Tricyclic Antidepressants

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Examples of least anticholinergic tricyclic antidepressants (TCAs) include amitriptyline 10-25 mg qhs and desipramine 10-25 mg qhs.

Best tolerated TCAs are desipramine 10-25 mg qhs, imipramine 10-25 mg/day, and nortriptyline 10-25 mg/day. Finally, the TCA that produces significant sedation is doxipin 25 mg qhs.

Nontricyclic antidepressants that have both serotonin and norepinephrine reuptake inhibition effects (norepinephrine reuptake inhibition is necessary for pain modulation) are venlafaxine (Effexor®, Pfizer, New York, NY) >150 mg for norepinephrine, duloxetine (Cymbalta®, Eli Lily, Indianapolis, IN) 30 mg/day advancing to 60-120 mg/day, bupropion (Wellbutrin®, Glaxo-Smith-Kline, Philadelphia, PA) SR 150-300 mg/day, and trazadone (Deseryl®, Bristol-Myers-Squibb, New York, NY) 50-300 mg/day (avoid in men due to risk of priapism) (Management of Chronic Pain Syndromes 2005).

The advantage of duloxetine is its lack of side effects and rapid onset of action, within a few days instead of weeks. Goldstein et al. (2005) studied the efficacy and safety of duloxe-tine, a balanced and potent dual reuptake inhibitor of serotonin and norepinephrine, in the management of diabetic peripheral neuropathic pain (Goldstein et al. 2005). Serotonin and norepinephrine are thought to inhibit pain via descending pain pathways. In a 12-week, multicenter, double-blind study, 457 patients experiencing pain due to polyneuropathy caused by Type 1 or Type 2 diabetes mellitus were randomly assigned to treatment with duloxe-tine 20 mg/day (20 mg QD), 60 mg/day (60 mg QD), 120 mg/day (60 mg BID), or placebo. The diagnosis was confirmed by a score of at least 3 on the Michigan Neuropathy Screening Instrument. The primary efficacy measure was the weekly mean score of the 24-h Average Pain Score (APS), which was rated on an 11-point (0-10) Likert scale (no pain to worst possible pain) and computed from diary scores between two site visits (Goldstein et al. 2005). Duloxetine 60 and 120 mg/day demonstrated statistically significant greater improvement compared with placebo on the 24-h APS, beginning 1 week after randomization and continuing through the 12-week trial. Duloxetine also separated from placebo on nearly all the secondary measures including health-related outcome measures. Significantly more patients in all three active-treatment groups achieved a 50% reduction in the 24-h APS compared with placebo. Duloxetine treatment was considered to be safe and well tolerated with less than 20% discontinuation due to adverse events. The authors concluded that Duloxetine at 60 and 120 mg/day was safe and effective in the management of diabetic peripheral neuropathic pain (Goldstein et al. 2005).

Bupropion (Wellbutrin®R , Zyban®, Glaxo Smith Kline, New York, NY) is an atypical antidepressant that acts as a norepinephrine and dopamine reuptake inhibitor, and nicotinic antagonist (Slemmer et al. 2000, Fryer and Lukas 1999). Bupropion belongs to the chemical class of aminoketones and is similar in structure to the stimulant cathinone, to the anorectic diethylpropion, and to phenethylamines in general.

Bupropion lowers seizure threshold, but at the recommended dose the risk of seizures is comparable to that observed for other antidepressants. Bupropion is an effective antide-pressant on its own but it is particularly popular as an add-on medication in the cases of incomplete response to the first-line SSRI antidepressant (Zisook et al. 2006).

In contrast to many psychiatric drugs, including nearly all antidepressants, bupropion does not cause weight gain or sexual dysfunction (Clayton 2003). It is helpful in patients with a history of prior substance abuse since it has dopamine reuptake inhibition in addition to norepinephrine reuptake effects (Slemmer et al. 2000, Fryer and Lukas 1999).

Dopamine is the neurotransmitter associated with the "pleasure system" of the brain. It provides feelings of enjoyment and reinforcement to motivate us to continue certain activities. Dopamine was originally known as the "reward chemical" because it is released during rewarding activities such as food and sex - this neurotransmitter is primarily involved in regulation of attention, motivation, pleasure, and reward. Lack of dopamine is associated with decreased ability to experience pleasure, decreased motivation, decreased attention, and cognitive slowing.

Very few agents with dopamine activity have been developed to date. Prodopaminergic agents represent a potential for treatment breakthrough for major depressive disorders, and agents with prodopaminergic activity may possess efficacy and tolerability advantages over traditional 5HT-selective agents (Zisook et al. 2006). To date, there are no specific studies indicating advantages of Buprion over other antidepressants in the treatment of pain. However, in this author's experience it seems to be a good adjunct in patients who have a history of substance abuse as an adjunct to their other medications.

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