One of the mainstays in the treatment of painful neuropathies has been the use of tricyclic antidepressants. And tricyclic antidepressants are divided into 2 major groups: tertiary amines, drugs such as imipramine and amitriptyline and secondary amines, drugs such as nortriptyline and desipramine.

The [putative antineuralgic] mechanism of action of the tricyclic antidepressants (TCAs) is that they inhibit the reuptake of the biogenic amines, mostly norepinephrine (NE), as well as serotonin (5HT). I talked about the 2 important descending inhibitory pathways originating from the brainstem to the spinal cord with 5HTand NE being their major neurotransmitters. So, basically the tricyclic works by enhancing inhibition from the brainstem to the spinal cord.

The tertiary amines inhibit the reuptake of NE as well as 5HT, whereas the secondary amines are relatively selective NE reuptake inhibitors.

The tricyclic antidepressants were tested in a number of clinical trials in patients with painful diabetic neuropathy. This one was published by Mitchell Max in the New England Journal of Medicine back in 1982. It was a double-blind, placebo-controlled, cross-over, [trial] and it compared the efficacy of a tertiary amine, amitriptyline, to that of a secondary amine, desipramine, to a selective serotonin reuptake inhibitor (SSRI), fluoxetine. The doses that were used were pretty appropriate, about 100 mg each for amitriptyline and desipramine, and 40 mg for fluoxetine. And when the data was analyzed, it was found that while on amitriptyline, 74% of patients experienced moderate or significant pain relief compared to 61% while on desipramine and 48% while on fluoxetine. And if you saw that data alone without an internal control you might conclude that patients on [fluoxetine] did pretty well since approximately half of them had moderate or significant improvement in their pain.

It's only when you compare it to the placebo response that you realize that 41% of placebo-treated patients also had moderate or significant pain relief. And perhaps, the most important message of this particular trial, is the importance of placebo-controlled clinical trials in any condition, but especially in pain, because unless you have that internal control, you are not going to be able to [scientifically] judge the efficacy of a particular drug.

And actually, when the data was statistically analyzed, it was found that while on amitriptyline or desipramine patients [fared] significantly better compared to placebo. But there was no statistically significant difference between the fluoxetine and the placebo phase of the trial. Virtually every clinical trial that was done using TCAs in the treatment of painful diabetic neuropathy replicated these results in the sense that there is a statistical trend favoring the tertiary amine over the secondary amine, but it rarely reaches statistical significance. And the other important point is that the SSRIs are not effective for the treatment of neuropathic pain except in patients with depression and pain. But if the patient is not depressed, the SSRIs are virtually useless.

A Medline search looking at the clinical trials done with TCAs in post-herpetic neuralgia yielded those 5 clinical trials. Three of them were placebo-controlled. Two of them were comparative trials. All of them were single-center, cross-over trials [that] randomized a relatively small number of patients - between 15 and 32 patients. But again, the results were concordant and showed the efficacy of the tertiary amine, amitriptyline, compared to placebo as well as the secondary amine, desipramine, compared to placebo and the fact that amitriptyline was significantly more efficacious than zimelidine, another SSRI.

Although the tricyclic antidepressants are very effective for the treatment of neuropathic pain, they can be associated with a number of side effects. Because of their antihistaminic properties they can lead to sedation. Obviously you can have the anticholinergic side effect, postural hypotension, which, especially in elderly patients, when coupled with the sedative side effects, can lead to significant falls. Arrhythmia in patients with cardiac disease, seizures in patients with epilepsy and weight gain.

Again, as a general rule the tertiary amines, amitriptyline and clomipramine, are associated with significantly more sedative and postural hypotension as compared to secondary amines, desipramine and nortriptyline. So, even though the tertiary amines are slightly more efficacious for the treatment of neuropathic pain, they do so at the expense of significantly more side effects. And you might want to take that into consideration in deciding on the drug of choice for a particular patient.

The [most important] point is the third bullet, the fact that the antineuralgic properties of the TCAs are independent from their antidepressant effects. And the way this was proven was by taking a cohort of patients who participated in those clinical trials, classifying them according to who was and who wasn't depressed at baseline. And showing that both groups had comparable efficacy in addition, of course, to the fact the doses that we tend to use for the treatment of neuropathic pain are much lower than what is [typically] needed for the treatment of depression.