Monotherapy Versus Combination Therapy in the Treatment of Painful Diabetic Neuropathy: A Systematic Review and Meta-analysis.

Background and objective: Painful peripheral neuropathy is a common and challenging complication of diabetes mellitus. Combination therapy is used widely by clinicians, although strong evidence for efficacy and safety is lacking. The goal of this study is to compare the efficacy and safety of combination versus monotherapy of first-line medications for peripheral diabetic neuropathy.

Methods: PubMed, Embase, Cochrane Central, and clinicaltrials.gov databases were searched on December 5, 2022, for randomized clinical trials comparing combined therapy with gabapentinoids and either tricyclic antidepressants (TCAs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) versus monotherapy with any of these drugs. Pooled mean differences (MD) with a 95% confidence interval (CI) were computed for pain outcomes, measured on an 11-point numeric rating scale averaging pain scores in the last 7 days. Risk ratios (RRs) were computed for binary endpoints. Risk assessment was performed using the Risk of Bias 2 tool.

Results: A total of five randomized studies and 916 patients were included. Follow-up ranged from 6 to 12 weeks. Mean pain reduction was greater for combination therapy than monotherapy (MD - 0.39; 95% CI - 0.67 to - 0.12; p = 0.005). Similarly, there was an improvement in ≥ 30% reduction in average pain (RR 1.16; 95% CI 1.07-1.26; p < 0.01) with combination therapy. In contrast, there was no significant difference between groups in ≥ 50% reduction in average pain (RR 1.21; 95% CI 0.99-1.49; p = 0.06). When comparing combination therapy versus gabapentinoid monotherapy, there was also a significant reduction in average pain (MD - 0.61; 95% CI - 0.85 to - 0.37; p < 0.01) with combination therapy.

Conclusion: In patients with painful diabetic peripheral neuropathy, the combination of gabapentinoids with TCAs or SNRIs is associated with a greater reduction in pain as compared with monotherapy, although this difference may not translate into a clinically important difference.