The role of the endocannabinoid system in the mechanism of action of nonopioid analgesics

Eur J Pharmacol. 2025 Sep 15:1003:177946. doi: 10.1016/j.ejphar.2025.177946. Epub 2025 Jul 12.

Abstract

The endocannabinoid system (eCBS) plays a crucial role in pain modulation through its components, including endocannabinoids, cannabinoid receptors (CB1 and CB2), and metabolic enzymes. Recent research highlights the interaction between the eCBS and non-opioid analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, and pyrazolones. These agents may enhance endogenous endocannabinoid levels or influence eCBS signaling pathways, providing a multifaceted approach to pain relief. This review examines the pharmacological mechanisms underlying these interactions, focusing on the potential of non-opioid eCBS interactions, detailing synergistic effects that could improve analgesic efficacy while minimizing side effects. Additionally, we explore the therapeutic implications of co-administering non-opioid analgesics with eCBS modulators to create more effective pain management strategies. The combined modulation of non-opioid pathways and the eCBS represents a promising treatment for acute and chronic pain, warranting further clinical investigation and translational research in this evolving field.

Keywords: Cannabinoid receptors; Endocannabinoid system; Metamizole; NSAIDs; Pain; Paracetamol; Pharmacology.

Publication types

  • Review

MeSH terms

  • Analgesics, Non-Narcotic* / pharmacology
  • Analgesics, Non-Narcotic* / therapeutic use
  • Animals
  • Endocannabinoids* / metabolism
  • Humans
  • Pain* / drug therapy
  • Pain* / metabolism
  • Receptors, Cannabinoid / metabolism
  • Signal Transduction / drug effects

Substances

  • Endocannabinoids
  • Analgesics, Non-Narcotic
  • Receptors, Cannabinoid