Prophylactic Regenerative Peripheral Nerve Interfaces for Prevention of Postamputation Pain: A Systematic Review and Meta-Analysis of Comparative Clinical Studies.

Background: Chronic postamputation pain-phantom limb pain (PLP) and residual limb pain-is a major barrier to rehabilitation, with symptomatic neuroma formation a key peripheral contributor. The regenerative peripheral nerve interface (RPNI) provides a physiologic target for transected nerves. This review evaluated the effect of prophylactic RPNI, performed at the time of amputation, on pain-related outcomes. Methods: PubMed, Cochrane CENTRAL, ScienceDirect, SpringerLink, and MinhaBVS were searched through 23 November 2025 for comparative studies of prophylactic RPNI versus standard nerve management in major limb amputation. Primary outcomes were symptomatic neuroma incidence and PLP; chronic opioid use was a secondary outcome. Dichotomous outcomes were pooled using random-effects risk ratios (RR); for outcomes with zero events in one arm, the fixed-effect Peto odds ratio (OR) was used as the primary estimate. Risk of bias was assessed with ROBINS-I and certainty with GRADE. Results: Five comparative cohort studies (238 patients) were included; the primary pooled outcomes were derived from three of these cohorts (symptomatic neuroma, 196 patients; phantom limb pain, 181 patients), with two further studies contributing supportive descriptive data. Prophylactic RPNI markedly reduced symptomatic neuroma formation (0/97 vs. 20/99; Peto OR 0.11, 95% CI 0.05-0.29; p < 0.001; I2 = 0%) and PLP (RR 0.52, 95% CI 0.40-0.69; p < 0.001; I2 = 0%). Chronic opioid use at 12 months was also reduced (Peto OR 0.12, 95% CI 0.05-0.29; p < 0.001). Findings were consistent across pediatric, dysvascular, and oncologic populations. Certainty was low to very low. Conclusions: Prophylactic RPNI is associated with substantial, consistent reductions in symptomatic neuroma, phantom limb pain, and chronic opioid use after limb amputation. Despite reliance on low-certainty observational data, these consistent findings suggest that prophylactic RPNI may be a useful component of active nerve management; confirmation in prospective, adequately powered comparative studies is required.