Electrocortical changes associating sedation and respiratory depression by the opioid analgesic fentanyl

Opioid drugs are the mainstay of pain management but present the side-effect of respiratory depression that can be lethal with overdose. In addition to their respiratory effect, opioids also induce a profound sedative state and produce electrocortical features characteristic of a state of reduced brain arousal, similar to anaesthesia or sleep. In such states, respiratory activity depends more on the integrity of the brainstem respiratory network than it does during wakefulness. Accordingly, we propose that sedation by fentanyl induces specific electrocortical changes consistent with reduced brain arousal, and that the magnitude of respiratory depression is associated with distinct electrocortical changes. To these aims, we determined the effects of systemic injections of fentanyl (dosage 100 µg ·kg) versus control on electrocortical  and respiratory activities of freely-behaving rats. We found that fentanyl induced electrocortical changes that differed from those observed in sleep or wakefulness. Fentanyl increased δ (1-3 Hz) frequency power (P < 0.001), but reduced α (7.5-13.5 Hz) and β₂ (20-30 Hz) powers (P = 0.012 and P < 0.001, respectively), when compared to wakefulness. Interestingly, respiratory rate depression by fentanyl was significantly correlated with increased θ power (R = 0.61, P < 0.001), therefore showing a clear association between electrocortical activity and the magnitude of respiratory rate depression. Overall, we provide new evidence linking specific electrocortical changes to the severity of respiratory depression by opioids, which highlights the importance of considering the cortical and subcortical effects of opioids in addition to their impacts on breathing when evaluating opioid-induced respiratory depression.