title: The Cannabinoid Use in Progressive Inflammatory brain Disease (CUPID) trial: a randomised double-blind placebo-controlled parallel-group multicentre trial and economic evaluation of cannabinoids to slow progression in multiple sclerosis. 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 Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex(®) ), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Cannabis in painful HIV-associated sensory neuropathy 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 Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial 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 The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Tetrahydrocannabinol (THC) for cramps in amyotrophic lateral sclerosis: a randomised, double-blind crossover trial Smoked Medicinal Cannabis for Neuropathic Pain in HIV: A Randomized, Crossover Clinical Trial Sativex successfully treats neuropathic pain characterised by allodynia: A randomised, double-blind, placebo-controlled clinical trial Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled 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 GRADE guidelines: 3. Rating the quality of evidence. Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration. Nabilone for the treatment of pain in fibromyalgia. 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 double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis 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 Dronabinol Is a Safe Long-Term Treatment Option for Neuropathic Pain Patients
abstract: BACKGROUND The Cannabinoid Use in Progressive Inflammatory brain Disease ( CUPID ) trial aim ed to determine whether or not oral Δ(9)-tetrahydrocannabinol ( Δ(9)-THC ) slowed the course of progressive multiple sclerosis ( MS ) ; evaluate safety of cannabinoid administration ; and , improve methods for testing treatments in progressive MS . OBJECTIVES There were three objectives in the CUPID study : ( 1 ) to evaluate whether or not Δ(9)-THC could slow the course of progressive MS ; ( 2 ) to assess the long-term safety of Δ(9)-THC ; and ( 3 ) to explore newer ways of conducting clinical trials in progressive MS . DESIGN The CUPID trial was a r and omised , double-blind , placebo-controlled , parallel-group , multicentre trial . Patients were r and omised in a 2 : 1 ratio to Δ(9)-THC or placebo . R and omisation was balanced according to Exp and ed Disability Status Scale ( EDSS ) score , study site and disease type . Analyses were by intention to treat , following a pre-specified statistical analysis plan . A cranial magnetic resonance imaging ( MRI ) sub study , Rasch measurement theory ( RMT ) analyses and an economic evaluation were undertaken . SETTING Twenty-seven UK sites . PARTICIPANTS Adults aged 18 - 65 years with primary or secondary progressive MS , 1-year evidence of disease progression and baseline EDSS 4.0 - 6.5 . INTERVENTIONS Oral Δ(9)-THC ( maximum 28 mg/day ) or matching placebo . ASSESSMENT VISITS Three and 6 months , and then 6-monthly up to 36 or 42 months . MAIN OUTCOME MEASURES Primary outcomes were time to EDSS progression , and change in Multiple Sclerosis Impact Scale-29 version 2 ( MSIS-29v2 ) 20-point physical subscale ( MSIS-29phys ) score . Various secondary patient- and clinician-reported outcomes and MRI outcomes were assessed . RMT analyses examined performance of MS-specific rating scales as measurement instruments and tested for a symptomatic or disease-modifying treatment effect . Economic evaluation estimated mean incremental costs and quality -adjusted life-years ( QALYs ) . RESULTS Effectiveness - recruitment targets were achieved . Of the 498 r and omised patients ( 332 to active and 166 to placebo ) , 493 ( 329 active and 164 placebo ) were analysed . PRIMARY OUTCOMES no significant treatment effect ; hazard ratio EDSS score progression ( active : placebo ) 0.92 [ 95 % confidence interval ( CI ) 0.68 to 1.23 ] ; and estimated between-group difference in MSIS-29phys score ( active-placebo ) -0.9 points ( 95 % CI -2.0 to 0.2 points ) . Secondary clinical and MRI outcomes : no significant treatment effects . Safety - at least one serious adverse event : 35 % and 28 % of active and placebo patients , respectively . RMT analyses - scale evaluation : MSIS-29 version 2 , MS Walking Scale-12 version 2 and MS Spasticity Scale-88 were robust measurement instruments . There was no clear symptomatic or disease-modifying treatment effect . Economic evaluation - estimated mean incremental cost to NHS over usual care , over 3 years £ 27,443.20 per patient . No between-group difference in QALYs . CONCLUSIONS The CUPID trial failed to demonstrate a significant treatment effect in primary or secondary outcomes . There were no major safety concerns , but unwanted side effects seemed to affect compliance . Participants were more disabled than in previous studies and deteriorated less than expected , possibly reducing our ability to detect treatment effects . RMT analyses supported performance of MS-specific rating scales as measures , enabled group- and individual person-level examination of treatment effects , but did not influence study inferences . The intervention had significant additional costs with no improvement in health outcomes ; therefore , it was dominated by usual care and not cost-effective . Future work should focus on determining further factors to predict clinical deterioration , to inform the development of new studies , and modifying treatments in order to minimise side effects and improve study compliance . The absence of disease-modifying treatments in progressive MS warrants further studies of the cannabinoid pathway in potential neuroprotection . TRIAL REGISTRATION Current Controlled Trials IS RCT N62942668 . FUNDING The National Institute for Health Research Health Technology Assessment programme , the Medical Research Council Efficacy and Mechanism Evaluation programme , Multiple Sclerosis Society and Multiple Sclerosis Trust . The report will be published in full in Health Technology Assessment ; Vol . 19 , No. 12 . See the NIHR Journals Library website for further project information 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 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 : 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 BACKGROUND Spasticity is a disabling complication of multiple sclerosis , affecting many patients with the condition . We report the first Phase 3 placebo-controlled study of an oral antispasticity agent to use an enriched study design . METHODS A 19-week follow-up , multicentre , double-blind , r and omized , placebo-controlled , parallel-group study in subjects with multiple sclerosis spasticity not fully relieved with current antispasticity therapy . Subjects were treated with nabiximols , as add-on therapy , in a single-blind manner for 4weeks , after which those achieving an improvement in spasticity of ≥20 % progressed to a 12-week r and omized , placebo-controlled phase . RESULTS Of the 572 subjects enrolled , 272 achieved a ≥20 % improvement after 4weeks of single-blind treatment , and 241 were r and omized . The primary end-point was the difference between treatments in the mean spasticity Numeric Rating Scale ( NRS ) in the r and omized , controlled phase of the study . Intention-to-treat ( ITT ) analysis showed a highly significant difference in favour of nabiximols ( P=0.0002 ) . Secondary end-points of responder analysis , Spasm Frequency Score , Sleep Disturbance NRS Patient , Carer and Clinician Global Impression of Change were all significant in favour of nabiximols . CONCLUSIONS The enriched study design provides a method of determining the efficacy and safety of nabiximols in a way that more closely reflects proposed clinical practice , by limiting exposure to those patients who are likely to benefit from it . Hence , the difference between active and placebo should be a reflection of efficacy and safety in the population intended for treatment Objective : To determine the effect of smoked cannabis on the neuropathic pain of HIV-associated sensory neuropathy and an experimental pain model . Methods : Prospect i ve r and omized placebo-controlled trial conducted in the inpatient General Clinical Research Center between May 2003 and May 2005 involving adults with painful HIV-associated sensory neuropathy . Patients were r and omly assigned to smoke either cannabis ( 3.56 % tetrahydrocannabinol ) or identical placebo cigarettes with the cannabinoids extracted three times daily for 5 days . Primary outcome measures included ratings of chronic pain and the percentage achieving > 30 % reduction in pain intensity . Acute analgesic and anti-hyperalgesic effects of smoked cannabis were assessed using a cutaneous heat stimulation procedure and the heat/capsaicin sensitization model . Results : Fifty patients completed the entire trial . Smoked cannabis reduced daily pain by 34 % ( median reduction ; IQR = −71 , −16 ) vs 17 % ( IQR = −29 , 8) with placebo ( p = 0.03 ) . Greater than 30 % reduction in pain was reported by 52 % in the cannabis group and by 24 % in the placebo group ( p = 0.04 ) . The first cannabis cigarette reduced chronic pain by a median of 72 % vs 15 % with placebo ( p < 0.001 ) . Cannabis reduced experimentally induced hyperalgesia to both brush and von Frey hair stimuli ( p ≤ 0.05 ) but appeared to have little effect on the painfulness of noxious heat stimulation . No serious adverse events were reported . Conclusion : Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy . The findings are comparable to oral drugs used for chronic neuropathic pain 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 & 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 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 Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background Many patients with amyotrophic lateral sclerosis ( ALS ) experience cramps during the course of the disease but so far , none of the medications used has been of proven benefit . The objective was to determine the effect of orally administered tetrahydrocannabinol ( THC ) on cramps in ALS patients . Methods The authors conducted a r and omised , double-blind , placebo-controlled crossover trial in 27 ALS patients suffering from moderate to severe ( visual analogue scale ( VAS ) ; VAS≥4 ) daily cramps . There were 7 women and 20 men with a mean age of 57 years and a mean functional ALS score ( ALSFRS-R ) of 38.4 . Patients were r and omly assigned to receive 5 mg THC twice daily followed by placebo or vice versa . Each treatment period lasted for 2 weeks and was preceded by a 2-week drug-free observation period ( run-in , wash-out period respectively ) . The primary outcome measure was change in cramp intensity as assessed by a VAS . Secondary outcome measures included the number of cramps per day , number of cramps during daytime and bedtime , intensity of fasciculations ( VAS ) as well as vali date d measures of quality of life ( ALSAQ-40 ) , quality of sleep ( SDQ ) , appetite ( FAACT ) and depression ( HADS ) . Results Complete data were available from 22 patients . THC was well tolerated . There was no evidence for a treatment effect on cramp intensity , number of cramps , fasciculation intensity or any of the other secondary outcome measures . Conclusions This interventional study with orally administered THC 5 mg twice daily did not demonstrate subjective improvement of cramp intensity in ALS patients 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 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 CONTEXT 1',1'dimethylheptyl-Delta8-tetrahydrocannabinol-11-oic acid ( CT-3 ) , a potent analog of THC-11-oic acid , produces marked antiallodynic and analgesic effects in animals without evoking the typical effects described in models of cannabinoids . Therefore , CT-3 may be an effective analgesic for poorly controlled resistant neuropathic pain . OBJECTIVE To examine the analgesic efficacy and safety of CT-3 in chronic neuropathic pain in humans . DESIGN AND SETTING R and omized , placebo-controlled , double-blind crossover trial conducted in Germany from May-September 2002 . PARTICIPANTS Twenty-one patients ( 8 women and 13 men ) aged 29 to 65 years ( mean , 51 years ) who had a clinical presentation and examination consistent with chronic neuropathic pain ( for at least 6 months ) with hyperalgesia ( n = 21 ) and allodynia ( n = 7 ) . INTERVENTIONS Patients were r and omized to two 7-day treatment orders in a crossover design . Two daily doses of CT-3 ( four 10-mg capsules per day ) or identical placebo capsules were given during the first 4 days and 8 capsules per day were given in 2 daily doses in the following 3 days . After a washout and baseline period of 1 week each , patients crossed over to the second 7-day treatment period . MAIN OUTCOME MEASURES Visual analog scale ( VAS ) and verbal rating scale scores for pain ; vital sign , hematologic and blood chemistry , and electrocardiogram measurements ; scores on the Trail-Making Test and the Addiction Research Center Inventory-Marijuana scale ; and adverse effects . RESULTS The mean differences over time for the VAS values in the CT-3-placebo sequence measured 3 hours after intake of study drug differed significantly from those in the placebo-CT-3 sequence ( mean [ SD ] , -11.54 [ 14.16 ] vs 9.86 [ 21.43 ] ; P = .02 ) . Eight hours after intake of the drug , the pain scale differences between groups were less marked . No dose response was observed . Adverse effects , mainly transient dry mouth and tiredness , were reported significantly more often during CT-3 treatment ( mean [ SD ] difference , -0.67 [ 0.50 ] for CT-3-placebo sequence vs 0.10 [ 0.74 ] for placebo-CT-3 sequence ; P = .02 ) . There were no significant differences with respect to vital signs , blood tests , electrocardiogram , Trail-Making Test , and Addiction Research Center Inventory-Marijuana scale . No carryover or period effects were observed except on the Trail-Making Test . CONCLUSIONS In this preliminary study , CT-3 was effective in reducing  chronic neuropathic pain  compared with placebo . No major adverse effects were observed 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 This article introduces the approach of GRADE to rating  quality of evidence .  GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence BACKGROUND Sativex ( ® ) , a cannabis extract oromucosal spray containing Δ(9)-tetrahydrocannabinol ( THC ) and cannabidiol ( CBD ) , is currently in phase III trials as an adjunct to opioids for cancer pain treatment , and recently received United Kingdom approval for treatment of spasticity . There are indications that CBD modulates THC 's effects , but it is unclear if this is due to a pharmacokinetic and /or pharmacodynamic interaction . METHODS Cannabis smokers provided written informed consent to participate in this r and omized , controlled , double-blind , double-dummy institutional review board-approved study . Participants received 5 and 15 mg synthetic oral THC , low-dose ( 5.4 mg THC and 5.0 mg CBD ) and high-dose ( 16.2 mg THC and 15.0 mg CBD ) Sativex , and placebo over 5 sessions . CBD , THC , 11-hydroxy-THC , and 11-nor- 9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS . Lower limits of quantification were ≤0.25 μg/L. RESULTS Nine cannabis smokers completed all 5 dosing sessions . Significant differences ( P < 0.05 ) in maximum plasma concentrations ( C(max ) ) and areas under the curve from 0 - 10.5 h postdose ( AUC(0→10.5 ) ) for all analytes were found between low and high doses of synthetic THC and Sativex . There were no statistically significant differences in C(max ) , time to maximum concentration or in the AUC(0→10.5 ) between similar oral THC and Sativex doses . Relative bioavailability was calculated to determine the relative rate and extent of THC absorption ; 5 and 15 mg oral THC bioavailability was 92.6 % ( 13.1 % ) and 98.8 % ( 11.0 % ) of low- and high-dose Sativex , respectively . CONCLUSION These data suggest that CBD modulation of THC 's effects is not due to a pharmacokinetic interaction at these therapeutic doses 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 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 Abstract Background : Muscle spasticity is common in multiple sclerosis ( MS ) , occurring in more than 60 % of patients . Objective : To compare Sativex with placebo in relieving symptoms of spasticity due to MS . Methods : A 15-week , multicenter , double-blind , r and omized , placebo-controlled , parallel-group study in 337 subjects with MS spasticity not fully relieved with current anti-spasticity therapy . Results : The primary endpoint was a spasticity 0–10 numeric rating scale ( NRS ) . Intention-to-treat ( ITT ) analysis showed a non-significant improvement in NRS score , in favor of Sativex . The per protocol ( PP ) population ( 79 % of subjects ) change in NRS score and responder analyses ( ≥30 % improvement from baseline ) were both significantly superior for Sativex , compared with placebo : −1·3 versus −0·8 points ( change from baseline , p=0·035 ) ; and 36 % versus 24 % ( responders , p=0·040 ) . These were supported by the time to response ( ITT : p=0·068 ; PP : p=0·025 ) analyses , carer global impression of change assessment ( p=0·013 ) and timed 10-meter walk ( p=0·042 ) . Among the subjects who achieved a ≥30 % response in spasticity  with Sativex , 98 , 94 and 73 % reported improvements of 10 , 20 and 30 % , respectively , at least once during the first 4 weeks of treatment . Sativex was generally well tolerated , with most adverse events reported being mild-to-moderate in severity . Discussion and conclusions : The 0–10 NRS and responder PP analyses demonstrated that Sativex treatment result ed in a significant reduction in treatment-resistant spasticity , in subjects with advanced MS and severe spasticity . The response observed within the first 4 weeks of treatment appears to be a useful aid to prediction of responder/non-responder status 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 Treatment of neuropathic pain ( NP ) symptoms associated with multiple sclerosis ( MS ) is frequently insufficient . Yet , cannabis is still rarely offered for treatment of pain . This clinical trial aim ed at showing the positive benefit-risk ratio of dronabinol .  Two hundred forty MS patients with central NP entered a 16-weeks placebo-controlled phase-III study followed by a 32-weeks open-label period . One hundred patients continued therapy for overall up to 119 weeks . Primary endpoint was change of pain intensity on the 11-point Numerical Rating Scale over a 16-weeks treatment period . Safety was assessed on the basis of adverse reactions ( ARs ) , signs of dependency and abuse . Pain intensity during 16-weeks dronabinol and placebo treatment was reduced by 1.92 and 1.81 points without significant difference in between ( p = 0.676 ) . Although the proportion of patients with ARs was higher under dronabinol compared to placebo ( 50.0 vs. 25.9 % ) , it decreased during long-term use of dronabinol ( 26 % ) . No signs of drug abuse and only one possible case of dependency occurred . The trial results demonstrate that dronabinol is a safe long-term treatment option
target: There was an increased risk of non-serious AEs with cannabinoids compared with placebo .
  Conclusions There was moderate evidence to support cannabinoids in treating chronic , non-cancer pain at 2 weeks .
  Similar results were observed at later time points , but the confidence in effect is low .
  There is little evidence that cannabinoids increase the risk of experiencing serious AEs , although non-serious AEs may be common in the short-term period following use
background: Background For patients with chronic , non-cancer pain , traditional pain-relieving medications include opioids , which have shown benefits but are associated with increased risks of addiction and adverse effects .
  Medical cannabis has emerged as a treatment alternative for managing these patients and there has been a rise in the number of r and omized clinical trials in recent years ; therefore , a systematic review of the evidence was warranted .
  Objective To analyze the evidence surrounding the benefits and harms of medical cannabinoids in the treatment of chronic , non-cancer-related pain .