The tricyclic antidepressants (TCAs) have been successfully used for the treatment of neuropathic pain for some 25 years. The mechanism of action for the alleviation of neuropathic pain is thought to be due to the inhibition of reuptake of serotonin and norepinephrine within the dorsal horn; however, other possible mechanisms of action include alpha-adrenergic blockade, sodium channel effects and NMDA receptor antagonism.
Amitriptyline is the prototypical tertiary amine. Other tertiary amines include imipramine, doxepine, clomipramine and trimipramine. Unlike the dosing regimen utilised for the treatment of depression, doses of TCAs used for the treatment of neuropathic pain are considerably lower. The typical dosing schedule for amitriptyline may be 10 mg orally nocte, with a gradual escalation every 3 days, in 10 mg increments, to a maximum of 30-50 mg. Furthermore, the onset analgesia usually occurs over several days, versus the 2 weeks that are required for the onset of the antidepressant effects of the drugs.
The side-effect profile of the TCAs include sedation and anticholinergic effects. The drugs have a number of effects on the heart, including slowing of atrioventricular and interventricular conduction. The recently introduced selective serotonin reuptake inhibitors (SSRIs) have not proven to be as effective against neuropathic pain as anticipated.
Fluoxetine only appears to relieve pain in patients with co-morbid depression. Paroxetine has found some utility in the treatment of chronic, daily headaches. In general, the SSRIs are partially effective in the treatment of diabetic neuropathy, but not to the extent of the TCAs. Venlafaxine may have some analgesic effects, since, similarly to the TCAs, it inhibits the reuptake of both serotonin and norepinephrine. Its side-effect profile is similar to that of the other SSRIs and can include agitation, insomnia or somnolence, gastrointestinal distress and inhibition of sexual functioning. It has fewer anticholinergic side-effects than the TCAs.
Although antidepressants have been used for over 30 years to manage neuropathic pain, in the UK no antidepressant has a products licence for this indication.
In conditions such as post-herpetic neuralgia, diabetic neuropathy and central pain, the number-needed-to-treat (NNT) to obtain >50% pain relief is approximately 2.5.
Amitryptyline 10-25 mg, increasing to 75 mg nocte
Venlafaxine 37.5 mg-7g mg nocte
Fluoxetine 20 mg nocte