A systematic review was performed to identify all randomised controlled trials (RCTs) of cannabinoids compared with placebo or other active agents for the treatment of cancer-related pain in adults. A meta-analysis was performed to determine cannabinoid effectiveness and adverse effects, including dropouts. A recent systematic review and meta-analysis that assessed the efficacy, tolerability and safety of medical cannabis and cannabis-based medicines for cancer pain reported very low quality evidence for a non-significant 50% reduction in pain (p=0.82). 8 This work supplements the systematic review by Häuser et al. 8 The current systematic review has a broader search strategy, and authors were contacted to provide additional findings and information on study design. The primary outcome in this systematic review was the absolute change in mean pain intensity, which is a more sensitive outcome than a dichotomous outcome, for example, proportion of participants who report a pain relief of 50% or greater from baseline to end of study. 9 10 The aim was to determine the beneficial and adverse effects of cannabinoids compared with placebo or other active agents for the treatment of cancer-related pain in adults from RCTs.

Patients with cancer use cannabinoids. An anonymous survey (2040 out of 3138 surveys (65%) were returned) in Canada showed that 356 (18%) patients reported cannabis use within the preceding 6 months. Of these, 80% acquired cannabis through friends and 46% of patients used it for cancer-related pain. 6 In another anonymous survey of adult patients with cancer in a cancer centre in a US state with legalised cannabis, random urine testing of sampled participants was used. 7 The response rate was 34% (926/2737); of these, 21% had used cannabis in the last month, most frequently for pain. 7

Cancer-related pain is common, occurring in up to 60% of patients undergoing anti-cancer therapy and 90% of those with advanced disease. 1 There is an increased recent interest in cannabinoids (including cannabis) for pain management along with more permissive legislative changes in many countries. 2 3 The medicinal use of cannabis is already legal in 40 countries and 29 US states. 4 The WHO guidelines for the pharmacological and radiotherapeutic management of cancer pain in adults and adolescents suggest that data analysis is needed on cannabinoids for cancer pain. 5

Where the analysis indicated significant heterogeneity, a random-effects model was chosen, otherwise a fixed-effects model was applied. Statistical heterogeneity was assessed using Cochran’s Q test. Cochran’s Q tests the presence versus the absence of heterogeneity and the p value is stated. The I 2 index describes the percentage of variation across studies that is due to heterogeneity rather than chance. Interpretation is as follows: low, moderate and high to I 2 values of 25%, 50% and 75%, respectively. 15 The importance of the observed value of I 2 depends on (1) magnitude and direction of effects and (2) strength of evidence for heterogeneity (eg, p value from the χ 2 test or a CI for I 2 ). A funnel plot was used to test for publication bias.

For the meta-analysis, the difference in the mean change from the randomisation baseline to the end of treatment in average pain NRS score was calculated and 95% CI was calculated for each study. Data on the numbers of patients experiencing adverse events for each group, the OR and 95% CI were calculated for each study adverse event. The mean difference or ORs were pooled using a fixed-effect model or random-effects model (the Mantel-Haenszel method) and the corresponding 95% CIs were calculated.

Assessment of risk of study bias was independently assessed by two authors (EGB and JWB) using the Cochrane Collaboration risk of bias tool for RCTs which graded the risk of bias as high, low or unclear in six domains (Selection bias: random sequence generation and allocation concealment; Performance bias: blinding of participant and personnel; Detection bias: blinding of outcome assessment; Attrition bias: incomplete outcome data; Reporting bias: selective reporting). 14 Disagreement at all stages was resolved by consensus and with recourse to a third review author (MIB). When this information was not available in the publication, authors were contacted.

Two authors (EGB and JWB) independently extracted data from each included paper regarding study aims/objectives, design, patient population, intervention (cannabinoid used and dose), comparator, clinical outcome measures (eg, pain) and results (association between cannabinoid use and pain and reported adverse events). Disagreement was resolved by consensus and with recourse to a third review author (MIB). When data were not reported in full, authors were contacted for additional information.

Disagreement at all stages was resolved by consensus and with recourse to a third review author (MIB). If a study was rejected at the full-text stage, a reason was given. The results of these searches and selections are shown in the PRISMA flow diagram ( figure 1 ). 12

Two authors (EGB and JWB) independently reviewed all titles and abstracts (in duplicate) to assess their relevance for inclusion. Full-text papers were retrieved for those fulfilling the criteria and also for those publications for which the ability to assess their eligibility could not be assessed on the basis of the titles and abstracts alone. EGB and JWB then independently assessed the full texts of all potentially relevant studies.

Studies were excluded if they did not meet the eligibility criteria ( table 1 ). Studies conducted in patients undergoing surgery, healthy volunteers or animals were excluded from this systematic review as these groups have different cannabinoid usage (duration, administration schedule) compared with patients on cannabinoids for cancer pain. Studies other than RCTs potentially have too much bias to be included. Studies not having pain as the primary outcome were not included as they would not be designed or powered to determine the effect of cannabinoids on pain.

Cochrane protocols determining studies for inclusion were followed, only including studies where the whole patient population had cancer pain. If this was not the case but results were presented separately for the cancer pain subgroup, the study and extracted data for the target subgroup were included.

Studies were included if they were RCTs which assessed the effect of cannabinoids (THC:CBD, THC extract, nabiximols, Sativex, medical cannabis) compared with placebo or other active agents for the treatment of cancer-related pain in adults, with pain as the primary outcome ( table 1 ).

In addition to the electronic search, reference lists from reviews on cannabis/cannabinoids to treat cancer pain were manually searched as were identified publications. Experts in the field were consulted to ensure that no articles were missed. Unpublished studies were also included in the search. When only a conference abstract was available and the full study was unpublished, authors were contacted to try to ascertain further information. No language date or publication type restrictions were applied to the search.

In August 2018, the following electronic databases were searched: Embase (Ovid); Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations; PsycINFO (Ovid); Conference Proceedings Citation Index–Science (Web Of Science; Thomson Reuters, New York City, NY); ClinicalTrials.gov (US NIH); ISRCTN registry (BMC); Cochrane Database of Systematic Reviews (Wiley); Cochrane Central Register of Controlled Trials (Wiley); Database of Abstracts of Reviews of Effect (Wiley). All searches were repeated on 1 August 2019 to ensure that there were no further publications since the original searches.

Strategies were devised to be inclusive of all potentially relevant studies using both Medical Subject Heading (MeSH) terms and text word searches to increase the search sensitivity. Terms for “cannabis/cannabinoids”, “cancer/neoplasms” and “pain” were combined to identify relevant studies. The search terms for cannabinoids included individual drug names and generic terms “cannabinoids” and “cannabis”. The cancer search included the MeSH term “exp neoplasms/” and text word searches for synonyms for cancer. The “pain” search included terms and synonyms for pain. The Embase search strategy is included as an online supplementary file . Search strategies from all other databases are available on request from the authors.

This systematic review was prepared according to the recommendations in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) statement 11 and was conducted/reported following an a priori protocol according to the PRISMA guidelines. 12

In Johnson et al, dropouts due to adverse events were 16.7% in the THC:CBD group and 5% in the placebo group. 16 In Portenoy et al, adverse event discontinuations were dose related: 19.8% in all patients on nabiximols and 17.6% in the placebo group. 17 In study 1 by Fallon et al, 19% Sativex patients and 14.6% placebo patients discontinued due to adverse events. 18 In study 2 by Fallon et al, during the 2-week single-blind Sativex titration period, 17.5% patients discontinued Sativex due to adverse events. 18 In the treatment period, 20.4% withdrew from the Sativex group and 12.6% withdrew from the placebo group. 18 In Lichtman et al, discontinuation due to adverse events was 20.1% in the Sativex group and 17.7% in the placebo group. 19 No treatment-related deaths were reported in any study. Figure 5 shows the dropouts due to adverse events which shows a higher odds of dropouts due to adverse events in the cannabinoid group (OR 1.33 (0.95 to 1.85, p=0.10)), but not statistically significant. In the meta-analysis, only the low dose (1–4 sprays) was used from Portenoy et al for consistency with the pain score meta-analysis.

The meta-analysis shows a higher odds of somnolence (OR 2.69 (1.54 to 4.71), p<0.001) and dizziness (OR 1.58 (0.99 to 2.51), p=0.05) in the cannabinoid group ( figure 4 ). 16–19 There was also a higher odds of nausea (OR 1.41 (0.97 to 2.05), p=0.08) and vomiting in the cannabinoid group (OR 1.34 (0.85 to 2.11, p=0.21)), but these were not statistically significant ( figure 4 ). 16–19

All studies reported on adverse events ( table 3 ). Dizziness, nausea, vomiting, somnolence and fatigue were the main reported adverse events. In general, cannabinoids were reported to have a higher risk of adverse events compared with placebo. Fallon et al, Lichtman et al and Portenoy et al reported only the adverse events in ≥5% of patients. 17–19 In Johnson et al, it is only those reported in three or more patients. 16 Lynch et al reported more adverse events compared with placebo, but as this study only included people with chronic neuropathic pain and was a small pilot study, it was not included in the meta-analysis. 20 In the meta-analysis, only the low dose (1–4 sprays) was used from Portenoy et al for consistency with the pain score meta-analysis.

The meta-analysis is shown in figure 2 . There was no difference between cannabinoids and placebo for the difference in the change in average NRS pain scores: mean difference −0.21 (−0.48 to 0.07, p=0.14). Including only phase III studies in the meta-analysis, there was no benefit from cannabinoid use: mean difference −0.02 (−0.21 to 0.16, p=0.80) ( figure 3 ). 18 19 The change in pain intensity was a secondary outcome in Portenoy et al; their primary outcome (30% reduction in baseline pain) was not statistically different between cannabinoids and placebo (p=0.59). 17 In Portenoy et al, data were not available for the mean pain difference of all three doses combined, 17 so only the low dose (1–4 sprays) was used in the meta-analysis as this was the most effective dose.

Change in pain intensity was the primary outcome of interest in this systematic review. Change in pain intensity was the primary outcome in the studies of Johnson et al, 16 Fallon et al 18 and Lichtman et al, 19 and a secondary outcome in Portenoy et al. 17 Lynch et al measured change in the NRS for pain intensity and reported that there was no statistically significant difference between the treatment and the placebo groups, but as this study only included people with chronic neuropathic pain and was a small exploratory study, it was not included in the meta-analysis. 20

Quality assessment of included studies was performed using the Cochrane Risk of Bias Tool ( online supplementary table 1 ). The studies included were at low risk of bias. Although the studies were funded (or had medication supplied) by industry, and publication bias is more common when most of the published studies are funded by industry, taken in the context of the results, these are overall negative studies making publication bias less likely. The funnel plot ( online supplementary figure 1 ) showed that distribution was roughly symmetrical, indicating that publication bias was not likely to be present.

Studies used a pump-action oromucosal spray for medication delivery which used 1:1 THC:CBD extract versus placebo. Some studies had additional arms, for example, THC extract. 16 Dose titration differed between studies. Patients self-titrated to the optimal dose 16 20 or were randomly assigned to different doses. 17 In the phase III studies, patients titrated medication according to a pre-specified dose escalation protocol until they achieved pain relief, developed adverse events or reached the maximum dose of 10 sprays/day. 18 19

The small cross-over pilot randomised study (n=18) assessed nabiximols versus placebo for use for treatment of chemotherapy-induced neuropathic pain and reported no statistically significant difference between nabiximols and placebo on the NRS for pain intensity: mean pretreatment score=6.75; and at the end of 4 weeks, nabiximols group score=6.00 while placebo group score=6.380. 20 However, further analysis in five patients who responded to treatment showed an average decrease of 2.6 on an 11-point NRS for pain intensity. 20

From the six included RCTs (two were reported in a single publication), one was a small cross-over pilot randomised study, two were phase II studies and three were phase III studies ( table 2 ). From the two early randomised double-blind phase II studies in patients with advanced cancer and pain unrelieved by opioids, 16 17 one reported that cannabinoids had analgesic effects, 16 and the primary outcome of the other was negative. 17 Subsequent to these studies, three phase III placebo RCTs with a similar methodology have been reported. Data from two RCTs were reported in a single publication, with the primary efficacy endpoints (percent improvement (study 1) and mean change (study 2) in average daily pain NRS scores). 18 Neither these nor the third RCT (primary endpoint: per cent change in the average pain NRS score) 19 reported a positive effect of nabiximols compared with placebo on their primary endpoints. These studies had a low risk of bias.

We identified 2805 unique records of which six RCTs were included in this systematic review. Due to the heterogeneous nature of some of these studies (in study design, duration/dose of cannabinoid administered, timing of outcome measurement), five studies were included in a meta-analysis (representing a total of 1442 participants) and six studies were included in a narrative analysis (representing a total of 1460 participants).

Discussion

Studies with a low risk of bias showed that for adults with advanced cancer, the addition of cannabinoids to opioids did not reduce cancer pain compared with placebo. This work complements and builds on the systematic review by Häuser et al.8 Although the same overall conclusions were attained, this systematic review and meta-analysis is based on additional methodological information and thus supported by higher-quality evidence (as included studies were deemed to have lower risk of bias). Furthermore, the primary outcome in this systematic review is a more sensitive outcome to detect minimal changes in pain.9 This systematic review provides good evidence that cannabinoids do not have a role in cancer-related pain.

In all the included RCTs, pain was the primary reason for administering cannabinoids and change in pain score or pain intensity was the primary outcome. Five RCTs were included in the meta-analysis (n=1442) where cannabinoids were given as an adjuvant treatment in addition to their existing stable dose of opioids. In the meta-analysis, the two phase II studies and three phase III studies included patients with chronic cancer pain (average pain duration of all studies of 1.2–2.0 years), with an average pain ≥4 and ≤8 on 0–10 NRS pain score, who were on regular opioids, randomised to the same THC:CBD medication and had a placebo comparator.

Five trials from four publications in the 1970s (including a total of 128 participants) were excluded as these were single-dose studies, assessing short-term effects of cannabinoids at 6–7 hours.21–24 Four of these studies evaluated delta-9-tetrahydrocannabinol (THC) or nitrogen-containing benzopyran derivative, modification of delta-1-trans-tetrahydrocannabinol (NIB).21 22 24 The fifth study used the cannabinoid benzopyranoperidine.23 Of these five single-dose studies assessing efficacy at 6–7 hours, three used THC or NIB and reported no different in efficacy compared with codeine.21 22 24 The fifth study used the cannabinoid benzopyranoperidine and reported that about 30% of patients had increased pain intensity with this drug.23

Side effects Cannabinoids are associated with short-term adverse effects including drowsiness, dizziness, confusion, hallucinations, euphoria, nausea and vomiting, and diarrhoea.25 A systematic review evaluating the adverse effects of medical cannabinoids reported patients using medical cannabinoids had 1.86 times higher risk of non-serious adverse effects compared with controls while there was no significant difference between serious adverse effects.26 Our analysis echoed this, showing that in general cannabinoids were reported to have a higher risk of adverse events compared with placebo with somnolence and dizziness reaching statistical significance.