Intrathecal Morphine Administration Reduces Postoperative Pain and Peripheral Endocannabinoid Levels in Total Knee Arthroplasty Patients: a Randomized Clinical Trial

Overview

Journal BMC Anesthesiol

Publisher Biomed Central

Specialty Anesthesiology

Date 2018 Mar 1

PMID 29486720

Citations 10

Authors

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

Affiliations

Soon will be listed here.

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.

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References

Cichewicz D, Martin Z, Smith F, Welch S . Enhancement mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and receptor identification. J Pharmacol Exp Ther. 1999; 289(2):859-67. View

Manzanares J, Corchero J, Romero J, Fernandez-Ruiz J, Ramos J, Fuentes J . Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharmacol Sci. 1999; 20(7):287-94. DOI: 10.1016/s0165-6147(99)01339-5. View

Yokota T, Uehara K, Nomoto Y . Intrathecal morphine suppresses NK cell activity following abdominal surgery. Can J Anaesth. 2000; 47(4):303-8. DOI: 10.1007/BF03020942. View

Cravatt B, Lichtman A . Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system. Curr Opin Chem Biol. 2003; 7(4):469-75. DOI: 10.1016/s1367-5931(03)00079-6. View

Rickham P . HUMAN EXPERIMENTATION. CODE OF ETHICS OF THE WORLD MEDICAL ASSOCIATION. DECLARATION OF HELSINKI. Br Med J. 1964; 2(5402):177. PMC: 1816102. DOI: 10.1136/bmj.2.5402.177. View

Brander V, Stulberg S, Adams A, Harden R, Bruehl S, Stanos S . Predicting total knee replacement pain: a prospective, observational study. Clin Orthop Relat Res. 2003; (416):27-36. DOI: 10.1097/01.blo.0000092983.12414.e9. View

. The burden of musculoskeletal conditions at the start of the new millennium. World Health Organ Tech Rep Ser. 2003; 919:i-x, 1-218, back cover. View

Cichewicz D . Synergistic interactions between cannabinoid and opioid analgesics. Life Sci. 2004; 74(11):1317-24. DOI: 10.1016/j.lfs.2003.09.038. View

Finn D, Beckett S, Roe C, Madjd A, Fone K, Kendall D . Effects of coadministration of cannabinoids and morphine on nociceptive behaviour, brain monoamines and HPA axis activity in a rat model of persistent pain. Eur J Neurosci. 2004; 19(3):678-86. DOI: 10.1111/j.0953-816x.2004.03177.x. View

10.

Cravatt B, Lichtman A . The endogenous cannabinoid system and its role in nociceptive behavior. J Neurobiol. 2004; 61(1):149-60. DOI: 10.1002/neu.20080. View

11.

Vigano D, Valenti M, Cascio M, Di Marzo V, Parolaro D, Rubino T . Changes in endocannabinoid levels in a rat model of behavioural sensitization to morphine. Eur J Neurosci. 2004; 20(7):1849-57. DOI: 10.1111/j.1460-9568.2004.03645.x. View

12.

Lo Verme J, Fu J, Astarita G, La Rana G, Russo R, Calignano A . The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol Pharmacol. 2004; 67(1):15-9. DOI: 10.1124/mol.104.006353. View

13.

Wieland H, Michaelis M, Kirschbaum B, Rudolphi K . Osteoarthritis - an untreatable disease?. Nat Rev Drug Discov. 2005; 4(4):331-44. DOI: 10.1038/nrd1693. View

14.

Fu J, Oveisi F, Gaetani S, Lin E, Piomelli D . Oleoylethanolamide, an endogenous PPAR-alpha agonist, lowers body weight and hyperlipidemia in obese rats. Neuropharmacology. 2005; 48(8):1147-53. DOI: 10.1016/j.neuropharm.2005.02.013. View

15.

Vigano D, Rubino T, Parolaro D . Molecular and cellular basis of cannabinoid and opioid interactions. Pharmacol Biochem Behav. 2005; 81(2):360-8. DOI: 10.1016/j.pbb.2005.01.021. View

16.

Hohmann A, Suplita R, Bolton N, Neely M, Fegley D, Mangieri R . An endocannabinoid mechanism for stress-induced analgesia. Nature. 2005; 435(7045):1108-12. DOI: 10.1038/nature03658. View

17.

van der Stelt M, Trevisani M, Vellani V, De Petrocellis L, Moriello A, Campi B . Anandamide acts as an intracellular messenger amplifying Ca2+ influx via TRPV1 channels. EMBO J. 2005; 24(17):3026-37. PMC: 1201361. DOI: 10.1038/sj.emboj.7600784. View

18.

Schelling G, Hauer D, Azad S, Schmoelz M, Chouker A, Schmidt M . Effects of general anesthesia on anandamide blood levels in humans. Anesthesiology. 2006; 104(2):273-7. DOI: 10.1097/00000542-200602000-00012. View

19.

Vogeser M, Hauer D, Azad S, Huber E, Storr M, Schelling G . Release of anandamide from blood cells. Clin Chem Lab Med. 2006; 44(4):488-91. DOI: 10.1515/CCLM.2006.065. View

20.

Loverme J, Russo R, La Rana G, Fu J, Farthing J, Mattace-Raso G . Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha. J Pharmacol Exp Ther. 2006; 319(3):1051-61. DOI: 10.1124/jpet.106.111385. View