Amitriptyline (median effective dose [ED50] 1.2 mg per kilogram of body weight), imipramine (ED50 2.3 mg/kg), and their demethylated derivatives nortriptyline (ED50 1.9 mg/kg) and desimipramine (ED50 3.2 mg/kg) are active analgesics as indicated by the mouse writhing assay. Although not as potent as morphine (ED50 0.2 mg/kg), the antidepressants were up to 70 times more potent than aspirin (ED50 91 mg/kg). The actions of amitriptyline were not affected by the specific opiate antagonist naloxone but were markedly attenuated in animals whose monoamine levels had been depleted with reserpine. Central mechanisms appear important since amitriptyline (ED50 4.6 micrograms) was potent when administered intracerebroventricularly.