Pharmacy & Therapeutics- July 2008 - (Page 410) CONTINUING EDUCATION CREDIT response.148,150,152 For most of the oral triptans, the onset of action ranges from 30 to 60 minutes, with a faster onset reported for rizatriptan (Maxalt, Merck), zolmitriptan (Zomig, AstraZeneca), and eletriptan (Relpax, Pfizer), possibly because of their greater bioavailability or CNS penetration.149,151,154 Differences in half-life may affect headache recurrence, suggesting a lower frequency of recurrence with frovatriptan (Frova, Endo) and naratriptan.148,150,151,153,165 The triptans are metabolized by two major pathways (see Table 2), the CYP 450 system, and/or the monoamine oxidase A (MAO-A) system; as a result, dose adjustments and assessment of potential drug interactions are necessary for patients with hepatic disease. 166,167 Because some triptans such as naratriptan and almotriptan (Axert, Ortho-McNeil) depend on renal elimination, dose adjustments are required for patients with renal impairment.150,152,164 CNS penetration may vary among the triptans, but these differences are not always correlated with clinical efficacy.164,168 Alternative dosing formulations (see Table 2), including subcutaneous (SQ) and intranasal products, have the fastest onset of action, although the oral dissolution products have only a perception of faster onset.148,149,151 The pharmacokinetic differences among the triptans have limited significance on clinical efficacy, but they may influence the most appropriate choice or preference for a given patient.162–166 Clinical efficacy among the triptans continues to be evaluated, although placebo-controlled trials with each of these agents have demonstrated efficacy.169–174 Differences in efficacy among the triptans are not clinically significant, and the American Academy of Neurology supports the role of all the triptans in the abortive management of moderate-to-severe migraine.36,175,176 The data suggest similar efficacy among the various triptans, but there is evidence to support the concept that failure or intolerance to one triptan warrants the trial of an alternative agent.177–183 Comparison trials with triptans and other migraine-abortive agents have included analgesics, NSAIDs, trimethobenzamide, diphenhydramine, metoclopramide, and ergot derivatives.55,61,184–186 Sumatriptan 50 mg was reported to be similar to ibuprofen 400 mg and to 1,000 mg effervescent ASA in reducing moderate-to-severe migraine pain, although sumatriptan provided greater pain-free effects at two hours.55 An emergency room study reported that sumatriptan was more effective at two hours in treating acute migraine pain compared with trimethobenzamide and diphenhydramine.186 A comparison trial of rizatriptan (Maxalt) and analgesics, NSAIDs, or ergot derivatives revealed an improved response at two hours in the triptan group.187,188 Trials with sumatriptan plus naproxen sodium (e.g., Aleve, Bayer; Naprosyn, Roche) showed additive effects and good tolerability in the acute management of migraine.84,189 Adverse Effects The selective pharmacotherapy with the triptans suggests a tolerable side-effect profile, and perhaps because the triptans have been primarily used and studied in young healthy patients, they are reported to be well tolerated and safe. Side effects include dizziness, paresthesias, somnolence, asthenia, fatigue, flushing sensations, myalgias, and transient increases in blood pressure. GI effects, including nausea, vomiting, and digestive complaints, can occur, but they may be a result of the migraine itself. Other effects, including chest and neck symptoms, may require follow-up (see Contraindications).148–154 SQ sumatriptan may be associated with injection-site reactions. The intranasal products may also cause some local reactions, nasal cavity discomfort, and taste disturbances.190,191 Although the adverse effects of the triptans are similar, there may be some differences in tolerability, and intolerance to one triptan may warrant a trial of an alternative agent. Contraindications Contraindications to the triptans are usually the result of their vasoconstrictive properties.192 The triptans and their association with chest symptoms, in contrast to true ischemic changes, contribute to one adverse event that is still not completely understood. The incidence of cardiac problems with the triptans is reported to be low, although cardiac events have been reported in patients with and without a significant cardiovascular history. It is not clear whether the etiology of these symptoms is a result of a true vascular pathology, esophageal effects, pulmonary mechanisms, reductions in skeletal muscle energy metabolism, or a central mechanism. Because of these potential adverse effects, appropriate evaluation is necessary when the triptans are used, especially among patients at risk.192–197 Because of the potential for ischemic complications, the triptans are contraindicated in patients with coronary artery disease, cerebrovascular disease, uncontrolled hypertension, rhythm disturbances, peripheral vascular disease, ischemic bowel disorders, and hemiplegic or basilar migraine. To avoid potential complications, pretreatment screening should be conducted in postmenopausal women, men older than 40 years of age, smokers, obese patients, and those with diabetes mellitus or a strong family history of cardiac disease.192–197 Other ischemic complications reported with the triptans include splenic and renal infarction and intestinal ischemia.198–200 Although the triptans are not recommended for pregnant patients, as a result of their class C status, there is no evidence of early or late pregnancy loss, onset of premature or preterm labor, placental abruption, or malformations. Triptans should be used in pregnancy only after the risk–benefit ratio for individual patients is evaluated.148–154, 201–203 Drug–Drug Interactions Potential drug interactions with the triptans can be caused by other serotonergic agents (Table 3) that can increase the risk of serotonin syndrome, an adverse reaction to medications that enhance serotonergic activity. The risk of serotonin syndrome from triptans alone is low, but it can result from their 5-HT receptor activity profiles, which may differ from agents involved with this syndrome.204–206 Triptans that are metabolized by the CYP 450 system, specifically 3A4 and 2D6 (see Table 2), may require dose adjustments when they are used with inhibitors of these pathways, such as paroxetine (Paxil, GlaxoSmithKline) and erythromycin. Because of potentially significant drug interactions, triptans should not be taken concurrently with ergots or other triptans within 24 hours of use. Monitoring triptans metabo- 410 P&T® • July 2008 • Vol. 33 No. 7
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