Biomedicine

Opioids without Addiction

Nektar Therapeutics is developing a painkiller that may enter the brain too slowly to be abused.

Addiction is a common and sometimes fatal consequence of using opioid drugs to treat severe pain associated with cancer, surgery, and more.

A new kind of opioid could offer patients pain relief with less risk of addiction and sedation.

In human tests, painkiller abusers found the investigational opioid “boring,” says Nektar Therapeutics’ chief medical officer, Rob Medve. “There is no joy or euphoria associated with the drug,” he says. And yet human trials show that the compound increases pain tolerance.

Opioids, which include morphine, remain the top choice for treating severe pain because they offer potent relief, but they also boost dopamine pathways in the brain, which causes an intensely rewarding high that can trigger repeated, chronic use and eventually addiction. According to the U.S. Department of Health and Human Services, nearly two million American abuse or are addicted to opioids, and nearly 14,000 overdose on these drugs in a year.

Researchers have been working for decades to develop more benign forms of these effective painkillers. “People have been trying to separate the beneficial analgesic effects of opioids from the side effects,” says Jane Aldrich, a medicinal chemist studying opioids at the University of Kansas. “It’s been a challenge, and one that we haven’t solved yet.”

Nektar’s approach is to add a side chain to a derivative of morphine, which changes the way the molecule behaves in the body. The addition slows the rate at which the compound enters the brain, in part by making it more difficult for it to cross the blood-brain barrier, the protective layers that surrounds blood vessels in the brain and regulates what can enter, says Steve Doberstein, chief scientific officer of Nektar. That reduces the risk of abuse, he says.

“Opioid drugs have a higher abuse liability the faster they get into the brain,” Doberstein says. Heroin, for example, is a form of morphine that moves very quickly into the brain, and that rush of the drug into the nervous system is associated with euphoria.

But the Nektar compound still provides pain control, says Medve. “We know you can get very good analgesia by having an opioid go in slowly to the brain and not produce the dopamine spike,” he says. “They are separable.” Other side effects, such as sedation and respiratory depression, may also be reduced, he says. The company has completed human safety trials and expects to have results from early efficacy tests in September.

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