PNP is a chronic and disabling manifestation of generalized peripheral nerve damage, most commonly due to diabetes mellitus, chemotherapy-induced, alcoholism induced or hereditary neuropathy. This systematic review and meta-analysis aims to evaluate the efficacy and safety of gabapentinoid along with tricyclic antidepressant (TCA) combination therapy, compared to gabapentinoid mono-therapy in poly-neuropathic pain.

A comprehensive search was conducted across PubMed, Cochrane (CENTRAL), ClinicalTrials.gov, and Google Scholar from inception to 17 July 2025. A total of five RCTS (N=467) were included in this study in order to assess pain reduction (Numeric Rating Scale [NRS], Neuropathic Pain Intensity Score [NPIS]) and adverse events. The secondary outcomes were >30%, and >50% response rates and adverse effects.

 The pooled mean differences for pain reduction favored combination therapy: short-term (1 week) -1.47 (95% CI -1.96 to -0.97), mid-term (4-6 weeks) -0.79 (95% CI -0.89 to -0.70), and long-term (>10 weeks) -0.49 (95% CI -0.96 to -0.02), with moderate heterogeneity (I²=53%). The risk ratio of >30% and 50% response rate was of 1.32(0.90, 1.93) and (1.30[0.76, 2.24]) with low to moderate heterogeneity. Combination therapy significantly raised the incidence of dry mouth (OR 4.21, 95% CI 2.75–6.45; I²=0%), which is one of TCAs' anticholinergic effects. Notably, the combination resulted in less edema (OR 0.35, 95% CI 0.15–0.81; I2=0%), other adverse effects were also minimized, while some other mild events were increased.

 These findings help to highlight that Gabapentinoid-TCA combination therapy suggests a superior analgesia across a diverse neuropathic conditions, with a tolerable profile, which favors its use where monotherapy is insufficient.