tamoxifen to its more potent metabolite, endoxifen.[11] Paroxetine has been shown to interact with tamoxifen, whereas gabapentin has not.[12] A retrospective study of women with breast cancer who were taking tamoxifen and paroxetine showed that combined use of both agents was associated with a significantly increased risk of death from breast cancer.[47] Gabapentin could be a promising pharmacologic hot flush treatment for survivors of breast cancer who are taking tamoxifen.

The strengths of this study, compared with the meta-analysis published in 2009[13] which analyzed gabapentin and menopause symptoms, are as follows: first, this meta-analysis included only RCTs, and three new studies have been added since the previous review. Second, an additional variable was added to assess the efficacy of gabapentin. Third, the measurement of efficacy of gabapentin was changed from percentage of reduction to mean difference in hot flush parameters. The reason for this change is that the additional three new RCT studies described outcomes using the mean difference to present data before and after administration of gabapentin. Fourth, we used various statistical methods to verify whether the heterogeneity could be explained and to investigate the efficacy of gabapentin according to dosage. Specifically, we performed subgroup and meta-regression analyses according to gabapentin dosage, which were not performed in the previous meta-analysis.

Nonetheless, the results of this study should be interpreted with caution because of several limitations. First, our meta-analysis included seven studies, despite attempts to conduct an extensive systematic literature search and identify all relevant articles. Some bias may have been introduced because we only included articles published in English. Attempts to communicate with authors to obtain additional information and missing data were unsuccessful. Second, the small number of RCTs included in the meta-analysis reduces the reliability of the results, along with the significant heterogeneity observed across the studies (I2 > 90%). In addition, we analyzed different variables to assess the efficacy of gabapentin, and included different doses and treatment durations in our main analysis, which created heterogeneity within the analysis. We used a random-effects meta-analysis to explain heterogeneity and performed a number of sensitivity and subgroup and meta-regression analyses. Third, it was not possible to conduct subgroup analysis of an aggregated population comprising women with either natural or tamoxifen-induced menopause and with a history of breast cancer. Finally, the authors reported conflicts of interest in three of the seven studies included in the meta-analysis.

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