Study protocol for a phase II, double-blind, randomised controlled trial of cannabidiol (CBD) compared with placebo for reduction of brain neuroinflammation in adults with chronic low back pain

Chelsea K Pike, Minhae Kim, Kristina Schnitzer, Nathaniel Mercaldo, Robert Edwards, Vitaly Napadow, Yi Zhang, Erin Janas Morrissey, Zeynab Alshelh, A Eden Evins, Marco L Loggia, Jodi M Gilman, Chelsea K Pike, Minhae Kim, Kristina Schnitzer, Nathaniel Mercaldo, Robert Edwards, Vitaly Napadow, Yi Zhang, Erin Janas Morrissey, Zeynab Alshelh, A Eden Evins, Marco L Loggia, Jodi M Gilman

Abstract

Introduction: Chronic pain is a debilitating medical problem that is difficult to treat. Neuroinflammatory pathways have emerged as a potential therapeutic target, as preclinical studies have demonstrated that glial cells and neuroglial interactions play a role in the establishment and maintenance of pain. Recently, we used positron emission tomography (PET) to demonstrate increased levels of 18 kDa translocator protein (TSPO) binding, a marker of glial activation, in patients with chronic low back pain (cLBP). Cannabidiol (CBD) is a glial inhibitor in animal models, but studies have not assessed whether CBD reduces neuroinflammation in humans. The principal aim of this trial is to evaluate whether CBD, compared with placebo, affects neuroinflammation, as measured by TSPO levels.

Methods and analysis: This is a double-blind, randomised, placebo-controlled, phase II clinical trial. Eighty adults (aged 18-75) with cLBP for >6 months will be randomised to either an FDA-approved CBD medication (Epidiolex) or matching placebo for 4 weeks using a dose-escalation design. All participants will undergo integrated PET/MRI at baseline and after 4 weeks of treatment to evaluate neuroinflammation using [11C]PBR28, a second-generation radioligand for TSPO. Our primary hypothesis is that participants randomised to CBD will demonstrate larger reductions in thalamic [11C]PBR28 signal compared with those receiving placebo. We will also assess the effect of CBD on (1) [11C]PBR28 signal from limbic regions, which our prior work has linked to depressive symptoms and (2) striatal activation in response to a reward task. Additionally, we will evaluate self-report measures of cLBP intensity and bothersomeness, depression and quality of life at baseline and 4 weeks.

Ethics and dissemination: This protocol is approved by the Massachusetts General Brigham Human Research Committee (protocol number: 2021P002617) and FDA (IND number: 143861) and registered with ClinicalTrials.gov. Results will be published in peer-reviewed journals and presented at conferences.

Trial registration number: NCT05066308; ClinicalTrials.gov.

Keywords: Back pain; Clinical trials; Magnetic resonance imaging; NEUROPHYSIOLOGY; PAIN MANAGEMENT.

Conflict of interest statement

Competing interests: The study drug was donated by Jazz Pharmaceuticals. MLL consulted for Shionogi in 2018. AEE reported receiving grants from Charles River Analytics and nonfinancial support from Pfizer as well as serving as the chair of the data monitoring board of Karuna Pharmaceuticals outside the submitted work. VN consults for Cala Health, Inc. and Click Therapeutics, Inc.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Study schema. CBD, cannabidiol; cLBP, chronic low back pain.

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