Last year, scientists enlisted 40 recreational drug users to test one of the hottest questions in pharmaceutical research: Is it possible to develop a strong painkiller that doesn’t make people high?

The participants, who acknowledged a history of illicit drug use, received three different injections—an experimental painkiller from Cara Therapeutics Inc., an older painkiller and saline. After each, the researchers checked participants’ vitals and asked a series of questions: How high do you feel? How much do you like this drug? Would you want to take it again?

Answers to studies like these will help determine whether pharmaceutical companies can develop new analgesics that don’t cause euphoria or lead to abuse—an urgent need amid a growing crisis of painkiller misuse.

Prescription pain relievers are a $57 billion global market, according to IMS Health, taken by cancer patients, chronic back-pain sufferers and people recovering from surgery. But abuse of painkillers has soared in recent years, prompting stricter U.S. Drug Enforcement Administration regulations that make some medications tough to prescribe and refill. Prescription painkillers contributed to 16,000 overdose deaths in the U.S. in 2013, roughly quadruple the number in 1999, according to the U.S. Centers for Disease Control and Prevention.

Biotech startups from Cara Therapeutics to Nektar Therapeutics and pharmaceutical giants including Pfizer Inc. and Biogen Idec Inc. are developing new classes of painkillers, often based on different mechanisms than traditional opioids like morphine. Industry experts believe a safer painkiller could achieve annual sales totaling many billions of dollars.

Finding one is “a Holy Grail of pain research,” said Stephen Waxman, a professor of neurology at Yale University School of Medicine and a senior researcher at Veterans Affairs Connecticut Healthcare System.

The most widely abused analgesics today are opioids, such as morphine, oxycodone or hydrocodone. They work by activating mu-opioid receptors on the surface of cells in the brain, spinal cord and other organs, which are responsible for modulating pain perception. Activating these receptors triggers a release of dopamine in the brain, which can cause euphoric effects in many people, doctors say.

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