# A novel drug delivery system for the prevention and rescue of fentanyl and other opioid overdoses > **NIH NIH R01** · UNIVERSITY OF THE PACIFIC-STOCKTON · 2023 · $337,500 ## Abstract Opioids have significant adverse effects highlighted by the large number of patients with opioid use disorder (OUD) and the increasing number of overdose deaths in the United States and elsewhere. In just the 12-month period ending in November 2021, more than 107,000 Americans died from drug overdose. Around 66% of these deaths involved illicit synthetic opioids like fentanyl (approximately 50 times more potent than heroin and 100 times more potent than morphine), which is the primary driver of the opioid epidemic today. Many of the opioid overdose deaths are attributed to fentanyl mixed with other illicit drugs like heroin, cocaine, and methamphetamine. The potential lethal dose of fentanyl is around two milligrams, and it is particularly dangerous for opioid naïve people who do not have a tolerance to opioids. Overdose deaths among high school-aged Americans have more than doubled since 2019, which has been attributed to counterfeit pills (e.g., Xanax, Percocet, Adderall) laced with a lethal amount of fentanyl. Sadly, many users often ingest the deadly drug unknowingly. Unfortunately, there is not a happy ending for this devastating story and there is no easy solution to the synthetic opioid problem. The vulnerability of our nation to the weaponization of highly potent fentanyl analogs, such as carfentanil (20-fold more potent than fentanyl), poses a significant public health risk not only to civilians, but also to first responders, law enforcement personnel, and the military. The relatively short duration of action (DOA) of the mu-opioid receptor antagonists, naloxone and nalmefene, poses a major challenge for its efficacy against fentanyl overdose. It is difficult to imagine how naloxone and nalmefene could be deployed effectively in a mass casualty situation involving synthetic opioids (where duration of overdose could last up to 24 hr). The overall goal of this proposal is to develop a fundamentally novel drug delivery approach for extending the DOA of currently FDA-approved opioid overdose antidotes (naloxone and nalmefene) for 24 hr or more. Here we report the development of a new generation of opioid antagonist prodrugs as a countermeasure for synthetic opioid overdose. The main advantages of our system include the following: (i) use of two FDA-approved antidotes, naloxone and nalmefene, with well-established safety and efficacy profiles; (ii) potential to reverse AND effectively protect against re-narcotization by synthetic opioid overdose; (iii) potential to avoid the precipitation of opioid withdrawal symptoms; and (iv) ability to administer the prodrugs subcutaneously. The main hypothesis of this proposal is to test whether conjugation of FDA-approved opioid antagonists through a cleavable ester linker to a selective ligand for the serum protein, transthyretin (TTR), would allow us to generate opioid antagonist prodrugs that are hydrophilic and can bind reversibly to TTR in serum. The balanced hydrophilicity of prodrug will be import... ## Key facts - **NIH application ID:** 10636330 - **Project number:** 1R01DA058024-01 - **Recipient organization:** UNIVERSITY OF THE PACIFIC-STOCKTON - **Principal Investigator:** Mamoun M Alhamadsheh - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2023 - **Award amount:** $337,500 - **Award type:** 1 - **Project period:** 2023-04-01 → 2028-02-29 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10636330 ## Citation > US National Institutes of Health, RePORTER application 10636330, A novel drug delivery system for the prevention and rescue of fentanyl and other opioid overdoses (1R01DA058024-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10636330. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*