A study and commentary in The Lancet highlight unique challenges posed by controlled-release drugs.
The ongoing opioid epidemic in the United States has been linked with a number of collateral public health challenges, including case clusters of hepatitis C and HIV, homelessness, and, of course, both intentional and unintentional overdose deaths.
Although, to date, much of the evidence tying these various issues together has been anecdotal—albeit compelling—that may be changing now. A study published in The Lancet has concluded that risk for infective endocarditis (IE) is significantly higher for those exposed to controlled-release hydromorphone, one of many prescription opioid analgesics associated with the abuse epidemic, than it is among users of other drugs in the class.
The authors of the study suggest that this elevated risk may be due to drug’s “mechanism,” and recommend that that be the focus of future research on the relationship.
“I think in Canada we have enough data [showing] that [the drug] should be removed from the market or at least have some restrictions on its use instituted,” study co-author Matthew Weir, MD, a nephrologist—more on that in a moment—at Western University in London (Ontario), told Contagion®.
For their research, Weir and his colleagues used administrative databases in Ontario, Canada, to create a retrospective cohort of adults between 18 and 55 years of age who injected drugs between April 2006 and September 2015. They then identified cases of IE within this cohort, estimating exposure to hydromorphone and risk for the disease via a population-level and patient-level analysis.
For the population-level analysis, they identified those living in regions with high (≥25%) and low (≤15%) hydromorphone prescription rates and compared the incidence of IE among users and nonusers (matched as controls). For the patient-level analysis, they isolated those who had filled prescriptions for controlled-release or immediate-release hydromorphone and compared the incidence of IE in this group with that of patients who had filled prescriptions for other opioids.
In all, more than 60,000 people included in their analysis had evidence of injection drug use, of whom 733 (1.2%) had IE. And, among more than 32,000 matched patients, the team found that there were 254 (1.6%) admissions for IE in areas with high hydromorphone use compared to 113 (0.7%) in areas with low use.
In addition, they also noted that the incidence of IE was higher among patients who filled prescriptions for hydromorphone than among those who filled prescriptions for non-hydromorphone opioids (2.8% vs 1.1%). And, finally, the authors found that this association was seen for controlled-release hydromorphone (3.9%), but not immediate-release hydromorphone (1.8%).
“In other areas where it isn’t in wide use, but where IE rates are increasing, we think researchers should explore other products in which the controlled-release mechanism involves polymer beads,” Weir explained. “Our theory is that the risk associated with hydromorphone relates to the controlled-release beads. There are a number of other products that use the same or similar beads. I think it makes sense to reconsider whether drugs with controlled-release beads should be available without restriction or at all. In terms of how to approach patients, I think educational campaigns aimed at people who inject drugs advising them to either avoid hydromorphone controlled-release or at least cook it before injecting would probably be helpful.”
That a nephrologist such as Weir is investigating this issue at all speaks volumes about the scope of the opioid problem. He acknowledges that he came to this research in a rather “roundabout” way. As a nephrologist, he was treating patients with acute kidney injury in the setting of IE linked with drug use.
One of his colleagues (and coauthors on the paper) noticed that there seemed to be more cases of IE in their clinic among injection-drug users after oxycodone was removed from the market in Canada.
Another colleague and collaborator, Michael Silverman, MD, an infectious disease specialist at Western University, had already done research that “showed pretty clearly that hydromorphone [controlled-release] supported the survival of Staphylococcus aureus” on contaminated cookers used by addicts.
“In addition, we became aware of the different equipment storage and reuse patterns when people who inject drugs who used hydromorphone controlled-release,” he said. “That new information allowed us to focus our database work.”
Indeed, and while they offer solutions to address this issue of IE among nonprescription users of hydromorphone controlled release, a related commentary authored by experts not involved in the Ontario research characterizes the challenges in blunt terms: “Within efforts to address the current opioid crisis, there has been great interest in so-called abuse-deterrent formulations... Yet, experience has shown that these mechanisms can be overcome, and the study by Silverman and colleagues suggests that the techniques undertaken to make such drugs suitable for injection could increase the risk of infectious complications. Reformulating opioid tablets represents a supply-side approach to curbing opioid misuse. More broadly, supply-side strategies to stem opioid prescribing could lead to a shift from prescription drug use to non-prescription opioids, such as heroin and fentanyl, and in turn an increase in fatal overdoses. To fully reduce drug-related harms, these interventions need to be coupled with efforts to build treatment capacity for substance use disorders and to implement harm reduction services, such as syringe exchange programs.”
Or else the evidence linking infectious disease outbreaks and illegal opioid use will only continue to grow.