Results from experimental and clinical studies indicate that antidepre
ssants have specific analgesic properties in chronic pain. The exact s
ite of action of these drugs (spinal or supraspinal) has yet to be est
ablished. The most likely mechanism of action of antidepressants in pa
in relief is via effects on monoaminergic and opioidergic systems. The
most frequently postulated mechanism of action is an effect on seroto
nergic mechanisms; however, data are equivocal. Some data suggest that
antidepressants that inhibit both serotonin (5-hydroxytryptamine; 5-H
T) and noradrenaline (norepinephrine) reuptake are the most effective
agents in relieving pain, suggesting that there may be some noradrener
gic involvement. The analgesic effects of antidepressants are reversed
by the opioid antagonist naloxone. and changes in opioid levels are i
nduced 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 nee
ded to better elucidate the mechanism of action of antidepressants in
pain relief.