Patient-controlled analgesia in transition: opioid-sparing strategies and the emergence of mechanism-based alternatives

Opioids have long been central to patient-controlled analgesia (PCA) for postoperative pain management. However, increasing recognition of opioid-related adverse effects such as nausea, vomiting, sedation, respiratory depression, and the risk of dependence has prompted a paradigm shift toward opioid-sparing or opioid-free analgesic strategies [1]. This transition is particularly relevant in the context of Enhanced Recovery After Surgery (ERAS) protocols, which prioritize multimodal analgesia to reduce opioid consumption, accelerate rehabilitation, and shorten hospital stays [2].

In this issue of the Korean Journal of Anesthesiology, Han et al. [3] report a randomized, double-blind, non-inferiority trial comparing opioid-based PCA (fentanyl 1200 µg as continuous basal infusion) with an opioid-sparing PCA (ketorolac 150 mg + nefopam 100 mg) in 98 patients undergoing elective total knee arthroplasty (TKA) under spinal anesthesia [3]. A notable methodological strength of this study was the use of a dual-chamber PCA device that physically separated the continuous non-opioid basal infusion from the patient-controlled opioid bolus channel. This design eliminated drug-compatibility concerns that are inherent in single-chamber systems and provided a reproducible and scalable platform for future opioid-sparing PCA research.

The primary outcome of this study demonstrated that opioid-sparing PCA was non-inferior to opioid-based PCA in controlling pain at rest on postoperative day (POD) 1, with a mean visual analog scale (VAS) difference of 0.45 points (95% CI [−0.36, 1.25]), well within the pre-specified non-inferiority margin of 1.5 points. Notably, the observed difference represented approximately 20% of the established minimal clinically important difference (MCID) of 2.26 points for VAS pain after TKA [4], confirming that the analgesic gap between strategies was not only statistically but also clinically negligible.

Beyond statistical non-inferiority, the opioid-sparing strategy reduced basal PCA opioid exposure infusion by approximately 55% over the first two PODs compared with the opioid-based group. Importantly, this reduction in basal opioid delivery was not offset by an increased patient-initiated bolus demand. Furthermore, rescue analgesic use on POD 2 was significantly lower in the opioid-sparing group (P = 0.006), indicating that the non-opioid regimen provided sustained analgesic coverage without compensatory opioid escalation. The incidence of postoperative nausea and vomiting (PONV) on POD 1 was also markedly reduced in the opioid-sparing group (12.2% vs. 34.7%; P = 0.009), a clinically meaningful benefit given that PONV remains one of the most distressing and mobility-limiting complications after TKA.

Certain limitations of this study warrant further consideration. Despite randomization, an imbalance in the American Society of Anesthesiologists (ASA) physical status distribution was observed, with 98.0% of patients in the opioid-sparing group classified as ASA II compared to 79.6% in the opioid-based group. As a higher ASA classification generally reflects a greater comorbidity burden, this imbalance may have influenced baseline pain sensitivity and analgesic requirements, potentially introducing a conservative bias favoring the opioid-sparing arm. Additionally, the continuous basal opioid infusion used in the control group deviates from the current demand-only ERAS recommendations, which may limit direct applicability. The study also lacks long-term follow-up data on persistent opioid use, functional recovery, and chronic post-surgical pain.

This study is also notable for positioning nefopam as a principal component of basal analgesia rather than as an adjunct. As a centrally acting analgesic with monoaminergic reuptake inhibition and N-methyl-D-aspartate receptor modulation [5,6], nefopam addresses both spinal sensitization and descending inhibitory dysfunction, mechanisms that are particularly relevant to the pronounced inflammatory and nociceptive environments associated with TKA [5,7]. Combined with the peripheral cyclooxygenase inhibition associated with ketorolac, this pairing exemplifies mechanism-based multimodal analgesia simultaneously targeting distinct nociceptive pathways. Emerging intravenous analgesics such as VVZ-149, first-in-class dual-target analgesic shown to reduce postoperative opioid consumption [8], together with low-dose ketamine and dexmedetomidine [9], may further expand the non-opioid analgesic armamentarium for PCA.

The future of PCA may therefore lie not in eliminating opioids entirely but in redefining PCA as a flexible, multimodal, mechanism-based platform in which opioids serve as rescue rather than primary analgesics. The trial conducted by Han et al. [3] provides a timely and well-designed proof-of-concept, reinforcing that opioid stewardship in the perioperative setting is achievable without sacrificing analgesic efficacy, a broadly relevant conclusion as the specialty continues to navigate the opioid crisis.