Abstract: The disclosure provides methods of managing opioid therapy, particularly, for pain management. The methods comprise determining in a subject, for example, a subject who has received an opioid treatment, pupillary unrest in ambient light (PUAL). Low values of PUAL can be used to identify patients at risk for opioid side-effects, such as opioid-related respiratory depression (OIRD), and who warrant attention to prevent such side effects. Accordingly, the methods include monitoring the patients having low values of PUAL for signs of adverse side-effects and/or limiting or avoiding administration of opioids.