CLINICAL NEWS
Written in Blood
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-PE O–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
52
ASH Clinical News
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.”
“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.”
–RYAN HUNT, MD
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 fr equency, 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]
December 2016