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

Project Summary Title and Description

Title: Living Systematic Review on Cannabis and Other Plant-Based Treatments for Chronic Pain
Description: 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.
Attribution: 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
PROSPERO: CRD42021229579
DOI: https://doi.org/10.23970/AHRQEPCCER250
Notes: https://effectivehealthcare.ahrq.gov/products/plant-based-chronic-pain-treatment/living-review 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

Type
Standard

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., Marziniak, M., Neubauer, C., Kugler, E. M., Werner, G., Abramov-Sommariva, D.	2017
A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment	Serpell, M., Ratcliffe, S., Hovorka, J., Schofield, M., Taylor, L., Lauder, H., Ehler, E.	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
Oral capsules of tetra-hydro-cannabinol (THC), cannabidiol (CBD) and their combination in peripheral neuropathic pain treatment	Zubcevic, Kanita, Petersen, Merete, Bach, Flemming Winther, Heinesen, Aksel, Enggaard, Thomas Peter, Almdal, Thomas Peter, Holbech, Jakob Vormstrup, Vase, Lene, Jensen, Troels Stahelin, Hansen, Christian Stevns, Finnerup, Nanna Brix, Sindrup, Soren H.	2022
Medical cannabis for pain management in patients undergoing chronic hemodialysis: randomized, double-blind, cross-over, feasibility study	O. Kliuk-Ben Bassat, M. Schechter, N. Ashtamker, I. Yanuv, A. Rozenberg, B. Hirshberg, et al.	2023
Clinical outcome data of chronic pain patients treated with cannabis-based oils and dried flower from the UK Medical Cannabis Registry	J. Tait, S. Erridge, C. Holvey, R. Coomber, A. Usmani, M. Sajad, et al.	2023
Medicinal cannabis for Australian patients with chronic refractory pain including arthritis	Schubert, Elise A., Johnstone, Masego T., Benson, Melissa J., Alffenaar, Johannes C., Wheate, Nial J.	2023
Cannabis-based medicine for neuropathic pain and spasticity—A multicenter, randomized, double-blinded, placebo-controlled trial	Hansen, J. S., Gustavsen, S., Roshanisefat, H., Kant, M., Biering-Sørensen, F., Andersen, C., Olsson, A., Chow, H. H., Asgari, N., Hansen, J. R., Nielsen, H. H., Hansen, R. M., Petersen, T., Oturai, A. B., Sellebjerg, F., Sædder, E. A., Kasch, H., Rasmussen, P. V., Finnerup, N. B., Svendsen, K. B.	2023a
Cannabis for chronic pain: cardiovascular safety in a nationwide Danish study	Holt, Anders, Nouhravesh, Nina, Strange, Jarl E., Kinnberg Nielsen, Sebastian, Schjerning, Anne-Marie, Vibe Rasmussen, Peter, Torp-Pedersen, Christian, Gislason, Gunnar H., Schou, Morten, McGettigan, Patricia, Lamberts, Morten	2024
Oral cannabidiol (CBD) as add-on to paracetamol for painful chronic osteoarthritis of the knee: a randomized, double-blind, placebo-controlled clinical trial	Pramhas, S., Thalhammer, T., Terner, S., Pickelsberger, D., Gleiss, A., Sator, S., Kress, H. G.	2023
Cannabidiol Intervention for Muscular Tension, Pain, and Sleep Bruxism Intensity—A Randomized, Double-Blind Clinical Trial	Walczyńska-Dragon, K., Kurek-Górecka, A., Niemczyk, W., Nowak, Z., Baron, S., Olczyk, P., Nitecka-Buchta, A., Kempa, W. M.	2024

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