This review addresses the following Key Questions (KQs):

KQ 1: In adults with chronic pain, what are the benefits of cannabinoids for treatment of chronic pain?

KQ 2: In adults with chronic pain, what are the harms of cannabinoids for treatment of chronic pain?

KQ 3: In adults with chronic pain, what are the benefits of kratom or other plant-based substances for treatment of chronic pain?

KQ 4: In adults with chronic pain, what are the harms of kratom or other plant-based substances for treatment of chronic pain?

Organizing principle of cannabis-related studies based on ratios of THC to CBD

Definitions of effect sizes

Implications for Clinical Practice, Education, Research, or Health Policy

The implications of the present findings for clinical practice are mixed. These results suggest that select individuals with chronic neuropathic pain may experience moderate short-term improvements in pain when using cannabis products (synthetic or extracted from whole-plant) that have a high-THC to CBD ratio. The impact of this intervention on moderate or long-term outcomes is unknown. Cannabis products with a comparable THC to CBD ratio may also result in small improvements in pain severity. Those who take products containing comparable or high ratios of THC are also at increased risk for adverse events, including dizziness, sedation and nausea. The expected benefit of this treatment is comparable to prescription opioids, several nonopioid medications, and nonpharmacological interventions. The evidence on adverse events with cannabis-related products is much less robust than the evidence on similar outcomes with opioids or nonopioid medications. The risk of sedation and dizziness appears similar with cannabis-related products, opioids, and the anticonvulsants pregabalin and gabapentin, while the risk for nausea appears to be larger with opioids and the antidepressant duloxetine than with cannabis-related products. These are only indirect comparisons, with very limited evidence on cannabis products relative to the other drugs, and comparisons of effects on serious and long-term harms are not possible even indirectly. Understanding how cannabis products' adverse event profiles compare with other available treatments for chronic pain, particularly opioid and non-opioid medications, is essential to determining the benefit to harm ratio. However, the strength of this evidence is mostly low, and more data are needed to confidently recommend this as a treatment for various chronic pain-related conditions or for patients with diverse demographic or clinical characteristics.

As noted in the limitations above, baseline use of opioids for pain and the impact of cannabinoids on the use of opioids for pain were very poorly reported. In an effort to address the opioid epidemic, a prominent goal of current research is to identify alternative treatments with equal or better benefits for pain while avoiding potential unintended consequences that could result in harms. Unfortunately, much of the findings to date are low SOE or insufficient evidence, and more high-quality studies are needed.

Our synthesis of the evidence leads to several important additional questions that could be addressed most effectively in a clinical practice guideline. Examples of questions that could be best addressed through a guideline process include: At what point in the treatment decision tree should cannabis-based medicines be considered? How should patient preferences be taken into account? What are pragmatic dosing guidelines? And finally, what are the comparative effects on costs of care?

Implications for Future Research

The gaps in the research evidence that are outlined above lead to specific recommendations for conducting future studies that will improve the strength of the conclusions that can be drawn, and provide better guidance for policymakers, clinicians and patients alike.

This review does not provide cost information.

Strengths and Limitations

The evidence base on cannabis and other plant-based treatments for chronic pain has multiple important limitations. Eighty percent of trials enrolled patients with chronic pain due to a neuropathic cause (7 in patients with multiple sclerosis, 4 with a mix of conditions or not specified, 2 with diabetic neuropathy, and 1 each with chemotherapy, HIV, or spinal cord injury). There is little or no evidence on other types of chronic pain, including low back pain, osteoarthritis, fibromyalgia, and inflammatory arthritis. In terms of age, there is limited evidence on younger and older populations, with most patients being middle-aged (mean age 52 years). Studies generally excluded patients with a history of psychiatric disorders other than prior history of depression or anxiety. Importantly, there was either no evidence or inadequate evidence to evaluate important patient populations based on sex/gender, race/ethnicity, age, or pregnancy/lactating status.

Another limitation is the lack of consistent nomenclature detailing the interventions and products studied. For example, products are described as extracted in some studies, but without a consistent way of describing the process or the resulting purity of the products. Other studies used words such as "standardized" to describe the amount of THC in a whole-plant cannabis product, again with lack of description of how this was defined or determined. Studies did not consistently report the ratio of THC to CBD in the products, particularly outside of the products that are close to a 1 to 1 ratio (oromucosal spray, Sativex). Other limitations include the complete lack of evidence on other plant-based compounds like kratom, no RCT evidence on whole-plant cannabis products, and only a single, small study each for topical CBD or cannabinoids other than THC or CBD.

Change in pain severity was the most commonly reported outcome. Other important outcomes were mainly not reported or inconsistently reported or defined. Pain response, defined as a 30 percent or greater improvement in pain, was reported in 5 of 23 studies (22%); 6 of 23 studies (26%) reported specifically on pain interference, and 8 of 23 (35%) reported measures of physical function or disability. The studies poorly reported baseline use of opioids for pain, and only one high risk of bias observational study reported the impact of cannabis interventions on changes to prescription opioid use. While almost all studies reported the number of patients who withdrew from studies due to adverse events, 30 percent did not report serious adverse events, and 65 percent did not report the overall adverse events, particularly by group. When serious adverse events were reported, studies either used a unique definition, or did not provide one. In reporting on specific adverse events, not all studies were clear about whether the events were the number of individuals with at least one event, or if a single patient could contribute to an event more than once. Other adverse events that have been reported in noncomparative observational studies and were prioritized for this review (development or exacerbation of psychosis, CUD, and cognitive deficits) were not reported.

Trials were limited by study design and small sample sizes (range 9 to 339; mean 89), particularly for assessing harms. The SOE of the findings was very commonly downgraded due to imprecise estimates as a result of too few patients enrolled (see Appendix G). There were also differences in some key baseline characteristics, including baseline pain scores, which were frequently not adjusted for in study analyses. Another methodologic concern is that many conclusions in the included studies were drawn from post-hoc analyses. Study durations were short-term and included less than 6 months followup; 37 percent of studies were 4 to 6 weeks long. This is a key limitation, as pain severity in patients with chronic pain may vary substantially in the short-term and may be influenced temporarily by an intervention or treatment; it is most useful to understand the enduring impact of a treatment on pain severity. Similarly, adverse events such as CUD, cognitive deficits, and serious adverse events may take time to develop and longer studies are required to capture such events. Well-designed head to head studies comparing a plant-based product with a standard of care treatment for chronic pain are lacking. The current evidence consists only of small, poorly designed, crossover or observational studies.

Despite limitations in the evidence base, our review has several strengths. First the living systematic review approach allows us to add new studies soon after they are published, thereby providing an opportunity to update conclusions in a rapid fashion. This may be important as cannabis and other plant-based treatments become more readily available to patients, providers and researchers. Also, using an organizational framework that categorizes cannabis-related products by both their THC and CBD ratios and their origin (plant-based versus synthetic) allows a way to conceptualize the evidence on these two prominent cannabinoids that is consistent with how they are available to consumers. A final strength that separates this review from others is the exclusion of very short-term studies (e.g., a small number of dosing sessions), improving the applicability of the findings to chronic pain.

There are also some limitations to our review process. We excluded non-English language publications and study results published only as abstracts. We categorized nabilone as a synthetic high-THC product though it is more accurately described as a synthetic cannabinoid – a chemical analog to THC, and could have differing effects to THC. To address this possibility, we performed stratified analyses among outcomes that were pooled for synthetic high-THC interventions. The effect size for change in pain severity was larger with nabilone than with dronabinol, but the difference between the effect sizes was not statistically significant. Our inclusion criteria required that the study population have chronic pain, or have subgroup analyses for this group, which may be why we did not find evidence related to kratom. We were unable to assess publication bias (small sample size bias) for most outcomes, as most meta-analyses included fewer than eight studies. The exception was the analysis of change in pain severity with high-THC interventions, where we were unable to rule out important publication bias. Additional studies are needed to clarify the effect size estimates and our confidence in the findings. Since this is a living systematic review, new evidence will be incorporated into the review and findings updated on a regular basis. As in other recent systematic reviews of interventions to treat chronic pain, we grouped the magnitude of effects into small, moderate and large effects, rather than according to published minimal clinically important difference (MCID) thresholds. Defining clinical significance in chronic pain is difficult because it is subjective and difficult to correlate with real-life experiences of patients. For example, the MCID for improvement in pain is 15 points on a 0 to 100 scale. However, interventions commonly used for chronic pain, including opioids and nonsteroidal anti-inflammatory drugs do not achieve this level of reduction.11,12 The typical reduction with opioids, nonopioid medications, nonpharmacological interventions, and cannabinoids is small, 5 to 10 points and may be considered a clinically important effect by patients and clinicians.

Applicability

A number of factors could impact the applicability of our findings. The evidence currently is most applicable to patients with neuropathic pain with mostly moderate to severe pain (mean baseline score was 6.6 on a 0 to 10 scale, with a range of 4 to 7.9). There is also considerable variability within the included studies among the types of neuropathic pain patients experience, and treatment effects might be different depending on the specific neuropathic pain condition.

The evidence base is generally applicable to women with around 71 percent of enrolled participants being female. While the age range across studies was broad, 18 to 84 years, the evidence is mainly applicable to middle-aged patients (mean age 50 years). Currently, the evidence is poorly applicable to patients of non-White race. It is also unclear how the evidence applies to patients currently taking prescription opioids to treat chronic pain or patients with serious mental illness or other comorbidities who are often excluded from trials. In terms of interventions, this evidence is applicable to comparable THC to CBD ratio oromucosal spray and to high-THC synthetic medications. The evidence for comparable THC to CBD oral spray is applicable to mean dosing of 8.4 sprays per day (21 mg THC/23 mg CBD). The evidence for high-THC to CBD ratio synthetic drugs applies to dosing that was titrated upward, with a maximum dose of 15 to 20 mg per day of dronabinol and 0.5 to 2 mg per day of nabilone (mean doses not reported). For high-THC to CBD products extracted from whole-plants, the evidence was too heterogeneous and limited (2 RCTs) to describe an applicable dose. Applicability to other products including whole plant cannabis is very low or non-existent.

This evidence applies to short-term treatment and mainly informs the impact on mean changes in pain severity and common adverse events. The outcomes after longer term treatment may be different and could influence other outcomes not considered in short-term studies included here (e.g. psychosis, CUD, cognitive deficits). None of the studies reported other information relevant for assessing applicability, such as the description of the source of potential study participants or the number of women randomized relative to the number of women enrolled.

Although 60 percent of studies were conducted in the United States, we were unable to assess the impact of country of study or other geographic location characteristics (e.g., rural, metropolitan) on the applicability of specific results.

A number of evidence gaps or limitations in the evidence potentially impacted the applicability of our findings including lack of evidence on extracted whole-plant or purified interventions, whole-plant cannabis, and kratom.