Circadian rhythmicity and biopsychosocial characteristics influence opioid use in chronic low back pain
Doriana Taccardi, Amanda M. Zacharias, Hailey G.M. Gowdy, Mitra Knezic, Marc Parisien, Etienne J. Bisson, Zhi Yi Fang, Sara A. Stickley, Elizabeth Brown, Daenis Camiré, Rosemary Wilson, Lesley N. Singer, Jennifer Daly-Cyr, Manon Choinière, Zihang Lu, M. Gabrielle Pagé, Luda Diatchenko, Qingling Duan, Nader Ghasemlou
Doriana Taccardi, Amanda M. Zacharias, Hailey G.M. Gowdy, Mitra Knezic, Marc Parisien, Etienne J. Bisson, Zhi Yi Fang, Sara A. Stickley, Elizabeth Brown, Daenis Camiré, Rosemary Wilson, Lesley N. Singer, Jennifer Daly-Cyr, Manon Choinière, Zihang Lu, M. Gabrielle Pagé, Luda Diatchenko, Qingling Duan, Nader Ghasemlou
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Clinical Research and Public Health Clinical Research Inflammation Neuroscience

Circadian rhythmicity and biopsychosocial characteristics influence opioid use in chronic low back pain

Abstract

BACKGROUND Inter- and intraindividual fluctuations in pain intensity pose a major challenge to treatment efficacy, with a majority of people perceiving their pain relief as inadequate. Recent preclinical studies have identified circadian rhythmicity as a potential contributor to these fluctuations and a therapeutic target.METHODS We therefore sought to determine the impact of circadian rhythms in people with chronic low back pain (CLBP) through a detailed characterization, including questionnaires to evaluate biopsychosocial characteristics, ecological momentary assessment (7 day e-diaries at 8:00/14:00/20:00) to observe pain fluctuations, and intraday blood transcriptomics (at 8:00/20:00) to identify genes/pathways of interest.RESULTS While most individuals displayed constant or variable/mixed pain phenotypes, a distinct subset had daily fluctuations of increasing pain scores (>30% change in intensity over 12 hours in ≥4/7 days). This population had no opioid users, better biopsychosocial profiles, and differentially expressed transcripts relative to other pain phenotypes. The circadian-governed neutrophil degranulation pathway was particularly enriched among arrhythmic individuals; the link between neutrophil degranulation and opioid use was further confirmed in a separate CLBP cohort.CONCLUSION Our findings identified pain rhythmicity and the circadian expression of neutrophil degranulation pathways as indicators of CLBP outcomes, which may help provide a personalized approach to phenotyping biopsychosocial characteristics and medication use. This highlights the need to better understand the impact of circadian rhythmicity across chronic pain conditions.FUNDING This work was funded by grants from the Canadian Institutes of Health Research (CIHR; grant PJT-190170, to NG and MGP) and the CIHR-Strategy for Patient-Oriented Research Chronic Pain Network (grant SCA-145102, to NG, QD, LD, MGP, and MC). DT was funded by a MS Canada endMS Doctoral Research Award, AMZ by an Ontario Graduate Scholarship, HGMG by a CIHR Doctoral Research Award, MGP by a Junior 2 Research Scholarship from the Fonds de recherche du Québec – Santé, and LD by a Canadian Excellence Research Chairs and Pfizer Canada Professorship in Pain Research.

Authors

Doriana Taccardi, Amanda M. Zacharias, Hailey G.M. Gowdy, Mitra Knezic, Marc Parisien, Etienne J. Bisson, Zhi Yi Fang, Sara A. Stickley, Elizabeth Brown, Daenis Camiré, Rosemary Wilson, Lesley N. Singer, Jennifer Daly-Cyr, Manon Choinière, Zihang Lu, M. Gabrielle Pagé, Luda Diatchenko, Qingling Duan, Nader Ghasemlou

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Figure 4

Previous findings were replicated in an independent transcriptomic LBP cohort.

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Previous findings were replicated in an independent transcriptomic LBP c...
(A) Transcriptomics study design. Whole-blood transcriptomics were determined at a baseline visit (t0) and at a 3 month follow-up visit (t1), enabling tracking of gene expression with time in those using opioids and in those who were not. Regression of gene expression on an opioid use × time interaction term determines if the time trajectory of expression of a gene in opioid users (orange) differs from those not using (gray). The sign of the effect of the interaction term will illustrates how the time trajectory of nonusers must be rotated to match that of users, in this case, counterclockwise when positive (black curved arrow). (B) Number of opioid users versus number of participants whose acute back pain resolved by the time of the follow-up visit. OR and 95% CI are indicated for pain persistence versus opioid intake. (C) Enrichment of activation pathways across cell types. Enrichment for cell degranulation pathways across cell types of hemopoietic lineage. Bars in green indicate FDR < 1%. (D) Pathway enrichment plot for the neutrophil degranulation pathway. All genes were ranked from the most positive effect of opioid use × time (left) to the most negative (right). Genes in the neutrophil degranulation pathway are shown (vertical green bars), along with the 3 top-ranking genes (far left). The pathway’s enrichment score and unadjusted P value are indicated.