Top

Published in:

Open Access 01-12-2018 | Research article

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

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

Published in: BMC Anesthesiology | Issue 1/2018

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.

Agarwal N, Pacher P, Tegeder I, Amaya F, Constantin CE, Brenner GJ, et al. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci. 2007;10(7):870–9. Epub 2007/06/15. doi: nn1916.2.1038/nn1916. PubMed PMID: 17558404; PubMed Central PMCID: PMC2234438CrossRefPubMedPubMedCentral

Cravatt BF, Lichtman AH. The endogenous cannabinoid system and its role in nociceptive behavior. J Neurobiol. 2004;61(1):149–60. https://doi.org/10.1002/neu.20080. Epub 2004/09/14. PubMed PMID: 15362158CrossRefPubMed

Fine PG, Rosenfeld MJ. The endocannabinoid system, cannabinoids, and pain. Rambam Maimonides Med J. 2013;4(4):e0022. https://doi.org/10.5041/RMMJ.10129. PubMed PMID: 24228165; PubMed Central PMCID: PMC3820295CrossRefPubMedPubMedCentral

Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, et al. An endocannabinoid mechanism for stress-induced analgesia. Nature. 2005;435(7045):1108–12. https://doi.org/10.1038/nature03658. PubMed PMID: 15973410CrossRefPubMed

Koltyn KF, Brellenthin AG, Cook DB, Sehgal N, Hillard C. Mechanisms of exercise-induced hypoalgesia. J Pain. 2014;15(12):1294–304. https://doi.org/10.1016/j.jpain.2014.09.006. PubMed PMID: 25261342; PubMed Central PMCID: PMCPMC4302052CrossRefPubMedPubMedCentral

Racz I, Nent E, Erxlebe E, Zimmer A. CB1 receptors modulate affective behaviour induced by neuropathic pain. Brain Res Bull. 2015;114:42–8. https://doi.org/10.1016/j.brainresbull.2015.03.005. PubMed PMID: 25863168CrossRefPubMed

Maccarrone M, Bab I, Biro T, Cabral GA, Dey SK, Di Marzo V, et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015; https://doi.org/10.1016/j.tips.2015.02.008. PubMed PMID: 25796370

Maione S, Costa B, Di Marzo V. Endocannabinoids: a unique opportunity to develop multitarget analgesics. Pain. 2013;154(Suppl 1):S87–93. https://doi.org/10.1016/j.pain.2013.03.023. PubMed PMID: 23623250CrossRefPubMed

Kinsey SG, Long JZ, O'Neal ST, Abdullah RA, Poklis JL, Boger DL, et al. Blockade of endocannabinoid-degrading enzymes attenuates neuropathic pain. J Pharmacol Exp Ther. 2009;330(3):902–10. Epub 2009/06/09. doi: jpet.109.155465. 11.1124/jpet.109.155465. PubMed PMID: 19502530CrossRefPubMedPubMedCentral

10.

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. https://doi.org/10.1016/j.neuropharm.2005.02.013. Epub 2005/05/25. PubMed PMID: 15910890CrossRefPubMed

11.

Lo Verme J, Fu J, Astarita G, La Rana G, Russo R, Calignano A, et al. The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol Pharmacol. 2005;67(1):15–9. https://doi.org/10.1124/mol.104.006353. Epub 2004/10/07. PubMed PMID: 15465922CrossRefPubMed

12.

LoVerme J, Russo R, La Rana G, Fu J, Farthing J, Mattace-Raso G, et al. Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-alpha. J Pharmacol Exp Ther. 2006;319(3):1051–61. https://doi.org/10.1124/jpet.106.111385. Epub 2006/09/26. PubMed PMID: 16997973CrossRefPubMed

13.

Solorzano C, Zhu C, Battista N, Astarita G, Lodola A, Rivara S, et al. Selective N-acylethanolamine-hydrolyzing acid amidase inhibition reveals a key role for endogenous palmitoylethanolamide in inflammation. Proc Natl Acad Sci U S A. 2009;106(49):20966–71. https://doi.org/10.1073/pnas.0907417106. Epub 2009/11/21. PubMed PMID: 19926854; PubMed Central PMCID: PMC2791595CrossRefPubMedPubMedCentral

14.

Sasso O, Moreno-Sanz G, Martucci C, Realini N, Dionisi M, Mengatto L, et al. Antinociceptive effects of the N-acylethanolamine acid amidase inhibitor ARN077 in rodent pain models. Pain. 2013;154(3):350–60. https://doi.org/10.1016/j.pain.2012.10.018. PubMed PMID: 23218523; PubMed Central PMCID: PMC3723234CrossRefPubMed

15.

Fichna J, Wood JT, Papanastasiou M, Vadivel SK, Oprocha P, Salaga M, et al. Endocannabinoid and cannabinoid-like fatty acid amide levels correlate with pain-related symptoms in patients with IBS-D and IBS-C: a pilot study. PLoS One. 2013;8(12):e85073. https://doi.org/10.1371/journal.pone.0085073. PubMed PMID: 24386448; PubMed Central PMCID: PMC3874007CrossRefPubMedPubMedCentral

16.

Manzanares J, Corchero J, Romero J, Fernandez-Ruiz JJ, Ramos JA, Fuentes JA. Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharmacol Sci. 1999;20(7):287–94. Epub 1999/07/03. doi: S0165-6147(99)01339-5. PubMed PMID: 10390647CrossRefPubMed

17.

Cichewicz DL. Synergistic interactions between cannabinoid and opioid analgesics. Life Sci. 2004;74(11):1317–24. Epub 2004/01/07. doi: S0024320503010129. PubMed PMID: 14706563CrossRefPubMed

18.

Vigano D, Rubino T, Parolaro D. Molecular and cellular basis of cannabinoid and opioid interactions. Pharmacol Biochem Behav. 2005;81(2):360–8. Epub 2005/06/02. doi: S0091-3057(05)00145-0. 21.1016/j.pbb.2005.01.021. PubMed PMID: 15927245CrossRefPubMed

19.

Pacheco Dda F, Klein A, Perez AC, Pacheco CM, de Francischi JN, Reis GM, et al. Central antinociception induced by mu-opioid receptor agonist morphine, but not delta- or kappa-, is mediated by cannabinoid CB1 receptor. Br J Pharmacol. 2009;158(1):225–31. Epub 2009/07/15. doi: BPH310. 23.1111/j.1476–5381.2009.00310.x. PubMed PMID: 19594755; PubMed Central PMCID: PMC2795241CrossRefPubMed

20.

Maguire DR, Yang W, France CP. Interactions between mu-opioid receptor agonists and cannabinoid receptor agonists in rhesus monkeys: antinociception, drug discrimination, and drug self-administration. J Pharmacol Exp Ther. 2013;345(3):354–62. https://doi.org/10.1124/jpet.113.204099. PubMed PMID: 23536317; PubMed Central PMCID: PMC3657106CrossRefPubMedPubMedCentral

21.

Maguire DR, France CP. Impact of efficacy at the mu-opioid receptor on antinociceptive effects of combinations of mu-opioid receptor agonists and cannabinoid receptor agonists. J Pharmacol Exp Ther. 2014;351(2):383–9. https://doi.org/10.1124/jpet.114.216648. PubMed PMID: 25194020; PubMed Central PMCID: PMC4201274CrossRefPubMedPubMedCentral

22.

Cichewicz DL, Martin ZL, Smith FL, Welch SP. Enhancement mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and receptor identification. J Pharmacol Exp Ther. 1999;289(2):859–67. Epub 1999/04/24. PubMed PMID: 10215664PubMed

23.

Finn DP, Beckett SR, Roe CH, Madjd A, Fone KC, Kendall DA, et al. 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. Epub 2004/02/27. doi: 3177. PubMed PMID: 14984418CrossRefPubMed

24.

Benedetti F, Amanzio M, Rosato R, Blanchard C. Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nat Med. 2011;17(10):1228–30. https://doi.org/10.1038/nm.2435. PubMed PMID: 21963514CrossRefPubMed

25.

Benedetti F, Thoen W, Blanchard C, Vighetti S, Arduino C. Pain As a reward: changing the meaning of pain from negative to positive co-activates opioid and cannabinoid systems. Pain. 2013;154(3):361–7. https://doi.org/10.1016/j.pain.2012.11.007. PubMed PMID: 23265686CrossRefPubMed

26.

Sagar DR, Gaw AG, Okine BN, Woodhams SG, Wong A, Kendall DA, et al. Dynamic regulation of the endocannabinoid system: implications for analgesia. Mol Pain. 2009;5:59. Epub 2009/10/10. doi: 1744-8069-5-59. 31.1186/1744–8069–5-59. PubMed PMID: 19814807; PubMed Central PMCID: PMC2770047CrossRefPubMedPubMedCentral

27.

Rani Sagar D, Burston JJ, Woodhams SG, Chapman V. Dynamic changes to the endocannabinoid system in models of chronic pain. Philos Trans R Soc Lond Ser B Biol Sci. 2012;367(1607):3300–11. https://doi.org/10.1098/rstb.2011.0390. PubMed PMID: 23108548; PubMed Central PMCID: PMC3481532CrossRef

28.

Fowler CJ, Naidu PS, Lichtman A, Onnis V. The case for the development of novel analgesic agents targeting both fatty acid amide hydrolase and either cyclooxygenase or TRPV1. Br J Pharmacol. 2009;156(3):412–9. Epub 2009/02/20. doi: BPH029. 34.1111/j.1476–5381.2008.00029.x. PubMed PMID: 19226258; PubMed Central PMCID: PMC2697682CrossRefPubMedPubMedCentral

29.

Cravatt BF, Lichtman AH. Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system. Curr Opin Chem Biol. 2003;7(4):469–75. Epub 2003/08/28. doi: S1367593103000796. PubMed PMID: 12941421CrossRefPubMed

30.

Millennium WHOSGotBoMCatSotN. 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. PubMed PMID: 14679827

31.

Wieland HA, Michaelis M, Kirschbaum BJ, Rudolphi KA. Osteoarthritis - an untreatable disease? Nat Rev Drug Discov. 2005;4(4):331–44. https://doi.org/10.1038/nrd1693. PubMed PMID: 15803196CrossRefPubMed

32.

Brander VA, Stulberg SD, Adams AD, Harden RN, Bruehl S, Stanos SP, et al. Predicting total knee replacement pain: a prospective, observational study. Clin Orthop Relat Res. 2003;416:27–36. https://doi.org/10.1097/01.blo.0000092983.12414.e9. PubMed PMID: 14646737CrossRef

33.

Vigano D, Valenti M, Cascio MG, 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. https://doi.org/10.1111/j.1460-9568.2004.03645.x. Epub 2004/09/24. EJN3645. PubMed PMID: 15380006CrossRefPubMed

34.

Sundarathiti P, Thammasakulsiri J, Supboon S, Sakdanuwatwong S, Piangjai M. Comparison Of continuous femoral nerve block (CFNB/SA) and continuous femoral nerve block with mini-dose spinal morphine (CFNB/SAMO) for postoperative analgesia after total knee arthroplasty (TKA): a randomized controlled study. BMC Anesthesiol. 2016;16(1):38. https://doi.org/10.1186/s12871-016-0205-2. PubMed PMID: 27422406; PubMed Central PMCID: PMCPMC4947328CrossRefPubMedPubMedCentral

35.

Pellkofer HL, Havla J, Hauer D, Schelling G, Azad SC, Kuempfel T, et al. The major brain endocannabinoid 2-AG controls neuropathic pain and mechanical hyperalgesia in patients with neuromyelitis optica. PLoS One. 2013;8(8):e71500. https://doi.org/10.1371/journal.pone.0071500. PubMed PMID: 23951176; PubMed Central PMCID: PMC3739748CrossRefPubMedPubMedCentral

36.

Sarchielli P, Pini LA, Coppola F, Rossi C, Baldi A, Mancini ML, et al. Endocannabinoids in chronic migraine: CSF findings suggest a system failure. Neuropsychopharmacology. 2007;32(6):1384–90. Epub 2006/11/23. doi: 1301246. 44.1038/sj.npp.1301246. PubMed PMID: 17119542CrossRefPubMed

37.

Kaufmann I, Schelling G, Eisner C, Richter HP, Krauseneck T, Vogeser M, et al. Anandamide and neutrophil function in patients with fibromyalgia. Psychoneuroendocrinology. 2008;33(5):676–85. Epub 2008/04/09. doi: S0306-4530(08)00059-0. 46.1016/j.psyneuen.2008.02.009. PubMed PMID: 18395993CrossRefPubMed

38.

Hassett P, Ansari B, Gnanamoorthy P, Kinirons B, Laffey JG. Determination of the efficacy and side-effect profile of lower doses of Intrathecal morphine in patients undergoing Total knee Arthroplasty. BMC Anesthesiol. 2008;8:5. https://doi.org/10.1186/1471-2253-8-5. PubMed PMID: 18816386; PubMed Central PMCID: PMCPMC2559822CrossRefPubMedPubMedCentral

39.

Rickham PP. Human Experimentation. Code of Ethics of the World Medical Association. Declaration of Helsinki. Br Med J. 1964;2(5402):177. PubMed PMID: 14150898; PubMed Central PMCID: PMCPMC1816102CrossRefPubMed

40.

Nicholson J, Azim S, Rebecchi MJ, Galbavy W, Feng T, Reinsel R, et al. Leptin levels are negatively correlated with 2-Arachidonoylglycerol in the cerebrospinal fluid of patients with osteoarthritis. PLoS One. 2015;10(4):e0123132. https://doi.org/10.1371/journal.pone.0123132. PubMed PMID: 25835291CrossRefPubMedPubMedCentral

41.

Azim S, Nicholson J, Rebecchi MJ, Galbavy W, Feng T, Reinsel R, et al. Endocannabinoids and acute pain after total knee arthroplasty. Pain. 2015;156(2):341–7. https://doi.org/10.1097/01.j.pain.0000460315.80981.59. PubMed PMID: 25599456; PubMed Central PMCID: PMC4299927CrossRefPubMedPubMedCentral

42.

Azim S, Sangster R, Curcio C, Coleman D, Shah U, Zhang S, et al. Characterization of patients with difficult-to-treat acute pain following Total knee Arthroplasty using multi-modal analgesia. The Open Pain Journal. 2013;6:1–6.CrossRef

43.

Yardeni IZ, Shavit Y, Bessler H, Mayburd E, Grinevich G, Beilin B. Comparison of postoperative pain management techniques on endocrine response to surgery: a randomised controlled trial. Int J Surg. 2007;5(4):239–43. https://doi.org/10.1016/j.ijsu.2006.09.008. PubMed PMID: 17660130CrossRefPubMed

44.

Hill MN, Karatsoreos IN, Hillard CJ, McEwen BS. Rapid elevations in limbic endocannabinoid content by glucocorticoid hormones in vivo. Psychoneuroendocrinology. 2010;35(9):1333–8. https://doi.org/10.1016/j.psyneuen.2010.03.005. PubMed PMID: 20399021; PubMed Central PMCID: PMCPMC2914801CrossRefPubMedPubMedCentral

45.

Hill MN, Bierer LM, Makotkine I, Golier JA, Galea S, McEwen BS, et al. Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the world trade center attacks. Psychoneuroendocrinology. 2013;38(12):2952–61. https://doi.org/10.1016/j.psyneuen.2013.08.004. PubMed PMID: 24035186; PubMed Central PMCID: PMC3870889CrossRefPubMed

46.

Bowles NP, Karatsoreos IN, Li X, Vemuri VK, Wood JA, Li Z, et al. A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome. Proc Natl Acad Sci U S A. 2015;112(1):285–90. https://doi.org/10.1073/pnas.1421420112. PubMed PMID: 25535367; PubMed Central PMCID: PMCPMC4291642CrossRefPubMed

47.

Nomura DK, Morrison BE, Blankman JL, Long JZ, Kinsey SG, Marcondes MC, et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science. 2011;334(6057):809–13. https://doi.org/10.1126/science.1209200. PubMed PMID: 22021672; PubMed Central PMCID: PMC3249428CrossRefPubMedPubMedCentral

48.

Feng CC, Yan XJ, Chen X, Wang EM, Liu Q, Zhang LY, et al. Vagal anandamide signaling via cannabinoid receptor 1 contributes to luminal 5-HT modulation of visceral nociception in rats. Pain. 2014;155(8):1591–604. https://doi.org/10.1016/j.pain.2014.05.005. PubMed PMID: 24813296CrossRefPubMed

49.

Gray JM, Vecchiarelli HA, Morena M, Lee TT, Hermanson DJ, Kim AB, et al. Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety. J Neurosci. 2015;35(9):3879–92. https://doi.org/10.1523/JNEUROSCI.2737-14.2015. PubMed PMID: 25740517; PubMed Central PMCID: PMC4348185CrossRefPubMedPubMedCentral

50.

Vogeser M, Hauer D, Christina Azad S, Huber E, Storr M, Schelling G. Release of anandamide from blood cells. Clin Chem Lab Med. 2006;44(4):488–91. https://doi.org/10.1515/CCLM.2006.065. Epub 2006/04/08. PubMed PMID: 16599845CrossRefPubMed

51.

Bisogno T, Maurelli S, Melck D, De Petrocellis L, Di Marzo V. Biosynthesis, uptake, and degradation of anandamide and palmitoylethanolamide in leukocytes. J Biol Chem. 1997;272(6):3315–23. Epub 1997/02/07. PubMed PMID: 9013571CrossRefPubMed

52.

Yokota T, Uehara K, Nomoto Y. Intrathecal morphine suppresses NK cell activity following abdominal surgery. Can J Anaesth. 2000;47(4):303–8. https://doi.org/10.1007/BF03020942. PubMed PMID: 10764172CrossRefPubMed

53.

Duggan KC, Hermanson DJ, Musee J, Prusakiewicz JJ, Scheib JL, Carter BD, et al. (R)-Profens are substrate-selective inhibitors of endocannabinoid oxygenation by COX-2. Nat Chem Biol. 2011;7(11):803–9. PubMed PMID: 22053353; PubMed Central PMCID: PMC3298755CrossRefPubMedPubMedCentral

54.

van der Stelt M, Trevisani M, Vellani V, De Petrocellis L, Schiano Moriello A, Campi B, et al. Anandamide acts as an intracellular messenger amplifying Ca2+ influx via TRPV1 channels. EMBO J. 2005;24(17):3026–37. Epub 2005/08/19. doi: 7600784. 64.1038/sj.emboj.7600784. PubMed PMID: 16107881CrossRefPubMedPubMedCentral

55.

Dickenson AH, Sullivan AF. Electrophysiological studies on the effects of intrathecal morphine on nociceptive neurones in the rat dorsal horn. Pain. 1986;24(2):211–22. PubMed PMID: 3754322CrossRefPubMed

56.

Weis F, Beiras-Fernandez A, Hauer D, Hornuss C, Sodian R, Kreth S, et al. Effect of anaesthesia and cardiopulmonary bypass on blood endocannabinoid concentrations during cardiac surgery. Br J Anaesth. 2010;105(2):139–44. https://doi.org/10.1093/bja/aeq117. PubMed PMID: 20525978CrossRefPubMed

57.

Schelling G, Hauer D, Azad SC, Schmoelz M, Chouker A, Schmidt M, et al. Effects of general anesthesia on anandamide blood levels in humans. Anesthesiology. 2006;104(2):273–7. Epub 2006/01/27. doi: 00000542-200602000-00012. PubMed PMID: 16436846CrossRefPubMed

58.

Jarzimski C, Karst M, Zoerner AA, Rakers C, May M, Suchy MT, et al. Changes of blood endocannabinoids during anaesthesia: a special case for fatty acid amide hydrolase inhibition by propofol? Br J Clin Pharmacol. 2012;74(1):54–9. https://doi.org/10.1111/j.1365-2125.2012.04175.x. PubMed PMID: 22242687; PubMed Central PMCID: PMC3394128CrossRefPubMedPubMedCentral

59.

Saglik Y, Yazicioglu D, Cicekler O, Gumus H. Investigation of effects of epidural Anaesthesia combined with general Anaesthesia on the stress response in patients undergoing hip and knee Arthroplasty. Turk J Anaesthesiol Reanim. 2015;43(3):154–61. https://doi.org/10.5152/TJAR.2015.26818. PubMed PMID: 27366488; PubMed Central PMCID: PMCPMC4917183CrossRefPubMedPubMedCentral

60.

Roberts CJ, Stuhr KL, Hillard CJ. Swim stress differentially affects limbic contents of 2-arachidonoylglycerol and 2-oleoylglycerol. Neuroscience. 2012;204:74–82. https://doi.org/10.1016/j.neuroscience.2011.11.065. PubMed PMID: 22192839; PubMed Central PMCID: PMC3288304CrossRefPubMed

61.

Wang M, Hill MN, Zhang L, Gorzalka BB, Hillard CJ, Alger BE. Acute restraint stress enhances hippocampal endocannabinoid function via glucocorticoid receptor activation. J Psychopharmacol. 2012;26(1):56–70. https://doi.org/10.1177/0269881111409606. PubMed PMID: 21890595; PubMed Central PMCID: PMC3373303CrossRefPubMed

62.

Dlugos A, Childs E, Stuhr KL, Hillard CJ, de Wit H. Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans. Neuropsychopharmacology. 2012;37(11):2416–27. https://doi.org/10.1038/npp.2012.100. PubMed PMID: 22763622; PubMed Central PMCID: PMC3442338CrossRefPubMedPubMedCentral

63.

Vachon-Presseau E, Martel MO, Roy M, Caron E, Albouy G, Marin MF, et al. Acute stress contributes to individual differences in pain and pain-related brain activity in healthy and chronic pain patients. J Neurosci. 2013;33(16):6826–33. https://doi.org/10.1523/JNEUROSCI.4584-12.2013. PubMed PMID: 23595741CrossRefPubMed

64.

Morena M, Patel S, Bains JS, Hill MN. Neurobiological interactions between stress and the Endocannabinoid system. Neuropsychopharmacology. 2016;41(1):80–102. https://doi.org/10.1038/npp.2015.166. PubMed PMID: 26068727; PubMed Central PMCID: PMCPMC4677118CrossRefPubMed

Title: Intrathecal morphine administration reduces postoperative pain and peripheral endocannabinoid levels in total knee arthroplasty patients: a randomized clinical trial
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
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: BMC Anesthesiology / Issue 1/2018
Electronic ISSN: 1471-2253
DOI: https://doi.org/10.1186/s12871-018-0489-5

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

Background

Methods

Results

Conclusions

Trial registration

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2018

Inhospital outcome of elderly patients in an intensive care unit in a Sub-Saharan hospital

The role of Gabapentin oral solution in decreasing desflurane associated emergence agitation and delirium in children after stabismus surgery, a prospective randomized double-blind study

Gender differences in career development awards in United States’ anesthesiology and surgery departments, 2006–2016

Assessment of changes of regional ventilation distribution in the lung tissue depending on the driving pressure applied during high frequency jet ventilation

Perioperative incidence of airway obstructive and hypoxemic events in patients with confirmed or suspected sleep apnea - a prospective, randomized pilot study comparing propofol/remifentanil and sevoflurane/remifentanil anesthesia

RETRACTED ARTICLE: Effect of perioperative infusion of Dexmedetomidine combined with Sufentanil on quality of postoperative analgesia in patients undergoing laparoscopic nephrectomy: a CONSORT-prospective, randomized, controlled trial