Non-Opioid versus Opioid Peri-Operative Analgesia in Neurosurgery (Nopain): A Multi-Centre Randomised Controlled Trial

Abstract

Background Up to 70 % of patients report moderate-to-severe pain after craniotomy despite intra-operative opioid titration. Opioids delay neurological evaluation and are frequently complicated by respiratory depression, sedation, nausea, and ileus—effects that are particularly hazardous in neurosurgical patients. Small, single-centre trials suggest that the α2-agonist dexmedetomidine provides comparable analgesia with fewer opioid-related adverse events, but imprecision and heterogeneity have precluded practice change.

Methods The NOPAIN trial is a prospective, parallel-group, assessor-blinded, multi-centre RCT conducted at five high-volume Indian neurosurgical centres. Five-hundred adults (18–65 y) undergoing elective supratentorial tumour resection are randomised (1:1) to an intra-operative infusion of fentanyl 1 µg kg-1 h-1 (opioid arm) or dexmedetomidine 0.5 µg kg-1 h-1 (non-opioid arm). Primary end-points are (a) rescue fentanyl consumption during surgery and (b) numerical rating scale (NRS) pain score in the post-anaesthesia care unit (PACU). Key secondary end-points include haemodynamic stability, opioid-related adverse events, emergence quality, patient-reported sleep and satisfaction, and persistent pain/health-related quality of life (HRQoL) at 3 and 6 months. Intention-to-treat analysis with mixed-effects models is pre-specified.

Results Between 19 October 2022 and 15 March 2024, 500 participants were enrolled; 493 (98.6 %) completed primary outcome assessment. Baseline demographic and surgical variables were comparable. Median (IQR) intra-operative rescue fentanyl was 50 µg (30–75) in the opioid arm versus 0 µg (0–25) in the dexmedetomidine arm (p < 0.001). Median PACU NRS was 4 (3–5) versus 3 (2–4), respectively (p = 0.002). Dexmedetomidine reduced early PACU nausea (12 % vs 28 %) and coughing at extubation (8 % vs 23 %) without prolonging extubation time.

Conclusions Intra-operative dexmedetomidine markedly decreases rescue opioid requirements and modestly improves early postoperative pain and recovery quality after elective supratentorial craniotomy. Long-term pain and HRQoL follow-up is ongoing.