Twenty-one RCTs were included in the review. All trials were double-blinded. Four trials had a cross-over design. All trials had a quality score of at least three.
Compared with placebo, a significant benefit of 50% improvement in pain response was observed in patients treated with duloxetine (RR 1.60, 95% CI 1.22 to 2.10; two RCTs), milnacipran 200mg/day (RR 1.39, 95% CI 1.05 to 1.84; two RCTs), pregabalin 300mg/day (RR 1.53, 95% CI 1.09 to 2.15; two RCTs), pregabalin 450mg/day (RR 1.94, 95% CI 1.41 to 2.68; two RCTs), and tramadol plus paracetamol (RR 1.87, 95% CI 1.26 to 2.78; one RCT).
Compared with placebo, a significant benefit of 30% improvement in pain response was observed in patients treated with fluoxetine (RR 4.01, 95% CI 1.68 to 9.56; two RCTs), gabapentin (RR 1.65, 95% CI 1.10 to 2.48; one RCT), milnacipran 100mg/day (RR 1.31, 95% CI 1.12 to 1.52; two RCTs), duloxetine (RR 1.52, 95% CI 1.24 to 1.86; two RCTs), milnacipran 200mg/day (RR 1.40, 95% CI 1.22 to 1.62; three RCTs), pregabalin 300mg/day (RR 1.31, 95% CI 1.11 to 1.55; three RCTs), pregabalin 450mg/day (RR 1.50, 95% CI 1.20 to 1.88; three RCTs) and tramadol plus paracetamol (RR 1.77, 95% CI 1.26 to 2.48; one RCT).
A significantly increased risk of discontinuation due to adverse events was observed for milnacipran 100mg/day (RR 2.00, 95% CI 1.50 to 2.67; two RCTs), milnacipran 200mg/day (RR 2.58, 95% CI 1.98 to 3.37; three RCTs), pregabalin 300mg/day (RR 1.57, 95% CI 1.12, 95% CI 2.20; three RCTs) and pregabalin 450mg/day (RR 2.06, 95% CI 1.50 to 2.83; three RCTs).
No significant heterogeneity was observed in any pooled outcome. The mixed treatment comparison analyses showed no significant differences between any pairwise combinations of active treatments for either pain response endpoint.