PMID- 30079432 OWN - NLM STAT- MEDLINE DCOM- 20181211 LR - 20200611 IS - 1432-2072 (Electronic) IS - 0033-3158 (Print) IS - 0033-3158 (Linking) VI - 235 IP - 10 DP - 2018 Oct TI - Assessment of pioglitazone and proinflammatory cytokines during buprenorphine taper in patients with opioid use disorder. PG - 2957-2966 LID - 10.1007/s00213-018-4986-5 [doi] AB - BACKGROUND: Preliminary evidence suggested that the PPARgamma 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. FAU - Schroeder, Jennifer R AU - Schroeder JR AD - Johns Hopkins Bayview Medical Center, Baltimore, MD, 21224, USA. FAU - Phillips, Karran A AU - Phillips KA AD - National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 251 Bayview Blvd., BRC Building, Suite 200, Baltimore, MD, 21224, USA. FAU - Epstein, David H AU - Epstein DH AD - National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 251 Bayview Blvd., BRC Building, Suite 200, Baltimore, MD, 21224, USA. FAU - Jobes, Michelle L AU - Jobes ML AD - National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 251 Bayview Blvd., BRC Building, Suite 200, Baltimore, MD, 21224, USA. FAU - Furnari, Melody A AU - Furnari MA AD - National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 251 Bayview Blvd., BRC Building, Suite 200, Baltimore, MD, 21224, USA. FAU - Kennedy, Ashley P AU - Kennedy AP AD - National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 251 Bayview Blvd., BRC Building, Suite 200, Baltimore, MD, 21224, USA. FAU - Heilig, Markus AU - Heilig M AD - Center for Social and Affective Neuroscience, IKE, Linkoping Univ, 58183, Linkoping, Sweden. FAU - Preston, Kenzie L AU - Preston KL AUID- ORCID: 0000-0003-0603-2479 AD - National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, 251 Bayview Blvd., BRC Building, Suite 200, Baltimore, MD, 21224, USA. kpreston@intra.nida.nih.gov. LA - eng SI - ClinicalTrials.gov/NCT01517165 GR - ZIA DA000624/Intramural NIH HHS/United States GR - Z01 DA000536/National Institute on Drug Abuse/ PT - Journal Article PT - Randomized Controlled Trial DEP - 20180806 PL - Germany TA - Psychopharmacology (Berl) JT - Psychopharmacology JID - 7608025 RN - 0 (Analgesics, Opioid) RN - 0 (Cytokines) RN - 0 (Narcotic Antagonists) RN - 40D3SCR4GZ (Buprenorphine) RN - X4OV71U42S (Pioglitazone) SB - IM MH - Adult MH - Analgesics, Opioid/*therapeutic use MH - Buprenorphine/*therapeutic use MH - Cytokines/blood/cerebrospinal fluid MH - Double-Blind Method MH - Female MH - Humans MH - Male MH - Middle Aged MH - Narcotic Antagonists/*therapeutic use MH - Opiate Substitution Treatment/*methods MH - Opioid-Related Disorders/blood/cerebrospinal fluid/*drug therapy MH - Pioglitazone/*therapeutic use MH - Substance Withdrawal Syndrome/drug therapy PMC - PMC7286070 MID - NIHMS1592103 OTO - NOTNLM OT - Buprenorphine OT - Cytokines OT - Opioid dependence OT - Opioid withdrawal OT - Pioglitazone COIS- Compliance with ethical standards Conflict of interest The authors declare that they have no conflict of interest. EDAT- 2018/08/07 06:00 MHDA- 2018/12/12 06:00 PMCR- 2020/06/10 CRDT- 2018/08/07 06:00 PHST- 2017/08/09 00:00 [received] PHST- 2018/07/24 00:00 [accepted] PHST- 2018/08/07 06:00 [pubmed] PHST- 2018/12/12 06:00 [medline] PHST- 2018/08/07 06:00 [entrez] PHST- 2020/06/10 00:00 [pmc-release] AID - 10.1007/s00213-018-4986-5 [pii] AID - 10.1007/s00213-018-4986-5 [doi] PST - ppublish SO - Psychopharmacology (Berl). 2018 Oct;235(10):2957-2966. doi: 10.1007/s00213-018-4986-5. Epub 2018 Aug 6.