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.