Friday, November 12, 2010

Tricyclic Antidepressants for Headaches Reviewed

HeadacheMigraine headaches afflict between 8.4% and 18% of the worldwide population, and tension-type headaches are even more pervasive, occurring in up to 30% of adults. A recently reported analysis of available data found that tricyclic antidepressants, specifically amitriptyline, offer advantages over placebo or selective serotonin reuptake inhibitors; however, patient tolerability of the drugs may be a concern and a number of research questions remain unanswered.

Researchers from the United States, writing in the British Medical Journal, report a data meta-analysis to evaluate the efficacy and relative adverse effects of tricyclic antidepressants (eg, amitriptyline, clomipramine, desipramine, and others) in the treatment of migraine and tension-type headaches [Jackson et al. 2010]. An extensive literature search for randomized trials of adults administered tricyclics as monotherapy for at least 4 weeks produced 37 studies meeting the inclusion criteria; most of the studies (81%) investigated amitriptyline as the tricyclic agent.

Compared with placebo, prophylactic treatment with tricyclics significantly reduced the number of days with tension-type headache and the number of headache attacks from migraine; however, the reductions were not significantly different from selective serotonin reuptake inhibitors (SSRIs). Overall, patients with tension-type or migraine headaches were 40% to 70% more likely to report at least a 50% improvement in headaches, and patients taking tricyclics for tension-type headaches used fewer analgesics. Beneficial effects of tricyclics increased with longer duration of treatment, and tricyclics were also more likely to reduce the intensity of headaches by at least 50% than either placebo or SSRIs. At the same time, tricyclics were significantly more likely to cause adverse anticholinergic effects than placebo or SSRIs, including dry mouth, drowsiness, and weight gain, but these did not increase study dropout rates among persons taking tricyclics.

COMMENTARY: Jackson and colleagues conclude that tricyclic antidepressants are effective in preventing migraine and tension-type headaches, with effectiveness increasing over time, and they are more effective than selective serotonin reuptake inhibitors but incur greater adverse effects. This is not an entirely new observation, since tricyclics were first shown to be effective in preventing headaches in 1964 and have become a standard modality in headache prevention. However, Jackson et al. note that, based on current standards for preventive treatment in the United States, 43% of males and 34% of females who are candidates for such treatment are not receiving it. “This may result from insufficient understanding of the magnitude of beneficial effects, an overestimation of adverse effects, or the presumption that efficacy is only confined to migraine headaches,” they state.

In an editorial accompanying the study, Kenneth A Holroyd and Lars Bendtsen [2010] observe that the number and quality of available trials for analysis was not large, most were small and of short duration, and many date back more than 20 years and might not meet current standards of methodological quality. As a result, they believe, “convincing evidence is available for only the most general conclusion: [the tricyclic antidepressant] amitriptyline is more effective than placebo for migraine and tension headache. Amitriptyline also seems to be more effective than serotonin reuptake inhibitors, although few direct comparisons are available.” And, a question remains as to whether observed benefits of amitriptyline are a class effect of all tricyclics or specific to that agent. There also are unresolved questions regarding comparative advantages of newer dual action antidepressants (eg, serotonin and noradrenaline reuptake inhibitors, SNRIs), as well as other preventive drugs over tricyclics — necessary comparative trials have not been conducted and are unlikely to be initiated, Holyroyd and Bendtsen assert.

Furthermore, questions about relative adverse effects of preventive treatments for headache are important, because many patients cannot or will not take medications that they find to be intolerable. Also of some possible concern, tricyclics as well as certain other antidepressants are on a conditional list of drugs [here] that, in some reports, have been associated with cardiac arrhythmias (QT-interval prolongation and/or torsades de pointes); albeit, this would be most problematic in patients with other risk factors (eg, bradycardia, electrolyte disturbances, congenital long-QT syndrome, or taking concomitant QT-prolonging or metabolism-inhibiting drugs). In the latter regard, tricyclics are extensively metabolized by liver enzymes (primarily CYP2C19 in the case of amitriptyline) so their serum concentrations may be affected by other drugs or liver disorders and prescribers need to take such factors into account. Finally, we should note that in a recent blogpost [here] we presented new research on β blockers (eg, propranolol or nadolol) as migraine preventative medications, which may be of interest to readers.

> Holroyd KA, Bendtsen L. Tricyclic antidepressants for migraine and tension-type headaches [editorial]. BMJ. 2010;341:c5250, online first [
full-text article here].
> Jackson JL, Shimeall W, Seeums L, et al. Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ. 2010;341:c5222, online first [
full-text article here].