Living Systematic Review on Cannabis and Other Plant-Based Treatments for Chronic Pain

Project Summary Title and Description

Living Systematic Review on Cannabis and Other Plant-Based Treatments for Chronic Pain
Objectives. To evaluate the evidence on benefits and harms of cannabinoids and similar plant-based compounds (PBCs) to treat chronic pain. Data sources. Ovid® MEDLINE®, PsycINFO®, Embase®, the Cochrane Library, and SCOPUS® databases, reference lists of included studies, submissions received after Federal Register request, were searched to July, 2021. Review methods. Using dual review, we screened search results for randomized controlled trials (RCTs) and observational studies of patients with chronic pain evaluating cannabis, kratom, and similar compounds with any comparison group and at least 1 month of treatment or followup. Dual review was used to abstract study data, assess study-level risk of bias, and rate the strength of evidence. Prioritized outcomes included pain, overall function, and adverse events. We grouped studies that assessed tetrahydrocannabinol (THC) and/or cannabidiol (CBD) based on their THC to CBD ratio and categorized them as high-THC to CBD ratio, comparable THC to CBD ratio, and low-THC to CBD ratio. We also grouped studies by whether the product was a whole-plant product (cannabis), cannabinoids extracted or purified from a whole plant, or synthetic. We conducted meta-analyses using the profile likelihood random effects model and assessed between-study heterogeneity using Cochran’s Q statistic chi square and the I2 test for inconsistency. Magnitude of benefit was categorized into no effect, or small, moderate, and large effects. Results. From 2,850 abstracts, 20 RCTs (N=1,776) and 7 observational studies (N=13,095) assessing different cannabinoids were included; none of kratom. Studies were primarily short-term, and 75 percent enrolled patients with a variety of neuropathic pain. Comparators were primarily placebo or usual care. The strength of evidence (SOE) was low, unless otherwise noted. Compared with placebo, comparable THC to CBD ratio oral spray was associated with a small benefit in change in pain severity (7 RCTs, N=632, 0 to10 scale, mean difference [MD] −0.54, 95% confidence interval [CI], −0.95 to −0.19, I2=28%; SOE: moderate) and overall function (6 RCTs, N=616, 0 to 10 scale, MD −0.42, 95% CI, −0.73 to −0.16, I2=24%). There was no effect on study withdrawals due to adverse events. There was a large increased risk of dizziness and sedation and a moderate increased risk of nausea (dizziness: 6 RCTs, N=866, 30% vs. 8%, relative risk [RR] 3.57, 95% CI 2.42 to 5.60, I2=0%; sedation: 6 RCTs, N=866, 22% vs. 16%, RR 5.04, 95% CI 2.10 to 11.89, I2=0%; and nausea: 6 RCTs, N=866, 13% vs. 7.5%, RR 1.79, 95% CI 1.20 to 2.78, I2=0%). Synthetic high-THC to CBD was associated with a moderate improvement in pain severity, a moderate increase in sedation, and a large increase in nausea (pain: 6 RCTs, N=390 to 10 scale, MD −1.15, 95% CI −1.99 to −0.54, I2=39%; sedation: 3 RCTs, N=335, 19% vs. 10%, RR 1.73, 95% CI 1.03 to 4.63, I2=0%; nausea: 2 RCTs, N=302, 12% vs. 6%, RR 2.19, 95% CI 0.77 to 5.39; I²=0%). We found moderate SOE for a large increased risk of dizziness (2 RCTs, 32% vs. 11%, RR 2.74, 95% CI 1.47 to 6.86, I2=0%). Extracted whole-plant, high-THC to CBD (oral) was associated with a large increased risk of study withdrawal due to adverse events (1 RCT, 13.9% vs. 5.7%, RR 3.12, 95% CI 1.54 to 6.33) and dizziness (1 RCT, 62.2% vs. 7.5%, RR 8.34, 95% CI 4.53 to 15.34). We observed a moderate improvement in pain severity when combining all studies of high-THC to CBD (8 RCTs, N=684, MD −1.25, 95% CI −2.09 to −0.71, I2=50%; SOE: moderate). Evidence on whole-plant cannabis, topical, low-THC to CBD, other cannabinoids, comparisons with active products, and impact on use of opioids was insufficient to draw conclusions. Other important harms (psychosis, cannabis use disorder, and cognitive effects) were not reported. Conclusions. Low to moderate strength evidence suggests small to moderate improvements in pain (mostly neuropathic), and moderate to large increases in common adverse events (dizziness, sedation, nausea) and study withdrawal due to adverse events with high- and comparable THC to CBD ratio cannabis products in short-term treatment (1 to 6 months). Evidence for other comparisons, outcomes, and PBCs were unavailable or insufficient to draw conclusions. Small sample sizes, lack of evidence for moderate and long-term use and other key outcomes, such as other adverse events and impact on use of opioids during treatment indicate that more research is needed.
Pacific Northwest Evidence-based Practice Center
Authors of Report
Marian S. McDonagh, Pharm.D. Jesse Wagner, M.A. Azrah Y. Ahmed, B.A. Rongwei Fu, Ph.D. Benjamin Morasco, Ph.D. Devan Kansagara, M.D., M.C.R. Roger Chou, M.D., FACP
Methodology description
Systematic Review
Notes Data entered retrospectively into the SRDR+ data abstraction form.
Funding Source
Agency for Healthcare Research and Quality

Key Questions

1. KQ1 and KQ2: In adults with chronic pain, what are the benefits (KQ1) and harms (KQ2) of cannabinoids for treatment of chronic pain?
2. KQ3 and KQ4: In adults with chronic pain, what are the benefits (KQ3) and harms (KQ4) of kratom and other plant-based substances for treatment of chronic pain?

Associated Extraction Forms


Associated Studies (each link opens a new tab)

Title Authors Year
Dronabinol Is a Safe Long-Term Treatment Option for Neuropathic Pain Patients Schimrigk, S.; Abramov-Sommariva, D.; Kugler, E. M.; Marziniak, M.; Neubauer, C.; Werner, G. 2017
A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment Serpell, M.; Ehler, E.; Hovorka, J.; Lauder, H.; Ratcliffe, S.; Schofield, M.; Taylor, L. 2014
Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS) Ware, M. A.; Wang, T.; Shapiro, S.; Collet, J. P.; team, Compass study 2015
An open-label comparison of nabilone and gabapentin as adjuvant therapy or monotherapy in the management of neuropathic pain in patients with peripheral neuropathy Bestard, J. A.; Toth, C. C. 2011
Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis Blake, D. R.; Robson, P.; Ho, M.; Jubb, R. W.; McCabe, C. S. 2006
Effect of cannabis use in people with chronic non-cancer pain prescribed opioids: findings from a 4-year prospective cohort study Campbell, G.; Hall, W. D.; Peacock, A.; Lintzeris, N.; Bruno, R.; Larance, B.; Nielsen, S.; Cohen, M.; Chan, G.; Mattick, R. P.; Blyth, F.; Shanahan, M.; Dobbins, T.; Farrell, M.; Degenhardt, L. 2018
Ingestion of a THC-Rich Cannabis Oil in People with Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial Chaves, Carolina; Bittencourt, Paulo Cesar T.; Pelegrini, Andreia 2020
Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo-controlled Study de Vries, M.; van Rijckevorsel, D. C. M.; Vissers, K. C. P.; Wilder-Smith, O. H. G.; van Goor, H.; Pain; Nociception Neuroscience Research, Group 2017
Cannabidivarin for HIV-Associated Neuropathic Pain: A Randomized, Blinded, Controlled Clinical Trial Eibach, L.; Scheffel, S.; Cardebring, M.; Lettau, M.; Ozgur Celik, M.; Morguet, A.; Roehle, R.; Stein, C. 2020
Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study Frank, B.; Serpell, M. G.; Hughes, J.; Matthews, J. N.; Kapur, D. 2008
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 Langford, R. M.; Mares, J.; Novotna, A.; Vachova, M.; Novakova, I.; Notcutt, W.; Ratcliffe, S. 2013
Opioid use in medical cannabis authorization adult patients from 2013 to 2018: Alberta, Canada Lee, Cerina; Lin, Mu; Martins, Karen J. B.; Dyck, Jason R. B.; Klarenbach, Scott; Richer, Lawrence; Jess, Ed; Hanlon, John G.; Hyshka, Elaine; Eurich, Dean T. 2021
A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain Lynch, M. E.; Cesar-Rittenberg, P.; Hohmann, A. G. 2014
Marijuana Use Is Not Associated With Changes in Opioid Prescriptions or Pain Severity Among People Living With HIV and Chronic Pain Merlin, J. S.; Long, D.; Becker, W. C.; Cachay, E. R.; Christopolous, K. A.; Claborn, K. R.; Crane, H. M.; Edelman, E. J.; Lovejoy, T. I.; Mathews, W. C.; Morasco, B. J.; Napravnik, S.; O'Cleirigh, C.; Saag, M. S.; Starrels, J. L.; Gross, R.; Liebschutz, J. M. 2019
Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial Nurmikko, T. J.; Serpell, M. G.; Hoggart, B.; Toomey, P. J.; Morlion, B. J.; Haines, D. 2007
Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial Pini, L. A.; Guerzoni, S.; Cainazzo, M. M.; Ferrari, A.; Sarchielli, P.; Tiraferri, I.; Ciccarese, M.; Zappaterra, M. 2012
Effect of dronabinol on central neuropathic pain after spinal cord injury: a pilot study Rintala, D. H.; Fiess, R. N.; Tan, G.; Holmes, S. A.; Bruel, B. M. 2010
Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis Rog, D. J.; Nurmikko, T. J.; Friede, T.; Young, C. A. 2005
Randomized placebo-controlled double-blind clinical trial of cannabis-based medicinal product (Sativex) in painful diabetic neuropathy: depression is a major confounding factor Selvarajah, D.; Gandhi, R.; Emery, C. J.; Tesfaye, S. 2010
Nabilone for the treatment of pain in fibromyalgia Skrabek, R. Q.; Galimova, L.; Ethans, K.; Perry, D. 2008
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 Toth, C.; Mawani, S.; Brady, S.; Chan, C.; Liu, C.; Mehina, E.; Garven, A.; Bestard, J.; Korngut, L. 2012
Nabilone as an adjunctive to gabapentin for multiple sclerosis-induced neuropathic pain: a randomized controlled trial Turcotte, D.; Doupe, M.; Torabi, M.; Gomori, A.; Ethans, K.; Esfahani, F.; Galloway, K.; Namaka, M. 2015
Associations between medical cannabis and prescription opioid use in chronic pain patients: A preliminary cohort study Vigil, J. M.; Stith, S. S.; Adams, I. M.; Reeve, A. P. 2017
Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain : a double-blind placebo-controlled cross-over trial Wissel, J.; Haydn, T.; Muller, J.; Brenneis, C.; Berger, T.; Poewe, W.; Schelosky, L. D. 2006
The Effectiveness of Topical Cannabidiol Oil in Symptomatic Relief of Peripheral Neuropathy of the Lower Extremities Xu, D. H.; Cullen, B. D.; Tang, M.; Fang, Y. 2020
Multiple sclerosis and extract of cannabis: results of the MUSEC trial Zajicek, J. P.; Hobart, J. C.; Slade, A.; Barnes, D.; Mattison, P. G.; Group, Musec Research 2012
No pain, all gain? Interim analyses from a longitudinal, observational study examining the impact of medical cannabis treatment on chronic pain and related symptoms Gruber, Staci A.; Smith, Rosemary T.; Dahlgren, M. Kathryn; Lambros, Ashley M.; Sagar, Kelly A. 2021
Cannabidiol treatment in hand osteoarthritis and psoriatic arthritis: a randomized, double-blind placebo-controlled trial Vela, J.; Dreyer, L.; Petersen, K. K.; Lars, A. N.; Duch, K. S.; Kristensen, S. 2021
Comparison of the Effectiveness and Tolerability of Nabiximols (THC:CBD) Oromucosal Spray versus Oral Dronabinol (THC) as Add-on Treatment for Severe Neuropathic Pain in Real-World Clinical Practice: Retrospective Analysis of the German Pain e-Registry Ueberall, M. A.; Essner, U.; Silvn, C. V.; Mueller-Schwefe, G. H. H. 2022
Effectiveness, Safety, and Tolerability of Nabiximols Oromucosal Spray vs Typical Oral Long-Acting Opioid Analgesics in Patients with Severe Neuropathic Back Pain: Analysis of 6-Month Real-World Data from the German Pain e-Registry Ueberall, Michael A.; Vila Silvan, Carlos; Essner, Ute; Mueller-Schwefe, Gerhard H. H. 2022b

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