Role of Cannabinoids in the Treatment of Pain and (Painful) Spasticity
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Abstract
Both the discovery of the endocannabinoid system (ECS) and its role in the control of pain and habituation to stress, as well as the significant analgesic and antihyperalgesic effects in animal studies, suggest the usefulness of cannabinoids in pain conditions. However, in human experimental or clinical trials, no convincing reduction of acute pain, which may be caused by a pronociceptive, ECS-triggered mechanism on the level of the spinal cord, has been demonstrated. In contrast, in chronic pain and (painful) spasticity, an increasing number of randomized, double-blind, placebo-controlled studies have shown the efficacy of cannabinoids, which is combined with a narrow therapeutic index. Patients with unsatisfactory response to other methods of pain therapy and who were characterized by failed stress adaptation particularly benefited from treatment with cannabinoids. None of the attempts to overcome the disadvantage of the narrow therapeutic index, either by changing the route of application or by formulating balanced cannabinoid preparations, have resulted in a major breakthrough. Therefore, different methods of administration and other types of cannabinoids, such as endocannabinoid modulators, should be tested in future trials.
Keywords
Neuropathic Pain Anandamide Mechanical Allodynia Chronic Constriction Injury Fatty Acid Amide HydrolaseNotes
Acknowledgments
We would like to thank Gabriele Huwald for her support in editing the reference list. The authors state no conflict of interest. No type of funding was received from the pharmaceutical industry.
References
- 1.Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990; 346: 561–4PubMedGoogle Scholar
- 2.Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993; 365: 61–5PubMedGoogle Scholar
- 3.Jhaveri MD, Sagar DR, Elmes SJR, et al. Cannabinoid CB2 receptor-mediated anti-nociception in models of acute and chronic pain. Mol Neurobiol 2007; 36: 26–35PubMedGoogle Scholar
- 4.Devane WA, Hanus L, Breuer R, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992; 2581: 946–9Google Scholar
- 5.Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 1995; 50: 83–90PubMedGoogle Scholar
- 6.Jonsson K-O, Holt S, Fowler CJ. The endocannabinoid system: current pharmacological research and therapeutic possibilities. Basic Clin Pharmacol Toxicol 2006; 98: 124–34PubMedGoogle Scholar
- 7.Hohmann AG, Suplita II RL. Endocannabinoid mechanisms of pain modulation. AAPS J 2006; 8: 693–708Google Scholar
- 8.DiMarzo V, De Petrocellis L. Plant, synthetic, and endogenous cannabinoids in medicine. Annu Rev Med 2006; 57: 553–74Google Scholar
- 9.Maejima T, Ohno-shosaku T, Kano M. Endogenous cannabinoid as a retrograde messenger from postsynaptic neurons to presynaptic terminals. Neurosci Res 2001; 40: 205–10PubMedGoogle Scholar
- 10.Staton PC, Hatcher JP, Walker DJ, et al. The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain. Pain 2008; 139(1): 225–36PubMedGoogle Scholar
- 11.Schneider U, Seifert J, Karst M, et al. Das endogene Cannabinoidsystem. Nervenarzt 2005; 76: 1062–76PubMedGoogle Scholar
- 12.Russo EB, Burnett A, Hall B, et al. Agonistic properties of cannabidiol at 5-HT-1A receptors. Neurochem Res 2005; 30(8): 1037–43PubMedGoogle Scholar
- 13.Sun Y, Bennett A. Cannabinoids: a new group of agonists of PPARs. PPAR Res 2007; 2007: 23513PubMedGoogle Scholar
- 14.Burstein S. PPAR-gamma: a nuclear receptor with affinity for cannabinoids. Life Sci 2005; 77(14): 1674–84PubMedGoogle Scholar
- 15.Cravatt BF, Demarest K, Patricelli MH, et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci U S A 2001; 98: 9371–6PubMedGoogle Scholar
- 16.Jhaveri MD, Richardson D, Chapman V. Endocannabinoid metabolism and uptake: novel targets for neuropathic and inflammatory pain. Br J Pharmacol 2007; 152: 624–32PubMedGoogle Scholar
- 17.Fowler CJ. The pharmacology of the cannabinoid system: a question of efficacy and selectivity. Mol Neurobiol 2007; 36: 15–25PubMedGoogle Scholar
- 18.Fowler CJ, Holt S, Tiger G. Acidic non-steroidal antiinflammatory drugs inhibit rat brain fatty acid amide hydrolase in a ph-dependent manner. J Enzym Inhib Med Chem 2003; 18: 55–8Google Scholar
- 19.Agarwal N, Pacher P, Tegeder I, et al. Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. Nat Neurosci 2007; 10: 870–9PubMedGoogle Scholar
- 20.Wotherspoon GA, Fox P, McIntyre S, et al. Peripheral nerve injury induces cannabinoid receptor 2 protein expression in rat sensory neurons. Neuroscience 2005; 35: 235–45Google Scholar
- 21.Romero-Sandoval A, Eisenach JC. Spinal cannabinoid receptor type 2 activation reduces hypersensitivity and spinal cord glial activation after paw incision. Anesthesiology 2007; 106: 787–94PubMedGoogle Scholar
- 22.Hohmann AG, Suplita RL, Bolton NM, et al. An endocannabinoid mechanism for stress-induced analgesia. Nature 2005; 435: 1108–12PubMedGoogle Scholar
- 23.Finn DP. Endocannabinoid-mediated modulation of stress responses: physiological and pathophysiological signif-icance. Immunobiology 2010; 215(8): 629–46PubMedGoogle Scholar
- 24.Schlosburg JE, Kinsey SG, Lichtman AH. Targeting fatty acid amide hydrolase (FAAH) to treat pain and inflammation. AAPS J 2009; 11(1): 39–44PubMedGoogle Scholar
- 25.Naidu PS, Kinsey SG, Guo TL, et al. Regulation of inflammatory pain by inhibition of fatty acid amide hydrolase. J Pharmacol Exp Ther 2010; 334(1): 182–90PubMedGoogle Scholar
- 26.Hohmann AG. Inhibitors of monoacylglycerol lipase as novel analgesics. Br J Pharmacol 2007; 150(6): 673–5PubMedGoogle Scholar
- 27.Gaoni Y, Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc 1964; 86: 1646–7Google Scholar
- 28.Rahn EJ, Hohmann AG. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics 2009; 6(4): 713–37PubMedGoogle Scholar
- 29.Hosking RD, Zajicek JP. Therapeutic potential of cannabis in pain medicine. Br J Anaesth 2008; 101: 59–68PubMedGoogle Scholar
- 30.Killestein J, Uitdehaag BMJ, Polman CH. Cannabinoids in multiple sclerosis. Drugs 2004; 64(1): 1–11PubMedGoogle Scholar
- 31.Product monograph Sativex® [online]. Available from URL: http://www.ukcia.org/research/SativexMonograph.pdf [Accessed 2010 Nov 20]
- 32.Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17(1): 1–12PubMedGoogle Scholar
- 33.Dixon WE. The pharmacology of cannabis indica. BMJ 1899; 2: 1354–7Google Scholar
- 34.Sanudo-Pena MC, Romero J, Seale GE, et al. Activational role of cannabinoids on movement. Eur J Pharmacol 2000; 391: 269–74PubMedGoogle Scholar
- 35.Smith PB, Welch SP, Martin BR. Interactions between delta 9-tetrahydrocannabinol and kappa opioids in mice. J Pharmacol Exp Ther 1994; 268: 1381–7PubMedGoogle Scholar
- 36.Burstein SH, Friderichs E, Kogel B, et al. Analgesic effects of 1′,1′ dimethylheptyl-delta8-THC-11-oic acid (CT3) in mice. Life Sci 1998; 63: 161–8PubMedGoogle Scholar
- 37.Smith FL, Fujimori K, Lowe J, et al. Characterization of delta9-tetrahydrocannabinol and anandamide antinociception in nonarthritic and arthritic rats. Pharmacol Biochem Behav 1998; 60: 183–91PubMedGoogle Scholar
- 38.Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 1997; 74: 129–80PubMedGoogle Scholar
- 39.Ibrahim MM, Rude ML, Stagg NJ, et al. CB2 cannabinoid receptor mediation of antinociception. Pain 2006; 122: 36–42PubMedGoogle Scholar
- 40.Costa B, Colleoni M, Conti S, et al. Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn Schmiedebergs Arch Pharmacol 2004; 369: 294–9PubMedGoogle Scholar
- 41.Conti S, Costa B, Colleoni M, et al. Antiinflammatory action of endocannabinoid palmitoylethanolamide and the synthetic cannabinoid nabilone in a model of acute inflammation in the rat. Br J Pharmacol 2002; 135: 181–7PubMedGoogle Scholar
- 42.Nackley AG, Makriyannis A, Hohmann AG. Selective activation of cannabinoid CB(2) receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience 2003; 119: 747–57PubMedGoogle Scholar
- 43.Quartilho A, Mata HP, Ibrahim MM, et al. Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Anesthesiology 2003; 99: 955–60PubMedGoogle Scholar
- 44.Gutierrez T, Farthing JN, Zvonok AM, et al. Activation of peripheral cannabinoid CB1 and CB2 receptors suppresses the maintenance of inflammatory nociception: a comparative analysis. Br J Pharmacol 2007; 150: 153–63PubMedGoogle Scholar
- 45.Honore P, Buritova J, Besson JM. Aspirin and acetaminophen reduced both Fos expression in rat lumbar spinal cord and inflammatory signs produced by carrageenin inflammation. Pain 1995; 63: 365–75PubMedGoogle Scholar
- 46.Nackley AG, Zvonok AM, Makriyannis A, et al. Activation of cannabinoid CB2 receptors suppresses C-fiber responses and windup in spinal wide dynamic range neurons in the absence and presence of inflammation. J Neurophysiol 2004; 92: 3562–74PubMedGoogle Scholar
- 47.Richardson JD, Kilo S, Hargreaves KM. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain 1998; 75: 111–9PubMedGoogle Scholar
- 48.Sokal DM, Elmes SJ, Kendall DA, et al. Intraplantar injection of anandamide inhibits mechanically-evoked responses of spinal neurones via activation of CB2 receptors in anaesthetised rats. Neuropharmacology 2003; 45: 404–11PubMedGoogle Scholar
- 49.Elmes SJ, Jhaveri MD, Smart D, et al. Cannabinoid CB2 receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in naive rats and in rat models of inflammatory and neuropathic pain. Eur J Neurosci 2004; 20: 2311–20PubMedGoogle Scholar
- 50.Elmes SJ, Winyard LA, Medhurst SJ, et al. Activation of CB1 and CB2 receptors attenuates the induction and maintenance of inflammatory pain in the rat. Pain 2005; 118: 327–35PubMedGoogle Scholar
- 51.Hohmann AG, Farthing JN, Zvonok AM, et al. Selective activation of cannabinoid CB2 receptors suppresses hyperalgesia evoked by intradermal capsaicin. J Pharmacol Exp Ther 2004; 308: 446–53PubMedGoogle Scholar
- 52.Succar R, Mitchell VA, Vaughan CW. Actions of Narachidonyl-glycine in a rat inflammatory pain model. Mol Pain 2007; 3: 24PubMedGoogle Scholar
- 53.Whiteside GT, Gottshall SL, Boulet JM, et al. A role for cannabinoid receptors, but not endogenous opioids, in the antinociceptive activity of the CB2-selective agonist, GW 405833. Eur J Pharmacol 2005; 528: 65–72PubMedGoogle Scholar
- 54.Valenzano KJ, Tafesse L, Lee G, et al. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology 2005; 48: 658–72PubMedGoogle Scholar
- 55.Mitchell VA, Aslan S, Safaei R, et al. Effect of the cannabinoid ajulemic acid on rat models of neuropathic and inflammatory pain. Neurosci Lett 2005; 382: 231–5PubMedGoogle Scholar
- 56.Guindon J, Hohmann AG. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br J Pharmacol 2008; 153: 319–34PubMedGoogle Scholar
- 57.Comelli F, Giagnoni G, Bettoni I, et al. Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: mechanisms involved. Phytother Res 2008; 22: 1017–24PubMedGoogle Scholar
- 58.Di Marzo V, De Petrocellis L. Endocannabinoids as regulators of transient receptor potential (TRP) channels: a further opportunity to develop new endocannabinoidbased therapeutic drugs. Curr Med Chem 2010; 17(14): 1430–49PubMedGoogle Scholar
- 59.Liu C, Walker JM. Effects of a cannabinoid agonist on spinal nociceptive neurons in a rodent model of neuropathic pain. J Neurophysiol 2006; 96: 2984–94PubMedGoogle Scholar
- 60.Hu B, Doods H, Treede RD, et al. Depression-like behaviour in rats with mononeuropathy is reduced by the CB2-selective agonist GW 405833. Pain 2009; 143: 206–12PubMedGoogle Scholar
- 61.Costa B, Siniscalco D, Trovato AE, et al. AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain. Br J Pharmacol 2006; 148: 1022–32PubMedGoogle Scholar
- 62.La Rana G, Russo R, Campolongo P, et al. Modulation of neuropathic and inflammatory pain by the endocannabinoid transport inhibitor AM404 [N-(4-hydroxyphenyl)eicosa-5,8,11, 14-tetraenamide]. J Pharmacol Exp Ther 2006; 317: 1365–71PubMedGoogle Scholar
- 63.Seltzer Z, Dubner R, Shir Y. A novel behavioural model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 1990; 43(2): 205–18PubMedGoogle Scholar
- 64.Helyes Z, Nemeth J, Than M, et al. Inhibitory effect of anandamide on resiniferatoxin-induced sensory neuropeptide release in vivo and neuropathic hyperalgesia in the rat. Life Sci 2003; 73: 2345–53PubMedGoogle Scholar
- 65.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: 814–23PubMedGoogle Scholar
- 66.Desroches J, Guindon J, Lambert C, et al. 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: 913–24PubMedGoogle Scholar
- 67.Fox A, Kesingland A, Gentry C, et al. The role of central and peripheral Cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. Pain 2001; 92: 91–100PubMedGoogle Scholar
- 68.Dyson A, Peacock M, Chen A, et al. Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat. Pain 2005; 116: 129–37PubMedGoogle Scholar
- 69.Guindon J, Desroches J, Dani M, et al. Pre-emptive antinociceptive effects of a synthetic cannabinoid in a model of neuropathic pain. Eur J Pharmacol 2007; 568: 173–6PubMedGoogle Scholar
- 70.Yamamoto W, Mikami T, Iwamura H. Involvement of central cannabinoid CB(2) receptor in reducing mechanical allodynia in a mouse model of neuropathic pain. Eur J Pharmacol 2008; 583: 56–61PubMedGoogle Scholar
- 71.Bridges D, Ahmad K, Rice AS. The synthetic cannabinoid WIN55,212-2 attenuates hyperalgesia and allodynia in a rat model of neuropathic pain. Br J Pharmacol 2001; 133: 586–94PubMedGoogle Scholar
- 72.Scott DA, Wright CE, Angus JA. Evidence that CB-1 and CB-2 cannabinoid receptors mediate antinociception in neuropathic pain in the rat. Pain 2004; 109: 124–31PubMedGoogle Scholar
- 73.Ibrahim MM, Deng H, Zvonok A, et al. Activation of CB2 cannabinoid receptors by AM 1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci U S A 2003; 100: 10529–33PubMedGoogle Scholar
- 74.Leichsenring A, Andriske M, Backer I, et al. Analgesic and antiinflammatory effects of cannabinoid receptor agonists in a rat model of neuropathic pain. Naunyn Schmiedebergs Arch Pharmacol 2009; 379: 627–36PubMedGoogle Scholar
- 75.Raft D, Gregg J, Ghia J, et al. Effects of intravenous tetrahydrocannabinol on experimental and surgical pain. Clin Pharmacol Ther 1977; 21: 26–33PubMedGoogle Scholar
- 76.Jain AK, Ryan JR, McMahon FG, et al. Evaluation of intramuscular levonantradol and placebo in acute postoperative pain. J Clin Pharmacol 1981; 21: 320S–6SPubMedGoogle Scholar
- 77.Greenwald MK, Stitzer ML. Antinociceptive, subjective and behavioral effects of smoked marijuana in humans. Drug Alcohol Depend 2000; 59: 261–75PubMedGoogle Scholar
- 78.Buggy DJ, Toogood L, Maric S, et al. Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain 2003; 106: 169–72PubMedGoogle Scholar
- 79.Naef M, Curatolo M, Petersen-Felix S, et al. The analgesic effect of oral delta9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain 2003; 105: 79–88PubMedGoogle Scholar
- 80.Rukwied R, Watkinson A, McGlone F, et al. Cannabinoid agonists attenuate capsaicin-induced responses in human skin. Pain 2003; 102: 283–8PubMedGoogle Scholar
- 81.Seeling W, Kneer L, Büchele B, et al. Keine synergistische Wirkung der Kombination von Delta9-Tetrahydrocannabiol und Piritramid bei postoperativen Schmerzen. Anaesthesist 2005; 55: 391–400Google Scholar
- 82.Holdcroft A, Maze M, Doré C, et al. A multicenter doseescalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Anesthesiology 2006; 104: 1040–6PubMedGoogle Scholar
- 83.Roberts JD, Gennings C, Shih M. Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine. Eur J Pharmacol 2006; 530: 54–8PubMedGoogle Scholar
- 84.Beaulieu P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can J Anesth 2006; 53: 769–75PubMedGoogle Scholar
- 85.Wallace M, Schulteis G, Atkinson JH, et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology 2007; 107: 785–96PubMedGoogle Scholar
- 86.Kraft B, Frickey NA, Kaufmann RM, et al. Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers. Anesthesiology 2008; 109: 101–10PubMedGoogle Scholar
- 87.Redmond WJ, Goffaux P, Potvin S, et al. Analgesic and antihyperalgesic effects of nabilone on experimental heat pain. Curr Med Res Opin 2008; 24(4): 1017–24PubMedGoogle Scholar
- 88.Tart CT. On being stoned: a psychological study of marijuana intoxication. Palo Alto (CA): Science and Behavior Books, 1971Google Scholar
- 89.Sulcova E, Mechoulam R, Fride E. Biphasic effects of anandamide. Pharmacol Biochem Behav 1998; 59: 347–52PubMedGoogle Scholar
- 90.Pernía-Andrade AJ, Kato A, Witschi R, et al. Spinal endocannabinoids and CB1 receptors mediate C-fiberinduced heterosynaptic pain sensitization. Science 2009; 325(5941): 760–4PubMedGoogle Scholar
- 91.Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinol Lett 2004; 25(1/2): 31–9PubMedGoogle Scholar
- 92.Campbell FA, Tramèr MR, Carroll D, et al. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ 2001; 323: 1–6Google Scholar
- 93.Walker JM, Huang SM. Cannabinoid analgesia. Pharmacol Ther 2002; 95: 127–35PubMedGoogle Scholar
- 94.Grant I, Cahn BR. Cannabis and endocannabinoid modulators: therapeutic promises and challenges. Clin Neurosci Res 2005; 5: 185–99PubMedGoogle Scholar
- 95.Azad SC, Rammes G. Cannabinoids in anaesthesia and pain therapy. Curr Opin Anaesthesiol 2005; 18: 424–27PubMedGoogle Scholar
- 96.Amar MB. Cannnabinoids in medicine: a review of their therapeutic potential. J Ethnopharmacol 2006; 105: 1–25PubMedGoogle Scholar
- 97.McCarberg BH, Barkin RL. The future of cannabinoids as analgesic agents: a pharmacologic, pharmacokinetic, and pharmacodynamic overview. Am J Ther 2007; 14(5): 475–83PubMedGoogle Scholar
- 98.Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manage 2008; 4(1): 245–59Google Scholar
- 99.Beaulieu P, Ware M. Reassessment of the role of cannabinoids in the management of pain. Curr Opin Anaesthesiol 2007; 20: 473–7PubMedGoogle Scholar
- 100.Noyes Jr R, Brunk SF, Avery DH, et al. The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 1975; 18(1): 84–9PubMedGoogle Scholar
- 101.Noyes Jr R, Brunk SF, Baram DA, et al. Analgesic effect of delta9-tetrahydrocannabinol. J Clin Pharmacol 1975; 15: 139–43PubMedGoogle Scholar
- 102.Jochimsen PR, Lawton RL, VerSteeg K, et al. Effect of benzopyranoperidine, a delta-9-THC congener, on pain. Clin Phamacol Ther 1978; 24: 223–7Google Scholar
- 103.Staquet M, Gantt C, Machin D. Effect of nitrogen analog of tetrahydrocannabinol on cancer pain. Clin Pharmacol Ther 1978; 23: 397–401PubMedGoogle Scholar
- 104.Holdcroft A, Smith M, Jacklin A, et al. Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia 1997; 52: 483–8PubMedGoogle Scholar
- 105.Notcutt W, Price M, Miller R, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies. Anaesthesia 2004; 59: 440–52PubMedGoogle Scholar
- 106.Schley M, Legler A, Skopp G, et al. Delta-9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief. Curr Med Res Opin 2006; 22(7): 1269–76PubMedGoogle Scholar
- 107.Pinsger M, Schimetta W, Volc D, et al. Benefits of an addon treatment with the synthetic cannabinomimetic nabilone on patients with chronic pain: a randomized controlled trial. Wien Klin Wochenschr 2006; 118: 327–35PubMedGoogle Scholar
- 108.Blake DR, Robson P, Ho M, et al. Preliminary assessment of the efficacy, tolerability and safety of cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology 2006; 45: 50–2PubMedGoogle Scholar
- 109.Narang S, Gibson D, Wasan AD, et al. Efficacy of dornabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain 2008; 9(3): 254–64PubMedGoogle Scholar
- 110.Haroutiunian S, Rosen G, Shouval R, et al. Add-on study of tetrahydrocannabinol for chronic non-malignant pain. J Pain Pall Care Pharmacol 2008; 22(3): 213–17Google Scholar
- 111.Skrabek RQ, Galimova L, Ethans K, et al. Nabilone for the treatment of pain in fibromyalgia. J Pain 2008; 9(2): 164–73PubMedGoogle Scholar
- 112.Ware MA, Fitzcharles M-A, Joseph L, et al. The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesth Analg 2010; 110: 604–10PubMedGoogle Scholar
- 113.Johnson JR, Burnell-Nugent M, Lossignol D, et al. Multi-center, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Sympt Manage 2010; 39(2): 167–78Google Scholar
- 114.Petro DJ, Ellenberger C. Treatment of human spasticity with delta9-tetrahydrocannabinol. J Clin Pharmacol 1981; 21: 413S–6SPubMedGoogle Scholar
- 115.Ungerleider JT, Andrysiak T, Fairbanks L. Delta-9-THC in the treatment of spasticity associated with multiple sclerosis. Adv Alcohol Subst Abuse 1987; 7: 39–50PubMedGoogle Scholar
- 116.Martyn CN, Illis LS, Thom J. Nabilone in the treatment of multiple sclerosis [letter]. Lancet 1995; 345: 579PubMedGoogle Scholar
- 117.Killestein J, Hoogervorst ELJ, Reif M, et al. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology 2002; 58: 1404–7PubMedGoogle Scholar
- 118.Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicenter randomised placebo-controlled trial. Lancet 2003; 362: 1517–26PubMedGoogle Scholar
- 119.Wade DT, Robson P, House H, et al. A preliminary controlled study to determine whether whole plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehab 2003; 17: 21–9Google Scholar
- 120.Wade DT, Makela P, Robson P, et al. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler 2004; 10: 434–41PubMedGoogle Scholar
- 121.Svendsen KB, Jensen TS, Back FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? BMJ 2004; 329: 253–61PubMedGoogle Scholar
- 122.Vaney C, Heinzel-Gutenbrunner M, Jobin P, et al. Efficacy, safety, and tolerability of an oral administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebocontrolled, crossover study. Mult Scler 2004; 10: 417–24PubMedGoogle Scholar
- 123.Zajicek JP, Sanders HP, Wright DE, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow-up. J Neurol Neurosurg Psychiatry 2005; 76: 1664–9PubMedGoogle Scholar
- 124.Rog DJ, Nurmikko TR, Friede T, et al. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005; 65: 812–9PubMedGoogle Scholar
- 125.Wissel J, Haydn T, Muller J, et al. Low dose treatment with the synthetic cannabinoid nabilone significantly reduces spasticity-related pain: a double-blind placebo-controlled cross-over trial. J Neurol 2006; 253: 1337–41PubMedGoogle Scholar
- 126.Collin C, Davies P, Mutiboko IK, et al. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol 2007; 14: 290–6PubMedGoogle Scholar
- 127.Conte A, Bettolo CM, Onesto E, et al. Cannabinoidinduced effects on the nociceptive system: a neurophysiological study in patients with secondary progressive multiple sclerosis. Eur J Pain 2009; 13: 472–7PubMedGoogle Scholar
- 128.Collin C, Ehler E, Waberzinek G, et al. A double-blind, randomized, placebocontrolled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res 2010; 32(5): 451–59PubMedGoogle Scholar
- 129.Wade DT, Makela PM, House H, et al. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult Scler 2006; 12: 639–45PubMedGoogle Scholar
- 130.Rog DJ, Nurmikko TJ, Young CA. Oromucosal D9-tetrahydro-cannabinol/ cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, openlabel, 2-year extension trial. Clin Ther 2007; 29(9): 2068–79PubMedGoogle Scholar
- 131.Centonze D, Mori F, Koch G. Lack of effect of cannabisbased treatment on clinical and laboratory measures in multiple sclerosis. Neurol Sci 2009; 30: 531–4PubMedGoogle Scholar
- 132.Scully C. Cannabis; adverse effects from an oromucosal spray. Br Dent J 2007; 203(6): E12; discussion 336-7PubMedGoogle Scholar
- 133.Maurer M, Henn V, Dittrich A, et al. Delta-9-tetra-hydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. Eur Arch Psychiatry Clin Neurosci 1990; 240: 1–4PubMedGoogle Scholar
- 134.Karst M, Salim K, Burstein S, et al. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 2003; 290: 1757–62PubMedGoogle Scholar
- 135.Salim K, Schneider U, Burstein S, et al. Pain measurements and side effect profile of the novel cannabinoid ajulemic acid. Neuropharmacology 2005; 48: 1164–71PubMedGoogle Scholar
- 136.Berman JS, Symonds C, Birch R. Efficacy of two cannabis based medicinal extracts for relief on central neuropathic pain from brachial plexus avulsion: results of a randomized controlled trial. Pain 2004; 112: 299–306PubMedGoogle Scholar
- 137.Nurmikko TJ, Serpell MG, Hoggart B, et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trail. Pain 2007; 133(1–3): 210–20PubMedGoogle Scholar
- 138.Frank B, Serpell MG, Hughes J, et al. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for neuropathic pain: randomised, crossover, double blind study. BMJ 2008; 336(7637): 167–8Google Scholar
- 139.Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007; 68: 515–21PubMedGoogle Scholar
- 140.Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain 2008; 9(6): 506–21PubMedGoogle Scholar
- 141.Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009; 34: 672–80PubMedGoogle Scholar
- 142.Selvarajah D, Emery CJ, Gandhi R, et al. Randomized placebo-controlled double-blind clinical trial of cannabisbased medicinal product (Sativex) in painful diabetic neuropathy. Diabetes Care 2010; 33(1): 128–30PubMedGoogle Scholar
- 143.Rintala DH, Fiess RN, Tan G, et al. Effect of dronabinol on central neuropathic pain after spinal cord injury: a pilot study. Am J Phys Med Rehabil 2010; 89: 840–8PubMedGoogle Scholar
- 144.Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ 2010; 182(14): E694–701PubMedGoogle Scholar
- 145.Attal N, Brasseur L, Guirimand D, et al. Are oral cannabinoids safe and effective in refractory neuropathic pain? Eur J Pain 2004; 8(2): 173–7PubMedGoogle Scholar
- 146.Hagenbach U, Luz S, Ghafoor N, et al. The treatment of spasticity with D9-tetrahydrocannabinol in persons with spinal cord injury. Spinal Cord 2007; 45: 551–62PubMedGoogle Scholar
- 147.Weber J, Schley M, Casutt M, et al. Tetrahydrocannabinol (delta 9-THC) treatment in chronic central neuropathic pain and fibromyalgia patients: results of a multicenter survey. Anaesthesiol Res Pract 2009; 2009: 827290Google Scholar
- 148.Fox A, Gentry C, Patel S, et al. Comparative activity of the anti-convulsants oxcarbazepin, carbamazepin, lamotrigine and gabapentin in a model of neuropathic pain in the rat and guinea-pig. Pain 2003; 105: 355–62PubMedGoogle Scholar
- 149.Kaufman I, Hauer D, Huge V, et al. Enhanced anandamide plasma levels in patients with complex regional pain syndrome following traumatic injury: a preliminary report. Eur Surg Res 2009; 43: 325–9Google Scholar
- 150.Wang T, Collet J-P, Shapiro S, et al. Adverse effects of medical cannabinoids: a systematic review. CMAJ 2008; 178(13): 1669–78PubMedGoogle Scholar
- 151.Tetrault JM, Crothers K, Moore BA, et al. Effects of marijuana smoking on pulmonary function and respiratory complications. Arch Intern Med 2007; 167: 221–8PubMedGoogle Scholar
- 152.Di Forti M, Morgan C, Dazzan P, et al. High-potency cannabis and the risk of psychosis. Br J Psychiatry 2010; 195: 488–91Google Scholar
- 153.Perez-Reyes M. Pharmacodynamics of certain drugs of abuse. In: Barnett G, Chang CN, editors. Pharmacokinetics and pharmacodynamics of psychoactive drugs. Foster City (CA): Biomedical Publishers, 1985: 287–310Google Scholar
- 154.Loev B, Bender PE, Dowalo F, et al. Cannabinoids: structure-activity studies related to 1,2-dimethylheptyl derivatives. J Med Chem 1973; 16: 1200–6PubMedGoogle Scholar
- 155.Burstein SH. Inhibitory and stimulatory effects of cannabinoids on eicosanoid synthesis. NIDA Res Monogr 1987; 79: 158–72PubMedGoogle Scholar
- 156.Dziadulewicz EK, Bevan SJ, Brain CT, et al. Naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl) methanone: a potent, orally bioavailable human CB1/CB2 dual agonist with antihyperalgesic properties and restricted central nervous system penetration. J Med Chem 2007; 50: 3851–6PubMedGoogle Scholar
- 157.Day A. Neuropathic pain: emerging treatments. Br J Anaesth 2008; 101: 48–58Google Scholar
- 158.Cichewicz DL. Synergistic interactions between cannabinoid and opioid analgesics. Life Sci 2004; 74: 1317–24PubMedGoogle Scholar
- 159.Yesilyurt O, Dogrul A, Gul H, et al. Topical cannabinoid enhances topical morphine antinociception. Pain 2003; 105: 303–8PubMedGoogle Scholar
- 160.Martin-Sánchez E, Furukawa T, Taylor J, et al. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Med 2009; 10(8): 1353–68PubMedGoogle Scholar
- 161.Farrar JT, Young Jr JP, LaMoreaux L, et al. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001; 94(2): 149–58PubMedGoogle Scholar
- 162.European Medicines Agency (EMEA). Doc. ref. CPMP/ EWP/252/03 rev. 1 [online]. Available from URL: http://www.emea.europa.eu [Accessed 2010 Nov 20]
- 163.Watson CPN, Moulin D, Watt-Watson J, et al. Controlledrelease oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain 2003; 105: 71–8PubMedGoogle Scholar
- 164.Eisenberg E, McNicol E, Carr DB. Opioids for neuropathic pain. Cochrane Database Syst Rev 2006 Jul 19; 3: CD006146PubMedGoogle Scholar
- 165.Ballantyne JC, Shin NS. Efficacy of opioids for chronic pain. Clin J Pain 2008; 24(6): 469–78PubMedGoogle Scholar
- 166.Karst M, Wippermann S. Cannabinoids against pain. Efficacy and strategies to reduce psychoactivity: a clinical perspective. Expert Opin Investig Drugs 2009; 18(2): 125–33Google Scholar
- 167.Pertwee RG. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol 2009; 156: 397–411PubMedGoogle Scholar