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Cannabinoids for the treatment of neuropathic pain: are they safe and effective?

2011; Future Medicine; Volume: 6; Issue: 2 Linguagem: Inglês

10.2217/fnl.11.6

1748-6971

Tannia Gutierrez, Andrea G. Hohmann,

Neurotransmitter Receptor Influence on Behavior

Future NeurologyVol. 6, No. 2 EditorialFree AccessCannabinoids for the treatment of neuropathic pain: are they safe and effective?Tannia Gutierrez & Andrea G HohmannTannia GutierrezDepartment of Psychological & Brain Sciences, Indiana University Bloomington, Bloomington, IN 47405-2204, USA & Andrea G Hohmann† Author for correspondencePublished Online:7 Mar 2011https://doi.org/10.2217/fnl.11.6AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: allodyniacannabinoidendocannabinoidhyperalgesianeuropathic painThe isolation of Δ9-tetrahydrocannabinol (THC), the major psychoactive ingredient in cannabis, set the stage for the discovery of an endogenous cannabinoid (endocannabinoid) transmitter system [1]. Endogenous signaling molecules for this system were subsequently isolated [2,3]. Anandamide [4] and 2-arachidonoylglycerol (2-AG) [2,3], the best characterized endocannabinoids isolated to date, bind to and activate cannabinoid CB1 and CB2 receptors. CB1 is the primary cannabinoid receptor found in the CNS [5], whereas CB2 is predominantly, but not exclusively, found in the immune system [6–8]. The discovery of cannabinoid receptors allowed researchers to synthesize cannabinoids and characterize their pain-relieving properties. Anandamide and 2-AG are degraded by the enzymes fatty-acid amide hydrolase and monoacylglycerol lipase [9], respectively. Enzymes catalyzing endocannabinoid breakdown also represent targets for analgesic drug development. This article will briefly summarize the findings of preclinical and clinical studies evaluating the therapeutic and side-effect profile of cannabinoids as pharmacotherapies for neuropathic pain.Neuropathic painNeuropathic pain is caused by a primary lesion or dysfunction in the nervous system [10]. Spontaneous (ongoing, paroxysm) and evoked types of pain (hyperalgesia and allodynia) are present [11]. Hyperalgesia refers to an increase in response to stimuli that normally produces pain. Allodynia refers to pain caused by stimuli that are normally not painful. Neuropathic pain may arise from illness, be drug-induced or caused by toxin exposure [11]. Different patients or types of neuropathic pain may respond differently to standard drug interventions. NSAIDs [12], antidepressants, anticonvulsants and opioids [11,12] are all used to treat neuropathic pain. However, no single treatment provides complete relief from neuropathic pain, and adverse side effects limit their therapeutic efficacy. For example, patients treated with opioids develop sedation, nausea, constipation, respiratory depression, tolerance and hyperalgesia [101]. Identification of alternative therapeutics that provide adequate pain relief in the absence of adverse side effects remains a strong clinical need.Preclinical studiesCannabinoids are efficacious in suppressing hyperalgesia and allodynia in animal models of neuropathic pain through CB1 and CB2 mechanisms [13–20]. Different classes of cannabinoids (i.e., synthetic endocannabinoids, CB1 agonists, mixed CB1/CB2 agonists, CB2 agonists and endocannabinoid modulators) all suppress neuropathic pain behavior in animals [21]. Efficacy has been demonstrated in animal models of traumatic nerve injury (i.e., chronic constriction injury [22], partial nerve ligation [23] and spinal nerve ligation [24] models) and in neuropathy models produced by metabolic challenges or toxins (streptozotocin- and chemotherapy-induced neuropathy) [21].In rodent nerve injury models, mixed cannabinoid CB1/CB2 agonists (i.e., WIN55,212-2, CP55,940 and HU-210) suppress thermal hyperalgesia and mechanical allodynia [21]. However, the resultant pain-relieving effects may be accompanied by side effects. CB1 receptor activation can lead to CNS side effects (e.g., hypoactivity, hypothermia and catalepsy) [25], which may translate into psychoactivity in humans. Antinociceptive efficacy of cannabinoids has also been reported in toxin-induced neuropathy (chemotherapy-induced neuropathy) and streptozotocin-induced diabetic neuropathy models [21].Cannabinoid CB2 agonists attenuate neuropathic pain [16,19,26–31] without the CNS side effects attributed to CB1[32]. However, it is important to verify that the antihyperalgesic efficacy observed in rodent models translates to humans and is not species-specific. This is particularly important because even low levels of CB1 occupancy can translate into unwanted CNS side effects.Other strategies that attempt to limit CNS side effects may enhance the therapeutic ratio of cannabinoid pharmacotherapies for neuropathic pain. For example, drugs targeting the metabolic breakdown of endocannabinoids and peripherally-acting agonists [33,34] all show promise for suppressing neuropathic pain in animal models (see [35]). AZ11713908, a peripherally restricted cannabinoid agonist, reduces mechanical allodynia with a magnitude comparable with that of the mixed cannabinoid agonist WIN55,212-2 that penetrates the CNS [34]. An irreversible inhibitor of the 2-AG-hydrolyzing enzyme monoacylglycerol produces a CB1-mediated suppression of nerve injury-induced mechanical allodynia but undergoes tolerance following repeated administration [36]. The recent identification of URB937, a brain impermeant inhibitor of fatty-acid amide hydrolase, is particularly noteworthy [33]. URB937 elevates anandamide outside the brain and produces a CB1-mediated suppression of neuropathic pain behavior, without producing tolerance or unwanted CNS side effects [33]. Adjunctive treatments, which combine cannabinoids with other analgesic agents, also offer the potential to produce synergistic antinociceptive effects with limited side-effect profiles.Clinical studiesDifferent classes of cannabinoid-based medications are being evaluated for efficacy in clinical trials [102]. However, cannabis contains approximately 460 chemically distinct constituents, and, consequently, smoked marijuana is not the same as synthetic Δ9-THC or mixtures of Δ9-THC and cannabidiol. Therefore, different chemical compounds tested in clinical trials are not identical, and so the therapeutic efficacy or side effects may differ [21]. The cannabinoid-based compounds that have been tested most extensively in clinical settings include smoked cannabis, Sativex® (GW Pharmaceuticals, UK; an oral mucosal spray containing cannabis extracts with a 1:1 ratio of Δ9-THC and cannabidiol), dronabinol (Marinol®; Solvay Pharmaceuticals, Belgium) and nabilone [21]. These compounds have been shown to reduce neuropathic pain. Smoked cannabis provides notable improvement of neuropathic pain in patients with HIV sensory-related neuropathy [37,38]. HIV patients, prior to cannabis treatment, had intractable pain despite concurrent treatment with opioids, NSAIDs and adjuvants [38]. Cannabis improved pain throughout both phases of a crossover study, as measured by the descriptor differential scale and the visual analog scale (VAS) [38]. No changes in blood pressure, HIV RNA (viral load) or blood CD4 lymphocytes were detected compared with placebo [38]. Smoked cannabis also reduced pain in HIV patients by greater than 30%, as measured by VAS, and decreased capsaicin-induced mechanical allodynia [37]. No patients withdrew from the study due to adverse events, indicating that the pain-relieving effects outweighed any negative side effects. Strikingly, a single inhalation of THC herbal cannabis (25 mg of 9.4%) decreased pain intensity in post-traumatic or post-surgery-induced neuropathic pain, as measured by a numeric rating scale [39]. This study thoroughly assessed pain intensity, sleep, concurrent medications and side effects [39]. A total of 248 mild and six moderate effects were detected. Headache, dry eyes, burning sensation, dizziness, numbness and cough were associated with the high dose of cannabis, but no changes were found in vital signs, heart rate or renal blood function [39].In a randomized, double-blind study, patients with neuropathic pain of peripheral origin were given oromucosal Sativex, and pain, sleep and allodynia were assessed [40]. Patients were allowed to continue concurrent medications and self-medicate with Sativex without exceeding the allowed limits. Sativex improved pain based on the numerical rating scale. Dynamic mechanical allodynia (measured by brushing the affected skin) decreased by 20%, and both punctate allodynia and sleep improved [40]. Side effects included sedation and gastrointestinal effects and were classified as severe in 10–11% of patients [40]. Nabilone, an orally administered synthetic cannabinoid, is approved in Canada to treat chemotherapy-induced nausea and vomiting. In a randomized, double-blind, placebo-controlled study, nabilone was given to patients with fibromyalgia in order to determine whether drug treatment would improve pain and quality of life [41]. Patients administered 1 mg twice daily of nabilone showed improved VAS pain ratings and improved scores in the fibromyalgia impact questionnaire (which evaluates daily functions such as depression and physical function, among others) [41]. The most common side effects were drowsiness, dry mouth, vertigo and ataxia [41]. Clinical trials are ongoing for nabilone (for diabetic neuropathy and phantom limb pain) and Sativex (for chemotherapy-induced neuropathy) in other neuropathic pain syndromes [102].A systematic review recently evaluated the safety of medical cannabinoids [42]. In this review, 4615 (96.6%) adverse events were not considered serious and 164 adverse events were considered serious [42]. However, serious adverse events (e.g., relapse to multiple sclerosis, vomiting and urinary tract infection) did not differ between treated and placebo groups [42]. Dizziness was the most common nonserious adverse event [42]. Oromucosal Δ9-THC and oral Δ9-THC were associated with more adverse events compared with controls [42].The presence of side effects that are associated with CB1 activation is indisputable among cannabis-based treatments in humans [21,42]. However, cannabinoids show efficacy for suppressing neuropathic pain in clinical studies and side effects are not unique to cannabinoids. Gabapentinoids, tricyclic antidepressants, anticonvulsants, cannabinoids (e.g., nabilone and Sativex) and topical agents were all associated with side effects in a prospective evaluation of specific chronic polyneuropathy syndromes and their responses to pharmacological therapies; the presence of intolerable side effects were comparable across these different classes of medications [43]. Importantly, however, cannabinoids have low toxicity. High doses of marijuana are not lethal because of the paucity of receptors in brainstem regions that control vital heart rate and respiratory functions. Moreover, several aspects of cannabinoid pharmacology (i.e., antiemetic effects and improved sleep) are particularly beneficial for a therapeutic intervention.ConclusionCannabinoids effectively suppress neuropathic pain in preclinical and clinical studies. The challenge is to balance analgesic efficacy with the presence of adverse side effects (i.e., dizziness or sedation). Endocannabinoid modulators and CB2 agonists do not produce the same spectrum of CNS side effects as those attributed to CB1 agonists, but more work is necessary to determine whether these strategies show efficacy in humans. In clinical settings, cannabinoid-based medications show therapeutic efficacy, and side effects are tolerable or no worse than those of conventional neuropathic pain medications (e.g., gabapentanoids, tricyclic antidepressants and anticonvulsants). Thus, cannabinoids show promise for managing neuropathic pain that is intractable to conventional treatments or as an adjunct to existing medications. Clinical trials are needed to evaluate the long-term effectiveness and safety of these compounds in humans.Financial & competing interests disclosureAndrea G Hohmann is supported by the NIH grants DA028200 and DA021644. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Bibliography1 Gaoni Y, Mechoulam R: Isolation, structure and partial synthesis of an active constituent of hashish. J. Am. Chem. Soc.86,1646–1647 (1964).Crossref, CAS, Google Scholar2 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.50(1),83–90 (1995).Crossref, Medline, CAS, Google Scholar3 Sugiura T, Kondo S, Sukagawa A et al.: 2-arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem. Biophys. Res. Commun.215(1),89–97 (1995).Crossref, Medline, CAS, Google Scholar4 Devane WA, Hanus L, Breuer A et al.: Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science258(5090),1946–1949 (1992).Crossref, Medline, CAS, Google Scholar5 Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI: Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl Acad. Sci. USA96(10),5780–5785 (1999).Crossref, Medline, CAS, Google Scholar6 Beltramo M, Bernardini N, Bertorelli R et al.: CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur. J. Neurosci.23(6),1530–1538 (2006).Crossref, Medline, CAS, Google Scholar7 Buckley NE, Mccoy KL, Mezey E et al.: Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB2 receptor. Eur. J. Pharmacol.396(2–3),141–149 (2000).Crossref, Medline, CAS, Google Scholar8 Van Sickle MD, Duncan M, Kingsley PJ et al.: Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science310(5746),329–332 (2005).Crossref, Medline, CAS, Google Scholar9 Pacher P, Batkai S, Kunos G: The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev.58(3),389–462 (2006).Crossref, Medline, CAS, Google Scholar10 Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. Merskey H, Bogduk N (Eds). IASP Press, WA, USA (1994).Google Scholar11 Baron R: Neuropathic pain: a clinical perspective. Handb. Exp. Pharmacol. (194),3–30 (2009).Crossref, Medline, Google Scholar12 Park HJ, Moon DE: Pharmacologic management of chronic pain. Korean J. Pain23(2),99–108 (2010).Crossref, Medline, CAS, Google Scholar13 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.133(4),586–594 (2001).Crossref, Medline, CAS, Google Scholar14 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. Pain92(1–2),91–100. (2001).Crossref, Medline, CAS, Google Scholar15 Herzberg U, Eliav E, Bennett GJ, Kopin IJ: The analgesic effects of R+-WIN 55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain. Neurosci. Lett.221(2–3),157–160 (1997).Crossref, Medline, CAS, Google Scholar16 Ibrahim MM, Deng H, Zvonok A et al.: Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc. Natl Acad. Sci. USA100(18),10529–10533 (2003).Crossref, Medline, CAS, Google Scholar17 Jhaveri MD, Elmes SJ, Richardson D et al.: Evidence for a novel functional role of cannabinoid CB2 receptors in the thalamus of neuropathic rats. Eur. J. Neurosci.27(7),1722–1730 (2008).Crossref, Medline, CAS, Google Scholar18 Labuda CJ, Koblish M, Little PJ: Cannabinoid CB2 receptor agonist activity in the hindpaw incision model of postoperative pain. Eur. J. Pharmacol.527(1–3),172–174 (2005).Crossref, Medline, CAS, Google Scholar19 Sagar DR, Kelly S, Millns PJ, O'Shaughnessey CT, Kendall DA, Chapman V: Inhibitory effects of CB1 and CB2 receptor agonists on responses of DRG neurons and dorsal horn neurons in neuropathic rats. Eur. J. Neurosci.22(2),371–379 (2005).Crossref, Medline, Google Scholar20 Whiteside GT, Lee GP, Valenzano KJ: The role of the cannabinoid CB2 receptor in pain transmission and therapeutic potential of small molecule CB2 receptor agonists. Curr. Med. Chem.14(8),917–936 (2007).Crossref, Medline, CAS, Google Scholar21 Rahn EJ, Hohmann AG: Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics6(4),713–737 (2009).Crossref, Medline, CAS, Google Scholar22 Bennett GJ, Xie YK: A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain33(1),87–107 (1988).Crossref, Medline, CAS, Google Scholar23 Seltzer Z, Dubner R, Shir Y: A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain43(2),205–218 (1990).Crossref, Medline, CAS, Google Scholar24 Kim SH, Chung JM: An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain50(3),355–363 (1992).Crossref, Medline, CAS, Google Scholar25 Martin BR, Compton DR, Thomas BF et al.: Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs. Pharmacol. Biochem. Behav.40(3),471–478 (1991).Crossref, Medline, CAS, Google Scholar26 Clayton N, Marshall FH, Bountra C, O'Shaughnessy CT: CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain96(3),253–260 (2002).Crossref, Medline, CAS, Google Scholar27 Gutierrez T, Farthing JN, Zvonok AM, Makriyannis A, Hohmann AG: Activation of peripheral cannabinoid CB1 and CB2 receptors suppresses the maintenance of inflammatory nociception: a comparative analysis. Br. J. Pharmacol.150(2),153–163 (2007).Crossref, Medline, CAS, Google Scholar28 Hsieh GC, Pai M, Chandran P et al.: Central and peripheral sites of action for CB2 receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats. Br. J. Pharmacol.162(2),428–440 (2011).Crossref, Medline, CAS, Google Scholar29 Nackley AG, Makriyannis A, Hohmann AG: Selective activation of cannabinoid CB2 receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience119(3),747–757 (2003).Crossref, Medline, CAS, Google Scholar30 Quartilho A, Mata HP, Ibrahim MM et al.: Inhibition of inflammatory hyperalgesia by activation of peripheral CB2 cannabinoid receptors. Anesthesiology99(4),955–960 (2003).Crossref, Medline, CAS, Google Scholar31 Rahn EJ, Makriyannis A, Hohmann AG: Activation of cannabinoid CB1 and CB2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats. Br. J. Pharmacol.152(5),765–777 (2007).Crossref, Medline, CAS, Google Scholar32 Guindon J, Hohmann AG: Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br. J. Pharmacol.153(2),319–334 (2008).Crossref, Medline, CAS, Google Scholar33 Clapper JR, Moreno-Sanz G, Russo R et al.: Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. Nat. Neurosci.13(10),1265–1270 (2010).Crossref, Medline, CAS, Google Scholar34 Yu XH, Cao CQ, Martino G et al.: A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain. Pain151(2),337–344 (2010).Crossref, Medline, CAS, Google Scholar35 Pertwee RG: Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br. J. Pharmacol.156(3),397–411 (2009).Crossref, Medline, CAS, Google Scholar36 Schlosburg JE, Blankman JL, Long JZ et al.: Chronic monoacylglycerol lipase blockade causes functional antagonism of the endocannabinoid system. Nat. Neurosci.13(9),1113–1119 (2010).Crossref, Medline, CAS, Google Scholar37 Abrams DI, Jay CA, Shade SB et al.: Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology68(7),515–521 (2007).Crossref, Medline, CAS, Google Scholar38 Ellis RJ, Toperoff W, Vaida F et al.: Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology34(3),672–680 (2009).Crossref, Medline, CAS, Google Scholar39 Ware MA, Wang T, Shapiro S et al.: Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ182(14),E694–E701 (2010).Crossref, Medline, Google Scholar40 Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D: Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain133(1–3),210–220 (2007).Crossref, Medline, CAS, Google Scholar41 Skrabek RQ, Galimova L, Ethans K, Perry D: Nabilone for the treatment of pain in fibromyalgia. J. Pain9(2),164–173 (2008).Crossref, Medline, CAS, Google Scholar42 Wang T, Collet JP, Shapiro S, Ware MA: Adverse effects of medical cannabinoids: a systematic review. CMAJ178(13),1669–1678 (2008).Crossref, Medline, Google Scholar43 Toth C, Au S: A prospective identification of neuropathic pain in specific chronic polyneuropathy syndromes and response to pharmacological therapy. Pain138(3),657–666 (2008).Crossref, Medline, Google Scholar101 Attal N, Finnerup NB: Pain Clinical Updates: Pharmacological management of neuropathic pain (2010) www.iasp-pain.org/AM/AMTemplate.cfm?Section=Clinical_Updates&SECTION=Clinical_Updates&CONTENTID=12215&TEMPLATE=/CM/ContentDisplay.cfmGoogle Scholar102 Registry of federally and privately supported clinical trials conducted in the USA and around the world www.clinicaltrials.govGoogle ScholarFiguresReferencesRelatedDetailsCited ByCannabis Chemistry: Cannabinoids in Cannabis, Humans, and Other Species Vol. 6, No. 2 STAY CONNECTED Metrics History Published online 7 March 2011 Published in print March 2011 Information© Future Medicine LtdKeywordsallodyniacannabinoidendocannabinoidhyperalgesianeuropathic painFinancial & competing interests disclosureAndrea G Hohmann is supported by the NIH grants DA028200 and DA021644. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download