Therapeutics for Fentanyl Overdose

“Our goal is to increase survival from fentanyl overdose. As an anesthesiologist and clinical expert with fentanyl, I can tell you that the lethal airway effects of high dose fentanyl can be resistant to reversal by naloxone. If you witness an overdose with a rapid loss of consciousness and/or muscle rigidity, it is probably fentanyl. Call 911 immediately and be prepared to give multiple doses of naloxone and provide CPR until medical help arrives. Every second counts with fentanyl. For now, naloxone is the best thing we’ve got, but it has limits.”

— Phillip R. Torralva, MD, Anesthesiologist, Addictionologist and Founder TMT-Rx

  • Research begins in 2016. Survivors of fentanyl overdose are interviewed and confirm that fentanyl overdose is rapid in onset and different than heroin. With several years of strong data and encouraging results, papers are published and patent applications are filed.

  • Continued research yields new discoveries. TMT-Rx is launched in 2020 with an award from the National Institute on Drug Abuse “Start a Substance Abuse Startup Challenge.”

    With persistence and dedication —and more than a year of continuous effort to secure funding —TMT-Rx is awarded a prestigious “America’s Seed Fund” small business innovation research phase I grant from the National Institutes of Health in 2021, followed by NIDA STTR and NIDA SBIR FAST-track grants for drug development in 2022.

  • In 2022, TMT-Rx joins a select cohort of start up companies selected for:

    —The I-Corps™ at NIH program, which provides funding, mentoring, and networking opportunities to help commercialize promising biomedical technology.

    — The NIH Fast-Track program, which expedites award decisions and funding of small business innovation research for scientifically meritorious projects that have a high potential for commercialization.

Fentanyl presents a unique problem due to its potency at opioid receptors and from non-opioid receptor mechanisms

The human toll is devastating and unlikely to improve with the limitations of current therapeutics

Naloxone (NARCAN®), the most commonly used FDA-approved treatment for opioid overdose, can fail to rescue fentanyl overdose.

  • The number of U.S. deaths attributed to fentanyl and fentanyl analogues (F/FA) increased from a little over 1,000 in 2010 to almost 80,000 deaths in 2022, according to the U.S. Center for Disease Control (CDC).

  • Fentanyl is now found in nearly all illicit drug supplies, including stimulants, and is the most common cause of overdose death in the U.S.

  • The amount of fentanyl powder it takes for lethal overdose is about the size of 3-5 grains of salt (~ 2000 mcg).

Why does NARCAN® sometimes fail?

  • High dose fentanyl (>25mcg/kg) causes chest wall stiffness and rapidly closes the vocal cords, making it impossible for the victim to breathe. These effects are ultimately not controlled by opioid receptors or naloxone.

  • Pharmacology studies show that nasal NARCAN® takes more than 10 minutes to reach the brain, where fentanyl induces its most lethal activity.

  • Fentanyl overdose often requires two to fives times higher doses of naloxone than traditional opioid overdose. High dose naloxone can lead to other life-threatening side-effects including cardiac arrhythmias, hemodynamic instability and pulmonary edema.

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“Fentanyl induces clinical effects that are different from morphine based opiates. These effects include the rapid onset of muscle rigidity and vocal cord closure that lead to rapid death. We were the first to demonstrate in an experimental model of fentanyl overdose, that fentanyl but not morphine, binds a different set of brain receptors that cause these clinical differences.”
— Phillip R. Torralva, MD

Groundbreaking Research

Novel Discoveries

TMT-Rx Research Discoveries:

Visualized physiological effects of opioids on vocal cords while testing pharmacological treatments.

  • Identified closure of vocal cords as the major cause of difficult ventilation after opioid-induced anesthesia.

  • Demonstrated that fentanyl binds non-opioid receptors that can cause the rapid onset of muscle rigidity in the chest wall and larynx.

Discovered new receptor targets that play a significant role in fentanyl-induced muscle rigidity and fentanyl-induced vocal cord closure.

  • Identified candidate drugs for pre-clinical testing and have identified targets for new chemical entity design.