OREX-1038: A potential new treatment for pain with low abuse liability and limited adverse effects

Lisa R. Gerak, David R. Maguire, Gerta Cami-Kobeci, Keith M. Olson, John R. Traynor, Stephen M. Husbands, Charles P. France, Lisette Acevedo, Barbara Belli, Peter Flynn

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Drugs targeting mu opioid receptors are the mainstay of clinical practice for treating moderate-to-severe pain. While they can offer excellent analgesia, their use can be limited by adverse effects, including constipation, respiratory depression, tolerance, and abuse liability. Multifunctional ligands acting at mu opioid and nociceptin/orphanin FQ peptide receptors might provide antinociception with substantially improved adverse-effect profiles. This study explored one of these ligands, OREX-1038 (BU10038), in several assays in rodents and nonhuman primates. Binding and functional studies confirmed OREX-1038 to be a low-efficacy agonist at mu opioid and nociceptin/orphanin FQ peptide receptors and an antagonist at delta and kappa opioid receptors with selectivity for opioid receptors over other proteins. OREX-1038 had long-acting antinociceptive effects in postsurgical and complete Freund's adjuvant (CFA)-induced thermal hyperalgesia assays in rats and a warm water tail-withdrawal assay in monkeys. OREX-1038 was active for at least 24 h in each antinociception assay, and its effects in monkeys did not diminish over 22 days of daily administration. This activity was coupled with limited effects on physiological signs (arterial pressure, heart rate, and body temperature) and no evidence of withdrawal after administration of naltrexone or discontinuation of treatment in monkeys receiving OREX-1038 daily. Over a range of doses, OREX-1038 was only transiently self-administered, which diminished rapidly to nonsignificant levels; overall, both OREX-1038 and buprenorphine maintained less responding than remifentanil. These results support the concept of dual mu and nociceptin/orphanin FQ peptide receptor partial agonists having improved pharmacological profiles compared with opioids currently used to treat pain.

Original languageEnglish
Pages (from-to)377-394
Number of pages18
JournalBehavioural Pharmacology
Issue number6
Publication statusPublished - 1 Sept 2022

Bibliographical note

Industrial funding; the majority of this work was funded by Orexigen Therapeutics Inc. LA, BB, and PF were employed by Orexigen Therapeutics while engaged in this research project. SMH is an inventor on the patent that describes OREX-1038/BU10038 and was a consultant to Orexigen Therapeutics during this project. Other sources of support include the National Institutes of Health [Grant R37DA039997 (JRT) and T32DA007268 (KMO; PI:JRT)] and the Welch Foundation [Grant AQ-0039 (CPF)].


  • antinociception
  • dependence
  • opioids
  • OREX-1038
  • rat
  • self-administration
  • tolerance

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health


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