When immunotherapy hurts: neoadjuvant PD-1 inhibitors increase opioid use after mastectomy with reconstruction.

PURPOSE: Programmed cell death protein-1 (PD-1) inhibitors have transformed cancer therapy, but evidence suggests PD-1 signaling modulates µ-opioid receptor activity, potentially attenuating opioid analgesia. This study evaluated the effect of PD-1-based neoadjuvant chemotherapy (NAC) on perioperative opioid use and pain outcomes following mastectomy with immediate reconstruction. METHODS: We retrospectively reviewed consecutive mastectomies with immediate reconstruction following NAC between 2020 and 2024. Patients were grouped by PD-1-based NAC (NAC + PD-1) versus NAC without PD-1 inhibitors (NAC). Patient and procedural characteristics, perioperative opioid use, pain scores, and post-discharge opioid refills were analyzed. Multivariable analysis identified predictors of post-anesthesia care unit (PACU) opioid use per hour, postoperative pain, and post-discharge refills. RESULTS: Among 277 patients, 54 received NAC + PD-1 and 223 received NAC. BRCA1/2 mutations (38.9% vs. 7.2%, p < 0.001), bilateral surgery (92.6% vs. 67.7%, p < 0.001), and sentinel lymph node biopsy (87.0% vs. 64.6%, p = 0.001) were more common in the NAC + PD-1 group. Despite comparable preoperative analgesia and intraoperative opioids, NAC + PD-1 patients had higher PACU opioid use per hour (3.5 vs. 2.1 OMEs/hour, p = 0.029), higher maximum PACU pain scores (6.3 vs. 5.4 p = 0.011), and post-discharge opioid refills (38.9% vs. 17.0%, p = 0.001). On multivariable analysis, NAC + PD-1 (β = 1.189, p = 0.044), breast volume > 700 cm3 (β = 1.065, p = 0.029) and preoperative analgesia medications (β=-0.541, p = 0.034) predicted PACU opioid use per hour, while NAC + PD-1 (OR = 3.574, p < 0.001) and axillary lymph node dissection (OR = 1.935, p = 0.048) predicted opioid refill likelihood. CONCLUSION: Neoadjuvant PD-1 inhibitors were associated with increased perioperative opioid requirements. Clinicians should consider potential PD-1-related alterations in analgesic response when managing pain in this population.