Page 2 - The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews

8 Page 2 of 12 Curr Neurol Neurosci Rep (2018) 18:8

distressing and/or disabling symptoms of multiple sclerosis e.g. tetrahydrocannabinolic acid (thca), cannabidiolic acid,
include anticonvulsants for neuropathic pain, anticholinergic cannabidivarin, and the synthetic delta-9-tetrahydrocannabinol
drugs for bladder dysfunction and dysphagia, and botulinum formulations (nabilone and dronabinol).
toxin injections for spasticity [1]. The use of these symptom-
atic therapies may be limited by their toxicity [8]. Types of Outcomes
Anecdotal reports that patients with multiple sclerosis ex-
perience symptomatic relief after smoking cannabis have This review considered the following eight key outcomes in
prompted research using cannabinoids to manage symptoms trials of cannabinoids for symptom relief in multiple sclerosis
[9]. Research is now also examining the potential for canna- [19•]:
binoids to slow disease progression as well as palliate spastic-
ity and pain [10]. & Disability and disability progression
Neuropathic pain and pain in association with muscle & Pain
spasms are common distressing symptoms in multiple sclero- & Spasticity
sis [11]. Animal models have suggested that cannabinoid & Bladder function
(CB)-1 receptor activation may reduce neuropathic, visceral & Ataxia and tremor
and inflammatory pain [12, 13]. Several preclinical studies & Sleep
have demonstrated that systemic administration of cannabi- & Quality of life
noid receptor ligands produce analgesia in acute and chronic & Adverse effects
pain models [14]. Research has also explored the role of CB2
receptors, which seem to mediate anti-hyperalgesia in inflam-
matory pain states, [15, 16] and reduce inflammation and neu- Inclusion Criteria
ropathic pain [17]. Cannabinoids, and the endocannabinoid
system, have been demonstrated to have a role in reducing We included reviews of experimental and epidemiological
spasticity in animal models [18]. study designs. These included randomised controlled trials,
Multiple reviews on this topic have been conducted with non-randomised controlled trials, quasi-experimental, before
varying conclusions. This systematic review of reviews and after studies, prospective and retrospective cohort studies,
synthesises moderate to high quality reviews assessing the case control studies and analytical cross sectional studies.
effectiveness of cannabis and cannabinoids for treating multi- Reviews were required to meet the minimum standards of
ple sclerosis. More specifically, the objectives are to identify describing a systematic search and providing study level data
the effectiveness of plant-based cannabinoids, and pharma- within the review (i.e. met the AMSTAR criteria 3 and 6, see
ceutical cannabinoids (plant-derived or synthetically Appendix 2). Review articles that were not published in
manufactured) in reducing disability and disability progres- English were considered for inclusion. Where these reviews
sion, pain, spasticity and improving quality of life in people used high quality methodology or provided research evidence
with multiple sclerosis. These outcomes are patient-centred, that was not included in existing reviews we planned to obtain
short to medium term, and relevant to the daily lives and translations; however, no such reviews were identified.
experiences of people living with multiple sclerosis.
Exclusion Criteria

Methods We did not include reports of single studies, reviews of mech-
anisms of cannabinoid systems, or commentary articles and
Inclusion Criteria clinical overviews that did not describe a systematic review or
assess and synthesise evidence at the individual study level.
Types of Participants
Search Strategy
The review considered systematic reviews of studies that in-
cluded participants with multiple sclerosis. Eight databases (Medline, Medline In-Process & Other Non-
Indexed Citations/Ovid; Embase/Ovid; PsycINFO/Ovid;
Types of Intervention EBM Reviews—Cochrane Central Register of Controlled
Trials/Ovid) were searched with the terms below (and their
We included reviews of studies that evaluated plant-based and corresponding subject headings in each database where
pharmaceutical cannabinoids: tetrahydrocannabinol; specialised thesauri existed). The searches were limited to
cannabidiol; combination tetrahydrocannabinol + cannabidiol; studies published from 1980 to the end of 2016 (a sample
Cannabis sativa; and where evidence exists, other cannabinoids Medline search is reproduced, Appendix 1).