Combating Opioids With A Supplemental Painkiller: Nalfurafine, An Anti-itch Medicine
Pain relievers are as diverse as with the type of pains that a person experiences. By interacting with different parts of the nervous system, pain relievers treat some pains better than others.
Researchers from West Virginia University led by Dr Shane Kaski have recently discovered that an anti-itch medication that targets a specific part of our nerve cells can make morphine, which targets a different part more effective.
These new findings may enable doctors to prescribe lower doses of morphine by supplementing it with the drug, called
nalfurafine, and still soothe their patients' pain.
Typically, morphine is a classic, widely used opioid. Using less of it could mean fewer morphine-related side effects such as constipation and nausea and a lower risk of addiction.
Dr Shane Kaski told
Thailand Medical News, "Right now there's a lot of work looking for replacements for
opioids, for obvious reasons. Maybe
nalfurafine is not so great as a replacement on its own, but maybe it does enough that we could put it together with other
opioids and get this dose-sparing effect."
In the research, which the National Institute of Drug Abuse funded, Kaski used animal models to test how well morphine treated pain on its own and in combination with
nalfurafine. He administered the drugs in different amounts to determine which relieved the most pain at the lowest dose. Then he compared each regimen's effectiveness as a pain reliever.
The researchers discovered that using a small supplement of
nalfurafine alongside a lower dose of morphine reduced pain as dramatically as using a large dose of morphine alone. His findings appeared in the
Journal of Pharmacology and Experimental Therapeutics.
He further added, "It's possible that you just need a tiny smidgen of
nalfurafine with a smidgen of this other addictive drug to get the equivalent pain relief from a larger dose of your addictive drug. That's what we're seeing in our early work. That's the promise that we saw."
Should future studies including eventual clinical trials affirm Dr Kaski's results, then doctors may be able to combat the
opioid epidemic by prescribing
nalfurafine as a supplemental
painkiller. That's especially significant for West Virginia, which leads the nation in
opioid-related deaths, according to NIDA.
Dr David Siderovski, professor of pharmacology in the School of Medicine, West Virginia University commented, "Shane's demonstration of the anti-addictive and dose-sparing effects of
nalfurafine will end up rescuing
opioid painkillers from the dustbin of pharmacology, turning the tide against avoiding
opioid prescriptions that greatly relieve pain but led to the present opioid crisis in West Virginia and the Appalachian region."
However, like morphine,
nalfurafine is an
o
pioid.
Dr Shane Kaski added, "That might sound weird. Why are you going to use another
opioid on top of morphine? It comes down to the specifics of the biology of
opioid receptors. Opioid receptors are like assigned parking spaces on the surface of a nerve cell. Certain molecules but not others can "park" in them. From there, the molecules can amplify or inhibit the nerve cell's activity. The biggest three
opioid receptors you'll hear about are mu, kappa and delta."
Like typical conventional
opioids, morphine parks in the mu receptor, where it quiets the nerve's pain signal. It also activates the brain's reward circuit.
On a basic level, "if something feels good, it increases dopamine in the right circuits and motivates you to do that thing more often," he said. "The mu opioid receptor does that."
The issue is, those surges of dopamine make classic opioids like morphine, oxycodone and codeine addictive.
However,
Nalfurafine is unusual. Even though it's an
opioid, it doesn't have a permit to park in mu. Instead it parks in the kappa receptor. Once it does, it alleviates pain while also "putting the brakes on" the reward circuit that can lead to addiction, Kaski said. But muting those dopamine swells can cause an unpleasant side effect: dysphoria, the opposite of euphoria.
"Typically
, opioid pain relievers, at least in the short term, produce euphoria in many but not all people. However, with long-term use,
opioid pain medications can change the levels of important brain molecules, including those that regulate mood," said Vincent Setola, an assistant professor of neuroscience, physiology and pharmacology, and behavioral medicine and psychiatry. He and Siderovski are mentors to Kaski.
For eons, physicians and researchers alike believed drugs that targeted the kappa opioid receptor weren't worthwhile because they could extinguish happiness. Yes, they relieved pain, but they were distressing, causing anxiety and even symptoms of psychosis at high doses.
Dr Kaski said, "The reason we thought this could still be something worth trying is
nalfurafine itself. This drug is apparently one that doesn't cause dysphoria as much. It's actually used in humans in Japan to treat itching related to renal failure. It's used for itch because it's very good at alleviating that type of pain, but it's also good at relieving other kinds of pain."
Dr Kaski wanted to pin down the effect that the
nalfurafine/morphine combination had on the animal models' disposition. When
nalfurafine was given on its own, the drug did seem to trigger dysphoria in the animals, but when it was coupled with morphine, the dysphoria disappeared.
In reality, administering
nalfurafine alongside morphine had a beneficial emotional effect. It neutralized the rewarding effects of morphine which, on its own, was very rewarding to the animals. This effect might make morphine less addictive. And according to Setola, ongoing studies show that nalfurafine has similar dose-sparing and anti-rewarding effects on oxycodone, "another commonly used and addiction-fraught
opioid pain medication."
Reference : Shane W. Kaski et al, Preclinical Testing of Nalfurafine as an Opioid-sparing Adjuvant that Potentiates Analgesia by the Mu Opioid Receptor-targeting Agonist Morphine, Journal of Pharmacology and Experimental Therapeutics (2019). DOI: 10.1124/jpet.118.255661
