07/14/2025
This research is redefining how we think about fentanyl overdose
As fentanyl continues to drive record overdose deaths across the United States, physicians at Cleveland Clinic’s Integrated Hospital Care Institute (IHI) are reexamining how this potent drug affects the body and how we can better respond.
Rather than viewing overdose as a purely respiratory event, an NIH-supported investigator and Pulmonary Medicine physician, Philippe Haouzi, MD, PhD, and his team, in collaboration with Annick Haouzi-Judenherc, MD of the Heart, Vascular and Thoracic Institute, have uncovered a more complex picture. Their experimental work, harbored at the Neurological Institute, revealed that fentanyl doesn't just disrupt breathing. It also affects circulatory function, and thus oxygen delivery, in turn preventing the antidotal properties of naloxone. These insights provide critical context needed to improve how we deliver clinical care and develop new avenues to treat the deadly consequences of the opioid epidemic.
The Cleveland Clinic’s Integrated Hospital Care Institute (IHI) unites five departments (Pulmonary and Critical Care Medicine, Anesthesiology, Emergency Medicine, Infectious Disease and Hospital Medicine) to tackle complex clinical challenges through collaborative research. The IHI is led by Raed Dweik, MD, who is also chair of Cleveland Clinic’s Department of Pulmonary and Critical Care Medicine and the recent recently elected president of the American Thoracic Society. The IHI supports more than 730 active research projects annually and enrolls over 3,000 participants each year.
“We’re proud to support science that directly informs patient care,” says Kristin Highland, MD, IHI’s Vice Chair for Research. “This work exemplifies how integrated research can change how we respond at the bedside.”
A hidden cardiac threat
In a recent study published in the American Journal of Physiology – Regulatory, Integrative and Comparative Physiology, Dr. Haouzi and colleagues found that a fentanyl overdose can cause a sudden and severe drop in cardiac function. This cardiac depression, marked by a reduced heart rate (bradycardia) and a reduced ability to pump blood (cardiac contractility) prevents breathing from restarting, even after naloxone is administered.
“Fentanyl’s impact on circulation is more profound than we realized,” Dr. Haouzi says. “It’s not just that breathing stops. It’s that the heart can’t support oxygen delivery, which blocks the body’s ability to recover.”
The team also identified hypoxemia, severe oxygen depletion in arterial blood, as a key driver of this cascade. When fentanyl is combined with other cardiovascular depressants like xylazine or cocaine, the risk of a fatal outcome increases dramatically. These studies were supported by the NIH (Grant R61/R33 HL156248).
Exploring new rescue strategies
To address these challenges, Dr. Haouzi’s lab is investigating alternative treatments. They are especially interested in the effects of preexisting drugs, because repurposing FDA-approved drugs could accelerate clinical translation and reduce regulatory hurdles. The team recently published their research on one promising candidate, an anti-itch drug called nalfurafine, in the Journal of Applied Physiology.
In their study, the team reported that nalfurafine was able to reduce fentanyl-induced muscle rigidity and improve breathing in preclinical models. The treatment was able to do this without interfering with pain relief or sedation.
“This could be a game-changer in clinical settings where preserving a patient's pain relief is critical,” Dr. Haouzi says. “It’s about reversing overdose safely, without triggering withdrawal or compromising analgesia.”
This work was supported by an NIH grant (R21DA053551).
Connecting the dots across systems
Other IHI-supported projects are examining how environmental factors, metabolic dysfunction and social determinants of health contribute to lung disease. For example, pulmonary hypertension researchers in the institute are shifting focus from blood pressure in the lungs to right heart failure and metabolic dysfunction.
“Like Dr. Haouzi’s fentanyl project, these researchers are redefining the way we think about these diseases and discovering new targets for treatment,” Dr. Highland says. “These projects are all examples of how Cleveland Clinic’s IHI is driving innovative, patient-focused research at the intersection of science, public health, and clinical care.”
