Medicine is a constantly evolving field where technological and research advancements bring revolutionary changes to the diagnosis, treatment, and prevention of diseases. Each year, groundbreaking discoveries emerge, potentially transforming how we approach health. However, alleviating chronic pain (e.g., cancer-related or neuropathic pain) and providing effective palliative care remains a challenge yet to be fully resolved in modern medicine. It is widely believed that the intensity of pain should dictate the strength of the analgesic used. Opioids are among the most effective pain relievers, but their use is often limited by dose-dependent side effects (e.g., respiratory depression, cognitive impairment) and time-dependent adverse effects (e.g., chronic constipation, tolerance development). Therefore, co-administration of opioids with substances enhance their analgesic efficacy or delay the development of tolerance, without exacerbating side effects, is a significant focus of clinical research. Studies have shown that combining different classes of drugs with varied mechanisms of action can reduce opioid consumption and minimize associated side effects [White, 2008; Costantini et al., 2011]. One such innovative agent is magnesium, most administered intravenously alongside opioids. Magnesium sulfate has been widely used as a tocolytic and anticonvulsant in the treatment of preterm labor and preeclampsia [Berhan and Berhan, 2015; Lyell et al., 2007]. Magnesium ions were initially identified as N-methyl-D-aspartate (NMDA) receptor blockers, which alter pain perception and duration, as confirmed in animal studies [McCarthy et al., 1998]. Since then, magnesium ions (Mg2+) has been studied over many years as an adjuvant to minimize pain, such as postoperative pain. Magnesium has been investigated for various routes of administration (systemic, topical, intrathecal, and epidural) [Bujalska-Zadrożny and Duda, 2014; Bujalska-Zadrożny et al., 2016; Bujalska-Zadrożny et al., 2017; Dube and Granry, 2003; Rudzki et al., 2021]. The exact mechanism of interaction between Mg2+ and opioids in enhancing analgesic effects has not been fully elucidated. Additionally, the precise dose of magnesium ions required for optimal co-administration with opioids remains unclear. Rudzki et al. (2021) demonstrated that Mg2+ elicit an antinociceptive effect of opioids, enhancing analgesia in cases of acute, chronic (e.g., neuropathic or cancer-related), and even inflammatory pain. Combining Mg2+ with opioids utilizes the antagonistic action of Mg2+ on NMDA receptors, amplifying the antinociceptive effects of opioids [Rudzki et al., 2021]. Data collected by Bujalska-Zadrożny et al. (2017) suggest a positive effect of using Mg2+ in combination with opioids in animal models, showing effectiveness not only in perioperative and postoperative pain but also in chronic pain where opioids alone often fail to achieve the desired outcomes. In experiments on male Wistar rats, Bujalska-Zadrożny and Duda et al. (2014) demonstrated that administering Mg2+ alongside morphine via intraperitoneal injections significantly increased analgesic effects. Most studies examining the role of Mg2+ in intensifying opioid analgesia involved administering magnesium and opioids intravenously (i.v.) or intraperitoneally (i.p.). However, in treating chronic pain (e.g., cancer-related or neuropathic pain) and providing palliative care, oral administration in the form of tablets or capsules is critical. When opioids are formulated for oral use, additional variables, such as the gastrointestinal absorption of both the opioid and magnesium ions, potential interactions between tablet components post-ingestion, and the blood-brain barrier penetration of magnesium ions, must be considered. The latter is essential for Mg2+ to function as an NMDA receptor antagonist [Bujalska-Zadrożny et al., 2016, 2017]. The bioavailability of magnesium forms from the gastrointestinal tract depends on the specific chemical structure of magnesium, as well as factors such as stomach pH, the presence of other dietary components, and individual differences among patients. Generally, magnesium lactate forms demonstrate higher bioavailability in human studies compared to inorganic forms, averaging 20 %–30 % [Shechter et al., 2000], although the available literature on this subject is relatively limited. Similar results were observed in animal studies. Research by Coudray et al. (2005) indicated that the bioavailability of magnesium ions from organic salts is higher than from inorganic salts, ranging from 59.7 % for magnesium pidolate to 66.5 % for magnesium gluconate, with magnesium lactate achieving approximately 59 % bioavailability [Coudray et al., 2005]. Bujalska-Zadrożny et al. (2016) applied particle micronization of magnesium to enhance gastrointestinal absorption of Mg2+. This process allowed for the almost immediate achievement of the antinociceptive effect of opioids. Single doses of micronized Mg2+ combined with various opioids showed an improvement in the antinociceptive effect within 5 min for tramadol and oxycodone and within 30 min for morphine. However, these studies focused on i.p. administration of opioids and magnesium lactate. Analysis of the literature regarding the doses of Mg2+ and opioids used in in vivo studies suggests that magnesium ions significantly enhance morphine-, oxycodone-, or tramadol-induced analgesia. This effect has been attributed to the antagonistic action of Mg2+ on NMDA receptors when administered at doses ranging from 30 to 150 mg Mg2+/kg of rat body weight [McCarthy et al., 1998; Dube and Granry, 2003; Bujalska-Zadrożny and Duda, 2014; Bujalska-Zadrożny et al., 2016, 2017]. In humans, doses of 30–50 mg Mg2+/kg allowed for a 30 %–40 % reduction in the amount of morphine required for managing acute postoperative pain [Arumugam et al., 2016]. A crucial factor is the bioavailability of oxycodone, which under normal conditions ranges from 60 % to 87 % for oral administration (p.o.). Notably, oxycodone is absorbed in the upper gastrointestinal tract, even in the oral cavity, resulting in a lower first-pass effect [Lalovic et al., 2006]. This raises the question of whether simultaneous oral administration of an opioid like oxycodone and high doses of Mg2+, e.g., as magnesium lactate (a well-absorbed organic form), could disrupt oxycodone pharmacokinetics, particularly its bioavailability. This is a critical consideration when designing new drug formulations. Due to the lack of data on the simultaneous administration of oxycodone and Mg2+ and its impact on bioavailability, an experiment was conducted to develop a medicinal product containing oxycodone hydrochloride and a high concentration of Mg2+ in the form of micronized magnesium lactate. The study aimed to determine the in vitro bioavailability of oxycodone after p.o. administration of this formulation. The results are significant for designing innovative opioid-based medications that utilize the antinociceptive effects of opioids in combination with Mg2+. This approach may increase the efficacy of pain management while reducing the required opioid dose in pharmaceutical formulations.