Efficacy and analgesic potency of cannabinoids considering current available data
A eficácia e o poder analgésico dos canabinoides à luz dos dados atuais disponíveis
Marcus Vinícius Morais; Mauro Almeida; José Oswaldo de Oliveira Junior
Abstract
BACKGROUND AND OBJECTIVES: Several studies have shown the growing interest and consumption of cannabinoids and medical cannabis (MC), with management of chronic pain being one of its main therapeutic recommendations. The objective of this study was to review and analyze the results of the most recent preclinical and clinical research on the application of MC and cannabinoids to understand their analgesic efficacy.
CONTENTS: A literature review was performed in Pubmed. Preclinical research has shown the role of the endocannabinoid system in pain pathways through the identification of its action sites and pain modulation mechanisms. Numerous clinical studies have endeavored to demonstrate the efficacy of CM and cannabinoids in the management of various pain syndromes. Some international guidelines have already incorporated the use of MC and cannabinoids, but as third or fourth-line treatment and, in most cases, with weak recommendation.
CONCLUSION: Despite the growing production of scientific knowledge, the data currently available still lack high-quality evidence to define the efficacy and analgesic potency of cannabinoids. Larger preclinical and clinical research are needed to understand the status of cannabinoids in pain management, as well as to generate high-quality evidence to include or not the use of MC and cannabinoids in guidelines for the management of the various pain syndromes.
Keywords
Resumo
JUSTIFICATIVA E OBJETIVOS: Diversos trabalhos têm constatado o crescente interesse e o consumo de canabinoides e cannabis medicinal (CM), sendo o auxílio no manejo da dor crônica uma de suas principais indicações terapêuticas na atualidade. O objetivo deste estudo foi revisar e analisar os resultados das mais recentes pesquisas pré-clínicas e clínicas da aplicação da CM e dos canabinoides para compreensão de sua eficácia analgésica.
CONTEÚDO: Foi realizada uma revisão de literatura no sistema de busca Pubmed. Pesquisas pré-clínicas têm evidenciado o papel do sistema endocanabinoides nas vias da dor, através da identificação de seus locais de atuação e mecanismos de modulação da dor. Inúmeros estudos clínicos têm mostrado eficácia da CM e dos canabinoides para manejo de diversas síndromes dolorosas. Algumas diretrizes internacionais já incorporaram o uso de CM e canabinoides, mas como tratamento de terceira ou quarta linha e, na maioria dos casos, com poucas recomendações.
CONCLUSÃO: Apesar da crescente produção de conhecimento científico, os dados atualmente disponíveis ainda carecem de evidências de alta qualidade para definição da eficácia e poder analgésico dos canabinoides. São necessários maiores estudos pré-clínicos e clínicos para que se possa compreender melhor o status dos canabinoides no manejo da dor, assim como gerar evidências de alta qualidade para incluir ou não o uso da CM e dos canabinoides nos guidelines de manejo das diversas síndromes dolorosas.
Palavras-chave
References
1 Narouze S, Strand N, Roychoudhury P. Cannabinoids-based medicine pharmacology, drug interactions, and perioperative management of surgical patients. Adv Anesth. 2020;38:167-88.
2 Di Marzo V, Piscitelli F. The endocannabinoid system and its modulation by phytocannabinoids. Neurotherapeutics. 2015;12(4):692-8.
3 Mouslech Z, Valla V. Endocannabinoid system: an overview of its potential in current medical practice. Neuro Endocrinol Lett. 2009;30(2):153-79.
4 Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002;54(2):161-202.
5 Pertwee RG, Ross RA. Cannabinoid receptors and their ligands. Prostaglandins Leukot Essent Fatty Acids. 2002;66(2-3):101-21.
6 Pertwee RG. Cannabinoid receptors and pain. Progr Neurobiol. 2001;63:569-611.
7 Hu SS, Mackie K. Distribution of the endocannabinoid system in the central nervous system. Handb Exp Pharmacol. 2015;231:59-93.
8 Zavala CA, Thomaz AC, Iyer V, Mackie K, Hohmann AG. Cannabinoid CB2 receptor activation attenuates fentanyl-induced respiratory depression. Cannabis Cannabinoid Res. 2021;6(5):389-400.
9 Bukiya AN. Physiology of the endocannabinoid system during development. Adv Exp Med Biol. 2019;1162:13-37.
10 Starowicz K, Finn DP. Cannabinoids and Pain: Sites and Mechanisms of Action. 1st ed. Vol. 80, Advances in Pharmacology. Elsevier Inc.; 2017. 437-75p.
11 Burston JJ, Woodhams SG. Endocannabinoid system and pain: an introduction. Proc NutrSoc. 2014;73(1):106-17.
12 Woodhams SG, Sagar DR, Burston JJ, Chapman V The role of the endocannabinoid system in pain. Handb Exp Pharmacol. 2015;227:119-43.
13 Finn DP, Haroutounian S, Hohmann AG, Krane E, Soliman N, Rice ASC. Cannabinoids, the endocannabinoid system, and pain: a review of preclinical studies. Pain. 2021;162(Suppl 1):S5-S25.
14 Lu HC, Mackie K. Review of the endocannabinoid system. Biol Psychiatry Cogn Neurosci Neuroimaging. 2021;6(6):607-15.
15 De Petrocellis L, D1 Marzo V Non-CB1, Non-CB2 receptors for endocannabinoids, plant cannabinoids, and synthetic cannabimimetics: focus on G-protein-coupled receptors and transient receptor potential channels. J Neuroimmune Pharmacol. 2010;5(1):103-21.
16 Vučkovic S, Srebro D, Vujovic KS, Vučetic Č, Prostran M. Cannabinoids and pain: new insights from old molecules. Front Pharmacol. 2018;9:1259.
17 Zou S, Kumar U. Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci. 2018;19(3):833.
18 Jardin I, López JJ, Diez R, Sánchez-Collado J, Cantonero C, Albarran L, Woodard GE, Redondo PC, Salido GM, Smani T, Rosado JA. TRPs in pain sensation. Front Physiol. 2017;8:392.
19 Ilgen MA, Bohnert K, Kleinberg F, Jannausch M, Bohnert AS, Walton M, Blow FC. Characteristics of adults seeking medical marijuana certification. Drug Alcohol Depend. 2013;132(3):654-9.
20 Bourke JA, Catherwood VJ, Nunnerley JL, Martin RA, Levack WMM, Thompson BL, Acland RH. Using cannabis for pain management after spinal cord injury: a qualitative study. Spinal Cord Ser Cases. 2019;5:82.
21 Boland EG, Bennett MI, Allgar V, Boland JW. Cannabinoids for adult cancer-related pain: Systematic review and meta-Analysis. BMJ Supp Palliat Care. 2020;10(1):l4-24.
22 Jennings JM, Johnson RM, Brady AC, Dennis DA. Patient perception regarding potential effectiveness of cannabis for pain management. J Arthroplasty. 2020;35(12):3524-7.
23 Byars T, Theisen E, Bolton DL. Using cannabis to treat cancer-related pain. Semin Oncol Nurs. 2019;35(3):300-9.
24 Levinsohn EA, Hill KP. Clinical uses of cannabis and cannabinoids in the United States. J Neurol Sci. 2020;411:116717.
25 Koppel BS. Cannabis in the treatment of dystonia, dyskinesias, and tics. Neurotherapeutics. 2015;12(4):788-92.
26 Baron EP, Lucas P, Eades J, Hogue O. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort. J Headache Pain. 2018;19(1):37.
27 Boehnke KF, Litinas E, Clauw DJ. Medical cannabis use is associated with decreased opiate medication use in a retrospective cross-sectional survey of patients with chronic pain. J Pain. 2016;17(6):739-44.
28 Jarjou'i A, Izbicki G. Medical cannabis in asthmatic patients. Isr Med Assoc J. 2020;22(4):232-5.
29 Pergam SA, Woodfield MC, Lee CM, Cheng GS, Baker KK, Marquis SR, Fann JR. Cannabis use among patients at a comprehensive cancer center in a state with legalized medicinal and recreational use. Cancer. 2017;123(22):4488-97.
30 Balash Y, Bar-Lev Schleider L, Korczyn AD, Shabtai H, Knaani J, Rosenberg A, Baruch Y, Djaldetti R, Giladi N, Gurevich T. Medical cannabis in Parkinson disease: real-life patients' experience. Clin Neurophamacol. 2017;40(6):268-72.
31 Campbell G, Hall WD, Peacock A, Lintzeris N, Bruno R, Larance B, Nielsen S, Cohen M, Chan G, Mattick RP, Blyth F, Shanahan M, Dobbins T, Farrell M, Degenhardt L. Cannabis use, pain and prescription opioid use in people living with chronic non-cancer pain: findings from a 4-year prospective cohort study. Lancet Public health. 2018;3(7):e34l-e350.
32 Piper BJ, Beals ML, Abess AT, Nichols SD, Martin MW, Cobb CM, DeKeuster RM. Chronic pain patients' perspectives of medical cannabis. Pain. 2017;158(7):1373-9.
33 Drosdowsky A, Blaschke S, Koproski T, Fullerton S, Thakerar A, Ellen S, Phipps-Nelson J, de Neef C. Cancer patients' use of and attitudes towards medicinal cannabis. Aust Health Rev. 2020;44(4):650-5.
34 Smith JM, Mader J, Szeto ACH, Arria AM, Winters KC, Wilkes TCR. Cannabis use for medicinal purposes among Canadian University students. Can J Psychiatry 2019;64(3):351-5.
35 New York State Department of Health. Medical Use of Marijuana Under the Compassionate Care Act - Two-Year Report. 2018; (
36 Physician Certification Pattern Review. The Florida Board of Board Medicine and Board of Osteopathic Medicine. 2020;(
37 Dixon W The pharmacology of cannabis indica. Br Med J. 1899;2(2030):1899.
38 Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR, Rice KC. Cannabinoid receptor localization in brain. Proc Natl Acad Sci USA 1990;87(5):1932-6.
39 Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci. 1991;11 (2):563-83.
40 Mailleux P, Parmentier M, Vanderhaeghen JJ. Distribution of cannabinoid receptor messenger RNA in the human brain: An in-situ hybridization histochemistry with oligonucleotides. Neuroscience Letters. 1992;l43(112):200-4.
41 Thomas BF, Wei X, Martin BR. Characterization and autoradiographic localization of the cannabinoid binding site in rat brain using [3H]11-OH-Δ9-THC-DMH. J Pharmacol Exper Ther. 1992;263(3): 1383-90.
42 Glass M, Dragunow M, Faull RLM. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience. 1997;77(2):299-318.
43 Tsou K, Brown S, Sanudo-Pena MC, Mackie K, Walker JM. Immunohistochemical distribution of neuropeptides in the rat central nervous system. Neuroscience. 1998;83(2):393-411.
44 Hohmann AG, Herkenham M. Regulation of cannabinoid and mu opioid receptors in rat lumbar spinal cord following neonatal capsaicin treatment. Neurosci Lett. 1998;252(l):13-6.
45 Sanudo-Pena MC, Strangman NM, Mackie K, Walker JM, Kang T. CB1 receptor localization in rat spinal cord and roots, dorsal root ganglion, and peripheral nerve. Zhongguo Yao Xue Bao. 1999;20(12):1115-20.
46 Hohmann AG, Briley EM, Herkenham M. Pre- and postsynaptic distribution of cannabinoid and mu opioid receptors in rat spinal cord. Brain Res. 1999;822(1-2):17-25.
47 Hohmann AG, Herkenham M. Cannabinoid receptors undergo axonal flow in sensory nerves. Neuroscience. 1999;92(4):1171-5.
48 Hohmann AG, Herkenham M. Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: A double-label in situ hybridization study. Neuroscience. 1999;90(3):923-31.
49 Lichtman AH, Martin BR. Cannabinoid-induced antinociception is mediated by a spinal α2-noradrenergic mechanism. Brain Res. 1991;559(2):309-l4.
50 Lichtman AH, Martin BR. Spinal and supraspinal components of cannabino id-induced antinociception. J Pharmacol Exp Ther. 1991;258(2):517-23.
51 Yaksh TL. The antinociceptive effects of intrathecally administered levonantradol and desacetyllevonantradol in the rat. J Clin Pharmacol. 1981;21(8-9 Suppl) 334S-340S.
52 Buxbaum DM. Analgesic activity of 89-tetrahydrocannabinol in the rat and mouse. Psychopharmacologia. 1972;25(3):275-80.
53 Bloom AS, Dewey WL, Harris LS, Brosius KK 9 nor 9β Hydroxyhexahydrocannabinol, a cannabinoid with potent antinociceptive activity: comparisons with morphine. J Pharmacol Exp Ther. 1977;200(2):263-70.
54 Sofia RD, Nalepa SD, Harakal JJ, Vassar HB. Anti-edema and analgesic properties of Δ 9 - tetrahydrocannabinol (THC). J Pharmacol Exp Ther. 1973;186(3):646-55.
55 Formukong EA, Evans AT, Evans FJ. Analgesic and antiinflammatory activity of constituents of Cannabis sativa L. Inflammation. 1988;12(4):361-71.
56 Jacob JJ, Ramabadran K, Campos-Medeiros M. A pharmacological analysis of levonantradol antinociception in mice. J Clin Pharmacol. 1981;21(Sl):327-33.
57 Herzberg U, Eliav E, Bennett GJ, Kopin IJ. The analgesic effects of R(+)-WIN 55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain. Neurosci Lett. 1997;221(2-3):157-60.
58 Walker JM, Huang SM, Strangman NM, Tsou K, Sañudo-Peña MC. Pain modulation by release of the endogenous cannabinoid anandamide. Proc Natl Acad Sci USA 1999;96(21):12198-203.
59 Martin WJ, Tsou K, Walker JM. Cannabinoid receptor-mediated inhibition of the rat tail-flick reflex after microinjection into the rostral ventromedial medulla. Neurosci Lett. 1998;242(l):33-6.
60 Woodhams SG, Chapman V, Finn DP, Hohmann AG, Neugebauer V The cannabinoid system and pain. Neuropharmacology. 2017;124:105-20.
61 Donvito G, Nass SR, Wilkerson JL, Curry ZA, Schurman LD, Kinsey SG, Lichtman AH. The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain. Neuropsychopharmacology. 2018;43(1):52-79.
62 Toniolo EF, Gupta A, Franciosi AC, Gomes I, Devi LA, Dale CS. Interactions between cannabinoid and opioid receptors in a mouse model of diabetic neuropathy Pain. 2021;163(7):l4l4-23.
63 Walker JM, Huang SM. Cannabinoid analgesia. Pharmacol Ther. 2002;95:127-35.
64 Starowicz K, Makuch W, Osikowicz M, Piscitelli F, Petrosino S, Di Marzo V, Przewlocka B. Spinal anandamide produces analgesia in neuropathic rats: possible CB 1- and TRPV1-mediated mechanisms. Neuropharmacology. 2012;62(4):1746-55.
65 Guindon J, Desroches J, Beaulieu P. The antinociceptive effects of intraplantar injections of 2-arachidonoyl glycerol are mediated by cannabinoid CB 2 receptors. Br J Pharmacol. 2007;150(6):693-701.
66 Ross RA, Coutts AA, McFarlane SM, Anavi-Goffer S, Irving AJ, Pertwee RG, MacE-wan DJ. Scott RH. Actions of cannabinoid receptor ligands on rat cultured sensory neurones: implications for antinociception. Neuropharmacology. 2001;40(2):221-32.
67 Maresz K, Carrier EJ, Ponomarev ED, Hillard CJ, Dittel BN. Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. J Neurochem. 2005;95(2):437-45.
68 Romero-Sandoval A, Eisenach JC. Spinal cannabinoid receptor type 2 activation reduces hypersensitivity and spinal cord glial activation after paw incision. Anesthesiology. 2007;106(4):787-94.
69 Baek JH, Zheng Y, Darlington CL, Smith PR Cannabinoid CB2 receptor expression in the rat brainstem cochlear and vestibular nuclei. Acta Otolaryngol. 2008;128(9):961-7.
70 Romero-Sandoval A, Nutile-McMenemy N, DeLeo JA. Spinal microglial and perivascular cell cannabinoid receptor type 2 activation reduces behavioral hypersensitivity without tolerance after peripheral nerve injury. Anesthesiology. 2008;108(4):722-34.
71 Roche M, Finn DP. Brain CB2 receptors: Implications for neuropsychiatric disorders. Pharmaceuticals. 2010;3(8):2517-33.
72 Hsieh GC, Pai M, Chandran P, Hooker BA, Zhu CZ, Salyers AK, Wensink EJ, Zhan C, Carroll WA, Dart MJ, Yao BB, Honore P, Meyer MD. Central and peripheral sites of action for CB 2 receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats. Br J Pharmacol. 2011;162(2):428-40.
73 Svíženská IH, Brázda V, Klusáková I, Dubový P. Bilateral changes of cannabinoid receptor type 2 protein and mrna in the dorsal root ganglia of a rat neuropathic pain model. J Histochem Cytochem. 2013;61(7):529-47.
74 Zhang HY, Gao M, Liu QR, Bi GH, Li X, Yang HJ, Gardner EL, Wu J, Xi ZX Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice. Proc Natl Acad Sci USA. 2014;111(46):E5007-15.
75 Concannon RM, Okine BN, Finn DP, Dowd E. Differential upregulation of the cannabinoid CB2 receptor in neurotoxic and inflammation-driven rat models of Parkinson's disease. Exp Neurol. 2015;269:133-41.
76 Shiue SJ, Peng HY, Lin CR, Wang SW, Rau RH, Cheng JK. Continuous intrathecal infusion of cannabinoid receptor agonists attenuates nerve ligation-induced pain in rats. Reg Anesth Pain Med. 2017;42(4):499-506.
77 Gonçalves TC, Londe AK, Albano RI, de Araújo Júnior AT, de Aguiar Azeredo M, Biagioni AF, Vasconcellos TH, Dos Reis Ferreira CM, Teixeira DG, de Souza Crippa JA, Vieira D, Coimbra NC. Cannabidiol and endogenous opioid peptide-mediated mechanisms modulate antinociception induced by transcutaneous electrostimulation of the peripheral nervous system. J Neurol Sci. 2014;347(l-2):82-9.
78 Ludtke DD, Siteneski A, Galassi TO, Buffon AC, Cidral-Filho FJ, Reed WR, Salgado ASI, Dos Santos ARS, Martins DF. High-intensity swimming exercise reduces inflammatory pain in mice by activation of the endocannabinoid system. Scand J Med Sci Sports. 2020;30(8):1369-78.
79 Madeira F, Brito RN, Emer AA, Batisti AP, Turnes BL, Salgado ASI, Cidral-Filho FJ, Mazzardo-Martins L, Martins DF. The role of spinal inhibitory neuroreceptors in the antihyperalgesic effect of warm water immersion therapy. Braz J Phys Ther. 2021;25(1):56-61.
80 Klinger-Gratz PP, Ralvenius WT, Neumann E, Kato A, Nyilas R, Lele Z, Katona I, Zeilhofer HU. Acetaminophen relieves inflammatory pain through CB1 cannabinoid receptors in the rostral ventromedial medulla. J Neurosci. 2018;38(2):322-34.
81 Jergova S, Perez C, Imperial JS, Gajavelli S, Jain A, Abin A, Olivera BM, Sagen J. Cannabinoid receptor agonists from Conus venoms alleviate pain-related behavior in rats. Pharmacol Biochem Behav. 2021;205:173182.
82 Petrosino S, Palazzo E, de Novellis V, Bisogno T, Rossi F, Maione S, Di Marzo Y Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats. Neuropharmacology. 2007;52(2):4l5-22.
83 Starowicz K, di Marzo V. Non-psychotropic analgesic drugs from the endocannabinoid system: “Magic bullet” or “multiple-target” strategies? Eur J Pharmacol. 2013;716(l-3):4l-53.
84 Helyes Z, Németh J, Thán M, Bölcskei K, Pintér E, Szolcsányi J. Inhibitory effect of anandamide on resiniferatoxin-induced sensory neuropeptide release in vivo and neuropathic hyperalgesia in the rat. Life Sci. 2003;73(18):2345-53.
85 Guindon J, Beaulieu P. Antihyperalgesic effects of local injections of anandamide, ibuprofen, rofecoxib and their combinations in a model of neuropathic pain. Neuropharmacology. 2006;50(7):8l4-23.
86 Desroches J, Guindon J, Lambert C, Beaulieu P. Modulation of the anti-nociceptive effects of 2-arachidonoyl glycerol by peripherally administered FAAH and MGL inhibitors in a neuropathic pain model. Br J Pharmacol. 2008;155(6):913-24.
87 Xiong W, Cui T, Cheng K, Yang F, Chen SR, Willenbring D, Guan Y, Pan HL, Ren K, Xu Y, Zhang L. Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors. J Exp Med. 2012;209(6): 1121-34.
88 Vigil JM, Montera MA, Pentkowski NS, Diviant JP, Orozco J, Ortiz AL, Rael LJ, Westlund KN. The therapeutic effectiveness of full spectrum hemp oil using a chronic neuropathic pain model. Life. 2020;10(5):69.
89 Abraham AD, Leung EJY, Wong BA, Rivera ZMG, Kruse LC, Clark JJ, Land BB. Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain. Neuropsychopharmacology. 2020;45(7): 1105-14.
90 Casey SL, Atwal N, Vaughan CW Cannabis constituent synergy in a mouse neuropathic pain model. Pain. 2017;158:2452-60.
91 Sideris A, Piskoun B, Russo L, Norcini M, Blanck T, Recio-Pinto E. Cannabinoid 1 receptor knockout mice display cold allodynia, but enhanced recovery from spared-nerve injury-induced mechanical hypersensitivity. Mol Pain. 2016;12: 1744806916649191.
92 Wilkerson JL, Gentry KR, Dengler EC, Wallace JA, Kerwin AA, Armijo LM, Kuhn MN, Thakur GA, Makriyannis A, Milligan ED. Intrathecal cannabilactone CB(2)R agonist, AM1710, controls pathological pain and restores basal cytokine levels. Pain. 2012 May;153(5):1091-106.
93 Kinsey SG, Naidu PS, Cravatt BF, Dudley DT, Lichtman AH. Fatty acid amide hydrolase blockade attenuates the development of collagen-induced arthritis and related thermal hyperalgesia in mice. Pharmacol Biochem Behav. 2011;99(4):718-25.
94 Cabanero D, Ramirez-Lopez A, Drews E, Schmöle A, Otte DM, Wawrzczak-Bargiela A, Huerga Encabo H, Kummer S, Ferrer-Montiel A, Przewlocki R, Zimmer A, Maldonado R. Protective role of neuronal and lymphoid cannabinoid CB2 receptors in neuropathic pain. Elife. 2020;9:e55582.
95 Elmes SJR, Jhaveri MD, Smart D, Kendall DA, Chapman V. Cannabinoid CB2 receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in naïve rats and in rat models of inflammatory and neuropathic pain. Eur J Neurosci. 2004;20(9):2311-20.
96 De Gregorio D, McLaughlin RJ, Posa L, Ochoa-Sanchez R, Enns J, Lopez-Canul M, Aboud M, Maione S, Comei S, Gobbi G. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain. 2019;160(1):136-50.
97 Harris HM, Sufka KJ, Gul W, Elsohly MA. Effects of Delta-9-tetrahydrocannabinol and cannabidiol on cisplatin-induced neuropathy in mice. Planta Med. 2016;82(13):1169-72.
98 Schuelert N, McDougall JJ. Cannabinoid-mediated antinociception is enhanced in rat osteoarthritic knees. Arthritis Rheum. 2008;58(1):l45-53.
99 Akopian AN, Ruparel NB, Patwardhan A, Hargreaves KM. Cannabinoids desensitize capsaicin and mustard oil responses in sensory neurons via TRPA1 activation. J Neurosci. 2008;28(5):1064-75.
100 Hama A, Sagen J. Centrally mediated antinociceptive effects of cannabinoid receptor ligands in rat models of nociception. Pharmacol Biochem Behav. 2011;100(2):340-6.
101 Sánchez Robles EM, Bagües Arias A, Martín Fontelles MI. Cannabinoids and muscular pain. Effectiveness of the local administration in rat. Eur J Pain. 2012;16(8):1116-27.
102 Mazzari S, Canella R, Petrelli L, Marcolongo G, Leon A. N-(2-Hydroxyethyl) hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation. Eur J Pharmacol. 1996;300(3):227-36.
103 Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, Feldmann M. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci USA 2000;97(17):9561-6.
104 Escobar W, Ramirez K, Avila C, Limongi R, Vanegas H, Vazquez E. Metamizol, a non-opioid analgesic, acts via endocannabinoids in the PAG-RVM axis during inflammation in rats. Eur J Pain. 2012;16(5):676-89.
105 Nackley AG, Makriyannis A, Hohmann AG. Selective activation of cannabinoid CB2 receptors suppresses spinal Fos protein expression and pain behavior in a rat model of inflammation. Neuroscience. 2003;119(3):747-57.
106 Verrico CD, Wesson S, Konduri V, Hofferek CJ, Vazquez-Perez J, Blair E, Dunner K Jr, Salimpour P, Decker WK, Halpert MM. A randomized, double-blind, placebo--controlled study of daily cannabidiol for the treatment of canine osteoarthritis pain. Pain. 2020;161(9):2191-202.
107 Kozela E, Lev N, Kaushansky N, Eilam R, Rimmerman N, Levy R, Ben-Nun A, Juknat A, Vogel Z. Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis-like disease in C57BL/6 mice. Br J Pharmacol. 2011 ;163(7):1507-19.
108 Macari DM, Gbadamosi B, Jaiyesimi I, Gaikazian S. Medical cannabis in cancer patients: a survey of a community hematology oncology population. Am J Clin Oncol. 2020;43(9):636-9.
109 Luckett T, Phillips J, Lintzeris N, Allsop D, Lee J, Solowij N, Martin J, Lam L, Aggarwal R, McCaffrey N, Currow D, Chye R, Lovell M, McGregor I, Agar M. Clinical trials of medicinal cannabis for appetite-related symptoms from advanced cancer: a survey of preferences, attitudes and beliefs among patients willing to consider participation. Intern Med J. 2016;46(11): 1269-75.
110 Nugent SM, Morasco BJ, O'Neil ME, Freeman M, Low A, Kondo K, Elven C, Zakher B, Motu'apuaka M, Paynter R, Kansagara D. The effects of cannabis among adults with chronic pain and an overview of general harms: a systematic review. Ann Intern Med. 2017;167(5):319-31.
111 Chang Y, Zhu M, Vannabouathong C, Mundi R, Chou RS, Bhandari M. Medical cannabis for chronic noncancer pain: a systematic review of health care recommendations. Pain Res Manag. 2021;4;2021:8857948.
112 Gazendam A, Nucci N, Gouveia K, Abdel Khalik H, Rubinger L, Johal H. Cannabinoids in the management of acute pain: a systematic review and meta-analysis. Cannabis Cannabinoid Res. 2020;5(4):290-7.
113 Aly E, Masocha W Targeting the endocannabinoid system for management of HLV-associated neuropathic pain: a systematic review. IBRO Neurosci Rep. 2021;10:109-18.
114 Häuser W, Finnerup NB, Moore RA. Systematic reviews with meta-analysis on cannabis-based medicines for chronic pain: a methodological and political minefield. Pain. 2018;159(10):1906-7.
115 Wright P, Walsh Z, Margolese S, Sanchez T, Arlt S, Belle-Isle L, St Pierre M, Bell A, Daeninck P, Gagnon M, Lacasse G, MacCallum C, Mandarino E, Yale J, O'Hara J, Costiniuk C. Canadian clinical practice guidelines for the use of plant-based cannabis and cannabinoid-based products in the management of chronic non-cancer pain and co-occurring conditions: protocol for a systematic literature review. BMJ Open. 2020;10(5):e0361l4.
116 Johal H, Devji T, Chang Y, Simone J, Vannabouathong C, Bhandari M. Cannabinoids in chronic non-cancer pain: a systematic review and meta-analysis. Clin Med Insights Arthritis Musculoskelet Disord. 2020;13: 1179544120906461.
117 Longo R, Oudshoorn A, Befus D. Cannabis for chronic pain: a rapid systematic review of randomized control trials. Pain Manage Nurs. 2021;22(2):141-9.
118 Guillouard M, Authier N, Pereira B, Soubrier M, Mathieu S. Cannabis use assessment and its impact on pain in rheumatologic diseases: A systematic review and meta-analysis. Rheumatology. 2021;60(2):549-56.
119 Okusanya BO, Asaolu IO, Ehiri JE, Kimaru LJ, Okechukwu A, Rosales C. Medical cannabis for the reduction of opioid dosage in the treatment of non-cancer chronic pain: a systematic review. Syst Rev. 2020;9(1):167.
120 Fisher E, Moore RA, Fogarty AE, Finn DP, Finnerup NB, Gilron I. Cannabinoids, cannabis, and cannabis-based medicine for pain management: a systematic review of randomised controlled trials. Pain. 2021;162(Suppl l):S45-66.
121 Stockings E, Campbell G, Hall WD, Nielsen S, Zagic D, Rahman R, Murnion B, Farrell M, Weier M, Degenhardt L. Cannabis and cannabinoids for the treatment of people with chronic noncancer pain conditions: a systematic review and meta-analysis of controlled and observational studies. Pain. 2018;159(10):1932-54.
122 First L, Douglas W, Habibi B, Singh JR, Sein MT. Cannabis use and low-back pain: a systematic review. Cannabis Cannabinoid Res. 2020;5(4):283-9.
123 Meng H, Johnston B, Englesakis M, Moulin DE, Bhatia A. Selective cannabinoids for chronic neuropathic pain: a systematic review and meta-analysis. Anesth Analg. 2017;125(5):1638-52.
124 Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2018;3(3):CD012182.
125 Montero-Oleas N, Arevalo-Rodriguez I, Nuñez-González S, Viteri-García A, Simancas-Racines D. Therapeutic use of cannabis and cannabinoids: an evidence mapping and appraisal of systematic reviews. BMC Complement Med Ther. 2020;20(1):12.
126 Kurlyandchik I, Tiralongo E, Schloss J. Safety and efficacy of medicinal cannabis in the treatment of fibromyalgia: a systematic review. J Altern Complement Med. 2021;27(3):198-213.
127 Aviram J, Samuelly-Leichtag G. Efficacy of cannabis-based medicines for pain management: a systematic review and meta-analysis of randomized controlled trials. Pain Physician. 2017;20:E755-96.
128 Häuser W, Petzke F, Fitzcharles MA. Efficacy, tolerability and safety of cannabis-based medicines for chronic pain management — an overview of systematic reviews. Eur J Pain. 2018;22(3):455-70.
129 Stevens AJ, Higgins MD. A systematic review of the analgesic efficacy of cannabinoid medications in the management of acute pain. Acta Anaesthesiol Scand. 2017;61(3):268-80.
130 Häuser W, Welsch P, Klose P, Radbruch L, Fitzcharles MA. Efficacy, tolerability and safety of cannabis-based medicines for cancer pain: A systematic review with meta-analysis of randomised controlled trials. Schmerz. 2019;33(5):424-36.
131 Boychuk DG, Goddard G, Mauro G, Orellana MF. The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain: a systematic review. J Oral Facial Pain Headache. 2015;29(1):7-14.
132 Madden K, George A, van der Hoek NJ, Borim FM, Mammen G, Bhandari M. Cannabis for pain in orthopedics: a systematic review focusing on study methodology. Can J Surg. 2019;62(6):367-8.
133 De Vita MJ, Moskal D, Maisto SA, Ansell EB. Association of cannabinoid administration with experimental pain in healthy adults: a systematic review and meta-analysis. JAMA Psychiatry. 2018;75(11):1118-27.
134 Fitzcharles MA, Baerwald C, Ablin J, Häuser W Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): A systematic review of randomized controlled trials. Schmerz. 2016;30(1):47-61.
135 Yanes JA, McKinnell ZE, Reid MA, Busier JN, Michel JS, Pangelinan MM, Sutherland MT, Younger JW, Gonzalez R, Robinson JL. Effects of cannabinoid administration for pain: A meta-analysis and meta-regression. Exp Clin Psychopharmacol. 2019;27(4):370-82.
136 Moore RA, Fisher E, Finn DP, Finnerup NB, Gilron I, Haroutounian S. Cannabinoids, cannabis, and cannabis-based medicines for pain management : an overview of systematic reviews. Pain. 2021;162(Suppl 1):S67-79.
137 Bell RF, Kalso EA. Cannabinoids for pain or profit? Pain. 2021;162(Suppl l):S125-6.
138 Weizman L, Dayan L, Brill S, Nahman-Averbuch H, Hendler T, Jacob G, et al. Cannabis analgesia in chronic neuropathic pain is associated with altered brain connectivity. Neurology. 2018;91:el285-94.
139 Naccache DD. Cannabis alleviates neuropathic pain and reverses weight loss in diabetic neuropathic cachexia in a previous heroin abuser. Endocrinol Diabetes Metab Case Rep. 2020;2020:20-0108.
140 Odonkor CA, AlFarra T, Adekoya P, Orhurhu V, Rodriguez T, Sottosanti E, Kaye AD. Dorsal column stimulation and cannabinoids in the treatment of chronic nociceptive and neuropathic pain: a review of the clinical and pre-clinical data. Curr Pain Headache Rep. 2022;26(2):103-18.
141 Dykukha I, Malessa R, Essner U, Überall MA. Nabiximols in chronic neuropathic pain: a meta-analysis of randomized placebo-controlled trials. Pain Med. 2021;22(4):861-74.
142 Lee G, Grovey B, Furnish T, Wallace M. Medical cannabis for neuropathic pain. Curr Pain Headache Rep. 2018;22(1):8.
143 Andreae MH, Carter GM, Shaparin N, Suslov K, Ellis RJ, Ware MA, Abrams DI, Prasad H, Wilsey B, Indyk D, Johnson M, Sacks HS. Inhaled cannabis for chronic neuropathic pain: a meta-analysis of individual patient data. J Pain. 2015;16(12):1221-32.
144 Sainsbury B, Bloxham J, Pour MH, Padilla M, Enciso R. Efficacy of cannabis-based medications compared to placebo for the treatment of chronic neuropathic pain: a systematic review with meta-analysis. J Dent Anesth Pain Med. 2021;21(6):479-506.
145 O'Brien M, McDougall JJ. Cannabis and joints: scientific evidence for the alleviation of osteoarthritis pain by cannabinoids. Curr Opin Pharmacol. 2018;40:104-9.
146 Johal H, Vannabouathong C, Chang Y, Zhu M, Bhandari M. Medical cannabis for orthopaedic patients with chronic musculoskeletal pain: does evidence support its user TherAdvMuculoskelet Dis. 2020;12:1759720X20937968.
147 Bebee B, Taylor DM, Bourke E, Pollack K, Foster L, Ching M, Wong A. The CAN-BACK trial: a randomised, controlled clinical trial of oral cannabidiol for people presenting to the emergency department with acute low back pain. Med J Aust. 2021;2l4(8):370-5.
148 Kim TE, Townsend RK, Branch CL, Romero-Sandoval EA, Hsu W Cannabinoids in the treatment of back pain. Neurosurgery. 2020;87(2):166-75.
149 Cameron EC, Hemingway SL. Cannabinoids for fibromyalgia pain: a critical review of recent studies (2015-2019). J Cannabis Res. 2020;2(1):19.
150 Berger AA, Keefe J, Winnick A, Gilbert E, Eskander JP, Yazdi C, Kaye AD, Viswanath O, Urits I. Cannabis and cannabidiol (CBD) for the treatment of fibromyalgia. Best Pract Res Clin Anaesthesiol. 2020;34(3):617-31.
151 Fiz J, Durán M, Capellà D, Carbonell J, Farré M. Cannabis use in patients with fibromyalgia: effect on symptoms relief and health-related quality of life. PLoS ONE. 2011;6(4):el8440.
152 Chung M, Kim HK, Abdi S. Update on cannabis and cannabinoids for cancer pain. Curr Opin Anaesthesiol. 2020;33(6):825-31.
153 Tsang CC, Giudice MG. Nabilone for the management of pain. Pharmacotherapy. 2016;36(3):273-86.
154 Zylla DM, Eklund J, Gilmore G, Gavenda A, Guggisberg J, VazquezBenitez G, Pawloski PA, Arneson T, Richter S, Birnbaum AK, Dahmer S, Tracy M, Dudek A. A randomized trial of medical cannabis in patients with stage IV cancers to assess feasibility, dose requirements, impact on pain and opioid use, safety, and overall patient satisfaction. Support Care Cancer. 2021;29(12):7471-8.
155 Nielsen S, Sabioni P, Trigo JM, Ware MA, Betz-Stablein BD, Murnion B, Lintzeris N, Khor KE, Farrell M, Smith A, Le Foll B. Opioid-sparing effect of cannabinoids: a systematic review and meta-analysis. Neuropsychopharmacology. 2017;42(9):1752-65.
156 Gusho CA, Court T. Cannabidiol: a brief review of its therapeutic and pharmacologic efficacy in the management of joint disease. Cureus. 2020;12(3):e7375.
157 Abdallah FW, Hussain N, Weaver T, Brull R. Analgesic efficacy of cannabinoids for acute pain management after surgery: A systematic review and meta-analysis. Reg Anesth Pain Med. 2020;45:509-19.
158 Jugl S, Okpeku A, Costales B, Morris EJ, Alipour-Haris G, Hincapie-Castillo JM, Stetten NE, Sajdeya R, Keshwani S, Joseph V, Zhang Y, Shen Y, Adkins L, Winterstein AG, Goodin A. A mapping literature review of medical cannabis clinical outcomes and quality of evidence in approved conditions in the USA from 2016 to 2019. Med Cannabis Cannabinoids. 2021;4(l):21-42.
159 Haroutounian S, Arendt-Nielsen L, Belton J, Blyth FM, Degenhardt L, Di Forti M, Eccleston C, Finn DP, Finnerup NB, Fisher E, Fogarty AE, Gilron I, Hohmann AG, Kalso E, Krane E, Mohiuddin M, Moore RA, Rowbotham M, Soliman N, Wallace M, Zinboonyahgoon N, Rice ASC. International Association for the Study of Pain Presidential Task Force on Cannabis and Cannabinoid Analgesia: research agenda on the use of cannabinoids, cannabis, and cannabis-based medicines for pain management. Pain. 2021;162(Suppl 1):S117-S124.
Submitted date:
06/23/2022
Accepted date:
01/06/2023