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©2014 American Academy of Neurology Systematic Review: Efficacy and Safety of Medical Marijuana (Cannabis) in Selected Neurologic Disorders Report of the Guideline Development Subcommittee of the American Academy of Neurology ©2014 American Academy of Neurology Systematic Review Endorsement • This systematic review was endorsed by the American Autonomic Society, the American Epilepsy Society, the Consortium of Multiple Sclerosis Centers, the International Organization of Multiple Sclerosis Nurses, and the International Rett Syndrome Foundation. ©2014 American Academy of Neurology Slide 2 Authors • Barbara S. Koppel, MD, FAAN • John C.M. Brust, MD, FAAN • Terry Fife, MD, FAAN • Jeff Bronstein, MD, PhD • Sarah Youssof, MD • Gary Gronseth, MD, FAAN • David Gloss, MD ©2014 American Academy of Neurology Slide 3 Sharing This Information • The American Academy of Neurology (AAN) develops these presentation slides as educational tools for neurologists and other health care practitioners. You may download and retain a single copy for your personal use. Please contact [email protected] to learn about options for sharing this content beyond your personal use. ©2014 American Academy of Neurology Slide 4 Presentation Objective • To present the findings for the efficacy of medical marijuana (cannabis) in several neurologic conditions. ©2014 American Academy of Neurology Slide 5 Overview • Background • Gaps in care • AAN systematic review process • Analysis of evidence with conclusions • Recommendations for future research ©2014 American Academy of Neurology Slide 6 Background • Marijuana contains approximately 60 pharmacologically active compounds (“cannabinoids”). • The presence of cannabinoid receptors in the brain led to discovery of endogenous ligands (endocannabinoids). The endocannabinoid system is widely distributed in the brain and spinal cord.1,2 ©2014 American Academy of Neurology Slide 7 Background, cont. • The concentration of Δ-9-tetrahydrocannabinol (THC) present in formulations and the ratio of THC to cannabidiol (CBD) (which limits THC’s psychoactive effects) play a role in therapeutic effects of cannabis products. • Physiologic responses include feelings of well-being or psychosis (depending on the “dose” of THC), impaired memory and cognitive processing, slowed locomotor function, as well as antinociceptive,3 antiemetic, antispasticity, and sleep-promoting effects. ©2014 American Academy of Neurology Slide 8 Background, cont. • A variety of formulations with differing amounts of THC and CBD were used in studies examined for this systematic review. Some formulations were pills, one was a mucosal spray, and some were vaporized or smoked. ©2014 American Academy of Neurology Slide 9 Clinical Questions What is the safety and efficacy of cannabinoids in relieving/reducing: 1. Spasticity in patients with multiple sclerosis (MS)? 2. Central pain and painful spasms in MS (pain from any etiology, including spasticity, but excluding neuropathic pain)? 3. Bladder dysfunction in MS? ©2014 American Academy of Neurology Slide 10 Clinical Questions, cont. 4. Involuntary movements, including tremor, in MS? 5. Dyskinesias of Huntington disease (HD), levodopa6. induced dyskinesias of Parkinson disease, cervical dystonia, and tics of Tourette syndrome? Seizure frequency in epilepsy? ©2014 American Academy of Neurology Slide 11 AAN Systematic Review Process • Clinical Question • Evidence • Conclusions ©2014 American Academy of Neurology Slide 12 AAN Systematic Review Process, cont. • Rigorous, Comprehensive, Transparent Search Search Review abstracts Review full text Relevant ©2014 American Academy of Neurology Select articles Slide 13 AAN Classification of Evidence • All studies meeting inclusion/exclusion criteria defined a priori rated Class I, II, III, or IV • Five different classification systems Therapeutic –Randomization, control, blinding Diagnostic –Comparison with reference standard Prognostic Screening Causation ©2014 American Academy of Neurology Slide 14 Applying the Process to the Issue • We will now turn our attention to the systematic review. ©2014 American Academy of Neurology Slide 15 Methods • Medline (1948—Jan 2013), EMBASE, PsycINFO, Web of Science, and Scopus searched • Each selected article reviewed for inclusion • Risk of bias determined (classification of evidence scheme for therapeutic articles) • Conflicts of interest disclosed ©2014 American Academy of Neurology Slide 16 Literature Search/Review • Rigorous, Comprehensive, Transparent 1,729 abstracts Inclusion criteria: - - Human randomized, controlled trials of all formulations of cannabis (pills, oral sprays, smoked cigarettes), including synthetic THC and cannabinoid extracts , alone or in combination, in the treatment of various symptoms of several neurologic illnesses Case series (for addressing adverse effects, not efficacy) Exclusion criteria: - Surveys, case reports/series, and non–placebo-controlled trials 34 articles met inclusion criteria ©2014 American Academy of Neurology Slide 17 AAN Classification of Evidence for Therapeutic Studies • Class I: A randomized, controlled clinical trial of the intervention of interest with masked or objective outcome assessment, in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are also required: a. b. c. d. Concealed allocation Primary outcome(s) clearly defined Exclusion/inclusion criteria clearly defined Adequate accounting for dropouts (with at least 80% of enrolled subjects completing the study) and crossovers with numbers sufficiently low to have minimal potential for bias. ©2014 American Academy of Neurology Slide 18 AAN Classification of Evidence for Therapeutic Studies, cont. e. For noninferiority or equivalence trials claiming to prove efficacy for one or both drugs, the following are also required*: –The authors explicitly state the clinically meaningful difference to be excluded by defining the threshold for equivalence or noninferiority. –The standard treatment used in the study is substantially similar to that used in previous studies establishing efficacy of the standard treatment (e.g., for a drug, the mode of administration, dose and dosage adjustments are similar to those previously shown to be effective). –The inclusion and exclusion criteria for patient selection and the outcomes of patients on the standard treatment are comparable to those of previous studies establishing efficacy of the standard treatment. –The interpretation of the results of the study is based upon a perprotocol analysis that takes into account dropouts or crossovers. ©2014 American Academy of Neurology Slide 19 AAN Classification of Evidence for Therapeutic Studies, cont. • Class II: A randomized controlled clinical trial of the • intervention of interest in a representative population with masked or objective outcome assessment that lacks one criteria ae above or a prospective matched cohort study with masked or objective outcome assessment in a representative population that meets be above. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.** ©2014 American Academy of Neurology Slide 20 AAN Classification of Evidence for Therapeutic Studies, cont. • Class IV: Studies not meeting Class I, II, or III criteria, including consensus or expert opinion. *Note that numbers 13 in Class I, item 5, are required for Class II in equivalence trials. If any one of the three is missing, the class is automatically downgraded to Class III. **Objective outcome measurement: an outcome measure that is unlikely to be affected by an observer’s (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data). ©2014 American Academy of Neurology Slide 21 Clinical Question 1 • Do cannabinoids relieve spasticity in patients with MS? ©2014 American Academy of Neurology Slide 22 Spasticity in MS Conclusions For patients with spasticity: • Oral cannabis extract (OCE) is established as effective for reducing patient-reported scores (2 Class I studies7,8). OCE is probably ineffective for reducing objective measures at 12 to 15 weeks (1 Class I study7) but possibly effective at 1 year (1 Class II study11). • THC is probably effective for reducing patient-reported scores (1 Class I study7). THC is probably ineffective for reducing objective measures at 15 weeks (1 Class I study7) but possibly effective at 1 year (1 Class II study11). ©2014 American Academy of Neurology Slide 23 Spasticity in MS, cont. Conclusions For patients with spasticity: • Nabiximols is probably effective for reducing patient-reported symptoms at 6 weeks (1 Class I study6) and probably ineffective for reducing objective measures at 6 weeks (1 Class I study6). • Smoked marijuana is of uncertain efficacy (insufficient evidence). ©2014 American Academy of Neurology Slide 24 Spasticity in MS, cont. Clinical Context • More improvements were seen in subjective measures than objective measures, possibly explained in part by the overall improvements in “feelings” or well-being provided by marijuana, or by pain relief allowing improved mobility. ©2014 American Academy of Neurology Slide 25 Clinical Question 2 • What is the efficacy of using cannabinoids to treat central pain or painful spasms in MS? ©2014 American Academy of Neurology Slide 26 Pain in MS Conclusions • For patients with MS with central pain or painful spasms, OCE is effective for reduction of central pain (2 Class I studies7,8). • THC or nabiximols (1 Class I study each7,24) are probably effective for treating MS-related pain or painful spasms. • Smoked marijuana is of unclear efficacy for reducing pain (2 Class III studies that examined different issues14,15). ©2014 American Academy of Neurology Slide 27 Clinical Question 3 • Do cannabinoids help treat bladder dysfunction in MS? ©2014 American Academy of Neurology Slide 28 Bladder Dysfunction in MS Conclusions • Nabiximols is probably effective for reducing the number of bladder voids per day at 10 weeks (1 Class I study26). • THC and OCE are probably ineffective for reducing bladder complaints (1 Class I study7). • Nabiximols is of unknown efficacy in reducing overall bladder symptoms (contradictory Class I studies). ©2014 American Academy of Neurology Slide 29 Clinical Question 4 • Do cannabinoids help treat tremor in MS? ©2014 American Academy of Neurology Slide 30 Tremor in MS Conclusions • THC and OCE are probably ineffective for treating MS-related tremor (1 Class I study7). • Nabiximols is possibly ineffective (1 Class II study10). ©2014 American Academy of Neurology Slide 31 Clinical Question 5 • Do cannabinoids reduce symptoms in involuntary movement disorders? ©2014 American Academy of Neurology Slide 32 Huntington Disease Conclusion • Whereas 1 Class I study31 and 1 Class III study35 suggest lack of benefit, both were underpowered to detect differences, and thus no reliable conclusions can be drawn. ©2014 American Academy of Neurology Slide 33 Parkinson Disease Conclusion • OCE is probably ineffective for treating dopainduced dyskinesias in patients with Parkinson disease (1 Class I study36). ©2014 American Academy of Neurology Slide 34 Tourette Syndrome Conclusion • For patients with Tourette syndrome, data are insufficient to support or refute efficacy of THC for reducing tic severity (1 Class II study, 1 Class III study39,40). ©2014 American Academy of Neurology Slide 35 Cervical Dystonia Conclusion • For patients with cervical dystonia, data are insufficient to support or refute the efficacy of dronabinol. ©2014 American Academy of Neurology Slide 36 Clinical Question 6 • Do cannabinoids decrease seizure frequency in epilepsy? ©2014 American Academy of Neurology Slide 37 Seizures in Epilepsy Conclusion • For patients with epilepsy, data are insufficient to support or refute the efficacy of cannabinoids for reducing seizure frequency (no Class IIII studies). ©2014 American Academy of Neurology Slide 38 Seizures in Epilepsy, cont. Clinical Context • Neither the present review, nor a Cochrane review which includes abstracts, nonpeerreviewed literature, and anecdotal reports of smoked cannabis use by patients with seizure disorders,e4 concluded there is sufficient evidence to prescribe CBDs or recommend selftreatment with smoked marijuana. ©2014 American Academy of Neurology Slide 39 Adverse Effects • Overall, 1,619 patients were treated with cannabinoids for less than 6 months. • Simple meta-analysis yielded 6.9% who stopped the medication because of adverse effects (AEs). Of the 1,118 who received placebo, 2.2% stopped because of AEs. • Data on the symptom(s) that caused medication withdrawal were often incomplete. ©2014 American Academy of Neurology Slide 40 Adverse Effects, cont. • Among patients treated with cannabinoids, the following symptoms appeared in at least 2 studies: Nausea Increased weakness Behavioral or mood changes (or both) Suicidal ideation or hallucinations (or both) Dizziness or vasovagal symptoms (or both) Fatigue Feelings of intoxication ©2014 American Academy of Neurology Slide 41 Adverse Effects, cont. • Psychosis, dysphoria, and anxiety are associated with higher concentrations of THC, which were not typical of the studies analyzed. • There was 1 death "possibly related" to treatment (a seizure, followed by fatal aspiration pneumonia).18 ©2014 American Academy of Neurology Slide 42 Adverse Effects, cont. Clinical Context • AEs are a significant concern with marijuana use. • It is especially concerning that a medication that may have an AE of suicide may be prescribed in a population such as patients with MS who already are at increased suicide risk.e7 ©2014 American Academy of Neurology Slide 43 Future Research Recommendations • Cannabinoids should be studied as other drugs are, to determine their efficacy, and when evidence is available, should be prescribed as other drugs are. Twenty states and the District of Columbia have legalized the medical use of marijuana, and 2 have decriminalized all use. This should encourage researchers to continue seeking answers to the benefits of marijuana use in patients who have neurologic illness. ©2014 American Academy of Neurology Slide 44 Future Research Recommendations, cont. • Future research with randomized, controlled studies is necessary in order to determine the efficacy of this medication class. ©2014 American Academy of Neurology Slide 45 References • References cited here can be found in the published systematic review. • To locate references, please access the systematic review at AAN.com/guidelines. ©2014 American Academy of Neurology Slide 46 Access Systematic Review and Summary Tools • To access the complete systematic review and related summary tools, visit AAN.com/guidelines. ©2014 American Academy of Neurology Slide 47 Questions? ©2014 American Academy of Neurology