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

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

Abstract

Background: 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).

Methods: Forty 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.

Results: Administration 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.

Conclusions: These 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 registration: This trial was registered retrospectively.

Trial registry: NCT02620631 . Study to Examine Pain Relief With Supplemental Intrathecal Morphine in TKA Patients, NCT02620631 , 12/03/2015.

Keywords: Anandamide; Endocannabinoid; Morphine; Pain; Total knee arthroplasty.

Conflict of interest statement

Ethics approval and consent to participate

All the experiments conducted were approved by the Stony Brook University institutional review board (#200362). Written consent was obtained from each patient.

Consent for publication

Not applicable

Competing interests

MK is an Associate Editor at BMC Anesthesiology. The remaining authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Consolidated Standards Of Reporting Trials flowchart of patient recruitment
Fig. 2
Fig. 2
Postoperative pain at rest and analgesic use in patients receiving intrathecal morphine or placebo. a Average NRS pain scores were obtained during the first 4 h after TKA surgery. Bars represent the median and all data points are shown. Intrathecal morphine reduced acute postoperative pain (p = 0.0049). b Postoperative opioid use (morphine equivalent dose) measured via patient controlled analgesia during the first 12 h after surgery. Bars represent the median and all data points are shown. Intrathecal morphine reduced postoperative opioid use (p = 0.001)
Fig. 3
Fig. 3
Serum levels of NAEs and endocannabinoids in patients receiving intrathecal morphine or placebo. The levels of PEA, OEA, AEA, and 2-AG were quantified in serum obtained preoperatively and 4 h after TKA surgery. *, p < 0.05; **, p < 0.01; ***, p < 0.001
Fig. 4
Fig. 4
Trajectories of serum NAE and endocannabinoid levels. Levels of serum PEA, OEA, AEA, and 2-AG levels for each patient at baseline and 4 h after TKA surgery
Fig. 5
Fig. 5
Serum cortisol levels in patients receiving intrathecal morphine or placebo. Levels of cortisol were quantified at baseline and 4 h after TKA surgery. *, p < 0.05

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