Cannabinoids in the management of difficult to treat pain Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial Are oral cannabinoids safe and effective in refractory neuropathic pain? A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. Nabilone for the treatment of pain in fibromyalgia. [Effect of the synthetic cannabinoid dronabinol on central pain in patients with multiple sclerosis--secondary publication]. An open-label extension study to investigate the long-term safety and tolerability of THC/CBD oromucosal spray and oromucosal THC spray in patients with terminal cancer-related pain refractory to strong opioid analgesics. Cannabinoid–Opioid Interaction in Chronic Pain Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study Efficacy, tolerability and safety of cannabis‐based medicines for chronic pain management – An overview of systematic reviews Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine. Medical Marijuana: Is the Cart Before the Horse? Safety, tolerability, and efficacy of orally administered cannabinoids in MS FAAH selectively influences placebo effects Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up The Effects of Nabilone on Sleep in Fibromyalgia: Results of a Randomized Controlled Trial Potency trends of Δ9-tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the Netherlands: 2005-15. An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain The Subjective Psychoactive Effects of Oral Dronabinol Studied in a Randomized, Controlled Crossover Clinical Trial for Pain MUltiple Sclerosis and Extract of Cannabis: results of the MUSEC trial Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo‐controlled Study Analgesic and antihyperalgesic effects of nabilone on experimental heat 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 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 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 CONTEXT Neuropathic pain caused by chemotherapy limits dosing and duration of potentially life-saving anti-cancer treatment and impairs quality of life . Chemotherapeutic neuropathy responds poorly to conventional treatments , and there is an urgent medical need for new treatments . Recent pre clinical studies demonstrate that cannabinoid agonists suppress established chemotherapy-evoked neuropathy . OBJECTIVES This was a pilot trial to begin to investigate a currently available cannabinoid agent , nabiximols ( oral mucosal spray containing cannabinoids ) , in the treatment of chemotherapy-induced neuropathic pain . METHODS A r and omized , placebo-controlled crossover pilot study was done in 16 patients with established chemotherapy-induced neuropathic pain . A 0 - 10 point numeric rating scale for pain intensity ( NRS-PI ) was used as the primary outcome measure . RESULTS When examining the whole group , there was no statistically significant difference between the treatment and the placebo groups on the NRS-PI . A responder analysis demonstrated that there were five participants who reported a two-point or greater reduction in pain that trended toward statistical significance and the number needed to treat was five . CONCLUSION Chemotherapy-induced neuropathic pain is particularly resistant to currently available treatments . This pilot trial found a number needed to treat of five and an average decrease of 2.6 on an 11-point NRS-PI in five " responders " ( as compared with a decrease of 0.6 with placebo ) and supports that it is worthwhile to study nabiximols in a full r and omized , placebo-controlled trial of chemotherapy-induced neuropathic pain UNLABELLED A r and omized , double-blind , placebo-controlled trial was conducted to determine the benefit of nabilone in pain management and quality of life improvement in 40 patients with fibromyalgia . After a baseline assessment , subjects were titrated up on nabilone , from 0.5 mg PO at bedtime to 1 mg BID over 4 weeks or received a corresponding placebo . At the 2- and 4-week visits , the primary outcome measure , visual analog scale ( VAS ) for pain , and the secondary outcome measures , number of tender points , the average tender point pain threshold , and the Fibromyalgia Impact Question naire ( FIQ ) , were evaluated . After a 4-week washout period , subjects returned for re assessment of the outcome measures . There were no significant differences in population demographics between groups at baseline . There were significant decreases in the VAS ( -2.04 , P < .02 ) , FIQ ( -12.07 , P < .02 ) , and anxiety ( -1.67 , P < .02 ) in the nabilone treated group at 4 weeks . There were no significant improvements in the placebo group . The treatment group experienced more side effects per person at 2 and 4 weeks ( 1.58 , P < .02 and 1.54 , P < .05 ) , respectively . Nabilone appears to be a beneficial , well-tolerated treatment option for fibromyalgia patients , with significant benefits in pain relief and functional improvement . PERSPECTIVE To our knowledge , this is the first r and omized , controlled trial to assess the benefit of nabilone , a synthetic cannabinoid , on pain reduction and quality of life improvement in patients with fibromyalgia . As nabilone improved symptoms and was well-tolerated , it may be a useful adjunct for pain management in fibromyalgia 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 CONTEXT Chronic pain in patients with advanced cancer poses a serious clinical challenge . The Δ9-tetrahydrocannabinol (THC)/cannabidiol ( CBD ) oromucosal spray ( U.S. Adopted Name , nabiximols ; Sativex ( ® ) ) is a novel cannabinoid formulation currently undergoing investigation as an adjuvant therapy for this treatment group . OBJECTIVES This follow-up study investigated the long-term safety and tolerability of THC/CBD spray and THC spray in relieving pain in patients with advanced cancer . METHODS In total , 43 patients with cancer-related pain experiencing inadequate analgesia despite chronic opioid dosing , who had participated in a previous three-arm ( THC/CBD spray , THC spray , or placebo ) , two-week parent r and omized controlled trial , entered this open-label , multicenter , follow-up study . Patients self-titrated THC/CBD spray ( n=39 ) or THC spray ( n=4 ) to symptom relief or maximum dose and were regularly review ed for safety , tolerability , and evidence of clinical benefit . RESULTS The efficacy end point of change from baseline in mean Brief Pain Inventory-Short Form scores for " pain severity " and " worst pain " domains showed a decrease ( i.e. , improvement ) at each visit in the THC/CBD spray patients . Similarly , the European Organization for Research and Treatment of Cancer Quality of Life Question naire-C30 scores showed a decrease ( i.e. , improvement ) from baseline in the domains of insomnia , pain , and fatigue . No new safety concerns associated with the extended use of THC/CBD spray arose from this study . CONCLUSION This study showed that the long-term use of THC/CBD spray was generally well tolerated , with no evidence of a loss of effect for the relief of cancer-related pain with long-term use . Furthermore , patients who kept using the study medication did not seek to increase their dose of this or other pain-relieving medication over time , suggesting that the adjuvant use of cannabinoids in cancer-related pain could provide useful benefit 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 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 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 UNLABELLED Patients with advanced cancer who have pain that responds poorly to opioid therapy pose a clinical challenge . Nabiximols ( Nabiximols is the U.S. Adopted Name [ USAN ] for Sativex [ GW Pharma Ltd , Wiltshire , U.K. ] , which does not yet have an INN ) , a novel cannabinoid formulation , is undergoing investigation as add-on therapy for this population . In a r and omized , double-blind , placebo-controlled , grade d-dose study , patients with advanced cancer and opioid-refractory pain received placebo or nabiximols at a low dose ( 1 - 4 sprays/day ) , medium dose ( 6 - 10 sprays/day ) , or high dose ( 11 - 16 sprays/day ) . Average pain , worst pain and sleep disruption were measured daily during 5 weeks of treatment ; other question naires measured quality of life and mood .  A total of 360 patients were r and omized ; 263 completed . There were no baseline differences across groups . The 30 % responder rate primary analysis was not significant for nabiximols versus placebo ( overall P = .59 ) . A secondary continuous responder analysis of average daily pain from baseline to end of study demonstrated that the proportion of patients reporting analgesia was greater for nabiximols than placebo overall ( P = .035 ) , and specifically in the low-dose ( P = .008 ) and medium-dose ( P = .039 ) groups . In the low-dose group , results were similar for mean average pain ( P = .006 ) , mean worst pain ( P = .011 ) , and mean sleep disruption ( P = .003 ) . Other question naires showed no significant group differences . Adverse events were dose-related and only the high-dose group compared unfavorably with placebo . This study supports the efficacy and safety of nabiximols at the 2 lower-dose levels and provides important dose information for future trials . PERSPECTIVE Nabiximols , a novel cannabinoid formulation , may be a useful add-on analgesic for patients with opioid-refractory cancer pain . A r and omized , double-blind , placebo-controlled , grade d-dose study demonstrated efficacy and safety at low and medium doses 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 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 Abstract —The authors conducted a r and omized , double-blind , placebo-controlled , twofold crossover study in 16 patients with MS who presented with severe spasticity to investigate safety , tolerability , and efficacy of oral & Dgr;9-Tetrahydrocannabinol ( THC ) and Cannabis sativa plant extract . Both drugs were safe , but adverse events were more common with plant-extract treatment . Compared with placebo , neither THC nor plant-extract treatment reduced spasticity . Both THC and plant-extract treatment worsened the participant ’s global impression 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 Objective : To test the effectiveness and long term safety of cannabinoids in multiple sclerosis ( MS ) , in a follow up to the main Cannabinoids in Multiple Sclerosis ( CAMS ) study . Methods : In total , 630 patients with stable MS with muscle spasticity from 33 UK centres were r and omised to receive oral Δ9-tetrahydrocannabinol ( Δ9-THC ) , cannabis extract , or placebo in the main 15 week CAMS study . The primary outcome was change in the Ashworth spasticity scale . Secondary outcomes were the Rivermead Mobility Index , timed 10 metre walk , UK Neurological Disability Score , postal Barthel Index , General Health Question naire-30 , and a series of nine category rating scales . Following the main study , patients were invited to continue medication , double blinded , for up to12 months in the follow up study reported here . Results : Intention to treat analysis of data from the 80 % of patients followed up for 12 months showed evidence of a small treatment effect on muscle spasticity as measured by change in Ashworth score from baseline to 12 months ( Δ9-THC mean reduction 1·82 ( n = 154 , 95 % confidence interval ( CI ) 0.53 to 3.12 ) , cannabis extract 0.10 ( n = 172 , 95 % CI −0.99 to 1.19 ) , placebo −0.23 ( n = 176 , 95 % CI −1.41 to 0.94 ) ; p = 0.04 unadjusted for ambulatory status and centre , p = 0.01 adjusted ) . There was suggestive evidence for treatment effects of Δ9-THC on some aspects of disability . There were no major safety concerns . Overall , patients felt that these drugs were helpful in treating their disease . Conclusions : These data provide limited evidence for a longer term treatment effect of cannabinoids . A long term placebo controlled study is now needed to establish whether cannabinoids may have a role beyond symptom amelioration in MS BACKGROUND : Sleep disorders affect many patients with chronic pain conditions . Cannabis has been reported by several patient population s to help sleep . We evaluated the safety and efficacy of nabilone , a synthetic cannabinoid , on sleep disturbance in fibromyalgia ( FM ) , a disease characterized by widespread chronic pain and insomnia . METHODS : We conducted a r and omized , double-blind , active-control , equivalency crossover trial to compare nabilone ( 0.5–1.0 mg before bedtime ) to amitriptyline ( 10–20 mg before bedtime ) in patients with FM with chronic insomnia . Subjects received each drug for 2 wk with a 2-wk washout period . The primary outcome was sleep quality , measured by the Insomnia Severity Index and the Leeds Sleep Evaluation Question naire . Secondary outcomes included pain , mood , quality of life , and adverse events ( AEs ) . RESULTS : Thirty-one subjects were enrolled and 29 completed the trial ( 26 women , mean age 49.5 yr ) . Although sleep was improved by both amitriptyline and nabilone , nabilone was superior to amitriptyline ( Insomnia Severity Index difference = 3.2 ; 95 % confidence interval = 1.2–5.3 ) . Nabilone was marginally better on the restfulness ( Leeds Sleep Evaluation Question naire difference = 0.5 [ 0.0–1.0 ] ) but not on wakefulness ( difference = 0.3 [ −0.2 to 0.8 ] ) . No effects on pain , mood , or quality of life were observed . AEs were mostly mild to moderate and were more frequent with nabilone . The most common AEs for nabilone were dizziness , nausea , and dry mouth . CONCLUSIONS : Nabilone is effective in improving sleep in patients with FM and is well tolerated . Low-dose nabilone given once daily at bedtime may be considered as an alternative to amitriptyline . Longer trials are needed to determine the duration of effect and to characterize long-term safety BACKGROUND AND AIMS Between 2000 and 2005 the average percentage of Δ(9 ) -tetrahydrocannabinol ( THC ) in marijuana as sold in Dutch coffeeshops has increased substantially ; the potency of domestic products ( Nederwiet and Nederhasj ) has particularly increased . In contrast with imported marijuana , Nederwiet hardly contained any cannabidiol ( CBD ) , a cannabinoid that is thought to offset some of the adverse effects of THC . In 2005 , the THC content in Nederwiet was significantly lower than in 2004 . This study investigates the further decrease or increase of cannabinoids in these cannabis products . METHODS From 2005 to 2015 five different cannabis products were bought anonymously in 50 coffeeshops that were selected r and omly each year from all coffeeshops in the Netherl and s. A total of 2126 cannabis sample s were bought , consisting of 664 Nederwiet sample s ( most popular ) , 537 Nederwiet sample s ( supposed strongest varieties ) , 183 imported herbal cannabis sample s , 140 sample s of  cannabis resin made of Nederwiet and 602 sample s of imported cannabis resin . All sample s were analysed chemically for their THC , CBD and cannabinol ( CBN ) content . RESULTS Between 2005 and 2015 , the mean potencies of the most popular and the strongest Nederwiet and of imported cannabis resin were 16.0±4.0 % , 17.0±3,9 % and 16.5±6.3 % , respectively . Imported herbal cannabis ( 6.5±3.5 % ) and cannabis resin made from Nederwiet ( 30.2±16.4 % ) contained , respectively , less ( β=-10.0 , P<0.001 ) and more ( β=13.7 , P<0.001 ) THC than imported cannabis resin . Linear regression models were used to study the trends in THC of the different cannabis products over time . A marginal , but significant ( P<0.001 ) , overall decline of THC per year of 0.22 % was found in all cannabis products . However , no significant difference was found between the five products in the THC linear trajectories across time . Of all the cannabis products , only imported cannabis resin contained a relatively high CBD/THC ratio ( median 0.42 ) . CONCLUSION The average tetrahydrocannabinol ( THC ) content of the most popular herbal cannabis products in the Netherl and s has decreased slightly since 2005 . The popular Nederwiet type still has a relatively high THC to cannabidiol ratio TOC summary This enriched‐enrollment , r and omized , double‐blind , placebo‐controlled , flexible‐dose adjuvant study demonstrated that nabilone provided improvements in pain , anxiety , quality of life and patient satisfaction for patients with diabetic neuropathic pain . ABSTRACT Cannabinoids are emerging as potential options for neuropathic pain treatment . This study evaluated an oral cannabinoid , nabilone , in the treatment of refractory human diabetic peripheral neuropathic pain ( DPN ) . We performed a single‐center , r and omized , double‐blind , placebo‐controlled , flexible‐dose study with an enriched enrolment r and omized withdrawal design . DPN subjects with a pain score ⩾4 ( 0‐10 scale ) continued regular pain medications and were administered single‐blinded adjuvant nabilone for 4 weeks . Subjects achieving ⩾30 % pain relief ( 26/37 ) were then r and omized and treated with either flexible‐dose nabilone 1‐4 mg/day ( n = 13 ) or placebo ( n = 13 ) in a further 5‐week double‐blind treatment period , with 30 % ( 11/37 ) of subjects deemed run‐in‐phase nabilone nonresponders . For nabilone run‐in‐phase responders , there was an improvement in the change in mean end‐point neuropathic pain  vs placebo ( mean treatment reduction of 1.27 ; 95 % confidence interval 2.29‐0.25 , P = 0.02 ) , with an average nabilone dose at end point of 2.9 ± 1.1 mg/day , and improvements from baseline for the anxiety subscale of the Hospital Anxiety and Depression Scale , the Medical Outcomes Study sleep scale problems index , and the European Quality of Life‐5‐Domains index score ( each P < 0.05 ) . Nabilone run‐in‐phase responders reported greater global end‐point improvement with nabilone than with placebo ( 100 % vs 31 % ; P < 0.05 ) . Medication‐related confusion led to discontinuation in 2/37 subjects during single‐blind nabilone treatment . Potential unmasking occurred in 62 % of both groups . Flexible‐dose nabilone 1‐4 mg/day was effective in relieving DPN symptoms , improving disturbed sleep , quality of life , and overall patient status . Nabilone was well tolerated and successful as adjuvant in patients with DPN Background : Many cannabinoid medications are approved in North America or in phase III trials , such as dronabinol , nabilone , or nabiximols . Little is known about their subjective psychoactive effects when used for pain management . We hypothesized that when used for pain , dronabinol has psychoactive effects in a dose-response relationship , whose peak effects are comparable with smoking marijuana . Methods : This was a r and omized controlled trial of single dose placebo , 10 or 20 mg dronabinol in 30 chronic noncancer pain patients taking opioids and not using marijuana . Participants completed the Addiction Research Center Inventory ( ARCI ) hourly for 8 hours during 3 monitored sessions . Comparison sample was the ARCI ratings in participants with no pain ( N=20 ) , monitored every 30 minutes after smoking a 1.99 % THC ( low ) and a 3.51 % ( high strength ) marijuana cigarette . Results : The 10 and 20 mg dronabinol doses had significantly elevated scores over time on 4/5 subscales versus placebo ( P<0.05 ) . Average daily morphine use , total pain relief ( TOTPAR ) , age , sex , and baseline pain level were not significant covariates . ARCI peak effects at 2 hours were similar to peak effects of smoked marijuana at 30 minutes ( P=0.80 , 10 mg = low strength , 20 mg = high strength ) . Conclusions : In pain patients , oral dronabinol has similar psychoactive effects to smoking marijuana . This risk must be considered in any decision to prescribe cannabinoid medications for pain Objective Multiple sclerosis ( MS ) is associated with chronic symptoms , including muscle stiffness , spasms , pain and insomnia . Here we report the results of the Multiple Sclerosis and Extract of Cannabis ( MUSEC ) study that aim ed to substantiate the patient based findings of previous studies . Patients and methods Patients with stable MS at 22 UK centres were r and omised to oral cannabis extract ( CE ) ( N=144 ) or  placebo ( N=135 ) , stratified by centre , walking ability and use of antispastic medication . This double blind , placebo controlled , phase III study had a screening period , a 2 week dose titration phase from 5 mg to a maximum of 25 mg of tetrahydrocannabinol daily and a 10 week maintenance phase . The primary outcome measure was a category rating scale ( CRS ) measuring patient reported change in muscle stiffness from baseline . Further CRSs assessed body pain , spasms and sleep quality . Three vali date d MS specific patient reported outcome measures assessed aspects of spasticity , physical and psychological impact , and walking ability . Results The rate of relief from muscle stiffness after 12 weeks was almost twice as high with CE than with placebo ( 29.4 % vs 15.7 % ; OR 2.26 ; 95 % CI 1.24 to 4.13 ; p=0.004 , one sided ) . Similar results were found after 4 weeks and 8 weeks , and also for all further CRSs . Results from the MS scales supported these findings . Conclusion The study met its primary objective to demonstrate the superiority of CE over placebo in the treatment of  muscle stiffness in MS . This was supported by results for secondary efficacy variables . Adverse events in participants treated with CE were consistent with the known side effects of cannabinoids . No new safety concerns were observed . Trial registration number NCT00552604 BACKGROUND & AIMS Delta‐9‐tetrahydrocannabinol ( THC ) is the most abundant cannabinoid from the plant Cannabis sativa . There is only equivocal evidence that THC has analgesic effects . We performed a phase 2 controlled trial to evaluate the analgesic efficacy , pharmacokinetics , safety , and tolerability of an oral tablet containing purified THC in patients with chronic abdominal pain . METHODS Sixty‐five patients with chronic abdominal pain for 3 months or more ( numeric rating scale scores of 3 or more ) after surgery or because of chronic pancreatitis were r and omly assigned to groups given the THC tablet or identical matching placebos for 50–52 days . Subjects in the THC group were given the tablet first in a step‐up phase ( 3 mg 3 times daily for 5 days and then 5 mg 3 times daily for 5 days ) , followed by a stable dose phase ( 8 mg 3 times daily until days 50–52 ) . Preceding and during the entire study period , patients were asked to continue taking their medications ( including analgesics ) according to prescription . Patients reported any additional pain medications in a diary . Efficacy and safety assessment s were conducted preceding medication intake ( day 1 ) , after 15 days , and at 50–52 days . Plasma sample s were collected on study days 1 , 15 , and 50–52 ; mean plasma concentration curves of THC and 11‐OH‐THC were plotted . The primary end point was pain relief , which was measured by a visual analogue scale ( VAS ) of the mean pain ( VAS mean scores ) on the basis of information from patient diaries . Secondary end points included pain and quality of life ( determined from patient question naires ) , pharmacokinetics , and safety . RESULTS At days 50–52 , VAS mean scores did not differ significantly between the THC and placebo groups ( F1,46 = 0.016 ; P = .901 ) . Between the start and end of the study , VAS mean scores decreased by 1.6 points ( 40 % ) in the THC group compared with 1.9 points ( 37 % ) in the placebo group . No differences were observed in secondary outcomes . Oral THC was generally well‐absorbed . Seven patients in the THC group stopped taking the tablets because of adverse events , compared with 2 patients in the placebo group . All ( possibly ) related adverse events were mild or moderate . CONCLUSIONS In a phase 2 study , we found no difference between a THC tablet and a placebo tablet in reducing pain measures in patients with chronic abdominal pain . THC , administered 3 times daily , was safe and well‐tolerated during a 50‐day to 52‐day treatment period . Clinical Trials.gov number : NCT01562483 and NCT01551511 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
DISCUSSION Although cannabinoids are now being used to manage different pain conditions , the evidence for the clinical effects are unclear .
INTRODUCTION Pain is a frequent clinical symptom with significant impact on the patient 's well-being .
Therefore , adequate pain management is of utmost importance .
While cannabinoids have become a more popular alternative to traditional types of pain medication among patients , the quality of evidence supporting the use of cannabinoids has been question ed .
The beneficial and harmful effects of cannabinoids in patients with pain is unknown .
Accordingly , we aim to assess the efﬁcacy , tolerability and safety of cannabinoids ( herbal , plant-derived extracts and synthetic ) compared with placebo or no intervention for any type of pain .