These are the drugs that could end the opioid crisis

Not only do they slow down breathing, they also act on the same brain systems as heroin. As such, prescription painkillers carry serious risks, from overdose to, in rarer cases, addiction.

So far, our pharmaceutical solutions have been focused on designing painkillers that are called "abuse deterrents." Their allegedly adult-proof packaging is supposed to make them hard to get high on, but there's little evidence to suggest that these drugs alone will be enough to end the opioid crisis.

Instead, the solution may lie in a slightly more complex task: Creating drugs that can't possibly get you high in the first place.

A handful of companies is working on formulations of drugs that are designed to relieve pain while simultaneously preventing the warm, snug, all-enveloping high that can be achieved when the pills we have now are taken in high enough doses. Several have already made it past some of the more preliminary hurdles of drug testing; others are still being studied in mice.

The drug that enters the brain too slowly to get you high

In San Francisco, California, researchers employed by a company called Nektar Therapeutics are working to build a drug designed to enter the brain too slowly to cause a high.

"It's a medicine that I'm very passionate about," Dr. Stephen K. Doberstein, the company's senior vice president and cheif scientific officer, told Business Insider during a recent phone call. "We have a chance to really positively impact medicine here."

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; 30 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.

" ... The promise that we are on a path toward products that are effective in preventing abuse both by patients and non-patients is real. And the agency intends to fully support efforts to advance this technology," said Califf.

REUTERS/Gary CameronFood and Drug Administration Commissioner nominee Doctor Robert Califf (C) arrives to testify during his nomination hearing before the Senate Health, Education, Labor and Pensions Committee on Capitol Hill in Washington, November 17, 2015.Several people at the address warned that these pills might not be enough for several reasons, the Associated Press reported. First, overstating the benefits of abuse-resistant drugs could encourage doctors to continue overprescribing them. Second, we still don't know that the new pills will actually reduce overdoses or deaths. Most of them, the AP pointed out, 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 AP.

This is where Nektar's drug, so far called only NKTR-181, comes in.

"We have a chance here to actually separate analgesia [pain-relief] from euphoria [the drugs' characteristic 'high']. We should do that," said Doberstein.

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.

A drug that won't trigger a dopamine 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 centers, they can work to reinforce behavior, 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 recognized 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.