Tricylics: The Complex Analgesics

In the 1960s, researchers found that tricyclic antidepressants (TCAs) alleviated neuropathic pain, such as post-herpetic neuralgia. For 40 years, however, TCAs' mode of action remained mysterious. Now some hints as to a possible mechanism, which encompasses actions at Na⁺ channels and neuronal plasticity, are beginning to emerge.

TCAs alleviate depression by inhibiting reuptake of serotonin and noradrenaline, although they interact with a plethora of transporters, receptors, and channels. Juan-Antonio Micó, University of Cádiz, Spain, notes that in addition to serotonin and noradrenaline reuptake, TCAs modulate sodium and potassium channels and N-methyl D-aspartate and adenosine receptors, and they inhibit production of tumor necrosis factor in the brain. This complex pharmacology means that is unclear what underlies their analgesic actions.

Researchers' poor understanding of neuropathic pain exacerbates the lack of understanding of TCAs' mechanism. David Bowsher, University Hospital Aintree, Liverpool, UK, for example, notes that only 15% of people with shingles and 25% of people with thalamic strokes develop neuropathic pain, but an explanation for such differences remains elusive. To complicate matters further, Micó remarks that TCAs' mode of action in neuropathic pain may be different than that in other conditions--such as fibromyalgia--for which TCAs often also prove efficacious.

Nevertheless, Ging Kuo Wang, from Brigham and Women's Hospital, says that blockade of voltage-gated Na⁺ channels may explain, in part, TCAs' analgesic efficacy. Wang suggests that TCAs might act in part by silencing abnormal sodium channels that open persistently during high-frequency firings at the injured site or in the central nervous system that theoretically cause neuropathic pain. "Identifying the specific sodium channel isoform responsible for ectopic high-frequency discharges could be a rewarding approach and may lead to the development of novel drugs," he says.

On the other hand, Mike Briley, scientific director at the French consulting company NeuroBiz, adds that antidepressants that block serotonin and noradrenaline uptake without TCAs' other actions--such as venlafaxine, milnacipran, and duloxetine--also show analgesic actions. "This shows that it's uptake blockade that's important and not one of the many other actions of TCAs." Certainly, the dual action seems critical. Bowsher points out that antidepressants that act only on serotonin (e.g., fluoxetine) do not alleviate neuropathic pain.

Furthermore, the anatomical location of TCAs' actions is open to conjecture. Briley comments that stimulation of descending inhibitory pathways is the most widely accepted activity, "but the jury is still out." He adds that TCAs' full effects may take several weeks to emerge. This suggests that neuronal "plastic" changes contribute to their clinical actions. But once again, the site remains elusive.