Background:Targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) procedures have been shown to improve patient-reported outcomes for the treatment of symptomatic neuromas after amputation; however, the specific indications and comparative outcomes of each are unclear. The primary research questions were what complement of nerves most frequently requires secondary pain intervention after conventional amputation, whether this information can guide the focused application of TMR and RPNI to the primary amputation setting, and how the outcomes compare in both settings.Methods:We performed a retrospective review of records for patients who had undergone lower-extremity TMR and/or RPNI at our institution. Eighty-seven procedures were performed: 59 for the secondary treatment of symptomatic neuroma pain after amputation and 28 for primary prophylaxis during amputation. We reviewed records for the amputation level, TMR and/or RPNI timing, pain scores, patient-reported resolution of nerve-related symptoms, and complications or revisions. We evaluated the relationship between the amputation level and the frequency with which each transected nerve required neurologic intervention for pain symptoms.Results:The mean pain score decreased after delayed TMR or RPNI procedures from 4.3 points to 1.7 points (p < 0.001), and the mean final pain score (and standard deviation) was 1.0 ± 1.9 points at the time of follow-up for acute procedures. Symptom resolution was achieved in 92% of patients. The sciatic nerve most commonly required intervention for symptomatic neuroma above the knee, and the tibial nerve and common or superficial peroneal nerve were most problematic following transtibial amputation. None of our patients required a revision pain treatment procedure after primary TMR targeting these commonly symptomatic nerves. Failure to address the tibial nerve during a delayed procedure was associated with an increased risk of unsuccessful TMR, resulting in a revision surgical procedure (odds ratio, 26 [95% confidence interval, 1.8 to 368]; p = 0.02).Conclusions:There is a consistent pattern of symptomatic nerves that require secondary surgical intervention for the management of pain after amputation. TMR and RPNI were translated to the primary amputation setting by using this predictable pattern to devise a surgical strategy that prevents symptomatic neuroma pain.