Pharmacy & Therapeutics- August 2008 - (Page 482) CONTINUING EDUCATION CREDIT pramin, Sanofi-Aventis) may be better tolerated in some patients and may be an additional option. More serious adverse effects include potential cardiac events, such as sinus tachycardia, corrected QT (QTc) prolongation, and blood pressure fluctuations. Drug interactions involve other central-acting agents, anticholinergic drugs, and serotonergic agents (Table 2). These medications are contraindicated for patients with angle-closure glaucoma, urinary retention, and orthostatic hypotension, which are seen primarily in the elderly. Monitoring in young migraine patients should include efficacy and adverse effects such as weight gain.38–42 Within the antidepressant class, the TCAs are considered a first-line option for preventing migraine in patients who do not have any contraindications. These agents may be an excellent choice for patients with a concurrent comorbidity such as depression, anxiety, or insomnia.4,41,44,45 Other Antidepressants The selective serotonin reuptake inhibitors (SSRIs) have not shown consistent benefits in migraine prophylaxis. A few small, short-term trials with fluoxetine (Prozac, Eli Lilly) reported benefits,46,47 although a more recent analysis that looked at the class as a whole reported a lack of efficacy in migraine.48 Antidepressants that have been studied in small trials with some reported efficacy include venlafaxine (Effexor, Wyeth), mirtazapine (Remeron, Organon), the monoamine oxidase inhibitors (MAOIs), and nefazodone HCl.49–58 Anticonvulsant Medications Valproic Acid and Topiramate The anticonvulsants are another class of medications that have demonstrated efficacy in the prophylaxis of migraine, with valproic acid and topiramate having the strongest evidence to support this indication (see Table 1).4,59,60 The rationale for their use is thought to be related to common Table 2 Common Drugs with Serotonergic Properties Monoamine oxidase inhibitors Phenelzine (Nardil) Selegiline (Zelapar, Eldepryl, Emsam) Isocarboxazid (Marplan) Tranylcypromine (Parnate) Tricyclics: amitriptyline, others SSRIs: fluoxetine (Prozac), others Miscellaneous: nefazodone (Serzone*), trazodone (Desyrel), venlafaxine (Effexor), bupropion ( Wellbutrin) Buspirone (BuSpar) Dextromethorphan Lithium Amantadine (Symmetrel) Cocaine Antidepressants Others mechanisms shared in seizure disorders and migraine involving imbalances between excitatory glutamate activity and gamma-aminobutyric acid (GABA)–mediated inhibition in the brain.61 Valproic acid. Valproic acid and its derivatives were the first class of anticonvulsants approved for migraine prophylaxis. Trials dating back to the 1980s have been conducted with efficacy reported at variable doses but without a consistent correlation between effective dose and serum levels. Efficacy was described as a reduction in the severity and duration of migraine, with good tolerability reported with titration and individualized doses (see Table 1).62–67 Compared with other preventative agents, valproic acid is similar to propranolol in terms of its efficacy and tolerability, as noted with the beta blockers.30,31,33 Adverse events associated with valproic acid, including central nervous system (CNS) effects (e.g., sedation, tremor, confusion, gastrointestinal problems, and weight gain) may be problematic in some patients. More serious adverse events (e.g., blood dyscrasias, pancreatitis, and liver problems) are rare, but periodic monitoring is required if they occur. Valproic acid and its derivatives should be avoided in women who are planning pregnancy or in women of childbearing age because of the significant risk of teratogenicity with this agent. Drug interactions include other central-acting agents and drugs whose metabolism may be inhibited by valproic acid.44,45,68 Topiramate. The other anticonvulsant that has been studied extensively and has reported efficacy in migraine prophylaxis is topiramate (Topamax) (see Table 1).69–78 The drug’s proposed mechanism of action in migraine is probably similar to that of valproic acid, involving GABA-mediated inhibition in the CNS. Although serious adverse effects (kidney stones, myopia with angle-closure glaucoma, sedation, and cognitive changes) can occur,44,45,79 clinical trials reported good tolerability in most patients, especially with lower daily doses.69–74 Drug interactions may include other central-acting drugs, antidepressants, and oral contraceptives.44,45,79 In comparison trials, topiramate was similar to valproic acid80,81 and propranolol32 in terms of efficacy and tolerability. Because of concerns about potential dose-related effects on cognition, patients who are taking topiramate must be monitored regularly, although the drug has excellent clinical utility and can be an option, especially if weight gain is a concern.1,79,82 Migraine patients who take topiramate should be apprised of the drug’s potential for visual and cognitive changes and their need to ensure adequate hydration.79 Summary. Valproic acid and topiramate provide an additional option in the prophylactic treatment of migraine headaches, but adverse effects may limit their use in some patients. Although they are probably considered second-line agents in many cases, they may be excellent choices for patients with a history of seizures disorders; obese patients (especially because of topiramate’s weight-loss benefits); or patients for whom beta blockers or antidepressants may be contraindicated.44,45,68,79 SSRI = selective serotonin reuptake inhibitor. * Serzone has been discontinued, but generic brands are available. Adapted from references 49–53. 482 P&T® • August 2008 • Vol. 33 No. 8
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