Examining the Association Between Misuse of the Opioid Oxymorphone and Cases of Thrombotic Microangiopathy

Ingredient mixtures added to oral prescription opioid formulations to deter misuse and abuse have the unfortunate side effect of increasing the risk of developing thrombotic microangiopathy (TMA), according to results from an animal study published in Blood.

Prescription opioids are effective analgesics in the setting of severe and chronic pain, but their high potential for dependency and abuse has created what the U.S. Department of Health & Human Services has termed “The Opioid Epidemic.” According to the Centers for Disease Control & Prevention (CDC), misuse and abuse of prescription opioids “commonly involves crushing, heating and liquid extraction of tablets followed by nasal inhalation or injection.”
In 2012, the manufacturer of extended-release oxymorphone hydrochloride developed a new oral formulation of the drug that contained a high-molecular-weight polyethylene oxide (HMW-PEO), a crush-resistant ingredient mixture of hypromelloses, macrogol, alpha-tocopherol, and citric acid.

The authors investigated the association between injection of this new HMW-PEO–containing formulation and TMA in human patients and guinea pigs based on prior reports of patients with opioid injection abuse experiencing thrombocytopenia, microangiopathic hemolytic anemia, and renal failure and based on previous animal research.

“Syndromes of TMA [associated with opioid abuse] include a variety of pathogenic mechanisms with unique approaches to care [ranging] from early plasma exchange therapy to aggressive supportive care alone, but the mechanistic basis for these cases of TMA remains unclear,” Ryan Hunt, MD, from the Hematology Division of the Office of Blood Research and Review and the Center for Biologics Evaluation and Research at the U.S. FDA in Silver Spring, Maryland, wrote. “We show that the inert ingredients generate an acute hematotoxicity and kidney injury, consistent with a mechanistic link between the tablet’s constituents and cases of TMA following its intravenous abuse in humans.”

Dr. Hunt and authors reported on the clinical features of patients who presented with TMA during intravenous abuse of extended-release HMW-PEO oxymorphone tablets, and investigated the exposure to the tablet’s inert ingredients as a possible causal mechanism in an animal model of three guinea pigs.

The authors identified three patients who experienced TMA following intravenous abuse of extended-release oxymorphone: two female and one male patient who presented to the emergency department of Erlanger Medical Center in Chattanooga, Tennessee, with complaints of chest pain, dyspnea, and varying degrees of visual impairment.

Two patients had acute renal failure and all three had marked anemia and thrombocytopenia. Laboratory data revealed elevated lactate dehydrogenase and undetectable serum haptoglobin levels.

Dr. Hunt and authors also described cardiac involvement and atypical clinical features of TMA (including pulmonary involvement and dyspnea), which was not observed in previous case reports. All three patients had elevated troponin levels, and the male patient’s electrocardiogram revealed diffuse ST segment elevation and PR segment depression – features consistent with acute pericarditis. Evidence of foreign material within the plasma of these three patients was also found. Peripheral blood smears showed features consistent with macroangiopathic hemolytic anemia.

The patients were started on plasma exchange therapy until ADAMTS13 levels could be determined; the male patient also required hemodialysis throughout his hospitalization. Kidney biopsies, which were performed in two patients, confirmed TMA. Plasma exchange was continued through at least five cycles, and all patients demonstrated complete or partial recovery of renal function prior to discharge.

All three patients’ vision worsened during hospitalization, with the male patient developing near total blindness. He was discharged with chronic renal disease (serum creatinine 2.3 mg/dL) and continued to intravenously abuse oxymorphone. “He was admitted a second time with TMA and became hemodialysis-dependent. With continued abuse, he died approximately 18 months after his initial presentation,” the authors reported. “The other two patients were not re-admitted and lost to follow-up.”

To investigate the hematoxic potential of the tablet’s inert ingredients, Dr. Hunt and authors simulated intravenous abuse by crushing 14 mg of HMW-PEO (the amount of inert ingredients that would likely be extracted and delivered through a typical adulteration process) into a solution, then administered the solution intravenously to the three guinea pigs in three different injection frequencies. Blood samples were obtained at baseline, four, eight, 24, and 48 hours after initial injection to analyze red blood cell count, hematocrit, platelet count, and concentration of PEO. Tissue samples were also collected for histopathologic examination.

“Assuming complete distribution within the plasma volume of a 70 kg adult, the resulting plasma concentration of HMW-PEO would be approximately 5 μg/mL,” the authors noted.

The authors also observed a dose-dependent effect of HMW-PEO administration, finding “an abrupt, dose-dependent increase in free hemoglobin in the plasma accompanied by modest declines in total RBC hemoglobin, hematocrit, and platelet count with HMW-PEO dosing.”

Animals who received multiple doses of HMW-PEO appeared to have more substantial kidney damage than those who received single doses. For example, multi-dosed guinea pigs had significant elevations of plasma creatinine, with a two- and four-fold increase over control animals at 24 hours. Iron content was elevated in all animals.

Injections of the inert ingredients elicited “hallmark features” of TMA, which the authors attributed to a state of high shear stress in the microvasculature of guinea pigs injected with the HMW-PEO oxymorphone formulation. Previous research has shown that HMW polymers “decrease the thickness of the cell-free plasma layer that naturally abuts the microvascular wall, directing RBC traffic more proximal to the vessel wall, thereby generating increased wall shear stress.”

“Abuse-deterrent formulations (ADFs) are an important mechanism to limit prescription opioid misuse and are part of the FDA’s comprehensive action plan to address the public health crisis of opioid addiction, abuse, and overdose,” the authors noted. “However, this study demonstrates a potential for HMW-PEO–based deterrent formulations to cause hematoxicity, TMA, and end-organ injury in the setting of intravenous misuse.”

One limitation of the study is the small number of cases in a region that has been known to have a high concentration of injection abuse of prescription opioids, and the results might not be generalizable to other areas in the United States. Using the animal model, the authors also had to make assumptions about the variation in injection frequency, which may not reflect real-world conditions. However, they added that “all physicians should be highly inquisitive of intravenous drug abuse when presented with cases of TMA.”


Reference

Hunt R, Yalamanoglu A, Tumlin J, et al. A mechanistic investigation of thrombotic microangiopathy associated with intravenous abuse of Opana ER. Blood. 2016 November 18. [Epub ahead of print]

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