Pupillary dilation to monitor nociception in awake volunteers: A stimuli-randomised placebo-controlled study.

Background: Pupillary reflex dilation (PRD) quantifies nociception in anaesthetised patients, enabling tailored opioid administration, which in turn reduces catecholamine levels and postoperative pain intensity. However, its utility in objectively assessing pain in awake individuals remains challenging.

Objective: To investigate whether PRD can differentiate between painful and nonpainful stimuli in awake volunteers.

Design: This was a randomised, placebo-controlled, stimuli-randomised study conducted after ethical approval and registration (DRKS00024791).

Setting: This single-centre study was performed at BG University Hospital Bergmannsheil Bochum, Germany, between November 2021 and January 2022.

Volunteers: Thirty healthy volunteers (25 ± 2 years, 50% male) were included in the study.

Interventions: After a rest, the following were stimuli applied to one ventral forearm: an unannounced electric pain stimulus (UPS) and a randomised sequence of either an announced painful stimulus (APS), a placebo or a nonpainful stimulus (NPS).

Main outcome measures: Pupil dilatation was measured as PRD (%) for 60 s during the experimental condition "rest", and during and after each stimulus application using an AlgiScan device. The participants rated stimulus pain intensity via a numeric rating scale (NRS: 0 = no pain, 10 = most intense pain imaginable). Statistics: Paired t-test, rmANOVA, Spearman's correlation and receiver operating characteristics (ROC), P < 0.05.

Results: The subjective pain intensity ratings were higher after APS (6.0 ± 1.9) than after UPS (5.5 ± 1.7, P = 0.007), placebo (0.0 ± 0.0, P = 0.027) and NPS (0.0 ± 0.0, P = 0.001). Similarly, objective pupillary reaction to the stimuli measured using PRD was higher for APS: 13 (97.6% CI, 10.0 to 19.0)% vs. NPS 13 (97.6% CI, 7.0 to 20.0), P = 0.024). UPS elicited the highest PRD of 25 (95.7% CI, 18.0 to 30.0)% vs. rest, P < 0.001; significantly greater than placebo at 13.5 (96.4% CI, 10.0 to 22.0)%, P < 0.001); and NPS at 13 (97.6% CI, 7.0 to 20.0)%, P < 0.0001). However, no significant differences in PRD were observed between APS and UPS despite their electrical similarity. PRD correlated with pain intensity (r = 0.35, P < 0.0001).

Conclusions: In awake volunteers, PRD differentiates between painful and nonpainful stimuli and correlates with pain intensity. Noninvasive PRD measurement may be suitable for nociception monitoring in awake individuals.

Trial registration: Prospectively DRKS00024791, March 2021.