The impact of repeat opioid use (ROU) on fentanyl-induced respiratory depression

Abstract

Objective: Repeat opioid use (ROU) is a primary driver for the ongoing opioid epidemic, and while a substantial understanding exists for the impact of ROU on behavioral neurophysiology, the consequences of ROU on respiratory-related physiology including opioid-induced respiratory depression (OIRD) remain poorly understood. Hypothesis: ROU leads to respiratory tolerance to fentanyl that is characterized by the blunting of respiratory depression and improvement of O2 consumption (VO2). Methods: We utilized a pre-clinical rodent model. Breathing was measured via whole body-plethysmography in freely behaving adult mice (P>90) prior to and immediately following fentanyl administration. A single dose of fentanyl (0.7 mg/kg, i.p.) was given for up to 6 consecutive days. In a subset of experiments, O2 consumption was measured simultaneously using whole-body plethysmography. Results: We identified two distinct respiratory phenotypes in response to OIRD following ROU. Type 1 phenotype (n=18) adapted over time where breathing during OIRD is greater on day 5 versus day 1. In contrast, the Type 2 phenotype (n=5) showed no such adaptation, with unchanged or worsened breathing by day 5. In a subset of animals (n=12) the relationship between breathing (i.e. minute ventilation (Ve)) and oxygen consumption (VO2) was examined before and following ROU. Under baseline conditions the Ve to VO2 relationship positively correlated on day 1 and 5. During OIRD on day 1 this correlation became negative, but began to normalize by day 5, resembling the baseline relationship. These phenomena also coincided with an increase in the ventilatory drive observed at the whole-animal level and in the isolated preBötzinger complex following ROU. Conclusions: ROU leads to two distinct respiratory phenotypes in response to OIRD, where the majority of subjects show a blunted respiratory depression. Additionally, ROU improves the relationship between breathing and oxygen consumption and enhances inspiratory drive in the presence of fentanyl. These findings suggest that fentanyl-induced hypoxia experienced by repeat opioid users vastly differ from naïve users. Such differences may contribute to the unpredictable occurrence of overdose amongst repeat users. This work was supported by NIH: R01 HL163965 and DA057767. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.