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NEW DRUGS IN CLINICAL DEVELOPMENT
Advance Evaluated Information for Confidential use by NHS Managers and Budget Holders with additional data on health service impact
Cannabis-based medicinal extract – THC:CBD oromucosal spray
Clinical Impact • Whole plant extracts containing two principal cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have been formulated into an oromucosal spray for the treatment of neuropathic pain and the symptoms of multiple sclerosis (MS). These cannabis-based medicinal extracts (CBME) may have unique modes of action compared to existing licensed alternatives. • There have been a number of difficulties in designing and conducting trials of this CBME product. These include small numbers of available trial participants and ethical considerations raised by regulatory authorities. Completed phase II and III studies have investigated the addition of the CBME product to existing treatments and have reported mixed results. Only one study has been published in full to date. The information available from the manufacturer is lacking in details of outcome measures used in the studies and provides little quantitative data of the results obtained. Therefore, it is not possible to determine the clinical significance of the results provided. Details of adverse effects are also lacking, but based on the available information, these are likely to mainly affect the site of administration and central nervous system (e.g. dizziness, feelings of intoxication). Long-term effects of chronic CBME use are not known.
Financial Issues and NHS Impact • Due to the limited data available to us, it is not possible to assess the efficacy of this CBME product and its possible role within the NHS. The cost of the product is not yet known, but it is usual for novel drugs and formulations to be priced at a premium over existing therapies. A conservative estimate could be in the region of £100 per month per patient treated at reported usual doses. It should be noted that this could be in addition to, rather than instead of, the costs of existing treatments. • There is a need for more efficacious and/or better tolerated treatments for the symptoms of MS and various types of chronic pain. Therefore, if the product is licensed, there is likely to be considerable interest from patients and other groups.
Date Published: August 2003 Monograph Number: 3/03/02 Region of Origin to whom queries should be directed: Wessex Drug and Medicines Information Centre
• • Monographs for unlicensed drugs/indications must not be circulated to prescribers. Not to be used for commercial purposes. • The information contained herein will be superseded in due course.
Cannabis-based medicinal extract
APPROVED NAME To be determined. The product contains a mixture of delta-9tetrahydrocannabinol (THC, Tetranabinex) and cannabidiol (CBD, Nabidiolex). Sativex (GW Pharmaceuticals). Cannabis-based medicinal extract, cannabinoids, THC:CBD. (i) Multiple sclerosis (MS) symptoms. (ii) Neuropathic pain. Oromucosal pump action spray device containing 2.7mg of THC plus 2.5mg of CBD per actuation. Each spray device contains 48 doses. GW Pharmaceuticals submitted a licence application to the Medicines and Healthcare products Regulatory Agency (MHRA) in March 2003. Phase III trials for spasticity, bladder dysfunction, spinal cord pain, neuropathic pain and cancer pain are ongoing. It is likely that this product will be subject to controlled drug regulations if licensed [Personal communication, GW Pharmaceuticals, 01/07/03]. THERAPEUTIC CLASS DOSE To be confirmed. The recommended starting dose is one spray every four hours, with patients self-titrating up to their effective dose. Most patients have used between eight and ten doses per day in trials. The maximum recommended daily dose is 48 sprays [Personal communication, GW Pharmaceuticals, 19/05/03]. Currently unknown. As a novel product it is likely to be more expensive than existing licensed, oral treatments. The preparations below are examples of possible treatment alternatives. The costs refer to 28 days at the doses stated (MIMS/Drug Tariff – July 2003): Amitriptyline 75mg daily (tabs) [unlicensed indication] Baclofen 10mg tds (tabs) Dantrolene 75mg tds (Dantrium caps) Gabapentin 600mg tds (Neurontin tabs) Morphine m/r 30mg bd (MST continus tabs) Tizanidine 8mg tds (Zanaflex tabs) £2.01 £3.06 £31.05 £89.04 £13.65 £135.63
BRAND NAME SYNONYM PROPOSED INDICATION
AREAS OF POTENTIAL USE
Primary Care [Y]
Cannabis-based medicinal extract
INTRODUCTION Neuropathic pain and muscle-related pain associated with neurological disorders, such as multiple sclerosis (MS), are not always amenable to treatment with conventional analgesic drugs. In addition, some patients may not tolerate existing treatment options well. Patients with MS may also have to contend with muscle spasticity, tremor, impaired bladder control, muscle weakness, dystonia and ataxia, and currently available drugs may not offer adequate control of these symptoms. An agent with a different mode of action to currently available drugs, which can address many of these issues would, therefore, be desirable. Cannabis-based medicinal extracts (CBME) are being investigated as such agents for patients experiencing these problems. The Medical Research Council (MRC) is sponsoring a large study (n=667) of a natural cannabis oil oral capsule (Cannador) and a synthetic THC oral capsule (Marinol) for the relief of MS symptoms. This is the Cannabinoids in Multiple Sclerosis (CAMS) study and first phase results are due to be made public in September 2003. However, GW Pharmaceuticals submitted a licence application to MHRA in March 2003 for their CBME product, Sativex, for the treatment of the symptoms of MS and neuropathic pain [Personal communication, GW Pharmaceuticals, 19/05/03]. This is a pump action oromucosal spray device that contains 2.7mg THC and 2.5mg CBD per actuation. If licensed, this product will be marketed and distributed in the UK by Bayer plc. This monograph discusses the GW Pharmaceuticals CBME product. are then released slowly over a prolonged period . In one study of 86 chronic cannabis users, some had intermittently positive urine tests for up to 77 days after last smoking cannabis, but with negative tests occurring periodically during that time . The average elimination time in these chronic, heavy users is probably about 4 weeks. It is not clear what the implications of this delayed elimination are for the persistence of any adverse effects or interactions. CBD has a half-life of 2 to 5 days when taken orally .
EFFICACY Early published research on cannabis and CBME Anecdotal reports have frequently suggested that cannabis has beneficial effects in a range of neurological conditions. Questionnaires conducted in cannabis users have found positive effects for a wide range of symptoms [4-6]. However, the subjects involved in these studies represent a highly select group of people, which limits interpretation of their findings. Several clinical studies have, in the past, attempted to investigate the therapeutic value of cannabis, THC or CBD in neurological conditions, such as MS and spinal cord injury [7-12]. However, these have involved very small patient numbers, and have used different patient groups, study designs and endpoints. Furthermore, whilst some used oral THC or CBD, others have investigated smoked cannabis. The collective results are inconsistent, difficult to interpret and do not provide robust, scientific evidence of beneficial effects of cannabis or cannabinoids in the treatment of spasticity, pain, or other symptoms associated with neurological conditions. Larger studies with a more systematic approach are needed. New research on GW Pharmaceuticals’ CBME product There have been a number of difficulties in designing and conducting trials of the GW Pharmaceuticals CBME product. The relatively small patient population from which to draw trial recruits has limited the size of the trials, and ethical considerations raised by regulatory authorities have meant that phase II trials had to involve a run in period using open label active CBME so that all patients had experience of the effects of the active product [Personal communication, GW Pharmaceuticals, 19/05/03]. In addition, as patients using CBME may experience discernible physical effects, such as dizziness or feelings of intoxication, the risk of unblinding in the blinded phases of all trials has been increased. This could have introduced bias and influenced trial outcomes. Only one study of the GW Pharmaceuticals CBME product has been fully published to date . This involved a consecutive series of double-blind, randomised, placebocontrolled, single-patient, cross-over trials (n=24, 18 had MS), with four two-week treatment periods. Patient-rated estimates of muscle spasm and sleep, using visual analogue scales, were statistically significantly better with the CBME product compared with placebo. However, the observer-rated Ashworth scale for spasticity (the primary outcome measure used in the MRC sponsored CAMS study) and other 3
PHARMACOLOGY The hemp plant, Cannabis sativa, is native to central Asia and has been used as a treatment for medical symptoms for at least 2600 years. It is also widely used recreationally for its psychoactive effects. The plant contains over 60 different, but related, constituents, known collectively as cannabinoids. One of these, THC, is the principal psychoactive constituent. This, and another cannabinoid, CBD, are the two constituents that have attracted most therapeutic interest. The precise mode of action of cannabis and cannabinoids is unknown, but there are at least two types of cannabinoid receptor in humans. Those known as CB1 are found in the central nervous system (CNS) and the periphery, while CB2 receptors are found only in the periphery .
PHARMACOKINETICS The pharmacokinetics of cannabis and cannabinoids are complex. The duration of pharmacological effects varies with the route of administration. The elimination rate of cannabinoids after smoking cannabis (which consists mainly of THC), varies markedly between individuals . Cannabinoids are lipophilic and accumulate in body fat. They
Cannabis-based medicinal extract
standard measures of disability were not significantly different . GW Pharmaceuticals has provided limited data of other unpublished studies of its CBME product  and these have been reproduced in the Summary Table on page 6. Most have involved patients with MS, but the total number of patients with MS involved in the phase III studies that have been completed amounts to less than 300. In all studies, patients continued taking their existing medication and no comparative studies with existing drug treatments have been conducted. Two small, phase III studies (n=66 and n=70) suggest that the CBME spray statistically significantly relieves neuropathic pain compared with placebo in patients with MS, but another study (total n=160), with a subpopulation of 37 patients identifying pain as a primary symptom, did not support a significant pain improvement. This latter study did find a statistically significant reduction in spasticity when considering this symptom in a sub-population of 39 patients. As these trials have not yet been published in full, details of outcome measures and the actual results achieved have not been made available. Therefore, it is not possible to determine the clinical significance of any of the statistics that have been provided. Two further randomised, double-blind, placebo-controlled studies are ongoing in MS patients with spasticity (n=225) and bladder problems (n=130) [Personal communication, GW Pharmaceuticals, 19/05/03], but a comprehensive assessment of the efficacy of this CBME product is not yet possible based on the data currently available to us. The manufacturer reports that adverse effects have usually been mild or moderate in severity, and that there have been few trial withdrawals due to adverse effects .
PRECAUTIONS/CONTRAINDICATIONS It is expected that patients will be warned that the product may cause drowsiness and not to drive or operate machinery if affected. When used recreationally, cannabis also exacerbates impaired performance due to alcohol , so alcohol use should be avoided with cannabis-based medicines. We have been unable to assess the product’s abuse potential.
EPIDEMIOLOGY & ESTIMATED COSTS TO THE HEALTH SERVICE In England and Wales, it is estimated that there are between 100 and 120 people with MS per 100,000 population. The cost of MS to the NHS is estimated to be around £3,400 per patient per year . Equivalent figures for non-MS neuropathic pain are not readily available. The cost of the CBME product developed by GW Pharmaceuticals is not yet known, but it is usual for novel drugs and formulations to be priced at a premium over existing therapies. As a guide, the 28day cost of treatment with gabapentin 600mg tablets, taken three times a day for neuropathic pain, is £89.04, and with tizanidine 2x4mg tablets, taken three times a day for spasticity in MS or spinal cord injury, it is £135.63 ( MIMS – July 2003 ). A conservative estimate of the cost of 28 days of treatment with the CBME spray device could, therefore, be around £100. Each pump action spray device contains approximately 48 CBME doses and the manufacturer reports that most patients in the trials self-titrated to between eight and 10 doses per day (range two to 48 doses per day) [Personal communication, GW Pharmaceuticals, 01/07/03]. Based on this information, approximately five spray devices would typically be required to provide 28 days of treatment. Each spray device could, therefore, cost around £20. Based on this assumption, and the range of daily doses reported to have been used in the trials, the cost of the CBME product could range between £1 and £20 per day. It should be noted that all of the trials to date have involved the addition of the CBME product to existing therapies, rather than the replacement of therapies. The costs of the CBME product could, therefore, be in addition to the existing costs of therapy. 4
PHARMACOECONOMIC DATA No data are currently available to us.
ADVERSE EFFECTS Adverse effects are likely to mainly affect the site of administration and the CNS. The one fully published study (n=24) of the CBME product notes that hypotension and marked intoxication occurred in some patients when administration was rapid. One patient could not derive benefit from the product without intoxication and four patients reported soreness or numbness of the mouth and throat . Other adverse effects include disturbance in attention, dissociation, dizziness, somnolence and fatigue, dry mouth, and thirst [14, Personal communication, GW Pharmaceuticals, 01/07/03]. Long-term effects of chronic use of CBME are not yet known, but could be important.
Cannabis-based medicinal extract
References A NICE technology appraisal of the GW Pharmaceuticals CBME product for symptom relief in MS is in progress and guidance is anticipated for August 2004. A clinical guideline on the management of MS in primary and secondary care is also due to be published by NICE in October 2003. The draft of this guideline states that, if they are licensed, cannabis derivatives should be considered for the treatment of spasticity or spasms; however, initial drug treatment should be with baclofen or gabapentin . There is a need for more efficacious and/or better tolerated treatments for the symptoms of MS. Therefore, if the product is licensed, there is likely to be considerable interest from patients and other groups.
1. House of Lords Select Committee on Science and Technology. Session 1997-8, 9th report: Cannabis – the scientific and medical evidence. London: The Stationery Office, 1998. 2. Ellis GM, Mann MA, Judson BA, et al. Excretion patterns of cannabinoid metabolites after last use in a group of chronic users. Clin Pharmacol Ther 1985; 38: 572-8. 3. Consroe P, Kennedy K, Schram K. Assay of plasma cannabidiol by capillary gas chromatography/ion trap mass spectroscopy following high-dose repeated daily oral administration in humans. Pharmacology, Biochemistry & Behavior 1991; 40: 517-22. 4. Dunn M, Davis R. The perceived effects of marijuana on spinal cord injured males. Paraplegia 1974; 12: 175. 5. Consroe P, Musty R, Rein J, et al. The perceived effects of smoked cannabis on patients with multiple sclerosis. Eur Neurol 1997; 38: 44-8. 6. Malec J, Harvey RF, Cayner JJ. Cannabis effect on spasticity in spinal cord injury. Arch Phys Med Rehabil 1982; 63: 116-8. 7. Petro DJ, Ellenberger C. Treatment of human spasticity with delta-9-tetrahydrocannabinol. J Clin Pharmacol 1981; 21: 413S-6S. 8. Clifford DB. Tetrahydrocannabinol for tremor in multiple sclerosis. Ann Neurol 1983; 13: 669-71. 9. Consroe P, Sandyk R, Snider SR. Open label evaluation of cannabidiol in dystonic movement disorders. Intern J Neuroscience 1986; 30: 277-82. 10. Ungerleider JT, Andyrsiak T, Fairbanks L, et al. Delta-9THC in the treatment of spasticity associated with multiple sclerosis. Adv Alcohol Substance Abuse 1988; 7: 39-50. 11. Greenberg HS, Werness SAS, Pugh JE, et al. Short-term effects of smoking marijuana on balance in patients with multiple sclerosis and normal volunteers. Clin Pharmacol Ther 1994; 55: 324-8. 12. Killestein J, Hoogervost ELJ, Reif M, et al. Safety, tolerability and efficacy of orally administered cannabinoids in MS. Neurology 2002; 58: 1404-7. 13. Wade DT, Robson P, House H, et al. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clinical Rehabilitation 2003;17:18-26. 14. Data on file from GW Pharmaceuticals. Letter dated 24th January 2003. 15. Perez-Reyes M, Hicks RE, Bumberry J, et al. Interaction between marihuana and ethanol: effects on psychomotor performance. Alcohol Clin Exp Res 1988; 12: 268-76. 16. National Institute for Clinical Excellence. Multiple sclerosis – National clinical guidelines for NHS management in primary and secondary care. Draft for 2nd round stakeholder consultation, March 2003. Available from www.nice.org.uk (accessed 16/06/03).
SUMMARY DATA OF UNPUBLISHED CLINICAL TRIALS
Study Population Central neuropathic pain in MS. Chronic refractory pain in MS and other neurological defects. Multiple symptoms in MS. Study Design Phase III. 66 patients. Double-blind, randomised, parallel-group placebo-controlled study. Phase III. 70 patients. Double-blind, randomised, parallel-group placebo-controlled study. Phase III. Five sub-studies with total of 160 patients (primary symptom assessed: pain [n=37], spasticity [n=39], spasm [n=38], tremor [n=14], bladder dysfunction [n=32]). Double-blind, randomised, parallel-group, placebo-controlled study. Phase III. 48 patients. Double-blind, randomised, three-way crossover, placebo-controlled study. Phase II. 34 patients unresponsive to alternative pain relief measures. Series of single-case, double-blind, randomised crossover, placebo-controlled studies lasting 10 weeks (2 of which were open-label). Phase II. 21 patients. Open-label. Drug Treatment THC:CBD oromucosal spray Results
Cannabis-based medicinal extract
Statistically significant reduction in pain and sleep disturbance (p<0.01)
THC:CBD oromucosal spray
Statistically significant reduction in pain as evidenced by use of escape medication (p<0.05). Reduction in sleep disturbance, but no indication of statistical significance is available. Statistically significant improvement in spasticity when this symptom was assessed in a sub-population (p<0.01). Positive trend, but not statistically significant for other sypmtoms assessed in other subpopulations.
THC: CBD oromucosal spray
Pain in brachial plexus avulsion. Chronic refractory neuropathic pain in MS and other neurological conditions.
THC:CBD vs. THC vs. placebo, all as oromucosal sprays. THC:CBD vs. THC vs. CBD vs. placebo all as oromucosal sprays.
Statistically significant reduction in pain and sleep disturbance for both active sprays (p<0.01). Statistically significant reduction in pain for all active sprays (p<0.01). Highly significant improvement in sleep duration and reduction in sleep disturbance for THC:CBD and THC sprays (p<0.01)
Bladder dysfunction in MS.
THC:CBD or THC oromucosal sprays.
Statistically significant reduction in incontinence episodes, nocturia, frequency and urgency for both sprays (p<0.05). Only THC statistically significantly increased bladder capacity (p<0.05).
Note: None of these studies has yet been published in a peer review journal and all details have been provided by GW Pharmaceuticals . There are little or no details of patient characteristics, doses of the sprays used, outcome measures and methods of assessment, or the results obtained. THC:CBD refers to the CBME product, Sativex, for which GW Pharmaceuticals have submitted a licence application to the MHRA.
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