# Harms from Injecting Inactive Ingredients ## What we are studying Solid oral (e.g., pills) and transdermal (e.g., patches) formulations of pharmaceutical medicines are not intended to be injected (subcutaneous, intravenous or intra-arterial). But we know from a century of experience that some people will invariably try to inject opioids, stimulants, benzodiazepines and barbiturates. Solid oral and transdermal formulations of pharmaceutical opioids are not intended to be administered by any other means (subcutaneous, intravenous or intra-arterial). *Pill injection*<br> People who inject drugs may use any of these techniques to prepare solid formulations for injection: (1) modify a non-injectable dosage form, such as a capsule or transdermal patch, to suspend the active ingredient in a liquid solution, (2) separate the active ingredient from other non-desirable (in)active ingredients, and (3) overcome time-release and abuse-deterrent barriers that are engineered to be harder to crush. The tools to extract active ingredients include are well-known: crushing or scraping, applying heat or freezing, dilution, and dissolution with cirtus juice, vinegar, or household solvents. In general, medications that are designed for intravenous use are pH-buffered, isotonic, filtered and sterile. During drug preparation, the resulting solution may not have any of these life-saving characteristics, leading to potential health complications when injected. *Abuse- deterrent formulations*<br> In response to opioid misuse, pharmaceutical manufacturers have tried to make pills harder to crush and suck into a syringe. Abuse deterrent formulations (ADFs) attempt to deter tampering by making it more difficult to extract the active ingredient (via crush, cut, grate or grinding), make it difficult to solubilize extracted particles (e.g., high viscosity when in contact with water), or contain aversive agents (e.g., opioid antagonists naloxone or naltrexone are released when the tablet is crushed). In order to prepare solid formulations for injection, one or more of the following steps are usually required: (1) modify a non-injectable dosage form, such as a capsule or transdermal patch, to suspend the active ingredient (e.g., opioid, stimulant, barbiturate, benzodiazepine) in a liquid solution; (2) separate the active ingredient from other non-desirable ingredients; and (3) overcome time-release and abuse deterrent formulations. Main preparation techniques include crushing, heating, freezing, and/or dilution. Other chemical agents may be added to the solution that are (sometimes incorrectly) believed to aid in dissolution, such as lemon juice or vinegar. In general, liquid medications that are designed for intravenous use are pH-buffered, isotonic, filtered and sterile. But, street preparations lose these characteristics, leading to a host of health complications upon injection. *Harm from inactive ingredients*<br> Solid pharmaceutical opioids, particularly ADFs, may contain bulking agents or fillers (“excipients”) such as talc or starch. These inactive excipient ingredients are often insoluble and contribute to additional complications including, but not limited to, local skin irritation, vascular complications and pulmonary dysfunction. ## Why it matters Currently, there is limited research reviewing the unintended consequences and harms of excipients. Additionally, there is inconsistency in describing unintended harms from inactive ingredients in prescription opioids that make it difficult to compile existing evidence. For example, terms that describe pill fillers have evolved over decades, often described as excipients, adulterants or birefringent materials. This review will organize the extant literature and serve as a comprehensive resource. ## How we are studying it The goal of this review is to identify and summarize cases of excipient harm. We hope to identify cases of unintended harm attributed to the pharmaceutical properties of prescription opioids, separate from commonly observed general injection harms (i.e. overdose, abscess, nerve damage). We are conducting a systematic review of the published literature on injection harms, going back as far as possible, into the 1920s. We are searching biomedical databases, as well as those from social sciences. The the search strategy has three general components: 1. list of brand and generic names of all opioids, benzodiazepines, barbiturates, and stimulants 2. list of inactive ingredients found in these 4 medication classes 3. terms to focus in injection We will then using machine learning algorithms and metadata to identify the kinds of physical health harm that result from injecting solid pharmaceuticals. ## How to use the results We have an ethical responsibility to minimize harm. The results of this systematic review may be used to inform regulation and policy regarding the need for additional testing of excipients included in medicines that have a high likelihood of being crushed and injected, which could include all controlled substances. This will reduce likelihood of harm stemming the drug itself. The results may indicate a need to develop corresponding harm reduction strategies, such easily accessible drug filtering systems. Filtration methods have been tested in Australia and France as a strategy to decrease harm at administration. The results may also provide clinicians with a clearer understanding of how excipient harms present, increasing their ability to recognize, diagnose and provide adequate therapy after consumption. If you are interested in the harms from inactive ingredients, you can [comment directly to FDA](https://www.federalregister.gov/documents/2019/09/20/2019-20372/the-food-and-drug-administration-solicits-input-on-potential-role-for-abuse-deterrent-formulations) about stimulants until November 19, 2019. Click on the green box that says "Submit a Formal Comment" or [click here](https://www.federalregister.gov/documents/2019/09/20/2019-20372/the-food-and-drug-administration-solicits-input-on-potential-role-for-abuse-deterrent-formulations#open-comment); you can also read other's comments. ## Who is conducting and supporting the study The study is funded by the United States Food and Drug Administration, and conducted by a team of researchers at the University of North Carolina at Chapel Hill. All studies at the Opioid Data Lab are conducted by independent researchers at the University of Kentucky and the University of North Carolina at Chapel Hill, and do not necessarily represent the views of funders or partners. We are grateful to generations of taxpayers in Kentucky and North Carolina for supporting public universities. We are also grateful to US taxpayers for safeguarding public health by supporting FDA and this research project.