title: [Efficacy, tolerability and safety of cannabinoids for chronic neuropathic pain: A systematic review of randomized controlled studies].
abstract: BACKGROUND
  Recently published systematic reviews came to different conclusions with respect to the efficacy, tolerability and safety of cannabinoids for treatment of chronic neuropathic pain.
  
  
  METHODS
  A systematic search of the literature was carried out in MEDLINE, the Cochrane central register of controlled trials (CENTRAL) and clinicaltrials.gov up until November 2015. We included double-blind randomized placebo-controlled studies (RCT) of at least 2 weeks duration and with at least 9 patients per treatment arm comparing medicinal cannabis, plant-based or synthetic cannabinoids with placebo or any other active drug treatment in patients with chronic neuropathic pain. Clinical endpoints of the analyses were efficacy (more than 30 % or 50 % reduction of pain, average pain intensity, global improvement and health-related quality of life), tolerability (drop-out rate due to side effects, central nervous system and psychiatric side effects) and safety (severe side effects). Using a random effects model absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. The methodological quality of RCTs was rated by the Cochrane risk of bias tool.
  
  
  RESULTS
  We included 15 RCTs with 1619 participants. Study duration ranged between 2 and 15 weeks. Of the studies 10 used a plant-derived oromucosal spray with tetrahydrocannabinol/cannabidiol, 3 studies used a synthetic cannabinoid (2  with nabilone and 1  with dronabinol) and 2 studies used medicinal cannabis. The 13 studies with parallel or cross-over design yielded the following results with 95 % confidence intervals (CI): cannabinoids were superior to placebo in the reduction of mean pain intensity with SMD - 0.10 (95 % CI - 0.20- - 0.00, p = 0.05, 13 studies with 1565 participants), in the frequency of at least a 30 % reduction in pain with an RD of 0.10 [95 % CI 0.03-0.16, p = 0.004, 9 studies with 1346 participants, number needed to treat for additional benefit (NNTB) 14, 95 % CI 8-45] and in the frequency of a large or very large global improvement with an RD of 0.09 (95 % CI 0.01-0.17, p = 0.009, 7 studies with 1092 participants). There were no statistically significant differences between cannabinoids and placebo in the frequency of at least a 50 % reduction in pain, in improvement of health-related quality of life and in the frequency of serious adverse events. Patients treated with cannabinoids dropped out more frequently due to adverse events with an RD of 0.04 [95 % CI 0.01-0.07, p = 0.009, 11 studies with 1572 participants, number needed to treat for additional harm (NNTH) 19, 95 % CI 13-37], reported central nervous system side effects more frequently with an RD of 0.38 (95 % CI 0.18-0.58, p = 0.0003, 9 studies with 1304 participants, NNTH 3, 95 % CI 2-4) and psychiatric side effects with an RD of 0.11 (95 % CI 0.06-0.16, p < 0.0001, 9 studies with 1304 participants, NNTH 8, 95 % CI 7-12).
  
  
  CONCLUSIONS
  Cannabinoids were marginally superior to placebo in terms of efficacy and inferior in terms of tolerability. Cannabinoids and placebo did not differ in terms of safety during the study period. Short-term and intermediate-term therapy with cannabinoids can be considered in selected patients with chronic neuropathic pain after failure of first-line and second-line therapies.
authors.affiliation: Schmerz-Tagesklinik und -Ambulanz, Klinik für Anästhesiologie, Universitätsmedizin Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Deutschland. frank.petzke@med.uni-goettingen.de.
authors.forename: F
authors.initials: F
authors.lastname: Petzke
authors.affiliation: Neurologische Klinik, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil GmbH, Ruhr-Universität Bochum, 44789, Bochum, Deutschland.
authors.forename: E K
authors.initials: EK
authors.lastname: Enax-Krumova
authors.affiliation: Innere Medizin I, Klinikum Saarbrücken GmbH, Winterberg 1, 66119, Saarbrücken, Deutschland.|Klinik und Poliklinik für Psychosomatische Medizin und Psychotherapie, Technische Universität München, 81675, München, Deutschland.
authors.forename: W
authors.initials: W
authors.lastname: Häuser
mesh_terms: D002186:Cannabinoids / Q000009:adverse effects* / Q000627:therapeutic use*; D059350:Chronic Pain / Q000188:drug therapy*; D006801:Humans; D009437:Neuralgia / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic
chemical_list: D002186:Cannabinoids
keywords: Cannabidiol; Cannabis; Dronabinol; Nabilone; Tetrahydrocannabinol
references.citation: J Oral Facial Pain Headache. 2015 Winter;29(1):7-14
references.pmid: 25635955
references.citation: Schmerz. 2015 Feb;29(1):8-34
references.pmid: 25472889
references.citation: J Clin Epidemiol. 2009 Oct;62(10):e1-34
references.pmid: 19631507
references.citation: JAMA. 2015 Jun 23-30;313(24):2456-73
references.pmid: 26103030
references.citation: Int Clin Psychopharmacol. 2005 Jan;20(1):49-52
references.pmid: 15602117
references.citation: Clin Ther. 2007 Sep;29(9):2068-79
references.pmid: 18035205
references.citation: Pain Res Manag. 2014 Nov-Dec;19(6):328-35
references.pmid: 25479151
references.citation: Lancet Neurol. 2015 Feb;14(2):162-73
references.pmid: 25575710
references.citation: BMJ Open. 2014 Nov 20;4(11):e006112
references.pmid: 25412864
references.citation: Schmerz. 2015 Feb;29(1):109-30
references.pmid: 25616996
references.citation: Pain. 2011 Oct;152(10):2204-5
references.pmid: 21764514
references.citation: Br J Clin Pharmacol. 2011 Nov;72(5):735-44
references.pmid: 21426373
references.citation: J Pain. 2008 Feb;9(2):105-21
references.pmid: 18055266
references.citation: Neurology. 2014 Apr 29;82(17):1556-63
references.pmid: 24778283
references.citation: Qual Life Res. 2014 Feb;23(1):1-4
references.pmid: 23722635
references.citation: Clin Pharmacol Ther. 2015 Feb;97(2):135-42
references.pmid: 25670518
references.citation: J Pain. 2015 Dec;16(12):1221-1232
references.pmid: 26362106
references.citation: J Neurol Neurosurg Psychiatry. 2005 Dec;76(12):1664-9
references.pmid: 16291891
references.citation: Pain. 2014 Apr;155(4):654-62
references.pmid: 24291734
references.citation: Neurology. 2008 Apr 29;70(18):1630-5
references.pmid: 18003941
references.citation: J Neurol. 2015 Jan;262(1):27-40
references.pmid: 25270679
references.citation: Eur J Pain. 2013 Aug;17(7):953-6
references.pmid: 23339030
references.citation: Pain. 2010 Sep;150(3):386-9
references.pmid: 20627575
references.citation: Orthopade. 2004 May;33(5):568-75
references.pmid: 15067505