Are Gabapentinoids Effective at Reducing Pain and Improving Sleep After Nerve Injury? A Systematic Review and Meta-analysis.

Abstract

Background: Gabapentinoids are increasingly prescribed off-label to reduce the intensity of peripheral nerve injury-related pain and improve sleep. However, randomized controlled trials (RCTs) comparing gabapentinoids to placebo show differing results, and the crossover design used in some of these trials carries a significant risk of unblinding. Considering that side effects of gabapentinoids are common and misuse is increasing, we pooled the blinded data to provide the best available evidence on the efficacy of gabapentinoids compared with placebo.

Questions/purposes: In this meta-analysis of RCTs of patients with peripheral nerve injuries, we asked: Are gabapentinoids superior to placebo in terms of (1) pain reduction or (2) mitigating sleep disruption?

Methods: We searched PubMed, Embase, and Cochrane Library for RCTs from January 2000 up to January 2022. Only studies reporting on nerve injuries, measuring pain intensity with a VAS or numeric rating scale, were included. Our search yielded 1862 articles: 1218 from Embase, 559 from PubMed, and 85 from the Cochrane Library. We excluded 338 duplicate studies, leaving 1524 remaining studies. After an initial title and abstract screen, we excluded an additional 1512 studies. In all, 12 full texts were analyzed, and 4 studies were included in our meta-analysis, which involved 919 total patients: 402 were treated with either gabapentin or pregabalin, 394 with placebo, and 123 with both in two crossover trials. In the 3 of 4 studies wherein gender distribution of the patient populations was specified, women represented 57% (143 of 250) and 47% (118 of 250) of the patients in the treatment and placebo groups, respectively. The mean ± SD age was 52 ± 13 years for both the treatment and placebo groups. Risk of bias was assessed with the Cochrane Risk of Bias tool and was low for all included studies. We addressed the high risk of unblinding in the crossover trials by excluding the after crossover (unblinded) results. Certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was moderate. All included studies lacked an objective consensus reference test to diagnose peripheral nerve injury, therefore leading to indirectness of available results.

Results: Gabapentinoids did not reduce pain compared with placebo at 1 month (-0.21 [95% confidence interval (CI) -0.72 to 0.29]; p = 0.40) nor at 2 to 4 months (-0.38 [95% CI -0.76 to 0.00]; p = 0.05) after treatment. Additionally, gabapentinoids showed no clinically important difference in sleep interference compared with placebo at 2 to 4 months (-0.56 [95% CI -0.91 to -0.22]; p < 0.01), with a minimum clinically important difference of -1.5.

Conclusion: The best available evidence, now consisting of four RCTs, suggests that gabapentinoids should not be used to reduce pain intensity or sleep disruption in patients with peripheral nerve injuries, especially given their substantial side effects and potential for misuse.

Level of evidence: Level I, therapeutic study.