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The association between endogenous opioid function and morphine responsiveness

a moderating role for endocannabinoids

Bruehl, Stephena,*; Burns, John W.b; Morgan, Amandac; Koltyn, Kellid; Gupta, Rajnisha; Buvanendran, Asokumare; Edwards, Davida; Chont, Melissaa; Kingsley, Philip J.f,g; Marnett, Larryf; Stone, Amandaa; Patel, Sachinc

doi: 10.1097/j.pain.0000000000001447
Research Paper

We sought to replicate previous findings that low endogenous opioid (EO) function predicts greater morphine analgesia and extended these findings by examining whether circulating endocannabinoids and related lipids moderate EO-related predictive effects. Individuals with chronic low-back pain (n = 46) provided blood samples for endocannabinoid analyses, then underwent separate identical laboratory sessions under 3 drug conditions: saline placebo, intravenous (i.v.) naloxone (opioid antagonist; 12-mg total), and i.v. morphine (0.09-mg/kg total). During each session, participants rated low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects 4 times in sequence after incremental drug dosing. Mean morphine effects (morphine-placebo difference) and opioid blockade effects (naloxone-placebo difference; to index EO function) for each primary outcome (low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects) were derived by averaging across the 4 incremental doses. The association between EO function and morphine-induced back pain relief was significantly moderated by endocannabinoids [2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)]. Lower EO function predicted greater morphine analgesia only for those with relatively lower endocannabinoids. Endocannabinoids also significantly moderated EO effects on morphine-related changes in visual analog scale–evoked pain intensity (2-AG), drug liking (AEA and 2-AG), and desire to take again (AEA and 2-AG). In the absence of significant interactions, lower EO function predicted significantly greater morphine analgesia (as in past work) and euphoria. Results indicate that EO effects on analgesic and subjective responses to opioid medications are greatest when endocannabinoid levels are low. These findings may help guide development of mechanism-based predictors for personalized pain medicine algorithms.

Individual differences in endogenous opioid function predict morphine analgesic and subjective responses, and these effects are moderated by circulating endocannabinoids.

aDepartment of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, United States

bDepartment of Behavioral Science, Rush University, Chicago, IL, United States

cDepartment of Psychiatry, Vanderbilt University Medical Center, Nashville, TN, United States

dDepartment of Kinesiology, University of Wisconsin, Madison, WI, United States

eDepartment of Anesthesiology, Rush University, Chicago, IL, United States

fDepartment of Biochemistry, Vanderbilt University, Nashville, TN, United States

gA.B. Hancock Memorial Laboratory for Cancer Research, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, United States

Corresponding author. Address: Vanderbilt University Medical Center, 701 Medical Arts Building, 1211 Twenty-First Ave South, Nashville, TN 37212, United States. Tel.: (615) 936-1821; fax: (615) 936-8983. E-mail address: (S. Bruehl).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received September 10, 2018

Accepted November 08, 2018

© 2019 International Association for the Study of Pain
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