Skip to main content

Cannabinoids for Neuropathic Pain

Current Pain and Headache Reports volume 18, Article number: 451 (2014) Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

References

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

  1. Mechoulam R. Marihuana chemistry. Science. 1970;168:1159–66.

    PubMed  Article  CAS  Google Scholar 

  2. Adams R. Marihuana. Science. 1940;92:115–9.

    PubMed  Article  CAS  Google Scholar 

  3. Abel EL. Marihuana: the first twelve thousand years. New York: Phenum Press; 1980.

    Book  Google Scholar 

  4. Zias J, Stark H, Sellgman J, Levy R, Werker E, Breuer K, et al. Early medical use of cannabis. Nature. 1993;363:215.

    PubMed  CAS  Google Scholar 

  5. Mikuriya TH, editor. Marijuana medical papers: 1839–1972. Berkeley: Medicomp Press; 1972.

    Google Scholar 

  6. Zuardi AW. History of cannabis as medicine: a review. Rev Bras Psiquiatr. 2006;28:1253–7.

    Article  Google Scholar 

  7. Nicoll RA, Alger BN. The brain’s own marijuana. Sci Am. 2004;21:45–51.

    Google Scholar 

  8. Mandavilli A. Marijuana researchers reach for pot of gold. Nat Med. 2003;9:1227.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  10. Gertsch J. Anti-inflammatory cannabinoids in diet: towards a better understanding of CB(2) receptor action? Commun Integr Biol. 2008;1:S26–8.

    Article  Google Scholar 

  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.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  17. Beltramo M. Cannabinoid type 2 receptor as a target for chronic pain. Mini Rev Med Chem. 2009;9:11–25.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  29. Van Sickle MD, Duncan M, Kingsley PJ, et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005;310:329–32.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  34. Bushlin I, Rozenfeld R, Devi LA. Cannabinoid-opioid interactions during neuropathic pain and analgesia. Curr Opin Pharmacol. 2010;10:80–6.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  PubMed Central  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  42. Rahn EJ, Hohmann AG. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics. 2009;6:713–37.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  43. Pertwee RG. Cannabinoid receptors and pain. Prog Neurobiol. 2001;63:569–611.

    PubMed  Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  46. Iversen L, Chapman V. Cannabinoids: a real prospect for pain relief? Curr Opin Pharmacol. 2002;2:50–5.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  48. Gaoni Y, Mechoulam R. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc. 1964;86:1646–7.

    Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  50. Holdcroft A, Smith M, Jacklin A, et al. Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia. 1997;52:483–6.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  52. Lemberger L, Row H. Clinical pharmacology of nabilone, a cannabinol derivative. Clin Pharm. 1975;18:720–6.

    CAS  Google Scholar 

  53. Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for the treatment of pain in fibromyalgia. J Pain. 2008;9:164–73.

    PubMed  Article  CAS  Google Scholar 

  54. Beaulieu P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can J Anaesth. 2006;53:769–75.

    PubMed  Article  Google Scholar 

  55. Mechoulam R, Parker LA, Gallily R. Cannabidiol: an overview of some pharmacological aspects. J Clin Pharmacol. 2002;42:11S–9S.

    PubMed  Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  58. Morgan C, Curran H. Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis. Br J Psychiatry. 2008;192:306–7.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  61. Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008;4:245–59.

    PubMed  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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. 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.

    Article  Google Scholar 

  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.

    PubMed  Article  PubMed Central  Google Scholar 

  68. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011;163:1344–64.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  69. Gertsch J, Pertwee RG, Di Marzo V. Phytocannabinoids beyond the Cannabis plant—do they exist? Br J Pharmacol. 2010;160:523–9.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  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: http://www.cannabis-med.org/meeting/Cologne2009/reader.pdf. Accessed March 23, 2013.

  72. Dinarello CA. Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol. 2009;27:519–50.

    PubMed  Article  CAS  Google Scholar 

  73. Cichewicz DL, McCarthy EA. Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther. 2003;304:1010–5.

    PubMed  Article  CAS  Google Scholar 

  74. Zutler M, Holty JC. Opioids, sleep and sleep-disordered breathing. Curr Pharm Des. 2011;17:1443–9.

    PubMed  Article  CAS  Google Scholar 

  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. Walker JM, Huang SM. Cannabinoid analgesia. Pharmacol Ther. 2002;95:127–35.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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. 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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

Download references

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.

Author information

Affiliations

  1. Pain Research and Management Centers, School of Medicine, Department of Anesthesiology, University of Utah, Suite 200, 615 Arapeen Drive, Salt Lake City, UT, 84108, USA

    Perry G. Fine

  2. ISA Scientific, Inc., Draper, UT, 84020, USA

    Mark J. Rosenfeld

Authors
  1. Perry G. Fine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mark J. Rosenfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Perry G. Fine.

Additional information

This article is part of the Topical Collection on Neuropathic Pain

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fine, P.G., Rosenfeld, M.J. Cannabinoids for Neuropathic Pain. Curr Pain Headache Rep 18, 451 (2014). https://doi.org/10.1007/s11916-014-0451-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11916-014-0451-2

Keywords

  • Cannabinoids
  • Endocannabinoid system
  • Neuropathic pain