The Effects of Cannabis Among Adults With Chronic Pain and an Overview of General Harms

The use of medicinal cannabis has become increasingly accepted in the United States and globally (1, 2). Eight states and the District of Columbia have legalized cannabis for recreational purposes, and 28 states and the District of Columbia have legalized it for medical purposes (3). Between 45% and 80% of persons who seek medical cannabis do so for pain management (4, 5). Among patients who are prescribed long-term opioid therapy for pain, up to 39% are also using cannabis (6, 7). Physicians will increasingly need to engage in evidence-based discussions with their patients about the potential benefits and harms of cannabis use. However, little comprehensive and critically appraised information exists about the benefits and harms of using cannabis to treat chronic pain. The objectives of this systematic review were to assess the efficacy of cannabis for treating chronic pain and to provide a broad overview of the short- and long-term physical and mental health effects of cannabis use in chronic pain and general patient populations. Methods Topic Development This article is part of a larger report commissioned by the Veterans Health Administration (8). A protocol describing the review plan was posted to a publicly accessible Web site before the study began (9). Data Sources and Searches We searched MEDLINE, Embase, PubMed, PsycINFO, Evidence-Based Medicine Reviews (including Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, Health Technology Assessments, and Cochrane Central Register of Controlled Trials), and gray literature sources from database inception through February 2016. We updated this search specifically for new randomized controlled trials (RCTs) and systematic reviews in March 2017. We obtained additional articles from systematic reviews, reference lists, and expert recommendations. We also searched for ongoing, unpublished, or recently completed studies on ClinicalTrials.gov, the International Clinical Trials Registry Platform, the ISRCTN Registry, National Institutes of Health RePORTER, and the Agency for Healthcare Research and Quality Grants On-Line Database. Supplement 1 provides details on the search strategy, which we developed in consultation with a research librarian. Supplement. Online Supplement Study Selection We included English-language studies assessing the effect on nonpregnant adults of plant-based cannabis preparations or whole-plant extracts, such as nabiximols, a nonsynthetic pharmaceutical product with a standard composition and dose (oromucosal spray delivering tetrahydrocannabinol [THC], 2.7 mg, and cannabidiol, 2.5 mg). We did not include synthesized, pharmaceutically prepared cannabinoids, such as dronabinol or nabilone, because they are not available in dispensaries, and the efficacy of synthetic cannabinoid preparations for chronic pain was examined in 2 recent reviews (10, 11). We broadly defined plant-based cannabis preparations to include any preparation of the cannabis plant itself (for example, cannabis cigarettes and oils) or cannabis plant extracts to capture the variety of products available in U.S. dispensaries (12). To address the efficacy of cannabis for treating chronic pain, we included controlled clinical trials and cohort studies. This review focuses specifically on pain outcomes, although our larger report and search were designed to include other outcomes, such as sleep and quality of life (8). Because data about harms in the general population might be applicable to chronic pain populations, we examined harms broadly and reported whether the data were derived from studies of the general population or populations with chronic pain. To capture potential cannabis-related harms that may be of interest to clinicians and patients, but whose prevalence has not been well-characterized in larger-scale observational studies, we also included case series and descriptive studies of emerging harms. Supplement 2 provides the criteria we used for study selection. We searched for primary literature and systematic reviews; we dual-reviewed 5% of identified abstracts and all of the included full-text articles to ensure reliability. Disagreements were resolved by a third reviewer. Given the broad scope of this review, we summarized data from existing systematic reviews. We included only reviews that clearly reported their search strategy, reported inclusion and exclusion criteria, and appraised the internal validity of the included trials (13). We prioritized the most recent reviews and those with the broadest scope. In addition, we included individual studies that met inclusion criteria and either were published after the end search date of the included review or were not included in a prior systematic review. Data Extraction and Quality Assessment For all reports, 2 investigators abstracted details of study design, setting, patient population, intervention, and follow-up, as well as important co-interventions, health outcomes, health care use, and harms. Two reviewers independently assessed each trial (including those that were identified from a prior systematic review) as having low, high, or unclear risk of bias (ROB) for the pain outcome using a tool developed by the Cochrane Collaboration (14). Disagreements were resolved by consensus. To assess the ROB of observational studies for the pain outcome, we considered potential sources of bias most relevant to this evidence base and adapted existing assessment tools (15, 16) (Supplement 3). Data Synthesis and Analysis For the subgroup of neuropathic pain studies, we did a study-level meta-analysis of the proportion of patients experiencing clinically significant (30%) pain relief (Supplement 4), and we used the profile-likelihood random-effects model (17) to combine risk ratios. We assessed the magnitude of statistical heterogeneity among the studies using the standard Cochran chi-square test, the I 2 statistic (18). All analyses were done using Stata/IC, version 13.1 (StataCorp). Clinical heterogeneity, variation in outcomes reported, and the small number of trials precluded meta-analysis for other subgroups and outcomes, so we reported these qualitatively. After group discussion, we classified the overall strength of evidence for each outcome as high, moderate, low, or insufficient on the basis of the consistency, coherence, and applicability of the body of evidence as well as the internal validity of individual studies (19, 20). Role of the Funding Source The U.S. Department of Veterans Affairs Quality Enhancement Research Initiative supported the review but had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review, and approval of the manuscript; or decision to submit the manuscript for publication. Results After reviewing 13674 titles and abstracts, we included 13 systematic reviews and 62 primary studies (Figure). Table 1 provides study-level details and the ROB rating for each of the chronic pain trials. Table 2 summarizes findings, including the ROB rating, by pain subgroup. Table 3 summarizes the harms in both pain and general populations. Supplement 5 provides additional study-level data from pain studies not included in prior reviews and from studies on general harms. Figure. Literature flow diagram. * Includes Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessments, and Cochrane Central Register of Controlled Trials. Table 1. Characteristics and Findings of RCTs on Cannabis Extracts for Treating Chronic Pain* Table 2. Summary of Evidence of the Benefits of Cannabis in Populations With Chronic Pain Table 3. Summary of Evidence for the Harms of Cannabis in Chronic Pain and General Adult Populations Effects of Cannabis in Treating Chronic Pain We identified 22 RCTs (2142) from 2 recently published systematic reviews (10, 11) and an additional 8 studies (5 RCTs [4347] and 3 cohort studies [4850]) that met our inclusion criteria and were not included in prior reviews. The primary methods of continuous pain assessment were a visual analogue scale from 0 to 100 mm and a numerical rating scale (NRS) from 0 to 10 (where 0 indicated no pain and 10 indicated the worst possible pain). Some of the studies identified the proportion of participants who had clinically significant improvements in pain intensity (defined as 30% reduction, or approximately 2 points on the NRS and 20 mm on the visual analogue scale). Neuropathic Pain Thirteen trials examined the effects of cannabis-based preparations on neuropathic pain (Table 1). Participants had central or peripheral neuropathic pain related to various health conditions. Of these studies, 11 were rated as having low ROB (24, 27, 28, 30, 31, 33, 36, 39, 40, 43, 47), 1 as having unclear ROB (26), and 1 as having high ROB (35). Overall, we found low-strength evidence that cannabis may alleviate neuropathic pain in some patients (Table 2). Studies generally did not find clinically significant between-group differences on continuous pain scales, but a higher proportion of intervention patients had clinically significant pain relief up to several months later. Across 9 studies, intervention patients were more likely to report at least 30% improvement in pain (risk ratio, 1.43 [95% CI, 1.16 to 1.88]; I 2= 38.6%; P= 0.111) (Supplement 4). Most studies were small, few reported outcomes beyond 2 to 3 weeks, and none reported long-term outcomes. In the largest RCT, 246 patients with peripheral neuropathic pain self-titrated nabiximols up to a maximum dosage of 24 sprays per day or received a placebo (27). Those who completed the study (79 in the nabiximols group and 94 in the placebo group) and responded positively to the intervention had a significant decrease in pain (odds ratio, 1.97 [CI, 1.05 to 3.70]). However, among all participants, including those who did not have an intervention response, the reductio