Multiple Sclerosis

Painful muscle spasms are a common, distressing symptom that severely reduce the quality of life of multiple sclerosis (MS) patients. Anti-spasticity medications such as baclofen, tizanidine, dantrolene and gabapentin can produce intolerable side effects and often only provide partial relief. Anecdotal evidence, numerous small scale clinical trials and more recent large-scale, controlled clinical trials suggest that cannabinoids may play a role in alleviating muscle spasms, tremor, pain and bladder dysfunction associated with MS (1-5) A rapid response report compiled by the Canadian Agency for Drugs and Technologies in Health, identified 3 systematic reviews and 5 randomised controlled trials and deemed cannabinoid therapy in MS patients well tolerated and effective for patient-centered measures of spasticity.

 Efficacy and Safety Data

 A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex®), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Novotna et al 2011. (4).

Cohort: Phase A; n = 538 completed 4 weeks of Sativex treatment. Phase B; n = 272 achieved a ³ 20% improvement in Phase A and progressed to 12-week placebo controlled Phase B.

Completed Phase B; Sativex n = 109, placebo n = 115).

Results: The number of responders in the treatment group was significantly higher than in the placebo group (74% vs. 51%, P = 0.0003). Sativex significantly improved spasm frequency (P = 0.005) and sleep disruption (P < 0.0001). Modified Ashworth Score for spasticity: Sativex -0.1; Placebo +1.8 ; Adjusted Difference -1.75 (95% CI -3.80, 0.30) Spasm frequency (per day): Sativex -0.05; Placebo +2.41 Adjusted Difference -2.53 (95% CI -4.27, -0.79) Sleep disruption by spasticity: Sativex -0.25; Placebo +0.59 ; (0 to 10 NRS) Adjusted Difference -0.88 (95% CI -1.25, -0.51).

Safety: Sativex was found to be safe and well tolerated. The overall adverse event (AE) rate was similar to placebo. Two treatment-related serious AEs occurred, however, both resolved upon cessation of treatment.

 MUltiple Sclerosis and Extract of Cannabis: results of the MUSEC trial. Zajicek et al 2012 (7).

Cohort: MS patients completed cannabis extract (CE) treatment n = 109, MS patients completed placebo treatment n = 115.

Results: Self-reported relief: 29.4% in CE group, 15.7% in placebo group. Self-reported relief from muscle stiffness, muscle spasms, body pain and sleep disturbance was significantly higher in CE group vs placebo at 4, 8 and 12 weeks.

Safety: Treatment was well tolerated. Over 95% of AE’s were mild to moderate. Rates of AE’s were higher in CE group during titration period and decreased over the course of the study.

Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain. A double-blind placebo-controlled cross-over trial. Wissel et al 2006. (8).

Cohort: Completed trial n = 11. Group 1 received Nabilone for 4 weeks, 1 week wash out period, and then placebo for 4 weeks.  Group 2 received placebo for 4 weeks, 1 week wash out period, and then nabilone for 4 weeks.

 Results: Spasticity related pain (measured by the 11-Point-Box-Test) decreased by a median 2 points with Nabilone compared with placebo treatment (p < 0.05).

Safety: Nabilone found to be safe and well tolerated.

Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Zajicek et al 2003. (9)

Objective: Investigate the efficacy of oral cannabis extract and THC for the treatment of spasticity in MS patients.

Cohort: Total n = 630 participants were treated with (i) cannabis extract n = 211, THC n = 206 or placebo n = 213.

Results: No significant treatment effect on the primary outcome (change in overall spasticity score, Ashworth scale) was observed for cannabinoids vs placebo. Patients reported a treatment effect for both spasticity and pain (p = 0.003).

Conclusion: Although the primary endpoint was not reached, the reported improvements in motility and pain by the patients suggest cannabinoids may be clinically useful

Guidelines:

Multiple sclerosis: management of multiple sclerosis in primary and secondary care. London (UK): National Institute for Health and Care Excellence (NICE); 2014 Oct. Clinical guideline; no. 186). Available from: https://www.nice.org.uk/guidance/cg186

Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis. Yadav et al. 2014. Available from: http://www.neurology.org/content/82/12/1083.short (6)

Products most prescribed for this condition:
References
  1. Meinck, Schönle and Conrad. Effect of cannabinoids on spasticity and ataxia in multiple sclerosis. Journal of Neurology. 1989, Volume 236, Issue 2: pp 120–122
  2. Consroe, Musty, Rein et al. The Percieved Effects of Smoked Cannabis on Patients with Multiple Sclerosis. Eur Neurol. 1997:38:44-48
  3. Vaney, Heinzel-Gutenbrunner, Tschopp et al. Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study. Multiple Sclerosis, 2004; 10:417-424
  4. Novotna, A., Mares, J., Ratcliffe, S., Novakova, I. and others. (2011). A randomized, double-blind, placebo- controlled, parallel-group, enriched-design study of nabiximols* (Sativex((R)) ), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur.J.Neurol. 18: 1122-1131.
  5. Notcutt, Langford, Davies, Ratcliffe and Potts. A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex® (nabiximols).
  6. Yadav V, Bever C, Bowen J, Bowling A, Weinstock-Guttman B, Cameron M, Bourdette D, Gronseth GS, Narayanaswami P. Summary of evidence-based guideline: complementary and alternative medicine in multiple sclerosis. Neurology. 2014 Mar 25;82(12):1083-92. Available from: http://www.neurology.org/content/82/12/1083.short
  7. Zajicek, Hobart, Slade, Barnes, Mattison, MUltiple Sclerosis and Extract of Cannabis: results of the MUSEC trial J Neurol Neurosurg Psychiatry 2012;83:1125–1132.
  8. Wissel J, Haydn T, Müller J, Brenneis C, Berger T, Poewe W, Schelosky LD. (2006). Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain : a double-blind placebo-controlled cross-over trial. J Neurol. 2006 Oct;253(10):1337-41.
  9. Zajicek, Fox, Sanders, Wright, Vickery, Nunn, Thompson. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. The Lancet. 2003; 362(9395):1517-1526.
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