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Assessment of pioglitazone and proinflammatory cytokines during buprenorphine taper in patients with opioid use disorder

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Abstract

Background

Preliminary evidence suggested that the PPARγ agonist pioglitazone reduces opioid-withdrawal symptoms, possibly by inhibiting increases in proinflammatory cytokines.

Methods

A randomized, placebo-controlled clinical trial was conducted utilizing two different study designs (entirely outpatient, and a combination of inpatient and outpatient) to evaluate the safety and efficacy of pioglitazone as an adjunct medication for people with opioid physical dependence undergoing a buprenorphine taper. Participants were stabilized on buprenorphine/naloxone (sublingual, up to 16/4 mg/day), then randomized to receive oral pioglitazone (up to 45 mg/day) or placebo before, during, and after buprenorphine taper. Outcome measures included the Subjective Opiate Withdrawal Scale (SOWS) and Clinical Opiate Withdrawal Scale, use of rescue medications to alleviate opioid withdrawal symptoms, and opioid-positive urine specimens. Cerebrospinal fluid (CSF) and plasma were collected during the taper in a subset of participants for measurement of proinflammatory cytokines.

Results

The clinical trial was prematurely terminated due to slow enrollment; 40 participants per group were required for adequate statistical power to test study hypotheses. Twenty-four participants enrolled; 17 received at least one dose of study medication (6 pioglitazone, 11 placebo). SOWS scores were higher in the pioglitazone arm than in the placebo arm after adjusting for use of rescue medications; participants in the pioglitazone arm needed more rescue medications than the placebo arm during the post-taper phase. SOWS scores were positively correlated with monocyte chemoattractant protein-1 (MCP-1) in CSF (r = 0.70, p = 0.038) and plasma (r = 0.77, p = 0.015). Participants having higher levels of plasma MCP-1 reported higher SOWS, most notably after the buprenorphine taper ended.

Conclusions

Results from this study provide no evidence that pioglitazone reduces opioid withdrawal symptoms during buprenorphine taper. High correlations between MCP-1 and opioid withdrawal symptoms support a role of proinflammatory processes in opioid withdrawal.

Trial registration

clinicaltrials.gov identifier: NCT01517165

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Funding

This study was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, and the Swedish Research Council.

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Authors and Affiliations

  1. Johns Hopkins Bayview Medical Center, Baltimore, MD, 21224, USA

    Jennifer R. Schroeder

  2. National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 251 Bayview Blvd., BRC Building, Suite 200, Baltimore, MD, 21224, USA

    Karran A. Phillips, David H. Epstein, Michelle L. Jobes, Melody A. Furnari, Ashley P. Kennedy & Kenzie L. Preston

  3. Center for Social and Affective Neuroscience, IKE, Linköping Univ, 58183, Linköping, Sweden

    Markus Heilig

Authors
  1. Jennifer R. Schroeder
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  2. Karran A. Phillips
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  3. David H. Epstein
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  4. Michelle L. Jobes
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  5. Melody A. Furnari
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  6. Ashley P. Kennedy
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  7. Markus Heilig
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  8. Kenzie L. Preston
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Correspondence to Kenzie L. Preston.

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The authors declare that they have no conflict of interest.

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Schroeder, J.R., Phillips, K.A., Epstein, D.H. et al. Assessment of pioglitazone and proinflammatory cytokines during buprenorphine taper in patients with opioid use disorder. Psychopharmacology 235, 2957–2966 (2018). https://doi.org/10.1007/s00213-018-4986-5

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  • DOI: https://doi.org/10.1007/s00213-018-4986-5

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