Shannon M. Nugent, PhD; Benjamin J. Morasco, PhD; Maya E. O'Neil, PhD; Michele Freeman, MPH; Allison Low, BA; Karli Kondo, PhD; Camille Elven, MD; Bernadette Zakher, MBBS; Makalapua Motu'apuaka, BA; Robin Paynter, MLIS; Devan Kansagara, MD, MCR
Disclaimer: The authors of this article are responsible for its content. The views and conclusions expressed are those of the authors and do not necessarily represent the views of the U.S. Department of Veterans Affairs or the U.S. government. No statement in this article should be construed as an official position of the U.S. Department of Veterans Affairs.
Financial Support: By the U.S. Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Quality Enhancement Research Initiative.
Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-0155.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: Available at www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42016033623. Statistical code: Available from Dr. Kansagara (e-mail, email@example.com). Data set: See the .
Requests for Single Reprints: Shannon M. Nugent, PhD, VA Portland Health Care System, Mail Code R&D66, 3710 SW US Veterans Hospital Road, Portland, OR 97239; e-mail, Shannon.Nugent@va.gov.
Current Author Addresses: Drs. Nugent and O'Neil: VA Portland Health Care System, Mail Code R&D66, 3710 SW US Veterans Hospital Road, Portland, OR 97239.
Dr. Morasco: VA Portland Health Care System, Mail Code R&D99, 3710 SW US Veterans Hospital Road, Portland, OR 97239.
Ms. Freeman, Ms. Low, Drs. Kondo and Kansagara, Ms. Motu'apuaka, and Ms. Paynter: VA Portland Health Care System, Mail Code R&D71, 3710 SW US Veterans Hospital Road, Portland, OR 97239.
Dr. Elven: VA Portland Health Care System, 3710 SW US Veterans Hospital Road, Portland, OR 97239.
Dr. Zakher: Department of Public Health and Preventive Medicine, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239.
Author Contributions: Conception and design: B.J. Morasco, M. Freeman, A. Low, K. Kondo, M. Motu'apuaka, D. Kansagara.
Analysis and interpretation of the data: S.M. Nugent, B.J. Morasco, M.E. O'Neil, M. Freeman, A. Low, K. Kondo, C. Elven, B. Zakher, M. Motu'apuaka, D. Kansagara.
Drafting of the article: S.M. Nugent, M. Freeman, A. Low, K. Kondo, B. Zakher, D. Kansagara.
Critical revision of the article for important intellectual content: S.M. Nugent, B.J. Morasco, M.E. O'Neil, M. Freeman, A. Low, K. Kondo, C. Elven, R. Paynter, D. Kansagara.
Final approval of the article: S.M. Nugent, B.J. Morasco, M.E. O'Neil, M. Freeman, A. Low, K. Kondo, C. Elven, B. Zakher, M. Motu'apuaka, R. Paynter, D. Kansagara.
Provision of study materials or patients: R. Paynter.
Obtaining of funding: D. Kansagara.
Administrative, technical, or logistic support: M. Freeman, A. Low, M. Motu'apuaka, R. Paynter.
Collection and assembly of data: S.M. Nugent, B.J. Morasco, M.E. O'Neil, M. Freeman, A. Low, K. Kondo, C. Elven, B. Zakher, M. Motu'apuaka, D. Kansagara.
Cannabis is increasingly available for the treatment of chronic pain, yet its efficacy remains uncertain.
To review the benefits of plant-based cannabis preparations for treating chronic pain in adults and the harms of cannabis use in chronic pain and general adult populations.
MEDLINE, Cochrane Database of Systematic Reviews, and several other sources from database inception to March 2017.
Intervention trials and observational studies, published in English, involving adults using plant-based cannabis preparations that reported pain, quality of life, or adverse effect outcomes.
Two investigators independently abstracted study characteristics and assessed study quality, and the investigator group graded the overall strength of evidence using standard criteria.
From 27 chronic pain trials, there is low-strength evidence that cannabis alleviates neuropathic pain but insufficient evidence in other pain populations. According to 11 systematic reviews and 32 primary studies, harms in general population studies include increased risk for motor vehicle accidents, psychotic symptoms, and short-term cognitive impairment. Although adverse pulmonary effects were not seen in younger populations, evidence on most other long-term physical harms, in heavy or long-term cannabis users, or in older populations is insufficient.
Few methodologically rigorous trials; the cannabis formulations studied may not reflect commercially available products; and limited applicability to older, chronically ill populations and patients who use cannabis heavily.
Limited evidence suggests that cannabis may alleviate neuropathic pain in some patients, but insufficient evidence exists for other types of chronic pain. Among general populations, limited evidence suggests that cannabis is associated with an increased risk for adverse mental health effects.
U.S. Department of Veterans Affairs. (PROSPERO: CRD42016033623)
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
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August 15, 2017
Sad studies like this are popularized and mis-quoted by the lay press. High THC cannabis can intoxicate, often causes anxiety and does little to combat pain. On the other hand, high CBD cannabis neither intoxicates nor exacerbates anxiety, and CAN decrease chronic and neuropathic pain. I wish this study had made that point a little more clear. Though I believe it a mistake to consider all cannabis medicinal, leading the lay population to conclude that high CBD/ultra-low THC cannabis to be worthless in the treatment of PTSD and/or chronic pain is misguided, at best.
David A. Gorelick
Dept. of Psychiatry, University of Maryland School of Medicine
September 19, 2017
Taking route of administration into account
I believe there are two relevant omissions in the comprehensive and rigorous systematic review on the effects of cannabis on chronic pain in adults published by Nugent and colleagues in the 5 September, 2017 issue (vol. 167, no. 5). First, they do not mention the patient-level meta-analysis published by Andreae and colleagues (1), which included data from 178 participants in 5 controlled clinical trials of inhaled cannabis for chronic neuropathic pain. (These 5 trials were included in the study-level meta-analysis on neuropathic pain reported by Nugent and colleagues.) This patient-level meta-analysis estimated an odds ratio of 3.2 (Bayesian CRI 1.59, 7.26) for a greater than 30% reduction in pain scores (inhaled cannabis vs. placebo) and a number-needed-to-treat of 5.55 (3.35, 13.7). Results were robust to various sensitivity analyses.Second, Nugent and colleagues pay insufficient attention to differences generated by different cannabis routes of administration, especially regarding possible harms such as impaired pulmonary function and lung and head/neck/oral cancers. Cannabis smoke (product of burning plant material) contains amounts of bronchial irritants and known and suspected carcinogens (e.g., tars, ammonia, hydrogen cyanide, nitrosamines) comparable to those in tobacco smoke (2). Cannabis vapor (product of heated but not burning plant material) contains much less of these compounds (3). Oral and transmucosal cannabis products presumably generate none of these compounds. These differences may account for why inhaled vaporized cannabis (“vaping”) is reported by many users to be healthier (4) and produces less respiratory symptoms and acute impairment of pulmonary function (5) than smoked cannabis. Oral and vaporized cannabis products are increasingly popular in the medical cannabis market. Future reviews of the benefits and harms of medical cannabis should take into account these varied routes of administration. 1. Andreae MH, George M. Carter GM, Naum Shaparin N, Kathryn Suslov K, Ronald J. Ellis RJ, Mark A. Ware MA, Donald I. Abrams DI, et al. Inhaled cannabis for chronic neuropathic pain: A meta-analysis of individual patient data. J Pain. 2015;16(12):1221-1232.2. Tashkin DP. Effects of marijuana smoking on the lung. Ann. Am. Thorac. Soc. 2013; 10:239–247.3.Pomahacova B, Van der Kooy F, Verpoorte R. Cannabis smoke condensate III: the cannabinoid content of vaporised cannabis sativa. Inhal. Toxicol. 2009; 21:1108–1112.4. Lee DC, Crosier BS, Borodovsky JT, Sargent JD, Budney AJ. Online survey characterizing vaporizer use among cannabis users. Drug Alcohol Depend. 2016;159: 227–233.5. Van Dam NT, Earleywine M. Pulmonary function in cannabis users: Support for a clinical trial of the vaporizer. Int J Drug Policy. 2010;21(6):511-513.
Shannon M Nugent, PhD, Devan Kansagara, MD
VA Health System & Oregon Health & Science University
November 10, 2017
We appreciate Dr. Gorelick’s comments. We were aware of the Andreae paper and, we included all studies that were included in that patient-level analysis. However, we also included an additional four studies in our study-level meta-analysis. The studies included in the Andreae paper had larger effect sizes (e.g. – a greater proportion of intervention patients experienced significant reductions in pain) than the other four studies we additionally included, accounting for the difference in odds ratio reported in that study compared to ours. Of note, the five studies in the Andreae paper were of very short duration (hours), while the additional studies we included measured effects over weeks. The cannabis formulations were also different across studies. We rated the strength of evidence for the effects of cannabis on neuropathic pain as low in part because of the variability in findings across studies, and the variation in study design and intervention. The low strength of evidence underscores the uncertainty regarding the true treatment effect. We agree that various routes of administration may have differential impacts and safety concerns. When reporting our findings, for both the benefits and harms, we reported the route of administration used in the trial or observational study. As we reported, the highest quality prospective data that we identified in relation to pulmonary harms did not find a significant decrease longitudinally for most validated measures of pulmonary function (e.g. airflow obstruction or impairment of gas transfer) when controlling for relevant variables including tobacco use. However, the participants were young and relatively few had high levels of use (e.g. – daily use), and there was a trend towards reduced pulmonary function in those with the highest levels of lifetime exposure to smoked cannabis. Unfortunately, we did not find studies assessing the health effects of vaporized cannabis that met our inclusion criteria. We agree that further prospective data are needed to characterize the magnitude of harms associated with different routes of administration.
Nugent SM, Morasco BJ, O'Neil ME, Freeman M, Low A, Kondo K, et al. The Effects of Cannabis Among Adults With Chronic Pain and an Overview of General Harms: A Systematic Review. Ann Intern Med. ;167:319–331. doi: 10.7326/M17-0155
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Published: Ann Intern Med. 2017;167(5):319-331.
Published at www.annals.org on 15 August 2017
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