Assessing the Potential Anti-Neuroinflammatory Effect of Minocycline in Chronic Low Back Pain: Protocol for a randomized, double-blind, placebo-controlled trial

Abstract

ABSTRACTIntroductionChronic pain is an extremely prevalent public health issue. However, the underlying mechanisms are poorly understood, thus limiting effective treatment options. Both preclinical studies, and more recent clinical imaging studies, suggest that glia-mediated neuroinflammation may be implicated in chronic pain, and therefore might be a potential treatment target. However, it is currently unknown whether modulating neuroinflammation effectively alleviates pain in humans. This trial tests the hypothesis that minocycline, an FDA-approved tetracycline antibiotic and effective glial cell inhibitor in animals, reduces neuroinflammation and may reduce pain symptoms in humans with chronic low back pain.Methods and analysisThis study is a randomized, double-blind, placebo-controlled clinical trial. Subjects, aged 18-65, with a confirmed diagnosis of chronic (≥ six months) low back pain (cLBP) and a self-reported pain rating of at least four out of ten (for at least half of the days during an average week) are enrolled via written, informed consent. Eligible subjects are randomized to receive a 14-day course of either active drug (minocycline) or placebo. Before and after treatment, subjects are scanned with integrated Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) using [11C]PBR28, a second-generation radiotracer for the 18 kDa translocator protein (TSPO), which is highly expressed in glial cells and thus a putative marker of neuroinflammation. Pain levels are evaluated via daily surveys, collected seven days prior to the start of medication, and throughout the 14 days of treatment. General linear models are used to assess pain levels and determine the treatment effect on brain (and spinal cord) TSPO signal.Ethics and disseminationThis study was approved by the Massachusetts General Hospital Institutional Review Board (Protocol Number: 2017P000179) and the U.S. Food and Drug Administration (IND Number: 142546). The results of the study will be disseminated via publications in peer-reviewed journals, presentations at conferences globally, and through various media.Trial registration numberClinicalTrials.gov (NCT03106740)Strengths and limitations of this studyThis is the first project to image the potential neuro-inflammatory effect of minocycline in a chronic pain condition.The use of simultaneous PET/MRI allows us to collect additional, ancillary MRI data that can be used to perform a comprehensive neurophysiological assessment of subjects.The sample size (n∼50 per group) is relatively small to detect a clinical response. An additional limitation is the relatively short treatment duration (i.e., 2-weeks).