Monday, January 22, 2018

The Quest for Safer Opioid Drugs | The Scientist Magazine

Opioid drugs are well-established double-edged swords. Extremely effective at analgesia, they cause an array of harmful side effects throughout the body, including itching, constipation, and respiratory depression—the slowed breathing that ultimately causes death in overdose cases. What's more, the body's interaction with opioids is dynamic: our receptors for these compounds become desensitized to the drugs' activity over time, requiring ever larger doses to suppress pain and eventually provoking severe dependence and protracted withdrawal.

In the past few years, these side effects have plagued growing numbers of US citizens, plunging the country into the throes of a devastating opioid crisis in which nearly 100 people die from overdoses every day. Even so, opioids are still among the most effective pain-relief options available. "Over hundreds of years, [opioid receptors] have remained a target," says Laura Bohn, a biochemist at the Scripps Research Institute in Jupiter, Florida. "Therapeutically, it works."

Since the early 2000s, intriguing evidence has emerged suggesting that opioids' useful properties could be separated from their harmful attributes. (See "Pain and Progress," The Scientist, February 2014.) In 2005, Bohn, then at the Ohio State University College of Medicine, and colleagues showed that shutting down one of the signaling pathways downstream of the opioid receptor targeted by morphine not only amped up the drug's painkilling effects in mice, but also reduced constipation and respiratory depression (J Pharmacol Exp Ther, 314:1195-201).

That research opened the door to developing a new type of opioid: a "biased agonist" that could trigger analgesia without tripping the switches on other pathways that cause side effects. Now, more than a decade later, Trevena Inc.'s Olinvo (oliceridine)—a drug based on this principle and designated by the US Food and Drug Administration (FDA) as a breakthrough therapy—has completed Phase 3 clinical trials.

Olinvo is just one of many such drugs under development. From compounds that act only in specific regions of the body to those that engage multiple receptor types, researchers and pharmaceutical companies are trying many different tactics to produce less-dangerous opioids.

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