Public interest in cannabis products for medical purposes has been widely advocated, with legalization for recreational and medical use in North America and some European countries.6,8 Legalization of cannabis-based medicines (CBMs) (medical cannabis, plant-based cannabinoids [tetrahydrocannabinol, cannabidiol, and combinations], and synthetic tetrahydrocannabinol analogues) has bypassed usual drug regulatory procedures.6 Systematic reviews with meta-analyses of randomised controlled trials (RCTs) with CBM for chronic pain conditions help determine “post hoc” whether the preconditions of drug agencies for approval were met and to guide physicians and patients.
A systematic review of systematic reviews on CBM highlighted the uncertainty about whether CBMs improve pain, with only low or very low quality evidence available.1 Individual systematic reviews generally avoided issues of trial quality, usually had some flaws, and included different drugs, doses, durations, conditions, and outcomes. Most reviews agreed that there was no, or no clinically relevant, effect.
In this issue of PAIN, Stockings et al.12 provide the most comprehensive systematic review with meta-analysis of RCTs and observational studies with CBM, including 47 RCTs with 4271 patients with chronic noncancer pain. Study duration ranged between 1 day and 26 weeks. The authors avoid some methodology flaws of some of the systematic reviews mentioned above. They included “gray” literature and used all studies providing data in quantitative analyses. Average pain intensity, 30% and 50% or more pain relief, emotional and physical functioning, dropout rates, and adverse events were assessed. The impact of study duration and sample size on the effect sizes was studied. The quality of evidence for the outcomes ranged from moderate to very low quality. In pooled analyses, there was a clinically irrelevant number needed to treat to benefit of 24 for 30% pain relief or more and a number needed to treat to harm for any adverse event of 6. Consistent with most previous reviews, they conclude that it is “unlikely that cannabinoids are highly effective medicines for chronic noncancer pain.”
There remains a methodological minefield, through which we need to step carefully. For example:
- (1) Most studies analysed are of low methodology quality.
- (2) Most studies included fewer than 50 patients per treatment arm. Small CBM studies are often the most positive.
- (3) Short-duration experimental studies (hours, a single day) were included, unhelpful in judging longer-term efficacy.
- (4) Lumping all chronic pain syndromes together does not help in managing individual patients, given the heterogeneity of chronic pain and its mechanisms. Even the importance of subgroup analyses is limited: cancer pain might have nociceptive and/or neuropathic components; neuropathic pain can have many dimensions, and drugs might be effective for some dimensions of neuropathic pain but not for others.3 Whether heterogeneity of pain mechanisms is relevant for the efficacy of CBM, which are nonspecific centrally acting drugs is, however, unknown.
- (5) Lumping together all CBMs, including experimental drugs unavailable for clinical use, limits the clinical relevance of combined results.
- (6) There is the risk of overestimating the effects of CBM for pain relief because of unpublished studies, for example, with nabilone for chronic neuropathic pain.10
- (7) Long-term risk and severe but rare side effects are not captured in small, short-duration trials.
What can patients, clinicians, trialists, drug companies, and politicians conclude? On the one hand, they might conclude that, for any chronic pain condition, the evidence fails to meet EMA and FDA standards, and there are severe risks of addiction, long-term cognitive effects, and risk of psychosis,13 so their use in the clinic is to be discouraged. Yet, CBMs have already entered mainstream medicine in many countries. Some patients with chronic pain report substantial symptom improvement with CBM, and they, and politicians driven by the desire of public affirmation, really do not care about EMA and FDA standards. For them, CBMs can enrich drug treatment of chronic pain conditions.
It has been argued that the lack of high-quality evidence reflects the difficulty in conducting cannabis research due to government restrictions for medical and recreational use. If so, governments should support and encourage appropriate research to provide the high-quality evidence needed to guide decisions about CBM. As required by the European Medicines Agencies EMA and the Food and Drug Agency FDA, adequately powered randomized clinical trials with at least 4- to 12-week duration are necessary before approving a drug for any chronic condition.4 These studies should include patients with well-defined chronic pain conditions. How else is the efficacy and safety of defined dosages of CBM compared with standard treatments to be determined? Studies should also address the dosing of medical cannabis and the optimal ratio between tetrahydrocannabinal and cannabidiol. Cannabis registries would help with issues such as long-term efficacy and safety (driving accidents and abuse).
There is an uncomfortable parallel here with the situation with opioids, where the short-term demonstration of efficacy in chronic pain led to promotion and broad scale prescribing in the absence of good quality evidence. Information from studies so far suggests that problematic use of prescription CBMs exists in 10% to 20% of patients with chronic pain and is associated with greater amounts of CBM and smoking CBM as well as higher levels of depression and anxiety.5 A Canadian study found that medicinal cannabis was prescribed for a wide spectrum of rheumatic conditions, with over half diagnosed with osteoarthritis, that is to say for diseases with a lack of evidence. Medicinal users were younger, more likely unemployed or disabled, more likely previous recreational users, and with approximately 40% reporting concurrent recreational use.11 The demographic characteristics of these patients resemble, in an alarming way, those of the patients with abuse and misuse of prescribed opioids.9
The lessons of history are not to be mocked: we do not want to see a cannabis epidemic replacing that of opioids. The absence of any clinically relevant beneficial effects of CBM in most systematic reviews, the presence of clinically relevant side effects, and the concerns about long-term risks,2,7 make it the duty of physicians prescribing CBM for chronic pain conditions to document and monitor patients carefully by following recent clinical practice guidelines.
Conflict of interest statement
N.B. Finnerup has received consultancy fees from Grünenthal, Teva Pharmaceuticals, Novartis Pharma, and Mitshubishi Tanabe Pharma, and speaker's honoraria from Astellas, and personal fees from Mitshubishi Tanabe Pharma. W. Häuser received no honoraria or consulting fees by pharmaceutical companies in the past 3 years. He is chair of the task force of the European Pain Federation (EFIC) of a position paper on appropriate use of cannabis-based medicines and medical cannabis for chronic pain management and author of systematic reviews on cannabis-based medicines for chronic pain. R.A. Moore has received honoraria from RB, Perrigo Pharma, Futura Pharma, the UK Advertising Standards Authority, and Novartis, and grants from Novartis, mainly for advice about clinical study design and analysis.
. Allan GM, Finley CR, Ton J, Perry D, Ramji J, Crawford K, Lindblad AJ, Korownyk C, Kolber MR. Systematic review of systematic reviews for medical cannabinoids: pain, nausea and vomiting, spasticity, and harms. Can Fam Physician 2018;64:e78–94.
. Allan GM, Ramji J, Perry D, Ton J, Beahm NP, Crisp N, Dockrill B, Dubin RE, Findlay T, Kirkwood J, Fleming M, Makus K, Zhu X, Korownyk C, Kolber MR, McCormack J, Nickel S, Noël G, Lindblad AJ. Simplified guideline for prescribing medical cannabinoids in primary care. Can Fam Physician 2018;64:111–20.
. Attal N, Bouhassira D, Baron R, Dostrovsky J, Dworkin RH, Finnerup N, Gourlay G, Haanpaa M, Raja S, Rice AS, Simpson D, Treede RD. Assessing symptom profiles in neuropathic pain clinical trials: can it improve outcome? Eur J Pain 2011;15:441–3.
. D'Souza DC, Ranganathan M. Medical marijuana: is the cart before the horse? JAMA 2015;313:2431–2.
. Feingold D, Goor-Aryeh I, Bril S, Delayahu Y, Lev-Ran S. Problematic use of prescription opioids and medicinal cannabis among patients suffering from chronic pain. Pain Med 2017;18:294–306.
. Fitzcharles MA, Eisenberg E. Medical cannabis: a forward vision for the clinician. Eur J Pain 2018;22:485–91.
. Häuser W, Finn DP, Kalso E, Krcevski-Skvarc N, Kress HG, Morlion B, Perrot S, Schäfer M, Wells C, Brill S. European Pain Federation (EFIC) position paper on appropriate use of cannabis-based medicines and medical cannabis for chronic pain management. Eur J Pain 2018 In press.
. Krcevski-Skvarc N, Wells C, Häuser W. Availability and approval of cannabis-based medicines for chronic pain management and palliative/supportive care in Europe: a survey of the status in the chapters of the European Pain Federation. Eur J Pain 2018;22:440–54.
. Morley KI, Ferris JA, Winstock AR, Lynskey MT. Polysubstance use and misuse or abuse of prescription opioid analgesics: a multi-level analysis of international data. PAIN 2017;158:1138–44.
. Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2018;3:CD012182.
. Ste-Marie PA, Shir Y, Rampakakis E, Sampalis JS, Karellis A, Cohen M, Starr M, Ware MA, Fitzcharles MA. Survey of herbal cannabis (marijuana) use in rheumatology clinic attenders with a rheumatologist confirmed diagnosis. PAIN 2016;157:2792–7.
. Stockings E, Campbell G, Hall WD, Nielsen S, Zagic D, Rahman R, Murnion B, Farrel M, Weier M, Degenhardt L. Cannabis and cannabinoids for the treatment of people with chronic noncancer pain conditions: a systematic review and meta-analysis of controlled and observational studies. PAIN 2018;159:1932–54.
. Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med 2014;370:2219–27.