Effect of Inhaled Cannabis for Pain in Adults With Sickle Cell Disease: A Randomized Clinical Trial

Abstract

Importance: Sickle cell disease (SCD) is characterized by chronic pain and episodic acute pain caused by vasoocclusive crises, often requiring high doses of opioids for prolonged periods. In humanized mouse models of SCD, a synthetic cannabinoid has been found to attenuate both chronic and acute hyperalgesia. The effect of cannabis on chronic pain in adults with SCD is unknown.

Objective: To determine whether inhaled cannabis is more effective than inhaled placebo in relieving chronic pain in adults with SCD.

Design, setting, and participants: This pilot randomized clinical trial included participants with SCD with chronic pain admitted to a single inpatient clinical research center for 2 separate 5-day stays from August 2014 to April 2017. Participants inhaled either vaporized cannabis (4.4% Δ-9-tetrahydrocannabinol to 4.9% cannabidiol) 3 times daily or vaporized placebo cannabis. Pain and pain interference ratings using the Brief Pain Inventory were assessed throughout each 5-day period. Participants with SCD and chronic pain on stable analgesics were eligible to enroll. A total of 90 participants were assessed for eligibility; 56 participants were deemed ineligible, and 34 participants were enrolled. Of these, 7 participants dropped out before randomization. Of 27 randomized participants, 23 completed both treatment arms of the crossover study and were included in the final per protocol analysis. Data analysis was completed in June 2019, with the sensitivity analysis conducted in April 2020.

Interventions: Inhalation of vaporized cannabis plant (4.4% Δ-9-tetrahydrocannbinol to 4.9% cannabidiol) or placebo cannabis plant using a vaporizer 3 times daily for 5 days.

Main outcomes and measures: Daily pain assessed with visual analog scale and Brief Pain Inventory.

Results: A total of 23 participants (mean [SD] age, 37.6 [11.4] years; 13 [56%] women) completed the trial. The mean (SD) difference in pain rating assessment between the cannabis and placebo groups was -5.3 (8.1) for day 1, -10.9 (7.0) for day 2, -16.5 (9.2) for day 3, -8.9 (6.7) for day 4, and -8.2 (8.1) for day 5; however, none of these differences were statistically significant. There was no statistically significant mean (SD) difference in pain interference ratings between cannabis and placebo between days 1 and 5 for interference in general activities (day 1: 0.27 [0.35]; day 5: -1.0 [0.5]), walking (day 1: 0.14 [0.73]; day 5: -0.87 [0.63]), sleep (day 1: 0.59 [0.74]; day 5: -1.3 [0.8]), or enjoyment (day 1: 0.23 [0.69]; day 5: -0.91 [0.48]), but there was a statistically significant mean (SD) difference in decrease in interference with mood (day 1: 0.96 [0.59]; day 5: -1.4 [0.6]; P = .02). No differences in treatment-related adverse effects were observed. Use of concomitant opioids was similar during both treatment periods.

Conclusions and relevance: This randomized clinical trial found that, compared with vaporized placebo, vaporized cannabis did not statistically significantly reduce pain and associated symptoms, except interference in mood, in patients with SCD with chronic pain.

Trial registration: ClinicalTrials.gov Identifier: NCT01771731.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Abrams reported receiving personal fees from AXIM Biotechnologies, INSYS, Intec, Maui Wellness Group, MedLab Clinical Ltd, Scriptyx, Spectrum Cannabis, Tikun Olam, and VIVO Cannabis; and stock ownership in Cannformatics and Lumen outside the submitted work. Dr Connett reported receiving grants from the National Institutes of Health (NIH) and US Department of Defense outside the submitted work. Dr Gupta reported receiving grants from 1910 Genetics, Grifols, the Southern California Institute for Research and Education Foundation, and the University of Minnesota Foundation; personal fees from Tautona Group, Novartis, and CSL Behring; and serving as a board member of the Sickle Cell Disease Association of America outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Consort Diagram

Figure 2.. Daily Pain Rating During Cannabis and Placebo Treatment

Participants completed a self-reported assessment of pain on the Drug Effects Questionnaire during each day of cannabis and placebo treatment. Pain was rated on a visual analog scale from 0 to 100. Dots indicate mean and whiskers, 95% CI.

Figure 3.. Difference in Pain Interference Ratings Between Cannabis and Placebo Treatment

The brief pain inventory, a self-reported assessment of various chronic pain interference measures, was completed by each patient on days 1 and 5 of the cannabis and placebo treatment periods. Each of the interference criteria was rated on a scale from 1 to 10. Dots indicate mean and whiskers, 95% CI.