Should doctors prescribe cannabinoids?BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g2737 (Published 23 April 2014) Cite this as: BMJ 2014;348:g2737
All rapid responses
We thank our various correspondents for their comments on our short article in the BMJ Uncertainties Series which explored this complex issue.
The topic was difficult to address in a short space, given the wide variety of disorders for which cannabis has been advocated to ameliorate symptoms, the range of synthetic cannabinoids and cannabis extracts that have been studied, and the small number and small size of studies in most cases.
We attempted to find a balance between the claims of strong advocates and strong opponents of the medical use of cannabis and cannabinoids. Our review used the least partisan reviews of the evidence, such as those undertaken by Cochrane Collaboration, which conclude that the evidence remains modest. We acknowledged that there are medical conditions for which cannabinoids can be prescribed with care such as nausea and vomiting. These indications are not the major reasons for use among medical cannabis users in the Netherlands (Hazekamp and Heerdink, 2013) where reasons for medical use are not distorted by the prohibition on recreational use as in the USA. This is largely because there are now many more effective drugs for nausea and vomiting than the drugs with which cannabinoids were compared in the 1970s and 1980s.
We support the sort of research undertaken by Guy Pharmaceuticals and Dr Stephen Wright but note that our brief article covered all cannabinoids, not just Nabiximols. We stand corrected on the indications for their use in the UK. We included a link in the article to their company website so readers can check for any future changes in this situation.
Until much more research has been done on medical uses of the cannabinoids, doctors face real world uncertainties in advising patients who ask about unapproved medical uses of cannabinoids, cannabis extracts, or smoked cannabis. We aimed to provide advice on sensible, compassionate and caring responses in the face of these uncertainties.
Considerable uncertainty remains about many medical uses of cannabinoids which we believe our short article correctly and honestly reflected.
Michael Farrell, Rachelle Buchbinder, Wayne Hall
Hazekamp A1, Heerdink ER (2013) The prevalence and incidence of medicinal cannabis on prescription in The Netherlands. Eur J Clin Pharmacol. 2013 Aug;69(8):1575-80. doi: 10.1007/s00228-013-1503-y. Epub 2013 Apr 16.
Competing interests: No competing interests
Re: Farrell MJ, Buchbinder R, Hall W. Should doctors prescribe cannabinoids? BMJ. 2014; 348: g2737.
Putting aside the debate on the scientific evidences of the reported topic, I would like to make a few arguments on the ethical and moral aspects it involves for physicians:
a) Wholistic Medicine versus Modern Medicine[1-6]: Albert Schweitzer, physician, theologian, philosopher, musician, Nobel Peace Prize for 1952, wrote: “The witch doctor succeeds for the same reason the rest of us (doctors) succeed. Each patient carries his own doctor inside him. They come to us not knowing this truth. We are at our best when we give the doctor who resides within each patient a chance to go to work”. Some years later in 1958, the World Health Organization, independently and wisely, states: “The same drug, in the same dose, in the same subject may produce very different effects according to the precise interpersonal and motivational situation in which it is given”. Wholistic Medicine, beyond clinical guidelines consideration, requires time, perseverance, empathy, confidence, all rare qualities in our modern, busy, technological, medical context. The third millennium physicians have, likely, forgotten these obsolete but human recommendations (clinical guidelines were not born at all, in those times). In fact, physicians today apparently focus more often on the drugs than on the patient, even though the “THERAPY” is an essential element of the set and setting. The “THERAPISTS” role is to facilitate the natural healing process by working with the patient to create the set and setting for an optimal outcome. Moreover, it seems that most of the third millennium physicians, have forgotten the different meaning of three important words in Medicine: "disease", "illness" and "sickness". In effect, doctors pay attention to and treat only "diseases", maybe considering human being as simple organic machinery.
b) About the scarcity of evidence pro Medical Cannabis[7-9]: Like any natural substance, Cannabis can be helpful or harmful depending on the way it is used. How many medical and surgical treatments without solid scientific evidence, are routinely performed in clinical practice all over the world, every day? Maybe 30% of all treatments? Maybe more? Why this particular debate for lack of evidence in the case of Cannabis?
c) Guidelines based medical treatment[9-12]: As demonstrated by many honest authors, guidelines are still not following guidelines, so that, unfortunately, in guidelines we cannot trust. This statement is true for a lot of drugs commonly used in clinical practice. May it be true for medical Cannabis too? Why not if Cannabis might help some patients without harm?
d) Dangers and collateral effects of Cannabis[8,13-15]: Every day in the world, millions of pills are prescribed out of the related guidelines, often with severe dangers for patients. Cannabis shows the greater therapeutic index among ALL commonly prescribed drugs. I produce an impressive picture, personally taken at the British Museum in London, and representing the glass showcase containing the 14.000 (yes, fourteen-thousand!) pills ingested by an human being during a “typical western modern lifetime”.
e) Yes[8,16], doctors should prescribe Cannabis because, in this way, they will respect the Hippocratic Oath: “primum non nocere”.
1) Illich I. Medical nemesis. Bantam, Toronto / New York / London, 1977.
2) Barnes PM, Powell-Griner E, McFann K, Nahin RL. Complementary and alternative medicine use among adults: United States, 2002. Advance data from vital and health statistics; no 343. Hyattsville, Maryland: National Center for Health Statistics. 2004.
3) Wilson A. Porter versus Foucault on the 'Birth of the Clinic.' In: Bivins R, Pickstone JV, eds. Medicine, Madness, and Social History.New York, NY: Palgrave Macmillan; 2007:32.
4) Szasz TS. Ideology and Insanity. Essay on Psychiatric Dehumanization of Man. Anchor Books, Doubleday & Company, Inc., New York, 1970.
5) Szasz TS. Pharmacracy: medicine and politics in America. Prager, Westport, 2001
6) Kurzweil R. The Singularity Is Near: When Humans Transcend Biology. Viking Press, New York, 2005.
7) Manchikanti L, Singh V, Helm S, Trescot AM, Hirsch JA. A critical appraisal of 2007 American College of Occupational and Environmental Medicine (ACOEM) Practice Guidelines for Interventional Pain Management: an independent review utilizing AGREE, AMA, IOM, and other criteria. Pain Physician. 2008 May-Jun;11(3):291-310.
8) McPartland JM and Russo EB. Cannabis and Cannabis Extracts: Greater Than the Sum of Their Parts? Journal of Cannabis Therapeutics 2001; Vol.1: 103-132.
9) Tag Archives: scientific misconduct. http://cardiobrief.org/tag/scientific-misconduct/ accessed at 2014-06-26.
10) Shaneyfelt TM, Mayo-Smith MF, Rothwangl J: Are guidelines following guidelines? The methodological quality of clinical practice guidelines in the peer-reviewed medical literature. JAMA 1999; 281 (20): 1900-1905.
11) Diamond GA, Kaul S. The disconnect between practice guidelines and clinical practice: stressed out. JAMA. 2008;300(15):1817-1819.
12) Kung J, Miller RR, Mackowiak PA. Failure of Clinical Practice Guidelines to Meet Institute of Medicine Standards. Two More Decades of Little, If Any, Progress. Arch Intern Med. 2012;172(21):1628-1633.
13) Buajordet I, Ebbesen J, Erikssen J, et al. Fatal adverse drugs events: the paradox of drug treatment. J Int Med 2001;250:327-41.
14) Moynihan RN, Cooke GPE, Doust JA, Bero L, Hill S, Glasziou PP. Expanding Disease Definitions in Guidelines and Expert Panel Ties to Industry: A Cross-sectional Study of Common Conditions in the United States. PLoS Med 2013; 10(8): e1001500. doi:10.1371/journal.pmed.1001500
15) Kaur S, Mitchell G, Vitetta L, et al. Interventions that can reduce inappropriate prescribing in the elderly: a systematic review. Drugs Aging 2009;26:1013-28.
16) Dale Jacquette. Cannabis Philosophy for Everyone: What Were We Just Talking About? Edited by Dale Jacquette Blackwell Publishing Ltd, 2010, ISBN: 978-1-405-19967-4.
Gastone Zanette M.D., Assistant Professor of Anaesthesiology, Department of Neurosciences, Section of Dentistry, Chair of Dental Anaesthesia. University of Padua Via Giustiniani 2, 35128 Padova, Italy. e-mail: firstname.lastname@example.org
Competing interests: I report my personal use, since 35 years, of self-produced biological Cannabis Sativa/Indica for successful prevention of a disabling migraine. I get such successful result by means of the evening assumption of about 300 - 500 mg of Cannabis buds.
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.
Competing interests: President and elected leader of CLEAR Cannabis Law Reform
Re: Farrell MJ, Buchbinder R, Hall W. Should doctors prescribe cannabinoids? BMJ. 2014; 348: g2737
Farrell's article lists the different types of cannabinoid drugs. The list presented in box 1 shows that cannabis is defined as "Any product of the plant Cannabis sativa (such as marijuana or hash) that is smoked for its psychoactive effects." In addition, the side effects attributed to cannabis, as presented in box 3, are: "Adverse effects of chronic recreational cannabis smoking identified in epidemiological studies". The conclusions repeat that cannabis is defined as "the plant product that is smoked." But identifying smoking as the sole method of administration of cannabis is wrong.
As reported in the web page of the Office of Medicinal Cannabis, Ministry of Health, Welfare and Sports, The Netherlands, regarding the information for health care professional about the medical product “Cannabis dried flowers”: “Two methods of administration are recommended: oral administration or administration through inhalation (vaporization)...Smoking is not recommended.
Cannabis smoke contains harmful combustion products, including carbon monoxide and carcinogens. As a result, frequent use of smoked cannabis over a long period of time presumably exposes users to health risks associated with smoking....To limit the damage caused by combustion products, cannabis can be inhaled by a vaporizer.” (1)
Therefore it is possible to administrate medical cannabis as tea (or better, “decoction”), and also to prepare cannabis butter or cookies (2). Another possible oral preparation is cannabis oil.(3, 4). To assume that medical cannabis identifies with smoking, which, among other problems, is an economically disadvantageous method as it destroys up to 30 % of the active ingredients (5), is misleading.
1) http://www.cannabisbureau.nl/en/doc/pdf/Information%20for%20Health%20Car...(version%20October%202013)_18980.pdf (access 06/18/2014)
2) Hesselink JM, Kopsky DJ. Intractable neuropathic pain due to ulnar nerve entrapment treated with cannabis and ketamine 10% J Clin Anesth. 2012 Jan 5.
3) Romano L, Hazekamp A. Cannabis Oil: chemical evaluation of an upcoming cannabis-based medicine. Cannabinoids 2013; 1 (1) :1-11 (5 May 2013)
4) Y Singh, Bali C. Cannabis extract treatment for terminal acute lymphoblastic leukemia with Philadelphia chromosome mutation. Case Rep Oncol. November 28 2013, 6 (3) :585-92
5) Perez-Reyes M. Marijuana smoking: factors that influence the bioavailability of tetrahydrocannabinol. NIDA Res Monogr.1990;99:42-62.
Competing interests: I am president of Associazione Cannabis Terapeutica (Italian Association for Medical Cannabis) It is an association on a totally voluntary basis, so I have no financial interest nor other
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.  reported that “Dronabinol has a modest but clear and clinically relevant analgesic effect in multiple sclerosis patients with central pain”. Rog et al.  found that the nabiximols was superior on just about every measure. Wade et al.  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.
Competing interests: L. Mather was a member of the Working Party on the Use of Cannabis for Medical Purposes convened by the Premier of NSW in 1999 chaired by Professor Wayne Hall and contributed evidence to inquiry held by the General Purpose Standing Committee No.4 of the Legislative Council of NSW in 2013. He has been an Emeritus Professor of Sydney Medical School since 2007, and has received both research grant support and consultancy fees from various sources unrelated to the present topic. A. Wodak contributed evidence to inquiry held by the General Purpose Standing Committee No.4 of the Legislative Council of NSW in 2013 and is a member of the Australian Drug Law Reform Foundation. He has been an Emeritus Consultant of St Vincent’s Hospital, Sydney since 2012, and has received consultancy fees from various sources unrelated to the present topic. W. Notcutt has participated in research into cannabinoids sponsored by GW Pharmaceuticals and MEDA. He has received consultancy fees for Advisory Boards and been sponsored to speak at meetings. He is a past Chair of the International Association for Cannabis Medicines.
We are grateful to Farrell and colleagues for including our Expert Opinion review of nabiximols1 in the symptomatic treatment of MS in their recent “Uncertainties Page” issue of the BMJ2. However, we feel that their interpretation of the conclusion of our paper is inexact. Farrell and colleagues state that our article “concluded that, although nabiximols may have a role as adjunctive treatment of muscle spasticity in multiple sclerosis, its efficacy and tolerability were poorly documented and that further data were needed on its long-term safety".
In the 'Expert Opinion' section at the end of our article we write "This review suggests that nabiximols can be used in the treatment of difficult symptoms such as spasticity not wholly responding to the current medications." We also conclude that the positive results of trials, the tolerability, the lack of psychotropic effects in the medium term, are in favour of nabiximols as a treatment option. We do refer to the possibility that long term treatment trials select for the responders, but that nabiximols is indeed a viable option in the substantial number of patients who show responsiveness.
Farrell and colleagues also state that our review did not refer to "an additional, high-quality randomised controlled study (n=339), not included in this review..". Yet our review states " A Phase III trial was conducted on a sample of 339 patients with MS and neuropathic pain who still experienced pain despite treatment [reference 32 in our paper]".
In conclusion, we do not believe that interpretation of the conclusions of our review coincides with its actual conclusions.
Cris S Constantinescu
University of Nottingham
1 Podda G, Constantinescu CS. Nabiximols in the treatment
of spasticity, pain and urinary symptoms due to multiple sclerosis. Expert Opin Biol Ther 2012;12:1517-31
2 Farrell M, Buchbinder R, Hall W. Should doctors prescribe cannabinoids? BMJ 2014;341:g2737
Competing interests: I have received research support from Bayer and GW
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  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” . 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 . 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 , 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” . 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 , 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 . 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 . 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.
1. Farrell M, Buchbinder R, Hall W. Should doctors prescribe cannabinoids? Br Med J. 2014; 348: 2737
2. Sativex: Summary of Product Characteristics.
3. Novotna A, Mares J, Ratcliffe S, et al. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols (Sativex), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol 2011;18:1122-1131.
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.
5. Sativex Public Assessment Report, 2010 http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con084...
6. Shakespeare DT, Boggild M, Young C. Anti-spasticity agents for multiple sclerosis
(Cochrane Review). In: The Cochrane Library, Issue 2, 2004. Chichester, UK: John Wiley
& Sons, Ltd.
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.
8. Flachenecker P, Henze T, Zettl U. Nabiximols (THC/CBD Oromucosal Spray, Sativex ® ) in Clinical Practice – Results of a Multicenter, Non-Interventional Study (MOVE 2) in Patients with Multiple Sclerosis Spasticity. Eur Neurol. 2014; 71: 173-187.
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
10. 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.
11. Wade DT, Makela PM, House H, Bateman C, Robson P. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. . Mult Scler. 2006 Oct;12(5):639-45.
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,
17. Swedish MS Management Guidelines, MS healthcarers official guidelines:
Spasticitet Metodboken, Svenska MS sällskapet J Lycke 2014
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.
Competing interests: Fully paid employee of GW Research Ltd
Marijuana and hashish are addictive hallucinogens that trick and trap us by creating the fleeting euphoria of knowledge and wisdom, but the sustained sickness of confusion and paranoia. The euphoria of knowledge and wisdom, and the sickness of confusion and paranoia, are polar opposites that reinforce each other: the euphoria blinds us to the sickness, and the sickness makes us crave the euphoria. Perversely but predictably, marijuana and hashish create, aggravate, and perpetuate the very sickness of confusion and paranoia that they falsely seem to cure, thus placing all hallucinogens in a very bad light.
Competing interests: No competing interests