human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 ( CB 
    Output:
    
agent
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
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 ( CB 
    Output:
    