BACKGROUND: Analgesia monitoring is essential to preserve comfort in critically ill sedated patients with traumatic brain injury (TBI). Although pupil dilation (PD) and pain behaviors can be used to assess analgesia, these indicators require application of noxious stimulations for elicitation. Recently, the pupillary light reflex (PLR) has emerged as a nonnoxious parameter that may be used to predict analgesia requirements in non-brain-injured patients. Here, we explored whether PLR can be used for the purpose of analgesia monitoring in critically ill sedated TBI patients. METHODS: Fifteen mechanically ventilated TBI patients (11 men; 54 ± 20 years) under continuous analgesia and sedation infusions were assessed at predefined time within 72 hours of intensive care unit admission. Data collection was performed using video-pupillometry and the Behavioral Pain Scale. At each assessment, pupil size and PLR at rest were recorded followed immediately by the documentation of PD and pain behaviors elicited by a calibrated noxious stimulus. Blood concentrations of analgesics/sedatives were monitored. RESULTS: One hundred three assessments were completed. PLR resulted in an average decrease of 19% in pupil diameter, and PD resulted in an average increase of 10% in pupil diameter. Variations in PLR and PD were more pronounced in subjects who showed a Behavioral Pain Scale score greater than 3 (a recognized sign of subanalgesia) compared with those with no behavioral reaction. Multiple regression analyses suggest a significant overlap between fluctuations in pupillary reflexes and blood levels of fentanyl, not propofol. CONCLUSION: In our sample, percentages of variation in PLR and PD were found to be directly representative of TBI patients' fentanyl blood concentration. Considering information about blood drug concentration is generally not available at bedside, PLR could be used as a proxy to assess analgesia requirements before a nociceptive procedure in critically ill sedated TBI patients who are vulnerable to stress.