The misuse and abuse of prescription opioids represents a major public health issue in the United States and worldwide (Humphreys et al., 2022). One strategy to limit opioid abuse is to develop abuse-deterrent formulations (ADFs) for opioid products. The basis for developing these formulations is described in the FDA's comprehensive action plan to address opioid addiction, abuse, and overdose (Califf et al., 2016). However, recent post-market data on reformulated oxymorphone extended-release tablets (e.g., Opana ER) have highlighted serious safety concerns associated with the unintended intravenous (IV) use of the ADF. For example, immediately after the introduction of the newly reformulated Opana ER tablet, epidemiological data revealed a shift in how the drug was abused from snorting to IV injection (Marder et al., 2013). This shift in unintended means of administration was accompanied by an increase in cases of a syndrome that resembled thrombotic thrombocytopenic purpura (TTP)—a potentially fatal blood disorder in primary thrombotic microangiopathy (TMA)—and an outbreak of HIV due to needle sharing (Peters et al., 2016). These outcomes led to the formation of a joint FDA advisory committee meeting in March 2017 and ultimately to the withdrawal of Opana ER from the market (FDA News Release, 2017). Among the many possible causes for these new adverse events was the abuse-deterrent excipient used in the product. Specifically, the polyethylene oxide (PEO) excipient was believed to be a major contributing factor associated with the reported TMA-associated events. Similar PEO formulations and other polymers are often used in ADF products, raising concern over the general safety of this category of ADF. This issue has also contributed to only brand name ADF opioids being available to the public, creating a lack of generic product competition that can impact the affordability and availability of pain treatment for patients.

Three centers within the FDA—Center for Drug Evaluation and Research (CDER), Center for Devices and Radiological Health (CDRH), and Center for Biologics Evaluation and Research (CBER)—along with the University of Maryland's Center for Regulatory Science and Innovation (M-CERSI), collaborated to better understand and evaluate common excipients, challenges with tablet manipulation, and toxicological outcomes associated with opioid ADFs. It is important to develop least burdensome, non-clinical tools to evaluate ADF safety prior to human use. A study in guinea pigs conducted by CBER and M-CERSI scientists confirmed that neat high molecular weight (HMW) PEO (4 and 7 MDa) used in opioid tablets can cause hematotoxicity (hemolysis and thrombocytopenia) as well as end organ injury, most notably hemoglobinuria and acute kidney injury, following intra-day short-interval repeat dose intravenous administration (Baek et al., 2020). Persich, et al., further confirmed the critical role of HMW PEO (> 1 MDa) on hemolysis by using an in vitro needle model and found that blood-PEO mixtures subjected to high fluid shear rates above 20,000 1/s caused elevated plasma free hemoglobin levels (Persich et al., 2020).

The aims of this project were: (i) to better understand the relationship between excipients, manufacturing and manipulation methods, and toxicological outcomes associated with non-intended IV use of ADF opioids, and (ii) to develop in vitro tools to evaluate the safety of ADFs. This work can help the community to better understand the safety implications of ADF opioids in patients and the propensity to misuse or abuse these drugs. The availability of in vitro test methods may also help facilitate product development by providing least burdensome ways to assess critical safety risks.