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Effect of Inhaled Cannabis for Pain in Adults With Sickle Cell Disease: A Randomized Clinical Trial Original Investigation | Hematology Effect of Inhaled Cannabis for Pain in Adults With Sickle Cell Disease A Randomized Clinical Trial Donald I. Abrams, MD; Paul Couey, BA; Niharika Dixit, MD; Varun Sagi, BAS; Ward Hagar, MD; Elliott Vichinsky, MD; Mary Ellen Kelly, MPH; John E. Connett, PhD; Kalpna Gupta, PhD 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. (continued) Key Points Question Is inhaled cannabis with an approximately 1:1 ratio of Δ-9-tetrahydrocannabinol to cannabidiol a safe and effective adjunct to opioids in adults with sickle cell disease–related pain? Findings This randomized clinical trial including 23 participants found that inhaled cannabis was safe. Inhaled cannabis was more effective than inhaled placebo in interference in mood, but there was no statistically significant difference in pain rating between cannabis and placebo. Meaning These findings suggest that cannabis should be investigated further in larger and longer clinical trials in adults with sickle cell disease with chronic pain as an adjunct or alternative to opioids. + Visual Abstract + Supplemental content Author affiliations and article information are listed at the end of this article. Open Access. This is an open access article distributed under the terms of the CC-BY License. JAMA Network Open. 2020;3(7):e2010874. doi:10.1001/jamanetworkopen.2020.10874 (Reprinted) July 17, 2020 1/11 Downloaded From: https://jamanetwork.com/ on 04/19/2021 https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.10874&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.10874 https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.10874&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.10874 Abstract (continued) 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 JAMA Network Open. 2020;3(7):e2010874. doi:10.1001/jamanetworkopen.2020.10874 Introduction Cannabis is currently available for medicinal use in 33 states and the District of Columbia.1 Pain is the principle reason individuals report for accessing cannabis from dispensaries nationwide.2 A report by the National Academies of Sciences, Engineering and Medicine3 cited pain as the therapeutic indication with the strongest evidence base in the published medical literature. However, little data from controlled human clinical trials are currently available to support the widespread use of medicinal cannabis in painful conditions, including sickle cell disease (SCD). Sickle cell disease is characterized by chronic pain with intermittent acute painful vasoocclusive crises. Recently, several new drugs have demonstrated effectiveness in preventing or decreasing the frequency of vasoocclusive crisis pain.4,5 However, therapies for chronic pain in SCD remain underinvestigated, although 55% of individuals with SCD report having pain more than 50% of the time.6 Opioids remain the mainstay for treatment, despite downsides that include constipation, pruritus, respiratory depression, and risk of addiction. The increasing incidence of opioid-associated deaths has further escalated opioid hesitancy among clinicians, potentially compromising the treatment of pain in SCD.7 An incomplete understanding of the mechanisms underlying SCD pain contributes to the lack of effective treatments.8 Pain in SCD is complex, demonstrating neuropathic as well as inflammatory characteristics.9 Likely contributors include systemic inflammation, neurogenic inflammation, oxidative stress, hypoxia and reoxygenation, vascular dysfunction, and end-organ damage. Preclinical studies suggest that cannabinoids may ameliorate pain and address the underlying pathophysiologic changes in SCD.10,11 Intraperitoneal CP55,940, a synthetic nonselective high affinity agonist of cannabinoid receptors 1 and 2 significantly reduced chronic and hypoxia–reoxygenation- evoked pain in HbSS-BERK sickle mice.10-12 These mice closely recapitulate clinical and pathophysiological features of SCD. Cannabinoids have analgesic and anti-inflammatory properties and may ameliorate mast cell activation, leukocyte trafficking and adhesion, neurogenic inflammation, oxidative stress, endothelial activation, and hyperalgesia via cannabinoid receptors 1 and 2.11,13 Several trials have suggested that cannabis may effectively treat neuropathic pain.1,14,15 In addition to the analgesic effects of Δ-9-tetrahydrocannabinol (THC), the main psychoactive cannabinoid in cannabis, there are anti-inflammatory and analgesic properties purportedly associated with cannabidiol (CBD).16,17 These findings provided the basis for conducting this human proof of principle study of the safety and effectiveness of vaporized cannabis in adults with SCD with chronic pain. Methods The study was approved by the institutional review boards at the University of California, San Francisco, and the University of Minnesota, as well as the Research Advisory Panel of California, Drug Enforcement Administration, Food and Drug Administration, and National Institute on Drug Abuse. Written informed consent was obtained from all participants prior to initiating the study. The study was conducted in the University of California, San Francisco, Clinical and Translational Science JAMA Network Open | Hematology Effect of Inhaled Cannabis for Pain in Adults With Sickle Cell Disease JAMA Network Open. 2020;3(7):e2010874. doi:10.1001/jamanetworkopen.2020.10874 (Reprinted) July 17, 2020 2/11 Downloaded From: https://jamanetwork.com/ on 04/19/2021 https://clinicaltrials.gov/ct2/show/NCT01771731 https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.10874&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.10874 Institute’s inpatient clinical research center at Zuckerberg San Francisco General Hospital. This study is reported following the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. Selection Criteria and Study Participants Adults with hemoglobin SS and chronic SCD-related pain receiving opioid analgesic therapy were enrolled between August 2014 and April 2017 (Trial Protocol and Statistical Analysis Plan in Supplement 1). All participants were using a stable pain medication regimen for at least 2 weeks. All participants were required to have prior experience smoking cannabis so they would know how to inhale and what neuropsychological effects to expect. Current users were asked to discontinue any cannabis use for 1 week prior to study admission. Because the Food and Drug Administration considered inhaled CBD to be a Novel Molecular Entity, participants were required to have prior CBD exposure so they would not be exposed to further risk. A negative pregnancy test result was required for women, and men and women were asked to use adequate birth control during the study. Exclusion criteria included severe coronary artery disease, uncontrolled hypertension, cardiac ventricular conduction abnormalities, orthostatic mean blood pressure drop of greater than 24 mm Hg, severe chronic obstructive pulmonary disease, history of renal or hepatic failure, evidence of clinically significant hepatic or renal dysfunction based on judgment of physician, active substance abuse, neurological dysfunction or psychiatric disorder severe enough to interfere with assessment of pain, current use of smoked tobacco products or a confirmed cotinine level, pregnant or breast- feeding women, or not practicing adequate birth control. Study Medication The National Institute on Drug Abuse provided cannabis plant material containing 4.4% THC and 4.9% CBD as well as placebo cannabis from which the cannabinoids had been extracted. The study medications were vaporized in a vaporizer (Model #0100; Volcano) heated to 190 °C.18 This device inflates a bag with vapors derived from heating the cannabis plant material; this process should not be confused with inhalation of a heated oil from an e-cigarette, known as vaping. We previously demonstrated that this vaporization procedure results in plasma THC levels similar to that of smoked cannabis without significant exposure to carbon monoxide and other combustion products.18 To standardize doses, participants followed a uniform Foltin puff procedure.19 Participants self-titrated their doses but were encouraged to inhale at least 1 full bag of vapor. Study Timeline and Procedures Eligible participants were admitted for 2 inpatient stays of 5 days and 4 nights in the clinical research center that were separated by at least 30 days. During 1 stay, participants inhaled vaporized cannabis 3 times daily, at 8 AM, 2 PM, and 8 PM; during the other stay, they inhaled vaporized placebo cannabis on the same schedule. Participants continued their outpatient analgesic regimen with additional inpatient analgesics prescribed as needed for increased pain. Participants who developed an acute painful crisis were transferred to the Zuckerberg San Francisco General Hospital emergency department for evaluation and admission as needed. Effects Monitoring Participants scored their chronic pain on a visual analogue scale from 0 to 100 administered on arrival and repeated daily, 2 hours after morning drug inhalation, during the admission. The Brief Pain Inventory was administered on day 1 and repeated on day 5.20 Participants were evaluated for side effects by nursing staff every 4 hours while awake. Statistical Analysis The study followed a crossover design. Each participant was exposed to a period of 5 inpatient days of either vaporized cannabis or vaporized placebo,