Oxycodone at the Crossroads of Pain Management, Misuse, and Toxicological Investigation

Background: Since the 1990s, the United States has been facing the recurring problem of widespread misuse, addiction and overdoses involving opioid compounds. This phenomenon is known as the opioid crisis or the opioid epidemic. Every day, around 200 Americans die due to opioid use. Nowadays the country is facing the fourth wave, dominated by fentanyl combined with stimulants. The problem of opioid abuse is not confined to the United States alone, but is a global issue. Objective: In this paper, we do not focus on fentanyl, but on another painkiller, oxycodone, as it is often overlooked in discussions of the current crisis, whilst its sale and use are becoming increasingly common. In Poland alone, the number of prescriptions increased by 50% between 2019 and 2023, and nearly 200 Poles have died as a result of an opioid use disorder. This narrative review examines oxycodone at the intersection of pain management, non-medical use, and toxicological investigation, with emphasis on its pharmacology, clinical applications, abuse liability, overdose risk, and detection in biological matrices. Methods: PubMed and Google Scholar were searched using terms related to oxycodone, toxicology, addiction, the opioid crisis, detection methods, biological matrices, analgesic effects, pharmacokinetics, metabolism, overdose, and hospital treatment. English- and Polish-language publications from January 2020 to July 2026 were prioritised, with the search extended to 2000 where necessary. No formal systematic-review protocol was applied. Results: By interacting with opioid receptors, oxycodone relieves moderate to severe pain. It is therefore used as an analgesic for various types of pain—intraoperative, postsurgical or chronic pain, including cancer-related pain. It has good bioavailability following oral administration and accumulates in tissue less than, for example, morphine. A further advantage is the availability of a variety of routes of administration: in addition to oral administration (including through immediate- and extended-release formulations), oxycodone can also be administered, inter alios, intravenously, intranasally, and rectally. On the other hand, oxycodone causes a range of adverse effects—it can lead to respiratory depression and constipation and has high potential of addiction. Its use is associated with a risk of developing tolerance, and discontinuation may trigger withdrawal symptoms. Oxycodone’s high utility for medical purposes makes it a widely used drug in hospital settings. At the same time, there is an increasing number of cases of inappropriate oxycodone use. This results in the need for analytical methods to monitor concentrations in hospitalised patients and to investigate concentrations in cases of suspected poisoning. The toxicological methods used for detection of oxycodone include both screening tests, such as immunoenzymatic assays, and confirmatory tests—i.e., liquid chromatography/mass spectrometry. The process of choosing an appropriate method begins at the stage of selecting the diagnostic sample. Both standard samples, such as blood (including dried blood spots—a novelty) and urine, and alternative samples—oral fluid, hair, nails and vitreous humour—are useful, depending on the patient’s condition, their availability and the time elapsed since the substance was ingested. Conclusions: Oxycodone remains an important analgesic but carries substantial risks of misuse, addiction, and fatal toxicity. Safe prescribing and monitoring, recognition of drug interactions and individual variability, and integrated interpretation of individual case circumstances, appropriate biological samples, and confirmatory mass-spectrometric findings are essential in clinical and forensic practice.