Disrupted circadian rhythms and opioid-mediated adverse effects: Bidirectional relationship and putative mechanisms.

Recent studies have shown a link between disrupted circadian rhythms and the development of chronic opioid-induced negative effects. Both animal and human studies show a significant bidirectional relationship between the circadian system and opioid effects. Opioids can perturb circadian rhythms, and perturbation of the circadian rhythms can aggravate opioid-mediated adverse effects. These bidirectional interactions may attenuate the outcomes of long-term opioid therapy when not considered. A better understanding of the potential mechanisms underlying these interactions may be essential for more effective management of opioid-induced adverse effects. This review highlights the association between circadian rhythms and opioid-induced hyperalgesia, dependence, and withdrawal, and the possible role of the dopaminergic, serotoninergic, and noradrenergic systems, redox state, and stress in this association. We also highlight the existence of an interaction between other rhythmic biological processes, including the sleep-wake cycle as well as melatonin and glucocorticoid rhythms on the circadian and opioid systems and their possible effects on opioid-related negative effects.