Cannabinoids for Neuropathic Pain

  • Perry G. FineEmail author
  • Mark J. Rosenfeld
Neuropathic Pain (E Eisenberg, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Neuropathic Pain


Treatment options for neuropathic pain have limited efficacy and use is fraught with dose-limiting adverse effects. The endocannabinoid system has been elucidated over the last several years, demonstrating a significant interface with pain homeostasis. Exogenous cannabinoids have been demonstrated to be effective in a range of experimental neuropathic pain models, and there is mounting evidence for therapeutic use in human neuropathic pain conditions. This article reviews the history, pharmacologic development, clinical trials results, and the future potential of nonsmoked, orally bioavailable, nonpsychoactive cannabinoids in the management of neuropathic pain.


Cannabinoids Endocannabinoid system Neuropathic pain 


Compliance with Ethics Guidelines

Conflict of Interest

Perry G. Fine and Mark J. Rosenfeld serve on the Board of Directors of ISA Scientific, Inc., a medicinal cannabinoid research and development company.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Mechoulam R. Marihuana chemistry. Science. 1970;168:1159–66.PubMedCrossRefGoogle Scholar
  2. 2.
    Adams R. Marihuana. Science. 1940;92:115–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Abel EL. Marihuana: the first twelve thousand years. New York: Phenum Press; 1980.CrossRefGoogle Scholar
  4. 4.
    Zias J, Stark H, Sellgman J, Levy R, Werker E, Breuer K, et al. Early medical use of cannabis. Nature. 1993;363:215.PubMedGoogle Scholar
  5. 5.
    Mikuriya TH, editor. Marijuana medical papers: 1839–1972. Berkeley: Medicomp Press; 1972.Google Scholar
  6. 6.
    Zuardi AW. History of cannabis as medicine: a review. Rev Bras Psiquiatr. 2006;28:1253–7.CrossRefGoogle Scholar
  7. 7.
    Nicoll RA, Alger BN. The brain’s own marijuana. Sci Am. 2004;21:45–51.Google Scholar
  8. 8.
    Mandavilli A. Marijuana researchers reach for pot of gold. Nat Med. 2003;9:1227.PubMedCrossRefGoogle Scholar
  9. 9.
    Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive response of the nervous system to damage. Annu Rev Neurosci. 2009;32:1–32.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Gertsch J. Anti-inflammatory cannabinoids in diet: towards a better understanding of CB(2) receptor action? Commun Integr Biol. 2008;1:S26–8.CrossRefGoogle Scholar
  11. 11.
    Gerard CM, Mollereau C, Vassart G, Parmentier M. Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem J. 1991;279:129–34.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Glass M, Faull RLM, Dragunow M. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study on the fetal, neonatal and adult human brain. Neuroscience. 1997;77:299–318.PubMedCrossRefGoogle Scholar
  13. 13.
    Ishac EJN, Jiang L, Lake KD, Varga K, Abood ME, Kumos G. Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves. Br J Pharmacol. 1996;118:2023–8.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Galiegue S, Mary S, Marchand J, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995;232:54–61.PubMedCrossRefGoogle Scholar
  15. 15.
    Rice W, Shannon JM, Burton F, Fiedeldey D. Expression of a brain type cannabinoid receptor (CB1) in alveolar type-II cells in the lung-regulation by hydrocortisone. Eur J Pharmacol. 1997;327:227–32.PubMedCrossRefGoogle Scholar
  16. 16.•
    Hulsebosch CE. Special issue on microglia and chronic pain. Exp Neurol. 2012;234:253–4. The role of microglial proliferation on neuroinflammation is gaining importance in understanding mechanisms involved in inciting and maintaining neuropathic pain. Recognition of cannabinoid receptors on microglia adds 1 more element for potential therapeutic manipulation to prevent or treat neuropathic pain. PubMedCrossRefGoogle Scholar
  17. 17.
    Beltramo M. Cannabinoid type 2 receptor as a target for chronic pain. Mini Rev Med Chem. 2009;9:11–25.PubMedCrossRefGoogle Scholar
  18. 18.
    Felder CC, Joyce KE, Briley EM, et al. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol. 1995;48:443–50.PubMedGoogle Scholar
  19. 19.
    Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258:1946–9.PubMedCrossRefGoogle Scholar
  20. 20.
    Felder CC, Nielsen A, Briley EM, et al. Isolation and measurement of the endogenous cannabinoid receptor agonist, anandamide in brain and peripheral tissues of human and rat. FEBS Lett. 1996;393:231–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Kozono S, Matsuyama T, Biwasa KK, et al. Involvement of the endocannabinoid system in periodontal healing. Biochem Biophys Res Commun. 2010;394:928–33.PubMedCrossRefGoogle Scholar
  22. 22.
    De Petrocellis L, Bisogno T, Maccarrone M, et al. The activity of anandamide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabolism. J Biol Chem. 2001;276:12856–63.PubMedCrossRefGoogle Scholar
  23. 23.
    Vogel Z, Barg J, Levy R, Saya D, Heldman E, Mechoulam R. Anandamide, a brain endogenous compound, interacts specifically with cannabinoid receptors and inhibits adenylate cyclase. J Neurochem. 1993;61:352–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Smith PB, Compton DR, Welch SP, Razdan RK, Mechoulam R, Martin BR. The pharmacological activity of anandamide, a putative endogenous cannabinoid, in mice. J Pharmacol Exp Ther. 1994;270:219–27.PubMedGoogle Scholar
  25. 25.
    Welch SP. Blockade of cannabinoid-induced antinociception by norbinaltorphimine, but not N-, N-, diallyltyrosine-Aib-phenylalanine-leucine, ICL 174,864 or naloxone in mice. J Pharmacol Exp Ther. 1993;265:633–40.PubMedGoogle Scholar
  26. 26.
    Pertwee RG, Howlett AC, Abood ME, et al. International union of basic and clinical pharmacology. LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev. 2010;62:588–631.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.•
    Thiago RL, Romero L, Resende LC, Guzzo LS, Duarte IDG. CB1 and CB2 cannabinoid receptor agonists induce peripheral antinociception by activation of the endogenous noradrenergic system. Anesth Analg. 2013;116:463–72. This research report provides insight into one of the several putative mechanism by which peripherally acting cannabinoids reduce pain in both experimental models and clinical syndromes of neuropathic pain. CrossRefGoogle Scholar
  28. 28.
    Beltramo M, Bernardini N, Bertorelli R, et al. CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur J Neurosci. 2006;23:1530–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Van Sickle MD, Duncan M, Kingsley PJ, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005;310:329–32.PubMedCrossRefGoogle Scholar
  30. 30.
    Jhaveri MD, Elmes SJ, Richardson D, et al. Evidence for a novel functional role of cannabinoid CB(2) receptors in the thalamus of neuropathic rats. Eur J Neurosci. 2008;27:1722–30.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Anand U, Otto WR, Sanchez-Herrera D, et al. Cannabinoid receptor CB2 localisation and agonist mediated inhibition of capsaicin responses in human sensory neurons. Pain. 2008;138:667–80.PubMedCrossRefGoogle Scholar
  32. 32.
    Jhaveri MD, Sagar DR, Elmes SJ, Kendall DA, Chapman V. Cannabinoid CB2 receptor-mediated anti-nociception in models of acute and chronic pain. Mol Neurobiol. 2007;36:26–35.PubMedCrossRefGoogle Scholar
  33. 33.
    Ibrahim MM, Porreca F, Lai J, et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A. 2005;102:3093–8.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Bushlin I, Rozenfeld R, Devi LA. Cannabinoid-opioid interactions during neuropathic pain and analgesia. Curr Opin Pharmacol. 2010;10:80–6.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Nackley AG, Zvonok AM, Makriyannis A, Hohmann AG. 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;92:3562–74.PubMedCrossRefGoogle Scholar
  36. 36.
    Quartilho A, Mata HP, Ibrahim MM, et al. Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Anesthesiology. 2003;99:955–60.PubMedCrossRefGoogle Scholar
  37. 37.
    Richardson D, Pearson RG, Kurian N, et al. Characterisation of the cannabinoid receptor system in synovial tissue and fluid in patients with osteoarthritis and rheumatoid arthritis. Arthritis Res Ther. 2008;10:R43.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Walczak JS, Pichette V, Leblond F, Desbiens K, Beaulieu P. Behavioral, pharmacological and molecular characterization of the saphenous nerve partial ligation: a new model of neuropathic pain. Neuroscience. 2005;132:1093–102.PubMedCrossRefGoogle Scholar
  39. 39.
    Wotherspoon G, Fox A, McIntyre P, Colley S, Bevan S, Winter J. Peripheral nerve injury induces cannabinoid receptor 2 protein expression in rat sensory neurons. Neuroscience. 2005;135:235–45.PubMedCrossRefGoogle Scholar
  40. 40.
    Brusberg M, Arvidsson S, Kang D, et al. CB1 Receptors mediate the analgesic effects of cannabinoids on colorectal distension-induced visceral pain in rodents. J Neurosci. 2009;29:1554–64.PubMedCrossRefGoogle Scholar
  41. 41.••
    Xiong W, Cui T, Cheng K, et al. Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors. J Exp Med. 2012;209:1121–34. This insightful research study supports a previously undisclosed, novel mechanism for observed clinical efficacy of cannabinoids. PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Rahn EJ, Hohmann AG. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics. 2009;6:713–37.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Pertwee RG. Cannabinoid receptors and pain. Prog Neurobiol. 2001;63:569–611.PubMedCrossRefGoogle Scholar
  44. 44.
    Campbell FA, Tamer MR, Carroll D, et al. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systemic review. BMJ. 2001;323:1–6.CrossRefGoogle Scholar
  45. 45.
    Dogrul A, Seyrek M, Yalcin B, Ulugol A. Involvement of descending serotonergic and noradrenergic pathways in CB1 receptor-mediated antinociception. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38:97–105.PubMedCrossRefGoogle Scholar
  46. 46.
    Iversen L, Chapman V. Cannabinoids: a real prospect for pain relief? Curr Opin Pharmacol. 2002;2:50–5.PubMedCrossRefGoogle Scholar
  47. 47.
    Lee MC, Ploner M, Wiech K, et al. Amygdala activity contributes to the dissociative effect of cannabis on pain perception. Pain. 2013;154:124–34.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964;86:1646–7.CrossRefGoogle Scholar
  49. 49.
    Buggy DJ, Toogood L, Maric S, Sharpe P, Lambert DG, Rowbotham DJ. Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain. 2003;106:169–72.PubMedCrossRefGoogle Scholar
  50. 50.
    Holdcroft A, Smith M, Jacklin A, et al. Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia. 1997;52:483–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Naef M, Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Zbinden A, Brenneisen R. The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain. 2003;105:79–88.PubMedCrossRefGoogle Scholar
  52. 52.
    Lemberger L, Row H. Clinical pharmacology of nabilone, a cannabinol derivative. Clin Pharm. 1975;18:720–6.Google Scholar
  53. 53.
    Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for the treatment of pain in fibromyalgia. J Pain. 2008;9:164–73.PubMedCrossRefGoogle Scholar
  54. 54.
    Beaulieu P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can J Anaesth. 2006;53:769–75.PubMedCrossRefGoogle Scholar
  55. 55.
    Mechoulam R, Parker LA, Gallily R. Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol. 2002;42:11S–9S.PubMedCrossRefGoogle Scholar
  56. 56.
    Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:1–7.CrossRefGoogle Scholar
  57. 57.
    Thomas A, Baillie GL, Phillips AM, et al. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol. 2007;150:613–23.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Morgan C, Curran H. Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis. Br J Psychiatry. 2008;192:306–7.PubMedCrossRefGoogle Scholar
  59. 59.
    Morgan C. Impact of cannabidiol on the acute memory and psychotomimetic effects of smoked cannabis: naturalistic study. Br J Psychiatry. 2010;197:285–90.PubMedCrossRefGoogle Scholar
  60. 60.
    Iskedjian M, Bereza B, Gordon A, Piwko C, Einarson TR. Meta-analysis of cannabis based treatments for neuropathic and multiple sclerosis-related pain. Curr Med Res Opin. 2007;23:17–24.PubMedCrossRefGoogle Scholar
  61. 61.
    Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008;4:245–59.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized crossover clinical trial. Neuropsychopharmacology. 2009;34:672–80.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    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;107:785–96.PubMedCrossRefGoogle Scholar
  64. 64.
    Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain. 2008;9:506–21.PubMedCrossRefGoogle Scholar
  65. 65.
    Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain. 2013;14:1236–48.Google Scholar
  66. 66.
    St Gieringer D, Laurent J, Goodrich S. Cannabis combines efficient delivery of THC with effective suppression of pyrolytic compounds. J Cannabis Ther. 2004;4:2–27.CrossRefGoogle Scholar
  67. 67.
    Michalski CW, Oti FE, Erkan M, et al. Cannabinoids in pancreatic cancer: correlation with survival and pain. Int J Cancer. 2008;122:742–50.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163:1344–64.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Gertsch J, Pertwee RG, Di Marzo V. Phytocannabinoids beyond the Cannabis plant—do they exist? Br J Pharmacol. 2010;160:523–9.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci U S A. 2008;105:9099–114.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Zimmer A, Racz I, Klauke AL, Markert A, Gertsch J. Betacaryophyllene, a phytocannabinoid acting on CB2 receptors. IACM 5th Conference on cannabinoids in medicine. Cologne, Germany; 2009. Available at: Accessed March 23, 2013.
  72. 72.
    Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–50.PubMedCrossRefGoogle Scholar
  73. 73.
    Cichewicz DL, McCarthy EA. Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther. 2003;304:1010–5.PubMedCrossRefGoogle Scholar
  74. 74.
    Zutler M, Holty JC. Opioids, sleep and sleep-disordered breathing. Curr Pharm Des. 2011;17:1443–9.PubMedCrossRefGoogle Scholar
  75. 75.
    Carley DW, Pavlovic S, Janelidze M, Radulovacki M. Functional role of cannabinoids in respiratory stability during sleep. Sleep. 2002;25:388–95.Google Scholar
  76. 76.
    Walker JM, Huang SM. Cannabinoid analgesia. Pharmacol Ther. 2002;95:127–35.PubMedCrossRefGoogle Scholar
  77. 77.
    Burns TL, Ineck JR. Cannabinoid analgesia as a potential new therapeutic option in the treatment of chronic pain. Ann Pharmacother. 2006;40:251–60.PubMedCrossRefGoogle Scholar
  78. 78.
    Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68:515–21.PubMedCrossRefGoogle Scholar
  79. 79.
    Notcutt W, Price M, Miller A, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies. Anaesthesia. 2004;59:440–52.PubMedCrossRefGoogle Scholar
  80. 80.
    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;290:1757–62.PubMedCrossRefGoogle Scholar
  81. 81.
    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;76:1664–9.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ. 2004;329:253.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    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;12:639–45.PubMedCrossRefGoogle Scholar
  84. 84.
    Rog DJ, Nurmiko T, Friede T, et al. Randomized controlled trial of cannabis based medicine in central neuropathic pain due to multiple sclerosis. Neurology. 2005;65:812–9.PubMedCrossRefGoogle Scholar
  85. 85.
    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 Rehabil. 2003;17:18–26.Google Scholar
  86. 86.
    Berman JS, Symonds C, Birch R. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain. 2004;112:299–306.PubMedCrossRefGoogle Scholar
  87. 87.
    Nurmikko TJ, Serpell MG, Hoggart B, et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain. 2007;133:210–20.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Pain Research and Management Centers, School of Medicine, Department of AnesthesiologyUniversity of UtahSalt Lake CityUSA
  2. 2.ISA Scientific, Inc.DraperUSA

Personalised recommendations