Safer, Less Addictive Opioid Breakthrough – In the Lab

Researchers are pointing the way toward safer opioids…via computer simulation. Their work, “Analgesic effects of a novel pH-dependent μ-opioid receptor agonist in models of neuropathic and abdominal pain,” appears in the July 2018 edition of Pain.

Prof. Dr. Christoph Stein, medical director of the department of Anesthesiology and Operative Intensive Care Medicine at Charité Campus Benjamin Franklin in Berlin, Germany, and co-author on the study, told OTW, “We have been working on the design of safer opioid analgesics for over 25 years. Our work indicates that adverse opioid side effects (e.g., apnea, sedation, addiction) can be avoided by selective activation of opioid receptors outside the brain.”

The authors wrote, “Here, we investigated MOR [μ-opioid receptor] binding of NFEPP [(±)-N-(3-fluoro-1-phenethylpiperidin-4-yl)-N-phenylpropionamide] in brain and dorsal root ganglia, pH in injured tissues, and the analgesic efficacy of NFEPP compared with fentanyl in a chronic constriction injury model of neuropathic pain, and in the acetic acid–induced abdominal writhing assay in rats.”

Significantly, the researchers found that MOR did not bind in the brain and dorsal root ganglia as aggressively as fentanyl. “Binding experiments revealed significantly lower affinity of NFEPP compared with fentanyl at pH 7.4.”

“In vivo, pH significantly dropped both at injured nerves after chronic constriction injury and in the abdominal cavity after acetic acid administration. Intravenous NFEPP as well as fentanyl dose-dependently diminished neuropathy-induced mechanical and heat hypersensitivity, and acetic acid–induced abdominal constrictions.”

“In both models, NFEPP-induced analgesia was fully reversed by naloxone methiodide, a peripherally restricted opioid receptor antagonist, injected at the nerve injury site or into the abdominal cavity.”

Dr. Stein commented to OTW, “Our latest publications have shown that such drugs can be designed with the help of computer simulations. This way we have developed novel opioids that selectively activate opioid receptors in peripheral injured tissue without affecting opioid receptors in the brain.”

“So far, these novel compounds are not available for use in humans. We are seeking collaborations with the pharmaceutical industry to further develop these drugs. In the future, such drugs may serve as potent pain killers without the detrimental side effects of currently available opioids.”