Severe pain, often resulting from late-stage cancer, treatment side effects, or major surgeries, significantly impairs the daily function of an individual and often necessitates the use of strong opioids for adequate relief [1,2,3]. However, opioid-based analgesics present multifaceted issues, including opioid use disorder (OUD) [4], which is characterized by opioid dependence and addiction [5,6,7], and critical social issues, such as the unauthorized distribution of opioids to the black market [8, 9]. Owing to the illegal acquisition of many opioids and the rise in drug overdose deaths, which reached more than 80,000 in 2021 [10], stricter prescribing limits for healthcare professionals became necessary. Therefore, for long-term treatment, patients need more frequent hospital visits, and clinicians need to issue prescriptions more frequently [11].

To prevent opioid abuse, abuse deterrent formulations (ADFs), which generally incorporate both opioids and antagonists, have been developed [12]. These formulations exploit the differences in the bioavailability of agonists and antagonists, depending on the administration route. Thus, the opioid was absorbed better than its antagonist when taken as prescribed (e.g., orally), whereas the antagonist was absorbed more easily than the opioid when administered by non-prescribed routes (e.g., injected or inhaled), thereby reducing or eliminating the efficacy of the opioid [13]. However, this deterrent strategy is fundamentally administration route dependent; thus, a holder may still take an excessive amount of drug beyond what is prescribed or safe [14]. Consequently, social issues related to unethical opioid distribution may remain unresolved, necessitating dose-limiting prescriptions through regulations that require frequent patient hospital visits and more frequent prescriptions by clinicians.

Therefore, in this study, we propose a wearable device equipped with abuse-deterrent functionality (i.e., abuse deterrent device (ADD)). The ADD herein incorporates two distinguished key features, which involve sustained drug release and abuse-deterrent functionality. When the ADD is attached to skin, it enables continuous drug release at a predetermined rate, ensuring consistent dosing and preventing overdosing. However, if an attempt is made to detach the ADD, it automatically contaminates the remaining drug and ceases drug release. This design aims to discourage unethical attempts to remove drugs from the ADD. With this safeguard configuration, ADD can contain a reservoir of therapeutic opioids that can provide a comparable amount needed for long-term treatment, thereby extending therapy with a single prescription.

In this study, we designed an ADD without electronics to prioritize simplicity, reliability, and potentially lower production costs. To maintain the abuse-deterrent functionality, the ADD operated based on mechanical actuation principles, which varies depending on whether the device was attached or detached from the skin. ADD primarily consists of a drug reservoir adjacent to a contaminant reservoir separated by a thin membrane. Within this straightforward configuration, a piston was installed in the ADD, which moves forward in steps by releasing the pins upon skin attachment and detachment. For skin attachment, a needle unit was installed on the ADD and inserted into the skin. The onset pin was then released to advance the piston, filling space between empty needle and the drug reservoir with drug and initiating drug release. Upon skin detachment, the security pin was automatically released to cause the piston to move further, plugging the needle to stop the drug release and tearing the membrane to mix the drug with the contaminant.

To assess the proof-of-principle design, the ADD in this study was fabricated by assembling each constituent unit prepared using 3D printing. The assembled ADD was loaded with fluorescein as a model drug and rhodamine B as a model contaminant. To test the drug-release profiles, the ADD was attached to an artificial skin layer. Next to the skin layer, a chamber filled with simulated biological fluid (phosphate-buffered saline (PBS) at pH 7.4) served as the medium for drug release, with the needle inserted into it. Under these conditions, we examined drug release profiles upon skin attachment scenario. Additionally, we intentionally detached the ADD to examine the drug release behavior, and identify the actuator’s operation followed by membrane rupture and drug contamination.