Groundbreaking research could reduce opioids side effects

Professor Alhamadsheh and research assistants in the lab

A research team led by Mamoun M. Alhamadsheh, PhD, professor of pharmaceutics and medicinal chemistry, recently published their research on a novel pharmacological probe that could lead to the development of pain medications with reduced side effects. Pharmacological probes are similar to drugs but investigate rather than treat. Probes investigate the site action of the drug, allowing researchers to better understand what causes side effects.

“Opioids are effective in the management of severe acute and chronic pain,” said Dr. Alhamadsheh. “However, they are often associated with dose-limiting side effects, such as sedation, nausea, vomiting, constipation and respiratory depression. Opioid induced constipation (OIC) is the most common side effect of opioid usage affecting 80 percent of patients who receive opioids for chronic or cancer-related pain. OIC can be difficult to manage and can be severe enough to require opioid discontinuation, exposing patients to unnecessary pain.”

Several peripherally acting mu-opioid receptor antagonists (PAMORAs) have been developed to lessen side effects such as OIC, but they are not very effective and often reverse the intended action of the opioid. Dr. Alhamadsheh’s research team has developed a new class of PAMORAs that does not cross the blood-brain barrier and as a result is effective in reducing side effects without lessening the efficacy of the opioid.

“The immediate application of this research is a more effective therapy for OIC; and potentially lowering the brain toxicity of some drug molecules,” he said.

Further, their research shows opioid receptors in the brain are linked to the cause of OIC, contrary to existing literature which suggests OIC is caused primarily by opioid receptors in the gastrointestinal tract.

Professor Alhamadsheh and research assistants

Md Tariqul Haque Tuhin ’22, PhD, Dengpan Liang ’22, PhD, Fang Liu ’21, PhD, Hala Aldawod ’23, Toufiq Ul Amin ’23, Joshua S. Ho ’21, ’25, Rasha Emara ’24, Arjun D. Patel ’21, PhD, Melanie A. Felmlee, PhD, associate professor of pharmaceutics and medicinal chemistry, Miki Susanto Park, PhD, professor of pharmaceutics and medicinal chemistry, James A. Uchizono, PharmD, PhD, professor of pharmaceutics and medicinal chemistry, and Dr. Alhamadsheh published “Peripherally restricted transthyretin-based delivery system for probes and therapeutics avoiding opioid-related side effects” in Nature Communications on June 23, 2022.

Recent graduates Drs. Tuhin, Liang and Liu contributed equally to the initiation of the research and were supported by their fellow graduate students, and they worked together as a team to synthesize the new chemical molecules.