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A clinical trial published in late September in the journal Neurology demonstrates that the cannabis-based medicine Sativex® is effective in reducing central neuropathic pain and sleep disturbance in people with multiple sclerosis (MS).1 Sativex is an oral-mucosal spray produced from cannabis, aka marijuana (Cannabis sativa L., subssp. sativa, Cannabaceae) and manufactured by GW Pharmaceuticals PLC in the United Kingdom (UK).
In the randomized, placebo-controlled trial conducted in the UK, Sativex was shown to be significantly superior to placebo in reducing the mean intensity of pain (p=0.005) and sleep disturbance (p=0.003) in people with MS. The study was conducted in 66 patients, 65% of whom required support to walk or were wheelchair-bound and suffering from moderate to severe central neuropathic pain which had not been alleviated by currently available conventional pharmaceutical pain medications. In this trial design, the patients continued to take their existing medication (i.e., the medication prescribed prior to the onset of the trial) throughout the duration of the study.
Sativex is derived from whole plant extracts of 2 specifically bred cannabis plant varieties. The extracts are combined to produce a standardized formulation containing 2 major components of cannabis, the cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD).2 The final preparation also contains range of phytocannabinoids, terpenoids and flavonoids (E. Russo. Personal communication to M. Blumenthal, Oct. 30, 2005). Sativex is thus significantly chemically distinct from the only other currently approved cannabis-related medication, Marinol® (aka dronabinol, Solvay Pharmaceuticals Inc., Marrietta, GA), a synthetic form of THC which is approved for chemotherapy-induced nausea.
In this trial Sativex was administered as an oromucosal (mouth) pump spray designed for self-administration by the patient, allowing flexible dosing (i.e., the patients can take as little or [almost] as much as they deem necessary, based on their own assessment of pain). GW Pharmaceuticals states that this is ideally suited to the variable nature of MS.2 Each spray of Sativex delivers a fixed dose of 2.7mg THC and 2.5mg CBD. To ensure safety, the patients were advised to take no more than 8 sprays (a total of 21.6 mg THC, CBD 20 mg CBD) within any 3-hour interval and refrain from increasing the daily dose by more than 50% from the previous day. If the patients experienced an intoxicating effect, they were told to reduce or omit a dose. The mean daily dose achieved in the trial was 25.9 mg THC, and 24 mg CBD.
The proportion of patients rating themselves as “much” or “very much improved” in the Sativex group (9 of 34; 26.5%) was more than twice that of patients receiving placebo (4 of 32; 12.5%). In the patients’ Clinical Global Impression of Change (CGIC, a self-assessment of changes from the baseline, either improvement or worsening of conditions), patients on Sativex were 3.9 times more likely to rate themselves in any improved category than those on placebo (p = 0.005).
Sativex was generally well tolerated in the study, producing relatively mild adverse side effects. In the Sativex group, 30 of 34 patients (88.2%) experienced at least one adverse event (AE), compared with 22 of 32 patients (68.8%) on placebo. Nervous system AEs included dizziness (18 Sativex, 5 placebo), somnolence (3,0), disturbance in attention (2,0), and headache (1,3). Psychiatric AEs included disassociation (3,0) and euphoria (2,0). Several of the psychiatric AEs occurred in the same patient.
Two women patients withdrew from the trial, both on Sativex. One developed an AE of agitation with tachycardia (rapid heartbeat) and hypertension after 4 sprays, which settled with conservative management within 3 hours. She declined further use of the medication and withdrew 7 days later without completing further scores. The second patient developed paranoid ideation and was withdrawn from study medication at the investigator’s discretion in the second treatment week but subsequently completed all study diaries and assessments (her scores are included in the final results).
Carolyn Young, MD, principal investigator and Consultant Neurologist based at the Walton Centre for Neurology and Neurosurgery in Liverpool, explained, “Central neuropathic pain occurs frequently in people with MS. It can be tremendously debilitating and unresponsive to existing therapies. Our findings demonstrate that Sativex was effective in reducing both central pain in MS and pain-related sleep disturbance in a population with moderate to severe central pain inadequately relieved by existing medication.”2
Neuropathic pain is caused by damage to or dysfunction of the nervous system. It is usually chronic and accompanied by unpleasant burning or shooting sensations, or extreme sensitivity to touch. It is estimated that at least 2.4% of the world’s population suffers from neuropathic pain,3 including over 1.4 million patients in UK. It is estimated that central neuropathic pain (pain initiated or caused by damage to the central nervous system, i.e., the brain or spinal cord) occurs in up to 52% of people with multiple sclerosis.4 Up to 32% of patients with MS regard pain among their most severe symptoms5 describing it as frequent, disabling and inadequately managed.6
Sativex has been developed by UK-based GW Pharmaceuticals PLC (www.gwpharm.com) and has been approved recently as a prescription medicine in Canada for the symptomatic relief of neuropathic pain in adults with MS. Sativex is marketed in Canada by Bayer HealthCare. According to GW, an ongoing clinical trial program is currently being conducted by the company to support regulatory approval in the UK. Upon approval in the UK, GW has a licensing agreement that Sativex will be exclusively marketed by Bayer HealthCare.
---Mark Blumenthal
References
1. D.J.Rog, T.J.Nurmikko, T.Friede, and C.A Young. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005;65:812-819.
2. Anon. Sativex®, a Cannabis-Based Medicine, Significantly Reduces Central Neuropathic Pain in People with Multiple Sclerosis [press release]. London: GW Pharmaceuticals, Sep. 27, 2005.
3. Neuropathy Trust 2005. http://www.neurocentre.com/ (Sep. 2005).
4. Biovie J. Central Pain. In: Wall PD, Melzack R, eds. Textbook of Pain, 4th ed. Hong Kong: Harcourt Publishers Ltd, 1999:879-914.
5. Stenager E, Knudsen L, Jensen K. Acute and chronic pain syndromes in multiple sclerosis. Acta Neurol Scand 1991;84:197-200.
6. Thompson AJ. Symptomatic treatment in multiple sclerosis. Curr Opin Neurol. 1998 Aug;11(4):305-9.
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