title: Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial Randomized Placebo-Controlled Double-Blind Clinical Trial of Cannabis-Based Medicinal Product (Sativex) in Painful Diabetic Neuropathy Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis Efficacy, tolerability and safety of cannabis‐based medicines for chronic pain management – An overview of systematic reviews An Exploratory Human Laboratory Experiment Evaluating Vaporized Cannabis in the Treatment of Neuropathic Pain From Spinal Cord Injury and Disease. Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo‐controlled Study Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients With Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial Smoked cannabis for chronic neuropathic pain: a randomized controlled trial MUltiple Sclerosis and Extract of Cannabis: results of the MUSEC trial The Effects of Nabilone on Sleep in Fibromyalgia: Results of a Randomized Controlled Trial Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Δ9-tetrahydrocannabinol in Patients WithProgressive Multiple Sclerosis. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Initial experiences with medicinal extracts of cannabis for chronic pain: Results from 34 ‘N of 1’ studies Efficacy of Inhaled Cannabis on Painful Diabetic Neuropathy. The Subjective Psychoactive Effects of Oral Dronabinol Studied in a Randomized, Controlled Crossover Clinical Trial for Pain Opioids for chronic non-cancer pain Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial Pain measurements and side effect profile of the novel cannabinoid ajulemic acid Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study Vaporization as a Smokeless Cannabis Delivery System: A Pilot Study Sativex successfully treats neuropathic pain characterised by allodynia: A randomised, double-blind, placebo-controlled clinical trial Sativex® and clinical–neurophysiological measures of spasticity in progressive multiple sclerosis 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 A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee Defining the clinically important difference in pain outcome measures Nabilone for the treatment of pain in fibromyalgia. Effect of Dronabinol on Central Neuropathic Pain After Spinal Cord Injury: A Pilot Study Comorbid Psychiatric Disorders and Predictors of Pain Management Program Success in Patients With Chronic Pain. Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial. Dronabinol increases pain threshold in patients with functional chest pain: a pilot double-blind placebo-controlled trial. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in 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. Sativex® as add-on therapy vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity: a double-blind, placebo-controlled randomised clinical trial Medical Marijuana: Is the Cart Before the Horse?
abstract: UNLABELLED We assessed the efficacy of dronabinol ( Marinol capsules ; Solvay Pharmaceuticals , Brussels , Belgium ) , a synthetic Delta(9)-THC ( tetrahydrocannabinol ) , in 30 patients taking opioids for chronic pain to determine its potential analgesic effects as an adjuvant treatment . Phase I of this 2-phase study was a r and omized , single-dose , double-blinded , placebo-controlled , crossover trial in which subjects were r and omly administered either 10 mg or 20 mg of dronabinol or identical placebo capsules over the course of three , 8-hour visits . Baseline self-report measures , hourly ratings of pain intensity , pain relief , pain bothersomeness , treatment satisfaction , mood , side effects , and blood serum levels were obtained . Phase II was an extended open-label titrated trial of dronabinol as add-on medication to patients on stable doses of opioids . Results of the Phase I study showed that patients who received dronabinol experienced decreased pain intensity and increased satisfaction compared with placebo . No differences in benefit were found between the 20 mg and 10 mg doses . In the Phase II trial , titrated dronabinol contributed to significant relief of pain , reduced pain bothersomeness , and increased satisfaction compared with baseline . The incidence of side effects was dose-related . Overall , the use of dronabinol was found to result in additional analgesia among patients taking opioids for chronic noncancer pain . PERSPECTIVE This study examines the effect of adding a cannabinoid to the regimen of patients with chronic pain who report significant pain despite taking stable doses of opioids . The results of our preliminary study suggest that dronabinol , a synthetic THC , may have an additive effect on pain relief Abstract Objective To evaluate the effect of the oral synthetic δ-9-tetrahydrocannabinol dronabinol on central neuropathic pain in patients with multiple sclerosis . Design R and omised double blind placebo controlled crossovertrial . Setting Outpatient clinic , University Hospital of Aarhus , Denmark . Participants 24 patients aged between 23 and 55 years with multiple sclerosis and central pain . Intervention Orally administered dronabinol at a maximum doseof 10 mg daily or corresponding placebo for three weeks ( 15 - 21days ) , separated by a three week washout period . Main outcome measure Median spontaneous pain intensity ( numericalrating scale ) in the last week of treatment . Results Median spontaneous pain intensity was significantlylower during dronabinol treatment than during placebo treatment(4.0 ( 25th to 75th centiles 2.3 to 6.0 ) v 5.0 ( 4.0 to 6.4),P = 0.02 ) , and median pain relief score ( numerical rating scale)was higher ( 3.0 ( 0 to 6.7 ) v > 0 ( 0 to 2.3 ) , P = 0.035 ) . Thenumber needed to treat for 50 % pain relief was 3.5 ( 95 % confidenceinterval 1.9 to 24.8 ) . On the SF-36 quality of life scale , thetwo items bodily pain and mental health indicated benefits fromactive treatment compared with placebo . The number of patients with adverse events was higher during active treatment , especiallyin the first week of treatment . The functional ability of themultiple sclerosis patients did not change . Conclusions Dronabinol has a modest but clinical ly relevantanalgesic effect on central pain in patients with multiple sclerosis . Adverse events , including dizziness , were more frequent withdronabinol than with placebo during the first week of treatment The objective was to determine whether a cannabis-based medicinal extract ( CBME ) benefits a range of symptoms due to multiple sclerosis ( MS ) . A parallel group , double-blind , r and omized , placebo-controlled study was undertaken in three centres , recruiting 160 out patients with MS experiencing significant problems from at least one of the following : spasticity , spasms , bladder problems , tremor or pain . The interventions were oromucosal sprays of matched placebo , or whole plant CBME containing equal amounts of delta-9- tetrahydrocannabinol ( THC ) and cannabidiol ( CBD ) at a dose of 2.5- 120 mg of each daily , in divided doses . The primary outcome measure was a Visual Analogue Scale ( VAS ) score for each patient ’s most troublesome symptom . Additional measures included VAS scores of other symptoms , and measures of disability , cognition , mood , sleep and fatigue . Following CBME the primary symptom score reduced from mean ( SE ) 74.36 ( 11.1 ) to 48.89 ( 22.0 ) following CBME and from 74.31 ( 12.5 ) to 54.79 ( 26.3 ) following placebo [ ns ] . Spasticity VAS scores were significantly reduced by CBME ( Sativex ) in comparison with placebo ( P- 0.001 ) . There were no significant adverse effects on cognition or mood and intoxication was generally mild Objectives : To determine whether plant-derived cannabis medicinal extracts ( CME ) can alleviate neurogenic symptoms unresponsive to st and ard treatment , and to quantify adverse effects . Design : A consecutive series of double-blind , r and omized , placebo-controlled single-patient cross-over trials with two-week treatment periods . Setting : Patients attended as out patients , but took the CME at home . Subjects : Twenty-four patients with multiple sclerosis ( 18 ) , spinal cord injury ( 4 ) , brachial plexus damage ( 1 ) , and limb amputation due to neurofibromatosis ( 1 ) . Intervention : Whole-plant extracts of delta-9-tetrahydrocannabinol ( THC ) , cannabidiol ( CBD ) , 1:1 CBD : THC , or matched placebo were self-administered by sublingual spray at doses determined by titration against symptom relief or unwanted effects within the range of 2.5–120 mg/24 hours . Measures used : Patients recorded symptom , well-being and intoxication scores on a daily basis using visual analogue scales . At the end of each two-week period an observer rated severity and frequency of symptoms on numerical rating scales , administered st and ard measures of disability ( Barthel Index ) , mood and cognition , and recorded adverse events . Results : Pain relief associated with both THC and CBD was significantly superior to placebo . Impaired bladder control , muscle spasms and spasticity were improved by CME in some patients with these symptoms . Three patients had transient hypotension and intoxication with rapid initial dosing of THC-containing CME . Conclusions : Cannabis medicinal extracts can improve neurogenic symptoms unresponsive to st and ard treatments . Unwanted effects are predictable and generally well tolerated . Larger scale studies are warranted to confirm these findings Medication overuse headache ( MOH ) is a severe burden to sufferers and its treatment has few evidence -based indications . The aim of this study is to evaluate efficacy and safety of nabilone in reducing pain and frequency of headache , the number of analgesic intake and in increasing the quality of life on patients with long-st and ing intractable MOH . Thirty MOH patients were enrolled at the University of Modena ’s Interdepartmental Centre for Research on Headache and Drug Abuse ( Italy ) in a r and omized , double-blind , active-controlled , crossover study comparing nabilone 0.5 mg/day and ibuprofen 400 mg . The patients received each treatment orally for 8 weeks ( before nabilone and then ibuprofen or vice versa ) , with 1 week wash-out between them . R and omization and allocation ( ratio 1:1 ) were carried out by an independent pharmacy through a central computer system . Participants , care givers , and those assessing the outcomes were blinded to treatment sequence . Twenty-six subjects completed the study . Improvements from baseline were observed with both treatments . However , nabilone was more effective than ibuprofen in reducing pain intensity and daily analgesic intake ( p < 0.05 ) ; moreover , nabilone was the only drug able to reduce the level of medication dependence ( −41 % , p < 0.01 ) and to improve the quality of life ( p < 0.05 ) . Side effects were uncommon , mild and disappeared when nabilone was discontinued . This is the first r and omized controlled trial demonstrating the benefits of nabilone on headache , analgesic consumption and the quality of life in patients with intractable MOH . This drug also appears to be safe and well-tolerated . Larger scale studies are needed to confirm these preliminary findings OBJECTIVE To assess the efficacy of Sativex , a cannabis-based medicinal extract , as adjuvant treatment in painful diabetic peripheral neuropathy ( DPN ) . RESEARCH DESIGN AND METHODS In this r and omized controlled trial , 30 subjects with painful DPN received daily Sativex or placebo . The primary outcome measure was change in mean daily pain scores , and secondary outcome measures included quality -of-life assessment s. RESULTS There was significant improvement in pain scores in both groups , but mean change between groups was not significant . There were no significant differences in secondary outcome measures . Patients with depression had significantly greater baseline pain scores that improved regardless of intervention . CONCLUSIONS This first-ever trial assessing the efficacy of cannabis has shown it to be no more efficacious than placebo in painful DPN . Depression was a major confounder and may have important implication s for future trials on painful DPN Background : Central pain in multiple sclerosis ( MS ) is common and often refractory to treatment . Methods : We conducted a single-center , 5-week ( 1-week run-in , 4-week treatment ) , r and omized , double-blind , placebo-controlled , parallel-group trial in 66 patients with MS and central pain states ( 59 dysesthetic , seven painful spasms ) of a whole-plant cannabis-based medicine ( CBM ) , containing delta-9-tetrahydrocannabinol : cannabidiol ( THC : CBD ) delivered via an oromucosal spray , as adjunctive analgesic treatment . Each spray delivered 2.7 mg of THC and 2.5 of CBD , and patients could gradually self-titrate to a maximum of 48 sprays in 24 hours . Results : Sixty-four patients ( 97 % ) completed the trial , 34 received CBM . In week 4 , the mean number of daily sprays taken of CBM ( n = 32 ) was 9.6 ( range 2 to 25 , SD = 6.0 ) and of placebo ( n = 31 ) was 19.1 ( range 1 to 47 , SD = 12.9 ) . Pain and sleep disturbance were recorded daily on an 11-point numerical rating scale . CBM was superior to placebo in reducing the mean intensity of pain ( CBM mean change −2.7 , 95 % CI : −3.4 to −2.0 , placebo –1.4 95 % CI : −2.0 to −0.8 , comparison between groups , p = 0.005 ) and sleep disturbance ( CBM mean change –2.5 , 95 % CI : −3.4 to −1.7 , placebo –0.8 , 95 % CI : −1.5 to −0.1 , comparison between groups , p = 0.003 ) . CBM was generally well tolerated , although more patients on CBM than placebo  reported dizziness , dry mouth , and somnolence . Cognitive side effects were limited to long-term memory storage . Conclusions : Cannabis-based medicine is effective in reducing pain and sleep disturbance in patients with multiple sclerosis related central neuropathic pain and is mostly well tolerated 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 Using 8-hour human laboratory experiments , we evaluated the analgesic efficacy of vaporized cannabis in patients with neuropathic pain related to injury or disease of the spinal cord , most of whom were experiencing pain despite traditional treatment . After obtaining baseline data , 42 participants underwent a st and ardized procedure for inhaling 4 puffs of vaporized cannabis containing either placebo , 2.9 % , or 6.7 % delta 9-THC on 3 separate occasions . A second dosing occurred 3 hours later ; participants chose to inhale 4 to 8 puffs . This flexible dosing was used to attempt to reduce the placebo effect . Using an 11-point numerical pain intensity rating scale as the primary outcome , a mixed effects linear regression model showed a significant analgesic response for vaporized cannabis . When subjective and psychoactive side effects ( eg , good drug effect , feeling high , etc ) were added as covariates to the model , the reduction in pain intensity remained significant above and beyond any effect of these measures ( all P < .0004 ) . Psychoactive and subjective effects were dose-dependent . Measurement of neuropsychological performance proved challenging because of various disabilities in the population studied . Because the 2 active doses did not significantly differ from each other in terms of analgesic potency , the lower dose appears to offer the best risk-benefit ratio in patients with neuropathic pain associated with injury or disease of the spinal cord . PERSPECTIVE A crossover , r and omized , placebo-controlled human laboratory experiment involving administration of vaporized cannabis was performed in patients with neuropathic pain related to spinal cord injury and disease . This study supports consideration of future research that would include longer duration studies over weeks to months to evaluate the efficacy of medicinal cannabis in patients with central neuropathic pain 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 Importance Limited evidence is available regarding long-term outcomes of opioids compared with nonopioid medications for chronic pain . Objective To compare opioid vs nonopioid medications over 12 months on pain-related function , pain intensity , and adverse effects . Design , Setting , and Participants Pragmatic , 12-month , r and omized trial with masked outcome assessment . Patients were recruited from Veterans Affairs primary care clinics from June 2013 through December 2015 ; follow-up was completed December 2016 . Eligible patients had moderate to severe chronic back pain or hip or knee osteoarthritis pain despite analgesic use . Of 265 patients enrolled , 25 withdrew prior to r and omization and 240 were r and omized . Interventions Both interventions ( opioid and nonopioid medication therapy ) followed a treat-to-target strategy aim ing for improved pain and function . Each intervention had its own prescribing strategy that included multiple medication options in 3 steps . In the opioid group , the first step was immediate-release morphine , oxycodone , or hydrocodone/acetaminophen . For the nonopioid group , the first step was acetaminophen ( paracetamol ) or a nonsteroidal anti-inflammatory drug . Medications were changed , added , or adjusted within the assigned treatment group according to individual patient response . Main Outcomes and Measures The primary outcome was pain-related function ( Brief Pain Inventory [ BPI ] interference scale ) over 12 months and the main secondary outcome was pain intensity ( BPI severity scale ) . For both BPI scales ( range , 0 - 10 ; higher scores = worse function or pain intensity ) , a 1-point improvement was clinical ly important . The primary adverse outcome was medication-related symptoms ( patient-reported checklist ; range , 0 - 19 ) . Results Among 240 r and omized patients ( mean age , 58.3 years ; women , 32 [ 13.0 % ] ) , 234 ( 97.5 % ) completed the trial . Groups did not significantly differ on pain-related function over 12 months ( overall P = .58 ) ; mean 12-month BPI interference was 3.4 for the opioid group and 3.3 for the nonopioid group ( difference , 0.1 [ 95 % CI , −0.5 to 0.7 ] ) . Pain intensity was significantly better in the nonopioid group over 12 months ( overall P = .03 ) ; mean 12-month BPI severity was 4.0 for the opioid group and 3.5 for the nonopioid group ( difference , 0.5 [ 95 % CI , 0.0 to 1.0 ] ) . Adverse medication-related symptoms were significantly more common in the opioid group over 12 months ( overall P = .03 ) ; mean medication-related symptoms at 12 months were 1.8 in the opioid group and 0.9 in the nonopioid group ( difference , 0.9 [ 95 % CI , 0.3 to 1.5 ] ) . Conclusions and Relevance Treatment with opioids was not superior to treatment with nonopioid medications for improving pain-related function over 12 months . Results do not support initiation of opioid therapy for moderate to severe chronic back pain or hip or knee osteoarthritis pain . Trial Registration clinical trials.gov Identifier : Background : Spasticity is a common and poorly controlled symptom of multiple sclerosis . Our objective was to determine the short-term effect of smoked cannabis on this symptom . Methods : We conducted a placebo-controlled , crossover trial involving adult patients with multiple sclerosis and spasticity . We recruited participants from a regional clinic or by referral from specialists . We r and omly assigned participants to either the intervention ( smoked cannabis , once daily for three days ) or control ( identical placebo cigarettes , once daily for three days ) . Each participant was assessed daily before and after treatment . After a washout interval of 11 days , participants crossed over to the opposite group . Our primary outcome was change in spasticity as measured by patient score on the modified Ashworth scale . Our secondary outcomes included patients ’ perception of pain ( as measured using a visual analogue scale ) , a timed walk and changes in cognitive function ( as measured by patient performance on the Paced Auditory Serial Addition Test ) , in addition to ratings of fatigue . Results : Thirty-seven participants were r and omized at the start of the study , 30 of whom completed the trial . Treatment with smoked cannabis result ed in a reduction in patient scores on the modified Ashworth scale by an average of 2.74 points more than placebo ( p < 0.0001 ) . In addition , treatment reduced pain scores on a visual analogue scale by an average of 5.28 points more than placebo ( p = 0.008 ) . Scores for the timed walk did not differ significantly between treatment and placebo ( p = 0.2 ) . Scores on the Paced Auditory Serial Addition Test decreased by 8.67 points more with treatment than with placebo ( p = 0.003 ) . No serious adverse events occurred during the trial . Interpretation : Smoked cannabis was superior to placebo in symptom and pain reduction in participants with treatment-resistant spasticity . Future studies should examine whether different doses can result in similar beneficial effects with less cognitive impact Background : Chronic neuropathic pain affects 1%–2 % of the adult population and is often refractory to st and ard pharmacologic treatment . Patients with chronic pain have reported using smoked cannabis to relieve pain , improve sleep and improve mood . Methods : Adults with post-traumatic or postsurgical neuropathic pain were r and omly assigned to receive cannabis at four potencies ( 0 % , 2.5 % , 6 % and 9.4 % tetrahydrocannabinol ) over four 14-day periods in a crossover trial . Participants inhaled a single 25-mg dose through a pipe three times daily for the first five days in each cycle , followed by a nine-day washout period . Daily average pain intensity was measured using an 11-point numeric rating scale . We recorded effects on mood , sleep and quality of life , as well as adverse events . Results : We recruited 23 participants ( mean age 45.4 [ st and ard deviation 12.3 ] years , 12 women [ 52 % ] ) , of whom 21 completed the trial . The average daily pain intensity , measured on the 11-point numeric rating scale , was lower on the prespecified primary contrast of 9.4 % v. 0 % tetrahydrocannabinol ( 5.4 v. 6.1 , respectively ; difference = 0.7 , 95 % confidence interval [ CI ] 0.02–1.4 ) . Preparations with intermediate potency yielded intermediate but nonsignificant degrees of relief . Participants receiving 9.4 % tetrahydrocannabinol reported improved ability to fall asleep ( easier , p = 0.001 ; faster , p < 0.001 ; more drowsy , p = 0.003 ) and improved quality of sleep ( less wakefulness , p = 0.01 ) relative to 0 % tetrahydrocannabinol . We found no differences in mood or quality of life . The most common drug-related adverse events during the period when participants received 9.4 % tetrahydrocannabinol were headache , dry eyes , burning sensation in areas of neuropathic pain , dizziness , numbness and cough . Conclusion : A single inhalation of 25 mg of 9.4 % tetrahydrocannabinol herbal cannabis three times daily for five days reduced the intensity of pain , improved sleep and was well tolerated . Further long-term safety and efficacy studies are indicated . ( International St and ard R and omised Controlled Trial Register no. IS RCT N68314063 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 : 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 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 & NA ; The objective was to investigate the effectiveness of cannabis‐based medicines for treatment of  chronic pain associated with brachial plexus root avulsion . This condition is an excellent human model of central neuropathic pain as it represents an unusually homogenous group in terms of anatomical location of injury , pain descriptions and patient demographics . Forty‐eight patients with at least one avulsed root and baseline pain score of four or more on an 11‐point ordinate scale participated in a r and omised , double‐blind , placebo‐controlled , three period crossover study . All patients had intractable symptoms regardless of current analgesic therapy . Patients entered a baseline period of 2 weeks , followed by three , 2‐week treatment periods during each of which they received one of three oromucosal spray preparations . These were placebo and two whole plant extracts of Cannabis sativa L. : GW‐1000‐02 ( Sativex ® ) , containing Δ9tetrahydrocannabinol (THC):cannabidiol ( CBD ) in an approximate 1:1 ratio and GW‐2000‐02 , containing primarily THC . The primary outcome measure was the mean pain severity score during the last 7 days of treatment . Secondary outcome measures included pain related quality of life assessment s. The primary outcome measure failed to fall by the two points defined in our hypothesis . However , both this measure and measures of sleep showed statistically significant improvements . The study medications were generally well tolerated with the majority of adverse events , including intoxication type reactions , being mild to moderate in severity and resolving spontaneously . Studies of longer duration in neuropathic pain are required to confirm a clinical ly relevant , improvement in the treatment of this condition AIM We aim ed to assess the analgesic efficacy , pharmacokinetics , tolerability and safety of a single dose of Δ9-THC in patients with chronic abdominal pain result ing from chronic pancreatitis ( CP ) . METHODS This was a r and omized , single dose , double-blinded , placebo-controlled , two way crossover study in patients suffering from abdominal pain as result of CP ( n = 24 ) , post hoc subdivided into opioid and non-opioid users .  Δ9-THC ( 8 mg ) or active placebo ( 5 mg/10 mg diazepam ) was administered orally in a double dummy design . RESULTS No treatment effect was shown for delta VAS pain scores after Δ9-THC compared with diazepam . Δ9-THC was well absorbed with a mean tmax of 123 min . No significant differences were found between Δ9-THC vs. diazepam for alertness , mood , calmness or balance . Feeling anxious and heart rate were significantly increased after Δ9-THC compared with diazepam . The most frequently reported adverse events ( AEs ) after Δ9-THC administration were somnolence , dry mouth , dizziness and euphoric mood . CONCLUSIONS A single dose of Δ9-THC was not efficacious in reducing chronic pain result ing from CP , but was well tolerated with only mild or moderate AEs . The PK results in CP patients showed delayed absorption and an increased variability compared with healthy volunteers OBJECTIVES To assess the efficacy of a cannabis-based medicine ( CBM ) in the treatment of  pain due to rheumatoid arthritis ( RA ) . METHODS We compared a CBM ( Sativex ) with placebo in a r and omized , double-blind , parallel group study in 58 patients over 5 weeks of treatment . The CBM was administered by oromucosal spray in the evening and assessment s were made the following morning . Efficacy outcomes assessed were pain on movement , pain at rest , morning stiffness and sleep quality measured by a numerical rating scale , the Short-Form McGill Pain Question naire ( SF-MPQ ) and the DAS28 measure of disease activity . RESULTS Seventy-five patients were screened and 58 met the eligibility criteria . Thirty-one were r and omized to the CBM and 27 to placebo .  Mean ( S.D. ) daily dose achieved in the final treatment week was 5.4 ( 0.84 ) actuations for the CBM and 5.3 ( 1.18 ) for placebo . In comparison with placebo , the CBM produced statistically significant improvements in pain on movement , pain at rest , quality of sleep , DAS28 and the SF-MPQ pain at present component . There was no effect on morning stiffness but baseline scores were low . The large majority of adverse effects were mild or moderate , and there were no adverse effect-related withdrawals or serious adverse effects in the active treatment group . CONCLUSIONS In the first ever controlled trial of a CBM in RA , a significant analgesic effect was observed and disease activity was significantly suppressed following Sativex treatment . Whilst the differences are small and variable across the population , they represent benefits of clinical relevance and show the need for more detailed investigation in this indication PURPOSE The aim of the present study was to evaluate the efficacy of an oral formulation of Δ9-tetrahydrocannabinol ( ECP002A ) in patients with progressive multiple sclerosis ( MS ) . METHODS This accelerated proof-of-concept study consisted of 2 phases : a crossover challenge ( dose-finding ) phase and a 4-week , parallel , r and omized , placebo-controlled treatment phase . Twenty-four patients with progressive MS and moderate spasticity were enrolled . During the treatment phase , biomarkers for efficacy and secondary pharmacodynamic effects were measured at baseline and after 2 and 4 weeks of treatment . Serum sample s were collected to determine pharmacokinetic properties and perform population modeling . Safety and tolerability profiles were assessed based on adverse events and safety measurements . FINDINGS Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary . A similar pattern was observed in subjective muscle spasticity . Other clinical outcomes were not significantly different between active treatment and placebo . Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo . Implication s This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population . Despite the complex interplay of psychoactive effects and analgesia , the current oral formulation of Δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile BACKGROUND Peripheral neuropathic pain ( PNP ) associated with allodynia poses a significant clinical challenge . The efficacy of Δ(9 ) -tetrahydrocannabinol/cannabidiol ( THC/CBD ) oromucosal spray , a novel cannabinoid formulation , was investigated in this 15-week r and omized , double-blind , placebo-controlled parallel group study . METHODS In total , 303 patients with PNP associated with allodynia were screened ; 128 were r and omized to THC/CBD spray and 118 to placebo , in addition to their current analgesic therapy . The co- primary efficacy endpoints were the 30 % responder rate in PNP 0 - 10 numerical rating scale ( NRS ) score and the mean change from baseline to the end of treatment in this score . Various key secondary measures of pain and functioning were also investigated . RESULTS At the 30 % responder level , there were statistically significant treatment differences in favour of THC/CBD spray in the full analysis ( intention-to-treat ) data set [ p = 0.034 ; 95 % confidence interval ( CI ) : 1.05 - 3.70 ] . There was also a reduction in mean PNP 0 - 10 NRS scores in both treatment groups that was numerically higher in the THC/CBD spray group , but which failed to reach statistical significance . Secondary measures of sleep quality 0 - 10 NRS score ( p = 0.0072 ) and Subject Global Impression of Change ( SGIC ) ( p = 0.023 ) also demonstrated statistically significant treatment differences in favour of THC/CBD spray treatment . CONCLUSIONS These findings demonstrate that , in a meaningful proportion of otherwise treatment-resistant patients , clinical ly important improvements in pain , sleep quality and SGIC of the severity of their condition are obtained with THC/CBD spray . THC/CBD spray was well tolerated and no new safety concerns were identified Three Cannabis Based Medicinal Extracts ( CBMEs ) for sublingual use became available in 2000 . A total of 34 ‘ N of 1 ’ studies were undertaken using this novel therapy for patients with chronic , mainly neuropathic , pain and associated symptoms to explore efficacy , tolerability , safety and dosages . Three CBMEs ( Δ9 Tetrahydrocannabinol ( THC ) , Cannabidiol ( CBD ) and a 1 : 1 mixture of them both ) were given over a 12‐week period . After an initial open‐label period , the CBMEs were used in a r and omised , double‐blind , placebo controlled , crossover trial . Extracts which contained THC proved most effective in symptom control . Regimens for the use of the sublingual spray emerged and a wide range of dosing requirements was observed . Side‐effects were common , reflecting a learning curve for both patient and study team . These were generally acceptable and little different to those seen when other psycho‐active agents are used for chronic pain . These initial experiences with CBME open the way to more detailed and extensive studies UNLABELLED A r and omized , double-blinded , placebo controlled crossover study was conducted in 16 patients with painful diabetic peripheral neuropathy to assess the short-term efficacy and tolerability of inhaled cannabis . In a crossover design , each participant was exposed to 4 single dosing sessions of placebo or to low ( 1 % tetrahydrocannabinol [ THC ] ) , medium ( 4 % THC ) , or high ( 7 % THC ) doses of cannabis . Baseline spontaneous pain , evoked pain , and cognitive testing were performed . Subjects were then administered aerosolized cannabis or placebo and the pain intensity and subjective " highness " score was measured at 5 , 15 , 30 , 45 , and 60 minutes and then every 30 minutes for an additional 3 hours . Cognitive testing was performed at 5 and 30 minutes and then every 30 minutes for an additional 3 hours . The primary analysis compared differences in spontaneous pain over time between doses using linear mixed effects models . There was a significant difference in spontaneous pain scores between doses ( P < .001 ) . Specific significant comparisons were placebo versus low , medium , and high doses ( P = .031 , .04 , and < .001 , respectively ) and high versus low and medium doses ( both P < .001 ) . There was a significant effect of the high dose on foam brush and von Frey evoked pain ( both P < .001 ) . There was a significant negative effect ( impaired performance ) of the high dose on 2 of the 3 neuropsychological tests ( Paced Auditory Serial Addition Test , Trail Making Test Part B. PERSPECTIVE This small , short-term , placebo-controlled trial of inhaled cannabis demonstrated a dose-dependent reduction in diabetic peripheral neuropathy pain in patients with treatment-refractory pain . This adds preliminary evidence to support further research on the efficacy of the cannabinoids in neuropathic pain 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 A 36 year old carpenter has a six month history of lower back pain with no specific clinical or radiological findings . As his pain has not responded to paracetamol and non-steroidal anti-inflammatory drugs ( NSAIDs ) , he asks his doctor if he can have “ stronger painkillers ” such as morphine . Opioids are a group of compounds that act by binding to opioid receptors ( μ , κ , and δ ) , which are widely distributed in the brain , spinal cord , and peripheral tissues . They are the mainstay in the management of cancer pain , but published data show a continual increase in the volume of prescribed opioids to manage moderate to severe , chronic , non-cancer pain.1 2 Changes in attitude and aggressive marketing have driven a dramatic increase in use , with more adverse events , including deaths from overdose ( now the second leading cause of accidental death in the US).3 Proponents cl aim that opioids are underused for chronic pain,4 but lack of good scientific data has prevented the formulation of evidence based guidelines for their use , especially in primary care . Several meta-analyses of the effectiveness of opioids have been published . Most of the r and omised clinical trials summarised in these meta-analyses were funded by the pharmaceutical industry and report heterogeneous , short term outcomes in highly selected patients . Non-r and omised and uncontrolled observational studies make up the rest of the literature . Nevertheless , most studies have consistently shown some effectiveness in chronic non-cancer pain by reducing pain intensity . In particular , meta-analyses show the efficacy of opioids in neuropathic pain,5 6 7 although most guidelines regard opioids only as second or third line treatment for such pain because of their risk : benefit profile.8 9 The data are even less encouraging for chronic non-neuropathic pain , the focus of this paper . A 2009 Cochrane review of 10 r and omised or quasi-r and omised controlled trials compared Despite management with opioids and other pain modifying therapies , neuropathic pain continues to reduce the quality of life and daily functioning in HIV-infected individuals . Cannabinoid receptors in the central and peripheral nervous systems have been shown to modulate pain perception . We conducted a clinical trial to assess the impact of smoked cannabis on neuropathic pain in HIV . This was a phase II , double-blind , placebo-controlled , crossover trial of analgesia with smoked cannabis in HIV-associated distal sensory predominant polyneuropathy ( DSPN ) . Eligible subjects had neuropathic pain refractory to at least two previous analgesic classes ; they continued on their pre study analgesic regimens throughout the trial . Regulatory considerations dictated that subjects smoke under direct observation in a hospital setting . Treatments were placebo and active cannabis ranging in potency between 1 and 8 % Δ-9-tetrahydrocannabinol , four times daily for 5 consecutive days during each of 2 treatment weeks , separated by a 2-week washout . The primary outcome was change in pain intensity as measured by the Descriptor Differential Scale ( DDS ) from a pretreatment baseline to the end of each treatment week . Secondary measures included assessment s of mood and daily functioning . Of 127 volunteers screened , 34 eligible subjects enrolled and 28 completed both cannabis and placebo treatments . Among the completers , pain relief was greater with cannabis than placebo ( median difference in DDS pain intensity change , 3.3 points , effect size=0.60 ; p=0.016 ) . The proportions of subjects achieving at least 30 % pain relief  with cannabis versus placebo were 0.46 ( 95%CI 0.28 , 0.65 ) and 0.18 ( 0.03 , 0.32 ) . Mood and daily functioning improved to a similar extent during both treatment periods . Although most side effects were mild and self-limited , two subjects experienced treatment-limiting toxicities . Smoked cannabis was generally well tolerated and effective when added to concomitant analgesic therapy in patients with medically refractory pain due to HIV DSPN Pre clinical findings on ajulemic acid ( AJA ) showed analgesic and anti-allodynic effects without psychoactive properties making it an appealing substance for the treatment of pain . A recently published r and omized double-blind crossover clinical trial described the pain-reducing effects and side effect profile of AJA on 21 patients with chronic neuropathic pain . In this report from this same sample the effects of AJA on the mechanical hypersensitivity , on pain , and on psychological and physical performance were further characterized . During a 5-week study period , patients were divided into two 7-day treatment groups receiving either AJA or placebo capsules first , respectively . All patients received 40 and 80 mg of AJA or placebo daily in each treatment period . Pain measurements included the determination of mechanical hypersensitivity using the von Frey hair method as well as the visual analog scale ( VAS ) , for which the number needed to treat ( NNT ) was calculated . The side effect profile of the compound was evaluated using psychotropic and physical measurements as well as obtaining reports on possible subjective side effects . The results showed no significant reduction in mechanical hypersensitivity ( p=0.052 ) , although a tendency towards pain reduction could be seen . The VAS score showed significant pain reduction ( p=0.021 ) and NNT values for 30 % pain relief were 2.14 for the first treatment group and 5.29 for the second treatment group . No significant findings were observed regarding psychotropic or physical measurements . Reported subjective side effects were mainly dry mouth , tiredness and dizziness and did not increase with dose elevation . Overall , these study findings indicate that AJA shows pain-reducing effects on patients with chronic neuropathic pain without clinical ly relevant psychotropic or physical 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 Although cannabis may have potential therapeutic value , inhalation of a combustion product is an undesirable delivery system . The aim of the study was to investigate vaporization using the Volcano ® device as an alternative means of delivery of inhaled Cannabis sativa . Eighteen healthy inpatient subjects enrolled to compare the delivery of cannabinoids by vaporization to marijuana smoked in a st and ard cigarette . One strength ( 1.7 , 3.4 , or 6.8 % tetrahydrocannabinol ( THC ) ) and delivery system was r and omly assigned for each of the 6 study days . Plasma concentrations of Δ‐9‐THC , expired carbon monoxide ( CO ) , physiologic and neuropsychologic effects were the main outcome measures . Peak plasma concentrations and 6‐h area under the plasma concentration – time curve of THC were similar . CO levels were reduced with vaporization . No adverse events occurred . Vaporization of cannabis is a safe and effective mode of delivery of THC . Further trials of clinical effectiveness of cannabis could utilize vaporization as a smokeless delivery system 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 Despite the proven efficacy of Sativex ® ( 9-delta-tetrahydrocannabinol plus cannabidiol ) oromucosal spray in reducing spasticity symptoms in multiple sclerosis ( MS ) , little is known about the neurophysiological correlates of such effects . The aim of the study was to investigate the effects of Sativex on neurophysiological measures of spasticity ( H/M ratio ) and corticospinal excitability in patients with progressive MS . This was a r and omized , double-blind , placebo-controlled , crossover study . Consecutive subjects with progressive MS and lower limb spasticity referred to our center were r and omized to 4 weeks ’ treatment ( including 2 weeks ’ titration ) with Sativex or placebo , with crossover after a 2-week washout . Clinical and neurophysiological measures ( H/M ratio and cortical excitability ) of spasticity were assessed . The H/M ratio was the primary outcome , with sample size calculation of 40 patients . Of 44 recruited patients , 34 were analyzed due to 6 drop-outs and 4 exclusions , which lowered the power of the study to show differences between treatments . Neurophysiological measures did not differ significantly according to treatment and did not correlate significantly with clinical response . Response on the modified Ashworth scale ( at least 20 % improvement ) was significantly more frequent after Sativex than placebo ( 50 vs 23.5 % ; p = 0.041 ; McNemar ) . Side effects did not differ significantly according to treatment . Our findings confirm the clinical benefit of Sativex  on MS spasticity . The lack of corresponding changes in corticospinal excitability and on the monosynaptic component , of the stretch reflex , although in a limited sample size , points to the involvement of other spinal and supraspinal mechanisms in the physiopathology of spasticity in progressive MS 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 Abstract Central neuropathic pain ( CNP ) occurs in many multiple sclerosis ( MS ) patients . The provision of adequate pain relief to these patients can very difficult . Here we report the first phase III placebo-controlled study of the efficacy of the endocannabinoid system modulator delta-9-tetrahydrocannabinol (THC)/cannabidiol ( CBD ) oromucosal spray ( USAN name , nabiximols ; Sativex , GW Pharmaceuticals , Salisbury , Wiltshire , UK ) , to alleviate CNP . Patients who had failed to gain adequate analgesia from existing medication were treated with THC/CBD spray or placebo as an add-on treatment , in a double-blind manner , for 14 weeks to investigate the efficacy of the medication in MS-induced neuropathic pain . This parallel-group phase of the study was then followed by an 18-week r and omized-withdrawal study ( 14-week open-label treatment period plus a double-blind 4-week r and omized-withdrawal phase ) to investigate time to treatment failure and show maintenance of efficacy . A total of 339 patients were r and omized to phase A ( 167 received THC/CBD spray and 172 received placebo )  . Of those who completed phase A , 58 entered the r and omized-withdrawal phase . The primary endpoint of responder analysis at the 30 % level at week 14 of phase A of the study was not met , with 50 % of patients on THC/CBD spray classed as responders at the 30 % level compared to 45 % of patients on placebo ( p = 0.234 ) . However , an interim analysis at week 10 showed a statistically significant treatment difference in favor of THC/CBD spray at this time point ( p = 0.046 ) . During the r and omized-withdrawal phase , the primary endpoint of time to treatment failure was statistically significant in favor of THC/CBD spray , with 57 % of patients receiving placebo failing treatment versus 24 % of patients from the THC/CBD spray group ( p = 0.04 ) . The mean change from baseline in Pain Numerical Rating Scale ( NRS ) ( p = 0.028 ) and sleep quality NRS ( p = 0.015 ) scores , both secondary endpoints in phase B , were also statistically significant compared to placebo , with estimated treatment differences of −0.79 and 0.99 points , respectively , in favor of THC/CBD spray treatment . The results of the current investigation were equivocal , with conflicting findings in the two phases of the study . While there were a large proportion of responders to THC/CBD spray treatment during the phase A double-blind period , the primary endpoint was not met due to a similarly large number of placebo responders . In contrast , there was a marked effect in phase B of the study , with an increased time to treatment failure in the THC/CBD spray group compared to placebo . These findings suggest that further studies are required to explore the full potential of THC/CBD spray in these patients Summary A r and omised , placebo‐controlled clinical trial with PF‐04457845 , a novel irreversible fatty acid amide hydrolase‐1 inhibitor , increases endocannabinoids , but does not induce analgesia in patients with osteoarthritis . Abstract The effect of PF‐04457845 , a potent and selective fatty acid amide hydrolase‐1 ( FAAH1 ) inhibitor , on  pain due to osteoarthritis of the knee was investigated in a r and omised placebo and active‐controlled clinical trial . The trial involved 2 periods ( separated by a 2‐week washout ) consisting of a 1‐week wash‐in phase followed by 2 weeks double‐blind treatment . Patients received single‐blind placebo throughout the wash‐in and washout periods . Patients were r and omised to receive either 4 mg q.d . PF‐04457845 followed by placebo ( or vice versa ) , or 500 mg b.i.d . naproxen followed by placebo ( or vice versa ) . The primary end point was the Western Ontario and McMaster Universities Osteoarthritis Index ( WOMAC ) pain score . The trial had predefined decision rules based on likelihood that PF‐04457845 was better or worse than the st and ard of care ( considered to be a 1.8 reduction in WOMAC pain score compared to placebo ) . A total of 74 patients were r and omised to 1 of 4 treatment sequences . The mean differences ( 80 % confidence intervals ) from placebo in WOMAC pain score were 0.04 ( −0.63 to 0.71 ) for PF‐04457845 and −1.13 ( −1.79 to −0.47 ) for naproxen , indicating that whilst naproxen seemed efficacious , PF‐04457845 was not differentiated from placebo . The study was stopped at the interim analysis for futility . PF‐04457845  decreased FAAH activity by > 96 % and substantially increased 4 endogenous substrates ( fatty acid amides ) . PF‐04457845 was well tolerated in osteoarthritis patients , and there was no evidence of cannabinoid‐type adverse events . The lack of analgesic effect of FAAH1 inhibition in humans is in contrast to data from animal models . This apparent disconnect between species needs further study & NA ; The purpose of this study was to determine the levels of change on st and ard pain scales that represent clinical ly important differences to patients . Data from analgesic studies are often difficult to interpret because the clinical importance of the results is not obvious . Differences between groups , as summarized by a change in mean values over time , can be difficult to apply to clinical care . Baseline scores vary widely and group mean differences could reflect large changes in a few patients , small changes in many patients , or any combination of these outcomes . Determination of the proportion of patients who have a clinical ly important improvement in their pain would provide a more interpretable result with direct clinical implication s. However , determining a clinical ly important outcome requires information about the degree of change over time that is clinical ly important . Data from the titration phase of a multiple cross‐over r and omized clinical trial of oral transmucosal fentanyl citrate ( OTFC )  for the treatment of cancer‐related breakthrough pain were re‐analyzed to examine the differences in pain scores between treatment episodes that did and did not yield adequate pain relief . The scales evaluated were absolute pain intensity difference ( PID , 0–10 scale ) , percentage pain intensity difference ( PID% , 0–100 % scale ) , pain relief ( PR , 0 ( none ) , 1 ( slight ) , 2 ( moderate ) , 3 ( lots ) , 4 ( complete ) ) , sum of the pain intensity difference ( SPID over 60 min ) , percentage of maximum total pain relief ( % Max TOTPAR over 60 min ) , and global medication performance ( 0 ( poor ) , 1 ( fair ) , 2 ( good ) , 3 ( very good ) , 4 ( excellent ) ) . Adequate relief was defined by the patient 's decision not to use another dose of opioid medication as a rescue , in addition to the study medication , to treat each painful episode . One hundred thirty OTFC naive patients contributed data on 1268 episodes of breakthrough pain . The scales that were converted to a percentage change yielded the best accuracy in predicting adequate relief , with balanced sensitivity and specificity . The best cut‐off point for both the % Max TOTPAR and the PID% was 33 % . The best cut‐off points for the absolute scales were absolute pain intensity difference of 2 , pain relief of 2 ( moderate ) , and SPID of 2 . The global medication performance of 2 ( good ) had excellent values as well . This study presents data ‐derived cut‐off points for the changes in several pain scales , each reflecting the clinical ly important improvement for patients treating breakthrough cancer pain episodes with OTFC . Confirmation in other patient population s and different pain syndromes will be needed . The use of consistent clinical ly important cut‐off points as the primary outcome in future pain therapy clinical trials will enhance their validity , comparability , and clinical applicability 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 Rintala DH , Fiess RN , Tan G , Holmes SA , Bruel BM : Effect of dronabinol on central neuropathic pain after spinal cord injury : A pilot study . Objective : To test the efficacy and safety of a cannabinoid , dronabinol , compared with an active control , diphenhydramine , in relieving neuropathic pain in persons with spinal cord injury . Design : A r and omized , controlled , double-blind , crossover pilot study . Results : Seven adults with spinal cord injury and neuropathic pain below the level of injury participated . Two participants withdrew while receiving dronabinol , their first medication . For the remaining five participants , change in pain on a scale of 0–10 from baseline to the end of the maintenance phase did not differ significantly between the two medications ( mean change , dronabinol : 0.20 ± 0.837 , range = −1.00 to 1.00 ; diphenhydramine : −1.80 ± 2.490 , range = −6.00 to 0 ; Wilcoxon Z = 1.63 , P = 0.102 ) . Similar results were found when the average of the two ratings during the maintenance phase was used ( dronabinol : −0.20 ± 0.671 , range = −0.50 to 1.00 ; diphenhydramine : −1.40 ± 1.245 , range = −3.50 to −0.50 ; Wilcoxon Z = 1.60 , P = 0.109 ) . The most common side effects were dry mouth , constipation , fatigue , and drowsiness for both medications . Conclusions : On average , dronabinol was no more effective than diphenhydramine for relieving chronic neuropathic pain below the level of injury BACKGROUND : This prospect i ve investigation assessed success rates of a pain management program for patients with and without DSM-III-R Axis I and II psychiatric disorders . METHOD : Subjects included 40 consecutive patients with chronic pain who were referred to a physical therapy-oriented , " st and ard " pain management program .  Serial ratings of pain levels were measured via a visual analogue scale ( VAS ) at baseline , weekly throughout a 12-week program , and during a follow-up interval 1 month after completion of the program . Weekly reports of hours of gainful employment were recorded . VAS scores and number of hours worked per week were combined into a measure of pain improvement . This dependent variable was used to compare groups of patients across psychiatric disorders diagnosed via the Diagnostic Interview Schedule ( DIS ) . Percentages of patients in each diagnostic group who met minimal criteria for improvement were computed and compared . A chi-square analysis was conducted on success rates between patients with and without any Axis I disorder , any Axis II disorder , and any substance abuse/dependence disorder . RESULTS : Overall , 70 % of patients ( N = 28 ) were found to have a DIS psychiatric disorder . There were differences in improvement between patients with and without Axis I disorders and between those with and without Axis II disorders . The presence of a diagnosis was associated with significantly lower improvement rates ( p < .05 ) . CONCLUSION : Patients with chronic pain enrolled in this clinic had a high prevalence of comorbid psychiatric disorders , and these comorbid patients were less likely to improve with st and ard chronic pain treatment . In a population of patients seeking treatment for chronic pain , these results suggest a need for detection and diagnosis of psychiatric disorders and further research on the efficacy of psychiatric treatment interventions in chronic pain management BACKGROUND Neuropathic pain ( NPP ) is a chronic syndrome suffered by patients with multiple sclerosis ( MS ) , for which there is no cure . Underlying cellular mechanisms involved in its pathogenesis are multifaceted , presenting significant challenges in its management . METHODS A r and omized , double-blind , placebo-controlled study involving 15 relapsing-remitting MS patients with MS-induced NPP was conducted to evaluate nabilone combined with gabapentin ( GBP ) .  Eligible patients stabilized on GBP ( ≥1,800 mg/day ) with inadequate pain relief were recruited . Nabilone or placebo was titrated over 4 weeks ( 0.5 mg/week increase ) followed by 5-week maintenance of 1 mg oral nabilone ( placebo ) twice daily . Primary outcomes included two daily patient-reported measures using a 100-mm visual analog scale ( VAS ) , pain intensity ( VASpain ) , and impact of pain on daily activities ( VASimpact ) . Hierarchical regression modeling was conducted on each outcome to determine if within-person pain trajectory differed across study groups , during 63-day follow-up . RESULTS After adjustment for key patient-level covariates ( e.g. , age , sex , Exp and ed Disability Status Scale , duration of MS , baseline pain ) , a significant group × time(2 ) interaction term was reported for both the VASpain ( P < 0.01 ) and VASimpact score ( P < 0.01 ) , demonstrating the adjusted rate of decrease for both outcomes was statistically greater in nabilone vs placebo study group . No significant difference in attrition rates was noted between treatments . Nabilone was well tolerated , with dizziness/drowsiness most frequently reported . CONCLUSION Nabilone as an adjunctive to GBP is an effective , well-tolerated combination for MS-induced NPP . The results of this study identify a novel therapeutic combination for use in this population of patients predisposed to tolerability issues that may otherwise prevent effective pain management Noncardiac chest pain is associated with poor quality of life and high care expenditure . The majority of noncardiac chest pain is either gastresophageal reflux disease related or due to esophageal motility disorders , and the rest are considered functional chest pain ( FCP ) due to central and peripheral hypersensitivity . Current treatment of FCP improves 40 - 50 % of patients . Cannabinoid receptors 1 ( CB1 ) and 2 ( CB2 ) modulate release of neurotransmitters ; CB1 is located in the esophageal epithelium and reduces excitatory enteric transmission and potentially could reduce esophageal hypersensitivity . We performed a prospect i ve study to evaluate its effects on pain threshold , frequency , and intensity in FCP . Subjects with FCP received dronabinol ( 5 mg , twice daily ; n = 7 ; average age , 44 years ; mean body mass index , 26.7 ) or placebo ( n = 6 ; average age , 42 years ; mean body mass index , 25.9 ) for 28 days ( 4 weeks ) . Chest pain , general health , and anxiety/depression question naires were assessed at baseline and at 4 weeks . Subjects underwent an esophageal balloon distention test prior to treatment and on last day of the study . Dronabinol  increased pain thresholds significantly ( 3.0 vs. 1.0 ; P = 0.03 ) and reduced pain intensity and odynophagia compared to placebo ( 0.18 vs. 0.01 and 0.12 vs. 0.01 , respectively , P = 0.04 ) . Depression and anxiety scores did not differ between the groups at baseline or after treatment . No significant adverse effects were observed . In this novel study , dronabinol increased pain threshold and reduced frequency and intensity of pain in FCP . Further , large scale studies are needed to substantiate these findings UNLABELLED The Food and Drug Administration ( FDA ) , Substance Abuse and Mental Health Services Administration ( SAMHSA ) , and the National Institute for Drug Abuse ( NIDA ) report that no sound scientific studies support the medicinal use of cannabis . Despite this lack of scientific validation , many patients routinely use " medical marijuana , " and in many cases this use is for pain related to nerve injury . We conducted a double-blinded , placebo-controlled , crossover study evaluating the analgesic efficacy of smoking cannabis for neuropathic pain . Thirty-eight patients with central and peripheral neuropathic pain underwent a st and ardized procedure for smoking either high-dose ( 7 % ) , low-dose ( 3.5 % ) , or placebo cannabis . In addition to the primary outcome of pain intensity , secondary outcome measures included evoked pain using heat-pain threshold , sensitivity to light touch , psychoactive side effects , and neuropsychological performance . A mixed linear model demonstrated an analgesic response to smoking cannabis . No effect on evoked pain was seen . Psychoactive effects were minimal and well-tolerated , with some acute cognitive effects , particularly with memory , at higher doses . PERSPECTIVE This study adds to a growing body of evidence that cannabis may be effective at ameliorating neuropathic pain , and may be an alternative for patients who do not respond to , or can not tolerate , other drugs . However , the use of marijuana as medicine may be limited by its method of administration ( smoking ) and modest acute cognitive effects , particularly at higher doses 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 Abstract Purpose / aim : To evaluate the efficacy of tetrahydrocannabinol (THC):cannabidiol ( CBD ) oromucosal spray ( Sativex ® ) as add-on therapy to optimised st and ard antispasticity treatment in patients with moderate to severe multiple sclerosis ( MS ) spasticity . Methods : Sativex ® as add-on therapy vs. further optimised first-line ANTispastics ( SAVANT ) was a two-phase trial . In Phase A , eligible patients received add-on THC : CBD spray for 4 weeks to identify initial responders [ ≥20 % improvement from baseline in spasticity 0–10 numerical rating scale ( NRS ) score ] . Following washout , eligible initial responders were r and omised to receive THC : CBD spray or placebo for 12 weeks ( double-blinded , Phase B ) . Optimisation of underlying antispasticity medications was permitted in both groups across all study periods . Results : Of 191 patients who entered Phase A , 106 were r and omised in Phase B to receive add-on THC : CBD spray ( n = 53 ) or placebo ( n = 53 ) . The proportion of clinical ly relevant responders after 12 weeks ( ≥30 % NRS improvement ; primary efficacy endpoint ) was significantly greater with THC : CBD spray than placebo ( 77.4 vs. 32.1 % ; p < 0.0001 ) . Compared with placebo , THC : CBD spray also significantly improved key secondary endpoints : changes in mean spasticity NRS ( p < 0.0001 ) , mean pain NRS ( p = 0.0013 ) , and mean modified Ashworth ’s scale ( p = 0.0007 ) scores from Phase B baseline to week 12 . Adverse events , when present , were mild/moderate and without new safety concerns . Conclusions : Add-on THC : CBD oromucosal spray provided better and clinical ly relevant improvement of resistant MS spasticity compared with adjusting first-line antispasticity medication alone 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
target: Pain intensity of chronic non-cancer patients was reduced by cannabinoids consumption , but effect sizes were small .
  Efficacy for neuropathic and non-neuropathic pain was similar
background: There is growing interest in using cannabinoids for chronic pain .
  We performed a systematic review and meta- analysis of r and omized controlled trials to evaluate the analgesic efficacy and adverse effects of cannabinoids for chronic non-cancer pain .