Too Good to Be True? A Nonaddictive Opioid without Lethal Side Effects Shows Promise
With nearly 50,000 drug overdose deaths from opioids last year and an estimated two million Americans addicted, the opioid crisis continues to rage throughout the U.S. This statistic must be contrasted with another: 25 million Americans live with daily chronic pain, for which few treatment options are available apart from opioid medications.
Opioid drugs like morphine and Oxycontin are still held as the gold standard when it comes to relieving pain. But it has become brutally obvious that opioids have dangerous side effects, including physical dependence, addiction and the impaired breathing that too often leads to death from an overdose. Researchers have long been searching for a drug that would relieve pain without such a heavy toll, with few results so far.
Now a study in monkeys published in Science Translational Medicine shows a new type of opioid drug met all the criteria on drug developers’ wish list. The findings even suggest that instead of causing addiction, the new compound might be used to curb addiction and pain all at once. The study was led by Mei-Chuan (Holden) Ko, a researcher at Wake Forest University, and medical chemist Nurulain Zaveri, founder of California-based Astraea Therapeutics. “They’ve got something here that’s really important,” says William Schmidt, a pharmaceutical consultantbased in Davis, Calif., who was not involved in the work. “I think the chances of a compound with these properties moving forward are high, and simultaneously pretty exciting.”
Opioid drugs relieve pain by acting at four types of opioid receptors found throughout the nervous system. The mu opioid receptor is primarily responsible for opioids’ pain-relieving effects—and for their side effects as well. Delta and kappa opioid receptors can also modulate pain signals, but they come with their own side effects. A fourth receptor, called the nociceptin/orphanin FQ peptide (NOP) receptor was discovered relatively recently, in the 1990s, and researchers are still figuring out how it works.
Studies of NOP have shown that it too has analgesic effects in rodents—but seemingly without the side effects that come with mu receptor activation. And an additional benefit comes when the two receptors interact with each other. The inspiration for the new compound, called AT-121, came when Ko discovered that by activating NOP, he could enhance the pain-relieving effects at the mu receptor. “We hypothesized that if we could find a single molecule that activated both receptors, NOP could enhance mu’s analgesic effects and mediate the abuse potential,” he says.
The researchers investigated the effects of AT-121 in rhesus monkeys with tests commonly used to compare new painkiller drug candidates with opioids such as morphine. Monkeys were trained to sit with their tails in a bath of hot water, which they normally tolerate for only a couple of seconds. After an injection of AT-121 they kept their tails in hot water for up to 20 seconds, indicating a potent analgesic effect. After monkeys’ tails were treated with capsaicin, the ingredient that makes hot chilis hot, they developed pain hypersensitivity, making them even less tolerant of the hot water. But after receiving AT-121 they could keep their tails in the water much longer than expected.
Even at higher doses, AT-121 did not cause the side effects that make most opioids so dangerous—suppression of breathing and heart rate, itch and physical dependence (in which stopping use leads to withdrawal symptoms). Even after several doses AT-121 retained its analgesic effect whereas most opioids require an increasing dosage over time to achieve pain relief.
To test the compound’s addictive potential, the researchers allowed monkeys to self-administvariety of drugs. With remifentanil, powerful opioids or cocaine, monkeys pressed a lever repeatedly to receive increasing doses of the drugs, a hallmark of rewarding substances. In contrast, monkeys only pressed a lever to receive AT-121 at a similar rate as injections of a saline solution, indicating the drug was not rewarding.
More surprising was the finding pretreatment with AT-121 reduced the monkeys’ lever-pressing to receive Oxycontin, a widely used and highly addictive opioid. That suggests AT-121 could reduce the addictive properties of other opioids. “To have the combination of analgesia and the lack of mu receptor–related side effects, plus the ability to block the euphoric effects of Oxycontin—that’s unique,” Schmidt says.
“It gave very effective pain relief, the rewarding effects were not there and it suppressed the addictive potential of Oxycontin,” Zaveri says. “That suggests it could be a replacement for prescription pain opioids, and it could actually be given to someone who is addicted.”
The concept of trying to finesse pain relief by activating multiple opioid receptors is not new. A drug called cebranopadol, for example, also activates both the NOP and mu opioid receptors, and is in clinical trials for several pain conditions, but the drug might still be addictive.
There is little evidence traditional opioids provide benefits for people with chronic pain, and this drug might not either. The timing of the drug’s actions, Schmidt says, “is ideal for acute, postoperative pain. It might have the ideal properties for use in the hospital, but for broader use as a nonaddictive chronic pain drug, you would want an oral drug that works longer.”