Cannabinoids in Pain Management and Palliative Medicine
An Overview of Systematic Reviews and Prospective Observational Studies
Winfried Häuser, Mary-Ann Fitzcharles, Lukas Radbruch, Frank Petzke
The Deutsches Ärzteblatt International, 2017, 114, 627–634.
Doi : 10.3238/arztebl.2017.0627
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).
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.
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.
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).
Cannabis-based medicines and their availability in Germany :
● Medical cannabis (so-called medical marijuana)*
– Currently, 14 types of cannabis flowers can be prescribed, with THC concentrations varying between 1% and 22% and CBD concentrations varying between 0.05% and 9%. Dosing information for specific indications is not available.
– The German Narcotic Drugs Act sets the maximum amount that can be prescribed within a 30-day period at 100 g cannabis in form of flowers, regardless of THC content.
● Medicinal products containing cannabis plant extracts
– A THC/CBD-containing oromucosal spray, available as a formulated medicinal product, was approved in 2011 for the indication moderate to severe spasticity in multiple sclerosis which did not respond adequately to other anti-spasticity treatments and showed significant clinical improvement following a treatment trial. Posology: 1 puff 2.7 mg THC/2.5 mg CBD; maximum of 12 puffs/day.
– THC-containing capsules and oil are not permitted under the German Narcotic Drugs Act. These can be prescribed for individual therapeutic trials as compounded medications in the form of drops, capsules or inhalation solution and be prepared by pharmacies. Specific indications are not stated. The recommended daily doses range between 5 and 30 mg.
● Synthetic cannabinoids
– A synthetic THC analog (nabilone) was approved in Germany in December 2016 for the indication of nausea and vom iting in patients undergoing chemotherapy and not adequately responding to other medications and is available as a formulated medicinal product. The recommended dosage is 2–4 mg/day.
* Cannabis (Latin: hemp) is a collective term for substances from the female hemp plant of the genus Cannabis sativa. Cannabinoids are a collective term for substances from the resin of the hemp plant. The female hemp plant contains more than 100 phytocannabinoids. The best characterized phyto-cannabinoids are the psychotropic tetrahydrocannabinol (THC) and the primarily anti inflammatory cannabidiol (CBD).