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

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.

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.

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.

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.