Objective <p>We examined the relationship between modeled opioid concentration and quantitative pupillary measures during remifentanil infusion sequences with particular attention to the “light-off” (LO) reflex.</p> Methods <p>Ten volunteer subjects were recruited to undergo two 10-min remifentanil infusion protocols. Pupillary unrest in ambient light (PUAL) and LO were measured at baseline and every 2.5 min during the first 10-min infusion–25-min recovery sequence, and after a wash-out period, the Neurological Pupillary index (NPi) and LO were measured during an identical infusion–recovery sequence. We tested proportional change in each parameter from baseline as indicators of dynamic opioid effect.</p> Results <p>On average, remifentanil decreased both LO dilation and PUAL by &gt; 85%, decreased pupil diameter by &gt; 48%, but did not significantly alter the NPi. Hypoxia occurred in 15/16 sequences. LO and PUAL both showed excellent discrimination between high-toxic versus zero-moderate opioid effect. In contrast to PUAL and LO, the scaled pupillary light reflex measurement (NPi) was not altered by opioids.</p> Conclusion <p>LO and PUAL were robust indicators of opioid effect and provided equivalent estimates of respiratory depression risk in our healthy awake subjects. Compared with PUAL, LO offers the advantage of being intuitive and easily derived at the bedside without need for specialized software.</p> Significance <p>Measurement of the pupillary LO reflex with a portable pupillometer provides a simple, discriminating measure of opioid effect.</p> Summary statement <p>Remifentanil blocks the pupillary LO reflex.</p>