Research of Pain Medication without Addiction and Sedation

Epidemics of pain and opioid abuse underscore the need for new nonopioid therapeutics to treat pain. Many nonopioid receptors are involved in pain processing (nociception), but only a few have been validated therapeutically. Of particular interest is the α2A-adrenergic receptor (α2AAR), a G protein–coupled receptor (GPCR) whose activation in the central nervous system has pain-relieving effects. The known therapeutics targeting the α2AAR, like clonidine and dexmedetomidine, are known to be analgesic. They are also strongly sedating, which is important for the primary indication of dexmedetomidine. This, however, has restricted the use of these drugs to hospital settings and kept them from being used in broader patient populations.

Opiates cause addiction, new substances do not

They are a blessing for patients suffering from severe pain, but they also have serious side effects: Opioids, and above all morphine, can cause nausea, dizziness and constipation and can also often cause slowed breathing that can even result in respiratory failure. In addition, opiates are addictive — a high percentage of the drug problem in the USA is caused by pain medication, for example.

In order to tackle the unwanted medical and social effects of opioids, researchers all over the world are searching for alternative analgesics. Prof. Dr. Peter Gmeiner, Chair of Pharmaceutical Chemistry is one of these researchers. “We are focusing particularly on the molecular structures of the receptors that dock onto the pharmaceutical substances,” says Gmeiner. “It is only when we understand these on the atomic level that we can develop effective and safe active substances.” Collaborating with an international team of researchers, Prof. Gmeiner discovered an active substance in 2016 that bonds to known opioid receptors and that offers the same level of pain relief as morphine, even though it has no chemical similarity to opiates.

New approach: Adrenaline receptors instead of opioid receptors

Peter Gmeiner is currently following a lead that seems very promising: “Many non-opioid receptors are involved in pain processing, but only a small number of these alternatives have as yet been validated for use in therapies,” he explains. Gmeiner and a team of researchers from Erlangen, China, Canada and the USA have now turned their attention to a new receptor that is responsible for binding adrenaline — the alpha 2A adrenergic receptor. There are already some analgesics that target this receptor such as brimonidine, clonidine and dexmedetomidine. Gmeiner: “Dexmedetomidine relieves pain, but has a strong sedative effect, which means its use is restricted to intensive care in hospital settings and is not suitable for broader patient groups.”

Pain relief without sedation in animal models

By further optimizing the identified molecules, for which extremely high-resolution cryo-electron microscopic imaging was used, the researchers were able to synthesize agonists that produced high concentrations in the brain and reduced the sensation of pain effectively in investigations with animal models. “Various tests confirmed that docking on the receptor was responsible for the analgesic effect,” explains Gmeiner. “We are particularly pleased about the fact that none of the new compounds caused sedation, even at considerably higher doses than those that would be required for pain relief.”

The successful separation of analgesic properties and sedation is a milestone in the development of non-opioid pain medication, especially as the newly-identified agonists are comparatively easy to manufacture and administer orally to patients. 

The aim of the research consortium is to find a chemical compound that activates the receptor in the central nervous system without a sedative effect.


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, Peter Gmeiner (September 30, 2022). Structure-based discovery of nonopioid analgesics acting through the α 2A -adrenergic receptor. Science. Retrieved from :