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KSR Number: KSRA81247

Assessment of efficacy and tolerability of medicinal cannabinoids in patients with multiple sclerosis: a systematic review and meta-analysis

Risk of Bias Assessment

Overall summary: Low risk of bias in the review

Bottom Line

Results of this systematic review showed that cannibinoids might be more effective than placebo in addressing spasticity of adults with MS. However, this was limited to self-reported spasticity, i.e. when spasticity was assessed by the more objective Ashworth scale, no statistically significant differences were seen. Similarly, cannabinoids might be beneficial for the treatment of pain and bladder dysfunction in adults with MS. More adverse events were seen in patients treated with cannabinoids compared to placebo, however, no differences in serious adverse events were noted. There are some differences in different forms of medicinal cannabinoids which need to be considered. Overall, the systematic review was well conducted and the results are likely to be reliable. Future research should focus further on the effectiveness of different drug forms and the clinical relevance of these findings.

Risk of Bias Assessment

Overall summary Low risk of bias in the review

Low

The assessment identified no major methodological shortcomings with the systematic review. The abstract focused on statistically significant results, however, full results are presented in the study and the appendices.

A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4? Yes
B. Was the relevance of identified studies to the review's research question appropriately considered? Yes
C. Did the reviewers avoid emphasizing results on the basis of their statistical significance? Probably yes
Risk of bias in the review Low

Details of Review

Number of studies 17
Number of participants 3161
Last search date July 2016
Review type Intervention
Objective To assess efficacy and safety of medicinal cannabinoids for adults with multiple sclerosis.
Population Adult patients with multiple sclerosis.
Interventions Medicinal cannabinoids (oral or oralmucosal): cannabis extract (mixture of δ-9-tetrahydrocannabinol and cannabidiol; THC and CBD), nabiximols (THC and CBD), dronabinol (THC), or nabilone (THC).
Comparator Placebo.
Outcome Symptoms of spasticity, pain, or bladder dysfunction; adverse events.
Study design Randomised controlled trials. Minimum study length of two weeks.

Results

For spasticity assessed by the (modified) Ashworth scale, no statistically significant differences were found when comparing any of the assessed drug forms against placebo: cannabis extract (standardised mean difference [SMD] 0.01, 95% confidence interval [CI] -0.18 to 0.20; 3 studies, 456 participants), nabiximols (SMD -0.11, 95% CI -0.22 to 0.01; 7 studies, 1,170 participants), and dronabinol (SMD -0.16, 95% CI -0.38 to 0.07; 2 studies, 336 participants). Across all drug forms, no statistically significant difference was seen (SMD -0.09, 95% CI -0.18 to 0.00027; 10 studies, 1,962 participants).

For spasticity assessed by subjective patient-reported measures, statistically significant differences were found when comparing two drug forms (cannabis extract, nabiximols) against placebo but not for dronabinol compared to placebo: cannabis extract (SMD -0.27, 95% CI -0.44 to -0.09; 2 studies, 595 participants), nabiximols (SMD -0.29, 95% CI -0.47 to -0.12; 8 studies, 1,509 participants), and dronabinol (SMD -0.13, 95% CI -0.46 to 0.20; 2 studies, 805 participants). Across all drug forms, a statistically significant difference was seen (SMD -0.25, 95% CI -0.38 to -0.13; 11 studies, 2,909 participants).

For pain, statistically significant differences were seen for the comparison of cannabis extract or nabilone versus placebo but not when comparing the other drug forms (nabiximols, dronabinol) or all drug forms to placebo: cannabis extract (SMD -0.33, 95% CI -0.50 to -0.16; 2 studies, 595 participants), nabilone (SMD -1.40, 95% CI -2.78 to -0.03; 1 study, 15 participants), nabiximols (SMD -0.07, 95% CI -0.26 to 0.12; 6 studies, 1,229 participants), dronabinol (SMD -0.23, 95% CI -0.55 to 0.09; 3 studies, 853 participants), and across all drug forms (SMD -0.17, 95% CI -0.31 to -0.03; 11 studies, 2,909 participants).

Regarding bladder dysfunction, statistically significant differences were seen for the comparison of cannabis extract or across all drug forms versus placebo but not when comparing nabiximols or dronabinol to placebo: cannabis extract (SMD -0.29, 95% CI -0.50 to -0.09; 2 studies, 432 participants), across all drug forms (SMD -0.11, 95% CI -0.22 to -0.0008; 6 studies, 2,208 participants), nabiximols (SMD -0.07, 95% CI -0.22 to 0.08; 4 studies, 971 participants), and dronabinol (SMD -0.06, 95% CI -0.27 to 0.16; 2 studies, 805 participants).

In terms of adverse events, statistically significantly more adverse events were seen for nabiximols or dronabinol compared to placebo but not for cannabis extract or across all drug forms versus placebo: nabiximols (SMD 1.80, 95% CI 1.53 to 2.12; 10 studies, 1,710 participants), dronabinol (SMD 1.62, 95% CI 1.12 to 2.34; 4 studies, 877 participants), cannabis extract (SMD 1.51, 95% CI 0.87 to 2.63; 4 studies, 733 participants) and across all drug forms (SMD 1.72, 95% CI 1.46 to -2.02; 16 studies, 3,320 participants).

In regards to serious adverse events, no statistically significant differences were seen for any of the comparators versus placebo: cannabis extract (SMD 0.99, 95% CI 0.26 to 3.74; 2 studies, 595 participants), nabiximols (SMD 1.43, 95% CI 0.66 to 3.09; 8 studies, 1,608 participants), dronabinol (SMD 1.21, 95% CI 0.89 to 1.63; 3 studies, 853 participants), and across all drug forms (SMD 1.23, 95% CI 0.82 to 1.85; 12 studies, 3,056 participants).

The authors assessed the impact of industry-funded studies in sensitivity analyses excluding these studies. The only study on nabilone and all studies on nabiximols were funded by pharmaceutical companies. These sensitivity analyses showed no differences between nabiximols and placebo in all the efficacy outcomes (results for safety outcomes not reported).

Full Risk of Bias Assessment

The systematic review followed objectives and eligibility criteria which were predefined and published on PROSPERO. Eligibility criteria appeared to be appropriate and unambiguous. Minimum study length of two weeks was required for inclusion, which was found to be appropriate. Only published studies were included. No other restrictions in eligibility criteria based on study characteristics were applied.

1.1 Did the review adhere to pre-defined objectives and eligibility criteria? Yes
1.2 Were the eligibility criteria appropriate for the review question? Probably yes
1.3 Were eligibility criteria unambiguous? Probably yes
1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)? Yes
1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)? Probably yes
Concerns regarding specification of study eligibility criteria Low

Searches were conducted in Medline and the Cochrane Library Plus up to 26/07/2016, and were not limited by date, language or publication type. The reported PubMed strategy was very simple, and only included the phrase "multiple sclerosis" as the disease facet. As a consequence, the number of references identified was low. Inclusion of additional disease synonyms, such as chariot disease or the abbreviation MS, would have benefited the search to improve sensitivity. Clinicaltrials.gov was also searched. Reference checking was conducted, and other sources of information were considered, including books, monographs and reports. Researchers reported contacting lead authors of included studies to request further information.

2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports? Probably no
2.2 Were methods additional to database searching used to identify relevant reports? Probably yes
2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible? Probably no
2.4 Were restrictions based on date, publication format, or language appropriate? Yes
2.5 Were efforts made to minimise error in selection of studies? Yes
Concerns regarding methods used to identify and/or select studies Low

Study selection and data collection "were jointly conducted" by two authors which is ambiguous, i.e. it is not clear whether these steps were done independently (according to current recommendations) or not. The systematic review presents sufficient details for all relevant studies, with results complemented from the respective clinical trial registration entry. The risk of bias (ROB) of included studies was assessed using the Cochrane ROB tool for randomised controlled trials. While this is appropriate, it is unclear how many reviewers were involved in the ROB assessment for each study. Potentially, this was also "jointly conducted".

3.1 Were efforts made to minimise error in data collection? Probably yes
3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results? Yes
3.3 Were all relevant study results collected for use in the synthesis? Yes
3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria? Yes
3.5 Were efforts made to minimise error in risk of bias assessment? Probably yes
Concerns regarding methods used to collect data and appraise studies Low

All relevant studies appeared to have been analysed using appropriate methods and results for all predefined analyses have been reported. Sensitivity analyses were conducted to investigate pooled estimates further, e.g. to exclude studies rated as high risk of bias.

4.1 Did the synthesis include all studies that it should? Probably yes
4.2 Were all pre-defined analyses reported or departures explained? Yes
4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies? Probably yes
4.4 Was between-study variation minimal or addressed in the synthesis? Probably yes
4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses? Probably yes
4.6 Were biases in primary studies minimal or addressed in the synthesis? Probably yes
Concerns regarding synthesis and findings Low

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