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Will These Novel Drugs Replace Opioids?

Subclass of adrenergic agonists give pain relief without addiction or sedation.

Key points

  • Alpha 2A adrenergic agonists provide analgesia without sedation and offer non-addictive alternative to opioids.
  • Comparatively easy to manufacture and administer orally, the new compounds are still a long way from use in patients.
Image by Ewa Urban from Pixabay
Source: Image by Ewa Urban from Pixabay

Earlier this year, the U.S. Food and Drug Administration (FDA) took steps to foster the development of non-addictive alternatives to opioids by issuing a draft guidance to companies developing non-opioid analgesics with recommendations for how to best approach their drug development and labeling strategies.

“Opioid misuse and abuse remain a serious public health crisis facing the country. Preventing new addiction through fostering the development of novel non-opioid analgesics is an important priority for the FDA,” said Patrizia Cavazzoni, M.D., Director of the FDA’s Center for Drug Evaluation and Research.

Now an international team of researchers has reported the discovery of a group of non-opioid compounds that provide analgesia without addiction or sedation. The team was led by Dr. Peter Gmeiner, Chair of Pharmaceutical Chemistry at Friedrich Alexander Universitat, and their research was published in the September 30 issue of Science.

“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,” said Gmeiner. And validated alternatives come with their own side effects. For example, non-opioid analgesics that target alpha 2A adrenergic receptors, such as brimonidine, clonidine, and dexmedetomidine, are powerful sedatives. “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,” said Gmeiner.

The researchers decided to see if they could identify non-opioid compounds that target alpha 2A adrenergic receptors but that do not have such strong sedative effects. They used computer modeling to screen over 300 million molecules to find candidates that would bind alpha 2A adrenergic receptors. From there the researchers focused on 50 molecules to synthesize and test, from which two were chosen for optimization to improve potency.

The resulting alpha 2A adrenergic agonists reduced pain without producing sedation, marking a milestone in the development of non-opioid pain medication. “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,” said Gmeiner.

The new compounds are also comparatively easy to manufacture and administer orally to patients. However, the researchers caution that these drugs are still a long way from being used in patients. According to Gmeiner, “We are currently still talking about basic research. The development of medication is subject to strict controls and in addition to significant amounts of funding, it takes a long time. However, these results still make us very optimistic.”


Fink, E.A. et al. (2022). Structure-based discovery of nonopioid analgesics acting through the α2A-adrenergic receptor, Science, 377: 30 September 2022.