The opioids of the future won’t get you high

Pill medicine

So far, our pharmaceutical solutions to skyrocketing overdose deaths from legal painkillers have focused on one thing: Making pain pills that are harder to abuse.

With little evidence that these “adult-proof” painkillers will be enough to curb deaths, a handful of researchers is stepping in to try something new.

They are making pain-relieving drugs that don’t get you high in the first place.

“We have a chance here to actually separate analgesia [pain-relief] from euphoria [the ‘high’],” Dr. Stephen K. Doberstein, the senior vice president and chief scientific officer of a company called Nektar Therapeutics told Business Insider. “We should do that.”

Abuse-deterrents may not actually deter abuse

The problem, as Doberstein sees it, is simple: “There’s almost no new development of new opioid molecules. Everyone just wants to figure out how to lock it up in a pill better,” he said.


Indeed since 2010, the US Food and Drug Administration has approved a handful of “abuse deterrent” drug formulations — drugs that are designed so they can’t be melted down and injected or smashed and snorted. Some thirty more are currently in development. In a March address to a panel of advisers, FDA commissioner Dr. Robert Califf focused on these drugs as one of the biggest solutions to curbing the overdose epidemic.

But there’s little evidence that these drugs alone will be enough to stem the tide of overdose deaths. Overstating the benefits of abuse-resistant drugs could encourage doctors to continue overprescribing them. Plus, we still don’t know that the new pills will actually reduce overdoses or deaths. Most of them can still be abused simply when swallowed.

“I am not convinced that we can engineer our way out of this epidemic, and I would caution against over-relying on abuse deterrent formulations to do so,” Dr. Caleb Alexander, an associate professor of epidemiology at Johns Hopkins and the founding co-director of the Johns Hopkins Center for Drug Safety and Effectiveness, told the Associated Press shortly after Califf’s address.

NKTR-181: The drug that enters the brain too slowly to get you high

So instead of trying to design a drug that would simply be tougher to abuse, Nektar researchers based in San Francisco are building a drug that Doberstein says addresses the real problem. Their medication would enter the brain too slowly to cause a high.


“It’s a medicine that I’m very passionate about,” Doberstein said. “We have a chance to really positively impact medicine here.”

Tests of NKTR-181 in recreational drug users have so far yielded promising results.

“We gave the drug to a set of patients and we asked them, ‘How high do you feel right now? Would you pay money to have this experience again?’ And what we found was that in most doses, the 181 was essentially indistinguishable to a placebo. They weren’t feeling anything with respect to getting high,” said Doberstein.

“That was really a remarkable finding,” said Doberstein. “I don’t think we’ve seen anything like that in the literature for these types of drugs before.”

In tests of the same group of people designed to determine if the drug was working for temporary pain relief against a placebo or sugar pill, the drug performed well. Now, the company needs to show that the drug can work for chronic, severe pain. The company began Phase III tests of NKTR-181 in people with chronic low back pain in February of last year. Those results are expected this coming spring.

PZM21: The drug that won’t trigger a feel-good surge

A brand new company called Epiodyne started by a research team at the University of San Francisco’s School of Pharmacy is designing a drug that wouldn’t trigger a surge in dopamine, a chemical messenger in the brain that is involved in emotions like desire and pleasure.

Across the US but primarily in Eastern states hit the hardest in recent months by the the opioid epidemic, many people are becoming addicted to painkillers because of the complex set of effects they can have on the brain in people who are predisposed to addiction. The results are often tragic.

“What we’re seeing here in New Hampshire is people get hooked on opioids and then they switch to heroin because it’s easier to get,” Senator Jeanne Shaheen (D-New Hampshire) said on a call with reporters in June. “We’re losing more than a person a day due to overdose deaths,” she added.

The way opioids work to relieve pain is often described by experts as a double-edged sword. While they can reduce the burning sensation of an aching back or a stinging wound, they also act in the brain in ways that can affect complex emotions like desire and pleasure.

The reason we feel good when we eat a good meal or have sex, for example, can be chalked up to a series of naturally produced keys (“ligands”) and keyholes (“receptors”) that fit together to switch on our brain’s natural reward system. Opioids mimic the natural keys in our brain. When they click in, we can feel an overwhelming sense of euphoria. More importantly, though, when prescription painkillers act on our brain’s pleasure and reward centres, they can work to reinforce behaviour, which in some people can trigger a repeated desire to use.

Epiodyne thinks it may have a drug candidate as powerful as morphine that could help avoid this problem. But it’s still too early to say if the drug, known only as PZM21, might help people — so far it’s only been tested in mice.

“What we know is that mice don’t seem to like it, meaning they don’t go back for more if given the choice. That gives us hope that it might not be addictive,” Dr. Brian Shoichet, the chief scientist behind the drug who also runs the Shoichet Lab at the University of California San Francisco, told Business Insider.

He and his team have a steep hill to climb. Drugs like these tend to followed a pretty dismal pattern of development: They make it to animal testing, but never get past that stage to be tried in humans. At best, “the odds seem to be 1 in 10,” Pinar Karaca-Mandic, a health policy researcher at the University of Minnesota, recently told Reuters.

Still, one of the characteristics of PZM21 that could put it a step ahead of NKTR-181 — if its promising results are borne out in extended trials — is that it is fundamentally different from traditional opioids in two major ways: First, it doesn’t appear to slow breathing like traditional opioids; and second, it only affects a type of pain called affective pain, which refers to chronic pain that’s typically felt consistently, like the ache of a sore back. Conversely, it appears to have no impact on something called reflex pain, the type of pain that is recognised immediately, like the painful heat of your hand on a hot stove.

This could be a big benefit that the drug would have against other traditional painkillers, since it ideally wouldn’t block people’s ability to respond to a sudden shock of pain in their environment. “You don’t want someone doped up on pain relief medication and not being able to feel a hot stove,” Shoichet pointed out.

Taken together, all of these observed effects suggest that PZM21 is fundamentally different from traditional opioids. And that’s a big deal.

“That’s completely unprecedented. That says this molecule is working in ways that no other molecule has,” said Shoichet.