A systematic review and meta-analysis depicted that among individuals experiencing painful diabetic peripheral neuropathy, gabapentinoids in combination with serotonin and norepinephrine reuptake inhibitors (SNRIs) or tricyclic antidepressants (TCAs) was linked to a more substantial pain alleviation compared to using these medications alone. Researchers sought to evaluate the safety and effectiveness of combining Gabapentinoids with either TCAs or SNRIs in comparison to using any of these medications alone for the treatment of peripheral diabetic neuropathy.

A systematic search was conducted across clinicaltrials.gov, Cochrane Central, Embase, and PubMed databases to identify randomized clinical trials contrasting the combined therapy of gabapentinoids with either SNRIs or TCAs against the monotherapy of any of these drugs. The study computed pooled mean differences (MD) along with a 95% confidence interval (CI) to analyze pain outcomes. The average pain scores over the past 7 days were considered for the analysis, and pain assessments were conducted using an 11-point numeric rating scale (NRS).

Risk ratios (RRs) were determined for binary outcomes, and risk evaluation was conducted with the utilization of the Risk of Bias 2 tool. The analysis encompassed a total of five randomized studies involving 916 subjects, with follow-up durations ranging from 6 to 12 weeks. The results revealed a higher mean pain decrease in cases of combination therapy compared to monotherapy (MD − 0.39). Likewise, there was an enhancement observed in achieving a ≥ 30% decline in average pain (RR 1.16) with combination therapy.

Nevertheless, there was no profound distinction between the groups regarding the attainment of a ≥ 50% drop in average pain (RR 1.21). In the context of comparing combination therapy to gabapentinoid monotherapy, a profound decline in average pain (MD − 0.61) was also noted with combination therapy. The use of combined therapy involving gabapentinoids with TCAs or SNRIs offered more pain relief in the treatment of diabetic peripheral neuropathy compared to monotherapy. However, it's noteworthy that this difference might lack a clinically meaningful impact.