Duration of clinically meaningful improvement in pain as a patient-centered endpoint in acute pain trials.

Summary

Using data from 34 phase 2/3 analgesic trials (N=11,028), the study proposes ROOT—the proportion of time with clinically important pain reduction without recent rescue—as a patient-centered endpoint. ROOT reached concordant conclusions with SPID in 92.2% of 204 comparisons while avoiding last-observation-carried-forward imputation after rescue, which distorted temporal treatment effects. ROOT preserves interpretability and statistical efficiency, offering a credible alternative to SPID.

Key Findings

• ROOT is defined as the proportion of study time with ≥50% pain reduction without recent rescue or early discontinuation.
• Across 34 trials (N=11,028), ROOT and SPID produced concordant statistical conclusions in 92.2% of 204 comparisons.
• LOCF imputation after rescue distorted temporal treatment effects, especially during periods of high rescue use; ROOT avoided this bias.

Clinical Implications

Sponsors and investigators can adopt ROOT to reduce reliance on imputation after rescue analgesia and to better reflect clinically meaningful benefit, potentially improving decision-making in analgesic development.

Limitations

• ROOT thresholds (eg, 50% reduction) may require disease- or context-specific validation.
• Heterogeneity across included trials could influence generalizability despite high concordance.

Future Directions

Prospective validation of ROOT as a primary endpoint in diverse acute pain indications; exploration of alternative responder thresholds and integration into adaptive and Bayesian trial designs.