Current evidence for central analgesic effects of NSAIDs: an overview of the literature

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for a variety of painful conditions. Their peripheral anti-inflammatory effect due to inhibition of prostaglandin synthesis is well documented. In the late 1980's, animal data suggested for the first time that NSAIDs might have central effects as well. Since that time, central inflammatory and nociceptive pathways that are potential targets of NSAIDs have been extensively studied in both animal and human models. This review provides an overview of the relevant literature implicated in the central effects of NSAIDs. The role of different enzymes and mediators, as well as the central effects of NSAIDs are discussed. Literature search was performed by PubMed NCBI. A large body of evidence supports the central effects of NSAIDs in animal models of inflammatory pain conditions. Relevant mechanisms that underlie this central action involve spinal upregulation of the enzyme cyclooxygenase, increased spinal prostaglandin E2 production, modulation of inhibitory fast synaptic currents in lamina I and II of the dorsal horn, and glycine-dependent modulation of pain. Results from animal models are not yet sufficiently supported by human studies. This does not necessarily imply that the central effects of NSAIDs are irrelevant to human pain, but rather that methodological and regulatory barriers are the limiting step to translating findings from animal studies to human research protocols.

A Glra3 phosphodeficient mouse mutant establishes the critical role of protein kinase A–dependent phosphorylation and inhibition of glycine receptors in spinal inflammatory hyperalgesia

“…This concept remains to be thoroughly tested in humans. 34 On the other hand, the lack of a phenotype in GlyRα3(S346A) point-mutated and GlyRα3-deficient mice corresponds well with the low efficacy of COX inhibitors against neuropathic pain in patients.…”

Mechanisms of Transmission and Processing of Pain: A Narrative Review

“…The action of PGE2 occurs mainly on proximal ion channels and acts as a sensitizer for nociceptor activity, instead of as a direct activator of nociceptive neurons. This process is the key to understanding the analgesic effect and the analgesic power of NSAIDs [ 134 ]. PGE2 may induce persistent hyperalgesia via the PKA and PKC-mediated activation of NF-κB in DRG neurons if it is present over a long period of time [ 135 ].…”

Using Experimental Models to Decipher the Effects of Acetaminophen and NSAIDs on Reproductive Development and Health

“…Central inflammatory and nociceptive pathways also are potential NSAID targets. This central action involves COX enzyme upregulation in spinal cord that increases PGE2 production ( Vuilleumier et al, 2018 ). NSAIDs and APAP interact with endocannabinoids, and the serotonergic, noradrenergic and cholinergic systems in the central nervous system, and this contributes to their analgesic effect ( Hamza and Dionne, 2009 ).…”