Evolution and challenges of opioids in pain management: Understanding mechanisms and exploring strategies for safer analgesics.

Opioids traced back to ancient civilizations, have evolved in their usage for acute and chronic pain treatment. Their interaction with the endogenous opioidergic system modulates pain thresholds, neurological functions, and beyond. The discovery of opioid receptor subtypes (MOP, KOP, DOP, and NOP) revolutionized pharmacology, shedding light on their distinctive roles and signaling pathways. However, despite the efficacy of opioids, complications such as tolerance, addiction, and adverse behavioral effects pose significant challenges. This article explores the mechanisms of opioid activity in cells, emphasizing the role of biased agonism in the analgesic and adverse effects of opioids. We further reviewed strategies to mitigate the side effects, including the development of biased agonists targeting G-proteins, exploration of opioid receptor heterodimers, allosteric activation, and selective targeting of receptor splice variants. Insights into the sodium channel's role and bitopic modulators also offer new avenues for drug design. The quest to develop safer and more effective analgesics while minimizing adverse effects drives ongoing research. The comprehensive understanding of opioid receptors and innovative strategies offer hope for addressing the opioid crisis and advancing pain management paradigms. [ABSTRACT FROM AUTHOR]