Antidepressant drugs are used in the treatment of patients with chronic pain. Pain is an unpleasant phenomenon and is often linked with depression. The observation that antide-pressant drugs are beneficial, even in the absence of depression, suggests that these drugs could have intrinsic analgesic activity independent oftheir antidepressive effects (Feinmann 1985). The analgesic effects tend to be independent of the doses of heterocyclic antidepres-sants used for analgesia, as they are less than those considered effective in the treatment of depression (Egbunike and Chaffee 1990).
Almost all norepinephrine-containing terminals in the dorsal horn of the spinal cord are supraspinal in origin. Baba et al. studied the mechanism of descending pain-control pathways and how they inhibit nociceptive transmission at the spinal level (Baba et al. 2000). They proposed that activation of noradrenergic descending systems releases norepinephrine, which can directly hyperpolarize a proportion of the substantia gelatinosa (SG) neurons that may be excitatory interneurons in the pain pathway (postsynaptic inhibition) (Baba et al. 2000).
Alternatively, norepinephrine could depolarize inhibitory interneurons that contain GABA, glycine, or other inhibitory peptides. Iontophoretic application of norepinephrine near nociceptive dorsal horn neurons generally inhibits background activity of these cells and the responsiveness to excitatory amino acids (Baba et al. 2000). This inhibition most likely results from a-2-receptor activation, which increases K+ conductance, thereby evoking a membrane hyperpolarization.
However, norepinephrine (and brain stem stimulation) has also been reported to produce excitatory effects. The neurons excited by iontophoretically applied norepinephrine and electrical stimulation of the periaqueductal gray were low-threshold cells, possibly inhibitory interneurons that synapse onto high-threshold and wide-dynamic-range neurons (Baba et al. 2000).
Antidepressants, such as amitriptyline, nortriptyline, imipramine, doxepin, trim-ipramine, and trazadone, have been used to treat diabetic neuropathy, postherpetic neuralgia, headache, arthritis, chronic back pain, cancer pain, facial pain, and phantom limb. Many of the antidepressants currently available have marked anticholinergic activity, which can cause dry mouth, visual disturbance, constipation, difficulty in micturition, and alterations in heart rate. Rani et al. compared amitriptyline to fluoxetine selective serotonin reuptake inhibitor (SSRI) as analgesic adjuvants in the treatment of rheumatic pain. Fluoxetine was more effective after 4 weeks with fewer side effects, especially autonomic side effects (Rani et al. 1996).
In recent years, tricyclic antidepressant drugs have experienced resurgence in their use as valuable pharmacological tools in the treatment of pain. Along with the evolution in our understanding of their analgesic mechanisms of action, there have been concurrent breakthroughs regarding their indications for use and modes of administration. The mechanisms of the antinociceptive effects of the antidepressant drugs were reviewed by Cohen and Abdi (2001). Antidepressants that have been used in pain management are list below along with starting doses and tolerability (Management of Chronic Pain Syndromes 2005).
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