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We would like to address several of the points raised in a recent editorial in your journal (Killestein J, Uitdehaag BM. Cannabinoids in multiple sclerosis: urgent need for long term trials. J Neurol Neurosurg Psychiatry. 2005 Dec;76(12):1612), pertaining to the safety and efficacy of cannabis-based medicines in the symptomatic treatment of multiple sclerosis, and propose that the true situation is much mor...
We would like to address several of the points raised in a recent editorial in your journal (Killestein J, Uitdehaag BM. Cannabinoids in multiple sclerosis: urgent need for long term trials. J Neurol Neurosurg Psychiatry. 2005 Dec;76(12):1612), pertaining to the safety and efficacy of cannabis-based medicines in the symptomatic treatment of multiple sclerosis, and propose that the true situation is much more encouraging than the editorial states, as the most convincing data available in this context were not considered by the authors.
The editorial focused on the results of the cannabinoids in multiple sclerosis (CAMS) long-term study without addressing its methodological problems. The study employed Cannador, an oral cannabis extract with a 2:1 ratio of tetrahydrocannabinol (THC) to cannabidiol (CBD) in a twice daily fixed dosage regimen based on body weight, titrated upwards over one month. Most patients failed to attain established target dosages or optimal therapeutic benefit due to adverse events. Average dosage for daily THC administered was not stated, but seemingly was under the 20mg benchmark for a 70 kg person.
Practical cannabinoid therapeutics demand, in contrast, that these agents, with their variable gastrointestinal absorption and idiosyncratic responses, be preferentially administered with highly individualised dosing according to symptomatic need and personal tolerance. Additionally, the provision of greater proportions of CBD may serve to augment therapeutic benefits while blunting adverse events such as intoxication, tachycardia, etc., attendant to THC. In short, the dosing regimen used in the CAMS study was far from optimal.
The CAMS study relied on the Ashworth scale to assess spasticity, despite its proven objective variability and failure to correlate to clinical efficacy. There is now a consensus that patient-reported outcomes are the most appropriate measures of treatment efficacy. Thus, subjective measures of spasticity are just as appropriate as the numerical rating scales now considered mandatory in clinical trials in pain. It was this approach that was applied in studies of various symptoms of MS with the highly standardised Sativex oromucosal cannabis-based medicine containing 2.7 mg of THC and 2.5 mg of CBD per 100 µL spray, in which positive results were noted in an initial Phase III double-blind controlled study with respect to spasticity (p=0.001) and sleep disturbance (p=0.047). A long-term extension study of the same cohort for one to four years established persisting improvement in these symptoms, as well as for central neuropathic pain, tremor, spasms and bladder function in affected individuals with no evidence of tolerance to benefits, or withdrawal syndrome upon sudden cessation. Further clinical trials with Sativex (reviewed) support its statistically significant benefits in Phase II clinical trials of morning pain and stiffness in rheumatoid arthritis and bladder symptoms in MS, and Phase III trials of peripheral neuropathic pain (p=0.004), brachial plexus injury (p=0.005), and intractable cancer pain (p=0.014).
Issues of blinding were raised in the CAMS studies, primarily on the basis of evident intoxication with Cannador. In contrast, outside of initial dose titration periods of 7-10 days, Sativex yields subjective intoxication scores on a visual analogue scale in the single digits out of 100, indistinguishable from placebo. Similarly, the differential benefit of Sativex upon spasticity and sleep acutely, but not other symptoms suggests effective blinding with this preparation.
Cognitive issues attendant with cannabinoid therapeutics remain a prime concern, but available data to date support a lack of neuropsychological sequelae attached to Sativex usage in another successful Phase III therapeutic trial in central pain in MS (p=0.005), and other studies.
Killestein and Uitdehaag correctly point to the generous safety profile demonstrated by Cannador and Marinol in the CAMS follow-up, but question that the proper risk-benefit ratio has been attained for cannabinoid medicines. They raise the possibility of producing better synthetic cannabinoids, while failing to address the disadvantage inherent in employing more potent full cannabinoid agonists as opposed the current approach of utilising a natural weak partial agonist (THC), particularly coupled with adequate provision of a cannabinoid antagonist (CBD) with its own synergistic benefits.
A comparison between the adverse event profile of Cannador, Marinol, placebo and Sativex (Figure 1) is illuminating, in that the oromucosal spray generally produces comparable or lower rates of complaints, despite the administration of higher net doses of daily THC (mean 29.7 mg). Such illustrations support the premise that cannabinoid therapeutics require strict adherence to specific preparations via defined delivery systems, and results must not be generalised from one preparation to another.
Sativex is currently approved for prescription usage in Canada for treatment of central neuropathic pain in MS under a Notice of Compliance with Conditions, and is also available on named patient prescription basis for any condition in the United Kingdom and Catalunya. Further regulatory submissions are in process. The weight of current evidence amply supports the safety and efficacy of Sativex both acutely and in the long-term in treatment of various symptoms of MS, and other diseases. Further long-term studies will identify whether the theoretical neuroprotective effects of THC and CBD in MS will be realised in practice with Sativex or other cannabinoid agents.
Ethan B. Russo, MD corresponding author
Senior Medical Advisor, GW Pharmaceuticals
2235 Wylie Avenue
Missoula, MT 59802
Geoffrey W. Guy
Philip J. RobsonGW Pharmaceuticals
Porton Down Science Park
Wiltshire SP4 OJQ
Dr. Russo is a consultant to GW Pharmaceuticals. Drs. Guy, Wright and Robson are officers in GW Pharmaceuticals, the developer and manufacturer of Sativex, a cannabis-based medicine.
1. Zajicek JP, Sanders HP, Wright DE, Vickery PJ, Ingram WM, Reilly SM, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry. 2005 Dec;76(12):1664-9.
2. Russo EB, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol (THC) and cannabidiol (CBD). Medical Hypotheses. 2005;(in press).
3. Wade DT, Makela P, Robson P, House H, Bateman C. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler. 2004 Aug;10(4):434-41.
4. Wade DT, Makela PM, House H, Bateman C, Robson PJ. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Multiple Sclerosis. 2006;(in press).
5. Rog DJ, Nurmiko T, Friede T, Young C. Randomized controlled trial of cannabis based medicine in central neuropathic pain due to multiple sclerosis. Neurology. 2005;65(6):812-9.
Figure 1: Comparison of adverse event profiles of Cannador (N=219), Marinol (N=216), placebo (N=222) and Sativex (N=137) in long-term clinical trials in multiple sclerosis patients. Data taken from Zajicek et al., and Wade et al., plus additional data on file from GW Pharmaceuticals. Dosing comparisons are discussed in the text.