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Medical Cannabis for the Treatment of Chronic Pain: A Review of Clinical Effectiveness and Guidelines

CADTH Rapid Response Report: Summary with Critical Appraisal

and .

Abbreviations

CBD

cannabidiol

CFPC

College of Family Physicians of Canada

THC

Delta-9-tetrahydrocannabinol

Context and Policy Issues

Chronic pain is defined as pain that persists for more than three months.1 It may present as headache, musculoskeletal pain, visceral pain, neuropathic pain, pain arising from rheumatic disease, and cancer pain.1

Chronic pain is a global problem.2 In Canada, approximately 25% adults have a chronic pain condition.2 The prevalence estimates of chronic pain are likely to vary depending on the sample population surveyed, and the assessment method.3 Costs associated with chronic pain include both direct and indirect costs. It is estimated that in Canada the annual direct cost to the healthcare system is over six billion dollars and the annual indirect cost due to job loss and sick days is over 37 billion dollars.2 Chronic pain is a problem for the individual suffering, and also a societal burden.

Therapies for management for chronic pain include several pharmacological agents (such as tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors, and opioid analgesics).4,5 However, these medications offer limited pain relief and are associated with adverse effects.4,5 There is increasing interest in the use of cannabis-based medicines. Cannabis-based medicines contain cannabinoids derived from the cannabis plant, including delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD), or a combination of THC and CBD6. There is, however, uncertainty and controversy regarding the use of cannabis-based medicines for the management of chronic pain.7

The purpose of this report is to review the clinical effectiveness of medical cannabis for the treatment of chronic pain. Additionally, this report aims to review the evidence-based guidelines regarding associated with the use of medical cannabis for the treatment of chronic pain.

Research Questions

  1. What is the clinical effectiveness of medical cannabis for the treatment of chronic pain?
  2. What are the evidence-based guidelines associated with the use of medical cannabis for the treatment of chronic pain?

Key Findings

Based on four overviews (with overlapping systematic reviews), and one systematic review of guidelines,8 there is some suggestion of benefit with cannabis-based medicines for neuropathic pain. However, benefits need to be weighed against harms. Findings are inconsistent for effect of cannabis-based medicines in patients with fibromyalgia, musculoskeletal pain, Crohn’s disease, and multiple sclerosis.

Six evidence-based guidelines were identified. The majority of the guidelines present recommendations for chronic neuropathic pain. The guidelines report that cannabis-based medicines may be considered as a treatment option for patients with neuropathic pain, with chronic non-cancer pain, and with chronic non-cancer, non-neuropathic pain, but with some caveats. Recommendations are against the use of cannabis-based medicines for pain associated with fibromyalgia and back pain in two guidelines and for pain associated with headache, rheumatoid arthritis and osteoarthritis in one guideline. For pain management in multiple sclerosis patients, one guideline mentions that cannabis-based medicines may or may not be offered, depending on the type cannabis-based medicine and patient condition.

Findings need to be interpreted considering the limitations (such studies of variable quality [low to moderate], and studies of short duration)

Methods

Literature Search Methods

A limited literature search was conducted by an information specialist on key resources including Medline, the Cochrane Library, the University of York Centre for Reviews and Dissemination (CRD) databases, the websites of Canadian and major international health technology agencies, as well as a focused Internet search. The search strategy was comprised of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Medical Marijuana and chronic pain. No filters were applied to limit the retrieval by study type. The search was also limited to English language documents published between January 1, 2014 and June 24, 2019.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1. Selection Criteria.

Table 1

Selection Criteria.

Exclusion Criteria

Studies were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published prior to 2014. Studies on acute pain or cancer pain were excluded. Guidelines with unclear methods were excluded.

Critical Appraisal of Individual Studies

The included overviews (systematic reviews of systematic reviews) were critically appraised by one reviewer using AMSTAR 2,9 and evidence-based guidelines were critically assessed using AGREE 2.10 Summary scores were not calculated for the included studies, rather, the strengths and limitations of each individual study were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 644 citations were identified in the literature search. Following screening of titles and abstracts, 594 citations were excluded and 50 potentially relevant reports from the electronic search were retrieved for full-text review. Two potentially relevant publications were retrieved from the grey literature search for full text review. Of these potentially relevant articles, 41 publications were excluded for various reasons, and 11 publications met the inclusion criteria and were included in this report. These comprised four overviews (systematic review of systematic reviews),1114 one systematic review of guidelines,8 and six guidelines.7,1519 Appendix 1 presents the PRISMA20 flowchart of the study selection.

Additional references of potential interest are provided in Appendix 6.

Summary of Study Characteristics

Characteristics of the overviews, systematic review of guidelines, and guidelines are summarized and additional details are provided in Appendix 2, Table 2 and Table 3

Study Design

Four relevant overviews1114 identified were published between 2017 and 2018. One overview11 included 23 relevant systematic reviews published between 2007 and 2017. The second overview included 10 systematic reviews published between 2009 and 2016. The third overview included 11 systematic reviews published between 2003 and2016. The last overview included 11 systematic reviews published between 2013 and 2016. There was overlap in the systematic reviews included in the overviews (Appendix 5).

One systematic review8 of guidelines and six guidelines7,1519 were selected. The systematic review8 of guidelines was published in 2016 and included three relevant guidelines published between 2007 and 2010. The six guidelines7,1519 were published between 2014 and 2018. In three guidelines,15,17,18 the recommendations were graded and in three guidelines7,16,19 the recommendations were not graded.

Country of Origin

Countries indicated for the first authors of the overviews were Canada,11 Australia,14 and Germany.12,13

The country indicated for the systematic review8 of guidelines was China. Countries indicated for the first author of the guideline document, or the guideline development groups were Canada,15,16,18 US,17 Australia,19 and Germany.7

Population

The populations assessed were patients with chronic pain, neuropathic pain, rheumatologic pain, fibromyalgia, and myasthenia gravis (MS) in one overview,11 patients with chronic pain in the second overview,12 patients with MS in the third overview,14 and patients requiring pain management or palliative care in the last overview.13

The systematic review8 of guidelines assessed patients with neuropathic pain. Of the six guidelines,7,1519 one guideline,15 was on patients who were refractory to standard medical therapy; the second guideline,7 was on patients with chronic pain; the third guideline,19 was on patients with chronic non-cancer pain; the fourth guideline,18 was on patients with chronic pain or anxiety; the fifth guideline,16 was on patients with chronic neuropathic pain; and the last guideline.17 was on patients with MS. The guidelines were intended for health care providers involved with pain management.

Interventions and Comparators

In the overviews1114 the interventions were various types of cannabis-based medicines and comparators were placebo; in two overviews12,13 an active comparator (amitriptyline) was also mentioned and in one overview14 other treatments were compared but specifics were not reported.

The systematic review8 of guidelines reviewed guidelines which reported on cannabinoids and also other pharmacologic agents (such as anticonvulsants, topical treatments, and opioids). Four guidelines7,15,18,19 considered cannabis-based medicines and one guideline16 considered complimentary and alternative medicines, which included as well cannabis-based medicine; and one guideline17 included several pharmacological agents including as well cannabis-based medicines.

Outcome

Outcomes considered in the overviews included pain reduction,1114 quality of life,14 tolerability,13 withdrawal,11 adverse events,1114 and serious adverse events.11,13

The systematic review8 of guidelines and all six guidelines7,1519 presented recommendations on pain management. Details regarding levels and grades of recommendations are presented in Appendix 2, Table 3.

Summary of Critical Appraisal

Critical appraisal of the included overviews, systematic review of guidelines, and guidelines are summarized below, and details for the overviews and systematic review of guidelines are presented in Appendix 3, Table 4; and details for the guidelines are presented in Appendix 3, Table 5 and Table 6.

The four overviews1114 were generally well conducted. In all four overviews, the objective was stated; a comprehensive literature was conducted; study selection was described; a list of included systematic reviews was presented, data extraction was done in duplicate, quality assessment was conducted, and the quality of the included systematic reviews were found to be variable. Article selection and quality assessment were done in duplicate in three overviews11,12,14 and was unclear in one overview,13 Publication bias was investigated in one overview11 using a Funnel plot, but as both cancer (which is out of scope of this review) and non-cancer pain studies were included in the same plot it was unclear if there was any publication bias with respect to studies on non-cancer pain. In the remaining three overviews1214 publication bias was not investigated. In two overviews11,13 it was mentioned that there were no conflicts of interest, and in two overviews12,14 conflicts of interest were declared; some of the authors had association with pharmaceutical companies and it was unclear if there was any associated risk of bias with respect to the conduct of the overviews.

The systematic review8 of the guidelines was generally well conducted. The objective was stated; a comprehensive literature was conducted; study selection was described; a list of included systematic reviews was presented, article selection was done by two reviewers, quality assessment was conducted, and the quality of the included guidelines were found to be variable. It was unclear if data extraction and quality assessment were done in duplicate; publication bias was not investigated The authors mentioned that there were no conflicts of interest.

In all six guidelines,7,1519, the scope and purpose were mentioned or apparent, the guideline development group comprised experts in the area, and the target users were mentioned. Patient preferences were considered in one guideline,15 and not in the remaining five guidelines.7,1619 In four guidelines1517,19 systematic methods were used to search for evidence, and in two guidelines7,18 systematic methods appeared to have been used but details were lacking. The strengths and limitations of the evidence was mentioned in four guidelines,15,1719 and were not stated in two guidelines7,16 The method of formulating the recommendation was mentioned in four guidelines7,15,16,18 and was not stated in two guidelines.17,19 Health benefits and harms were considered in five guidelines,7,1517,19 and was unclear in one guideline.18 Four guidelines7,1517 were externally reviewed, and in two guidelines it was unclear.18,19 In three guidelines15,17,18 it was mentioned that there were no conflicts of interest, in two guidelines7,16 conflicts of interest were declared but procedure to address the issue was not presented, and for one guideline19 conflicts of interest were not presented.

Summary of Findings

Relevant study findings are summarized and a table of the main study findings and authors’ conclusions are presented in Appendix 4, Table 7 and Table 8.

Clinical Effectiveness of cannabis-based medicines

Four overviews,1114 were identified regarding the use of cannabis-based medicines for patients with non-cancer pain. Relevant findings are summarized, and a table of the main study findings and authors’ conclusions are presented in Appendix 4, Table 7.

In the overviews, cannabis-based medicines were mostly compared with placebo. The findings reported below for cannabis-based medicines are with respect to placebo.

One overview11 reported that there was uncertainty with regard use of cannabinoids for pain management. It reported that there appeared to be some benefit with cannabinoids for neuropathic pain, but adverse effects were common, and benefits need to be weighed against harms.

The second overview12 reported that findings were inconsistent for the use of cannabis-based medicines for the management of chronic pain; there appeared to be some benefit with respect to chronic neuropathic pain, and the evidence was insufficient with respect to pain associated with rheumatic diseases and fibromyalgia, precluding any definitive conclusions.

The third overview13 reported that for chronic neuropathic pain there was some reduction in pain with cannabinoids, however there was limited evidence available. The authors reported that there was inadequate evidence to support treatment with cannabinoids in patients with fibromyalgia, Crohn’s disease, musculoskeletal pain, and rheumatoid arthritis. Cannabinoid use in pain management may cause adverse effects related to the central nervous system and psychiatric adverse events.

The fourth overview,14 based on mostly low-quality evidence, reported that cannabis-based medicines had a positive effect or mixed effect with respect to pain management in MS patients, and the effect sizes were generally small. Effects of cannabis-based medicines on quality of life were mixed. Adverse effects with cannabis-based medicines were generally mild to moderate.

In summary, there is some suggestion of benefit with cannabis-based medicines for neuropathic pain. However, benefits need to be weighed against harms. Findings are inconsistent for the effect of cannabis-based medicines in patients with rheumatic disease, fibromyalgia, musculoskeletal pain, Crohn’s disease, and MS.

Guidelines

One systematic review8 of guidelines and six guidelines7,1519 were selected. Relevant recommendations are summarized and related details are presented in Appendix 4, Table 8.

Chronic non-cancer pain

The guideline19 of the Australian government mentions that cannabinoids should not replace current approved first-line treatments for chronic non-cancer pain.

Chronic non-neuropathic non-cancer pain

The guideline by Hauser et al.7 mentions that in exceptional cases after careful assessment, cannabis-based medicines can be considered if all established treatments have failed,

Neuropathic pain

One systematic review8 of guidelines and four guidelines7,15,16,18 presented recommendations on neuropathic pain. The systematic review of guidelines by Deng et al.8 recommends the use of cannabinoids as fourth-line treatment of neuropathic pain. The guideline by Hauser et al.7 mentions that cannabis-based medicines can be considered as third-line therapy for chronic neuropathic pain. The guideline by Allan et al. 15 recommends against the use of medical cannabinoids for first- and second-line therapy for neuropathic pain (strong recommendation). It also mentions that under certain circumstances, medical cannabis could be considered for patients with refractory neuropathic pain (weak recommendation). The College of Family Physicians of Canada (CFPC) guideline18 mentions that, before authorizing dried cannabis for treating neuropathic pain the physician should first adequately try other pharmacologic and non-pharmacologic therapies, followed by pharmaceutical cannabinoids. The guideline by Moulin et al.16 recommends cannabinoids for the management of neuropathic pain but cautions that judicious prescribing practices are required.

Pain associated with other conditions

The guideline by Allan et al.15 recommends against the use of medical cannabinoids for headache and pain due to rheumatologic conditions (including fibromyalgia, osteoarthritis, rheumatoid arthritis, and back pain) (strong recommendation). The guideline by CFPC18 does not support the authorization of dried cannabis for treatment of pain conditions commonly seen in primary care, such as fibromyalgia or low back pain (Level III). The guideline by Yadav et al.17 mentions that for reduction of patient-reported symptoms of spasticity and pain (excluding central neuropathic pain) in patients with MS, the clinicians may offer oral cannabis extract (Level A), and THC (Level B), It also mentions that for reduction of patient-reported symptoms of spasticity, pain or urinary frequency in patients with MS, the clinicians may offer Savitex, oromucosal cannabinoid spray (Level B). There is insufficient evidence to support or refute the use of smoked cannabis for the management of spasticity, pain, balance/posture, and cognition in MS patients (Level U).

In summary, majority of the guidelines present recommendations for chronic neuropathic pain.7,15,16,18 It is reported that cannabis-based medicines may be considered as a treatment option for patients with neuropathic pain, but with some caveats. It is also mentioned that cannabis-based medicines may be considered for patients with chronic non-cancer pain,19 and for patients with chronic non-cancer, non-neuropathic pain,7 but with some caveats. Three guidelines15,17,18 mention pain associated with other conditions (such as fibromyalgia, rheumatologic disease, headache, and MS); recommendations were inconsistent. Recommendations are against the use of cannabis-based medicines for pain associated with fibromyalgia and back pain in two guidelines15,18 and for pain associated with headache, rheumatoid arthritis, and osteoarthritis in one guideline.15 For pain management in MS patients, one guideline17 mentions that cannabis-based medicines may or may not be offered, depending on the type cannabis-based medicine and patient condition.

Limitations

This report has several imitations. This report is intended as an overall summary of the efficacy and safety of cannabis treatment for chronic pain associated with a variety of disease conditions. Considering the many types of cannabis-based medicines studied, and many conditions associated with chronic pain, an exhaustive evaluation of specific cannabis-based medicines for specific pain conditions were beyond the scope of this report.

Though there were several systematic reviews included in the selected overviews, it should be noted that there was some overlap in the included systematic reviews (Appendix 5, Table 9). The overviews were well conducted but the evidence on which the findings were based were of variable quality (low to moderate quality) or insufficient, hence definitive conclusions are not possible. Sometimes results include both cancer and non-cancer pain. Though there were fewer studies on cancer pain compared to non-cancer pain, their impact on the results was uncertain. There was limited amount of evidence regarding the comparison of cannabis-based medicines with an active comparator. The studies were generally of short term varying between 4 days to 14 weeks (when reported) and long-term effects are not known. Findings should be interpreted with caution considering the limitations mentioned.

Conclusions and Implications for Decision or Policy Making

Four overviews (systematic review of systematic reviews),1114 one systematic review of guidelines,8 and six evidence-based guidelines.7,1519 were identified

Based on four overviews1114 (with overlapping systematic reviews), one systematic review of guidelines,8 there is some suggestion of benefit with cannabis-based medicines for neuropathic pain. However, benefits need to be weighed against harms. Findings are inconsistent for effect of cannabis-based medicines in patients with fibromyalgia, musculoskeletal pain, Crohn’s disease, and MS.

The majority of the guidelines present recommendations for chronic neuropathic pain.7,15,16,18 The guidelines report that cannabis-based medicines may be considered as a treatment option for patients with neuropathic pain,7,15,16,18 with chronic non-cancer pain,19 and with chronic non-cancer, non-neuropathic pain,7 but with some caveats. Recommendations are against the use of cannabis-based medicines for pain associated with fibromyalgia and back pain in two guidelines15,18 and for pain associated with headache, rheumatoid arthritis and osteoarthritis in one guideline15 For pain management in MS patients, one guideline17 mentions that cannabis-based medicines may or may not be offered, depending on the type cannabis-based medicine and patient condition. Findings need to be interpreted considering the limitations mentioned.

Potential of adverse events associated with cannabis-based medicines need to be considered. Specific populations of patients may be more vulnerable to adverse effects of cannabis-based medications. High quality studies of longer duration are needed to determine definitively the clinical effectiveness and safety of cannabis-based medicines.

References

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Nielsen S, Germanos R, Weier M, et al. The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews. Curr Neurol Neurosci Rep. 2018;18(2):8. [PubMed: 29442178]
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Allan GM, Ramji J, Perry D, et al. Simplified guideline for prescribing medical cannabinoids in primary care. Can Fam Physician. 2018;64(2):111–120. [PMC free article: PMC5964385] [PubMed: 29449241]
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Edlund W, Gronseth G, So Y, Franklin G, for the Quality Standards Subcommittee (QSS) and the Therapeutics and Technology Assessment Subcommittee (TTA). Clinical Practice Guideline Process Manual. St. Paul (MN): American Academy of Neurology; 2004: https://www​.aan.com/siteassets​/home-page​/policy-and-guidelines​/guidelines/about-guidelines​/2004_guideline_process.pdf. Accessed 2019 Jul 22.

Appendix 1. Selection of Included Studies

Image app1f1

Appendix 2. Characteristics of Included Publications

Table 2Characteristics of Included Overviews (systematic review of systematic reviews)

First Author, Publication Year, CountryStudy Designs and Numbers of Systematic Reviews IncludedPopulation CharacteristicsIntervention and Comparator(s)Clinical Outcomes, Length of Follow-Up
Overviews (Systematic reviews of systematic reviews)

Allan,11 2018, Canada

Overview (systematic review of systematic reviews) on the use of medical cannabinoids. The overview included 23 relevant systematic reviews, published between 2007 and 2017. Numbers of RCTs included in the SRs varied between 2 and 28, and the numbers of patients in the SRs varied between 44 and 2454

Exclusion criteria: SRs not focused on medical cannabinoids, SRs focused on conditions besides pain, spasticity, or nausea and vomiting, SRs of observational studies, SRs in which >50% of the RCTs involved pediatric patients, SRs including <2 RCTs were excluded.

This overview had a broad focus and included SRs on acute pain, and cancer related pain. 31 SRs (published between 2001 and 2017) of which 23 reporting on pain and/or adverse events are discussed here.

Objective: To assess the effects of medical cannabinoids on pain, spasticity, and nausea and vomiting; and adverse events.

Patients with chronic pain, neuropathic pain, rheumatologic pain, fibromyalgia, and MS

Age: NR

Intervention: Cannabinoids

Comparator: placebo

Pain, adverse events

Study duration: NR

Hauser,12 2018, Germany

Overview on the use of cannabis-based medicines. This overview was a qualitative SR of RCTs. This overview included 10 SRs, published between 2009 and 2016. Country of origin of the systematic reviews were not reported.

Exclusion criteria: Qualitative systematic reviews which did not explicitly mention the reasons for not performing meta-analysis were excluded.

Objective: To summarize the efficacy, tolerability, and safety of the use of cannabis medicine-based for treating chronic pain (non-cancer and cancer pain)

Patients with chronic pain (non-cancer and cancer pain).

Age: Any age (specific ages of patients in the SRs were not reported)

Interventions: medical cannabis; plant-derived cannabinoids (THC, THC/CBD); synthetic cannabinoid analogues nabilone); or synthetic drugs which manipulate the endocannabinoid system

Comparator: placebo (mostly) or active comparator (amitriptyline)

Change in pain status, tolerability (withdrawals due to adverse events), and safety (frequency of serious adverse events)

Study duration for RCTs included in the SRs: 4 hours to 14 weeks

Nielsen,14 2018, Australia

Overview on the use of cannabis-based medicines. This overview included 11 SRs, published between 2003 and 2016. Country of origin of the systematic reviews were not reported.

Exclusion criteria: SRs that did not meet the minimum criteria (i.e. GRADE criteria: comprehensive literature search was conducted and characteristics of the included studies were presented) were excluded

Objective: To evaluate the therapeutic potential of cannabinoids for treating MS symptoms

Patients with MS

Age: not reported

Interventions: Cannabis Savita, Dronabinol, THC extract, Nabiximols, THC:CBD extracts, Nabilone, CBD extract.

Comparator: Placebo (mostly) or active comparator (not specified)

Pain, quality of life, adverse events

Other outcomes not relevant for this current report: spasticity; bladder function; ataxis and tremor; and sleep.

Study duration of included studies in the included SRs: 3 to 14 weeks

Hauser,13 2017, Germany

Overview on the use of cannabis-based medicines. This overview included 11 SRs, published between 2013 and 2016. It also included 3 long-term, prospective observational studies (> 6 months duration) published in 2015, or 2016. Country of origin of the systematic reviews were not reported.

Exclusion criteria: Systematic reviews which did not include quantitative analysis and which did not explicitly mention the reasons for not performing meta-analysis were excluded.

Objective: To assess the efficacy and risks associated with use of cannabinoids for pain management and palliative care, based on systematic reviews of RCTs and to review prospective observational studies to assess long-term risks

Patients requiring pain management or palliative care.

Age: not reported

Interventions: medical marijuana, Nabilone, THC/CBD, and Dronabinol.

Comparator: Placebo or active comparator (amitriptyline)

Pain, adverse events

(Other outcomes not relevant for this report included: dyspnea, loss of appetite.)

Study duration: ranged between for the included systematic reviews 5 hours to 14 weeksranged between 6 weeks and 52 weeks in the 3 observational studies

Systematic review of Guidelines
Deng,8 2016, China

Included 3 CPGs relevant for the current report. The CPGs were published between 2007 and 2010. One CPG was from NICE (UK), the second CPG was from IASP (international), and the third CPG was from Latin America.

Intended users of the CPGs: physicians involved in the management of neuropathic pain.

Exclusion criteria: consensus statements based on expert opinion, and documents focused entirely on a single unique condition were excluded

(This systematic review had a broad objective [management of neuropathic pain] and included 16 CPGs published between 2004 and 2014. Of these 16 CPGs, 3 CPGs reported on cannabinoids and are relevant for this current report. The remaining 13 CPGs did not report on cannabinoids, hence are not discussed here)

Patients with neuropathic pain

Age: NR

Interventions: Cannabinoids and other pharmacologic agents (such as anticonvulsants, topical treatments, SNRIs, opioids, sodium channel blockers)

Outcomes: Recommendations

Follow-up: Not applicable

CBD = cannabidiol; CPG = Clinical Practice Guideline; IASP = International Association for the Study of Pain; NICE = National Institute of Health and Care Excellence; NR = not reported; SNRIs = selective serotonin/noradrenaline reuptake inhibitors; SRs = systematic reviews; THC = delota-9-tetrahydrocannabinol

Table 3Characteristics of Included Guidelines

Intended Users, Target PopulationIntervention and Practice ConsideredMajor outcomes consideredEvidence Collection, Selection, and SynthesisEvidence Quality AssessmentRecommendations Development and EvaluationGuideline Validation
Systematic review of Guidelines
Deng,8 2016, China
As this is a systematic review of guidelines, characteristics are presented in Table 2
Guidelines
Allan,15 2018, Canada

Intended users: primary care providers.

Target population: not specified, appears to be for patients whose conditions are refractory to standard medical therapy

Cannabis

Pain, nausea and vomiting, spasticity, and adverse events

The method used for the development of the guideline was based on the Institute of Medicine’s outline for Clinical Practice Guidelines We Can Trust21 and the GRADE methodology.22

A systematic review of systematic reviews of RCTs was conducted

Recommendations were classified as strong or weak according to the GRADE methodology.22

Recommendations were based on consensus.

GDG comprised 2 generalist family physicians, 2 pain-management focused family physicians, 1 inner-city family physician, 1 neurologist, 1 oncologist, 1 nurse practitioner, 1 pharmacist, and 1 patient representative

Recommendations were graded

Externally reviewed (by clinicians and patients)

Hauser,7 2018, Germany

Intended user: specialist and nonspecialist prescribers

Target population: Patients with chronic pain

Cannabisbased medicines

Pain, adverse events

The method used for the development of the position paper was based on the recommendations of a clinical consensus statement development manual by Rosenfeld et al.23

A selective literature search was conducted. In addition, systematic reviews and guidelines not identified in the search was provided by members of the task force.

Evidence was not graded

Recommendations were based on consensus and finally approved by all members of the task force after two Delphi procedures

Members of the task were comprised individuals with clinical and scientific experience.

Recommendations were not graded

Externally reviewed

Australian Government,19 2017, Australia

Intended user: Doctors who prescribe medicinal cannabis and their patients

Medicinal cannabis use for CNCP (in palliative care, epilepsy, CINV, MS and chronic pain

Pain intensity, physical functioning, emotional functioning, patient global impression of change, withdrawals from the study, and adverse events

The method used for the development of the guideline was based on the GRADE system.24

A systematic review of previously published systematic reviews was conducted based on PRISMA

The GRADE system24 was used.

Recommendations were made by the Chronic Pain Working Group.

Also a workshop was held to review the available evidence and included representatives from consumer groups, medical colleges, special societies, and states and territories

Method used to formulate the recommendations were not specified.

Recommendations were not grade

Not reported

CFPC,18 2014, Canada

Intended users: Not specifically stated but appears to be for prescribers of dried cannabis

Target population: Appears to be for patients with chronic pain or anxiety

Chronic pain or anxiety

Cannabis effectiveness, safety, and adverse effects

Literature search was conducted and evidence was reviewed. No details were presented.

Recommendations were classified as Level I (if based on well-conducted controlled trials or meta-analyses), Level II (if based on well-conducted observational studies), Level III (if based on expert opinion)

Recommendations were formulated based on consensus.

GDG comprised members of the Addiction Medicine and Chronic Pain Program Committees of the SIFP of the CFPC as well as other SIFP program committee members

Recommendations were graded.

Not reported

Moulin,16 2014, Canada

Intended users: physiciuans, nurse practitioner, , and other allied health care individuals involved in the management of neuropathic pain.

Target population: not explicitly specified but appears to be individuals with chronic neuropathic pain

Pharmacologic management of chronic neuropathic pain (includes cannabis and other agents)

Efficacy and safety (details not presented)

A systematic literature search was conducted (to identify systematic reviews, meta-analyses, and treatment recommendations, guidelines and/or consensus statements) and evidence was reviewed

First line: “if there was high-quality evidence of efficacy (at least one class I study or two consistent class II studies - level of recommendation grade B or better)

[…]; positive results in at least two NeP models

[….], and if they were considered to be straight-forward and of sufficient tolerability to prescribe and monitor” (p329)

Second or third line: “if there was high-quality evidence, but the medication required more specialized follow-up and monitoring” (p329)

Fourth line: if there was at least one positive RCT, but further study was required

Recommendations were formulated based on consensus.

GDG comprised individuals with research and clinical expertise relevant to the pathophysiology and management of neuropathic pain.

Recommendations were not graded. However, they were classified as first-line, second-line, third-line or fourth-line.

Externally reviewed – published in peer-reviewed journal

Yadav,17 2014, US

Intended users: Appears to be for health care professional involved in the care of MS patients

Target population: Patients with MS

Cannabinoids and other complimentary, and alternative medicines (such as ginkgo biloba, Chinese medicine, glucosamine sulphate, massage therapy, mindfulness training, yoga)

Pain and other outcomes (such as spasticity, bladder symptoms, depression, anxiety, sleep, fatigue, cognitive function, tremor, paresthesia, and QoL)

The method used for the development of the guideline was not presented in detail however according to the ANN CPG process manual rigorous methods are followed.

A systematic review was conducted

Details were not presented however according to the AAN CPG process manual25 rigorous methods are followed.

According to the manual: levels of recommendation were A, B, C and U.

“Level A rating requires at least two consistent Class I studies” (p.49)a

Level B rating requires at least one Class I study or two consistent Class II studies” (p.49)a

“Level C rating requires at least one Class II study or two consistent Class III studies” (p.49)a

Level U is based on insufficient evidence or Class IV studies (i.e., not meeting criteria for Class I to Class III) (p.49)a

Details were not presented however according to the AAN CPG process manual25 rigorous methods are followed.

GDG comprised experts in the area.

Recommendations were graded

Externally reviewed - published in a peer-reviewed journal

CINV = chemotherapy induced nausea and vomiting; CFPC = College of Family Physicians of Canada; CNCP = chronic non-cancer pain; GDG = Guideline Development Group; GRADE = Grading of Recommendations, Assessment, Development, and Evaluation; MS = multiple sclerosis; NeP = neuropathic pain;PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-analyses; RCT = randomized controlled trial; SIFP = Section of Family Physicians with Special Interests or Focused Practices

a

Study class: “Class I: Prospective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required: a) primary outcome(s) clearly defined b) exclusion/inclusion criteria clearly defined c) adequate accounting for drop-outs and cross-overs with numbers sufficiently low to have minimal potential for bias d) relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences.

Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets a-d above OR a RCT in a representative population that lacks one criteria a-d.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement

Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion.” (p49 of ANN CPG process manual25)

Appendix 3. Critical Appraisal of Included Publications

Table 4Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR 29

StrengthsLimitations
Allan,11 2018, Canada
  • The objective was clearly stated
  • MEDLINE was searched from 1946 to April 2017, and the Cochrane Library was searched in 2017 were searched until April 2015, starting 1946 for MEDLINE and 1974 for EMBASE. Also, reference list of the included studies and the authors’ personal collections were searched.
  • Study selection was described, and a flow chart was presented
  • A list of included studies was provided
  • A list of excluded studies was provided
  • Article selection was done independently by two reviewers
  • Data extraction was done independently by two reviewers
  • Quality assessment was conducted independently by two reviewers using the modified version of AMSTAR (6 criteria were considered instead of 11, scores ranged between 0 and 6, with higher scores indicating better quality; scores ranged between 4 and 6 for >50% of the SRs)
  • Characteristics of the included systematic reviews were presented
  • Publication bias was explored using Funnel plots. However, presence of bias could not be ascertained definitely as systematic reviews for both cancer and non-cancer pain were considered.
  • Mata-analyses were conducted
  • It was mentioned that there were on conflicts of interest and the project received no external funding
  • No major issues were found
Hauser,12 2018, Germany
  • The objective was clearly stated
  • The Cochrane database of SRs, database of abstracts and of reviews and effects (DARE), and PubMed were searched. Also, reference lists of the included systematic reviews were searched and pain medicine experts were contacted.
  • Study selection was described, and a flow chart was presented
  • A list of included studies was provided
  • Article selection was done independently by two reviewers
  • Data extraction was done independently by two reviewers
  • Quality assessment was conducted independently by two reviewers using AMSTAR, and it was reported that 4 SRs were of high quality and the remaining 6 SRs were of moderate quality
  • Characteristics of the included systematic reviews were presented
  • Mata-analyses were not conducted as the objective was to conduct a qualitative systematic review
  • A list of excluded studies was not provided
  • Publication bias does not appear to have been examined
  • Conflicts of interest were Two of the three authors were associated with pharmaceutical companies. No funding was received for the current SR
Nielsen,14 2018, Australia
  • The objective was clearly stated
  • Eight databases were searched (Medline, Medline In-Process & Other Non-indexed citations/Ovi, Embase/Ovid, PsycINFO/Ovid, EBM reviews- Cochrane Central Register of Controlled Trials/Ovid from 1980 to 2016 end.
  • Study selection was described, and a flow chart was presented
  • A list of included studies was provided
  • A list of excluded studies was provided
  • Article selection was done independently by two reviewers
  • Data extraction was done independently by two reviewers
  • Quality assessment was conducted independently by two reviewers using AMSTAR. AMSTAR score (0 to 11, higher scores indicating better quality) for the included SRs ranged from 2 to 10.
  • Characteristics of the included systematic reviews were presented
  • Publication bias does not appear to have been examined
  • Meta-analyses were not conducted
  • Conflicts of interest were declared. Three authors had association with pharmaceutical companies and the remaining four authors had no conflicts of interest
Hauser,13 2017, Germany
  • The objective was clearly stated
  • The Cochrane database of SRs, database of abstracts and of reviews and effects (DARE), and Medline were searched January 2009 to January 2017. Also, reference lists of the included systematic reviews were searched, and experts in pain medicine or palliative care were contacted to identify further SRs and long-term studies.
  • Study selection was described, and a flow chart was presented
  • A list of included studies was provided
  • Data extraction was done independently by two reviewers
  • Quality assessment was conducted using AMSTAR AMSTAR score (0 to 11, higher scores indicating better quality) for the included SRs ranged from 7 to 10 (3 SRs had scores of 9 or 10, and the remaining 8 SRs had scores 7 or 8).
  • Characteristics of the included systematic reviews were presented
  • It was mentioned that the authors had no conflicts of interest.
  • Unclear if article selection was done in duplicate
  • Unclear if quality assessment was done in duplicate
  • List of excluded studies was not provided
  • Publication bias does not appear to have been examined
  • Meta-analyses were not conducted
Systematic review of Guidelines
Deng,8 2016, China
  • The objective was clearly stated
  • Multiple databases (MEDLINE, EMBASE, the National Guideline Clearing House, the Guideline International Network. And Canadian Medical Association Infobase) were searched (search period not specified). In addition, websites of related associations, institutes, societies, and communities were searched. Also, reference list of relevant articles were searched.
  • Study selection was described, and a flow chart was presented
  • A list of included studies was provided
  • Article selection was done by two experienced reviewers; unclear if done independently
  • Quality assessment of the included guidelines was done using AGREEII; unclear if done in duplicate. For the 6 domains: “Scope and Purpose”, “Stakeholder Involvement” “Rigor of Development”, “Clarity of Presentation”, “Applicability” and “Editorial Independence” the respective scores were 85%, 91%, 88%, 91%, 35%, and 60% for the CPG from NICE (UK); 78%, 33%, 48%, 91%, 0% and 93% for the CPG from IASP (international); and 76%, 35%, 38%, 52%, 33%, and 0% for the CPG from Latin America.
  • Characteristics of the included studies were presented, but details were lacking.
  • Meta-analysis not feasible, as guideline recommendations
  • The authors mentioned that there were no conflicts of interest.
  • A list of excluded studies was not provided
  • Unclear if data extraction was done in duplicate
  • Publication bias does not appear to have been examined

AGREE II = Appraisal of Guidelines Research and Evaluation II; CPG = Clinical Practice Guideline; IASP = International Association forthe Study of Pain; NICE = National Institute of Health and Care Excellence; SR = systematic review; SRs = systematic reviews

Table 5Strengths and Limitations of Guidelines using AGREE II10

ItemGuideline
Allan,15 2018, CanadaHauser,7, 2018, GermanyAustralian Government,19 2017, AustraliaCFPC,18 2014, Canada
Domain 1: Scope and Purpose
1. The overall objective(s) of the guideline is (are) specifically described.yyyy
2. The health question(s) covered by the guideline is (are) specifically described.Apparent but not specifically presented as questionsApparent but not specifically presented as questionsApparent but not specifically presented as questionsApparent but not specifically presented as questions
3. The population (patients, public, etc.) to whom the guideline is meant to apply is specifically described.Apparent but not specifically mentionedApparent but not specifically mentionedApparent but not specifically mentionedApparent but not specifically mentioned
Domain 2: Stakeholder Involvement
4. The guideline development group includes individuals from all relevant professional groups.yyyy
5. The views and preferences of the target population (patients, public, etc.) have been sought.yunclearunclearunclear
6. The target users of the guideline are clearly defined.yyyy
Domain 3: Rigour of Development
7. Systematic methods were used to search for evidence.yAppears to be so, details lackingyAppears to be so, details lacking
8. The criteria for selecting the evidence are clearly described.yNot statedNot statedNot stated
9. The strengths and limitations of the body of evidence are clearly described.yNot satedyTo some extent
10. The methods for formulating the recommendations are clearly described.yyNot statedy
11. The health benefits, side effects, and risks have been considered in formulating the recommendations.yyyunclear
12. There is an explicit link between the recommendations and the supporting evidence.yySometimes unclearUnclear -details lacking
13. The guideline has been externally reviewed by experts prior to its publication.yyNot statedNot stated
14. A procedure for updating the guideline is provided.Not statedNot statedWill be updated as new evidence emerges but updating procedure not specifiedNot stated
Domain 4: Clarity of Presentation
15. The recommendations are specific and unambiguous.yyyy
16. The different options for management of the condition or health issue are clearly presented.Not statedyNot statedNot stated
17. Key recommendations are easily identifiable.yyyy
Domain 5: Applicability
18. The guideline describes facilitators and barriers to its application.Not statedNot statedNot statedNot stated
19. The guideline provides advice and/or tools on how the recommendations can be put into practice.Not statedNot statedNot statedNot stated
20. The potential resource implications of applying the recommendations have been considered.Not statedNot statedNot statedNot stated
21. The guideline presents monitoring and/or auditing criteria.Not statedNot statedyNot stated
Domain 6: Editorial Independence
22. The views of the funding body have not influenced the content of the guideline.yyNot statedNot stated
23. Competing interests of guideline development group members have been recorded and addressed.yDeclared but procedure for addressing any conflicts of interest were not presentedNot statedy

y = yes (i.e. criteria were met);

Table 6: Strengths and Limitations of Guidelines using AGREE II10

ItemGuideline
Moulin,16 2014, CanadaYadav (AAN)a,17 2014, US
Domain 1: Scope and Purpose
1. The overall objective(s) of the guideline is (are) specifically described.yy
2. The health question(s) covered by the guideline is (are) specifically described.Apparent but not specifically presented as questionsy
3. The population (patients, public, etc.) to whom the guideline is meant to apply is specifically described.Apparent but not specifically mentionedy
Domain 2: Stakeholder Involvement
4. The guideline development group includes individuals from all relevant professional groups.yy
5. The views and preferences of the target population (patients, public, etc.) have been sought.unclearunclear
6. The target users of the guideline are clearly defined.yy
Domain 3: Rigour of Development
7. Systematic methods were used to search for evidence.yy
8. The criteria for selecting the evidence are clearly described.yNot stated
9. The strengths and limitations of the body of evidence are clearly described.Not statedTo some extent
10. The methods for formulating the recommendations are clearly described.yNot stated
11. The health benefits, side effects, and risks have been considered in formulating the recommendations.yy
12. There is an explicit link between the recommendations and the supporting evidence.yy
13. The guideline has been externally reviewed by experts prior to its publication.yy
14. A procedure for updating the guideline is provided.To be updated but procedure for updating not presentedNot stated
Domain 4: Clarity of Presentation
15. The recommendations are specific and unambiguous.yy
16. The different options for management of the condition or health issue are clearly presented.yy
17. Key recommendations are easily identifiable.yy
Domain 5: Applicability
18. The guideline describes facilitators and barriers to its application.Not statedNot stated
19. The guideline provides advice and/or tools on how the recommendations can be put into practice.A treatment algorithm presentedNot stated
20. The potential resource implications of applying the recommendations have been considered.Not statedNot stated
21. The guideline presents monitoring and/or auditing criteria.Not statedNot stated
Domain 6: Editorial Independence
22. The views of the funding body have not influenced the content of the guideline.Not statedNot stated
23. Competing interests of guideline development group members have been recorded and addressed.Several authors had association with pharmaceutical industriesy

ANN - American Academy of Neurology;

a

Of note the AAN guideline by Yadav et al. is a summary guideline and details of the guideline development process are available in the AAN CPG process manual25 which indicates that rigorous methods are followed

Appendix 4. Main Study Findings and Authors’ Conclusions

Table 7Summary of Findings Included Systematic Reviews and Meta-Analyses

Main Study FindingsAuthors’ Conclusion
Overviews (Systematic review of Systematic Reviews)
Allan,11 2018, Canada
Pain“There is some uncertainty about whether cannabinoids improve pain, but if they do, it is neuropathic pain and the benefit is likely small. Adverse effects are very common, meaning benefits would need to be considerable to warrant trials of therapy.” (p. e78)
OutcomeNo. of SRsNo. of RCTs (no. of patients) in each SRCannabinoids versus placebo
Effect measureEffect size
≥ 30% reduction in pain (neuropathic)28(1370), and 2 (537)RR1.62, and 1.34; significant for both
≥ 30% reduction in pain (chronic or palliative)25(405), and 9 (1346)RR1.23, and 1.34; nonsignificant for both
Pain (chronic)17 (278)SMD0.61, significant
Change in pain on VAS from 0 to 10 (MS)17 (298)Using VAS from 0 to 100.8 more pain reduction, significant

Two SRs reported insufficient evidence for benefit in rheumatologic pain and fibromyalgia

Adverse events

OutcomeNo. of SRsNo. of RCTs (no. of patients) in each SRCannabinoids versus placebo
Effect measureEffect size (range)
Overall adverse events44(1025), 3(666), 23 (2068), and 29 (3714)aRR1.18 to 1.86, significant in 4 SRs
Serious adverse events26(1031), 23(2068)RR1.15, and 1.04; not significant for both
111 (1568)RD1%, not significant
134 (3248)aOR1.41, significant
Withdrawals36(1031), 11 (1574), and 3 (666)RR1.20 to 3.04, significant in 2 SRs and nonsignificant in 1 SR
123 (2755)aOR2.94, significant
27 (508), and 24 (2737)Event rate4.3% versus 3.6%, and 7% versus 2%
aThis SR also included studies on cancer patients, and it is likely that outcomes for cancer patients were also included
Hauser,12 2018, Germany

Conclusions of each systematic review are presented below.

Systematic reviews of cannabis-based medicines for any type of chronic pain

Systematic Review by Whiting et al. (2015) “There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain” (p.462)

Systematic Review by Martin-Sanchez (2009)

“Currently available evidence suggests that cannabis treatment is moderately efficacious for treatment of chronic pain, but beneficial effects may be partially (or completely) offset by potentially serious harms” (p.462)

Systematic reviews of cannabis-based medicines for chronic neuropathic pain

Systematic Review by Petzke et al. (2016) “Short-term and intermediate-term therapy with cannabinoids can be considered in selected patients with chronic neuropathic pain after failure of first-line and second-line therapies” (p.463)

Systematic Review by Andreae et al. (2015): “Inhaled cannabis appears to provide short-term relief from chronic neuropathic pain for one in five to six patients treated” (p.463)

Systematic Review by Finnerup et al. (2015) “Cannabinoids have weak recommendations against their use in neuropathic pain” (p.463)

Systematic Review by Jawahar et al. (2013) “The relatively small number of trials in multiple sclerosis patients with chronic pain precludes specific recommendations for treatment strategies”(p.463)

Systematic reviews of cannabis-based medicines for rheumatic disease

Systematic Review by Fitzcharles et al. (2016a) “There is insufficient evidence for recommendation for any cannabinoid preparations for symptom management in patients with chronic pain associated with rheumatic diseases.” (p.464)

Systematic review by Fitzcharles et al. (2016b) “Pain relief and effect on sleep may have some potential therapeutic benefit, but with considerable mild to moderate adverse events. There is currently insufficient evidence to recommend cannabinoid treatments for management of rheumatic diseases pending further study.” (p.464)

Systematic Review by Walitt et al. (2016)

“We found no convincing, unbiased, high-quality evidence suggesting that nabilone is of value in treating people with fibromyalgia” (p.464)

Systematic reviews of cannabis-based medicines for cancer pain

Systematic review by Mucke et al. (2016) “due to the sparse amount of data, it is not possible to recommend a favoured use of cannabis products for cancer pain.” (p.466)

“We provide an overview of systematic reviews on the efficacy, tolerability and safety of cannabis-based medicines for chronic pain management.

There are inconsistent findings of the efficacy of cannabinoids in neuropathic pain and painful spasms in multiple sclerosis.

There are inconsistent results on tolerability and safety of cannabis-based medicines for any chronic pain.” (p455)

“The available evidence comparing patient outcomes following cannabis-based medicines treatment versus placebo appears insufficient to make well-founded conclusions about the clinical advantage and use of cannabis-based medicines for the management of cancer and non-cancer pain.” (p468)

Neilsen,14,Australia
Systematic reviews of cannabis-based medicines for treatment of pain in MS Outcome: Pain“In conclusion, reviews identified evidence that would support a trial of cannabinoids for pain […] in a patient with multiple sclerosis. Effect sizes are generally small suggesting only modest effects may be expected. Adverse events were generally mild to moderate, although caution is warranted in specific populations of patients with multiple sclerosis with greater vulnerability to adverse effects from cannabinoids.” (p10 of 12)
InterventionNo. of studies (No. of RCTs)FindingQuality assessment of evidenceConclusion
Cannabis sativa (smoked)1(1)Positive effectLowInsufficient evidence
Dronabinol4(3)Positive effectLow to highSome evidence of positive effect
THC extract3(2)Positive effectVery low to lowSome evidence of positive effect
Nabiximols8(5)Positive effectVery low to moderateInconsistent evidence
THC:CBD extract7(5)Mixed effectVery low to moderateInconsistent evidence
Nabilone1 (1)Positive effectVery lowInsufficient evidence
CBD extract2(2)Mixed effectLowInsufficient evidence
Outcome: Quality of life
InterventionNo. of studies (No. of RCTs)FindingQAof evidenceConclusion
Cannabis sativa (smoked)2(2)Mixed effectLowInsufficient evidence
Dronabinol2(2)Mixed effectLow to highInsufficient evidence
THC extractnoneNANANA
Nabiximols5(5)Mixed effectModerateSome evidence of positive effect
THC:CBD extract3(3)Mixed effectLow to highInconsistent evidence
Nabilone2(2)Mixed effectVery low to moderateInsufficient evidence
CBD extractnoneNANANA
Outcome: Adverse events
InterventionNo. of studies (No. of RCTs)FindingQA of evidenceConclusion
Cannabis sativa (smoked)2(2)AEs> comparatorLowInsufficient evidence
Dronabinol8(6)AEs> comparatorVery low to highMild AEs likely
THC extract1(1)AEs> comparatorLowMild AEs likely
Nabiximols10(7)AEs> comparatorVery low to moderateMild AEs likely
THC:CBD extract8(6)AEs> comparatorLow to highMild AEs likely
Nabilone3(3)AEs> comparatorVery low to lowMild AEs likely
CBD extract1(1)AEs> comparatorLowInsufficient evidence
(Note: Quality of evidence was based on the GRADE approach in Cochrane Handbook V5.1 High: RCTs or double-upgraded observational studies; Moderate: downgraded RCTs, or upgraded observational studies Low: double downgraded RCTs, or observational studies; Very low: triple-downgraded RCTs, or downgraded observational studies, or case series/case reports)
Hauser,13 2017, Germany

Conclusions of each systematic review are presented below.

Systematic reviews of cannabinoids for chronic neuropathic pain

Systematic review by Petzke et al. (2016) Studies: 15 studies (1619 patients with chronic neuropathic disease) Efficacy: For >30% pain relief with cannabinoids compared with placebo, RD (95% CI): 0.01 (0.03 to 0.16) Safety: For cannabinoids compared with placebo: discontinuation due to adverse event, RD 0.04 (0.01 to 0.07); central nervous system adverse events: RD (95% CI), 0.38 (0.18 to 0.58); psychiatric disorders: RD (95% CI), 0.11 (0.06 to 0.16). No statistically significant group difference for SAEs. Conclusion: “Short-term and mid-term treatment may be considered in selected patients with chronic neuropathic pain after failure of first- and second-line therapy.” (p.631)

Systematic review by Andreae et al. (2015) Studies: 5 studies (178 patients with chronic neuropathic pain) Efficacy: For medical marijuana compared with placebo, for >30% pain relief: OR (95% CI), 3.2 (1.59 to 7.24) Safety: No quantitative data synthesis Conclusion: “Inhaled cannabis appears to result in short-term relief of neuropathic pain in 1 of 5-6 patients treated.” (p631)

Systematic review by Jawar et al. (2013) Studies: 3 studies (400 patients neuropathic pain) Efficacy: For cannabinoids compared with placebo: SMD (95% CI), 0.08 (0.74 to 0.89) Safety: No quantitative data synthesis Conclusion: “Due to the comparatively small number of studies evaluating multiple-sclerosis patients with chronic pain, no specific treatment recommendations can be made.” (p.631)

Systematic reviews of cannabinoids for pain associated with rheumatic diseases

Systematic Review by Fitzcharles et al. (2016a) Studies: 4 RCTs (204 patients with fibromyalgia, rheumatoid arthritis, or osteoarthritis) Efficacy: For fibromyalgia patients THC/CBD reduced pain, and nabilone reduced pain in some patients but not in some patients. Study on osteoarthritis patients was terminated early as the FAAHI inhibitor showed no effect. Safety: Dizziness, cognitive problems, vertigo and nausea were reported by 50% of the patients Conclusion: “The current evidence is inadequate to recommend cannabinoids for the treatment of pain associated with rheumatic diseases” (Supplement: eTable 2)

Systematic review by Fitzcharles et al. (2016b) Studies: 4 RCTs (160 patients with fibromyalgia, rheumatoid arthritis or musculoskeletal pain) Efficacy: No statistically significant difference between nabilone and placebo with respect to pain relief in fibromyalgia patients and in patients with musculoskeletal pain.. THC/CBD spray showed significant improvement in morning resting pain relief and pain on motion, but not in reducing overall and current pain intensity in patients with rheumatoid arthritis. No statistically significant difference between nabilone and amitriptyline with respect to pain relief in fibromyalgia patients.

Safety: In fibromyalgia patients, discontinuation was numerically higher with nabilone compared to either placebo or amitriptyline. No SAE were reported in fibromyalgia or rheumatoid arthritis patients. One SAE was reported with nabilone in one patient with musculoskeletal pain.

Conclusion: “The current evidence is inadequate to recommend cannabinoids for the treatment of pain associated with rheumatic diseases.” (Supplement: eTable 2)

Systematic Review by Walitt et al. (2016)

Studies: 2 RCTs (72 patients with fibromyalgia)

Efficacy: Compared with placebo, there was greater pain relief with nabilone in patients with fibromyalgia. There was no statistically significant difference in pain relief with nabilone compared with amitriptyline.

Safety:

Conclusion: “There is no unbiased and high quality evidence available to show benefits of nabilone in FMS patients.” (Supplement: eTable 2)

Systematic reviews of cannabinoids for visceral pain

Systematic Review by Voltz et al. (2016)

1 RCT (21 patients with Crohn’s disease)

Efficacy: No significant difference in in remission rate; significant relief of abdominal pain (P < 0.05)

Safety: No difference in tolerability with medical marijuana compared with placebo. No withdrawals or serious adverse events were reported

Conclusion: “Currently, considering an individual therapeutic trial of tetrahydrocannabinol in gastroenterology is limited to symptomatic relief of pain and loss of appetite in patients with Crohn’s disease, but only after failure of all established pharmacotherapy options and careful risk-benefit assessment” (Supplement: eTable 3)

  • “Limited evidence is available to support the use of tetrahydrocannabinol/cannabidiol spray for the treatment of chronic neuropathic pain.
  • According to the quality criteria of evidence-based medicine, the available evidence for cannabinoids is inadequate for the indications of loss of appetite in patients with cancer or HIV/AIDS, fibromyalgia syndrome, Crohn’s disease, musculoskeletal pain, rheumatoid arthritis, chronic pancreatitis, and cancer pain.
  • The use of cannabinoids in pain management and palliative medicine should be regarded as individual therapeutic trials, except for chronic neuropathic pain.
  • Cannabinoid use in pain management and palliative medicine may cause relevant central nervous system (e.g. dizziness) and psychiatric adverse events (e.g. confusion, psychosis).” (p.633)
Systematic Review of Guidelines
Deng,8 2016, China
See recommendations in Table 8

AE = adverse events: CBD = cannabinoid; CI = confidence interval; CNCP = chronic non-cancer pain; FAAH1 = fatty-acid amide hydrolase; FMS = fibromyalgia syndrome; GRADE = Grading of Assessment, Development and Evaluation; MS = multiple sclerosis; NA = not applicable; OR = odds ratio; QA = quality assessment; RCT = randomized controlled trial; RD = risk difference; RR = relative risk; SAE = serious adverse events; SMD = standardized mean difference; SR = systematic reviews; SRs = systematic reviews; THC = delta-9-tetrahydrocannabinol; VAS = visual analog scale.

Table 8. Summary of Recommendations in Included Guidelines (PDF, 509K)

Appendix 5. Overlap between Included Systematic Reviews

Table 9Systematic Review Overlap between Included Overviews

Primary Study CitationSystematic Review Citation
Allan,15 2018, CanadaHauser,12 2018, GermanyNielsen,14 2018, AustraliaHauser,13 2017, Germany
Andreae, 2015XXX
Andrzejewski, 2016X
Ben Amar, 2006X
Boychuk, 2015X
CADTH, 2010aX
CADTH, 2010bX
CADTH, 2011X
CampbellX
Deshpande, 2015X
Finnerup, 2015X
Fitzcharles, 2016aXXX
Fitzcharles, 2016bXXX
Iskedjian, 2007X
Jawahar, 2013XXX
Jensen, 2015X
Karst, 2010X
Koppel, 2014XX
Lakhan, 2009X
Lynch, 2011X
Lynch, 2015X
Ludge, 2013X
Martin-Sanchez, 2009XX
Meza, 2017X
Mills, 2007X
Mücke, 2016XXX
Nugent, 2017X
Petzke, 2016XXX
Shakespeare, 2003X
Tsang, 2016X
Voltz, 2016X
Wade, 2010X
Wang, 2008XX
Walitt, 2016XXX
Whiting, 2015XXXX
Zhormitsky, 2012X

Appendix 6. Additional References of Potential Interest

Systematic reviews not included in the selected overviews. These were excluded as the decision was to include only overviews (systematic review of systematic reviews).

  • Ho C, Martinusen D, Lo C. A Review of Cannabis in Chronic Kidney Disease Symptom Management. Can J Kidney Health Dis. 2019;6:2054358119828391. [PMC free article: PMC6388458] [PubMed: 30828459]
  • Millar SA, Stone NL, Bellman ZD, Yates AS, England TJ, O’Sullivan SE. A systematic review of cannabidiol dosing in clinical populations. Br J Clin Pharmacol. 2019;20:20. [PMC free article: PMC6710502] [PubMed: 31222854]
  • Yanes JA, McKinnell ZE, Reid MA, et al. Effects of cannabinoid administration for pain: A meta-analysis and meta-regression. Exp Clin Psychopharmacol. 2019;23:23. [PMC free article: PMC6663642] [PubMed: 31120281]
  • IsHak WW, Wen RY, Naghdechi L, et al. Pain and Depression: A Systematic Review. Harv Rev Psychiatry. 2018;26(6):352–363. [PubMed: 30407234]
  • Stockings E, Campbell G, Hall WD, et al. 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(10):1932–1954. [PubMed: 29847469]
  • Vuckovic S, Srebro D, Vujovic KS, Vucetic C, Prostran M. Cannabinoids and Pain: New Insights From Old Molecules. Front Pharmacol. 2018;9:1259. [PMC free article: PMC6277878] [PubMed: 30542280]
  • Allende-Salazar RF, Rada G. Are cannabinoids an effective treatment for chronic non-cancer pain? Medwave. 2017;17(Suppl 2):e6972. [PubMed: 28622286]
  • Aviram J, Samuelly-Leichtag G. Efficacy of Cannabis-Based Medicines for Pain Management: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Pain physician. 2017;20(6):E755–E796. [PubMed: 28934780]
  • Goldenberg M, Reid MW, IsHak WW, Danovitch I. The impact of cannabis and cannabinoids for medical conditions on health-related quality of life: A systematic review and meta-analysis. Drug Alcohol Depend. 2017;174:80–90. [PubMed: 28319753]
  • Meng H, Johnston B, Englesakis M, Moulin DE, Bhatia A. Selective Cannabinoids for Chronic Neuropathic Pain: A Systematic Review and Meta-analysis. Anesth Analg. 2017;125(5):1638–1652. [PubMed: 28537982]
  • Meza R, Pena J, Garcia K, Corsi O, Rada G. Are cannabinoids effective in multiple sclerosis? Medwave. 2017;17(Suppl 1):e6865. [PubMed: 28306712]
  • Noel C. Evidence for the use of “medical marijuana” in psychiatric and neurologic disorders. Ment Health Clin. 2017;7(1):29–38. [PMC free article: PMC6007658] [PubMed: 29955495]
  • Norton C, Czuber-Dochan W, Artom M, Sweeney L, Hart A. Systematic review: interventions for abdominal pain management in inflammatory bowel disease. Aliment Pharmacol Ther. 2017;46(2):115–125. [PubMed: 28470846]
  • Nugent SM, Morasco BJ, O’Neil ME, et al. The Effects of Cannabis Among Adults With Chronic Pain and an Overview of General Harms: A Systematic Review. Ann Intern Med. 2017;167(5):319–331. [PubMed: 28806817]
  • Mehta S, McIntyre A, Janzen S, Loh E, Teasell R, Spinal Cord Injury Rehabilitation Evidence T. Systematic Review of Pharmacologic Treatments of Pain After Spinal Cord Injury: An Update. Arch Phys Med Rehabil. 2016;97(8):1381–1391.e1381. [PubMed: 26797114]
  • Merlin JS, Bulls HW, Vucovich LA, Edelman EJ, Starrels JL. Pharmacologic and non-pharmacologic treatments for chronic pain in individuals with HIV: a systematic review. AIDS Care. 2016;28(12):1506–1515. [PMC free article: PMC5053858] [PubMed: 27267445]
  • Hill KP. Medical Marijuana for Treatment of Chronic Pain and Other Medical and Psychiatric Problems: A Clinical Review. JAMA. 2015;313(24):2474–2483. [PubMed: 26103031]

About the Series

CADTH Rapid Response Report: Summary with Critical Appraisal
ISSN: 1922-8147

Version: 1.0

Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.

Suggested citation:

Medical Cannabis for the Treatment of Chronic Pain: A Review of Clinical Effectiveness and Guidelines. Ottawa: CADTH; 2019 Jul. (CADTH rapid response report: summary with critical appraisal).

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Bookshelf ID: NBK546424PMID: 31532599

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