mVY\P-035 New Jersey Department of Health Medicinal Marijuana Program PO 360 Trenton, NJ 08625-0360 MEDICINAL MARIJUANA PETITION (N.J.A.C. 8:64-5.1 et seq.)
INSTRUCTIONS This petition fonn is to be used onlv for requesting approval of an additional medical condition or treatment thereof as a "debilitating medical condition" pursuant to the New Jersey Compassionate Use Medical Marijuana Act, N.J.S.A. 24:61-3. Only one condition or treatment may be identified per petition fonn. For additional conditions or treatments, a separate petition fonn must be submitted. NOTE: This Petition fonn tracks the requirements of N.J.A.C. 8:64-5.3. Note that if a petition does not contain al/ information required by N.J.A.C. 8:64-5.3, the Department will deny the petition and return it to petitioner without further review. For that reason the Department strongly encourages use of the Petition fonn. This completed petition must be postmarked August 1 through August 31, 2016 and sent by certified mail to: New Jersey Department of Health Office of Commissioner - Medicinal Marijuana Program Attention: Michele Stark 369 South Warren Street Trenton, NJ 08608 Please complete each section of this petition. If there are any supportive documents attached to this petition, you should reference those documents in the text of the petition. If you need additional space for any item. please use a separate piece of paper, number the item accordingly, and attach it to the petition.
R ECEIVED
SEP G Z016
O FF ~ ' E C HIFf 1..,) ~ Ir. -F MEDICINAL MARIJUANA PETITION (Continued)
1. Petitioner Information Name: Street Address: City, State, Zip Code:...... ;D:: ______Telephone Number: ______Email Address:
2. Identify the medical condition or treatment thereof proposed. Please be specifiC. Do not submit broad categories (such as "mental illness"). Chronic pain as a result of daily sciatic nerve pain (Sciatica)
3. Do you wish to address the Medical Marijuana Review Panel regarding your petition? Igj Yes, in Person o Yes, by Telephone DNo
4. Do you request that your personally identifiable information or health information remain confidential? DYes Igj No If you answer "Yes' to Question 4, your name, address, phone number, and email, as well as any medical or health information specific to you, will be redacted from the petition before forwarding to the panel for review.
5. Describe the extent to which the condition is generally accepted by the medical community and other experts as a valid, existing medical condition. In response to Sciatica as a valid medical condition , here is the definitionllisting as per The Mayo Clinic website (The Mayo clinic is generally regarded as one of the leading medical organizations in the country):
"Sciatica refers to pain that radiates along the path of the sciatic neNe, which branches from your lower back through your hips and buttocks and down each leg. Typically, sciatica affects only one side of your body. Sciatica most commonly occurs when a herniated disk, bone spur on the spine or narrowing of the spine (spinal stenosis) compresses part of the neNe. This causes inflammation, pain and often some numbness in the affected leg.'
Source: http://www.mayoclinic.org/diseases-conditionsisciatica/basics/definition/con-20026478
6. If one or more treatments of the condition, rather than the condition itself, are alleged to be the cause of the patient's suffering, describe the extent to which the treatments causing suffering are generally accepted by the medical community and other experts as valid treatments for the condition. The extent of my suffering is due to the Sciatica condition itself, however treatments with opiod painkillers such as Hydrocodone (Percocet & Vicodin) had proven to be troublesome as they brought an all too brief respite from the pain, and ultimately led to dependency issues and extreme lethargy throughout my daily routine. I avoid those medicationsitreatments for those reasons, and prefer to use products containing the cannabinoids THC, CBD, and CBN for non-addictive pain remedies that allow me to still be active and participate in my life. MEDICINAL MARIJUANA PETITION (Continued)
7. Describe the extent to which the condition itself and/or the treatments thereof cause severe suffering, such as severe and/or chronic pain, severe nausea and/or vomiting or otherwise severely impair the patient's ability to carry on activities of daily living. Sciatica causes daily, everyday, chronic pain (Neuropathy) that radiates all the way from my lower back down to my big toe. The pain is only on my right side, which is my active side because I am right-handed. Any simple activities such as walking, running, and sitting are met with reoccuring pain from the nerve damage that is a result of Sciatica. I especially have difficulty while at work, as my profession requires me to sit for long periods of time, which causes pain from the muscles and tendons being inactive. That pain is usually introduced in the morning on my drive into work, whereby I sit in traffic for upwards of 45 minutes - 1 hour, and the pain in my ankle and calves is amplified from my leg's need to always be either on the brake pedal or accelerator so as to maintain the flow of traffic and avoid any careless driving on the road. This pain builds up during the course of the day, and is again amplified on the commute home from work. Sometimes the pain is too severe to even do anything or be involved with my family when I get home from work. I need to either ice, stretch, or soak my leg for long periods of time; something of which often takes me away from the brief amount of time I get spend with my family.
8. Describe the availability of conventional medical therapies other than those that cause suffering to alleviate suffering caused by the condition and/or the treatment thereof. I have often read that surgery is a feasible option to help remedy SCiatica, and I would love to even have that as an option for myself, Unfortunately, the reality is that my wife and I simply do not make enough money and have a large quanitity of debt that would only be added to with the vast and large medical bills that would stem from such a thing. Though I continue to have an active lifestyle that involves exercise, proper nutrition, and stretching of the problem area -I still have pain that returns through it all. As mentioned before, opiod painkillers are not an effective treatment, and are a dangerously addictive temporary solution that many people unfortunately think is the answer.
9. Describe the extent to which evidence that is generally accepted among the medical community and other experts supports a finding that the use of marijuana alleviates suffering caused by the condition and/or the treatment thereof. [Note: You may attach articles published in peer-reviewed scientific joumals reporting the results of research on the effects of marijuana on the medical condition or treatment of the condition and supporting why the medical condition should be added to the list of debilitating medical conditions. Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside
I have attached a published, peer-reviewed scientific atticle that through extensive research, supports the claim that cannabinoids should be used as pharmacotherapies for neuropathic pain and chronic pain that includes Sciatica. I have also included links to the article: hnp:/Iwww.ncbLnlm.nih.gov/pmc/articles/PMC2755639 http://download.springer.com/staticlpdf/639/att%253 A I 0.1 0 16%252 Fj .nurt.2009.08 .002.pdf?origin Url=hnp%3 A%2F %2Flink.springer.com%2Fatticle%2F I 0.10 16%2Fj .nurt.2009 .08 .002&token2=exp-14 72573 720- acl=%2Fslalic%2Fpdf %2F639%2Farl%25253A I 0.10 16%25252Fj.nurt.2009 .08 .002.pdf''103 ForiginUrl%3 Dhttp%253A%252F%252Flink.spriJlger.com %252Fatticle %252F I 0. 10 16%252Fj.nurt.2009.08.002 *- lunac=11 12e2gea0999d50773b I b6548d773af9c5b35efd08aa38 11 090e049c29df5 1b
Calmabl. and It. Derivative.: Review of Medical Use
I have attached an article from the Journal of the American Board of Family Medicine that highlights the outdated social outlook that affects patients suffering from neuropathy from getting marijuana for treatment, as opposed to apia ids. Evidence is also given that SUPPOl'ts receptors in the brain are not as likely to suffer addiction with marijuana vs. opiods. http://www.jabfm.org/contenV24/4/452. full
Cannabinoids for the Treabnent of Chronic Non-Cancer Pain: An Updated Systematic Review of Randomized Controlled Trial.
I have attached an abstract from the Journal of Neuroimmune Pharmacology that states that cannabinoids "are safe, modestly effective analgesics that provide a reasonable therapeutic optioll in the management ofchron ic nOIl-callcer pain." http;!/link,springer,com/article/ I 0.1 007/s 11481-0 15-9600-6 Lynch, M.E. & Ware, M.A. J Neuroimmune Pharmacol (2015) 10: 293. doi:10.1007/s11481-015-9600-6 MEDICINAL MARIJUANA PETITION (Continued)
A Randomized, Placebo-Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain
Attached is the abstract from this study from the Journal of Pain. This study adds to a growing body of evidence that cannabis may be effective at ameliorating neuropathic pain, and may be an alternative for patients who do not respond to, or cannot tolerate other drugs. http;llwww.jpain.orgiarticle/SI526-5900(08)00369-6/ppl
Low Dose Vaporized Cannabis Significantly Improves Neuropathic Pain
1:J!!Q;/Iwww.ncbi.nlm.nih.gov/pmclarticles/PMC3566631 1 J Pain. Author manuscript; available in PMC 2014 Feb 1. Published in final edited fann as; J Pain. 2013 Feb' 14(2)- 136:-148. Published online 2012 Dec 11 . doi: 10.10161i.joain.2012.10 009
10. Attach letters of support from physicians or other licensed health care professionals knowledgeable about the condition. List below the number of letters attached and identify the authors1 1 Letter - Dr. Igor Grant, MD
I certify, under penally of perjury, that I am 18 years of age or older; that the infonnation provided in this petition is true and accurate to the best 0 knowledge; and that the attached documents are authentic. SPECIAL COMMUNICATION Cannabis and Its Derivatives: Review of Medical Use
Lawrence Leung, MBBChir, MFM(C!in)
Background: Use of cannabis is often an under-reported activity in our society. Despite legal restric tion, cannabis is often used to relieve chronic and neuropathic pain, and it carries psychotropic and physical adverse effects with a propensity for addiction. This article alms to update the COlTent knowl edge and evidence of uSiug cannabis and its derivatives with a view to the sOciolegal context and per spectives for future research. Aletbods: Cannabis use can be traced back to ancient cultures and still continues in our present society despite legal curtaibnent. The active iugredient, A9-tetrahydrocannabinol, accounts for both the physical and psychotropic effects of caru-.=:s. '!'!;.~:;6h clinical trials demonstrate benefits in aIleviatiog chronic and ueuro ;:;:::!::z ;;~=., :!:~;:c ,s ~,!:;:) ~lg;-~~~~-;.t ;utciltlal physical and psychotropic side-effects of cannabis. Recent labo ,'",,,i1' :!::'-'l !!!~~':t 5j"~'~""c lnteractions between cannabiuoid and oploid receptors, with potential re duction of drug-seeking behavior and opiate sparing effects. Legal rulings also have changed in certain American states, which may lead to wider use of cann:wis among eligible persoli5. ConclllsiolZS: Family physicians need to be CQgn!:!?..!!! Qf ~!!~!! d:::::g~~g !;:E2~::'::::f!".': w~~k ~ r-~;:~~~::~~ knowledge on the pros and cons of medical marijuana, the legal implications of its use, and possible developments in the future. (J Am Board Fam Med 2011;24:452-462.)
Keywords: Cannabis, Clinical Effects, Controversy, Drug Therapy, Marijuana, Substance Abuse
Case I Suggested Managemellt Scellario The evidence of various forms of cannabis (smoked, You are a family physician in Ontario, Canada. A oral, and oromucosal spray) for treating neuropathic 54-year-old man suffering from multiple sclerosis pain caused by multiple sclerosis should be discussed came to your office aslcing for a prescription for against the known harms and challenges of usage. medical marijuana to control his pain. He was tak Sativex (legally available form of cannabis in Can ing continuous-release morphine, gabapentin, and ada; GW Pharmaceuticals, Salisbury, Wiltshire, lamotrigine, but this combination was still insuffi UK) could be recommended as a first-line treat cient. He visited Florida a few times, where he ment. If the patient still decided to pursue a smoked or oral extract of cannabis, referral should be made smoked cannabis, which helped tremendously to to recognized specialists in Quebec for a full assess reduce the neuropathic pain and detach his mind ment of eligibility of patient's use and possession of from it. He would like to continue using cannabis medical marijuana. Close monitoring of the patient but is worried about the legal implications and the would be necessary. purity of sample he may obtain on the street.
Case 2 Sctmarlo You are a family physician in the state of California. This article was externally peer reviewed. A 65-year-old male veteran came to your office as a Submitted 22 November 2010; revised 31 January 2011; accepted 14 March 2011. new patient. He had a history of chronic leg pain Pro-m the Department of Family Medicine, Queen's Uni- caused by a shrapnel injury he suffered during the versity, KinhTStoD, Ontario, Canada. Ftmdillg: none. Vietnam War in 1968. Since the 1970s, he has been Conflict of interest: none declared. u'eated at the local veterans hospital under a pain Corresponding nuthm-: Lawrence Leung, Deparnnent of Family Medicine, Queen's University, Kingston ON K7L management program, but control has been unsat 5E9, Canada (E-mail: [email protected]). isfactory. When asked if he used any recreational
452 JABFM July-August 2011 Vol. 24 No.4 http;//www.jabfm.org 5 drugs, including marijuana, he evaded your ques and autonomic nervous system, whereas CBz re tion and said he needed to stay on the pain pro ceptors are found both in the neurons and immune gram. You suspected he was using marijuana for his cells! THC exerts its effects primarily via CB, chronic pain. receptors.
Suggested lIfmlagemellt The Laws Regarding Cannabis The patient should be infOimed of the new direc In the United States, cannabis is an illicit dmg tive from the Veterans Health Administration re either to possess or trade. Since the inception of the garding veterans' use of marijuana and be reassured Controlled Substance Act in 1970, the US Federal that he would not be denied his pain management Law penalizes any act of possessing, dispensing, services at the veterans hospital on that basis. He and prescribing marijuana. Enforcement of prohi also should be encouraged to discuss his marijuana bition carries an annual price tag of up to $7.7 lise with you so that you can monitor his progress. billion in the United States alone.' However, since Liaising with an addiction medicine specialist can 1996 the situation has been changing rapidly-14 be helpful to ensure the best follow-up of this states (California, Alaska, Oregon, Washington, Maine, patient. Hawaii, Colorado, Nevada, Vemlont, Montana, Rhode Cannabis, also known as marijuana, refers to Island, New Mexico, Michigan, and New Jersey) ah'eady the preparation 53 from the plant belonging to the have amended their state laws to allow the use of family Cannabaceae, the genus Cannabis, and the spe marijuana by persons with debilitating medical 8 cies Cannabis sativa, which possess psychoactive ef conditions as certified by licensed physicians. ,9 fects. The flowering tops, leaves, and stalks of the The impact has been significant: a recent study in mature female plant are commonly used as the Washington estimated that per annum, up to 2000 herbal form of cannabis, but sometimes the resin licensed physicians have prescribed medical canna ous extract of compressed herb is also used and is bislO; in California, more than 350,000 patients called "hash." Archaeologists have identified fibers already possess a physician's recommendation to from cannabis stems in specimens dating back to use cannabis." Nevertheless, among these 14 4000 BC, and its incorporation into textiles and states, there is substantial variation in the regula paper was found in the tombs of the Chinese Han tion of the quality control, prescription limit, pa dynasty (-100 BC).' The first record of cannabis as tient registry, and dispensing outlets. For example, a medicine can be found in the oldest Chinese in Oregon and Washington, it is legal to possess up pharmacopeia, Shen Nong Bell Cao Jing, written in to 24 ounces of marijuana, but in Nevada, Mon the Eastern Han Dynasty (AD 25 to AD 220), tana, and Alaska, the legal limit is only 1 ounce.s which was indicated for rheumatic pain, malaria, Cannabis is currently schedule I; additional re constipation, and disorders of the female reproduc search would be facilitated if tlle drug were reclas tive system.' Though the cannabis leaf and stem is sified to schedule II." From a public health stand rarely used nowadays in Chinese herbal medicine, point, there is some evidence that decrinlinalization cannabis seeds, which contain vel}' few psychoac of cannabis could n-ee up law enforcement re tive ingredients, are still commonly prescribed for sources to curtail other trafficking activities without their laxative effects.' Smoking cannabis is often an leading to increased cannabis abuses12 Overall, under-reported behavior in our society, with a re however, the US Federal law remains unchanged ported prevalence from the vVorld Health Organi regarding the penal stance toward marijuana, cre zation of 3.9% among the global population aged ating various ambiguities and difficulties. For those 15 to 64 years.' There are more than 70 psychoac veterans who are permitted to use medical mari tive compounds called "c31mabinoids" that have juana by law of tlleir state, tllese difficulties have been identified in cannabis,' among which 119- been lessened. This has posed an administrative tettahydrocannabinol (THC) accounts for most of dilemma for those veterans who are allowed to use; the psychological and physical effects, and its con the Departtnent of Veterans Mfairs issued a direc tent is often used as a measure of sample potency. tive in July 2010 that permits veterans to continue We now know that THC acts on 2 types of can their use of lnedical marijuana in states where it is nabinoid receptors: CB, and CB,. CB , receptors legal without losing tlleir medical benefits from are mainly found in the brain, peripheral nerves, Veterans Affairs. 13 doi: 10.3122/jabfm.2011.04.100280 Cannabis and Its Derivatives 453 Recent news from USA Tot/a/4 reports that the and grow their own supply provided iliey meet US federal government has issued warning letters specific and detailed criteria. to several states that have approved the use of medical marijuana with an irnplication that anyone involved in the growth, operation, or legal regula The Harms of Cannabis Physical alld Psychiatric Effects tion of medical marijuana will be subjected to pros Among naive users, cannabis smoking often leads ecution. These states include Washington, Califor to adverse effects. Physical symptoms include in nia, Montana, and Rode Island. This was coupled creased heart rate and fluctuations in blood pres by recent large-scale raids at marijuana growing l5 sure ; psychomotor sequelae include euphoria, operations in iVlontana. Despite reassurance trOln Eric Holder, US Attorney General, that the penal anxiety, psychomotor retardation, and impairment of cognition and memory.16 The estimated lethal policy is directed at those who violate both deferral dose for humans is between 15 g and 70 g.' When and state laws, this unexpected siren from the fed eral goverrunent has been heard loud and clear cOlnpared with cigarette smoke, cannabis con tains a similar array of detrimental and carcino leading Governor Chris Gregoire, of the state of genic compounds, some of which are present Washington, to abort a proposal to create licensed even at higher concentrations. 17 Among chronic marijuana dispensaries and Governor Chris Chris tie, of the state of New Jersey, to postpone plans for users, population studies have associated canna bis use with decreased pulmonary function, marijuana operators. In Canada, it is also illegal to trade or possess chronic obstructive airway diseases, and pulmo nary infections,18 aliliough data may be con 104 marijuana according to provincial and govern founded by concomitant tobacco smoking and ment laws. I-Iowever, access to marijuana for med ical use is possible under Health Canada's Mari other social factors. In vitro and in vivo animal juana Medical Access Regulations, which came into studies have demonstrated mutagenic effects of cannabis smoke, and precancerous pulmonary pathol force on July 30, 2001.14 The regulations clearly ogy as seen in tobacco smokers has been described in outline 2 categories of persons who can apply to cannabis users. 19 Nevertheless, there is still inconsis possess for an authorization to possess marijuana tency from the published literature regarding an in for medical purposes. Category 1 refers to people creased risk for upper respiratory tract cancer with end-of-Bfe care; seizures from epilepsy; severe caused by cannabis smoking.3,18 Various reports pain andior persistent muscle spasms caused by have associated cannabis with cardiac arrhyth- multiple sclerosis, spinal cord diseases, or spinal nnas,. 20,21 coronary msu. fli· IClency P?4--- an d myocar- cord injury; severe pain; cachexia; anorexia; weight · I . r . 25 26 loss and/or severe nausea from cancer or I-IIVI dla In1arctIOn. ' A retrospective cross-sectional AIDS infection. A medical declaration from a li study revealed a +.8-times increased risk of devel oping myocardial infarction witllin the first hour censed medical practitioner is required. Category 2 after smoking catnlabis. Earlier data from popula refers to people who have debilitating symptom(s) 27 29 tion studies ,28 and meta-analvsis have associated of medical condition(s), other than those desctibed cannabis smoking with low bi;th weight,'" which is in category 1, which have failed conventional med ical treatment. An assessment by a designated spe maybe confounded by cigarette smoking and socio cialist is necessary along witll a medical declaration economic status and is not supported by more re cent studies.lO,)1 Finally, the controversial link of from a licensed medical practitioner. cannabis use and psychosis has found more support Under the regulations, the nlaximum amount 32 34 in recent publications. - of marijuana that can be possessed by any autllO rized user is a 30-day total of daily requirement. Health Canada sources its supply of dried mari DepelUiellce a1ld Ab1lse juana and seeds from Prairie Plant Systems In Catnlabis is recognized as a substance \vith a high corporated (Saskatoon, Saskatchewan, Canada), a potential for dependence, which occurs in lout of company that specializes in the growing, harvest 10 people who have ever used catnlabis. It leads to ing, and processing of plants for pharmaceutical behaviors of preoccupation, compulsion, reinforce products and research. Alternatively, authorized ment, and withdrawal after chronic use.35 An Aus marijuana users can apply for a permit to produce tralian survey found that symptoms of cannabis
454 JABFM July August 2011 Vol. 24 No.4 http://www.jabfin.org withdrawal satisfied the diagnostic criteria of both Analgesic Potential and Synergism With International Classification of Diseases 10 and Di Opioids agnostic and Statistical Manual of Mental Disor Despite legal curtailment, cannabis is still used by ders IV for substance dependence, which included 10% to 15% of patients \vith multiple sclerosis" sleep disturbance, anorexia, irritability, dysphoria, and noncancer types of chronic pain44 for both lethargy, and cravings.36 In the United States, can analgesia and psychological detachment. Various nabis is now ranked among alcohol and tobacco as well-designed, randomized, placebo-controlled tri one of the most common substances of among als have shown that smoked cannabis can relieve 37 adolescents There is also ample evidence indi peripheral,45 posttraumaric,46 and HIV_induced47,+s cating that regnlar use of cannabis predicts subse neuropathic pain. Evidence has been accumulating quent psychosocial problems and abuse behavior of from molecular and cell-signaling studies that suggest other addictive substances. A review of cohort stud that the opioids and cannabinoid systems can interact ies by McLaren et al'" supported a causal link synergistically to enhance analgesic effects.49 Animal between cannabis use and psychosis. A recent 10- studies have shown that topical cannabinoid enhances year follow-up study of adolescents in AustTalia the action of topical morphine,'o an effect that is who used cannabis occasionally were found to be at preserved in a morphine-tolerant state.51 More higher risks of drug abuse and educational prob over, cannabinoids are increasingly being recog 39 lems. I-Iowever, several issues have been identi nized in animal models for their potential sparing fied in the published literature about cannabis, effects with opioids52 of neuropathic pain and ar which have limited our understanding on the ad tl,ritic painB AltllOugh similar effects have not verse effects of cannabis: (1) lack of consensus on been translated to human studies, Robert et al54 the definition and classification of different types of found a synergistic affective analgesia between 119- cannabis users (heavy, regular, occasional, and non THC and morphine in experimentally induced users); (2) variable quality of studies regarding de pain in human volunteers. sign, effect sizes, and control of confounding fac tors; and (3) the polarization of the approach to either studying nonusers versus lightlinfTequent users or, infrequentllightlnondependent users ver Evidence from Clinical Stndies sus frequentlheavy/dependent users.40 To review the latest evidence of cannabis use and its derivatives, a literature search was conducted New Kids on the Block from the MEDLINE, EMBASE, PsycINFO, and Recently, synthetic analogues of marijuana, known Cochrane Database of Systematic Reviews from generically as "spice" or "K2," have gained rapid their inception dates to 30 November 2010, using popularity among YOUtllS in the Unites States and the following keywords: "c31mabis," "marijuana," Europe. Marketed as an incense or herbal blend, "Ll,9-tetrahydrocannabinol," "clinical trial," "ben the exact constituents of spice has been a myth, and efits," and "side effects." Relevant articles were its place of origin is often unclear. Despite sharing selected and their quality of evidence was rated similar psychotropic effects as genuine cannabis, according to the Strength of Reconunendations spice cannot be reliably tested by drug screens and Taxonomy (SORT),'· with recommendations poses a technical problem for the law enforcement; rated as A, B, or C. The results are summarized hence it is capable of evading legal scrutiny among in Table 1. In brief, the efficacy of smoked cannabis most states in America. A report from the Drug has been studied for Gilles de la Tourette syn Enforcement Administration of the US Depart drome, glaucoma, and pain, willi good evidence for ment of Justice in June 2010 had divulged the clinical benefits in HIV-induced neuropathic pain. possible constituents of spice (or K2), which in Oral extract of cannabis has better evidence of cluded HU-21O, JWH-018, J"VH-073 and CP- relieving self-reported symptoms of spasticity 47,497,+1 all of which were 'Y',tl,etic cannabinoids caused by multiple sclerosis. Finally, tl,e oromuco legally endorsed for scientific research. This was sal form of cannahis extract (Sativex, GW Phaffila echoed by a recent research publication that iden ceuticals) is efficacious for peripheral and central tified a synthetic cannabinoid in commercially ob neuropathic pain, especially that caused by multiple 42 tained spice, JWH-018, which activated CB I sclerosis. doi: I0.3122/jabfm.2011.04.100280 Cannabis and Its Derivatives 455 +-v, 0- Table 1. Clinical Studies of Cannabis and Its Derivatives with SORT Level ofReconunendation56
SORT Lt:Vd of Agent Condition Indicated Fonn of dc!h"err Nature of Study Patients (n) Oun::ome n'leasures Outcome Recommendatiun Reference
7 I Cannabis Gilles de Ia Tourette Smoking Case n:pOf( Self-reported frequencr 50% to 70% remission C Sand)'k et :11,1 '--< Syndrome of motor tics Cannabis Gilles de la Tomcac Smoking Case report Self-reponed S~1npwms 100% remission C Hemming ct aIls " Smciromc '1 5 g- Cannabis Gla~oom~ Smoking single dose Double-blinded cros.s-on~r Intraocular pres~1lrc Significant reduction B :\Icrrin et :l1 ? placebo-controlled ReT " 4 ~ Cannabis Neuropathic pain in Smoking 5 days a Prospective placebo- 2S Pain il1t<:nsity using Improl'ement in pain A Ellis cr a1 ? ~ ~ HIVpatient week for 2 weeks controlled RCT Descriptor (P"" .0[6) N 0 Differential Scale ~ Cann3bi~ Sensory neurop~thic Smoking 3 times ~ Double-blinded cross-over 50 Chronic pain T;1rings Reducclon of pain by H% A Ahfllms ct ~l~s pain in HIV day for 5 dars placebo-controlled ReT (p;: .03) patient Cmmabis Capsaicin-induced Smoking single dose Double-blinded cross-over 15 P~in scores and McGill P~in reduction at mediullI H \\'allaee et al'") ~ pain in volunteers at various placeho-controlled RCI" Pain Questit)Onaire dose within a certain ,~ concentrations timc fmme only +- B Kraft et aiM Z Cannabis Acute in!lamm~tory Single oral dose of Double-blinded eross-on:r 18 Threshold to heat and t-;o effect on pain 0 pain in volunteers enll1psulatc pbcebo-conrro1!cd Rcr electricity in areas thresholds eXlml't Wllh UV-induced +- sunburnt Cannabis Spasticity due to Escalating dose of Doublc-blinded cross-over 50 Spasms frequency and Improvement in spasms A V:mer et al(,2 muh:iple sdero~is ora! enCall~\I.hte placebo-controlled RCT mobility frequ<;m.:y (P = .013) and exmct mobility (1)= ,01) oJ Cann~bis Sp;)sticity camed by Titrating oflll dose of Double-blinded placclm- 327 A.~hworth Sl-ore and self- Improvement of self- A Zajicek ct al multiplt: sclerosis cannabis c.~tract contro1!ed ReT reported spasticity report ratings of pain and spasticity (P '" .003) ~?-·n-lC Gilles de b Tonrette Sil1gle oral dose Crms-over placebo- 12 TSSL, STSS, YGTSS Significant reduction in A "liil!er~Vahl et al6-1 Syndrome controlled RCT scores TSSL score (P "" ,015), nil for STSS and YGTSS 6S ~9_THC Gilles de la Tourcttc Daily oral do~c for Ii Placebo-controlled RCT 24 TSSL,TS-CGI, STSSj Significant reduction in A Muller-Vahl et al Srndrome weeks YGTSS TSSL score using ANOVA (P '" .U37), nil for TS-CGI, STSS, YGTSS :l9_THC Spasticity caused by Escalating dose for 5 Double-blinded cross~over 13 Subjective ruting and Si!,rnificdnr in both scores A Ungcdeidcr et aIM muh:iple sderosL~ days placebo-control!ed RCT objectiv ,~ -,~ Table 1. Continued """0- 3' ;~ SORT Level of ;:: Agent Condition lndic;lrcd Form of de!hwy N~ture of Study Patients (n) Outcome Measures Outcome Recommendation Referencc o 69 ,..- a'I."nlC G!iobl~Homa Daily intr.1crania! Phase I cohort pilot study 9 Safety of intracnmial Intr;lcr.lIlial rome seems to c Guunan cr al muh:iformc tumour injection route of be safe and mar slow Ill) to 64 days a 458 JABFM July-August 2011 Vol. 24 No.4 http://www.jabfm.org flammatOlY antipsychotic and neuroprotective ef 12. Single E, Christie P, Ali R. The impact of cannabis fects. 91,n Another observational study of the ratio decriminalisation in Australia and the United States. ] Public Health Policy 2000,21(2):157-86. of CBD:THC from street cannabis samples sug 13. US Department of Veterans Affairs. Medical marijuana. gests that a higher CBD content reduced reinforc VHA Directive 2010-035. Washington DC: Veterans ing behavior and attention bias to marijuana. Fur Health Administration, ]u1y 2010. Available at hnp:11 ther directions of research include a better www.va.gov/vhapublicationsNiewPublication.asp? understanding of the mechanisms of action of CBD pub_ID =22 76. Accessed. and its interplay with THC, plus bioengineering a 14. Lifland JB. States reassess medical marijuana laws safer marijuana strain that contains the appropriate after warnings. 3 May 2011. Available at: hnp:11 yourH fe. usa today .com/health/medicallstoryl20 111 composition of CBD and THC for optimal thera OSIStates-re 460 JABFM ]uly-Augnst 2011 Vol. 24 No.4 http://www.jabfm.org 61. Kraft B, Frickey NA, ](.,ufmann RM, et al. Lack of 75. Nunnikko TJ, Serpell MG, Hoggan B, Toomey PJ, analgesia by oral standardized cannabis extract on NIorlion B], Haines D. Sativex successfully treats acute inflammatory pain and hyperalgesia in volun neuropathic pain characterised by allodynia: a ran teers. Anesthesiology 2008;109(1):101-10. domised, double-blind, placebo-controlled clinical 62. 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Hurd YL. Cannabidiol, a nonpsychotropic compo 93. Zuardi AW, Crippa JA, Hallak JE, Moreira FA, nent of cannabis, inhibits cue-induced heroin seek Guimaraes FS. Cannabidiol, a Cannabis sativa con ing and normalizes discrete mesolimbic neuronal stituent, as an antipsychotic drug. Braz J Med BioI disturbances. J Neurosci 2009;29(47):14764-9. Res 2006;39(4):421-9. 462 JABFM July-August 2011 Vol. 24 No.4 http://www.jabfm.org Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside Elizabeth J. Rahn and Andrea G. Hohmann Neuroscience and Behavior Program, Department of P~)'cllOlog)', University of Georgia, Athens, Georgia 30602 Summary: Neuropathic pain is a debilitating form of chronic degradation) are compared. Effects of genetic disruption of pain resulting from nerve injury, disease states, or toxic insults. cannabinoid receptors or enzymes controlling endocannabinoid Neuropathic pain is often refractory to conventional pharma degradation on neuropathic nociception are described. Spedlic cotherapies, necessitating validation of novel analgesics. Can forms of aUodynia and hyperalgesia modulated by cannabi nabinoids, drugs that share the same target as il9-tetrahydro noids arc also considered. In humans, effects of smoked mar cannabinol (6.9-THC), the psychoactive ingredient in cannabis, ijuana' synthetic il9 -THC analogs (e.g., Marinol, Cesamet) and have the potential to address this urunet need. Here, we review medicinal cannabis preparations containing both 6. <} -THe and studies evaluating cannabinoids for neuropathic pain manage cannabidiol (e.g., Sativex. Cannador) in neuropathic pain states ment in the c1inical and preclinical literature. Neuropathic pain are reviewed. Clinical studies largely affirm that neuropathic associated with nerve injury, diabetes, chemotherapeutic treat pain patients derive benefits from cannabinoid treatment. ment, human immunodeficiency virus, multiple sclerosis, and Subjective (i.e., rating scales) and objective (i.e .. stimulus herpes zoster infection is considered. In animals, cannabinoids evoked) measures of pain and quality of life are considered. attenuate neuropathic nociception produced by traumatic nerve Finally, limitations of cannabinoid pharmacotherapies are injury, disease, and toxic insults. Effects of mixed cannabinoid discussed together with directions for future research. Key CB /CB2 agonists, CB 2 selective agonists, and modulators of Words: Endocannabinoid, marijuana, neuropathy, multiple the endocannabinoid system (i.e., inhibitors of transport or sclerosis, chemotherapy, diabetes. NEUROPATffiC PAIN CANNABINOID RECEPTOR PHARMACOLOGY Neuropathic pain is a debilitating fonn of treatment Evidence for the use of Cannabis sativa as a treatment resistant chronic pain caused by damage to the nervous for pain can be traced back to the beginnings of recorded system. Neuropathic pain may result from peripheral history. The discovery by Gaoni and Mechoulam' of 1::,9_ nerve injury, toxic insults, and disease states. Neuro tetrahydrocannabinol (1::,9_THC), the primary psychoactive pathic pain remains a significant clinical problem be ingredient in cannabis, set the stage for the identification of cause it responds poorly to available therapies. More an endogenous cannabinoid (endocannabinoid) transmitter over, adverse side effect profiles may limit therapeutic system in the brain. The endocannabinoid signaling system dosing and contribute to inadequate pain relief. Drug includes cannabinoid receptors (e.g., CB, and CB,), their discovery efforts have consequently been directed to endogenous ligands (e.g., anandamide and 2-arachido ward identifying novel analgesic targets for drug devel noylglycerol), and the synthetic and hydrolytic enzymes opment. This review will evaluate the efficacy of canna that control the bioavailability of the endocannabinoids. binoids as analgesics for the treatment of neuropathic Both CB ,2 and CB/ receptors are G-coupled protein pain from the bench to the bedside. receptors that are negatively coupled to adenylate cy clase. Activation of CB, receptors suppresses calcium conductance and inhibits inward rectifying potassium conductance, thereby suppressing neuronal excitability and transmitter release. CB 2 receptor activation stimu Addre~~ corre~pondence and reprint request~ to: Andrea G. Hohm~ lates MAPK activity but does not modulate calcium or ann, Neuroscience and Behavior Program. Department of Psychology, 4 potassium conductances. The development of CB ,5 and University of Georgia, Athens, GA 30602-3013. E~mail: ahohmann@ 6 uga.edu. CB 2 receptor knockout mice has helped elucidate the 714 RAHN AND HOHMANN physiological roles of cannabinoid receptors in the ner by FAAH or by suppressing FAAH expression at the 1 vous system. Generation of CB I -/- mice that lack CB I transcriptional level.27.28 FAAH- - mice are hypoalge receptors in nociceptive neurons in the peripheral nerM sic in models of acute and inflammatory pain; these vous system while retaining CNS expression (SNS effects are blocked by a CB, antagonis!.29.3o This basal 1 CB 1-) has also documented a role for these receptors in hypoalgesia is absent in FAAH- - mice subjected to controlling nociception.7 nerve injury, where genotype differences in evoked neu 30 CB I and CB2 receptors exhibit disparate anatomical ropathic pain behaviors are not apparent. distributions.' CB 1 receptors are localized to the CNS Anandamide also acts as an endovanalloid at the and the periphery. CB1 receptors are found in sites as transient receptor potential cation channel (TRPVI) sociated with pain processing, including the periaque receptor.3l AEA shows affinity for TRPVl that is 5- to ductal gray: rostral ventromedial medulla: thalamus,9 20-fold lower than its affinity for CB ,. TRPV I is not s dorsal root ganglia (DRG)/o amygdala,' and cortex. activated by classical, nonclassical, or aminoalkylin Densities of CB I receptors are low in brainstem sites dole cannabinoid agonists. ABA can also activate the critical for controlling heart rate and respiration. This peroxisome proliferator receptor-y (PPARy) recep distribution explains the low toxicity and absence of tor.32 Thus, not all effects of AEA are mediated by lethality after marijuana intoxication. Activation of the cannabinoid receptors. CB, receptor also results in hypothermia, sedation, cat The metabolic pathways responsible for endocannabi alepsy, and altered mental status." Thus, it is critical for noid degradation are well-characterized. Several FAAH any cannabinoid-based pharmacotherapy targeting CB 1 inhibitors (e.g., OLl35, URB597) have been developed receptors to balance clinically relevant therapeutic ef and used to investigate physiological effects of in fects with unwanted side effects. The CB2 receptor was creasing accumulation of AEA and other fatty-acid originally believed to be restricted to the periphery, pri amides. Monoacylglycerol lipase (MGL) is a key en marily to immune cells (e.g., mast cells). 12 They may be 33 34 zyme implicated in the hydrolYSiS of 2_AG. • MGL present neuronally in some species. The CB receptor 2 inhibitors (e.g., URB602, JZLl84) have been devel protein has been reported in the DRG/3 brainstem, '4 oped and can be used to selectively increase accumu thalamus,15 periaqueductal gray.15 and cerebelIum15.16 of lation of this endocannabinoid. The endocannabinoid naive rats. eB receptor levels in most CNS sites are 2 system has complex relationships with other metabolic present at only low levels under basal conditions (or are pathways. Both AEA and 2-AG can be metabolized by below the threshold for detection). However, an upregu cyclooxygenase-2, a phenomenon that may contribute lation of CB receptor immunoreactivity or mRNA is 2 to the antinociceptive properties of nonsteroidal antiM observed in sites implicated in nociceptive processing inflammatory drugs that act through inhibition of cy under conditions of induced neuropathy. '7.18 CB recep 2 c1ooxygenase-24 Table I provides a summary of can tors are localized to microglia, a resident population of nabinoids and related compounds that have been macrophages within the CNS that are functionally and evaluated for efficacy in preclinical and clinical stud anatomically similar to mast cells. Microglia secrete pro ies of neuropathic pain. inflammatory factors and induce the release of several mediators (e.g., nitric oxide, neurotrophins, free radicals) that are associated with synaptogenesis and plasticity, CANNABINOID MODULATION OF leading to changes in neuronal excitability. NEUROPATIDC NOCICEPTION IN ANIMAL MODELS ENDOCANNABINOIDS W. E. Dixon" was the first scientist to systematically The first endogenous ligand for cannabinoid recep study the antinociceptive properties of Cannabis sativa. tors '9 was named anandamide (ABA) after the sankrit Dixon" reported that cannabis smoke delivered to dogs word for bliss. Several other endocannabinoids including attenuated their responsiveness to pin pricks. He ob 2-arachydonoylglycerol (2_AG),20.21 noladin ether,22 vi served that normally "evil-tempered and savage" dogs rodharnine,23 and N-arachidonoly-dopamine24 have been became "docile and affectionateU after exposure to can described. Fatty-acid amide hydrolase (FAAH) is the nabis, reflecting the psychotropic and mood-altering ef principle catabolic enzyme for fatty-acid amides includ fects of cannabinoids. Motor effects observed after high ing ABA and N-palmitoylethanolamine (PEA)." PEA doses of cannabinoids included drowsiness, awkward does not bind cannabinoid receptors and has recently gate, and ataxia. Work by Walker's group subsequently been described as an endogenous ligand for peroxisome demonstrated that cannabinoids suppress nociceptive 6 36 proliferator receptor-a (PP AR_a).2 PEA may indirectly transmission (for review see ). Early observations of the alter levels of endocannabinoids by competing with antinociceptive properties of cannabinoids laid a founda anandamide and other fatty-acid amides for degradation tion for future research examining the impact of canna- CANNABINOID MODULATION OF NEUROPATHIC PAIN 715 Table 1. Cannabinoids Evaluated for Suppression of different classes of cannabinoids on both neuropathic Neuropathic Nociceptioll nociception and central sensitization in each model. We also consider the impact of nerve injury on the endocan Natural cannabinoid ligands and synthetic analogues • Ll.9_THC (DronabinollMarinol) nabinoid signaling system. Where applicable, we review • Cannabidiol (CBD) effects of neuropathic injury on levels of endocannabi • Cannador (cannabis extract, Ll.9-THC:CBD, noids and related lipid mediators, and we describe reg 2.5 mg: 1.25 mg) ulatory changes in CB 1 and CB receptors induced by • Cannabis 2 • eCBD (Cannabis with high CBD content) nerve injury. Finally, we will consider implications of • Nabilone (Cesamet, Ll.9-THC analogue) the preclinical findings for cannabinoid-based pharmaco • Sativex (oral-mucosal spray, Ll.9-THC:CBD, therapies for neuropathic pain in humans. 2.7 mg:2.5 mg) Endocannabinoids Chronic constriction injury • Anandarrride (AJEA) • 2-arachydonoylglycerol (2-AG) Chronic constriction injUly (CCl) produces mechani Fatty acids cal allodynia as well as thermal allodynia and hyper • L-29 algesia in the ipsilateral paw as early as 2 days post • N-arachidonoyl glycine (NaGly) surgery.37 Initial reports failed to find mechanical • Palmitoylethanolamine (PEA) hyperalgesia, although several of the reviewed articles CBJ-selective agonists • ACEA report its presence after surgery. Very few studies have • Met-F-AJEA investigated the presence of cold aIlodynia after this Mixed CB /CB2 agonists nerve injury; however, those that have evaluated its pres • BAY59-3074 ence uniformly demonstrate efficacy of cannabinoids in • CP55,940 • CT-3 (Ajulemic acid) suppressing cold alIodynia. CB 1 receptors are upregu • HU-210 lated in the spinal cord after CCI; these effects are be • WIN55,212-2 lieved to be modulated by tyrosine kinase" and glu 39 CB2 -selective agonists cocorticoid receptors. Not surprisingly, several classes • A-796260 of cannabinoids have been shown to suppress CCI-in • A-836339 • AMI241 «R,S)-AMI241) duced neuropathic nociception in rodents and include • (R)-AM1241 mixed cannabinoid agonists, which target both CB 1 and • (S)-AM1241 CB2 receptors, CB 2 selective agonists, and modulators of • AMl714 the endocannabinoid system that inhibit FAAH or MGL • Compound 27 • GW405833 (L768242) (Tables 2 and 3). • JWHOl5 Chronic administration of synthetic analogues of nat • JWH133 ural cannabinoid ligands containing cannabidiol (CBD) • MDA7 attenuate or reverse established thermal and mechanical • MDAI9 Endocannabinoid modulators hyperalgesia in the CCI model. However, anti-hyperal Uptake Inhibitors: gesic effects observed with these compounds are likely • AM404 to be independent of cannabinoid receptors, and may be • VDMll mediated through TRPV I. Those studies investigating FAAH inhibitors: pharmacological specificity have demonstrated blockade • Compound 17 with the TRPVl antagonist capsazepine, but not a can • OL135 4 • URB597 nabinoid CB 1 or CB 2 antagonist O.41 The CB 1 specific MGL inhibitors: antagonist SR141716 has been tested in this model with • JZLl84 disparate results. SR14l7l6, administered acutely, is • URB602 pro-hyperalgesic and pro-allodynic in this model42 FAAH = fatty-acid amide hydrolase; MGL = monoacyJglyceroJ However, SR141716 (by mouth), administered chroni lipase; THe = tetrahydrocannabinol. cally, suppresses thermal and mechanical hyperalgesia in both rats and CB, +/+ mice, while failing to produce an binoids and modulation of the endocannabinoid system effect in CB -1- mice."' These reports are interspersed on neuropathic pain. 1 with a host of articles that indicate no antinociceptive or Models of surgically-induced traumatic nerve injnry pro-nociceptive effects of either CB 1 or CB 2 antagonists, Cannabinoids suppress neuropathic nociception in at administered alone. Thus, it is important to emphasize least nine different animal models of surgically-induced that the behavioral phenotype induced by antagonist traumatic nerve or nervous system injury. Here, we re treatment may depend on the level of endocannabinoid view the literature with a focus on uncovering effects of tone present in the system, the injection paradigm (chronic 716 RAHN AND HOHMANN Table 2. Antinociceptive Effects of Cannabilloids after Chronic Constriction Injury in Rats Mechanism Mechanical Mechanical Compound Route Thermal Hyperalgesia AlIodynia CB , CB 2 Ref No. Synthetic eCBD p.o . Yes Yes 41 Analogues of p.o.·• Yes Yes No (SRI i.p.) No (SR2 i.p.) Natural CBD p.o. No No 40 Cannabinoid No No 41 Ligands p.o.' Yes Yes 41 Yes Yes No (SRI i.p.) No (SR2 p.o.) 40 L\.9-THC p.o. Yes Yes 41, 171 p.o.; No No 41 pCBD+pTHC p.o.·• Yes Yes 41 Mixed CB "CB2 BAY 59-3074 p.o. Yes Yes 78 agonists CP55,940 i.p. Yes Yes 171 WIN55,212-2 s.c, No No 48 No No 172 Yes 173 s.c.* Yes Yes 48 Yes Yes Yes (SRI i.v.) Yes (SR2 i.v.) 54 Yes Yes Yes (SRI s.c.;) 57 i.p. Yes-heat Yes Yes Yes* (SRI Lp.) 42 Yes-cold Yes Yes Yes (SRI i.p.) 119 i.v. Yes 47 Lt. Yest Yesi' Yes (AM281 Lt.) 38 Yes 173 i.pl. Yest Vest 119 CB 2 Agonists A-796260 Lp. Yes 174 A-836339 Lp. Yes Yes (SR2 i.p.) 51 . ; '.p. Yes GW405833 i.p. Yes 50 (L768242) Endocannabinoid AM404 s.c. No No 52 Modulators Yes Yes 57 Yes 53 s.c.* Yes Yes Yes (SRI Lp.) Yes (SR2 Lp.) 52 Yes Yes Yes (SRI i.p.) No (SR2 i.p.) 53 Yes Yes Yes (SRI i.v.) No (SR2 Lv.) 54 Yes Yes Yes (SRI s.c'*) 57 VDMIl s.c.* Yes Yes 52 eCSD = Cannabis sativa with high CED content; i.p. = intraperitoneal; Lpl. = intraplantar; i.t. = intrathecal; i.v. = intravenous; peSD = pure cannabidiol; p.o, = perorem; pTHC = pure .6,9-tetrahydrocannabinol; s.c. = subcutaneous; SRI = SR141716; SR2 = SRl44528. *Only tested in thermal hyperalgesia and mechanical allodynia; tincreased measurements in contralateral paw at dose(s) tested; *chronic postinjury , vs acute), and the presence of regulatory changes in canna tion of the same compounds. A neurophysiological basis binoid receptors or endocannabinoids. for these findings is derived from the observation that Several mixed cannabinoid CB ,1CB 2 agonists have WJN55,212-2 (intravenously) dose dependently inhibits been shown to suppress all forms of neuropathic noci windup,46 as well as eel-induced increases in spontane ception observed in the CCI model, primarily through ous firing47 of spinal wide dynamic range (WDR) neu CB, mediated mechanisms. Several studies, including rons through a CB, dependent mechanism. Spontaneous the original study by Herzberg et a1. 42 were conducted firing of WDR neurons is believed to contribute to be before the development of a CB2 antagonist and rec havioral hypersensitivity and neuronal sensitization in ognition that CB2 receptor mechanisms modulate neu neuropathic pain states. WIN55,212-2 also normalizes ropathic pain.44 Mixed CB ,tCB2 agonists, such as prostaglandin E, levels and nitric oxide activity, two CP55,940 or WIN55,212-2, typically act as CB, selec mediators of neuropathic pain that are increased after tive agonists after systemic administration!' although CCL48 CB2 mediated effects may be unmasked after adminis Multiple CB 2 selective agonists have been demon tration of CB2 selective agents or after local administra- strated to suppress CCI-induced mechanical allodynia, CANNABINOID MODULATION OF NEUROPATHIC PAIN 717 although pharmacological specificity has not been con sistently assessed (Table 2). Thus, it is noteworthy that CB 2 receptor mRNA is upregulated in the lumbar spinal cord after CCL This upregulation is restricted to nonneu ronal cells (e.g., glia).49 Interestingly, GW405833, a CB 2 specific agonist, also reduces depression-like behavior associated with this mononeuropathy in the forced swim test.") Tolerance, a feature that may contribute to loss of analgesic efficacy of currently available analgesics, failed to develop after repeated administration of the CB 2 specific agonist, A-836339. Thus, CB 2 agonists may show therapeutic potential for suppressing neuropathic I;;;:;;;: I pain without producing tolerance when administered ei ~~ 51 00 00 ther alone or as adjuncts to exisiting treatments. >!>! Endocannabinoid modulators suppress neuropathic pain symptoms associated with CCI (Tables 2 and 3). AM404, an endocannabinoid transport inhibitor, in creases accumulation and, hence, bioavailability, of anandamide (and potentially other endocannabinoids) through a mechanism that remains incompletely under stood. AM404 also normalizes CCI-induced changes in nitric oxide activity,52.53 cyclooxygenase-253 activity, cytokine levels (e.g., tumor necrosis factor-a and inter leukin-lO),52 and nuclear factor-KB 52 levels. In CCI rats, chronic administration of either AM404 or URB597 sup presses plasma extravasation, a condition associated with 54 55 neuropeptide release at peripheral levels. . AM404, administered chronically or acutely, does not affect lo comotor behavior, indicating a low propensity of this I I I I ~~ I I I I agent to produce unwanted motor side effects associated 52 53 with direct activation of CB) receptors. • CCI produces regulatory changes in endocannabinoid levels. CCI increases AEA and 2-AG levels in the peri aqueductal gray and rostral ventromedial medulla, sites implicated in the descending modulation of pain.56 CCI also increases levels of endogenous AEA, but not 2-AG, in the dorsal raphe, which was an observation that may help explain the antibyperalgesic efficacy of an anand amide transport inhibitor in this model.57 CCI increases serotonin (5-HT) levels in the dorsal raphe and this effect was suppressed by both WIN55,212-2 and AM404 in a 57 CB I dependent manner. CCI-induced Fos expression ci" ".0 • 0.. * was observed in response to non-noxious mechanical . 0., 0...... ~ .5- .5-.~ stimulation in spinal cord laminae I and II, the site of termination of AS and C fibers, which carry nociceptive sensory information from the periphery to the CNS. Lower levels of evoked Fos expression were observed in laminae ill and IV of CCI rats. Chronic administration of AM404 significantly decreased CCI-induced Fos expres sion in the lumbar spinal cord through CB /CB2 and TRPVI-mediated mechanisms." Antinociceptive effects of FAAH inhibitors (OL135 and URB597) have also been reported in mice after CCI. 0L135 and URB597 attenuate cold and mechanical allodynia in a manner that is dependent on activation of both CB I and CB 2 recep- 718 RAHN AND HOHMANN tors 59 In addition, both OLl35 and URB597 are antino binoid CB ,fCB2 agonists in this model, although CNS ciceptive in FAAH+/+ mice, but fail to produce an effect side effects were nonetheless observed in the same dose I in FAAH- - mice.'9 The novel MOL inhibitor, JZLl84, range that resulted in fall reversal of neuropathic noci attenuates CCI-induced mechanical and cold allodynia ception.68 Ajulemic acid (CT-3), which was developed through indirect activation of the CB I receptor; JZL184 as a peripherally restricted cannabinoid analogue, also was efficacious in attenuating neuropathic nociception in produced activity in the tetrad, but antihyperalgesic ef both FAAH+/+ and FAAH-/- mice.59 The fatty acid fects occurred at doses lower than those producing side 9 PEA, administered chronically, attenuated the develop effects.· ment of thermal hyperalgesia and mechanical allodynia Structurally distinct CB2 specific agonists are effica in the CCI model through CB,. PPARy, and TRPVl cious in suppressing neuropathic nociception in this 60 mediated mechanisms. Chronic administration of PEA model. Moreover, CB2 receptors in the spinal cord con also normalized levels of three neutrophic factors (nerve tribute to CB 2 mediated suppression of mechanical allo 70 growth factor, glial cell line-derived neurotrophic factor, dynia. CB 2 -/- mice reportedly develop thermal hyper and neurotrophin-3) that were increased by CCI.60 Thus, algesia and mechanical a1lodynia in the contralateral paw after surgery, whereas CB +1+ do not.·3 Microglia and activation of CB I and CB 2 receptors, as well as pharma 2 cological manipulation of endocannabinoid accumula astrocyte expression in the spinal dorsal horn is observed tion or breakdown, suppresses neuropathic nociception in both CB 2 -/- and CB 2 +/+ mice ipsilateral to nerve in rodents. injury. However, CB 2 -/- mice notably exhibit increased microglial and astrocyte expression in the contralateral Partial sciatic nerve ligation (Seltzer Model) spinal dorsal hom, a mechanism which may help to Mechanical hyperalgesia and allodynia are observed explain differences in neuropathic nociception between after partial ligation of the sciatic nerve.·l Thermal hy wild-types and knockouts.·3 Further support for this hy peralgesia was present in all studies reviewed here that pothesis is derived from the observation that overexpres 62 evaluated this measure with one exception. Only two sion of the CB 2 receptor attenuated enhanced expression studies we reviewed examined the presence of cold al of microglia.·3 These results suggest that genetic disrup lodynia after partial sciatic nerve ligation; the first study tion of the CB 2 receptor has a disinhibitory effect on the found that both CB 2 +/+ and CB 2 -/- mice showed evi responses of glial cells after partial sciatic nerve ligation. dence of cold allodynia after surgery.·3 Cold allodynia The cytokine, interferon-gamma, is produced by astro has also been reported in rats after partial sciatic nerve cytes and neurons ipsilateral to injury in both CB 2 +/+ 4 -/- -/- ligation.· All classes of cannabinoids evaluated pro and CB 2 mice. However, CB 2 mice exposed to duced anti-allodynic and antihyperalgesic effects in the partial sciatic nerve ligation exhibit interferon-gamma Seltzer model (Table 4). immunoreactivity in the spinal dorsal hom contralateral PrO-hyperalgesic effects of SR141716 and SRl44528 to injury. Interferon-y -1-ICB2 -/- mice showed no evi have been reported in the Seltzer model,.s indicating a dence of neuropathic nociception when the contralateral potential alteration in endocannabinoid tone after nerve paw was stimulated after surgery, suggesting that im injury. No other articles we reviewed reported similar mune responses underlie neuropathic pain responses ob 7l effects of cannabinoid antagonists administered alone in servable in the contralateral paw of CB2 -/- mice. De this model. Exogenously applied endocannabinoids, letion of a putative novel cannabinoid receptor, OPR55, AEA and 2-AO, suppress changes in neuropathic noci is also associated with the failure to develop mechanical ception induced by partial sciatic nerve ligation. Inter hyperalgesia after partial sciatic nerve ligation.72 estingly, AEA produced anti-hyperalgesic and anti-allo Compounds targeting three distinct mechanisms for dynic effects through a CB I mechanism"s,•• whereas modulating endocannabinoid levels also suppress neuro 2-AO produced anti-hyperalgesic and anti-allodynic ef pathic nociception after partial sciatic nerve ligation. The fects through activation of both peripheral CB I and CB 2 transport inhibitor AM404, administered systemically, 7 receptors.· AEA and PEA exerts effects, at least in part, suppressed mechanical a1lodynia in a CB I dependent through a peripheral mechanism; both fatty-acid amides manner without producing motor effects.73 The F AAH suppressed release of calcitonin gene-related peptide and inhibitor URB597, administered locally in the paw,·7 but somatostatin evoked by the irritant resiniferotoxin without not systemically,.2 suppressed both thermal hyperalgesia s altering peptide release under basal conditions· Antihy and mechanical allodynia through a CB I mechanism. peralgesic effects of AEA and PEA were blocked by a CB I The MOL inhibitor URB602 (which can not be used and CB2 antagonist, respectivelY.·s One limitation with systemically as a selective MOL inhibitor), administered studies using exogenous administration of endocannabi locally in the paw, also suppressed neuropathic nocicep noids is that they do not imply that endocannabinoids are tion in this model through activation of both CB I and 7 released under physiological conditions to produce these CB2 receptors· The fatty-acid analogue of PEA, L-29, effects. Several studies report efficacy of mixed canna- also suppressed thermal hyperalgesia and mechanical a1- Table 4. Antinociceptive EfJ'ects of Call1labinoitis after Partial Sciatic Nerve Ligation (Seltzer Model) Mechanism Mechanical Mechanical Compound Route Thermal Hyperalgesia Allodynia CB I CB 2 Ref No. Exogenous ABA i.p. Yes Yes (SRI i.p.) 65 Endocannabinoids i.paw Yes Yes Yes (AM251 i.paw) No (AM630 i.paw) 66 2-AG Lpaw Yes Yes Yes (AM251 i.paw) Yes (AM630 i.paw) 67 Mixed CB I/CB2 CT-3 (AJA) p.o. Yes Yes (SRI s.c.) No (SR2 s.c.) 69 ~ Agonists i.p. Yes 175 ~ CP55,940 s.c. Yes 68 HU-210 s.c. Yes 68 :;:'" i.p. NP Yes 62 a Yes 175 ~ Lt. Yes Yes (AM251 i.t.) Yes (SR2 i.t.) 75 WIN55,2I2-2 s.c. Yes* Yes Yes 68 g s.c. t Yes:!: Yes§ Yes (AM251 chronic s.c.!) Yes (AM630 chronic s.c. ') 176 i.t. Yes Yes (SRI i.t.) 68 ~ i.pl. Yes Yes (blocked by SRI s.c., 68 ::j but not i.t.) §l CB 2 Agonists GW405833 (L768242) i.p. Yes 177 Yes 178 JWH133 i.p. No 70 ~ / Lt. Yes (CB,t +) ~ No(CB2~/-) Lpaw N6 a~ Endocannabinoid AM404 i.p. Yes Yes (AM251 i.p.) 73 Modulators URB597 i.p. NP No 62 ~ Lpaw Yes Yes Yes (AM251 i.paw) No (AM630 i.paw) 67 Sl URB602 Lpaw Yes Yes Yes (AM251 i.paw) Yes (AM630 i.paw) 67 (-) Fatty Acids L-29 i.p. Yes-heat Yes Yes (SRI i.p.) Yes' (SR2 i.p.) 64 No-cold ~ NaGIy s.c. No 75 ~ Lt. Yes No (AM251 i.t.) No (SR2 i.t.) PEA i.p. Yes Yes (SR2 i.p.) 65 AEA = anandamide; 2-AG = 2-arachydonoylglycerol; AlA = ajulemic acid; i.p. = intraperitoneal; LpI. = intraplantar; i.paw = intra-paw; i.t. = intrathecal; NaGJy = N-arachidonoyl glycine; NP = not present; PEA = palmitoylethanolamine; p.o. = per orem; s.c. = subcutaneous; SRI = SR141716; SR2 = SR144528. White cells = tested in rats. Shaded cells = tested in mice. *Increased measurements in contralateral paw at dose(s) tested; tChronic pre-emptive/postinjury or both; :l:Postinjury; §Pre-emptive and postinjury combined; ':lOnly observed blockade for mechanical allodynia, not thennal hyperalgesia. ;::: \C 720 RAHN AND HOHMANN lodynia in the Seltzer model. The L29-induced suppres CB, -/- mice subjected to SNL, suggesting that activity sion of thermal hyperalgesia was mediated by both the at CB 1 dominates the antinocieptive profile of mixed 5 CB 1 receptor and PPAR-a, whereas suppression of me CB ,/CB2 agonists after systemic administration: Spi chanical allodynia was mediated by CB /CB2 and nal, but not systemic, administration of HU-210 has heen PPAR-a receptors.64 PEA abolished mechanical hyper reported to reduce Ali fiber-evoked responses on spinal algesia after partial sciatic nerve ligation through a WDR neurons in both shams and SNL rats, whereas 65 mechanism that was blocked by a CB 2 antagonist HU-210 showed no effect on C-fiber responses of SNL When considering the effects of PEA, it is important to rats,S2 1 emphasize that PEA does not bind directly to CB 2 re SNL produces regulatory changes in CB mRNA and 74 1 ceptors ; therefore, blockade by a CB 2 specific antago endocannabinoid levels. Increases in CB mRNA are nist could indicate indirect modulation of receptor activ observed in the uninjured (but abnormal) L4 ORG ipsi ity (e.g., via activation of PPAR-a or entourage effects) lateral to injury.S3 Increases in both ABA and 2-AG have or blockade of an uncharacterized cannabinoid receptor also been reported in the ipsilateral injured L5, but not 8 that binds the CB 2 antagonist SRl44528. Intrathecal N the uninjured L4 ORG. ' These findings collectively arachidonoyl glycine (NaGly), the arachodonic acid con document the presence of regnlatory changes in endo jugate, also attenuated mechanical allodynia in this cannabinoid levels associated with SNL, a finding which model; however, the anti-hyperalgesic actions of this may contribute to the efficacy of peripherally adminis compound are independent of spinal cannabinoid recep tered cannabinoid agonists that activate CB 1 receptors in torS."5 Locally injected (intra-paw) paracetamol sup this model. pressed mechanical allodynia and thermal hyperalgesia Noxious stimulation (e.g., C-fiber mediated activity) present after partial sciatic nerve ligation, and these ef induces phosphorylation of extracellular signal-regulated fects were blocked by local administration of either a protein kinase (ERK) in dorsal hom neurons. The CB 1 CB , or a CB 2 antagonist."6 Paracetomol may undergo specific agonist ACEA inhibits pERK expression in local metabolic transformation into AM404, resulting in duced by in vitro application of capsaicin to the spinal increased levels of endocannabiniods. cords of SNL rats. This observation contrasts with effects of opioids (i.e., morphine and OAMGO), which lose the Spinal nerve ligation (SNL) ability to inhibit C-fiber induced ERK activation in the All studies reviewed here documented the presence of L5 spinal cord after SNL.84 77 mechanical allodynia after SNL. All studies with the Multiple CB 2 specific agonists suppress neuropathic exception of one78 indicated the presence of thermal nociceplion induced by SNL. The CB2 agonist AM 1241 hyperalgesia when animals were tested. One study eval suppresses both thermal hyperalgesia and mechanical uated the presence of cold allodynia and confirmed that allodynia after SNL in both rats'7.44.8' and mice.44 animals with this injury display hypersensitivity to non CB,-I- mice receiving AMl241 showed enhanced an noxious levels of cold stimulation.79 Gabapentin suc tihyperalgesia.44 An emerging body of literature now cessfully attenuated mechanical allodynia in this model, suggests that antinociceptive effects of CB2 agonists may however, several other commonly prescribed neuro be mediated by suppression of microglial activation: pathic pain medications, including amitriptyline, fluox Evidence for upregulation of CB 2 after SNL has been SO etine, and indomethacin failed to show similar effects reported by several groups. CB 2 mRNA was upregulated Thus, it is noteworthy that mixed cannabinoid agonists, in the lumbar spinal cord after SNL:9 coincident with cannabinoid CB2 selective agonists. and FAAH inhibi the expression of activated microglia. Colocalization tors all attenuated neuropathic nociception induced hy studies, however, were not performed. Upregulation of SNL (Table 5). CB 2 receptor immunoreactivity on sensory afferent ter As with other nerve injury models, several mixed can minals in the spinal cord has also been reported after 18 nabinoid CB "CB2 agonists suppress hyperalgesia and SNL. This group failed to find co-localization of CB 2 allodynia produced by SNL. Acute WIN55,212-2 sup with markers for glial cells in SNL ratq. and concluded presses all forms of neuropathic nocieeption tested in this that CB 2 receptors were upregulated on sensory neurons model. Chronic administration of WIN55,212-2 also at after spinal nerve ligation. '8 CB, mRNA was also shown tenuates the development of mechanical allodynia and to be upregulated in the ipsilateral (vs the contralateral) suppresses glial activation in the spinal cord after SNL, spinal cord and ORG after SNL, and the presence of CB 2 with no overt motor side effects." Chronic administra mRNA was confirmed in spinal cord microglial cells in tion of WIN55,212-2 produced anti-allodynic effects for culture,l7 up to 6 days after the final injection. A reappearance of The CB 2 specific agonist GW405833, administered glial activation was also associated with return of neu chronically, suppressed the development of mechanical ropathic nocieeption in this study." CP55,940 produces allodynia concomitant with suppression of glial activa 81 antinociception in CB I +1+, CB 2 +1+. CB2 -/-, but not tion at the level of the spinal cord. The structurally Table 5. Antinociceptive Effects of Camzabinoids after Spinal Nerve Ligation (Traditional and Modified) Mechanism Mechanical Compound Route Thennal Hyperalgesia Mechanical Allodynia CBI CB 2 Ref No. ~ Mixed CB /CB2 BAY 59-3074 p.o. NP Yes 78 ~ agonists CP55,940 i.p. Yes No (SRI i.p.) Yes (SR2 i.p.) 179 1 ~ Yes (CB 1+ +) 45 a No (CB, - ' -l ... ·.. . tJ Yes (CB 2 +/ and CB2 -;'-) i.t. Yes No (SRI i.t.) 179 g WIN55,212-2 i.p. Yes-heat Yes* Yes (SRI i.p.) Not (SR2 i.p.) 79 Yes-cold ~ Yes 80 :::j No 81 . ; l.p. Yes 81 ~ CB 2 Agonists AMI241 i.p. Yes Yes.. No (AM251 i.p.) Yes (AM630 i.p.) 44 Yes (CB/1+ andCB,-I-) yes (CB,+1"'andCB,-I,-) No (AM25li.p.) Yes (AM630 i.p.) 44 ~ Yes 85 Lv. Yes Yes (SR2 i.p.) 17 ~ Compound 27 i.p. Yes 180 §3 . ; GW405833 (L768242) l.p. Yes 81 ~ L768242 (GW405S33) i.p. Yes 17 :» MDAI9 i.p. Yes Yes (AM630 i.p.) lSI SJ MDA7 i.p. Yes No (AM251 i.p.) Yes (AM630 i.p.) 85 ?l Endocannabinoid Compound 17 Lv. Yes 90 Modulators OL135 i.p. Yes No (SRI i.p.) Yes (SR2 i.p.) 91 ~ ~ i.v. = intravenous; i.p. = intraperitoneal; p.o. = per orem; i.t. = intrathecal; NP = not present; SRI = SR141716; SR2 = SRl44528. White cells = tested in rats. Shaded cells = tested in mice. *Increased measurements in contralateral paw at dose(s) tested; tOnly cold allodynia tested; *Chronic postinjury. ....i;:l 722 RAHN AND HOHMANN 94 distinct CB 2 specific agonist, JWH133, also attenuates del WIN55,212-2 was more efficacious in suppressing mechanically-evoked responses ofWDR neurons in both mechanical allodynia versus thermal hyperalgesia in the naive and spinal nerve ligated rats.86 Local injection of chronic constriction injury of the infraorbital nerve JWHl33 into the ventroposterolateral nucleus of the model. High antibyperalgesic doses ofWIN55,212-2 de thalamus attenuated spontaneous and mechanically creased rotarod latencies and body temperature, whereas evoked neuronal activity in SNL, but not sham rats, in a HU21O, at the singular low dose used (10 J,tglkg), had no CB2 dependent manner.87 Thus, CB2 receptor activation effect on these dependent measures. CB, receptor up may exert little functional control under nonpathological regulation was observed in both the ipsilateral and con conditions. Systemic and spinal administration of tl,e tralateral superficial layer of the trigeminal caudal nu novel CB2 agonist, A-836339, also attenuates spontane cleus, and this effect was greater on the ipsilateral side. ous and mechanically-evoked neuronal firing of spinal These and earlier findings from the same group95 indi cate that cannabinoids are negative modulators of noci WDR neurons in a CB2 dependent manner in SNL, but not sham rats. S8 Interestingly, pretreatment with the CB, ceptive transmission at the superficial layer of the tri antagonist, SR141716, enhanced the effects of A-836339 geminal caudal subnucleus. when applied to the L5 DRO,"s indicating that blockade CB2 receptor immunoreactivity96 is increased in the of CB, receptors enhanced the antinociceptive effects of ipsilateral dorsal horn after L5 spillal nerve transec 89 97 a CB2 agonist, as previously reported. tion. Importantly, co-localization of CB 2 immunoreac Two endocannabinoid modulators have been evaluated tivity with markers of microglia and perivascular cells behaviorally in this model. Compound 17, a novel was observed on day 4 postsurgery?6 In this study, nei FAAH inhibitor, reversed mechanical allodyrtia in SNL ther neuronal cells nor astrocyctes expressed immunore rats with the same potency as a 5-fold higher dose of activity for CB 2 receptors?6 CP55,940 reversed mechan gabapentin.9o In addition, OLl35, a compound that ac ical allodynia in this model 1 h after a second intrathecal cesses the CNS and inhibits FAAH, suppressed mechan injection, although this dosing paradigm was also asso 96 ical allodynia in a CB2 dependent manner?' Low doses ciated with motor effects Intrathecal JWHOl5 dose of locally injected URB597 reduced mechanically dependently suppressed behavioral hypersensitivity after evoked responses of WDR neurons and increased endo a second injection, indicating a cumulative anti-allodyruc cannabinoid levels in ipsilateral paw tissue of sham effect of this drug. Intrathecal JWH0l5 reduced spinal operated rats?2 A 4-fold higher dose was required for nerve transection-induced increases in activated micro reduction of mechanically-evoked WDR neuronal re glia in a CB2 dependent manner, further supporting a role sponses in SNL rats; these rats showed no corresponding for nonneuronal CB 2 receptors in antihyperalesic effects 96 increase in endocannabinoid levels, suggesting that con of CB 2 agonists. 98 99 tributions ofFAAH to endocannabinoid metabolism may Two models developed by Walczak et al. . involved be modified under conditions of neuropathic nocicep injuries to tl1e saphenous nerve in rats and mice, respec tion.92 The antinociceptive effects of URB597 were tively. The advantage of injuring the saphenous nerve in blocked by a CB, specific antagonist in both sham and comparison with other nerves is that the saphenous nerve SNL rats.·2 In the same study, spinal administration of is an exclusively sensory nerve, whereas other nerve URB597 was eqUally efficacious at attenuating mechan injury models typically target nerves that subserve both ically-evoked responses and increasing levels of endog sensory and motor functions. The first model was pro enous cannabinoids in SNL and sham rats, and these duced in rats by saphenous partial nerve ligation, which effects were CB, mediated?2 involves trapping 30% to 50% of the saphenous nerve in a tight ligature"' Saphenous partial nerve ligation Otber nerve injury models rats presented with all symptoms except mechanical Cannabinoids alleviate neuropathic nociception in sev hyperalgesia, which was present inconsistently through eral other injury models. These studies support a role for out testing. WIN55,212-2, administered systemically, CB 1 in the anti-hyperalgesic effects of cannabinoids, suppressed all forms of hyperalgesia and allodynia although pharmacological specificity has not been con present.98 In rats, saphenous partial nerve ligation in sistently assessed in the literature and high doses of creased J,t-opioid, CB" and CB2 receptor protein in ip cannabinoid agonists can produce motor side effecl., silateral hind paw skin, DRO, and lumbar spinal cord?" which complicate interpretation of behavioral studies. In a second injury model, chronic constriction of the Chronic constriction injury of the infraorbital nerve re saphenous nerve was accomplished by tying two loose sults in thermal hyperalgesia and mechanical allodynia ligatures around the saphenous nerve in mice?" Systemic (as measured by head withdrawals) ipsilateral to the site WIN55,212-2 suppressed all forms of neuropathic noci of injury?3 WIN55,212-2 and HU-21O increased me ception present in this model, including thermal hyper chanical withdrawal responses and thermal withdrawal agesia, cold allodynia, mechanical hyperalgesia, and me latencies on the ipsilateral side of the head in tl1is mo- chanical allodynia?9 Mu-opioid, CB 1 and CB 2 receptor CANNABINom MODULATION OF NEUROPATHIC PAIN 723 protein was increased in the ipsilateral spinal cord and study we reviewed. Systemic BAY 59-3074 was shown hind paw skin at 7 days postsurgery99 In addition, in to attenuate both forms of neuropathic nociception, al creased CB I receptor protein was observed in contralat though pharmaCOlogical specificity was not assessed?" eral hind paw skin 7 days postsurgery and increased CB, Tibial nerve injury injury resulted in an upregulation of receptor expression was observed in the contralateral CB I receptor mRNA in the contralateral thalamus on day spinal cord I and 7 days postsurgery. The neurobiolog I postsurgery,106 indicating cannabinoid receptor regu ical rearrangement of cannabinoid and mu-opioid recep lation within an important relay nucleus in the ascending tors may contribute to the antinociceptive efficacy of pain pathway. WIN55,212-2 and morphine in this model. Disease-related models of neuropathic paiu The spared neroe injury (SNI) model reliably produces Cannabinoid agonists have been evaluated in animal thermal hyperalgesia and mechanical allodynia in studies models of disease-related neuropathic pain, although that tested for both measures. Initial reports of the SNI pharmacological specificity has not been consistently as model indicated the presence of cold allodynia and me sessed. Herein. we review effects of cannabinoids in chanical hyperalgesia, 100 but none of the articles reviewed preclinical models of neuropathic pain induced by diabe here assessed these behaviors in conjunction with cannabi tes, chemotherapeutic treatment, ffiV/antiretroviral treat noid treatment. Standard analgesics (e.g., morphine, gaba ment, demyelination disorders, multiple sclerosis (MS), and pentin, amitrYptiline) are efficacious in treating neuropathic postherpetic neuralgia. nociception resulting from a crush injury of the sciatic nerve, but showed limited efficacy after SNI. 'O' Two mixed Single injectiou of slreptozotocin-induced diabetic cannabinoid CB /CB, agonists have been tested in this neuropathy model. Acute WIN55,212-2 suppressed thermal hyperal Diabetic neuropathy induced by a single injection of gesia and mechanical allodynia in both mice lacking CB I streptozotocin (STZ) resulted in increased sensitivity to receptors in primary nociceptors (SNS-CB I -) and their noxious and non-noxious levels of mechanical stimula wild-type controls; however, differences in the antinoci tion, and failed to induce thermal hyperalgesia in the ceptive effects of WIN55,212-2 were observed between studies reviewed here (Table 6). None of the studies we genotypes, and these effects were greater with mechan reviewed evaluated the presence of cold allodynia. ical than thermal sensitivity. Comparable responses to 2-Methyl-2'-F-anandamide (Met-F-AEA), a CB , spe WIN55,212-2 were only observed at doses high enough cific agonist based on the structure of anandamide, the to induce sedation and rigidity in all mice. SNS-CB I - mixed cannabinoid agonist WIN55,212-2, and the CB, spe mice showed exaggerated sensitivity to noxious levels of cific agonist AM1241, administered chronically, sup mechanical stimulation and a cold plate relative to their pressed mechanical hyperalgesia associated with STZ.. wild-type counterparts, whereas differential sensitivity induced diabetic neuropathy. However, mediation by was not observed between genotypes with non-noxious cannabinoid receptors has not been assessed for agonists levels of mechanical stimulation and noxious levels of tested in this model. Daily pretreatment with indometh 7 thermal stimulation. Thus, CB I receptors on nociceptors acin (cyclooxygenase-l inhibitor) or L-NG-nitro argi in the periphery account for much of the antinociceptive nine ([L-NOArg] nonselective nitric oxide synthase in effects of cannabinoids.7 A dose-escalation study with hibitor) increased the antihyperalgesic actions of low BAY 59-3074 in the SNI model indicated that tolerance doses of WIN55,212-2, AM1241, and Met-F-AEA in rapidly develops to side effects observed after chronic STZ rats to a greater extent than the cannabinoid admin administration (e.g., hypothermia), whereas no loss in istered alone, suggesting the presence of antinociceptive analgesic efficacy was observed.7• synergism between cannabinoid and cyclooxygenase Spinal cord injwy (SCI)102 produces mechanical hy pathways.'07 Cyclooxygenase inhibitors may block oxi peralgesia and allodynia. WIN55,212-2 is the only com dative metabolism of endocannabinoids, thereby increas pound that has been evaluated in the SCI model. Acute ing endocannabinoids available to interact with cannabi WIN55,212-2, administered systemically, suppressed noid receptors. SCI-induced mechanical allodynia in a CB , dependent Diabetic rats exhibit a decrease in the density of CB I manner, although other parameters of neuropathic pain receptor protein in DRG.108 More work is necessary to were not assessed.103 Unlike morphine, chronic admin determine whether this loss of cannabinoid receptors istration of WIN55,212-2 reduced mechanical allodynia contributes to the neurodegenerative process in diabetes. in the SCI model with no decrease in effectiveness over Increased levels of endocannabinoids have been found in time. 104 obese patients suffering from type II diabetes,109 and this Tibial neroe injury is performed by unilaterally axoto effect is likely to result from downregulation of FAAH mizing the tibial branch of the sciatic nerve. Mechanical gene expression, an effect which has also been observed allodynia and thermal hyperalgesia were present in the in adipocytes sampled from obese women. 110 Lean males initial study describing this technique, 105 as well as the subjected to hyperinsulinemia show a 2-fold increase in Table 6. Antinocicepfive Effects of Canllabinoids in Animal Models of Disease~Related Neuropathic Pain ;:j ~ Mechanism Mechanical Mechanical Model Compound Route Thermal Hyperalgesia Allodynia CB I CB 2 Ref No. Diabetic Neuropathy Met-F-AEA i.p. Yes 107 Lp.* Yes WIN55,212-2 i.p. NP Yes 182. Yes 107 NP Yes 183 ·lop. * Yes 107 i.paw NP Yes 183 AMI241 Lp. Yes 107 lop.· * Yes Chemotherapy-induced Cisplatin Neuropathy WIN55,212-2 lop.· t Yes 116 Paclitaxell18, 120 WIN55,212-2 i.p. Yes Yes Yes (SRI i.p.) 119 Lpl. Yes' Yes' ~ MDA7 i.p. NP Yes 85 (R,S)-AMI24l i.p. NP Yes No (SRI i.p.) Yes (SR2 i.p.) 89 ~ (R)-AMI241 i.p. NP Yes (S)-AMI241 i.p. NP No ~ AMI714 i.p. NP Yes No (SRI i.p.) Yes (SR2 i.p.) Vincristine 121 ~ WIN55,212-2 i.p. NP Yes Yes (SRI Lp.) Yes (SR2 i.p.) 122 Lt. NP Yes Yes (SRI i.t.) Yes (SR2 Lt.) i.pl. NP No ~ (R,S)-AMI241 i.p. NP Yes No (SRI i.p.) Yes (SR2 i.p.) <: Other HIV·SN WIN55,212-2 1.p.· * NP-heat Yes§ 124, 123 NP-cold L-29 l.p.· 1 NP-heat Yes Yes (SRI Lp.) Yes (SR2 i.p.) 64 NP-cold LDPN WII>f55,212-2 i.t. Yes. Yes Yes (AM251Lt.) 125 VZV L-29 Lp. NP-heat Yes No (SRI i.p.) No (SR2 i.p.) 64 NP-cold WIN55,212-2 lop.· * NP-heat Yes 131 NP-cold ddc = zalcitabine; HIV-SN = HIY sensory neuropathy (includes antiretroviral treatment (ddc). HIV~gp120, and HIY-gp120 + antiretroviral treatment (ddc) models); i.t. = intrathecal; i.p. = intraperitoneal; i.pI. = intraplantar; LDPN = lysolecithin-induced demyelination-associated peripheral neuropathy of saphenous nerve; NP = not present; SRI = SR141716; SR2 = SRI44528; VZY = varicella zoster vims-induced neuropathy. White cells = tested in rats. Shaded cells = tested in mice. *Chronic postinjury; tChronic. pre-emptive and postinjury; :i:lncreased measurements in contralateral paw at dose(s) tested; §In antiretroviral (ddc), HIV-gp120, and HIV~gp120 + antiretroviral (ddc) models; 'lbnly tested in the antiretroviral (ddc) model. CANNABINOID MODULATION OF NEUROPATHIC PAIN 725 FAAH mRNA expression, whereas obese males sub failed to produce an anti-emetic benefit in this study. I 16 jected to the same conditions failed to show similar It is possible that the dose of cannabinoid employed, the alterations in gene expression. III These findings are sug species used (rat) or toxicity of cisplatin-dosing para gestive of a negative feedback mechanism that could digms may prevent detection of anti-emetic effects in result in dowmegulation of the endocannabinoid signal this model. Cannabinoids have been shown to suppress ing system. The CB I antagonist rimonabant (Acomplia cisplatin-induced emesis in the least shrew,1l7 [Sanofi-Aventis, Montpellier, France]) ameliorates insu Paclitaxel has been most frequently studied in the can lin resistance and decreases weight gain in patients suf nabinoid literature with three studies documenting can fering from metabolic syndromes. 1I2 In animal models, nabinoid-mediated suppression of paclitaxel-induced rimonabant improves resistance to insulin through path neuropathic nociception. Tn one study, paclitaxel'ls pro ways that are both dependent and independent of adi duced mechanical allodynia starting on day 5 that con ponectin, a hormone important for the regulation of glu tinued throughout the course of study, although thermal 113 cose and catabolism of fatty acids. Although adverse hyperalgesia was only present from days 18 to 21. 119 side effects have limited the potential therapeutic effi WIN55,212-2 suppressed neuropathic nociception in this cacy of Acomplia, drugs modulating the endocannabi model, but had no effect on body temperature or immo noid system should not be disregarded as targets for bility. WIN55,212-2-induced decreases in spontaneous potential treatments of diabetes and its associated syn motor activity were nonetheless observed. 119 A more dromes. STZ-diabetic mice showed a progressive decline recent study using the same paclitaxel dosing para in the radial arm maze and reduced neurological scores, digm11S reported the presence of mechanical allodynia both of which were recovered after treatment with HU- and the absence of thermal hyperalgesia." Naguib et 210114 However, these effects were not blocked by a 85 al demonstrated that a novel CB 2 specific agonist, CB, specific agonist. HU-21O did not alter the hypergly MDA 7, suppressed paclitaxel-induced mechanical ano cemia index; however. it did normalize cerebral oxida 114 dynia, although mediation by CB 2 receptors was not tive stress present in diabetic mice. An increase in the assessed. Using the paclitaxel dosing paradigm described number of apoptotic cells and impaired neurite growth by Flatters and Bennett,120 mechanical allodynia, but not was observed in PCl2 cells cultured under hyperglyce thermal hyperalgesia, was observed. In this model, rats mic conditions, and these were effectively treated by showed signs of mechanical allodynia up to 72 days HU_210114 post-paclitaxel.89 Systemic administration of either the Cannabinoids may show greater therapeutic potential CB agonist (R,S)-AMI241 or its receptor-active enan for treating painful diabetic neuropathy compared to opi 2 tiomer (R)-AMI241 produced CB mediated suppres oids. Interestingly, fl.9_THC exhibited enhanced antino 2 sions of paclitaxel-induced mechanical anodynia. (S) ciceptive efficacy in diabetic rats, whereas morphine AM1241, the enantiomer exhibiting lower affinity for the showed reduced antinociceptive efficacy. lIS Moreover, a CB receptor, failed to produce an anti-allodynic ef non-nociceptive dose of fl.9-THC, administered in con 2 89 junction with morphine, enhanced the antinociceptive fect. The novel cannabilactone, AM1714, also reversed properties of morphine in both diabetic and naive mechanical allodynia associated with paclitaxel treat ment in a CB dependent manner89 Thus, both mixed mice. I IS Thus, combinations of apioids and cannabinoids 2 may show promise as adjunctive analgesics in humans. CB /CB2 agonists and selective CB 2 agonists suppress Diabetic rats exhibit lower levels of dynorphin and /3-en paclitaxel-evoked mechanical anodynia. dorphins in CSF relative to nondiabetic rats treated under Cannabinoid modulation of neuropathic nociception the same conditions1l5 Administration of fl.9 -THC to has also been evaluated with vincristine, an agent from diabetic rats restored CSF levels of endogenous dynor the vinca-alkaloid class of chemotherapeutic agents. Vin phin and leu-enkephalin to levels observed after mor cristine produced mechanical allodynia, but not thermal l2I phine administration to nondiabetic rats. liS More work is hyperalgesia, in a lO-day injection paradigm. Sys necessary to understand the mechanism underlying these temic and intrathecal, but not intraplantar, WIN55,212-2 observations. suppressed vincristine-induced mechanical allodynia l22 through activation of CB 1 and CB2 receptors. These Chemotherapy-induced neuropathy findings implicate the spinal cord as an important site of Cannabinoid modulation of chemotherapy-induced action mediating anti-allodynic effect. of cannabinoids. nemopathy has been evaluated with agents from three Systemic (R,S)-AMI241 also partially reversed vincris major classes of chemotherapeutic agents (Table 6). A tine-induced mechanical allodynia in a CB2 dependent singular study has evaluated cannabinoid modulation of manner.l22 The anti-allodynic effects of WIN55,212-2 nemopathic nociception induced by cisplatin, a plati and (R,S)-AM1241 were observed at doses that did not num-derived agent. WIN55,212-2 prevented the devel produce intrinsic effects on motor behavior in the bar opment of mechanical allodynia induced by cisplatin, but test. l22 Our studies suggest that clinical trials of canna- 726 RAHN AND HOHMANN binoids for the management of chemotherapy-evoked binoid-mediated suppression of MS-induced neuropathic neuropathy are warranted. nociception. Lynch et al. 126 reported the presence of thermal hyperalgesia (tail immersion) and mechanical HIV-associated sensory neuropathy allodynia in mice that were infected with Theiler's mu The mixed cannabinoid agonist WTN55,212-2 is an rine encephalomyelitis virus. Interestingly, female mice effective anti-hyperalgesic agent in three distinct animal showed an increased rate of development and greater models of mv-associated sensory neuropathy (Table 6). allodynia than their male counterparts, a finding which Rats treated with the antiretroviral agent zalcitabine mimics the greater prevalence of neuropathic pain symp (ddc) developed mechanical allodynia that persisted up toms reported by female MS patients",7 Cold and me to 43 days postinjection and peaked between days 14 and chanical allodynia, but not thermal hyperalgesia, have 32.'23 No hypersensitivity to thermal stimuli or motor been reported in a model of autoimmune encephalomy deficits was observed after ddc treatment. mv-I has elitis in which mice were immunized with myelin oligo indirect interactions with neurons through its binding dendrocyte glycoprotein (MOG[35-55])'28; autoimmune affinity to the external envelope binding protein gp120; encephalomyelitis has been postulated to underlie the researchers have exploited this mechanism to demon development of neuropathic pain in MS. Interestingly, a strate development of peripheral neuropathy in rodents mouse model of MS (Theiler's murine encephalomyelitis after exposure of the sciatic nerve to the HIV-I gpl20 virus infection) is also characterized by an upregulation protein. Perineural HIV-gp 120 together with ddc treat of CB2 receptor mRNA and increases in levels of 2-AG ment resulted in mechanical allodynia that was greater and PEA. 129 Animals treated subchronicaUy with PEA than either treatment alone; no changes in paw with showed improvements in tests of motor performance, drawallatencies to thennal stimuli or motor deficits were measures that were impaired after Theiler's murine en reported. 123 Thigmotaxis was present in animals receiving cephalomyelitis virus infectionP9 Thus, we postulate ddc, either alone or in conjunction with HIV-gpI20, indi that cannabinoid CB agonists and modulators of endog '23 2 cating the presence of anxiety-like behavior in these rats. enous cannabinoids (e.g., MGL inhibitors) would exhibit Rats receiving ddc displayed modest levels of gliosis, anti-alIodynic efficacy in this model. whereas combined treatment with both HIV-gp120 and ddc increased levels of microglial activationl23 Importantly, Postherpetic neuralgia chronic WTN55,212-2 reversed mechanical allodynia in Cannabinoids and fatty-acid amides suppress neuro l23 duced by either ddc treatment or HIV-gp 120 expo pathic nociception in an animal model of postherpetic sure,124 whereas animals subjected to both HIV-gpI20 neuralgia (Table 6). However, pharmacological specific and ddc treatment exhibited a WIN55,212-2-induced ity has not been consistently assessed in this model. attenuation of mechanical allodynia. 123 Increases in the Approximately 50% of rats exposed to the varicella density of microglia and astrocytes were observed in zoster virus developed mechanical allodynia in the ipsi the ipsilateral dorsal horn after HIV-gpI20 treatment. lateral paw by 14 days postinfection; no thermal hyper Thus, activated microglia may be a common target algesia or cold alIodynia was observed.64 The PEA underlying cannabinoid-mediated suppressions of neuro analogue L-29 suppressed mechanical aUodynia in this pathic nociception. model with an earlier onset relative to gabapentin. How ever, neither a CB I nor CB specific antagonist blocked Demyelination-induced neuropathy 2 L-29 mediated suppression of varicella-zoster virus-in WIN55,212-2 has been evaluated in the lysolecithin-in duced mechanical alIodynia.64 This finding is perhaps duced demyelination model (Table 6). Heightened sensitiv unsurprising given that PPAR-a mediates effect. of PEA ity to both non-noxious and noxious mechanical stimulation in suppressing neuronal sensitization. 130 However, L-29. is observed in lysolecithin-treated rats; this hypersensitivity nonetheless, suppressed neuropathic nociception in the emerged 5 days postexposure and peaked between 9 and 15 Seltzer model via activation of CB I and CB receptors days postexposure.'25 Recovery to baseline levels was ob 2 (see Table 4). Systemic WIN55,212-2, administered served by day 23 post-lysolecithin. WIN55,212-2 attenu from days 18 to 21 postinfection, fully reversed mechan ated mechanical allodynia and thermal hyperalgesia in this ical allodynia to baseline levels in this model of posther model and remained efficacious for up to I hour postinjec petic neuralgia, although pharmacological specificity tion. l25 By contrast. DAMGO failed to produce an effect. was not assessed. 131 Notably, the anti hyperalgesic and anti-allodynic effects of WJN55,212-2 were reversed by a CBl specific antagonist in both tests. CANNABINOID MODULATION OF NEUROPATIDC PAIN IN CLINICAL STUDIES MS-associated neuropathy Animal models of MS have been described, although Cannabinoids have been evaluated in clinical studies to our knowledge, no study to date has evaluated canna- for their suppression of acute, postoperative and neuro- CANNABINOID MODULATION OF NEUROPATHIC PAIN 727 pathic pain. Based on our reviews of the literature, can nabis cigarettes administered to patients. Cannabis was nabinoids exhibit their greatest efficacy when used for superior to a placebo in either phase of the crossover, as the management of neuropathic pain (Tables 7 and 8).132 measured with the descriptor differential scale or VAS. There are approximately 460 known chemical constitu This study found no changes in heart rate, blood pres ents in cannabis. Thus. at the outset, it is important to sure, plasma HlV RNA (viral load; VL), or blood CD4+ emphasize that smoked cannabis is not the same as oral lymphocyte counts after cannabis treatment, suggesting d 9_THC or different mixtures of d 9-THC and CBD (e.g., that cannabis did not negatively impact the already com Sativex [GW Pharmaceuticals, United Kingdom] and promised immune system in these patients. An anony Cannador [Institute for Clinical Research, IKF, Berlin, mous cross-sectional questionnaire study revealed that as Germany]). Other drug delivery mechanisms (e.g., oral many as one third of patients suffering from HIV have mucosal sprays and rectal suppositories containing can used cannabis to treat symptoms.138 Patients reported nabinoids) have been developed. Evidence to date from self-dosing with marijuana primarily between 6 PM and clinical studies suggests that these compounds show 12 AM. Among the symptoms improved after cannabis therapeutic efficacy in suppressing neuropathic pain (Ta were appetite (97% reported improvement), pain (im ble 7 and 8). proved in 94% of the patients with pain), nausea (93% Three of the articles reviewed here used smoking as reported improvement), and anxiety (93% repotted im the route of administration, whereas the other 13 used provement).138 oral preparations in the form of pills or oral-mucosal Dronabinol (Marinol [Solvay Pharmaceuticals Inc, sprays. Side effects were reported in all studies in a Marietta, GA]) is used to counteract AIDS-related wast proportion of patients receiving cannabinoid-based med ing and promote appetite in patients suffering from ications. The most frequently reported side effects were AIDS-related anorexiaY9 The benefits of d 9-THC and dizziness, impairment of balance, feelings of intoxica Nabilone (Cesamet [Valeant Pharmaceuticals Interna tion, dry mouth, and dysgeusia (most commonly ob tional, Aliso Viejo, CA]) for the treatment of chemother served with oral-mucosal sprays), sedation, and hunger. apy-induced nausea and vomiting have also been vali One study reported severe gastrointestinal effects for dated.14o,l4J Thus, several features of cannabinoid 10% of patients taking Sativex versus 0% reporting sim pharmacology are patticularly desirable for an analgesic ilar problems in the placebo groUp.133 However, un intervention aimed at managing neuropathic pain in wanted side effects, in contrast to analgesic effects, may AIDS and cancer patients. undergo tolerance. l34 Side effects may be minimized using dosing paradigms employing low doses that are MS-induced neuropathic pain only gradually escalated. As follows, we review effects Several cannabinoid-based medicines have been eval of cannabinoid-based medications in clinical studies us uated in patients suffering from MS-related neuropathic ing populations of patients presenting with neuropathic pain. Cannabinoid-based medications have more fre pain. Neuropathic pain induced by HIV infection andlor quently been evaluated for efficacy in suppressing MS antiretroviral treatmen~ MS, brachial plexus avulsion, related spasticity.142 Dronabinol reduced spontaneous mixed treatment-resistant neuropathic pain, and others pain intensity as measured with a numerical rating scale were considered. (NRS) for a 3-week treatment period,134 and improved overall pain ratings on the category rating scale for a HIV-associated neuropathy IS-week treatment period. 143 In addition, this drug im Two studies have examined effects of smoked canna proved median radiating pain intensity and pressure bis for the treatment of HIV-associated sensory neurop tlrreshold,l34 sleep quality, spasms, and spasticityJ43 in athy (resulting from HIV infection, dideoxynucleoside MS patients. Cannador is a medicinal cannabis prepara 9 antiretroviral therapy, or both) and have reported positive tion containing d -THC and CBD in a 2: I ratio. CBD results (Table 7). Abrams et al. 135 reported that 52% of is a natural constituent in cannabis, which has very low patients (i.e., 13 of 25 receiving cannabis cigarettes) affinity for cannabinoid CB I and CB2 receptors. It may experienced a greater than 30% reduction in pain (visual act as a high potency antagonist of cannabinoid agonists l44 analogue scale daily ratings [VAS]). Stimulus-evoked and an inverse agonist at CB 2 receptors. CBD may pain testing revealed that the group receiving cannabis compete with cannabinoid agonists for cannabinoid re experienced a reduction in the area sensitive to mechan ceptor binding sites, thereby minimizing psychoactivity ical allodynia (with a foam brush or 26 g von Frey hair) of drugs that use a combination of d 9-THC and CBD. in the heat and capsaicin sensitization model. Moreover, The antinociceptive effects of CBD have also been at CD4+, CD8+, and T-cell counts were not negatively tributed to inhibition of anandamide degradation, the impacted by cannabinoid treatment in HIV patients. 136 In antioxidant properties of the compound, or binding to an 2009, Ellis et al. 137 reported similar results in a crossover nnknown cannabinoid receptoL I44 CBD also acts as an study using multiple concentrations of d 9_THC in can- agonist at serotonin 5-HTla receptors. l44 Cannador, ad- ;j Table 7. Effects of Cannabinoids on Disease-Related Neuropathic Pain ill Clinical Studies 00 CompoundJRoute Pdmary Outcome Measure Stimulus Evoked Pain Secondary Outcome Measures Ref No. HIV-SN Cannabis ci~arettes V AS daily pain ratings - 52% LTS - No effect; Heat and capasaicin POMS - No effect 135 (3.56% LI, -THC)* reported> 30% reduction sensitization model - Reduced area Smoking in pain sensitive to mechanical allodynia Cannabis cigarettes DDS and V AS pain ratings - POMS/SIP/BSIIplasma VL and CD4+ 137 (1-8% Ll,9_THC)t 46% reported", 30% lymphocyte counts - No effect Smoking reduction in pain Multiple Dronabinol NRS of median spontaneous Median radiating pain intensity/pressure SF-36 - Improvements in bodily pain 134 Sclerosis-related (Marinol)t p.o. pain intensity - Reduction pain tlrreshold - Improved; Cold and and mental health categories Neuropathic from BL on this measure warm sensibility/tactile detection! Pain was 20.5% (-0.6 pt.) with tactile pain detection/vibration sense! Drollabinol vs. placebo temporal summation!mechanical or cold allodynia - No effect Sativex*'* Oral *NRS-Il (pain) -- 1.25 pt NPSINRS-Il Pain-related sleep 146 Mucosal Spray reduction in favor of disturbances - Improved Sativex PGIC - Sativex treated 3.9X mOl'e likely than placebo to rate s; themselves in an improved category ~ HADSIMS-related disability scale - No effect *NRS-ll (pain) - No changes 44% of patients completed approximately 147 ~ in pain scores from 2 years of opell-label study. randomized 5-wk trial (up No increase in titration of dose - No ~ to 2 y) - Sativex still tolerance ~ suppressing pain vs. BL Dronabinol Ashworth spasticity score - Category-rating scales - Improved 143 ~ (Marinol)§ p.o. No effect pain, sleep quality, :,pasms and Cannador§ p.o. spasticity with CEM 10 m walk - Improved with CEM Rivermead Mobility IndexlBarthel IndexlGHQ-30IUKNDS - No effect Dronabinol Ashworth spasticity score - Category rating scales - Improved 145 (Marinol)' p.o. Improvement after pain, spasms, spasticity, sleep, Cannador1 p.o. dronabinol shakiness, energy level and tiredness with CBM Rivermead Mobility IndexlBarthel IndexlGHQ-30IUKNDSIl0 m walk - No effect BL = baseline; BSI = brief symptom inventory; CBM = cannabinoid-based medicine; DDS = descriptor differential scale; GHQ = general health questionnaire; HADS = hospital anxiety and depression scale; HIV-SN = HIV-associated sensory neuropathy; LTS = long-tenn thennal stimulation; MS = multiple sc1erosis; NPS = neuropathic pain scale; NRS = numerical rating scale; PGIC = patient global impression of change; p.o. = per orem; pt. = point; POMS = profile of mood states; SF-36 = short form health questionnaire; SIP = sickness impact profile; THC = tetrahydrocannabinol; UKNDS = United Kingdom neurological disability score; V AS = visual analogue scale; VL = viral load, *Double-blind, placebo-controlled; tdouble-blind, placebo-controlled crossover; topen label extension of randomized, double-blind, placebo-controlled study; §randomized, placebo-controlled; '1double-blind, placebo-controlled l-year extension. Table 8. Effects of Call11abinoids in InjUly~Related and Mixed Neuropathic Pain in Clinical Studies CompoundlRoute Primary Outcome Measure Stimulus Evoked Pain Secondary Outcome Measures Ref No. Brachial Plexus Sativex/A9-THC* Oral BS-ll (pain) - Sativex reduced pain by Pain review BS-II/Sleep quality ISO Avulsion Mucosal Spray 0.58 boxes vs. placebo BS-ll/Sleep disturbances - A9-THC reduced pain by 0.64 boxes vs. Improved with CBM placebo GHQ-12 - Improved with Sativex SF-MPQ Pain rating index and 9 VAS - Improved with A _ THC ~ PDI - No Effect Mixed Dronabinol (Marinol)' V AS daily pain ratings - No effect Brush-induced mechanical allodynia - MPQIBPIIHADSlNotingham 164 ! Neuropathy ';;: p.o. No effect health profile - No effect 0 Nabilone (Cesarnet)1 VAS daily pain ratings - DHC better SF-36 - Physical role improved 166 DHC' p.o. than Nabilone with nabilone; Bodily pain \3 improved with DHC CT-3 (AJA)' p.o. V AS (pain) - CT-3 reduced pain Decrease in mechanical hypersensitivity TMT; ARCI-M - No effect 152, 153 g ratings in the morning (3 h (von Frey) in group receiving AlA postdrug), but not aftemoon (8 hrs. prior to placebo (p = 0.052) ~ postdrug); VRS (pain) - No effect :::j Cannabis cigarettes Spontaneous pain relief VAS - Mechanical allodynia (foam brush) Pain Unpleasantness ISS (3.5-7% A9-THC)* Improved VAS; Thermal hyperalgesis VAS - V ASINPS - Improved ~ Smoking No effect Degree of pain relief ~ PGIC/Psychoactive effectsl Neurocognitive effects - ~ Greater with cannabis; Mood §:i VAS - No effect 0 9 A -THC/CBD/Sativex* V AS of 2 worst symptoms - Decrease Quality of sleep - Improved 156 ~ Oral-Mucosal Spray in symptoms following A9-THC and with all CBM ~ (Open-label phase Sativex relative to placebo Duration of sleep - No effect ('l with Sativex prior BDJ/GHQ-28- Qualitative to crossover) improvement in mood following CBM <:~ V AS daily ratings of target symptoms - Numerical symptom scale - 159 CBD and A9-THC improved pain; Spasticity severity improved A9_THC and Sativex improved with all CBM; frequency of spasms; Jl9-THC improved spasticity muscle spasms improved with A9-THC and Sativex VAS daily ratings - A9-THC improved appetite; Sativex improved sleep (Table continues) ~ 'C 730 RAHN AND HOHMANN o ministered for a 15-week treatment period, improved z overall pain ratings, as well as sleep quality, spasms, and ~ spasticity on category rating scales in patients suffering from MS-related neuropathic painl43 A I-year, double blind, placebo-controlled follow-up study in MS patients demonstrated improved symptoms of pain, spasms, spas ticity, sleep, shakiness, energy level, and tiredness after administration of either dronabinol or CannadoL 14' This study reported that 74% of the patients in the placebo group, versus 45% of the patients receiving cannabinoid based medications, cited a lack of benefit derived from experimental medication as the reason for discontinua l4 tion of the trial. ' MS patients receiving Sativex (a medicinal cannabis extract containing approximately a 1:1 ratio of CBD:Ll.9-THC, administered as an oral-mu cosal spray) reported significant reductions in pain symp toms, as measured with the NRS-Il and neuropathic pain scale in a 4-week treatment period, double-blind, placebo controlled study. 146 Ninety-five percent of the patients in the placebo-controlled study chose to enter a 2-year open-label study with Sativex. 147 Fifty-four percent of the patients completed 1 year and 44% of the patients completed 2 years of the study. Twenty-five percent withdrew due to adverse events, and 95% experienced one or more adverse events during the course of treat ment. The NRS-ll, completed at the end of the trial, or upon withdrawal, was not different from the earlier ran domized study indicating that Sativex was still suppress ing pain. In addition, patients did not increase the titra tion of their dose indicating that no tolerance developed to Sativex. Most doses of Sativex were administered between 6 PM and 12 AM, demonstrating that pain symptoms may be at their worst during normal sleeping hours for MS patients. A recent meta-analysis examining six studies of cannabinoid-based medications used for the treatment of MS-related neuropathic pain revealed that cannabis preparations were superior to a placebo. 148 Increased CB 2 immunoreactivity has been reported in spinal cords derived from MS patients. l49 Here, greater numbers of microglia/macrophage cells expressing CB 2 immunoreactivity were observed relative to controls. 149 Thus, cannabinoid-based pharmacotherapies consistently show efficacy for suppressing pain due to MS, a disease state associated with an upregulation of CB 2 receptors in microglia. Brachial plexns avulsion-indnced neuropathy A single study has examined patients wiIh neuropathic pain resulting exclusively from a brachial plexus avul sion (Table 8). This study150 used a 3-period crossover 9 design with patients self-administering Ll. -THC, Sati vex, or a placebo for 14 to 20 days per drug. Both Ll.9 -THC and Sativex reduced the primary outcome measure (box scale 11 ordinal rating scale) in patients suffering from brachial plexus avulsion, indicating a reduction in pain CANNABINOID MODUIATION OF NEUROPATHIC PAIN 731 symptoms versus placebo. Sleep quality disturbance reported improved pain ratings (VAS) and spasticity se 9 scores were improved in patients receiving either active verity after CBD and 11. _THe in patients with mixed drug versus placebo. Eighty percent of the patients chose neuropathic pain.'59 A9-THC and Sativex also improved to enter an open-label study with Sativex after comple muscle spasms and spasticity severity.159 tion of tills randomized study. Sativex improved pain ratings as measured with the CB 2 receptor immunoreactivity has been reported in NRS in a 5-week, double-blind, placebo-controlled study normal and injured human DRG neurons, brachial plexus performed in patients experiencing unilateral neuro nerves, and neuromas, as well as peripheral nerve fi pathic pain.133 In this study, Sativex reduced mechanical l51 bers. However, upregulation of CB 2 receptor immu dynamic and punctate allodynia, and improved sleep dis noreactivity was specifically observed in injured human turbances.133 Seventy-one percent of the patients tested nerve specimens and avulsed DRG obtained during sur chose to continue to the open-label study of Sativex with gery for brachial plexus repair.l5l These observations 63% withdrawing by the end of the study for various correspond to preclinical observations of cannabinoid reasons. Nabilone (Cesamet) decreased measures of receptor upregulation after nerve injury. IS However. pos spasticity-related pain (II-point box test) in patients ex sible changes in CB I receptor immunoreactivity were not periencing chronic upper motor neuron syndrome asso evaluated in the human tissue, and therefore can not be ciated with a number of pain syndromes. 160 In a retro excluded. spective review of patient charts at the Pain Center of the McGill University Health Center from 1999 to 2003,'61 Mixed neuropathic pain 75% of patients received some benefit from taking Recruitment of a patient population suffering from a Nabilone (whether it came in the form of pain relief, specific form of neuropathic pain can be a difficult pros improved sleep, decreased nausea, or increased appetite). pect; therefore, several studies include patients in which Two studies have examined the effects of cannabinoid neuropathic pain is associated with different disease based medications in patients suffering from spinal cord states or injuries (Table 8). A 21-patient study reported injuries. An early case study reported pain relief and that ajulemic acid (CT-3) suppressed mixed forms of improvement in spasticity in a patient with a spinal cord neuropathic pain, as assessed with the V AS, in the morn injury after oral A9_THC.'62 A later study reported that ing (3 h after drug administration), but not in the after 18% of the patients with spinal cord injuries reported noon (8 h after drug administration). 152 Eighteen of those pain relief after treatment with oral dronabinol (mean, 31 same patients participated in stimulus-evoked pain test mg per day), whereas 23% experienced enhancement of ing during the study, and those patients showed a trend pain resulting in subsequent withdrawal by several pa toward decreased mechanical allodynia after CT-3 ad tients. 163 Changes in experimental design after initiation ministration'53 CT-3 binds with high affinity to both ofthe study complicate interpretation of these latter find CB I and CB2 receptors, and also binds with low affinity ings.163 to PPAR'Y receptors.'54 CT-3 has limited CNS availabil ity,6" which translates into fewer CBI-mediated side Caveats effects. We are aware of only two clinical studies that have Smoking cannabis cigarettes also improved spontane failed to report efficacy of cannabinoids, relative to pla ous pain relief and pain unpleasantness VAS ratings in cebo, for treatment of mixed neuropathic pain.I64.165 Our patients suffering from nlixed forms of neuropathic pain, analysis of the study by Clermont-Gnamien et al.'·5 is but failed to alter stimulus-evoked pain.155 This study restricted to information provided in the abstract, pub reported that cannabinoids compounded the decreased lished in English. Both of these studies used eight or neurocognitive performance of patients that was present fewer subjects and evaluated dronabinol titrated to a dose at baseline. Using an "N of 1" preparation, Notcutt et of 25 mg/day (where tolerated). The mean dose was 156 al. determined if patient"; experienced improvements 16.6 :!: 6.5 mg oral dronabinol in one study l64 and 15 :!: in pain after a 2-week open-label phase with Sativex 6 mg in the other study. 165 The two studies associated prior to initiation of the double-blind, placebo-controlled with negative outcomes for cannabinoids in managing crossover phase of the study. A9_THC and Sativex, but neuropathic pain shared several common features: 1) not placebo or CBD, reduced the VAS rating of the two evaluation of nlixed neuropathic pain syndromes known worst pain symptoms during the crossover phase,'56 to be refractory to multiple analgesic treatments, 2) eval Quality of sleep was improved by all cannabinoid-based uation of orally-administered A"-THC (dronabinol) as medications156 and therefore may contribute to the ther opposed to mixtures of A"-THC and CBD, or smoked apeutic potential of the cannabinoids. By contrast, opioid marijuana, 3) small numbers of subjects, and 4) obser analgesics produce deleterious effects on sleep architec vation of prominent side effects (e.g., sedation) resulting ture, including reductions in slow wave sleep and pro in high dropout rates. One study reported side effects that motion of sleep apnea.157.158 A similarly structured study were more prominent in older patients and did not COf- 732 RAHN AND HOHMANN relate with analgesia. '64 Of course, one difficulty in eval A recent systematic review of adverse effects of med uating efficacy of analgesics in patients with neuropathic ical cannabinoids concluded that most adverse events pain refractory to all known treatments is that there is no (96.6%) were not serious and no serious adverse events indication that these patients would respond favorably to were related exclusively to cannabinoid administration. any analgesic under the study conditions. In a third Moreover, 99% of serious adverse events from random study, effects of Nabilone were compared with dihydro ized clinical trials were reported in only two trialsP" codeine in a randomized, crossover, double-blind study Greater numbers of nonserious adverse events were ob I70 of 3-months duration that did not include a pharmaco served after cannabinoid treattnent, as expected. Side logically inert placebo condition. In this latter study, 166 it effects were equally associated with the different canna was concluded that the weak opioid dibydrocodeine was binoid pharmacotherapies; the average rate of nonserious a statistically better treattnent for chronic neuropathic adverse events was higher in patients receiving Sativex 9 170 pain than Nabilone.'66 Patients in this study exhibited a or oral A _THC than controls. Thus, the main burden mean baseline VAS rating of 69.6 mm on a 0 to 100 mm for the clinician is to balance therapeutic efficacy with VAS scale; mean VAS ratings were 59.93 :': 24.42 mm the risk of intolerable side effects in the specific pa and 58.58 :': 24.08 mm for patients taking Nabilone and tient. '69 High-quality trials oflong-term exposure to can dihydrocodeine, respectively. However, the authors nabinoids-based medications, together with careful mon noted that a small number of subjects responded well to itoring of patients, are required to better characterize Nabilone, and side effects were generally mild and in the safety issues related to the use of medical cannabi noids,I70 expected range.!66 Benefits of an add-on treatment with Nabilone have nonetheless been noted in patients with chronic therapy-resistant pain (observed in a causal re CONCLUSIONS lationship with a pathological status of the skeletal and Cannabis has been used for pain relief for centuries, locomotor system).167 Oral dronabinol produced signif although the mechanism underlying their analgesic ef icant pain relief versus placebo when combined with fects was poorly understood until the discovery of can opioid therapy in both a double-blind, placebo-controlled nabinoid receptors, and their endogenous ligands in the crossover phase and a subsequent open-label exten 1990s. During the last two decades, a large number of sion. 168 Patients also reported improvements in sleep research articles have demonstrated the efficacy of can problems and disturbances while experiencing an in nabinoids and modulators of the endocannabinoid sys crease in sleep adequacy in the open-label phase of the tem in suppressing neuropathic pain in animal models. study.I68 Thus, caution should be exerted prior to con Cannabinoids suppress hyperalgesia and aIlodynia (i.e., cluding that side effects of cannabinoids seriously limit mechanical allodynia, mechanical hyperalgesia, thermal the therapeutic potential of cannabinoid pharmacothera hyperalgesia, and cold aIlodynia where evaluated), in pies for pain. Combination therapies, including a canna duced by diverse neuropathic pain states through CB 1 binoid and opioid analgesic, show efficacy for treattnent and CB 2 specific mechanisms. These studies have eluci resistant neuropathic pain and may be used to limit doses dated neuronal as well as nonneuronal sites (i.e., acti of analgesics or adjuvants associated with adverse side vated microglia) of action for cannabinoids in suppress effects. ing pathological pain states and documented regulatory changes in cannabinoid receptors and endocannabinoid Side effects accumulation in response to peripheral or central nervous Diverse neuropathic pain states (characterized as system injury. Clinical studies largely reaffirm that can idiopathic, diabetic, immune-mediated, cobalamin-de nabinoids show efficacy in suppressing diverse neuro ficiency related, monoclonal gammopathy-related, alco pathic pain states in humans. The psychoactive effects of hol abuse-related, and other) were recently examined in centrally-acting cannabinoid agonists, nonetheless, rep a prospective evaluation of specific chronic polyneurop resent a challenge for pain pharmacotherapies that di athy syndromes and their response to pharmacological rectly activate CB I receptors in the brain. However, non therapies. '69 Intolerable side effects were observed in all serious adverse event. (e.g., dizziness), which pose the groups of patients receiving either gabapentainoids, tri major limitation to patient compliance with pharmaco cyclic antidepressants, anticonvulsants, cannabinoids therapy, are not unique to cannabinoids. Approaches that I69 (Nabilone or Sativex), or topical agents. Notably, the serve to minimize unwanted CNS side effects (e.g., by presence of intolerable side effects was similar among combining A"-THC with CBD, or by targeting CB re I69 2 the different classes of medications. Tn this study, ceptors, peripheral CB, receptors, or the endocannabi most forms of neuropathic pain had similar preva1ence noid system) represent an important direction for future rates and responsiveness to the different pharmacother research and clinical evaluation. The present review sug apies evaluated. 169 gests that cannabinoids show promise for treattnent of CANNABINOID MODUIATION OF NEUROPATHIC PAIN 733 neuropathic pain in humans either alone or as an add-on 20. Mechoulam R, Ben-Shabat S, Hanus L, et al. Identification of an to other therapeutic agents. Therefore, further evalua endogenous 2-monoglyceride. present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 1995;50:83-90. tions of safety profiles associated with long-term effects 21. Sugiura T, Kondo S, Sukagawa A, et al. 2-Arachidonoylglycerol: of cannabinoids are warranted. a possible endogenous cannabinoid receptor ligand in brain. Bio chern Biophys Res Commun 1995;215:89-97. 22. 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Bioorg Med Chern Lett macological therapy. Pain 2008;138:657-666. 2008; 18:2830-2835. 170. Wang T, Collet IP, Shapiro S, Ware MA. Adverse effects of 181. Diaz p, Xu J, Astruc-Diaz F. Pan HM, Brown DL, Naguib M. medical cannabinoids: a systematic review. CMAJ 2008;178: Design and synthesis of a novel series of N-alkyJ isatin acylhy 1669-1678. drazone derivatives that act as selective cannabinoid receptor 2 171. De Vry J, Kuhl E, Franken-Kunkel P, Eckel G. Phamlacological agonists for the treatment of neuropathic pain. I Med Chern characterization of the chronic constriction injury model of neu 2008;51:4932-4947. ropathic pain. Eur J Pharmacal 2004;491: 137-148. 182. Dogrul A, Gul H, YiJdiz 0, Bilgin F, Guzeldemir ME. Can 172. Pedersen LH, Blackburn-Munro G. Pharmacological characteri nabinoids blocks tactile allodynia in diabetic mice without sation of place e.~cape/avoidance behaviour in Ihe fal chronic attenuation of its antinociceptive effect. Neurosci Lett 2004; constriction injury model of neuropathic pain. Psychopharmacol 368:82-86. ogy (Berl) 2006;185:208-217. 183. Ulugol A, Karadag HC, 1pci Y, Tamer M, Dokmeci 1. The effect 173. Hama AT. Urban MO. Anlihyperalgesic erfect of the cannabinoid of WIN 55,212-2, a cannabinoid agonist, on tactile aJIodynia in agonist WLN55,212-2 is mediated through an interaction with diabetic rats. Neurosci Lett 2004;371:167-170. Cannabinoids for the Treatment of Chronic Non-Cancer Pain: An Updated Systematic Review of Randomized Controlled Trials M. E. Lynch , MarkA. Ware INVITED REVIEW First Online: 22 March 2015 001: 10.1007/s11481-015-9600-6 Cite this article as: Lynch, M.E. & Ware, MA J Neuroimmune Pharmacol (2015) 10: 293. doi:10.1007/s11481-015-9600-6 11 Citations 53Shares 1.2kViews Abstract An updated systematic review of randomized controlled trials examining cannabinoids in the treatment of chronic non-cancer pain was conducted according to PRISMA guidelines for systematic reviews reporting on health care outcomes. Eleven trials published since our last review met inclusion criteria. The quality of the trials was excellent. Seven of the trials demonstrated a significant analgesic effect. Several trials also demonstrated improvement in secondary outcomes (e.g., sleep, muscle stiffness and spasticity). Adverse effects most frequently reported such as fatigue and dizziness were mild to moderate in severity and generally well tolerated. This review adds further support that currently available cannabinoids are safe, modestly effective analgesics that provide a reasonable therapeutic option in the management of chronic non-cancer pain. June 200aVolume 9, Issue 6, Pages 506-521 To read this article in full, please review your options for gaining access at the bottom of the page. A Randomized, Placebo-Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain Barth WilseJ;=ij' Press enter key for correspondence infonnatioJ : L s enter key to Email the author Thomas Marcone Alexander Tsodikov Jeanna Millman Heather Bentlev Ben Gouaux Scott Fishman ~~.trlc 6 DOl: http://dx.doi.orIliI O. 10 16/j.jpain.2007. 12.0 I 0 ...... __ '""' ,rticle Info Abstract Full r ext Images References Abstract The Food and Drug Administration (FDA), Substance Abuse and Mental Health Services Administration (SAMHSA), and the National Institute for Drug Abuse (NIDA) report that no sound scientific studies support the medicinal use of cannabis. Despite this lack of scientific validation, many patients routinely use "medical marijuana," and in many cases this use is for pain related to nerve injury. We conducted a double-blinded, placebo-controlled, crossover study evaluating the analgesic efficacy of smoking cannabis for neuropathic pain. Thirty-eight patients with central and peripheral neuropathic pain underwent a standardized procedure for smoking either high-dose (7%), low-dose (3.5%), or placebo cannabis. In addition to the primary outcome of pain intensity, secondary outcome measures included evoked pain using heat-pain threshold, sensitivity to light touch, psychoactive side effects, and neuropsychological performance. A mixed linear model demonstrated an analgesic response to smoking cannabis. No effect on evoked pain was seen. Psychoactive effects were minimal and well-tolerated, with some acute cognitive effects, particularly with memory, at higher doses. Perspective This study adds to a growing body of evidence that cannabis may be effective at ameliorating neuropathic pain, and may be an alternative for patients who do not respond to, or cannot tolerate, other drugs. However, the use of marijuana as medicine may be limited by its method of administration (smoking) and modest acute cognitive effects, particularly at higher doses. Low-Dose Vaporized Cannabis Significantly Improves Neuropathic Pain Barth Wilse.£RPress enter key for correspondence inforrnationElPress enter key to Email the author , Thomas Marcotte , Reena Deutsch , Ben Gouaux , Staci Sakai Haylee Donaghe l Alt.:"lrk 185 001: htlo:/Idx.doLorg/1 0.1016f!';pain .2012.10 .009 r ; *) l ",rticle Info Abstract Full Text Images References Abstract We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despne traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling medium-dose (3.53%), low-dose (1 .29%), or placebo cannabis with the primary outcome being visual analog scale pain intensITy. Psychoactive side effects and neuropsychological performance were also evaluated. Mixed..,ffects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the 2 active dose groups' results (P > .7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo versus low-dose, 2.9 for placebo versus medium-dose, and 25 for medium- versus low-dose. As these NNTs are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well tolerated, and neuropsychological effects were of limited duration and readily reversible within 1 to 2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain. Perspective The analgesia obtained from a low dose of delta-9-tetrahydrocannabinol (1.29%) in patients, most of whom were experiencing neuropathic pain despite conventional treatments, is a clinically significant outcome. In general, the effect sizes on cognitive testing were consistent with this minimal dose. As a result, one might not anticipate a significant impact on daily functioning. Igor Grant, MD Painful peripheral neuropathy comprises multiple symptoms that can severely erode quality of life. These include allodynia (pain evoked by light stimuli that are not normally pain-evoking) and various abnormal sensations termed dysesthesias (e.g., electric shock sensations, "pins and needles," sensations of coldness or heat, numbness, and other types of uncomfortable and painful sensations). Common causes of peripheral neuropathy include diabetes, HIV/AIDS, spinal cord injuries, multiple sclerosis, and certain drugs and toxins. Commonly prescribed treatments come from drugs of the tricyclic and selective serotonin reuptake inhibitor (SSRI) antidepressant classes, anticonvulsants, opioids, and certain topical agents. Many patients receive only partial benefit from such treatments, and some either do not benefit or cannot tolerate these medications. The need for additional treatment modalities is evident. Animal studies and anecdotal human evidence have for some time pointed to the possibility that cannabis may be effective in the treatment of painful peripheral neuropathy [1]. Recently, the Center for Medicinal Cannabis Research (CMCR) at the University of Califomia [2] completed five placebo-controlled phase" clinical trials with smoked or inhaled cannabis [3-7]. Another study reported from Canada [8]. Patients included people with HIV neuropathy and other neuropathic conditions, and one study focused on a human model of neuropathic pain. Overall, the efficacy of cannabis was comparable to that of traditional agents, somewhat less than that of the tricyclics, but better than SSRls and anticonvulsants, and comparable to gabapentin (see figure 1). Number Needed to Treat* Tricycllcs 2.2 Cannabis 3.6 Gabapentin 3.7 lamotrigine 5.4 SSRls 6.7 0 2 4 6 8 Figure 1. Common analgesics for neuropathic pain. *to achieve a 30% reduction in pain . Number needed to treat (NNT) = 1/(E-P), where E is the proportion improved in experimental condition and P is the proportion improved on placebo. Example: If 60% "improve" (according to a given definition) in the experimental condition, while 30% "improve" in the placebo condition, then NNT = 1/(.6-.3) = 3.3. Data adapted from Abrams et a!. [3] and Ellis et a!. [4]. The concentrations of tetrahydrocannabinol (THC) in these studies ranged from 2 to 9 percent, with a typical concentration of 4 percent resulting in good efficacy. Side effects were modest and included light- headedness, mild difficulties in concentration and memory, tachycardia, and fatigue. Serious side effects (e.g., severe anxiety, paranoia, psychotic symptoms) were not observed. Mild cognitive changes resolved within several hours of drug administration. While these were short-term trials with limited numbers of cases, the data suggest, on balance, that cannabis may represent a reasonable altemative or adjunct to treatment of patients with serious painful peripheral neuropathy for whom other remedies have not provided fully satisfactory results. Because oral administration of cannabinoids (e.g., as dronabinol, marketed as Marinol) can result in inconsistent blood levels due to variations in absorption and first-pass metabolism effects, inhalational (or potentially sublingual spray, e.g., nabiximols, marketed as Sativex) administration remains preferred to oral administration. Cannabis as a smoked cigarette, while demonstrating efficacy, poses a number of challenges, inasmuch as it remains illegal under federal law, even though it is permitted in an increasing number of jurisdictions on physician recommendation. Figure 2 provides a schematic approach for physician decision making in jurisdictions where medicinal cannabis is permitted [9]. See figure 2 This decision tree suggests key points that a physician should consider in making a determination. In the case of a patient assumed to have persistent neuropathic pain, the first determination to be made is that the patient's signs and symptoms are indeed consistent with a diagnosis of neuropathy. Assuming a patient does not respond favorably to or cannot tolerate more standard treatments (e.g., antidepressants, anticonvulsants) and is willing to consider medicinal cannabis, the physician proceeds to compare risk and benefit. Among these considerations is whether the patient has a history of substance abuse or a serious psychiatric disorder that might be exacerbated by medicinal cannabis. Even the presence of such a risk does not necessarily preclude the use of medicinal cannabis; rather, coordination with appropriate substance abuse and psychiatric resources is necessary, and, based on that conSUltation, a risk-benefit ratio can be formulated. In patients for whom the ratio appears favorable, the physician should discuss modes of cannabis administration including oral, smoked, or vaporized. Once risks and benefits are evaluated and discussed with the patient, cannabis treatment may commence as with other psychotropic medications, with attention being paid to side effects as well as efficacy. Attention must also be paid to possible misuse and diversion, which can then trigger a decision to discontinue the treatment. In summary, there is increasing evidence that cannabis may represent a useful altemative or adjunct in the management of painful peripheral neuropathy, a condition that can markedly affect life quality. Our society should be able to find ways to separate the medical benefits of making a treatment available to improve lives when indicated from broader social policy on recreational use, marijuana legalization, and unsubstantiated fears that medicinal cannabis will lead to widespread cannabis addiction