Gabapentin for the treatment of hot flashes in women with natural or tamoxifen-induced menopause: a systematic review and meta-analysis.
BACKGROUND
Various nonhormonal agents have been used for the treatment of hot flashes in women with natural or tamoxifen-induced menopause. Some studies have reported that gabapentin appears to be an effective and well-tolerated treatment modality.


OBJECTIVE
To investigate the efficacy and tolerability of gabapentin for the treatment of menopausal hot flashes, we performed a systematic review of all trials reporting on the efficacy and tolerability of gabapentin in women with hot flashes and a meta-analysis of the randomized controlled trials (RCTs) conducted in this patient population.


METHODS
For the systematic review, a literature search was conducted through MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for articles published in English from inception of the databases through November 2008. The reference sections of retrieved articles were searched, and a manual search of key journals and abstracts from major meetings in clinical pharmacology was conducted. To be included in the meta-analysis, RCTs had to compare gabapentin with placebo in the treatment of hot flashes in women with natural or tamoxifen-induced menopause, regardless of the sample size, dosage used, duration of treatment, or frequency of the episodes. Uncontrolled and openlabel trials were reviewed but excluded from the meta-analysis. The percent reduction in hot flash frequency (relative to baseline) and the composite score (summation of the number of hot flashes in each severity category multiplied by the severity score) were used as primary outcome measures. Dropout rates and the incidences of frequently reported adverse events (eg, dizziness/unsteadiness, fatigue/somnolence) were also investigated.


RESULTS
The systematic review included 7 trials conducted in 901 patients between 2002 and 2008. Study sizes ranged from 22 to 420 patients, total daily doses of gabapentin ranged from 900 to 2400 mg, and titration periods lasted 3 to 12 days. All of the trials were conducted in North America (6 in the United States and 1 in Canada); 4 of the trials enrolled subjects with a history of breast cancer, whereas the remaining 3 trials only enrolled postmenopausal women. Four RCTs were included in the meta-analysis. Data were expressed as weighted mean difference (WMD) or relative risk (RR), with the associated 95% CI. Women assigned to gabapentin reported a significantly greater percent reduction in both the frequency of hot flashes (WMD = 23.72 [95% CI, 16.46-30.97]; P < 0.001) and the composite score (WMD = 27.26 [95% CI, 21.24-33.29]; P < 0.001), with significant between-study heterogeneity (I(2) = 97.8% and 95.6%, respectively). Dropouts due to adverse events were more frequent in women randomized to gabapentin than in controls (RR = 2.09 [95% CI, 1.13-3.85]; P = 0.02; I(2) = 0%). The risk of symptom clustering also was significantly higher in the treatment group than in the controls (dizziness/unsteadiness: RR = 6.94 [95% CI, 3.19-15.13]; P < 0.001; I(2) = 63.1%; and fatigue/somnolence: RR = 4.78 [95% CI, 2.23-10.25]; P < 0.001; I(2) = 0%).


CONCLUSIONS
Comparisons of gabapentin and placebo revealed reductions of 20% to 30% in the frequency and severity of hot flashes with gabapentin, although data across the studies were too heterogeneous to provide a reliable summary effect. Clusterings of dizziness/unsteadiness and fatigue/somnolence were the most frequently reported adverse events associated with gabapentin and resulted in a higher dropout rate due to adverse events in the gabapentin-treated patients than in the controls. More studies are needed to consolidate the outcomes and elucidate useful details regarding this treatment.
Toulis
Konstantinos A
KA
Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynaecology, Aristotle University of Thessaloniki, Thessaloniki, Greece. touliskos@gmail.com
Tzellos
Thrasivoulos
T
Kouvelas
Dimitrios
D
Goulis
Dimitrios G
DG
D000588:Amines / Q000009:adverse effects / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects; D003509:Cyclohexanecarboxylic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D000077206:Gabapentin; D019584:Hot Flashes / Q000188:drug therapy* / Q000209:etiology; D006801:Humans; D008593:Menopause; D016032:Randomized Controlled Trials as Topic; D013629:Tamoxifen / Q000009:adverse effects; D005680:gamma-Aminobutyric Acid / Q000009:adverse effects / Q000627:therapeutic use*
D000588:Amines; D018931:Antineoplastic Agents, Hormonal; D003509:Cyclohexanecarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D013629:Tamoxifen; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin