Safer, non-addictive alternatives for opioid may be on the way

One of the problems being faced by the healthcare system today is the growing number of deaths caused by drug overdose, specifically opioids which are morphine-derived painkillers like heroin, Vicodin, or Oxycontin. According to estimates by the US Centers for Disease Control and Prevention (CDC), the number of fatalities in the US from opioid abuse has quadrupled since 1999 to 78 deaths every day.

In a 2016 Kaiser Health survey, almost half of the respondents said they know someone with an addiction to heroin, which is becoming a cheap and easily accessible alternative once their opioid prescription runs out.

Experts describe the way opioids work to relieve pain as a “double-edged sword” because while opioids 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. When these prescription painkillers act on the brain’s pleasure and reward centers, they can work to reinforce behavior as well, which in some people can trigger a repeated desire to use.

This makes opioids incredibly effective and dangerously addictive at the same time.

But scientists across four institutions – UC San Francisco (UCSF), Stanford University, the University of North Carolina, and the Friedrich-Alexander University Erlangen-Nurnberg in Germany – have developed a compound that kills pain just as effectively as opioids, but without triggering a surge in dopamine, a chemical messenger in the brain that is involved in emotions like desire and pleasure.

The researchers focused on finding a molecule that would bind well with the opioid receptor in the brain, which activates a signal in the dopamine circuit, without affecting dopamine levels.

Brian Shoichet, PhD, a professor of pharmaceutical chemistry in UCSF’s School of Pharmacy and co-senior author on the paper, said they screened three trillion molecules initially. They then narrowed that down to 23 until they were able to isolate a single molecule called PZM21.

“The chemical structure of this molecule is very different from opioids,” Shoichet said, adding that the PZM21 did not activate the dopamine circuit in mice, which the team tested for signs of addiction.

The PZM21 compound also doesn’t appear to slow down breathing like traditional opioids and 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.

It also 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 offers a huge benefit against other traditional painkillers since it ideally doesn’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.

“Like morphine, this molecule binds to the mu-opioid receptor,” he explains, but unlike morphine, PZM21 doesn’t activate the neural pathway that leads to side effects like depressed respiration and constipation.

Shoichet said his team was “totally blown away by the results,” calling their discovery a “triumph of basic science.”

Another alternative compound, the NKTR-181 is also being tested by the researchers at Nektar Therapeutics, a San Francisco, California-based biopharmaceutical company. This drug is designed to enter the brain too slowly to cause a high.

Dr. Stephen K. Doberstein, Nektar’s senior vice president and chief scientific officer, said that they have the opportunity to “actually separate analgesia (pain-relief) from euphoria (the drugs’ characteristic ‘high’)” and that is what they should do.

The NKTR-181 has been tested in recreational drug users and has, so far, yielded promising results.

The drugs were given to a set of patients and they were then asked questions like: “How high do you feel right now? Would you pay money to have this experience again?”

The researchers found that in most doses, the 181 was essentially indistinguishable to a placebo. The patients did not feel anything with respect to getting high, according to 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.”

The drug also performed well in tests, which are designed to determine if the drug was working for temporary pain relief against a placebo or sugar pill, with the same group of people.

Now, the company needs to show that the drug can work for chronic, severe pain. Phase III tests of NKTR-181 in people with chronic low back pain have already begun in February 2015. Results of those are expected to come out around March 2017.

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Category: Features, Health alert