Cannabinoids in the management of difficult to treat pain Analgesic and antihyperalgesic effects of nabilone on experimental heat pain. Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine. Cannabis in painful HIV-associated sensory neuropathy Are oral cannabinoids safe and effective in refractory neuropathic pain? Comparison of the Analgesic Effects of Dronabinol and Smoked Marijuana in Daily Marijuana Smokers Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study [Effect of the synthetic cannabinoid dronabinol on central pain in patients with multiple sclerosis--secondary publication]. Dose-dependent Effects of Smoked Cannabis on Capsaicin-induced Pain and Hyperalgesia in Healthy Volunteers Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. Cannabinoid–Opioid Interaction in Chronic Pain Sativex successfully treats neuropathic pain characterised by allodynia: A randomised, double-blind, placebo-controlled clinical trial Tetrahydrocannabinol (THC) impairs encoding but not retrieval of verbal information Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial Efficacy, tolerability and safety of cannabis‐based medicines for chronic pain management – An overview of systematic reviews Medical Marijuana: Is the Cart Before the Horse? Imipramine reduces experimental pain Lack of effect of central nervous system‐active doses of nabilone on capsaicin‐induced pain and hyperalgesia FAAH selectively influences placebo effects Short-Term Effects of Cannabinoids in Patients with HIV-1 Infection Dose-Related Modulation of Event-Related Potentials to Novel and Target Stimuli by Intravenous Δ9-THC in Humans Effects of nabilone, a synthetic cannabinoid, on postoperative pain
This article review s recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms , as well as r and omized clinical trials employing cannabinoids in pain treatment .  Tetrahydrocannabinol ( THC , Marinol ® ) and nabilone ( Cesamet ® ) are currently approved in the United States and other countries , but not for pain indications . Other synthetic cannabinoids , such as ajulemic acid , are in development . Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation . Sativex ® , a cannabis derived oromucosal spray containing equal proportions of THC ( partial CB1 receptor agonist ) and cannabidiol ( CBD , a non-euphoriant , anti-inflammatory analgesic with CB1 receptor antagonist and endocannabinoid modulating effects ) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis , and in 2007 for intractable cancer pain . Numerous r and omized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain , rheumatoid arthritis and cancer pain . An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006 . Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles . Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise OBJECTIVE In this study , we explored the analgesic and antihyperalgesic properties of a synthetic cannabinoid ( nabilone ) on experimental heat pain in men and women , as well as its effects on descending pain inhibitory systems . RESEARCH DESIGN AND METHODS A double-blind , placebo controlled , crossover study of nabilone single doses of 0.5 and 1 mg was conducted . Excitatory systems were elicited using a temporal summation test ( tonic heat pain evoked by a Peltier thermode ) administered before and after activation of descending inhibitory control ( triggered using a counter-irritation procedure ) . These tests were given before and after drug treatment . Primary outcome measures included average heat pain , temporal summation of heat pain , and drug-induced changes in the strength of descending analgesia . Possible adverse reactions were monitored throughout treatment . Seven men ( mean age = 22.5 years , SD = + /- 1.5 ) and 10 women ( mean age = 23.2 years , SD = + /- 2.8 ) completed this study . RESULTS Nabilone ( 1 mg and 0.5 mg ) did not reduce the global pain intensity experienced during tonic heat pain ( all values of p > 0.18 ) . It also failed to potentiate the strength of descending inhibitory responses ( all values of p > 43 ) . Nevertheless , at the highest dose ( 1 mg ) , and only for women , nabilone significantly ( p = 0.003 ) dampened the temporal summation experienced during the last portion of the tonic heat pulse test ( i.e. , the period of time during which temporal summation is greatest ) . This antihyperalgesic effect was not observed for men ( at either 0.5 mg or 1 mg dose ) , suggesting that the antihyperalgesic properties of cannabinoids are greater for women than for men . Adverse reactions encountered were generally mild and did not provoke the cessation of testing . CONCLUSIONS Nabilone failed to produce analgesic effects and it did not interact with descending pain inhibitory systems . However , we found that a single 1 mg dose of nabilone reduced temporal summation for women but not men . Although a titration regime and a larger sample of subjects might have provided more robust effects , these preliminary results suggest that nabilone appears effective at relieving hyperalgesic responses in women . Possible neurobiological mechanisms and clinical implication s are further discussed Evidence for an analgesic interaction between delta-9-tetrahydrocannabinol ( Delta(9)-THC ) and morphine was sought using an experimental pain model applied to normal volunteers . The study incorporated a double blinded , four treatment , four period , four sequence , crossover design . Subjects received Delta(9)-THC 5 mg orally or placebo and 90 min later morphine 0.02 mg/kg intravenously or placebo . Fifteen minutes later subjects rated the pain associated with the application of thermal stimuli to skin using two visual analog scales , one for the sensory and one for the affective aspects of pain . Among sensory responses , neither morphine nor Delta(9)-THC had a significant effect at the doses used , and there was no significant interaction between the two . Among affective responses , although neither morphine nor Delta(9)-THC had a significant effect , there was a positive analgesic interaction between the two ( p = 0.012 ) , indicating that the combination had a synergistic affective analgesic effect . The surprisingly limited reported experimental experience in humans does not support a role for Delta(9)-THC as an analgesic or as an adjunct to cannabinoid analgesia , except for our finding of synergy limited to the affective component of pain . Comparison of our results with those of others suggests that extrapolation from experimental pain models to the clinic is not likely to be a straight-forward process . Future studies of Delta(9)-THC or other cannabinoids in combination with opiates should focus upon clinical rather than experimental pain Objective : To determine the effect of smoked cannabis on the neuropathic pain of HIV-associated sensory neuropathy and an experimental pain model . Methods : Prospect i ve r and omized placebo-controlled trial conducted in the inpatient General Clinical Research Center between May 2003 and May 2005 involving adults with painful HIV-associated sensory neuropathy . Patients were r and omly assigned to smoke either cannabis ( 3.56 % tetrahydrocannabinol ) or identical placebo cigarettes with the cannabinoids extracted three times daily for 5 days . Primary outcome measures included ratings of chronic pain and the percentage achieving > 30 % reduction in pain intensity . Acute analgesic and anti-hyperalgesic effects of smoked cannabis were assessed using a cutaneous heat stimulation procedure and the heat/capsaicin sensitization model . Results : Fifty patients completed the entire trial . Smoked cannabis reduced daily pain by 34 % ( median reduction ; IQR = −71 , −16 ) vs 17 % ( IQR = −29 , 8) with placebo ( p = 0.03 ) . Greater than 30 % reduction in pain was reported by 52 % in the cannabis group and by 24 % in the placebo group ( p = 0.04 ) . The first cannabis cigarette reduced chronic pain by a median of 72 % vs 15 % with placebo ( p < 0.001 ) . Cannabis reduced experimentally induced hyperalgesia to both brush and von Frey hair stimuli ( p ≤ 0.05 ) but appeared to have little effect on the painfulness of noxious heat stimulation . No serious adverse events were reported . Conclusion : Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy . The findings are comparable to oral drugs used for chronic neuropathic pain Although cannabinoids have anti‐hyperalgesic effects in animal models of nerve injury , there are currently very few prospect i ve trials of the efficacy of cannabinoids in neuropathic pain in humans . This open label prospect i ve study investigated the safety , tolerability and analgesic benefit of oral Δ‐9‐tetrahydrocannabinol ( THC ) titrated to a maximal dosage of 25 mg/day in 8 consecutive patients with chronic refractory neuropathic pain .  Spontaneous ongoing and paroxysmal pain , allodynia and paresthesias were assessed . The sensory and affective components of pain using the McGill pain question naire , quality of life , mood , anxiety and functionality were also evaluated . Seven patients suffered from  side effects  necessitating premature arrest of the drug in 5 of them . THC ( mean dosage : 16.6 ± 6.5 mg/day ) did not induce any significant effects on ongoing and paroxysmal pain , allodynia , quality of life , anxiety/depression scores and functional impact of pain . These results do not support an overall benefit  of  THC in pain and quality of life in patients with refractory neuropathic pain Recent studies have demonstrated the therapeutic potential of cannabinoids to treat pain , yet none have compared the analgesic effectiveness of smoked marijuana to orally administered Δ9-tetrahydrocannabinol ( THC ; dronabinol ) . This r and omized , placebo-controlled , double-dummy , double-blind study compared the magnitude and duration of analgesic effects of smoked marijuana and dronabinol under well-controlled conditions using a vali date d experimental model of pain . Healthy male ( N=15 ) and female ( N=15 ) daily marijuana smokers participated in this outpatient study comparing the analgesic , subjective , and physiological effects of marijuana ( 0.00 , 1.98 , or 3.56 % THC ) to dronabinol ( 0 , 10 , or 20 mg ) . Pain response was assessed using the cold-pressor test ( CPT ) : participants immersed their left h and in cold water ( 4 ° C ) , and the time to report pain ( pain sensitivity ) and withdraw the h and from the water ( pain tolerance ) were recorded . Subjective pain and drug effect ratings were also measured as well as cardiovascular effects . Compared with placebo , marijuana and dronabinol decreased pain sensitivity ( 3.56 % ; 20 mg ) , increased pain tolerance ( 1.98 % ; 20 mg ) , and decreased subjective ratings of pain intensity ( 1.98 , 3.56 % ; 20 mg ) . The magnitude of peak change in pain sensitivity and tolerance did not differ between marijuana and dronabinol , although dronabinol produced analgesia that was of a longer duration . Marijuana ( 1.98 , 3.56 % ) and dronabinol ( 20 mg ) also increased abuse-related subjective ratings relative to placebo ; these ratings were greater with marijuana . These data indicate that under controlled conditions , marijuana and dronabinol decreased pain , with dronabinol producing longer-lasting decreases in pain sensitivity and lower ratings of abuse-related subjective effects than marijuana Neuropathic pain ( NeP ) , generated by disorders of the peripheral and central nervous system , can be particularly severe and disabling . Prevalence estimates indicate that 2 % to 3 % of the population in the developed world suffer from NeP , which suggests that up to one million Canadians have this disabling condition . Evidence -based guidelines for the pharmacological management of NeP are therefore urgently needed . R and omized , controlled trials , systematic review s and existing guidelines focusing on the pharmacological management of NeP were evaluated at a consensus meeting . Medications are recommended in the guidelines if their analgesic efficacy was supported by at least one method ologically sound , r and omized , controlled trial showing significant benefit relative to placebo or another relevant control group . Recommendations for treatment are based on degree of evidence of analgesic efficacy , safety , ease of use and cost-effectiveness .  Analgesic agents recommended for first-line treatments are certain antidepressants ( tricyclics ) and anticonvulsants ( gabapentin and pregabalin ) . Second-line treatments recommended are serotonin noradrenaline reuptake inhibitors and topical lidocaine . Tramadol and controlled-release opioid analgesics are recommended as third-line treatments for moderate to severe pain . Recommended fourth-line treatments include cannabinoids , methadone and anticonvulsants with lesser evidence of efficacy , such as lamotrigine , topiramate and valproic acid . Treatment must be individualized for each patient based on efficacy , side-effect profile and drug accessibility , including cost . Further studies are required to examine head-to-head comparisons among analgesics , combinations of analgesics , long-term outcomes , and treatment of pediatric and central Objective To compare the analgesic efficacy and side effects of the synthetic cannabinoid nabilone with those of the weak opioid dihydrocodeine for chronic neuropathic pain . Design R and omised , double blind , crossover trial of 14 weeks ’ duration comparing dihydrocodeine and nabilone . Setting Outpatient units of three hospitals in the United Kingdom . Participants 96 patients with chronic neuropathic pain , aged 23 - 84 years . Main outcome measures The primary outcome was difference between nabilone and dihydrocodeine in pain , as measured by the mean visual analogue score computed over the last 2 weeks of each treatment period . Secondary outcomes were changes in mood , quality of life , sleep , and psychometric function . Side effects were measured by a question naire . Intervention Patients received a maximum daily dose of 240 mg dihydrocodeine or 2 mg nabilone at the end of each escalating treatment period of 6 weeks . Treatment periods were separated by a 2 week washout period . Results Mean baseline visual analogue score was 69.6 mm ( range 29.4 - 95.2 ) on a 0 - 100 mm scale . 73 patients were included in the available case analysis and 64 patients in the per protocol analysis . The mean score was 6.0 mm longer for nabilone than for dihydrocodeine ( 95 % confidence interval 1.4 to 10.5 ) in the available case analysis and 5.6 mm ( 10.3 to 0.8 ) in the per protocol analysis . Side effects were more frequent with nabilone . Conclusion Dihydrocodeine provided better pain relief than the synthetic cannabinoid nabilone and had slightly fewer side effects , although no major adverse events occurred for either drug . Trial registration Current Controlled Trials IS RCT N15330757 Cannabinoids reduce allodynia/hyperalgesia in animal pain models , but few clinical studies evaluated the analgesic action in humans . We aim ed to evaluate the effect of delta-9-tetrahydrocannabinol ( dronabinol ) on central pain in MS patients . Twenty-four MS patients participated in a double-blind placebo-controlled crossover trial . Dronabinol reduced the spontaneous pain intensity significantly compared with placebo ( 4.0 ( 2.3 - 6.0 ) vs. 5.0 ( 4.0 - 6.4 ) , median ( 25th-75th percentiles ) , p = 0.02 ) . Though dronabinol 's analgesic effect is modest , its use should be evaluated considering the general difficulty in treating central pain Background : Although the pre clinical literature suggests that cannabinoids produce antinociception and antihyperalgesic effects , efficacy in the human pain state remains unclear . Using a human experimental pain model , the authors hypothesized that inhaled cannabis would reduce the pain and hyperalgesia induced by intradermal capsaicin . Methods : In a r and omized , double-blinded , placebo-controlled , crossover trial in 15 healthy volunteers , the authors evaluated concentration – response effects of low- , medium- , and high-dose smoked cannabis ( respectively 2 % , 4 % , and 8 % 9-&dgr;-tetrahydrocannabinol by weight ) on pain and cutaneous hyperalgesia induced by intradermal capsaicin . Capsaicin was injected into opposite forearms 5 and 45 min after drug exposure , and pain , hyperalgesia , tetrahydrocannabinol plasma levels , and side effects were assessed . Results : Five minutes after cannabis exposure , there was no effect on capsaicin-induced pain at any dose . By 45 min after cannabis exposure , however , there was a significant decrease in capsaicin-induced pain with the medium dose and a significant increase in capsaicin-induced pain with the high dose . There was no effect seen with the low dose , nor was there an effect on the area of hyperalgesia at any dose . Significant negative correlations between pain perception and plasma & dgr;-9-tetrahydrocannabinol levels were found after adjusting for the overall dose effects . There was no significant difference in performance on the neuropsychological tests . Conclusions : This study suggests that there is a window of modest analgesia for smoked cannabis , with lower doses decreasing pain and higher doses increasing pain CONTEXT 1',1'dimethylheptyl-Delta8-tetrahydrocannabinol-11-oic acid ( CT-3 ) , a potent analog of THC-11-oic acid , produces marked antiallodynic and analgesic effects in animals without evoking the typical effects described in models of cannabinoids . Therefore , CT-3 may be an effective analgesic for poorly controlled resistant neuropathic pain . OBJECTIVE To examine the analgesic efficacy and safety of CT-3 in chronic neuropathic pain in humans . DESIGN AND SETTING R and omized , placebo-controlled , double-blind crossover trial conducted in Germany from May-September 2002 . PARTICIPANTS Twenty-one patients ( 8 women and 13 men ) aged 29 to 65 years ( mean , 51 years ) who had a clinical presentation and examination consistent with chronic neuropathic pain ( for at least 6 months ) with hyperalgesia ( n = 21 ) and allodynia ( n = 7 ) . INTERVENTIONS Patients were r and omized to two 7-day treatment orders in a crossover design . Two daily doses of CT-3 ( four 10-mg capsules per day ) or identical placebo capsules were given during the first 4 days and 8 capsules per day were given in 2 daily doses in the following 3 days . After a washout and baseline period of 1 week each , patients crossed over to the second 7-day treatment period . MAIN OUTCOME MEASURES Visual analog scale ( VAS ) and verbal rating scale scores for pain ; vital sign , hematologic and blood chemistry , and electrocardiogram measurements ; scores on the Trail-Making Test and the Addiction Research Center Inventory-Marijuana scale ; and adverse effects . RESULTS The mean differences over time for the VAS values in the CT-3-placebo sequence measured 3 hours after intake of study drug differed significantly from those in the placebo-CT-3 sequence ( mean [ SD ] , -11.54 [ 14.16 ] vs 9.86 [ 21.43 ] ; P = .02 ) . Eight hours after intake of the drug , the pain scale differences between groups were less marked . No dose response was observed . Adverse effects , mainly transient dry mouth and tiredness , were reported significantly more often during CT-3 treatment ( mean [ SD ] difference , -0.67 [ 0.50 ] for CT-3-placebo sequence vs 0.10 [ 0.74 ] for placebo-CT-3 sequence ; P = .02 ) . There were no significant differences with respect to vital signs , blood tests , electrocardiogram , Trail-Making Test , and Addiction Research Center Inventory-Marijuana scale . No carryover or period effects were observed except on the Trail-Making Test . CONCLUSIONS In this preliminary study , CT-3 was effective in reducing  chronic neuropathic pain  compared with placebo . No major adverse effects were observed Cannabinoids and opioids share several pharmacologic properties and may act synergistically . The potential pharmacokinetics and the safety of the combination in humans are unknown . We therefore undertook a study to answer these questions . Twenty – one individuals with chronic pain , on a regimen of twice – daily doses of sustained – release morphine or oxycodone were enrolled in the study and admitted for a 5–day inpatient stay . Participants were asked to inhale vaporized cannabis in the evening of day 1 , three times a day on days 2–4 , and in the morning of day 5 . Blood sampling was performed at 12–h intervals on days 1 and 5 . The extent of chronic pain was also assessed daily . Pharmacokinetic investigations revealed no significant change in the area under the plasma concentration – time curves for either morphine or oxycodone after exposure to cannabis . Pain was significantly decreased ( average 27 % , 95 % confidence interval ( CI ) 9 , 46 ) after the addition of vaporized cannabis . We therefore concluded that vaporized cannabis augments the analgesic effects of opioids without significantly altering plasma opioid levels . The combination may allow for opioid treatment at lower doses with fewer side effects Abstract Cannabinoids are known to have analgesic properties . We evaluated the effect of oro‐mucosal sativex , ( THC : CBD ) , an endocannabinoid system modulator , on pain and allodynia , in 125 patients with neuropathic pain of peripheral origin in a five‐week , r and omised , double‐blind , placebo‐controlled , parallel design trial . Patients remained on their existing stable analgesia . A self‐titrating regimen was used to optimise drug administration . Sixty‐three patients were r and omised to receive sativex and 62 placebo .  The mean reduction in pain intensity scores ( primary outcome measure ) was greater in patients receiving sativex than placebo ( mean adjusted scores −1.48 points vs. −0.52 points on a 0–10 Numerical Rating Scale ( p = 0.004 ; 95 % CI : −1.59 , −0.32 ) . Improvements in Neuropathic Pain Scale composite score ( p = 0.007 ) , sleep NRS ( p = 0.001 ) , dynamic allodynia ( p = 0.042 ) , punctate allodynia ( p = 0.021 ) , Pain Disability Index ( p = 0.003 ) and Patient ’s Global Impression of Change ( p < 0.001 ) were similarly greater on sativex vs. placebo . Sedative and gastrointestinal side effects were reported more commonly by patients on active medication . Of all participants , 18 % on sativex and 3 % on placebo withdrew during the study . An open‐label extension study showed that the initial pain relief was maintained without dose escalation or toxicity for 52 weeks INTRODUCTION Cannabis and agonists of the brain cannabinoid receptor ( CB1R ) produce acute  memory impairments in humans . However , the extent to which cannabinoids impair the component processes of encoding and retrieval has not been established in humans . The objective of this analysis was to determine whether the administration of Δ9-Tetrahydrocannabinol ( THC ) , the principal psychoactive constituent of cannabis , impairs encoding and /or retrieval of verbal information . MATERIAL S AND METHODS Healthy subjects were recruited from the community . Subjects were administered the Rey-Auditory Verbal Learning Test ( RAVLT ) either before administration of THC ( experiment # 1 ) ( n=38 ) or while under the influence of THC ( experiment # 2 ) ( n=57 ) . Immediate and delayed recall on the RAVLT was compared . Subjects received intravenous THC , in a placebo-controlled , double-blind , r and omized manner at doses known to produce behavioral and subjective effects consistent with cannabis intoxication . RESULTS Total immediate recall , short delayed recall , and long delayed recall were reduced in a statistically significant manner only when the RAVLT was administered to subjects while they were under the influence of THC ( experiment # 2 ) and not when the RAVLT was administered prior . CONCLUSIONS THC acutely interferes with encoding of verbal memory without interfering with retrieval . These data suggest that learning information prior to the use of cannabis or cannabinoids is not likely to disrupt recall of that information . Future studies will be necessary to determine whether THC impairs encoding of non-verbal information , to what extent THC impairs memory consolidation , and the role of other cannabinoids in the memory-impairing effects of cannabis . CLINICAL TRIAL INFORMATION Cannabinoids , Neural Synchrony , and Information Processing ( THC-Gamma ) http:// clinical trials.gov/ct2/show/ study /NCT00708994 NCT00708994 Pharmacogenetics of Cannabinoid Response http:// clinical trials.gov/ct2/show/NCT00678730 NCT00678730 BACKGROUND Multiple sclerosis is associated with muscle stiffness , spasms , pain , and tremor . Much anecdotal evidence suggests that cannabinoids could help these symptoms . Our aim was to test the notion that cannabinoids have a beneficial effect on spasticity and other symptoms related to multiple sclerosis . METHODS We did a r and omised , placebo-controlled trial , to which we enrolled 667 patients with stable multiple sclerosis and muscle spasticity . 630 participants were treated at 33 UK centres with oral cannabis extract ( n=211 ) , Delta9-tetrahydrocannabinol ( Delta9-THC ; n=206 ) , or placebo ( n=213 ) . Trial duration was 15 weeks . Our primary outcome measure was change in overall spasticity scores , using the Ashworth scale . Analysis was by intention to treat . FINDINGS 611 of 630 patients were followed up for the primary endpoint . We noted no treatment effect of cannabinoids on the primary outcome ( p=0.40 ) . The estimated difference in mean reduction in total Ashworth score for participants taking cannabis extract compared with placebo was 0.32 ( 95 % CI -1.04 to 1.67 ) , and for those taking Delta9-THC versus placebo it was 0.94 ( -0.44 to 2.31 ) . There was evidence of a treatment effect on patient-reported spasticity and pain ( p=0.003 ) , with improvement in spasticity reported in 61 % ( n=121 , 95 % CI 54.6 - 68.2 ) , 60 % ( n=108 , 52.5 - 66.8 ) , and 46 % ( n=91 , 39.0 - 52.9 ) of participants on cannabis extract , Delta9-THC , and placebo , respectively . INTERPRETATION Treatment with cannabinoids did not have a beneficial effect on spasticity when assessed with the Ashworth scale . However , though there was a degree of unmasking among the patients in the active treatment groups , objective improvement in mobility and patients ' opinion of an improvement in pain suggest cannabinoids might be clinical ly useful Medicinal cannabis has already entered mainstream medicine in some countries . This systematic review ( SR ) aim ed at evaluating the efficacy , acceptability and safety of cannabis-based medicines for chronic pain management . Qualitative systematic review of SRs of r and omized controlled trials with cannabis-based medicines for chronic pain management . The Cochrane data bases of SRs , Data base of Abstract s of Review s of Effects and PubMed were search ed for SR published in the period January 2009 to January 2017 . Assessment of the method ological quality of SR was performed by the AMSTAR checklist . Out of 748 papers identified , 10 SRs met the inclusion criteria . The method ological quality was high in four and moderate in six SRs . There were inconsistent findings of four SRs on the efficacy of cannabis-based medicines in neuropathic pain and of one SR for painful spasms in multiple sclerosis . There were consistent results that there was insufficient evidence of any cannabis-based medicine for pain management in patients with rheumatic diseases ( three SRs ) and in cancer pain ( two SRs ) . Cannabis-based medicines undoubtedly enrich the possibilities of drug treatment of chronic pain conditions . It remains the responsibility of the health care community to continue to pursue rigorous study of cannabis-based medicines to provide evidence that meets the st and ard of 21st century clinical care . SIGNIFICANCE We provide an overview of systematic review s on the efficacy , tolerability and safety of cannabis-based medicines for chronic pain management . There are inconsistent findings of the efficacy of cannabinoids in neuropathic pain and painful spasms in multiple sclerosis . There are inconsistent results on tolerability and safety of cannabis-based medicines for any chronic pain There is apressingneed todevelopnewmedications formany debilitating conditions . Novel approaches based onmarijuana or its constituent cannabinoids , if proven , could be added to the armamentarium of available treatments . In this issue of JAMA , review s byWhiting et al1 and Hill2 provide detailed assessment of thepharmacology , indications , benefits , adverseeffects , and laws related tomedicalmarijuana and thecannabinoids , and the results and conclusions are consistent . There is some evidence to support the use of marijuana for nausea and vomiting related tochemotherapy , specificpain syndromes , and spasticity from multiple sclerosis . However , for most other indications that qualifyby state lawforuseofmedicalmarijuana , suchashepatitis C , Crohn disease , Parkinson disease , or Tourette syndrome , the evidence supporting its use is of poor quality . State laws vary widely regarding conditions for which marijuana is approved and thedispensable legal limit . Both review sraise important issues worthy of further discussion . First , for most qualifying conditions , approval has relied on low- quality scientific evidence , anecdotal reports , individual testimonials , legislative initiatives , and public opinion . Imagine if other drugs were approved through a similar approach . The US Food and Drug Administration ( FDA ) requires evidence from at least 2 adequately powered r and omized clinical trials before approving a drug for any specific indication . For most of the conditions that qualify for medical marijuanause , the evidence fails tomeet FDA st and ards . It has beenargued that the lackof high- quality evidence reflects the difficulty inconductingmarijuana research intheUnitedStates . If so , the federal and state governments should support and encourage such research so that high- quality evidence canbe generated to guidedecisions aboutmedicalmarijuanause for the conditions forwhich the existing evidence is either insufficient or of poor quality . Second , there are inconsistencies in how medical conditionsarequalified formedicalmarijuanausewithina state and between states . For example , in Connecticut , psoriasis and sickle cell disease but not Tourette syndrome qualify , even though the supporting evidence for all 3 conditions is uniformly of very low quality . Similarly , posttraumatic stress disorder ( PTSD ) is approvedas aqualifying condition in somebut not all US states . These differences reflect inconsistencies in evaluating and applyingcurrent evidence towarddecisionmaking about qualifying indications for medical marijuana use . Third , unlikemost FDA -approveddrugs that typicallyhave 1or2activeconstituents , marijuanaisacomplexofmorethan400 compounds including flavonoids and terpenoids and approximately 70 cannabinoids other than Δ9-tetrahydrocannabinol (THC)3.Thesecannabinoidshaveindividual , interactive , and even entourageeffects(effectsofacompoundthatareonlyappreciable inthepresenceofothercompounds)thatarenotfullyunderstood and thatcontributetotheneteffectofmarijuana . Although clinical trials forsomeof thequalifyingconditions and studies inanimalmodelsof thoseconditionshavebeenconductedwith individual cannabinoids ( eg , THCor cannabidiol [ CBD ] ) , given that marijuanahas somanyconstituents , the results of studies with individualcannabinoids(eg , THCorCBD)cannotbeextrapolated tomarijuana and vice versa . In addition , unlike FDA -approved medicationsthathavearelativelyuniformcomposition , thecompositionofcannabispreparationscanvarysubstantiallyinitscontent of THC and CBD , such that precise dosingmaybe difficult . Giventhevariablecomposition , patients willhavetoexperiment with different strains and doses to achieve the desired effects , withoutmuch input or oversight by physicians . Fourth , some individual cannabinoids are already commercially available in the form of dronabinol and nabilone . Thesedrugs are administeredorally , and somepublished data are available to guide dosing . In contrast , there are few data on dosing smoked medical marijuana for many of the qualifying medical conditions for which it is used . Fifth , while theacuteadverseeffectsofmarijuanaarequite well known , the effects of repeated exposure , aswould occur withmedicalmarijuana , need further study . Approximately 1 in 10 adult users of marijuana  develops addiction , and this number is evenhigher amongadolescents.4Tolerance and dependence with accompanying down-regulation and desensitization of type 1 cannabinoid receptors occur with repeated exposure.5 Based on this profile , marijuana dosing will have to be increased over time to achieve the same effect . A distinct withdrawal syndrome is also well recognized . There is also a small but definite risk of psychotic disorder associated with marijuana use , as well as a significant risk of symptom exacerbations and relapse in patients with an establishedpsychoticdisorder.6Thus , explicitcontraindicationssuch as schizophrenia , bipolar disorder , or substance dependence need tobe identifiedalongwith measures tominimize the likelihoodthatpersonswithcontraindicationswouldbeable toobtain medical marijuana . Perhaps US states should establish clinical follow-upprogramstomonitor long-term outcomes prospect ively , especiallynegative outcomes ( eg , newcasesofpsychosis ) in patients with contraindications . Author Audio Interview at & NA ; In a homogeneous sample of 20 healthy male students , the analgesic effects of the tricyclic antidepressant imipramine ( 100 mg ) were compared to those of the narcotic meperidine ( 150 mg ) and a further tricyclic compound with assumed analgesic properties ( fluradoline , 450 mg ) . Drugs were orally administered , using a placebo controlled , double‐blind repeated measures Latin Square design . Phasic pain was induced by intracutaneous electrical shocks with r and om intensities and interstimulus intervals . Each stimulus block consisted of 80 stimuli and lasted for 20 min . Pain estimates , somatosensory evoked cerebral potentials ( SSEPs ) and power spectral density of the electroencephalogram ( EEG ) were measured under each drug condition . Under placebo , pain ratings and SSEP amplitudes were constant within the entire session lasting for approximately 4 h.  Meperidine analgesia was evident within 30 min of drug application , reaching a maximum after about 90 min . Imipramine produced a comparable degree of pain reduction , however , with a delay of 2 h. Under both drugs , the decrease in pain ratings was accompanied by decreased amplitudes of the late components of the SSEP , as well as by a reduction in alpha activity and an enhancement of slow EEG waves . Effects of fluradoline on experimental pain could not be affirmed . These findings are discussed in terms of pain relief and decrease in vigilance The aim of the present study was to investigate the effects of nabilone on capsaicin‐induced pain and hyperalgesia , as well as on biomarkers of cannabinoid central nervous system ( CNS ) effects . A r and omized , double‐blind , placebo‐controlled , crossover study was conducted in 30 healthy male volunteers receiving single doses of nabilone ( 1 , 2 or 3 mg ) .  Pain intensity after intradermal capsaicin injections in the forearm was assessed by continuous visual analogue scale ( 0–100 mm ) . Capsaicin cream was applied to the calf to induce hyperalgesia . Primary hyperalgesia was assessed by measuring heat pain thresholds , whereas secondary hyperalgesia was assessed by measuring the area where light tactile stimulation was felt to be painful . Pain and hyperalgesia were measured at baseline and 2–3.5 h after dosing . The CNS effects were assessed at baseline and up to 24 h after dosing using visual analogue mood scales for feeling ‘ stimulated ’ , ‘ anxious ’ , ‘ se date d ’ and ‘ down ’ . Plasma sample s for pharmacokinetic analysis were obtained up to 24 h after drug administration . Nabilone did not significantly attenuate either ongoing pain or primary or secondary hyperalgesia , whereas dose‐dependent CNS effects were observed from 1.5 to 6 h after dosing , being maximal at 4–6 h. Plasma concentrations of nabilone and its metabolite carbinol were maximal 1–2 h after dosing . Adverse events ( AE ) were common on nabilone treatment . Four subjects withdrew due to pronounced CNS AE ( anxiety , agitation , altered perception , impaired consciousness ) . Although nabilone had marked CNS effects , no analgesic or antihyperalgesic effects were observed Endogenous opioid and cannabinoid systems are thought to act synergistically regulating antinociceptive and reward mechanisms . To further underst and the human implication s of the interaction between these two systems , we investigated the role of the common , functional missense variant Pro129Thr of the gene coding fatty acid amide hydrolase ( FAAH ) , the major degrading enzyme of endocannabinoids , on psychophysical and neurotransmitter ( dopaminergic , opioid ) responses to pain and placebo-induced analgesia in humans . FAAH Pro129/Pro129 homozygotes , who constitute nearly half of the population , reported higher placebo analgesia and more positive affective states immediately and 24 h after placebo administration ; no effects on pain report in the absence of placebo were observed . Pro129/Pro129 homozygotes also showed greater placebo-induced μ-opioid , but not D2/3 dopaminergic , enhancements in neurotransmission in regions known involved in placebo effects . These results show that a common genetic variation affecting the function of the cannabinoid system is serving as a probe to demonstrate the involvement of cannabinoid and opioid transmitters on the formation of placebo effects Context Because the same systems metabolize cannabinoids and protease inhibitors , cannabinoids might alter viral loads in HIV-infected patients taking protease inhibitors . Contribution In this r and omized trial , 62 HIV-infected patients taking indinavir or nelfinavir  received a marijuana cigarette , dronabinol capsule , or placebo capsule three times daily for 21 days . Half of the patients in all three groups had undetectable viral loads during the study , and average changes in viral load with marijuana and dronabinol , relative to placebo , were small . Caution s The findings of no large harmful effects on viral loads with either smoked or oral cannabinoids need to be confirmed in larger and longer trials . The Editors Marijuana has been smoked for medicinal purpose s for centuries ( 1 ) . Introduced into western medicine in 1842 , marijuana was used to treat various illnesses on the basis of its purported analgesic , anticonvulsant , sedative , hypnotic , and antispasmodic properties . With the passage of the Marihuana Tax Act in 1937 , use of marijuana as a therapeutic agent in the United States waned until the substance was removed from the U.S. Pharmacopoeia in 1942 . The Controlled Substances Act of 1970 placed marijuana in the Schedule I category along with other substances deemed to have no medicinal value and high potential for abuse . In 1986 , the U.S. Food and Drug Administration approved a synthetic , oral form of marijuana 's main psychoactive component , delta-9-tetrahydrocannabinol ( dronabinol , Marinol , Roxane Laboratories , Columbus , Ohio ) , for treating chemotherapy-induced nausea and vomiting ( 2 - 5 ) . A r and omized , controlled trial demonstrated that dronabinol increased self-reported appetite but not weight in patients with AIDS-related wasting syndrome ; these findings led to an expansion of the labeling indication for this use in 1992 ( 6 , 7 ) . Before the advent of highly active antiretroviral therapy in the 1990s , many patients infected with HIV-1 experienced wasting as a preterminal manifestation of the disease ( 8) . Patients with AIDS-related wasting syndrome often reported that they preferred smoked marijuana to dronabinol because it was easier to titrate the dose to achieve the desired effect ; smoked marijuana delivers cannabinoids to the bloodstream much more rapidly than dronabinol ( 9 ) . By the mid-1990s , cannabis buyers ' clubs in the San Francisco Bay area were reportedly selling marijuana to 11 000 patients with HIV infection ( 10 - 12 ) . With the increased availability of protease inhibitorcontaining antiretroviral regimens in the mid-1990s , the incidence of AIDS-related wasting syndrome decreased markedly , as did most of the other late-stage opportunistic manifestations of advanced HIV disease ( 13 - 15 ) . Protease inhibitors , which can inhibit or stimulate the hepatic cytochrome P-450 enzyme system , are subject to many significant drugdrug interactions with other agents used in treating HIV infection and its complications ( 16 , 17 ) . The potential for a drugdrug interaction between protease inhibitors and marijuana is worrisome since many HIV-infected patients continue to smoke marijuana as an appetite stimulant or to decrease nausea associated with their antiretroviral therapy ( 18 , 19 ) . The likelihood of such an interaction is supported by the facts that cannabinoids are metabolized by some of the same cytochrome P-450 enzyme isoforms that metabolize the more widely prescribed protease inhibitors and that tetrahydrocannabinol has been shown to inhibit the metabolism of other drugs ( 20 - 23 ) . Although few recent clinical trials have evaluated the potential therapeutic effects of smoked marijuana , significant progress has been made in underst and ing the pharmacology of cannabinoids in humans . Of the two cannabinoid receptors identified , CB1 ( found mainly in cells of the central nervous system ) is thought to be responsible for the neurologic and behavioral effects of marijuana ( 24 , 25 ) . The identification of a CB2 receptor , found predominantly on B lymphocytes and natural killer cells , suggests that cannabinoids may also affect the immune response . Some studies suggest that marijuana can impair the immune system through B-lymphocyte modulation , tumor necrosis factor inhibition , or changes in the phenotype and function of circulating lymphocytes ( 26 - 29 ) . The hallmark of successful antiretroviral therapy is sustained suppression of HIV RNA levels associated with increasing CD4 + cell counts ( 30 - 32 ) . Considering the potential for both a protease inhibitorcannabinoid interaction and an effect of smoked marijuana on the immune system , we design ed a study to determine the safety or toxicity profile of cannabinoids ( smoked and oral ) in persons with HIV infection . We chose HIV RNA levels as our primary outcome because an intervention that interacted unfavorably with either the antiretroviral agent pharmacokinetics or the immune system directly could cause a perturbation of viral suppression . We report the overall safety results of this r and omized , controlled inpatient clinical trial . Methods Study Group Study participants were recruited by referrals from local physicians and advertisements in newspapers . Volunteers from across the country telephoned to determine whether they might be eligible to participate . Participants were required to be at least 18 years of age , have documented HIV infection , and be receiving a stable antiretroviral treatment regimen of either indinavir ( Crixivan , Merck & Co. , Inc. , North Wales , Pennsylvania ) or nelfinavir ( Viracept , Agouron Pharmaceuticals , Inc. , La Jolla , California ) for at least 8 weeks before enrollment . When enrolled , participants who had been taking the recently recommended dose of nelfinavir  , 1250 mg twice daily , were switched to 750 mg three times daily for consistency of our pharmacokinetic evaluations ( 33 ) . No additional protease inhibitors were allowed for the duration of the study . Participants were also required to have a stable viral load , defined as less than a threefold ( 0.5 log10 ) change in HIV RNA level for the 16 weeks before enrollment . All participants were required to have previous experience smoking marijuana ( defined as six or more times ) to ensure that they knew how to inhale and what neuropsychiatric effects to expect . The institutional review board of the University of California , San Francisco , approved the study , and signed , informed consent was obtained from each participant before enrollment . Exclusion criteria included any active opportunistic infection or malignant condition requiring acute treatment , unintentional loss of 10 % or more of body weight during the previous 6 months , current substance dependence ascertained by completion of a confidential drug screening form and an alcohol screening form , methadone maintenance , use of tobacco or cannabinoids ( smoked or oral ) within 30 days of enrollment , history of serious pulmonary disease , pregnancy , or stage II or higher AIDS dementia complex . Laboratory exclusion criteria were hematocrit less than 0.25 and elevation of hepatic aminotransferase levels to greater than five times the upper limit of normal . Therapeutic exclusions were concurrent use within the past 8 weeks of anabolic hormones , prednisone , interleukin-2 , or other agents known to alter immune system function . Study Medications The National Institute on Drug Abuse provided prerolled marijuana cigarettes , weighing on average 0.9 g and containing 3.95 % delta-9-tetrahydrocannabinol . These cigarettes were kept in a locked and alarmed freezer until they were dispensed to a locked freezer in the General Clinical Research Center at the San Francisco General Hospital , where the inpatient study was conducted . The frozen marijuana cigarettes required rehydration overnight in a humidifier . Participants r and omly assigned to the smoked marijuana group were housed in a room with a fan ventilating to the outside . To maximize st and ardization of inhaled doses , research staff monitored participants while they followed the uniform puff procedure outlined by Foltin and colleagues ( 34 ) . Research staff weighed the marijuana cigarettes immediately before and after they were administered to participants and returned all leftover material to the pharmacy . Study participants smoked up to three complete marijuana cigarettes daily , as tolerated , 1 hour before meals . Study participants were r and omly assigned in a double-blind fashion to the oral regimens , which were given on the same schedule as the smoked marijuana . Research staff observed participants taking all treatments . Research Design and Procedures Study clinicians admitted study participants to the General Clinical Research Center for a 4-day lead-in period to obtain baseline variables . A urine sample obtained on the day of admission ( day 4 ) had to be negative for tetrahydrocannabinol . The second phase of the trial was a 21-day intervention period beginning with r and om assignment of treatments on day 0 . Patients were stratified by protease inhibitor ( indinavir or nelfinavir ) and then allocated with equal probability in blocks of 12 to the study agents ( marijuana , dronabinol , and placebo ) . The statistician generated the r and om allocation sequences , and the pharmacists maintained the sequences in a secure location and distributed the assignments to the study coordinator on day 0 . Study participants were not permitted to have visitors or to leave the General Clinical Research Center unless accompanied by research personnel during the 25-day study . All clinical laboratory tests and study procedures were obtained or performed in the center . Patients were weighed on the same calibrated scale each morning while wearing a hospital gown . Baseline blood specimens were collected on days 4 and 0 to examine within-participant variation in HIV RNA level in the absence of experimental therapies . Follow-up specimens were obtained on days 2 , 5 , 8 , 11 , 14 , 17 , 19 , and 21 . Sample s were stored at 70 C and batch-tested for HIV RNA at the end Cannabinoids induce a host of perceptual alterations and cognitive deficits in humans . However , the neural correlates of these deficits have remained elusive . The current study examined the acute , dose-related effects of delta-9-tetrahydrocannabinol ( Δ9-THC ) on psychophysiological indices of information processing in humans . Healthy subjects ( n=26 ) completed three test days during which they received intravenous Δ9-THC ( placebo , 0.015 and 0.03 mg/kg ) in a within-subject , double-blind , r and omized , cross-over , and counterbalanced design . Psychophysiological data ( electroencephalography ) were collected before and after drug administration while subjects engaged in an event-related potential ( ERP ) task known to be a valid index of attention and cognition ( a three-stimulus auditory ‘ oddball ’ P300 task ) . Δ9-THC dose-dependently reduced the amplitude of both the target P300b and the novelty P300a . Δ9-THC did not have any effect on the latency of either the P300a or P300b , or on early sensory-evoked ERP components preceding the P300 ( the N100 ) . Concomitantly , Δ9-THC induced psychotomimetic effects , perceptual alterations , and subjective ‘ high ’ in a dose-dependent manner . Δ9-THC -induced reductions in P3b amplitude correlated with Δ9-THC-induced perceptual alterations . Lastly , exploratory analyses examining cannabis use status showed that whereas recent cannabis users had blunted behavioral effects to Δ9-THC , there were no dose-related effects of Δ9-THC on P300a/b amplitude between cannabis-free and recent cannabis users . Overall , these data suggest that at doses that produce behavioral and subjective effects consistent with the known properties of cannabis , Δ9-THC reduced P300a and P300b amplitudes without altering the latency of these ERPs . Cannabinoid agonists may therefore disrupt cortical processes responsible for context updating and the automatic orientation of attention , while leaving processing speed and earlier sensory ERP components intact . Collectively , the findings suggest that CB1R systems modulate top-down and bottom-up processing Purpose Cannabinoids have been shown to have analgesic properties in animal studies , but a potential role for these drugs in acute pain management has not been established . It was hypothesized that nabilone , an oral cannabinoid synthetic tetrahydrocannabinol analogue , decreases morphine consumption , pain scores , nausea and vomiting following major surgery . Methods A double-blind , r and omized , placebo-controlled , parallel-group pilot trial compared the effects of two different doses , 1 mg ( n = 11 ) and 2 mg ( n = 9 ) of nabilone , ketoprofen 50 mg ( n = 11 ) or placebo ( n = 10 ) , given at eight-hour intervals for 24 hr . Outcomes included morphine consumption , pain scores and emesis after major surgery . Secondary outcomes included patient tolerability of the study medication . Results Forty-one patients ( mean age 52 ± 2 yr ) undergoing gynecologic ( 46 % ) , orthopedic ( 44 % ) , or other ( 10 % ) surgery were recruited . Cumulative 24-hr morphine consumption was not different between the four groups , but pain scores at rest and on movement were significantly higher in the 2 mg nabilone group compared to the other groups . There were no significant differences between groups with respect to episodes of nausea and vomiting , quality of sleep , sedation , euphoria , pruritus , or the number and severity of adverse events . No serious adverse event was recorded . Conclusions Contrary to the main hypothesis , high dose nabilone in the presence of morphine patient controlled analgesia is associated with an increase in pain scores in patients undergoing major surgery . RésuméObjectifLes propriétés analgésiques des cannabinoïdes ont été démontrées chez des animaux , mais leur rôle possible sur le contrôle de la douleur aiguë n’a pas été établi . Notre hypothèse voulait que la nabilone , analogue synthétique oral du cannabinoïde tétrahydrocannabinol , diminue la consommation de morphine , les scores de douleur , les nausées et les vomissements à la suite d’une opération chirurgicale majeure . MéthodeDans une étude pilote de groupes parallèles , r and omisée , à double insu et contrôlée contre placebo , les effets de deux doses de nabilone , 1 mg ( n = 11 ) et 2 mg ( n = 9 ) , de 50 mg de kétoprofène ( n = 11 ) ou d’un placebo  ( n = 10 ) , administrés à 8 h d’intervalle pendant 24 h , ont été comparés . La consommation de  morphine , les scores de douleur et les vomissements ont été notés après une chirurgie majeure . Les effets de la médication sur le patient étaient également étudiés . RésultatsQuarante et un patients ( moyenne d’âge de 52 ± 2 ans ) subissant une intervention gynécologique ( 46 % ) , orthopédique ( 44 % ) ou autre ( 10 % ) ont été recrutés . La consommation cumulative de morphine  sur 24 h était similaire dans les quatre groupes , mais les scores de douleur au repos et au mouvement ont été significativement plus élevés dans le groupe nabilone 2 mg . Aucune différence intergroupe significative n’est apparue quant aux épisodes de nausées et de vomissements , la qualité du sommeil , la sédation , l’euphorie , le prurit ou le nombre et la sévérité des événements indésirables . Aucun incident sérieux n’a été enregistré . Conclusion Contrairement à notre hypothèse , une forte dose de nabilone , en présence de morphine administrée comme analgésie auto-contrôlée , est associée à une hausse des scores de douleur chez les patients qui subissent une chirurgie majeure
Conclusions and Relevance Cannabinoid drugs may prevent the onset of pain by producing small increases in pain thresholds but may not reduce the intensity of experimental pain already being experienced ; instead , cannabinoids may make experimental pain feel less unpleasant and more tolerable , suggesting an influence on affective processes .
Cannabis-induced improvements in pain-related negative affect may underlie the widely held belief that cannabis relieves pain
Importance Cannabinoid drugs are widely used as analgesics , but experimental pain studies have produced mixed findings .
The analgesic properties of cannabinoids remain unclear .
Objective To conduct a systematic review and meta- analysis of the association between cannabinoid drug administration and experimental pain outcomes in studies of healthy adults .