The Role of the Cannabinoid System in Pain Control: Basic and Clinical Implications


Purpose of Review

The purpose of this review is to provide a comprehensive update of the different known components of the endogenous cannabinoid system and the mechanisms of action, as it applies to analgesia.

Recent Findings

Following the discovery of the endogenous cannabinoid system in the early 1990s and the subsequent characterization of the cannabinoid receptor, there has been a renewed interest in cannabinoid research. Recent work has demonstrated its efficacy as a pharmacologic agent. There is limited evidence in the literature about the understanding of the endocannabinoid system and its role in the treatment and management of acute and chronic pain. Further work may elucidate additional roles for the endocannabinoid system within our nervous system and, moreover, additional subtypes of cannabinoid receptors have yet to be discovered.


Cannabinoid compounds mediate their biological effects via binding and subsequent activation of cannabinoid receptors. These receptors are located throughout the body and make up the endocannabinoid system. These receptors are best understood and have been cloned, type 1 (CB1) and type 2 (CB2) [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)] [ (1, 2)]. The CB2 receptor is located primarily in the immune system. CB1 receptors are primarily located in the nervous system with the highest concentrations in the brain and lower concentrations in the spine and peripheral nervous tissues. Cannabinoids may be promising treatments for neuropathic pain with limited evidence, whereas, the evidence for other uses is insufficient.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2


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

  1. 1.

    Manchikanti L, Kaye AM, Knezevic NN, McAnally H, Trescot AM, Blank S, et al. Responsible, safe, and effective prescription of opioids for chronic non-cancer pain: American Society of Interventional Pain Physicians (ASIPP) guidelines. Pain Physician. 2017;20(2S):S3–S92.

    PubMed  Google Scholar 

  2. 2.

    Kaye AD, Jones MR, Kaye AM, Ripoll JG, Galan V, Beakley BD, et al. Prescription opioid abuse in chronic pain: an updated review of opioid abuse predictors and strategies to curb opioid abuse: part 1. Pain Physician. 2017;20(2S):S93–S109.

    PubMed  Google Scholar 

  3. 3.

    Kaye AD, Jones MR, Kaye AM, Ripoll JG, Jones DE, Galan V, et al. Prescription opioid abuse in chronic pain: an updated review of opioid abuse predictors and strategies to curb opioid abuse: part 2. Pain Physician. 2017;20(2S):S111–33.

    PubMed  Google Scholar 

  4. 4.

    •• Manchikanti L, Soin A, Mann DP, Bakshi S, Pampati V, Hirsch JA. Reversal of growth of utilization of interventional techniques in managing chronic pain in Medicare population post Affordable Care Act. Pain Physician. 2017;20(6):551–67 This is the latest manuscript describing the utilization of interventional techniques in managing chronic pain in the Medicare population. This updated analysis details various categories of procedures and their patterns of utilization.

    PubMed  Google Scholar 

  5. 5.

    Manchikanti L, Soin A, Mann DP, Bakshi S, Pampati V, Hirsch JA. Comparative analysis of utilization of epidural procedures in managing chronic pain in the Medicare population: pre and post affordable care act. Spine (Phila Pa 1976). 2019;44(3):220–32.

  6. 6.

    Manchikanti L, Pampati V, Benyamin RM, Hirsch JA. Declining utilization of percutaneous epidural adhesiolysis in Medicare population: evidence-based or over-regulated? Pain Medicine Case Reports. 2018;2(1):9–18.

  7. 7.

    • Manchikanti L, Sanapati J, Benyamin RM, Atluri S, Kaye AD, Hirsch JA. Reframing the prevention strategies of the opioid crisis: Focusing on prescription opioids, fentanyl, and heroin epidemic. Pain Physician. 2018;21(4):309–26 A manuscript of critical importance showing the influence of the opioid crisis on national care and interventions in the United States.

    PubMed  Google Scholar 

  8. 8.

    Chakravarthy K, Manchikanti L, Kaye AD, Christo PJ. Reframing the role of neuromodulation therapy in the chronic pain treatment paradigm. Pain Physician. 2018;21(6):507–13.

    PubMed  Google Scholar 

  9. 9.

    Fischer B, Jones W, Vojtila L, Kurdyak P. Patterns, changes, and trends in prescription opioid dispensing in Canada, 2005-2016. Pain Physician. 2018;21(3):219–28.

    PubMed  Google Scholar 

  10. 10.

    Campbell K, Kutz JW, Shoup A, Wen W, Lynch SY. Evaluation of the ototoxicity potential of once-daily, single-entity hydrocodone in patients with chronic pain: results of two phase-3 clinical studies. Pain Physician. 2017;20(1):E183–93.

    PubMed  Google Scholar 

  11. 11.

    Manchikanti L, Manchikanti KN, Kaye AD, Kaye AM, Hirsch JA. Challenges and concerns of persistent opioid use in cancer patients. Expert Rev Anticancer Ther. 2018;18(7):705–18.

    CAS  PubMed  Google Scholar 

  12. 12.

    Centers for Disease Control and Prevention, National Center for Health Statistics. Multiple cause of death 1999–2017 on CDC WONDER Online Database, released December, 2018.

  13. 13.

    Khan SP, Pickens TA, Berlau DJ. Perspectives on cannabis as a substitute for opioid analgesics. Pain Manag. 2019;9(2):191–203.

    PubMed  Google Scholar 

  14. 14.

    Maher DP, Carr DB, Hill K, McGeeney B, Weed V, Jackson WC, et al. Cannabis for the treatment of chronic pain in the era of an opioid epidemic: a symposium-based review of sociomedical science. Pain Med. 2019;20(11):2311–2323.

  15. 15.

    Tyree GA, Sarkar R, Bellows BK, Ellis RJ, Atkinson JH, Marcotte TD, et al. A cost-effectiveness model for adjunctive smoked cannabis in the treatment of chronic neuropathic pain. Cannabis Cannabinoid Res. 2019;4(1):62–72.

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Fales JL, Ladd BO, Magnan RE. Pain relief as a motivation for cannabis use among young adult users with and without chronic pain. J Pain. 2019;20:908–16.

    PubMed  Google Scholar 

  17. 17.

    Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999–2010. JAMA Intern Med. 2014;174(10):1668–73.

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Vigil JM, Stith SS, Adams IM, Reeve AP. Associations between medical cannabis and prescription opioid use in chronic pain patients: a preliminary cohort study. PLoS One. 2017;12(11):1–13.

    Google Scholar 

  19. 19.

    Corroon JM, Mischley LK, Sexton M. Cannabis as a substitute for prescription drugs – a cross-sectional study. J Pain Res. 2017;10:989–98.

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Lucas P, Walsh Z. Medical cannabis access, use, and substitution for prescription opioids and other substances: a survey of authorized medical cannabis patients. Int J Drug Policy. 2017;42:30–5.

    PubMed  Google Scholar 

  21. 21.

    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.

    PubMed  Google Scholar 

  22. 22.

    Pardo B. Cannabis policy reforms in the Americas: a comparative analysis of Colorado, Washington, and Uruguay. Int J Drug Policy. 2014;25(4):727–35.

    PubMed  Google Scholar 

  23. 23.

    Livingston MD, Barnett TE, Delcher C, Wagenaar AC. Recreational cannabis legalization and opioid-related deaths in Colorado, 2000–2015. Am J Public Health. 2017;107(11):1827–9.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Stith SS, Vigil JM, Adams IM, Reeve AP. Effects of legal access to cannabis on scheduled ii–v drug prescriptions. J Am Med Dir Assoc. 2018;19(1):59–64.

    PubMed  Google Scholar 

  25. 25.

    Sexton M, Cuttler C, Finnell JS, Mischley LK. A cross-sectional survey of medical cannabis users: patterns of use and perceived efficacy. Cannabis Cannabinoid Res. 2016;1(1):131–8.

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Ahrnsbrak R, Bose J, Hedden S, Lipari R, Park-Lee E. Key substance use and mental health indicators in the United States: results from the 2016 National Survey on drug use and health. Subst Abus Ment Heal Serv Adm. HHS publication no. SMA, NSDUH Series H-52, 17–5044 (2017).

  27. 27.

    Shi Y. Medical marijuana policies and hospitalizations related to marijuana and opioid pain reliever. Drug Alcohol Depend. 2017;173:144–50.

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Reiman A, Welty M, Solomon P. Cannabis as a substitute for opioid-based pain medication: patient self-report. Cannabis Cannabinoid Res. 2017;2(1):160–6.

    PubMed  PubMed Central  Google Scholar 

  29. 29.

    Nugent SM, Morasco BJ, O’Neil ME, Freeman M, Low A, Kondo K, et al. 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.

    PubMed  Google Scholar 

  30. 30.

    Amato L, Minozzi S, Mitrova Z, Parmelli E, Saulle R, Cruciani F, et al. Systematic review of safeness and therapeutic efficacy of cannabis in patients with multiple sclerosis, neuropathic pain, and in oncological patients treated with chemotherapy. Epidemiol Prev. 2017;41(5–6):279–93.

    PubMed  Google Scholar 

  31. 31.

    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:CD012182.

    PubMed  Google Scholar 

  32. 32.

    O’Neil ME, Nugent SM, Morasco BJ, Freeman M, Low A, Kondo K, et al. Benefits and harms of plant-based cannabis for posttraumatic stress disorder: a systematic review. Ann Intern Med. 2017;167(5):332–40.

    PubMed  Google Scholar 

  33. 33.

    Romero-Sandoval EA, Kolano AL, Alvarado-Vázquez PA. Cannabis and cannabinoids for chronic pain. Curr Rheumatol Rep. 2017;19(11):67.

    PubMed  Google Scholar 

  34. 34.

    Häuser W, Fitzcharles MA, Radbruch L, Petzke F. Cannabinoids in pain management and palliative medicine. Dtsch Arztebl Int. 2017;114(38):627–34.

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Walitt B, Klose P, Fitzcharles MA, Phillips T, Häuser W. Cannabinoids for fibromyalgia. Cochrane Database Syst Rev. 2016;7:CD011694.

    PubMed  Google Scholar 

  36. 36.

    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.

    PubMed  Google Scholar 

  37. 37.

    van de Donk T, Niesters M, Kowal MA, Olofsen E, Dahan A, van Velzen M. An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia. Pain. 2019;160(4):860–9.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Aviram J, Samuell-Leichtag G. Efficacy of cannabis-based medicines for pain management: a systematic review and meta-analysis of randomized controlled trials. Pain Physician. 2017;20(6):E755–96.

    CAS  PubMed  Google Scholar 

  39. 39.

    Petzke F, Enax-Krumova EK, Häuser W. Efficacy, tolerability and safety of cannabinoids for chronic neuropathic pain: a systematic review of randomized controlled studies. Schmerz. 2016;30(1):62–88.

    CAS  PubMed  Google Scholar 

  40. 40.

    Metrik J, Bassett SS, Aston ER, Jackson KM, Borsari B. Medicinal versus recreational cannabis use among returning veterans. Transl Issues Psychol Sci. 2018;4(1):6–20.

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Blake A, Wan BA, Malek L, DeAngelis C, Diaz P, Lao N, et al. A selective review of medical cannabis in cancer pain management. Ann Palliat Med. 2017;6(Suppl 2):S215–22.

    PubMed  Google Scholar 

  42. 42.

    Fitzcharles MA, Ste-Marie PA, Häuser W, Clauw DJ, Jamal S, Karsh J, et al. Efficacy, tolerability, and safety of cannabinoid treatments in the rheumatic diseases: a systematic review of randomized controlled trials. Arthritis Care Res. 2016;68(5):681–8.

    CAS  Google Scholar 

  43. 43.

    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.

    PubMed  Google Scholar 

  44. 44.

    Knezevic NN, Khan OM, Beiranvand A, Candido KD. Repeated quantitative urine toxicology analysis may improve chronic pain patient compliance with opioid therapy. Pain Physician. 2017;20(2S):S135–45.

    PubMed  Google Scholar 

  45. 45.

    Hall KE, Monte AA, Chang T, Fox J, Brevik C, Vigil DI, et al. Mental health-related emergency department visits associated with cannabis in Colorado. Acad Emerg Med. 2018;25(5):526–37.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Centers for Disease Control and Prevention. Health effects. Marijuana: how can it affect your health?

  47. 47.

    Kim HS, Anderson JD, Saghafi O, Heard KJ, Monte AA. Cyclic vomiting presentations following marijuana liberalization in Colorado. Acad Emerg Med. 2015;22(6):694–9.

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Relationship between marijuana and opioids. NORML.

  49. 49.

    Dangers of combining marijuana and morphine. Talbott Recovery.

  50. 50.

    Wang GS, Davies SD, Halmo LS, Sass A, Mistry RD. Impact of marijuana legalization in Colorado on adolescent emergency and urgent care visits. J Adolesc Health. 2018;63(2):239–41.

    PubMed  Google Scholar 

  51. 51.

    DiBenedetoo DJ, Weed VF, Wawrzyniak KM, Finkelman M, Paolini J, Schatman ME, et al. The association between cannabis use and aberrant behaviors during chronic opioid therapy for chronic pain. Pain Med. 2018;19(10):1997–2008.

    Google Scholar 

  52. 52.

    Ho C, Martinusen D, Lo C. A review of cannabis in chronic kidney disease symptom management. Can J Kidney Health Dis. 2019;6:2054358119828391.

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Sanger N, Bhatt M, Shams I, Shahid H, Luo C, Tam SL, et al. Association between socio-demographic and health functioning variables among patients with opioid use disorder introduced by prescription: a prospective cohort study. Pain Physician. 2018;21(6):E623–32.

    PubMed  Google Scholar 

  54. 54.

    Becker WC, Tetrault JM. Medical marijuana in patients prescribed opioids: a cloud of uncertainty. Mayo Clin Proc. 2016;91(7):830–2.

    PubMed  Google Scholar 

  55. 55.

    •• Manchikanti L, Knezevic NN, Boswell MV, Kaye AD, Hirsch JA. Epidural injections for lumbar radiculopathy and spinal stenosis: A comparative systematic review and meta-analysis. Pain Physician. 2016;19(3):E365–410 This manuscript compares in detail the systematic review and meta-analysis performed by Chou et al. for the Agency for Healthcare Research and Quality (AHRQ) that was published inAnnals of Internal Medicine. This manuscript shows the deficiencies in the design, methodologic quality assessment, and grading of evidence in the manuscript by Chou et al. and how their conclusions lack clinical relevance.

    PubMed  Google Scholar 

  56. 56.

    Manchikanti L, Boswell MV, Kaye AD, Helm S II, Hirsch JA. Therapeutic role of placebo: evolution of a new paradigm in understanding research and clinical practice. Pain Physician. 2017;20(5):363–86.

    PubMed  Google Scholar 

  57. 57.

    Beall DP, Tutton SM, Murphy K, Olan W, Warner CB, Test JB. Analysis of reporting bias in vertebral augmentation. Pain Physician. 2017;20(7):E1081–90.

    PubMed  Google Scholar 

  58. 58.

    Shen J, Xu S, Xu S, Ye S, Hao J. Fusion or not for degenerative lumbar spinal stenosis: a meta-analysis and systematic review. Pain Physician. 2018;21(1):1–8.

    PubMed  Google Scholar 

  59. 59.

    Zhang H, Xu C, Zhang T, Gao Z, Zhang T. Does percutaneous vertebroplasty or balloon kyphoplasty for osteoporotic vertebral compression fractures increase the incidence of new vertebral fractures? A meta-analysis. Pain Physician. 2017;20(1):E13–28.

    PubMed  Google Scholar 

  60. 60.

    Sanapati J, Manchikanti L, Atluri S, Jordan S, Albers SL, Pappolla MA, et al. Do regenerative medicine therapies provide long-term relief in chronic low back pain: a systematic review and metaanalysis. Pain Physician. 2018;21(6):515–40.

    PubMed  Google Scholar 

  61. 61.

    Fu X, Tang L, Wang C, Li M, Wu H, Li J, et al. A network meta-analysis to compare the efficacy of steroid and antiviral medications for facial paralysis from Bell’s palsy. Pain Physician. 2018;21(6):559–69.

    PubMed  Google Scholar 

  62. 62.

    Cho JH, Lee JH, Song KS, Hong JY, Joo YS, Lee DH, et al. Treatment outcomes for patients with failed back surgery. Pain Physician. 2017;20(1):E29–43.

    PubMed  Google Scholar 

  63. 63.

    Salazar AP, Stein C, Marchese RR, Plentz RD, Pagnussat AS. Electric stimulation for pain relief in patients with fibromyalgia: a systematic review and meta-analysis of randomized controlled trials. Pain Physician. 2017;20(2):15–25.

    PubMed  Google Scholar 

  64. 64.

    Gudala K, Bansal D, Vatte R, Ghai B, Schifano F, Boya C. High prevalence of neuropathic pain component in patients with low back pain: evidence from meta-analysis. Pain Physician. 2017;20(5):343–52.

    PubMed  Google Scholar 

  65. 65.

    Lewis R, Williams N, Matar HE, Din N, Fitzsimmons D, Phillips C, et al. The clinical effectiveness and cost effectiveness of management strategies for sciatica: systematic review and economic model. Health Technol Assess. 2011;15(39):1–578.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Lee JH, Shin KH, Park SJ, Lee GJ, Lee CH, Kim DH, et al. Comparison of clinical efficacy between transforaminal and interlaminar epidural injections in lumbosacral disc herniation: a systematic review and meta-analysis. Pain Physician. 2018;21(5):433–48.

    PubMed  Google Scholar 

  67. 67.

    Lee JH, Kim DH, Kim DH, Shin KH, Park SJ, Lee GJ, et al. Comparison of clinical efficacy of epidural injection with or without steroid in lumbosacral disc herniation: a systematic review and meta-analysis. Pain Physician. 2018;21(5):449–68.

    PubMed  Google Scholar 

  68. 68.

    Manchikanti L, Pampati V, Benyamin RM, Hirsch JA. Cost utility analysis of lumbar interlaminar epidural injections in the treatment of lumbar disc herniation, central spinal stenosis, and axial or discogenic low back pain. Pain Physician. 2017;20(4):219–28.

    PubMed  Google Scholar 

  69. 69.

    Manchikanti L, Pampati V, Kaye AD, Hirsch JA. Therapeutic lumbar facet joint nerve blocks in the treatment of chronic low back pain: cost utility analysis based on a randomized controlled trial. Korean J Pain. 2018;31(1):27–38.

    PubMed  PubMed Central  Google Scholar 

  70. 70.

    Manchikanti L, Pampati V, Kaye AD, Hirsch JA. Cost utility analysis of cervical therapeutic medial branch blocks in managing chronic neck pain. Int J Med Sci. 2017;14(13):1307–16.

    PubMed  PubMed Central  Google Scholar 

  71. 71.

    Woodhams SG, Chapman V, Finn DP, Hohmann AG, Neugebauer V. The cannabinoid system and pain. Neuropharmacology. 2017;124:105–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    De Gregorio D, McLaughlin RJ, Posa L, Ochoa-Sanchez R, Enns J, Lopez-Canul M, et al. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain. 2019;160(1):136–50.

    PubMed  Google Scholar 

  73. 73.

    Mackie K. Cannabinoid receptors: where they are and what they do. J Neuroendocrinol. 2008;20(s1):10–4.

    CAS  PubMed  Google Scholar 

  74. 74.

    Ibrahim MM, Porreca F, Lai J, Albrecht PJ, Rice FL, Khodorova A, et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci. 2005;102(8):3093–8.

    CAS  PubMed  Google Scholar 

  75. 75.

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Katona I, Rancz EA, Acsady L, Ledent C, Mackie K, Hajos N, et al. Distribution of CB1 cannabinoid receptors in the amygdala and their role in the control of GABAergic transmission. J Neurosci. 2001;21(23):9506–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Sañudo-Peña MC, Strangman NM, Mackie K, Walker JM, Tsou K. CB1 receptor localization in rat spinal cord and roots, dorsal root ganglion, and peripheral nerve. Zhongguo Yao Li Xue Bao. 1999;20(12):1115–20.

    PubMed  Google Scholar 

  78. 78.

    Manning BH, Martin WJ, Meng ID. The rodent amygdala contributes to the production of cannabinoid-induced antinociception. Neuroscience. 2003;120(4):1157–70.

    CAS  PubMed  Google Scholar 

  79. 79.

    Martin WJ, Hohmann AG, Walker JM. Suppression of noxious stimulus-evoked activity in the ventral posterolateral nucleus of the thalamus by a cannabinoid agonist: correlation between electrophysiological and antinociceptive effects. J Neurosci. 1996;16(20):6601–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Giuffrida A, Beltramo M, Piomelli D. Mechanisms of endocannabinoid inactivation: biochemistry and pharmacology. J Pharmacol Exp Ther. 2001;298(1):7–14.

    CAS  PubMed  Google Scholar 

  81. 81.

    Walker JM, Krey JF, Chu CJ, Huang SM. Endocannabinoids and related fatty acid derivatives in pain modulation. Chem Phys Lipids. 2002;121(1–2):159–72.

    CAS  PubMed  Google Scholar 

  82. 82.

    Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258(5090):1946–9.

    CAS  PubMed  Google Scholar 

  83. 83.

    Pertwee RG. Endocannabinoids and their pharmacological actions. In: Handbook of experimental pharmacology; 2015. p. 1–37.

    Google Scholar 

  84. 84.

    Starowicz K, Finn DP. Cannabinoids and pain: sites and mechanisms of action. Adv Pharmacol. 2017;80:437–475.

  85. 85.

    Ibsen MS, Connor M, Glass M. Cannabinoid CB 1 and CB 2 receptor signaling and bias. Cannabis Cannabinoid Res. 2017;2(1):48–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Hill KP, Palastro MD, Johnson B, Ditre JW. Cannabis and pain: a clinical review. Cannabis Cannabinoid Res. 2017;2(1):96–104.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Niu J, Huang D, Zhou R, Yue M, Xu T, Yang J, et al. Activation of dorsal horn cannabinoid CB2 receptor suppresses the expression of P2Y12 and P2Y13 receptors in neuropathic pain rats. J Neuroinflammation. 2017;14(1):185.

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Rahn EJ, Hohmann AG. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics. 2009;6(4):713–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Scavone JL, Sterling RC, Van Bockstaele EJ. Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal. Neuroscience. 2013;248:637–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Fine PG, Rosenfeld MJ. The endocannabinoid system, cannabinoids, and pain. Rambam Maimonides Med J. 2013;4(4):e0022.

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Morales P, Hurst DP, Reggio PH. Molecular targets of the phytocannabinoids: a complex picture. Prog Chem Org Nat Prod. 2017;103:103–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Lowin T, Straub RH. Cannabinoid-based drugs targeting CB1 and TRPV1, the sympathetic nervous system, and arthritis. Arthritis Res Ther. 2015;17(1):226.

    PubMed  PubMed Central  Google Scholar 

  93. 93.

    Cristino L, de Petrocellis L, Pryce G, Baker D, Guglielmotti V, Di Marzo V. Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Neuroscience. 2006;139(4):1405–15.

    CAS  PubMed  Google Scholar 

  94. 94.

    Hojo M, Sudo Y, Ando Y, Minami K, Takada M, Matsubara T, et al. mu-Opioid receptor forms a functional heterodimer with cannabinoid CB1 receptor: electrophysiological and FRET assay analysis. J Pharmacol Sci. 2008;108(3):308–19.

    CAS  PubMed  Google Scholar 

  95. 95.

    Nielsen S, Sabioni P, Trigo JM, Ware MA, Betz-Stablein BD, Murnion B, et al. Opioid-sparing effect of cannabinoids: a systematic review and meta-analysis. Neuropsychopharmacology. 2017;42(9):1752–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Urits I, Viswanath O, Orhurhu V, Gress K, Charipova K, Kaye AD, et al. The utilization of mu-opioid receptor biased agonists: oliceridine, an opioid analgesic with reduced adverse effects. Curr Pain Headache Rep. 2019;23(5):31.

    PubMed  Google Scholar 

  97. 97.

    Ruano G, Kost JA. Fundamental considerations for genetically-guided pain management with opioids based on CYP2D6 and OPRM1 polymorphisms. Pain Physician. 2018;21(6):E611–21.

    PubMed  Google Scholar 

  98. 98.

    Margarit C, Ballester P, Inda M, Roca R, Gomez L, Planelles B, et al. OPRM1 gene interaction with sleep in chronic pain patients treated with opioids. Pain Physician. 2019;22(1):97–107.

    PubMed  Google Scholar 

  99. 99.

    National Academies of Sciences, Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. Washington, DC: National Academies Press.

  100. 100.

    • CADTH CAfDaTH. Cannabinoid buccal spray for chronic noncancer or neuropathic pain: a review of clinical effectiveness, safety, and guidelines. Otawa (ON); 2016. This study concluded that there is no sufficient evidence to support the use of oromucosal cannabinoids for the treatment of chronic pain, and shows the conflicting results available in the literature for this form of administration.

Download references

Author information



Corresponding author

Correspondence to Ivan Urits.

Ethics declarations

Conflict of Interest

John Wolf, Vwaire Orhurhu, Jacquelin Peck, Mariam Salisu Orhurhu, Stephen Giacomazzi, Daniel Smoots, Charlie Piermarini, Laxmaiah Manchikanti, Rachel J. Kaye, and Omar Viswanath declare no conflict of interest.

Alan Kaye is a Section Editor for Current Headache and Pain Reports. He has not been involved in the editorial handling of this manuscript. Dr. Kaye is also a speaker for Merck.

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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Other Pain

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wolf, J., Urits, I., Orhurhu, V. et al. The Role of the Cannabinoid System in Pain Control: Basic and Clinical Implications. Curr Pain Headache Rep 24, 35 (2020).

Download citation


  • Endocannabinoid system
  • Cannabis
  • Cannabinoid receptor
  • Cannabinoids