Journal of Neurology

, Volume 260, Issue 1, pp 285–295 | Cite as

Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis

  • Michael G. Serpell
  • William Notcutt
  • Christine Collin
Original Communication

Abstract

Sativex is an endocannabinoid system modulator principally containing Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). During a 6-week randomised controlled trial, Sativex had a clinically relevant effect on spasticity associated with multiple sclerosis (MS). Patients self-titrated oromucosal Sativex to symptom relief or maximum tolerated dose (maximum of 130 mg THC and 120 mg CBD daily). The primary objective was to evaluate the safety and tolerability of long-term treatment by recording the incidence and severity of adverse events (AEs). Secondary outcomes were to determine evidence of developing tolerance and to assess the long-term dosing profile of Sativex. A validated 11-point Numerical Rating Scale of spasticity severity was used to assess efficacy. A total of 146 patients elected to enter this open-label follow-up safety trial. Mean treatment exposure was 334 days (standard deviation, SD = 209 days), and patients administered on average 7.3 (SD = 4.42) actuations per day. Fifty-two (36 %) patients withdrew from the study in the first year, 14 % due to AEs and 9 % due to lack of efficacy. Most AEs were mild/moderate in severity. Common (>10 %) treatment-related AEs were dizziness (24.7 %) and fatigue (12.3 %). Serious AEs occurred in five patients (3.4 %), with two psychiatric events reported by one patient. No psychoses, psychiatric AE trends, or withdrawal symptoms occurred following abrupt cessation of treatment. Baseline symptoms including spasticity did not deteriorate but were maintained to study completion in those patients who did not withdraw. No new safety concerns were identified with chronic Sativex treatment, and serious AEs were uncommon. There was no evidence of tolerance developing, and patients who remained in the study reported continued benefit.

Keywords

Cannabinoid Long-term safety Multiple sclerosis THC/CBD oromucosal spray Spasticity 

References

  1. 1.
    Richards RG, Sampson FC, Beard SM et al (2002) A review of the natural history and epidemiology of multiple sclerosis: implications for resource allocation and health economic models. Health Technol Assess 6(10):1–73Google Scholar
  2. 2.
    Fox CM, Bensa S, Bray I, Zajicek JP (2004) The epidemiology of multiple sclerosis in Devon: a comparison of the new and old classification criteria. J Neurol Neurosurg Psychiatry 75:56–60PubMedGoogle Scholar
  3. 3.
    Collin C, Davies P, Mutiboko IK, Ratcliffe S (2007) Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol 14:290–296PubMedCrossRefGoogle Scholar
  4. 4.
    Rizzo MA, Hadjimichael OC, Preiningerova J et al (2004) Prevalence and treatment of spasticity reported by multiple sclerosis patients. Mult Scler 10:589–595PubMedCrossRefGoogle Scholar
  5. 5.
    Shakespeare DT, Boggild M, Young C (2001) Anti-spasticity agents for multiple sclerosis (Cochrane Review). In: The Cochrane Library. Issue 3Google Scholar
  6. 6.
    Beard S, Hunn A, Wright J (2003) Treatments for spasticity and pain in multiple sclerosis: a systematic review. Health Technol Assess 7: iii, ix–x, 1–111Google Scholar
  7. 7.
    Vaney C, Heinzel-Gutenbrunner M, Jobin P et al (2004) 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. Mult Scler 10:417–424PubMedCrossRefGoogle Scholar
  8. 8.
    Pertwee RG (2000) Neuropharmacology and therapeutic potential of cannabinoids. Addict Biol 5:37–46PubMedCrossRefGoogle Scholar
  9. 9.
    Baker D, Pryce G, Croxford JL et al (2000) Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 404:84–87PubMedCrossRefGoogle Scholar
  10. 10.
    Zajicek J, Fox P, Nunn A et al (2003) Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet 362:1517–1526PubMedCrossRefGoogle Scholar
  11. 11.
    Zajicek JP, Sanders HP, Wright DE et al (2005) Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry 76:1664–1669PubMedCrossRefGoogle Scholar
  12. 12.
    Russo EB (2006) The solution to the medical cannabis problem. In: Schatman ME (ed) Ethical issues in chronic pain management. Taylor & Francis, Boca Raton, pp 165–194Google Scholar
  13. 13.
    Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimaraes FS (2006) Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 39:421–429PubMedCrossRefGoogle Scholar
  14. 14.
    Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D (2007) Sativex successfully treats neuropathic pain characterised by allodynia: a randomised double blind, placebo controlled clinical trial. Pain 133:210–220PubMedCrossRefGoogle Scholar
  15. 15.
    Rog DJ, Nurmikko TJ, Friede T, Young CA (2005) Randomized controlled trial of cannabis medicine in central pain due to multiple sclerosis. Neurology 65:812–819PubMedCrossRefGoogle Scholar
  16. 16.
    Rog DJ, Nurmikko TJ, Young CA (2007) Oromucosal delta-9-tetrahydrocannabinol/cannabidiol for neuropathic pain associated with multiple sclerosis: an uncontrolled, open-label, 2-year extension trial. Clin Ther 29(9):2068–2079PubMedCrossRefGoogle Scholar
  17. 17.
    MHRA 2010 (2010) MHRA Public Assessment Report. Nabiximols Oromucosal Spray (delta-9-tetrahydrocannabinol and cannabidiol)—PL 18024/0009; UK/H/2462/001/DC. http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con084961.pdf. Accessed January 2012
  18. 18.
    ICH 2004 (1994) ICH Topic E 1 A population exposure: the extent of population exposure to assess clinical safety (CPMP/ICH/375/95), November 1994Google Scholar
  19. 19.
    Farrar JT, Troxel AB, Stott C et al (2008) Validity, reliability, and clinical importance of change in a 0–10 Numerical Rating Scale measure of spasticity: a post hoc analyses of a randomized, double-blind, placebo-controlled trial. Clin Ther 30(5):974–985PubMedCrossRefGoogle Scholar
  20. 20.
    Wade DT, Collin C, Stott C, Duncombe P (2010) Meta-analysis of the efficacy and safety of Sativex (nabiximols) on spasticity in people with multiple sclerosis. Mult Scle 16:707–714CrossRefGoogle Scholar
  21. 21.
    Viktil KK, Blix HS, Moger TA, Reikvam A (2008) Polypharmacy as commonly defined is an indicator of limited value in the assessment of drug-related problems. Pharmacotherapy 28(2):207–213CrossRefGoogle Scholar
  22. 22.
    Chou R, Peterson K, Helfand M (2004) Comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions: a systematic review. J Pain Symptom Manage 28:140–175PubMedCrossRefGoogle Scholar
  23. 23.
    Gilron I, Flatters SJL (2006) Gabapentin and pregabalin for the treatment of neuropathic pain: A review of the laboratory and clinical evidence. Pain Res Manag 11(Suppl A):16A–29AGoogle Scholar
  24. 24.
    Wong JO, Tan TD, Tseng K, Cheu N, Wu J (2005) Gabapentin for the treatment of chronic intractable neuropathic pain: a long-term follow-up study. Pain Clinic 17:357–365CrossRefGoogle Scholar
  25. 25.
    Henquet C, Krabbendam L, Spauwen J et al (2005) Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people. Br Med J 330:11–15CrossRefGoogle Scholar
  26. 26.
    Fergusson DM, Horwood LJ, Ridder EM (2005) Tests of causal linkages between cannabis use and psychotic symptoms. Addiction 100:354–366PubMedCrossRefGoogle Scholar
  27. 27.
    Moore THM, Zammit S, Lingford-Hughes A et al (2007) Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 370:319–328PubMedCrossRefGoogle Scholar
  28. 28.
    Notcutt W, Langford R, Davies P, Ratcliffe S, Potts R (2012) A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex(R) (nabiximols). Mult Scler 18(2):219–228PubMedCrossRefGoogle Scholar
  29. 29.
    Huestis MA, Cone EJ (2004) Relationship of Delta 9-tetrahydrocannabinol concentrations in oral fluid and plasma after controlled administration of smoked cannabis. J Anal Toxicol 28:394–399PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Michael G. Serpell
    • 1
  • William Notcutt
    • 2
  • Christine Collin
    • 3
  1. 1.Pain Clinic, Division of Developmental Medicine, Department of Anaesthetics, Gartnavel General HospitalUniversity of GlasgowGlasgowUK
  2. 2.Pain Clinic, James Paget HospitalNorfolkUK
  3. 3.Neurorehabilitation DepartmentRoyal Berkshire HospitalReading, BerkshireUK

Personalised recommendations