Mechanistic Insights into the Potential Central Nervous System Effects of Chronic Analgesic Exposure Beyond Nephrotoxicity

Abstract Analgesic medications, particularly non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, are among the most widely used agents for the management of pain and fever. Their renal adverse effects are well recognized, but potential effects beyond the kidney have received comparatively less integrated attention. This narrative review examines evidence concerning the potential effects of prolonged analgesic exposure on the central nervous system (CNS), with particular emphasis on oxidative stress, mitochondrial disturbances, neuroinflammatory signaling, blood-brain barrier (BBB) considerations, synaptic plasticity, cognitive function, serotonergic adaptation, and medication-overuse headache (MOH). NSAIDs and acetaminophen are considered separately because their pharmacological and toxicological profiles differ substantially. Experimental studies in rodents indicate that prolonged acetaminophen exposure can be associated with altered synaptic structure, glutathione depletion, increased protein oxidation, microglial activation, neuroinflammatory signaling, reduced brain-derived neurotrophic factor, and behavioral changes (Lalert et al., 2020, 2021, 2023). However, these findings arise predominantly from preclinical models, and their relevance to therapeutic exposure in humans remains uncertain. NSAIDs can reach the CNS to varying degrees, but their effects on neural inflammation are complex rather than uniformly neurotoxic. Clinically, medication-overuse headache provides stronger human evidence that repeated exposure to acute pain medications can contribute to maladaptive changes in pain-processing networks. Overall, available evidence supports biological plausibility for CNS effects of prolonged or excessive analgesic exposure but does not establish generalized human CNS neurotoxicity from therapeutic use.