Opioid Overdose Deaths Fall by 34% in 2025 | ASHP Midyear 2025

The battle against the opioid crisis is seeing cautious progress, with drug overdose deaths reaching approximately 107,000 in 2023. This is projected to be the lowest level since 2019 after falling 34% in 2025, according to Lawrence Y. Chang, PharmD, APh, BCACP, BC-ADM, CDCES, a clinical pharmacist at the County of Santa Clara Health System. However, fentanyl remains the primary driver, accounting for about 70% of overdose fatalities. Pharmacists are instrumental in maintaining this positive trend, as medication for opioid use disorder (MOUD) agents is proven to be profoundly lifesaving.

“People on methadone had reduced all-cause mortality by 53%,” Chang said. “People on buprenorphine had even better cause mortality rates. It was reduced by 66%.”

In a session at the American Society of Health-System Pharmacists Midyear Clinical Meeting and Exhibition 2025, Chang was joined by Brian L. Erstad, PharmD, professor at the University of Arizona College of Pharmacy, and Damian Peterson, PharmD, APh, BCPP, BCPS, psychiatric clinical pharmacist at the San Francisco Department of Public Health, to discuss options for MOUD.

Pharmacological Differences and Regulatory Nuances

The 3 agents used for MOUD—methadone, naltrexone, and buprenorphine—each have unique profiles that dictate individualized patient care, Chang said.

Methadone functions as a full μ-receptor agonist and an N-methyl-D-aspartate (NMDA) antagonist and inhibits the reuptake of serotonin and norepinephrine, contributing to its analgesic properties for musculoskeletal and neuropathic pain. It has a prolonged and variable half-life ranging from 8 to 59 hours, which can complicate attempts to switch therapy down the road.

Although the analgesic effect lasts only 4 to 8 hours, necessitating frequent dosing for pain, methadone suppresses opioid use disorder (OUD) cravings for 24 to 36 hours, allowing for once-daily dosing at an opioid treatment program (OTP). Pharmacists should recognize that while 20 to 40 mg may address acute withdrawal, doses of 80 mg or much higher are often needed for full opioid blockade, particularly in patients with high opioid tolerance.

The main limitations are regulatory: methadone is highly regulated and must be dispensed at an OTP, which is often disruptive to a patient's work and life. However, the 72-hour rule allows any clinician to dispense methadone for OUD for up to 72 hours while arranging a referral for ongoing treatment.

Naltrexone, an opioid antagonist, requires patients to be opioid-free for at least 7 days before initiation to prevent precipitated withdrawal, as the drug will kick existing opioids off the receptor. The oral formulation shows no difference compared to placebo due to poor retention, but the injectable formulation (Vivitrol), which lasts 28 days, does show increased abstinence. Nevertheless, retention rates with the injectable form are low, especially in patients who are homeless, use intravenous (IV) opioids, or have co-occurring mental illness.

Buprenorphine is a partial μ-agonist and offers a superior safety profile compared to full agonists due to a ceiling effect on respiratory depression, making it nearly impossible to overdose solely on buprenorphine.

“It's able to bind to the receptor stronger than anything else,” Chang said. “It will protect the patient from overdose if they were to relapse.”

Although guidelines like treatment improvement protocol 40 suggest 32 mg as a maximum dose, and many pharmacy policies cap dispensing at 24 mg, the FDA package insert has been updated to reflect that there is no maximum recommended daily dose. Doses exceeding 24 mg are often needed and may offer potential benefit, particularly for heavy fentanyl users who need high serum concentrations consistently.

Managing Complex Fentanyl-Driven Inductions

Chronic fentanyl use is complicated by the drug’s high lipophilicity and volume of distribution, causing it to linger in the body for up to a week or two. Precipitated withdrawal (PPC) occurs when buprenorphine displaces these lingering full agonists. In the outpatient setting, if PPC occurs, patients often manage it by using excess full agonist medication to displace the buprenorphine, which may require more than expected due to buprenorphine’s tight binding affinity.

To avoid PPC, microdosing strategies are increasingly used, especially for patients who cannot stop using or who have a high fear of withdrawal, according to Peterson.

“The whole idea behind [microdosing] is the body is not great at detecting very small changes in your receptor occupancy,” Peterson said. “But what it notices is large dramatic shifts.”

Because these doses are so small, they do not relieve withdrawal, meaning the patient must continue to use their full agonist until the target buprenorphine dose is reached. Rapid microdosing protocols, such as a 3-day rapid protocol, exist, but they demand highly motivated and organized patients because they often require dosing up to 4 times a day.

For long-acting injectable (LAI) initiation, the weekly formulation, buprenorphine (Brixadi), can be initiated off-label in acute settings without the sublingual test dose if the patient’s Clinical Opioid Withdrawal Scale score is 4 or greater. This low-barrier approach works because the weekly injection’s particle kinetics result in a gradual offset of the drug over 24 hours, which avoids the rapid concentration spike that typically causes PPC. Furthermore, a newer "wait-free" 3-day protocol allows patients to receive an injection immediately before or after opioid use, eliminating the struggle to wait hours in withdrawal.

LAIs offer significant clinical and adherence benefits: they are "one shot and done," reducing the risk of diversion, minimizing fluctuations in peaks and troughs, and removing the need for daily patient compliance, Peterson said. They also serve as a natural taper for patients wishing to discontinue MOUD. The goal with LAIs is to achieve a stable serum concentration that allows for opioid blockade, which requires a minimum of 2 to 3 ng/mL; heavy fentanyl users often require higher, consistent concentrations of 4 to 5 ng/mL.

MOUD in Acute Care Settings

Hospital and intensive care unit settings face challenges due to a lack of sufficient data regarding MOUD use, especially when managing acute pain on top of existing OUD. Non-opioid agents, particularly alpha agonists like clonidine and lofexidine, are commonly used for withdrawal management. The IV formulation of buprenorphine (Buprenex), which is indicated for pain, has limited OUD utility due to its low, fixed dosage of 0.3 mg or 0.6 mg.

Furthermore, the IV formulation has a biphasic delay in reaching the active site and binds relatively slowly to the receptor, meaning clinicians may mistakenly conclude the drug is ineffective if they do not observe immediate analgesic results. Although continuing MOUD in the hospital is often studied, initiation of MOUD, particularly LAIs, in acute settings is still an area with limited data, with most current studies focusing on low-dose sublingual initiation.

READ MORE: ASHP Midyear Clinical Meeting and Exhibition

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REFERENCE

Chang LY, Erstad BL, Peterson D. Bridging the Gap: Prescribing and Optimizing Medications for Opioid Use Disorder (MOUD) Across the Spectrum of Care From Primary to Acute Care Settings. ASHP Midyear Clinical Meeting and Exhibition 2025. December 7-10, 2025. Las Vegas, Nevada.