title: A mechanistic investigation of thrombotic microangiopathy associated with IV abuse of Opana ER.
abstract: Since 2012, a number of case reports have described the occurrence of thrombotic microangiopathy (TMA) following IV abuse of extended-release oxymorphone hydrochloride (Opana ER), an oral opioid for long-term treatment of chronic pain. Here, we present unique clinical features of 3 patients and investigate IV exposure to the tablet's inert ingredients as a possible causal mechanism. Guinea pigs were used as an animal model to understand the hematopathologic and nephrotoxic potential of the inert ingredient mixture (termed here as PEO+) which primarily contains high-molecular-weight polyethylene oxide (HMW PEO). Microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury were found in a group of 3 patients following recent injection of adulterated extended-release oxymorphone tablets. Varying degrees of cardiac involvement and retinal ischemia occurred, with TMA evident on kidney biopsy. A TMA-like state also developed in guinea pigs IV administered PEO+. Acute tubular and glomerular renal injury was accompanied by nonheme iron deposition and hypoxia-inducible factor-1α upregulation in the renal cortex. Similar outcomes were observed following dosing with HMW PEO alone. IV exposure to the inert ingredients in reformulated extended-release oxymorphone can elicit TMA. Although prescription opioid abuse shows geographic variation, all physicians should be highly inquisitive of IV drug abuse when presented with cases of TMA.
authors.affiliation: Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies and.
authors.forename: Ryan
authors.identifier: 0000-0003-1418-9919
authors.initials: R
authors.lastname: Hunt
authors.affiliation: Division of Blood Components and Devices, Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.
authors.forename: Ayla
authors.identifier: 0000-0002-0203-9297
authors.initials: A
authors.lastname: Yalamanoglu
authors.affiliation: Department of Internal Medicine, University of Tennessee College of Medicine at Chattanooga, Chattanooga, TN.
authors.forename: James
authors.initials: J
authors.lastname: Tumlin
authors.affiliation: Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies and.
authors.forename: Tal
authors.initials: T
authors.lastname: Schiller
authors.affiliation: Division of Blood Components and Devices, Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.
authors.forename: Jin Hyen
authors.initials: JH
authors.lastname: Baek
authors.affiliation: Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies and.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wu
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Agnes B
authors.initials: AB
authors.lastname: Fogo
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN.
authors.forename: Haichun
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Pediatrics and.|Department of Pathology, George Washington School of Medicine and Health Sciences, Washington, DC.|Department of Coagulation, Quest Diagnostics/Nichols Institute, Chantilly, VA; and.
authors.forename: Edward
authors.initials: E
authors.lastname: Wong
authors.affiliation: Section on Hematology and Oncology, Department of Internal Medicine.|Section on Pulmonary, Critical Care, Allergy and Immunology, and.|Section on Critical Care Medicine, Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Peter
authors.initials: P
authors.lastname: Miller
authors.affiliation: Division of Blood Components and Devices, Office of Blood Research and Review, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, MD.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Buehler
authors.affiliation: Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies and.
authors.forename: Chava
authors.initials: C
authors.lastname: Kimchi-Sarfaty
mesh_terms: D058186:Acute Kidney Injury / Q000097:blood / Q000139:chemically induced / Q000150:complications / Q000473:pathology; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008297:Male; D010111:Oxymorphone / Q000008:administration & dosage / Q000009:adverse effects*; D011092:Polyethylene Glycols / Q000009:adverse effects; D057049:Thrombotic Microangiopathies / Q000097:blood / Q000139:chemically induced* / Q000150:complications / Q000473:pathology*
chemical_list: D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D011092:Polyethylene Glycols; D010111:Oxymorphone