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A New Path for Opioid-Free Pain Relief

Written by El Hebert '24

Edited by Lizzy Zhang '24

For millions of chronic and acute pain patients, opioids are the only option for relief. New research shows how we could change that. Ian Furst, 2019, hosted on Wikimedia Commons.


Until the past decade, doctors everywhere had a powerful first resort to treat pain: opioids. For nearly anyone who’s ever stumbled back to work after surgery, or any of the millions of Americans living with chronic pain, these chemicals provide freedom and functionality. At the same time, though, they cast a long shadow. They create unpleasant side effects, like nausea, constipation, or even worsened post-surgery pain [1]. They can also be highly addictive, and deadly. It’s because of this dark side that we live in the middle of a global social crisis of opioid addiction. In 2020, nearly 75% of drug overdose deaths involved an opioid [2].


With such stakes behind them, researchers around the globe are searching for safer compounds with similar pain-killing power.


Just this September, an international team based out of Erlangen, Germany announced their discovery of a promising new lead. Led by Dr. Peter Gmeiner, Chair of Pharmaceutical Chemistry at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), the researchers turned to a completely different mechanism of pain relief.


Traditional opioids don’t take effect at the site of injury, but in the brain, where alarm signals from the body are processed into pain. Some chemicals amplify these signals, but others shut them down - for example, the pain-dampening effects of laughter, sex, and even the “runner’s high” all stem from a set of naturally produced molecules called endorphins. Because opioids share a chemical structure with the body’s own endorphins, they can mimic their function, shutting down pain signals and causing a sense of euphoria [3]. But this same chemical structure confers the opioids’ side effects and addictive properties.


So instead, Dr. Gmeiner’s group probed another pathway: the adrenaline signaling system, used by neurons throughout the brain and body. Specifically, they focused on one of the chemical communication channels that lets these neurons respond to adrenaline signals, a protein called the α2A-adrenergic receptor, or α2AAR. The signals passing through the α2AAR protein famously influence blood pressure, vigilance, and parts of the fight-or-flight response [4]. Critically, they can also control pain. With drugs that physically lock into α2AAR, doctors can harness these properties.


This effect is already well-known by emergency room doctors, who use α2AAR-targeting drugs as part of anesthesia. Dexmedetomidine, for example, is recommended in the ICU for its effective pain relief and low risk of respiratory complications (a major danger of opioids). However, it and similar drugs are also heavy sedatives - powerful enough to be used during ventilator intubation procedures on awake patients [5]. For the many current pain patients who need to manage their condition in everyday life, it’s just not a possibility.


Luckily, today’s chemists have access to a truly staggering amount of computing power that allows them to search for new options by analyzing the shared properties of molecules. In their study, the Erlangen group accessed a digital library of 301 million chemicals, most of which had never been made in a real lab, and tested each, like a puzzle piece, against a virtual model of the α2AAR protein. The best fits were then compared to dexmedetomidine so similar molecules could be filtered out; the researchers hoped that this would exclude chemicals with comparable sedative effects. After more than a week of computer processing time, with each candidate molecule tested against α2AAR in hundreds of different positions, 64 candidates remained.

This image from the original study shows multiple potential new drugs being checked against a model of the larger, lumpy-looking α2AAR protein. Fink et al., 2022.


Now came the time to see if they worked as well in real life. The techniques of computer-based chemistry allow researchers to sort through massive data sets with ease, but they may fail to predict the complexities of the actual molecules. So the Erlangen group synthesized 48 of their candidates and tried the physical version of their fit test, mixing the custom compounds with real α2AAR proteins and tracking how the molecules interacted. More than half of them turned out to be good matches in the real world, too - one of the highest success rates for a virtual binding test to date.


Most promising of all, some of the best α2AAR matches appeared to produce different chemical changes in the protein than the currently-used sedative drugs. Finally, these chosen few could face the ultimate test - would they work in a living, breathing body?


Dr. Gmeiner and his group tested the four finalists on mice, and found significant pain-relief effects without sedation. The mice ignored injuries, but continued to keep their balance in obstacle courses. Additionally, none of the unpleasant digestive effects of opioids were observed [6].


These new molecules offer a promising lead, a new angle to attack the problem of pain. After all, more than 140 million opioid prescriptions are written in the U.S. every year, and each one has the potential to create addiction [7]. We could all use a better option.


Nevertheless, the Erlangen group’s new molecules have a long way to go. Getting from any exciting molecule to a real working drug takes years of chemical research, convoluted legal processes, and above all, safety testing. These candidates don’t even have names yet, and many safety considerations remain unaccounted for. Though they avoid the well-known sedative effect, other α2AAR side effects, like heart rate slowing, were not tested in this study.


Even so, this study shows the amazing potential of today’s technology to open up those options, from simulation to solution. The opioid crisis is only one example of a far-reaching problem that such research can attack. One day, a nameless molecule from a virtual library might save your life.

 

References

[1] Berlier J, Carabalona JF, Tête H, Bouffard Y, Le-Goff MC, Cerro V, Abrard S, Subtil F, Rimmelé T. Effects of opioid-free anesthesia on postoperative morphine consumption after bariatric surgery. Journal of Clinical Anesthesia. 1 Oct 2022 [cited 12 Nov 2022];81:110906. DOI: 10.1016/j.jclinane.2022.110906.


[2] Hedegaard H, Miniño AM, Spencer MR, Warner M. Drug Overdose Deaths in the United States, 1999–2020. National Center for Health Statistics, December 2021. In Opioids: Data Overview. Center for Disease Control. Last updated 2022 [cited 12 Nov 2022]. Available from: https://www.cdc.gov/opioids/data/index.html.


[3] Chaudhry SR, Gossman W. Biochemistry, endorphin. In StatPearls [Online] 8 Apr 2021 [cited 12 Nov 2022]. StatPearls Publishing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470306.


[4] Motiejunaite J, Amar L, Vidal-Petiot E. Adrenergic receptors and cardiovascular effects of catecholamines. Annales d'Endocrinologie. 1 Jun 2021 [cited 12 Nov 2022]; 82(3-4):193-197. Elsevier Masson. DOI: 10.1016/j.ando.2020.03.012.


[5] Reel B, Maani CV. Dexmedetomidine. In StatPearls [Online] 8 May 2022 [cited 12 Nov 2022]. StatPearls Publishing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK513303.


[6] Fink EA, Xu J, Hübner H, Braz JM, Seemann P, Avet C, Craik V, Weikert D, Schmidt MF, Webb CM, Tolmachova NA. Structure-based discovery of nonopioid analgesics acting through the α2A-adrenergic receptor. Science. 30 Sep 2022 [cited 12 Nov 2022];377(6614):eabn7065. DOI: 10.1126/science.abn7065.


[7] Center for Disease Control. U.S. Opioid Dispensing Rate Maps [Online]. Last updated 10 Nov 2021 [cited 12 Nov 2022]. Available from: https://www.cdc.gov/drugoverdose/rxrate-maps/index.html. Dispensing data sourced from IQVIA Xponent survey 2006–2020.

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