Abstract
Pain is a complex, unpleasant sensory experience that typically serves as a protective response to harmful stimuli. The transition from acute sensation to chronic pathology originates with early pathogenic events, defined by the activation of peripheral nociceptors following tissue injury. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used and the most commonly prescribed classes of medication in non-severe pain for their analgesic, antipyretic, and anti-inflammatory effects. They are effective for various pain conditions, including muscle pain, mild trauma, headaches, and various inflammatory conditions such as arthritis and fever-related diseases. Their primary mechanism of action is to block the synthesis of certain prostaglandins by inhibiting cyclooxygenase enzymes. However, long-term and frequent use of non-selective cyclooxygenase inhibitors is believed to be associated with a higher risk of gastrointestinal side effects, including gastrointestinal bleeding, obstruction, ulcers, and perforations. On the other hand, like opioids, repeated, chronic administration of NSAIDs leads to a progressive decrease in pain-relieving effectiveness, developing tolerance. Our extensive studies over almost twenty years manifest that this tolerance to NSAIDs (diclofenac, ketorolac, ketoprofen, and lornoxicam) developed over four to five days, involving the endogenous opioid and cannabinoid systems and showing cross-tolerance with morphine, suggesting shared pathways in long-term pain management. While NSAIDs primarily work by inhibiting cyclooxygenase and prostaglandin production, their tolerance is linked to the endogenous opioid and cannabinoid systems, as opioid antagonist (e.g., naloxone) and cannabinoid receptor antagonist (AM-251) block this tolerance. Thus, commonly used for acute and chronic pain, this evidence highlights that NSAIDs may have reduced efficacy over time due to adaptive changes in pain-control pathways, including limbic brain structures, central amygdala, and cingulate and insular cortices. This mechanism mediates the descending axis from the midbrain periaqueductal grey matter, rostral ventromedial medulla, and dorsal horn of the spinal cord.