Original article

Cannabinoids in Pain Management and Palliative Medicine

An overview of systematic reviews and prospective observational studies

Dtsch Arztebl Int 2017; 114(38): 627-34; DOI: 10.3238/arztebl.2017.0627

Häuser, W; Fitzcharles, M; Radbruch, L; Petzke, F

Background: There are conflicting interpretations of the evidence regarding the efficacy, tolerability, and safety of cannabinoids in pain management and palliative medicine.

Methods: We conducted a systematic review (SR) of systematic reviews of randomized controlled trials (RCT) and prospective long-term observational studies of the use of cannabinoids in pain management and palliative medicine. Pertinent publications from January 2009 to January 2017 were retrieved by a selective search in the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, and Medline. The methodological quality of the SRs was assessed with the AMSTAR instrument, and the clinical relevance of quantitative data syntheses was assessed according to the standards of the Cochrane Collaboration.

Results: Of the 750 publications identified, 11 SRs met the inclusion criteria; 3 of them were of high and 8 of moderate methodological quality. 2 prospective long-term observational studies with medical cannabis and 1 with tetrahydrocannabinol/cannabidiol spray (THC/CBD spray) were also analyzed. There is limited evidence for a benefit of THC/CBD spray in the treatment of neuropathic pain. There is inadequate evidence for any benefit of cannabinoids (dronabinol, nabilone, medical cannabis, or THC/CBD spray) to treat cancer pain, pain of rheumatic or gastrointestinal origin, or anorexia in cancer or AIDS. Treatment with cannabis-based medicines is associated with central nervous and psychiatric side effects.

Conclusion: The public perception of the efficacy, tolerability, and safety of cannabis-based medicines in pain management and palliative medicine conflicts with the findings of systematic reviews and prospective observational studies conducted according to the standards of evidence-based medicine.

As of 10 March 2017, according to the provisions of the “Act to Amend Narcotic Drugs Provisions and Other Related Provisions”, physicians in Germany may prescribe cannabinoids—with costs covered by statutory health insurances—for patients with severe diseases and no alternative treatment options available, as dried cannabis flowers (so-called medical cannabis or medical marijuana), standardized extracts (compounded medication dronabinol, finished medicinal product THC/CBD [tetrahydrocannabinol/cannabidiol] spray) or synthetic THC analog (finished medicinal product nabilone) (1) (Box). Recently, an article in Deutsches Ärzteblatt stated that chronic—especially neuropathic—pain, spasticity in multiple sclerosis and loss of appetite, nausea and vomiting are considered “established“ indications for cannabis-based medicines (2).

Cannabis-based medicines and their availability in German
Box
Cannabis-based medicines and their availability in German

Systematic reviews (SRs) with quantitative analyses (meta-analysis) of randomized clinical trials (RCTs) and overviews of SRs have the highest level of evidence in evidence-based medicine (3). Long-term efficacy and long-term risk can be assessed by prospective observational studies (4).

Thus, the aim of this paper is to identify potential indications for, but also risks of cannabinoids in pain management and palliative medicine, based on systematic reviews of RCTs and prospective long-term (≥ 6 months) observational studies.

Methods

This overview was prepared according to the recommendations of the Pain Palliative and Supportive Care Group of the Cochrane Collaboration (5), of the Cochrane Collaboration on the compilation of a Cochrane Overview on Reviews (6) and of the Joanna Briggs Institute on the conduction of umbrella reviews (7). For detailed information about the methods (literature search, inclusion criteria, endpoints, methodological quality, data extraction) refer to the eBox.

Methods
eBox
Methods

The analytic methods and inclusion criteria used were defined a priori (PROSPERO 2017; CRD 42017058875).

The methodological quality of the SRs was assessed using the AMSTAR rating (e1). The 11 items of AMSTAR—a measurement tool to assess systematic reviews—are listed in eTable 1. AMSTAR scores of 0–4, 5–8 and 9–11 were rated as low, moderate and high methodological quality, respectively (e2).

Characteristics of the randomized controlled trials with cannabinoids included in the systematic reviews
Table 1
Characteristics of the randomized controlled trials with cannabinoids included in the systematic reviews

Results

Literature search

Systematic reviews: Altogether 750 publications were identified by database searches and manual searches. Twenty full-text articles were assessed for suitability. Eight SRs were excluded as they lacked quantitative data analysis without giving reasons for this omission (815). One SR was excluded because the quantitative data synthesis was performed based on data on all types of chronic pain without subgroup analysis (16). Eleven SRs were included in our qualitative analysis, comprising 5 SRs with quantitative data analysis (1721) und 6 without quantitative analysis due to insufficient data quantity and/or quality (2227) (Figure). Six of the 11 included SRs had been prepared by our own working groups (19, 20, 22, 23, 26, 27).

Results of literature search
Figure
Results of literature search

Prospective observational studies: Our database search yielded 7 hits in Medline, 30 hits in ClinicalTrials.gov und 2 hits in the manual search. Three studies met the inclusion criteria (2830).

Study characteristics

An overview of the SRs included in this review is provided in Table 1. Two SRs required a minimum study duration (double-blind period) of 2 weeks (19, 20) for inclusion; 1 SR required a study duration of at least 4 weeks (23). The remaining studies had no study duration–based inclusion criteria.

Methodological quality of the RCTs analyzed in the SRs varied widely. The methodological quality of 3 SRs (17, 20, 27) was high, while it was moderate in the remaining SRs (eTable 1).

Assessment of methodological quality of systematic reviews on controlled trials with cannabinoids in pain management and palliative medicine using the AMSTAR instrument (e1) (in alphabetical order)
eTable 1
Assessment of methodological quality of systematic reviews on controlled trials with cannabinoids in pain management and palliative medicine using the AMSTAR instrument (e1) (in alphabetical order)

Neuropathic pain

Three SRs (17, 18, 20) analyzed up to 25 RCTs with 1837 participants and with study duration between 5 hours and 15 weeks (Table 2). In the meta-analysis on the use of medical marijuana, a clinically relevant number needed to treat for an additional benefit (NNTB) of 6 was calculated for pain relief of at least 30%. The authors concluded that medical marijuana was effective in reducing neuropathic pain in the short term (duration of the analyzed studies varied between 1 and 14 days) (17). One SR of all cannabinoids used to treat neuropathic pain, including “gray literature“, found an NNTB of 10 in a pooled analysis for this outcome parameter. In the subgroup analysis, the difference between the mean pain relief achieved with medical marijuana and that achieved with placebo was not statistically significant. However, with regard to a minimum pain relief of 30%, medical marijuana proved to be superior to placebo; this difference was both statistically significant and clinically relevant. Tetrahydrocannabinol/cannabidiol (THC/CBD) spray was superior to placebo with regard to mean pain relief (but not statistically significant) and at least 30% pain relief (statistically significant). The NNTB for at least 30% pain relief was clinically not relevant.

Results of systematic reviews of randomized controlled trials with cannabinoids for chronic neuropathic pain
Table 2
Results of systematic reviews of randomized controlled trials with cannabinoids for chronic neuropathic pain

In the pooled analysis of all cannabinoids, the number needed to harm (NNH) of 25 was clinically not relevant for adverse event–related study discontinuation. No statistically significant differences were found with regard to the rate of serious adverse events between the cannabinoid and placebo groups. The authors concluded that cannabinoids can be used as third-line therapy in carefully selected patients, if they were to be used at all (20).

One SR of multiple sclerosis studies found no statistically significant difference compared to placebo with regard to mean pain relief. The authors concluded that the number of available studies was too small to allow for recommendations for cannabinoids (18).

Pain associated with rheumatic diseases

Three SRs analyzed a total of 4 RCTs, comprising 1 RCT evaluating THC/CBD spray in 58 patients with rheumatoid arthritis, 2 RCTs with 72 patients with fibromyalgia and 1 RCT with 30 patients with musculoskeletal pain. The authors for all 3 SRs concluded that the current evidence base is inadequate to recommend cannabinoids for the treatment of pain associated with rheumatic diseases (22, 23, 27) (eTable 2).

Efficacy of cannabinoids in pain associated with rheumatic diseases—systematic reviews of randomized controlled trials
eTable 2
Efficacy of cannabinoids in pain associated with rheumatic diseases—systematic reviews of randomized controlled trials

Visceral pain

One SR analyzed 1 RCT evaluating medical marijuana administered as a joint compared to a cigarette not containing tetrahydrocannabinol (THC) in 21 patients with Crohn’s disease over a period of 8 weeks. While no significant differences were found with regard to remission rate and incidence of adverse events, a significant reduction in abdominal pain (p<0.05) and improvement in appetite was observed. The authors concluded that individual therapeutic trials of THC in patients with Crohn’s disease to alleviate pain and loss of appetite should only be considered after non-response to all established pharmacotherapy options and with a careful risk–benefit assessment (26) (eTable 3).

Efficacy of cannabinoids in visceral pain—systematic review of randomized controlled trials
eTable 3
Efficacy of cannabinoids in visceral pain—systematic review of randomized controlled trials

An additional study of the effect of oral THC in chronic pancreatitis was published subsequent to the literature search. This 3-month study evaluating 65 patients with pain associated with chronic pancreatitis reported the following: there was no statistically significant superiority of oral THC over placebo with regard to pain relief (31).

Cancer pain

Two SRs (19, 21) analyzed the same 2 RCTs with 307 patients and a study duration of 2 and 3 weeks, respectively (eTable 4). In both quantitative analyses, the significance levels of the cannabinoid–placebo comparison with regard to at least 30% pain relief were just above the threshold of p ≤ 0.05. No statistically significant differences in tolerability and safety were found between cannabinoid and placebo (19). One SR concluded that given the limited data available it was not possible to recommend the use of cannabinoids to treat cancer pain (19).

Efficacy of cannabinoids in cancer pain—systematic reviews of randomized controlled trials
eTable 4
Efficacy of cannabinoids in cancer pain—systematic reviews of randomized controlled trials

Appetite, weight and nausea/vomiting in advanced diseases

Two SRs analyzed a total of 6 RCTs with 350 patients with HIV/AIDS and study duration between 3 and 12 weeks. All studies were conducted prior to the introduction of highly active antiretroviral therapy (HAART). One SR identified clinically relevant increases in appetite and weight. No statistically significant differences with regard to tolerability and safety were found between cannabinoids and placebo (19). Both SRs concluded that insufficient evidence was available to support the use of cannabinoids to symptomatically treat loss of appetite, nausea and weight loss in patients with HIV/AIDS (19, 24).

One SR analyzing 3 RCTs with 441 cancer patients found no statistically significant differences with regard to increases in appetite, weight and calorie intake compared to placebo. The authors concluded that there is not sufficient evidence to recommend the use of cannabinoids for symptomatic treatment of loss of appetite and loss of weight in cancer patients (19).

Two SRs evaluating 1 RCT of dronabinol in 15 patients with Alzheimer-type dementia over a period of 12 weeks concluded that from published data the efficacy (calorie intake, body weight), tolerability and safety of cannabinoids cannot be determined and that there is no evidence to recommend the use of cannabinoids in patients with dementia (19, 24) (eTable 5).

Efficacy of cannabinoids in palliative medicine—systematic reviews of randomized controlled trials
eTable 5
Efficacy of cannabinoids in palliative medicine—systematic reviews of randomized controlled trials

Prospective long-term observational studies

Three prospective long-term studies were identified (eTable 6). Altogether 380 of 439 patients who had been enrolled in either an RCT evaluating painful diabetic polyneuropathy or an RCT evaluating neuropathic pain of various causes agreed to participate in a 38-week observational trial assessing THC/CBD spray. At least half of the patients reported pain relief of ≥ 30% and at least one-third of patients had pain relief of ≥ 50% at all time points. Altogether 23% of patients discontinued the study because of adverse events. In 11% of patients, serious adverse events were observed (28).

Cannabinoids in pain medicine – prospective long-term studies
eTable 6
Cannabinoids in pain medicine – prospective long-term studies

A Canadian prospective 1-year observational study compared 215 patients with non-cancer pain treated with standardized medical marijuana (12.5% THC) with 216 pain patients not treated with cannabis. In the cannabis group, a statistically significant pain relief compared with baseline of –0.92 points on an 11-step scale (95% confidence interval: [–0.62; –1.23]) was found, while this was not the case in the control group with –0.18 [0.13; –0.49]. The extent of pain relief of <1 point is not clinically relevant (5). The rate of non-serious adverse events was increased in the group treated with medical marijuana (adjusted incidence rate: 1.73 [1.41; 2.13]), but not the rate of serious adverse events (adjusted incidence rate: 1.08 [0.57; 2.04]). Only 7% of patients in the cannabis group were cannabis-naive, i.e. had never consumed cannabis before, compared with 64% in the control group. The authors stated that their study did not allow conclusions to be drawn regarding the safety of medical marijuana in cannabis-naive patients with chronic non-cancer pain (29).

A 1-year observational study examining the efficacy of medical marijuana and conducted in Israel recruited 216 patients with non-cancer pain. The reduction in pain severity scores from median 7.50 [6.75; 7.75] to 6.25 [5.75; 6.75] on an 11-step scale was clinically relevant. The study was discontinued by 5.3% patients because of adverse events. The rate of serious adverse events was 1% (30).

Discussion

Applying the quality criteria of evidence-based medicine, we found inadequate evidence to support the “established” indications claimed by proponents of medical marijuana therapy, such as chronic cancer pain or loss of appetite, nausea and vomiting in advanced disease stages. Likewise, there was no evidence to support the claimed positive effects in patients with internal disorders (arthritis, ulcerative colitis) (2). The current evidence with regard to cancer pain, loss of appetite, or nausea and vomiting in patients with HIV and dementia, as well as rheumatoid arthritis showed no clear benefit from the use of cannabinoids compared with placebo. There are no controlled trials for ulcerative colitis. Two RCTs investigating THC-containing cigarettes (e3) and oral CBD (e4), respectively, showed no statistically significant effects on disease activity in patients with Crohn’s disease.

By contrast, sufficient evidence is available for neuropathic pain. A meta-analysis based on individual patient data on the use of medical marijuana to treat neuropathic pain found an NNTB of 6 for pain relief of at least 30% (17). This finding meets the criteria for a clinically relevant benefit (4). However, the validity of the finding is limited by small sample sizes (23–50 participants/study) and short study durations (3 studies <1 week, 2 studies conducted over a period of 2 weeks). With small study sizes, therapeutic effects may be overestimated (e5). The European Medicines Agency (EMA) requires two studies with a minimum of 12 weeks’ duration for approval of a medication for pain management (e6).

In the SR on all cannabinoids, requiring a study duration of at least 2 weeks, a subgroup analysis found no superiority with regard to mean pain relief for medical marijuana compared with placebo (20). The NNTB of 12 for pain relief of at least 30% by THC/CBD spray was not clinically relevant (20). On clinicaltrials.gov, 3 RCTs with nabilone and 1 RCT with medical marijuana for neuropathic pain are registered, but their results have not yet been reported (20). Should these not yet published studies yield negative results, a pooled analysis would be even less favorable for cannabinoids.

Two SRs found no statistically significant increase in the incidence of serious adverse events for cannabinoids in comparison with placebo in neuropathic (20) or cancer pain (19). The NNTH of 25 for discontinuation due to adverse events calculated in the SR on neuropathic pain was clinically not relevant. However, this SR identified a clinically relevant NNTH of 3 for central nervous system adverse events and an NNTH of 9 for psychiatric disorders (20). Likewise, the 3 prospective observational studies on medical marijuana and THC/CBD spray detected frequent central nervous and psychiatric adverse events (2830).

Our more reserved view of the role of cannabinoids in pain management and palliative medicine is in line with current European guideline recommendations. The Special Interest Group on Neuropathic Pain (NeuPSIG) of the International Association for the Study of Pain (IASP) issued a weak recommendation against the use of cannabinoids (32). The guideline of the British National Institute for Health and Care Excellence (NICE) made a negative recommendation for the use of THC/CBD spray in multiple sclerosis, as it is not cost-effective (33). The German guideline (34) and the European League Against Rheumatism (EULAR) (35) issued negative recommendations for cannabinoids in fibromyalgia syndrome. By contrast, the Canadian guideline on neuropathic pain made a recommendation for cannabinoids as a third-line therapy with short-term or mid-term treatment duration (36) and an open recommendation for cannabinoids in fibromyalgia patients with severe insomnia (37). The American Academy of Neurology recommended that THC/CBD spray or oral THC may be given as a treatment trial for pain associated with multiple sclerosis. It was concluded that data are inadequate to support or refute use of medical marijuana (38). The authors of this review are not aware of any national or European guidelines recommending the use of cannabinoids in palliative medicine.

Data from existing studies do not allow for clear recommendations to guide prescribing physicians on how to dose medical marijuana, either with regard to THC:CBD ratio or to dosing for specific indications. In countries such as Canada und Israel where the option to prescribe herbal cannabis for medicinal purposes has been available for several years, the majority of physicians reported inadequate understanding of medical marijuana in general and, more specifically, poor knowledge of how to prescribe cannabinoids (e7, e8). Given the negative health impact of tobacco smoking, the German Medical Association advised against treatment with medical marijuana in the form of joints (39). According to the authors’ clinical experience, persons inexperienced in the recreational use of marihuana find it difficult to inhale medical marijuana via a vaporizer.

Outlook

A JAMA editorial titled “Is the cart before the horse” pointed out that the approval of medical marijuana in several US federal states was based on low-quality evidence, public opinion and political agenda. According to the author of this editorial, such disregard for the medicines agencies’ drug approval standards is unprecedented (40). In Germany, the process followed a similar pattern. In anticipation of this change in the law, the German Medical Association argued against allowing the prescription of medical marijuana, stating that the available evidence was inadequate to support this move (39). The German Pain Society (DSG, Deutsche Schmerzgesellschaft) and the German Society of Palliative Medicine (DGP, Deutsche Gesellschaft für Palliativmedizin) have, however, welcomed the law change, contending that existing barriers to the reimbursement of cannabis-containing compounded medications and formulated medicinal products will be eased. Currently available data provide sufficient evidence, according to evidence-based medicine criteria, to support the use of THC/CBD spray in carefully selected neuropathic pain patients who have shown insufficient response to standard pharmacotherapy. The results of 3 long-term observational studies support the observed benefit and tolerability of THC/CBD spray and medical marijuana in selected patients with chronic non-cancer pain syndromes. However, the use of all cannabinoids for any indication in pain management and palliative medicine should be regarded as an individual therapeutic trial, except for two approved indications (THC/CBD spray for spasticity in multiple sclerosis and nabilone for chemotherapy-induced vomiting). Cannabinoids, however, should not be used in isolation as the only treatment, but in combination with physiotherapy and pain-related psychotherapy (e9).

In Italy, all prescriptions of THC/CBD spray for spasticity in multiple sclerosis are linked to a web-based registry of the Agenzia Italiana del Farmaco, designed to prospectively collect data on the efficacy and tolerability of this medication (e10). It is to be hoped that the accompanying research required by the “Act to Amend Narcotic Drugs Provisions and Other Related Provisions” which was enacted on March 10, 2017 will be designed to assemble evidence based information with regard to the efficacy, tolerability and safety of medical marijuana for specific indications.

Conflict of interest

The authors declare that no conflict of interest exists.

Manuscript received on 6 April 2017; revised version accepted on
21 June 2017

Translated from the original German by Ralf Thoene, MD

Corresponding author
Prof. Dr. med. Winfried Häuser
Klinik Innere Medizin I, Klinikum Saarbrücken
Winterberg 1
66119 Saarbrücken, Germany
whaeuser@klinikum-saarbruecken.de

Supplementary material
For eReferences please refer to:
www.aerzteblatt-international.de/ref3817

eTables, eBox:
www.aerzteblatt-international.de/17m0627

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Department of Internal Medicine I, Klinikum Saarbrücken, Germany: Prof. Dr. med. Häuser
McGill University Health Centre, Division of Rheumatology and Alan Edwards Pain Management Unit, Montreal, Quebec, Canada: Prof. Fitzcharles, MRCP (UK), FRCP ©
Palliative Care Center, Malteser Krankenhaus Seliger Gerhard Bonn/Rhein-Sieg, Germany:
Prof. Dr. med. Radbruch
Department of Anesthesiology and Intensive Care Medicine, University Hospital Göttingen,
Göttingen, Germany: Prof. Dr. med. Petzke
Cannabis-based medicines and their availability in German
Box
Cannabis-based medicines and their availability in German
Results of literature search
Figure
Results of literature search
Key messages
Characteristics of the randomized controlled trials with cannabinoids included in the systematic reviews
Table 1
Characteristics of the randomized controlled trials with cannabinoids included in the systematic reviews
Results of systematic reviews of randomized controlled trials with cannabinoids for chronic neuropathic pain
Table 2
Results of systematic reviews of randomized controlled trials with cannabinoids for chronic neuropathic pain
Methods
eBox
Methods
Assessment of methodological quality of systematic reviews on controlled trials with cannabinoids in pain management and palliative medicine using the AMSTAR instrument (e1) (in alphabetical order)
eTable 1
Assessment of methodological quality of systematic reviews on controlled trials with cannabinoids in pain management and palliative medicine using the AMSTAR instrument (e1) (in alphabetical order)
Efficacy of cannabinoids in pain associated with rheumatic diseases—systematic reviews of randomized controlled trials
eTable 2
Efficacy of cannabinoids in pain associated with rheumatic diseases—systematic reviews of randomized controlled trials
Efficacy of cannabinoids in visceral pain—systematic review of randomized controlled trials
eTable 3
Efficacy of cannabinoids in visceral pain—systematic review of randomized controlled trials
Efficacy of cannabinoids in cancer pain—systematic reviews of randomized controlled trials
eTable 4
Efficacy of cannabinoids in cancer pain—systematic reviews of randomized controlled trials
Efficacy of cannabinoids in palliative medicine—systematic reviews of randomized controlled trials
eTable 5
Efficacy of cannabinoids in palliative medicine—systematic reviews of randomized controlled trials
Cannabinoids in pain medicine – prospective long-term studies
eTable 6
Cannabinoids in pain medicine – prospective long-term studies
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e6.European Medicines Agency: Guideline on clinical medicinal products intended for the treatment of neuropathic pain. 2017. www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003478.pdf (last accessed on 1 March 2017).
e7.Ablin JN, Elkayam O, Fitzcharles MA: Attitudes of Israeli rheumatologists to the use of medical cannabis as therapy for rheumatic disorders. Rambam Maimonides Med J 2016; 7: 2.
e8.Fitzcharles MA, Ste-Marie PA, Clauw DJ, et al.: Rheumatologists lack confidence in their knowledge of cannabinoids pertaining to the management of rheumatic complaints. BMC Musculoskelet Disord 2014; 30; 15: 258.
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