Sex-based differences in pain outcomes and opioid use following prophylactic regenerative peripheral nerve interface (RPNI) surgery: A propensity matched analysis.

Abstract

Regenerative peripheral nerve interface (RPNI) surgery effectively treats post-amputation pain. Although preclinical studies suggest sex-specific differences in pain modulation, these differences have not been well characterized clinically. We evaluated sex-based differences in pain and medication outcomes following RPNI surgery. A retrospective cohort study was conducted using the University of Michigan database. Adult patients undergoing major upper or lower extremity amputation between 2012 and 2025 were included. Patients receiving prophylactic RPNI surgery were compared with controls managed using standard nerve techniques. A 1:1 propensity score matching was performed using age, amputation level, and comorbidities. Outcomes included phantom limb pain (PLP) scores, symptomatic neuroma presence, and medication use. Opioids and benzodiazepines were quantified as morphine milligram equivalents (MME/day) and lorazepam milligram equivalents (LME/day). Propensity matching yielded 430 patients (215 RPNI; 215 controls; 151 females, 279 males; mean age 56.3±15.6 years; and mean follow-up 36.2±29.4 months). Males reported higher overall PLP severity across cohorts (p=0.039). In the RPNI surgery group, PLP severity decreased significantly over one year for both sexes (p<0.001), with no difference in pain reduction trajectory. Control patients showed minimal PLP improvement. Opioid use decreased significantly after RPNI surgery in both sexes, with greater reduction among males at 12 months (94% vs. 82%wang opioid-free; p=0.023). Females demonstrated higher overall MME/day. RPNI surgery significantly reduces PLP and medication use in both sexes. Females demonstrated higher overall narcotic use, supporting individualized postoperative pain management.