Impact of age on PUAL as an indicator of opioid effect in adult subjects

Opioid-induced respiratory depression (OIRD) remains a critical safety concern, particularly in older adults, yet timely, reliable detection methods are limited. Decline of pupillary unrest in ambient light (PUAL) has demonstrated potential as a marker of opioid effect in young adult subjects. We evaluated whether previously observed PUAL thresholds for high-risk opioid exposure in younger adults remain valid in 40-60-year-old subjects. Ten healthy volunteers 40-60 years of age underwent PUAL measurement at baseline and every 2.5 min during a 10-minute remifentanil infusion (0.2-0.3 µg/kg/min) and 25-minute recovery period. High-risk opioid exposure was defined primarily by modeled remifentanil effect-site concentration (CEREMI) threshold during infusion. Findings were then combined with previously collected data from 20 younger subjects (aged 20-39 years) undergoing an identical infusion protocol. PUAL declined consistently during infusion and increased toward baseline during recovery (p < 0.001). During infusion no significant difference in slope over time or CEREMI was observed between age groups, but during recovery a flatter slope was observed in older subjects (p = 0.016). PUAL reliably distinguished between high-versus low-risk opioid exposure during infusion (AUROC = 0.9833 [95% CI: 0.8935, 0.9995]), with interval likelihood ratio (iLR) for high-toxic opioid effect 27.98 (95% CI: 1.79, 438.33) for PUAL < 0.04, 0.75 (95% CI: 0.38, 1.50) for PUAL 0.04-< 0.14, and 0.030 (95% CI: 0.002, 0.477) for PUAL ≥ 0.14. Comparison of discriminatory performance to that of younger subjects showed no significant difference (chi2 = 1.02, p = 0.3129). PUAL thresholds for high-risk opioid exposure are consistent between younger and older adults and do not require age-specific adjustment up to age 60. PUAL offers a reliable, real-time marker of opioid effect with potential to enhance early OIRD detection in adults.