Forty-three RCTs (n=4,120) were included in the review.
Of the 43 included RCTs, 4 were classified as good quality, 19 as fair quality and 20 as poor quality. Most RCTs had trial groups with less than 50 participants and/or follow-ups of less than 80%. The kappa inter-rater agreement was 0.78.
SSRIs and SNRIs (6 RCTs).
There was a significant reduction in the number of daily hot flushes compared with placebo (WMD -1.13, 95% CI: -1.70, -0.57). The severity or composite score was improved in 4 of the 6 trials with SSRIs or SNRIs. Adverse events included dry mouth, headache, decreased appetite, nausea, constipation and insomnia, and occurred more commonly with SSRIs or SNRIs, particularly at higher doses.
Veralipride (3 RCTs).
The severity or composite score improved with veralipride. Adverse events included pain in the breast, continued discharge of milk and gastrointestinal complaints, and occurred more commonly with veralipride.
Moclobemide (1 RCT).
This study reported a reduction in the frequency and composite score of hot flushes in both the intervention and placebo arm. However, between-group differences were not reported. Two patients withdrew from the trial because of somnolence.
Clonidine (10 RCTs).
There was a significant reduction in the number of daily hot flushes compared with placebo at 4 weeks (WMD -0.95, 95% CI: -1.44, -0.47; 4 RCTs) and 8 weeks (WMD -1.63, 95% CI: -2.76, -0.05; 4 RCTs). The severity or composite score was improved in 4 of the 10 trials with clonidine. Adverse events included dry mouth, insomnia and drowsiness, and occurred more commonly with clonidine, particularly at higher doses.
Methyldopa (3 RCTs).
The severity or composite score improved with methyldopa in the 2 trials that reported this outcome. Adverse events included fatigue, dry mouth, drowsiness and dizziness, and occurred more commonly with methyldopa. There was a report of orthostatic hypotension in one patient.
Gabapentin (2 RCTs).
There was a significant reduction in the number of daily hot flushes compared with placebo (WMD -2.05, 95% CI: -2.80, -1.30). The severity or composite score was improved in both trials with gabapentin. Adverse events to gabapentin included drowsiness, fatigue, dizziness, rash, heart palpitations and peripheral oedema.
Bellergal Retard (1 RCT).
This study reported a reduction in the frequency of hot flushes in both the intervention and placebo arms, with no between-group differences. There were a similar number of withdrawals in both arms of the trial.
Red clover isoflavone extracts (6 RCTs).
There was no significant reduction in the number of daily hot flushes compared with placebo (WMD -0.44, 95% CI: -1.47, 0.58). There was also no difference in the severity or composite score between red clover isoflavone extracts and placebo.
Soy isoflavone extracts (11 RCTs).
There was no significant reduction in the number of daily hot flushes compared with placebo at 4 to 6 weeks (WMD -1.15, 95% CI: -2.33, 0.03; 5 RCTs), but there was a significant reduction at 12 to 16 weeks (WMD -0.97, 95% CI: -1.82, -0.12; 4 RCTs) and at 6 months (WMD -1.22, 95% CI: -2.02, -0.42; 2 RCTs). The severity or composite score was improved in 3 of the 7 RCTs with soy isoflavone extracts that reported this outcome.
Adverse events in trials evaluating isoflavone extracts were most commonly gastrointestinal symptoms. These were similar for both the isoflavone extracts and placebo.
The results of the sensitivity analyses were also presented. The results of the statistical assessment for heterogeneity were not reported for any of the meta-analyses, but a visual inspection of the forest plots indicates that heterogeneity was present in all but one meta-analysis, that of the trials evaluating clonidine. The authors reported that there was no evidence of publication bias.