PMID- 35510826 OWN - NLM STAT- MEDLINE DCOM- 20220506 LR - 20230506 IS - 1469-493X (Electronic) IS - 1361-6137 (Linking) VI - 5 IP - 5 DP - 2022 May 5 TI - Cannabis and cannabinoids for symptomatic treatment for people with multiple sclerosis. PG - CD013444 LID - 10.1002/14651858.CD013444.pub2 [doi] LID - CD013444 AB - BACKGROUND: Spasticity and chronic neuropathic pain are common and serious symptoms in people with multiple sclerosis (MS). These symptoms increase with disease progression and lead to worsening disability, impaired activities of daily living and quality of life. Anti-spasticity medications and analgesics are of limited benefit or poorly tolerated. Cannabinoids may reduce spasticity and pain in people with MS. Demand for symptomatic treatment with cannabinoids is high. A thorough understanding of the current body of evidence regarding benefits and harms of these drugs is required. OBJECTIVES: To assess benefit and harms of cannabinoids, including synthetic, or herbal and plant-derived cannabinoids, for reducing symptoms for adults with MS. SEARCH METHODS: We searched the following databases from inception to December 2021: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), CINAHL (EBSCO host), LILACS, the Physiotherapy Evidence Database (PEDro), the World Health Organisation International Clinical Trials Registry Platform, the US National Institutes of Health clinical trial register, the European Union Clinical Trials Register, the International Association for Cannabinoid Medicines databank. We hand searched citation lists of included studies and relevant reviews. SELECTION CRITERIA: We included randomised parallel or cross-over trials (RCTs) evaluating any cannabinoid (including herbal Cannabis, Cannabis flowers, plant-based cannabinoids, or synthetic cannabinoids) irrespective of dose, route, frequency, or duration of use for adults with MS. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane Risk of bias 2 tool for parallel RCTs and crossover trials. We rated the certainty of evidence using the GRADE approach for the following outcomes: reduction of 30% in the spasticity Numeric Rating Scale, pain relief of 50% or greater in the Numeric Rating Scale-Pain Intensity, much or very much improvement in the Patient Global Impression of Change (PGIC), Health-Related Quality of Life (HRQoL), withdrawals due to adverse events (AEs) (tolerability), serious adverse events (SAEs), nervous system disorders, psychiatric disorders, physical dependence. MAIN RESULTS: We included 25 RCTs with 3763 participants of whom 2290 received cannabinoids. Age ranged from 18 to 60 years, and between 50% and 88% participants across the studies were female. The included studies were 3 to 48 weeks long and compared nabiximols, an oromucosal spray with a plant derived equal (1:1) combination of tetrahydrocannabinol (THC) and cannabidiol (CBD) (13 studies), synthetic cannabinoids mimicking THC (7 studies), an oral THC extract of Cannabis sativa (2 studies), inhaled herbal Cannabis (1 study) against placebo. One study compared dronabinol, THC extract of Cannabis sativa and placebo, one compared inhaled herbal Cannabis, dronabinol and placebo. We identified eight ongoing studies. Critical outcomes * Spasticity: nabiximols probably increases the number of people who report an important reduction of perceived severity of spasticity compared with placebo (odds ratio (OR) 2.51, 95% confidence interval (CI) 1.56 to 4.04; 5 RCTs, 1143 participants; I(2) = 67%; moderate-certainty evidence). The absolute effect was 216 more people (95% CI 99 more to 332 more) per 1000 reporting benefit with cannabinoids than with placebo. * Chronic neuropathic pain: we found only one small trial that measured the number of participants reporting substantial pain relief with a synthetic cannabinoid compared with placebo (OR 4.23, 95% CI 1.11 to 16.17; 1 study, 48 participants; very low-certainty evidence). We are uncertain whether cannabinoids reduce chronic neuropathic pain intensity. * Treatment discontinuation due to AEs: cannabinoids may increase slightly the number of participants who discontinue treatment compared with placebo (OR 2.41, 95% CI 1.51 to 3.84; 21 studies, 3110 participants; I(2) = 17%; low-certainty evidence); the absolute effect is 39 more people (95% CI 15 more to 76 more) per 1000 people. Important outcomes * PGIC: cannabinoids probably increase the number of people who report 'very much' or 'much' improvement in health status compared with placebo (OR 1.80, 95% CI 1.37 to 2.36; 8 studies, 1215 participants; I(2) = 0%; moderate-certainty evidence). The absolute effect is 113 more people (95% CI 57 more to 175 more) per 1000 people reporting improvement. * HRQoL: cannabinoids may have little to no effect on HRQoL (SMD -0.08, 95% CI -0.17 to 0.02; 8 studies, 1942 participants; I(2) = 0%; low-certainty evidence); * SAEs: cannabinoids may result in little to no difference in the number of participants who have SAEs compared with placebo (OR 1.38, 95% CI 0.96 to 1.99; 20 studies, 3124 participants; I(2) = 0%; low-certainty evidence); * AEs of the nervous system: cannabinoids may increase nervous system disorders compared with placebo (OR 2.61, 95% CI 1.53 to 4.44; 7 studies, 1154 participants; I(2) = 63%; low-certainty evidence); * Psychiatric disorders: cannabinoids may increase psychiatric disorders compared with placebo (OR 1.94, 95% CI 1.31 to 2.88; 6 studies, 1122 participants; I(2) = 0%; low-certainty evidence); * Drug tolerance: the evidence is very uncertain about the effect of cannabinoids on drug tolerance (OR 3.07, 95% CI 0.12 to 75.95; 2 studies, 458 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Compared with placebo, nabiximols probably reduces the severity of spasticity in the short-term in people with MS. We are uncertain about the effect on chronic neurological pain and health-related quality of life. Cannabinoids may increase slightly treatment discontinuation due to AEs, nervous system and psychiatric disorders compared with placebo. We are uncertain about the effect on drug tolerance. The overall certainty of evidence is limited by short-term duration of the included studies. CI - Copyright (c) 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. FAU - Filippini, Graziella AU - Filippini G AD - Scientific Director's Office, Carlo Besta Foundation and Neurological Institute, Milan, Italy. FAU - Minozzi, Silvia AU - Minozzi S AD - Department of Epidemiology, Lazio Regional Health Service, Rome, Italy. FAU - Borrelli, Francesca AU - Borrelli F AD - Department of Pharmacy, School of Medicine and Surgery, University of Naples 'Federico II', Naples, Italy. FAU - Cinquini, Michela AU - Cinquini M AD - Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. FAU - Dwan, Kerry AU - Dwan K AD - Review Production and Quality Unit, Editorial & Methods Department, Cochrane Central Executive, London, UK. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Review PT - Systematic Review DEP - 20220505 PL - England TA - Cochrane Database Syst Rev JT - The Cochrane database of systematic reviews JID - 100909747 RN - 0 (Analgesics) RN - 0 (Cannabinoids) RN - 0 (Plant Extracts) RN - 7J8897W37S (Dronabinol) SB - IM UOF - doi: 10.1002/14651858.CD013444 MH - Activities of Daily Living MH - Adolescent MH - Adult MH - Analgesics/therapeutic use MH - *Cannabinoids/adverse effects MH - *Cannabis MH - *Chronic Pain/drug therapy MH - Dronabinol/adverse effects MH - Female MH - Humans MH - Male MH - Middle Aged MH - *Multiple Sclerosis/complications/drug therapy MH - *Neuralgia/drug therapy/etiology MH - Plant Extracts/therapeutic use MH - Quality of Life MH - Young Adult PMC - PMC9069991 COIS- GF: none SM: none FB: She received research grants from GW pharmaceuticals (Cambridge, UK) to perform preclinical studies on phytocannabinoids and intestinal diseases, and patents on phytocannabinoids and colorectal cancer or inflammatory bowel diseases MC: none KD: She is employed as statistical editor by Cochrane EDAT- 2022/05/06 06:00 MHDA- 2022/05/07 06:00 PMCR- 2023/05/05 CRDT- 2022/05/05 08:33 PHST- 2022/05/05 08:33 [entrez] PHST- 2022/05/06 06:00 [pubmed] PHST- 2022/05/07 06:00 [medline] PHST- 2023/05/05 00:00 [pmc-release] AID - CD013444.pub2 [pii] AID - 10.1002/14651858.CD013444.pub2 [doi] PST - epublish SO - Cochrane Database Syst Rev. 2022 May 5;5(5):CD013444. doi: 10.1002/14651858.CD013444.pub2.