A few new pain drugs in development

Spurred by opioid epidemic, new pain drugs may lower the risk of overdose and addiction | Science | AAAS By Robert F. ServiceAug 2018

This article gives a good summary of new opioid and non-opioid drugs being developed to treat our chronic pain.

multiple research groups are claiming progress in devising novel opioids—or alternatives—that seem to offer pain relief with far less risk of addiction or of the opioid-induced respiratory depression that all too commonly leads to death.

Most of these studies, reported at a meeting here and in a paper released this week, have only been done in animals, so the experimental compounds face significant hurdles before they can become approved medications.  

Opioids are powerful pain relievers because they bind to a key cell membrane protein, known as the µ-opioid receptor (MOR), on neurons in the brain and spinal cord. Once activated, the MOR triggers an intracellular “G protein” to initiate a molecular cascade that leads to pain relief.

But traditional opioids also activate another intracellular protein, β-arrestin, which produces respiratory depression and constipation, the most common opioid side effects for such drugs

Neel Anand, a senior director for medicinal chemistry at Nektar Therapeutics, a biotech firm in South San Francisco, California, described an approach that might help

Nektar’s drug, called NKTR-181, is a version of oxycodone to which researchers have linked a molecular tail called polyethylene glycol, a common pharmaceutical strategy for extending the life span of medicines in the blood.

Anand reported that in animal studies, NKTR-181 crosses the blood-brain barrier 70 times more slowly than oyxcodone. Instead of a sharp spike in both pain relief and euphoria, caused by an upsurge of the neurotransmitter dopamine in brain regions tied to addiction, NKTR-181 triggers a slower release of dopamine that produces flatter, more sustained pain relief and less euphoria.

It’s so frustrating that they always try to prevent “euphoria”  when I’ve never heard of a person with pain ever achieving it – unless you count the joy of experiencing pain relief as “euphoria”.

In clinical studies of more than 600 patients taking the compound, Nektar researchers found far fewer signs of addiction than in patients given oxycodone, as well as fewer side effects.

Again, they just assume that patients will exhibit “signs of addiction” when only about 3-4% have problems with opioids. How much is “far fewer” than what’s already just a tiny fraction?

“It clearly works” as a painkiller, says Steven McKerrall, a medicinal chemist with Genentech in South San Francisco. “They’ve built [a timed release] into the drug itself.”

I’d sure like to know how “clearly” it works as a painkiller because researchers seem to find all kinds of way to show whatever effectiveness they’re looking for when they’re funded by the company manufacturing these mostly useless drugs.

a compound developed by Astraea Therapeutics, a biotech company in Mountain View, California, that hits two brain molecules at once. AT-121 stimulates not only MOR, but also a close cousin known as the nociceptin opioid receptor (NOR).

When activated in the brain, NOR appears to counteract MOR. At the same time, it reinforces MOR’s pain relieving activity elsewhere in the central nervous system.

To me, this makes little sense. Why wouldn’t the drug also counteract MOR “elsewhere in the central nervous system”?

rhesus monkeys given AT-121 experienced 100-fold greater pain relief than the same dose of morphine provided.

Yet the drug did not trigger

  • respiratory depression,
  • addictivelike behaviors, or
  • even tolerance,

where more of a compound is needed over time to produce the same desirable effects such as pain relief.

Avoiding opioid receptors altogether is another appealing strategy for relieving pain with a reduced risk of addiction, says Roger Kroes, senior director for discovery science at Aptinyx, a biotech firm in Evanston, Illinois,

Called NYX-2925, it activates the NMDA receptor, which helps strengthen neural synapses involved in learning and memory.

This sounds like it would be a wonder drug for other purposes, like Alzheimer’s, but doesn’t seem like it would do much for our pain.

Although acute pain doesn’t involve a learned component, chronic pain is thought to bring about long-term neural changes orchestrated, in part, by NMDA receptors.

in preclinical studies on mice and rats, the compound reduced pain and led to a remodeling of synapses involved in learning and memory, essentially rewiring neural circuitry away from being habituated to pain.

I’m not sure (and neither are they) how much we are “habituated to pain” and how much our pain would be relieved if we weren’t.

Aptinyx is now testing NYX-2925 in two phase II clinical studies in people with diabetic nerve pain and fibromyalgia,

Drugs designed to deliver the benefits of opioids without the deadly risks can easily falter…

Robert F. Service Bob is a news reporter for Science in Portland, Oregon, covering chemistry, materials science, and energy stories.

16 thoughts on “A few new pain drugs in development

  1. peter jasz

    Lol. (RE: ” …new pain drugs may lower the risk of overdose and addiction ”

    Seriously ? “They” have been trying to “come up with a better” than natural opiate for the past ONE-HUNDRED-YEARS (100-years). Other than the current and very effective synthetic derivatives (all of which is available today and for past 50-years) further “research” is both bogus and a stunning waste of research time/energy. BUT, THEY know this.

    And, “May lower the risk of overdose” ?????? Gimme a break; if we can ‘overdose’ on water (we can), EVERYTHING (substance, natural or other) can/will be abused, inadvertently or not.

    And, “may lower the risk of addiction ” ??????? The risk of addiction remains a stable percentage (under 1%) of the general population -and has been stable/same for the past 50-100 years.

    Yet another fabricated crisis that (of course) requires millions/billions of $$ in research funding !
    Are we (the public) so stupid we can’t see through this ?


    Liked by 4 people

    1. Zyp Czyk Post author

      You are so right.

      Just taking prescribed opioid pain medication is not what’s causing overdose deaths. As you point out, the risk of addiction is a stable percentage and opioids are still by far the most effective pain meds – nothing has changed. (Except the number of people who have such a crummy life that they need some kind of chemical enhancer.

      The way they force people into shift work and/or pressure them with metrics to produce more and more and more… I used to joke they should put amphetamine dispensers in the restrooms along with water, soap, and paper towels because they are just as essential for doing the job.

      This isn’t a “drug crisis” – it’s a “quality of modern life crisis”.

      Liked by 2 people

  2. Kathy C

    One of the prerequisites for all of these drugs is overstating the horrors of opioids, and demeaning people with pain. Of course all of these potential drugs, are still in rodent trials. Some have already been hyped in various news outlets, while repeating the death toll, from heroin and fentanyl, making the need for the drug more urgent.

    They have been promoting these drugs for years, yet the research never pans out. They continue to mislead the general public about these so called alternatives, while blaming people with pain for the epidemic of despair. In France a clinical trial led to at least one death, this story was under reported here.

    Every other week there is an article about a new pain medication, spun by expensive PR generators. The use of the word opioid, addiction, or pain in the title, generates a lot of clicks. Further reading usually leads to disappointment, since these are all in rodent trials and there is little likelihood these drugs will be effective in humans. They use a lot of deceptive language, about receptors, or genetic information, but they all add up to zilch.

    Remember the “Cone Snail” they hyped non stop a decade ago? https://www.practicalpainmanagement.com/treatments/interventional/pumps/intrathecal-therapy-trials-ziconotide It was too dangerous for patients, yet they tried to market it for intrathecal use. They never did try to find out why 9 patients died after going back to opioids, after the Zicotinide.

    This list is pretty gruesome, they are evaluating various invasive procedures and “physicians attitudes and beliefs.” I wonder how they talk patients into any of this.

    Clinical Trials are now just another deceptive marketing trick. https://en.wikipedia.org/wiki/Seeding_trial There is an interesting reference to the Gapapentin Trials,
    “In the STEPS trial Pfizer presented their drug Neurontin in a way that merged pharmaceutical marketing with research.[13] This trial and other practices led to the company’s loss in Franklin v. Parke-Davis. ” They lost the court case, but went on to market their drug as an alternative to opioids, even though it was ineffective for pain.

    There has been virtually no enforcement of the various scams and online targeted patient information gathering they do under the guise of a Clinical Trial. No one is protecting patients from these con artists. The so called opioid crisis has brought deceptive marketers out in droves.

    Liked by 2 people

    1. Zyp Czyk Post author

      When capitalism is allowed to run amok in the healthcare “market”, these are exactly the results we should expect. That’s why there are supposed to be restraints on a system that makes profit a moral imperative.

      But lately, capitalism and a “free market” have almost been worshipped as a solution to all our woes as more and more social services are privatized, like the VA, retirement accounts (remember pensions?), prisons, utilities… too many to count.

      We are left at the mercy of social services that are gutted by profit-seeking.

      Liked by 1 person

    2. GZB

      Ugh, gabapentin is on my list of meds. that I have to take to get pain meds. I really hate to sound like such a wuss! I told PM doctor (actually a P.A.) that I was concerned about gabapentin. I got expected b.s. and was was pretty much told I had to take it. I notice no relief at all from gabapentin. I would be thrilled to report otherwise.

      Liked by 1 person

      1. Zyp Czyk Post author

        This seems to work mostly as a placebo because there are only a very few pain patients who find it effective. For the rest of us, it’s just another ineffective and mind-dulling unnecessary chemical burden on our brains.


    3. peter jasz

      Kathy: Thanks for that background information; “alternatives” to opiates (natural/or pharmacological derivatives) has been frantically explored for decades -more like the past 50-years- and “WOW” nothing to ‘fill-in’ our inherent opiate receptors -but opiates. Imagine that. !!

      Finally, it’s time we reference the Drug Culture Concerns as “Illegal Drug Trade OD’s”
      -and immediately STOP fuelling the false tag-line narrative of ” opioid crisis”

      peter j

      Liked by 2 people

      1. canarensis

        How much ya wanna bet they’re going to rush some “non-addictive” stuff into use & then discover –the hard way, for patients– that a lot more people are in a lot worse shape than the 4% or so that *might* have had addiction problems with the old tried & true? And/or, find out that the recreational users find a way to get high off the new stuff anyway*, thus creating whole new addictions? Will they ever learn that you can’t legislate away all addiction unless you kill off every living creature on Earth?? i’m not optimistic.

        *Did ANYone predict that gabapentin would be a recreational drug when they put it out?

        Liked by 2 people

        1. Flutterby

          I was wondering along the same lines when they said the animals “were not demonstrating addictive behaviors”… First of all, how do mice, rats, and primates exhibit addictive behaviors? I could imagine an oragutan panhandling, but not rats. They’d already be doing it.

          Ha! Just a little laugh before I have a long day at the hospital. 😁

          Liked by 2 people

      2. peter jasz

        RU sure about that ? Do “they” not monitor the animals ‘vital’ signs -and/or better yet do a (6-panel -Thank you Dr. Tennant) hormone investigation ?

        I’ll bet they do. AND I’ll also bet/claim “they” don’t give us all of the experiment results.

        There are two things “they” are hiding shamelessly -and ruthlessly- the severity and extent of pain conditions- and the only successful treatment (other than pathology repair) is what Mother Nature has provided for thousands of years: Opiates/Opiate receptors.
        OR, “they” are so stupid that they do not/have not determined ‘what/how’ and the degree of such brutal, intractable insufferable pain conditions -something I have a difficult time believing.

        And THAT would raise some serious unethical, in fact criminal behaviour/policy in that “they” know, yet refuse to provide effective pain control/relief for such suffering patients in agony ?
        Psychopaths ? Without doubt. Sociopath’s (individually/collectively) is more an apt descriptor of such beasts …


        Liked by 1 person


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