New Non-Addictive Compound Alleviates Pain Without Sedation

Back Pain Concept

The researchers believe it is unlikely that the new molecules are addictive.

According to UCSF researchers, the new molecules are the top prospects for narcotic alternatives.

A recent study led by researchers at the University of California, San Francisco found that a newly discovered group of molecules reduced pain in mice without having the sedative effects that limit the use of opiates. The molecules act on the same receptor as clonidine and dexmedetomidine, two sedatives routinely used in hospitals, but they are chemically unrelated and may not be addictive.

Both clonidine and dexmedetomidine are potent painkillers, but since they are so sedative, they are seldom used outside of hospitals.

“We showed that it’s possible to separate the analgesic and sedative effects related to this receptor, said Brian Shoichet, Ph.D., professor in the School of Pharmacy, and one of four senior authors of the study, which appears in the Sept. 30, 2022, issue of Science. “That makes it a very promising target for drug development.”

The study is part of a five-year grant from the Defense Advanced Research Projects Agency (DARPA) and began shortly before the COVID-19 outbreak, with the goal of discovering effective painkillers that may be used alongside or in conjunction with opioids.

The work brings together scholars from a variety of fields; among Shoichet’s co-authors are Allan Basbaum, Ph.D., chair of anatomy at UCSF, Peter Gmeiner, Ph.D., a chemist from Freidrichs Alexander University in Germany, Yang Du, Ph.D., a structural biologist from the Chinese University of Hong Kong, and Michel Bouvier, Ph.D., a molecular biologist from the University of Montreal.

“Together, we were able to take this from the most fundamental level to identifying new molecules that might be relevant, and then to demonstrating that, in fact, they are relevant,” said Basbaum. “That doesn’t happen very often.”

6 Molecules Out of 300 Million

Basbaum, who had examined this adrenergic receptor called alpha2a in his lab and discovered that it is linked to pain alleviation, encouraged Shoichet to hunt for substances that would activate it.

Shoichet computationally scanned through a virtual library of over 300 million molecules to begin the search for molecules that would firmly bind to the receptor, excluding those that were too large for the small receptor. The remaining tens of thousands were virtually “docked,” one by one, on a computer model of the receptor. 

Through a series of tests, Shoichet narrowed the field from an initial 48 candidates to six, based on how they bound to the receptor in cultured human and mouse cells. Each of the final six was tested on three different mouse models for acute and chronic pain, and successfully alleviated pain in all three instances.

The pain-relieving molecules, which were from chemically different families, are also entirely novel. None of them had previously been synthesized.

Whereas the older drugs, like dexmedetomidine, activate a broad spectrum of neuronal pathways, the new molecules trigger only a selective subset of these, Shoichet said. The molecules also concentrate in the brain, and bind tightly to the receptor, making them good candidates for further development.

Hope for 1 in 5 Americans

Basbaum cautions that it may take several years of research before any of the compounds could be tested in clinical trials. The researchers don’t yet understand the possible side effects of the new molecules, and whether there might be unintended consequences from long-term use.

He believes, however, that it’s unlikely the compound is addictive. “Substance abuse happens when the drug generates a reward, which we didn’t see any evidence of,” he said.

While opioids clearly help patients with pain from surgery or cancer, Basbaum noted that the majority of the 50 million Americans with chronic pain have other conditions, like back injuries, joint pain, and inflammatory disease, that often aren’t helped by the drugs. New analgesics could completely change the outlook for these patients.

“If we can create a drug that works in combination with a much lower dose of opiate, that would be the dream,” he said. “The need for that is huge.”

Reference: “Structure-based discovery of nonopioid analgesics acting through the α2A-adrenergic receptor” by Elissa A. Fink, Jun Xu, Harald Hübner, Joao M. Braz, Philipp Seemann, Charlotte Avet, Veronica Craik, Dorothee Weikert, Maximilian F. Schmidt, Chase M. Webb, Nataliya A. Tolmachova, Yurii S. Moroz, Xi-Ping Huang, Chakrapani Kalyanaraman, Stefan Gahbauer, Geng Chen, Zheng Liu, Matthew P. Jacobson, John J. Irwin, Michel Bouvier, Yang Du, Brian K. Shoichet, Allan I. Basbaum and Peter Gmeiner, 30 September 2022, Science.
DOI: 10.1126/science.abn7065

The study was funded by the Defense Advanced Research Projects Agency, the DFG, and the National Institutes of Health. 

25 Comments on "New Non-Addictive Compound Alleviates Pain Without Sedation"

  1. Clonidine is not a “potent painkiller”. It’s not a pain killer at all. It’s not an opiate. It’s a blood pressure medication.

  2. I had come to say the same. It’s VERY commonly used outside the hospital, especially in children with ADHD who can’t sleep. It is a blood pressure med that happens to be sedating, but does nothing for pain.

  3. Dr Victor Denis Purcell | November 9, 2022 at 7:07 am | Reply

    Disclaimer: not giving medical advice. This is for entertainment purposes only

    May I suggest for pain: homeopathic, magnesium phos. For nerve pain, Hypericum, or trauma with bruising Arnica for sciatic pain with burning apis for chronic headaches Natrum Mur. I would suggest researching CBD It is the next wave in medicine, especially prepared homeopathically as a Tincture . Again, this is not medical advice it is for pure entertainment.

    Be well, Dr. Victor, Denis Purcell Cert-Hom

  4. clonidine is of remarkable help in the treatment of resistant and painful headaches after Traumatic Brain Injury. To make blanket statements without considering off label uses is counterproductive.

  5. Susan J LaDuke | November 9, 2022 at 8:23 am | Reply

    Response to Jo
    While Clonidine is typically used to treat hypertension it’s also a potent Alpha-2 adrenergic agonist producing sedative & analgesic effects with minimal respiratory depression.

  6. Clonidine is not a pain killer. It has been used in addiction therapy for anxiety. Trust me, it does not work. Technically, it’s a POTENT HTN medication and overuse will drop people like flies from low blood pressure.

  7. Yes clonidine is a blood pressure medication and has no use in acute or chronic pain treatment. I think the author confused the enzyme that clonidine binds to with clonidine itself. This author should give up writing biomedical articles because there are many other factual mistakes and conceptual misunderstandings.

  8. Need it

  9. This is so incorrect it’s funny.
    This entire article is trash. I mean a simple Google search could tell a person clonidine is a BP med. Nevermind common sense.

  10. This is getting pathetic. How can this even be published? Clonidine does nothing for pain. I heard it can help with drug withdrawals and anxiety. I take it for my blood pressure. What misconstrued writing on these meds.

  11. B Myatt, PharmD | November 9, 2022 at 8:26 pm | Reply

    There are a few pubmed articles that explain the mechanism of action for clonidine and analgesia. It can be used topically as well, although the effect is mild when used in topical creams.
    https://www.ncbi.nlm.nih.gov/books/NBK459124/

  12. I occasionally spray myself with lidocaine which helps. Like a sore leg from overuse, spray all of the part that hurts. Spray you down like sunscreen. Jk don’t go overboard.

  13. Concerned Citizen | November 10, 2022 at 3:56 am | Reply

    The author should have been fact checked by their editor. All this article is doing is putting out false information. Therefore the entire article becomes suspect. Once I read the words ‘potent pain killer’ all creditably flew out the window and therefore the article means nothing. When I want to read about science and tech ESPECIALLY when it comes to our health, I WANT FACTS.

  14. Norma Gonzales | November 10, 2022 at 5:38 am | Reply

    Opiates have a very good place in the world for pain control and chronic pain.

  15. Wow, so many armchair Physicians, many medications are used off label, keep the misinformation to yourselves.

  16. People, everyone’s system is different. Clonidine can help with some people’s certain types of pain. Put this in context, they are researching for adjunct medications to use with opioids, which does sound like it could reduce the actual amount of addictive and potentially deadly medications needed on a daily basis. However, I would point out, that clonidine is rarely abused. Also, many people develop tolerance to it rather quickly. Also, potent?!

  17. Theresa oneill | November 13, 2022 at 7:23 am | Reply

    What a waste of time.Clonadine, really?

  18. The history of pain medication is that all pain medications produce a high even ibuprofen and Tylenol when the potency of the pain relief exceeds what is needed to cover the pain. Thus all pain med will carry addictive potential it’s a byproduct of all pain relief.

  19. Clonidine has very mild pain relief efficacy at best. Usually neuropathic pain can respond to it but as much as people would love to believe otherwise sometimes pain meds are addictive.

  20. Clonidine is an extremely useful and multi-purpose drug ORIGINALLY approved for and still also used for hypertension. *Clonidine interacts with the mu-opiod recepter in addition to alpha2a. There is another analog of clonidine called tizanidine that is an FDA approved for muscle relaxer. Clonidine is also effective for pain, ADHD, and tourette syndrome, among others. There is also a reformulated, extended release version of clonidine specifically fda approved for children with ADHD/add; and it can also help with adults with ADHD off-label. Among many other things it also works in addiction, probably because of it’s non-intoxicating effects on the mu-recepter; but it’s many side effects are why it’s absolutely almost never used for abuse. Imodium also interacts with the mu-opiod recepter but has much less addict-limiting side effects and is available OTC, and is abused all the time in comparison despite being used for Travers diarrhea AND OTC.

    It’s important to note that older drugs that have been in existence and on the approved market for decades, research and case reports build and build; and eventually we understand secondary effects of our approved drugs much more fully. They’re generally more complex than we first thought.

  21. I have to say SOMETHING, now I am a person who suffers from joint, bone, muscle and neuro issues. I DO PERSONALLY TAKE THE DRUG CLONIDINE FOR MY HIGH BLOOD PRESSURE ALONG WITH LISINOPRIL AND THE SEDATION IS DEFINITELY A SPOT ON EFFECT AND I HAVE TO TAKE THEM BOTH AT BEDTIME. I will say I get no pain relief from CLONIDINE at all just blood pressure relief and had a situation where it felt like I was on a brink of a mini stroke by all rights written in medical books but it was my BP THAT SOIKED DUE TO UNNEEDED STRESS AND YET AGAIN NO PAIN RELIEF.
    Now I will also say I have a son whose got autism on a higher spectrum and when he was younger he was prone to outburst and other aggression and was prescribed CLONIDINE. For his reasons of being given this it did the job with calming him and letting it take its course and worked but since getting older age 26 he hasn’t needed it since he was around puberty. SO I GUESS I CAN SAY I UNDERSTAND ON ONE LEVEL THAT IT IS USED AS BP MED BUT I DONT SEE IT EVER BEING USED as a PAIN MANAGEMENT DRUG PERIOD. When you have to start Messing with the compounds of a drug used specifically for a purpose then you create problems and the original drug never does it’s job!!!! I say STOP WITH THE MIRACLE BELIEFS OF OPIATES AND CHANGING CERTAIN DRUGS. There are people who need pain management and I have that with a great dr who not only puts the well being of his patient up FEONT but if his integrity as well!!! COMMUNICATION IS THE KEY AND TRYTH TO DEALING WITH PAIN AND OPIATES AND FINDING NEWER AGED MEDS BUT INJECTIONS ARE NOT BY FAR THE BEST SOLUTION EITHER DUE TO LASTING EFFECTS EVERY PUNCTURE CAUSES IN THE SPINE OR ELSEWHERE.

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