Intrathecal morphine administration reduces postoperative pain and peripheral endocannabinoid levels in total knee arthroplasty patients: a randomized clinical trial

Martin Kaczocha,Shivam Shodhan,Jamie L Romeiser,Ruth Reinsel,Tian Feng,Yong Lu,Mario J Rebecchi,James Nicholson,Helene Benveniste,Syed Azim,Sabeen Rizwan,Nora D Volkow

doi:10.1186/s12871-018-0489-5

Abstract

BackgroundThe primary goal of this study was to determine whether administration of intrathecal morphine reduces postoperative pain. The secondary goal was to determine the effect of intrathecal morphine upon circulating levels of the weakly analgesic endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the related lipids palmitoylethanolamide (PEA) and oleoylethanolamide (OEA).MethodsForty two total knee arthroplasty (TKA) patients were enrolled in a prospective, double-blinded, randomized study. The intervention consisted of intrathecal morphine (200 μg) or placebo administered at the time of the spinal anesthesia. Postoperative pain was measured during the first 4 h after surgery while serum levels of AEA, 2-AG, PEA, OEA, and cortisol were measured at baseline and 4 h after surgery.ResultsAdministration of intrathecal morphine reduced postoperative pain 4 h after TKA surgery compared to placebo (p = 0.005) and reduced postoperative systemic opioid consumption (p = 0.001). At baseline, intrathecal morphine led to a significant reduction in AEA, 2-AG, and OEA levels but did not affect PEA or cortisol levels. In patients administered intrathecal placebo, 2-AG levels were elevated 4 h after surgery; whereas patients receiving intrathecal morphine showed reductions in AEA, PEA, and OEA when compared to placebo. At 4 h after TKA surgery cortisol levels were significantly elevated in the placebo group and reduced in those receiving morphine.ConclusionsThese results indicate that intrathecal morphine reduces postoperative pain in TKA patients. Furthermore, activation of central opioid receptors negatively modulates the endocannabinoid tone, suggesting that potent analgesics may reduce the stimulus for production of peripheral endocannabinoids. This study is the first to document the existence of rapid communication between the central opioid and peripheral endocannabinoid systems in humans.Trial registrationThis trial was registered retrospectively. Trial registry: NCT02620631. Study to Examine Pain Relief With Supplemental Intrathecal Morphine in TKA Patients, NCT02620631, 12/03/2015.

Highlights

The primary goal of this study was to determine whether administration of intrathecal morphine reduces postoperative pain
As expected and consistent with previous data [34], patients receiving intrathecal morphine reported reduced acute postoperative pain after surgery compared to placebo (Fig. 2a, p = 0.0049)
Serum endocannabinoid and NAE levels were examined in patients receiving intrathecal morphine or placebo; and pre-surgical baseline (0 h) blood was drawn approximately 10–15 min after morphine administration

Summary

Introduction

The primary goal of this study was to determine whether administration of intrathecal morphine reduces postoperative pain. The secondary goal was to determine the effect of intrathecal morphine upon circulating levels of the weakly analgesic endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the related lipids palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). The endocannabinoids anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) are endogenous lipids that serve as agonists for cannabinoid receptors (CB1 and CB2) [7, 8]. The N-acylethanolamines (NAEs) palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are lipids structurally related to AEA but do not activate cannabinoid receptors; instead they serve as agonists at the nuclear peroxisome proliferatoractivated receptor alpha [10, 11]. Activation of peroxisome proliferator-activated receptor alpha by PEA produces antinociceptive effects in preclinical models of pain [11, 12]. Recent reports indicate that tissue PEA levels are suppressed in animal models of pain [13, 14] and circulating PEA levels are decreased in irritable bowel syndrome patients experiencing abdominal pain compared to pain-free patients [15], suggesting an antinociceptive role of PEA in certain active pain states

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