Cannabis for Chronic Pain

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Summary

Cannabis for Chronic Pain: A Living Systematic Review

This work was based on a living systematic review, Living Systematic Review on Cannabis and Other Plant-Based Treatments for Chronic Pain | Effective Health Care Program (ahrq.gov), by the Evidence-based Practice Center Program at the Agency for Healthcare Research and Quality (AHRQ). Used with authors’ permission. Citation available below.

Background
  • Approximately 100 million people in the US are affected by chronic pain.
  • Chronic pain is the most common reason people use cannabis for medical purposes.
  • Previous reviews suggest cannabis may hold promise in treating certain subgroups of patients with chronic neuropathic pain over the short term.
  • Variation in patient populations and cannabis formulations that have been studied, along with inconsistency of findings across studies has limited the certainty of the available evidence.
  • As more studies examining the effects of cannabis emerge, this living systematic review will help clarify and update our understanding of the benefits and harms of cannabis for chronic pain. 
Methods

Living systematic review

Search: 

  • Ovid MEDLINE
  • PsycINFO
  • Embase
  • Cochrane Library
  • SCOPUS

Screening:

Study Selection Criteria

PICOTS Element Inclusion Criteria Exclusion Criteria
Population Adults (including pregnant or breastfeeding women) aged 18 years and older with chronic pain (> 12 weeks or pain persisting past the time for normal tissue healing). See categorization of specifically included pain populations below. Children and adolescents < 18 years old; adults with acute or subacute pain; patients at end of life or in palliative care (e.g. with late-stage cancer-related pain)
Interventions Cannabinoids (including synthetics) using different delivery mechanisms such as oral, buccal, inhalational, topical, or other administration routes. Co-use of other drugs for pain. Non-plant-based interventions, capsaicin, herbal supplements
Comparators Any comparator or usual care No comparison
Outcomes Primary efficacy outcomes (i.e., pain, function, disability, pain interference); harms and adverse effects (e.g., dizziness, nausea, sedation, development of cannabis use disorder); secondary outcomes (i.e., psychological distress including depression and anxiety, quality of life, opioid use, sleep quality, sleep disturbance, health care utilization) Other outcomes
Time of follow-up Short term (1 to < 6 months), intermediate term (6 to < 12 months), long term (≥ 1 year) Studies with < 1 month of treatment or follow-up after treatment
Setting Any nonhospital setting or setting of self-directed care Hospital care, hospice care, emergency department care
Study design RCTs; observational studies with a concurrent control group for harms, and to fill gaps in the evidence for benefits Other study designs

Abbreviations. KQ: Key Question; PICOTS: population, interventions, comparators, outcomes, timing, setting; RCT: randomized controlled trial

Data synthesis: 

  • Random effects meta-analyses were performed when there was sufficient homogeneity among studies.
  • Risk of bias assessment: 
    • Cochrane Back Review Group methods for RCTs
    • US Preventive Services Task Force methods for observational studies

    Assessing the strength (certainty) of the body of evidence: 

    • AHRQ Methods Guide approach for all primary comparisons and outcomes. 
    • Of note, the AHRQ methods are very similar to GRADE with the following exceptions: the term strength of evidence is used rather than certainty of evidence, and the term “insufficient” evidence is used in place of the term “very low” strength (certainty) evidence.

    Living systematic review: 

    • Updates are done quarterly

    More detailed information about systematic review methods is available here.

    Findings

    (Searched as of January 2022)

    The tables below summarize the evidence for cannabinoids for chronic pain from 21 trials. For the full results see link below. 

    • Treatments were grouped according to the ratio of THC to CBD and to the source of the cannabinoids (synthetic, extract, whole plant)
    • Effect sizes are classified as no effect, small, moderate, or large according to methods used in other systematic reviews of chronic pain. 
    • Strength of evidence is indicated by plus signs, except where the effect is unclear.

    Definitions of effect sizes

    Effect Size Definition
    Small effect ·   MD 0.5 to 1.0 points on a 0 to 10-point scale, 5 to 10 points on a 0 to 100-point scale
    ·   SMD 0.2 to 0.5
    ·   RR/OR 1.2 to 1.4
    Moderate effect ·   MD >1 to 2 points on a 0 to10-point scale, >10 to 20 points on a 0 to 100-point scale
    ·   SMD >0.5 to 0.8
    ·   RR/OR 1.5 to 1.9
    Large effect ·   MD >2 points on a 0 to10-point scale, >20 points on a 0 to 100-point scale
    ·   SMD >0.8
    ·   RR/OR ≥2.0

    Abbreviations: MD = mean difference; OR = odds ratio; RR = relative risk; SMD = standardized mean difference.

    Example interpretation: 

    For the outcome of pain severity: From 5 trials, a high THC to CBD ratio oral treatment had moderate effect on the severity of pain in adults with chronic pain, and the confidence in this finding is low.

    Benefits of cannabinoids for chronic pain compared with placebo in the short term (4 weeks to < 6 months)

    THC to CBD Ratio Pain Response
    Effect Size (N Studies)
    [SOE]a
    Pain Severity
    Effect Size (N Studies)
    [SOE]a
    Overall Function
    Effect Size (N Studies)
    [SOE]a
    Comparable THC:CBD
    Oromucosal Spray
    Potential effect (4)b
    [+]
    Small effect (7)
    [++]
    Small effect (6)
    [++]
    High-THC – Synthetic, Oral Insufficient (1) Moderate effect (5)
    [+]
    No effect (3)
    [+]
    High-THC – Extracted from Whole-plant, Oral No evidence Insufficient (2) Insufficient (1)
    Low-THC – Topical CBD No evidence Insufficient (1) No evidence
    Low THC – Oral CBD No evidence Insufficient (1) Insufficient (1)
    Other Cannabinoids – CBDV, Oral Insufficient (1) Insufficient (1) No evidence
    Whole Plant Cannabis (12% THC) No evidence Insufficient (1) No evidence

    Abbreviations: CBD = cannabidiol; CBDV = cannabidivarin; SOE = strength of evidence; THC = tetrahydrocannabinol.
    a Effect size: none (i.e., no effect/no statistically significant effect), small, moderate, or large increased risk; SOE: [+] = low, [++] = moderate, [+++] = high.
    b Findings with small or larger magnitude of effect, not statistically significant; but with SOE rating of Low or higher (downgraded mainly for imprecision).

    Harms of cannabinoids for chronic pain compared with placebo in the short term (4 weeks to < 6 months)

    THC to CBD Ratio WAE
    Effect Size (N Studies)
    [SOE]a
    SAE
    Effect Size (N Studies)
    [SOE]a
    Dizziness
    Effect Size (N Studies)
    [SOE]a
    Nausea
    Effect Size (N Studies)
    [SOE]a

    Sedation

    Effect Size (N Studies)
    [SOE]a

    Comparable THC:CBD
    Oromucosal Spray
    Insufficient (5) No effect (2)
    [+]
    Large effect (6)
    [+]
    Moderate effect (6)
    [+]
    Large effect (6)
    [+]
    High-THC – Synthetic, Oral Potential effectb(4)
    [+]
    Insufficient (1) Large effect (2)
    [++]
    Potential effectb (2)
    [+]
    Moderate effect (3)
    [+]
    High-THC – Extracted From Whole-plant, Oral Large effect (1)
    [+]
    Insufficient (1) Large effect (1)
    [+]
    No evidence No evidence
    Low-THC – Topical CBD No evidence No evidence No evidence No evidence No evidence
    Low-THC – Oral CBD  

    Insufficient (1)

    Insufficient (1)

    No evidence

    No evidence

    No evidence

    Other Cannabinoids – CBDV, oral Insufficient (1) Insufficient (1) No evidence No evidence No evidence
    Whole Plant Cannabis (12% THC) Insufficient (1) Insufficient (1) Insufficient (1) Insufficient (1) Insufficient (1)

    Abbreviations: CBD = cannabidiol; CBDV = cannabidivarin; SAE = serious adverse event; SOE = strength of evidence; THC = tetrahydrocannabinol; WAE = withdrawal due to adverse event.
    a Effect size: none (i.e., no effect/no statistically significant effect), small, moderate, or large increased risk; SOE: [+] = low, [++] = moderate, [+++] = high.
    b Findings with small or larger magnitude of effect, not statistically significant; but with SOE rating of Low or higher (downgraded mainly for imprecision).

    Conclusions
    • An oromucosal spray with comparable amounts of THC and CBD probably reduces pain and improves function to a small extent in patients with neuropathic pain.
    • A synthetic form of THC may reduce pain to a moderate extent.
    • Compared with placebo, cannabis-related interventions resulted in greater risk of common, but not severe adverse events (e.g., dizziness, nausea, sedation), and withdrawals from studies due to adverse events.
    Gaps in Evidence
    • Whole plant formulations and CBD-predominant formulations remain unstudied.
    • No studies examined effects beyond 6 months.
    • There was relatively little evidence examining the harms of many preparations in patients with chronic pain.

    McDonagh MS, Wagner J, Ahmed AY, Morasco B, Kansagara D, Chou R. Living Systematic Review on Cannabis and Other Plant-Based Treatments for Chronic Pain – Quarterly Surveillance Report: January 2022. (Prepared by the Pacific Northwest Evidence-based Practice Center under Contract No. 75Q80120D00006.) AHRQ Publication No. XXX. Rockville, MD: Agency for Healthcare Research and Quality; January 2022. DOI: XXX. Posted final reports are located on the Effective Health Care Program search page. To see this report visit: Living Systematic Review on Cannabis and Other Plant-Based Treatments for Chronic Pain | Effective Health Care Program (ahrq.gov)