In observational studies with a comparison group, one small open-label study with a randomised withdrawal phase (n = 2680) found that nabilone was significantly more likely to produce a 30% reduction in pain relative to placebo (Table 4). In observational studies with no comparison group, the pooled prevalence of receiving cannabinoids reported achieving a 30% reduction in pain was 72% (95% CI 66%-78%) (Figure E5 and Appendix F, available online at http://links.lww.com/PAIN/A592).
Five of the 47 included RCTs assessed 50% reduction in pain, all of which provided sufficient data for meta-analysis. We found no significant evidence that cannabinoids reduced pain by 50% compared with placebo groups (OR 1.43, 95% CI 0.97-2.11, Table 4 and Table E1 and Figure E2 in Appendix E, available online at http://links.lww.com/PAIN/A592). We found no effect for any of the specific cannabinoids; however, among pain conditions, a significant effect was found for non–MS-related neuropathic pain (Table 4). No evidence of small study effects was detected (P = 0.12). No subgroup analysis was able to be conducted for overall study risk of bias, as all studies were classified as low risk. When examined by risk of bias due to sample size, effects were larger and had substantial uncertainty for studies of <100 participants per treatment arm compared with studies with 100+ participants, but all estimates fell within overlapping bounds of uncertainty and were nonsignificant (Figure E2.1.a, available online at http://links.lww.com/PAIN/A592). No differences were detected between studies with interventions of very short term (<4 weeks), short term (4-12 weeks), and intermediate term (13-26 weeks, Figures E2.1 and E2.2, available online at http://links.lww.com/PAIN/A592). All studies assessed outcomes using ITT analyses without imputation.
Two observational studies with a comparison group found evidence of a significant effect for 50% reduction in pain; however, the GRADE rating for this outcome was very low (Table 4 and Table E1 in Appendix E, available online at http://links.lww.com/PAIN/A592). Outcomes for observational studies with no comparison group were equivocal and are summarised narratively in Appendix F (available online at http://links.lww.com/PAIN/A592).
Of the 47 RCTs included in the review, 45 reported data on pain intensity, of which 30 (comprising 34 data points) reported sufficient data and were used in the meta-analysis for change in pain intensity. We found that cannabinoids overall produced a larger reduction in pain intensity than placebo groups (SMD −0.14, 95% CI −0.20 to −0.08, Table 4 and Table E1 and Figure E3 in Appendix E, available online at http://links.lww.com/PAIN/A592). We calculated this to be roughly equivalent to a reduction of 2.9 mm on a 100 mm VAS (95% CI −4.61 to −1.46) greater than placebo groups. Among the cannabinoids, there were significant effects for nabiximols and THC extract, both with a moderate GRADE rating (Table E1, available online at http://links.lww.com/PAIN/A592). We found an effect for neuropathic pain (MS and non–MS-related) and rheumatoid arthritis, but the latter was based on 1 small study and had a very low-grade rating (Table 4). No evidence of small study effects was detected (P = 0.49). Of the remaining 15 studies that assessed pain intensity but for which data were not reported or obtained from study authors, 12 reported a significant positive effect and 3 reported no benefit. When examined by overall risk of bias rating, the effect estimate remained significant for studies classified as low risk but was not significant for studies at unclear or high risk of bias (Figure E3.1, available online at http://links.lww.com/PAIN/A592), and effect sizes were larger for studies with smaller sample sizes (Figure E3.1a, available online at http://links.lww.com/PAIN/A592). When examined by study, intervention length effects seemed to dissipate with increasing study length: 1-day and very short term (<4 weeks) studies remained significant; however, studies conducted in the short (4-12 weeks), intermediate (13-26 weeks), or long term (>26 weeks) did not, with decreasing effect sizes as study length increased (Figure E3.2, available online at http://links.lww.com/PAIN/A592). The effect remained significant for studies using ITT analyses, however, was smaller and not significant for studies using last observation carried forward imputation methods, or where the handling of missing data was not reported (Figure E3.3, available online at http://links.lww.com/PAIN/A592).
In the observational studies with a comparison group, we found no significant evidence of effect for cannabinoids in reducing pain intensity (Table 4). A significant reduction in pain intensity was identified in within-person pre–post assessments of pain in observational studies with no comparison group (Appendix F, available online at http://links.lww.com/PAIN/A592). Five RCTs examined reductions in analgesic use. People taking nabiximols had a greater reduction in the frequency and quantity of use of rescue analgesics compared with placebo groups (SMD −0.13, 95% CI −0.26 to −0.01, I2 = 48%); this had a moderate GRADE rating.
No significant effect of cannabinoids on overall physical functioning in 18 RCTs, Table E2 and Figure E6 (available online at http://links.lww.com/PAIN/A592) or quality of life (n = 11 RCTs) compared with placebo groups was found (Table E2 and Figure E8, available online at http://links.lww.com/PAIN/A592). There was a significant effect of cannabinoids in reducing sleep problems when compared with placebo groups (SMD −0.29, 95% CI −0.40 to −0.19), but the GRADE assessment for this was low (Table E2 and Figure E7, available online at http://links.lww.com/PAIN/A592). We found a reduction in sleep problems when compared with placebo groups for nabiximols with a moderate GRADE rating (SMD −0.32, 95% CI −0.44 to −0.20, Table E3 in Appendix E, available online at http://links.lww.com/PAIN/A592). No small study effects were detected for any of these outcomes (P's range from 0.14 to 0.84).
Patients receiving any cannabinoids did not report any difference compared with comparator groups in overall emotional functioning, or in depressive or anxiety symptoms specifically (Table E2 and Figures E9–E11, available online at http://links.lww.com/PAIN/A592). No evidence of small study effects was identified for overall emotional functioning (P = 0.10) or anxiety symptoms (P = 0.06); however, a significant effect was detected for depression (P = 0.01). The trim and fill procedure to account for small study effects revealed that the adjusted estimate did not differ significantly from the original estimate (SMD 0.04, 95% CI −0.14 to 0.22, Table E2, availableonlineathttp://links.lww.com/PAIN/A592). A significant improvement in emotional functioning was identified for dronabinol compared with placebo based on a single study; we had low confidence in this effect (Table E3 in Appendix E, available online at http://links.lww.com/PAIN/A592).
In the 4 RCTs which reported PGIC as a continuous outcome on the 7-item PGIC scale, there were significant increases among patients receiving any cannabinoid compared with placebo (Table E2 and Figure E12, available online at http://links.lww.com/PAIN/A592), with no evidence of small study effects (P = 0.28). Nine RCTs reported PGIC scores as a dichotomous outcome (much or very much improved vs slightly improved, no change, or worse), with significant improvement among patients receiving any cannabinoid compared with placebo (Table 4 and Figure E13, available online at http://links.lww.com/PAIN/A592), and no evidence of small study effects (P = 0.3). Confidence in these outcomes was low to very low. Most of the evidence was for nabiximols, with some evidence for nabilone, C. sativa, and THC extract.
Patients with CNCP who received a cannabinoid had 2 times the odds of withdrawing from a trial for any reason than patients who received placebo (Table E4 in Appendix E, available online at http://links.lww.com/PAIN/A592). They had 3.47 times the odds of withdrawing because of AEs (Table 5); no evidence of small study effects was found (P = 0.44). Patients with CNCP who received placebo were slightly more likely to withdraw from trials because of a lack of efficacy than those receiving cannabinoids. There was some variation between cannabinoids in reasons for withdrawal (Table E4 in Appendix E, available online at http://links.lww.com/PAIN/A592).
Patients with CNCP receiving cannabinoids had 2.33 times the odds of experiencing an AE compared with placebo groups (Table 5 and Table E4 in Appendix E, available online at http://links.lww.com/PAIN/A592). Significant evidence of small study effects was detected (P = 0.01); however, the adjusted estimate did not differ significantly from the original (OR = 2.22, 95% CI 1.60-3.01). Serious AEs were reported in a smaller number of studies (Table 5), and patients receiving cannabinoids had higher rates of serious AEs, but this did not reach statistical significance. No small study effects were detected (P = 0.52). Compared with placebo groups, patients receiving cannabinoids were more likely to report individual AEs such as dizziness (OR 5.52, 95% CI 4.47-6.83), cognitive attention or disturbance (OR 5.67, 95% CI 2.72-11.79), and confusion and disorientation (OR 5.35, 95% CI 2.31-12.39, Table 5).
For cannabinoids' impact on pain outcomes, pooled event rates for 30% reduction in pain intensity were 29.0% vs 25.9%, respectively. The NNTB was 24 (95% CI 15-61, Table 6). For a 50% reduction in pain, the pooled event rate for cannabinoids was 18.2%, compared with 14.4% for placebo groups (Table 6). The NNTB for 50% reduction in pain was unable to be calculated, as the estimate crossed the line of no effect.
For studies where outcomes were presented dichotomously, participants receiving cannabinoids had slightly increased odds of reporting global improvements (PGIC) than patients who received placebo (Table 6). In participants receiving cannabinoids, the pooled percentage reporting “much” or “very much” global improvement was 18.9% compared with 11.8%; the NNT was 38 (95% CI 27-62).
We found moderate evidence for a reduction in pain for cannabinoids when compared with placebo groups. Pooled analyses suggested that 30% reduction in pain was reported by 29.0% in cannabinoids, compared with 25.9% in placebo groups. A 50% reduction in pain was reported by 18.2% in cannabinoid groups and 14.4% in placebo groups; however, this did not reach statistical significance. The NNTB to achieve a 30% reduction in pain for 1 person using cannabis or cannabinoids (compared with placebo groups) was estimated at 24 (95% CI 15-61), and the NNTH for 1 person to experience any AE was 6 (95% CI 5-8). Although caution needs to be used in comparing NNTs across studies involving different groups and timeframes,44 these NNTBs are much higher than those for other analgesics: previous studies in neuropathic pain suggested NNTs for strong opioids of 4.3 (95% CI 3.4-5.8), pregabalin (7.7, 95% CI 6.5-9.4), and tricyclic antidepressants (3.6, 95% CI 3.0-4.4).28 The NNTH in our review was similar to that for opioids for CNCP, with a recent Cochrane review indicating that the NNTH for 1 person using opioids to experience any AE (compared with placebo) was 5 (95% CI 4-9).27 When reexpressed as a mean change on the commonly used 100 mm VAS, the pooled SMD for the continuous outcome of change in pain intensity was equivalent to a 3 mm greater reduction on this scale compared with placebo, which is well below the 30 mm reduction regarded to represent a clinically important difference in pain intensity.41,58 In contrast to more optimistic conclusions from earlier reviews,2,48 our findings are largely consistent with a recent Cochrane review examining cannabinoids for neuropathic pain, indicating that these medicines are unlikely to be effective in the treatment of pain.46 In their review, Mücke et al.46 report an NNTB of 20 for 50% or greater reduction in pain, and NNTHs of 3 and 6 for AEs relating to nervous system and psychiatric disorders, respectively, suggesting a similar efficacy and safety profile of cannabinoids for pain as reported in our review.
The evidence on the effectiveness of cannabinoids for CNCP is limited for several reasons. First, sample size is an issue, with only 21 of the 104 included studies having at least 100 participants per treatment arm. Although we made multiple attempts to minimise risk of bias in the effect estimates due to small sample sizes, this risk cannot be fully mitigated. For some estimates, effect sizes were notably larger in studies with <30 participants per treatment arm compared with studies of 100+ per arm; however, these estimates fell within overlapping bounds of uncertainty. There is a growing body of evidence indicating that effect estimates tend to be larger in studies with small sample sizes,20 and as such, caution should be taken when interpreting outcomes based on studies with small sample sizes in this review. Well conducted, large RCTs comprising at least 100 participants per treatment arm should be considered a priority in this space. Second, most studies were of limited duration (median of 8 weeks): given that CNCP is a chronic condition, this sheds little light on the appropriateness of long-term use of cannabinoids in CNCP, in terms of both treatment efficacy and safety. Of the little evidence available, we found that reductions in pain intensity were largest for 1-day studies, and smaller and nonsignificant in studies of 13-week duration or longer, providing some initial suggestion that the effectiveness of cannabinoids for CNCP may diminish over time. Third, the issues of cannabinoid tolerance, risks of iatrogenic dependence, and of withdrawal symptoms if long-term cannabinoids are ceased, remain poorly understood. Short-term clinical trials such as those included in this review are often of insufficient power and duration to detect potential harms and AEs associated with long-term cannabis use, such as elevated risk of psychosis and substance dependence.32,45 It is crucial that these long-term outcomes identified in the epidemiological literature are considered alongside evidence of efficacy from clinical trials when determining overall suitability of cannabinoids as medicines for CNCP. Fourth, cannabinoid dose was often poorly recorded. Often, only a maximum recommended dose was reported and data on participants' actual cannabinoid consumption were seldom recorded, so it is difficult to make strong recommendations on doses that are maximally effective and safe. Fifth, by far, the greatest amount of high-quality evidence was for nabiximols, resulting in small numbers of studies (and in some cases, single study) in some analyses for other types and formulations of cannabinoids (eg, ajulemic acid), meaning that we are be less confident about their efficacy. Sixth, although almost all studies reported data on change in pain intensity, very few reported outcomes for 30% and 50% reduction in pain. Given that pain was a secondary outcome in many studies, it is possible that authors did not report these outcomes because they are drawn from the pain-specific IMMPACT guidelines; however, there is also the possibility that study authors chose not to report outcomes for 30% and 50% reduction in pain when the continuous pain intensity outcome indicated no benefit. Although we have made multiple attempts to account for publication bias throughout this review, there remains the possibility that the studies for which 30% and 50% reduction in pain were not reported did not find evidence of effect. If this is the case, NNTBs for these outcomes may be higher than those reported here; however, our overall conclusion that cannabinoids are unlikely to be effective medicines for CNCP will remain unchanged. Finally, to ensure that all the available evidence of cannabinoids as a treatment for CNCP was considered in this review, we included evidence from RCTs and less rigorous observational study designs. This approach allows researchers, clinicians, and policymakers to map current research activity and to identify knowledge gaps. Although observational studies provide some insight into the efficacy of cannabinoids for CNCP, ultimately only data from high-quality RCTs will be used to inform national treatment guidelines. We noted that most of the higher-quality RCT evidence was for neuropathic pain and MS-related pain. There is scant, low-quality evidence on cannabinoids used for fibromyalgia or visceral pain, and very few studies of cannabinoids' use in the most common and burdensome CNCP conditions, namely back/neck problems, migraines, and arthritides. Thus, the conclusions of this review primarily relate to neuropathic or MS-related pain. Several ongoing studies targeting these more common CNCP conditions were identified and will be analysed when results become available.
Most studies used a placebo comparator and added cannabinoids to stable doses of analgesics, nonsteroidal anti-inflammatory drugs, and antispasticity drugs, so the evidence for cannabinoid use in CNCP is largely around cannabinoids as adjuvant medicines. Often, multiple analgesics were used, which varied between groups, and the ways they were used were not consistently reported. Most studies held doses of other analgesic medications constant, although some studies documented changes in breakthrough medication or adjunctive analgesia.
The findings of this review need to be considered in light of several potential limitations. Some of these limitations have already been noted and include the high risk of bias in many studies because of small N and missing information on study design and rigour of controls; most studies also evaluated cannabinoids as adjunct to other analgesic medications. We attempted to assertively minimise these limitations. Many documents were reviewed by a small research team, which might have led to errors in assessing eligible studies. However, internal checks were conducted by members within this team and a process of double and triple checking existed; we also checked all identified reviews to ensure that no studies had been missed that had been reported in any other reviews of evidence. Third, errors may have been made in data interpretation. To reduce such errors, all sources and data extracted were double checked by at least 2 reviewers and conflicts were resolved by third reviewer when necessary.
It seems unlikely that cannabinoids are highly effective medicines for CNCP. There is moderate- to high-grade evidence supporting use of nabiximols to achieve modest reductions in pain as adjunctive therapy in MS-related pain. However, NNTBs were high and NNTHs low, with high rates of dropout for AEs, and long-term efficacy and safety is unknown. We also found minimal evidence that cannabinoids are effective in improving other important domains in people with CNCP such as emotional and physical functioning. Cannabinoids are unlikely to be a monotherapy for CNCP. People living with CNCP often have complex comorbidities,9,70 and multidisciplinary treatment that includes physical and psychological therapy rather than reliance on medicines alone is likely to be most effective.
G. Campbell, S. Nielsen, M. Farrell, and L. Degenhardt have all been investigators on untied investigator-driven educational grants funded by Reckitt Benckiser. M. Farrell and L. Degenhardt have received an untied educational grant from Mundipharma for post-marketing surveillance studies of a potentially tamper-resistant formulation of controlled-released oxycodone. S. Nielsen, M. Farrell, and L. Degenhardt have been investigators on untied investigator-driven educational grants funded by Indivior. M. Farrell and L. Degenhardt have been investigators on an untied investigator-driven educational grant funded by Seqirus. The remaining authors have no conflict of interest to declare.
Funding was received from the Commonwealth Department of Health, the NSW Government Centre for Medicinal Cannabis Research and Innovation, the Victorian Department of Health and Human Services, and the Queensland Department of Health. E. Stockings, G. Campbell, S. Nielsen, and L. Degenhardt are supported by NHMRC research fellowships (#1104600; #1119992; #1132433; and #1041472). The National Drug and Alcohol Research Centre at the University of NSW is supported by funding from the Australian Government under the Substance Misuse Prevention and Service Improvements Grant Fund.
The authors acknowledge Mary Kumvaj who assisted in the development of the search strategy.
Author contributions: L. Degenhardt and M. Farrell conceived the Review. E. Stockings, G. Campbell, S. Nielsen, D. Zagic, R. Rahman, and M. Weier did the systematic search, selected papers, and extracted data. E. Stockings conducted statistical analyses. G. Campbell, L. Degenhardt, and W.D. Hall drafted the manuscript with critical revisions from all authors. B. Murnion provided clinical important intellectual content. All authors reviewed the paper before submission.
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