Opioid pain relievers to reduce overdose risk

Researchers at the The Scripps Research Institute (TSRI) in Florida have developed opioid pain relievers that do not slow or stop breathing which is the cause of overdose. According to the U.S. Centers for Disease Control and Prevention, 91 Americans die every day from opioid overdoses when opiates like heroin, oxycontin, and fentanyl slow and later stop a person’s breathing.

The research shows that a range of compounds can deliver pain-blocking potency without affecting respiration. The study builds on two decades of research, where the researchres have long explored whether the painkilling pathway, the G protein pathway, could be unlinked from the breathing suppression pathway, the beta-arrestin pathway. The researchers had their doubts about being able to separate out the pathways and also wanted to know how much separation was needed to see analgesia without respiratory suppression.

For the study, the researchers worked to develop new potential drug molecules. Later the researchers tweaked their chemical structures to systematically vary the “bias” between G protein signaling and beta-arrestin recruitment. The group has developed more than 500 compounds in the past 6 years, and found more than 60 with bias between signaling assays. The researchers selected six compounds to represent a wide range in the degree of bias (from those that preferred barrestin2 recruitment to those that preferred G protein signaling) and determined their overall potency for inducing analgesia and respiratory suppression in mouse models. The researchers found the new compounds could indeed enter the brain. All of the compounds were as potent, and in some cases more, than morphine.

The compounds that were less able to promote barrestin2 associations in cells were less likely to induce respiratory suppression in mice. The painkiller fentanyl was shown to prefer receptor-barrestin2 associations and also had a narrower safety margin. The fentanyl dose needed to alleviate the perception of pain was closer to the dose that suppressed breathing, which may be why fentanyl is more likely to trigger respiratory suppression at low doses. Fentanyl is a powerful pain killer, but has a narrow therapeutic window and a history of overdoses. Separating the receptor’s ability to engage in the two pathways can provide a way to separate desired drug effects from side effects. This work suggests an opportunity to expand the “therapeutic window,” or the range of doses at which a drug may be administered safely.

It is important to see new pain relievers like the ones developed in this work to better help prevent dental deaths. Fentanyl has contributed to several dental deaths over the years see http://www.teethremoval.com/dental_deaths.html.

Source: Cullen L. Schmid, and et al., Bias Factor and Therapeutic Window Correlate to Predict Safer Opioid Analgesics. vol. 171, issue 5, Cell, 2017.

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