[PubMed – in process]
- Michael Farrell, professor and director1,
- Rachelle Buchbinder, director and professor2,
- Wayne Hall, professor, National Health and Medical Research Council Australia fellow, and deputy director (policy)3
- Correspondence to: M Farrell firstname.lastname@example.org
The medical use of cannabis was advocated in the United States in the 1970s and 1980s when clinical trials of oral synthetic tetrahydrocannabinol (THC) and other oral synthetic cannabinoids reported efficacy in controlling nausea in patients with cancer who were undergoing chemotherapy.1 Dronabinol (an oral synthetic THC) was approved by the Food and Drug Administration in 1985 for this indication,1 but it was not widely used because patients were unable to titrate doses or disliked its psychoactive effects.1 It is still available in the US, United Kingdom, and the rest of Europe.
Box 1 outlines the different formulations of cannabinoids, the term we use for the sake of clarity and convenience to refer to synthetic cannabinoids and drugs derived from the cannabis plant, such as nabiximols. Box 2 lists indications for which cannabinoids have been approved for medical use.
Box 1: Forms of cannabis and cannabinoids
Cannabis: Any product of the Cannabis sativa plant (such as marijuana or hash) that is smoked for its psychoactive effects
Cannabinoids: This term usually refers to a group of different chemical compounds that activate cannabinoid receptors in the body, including marijuana, endogenous neurotransmitters, and synthetic compounds. However, in this article, we use it to refer specifically to pharmaceutical drugs that are either:
Medical extracts from the cannabis plant, such as nabiximols (a patented formulation, trade name Sativex) or
Synthetic drugs that act on cannabinoid receptors, such as dronabinol and nabilone
Tetrahydrocannabinol (THC): The constituent of cannabis that by acting as an agonist on cannabinoid receptors is responsible for many of its psychoactive effects
Cannabinoid agonists: Cannabinoids that produce psychological effects similar to those produced by THC
Box 2: Approved medical uses for tetrahydrocannabinol and nabiximols
Controlling nausea and vomiting in cancer chemotherapy and radiotherapy (US)
Stimulating appetite in patients with AIDS related wasting (US)
Alleviating chronic neuropathic pain and muscle spasticity in multiple sclerosis (UK)
Should doctors be prescribing cannabinoids
Michael Farrell, professor and director of the National Drug and Alcohol Research Centre at the University of New South Wales in Sydney, talks to Mabel Chew, The BMJ’s practice editor, about prescription of cannabinoids.
They discuss the latest evidence on nausea and appetite, when cannabinoids may be effective for chronic pain, and which common problems to watch out for.
18 June 2014
Re: Should doctors prescribe cannabinoids?. 348:doi:10.1136/bmj.g2737
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.
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