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Wang L, Hong PJ, May C, et al. Medical cannabis or cannabinoids for chronic non-cancer and cancer related pain: a systematic review and meta-analysis of randomised clinical trials. BMJ. 2021 Sep 8;374:n1034. doi: 10.1136/bmj.n1034. (Systematic review)

OBJECTIVE: To determine the benefits and harms of medical cannabis and cannabinoids for chronic pain.

DESIGN: Systematic review and meta-analysis.

DATA SOURCES: MEDLINE, EMBASE, AMED, PsycInfo, CENTRAL, CINAHL, PubMed, Web of Science, Cannabis-Med, Epistemonikos, and trial registries up to January 2021.

STUDY SELECTION: Randomised clinical trials of medical cannabis or cannabinoids versus any non-cannabis control for chronic pain at =1 month follow-up.

DATA EXTRACTION AND SYNTHESIS: Paired reviewers independently assessed risk of bias and extracted data. We performed random-effects models meta-analyses and used GRADE to assess the certainty of evidence.

RESULTS: A total of 32 trials with 5174 adult patients were included, 29 of which compared medical cannabis or cannabinoids with placebo. Medical cannabis was administered orally (n=30) or topically (n=2). Clinical populations included chronic non-cancer pain (n=28) and cancer related pain (n=4). Length of follow-up ranged from 1 to 5.5 months. Compared with placebo, non-inhaled medical cannabis probably results in a small increase in the proportion of patients experiencing at least the minimally important difference (MID) of 1 cm (on a 10 cm visual analogue scale (VAS)) in pain relief (modelled risk difference (RD) of 10% (95% confidence interval 5% to 15%), based on a weighted mean difference (WMD) of -0.50 cm (95% CI -0.75 to -0.25 cm, moderate certainty)). Medical cannabis taken orally results in a very small improvement in physical functioning (4% modelled RD (0.1% to 8%) for achieving at least the MID of 10 points on the 100-point SF-36 physical functioning scale, WMD of 1.67 points (0.03 to 3.31, high certainty)), and a small improvement in sleep quality (6% modelled RD (2% to 9%) for achieving at least the MID of 1 cm on a 10 cm VAS, WMD of -0.35 cm (-0.55 to -0.14 cm, high certainty)). Medical cannabis taken orally does not improve emotional, role, or social functioning (high certainty). Moderate certainty evidence shows that medical cannabis taken orally probably results in a small increased risk of transient cognitive impairment (RD 2% (0.1% to 6%)), vomiting (RD 3% (0.4% to 6%)), drowsiness (RD 5% (2% to 8%)), impaired attention (RD 3% (1% to 8%)), and nausea (RD 5% (2% to 8%)), but not diarrhoea; while high certainty evidence shows greater increased risk of dizziness (RD 9% (5% to 14%)) for trials with <3 months follow-up versus RD 28% (18% to 43%) for trials with =3 months follow-up; interaction test P=0.003; moderate credibility of subgroup effect).

CONCLUSIONS: Moderate to high certainty evidence shows that non-inhaled medical cannabis or cannabinoids results in a small to very small improvement in pain relief, physical functioning, and sleep quality among patients with chronic pain, along with several transient adverse side effects, compared with placebo. The accompanying BMJ Rapid Recommendation provides contextualised guidance based on this body of evidence. SYSTEMATIC REVIEW REGISTRATION: https://osf.io/3pwn2.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Hospital Doctor/Hospitalists 6 / 7
Internal Medicine 6 / 7
Special Interest - Pain -- Physician 6 / 7
Anesthesiology 5 / 7
Oncology - General 5 / 7
Surgery - General 4 / 7
Neurology Coming Soon...
Comments from MORE raters

Anesthesiology rater

This systematic review examined the use of oral cannabis and found minimal benefit. The review did not examine the use of inhaled cannabis.

General Internal Medicine-Primary Care(US) rater

Patients certainly try to self-medicate with cannabinoids. This is a clue that the benefits are relatively small.

Hospital Doctor/Hospitalists rater

This review focuses more clearly on chronic pain. While there have been other general reviews (see JAMA) that have similar results, this is a more focused review. Clinicians can feel comfortable that the impact is relatively small and has to be balanced against some side effects. Despite public enthusiasm, the drug is not a solution for most of the symptoms that patients with chronic pain have.

Neurology rater

The meta-analysis reports the "small or very small effect" of cannabis and cannabinoids in oral or topical formulation for cancer and non-cancer pain. There is some risk of bias. This is a therapy that is not legally available in many regions or that a practitioner is willing to prescribe. It may have limited relevance.

Oncology - General rater

The meta-analysis shows that evidence of reasonable quality exists that cannabinoids have little/modest effect on pain control. It is difficult to exactly pinpoint which forms of cancer & non-cancer pain it does mitigate reliably and robustly. Although this is an interesting & a reasonably well-conducted meta-analysis, there is enough non-statistical heterogeneity in this study to question its relevance & utility w.r.t. general practice -- mixing different kinds of cancer & non-cancer pain is a flaw, IMO. An IPD (individual patient data) meta-analysis might have provided more detailed and granular information about this. This study may help guide new research on this issue, but no pragmatic, practice-changing recommendations emerge from this.

Oncology - General rater

Great to have this evidence located, collated, summarised, evaluated, and interpreted for clinicians on the firing line.

Special Interest - Pain -- Physician rater

The potential role of cannabinoids in the treatment of chronic pain has been debated for a long time. The benefit versus risk with its use must be adequately assessed. Current evidence is weak for its use in routine clinical practice.

Special Interest - Pain -- Physician rater

This study provides important guidance around the efficacy of cannabinoids in pain management as well as highlighting the paucity of high-quality evidence/clinical trials in this area.

Surgery - General rater

This is is a well performed systematic review of the role of noninhaled cannabinoids in chronic pain. There was a small but significant difference favoring the use of cannabinoids, but long-term follow-up was limited. Adverse side effects were transient. There is accumulating evidence that this approach is superior to opiates for this purpose.
Comments from EvidenceAlerts subscribers

Dr. ivan moschetti (9/22/2021 4:28 AM)

This study shows a small but significant difference favoring the use of cannabinoids. Also, if the information on long-term follow-up was limited, the uthors didn't find dangerous adverse events. On the other hand, in the chronic pain medical treatment field, most of the competitors could produce negative outcomes.