Should doctors prescribe cannabinoids?

Dear Editor,

It should be a matter of great regret for all those interested in the pursuit of scientific truth that Prof. Michael Farrell and Prof. Wayne Hall have failed to declare their long running association with the National Cannabis Prevention and Information Centre (NCPIC).

The NCPIC is a government funded propaganda organisation concerned with supporting political policies. It has no relationship with science except that it funds, publishes and promotes scientists who provide evidence supporting its aims. Similarly, its presence on the campus of the University of New South Wales invalidates any claim by the University to scientific rigour in any aspect of cannabis research.

This submission fails to pass the necessary tests of objectivity and impartiality which should be the first requirements for publication in a journal of the reputation of the BMJ.

From its first sentence it demonstrates a determination to overlook great swathes of empirical evidence. The medicinal use of cannabis is well established in archaeological evidence dating back 10,000 years and in written evidence dating back 5,000 years. Interest was revived in the US in the 1970s and 1980s and is now supported by tens of thousands of doctors and medical professionals in the US, Canada, Europe, Israel, Australia and New Zealand - not to say millions of patients who greatly value its efficacy and safety.

Box 1 defines cannabis as a substance that is smoked and overlooks completely the widespread acceptance and preference for medical vapourising which eliminates the dangers of inhaling the products of combustion but facilitates very effective titration of dosage.

The narratives on antiemetic and appetite stimulating effects; effects on muscle spasticity or neuropathic pain in multiple sclerosis; other neuropathic pain; cancer pain are merely exercises in excluding evidence that does not suit the authors predetermined conclusions.

Box 3 details "probable" and "possible" adverse effects of chronic recreational cannabis smoking. These are nothing but speculative scaremongering more suited to the pages of a tabloid newspaper than a clinical journal. How are these relevant to the subject of the article which concerns administration of cannabinoids for a specified medicinal purpose within the strict regulation of a doctor's prescription?

All in all this is nothing but an exercise in drug war propaganda. It has nothing to do with a responsible assessment of the benefits and risks of cannabinoid medicine. Even in its own terms, the only conclusions it reaches are that the evidence is unclear but it is itself an exercise in obfuscation, cherry picking and excluding evidence to suit the authors' agenda.

This paper falls well below the minimum requirement that should be expected of a professional review of medical. It does nothing to assist in answering the question it poses and is seriously misleading.

Professors Farrell, Buchbinder and Hall (1) argue that “there is no clear evidence for effectiveness [of cannabinoids] in treating pain [or, essentially any other conditions], any benefits are likely to be modest, and there is no clear evidence that putative benefits outweigh possible harms.”

We disagree. Well-reviewed evidence indicates that the benefits of medicinal cannabis far exceed the harms when used to palliate distressing symptoms in a number of chronic conditions.

Regardless of legality, many people successfully use cannabis to manage chronic conditions, as assessed by self-report. (2-5) In one study, patients legally using botanical cannabis for analgesia reported their average pain (‘0 to 10’ scale) decreased from 7.8 pre-treatment to 2.8 post-treatment. (6) In another, patients with multiple sclerosis (and their carers) reported improvements across a range of daily functional activities and a reduction in use of anti-spasticity medication and health-care resources. (7) Overall, a recent review identified 82 favourable controlled studies and only nine unfavourable controlled studies for symptoms of a range of serious medical conditions. (8)

Like many others, Farrell, Buchbinder and Hall project the harms reported from illicit recreational use to supervised medical use. We regard this as inappropriate. The side effects attributed to ‘street’ cannabis provide little help to assess the those of medicinally-used cannabinoids, just as assessing the side effects of ‘bootleg liquor’ or ‘street heroin’ are inaccurate guides to those of regulated alcohol or prescribed heroin. A longitudinal study of a large population found minimal impact of cannabis on life expectancy. (10) Degenhardt et al. concluded that recreational cannabis, consumed by an estimated global population of 147 million, accounts for 2 million DALYs, representing 10% of all DALYs due to illicit drugs, which in turn represent 0.8% of all causes of global DALYs. (11) Specific side effect and drug dependence safety evidence derived from medicinal cannabinoids (as Sativex®/nabiximols) shows that the side effects of chronic medical use are generally minimal and acceptable, with only 10% of patients choosing to discontinue their treatment. (12) This profile is very favourable in comparison to opioids or tricyclic antidepressants – or of no treatment!

The authors use the catchall ‘cannabinoids’ whilst failing to acknowledge that comparisons based on undifferentiated compounds, combined with pharmacokinetic/metabolic implications of undifferentiated enteral or parenteral administration, are hazardous. Furthermore, they pay scant attention to the cannabinoid dose effect/side effect relationship. With opioid analgesics, adverse effects result from an extension of the therapeutic effects, and this underpins patient controlled analgesia because the patient can self-titrate doses for an individually determined balance between pain relief and readily perceived side effects. (13) So, too, with cannabinoids. For many of the indications for cannabinoid pharmacotherapy (e.g. intractable neuropathic pain or muscle spasticity), even a small reduction in intensity may be significant for the patient, and individual titration of effects offers safe pharmacotherapy as the side effects are not life threatening.

Echoing others, (14) we believe that the authors’ arguments are often biased away from evidence finding benefits and towards finding problems with medicinal cannabis, thereby inexactly interpreting some of the original reports. Some examples are given. Considering antiemetic trials, they claimed that “the small size of most of the studies made it difficult to draw firm conclusions”, [Rocha et al. 8;Tramèr et al. 9]. Rocha et al., stated that “some side effects such as ‘high’ sensation, sleepiness, sedation and euphoria, which were more frequent when cannabinoids were used, would be potentially ‘beneficial’ for most patients as they would be pleasant during chemotherapeutic treatment”, i.e., the ‘adverse effects’ counter the essentially worse ‘adverse effects’ of chemotherapy. Tramèr et al. noted that when patients were asked which treatment they preferred for further chemotherapy cycles, between 38% and 90% of patients preferred cannabinoids. The authors identified several reviews considering cannabinoids for treatment of chronic non-cancer pain “that reported modest reductions in pain”. Svendsen et al. [14] reported that “Dronabinol has a modest but clear and clinically relevant analgesic effect in multiple sclerosis patients with central pain”. Rog et al. [15] found that the nabiximols was superior on just about every measure. Wade et al. [16] tested extracts that were THC rich, CBD rich, mixed THC/CBD, and placebo administered by oromucosal spray and found improved management of pain, muscle spasm, spasticity, appetite, muscle spasm, with benefits differing between agents.

Farrell, Buchbinder and Hall concluded that “the effectiveness of cannabinoids for the treatment of muscle spasticity or neuropathic pain in multiple sclerosis is unclear…and long term safety has not been established”. Uncited papers have reported longer-term safety. Serpell et al. (16) reported on patients having a mean nabiximols treatment exposure of 334 days; Notcutt et al. (17) reported on patients with a mean treatment duration of 3.6 years. The former reported “No new safety concerns were identified with chronic Sativex treatment, and serious AEs were uncommon. There was no evidence of tolerance.” The latter reported “Maintenance of Sativex efficacy in long-term symptomatic improvement of spasticity to a group of subjects with MS has been confirmed using this study design.”

Current evidence for medicinal cannabinoids being curative is yet weak, as with almost all pain therapies, but they often palliate symptoms when conventional therapies prove ineffective or have unacceptable side effects. If patients are not already using cannabis, then starting such treatment still has to be weighed against other treatments or no treatments, and with an open mind. There is good and growing evidence that the benefits of medicinal cannabis far exceed the harms for a number of conditions with distressing symptoms. For some patients, this may mean continuing treatment indefinitely. Patients should be encouraged to self titrate. Considering treatment costs, inhalation of the vapour from high quality botanical cannabis has been successful in research and clinical applications. (18) Oral preparations, however convenient, have particular problems for patients with dysphagia, nausea and vomiting. Cannabis ‘oil’, ‘juice’, etc. have a significant lay following, but yet scant ‘hard’ evidence in support.

The medicinal use of cannabis is a very different issue from the prohibition of recreational cannabis – morphine, ketamine and amphetamine are all used medically to great advantage, but the recreational use of these drugs is prohibited – why treat cannabis differently?

LE Mather, PhD, FANZCA, FRCA, Emeritus Professor of Anaesthesia, The University of Sydney, Sydney, NSW, Australia [corresponding author]

AD Wodak, AM, FRACP, FAChAM, FAFPHM Emeritus Consultant, Alcohol and Drug Service, St Vincent's Hospital, Sydney, NSW, Australia

WG Notcutt, FRCA, FFPMRCA, Consultant in Anaesthesia and Pain Specialist, James Paget University Hospital, Great Yarmouth, Norfolk, UK

1. Farrell M, Buchbinder R, Hall W. Should doctors prescribe cannabinoids? Brit Med J 2014 Apr 23;348:g2737. doi: 10.1136/bmj.g2737.
2. Swift W, Gates P, Dillon P. Survey of Australians using cannabis for medical purposes. Harm Reduct J 2005;2(1):18 doi:10.1186/1477-7517-2-18.
3. Bonn-Miller MO, Boden MT, Bucossi MM, Babson KA. Self-reported cannabis use characteristics, patterns and helpfulness among medical cannabis users. Am J Drug Alcohol Ab 2013;40:23-30.
4. Hazekamp A, Ware MA, Muller-Vahl KR, Abrams D, Grotenhermen F. The medicinal use of cannabis and cannabinoids—An international cross-sectional survey on administration forms. J Psychoactive Drugs 2013;45:199-210.
5. Bar-Sela G, Vorobeichik M, Drawsheh S, Omer A, Goldberg V, Muller E. The medical necessity for medicinal cannabis: prospective, observational study evaluating the treatment in cancer patients on supportive or palliative care. Evidence-Based Complementary and Alternative Medicine 2013; 2013, Article ID 510392, 8 pages, 2013. doi:10.1155/2013/510392 (http://dx.doi.org/10.1155/2013/510392 accessed 3 June 2014).
6. Webb CW, Webb SM. Therapeutic benefits of cannabis: a patient survey. Hawai’i J Pub Health 2014;73:109-111.
7. Notcutt WG. A questionnaire survey of patients and carers of patients prescribed Sativex as an unlicensed medicine. Pri Hlth Care Res Dev 2013;14:192–199.
8. Grotenhermen F, Müller-Vahl K. The therapeutic potential of cannabis and cannabinoids. Dtsch Arztebl Int 2012;109(29-30),495-501.
9. Adler JN, Colbert JA. Clinical decisions: medicinal use of marijuana — polling results. N Engl J Med 2013;368: e30.
10. Degenhardt L, Whiteford HA, Ferrari AJ, Baxter AJ, Charlson FJ, Hall WD, et al. Global burden of disease attributable to illicit drug use and dependence: findings from the Global Burden of Disease Study 2010. Lancet 2013;382(9904):1564-74.
11. Sidney S, Beck JE, Tekawa IS, Quesenberry CP, Friedman GD. Marijuana use and mortality. Am J Public Health 1997;87(4):585–590.
12. Robson P. Abuse potential and psychoactive effects of d-9-tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a new cannabinoid medicine. Expert Opin Drug Saf 2011;10:675-685.
13. Woodhouse A, Mather LE. Patient-controlled analgesia (PCA) for postoperative pain relief: What have we learnt and where do we go from here? Analgesia 1997;3:1-14.
14. http://www.bmj.com/content/348/bmj.g2737?tab=responses (accessed 3 June 2014)
15. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#antiemesis (accessed 28 May, 2014)
16. Serpell MG, Notcutt W, Collin C. Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis. J Neurol 2013;260:285-295.
17. Notcutt W, Langford R, Davies P, et al. 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). Mult Scler 2012:18:219-238
18. Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain 2013;14(2):136-148.

Dear Editor,

Re: Farrell MJ, Buchbinder R, Hall W. Should doctors prescribe cannabinoids? BMJ. 2014; 348: g2737

We write as the Market Authorisation Holder for Sativex, and are grateful for the opportunity to comment on the recently published article ‘Should doctors prescribe cannabinoids?’ by Farrell et al [1] Firstly, we would draw attention to the fact that Sativex (referred to as ‘nabiximols’ in the article, although this is not a recognised ‘generic name’ for the product in the EU) has received market authorisation from more than 25 National Competent Authorities around the world for the indication of “symptom improvement in patients with moderate to severe spasticity due to multiple sclerosis (MS) who have not responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy” [2]. And yet the authors did not discuss either of the 2 studies which demonstrate the efficacy of Sativex in the licensed indication [3,4]! The authors state that it has also been licensed for the treatment of neuropathic pain in the UK (their Box 2), which is not the case. Both of the studies which the authors fail to cite were designed in formal consultation with European regulatory agencies, and designed to answer the question of whether Sativex was effective in the patient population defined in the indication statement. A very detailed and wholly independent assessment of the integrity and results of those studies is publicly available as the Public Assessment Report, issued by the MHRA following approval of the medicine [5]. Surely the first duty of an opinion piece is whether the medicine should be used in the indication for which it has been licensed.
The preamble to the article draws attention to the fact that the series editor is also Editor in Chief of the Cochrane Library, giving the impression that the article has the Cochrane Library ‘seal of approval’. Yet the authors make no reference to the last Cochrane Library review of the efficacy of oral anti-spasticity agents in multiple sclerosis [6], which concluded “The absolute and comparative efficacy and tolerability of anti-spasticity agents in multiple sclerosis is poorly documented and no recommendations can be made to guide prescribing. The rationale for treating features of the upper motor neurone syndrome must be better understood and sensitive, validated spasticity measures need to be developed.” This Cochrane Review was published prior to the availability of any data on Sativex.

So when the article considers the treatment of spasticity in people with MS, instead of referring to any of this background information or reviewing the key evidence which supports the licensed indication for Sativex, the authors look at a single Phase 2 study with Sativex, and a single Phase 3 study with Sativex, each carried out in a patient population somewhat different to that for which the medicine is licensed. They refer to a single review article as though that article supports their conclusion, which it does not. Podda and Constantinescu (their reference 21) in fact cite the meta-analysis as a “Well-designed study in terms of number of patients and methods with statistically relevant results”. Podda and Constantinescu also conclude “This review suggests that nabiximols can be used in the treatment of difficult symptoms such as spasticity not wholly responding to the current medications” [7]. Farrell et al also omit any reference to a number of other more recent reviews which also support the use of Sativex in its licensed indication [8,9 for example]. When they refer to a randomised withdrawal phase in 58 patients in the context of the treatment of spasticity in MS they cite a reference that relates to a study in central neuropathic pain and has nothing to do with the treatment of spasticity. When referring to the overall results in the treatment of spasticity due to MS, they come to the conclusion that any benefit from Sativex ‘is likely to be modest’. There is no need to make a value judgement about the benefit, since there are published studies which define exactly what that benefit is. In the key efficacy and safety study there was a 23% difference in responder rate between Sativex and placebo - this compares very well with many medicines used routinely in the treatment of chronic neurological and psychiatric disorders.

Farrell et al go on to make comments about the long-term safety record of Sativex being uncertain, without referring to any of the published long-term studies [10, 11], the initial publication of the results of a comprehensive patient registry in the UK [12], where results are independently assessed. Nor do they refer to the fact that the EMA has recently removed the ‘Black Triangle’ from Sativex, suggesting at the least that there is a level of comfort at the European regulatory level with our understanding of the safety profile. They make no reference to the recently published clinical experience and review papers which outline the post-marketing experience in Germany [5,6], nor to the questionnaire survey of the effects of Sativex on various aspects of daily living [13]. They make no reference to the published results of a 12 month placebo-controlled study, also showing maintenance of effectiveness in long-term treatment, in the presence of no adverse effect on cognition [14]. They make no reference to the published guidelines in Germany, Spain and Sweden for example, which propose the place of Sativex in the treatment pathway for people with spasticity due to multiple sclerosis [15, 16, 17].

The authors make no reference to the fact that the patient-reported Numeric Rating Scale used in the GW studies has been comprehensively validated, and the clinically relevant improvement in patient-reported spasticity identified [18, 19].

Finally, the article discusses a study carried out in the US with smoked cannabis in a way that confuses it with the controlled studies carried out with Sativex, which is delivered as a metered dose oro-mucosal spray. There can be no reason these days to consider that 2 very different products, with very different composition, given by 2 very different routes of administration, with utterly different pharmacokinetic profiles, should be regarded as being essentially the same. This would be similar to arguing that a fentanyl patch is essentially the same as smoking opium.

When prescribers have exhausted conservative treatment options available to their patients with spasticity due to MS, the evidence from controlled clinical trials shows that Sativex has a positive risk/benefit. The evidence that has accumulated and published since Sativex has been available, covering more than 20,000 patient years of clinical experience, confirms that the medicine is of value in a particular patient population in the clinical setting. Surely this is what the authors should be addressing.

While we are aware that ‘opinion’ pieces will of course be published in medical journals and stimulate debate about the clinical utility of approved medicines, we also feel that the evidence that supports the licensed indication should form the basis for this discussion. In this article, that does not seem to have been the case.

REFERENCES
1. Farrell M, Buchbinder R, Hall W. Should doctors prescribe cannabinoids? Br Med J. 2014; 348: 2737
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4. Notcutt W, Langford R, Davies P, Ratcliffe S, Potts R. 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 2012;18:219-228.
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7. Podda G, Constantinescu CS. Nabiximols in the treatment of spasticity, pain and urinary symptoms due to multiple sclerosis. Exp Opin Biol Ther. 2012; 12: 1517-1531.
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9. Leussink VI, Husseini L, Warnke C et al. Symptomatic therapy in MS - the role of cannabinoids in treating spasticity. Ther Adv Neurol Disord. 2012; 5: 255-66
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12. Eltayb A, Etges T, Wright S. An observational post-approval registry study of patients prescribed Sativex®. Results from clinical practice. Multiple Sclerosis Journal 2013:19 (S1), P1041.
13. Notcutt W. A questionnaire survey of patients and carers of patients prescribed Sativex as an unlicensed medicine. Prim Health Care Res Dev. 2013; 14: 192-199.

14. Wright S Vachova MM, Novakova I. The effect of long-term treatment with a prescription cannabis based THC: CBD oromucosal spray on cognitive function and mood: a 12 month double blind placebo-controlled study in people with spasticity due to multiple sclerosis.
Multiple Sclerosis Journal 2013:19 (S1), P1206.
15. Spanish Neurology Society Consensus document on MS Spasticity management:
Oreja-Guevara C. el al, Rev Neurol 2013; 57 (8): 359-373.

16. DGN / KKNMS Leitlinie zur Diagnose und Therapie der MS - 12.04.2012
Gold et al,
http://www.dgn.org/component/content/article/45-leitlinien-der-dgn-2012/...

17. Swedish MS Management Guidelines, MS healthcarers official guidelines:
Spasticitet Metodboken, Svenska MS sällskapet J Lycke 2014
http://www.mssallskapet.se/Metodboken.html

18. Farrar JT, Troxel AB, Stott C, Duncombe P, Jensen MP. Validity, reliability, and clinical importance of change in a 0-10 numeric rating scale measure of spasticity: a post hoc analysis of a randomized, double-blind, placebo-controlled trial. Clinical Therapeutics 2008;30(5):974-985.
19. Anwar K, Barnes MP. A pilot study of a comparison between a patient scored numeric rating scale and clinician scored measures of spasticity in multiple sclerosis. NeuroRehabilitation 2009;24:333-340.