Interactions Between Endocannabinoid and Endogenous Opioid Systems Prospectively Influence Postoperative Opioid Use in Pregnant Patients Undergoing Cesarean Delivery

Both endocannabinoid (EC) and endogenous opioid systems are involved in nociceptive processing and may work together synergistically based on preclinical models. This study evaluated the interactive effects of preoperative beta-endorphin concentrations (a key analgesic endogenous opioid) in cerebrospinal fluid (CSF) and ECs (CSF and plasma 2-arachidonoylglycerol [2-AG] and plasma anandamide [AEA]) on postoperative opioid use and pain intensity in a prospective cohort of n = 112 pregnant patients undergoing scheduled cesarean delivery. Maternal blood and CSF samples were collected preoperatively for beta-endorphin and EC assays. Patients completed measures of outpatient opioid use (number of tablets used and days of use) and average pain intensity at 2 weeks postoperatively. Results of general linear model analyses controlling for maternal age, BMI at time of delivery, and race revealed significant interactions between EC and beta-endorphin concentrations on number of opioid tablets used (based on pill count) in the 2 week follow-up period (p’s <.04). Elevated preoperative plasma and CSF 2-AG and plasma AEA predicted reduced outpatient opioid analgesic use particularly for patients low in CSF beta-endorphin. Similar analyses for pain intensity at 2-week follow-up indicated a significant interaction (p<.02) characterized by higher beta-endorphin concentrations being associated with lower subsequent pain only for individuals with low plasma AEA concentrations. Further exploration of interactions between EC and endogenous opioid inhibitory systems as they influence responses to opioid analgesics in other clinical pain populations may help guide development of precision pain management approaches. Funding: Department of Obstetrics and Gynecology at Vanderbilt University Medical Center, K23HD104183, K23DA047476, R01DA050334.