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Results from experimental and clinical studies indicate that antidepressants have specific analgesic properties in chronic pain. The exact site of action of these drugs (spinal or supraspinal) has yet to be established. The most likely mechanism of action of antidepressants in pain relief is via effects on monoaminergic and opioidergic systems.The most frequently postulated mechanism of action is an effect on serotonergic mechanisms: however, data are equivocal. Some data suggest that antidepressants that inhibit both serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine) reuptake are the most effective agents in relieving pain, suggesting that there may be some noradrenergic involvement.The analgesic effects of antidepressants are reversed by the opioid antagonist naloxone, and changes in opioid levels are induced by these compounds. Therefore, antidepressants may also act via the opioid system. Nevertheless, direct binding of antidepressants to opioid receptors seems unlikely. Other less validated hypotheses have also been proposed. Further clinical and experimental studies are needed to better elucidate the mechanism of action of antidepressants in pain relief.