Minimum clinically important differences in acute pain: a patient-level re-analysis of randomized controlled analgesic trials submitted to the US Food and Drug Administration
Christopher J. Miller, Warren B. Bilker, Ian DeLorey, Charles E. Argoff, Russell L. Bell, Andrew Conroy, Jennifer S. Gewandter, Ian Gilron, Jennifer A. Haythornthwaite, Nathaniel P. Katz, Tara McWilliams, Katherine N. Theken, John T. Farrar
Abstract
ABSTRACT: The lack of established minimum clinically important differences in acute pain has made it challenging to interpret efficacy in analgesic trials. We performed a patient-level re-analysis of double-blind, placebo-controlled trials submitted to the US Food and Drug Administration to estimate minimum clinically important differences in acute postoperative pain. Trials were categorized by acute surgical pain model: dental extraction, bunionectomy, orthopedic surgery, and soft tissue surgery. Pain intensity was assessed using the 0 to 10 numeric rating scale (NRS) or 0 to 100 visual analog scale, with visual analog scale scores converted to NRS for analysis. To avoid misclassification from arbitrary thresholds on global impression of change or pain relief scales, meaningful pain relief was determined using the double-stopwatch technique, where patients actively indicated the times they experienced perceptible and meaningful relief. Across 29 trials, 9047 patients with moderate-to-severe baseline pain were included. Patients with severe baseline pain (NRS ≥7) reported meaningful relief at a higher absolute NRS and required larger absolute reductions in pain intensity than those with moderate baseline pain (NRS 4-<7). However, the percent reduction in pain at meaningful relief remained stable across baseline pain levels, suggesting patients assess meaningful relief in relative rather than absolute terms. No appreciable differences in the changes in pain at meaningful relief were observed by age, sex, drug, or route of administration. Receiver operating characteristic curve analysis identified a 50% reduction in pain intensity as a consistent and clinically meaningful threshold across surgical pain models, supporting its use as a standardized patient-centric metric for evaluating analgesic efficacy.