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Randomized Controlled Trial
. 2018 Oct;235(10):2957-2966.
doi: 10.1007/s00213-018-4986-5. Epub 2018 Aug 6.

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

Jennifer R Schroeder  1 , Karran A Phillips  2 , David H Epstein  2 , Michelle L Jobes  2 , Melody A Furnari  2 , Ashley P Kennedy  2 , Markus Heilig  3 , Kenzie L Preston  4
Affiliations
Randomized Controlled Trial

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

Jennifer R Schroeder et al. Psychopharmacology (Berl). 2018 Oct.

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.

Keywords: Buprenorphine; Cytokines; Opioid dependence; Opioid withdrawal; Pioglitazone.

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Conflict of interest statement

Compliance with ethical standards

Conflict of interest The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
CONSORT diagram showing participant disposition for the outpatient and inpatient versions of the study
Fig. 2
Fig. 2
Time trends in SOWS scores with rescue-medication use and urine opioid results for participants receiving pioglitazone (3 inpatients, 3 outpatients). The time points in the figure represent the portion of the study during which participants were receiving pioglitazone. The duration of the buprenorphine taper was 28 days for participants enrolled in the initial outpatient study design, and 13 days for participants enrolled in the subsequent inpatient study design. The color of the marker indicates opioid positivity (positive = black, negative = gray, not tested = white) while marker shape indicates use of adjunct medications (diamond = yes, circle = no). Participant sex (F = female, M = male) is indicated in parentheses
Fig. 3
Fig. 3
Time trends in SOWS scores with rescue-medication use and urine opioid results for participants receiving placebo (3 inpatients, 6 outpatients). The time points in the figure represent the portion of the study during which participants were receiving pioglitazone placebo. The duration of the buprenorphine taper was 28 days for participants enrolled in the initial outpatient study design, and 13 days for participants enrolled in the subsequent inpatient study design. The color of the marker indicates opioid positivity (positive = black, negative = gray, not tested = white) while marker shape indicates use of adjunct medications (diamond = yes, circle = no). Participant sex (F = female, M = male) is indicated in parentheses
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