Investigators Probe Kidney Effects of Opioid Abuse, Misuse

An uptick of thrombotic microangiopathy (TMA) cases with a presentation similar to that of a rare blood disorder, thrombotic thrombocytopenic purpura, at Wake Forest Baptist Health in Winston-Salem, North Carolina, tipped off hematologist Peter Miller, MD, that something unusual was going on. An assistant professor at Wake Forest University, Miller had read a report from the U.S. Centers for Disease Control and Prevention (CDC) about similar cases linked to the illicit intravenous injection of a newly reformulated version of extended-release oxymorphone, Opana ER, so he and his colleagues began asking patients with suspected cases whether they had injected this oral medication.

“As soon as we did that, it was very evident we were on the verge of a crisis in our local area,” Miller said.

North Carolina is one of many states grappling with an ongoing epidemic of opioid abuse and addiction. In 2017 alone, the state’s emergency departments treated 5762 opioid overdoses—a 25.5% increase over the 4177 opioid overdose–related visits in 2016, according to the North Carolina Injury and Violence Prevention Branch. This mirrors a nationwide 30% increase in opioid overdose visits to emergency departments during that same period, according to the CDC.

For physicians like Miller and his colleagues, little data is available on the potential kidney risks associated with such opioid abuse, so they and other researchers have tried to fill the gaps. Some studies have found increased kidney risks associated with illicit opioid use, but how such use may harm the kidney isn’t clear.

“It’s still very much a black box,” said Tess Novick, MD, a nephrology clinical fellow at Johns Hopkins University in Baltimore.

Kidney health and drug abuse

Before entering medical school, Novick was a social worker at a methadone clinic. Now she’s interested in understanding whether or how prescription opioid and illicit drug use may affect kidney health.

“Kidney disease might be significantly impacted by both illicit and prescription drug use,” Novick said.

In 2016, she and her colleagues published a prospective cohort study of 2286 people participating in the Healthy Aging in Neighborhoods of Diversity study, which found that lifetime use of opioids was associated with greater odds of a reduced estimated GFR (odds ratio [OR] 2.71, 95% confidence interval [CI] 1.5–4.89) and a greater likelihood of albuminuria (OR 1.20, 95% CI 0.83–1.73). In that sample, about 15% of participants reported lifetime illicit use of opioids, including 13.6% who reported nonmedical use of prescription opioids and 1.8% who reported use of heroin.

“The opioid epidemic has gotten significantly worse since [those data were collected],” Novick said. “It was just starting to become an issue when we started looking at this.”

Not all studies have found that increased risks to the kidney are associated with illicit drug use. But circumstances linked to inappropriate use of opioids, such as overdose-related dehydration, hypotension, rhabdomyolysis, and urine retention, can cause acute kidney injury (AKI), noted a recent review by Mary Mallappallil, MD, assistant professor at the State University of New York at Downstate Brooklyn, and colleagues.

Studying the health effects of illicit drug use is particularly challenging. Novick explained that studies often rely on self-reporting of drug use, which may not always be reliable. Changing patterns of substance abuse, including evolving methods of drug administration, varying drug formulations, adulterants, and often exposure to multiple toxins can make studying them a moving target that is hard to keep up with. For example, Mallappallil and her colleagues noted that cases of heroin-associated nephropathy, first described in the 1970s, appear to have been linked to adulterants.

Many basic questions still need to be answered about the potential kidney health effects of opioids themselves, including potential mechanisms of harm. Novick is now studying whether the risks associated with using opioid medications are different in patients with chronic kidney disease (CKD). She noted that many opioids are excreted by the kidney and that the drug’s metabolism may be affected by poor kidney function, which might put patients at increased risk of opioid-related adverse events like overdose, death, central nervous system depression, or respiratory depression. “We don’t know if the risk is different in patients with kidney disease, but theoretically they might be at increased risk because of their impaired ability to excrete these medications.”

Mallapallil noted the importance of recognizing that changes in liver or kidney function can affect drug metabolism. Sometimes even physicians aren’t aware that potential changes in drug metabolism may affect the safety of opioid medication use. She noted that there is evidence of medical misuse, leading to urine retention or rhabdomyolysis and eventually causing CKD.

“The liver and the kidney are the 2 main cleaning houses of toxins and medications,” she said. “If both or one is affected to the point it could change drug metabolism, we assume that it may be okay, but it may not be.”

AKI risks?

Many of the patients treated at Wake Forest after the intravenous abuse of extended-release oral oxymorphone received diagnoses of AKI, Miller said. So he and his colleagues followed up with an analysis of AKI in patients with a history of such use. They found that 47.8% of the 165 patients seen at Wake Forest in January 2012 and December 2015 with a history of such substance use had AKI. Most (59.4%) recovered from the kidney injury, but 13.9% experienced progression to ESRD, and 7.6% died at the hospital.

“We were able to determine that those that had the lowest degree of kidney injury tended to recover the most and the fastest,” he said. “Those that had higher degrees of kidney injury had the lowest rate of recovery, and if they recovered, it took the longest.”

The exact cause of the kidney injuries in these patients isn’t clear. Many patients also had bacterial infections or were treated with drugs like vancomycin that can affect kidney function, Miller and his co-authors note. But a possible theory is that high-molecular-weight polyethylene oxide in the reformulated extended-release Opana may have contributed, Miller said. He collaborated on a study with U.S. Food and Drug Administration (FDA) scientists, which found that injecting guinea pigs with high-molecular-weight polyethylene oxide was associated with TMA and renal injury.

“We can’t 100% say that is what it was, because it is likely multifactorial, but it seems to be something that is highly suspicious as the cause,” Miller said.

In June 2017, the FDA requested that Opana ER be removed from the market, citing abuse-related concerns. One month later, the company voluntarily removed the product from the market while defending its risk–benefit profile.

“The abuse and manipulation of reformulated Opana ER by injection has resulted in a serious disease outbreak,” said Janet Woodcock, MD, director of the FDA’s Center for Drug Evaluation and Research in a news release at the time. “When we determined that the product had dangerous unintended consequences, we made a decision to request its withdrawal from the market.”

The consequences of intravenous abuse, or repeated abuse, of extended-release oxymorphone may not yet be completely evident with regard to kidney injury. Miller noted that some patients who experienced AKI may not be aware of it if they were not hospitalized.

Novick said that it’s important for physicians to recognize that lifetime illicit drug use might be a risk factor for kidney disease. Miller noted that a history of intravenous drug use may also be a consideration in the creation of a permanent access for dialysis, which he and his colleagues worry could be used as a route of further abuse. To make sure patients receive appropriate and safe care, he said, it has become routine at his institution to ask patients throughout the hospital if they have a history of drug abuse.

“It’s almost become second nature to ask almost every single patient,” he said.