A Balancing Act: Learning from the Past to Build a Future-Focused Opioid Strategy

The harmful side effects of opioid drugs such as respiratory depression, tolerance, dependence, and abuse potential have limited the therapeutic utility of opioids for their entire clinical history. However, no previous attempt to develop effective pain drugs that substantially ameliorate these effe...

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Bibliographic Details
Published in:Annual review of physiology 2024-02, Vol.86 (1), p.1-25
Main Authors: Gooding, Sarah Warren, Whistler, Jennifer L
Format: Article
Language:English
Subjects:
Analgesics
Analgesics, Opioid - adverse effects
Arrestin
Drug abuse
Drug Tolerance
G protein
Humans
Liability
Narcotics
opioid
Opioid receptors (type mu)
Pain
receptor trafficking
Receptors
Side effects
Signal Transduction
signaling bias
Citations: Items that this one cites
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Summary:The harmful side effects of opioid drugs such as respiratory depression, tolerance, dependence, and abuse potential have limited the therapeutic utility of opioids for their entire clinical history. However, no previous attempt to develop effective pain drugs that substantially ameliorate these effects has succeeded, and the current opioid epidemic affirms that they are a greater hindrance to the field of pain management than ever. Recent attempts at new opioid development have sought to reduce these side effects by minimizing engagement of the regulatory protein arrestin-3 at the mu-opioid receptor, but there is significant controversy around this approach. Here, we discuss the ongoing effort to develop safer opioids and its relevant historical context. We propose a new model that reconciles results previously assumed to be in direct conflict to explain how different signaling profiles at the mu-opioid receptor contribute to opioid tolerance and dependence. Our goal is for this framework to inform the search for a new generation of lower liability opioid analgesics.
ISSN:0066-4278
1545-1585
DOI:10.1146/annurev-physiol-042022-015914