https://orcid.org/0000-0003-0855-6719
Figures
Abstract
Design
Systematic review of randomised clinical trials with meta-analysis, Trial Sequential Analysis, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.
Eligibility criteria for selecting studies
Published and unpublished randomised clinical trials comparing cannabinoids versus placebo in participants with any type of pain.
Main outcome measures
All-cause mortality, pain, adverse events, quality of life, cannabinoid dependence, psychosis, and quality of sleep.
Results
We included 65 randomised placebo-controlled clinical trials enrolling 7017 participants. Fifty-nine of the trials and all outcome results were at high risk of bias. Meta-analysis and Trial Sequential Analysis showed no evidence of a difference between cannabinoids versus placebo on all-cause mortality (RR 1.20; 98% CI 0.85 to 1.67; P = 0.22). Meta-analyses and Trial Sequential Analysis showed that cannabinoids neither reduced acute pain (mean difference numerical rating scale (NRS) 0.52; 98% CI -0.40 to 1.43; P = 0.19) or cancer pain (mean difference NRS -0.13; 98% CI -0.33 to 0.06; P = 0.1) nor improved quality of life (mean difference -1.38; 98% CI -11.81 to 9.04; P = 0.33). Meta-analyses and Trial Sequential Analysis showed that cannabinoids reduced chronic pain (mean difference NRS -0.43; 98% CI -0.72 to -0.15; P = 0.0004) and improved quality of sleep (mean difference -0.42; 95% CI -0.65 to -0.20; P = 0.0003). However, both effect sizes were below our predefined minimal important differences. Meta-analysis and Trial Sequential Analysis indicated that cannabinoids increased the risk of non-serious adverse events (RR 1.20; 95% CI 1.15 to 1.25; P < 0.001) but not serious adverse events (RR 1.18; 98% CI 0.95 to 1.45; P = 0.07). None of the included trials reported on cannabinoid dependence or psychosis.
Conclusions
Cannabinoids reduced chronic pain and improved quality of sleep, but the effect sizes are of questionable importance. Cannabinoids had no effects on acute pain or cancer pain and increased the risks of non-serious adverse events. The harmful effects of cannabinoids for pain seem to outweigh the potential benefits.
Citation: Barakji J, Korang SK, Feinberg J, Maagaard M, Mathiesen O, Gluud C, et al. (2023) Cannabinoids versus placebo for pain: A systematic review with meta-analysis and Trial Sequential Analysis. PLoS ONE 18(1): e0267420. https://doi.org/10.1371/journal.pone.0267420
Editor: Tariq Jamal Siddiqi, The University of Mississippi Medical Center, UNITED STATES
Received: April 7, 2022; Accepted: August 16, 2022; Published: January 30, 2023
Copyright: © 2023 Barakji et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: Funding JB received a grant for this research from A.V. Lykfeldt and Wife’s Grant (A.V. Lykfeldt og Hustrus Legat).
Competing interests: The authors have declared that no competing interests exist.
Introduction
Pain is the most commonly reported symptom in the general population and medical settings [1–3]. Persistent or chronic pain is a major universal health problem [4], prompting the WHO to endorse a global campaign against pain [5]. Pain has been associated with lower degree of health-related quality of life and may lead to psychosocial distress, insomnia, and depressive symptoms [6–14].
Cannabinoids
Cannabinoids have lately emerged as a potential alternative to other analgesics, e.g., opioids for the treatment of pain [15]. Cannabinoids are most commonly consumed via smoked, inhaled vapour, or oral routes of administration [16]. Sublingual administration is used for some medical cannabis preparations (e.g., nabiximol).
The endocannabinoid system consists of two types of cannabinoid receptors in the human body, type I and type II [17]. Cannabinoid receptor type I are most abundant in the central nervous system, especially in areas stimulating nociception and short-term memory, and in the basal ganglia. Cannabinoid receptor type II is mostly found in the periphery, often in conjunction with immune cells, but may appear in the central nervous system predominantly in association with microcytes during inflammation [17].
These receptors is thought to suppress the pain stimulus through different mechanisms [18]. Neurochemical, behavioral, and electrophysiological studies all demonstrated the modulation of inflammatory nociception through cannabinoid receptor type II activation [19].
Pain
Acute pain usually has a well-defined onset and most often a readily identifiable etiology (i.e., surgery, etc.). Acute pain is expected to run its course in a relatively short time frame and management of acute pain typically focuses on providing symptomatic relief until pain is reduced to an acceptable level [20].
Chronic pain is typically defined as pain lasting for more than three months [21]. Chronic pain may also have a well-defined onset related to tissue injury (e.g., surgery) and be mediated through an intact nervous system. It may, however, also be caused by nerve damage and dynamic changes in the nervous system, and be characterized by an ill-defined onset and a prolonged, fluctuating course [20].
Pain may also be classified based on whether it is cancer-related or non-cancer-related. Cancer-related pain is caused by the cancer itself (primary tumor and metastases) or its treatment (e.g., radiation therapy) [22].
Previous reviews have reported on serious adverse events (e.g., agitation, impaired memory, abuse, dissociation, acute psychosis, and death) [23–27] and non-serious adverse events (e.g., sedation, dizziness, dry mouth, increased appetite, somnolence, confusion and nausea) [23–25, 27–31] in users of cannabinoids for pain.
According to Canada’s Drug and Health Technology Agency (CADTH) there is some suggestion of benefit with cannabis-based medicines specifically for neuropathic pain. However, such benefits needs to be weighed against harms [32].
Before healthcare systems ought to endorse the applicability of cannabinoids for pain globally, the potential short- and long-term benefits and harms of cannabinoids must be investigated. We conducted this systematic review with meta-analysis and Trial Sequential Analysis (TSA) and based on available randomised trials to evaluate the effectiveness and safety of cannabinoids in participants with pain.
Methods
The objective of our systematic review was to assess the benefits and harms of cannabinoids versus placebo or no intervention for participants with any type of pain (acute and chronic pain, cancer pain, or any other types of pain). Our methodology is described in detail in our protocol published prior to conducting the literature search [33].
In short, we carried out this systematic review following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines [34]. We included all randomised clinical trials comparing cannabinoids versus placebo or no intervention for participants with any type of pain. Two authors (JB, SKK) independently searched for trials identified prior to January 2022 see ‘Supplement 1 in S1 File’ for a detailed list of databases and ‘Supplement 2 in S1 File’ for the search strategy. We included randomised clinical trials regardless of trial design, setting, publication status, year, language, and reporting of outcomes. Four authors (JB, SKK, JBF, and MM) working in pairs independently extracted data and assessed the risks of bias in included trials. We contacted trial authors by email if data were unclear or missing. Disagreements were resolved through discussion or by consulting a third author (JCJ).
Outcomes
Primary outcomes.
- All-cause mortality
- Pain assessment on visual analogue scale (VAS) or numerical rating scale (NRS)
- Proportion of participants with one or more serious adverse events. Serious adverse events were defined as any untoward medical occurrence that resulted in death; was life threatening; was persistent or led to significant disability, hospitalisation, or prolonged hospitalisation [35]. As we expected the trialists’ reporting of serious adverse events to be heterogeneous and not strictly according to the International Conference on Harmonisation—Good Clinical Practice (ICH-GCP) recommendations, we included the event as a serious adverse if the trialists either: (1) used the term ’serious adverse event’ but did not refer to ICH-GCP, or (2) reported the proportion of participants with an event we considered fulfils the ICH-GCP definition. If several of such events were reported then we choose the highest proportion reported in each trial
- Quality of life measured on any valid (published validation) continuous scale
Secondary outcomes.
- Cannabinoid dependence (as defined by trialists)
- Psychosis (as defined by trialists)
- Proportion of participants with one or more adverse event not considered to be serious
- Quality of sleep measured on any valid (published validation) continuous scale
Exploratory outcomes.
- Each type of serious adverse event separately
- Each type of adverse event not considered serious separately
- Twenty-four hours morphine consumption (as defined by trialists)
- Physical function (as defined by trialists)
- Depressive symptoms (e.g., Hamilton Depression Rating Scale)
Adverse events were included in our analysis regardless of whether it was defined as an outcome by the trialists.
For all outcomes, we used the trial results reported at maximal follow-up.
Patient and public involvement.
We conducted email correspondence with several patient associations in Denmark to select the most patient-relevant outcomes. The associations were the Danish Diabetes Association, the Danish Rheumatism Association, the Danish Multiple Sclerosis Society, and the Danish Cancer Society.
Sub-group analyses.
We pre-defined subgroup analyses for our primary outcomes assessing risk of bias, risk of vested interests, type of pain, type of chronic pain, and type of cannabinoids used [33].
Assessment of risk of bias.
We assessed risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions 5.1 [36]. We evaluated the risk of bias in the domains ‘random sequence generation’, ‘allocation concealment’, ‘blinding of participants and treatment providers’, ‘blinding of outcome assessment, ‘incomplete outcome data’, and ‘selective outcome reporting’. We used these domains to classify the included trials as being at overall low risk of bias or at overall high risk of bias as described in our protocol [33].
The domains ‘blinding of outcome assessment’, ‘incomplete outcome data’, and ‘selective outcome reporting’ were further assessed separately for each outcome result.
Assessment of effect.
We calculated risk ratios (RRs) with 95% and 98% confidence intervals (CIs) for our continuous and dichotomous outcomes (see "Assessment of statistical and clinical significance"). For our dichotomous outcomes we used the conventional direction with RR > 1.0 representing higher risk in the experimental intervention group.
We calculated mean differences (MDs) and standardised mean differences (SMDs) for our continuous outcomes. For pain assessment, we used the numerical rating scale to measure the mean difference between groups [37]. Visual analog scale (VAS) (0 to 100) was converted into the numerical rating scale (NRS) (0 to 10) by dividing with 10 [37].
Assessment of heterogeneity.
We investigated forest plots to visually assess any sign of heterogeneity. We secondly assessed the presence of statistical heterogeneity by Chi2 test (threshold P < 0.10) and measured the quantities of heterogeneity by I2 statistic and tau (τ)2 statistic [38, 39]. We also investigated heterogeneity through subgroup analyses. Ultimately, we decided whether the assessment of heterogeneity showed that meta-analysis should be avoided [36].
Assessment of reporting biases.
We used funnel plots to assess reporting bias, although it should be noted that funnel plots assess small-study effects [36]. Funnel plots were performed if 10 or more trials were included [36]. For dichotomous outcomes, we assessed asymmetry with the Harbord test [40] if τ2 was less than 0.1 and with the Rücker test if τ2 was more than 0.1. For continuous outcomes, we used the regression asymmetry test [41].
Assessment of statistical and clinical significance.
We performed all meta-analyses using Review Manager 5.4.1 and STATA 16.1 [42, 43]. We assessed our intervention effects with both random-effects meta-analyses (DerSimonian method) [44] and fixed-effect meta-analyses (DeMets method) [43, 45]. We primarily reported the more conservative point estimate of the two and the less conservative result as a sensitivity analysis [46]. To control random errors when analysing our primary outcomes, we adjusted the threshold for statistical significance using the procedure suggested by Jakobsen and colleagues [46]. We used four primary outcomes and therefore considered a P-value of 0.02 as the threshold for statistical significance [46]. When analysing secondary and exploratory outcomes, we considered a P-value of 0.05 as the threshold for statistical significance as these outcomes were considered hypothesis-generating only [46].
We used Trial Sequential Analysis (TSA) to control for the risks of random errors [47]. Traditional meta-analysis runs the risk of random errors due to sparse data and repetitive testing of accumulating data when updating reviews. We wished to control the risks of type I errors and type II errors [46]. By conducting TSA on the outcomes, we could calculate the required information size, i.e., the number of participants needed in a meta-analysis to detect or reject our anticipated intervention effects [46].
For dichotomous outcomes, we estimated the required information size based on the observed proportion of participants with an outcome in the control group, a relative risk reduction of 20% in the experimental group, an alpha of 2.0%, a beta of 10%, and the diversity suggested by the trials in the meta-analysis. For the outcome pain assessment on VAS or NRS, we used an analgesic effect equivalent to 10 mm on VAS or 1 point on NRS. For the outcome 24-hour morphine consumption we used an effect equivalent to at least 5 mg morphine. For the remaining continuous outcomes, we used the observed standard deviation (SD), a mean difference of the observed SD/2, an alpha of 2.0% for our primary and secondary outcomes, a beta of 10%, and the diversity suggested by the trials in the meta-analysis [33]. The above-mentioned intervention effects used in the TSA were also predefined as the minimal important differences (MIDs) of the review [33].
We used a ’best-worst case’ and a ’worst-best case’ sensitivity analysis to assess the impact of missing data (incomplete outcome data bias) [36]. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of the evidence [48, 49].
Results
Our literature search identified 5766 records. After removing duplicates, 4302 records remained. We excluded 4196 records based on title or abstract. We excluded another 41 records based on the full texts (Fig 1). We included a total of 65 clinical trials randomising 7017 participants [50–112].
All 65 trials compared cannabinoids versus placebo. The mean age of included participants was 50.4 years ranging from a mean of 20.7 years [74] to 63.7 years [63] (see Table 1 for more details).
The participants were included in the trials based on the different pain diagnoses. Forty-four trials randomised 4306 participants with chronic pain (34 trials in neuropathic pain, and 10 trials in chronic nociceptive pain); 9 trials randomised 1681 participants with cancer pain; 10 trials randomised 965 participants with acute pain; and 2 trials randomised 65 participants with fibromyalgia-related pain.
Length of maximum follow-up of the included trials varied between 7 hours [71] and 16 weeks [92] with a mean length of follow-up of 7.3 weeks.
Only 35 of the 65 trials provided data that could be included in our meta-analysis. The primary reason that trial data could not be included in the meta-analyses was that the trials were designed as cross-over trials and that they did not provide data at the end of the first phase. These trials are described qualitatively in the paragraph ‘Trials not contributing with data in our meta-analyses’. Fifty-nine of the 65 included trials were at high risk of bias, see ‘Supplement 4 in S1 File’ and ‘S4 File’ for more information on bias assessment.
Primary outcomes
All-cause mortality.
Seven trials randomising 2073 participants reported on all-cause mortality. Meta-analysis showed no evidence of a difference between cannabinoids versus placebo (RR 1.20; 98% CI 0.85 to 1.67; P = 0.22; low certainty of evidence; S1 Fig in S1 File). Visual inspection of the forest plot, I2-statistic (I2 = 7%), and tau2 statistic (τ2 = 0.01; τ = 0.1) indicated low heterogeneity. TSA showed that there was not enough information to confirm or reject that cannabinoids versus placebo increased the risk of all-cause mortality by 20% or more (S2 Fig in S1 File). We assessed this outcome result at high risk of bias, see ‘Supplement 4 in S1 File’ and S3 and S4 Figs in S1 File.
Test for interaction showed no evidence of a difference when comparing trials at high risk of bias to trials at low risk of bias (P = 0.87) (S5 Fig in S1 File); trials at risk of vested interests to trials at no risk of vested interests (P = 0.87) (S6 Fig in S1 File); trials assessing different types of pain, i.e., cancer pain and chronic pain (P = 0.43) (S7 Fig in S1 File); trials comparing the effects of different types of cannabinoids (P = 0.78) (S8 Fig in S1 File). The remaining planned subgroup analyses were not possible to conduct due to lack of relevant data.
Pain.
Twenty-six trials randomising 4110 participants assessed pain using either VAS (8 trials) or NRS (18 trials). We converted all pain measures to NRS as described in the ‘Methods’ section.
The visual inspection of the forest plot and test for subgroup difference (P = 0.02), showed that the effects of cannabinoids seemed to differ between trials randomising participants with acute pain, cancer pain, and chronic pain (S9 Fig in S1 File). It was therefore not justifiable to meta-analyse the results of trials including the different types of pain. Hence, we chose to report results separately for each group of trials (acute pain; cancer pain; and chronic pain).
Acute pain.
Four trials randomising 530 participants suffered from acute pain. Meta-analysis showed no evidence of a difference between cannabinoids versus placebo (mean difference NRS 0.52; 98% CI -0.40 to 1.43; P = 0.19; very low certainty of evidence; S10 Fig in S1 File). Visual inspection of the forest plot, I2-statistic (I2 = 90%), and tau2 statistic (τ2 = 0.67, τ = 0.82) indicated high heterogeneity that could not be resolved. TSA showed that we had not enough information to confirm or reject that cannabinoids versus placebo reduced acute pain (S11 Fig in S1 File). We assessed this outcome result at high risk of bias, see ‘Supplement 4 in S1 File’.
Test of interaction showed evidence of a difference when comparing trials at high risk of bias to trials at low risk of bias (P = 0.035) (S12 Fig in S1 File). When trials at low risk of bias and trials at high risk of bias were analysed separately we found no evidence of a difference between cannabinoids versus placebo (S12 Fig in S1 File).
Test of interaction showed no evidence of a difference when comparing trials at risk of vested interests to trials at no risk of vested interests (P = 0.25) (S13 Fig in S1 File).
All remaining planned subgroup analyses were not possible to conduct due to lack of relevant data.
A post-hoc subgroup analysis comparing trials with long-term follow-up to trials with short-term follow-up showed no evidence of a difference (P = 0.10) (S14 Fig in S1 File).
Cancer pain.
Six trials randomising 1550 participants suffered from cancer pain. Meta-analysis showed no evidence of a difference between cannabinoids versus placebo (mean difference NRS -0.13; 98% CI -0.33 to 0.06; P = 0.1; low certainty of evidence; S15 Fig in S1 File). Visual inspection of the forest plot, I2-statistic (I2 = 2%), and tau2 statistic (τ2 = 0.00) indicated low heterogeneity. TSA showed that there was enough information to reject that cannabinoids versus placebo reduced cancer pain (S16 Fig in S1 File). We assessed this outcome result as high risk of bias, see ‘Supplement 4 in S1 File’.
Test of interaction showed no evidence of a difference when comparing trials assessing the effects of different types of cannabinoids (P = 0.71) (S17 Fig in S1 File).
All remaining planned subgroup analyses were not possible to conduct due to lack of relevant data.
A post-hoc subgroup analysis comparing trials with long-term follow-up to trials with short-term follow-up showed no evidence of a difference (P = 0.06) (S18 Fig in S1 File).
Chronic pain.
Sixteen trials randomising 2030 participants suffered from chronic pain. Meta-analysis showed that cannabinoids reduced chronic pain, but the effect size was below the predefined MID and the MID was not included in the 98% confidence interval (mean difference NRS -0.43; 98% CI -0.72 to -0.15; P = 0.0004; low certainty of evidence; Fig 2, S19 Fig in S1 File). Visual inspection of the forest plot, I2-statistic (I2 = 64%), and tau2 statistic (τ2 = 0.11) indicated moderate heterogeneity that could not be resolved. TSA showed that there was enough information to confirm that cannabinoids versus placebo reduced chronic pain with a statistically significant effect (S20 Fig in S1 File). We assessed this outcome result as high risk of bias, see ‘Supplement 4 in S1 File’.
Test for interaction showed no evidence of a difference when comparing trials at high risk of bias to trials at low risk of bias (P = 0.31) (S21 Fig in S1 File); and trials at risk of vested interests to trials at no risk of vested interests (P = 0.57) (S22 Fig in S1 File). Test for interaction showed evidence of a difference when comparing trials assessing different types of chronic pain, i.e., neuropathic pain (including central, peripheral, and mixed), fibromyalgia, and visceral nociceptive pain (P = 0.01) (S23 Fig in S1 File); and trials comparing the effects of different types of cannabinoids (P < 0.001) (S24 Fig in S1 File).
The funnel plot showed no clear signs of small-study effects (S25 Fig in S1 File).
A post-hoc subgroup analysis comparing trials with long-term follow-up to trials with short-term follow-up showed no evidence of a difference (P = 0.59) (S26 Fig in S1 File).
Serious adverse events.
Eighteen trials randomising 3980 participants reported serious adverse events. Meta-analysis showed no evidence of a difference between cannabinoids versus placebo (RR 1.18; 98% CI 0.95 to 1.45; P = 0.07; low certainty of evidence; Fig 3, S27 Fig in S1 File). Visual inspection of the forest plot, I2-statistic (I2 = 0%), and tau2 statistic (τ2 = 0.00) indicated low heterogeneity. TSA showed that there was not enough information to confirm or reject that cannabinoids versus placebo increased the risk of serious adverse events by 20% or more (S28 Fig in S1 File). We assessed this outcome result at high risk of bias, see ‘Supplement 4 in S1 File’ and S29 and S30 Figs in S1 File.
Test for interaction showed no evidence of a difference when comparing trials at risk of vested interests to trials at no risk of vested interests (P = 0.97) (S31 Fig in S1 File); trials assessing different types of pain, i.e. acute pain, cancer pain and chronic pain (P = 0.96) (S32 Fig in S1 File); trials assessing different types of chronic pain, i.e., neuropathic pain (including central and peripheral) and nociceptive pain (P = 0.16) (S33 Fig in S1 File); and trials comparing the effects of different types of cannabinoids (P = 0.79) (S34 Fig in S1 File).
The remaining planned subgroup analyses were not possible to conduct due to lack of relevant data.
The funnel plot showed no clear signs of small-study effects (S35 Fig in S1 File).
When analysing each specific serious adverse event, cannabinoids did not seem to increase or decrease the risk of any single serious adverse events compared with placebo, see ‘S2 File’.
Quality of life.
Only four trials randomising 548 participants assessed quality of life using either EuroQol 5-D (3 trials) or EORTC-QLQC30 (1 trial). Meta-analysis showed no evidence of a difference between cannabinoids versus placebo (mean difference -1.38; 98% CI -11.8 to 9.04; P = 0.75; very low certainty of evidence; S36 Fig in S1 File). Visual inspection of the forest plot, I2-statistic (I2 = 86%), and tau2 statistic (τ2 = 61.98, τ = 7.87) indicated high heterogeneity which could not be resolved. TSA showed that there was not enough information to confirm or reject that cannabinoids versus placebo improved quality of life (S37 Fig in S1 File). We assessed this outcome result as high risk of bias, see ‘Supplement 4 in S1 File’.
Test for interaction showed no evidence of a difference when comparing trials assessing different types of pain, i.e., cancer pain and chronic pain (P = 0.33) (S38 Fig in S1 File) and trials comparing the effects of different types of cannabinoids (P = 0.56) (S39 Fig in S1 File).
All remaining planned subgroup analyses were not possible to conduct due to lack of relevant data.
Meta-analysing the standard mean difference showed no evidence of a difference between cannabinoids versus placebo (SMD -0.19; 95% CI -0.70, 0.32; P = 0.46).
Secondary outcomes
Dependence and psychosis.
None of the included randomised clinical trials reported results on the outcomes ‘dependence’ or ‘psychosis’ that could be analysed through a meta-analysis.
Non-serious adverse events.
Twenty-nine trials randomising 5536 participants reported non-serious adverse events. Meta-analysis showed evidence of a harmful effect of cannabinoids (RR 1.20; 95% CI 1.15 to 1.25; P < 0.001; very low certainty of evidence; Fig 4, S40 Fig in S1 File). The number needed to harm (NNH) was seven. Visual inspection of the forest plot, I2-statistic (I2 = 27%), and tau2 statistic (τ2 = 0.00) indicated low heterogeneity. TSA showed that there was enough information to confirm that cannabinoids versus placebo increased the risk of non-serious adverse events by 20% or more (S41 Fig in S1 File). We assessed this outcome result at high risk of bias, see ‘Supplement 4 in S1 File’ and S42 and S43 Figs in S1 File.
The funnel plot showed signs of small-study effects (S44 Fig in S1 File).
When analysing each specific non-serious adverse event, cannabinoids seemed to increase the risk of five non-serious adverse events versus placebo, see ‘S3 File’. These were ‘dizziness’, ‘fatigue’, ‘vertigo’, ‘nervous system disorders’, and ‘gastrointestinal disorder’.
Cannabinoids did not seem to decrease the risk of any non-serious adverse events.
Quality of sleep.
Seventeen trials randomising 3291 participants assessed quality of sleep using numerical rating scale (NRS). Meta-analysis showed that cannabinoids versus placebo improved quality of sleep, but the effect size was below the predefined MID and the MID was excluded in the confidence interval (mean difference NRS -0.42; 95% CI -0.65 to -0.20; P = 0.0003; low certainty of evidence; Fig 5, S45 Fig in S1 File). Visual inspection of the forest plot, I2-statistic (I2 = 74%), and tau2 statistic (τ2 = 0.15) indicated moderate heterogeneity that could not be resolved. TSA showed that there was enough information to confirm that cannabinoids versus placebo improved quality of sleep with a statistically significant effect (S46 Fig in S1 File). We assessed this outcome result at high risk of bias, see ‘Supplement 4 in S1 File’.
The funnel plot showed no clear signs of small-study effects (S47 Fig in S1 File).
Exploratory outcomes
Twenty-four hours morphine consumption.
Six trials randomising 1546 participants assessed 24-hours morphine consumption. Meta-analysis showed no evidence of a difference between cannabinoids versus placebo (mean difference -0.01; 95% CI -1.60 to 1.59; P = 0.99; low certainty of evidence; S48 Fig in S1 File). Visual inspection of the forest plot and I2-statistic (I2 = 21%) and tau2 statistic (τ2 = 29.78, τ = 5.46) indicated low heterogeneity. TSA showed that there was enough information to reject that cannabinoids versus placebo reduced 24-hours morphine consumption by five mg morphine equivalents or more (S49 Fig in S1 File). We assessed this outcome result at high risk of bias, see ‘Supplement 4 in S1 File’.
Physical function (measured by activities of daily living).
Three trials randomising 320 participants assessed ability to perform activities of daily living (ADL) using Barthel Index. Meta-analysis showed no evidence of a difference between cannabinoids versus placebo (mean difference 0.21; 95% CI -0.10 to 0.51; P = 0.18; very low certainty of evidence; S50 Fig in S1 File). Visual inspection of the forest plot and I2-statistic (I2 = 0%) and tau2 statistic (τ2 = 0.00) indicated low heterogeneity. TSA could not be performed due to inadequate information size. We assessed this outcome result at high risk of bias, see ‘Supplement 4 in S1 File’.
Depressive symptoms.
Five trials randomising 651 participants assessed depressive symptoms using either HADS-D (3 trials), MADRS (1 trial) or BDI-II (1 trial). Meta-analysis showed no evidence of a difference between cannabinoids versus placebo (mean difference -0.03; 95% CI -0.12 to 0.06; P = 0.49; low certainty of evidence; S51 Fig in S1 File). Visual inspection of the forest plot and I2-statistic (I2 = 0%) and tau2 statistic (τ2 = 0.00) indicated low heterogeneity. TSA showed that there was enough information to reject that cannabinoids versus placebo improved depressive symptoms (S52 Fig in S1 File). We assessed this outcome result at high risk of bias, see ‘Supplement 4 in S1 File’.
Trials not contributing with data in our meta-analyses.
Nineteen trials randomising 603 participants concluded in favor of an analgesic effect of cannabinoids compared with placebo [50, 52, 62, 67, 70, 71, 75, 82, 83, 85, 96–98, 101, 105, 107–110]. Fifteen trials assessed chronic pain including neuropathic pain (13/15) [50, 52, 62, 67, 82, 85, 98, 101, 105, 107–110] and visceral nociceptive pain (2/15) [70, 83], two trials assessed acute pain [71, 75], and two trials assessed cancer pain [96, 97]. Six trials assessed the use of plant-derived THC extract [50, 52, 62, 107–109], ten trials assessed the use of synthetic THC [70, 71, 75, 83, 85, 96–98, 101, 110], and three trials assessed plant-derived THC/CBD extract [67, 82, 105]. Cannabinoids were generally assessed as safe [50, 52, 62, 67, 82, 98, 101, 105, 108, 109]. Only one trial found a beneficial effect of cannabinoids on quality of life compared with placebo [98]. Mortality was not assessed by any of the trials.
Eleven trials randomising 391 participants concluded against an analgesic effect of cannabinoids compared with placebo [51, 53, 55, 56, 61, 63, 65, 66, 72, 77, 103]. Eight trials assessed chronic including neuropathic pain (4/8) [56, 61, 66, 77], visceral nociceptive pain (3/8) [51, 53, 65], and fibromyalgia (1/8) [103], two trials assessed acute pain [55, 63], and one trial assessed cancer pain [72]. Two trials assessed the use of plant-derived THC extract [53, 66], four trials assessed the use of synthetic THC [63, 65, 72, 77], one trial assessed the use of CBD [55] and four trials assessed plant-derived THC/CBD extract [51, 56, 61, 103]. Cannabinoids were generally assessed as safe [51, 56, 63, 65, 66, 77], however, cannabinoids were not assessed in regards to mortality or quality of life.
Discussion
The objective of this review was to assess the beneficial and harmful effects of cannabinoids in any dose, formulation, and duration versus placebo or no intervention for participants with any type of pain.
Meta-analysis and TSA showed no evidence of a difference between cannabinoids versus placebo on all-cause mortality, serious adverse events, and quality of life. Meta-analyses showed that cannabinoids compared with placebo reduced chronic pain (in particular central and peripheral neuropathic pain) and improved quality of sleep, but both effect sizes were below our predefined minimal important differences and the minimal important differences were excluded by both confidence intervals. Meta-analyses and TSA showed that cannabinoids increased the risks of non-serious adverse events, which corresponds to a number needed to harm of seven. None of the included trials reported on cannabinoid dependence or psychosis.
According to the European Medicines Agency, P-values are of limited value as relative or absolute differences in terms of adverse effects [113]. A non-significant difference between treatments will not allow for a conclusion on the absence of a difference in safety [113]. In cases of adjustment for multiplicity, the European Medicines Agency state that this can be counterproductive for considerations of safety [113]. Hence, even though meta-analysis and TSA did not show a statistically significant difference when assessing serious adverse events, our results show indications of a harmful effect which should be considered before prescribing cannabinoids for pain.
Our findings are in contrast to the majority of previous reviews which have indicated an adequate analgesic effect of cannabinoids and supported the use of cannabinoids for the treatment of chronic pain [23–26, 114, 115]. Our findings suggest that cannabinoids reduced chronic pain when compared with placebo, however, whether this effect is clinically important seems questionable.
Our findings are in agreement with position statement of the International Association for the Study of Pain (IASP) [116]. IASP have identified important research gaps and due to the lack of high- quality clinical evidence IASP does not currently endorse general use of cannabis and cannabinoids for pain relief [116].
Our findings regarding cancer pain and acute pain are in line with previous reviews on this topic [117–119].
Strengths
Our present review has several strengths. Our methodology was predefined and was described in detail in our published protocol [33]. To control the risk of random errors, we used TSA [47] and adjusted our thresholds for statistical significance [46]. We included more trials than any other previous review, which has increased our power and precision and strengthened our analyses. We assessed the risk of bias of all included trials to assess the risks of systematic errors [48, 49], and we used our eight-step procedure to assess if the thresholds for statistical and clinical significance were crossed [46]. Furthermore, we predefined MIDs for all outcomes to assess the clinical implications for patients of our results [33]. Pain level thresholds for acute pain and for chronic pain were predefined based on Olsen et al. [120, 121]. The MID of one point on NRS is considered lenient in comparison to previous reviews, and our predefined lenient quantification decreases the risk of erroneous rejections of cannabinoids’ beneficial effects on pain [23, 29]. We were also in contact with several relevant patient associations in Denmark at the protocol stage to select the most relevant patient-important outcomes [33].
Limitations
Our review also has several limitations. All trials except five [60, 80, 90, 111] were at high risk of bias. Therefore, there is a high risk that our results overestimate the beneficial effects and underestimate the harmful effects of cannabinoids [122–128]. We decided to combine the VAS scores and the NRS scores by converting the results to NRS scores. Even though the two scoring systems correspond very well, some information may be lost in the conversion [129]. Furthermore, a limitation of this systematic review is that we only compared the cannabinoid intervention with placebo. Hence, our results do not assess the effects of cannabinoids compared with other types of analgesics (e.g., opioids).
When conducting a subgroup analysis, one is at risk of study-level confounding because the subgroup analyses are based on aggregate data on a trial level and we did not obtain any individual patient data which may decrease the statistical power of our subgroup analyses. This is a common potential limitation in a meta-analysis of aggregate data.
Minimal important difference
Pain and quality of sleep measurements are subjective measures, why imprecision could be present when assessing these outcomes. We, therefore, need to be careful before dismissing such outcome results as clinically unimportant. Nevertheless, any outcome result should be related to a predefined minimal important difference (MID) to ensure the scientific validity of trial results and to avoid focus on statistically significant results without importance to patients. If a large number of trial participants are randomised, small and clinically irrelevant intervention effects may lead to statistically significant results and rejection of the null hypothesis [130]. Jaeschke et al. defined the MID as ‘the smallest difference in score in the domain of interest which patients perceive as beneficial’ [131]. Olsen et al. have conducted two systematic reviews on this matter in order to gather the evidence and present an estimate of the MID for pain [120, 121]. Olsen et al. conducted a systematic review on the MID in patients with acute pain and concluded that the median of the studies’ results was 17 mm on VAS (IQR 14 mm to 23 mm) [120]. Another systematic review conducted by Olsen et al. was on the MID in patients with chronic pain and the results showed a median of 23 mm on VAS (IQR 12 mm to 39 mm) when using the within-patient anchor-based method, while the median in studies using the sensitivity-based and specificity-based method was 20 mm on VAS (IQR 15 mm to 30 mm) [121].
Our MID for quality of sleep was not based on previous studies, because such studies have not been conducted. We, therefore, based our estimation of MID on Cohen’s D higher than 0.5 [132]. The 0.5 SMD threshold was originally proposed by Cohen (as a minimum for a ‘moderate’ effect) and has been used as a MID in several studies across medical specialties [132]. Nevertheless, it has to be considered that the MID estimation for quality of sleep compared to the MID for pain is more unclear because studies assessing the MID are lacking.
Several countries have recently either expanded or introduced the medical use of cannabinoids. Of the many different approaches introduced globally only a few have been presented by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) in their report [133]. Canada was one of the first countries to establish a national programme for the medical use of cannabinoids in 1999 and have since evolved to an expanded access programme [134]. New legislation in 2014 licensed more cannabis producers, allowed doctors greater latitude in prescribing, removed federal oversight of prescribing, and permitted patients to receive cannabis directly from licensed producers [135]. Similarly, numerous European countries have allowed the usage of cannabinoids for medical purposes [133]. The different national regulatory frameworks are complicated, but the most common initial approach implemented is to use some form of special access scheme. Examples of countries that have established some form of exceptional use programme or access programme to allow access to cannabinoid preparations for the treatment of pain are Croatia, Denmark, Finland, Norway, Poland, Sweden, Czechia, Germany, Italy, and The Netherlands [133]. According to our present results, the medical use of cannabinoids for pain ought to be reconsidered.
The NASEM report from 2017 on the health effects of marijuana reviewed the evidence on the use of cannabinoids as a treatment for chronic pain [136]. The primary source of information for this summary was based on the works of Whiting et al. suggesting that cannabinoids demonstrate a modest effect on pain [114]. Our present review represents the most comprehensive systematic assessment of the effects of cannabinoids on pain. This systematic review will furthermore work as recommendation for where focus needs to be in future randomised clinical trials.
Conclusions
Cannabinoids reduced chronic pain and improved quality of sleep, but the effect sizes are of questionable importance. Cannabinoids had no effects on acute pain or cancer pain and increased the risk of non-serious adverse events. The harmful effects of cannabinoids for pain seem to outweigh the potential benefits. The expanded medical use of cannabinoids for pain is at this point questionable.
Supporting information
S2 File. Each serious adverse event separately.
https://doi.org/10.1371/journal.pone.0267420.s003
(XLSM)
S3 File. Each adverse event not considered serious separately.
https://doi.org/10.1371/journal.pone.0267420.s004
(XLSM)
S4 File. ROB assessment and characteristics of included studies.
https://doi.org/10.1371/journal.pone.0267420.s005
(DOCX)
References
- 1. Verhaak P, Kerssens J, Dekker J, et al. Prevalence of chronic benign pain disorder among adults: a review of the literature. PAIN 1998;77(3):231–9. [published Online First: 1998/11/10] pmid:9808348
- 2. Kroenke K. Patients presenting with somatic complaints: epidemiology, psychiatric comorbidity and management. International Journal of Methods in Psychiatric Research 2003;12(1):34–43. [published Online First: 2003/06/28] pmid:12830308
- 3. Sternbach RA. Survey of pain in the United States: The nuprin pain report. The Clinical Journal of Pain 1986;2(1):49–53.
- 4. Gureje O, Von Korff M, Simon G, et al. Persistent pain and well-being: a World Health Organization Study in Primary Care. JAMA 1998;280(2):147–51. [published Online First: 1998/07/21] pmid:9669787
- 5. Breivik H. International association for the study of pain: update on WHO-IASP activities. Journal of Pain and Symptom Management 2002;24(2):97–101. [published Online First: 2002/09/17] pmid:12231125
- 6. Davison S. Chronic pain in end-stage renal disease. Advances in Chronic Kidney Disease 2005;12(3):326–34. [published Online First: 2005/07/13] pmid:16010647
- 7. Davison SN, Jhangri GS. Impact of pain and symptom burden on the health-related quality of life of hemodialysis patients. Journal of Pain and Symptom Management 2010;39(3):477–85. [published Online First: 2010/03/23] pmid:20303025
- 8. Davison SN, Jhangri GS, Johnson JA. Cross-sectional validity of a modified Edmonton symptom assessment system in dialysis patients: a simple assessment of symptom burden. Kidney International 2006;69(9):1621–5. [published Online First: 2006/05/05] pmid:16672923
- 9. Davison SN, Jhangri GS, Johnson JA. Longitudinal validation of a modified Edmonton symptom assessment system (ESAS) in haemodialysis patients. Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association—European Renal Association 2006;21(11):3189–95. [published Online First: 2006/09/08] pmid:16957010
- 10. Kimmel PL, Emont SL, Newmann JM, et al. ESRD patient quality of life: symptoms, spiritual beliefs, psychosocial factors, and ethnicity. American Journal of Kidney Diseases: The Official Journal of the National Kidney Foundation 2003;42(4):713–21. [published Online First: 2003/10/02] pmid:14520621
- 11. Leinau L, Murphy TE, Bradley E, et al. Relationship between conditions addressed by hemodialysis guidelines and non-ESRD-specific conditions affecting quality of life. Clinical Journal of the American Society of Nephrology: CJASN 2009;4(3):572–8. [published Online First: 2009/03/06] pmid:19261828
- 12. Weisbord SD, Carmody SS, Bruns FJ, et al. Symptom burden, quality of life, advance care planning and the potential value of palliative care in severely ill haemodialysis patients. Nephrology, Dialysis, Transplantation: Official Publication of the European Dialysis and Transplant Association—European Renal Association 2003;18(7):1345–52. [published Online First: 2003/06/17] pmid:12808172
- 13. Weisbord SD, Fried LF, Arnold RM, et al. Prevalence, severity, and importance of physical and emotional symptoms in chronic hemodialysis patients. Journal of the American Society of Nephrology: JASN 2005;16(8):2487–94. [published Online First: 2005/06/25] pmid:15975996
- 14. Gamondi C, Galli N, Schonholzer C, et al. Frequency and severity of pain and symptom distress among patients with chronic kidney disease receiving dialysis. Swiss Medical Weekly 2013;143:w13750. [published Online First: 2013/02/28] pmid:23443906
- 15. Vuckovic S, Srebro D, Vujovic KS, et al. Cannabinoids and Pain: New Insights From Old Molecules. Frontiers in Pharmacology 2018;9:1259. pmid:30542280
- 16. Gorelick D, Saxon A, Hermann R. Cannabis use and disorder: Pathogenesis and pharmacology. 2018; 2018(June).
- 17. Pertwee RG, Cannabis and Cannabinoids: Pharmacology and tationale for clinical use. Pharmacy and Pharmacology Communications 1997;3(11):539–45.
- 18. Anthony AT, Rahmat S, Sangle P, et al. Cannabinoid Receptors and Their Relationship With Chronic Pain: A Narrative Review. Cureus 2020;12(9):e10436. [published Online First: 2020/10/20] pmid:33072446
- 19. Guindon J, Hohmann AG. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. British Journal of Pharmacology 2008;153(2):319–34. [published Online First: 2007/11/13] pmid:17994113
- 20. Portenoy R and Dhingra L. Assessment of cancer pain. 2017.
- 21. Treede RD, et al., A classification of chronic pain for ICD-11. PAIN, 2015. 156(6): p. 1003–7.
- 22. Bennett M.I, Kaasa S, Barke A, et al., The IASP classification of chronic pain for ICD-11: chronic cancer-related pain. PAIN, 2019. 160(1): p. 38–44. pmid:30586069
- 23. 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–e96. [published Online First: 2017/09/22] pmid:28934780
- 24. Meng H, Johnston B, Englesakis M, et al. Selective cannabinoids for chronic neuropathic pain: a systematic review and meta-analysis. Anesthesia and Analgesia 2017;125(5):1638–52. [published Online First: 2017/05/26] pmid:28537982
- 25. Boychuk DG, Goddard G, Mauro G, et al. The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain: a systematic review. Journal of Oral & Facial Pain and Headache 2015;29(1):7–14. [published Online First: 2015/01/31] pmid:25635955
- 26. Martin-Sanchez E, Furukawa TA, Taylor J, et al. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Medicine (Malden, Mass) 2009;10(8):1353–68. [published Online First: 2009/09/08] pmid:19732371
- 27. Mucke M, Phillips T, Radbruch L, et al. Cannabis-based medicines for chronic neuropathic pain in adults. The Cochrane Database of Systematic Reviews 2018;3:Cd012182. [published Online First: 2018/03/08] pmid:29513392
- 28. Campbell FA, Tramèr MR, Carroll D, et al. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ (Clinical research ed) 2001;323(7303):13–16. pmid:11440935
- 29. Deshpande A, Mailis-Gagnon A, Zoheiry N, et al. Efficacy and adverse effects of medical marijuana for chronic noncancer pain: Systematic review of randomized controlled trials. Canadian Family Physician 2015;61(8):e372–81. [published Online First: 2015/10/28] pmid:26505059
- 30. Lynch M, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. British Journal of Clinical Pharmacology 2011;72(5):735–44. [published Online First: 2011/03/24] pmid:21426373
- 31. Walitt B, Klose P, Fitzcharles MA, et al. Cannabinoids for fibromyalgia. The Cochrane Database of Systematic Reviews 2016;7:Cd011694. [published Online First: 2016/07/19] pmid:27428009
- 32. Banerjee S. and McCormack S., CADTH rapid response reports, in medical cannabis for the treatment of chronic pain: A review of clinical effectiveness and guidelines. 2019, Canadian Agency for Drugs and Technologies in Health.
- 33. Barakji J.A., et al., Cannabinoids versus placebo or no intervention for pain: protocol for a systematic review with meta-analysis and trial sequential analysis. BMJ Open, 2019. 9(10): p. e031574. pmid:31676655
- 34. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLOS Medicine 2009;6(7):e1000097. pmid:19621072
- 35. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH) adopts consolidated guideline on good clinical practice in the conduct of clinical trials on medicinal products for human use. International Digest of Health Legislation 1997;48(2):231–4. [published Online First: 1997/01/01] pmid:11656783
- 36.
Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions version 5.1.0. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org or www.handbook.cochrane.org
- 37. Shafshak TS, Elnemr R. The visual analogue scale versus numerical rating scale in measuring pain severity and predicting disability in low back pain. J Clin Rheumatol 2020 [published Online First: 2020/01/28] pmid:31985722
- 38. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 2002;21(11):1539–58. [published Online First: 2002/07/12] pmid:12111919
- 39. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ (Clinical research ed) 2003;327(7414):557–60. [published Online First: 2003/09/06] pmid:12958120
- 40. Harbord RM, Egger M, Sterne JA. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Statistics in Medicine 2006;25(20):3443–57. [published Online First: 2005/12/14] pmid:16345038
- 41. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ (Clinical research ed) 1997;315(7109):629–34. [published Online First: 1997/10/06] pmid:9310563
- 42.
Review Manager (RevMan) [program]. 5.3 version: Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
- 43.
StataCorp: Stata: Release 14 [program]: College Station, TX: StataCorp LP., 2014.
- 44. DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials 1986;7(3):177–88. [published Online First: 1986/09/01] pmid:3802833
- 45. DeMets DL. Methods for combining randomized clinical trials: strengths and limitations. Statistics in Medicine 1987;6(3):341–50. [published Online First: 1987/04/01] pmid:3616287
- 46. Jakobsen JC, Wetterslev J, Winkel P, et al. Thresholds for statistical and clinical significance in systematic reviews with meta-analytic methods. BMC Medical Research Methodology 2014;14:120. [published Online First: 2014/11/25] pmid:25416419
- 47. Wetterslev J, Jakobsen JC, Gluud C. Trial Sequential Analysis in systematic reviews with meta-analysis. BMC Med Res Methodol 2017;17(1):39. [published Online First: 2017/03/08] pmid:28264661
- 48. Schünemann H, Brożek J, Guyatt G, et al. GRADE handbook for grading quality of evidence and strength of recommendations. The GRADE Working Group 2013.
- 49. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strenght of recommendations. BMJ 2008;336:924–26.
- 50. Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 2007;68(7):515–21. pmid:17296917
- 51. Abrams DI, Couey P, Dixit N, et al. Effect of inhaled cannabis for pain in ddults with sickle cell disease: a randomized clinical trial. JAMA network open 2020;3(7):e2010874–. pmid:32678452
- 52. Almog S, Aharon-Peretz J, Vulfsons S, et al. The pharmacokinetics, efficacy, and safety of a novel selective-dose cannabis inhaler in patients with chronic pain: a randomized, double-blinded, placebo-controlled trial. European Journal of Pain (United Kingdom) 2020;24(8):1505–16. pmid:32445190
- 53. Aronow WS, Cassidy J. Effect of marihuana and placebo-marihuana smoking on angina pectoris. 1974.
- 54. Beaulieu P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Canadian Journal of Anaesthesia 2006;53(8):769–75. pmid:16873343
- 55. Bebee B, Taylor DM, Bourke E, et al. The CANBACK trial: a randomised, controlled clinical trial of oral cannabidiol for people presenting to the emergency department with acute low back pain. Medical Journal of Australia 2021;214(8):370–75. pmid:33846971
- 56. Berman JS, Symonds C, Birch R. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain 2004;112(3):299–306. pmid:15561385
- 57. Blake DR, Robson P, Ho M, et al. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford, England) 2006;45(1):50–52. pmid:16282192
- 58. Buggy DJ, Toogood L, Maric S, et al. Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain 2003;106(1–2):169–72. pmid:14581124
- 59. Collin C, Ehler E, Waberzinek G, et al. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res 2010;32(5):451–9. [published Online First: 2010/03/24] pmid:20307378
- 60. Colwill AC, Alton K, Bednarek PH, et al. Cannabinoids for pain control during medical abortion: a randomized controlled trial. Obstetrics and Gynecology 2020;135(6):1289–95. pmid:32459420
- 61. Conte A, Bettolo CM, Onesti E, et al. Cannabinoid-induced effects on the nociceptive system: a neurophysiological study in patients with secondary progressive multiple sclerosis. European Journal of Pain (London, England) 2009;13(5):472–7. pmid:18603457
- 62. Corey-Bloom J, Wolfson T, Gamst A, et al. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ: Canadian Medical Association Journal 2012;184(10):1143–50. https://dx.doi.org/10.1503/cmaj.110837
- 63. Cote M, Trudel M, Wang C, et al. Improving quality of life with nabilone during radiotherapy treatments for head and neck cancers: a randomized double-blind placebo-controlled trial. The Annals of Otology, Rhinology, and Laryngology 2016;125(4):317–24. pmid:26503964
- 64. de Vries M, van Rijckevorsel DCM, Vissers KCP, et al. Tetrahydrocannabinol does not reduce pain in patients with chronic abdominal pain in a phase 2 placebo-controlled study. Clinical Gastroenterology and Hepatology: The Official Clinical Practice Journal of the American Gastroenterological Association 2017;15(7):1079–86.e4. pmid:27720917
- 65. de Vries M, Van Rijckevorsel DCM, Vissers KCP, et al. Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability. British Journal of Clinical Pharmacology 2016;81(3):525–37. pmid:26505163
- 66. Eibach L, Scheffel S, Cardebring M, et al. Cannabidivarin for HIV-Associated Neuropathic Pain: a randomized, blinded, controlled clinical trial. Clinical Pharmacology and Therapeutics pmid:32770831
- 67. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology 2009;34(3):672–80. pmid:18688212
- 68. Fallon MT, Albert Lux E, McQuade R, et al. Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies. Br J Pain. 2017 Aug;11(3):119–133. pmid:28785408
- 69. Hunter D, Oldfield G, Tich N, et al. Synthetic transdermal cannabidiol for the treatment of knee pain due to osteoarthritis. Osteoarthritis and Cartilage 2018;26:S26–.
- 70. Issa MA, Narang S, Jamison RN, et al. The subjective psychoactive effects of oral dronabinol studied in a randomized, controlled crossover clinical trial for pain. The Clinical Journal of Pain 2014;30(6):472–8. pmid:24281276
- 71. Jain AK, Ryan JR, McMahon FG, et al. Evaluation of intramuscular levonantradol and placebo in acute postoperative pain. Journal of Clinical Pharmacology 1981;21(S1):320S–26S. pmid:7028791
- 72. Jochimsen PR, Lawton RL, VerSteeg K, et al. Effect of benzopyranoperidine, a delta-9-THC congener, on pain. Clinical Pharmacology and Therapeutics 1978;24(2):223–7. pmid:354840
- 73. Johnson JR, Burnell-Nugent M, Lossignol D, et al. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. Journal of Pain and Symptom Management 2010;39(2):167–79. pmid:19896326
- 74. Kalliomaki J, Segerdahl M, Webster L, et al. Evaluation of the analgesic efficacy of AZD1940, a novel cannabinoid agonist, on post-operative pain after lower third molar surgical removal. Scandinavian Journal of Pain 2013;4(1):17–22. pmid:29913883
- 75. Kantor TG, Hopper MD. A study of levonantradol, a cannabinol derivative, for analgesia in post operative pain. Pain 1981;10(Suppl. 1):S37.
- 76. Karst M, Salim K, Burstein S, et al. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA 2003;290(13):1757–62. pmid:14519710
- 77. Killestein J, Hoogervorst EL, Reif M, et al. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology 2002;58(9):1404–07. pmid:12011290
- 78. Langford RM, Mares J, Novotna A, et al. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis. Journal of Neurology 2013;260(4):984–97. pmid:23180178
- 79. Leocani L, Nuara A, Houdayer E, et al. Effect of THC-CBD oromucosal spray (Sativex) on measures of spasticity in multiple sclerosis: A doubleblind, placebo-controlled, crossover study. Multiple Sclerosis (Houndmills, Basingstoke, England) 2014; Conference:: September 2014. http://dx.doi.org/10.1177/1352458514547847
- 80. Levin DN, Dulberg Z, Chan A-W, et al. A randomized-controlled trial of nabilone for the prevention of acute postoperative nausea and vomiting in elective surgery. Une etude randomisee controlee pour evaluer l’efficacite du nabilone pour la prevention des nausees et vomissements postoperatoires aigus lors de chirurgie non urgente Can J Anaesth. 2017 Apr;64(4):385–395. https://dx.doi.org/10.1007/s12630-017-0814-3
- 81. Lichtman AH, Lux EA, McQuade R, et al. Results of a double-blind, randomized, placebo-controlled study of nabiximols oromucosal spray as a adjunctive therapy in advanced cancer patients with chronic uncontrolled pain. J Pain Symptom Manage. 2018 Feb;55(2):179–188.e1. pmid:28923526
- 82. Lynch ME, Cesar-Rittenberg P, Hohmann AG. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. Journal of Pain and Symptom Management 2014;47(1):166–73. pmid:23742737
- 83. Malik Z, Bayman L, Valestin J, et al. Dronabinol increases pain threshold in patients with functional chest pain: a pilot double-blind placebo-controlled trial. Diseases of the Esophagus: Official Journal of the International Society for Diseases of the Esophagus 2017;30(2):1–8. pmid:26822791
- 84. Markova J. Sativex® as Add-on therapy Vs. further optimized first-line ANTispastics (SAVANT) in resistant multiple sclerosis spasticity double blind randomized clinical trial. Multiple sclerosis Journal 2017;23(3):990–.
- 85. Narang S, Gibson D, Wasan AD, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. The Journal of Pain: Official Journal of the American Pain Society 2008;9(3):254–64. pmid:18088560
- 86.
NCT01606202. ClinicalTrials Gov, National Institutes of Health [http://wwwclinicaltrials.gov], 2012.
- 87. Nurmikko TJ, Serpell MG, Hoggart B, et al. Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial. Pain 2007;133(1–3):210–20. pmid:17997224
- 88. Ostenfeld T, Price J, Albanese M, et al. A randomized, controlled study to investigate the analgesic efficacy of single doses of the cannabinoid receptor-2 agonist GW842166, ibuprofen or placebo in patients with acute pain following third molar tooth extraction. Clinical Journal of Pain 2011;27(8):668–76. pmid:21540741
- 89. Portenoy RK, Ganae-Motan ED, Allende S, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. Journal of Pain 2012;13(5):438–49. pmid:22483680
- 90. Riva N, Mora G, Soraru G, et al. The CANALS study: a randomized, double-blind, placebo-controlled, multicentre study to assess the safety and efficacy on spasticity symptoms of a Cannabis Sativa extract in motor neuron disease patients. The Lancet Neurology 2016;18(2).
- 91. Rog DJ, Nurmikko TJ, Friede T, et al. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 2005;65(6):812–19. pmid:16186518
- 92. Schimrigk S, Marziniak M, Neubauer C, et al. Dronabinol is a safe long-term treatment option for neuropathic pain patients. European Neurology 2017;78(5–6):320–29. RTY—Journal articles. pmid:29073592
- 93. Selvarajah D, Gandhi R, Emery CJ, et al. Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy: depression is a major confounding factor. Diabetes Care 2010;33(1):128–30. pmid:19808912
- 94. Serpell MG, Notcutt W, Collin C. Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis. Journal of Neurology 2013;260(1):285–95. pmid:22878432
- 95. Skrabek RQ, Galimova L, Ethans K, et al. Nabilone for the treatment of pain in fibromyalgia. Journal of Pain 2008;9(2):164–73. pmid:17974490
- 96. Stambaugh JD. Comparison of the analgesic effect of parenteral levonantradol to morphine and placebo in patients with moderate to severe pain of cancer. Pain 1981;10(Suppl. 1):S97.
- 97. Staquet M, Gantt C, Machin D. Effect of a nitrogen analog of tetrahydrocannabinol on cancer pain. Clinical pharmacology and therapeutics 1978;23(4):397–401. pmid:343969
- 98. Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ (Clinical research ed) 2004;329(7460):253. pmid:15258006
- 99. Toth C, Mawani S, Brady S, et al. An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. Pain 2012;153(10):2073–82. pmid:22921260
- 100. Turcott JG, Del Rocio Guillen Nunez M, Flores-Estrada D, et al. The effect of nabilone on appetite, nutritional status, and quality of life in lung cancer patients: a randomized, double-blind clinical trial. Supportive Care in Cancer 2018;26(9):3029–38. pmid:29550881
- 101. Turcotte D, Doupe M, Torabi M, et al. Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial. Pain Medicine (Malden, Mass) 2015;16(1):149–59. pmid:25288189
- 102. van Amerongen G, Kanhai K, Baakman AC, et al. Effects on spasticity and neuropathic pain of an oral formulation of Delta-9-tetrahydrocannabinol in patients with progressive multiple sclerosis. Clinical Therapeutics 2018;40(9):1467–82.
- 103. van de Donk T, Niesters M, Kowal MA, et al. An experimental randomized study on the analgesic effects of pharmaceutical-grade cannabis in chronic pain patients with fibromyalgia. Pain 2019;160(4):860–69. pmid:30585986
- 104. Vela J, Dreyer L, Petersen KK, et al. Cannabidiol treatment in hand osteoarthritis and psoriatic arthritis: a randomized, double-blind placebo-controlled trial. Pain 2021 pmid:34510141
- 105. Wade DT, Robson P, House H, et al. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clinical Rehabilitation 2003;17(1):21–9. pmid:12617376
- 106. Wade DT, Makela P, Robson P, et al. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Multiple Sclerosis (Houndmills, Basingstoke, England) 2004;10(4):434–41. pmid:15327042
- 107. Wallace MS, Marcotte TD, Umlauf A, et al. Efficacy of inhaled cannabis on painful diabetic neuropathy. The Journal of Pain: Official Journal of the American Pain Society 2015;16(7):616–27. pmid:25843054
- 108. Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ: Canadian Medical Association Journal 2010;182(14):E694–701. pmid:20805210
- 109. Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. The journal of pain: Official Journal of the American Pain Society 2008;9(6):506–21. pmid:18403272
- 110. Wissel J, Haydn T, Muller J, et al. Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain: a double-blind placebo-controlled cross-over trial. Journal of Neurology 2006;253(10):1337–41. pmid:16988792
- 111. Zajicek J, Fox P, Sanders H, et al. Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study): multicentre randomised placebo-controlled trial. Lancet (London, England) 2003;362(9395):1517–26. pmid:14615106
- 112. Zajicek John P, Hobart Jeremy C, Slade A, et al. MUltiple Sclerosis and Extract of Cannabis: results of the MUSEC trial. Journal of Neurology Neurosurgery & Psychiatry 2012(11):1125. pmid:22791906
- 113.
European Medicines Agency. Guideline on multiplicity issues in clinical trials. In: Committee for Human Medicinal Products, ed., 2017.
- 114. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. JAMA 2015;313(24):2456–73. pmid:26103030
- 115. Iskedjian M, Bereza B, Gordon A, et al. Meta-analysis of cannabis based treatments for neuropathic and multiple sclerosis-related pain. Current Medical Research and Opinion 2007;23(1):17–24. pmid:17257464
- 116. IASP Presidential Task Force on Cannabis: International Association for the Study of Pain presidential task force on cannabis and cannabinoid analgesia position statement. PAIN, 2021. 162.
- 117. Stevens AJ, Higgins MD. A systematic review of the analgesic efficacy of cannabinoid medications in the management of acute pain. Acta anaesthesiologica Scandinavica 2017;61(3):268–80. [published Online First: 2017/01/17] pmid:28090652
- 118. Boland EG, Bennett MI, Allgar V, et al. Cannabinoids for adult cancer-related pain: systematic review and meta-analysis. BMJ supportive & palliative care 2020;10(1):14–24. pmid:31959586
- 119. Abdallah FW, Hussain N, Weaver T, et al. Analgesic efficacy of cannabinoids for acute pain management after surgery: a systematic review and meta-analysis. Reg Anesth Pain Med 2020;45(7):509–19. [published Online First: 2020/05/31] pmid:32471924
- 120. Olsen MF, Bjerre E, Hansen MD, et al. Pain relief that matters to patients: systematic review of empirical studies assessing the minimum clinically important difference in acute pain. BMC Medicine 2017;15(1):35. [published Online First: 2017/02/22] pmid:28215182
- 121. Olsen MF, Bjerre E, Hansen MD, et al. Minimum clinically important differences in chronic pain vary considerably by baseline pain and methodological factors: systematic review of empirical studies. Journal of Clinical Epidemiology 2018;101:87–106.e2. [published Online First: 2018/05/25] pmid:29793007
- 122. Savovic J, Jones H, Altman D, et al. Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: combined analysis of meta-epidemiological studies. Health Technology Assessment (Winchester, England) 2012;16(35):1–82. [published Online First: 2012/09/20] pmid:22989478
- 123. Schulz KF, Chalmers I, Hayes RJ, et al. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408–12. [published Online First: 1995/02/01] pmid:7823387
- 124. Moher D, Cook DJ, Eastwood S, et al. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet (London, England) 1999;354(9193):1896–900. [published Online First: 1999/12/10] pmid:10584742
- 125. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Annals of Internal Medicine 2001;135(11):982–9. [published Online First: 2001/12/04] pmid:11730399
- 126. Gluud LL, Thorlund K, Gluud C, et al. Correction: reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Annals of Internal Medicine 2008;149(3):219. [published Online First: 2008/10/23] pmid:18942172
- 127. Wood L, Egger M, Gluud L, et al. Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study. BMJ (Clinical research ed) 2008;336(7644):601–05. pmid:18316340
- 128. Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. The Cochrane Database of Systematic Reviews 2012;12:Mr000033. [published Online First: 2012/12/14] pmid:23235689
- 129. Hjermstad MJ, Fayers PM, Haugen DF, et al. Studies comparing Numerical Rating Scales, Verbal Rating Scales, and Visual Analogue Scales for assessment of pain intensity in adults: a systematic literature review. Journal of Pain and Symptom Management 2011;41(6):1073–93. [published Online First: 2011/05/31] pmid:21621130
- 130. Hagg O, Fritzell P, Nordwall A. The clinical importance of changes in outcome scores after treatment for chronic low back pain. European Spine Journal: Official Publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society 2003;12(1):12–20. [published Online First: 2003/02/20] pmid:12592542
- 131. Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal clinically important difference. Controlled Clinical Trials 1989;10(4):407–15. [published Online First: 1989/12/01] pmid:2691207
- 132. Crosby RD, Kolotkin RL, Williams GR. Defining clinically meaningful change in health-related quality of life. Journal of Clinical Epidemiology 2003;56(5):395–407. [published Online First: 2003/06/19] pmid:12812812
- 133.
The European Monitoring Centre for Drugs and Drug Addiction,. Medical use of cannabis and cannabinoids. Publications Office of the European Union, Luxembourg, Dec. 2018. https://www.emcdda.europa.eu/system/files/publications/10171/20185584_TD0618186ENN_PD F.pdf
- 134. Freckelton I. Medicinal cannabis law reform: lessons from canadian litigation. J Law Med 2015;22(4):719–38. [published Online First: 2015/09/10] pmid:26349373
- 135. Ablin J, Ste-Marie PA, Schäfer M, et al. Medical use of cannabis products: Lessons to be learned from Israel and Canada. Schmerz 2016;30(1):3–13. [published Online First: 2016/01/16] pmid:26767992
- 136.
National Academies of Sciences E, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. washington, DC: The National Academies Press., 2017.