Amitriptyline reduces the pain caused by peripheral-nerve disease, but treatment is often limited by side effects related to the drug's many pharmacologic actions. Selective agents might be safer and more effective.We carried out two randomized, double-blind, crossover studies in patients with painful diabetic neuropathy, comparing amitriptyline with the relatively selective blocker of norepinephrine reuptake desipramine in 38 patients, and comparing the selective blocker of serotonin reuptake fluoxetine with placebo in 46 patients. Fifty-seven patients were randomly assigned to a study as well as to the order of treatment, permitting comparison among all three drugs and placebo as the first treatment. The patients rated the degree of pain present each day using verbal descriptors, and they also assessed the extent of pain relief globally at the end of each treatment period.After individual dose titration, the mean daily doses of the drugs were as follows: amitriptyline, 105 mg; desipramine, 111 mg; and fluoxetine, 40 mg. There was moderate or greater relief of pain in 28 of the 38 patients (74 percent) who received amitriptyline, 23 of the 38 patients (61 percent) who received desipramine, 22 of the 46 patients (48 percent) who received fluoxetine, and 19 of the 46 patients (41 percent) who received placebo. The differences in responses between amitriptyline and desipramine and between fluoxetine and placebo were not statistically significant, but both amitriptyline and desipramine were superior to placebo. Amitriptyline and desipramine were as effective in patients who were not depressed as in depressed patients, but fluoxetine was effective only in depressed patients.Desipramine relieves pain caused by diabetic neuropathy with efficacy similar to that of amitriptyline, offering an alternative for patients unable to tolerate the latter. Blockade of norepinephrine reuptake is likely to mediate the analgesic effect of these antidepressant drugs in diabetic neuropathy. Fluoxetine, which blocks serotonin uptake, is no more effective than placebo for the relief of pain.

Effects of Desipramine, Amitriptyline, and Fluoxetine on Pain in Diabetic Neuropathy