Pharmacy & Therapeutics- July 2008 - (Page 408) CONTINUING EDUCATION CREDIT ophen (see Table 1). The isometheptene component has sympathomimetic properties suggesting a vasoconstriction mechanism.104 Clinical trials dating back to the 1970s reported modest benefits in mild-to-moderate migraine,105,106 although one comparison trial reported similar efficacy in patients with mild-to-moderate migraine when sumatriptan was used early in attacks.107 The agent’s side effects include sedation and GI tract problems, and its vasoconstrictive properties may be a concern in patients with hypertension. Dosing should be limited because of the potential for medication-overuse headache (see Table 1). Drug interactions may include additive sedation with other central-acting drugs and monoamine oxidase inhibitors (MAOIs). The risk of APAP overuse should be monitored in patients using multiple APAP-containing analgesics. This combination analgesic may have a limited role as a second-line or third-line agent in some migraine patients, although its use should be restricted and monitored.36,41,42,107 Analgesic Overuse (Medication-Overuse Headache) The consequence of analgesic overuse is the clinical phenomenon known as medication-overuse headache. This unrecognized epidemic might involve millions of patients in the U.S alone. It results from the overuse of analgesics, primarily prescription opiate and barbiturate combinations, but it can also occur with simple analgesics. It has also been reported with triptans and ergot alkaloids (see Table 1).89,92,108–111 The IHS defines “medication overuse” as the use of simple analgesics for more than 15 days per month and the use of triptans, ergots, opioids, barbiturates, or combination medication for more than 10 days per month. The phenomenon occurs in patients with primary headache disorders, and it may prevent successful treatment if it is not addressed. The mechanism of action in medication-overuse headache is not clear, but it is thought to be related to dysregulation in serotonergic transmission.11,62,63,93,102,103 The clinical consequences are chronic daily headaches that may result in the need for extensive supportive care, such as inpatient-management programs, various treatment protocols, and preventive therapy. Practitioners as well as patients and their families should become part of the evaluation and monitoring process of analgesic use by keeping diaries to evaluate effectiveness and frequency of use.111–115 their use has declined because of the emergence of the more selective 5-HT receptor agonists (triptans). The ergot alkaloids that are used as migraine abortives include ergotamine tartrate (ET) and dihydroergotamine mesylate (DHE) (Migranol, Valeant), which are available in injectable and nasal spray formulations (see Table 1).36,127 The oral formulations of ET may also contain caffeine, belladonna alkaloids, and phenobarbital, which contribute to their side-effect profile.122,127–132 The ergot multireceptor action at serotonergic subtypes 5-HT1a,d,f,b and 5-HT2 results in their effects on neuropeptide release and neurogenically induced inflammation, which is their proposed mechanism of action in migraine.126–128 Additional receptor interactions, including activity at the alphaadrenergic and dopaminergic systems, may also contribute to their action but also result in more side effects.127–130 The pharmacokinetic properties of the ergots are dependent on the formulation; intravenous (IV) DHE has the fastest onset. Both ET and DHE are metabolized in the liver and excreted in bile.121,127–132 Clinical data for both ET and DHE have reported efficacy in 50% to 90% of patients, with most of the data favoring DHE.132–134 Data comparing DHE with meperidine (Demerol, Sanofi-Synthelabo) and sumatriptan reported similar efficacy, and the fastest onset is noted with sumatriptan. Fewer headache recurrences were observed with DHE.135,136 One systematic review of DHE reported efficacy similar to that of opiates, ketorolac, and valproate and less effective responses when compared with sumatriptan and phenothiazines.137 The DHE nasal product, an alternative formulation, was reported to be superior to sumatriptan in one trial.138–141 The longer half-life of DHE nasal spray may offer an advantage of a lower frequency of headache recurrence,141,142 although self-administration of this product may be difficult for some patients.142 The side-effect profile of the ergot’s derivatives include nausea and vomiting, muscle cramps, tingling in the extremities, sense of difficulty swallowing, chest discomfort, nasal congestion, depression, and fatigue.121,127,129 Any chest discomfort must be appropriately evaluated, because effects on cardiac function have been reported secondary to the ergot vasoconstrictive properties and because heart disease is considered a contraindication.129,142,143 Ergotism, a general term describing ischemic complications of major body systems, including the myocardium, can result from prolonged use or overuse. Additional complications may include fibrosis and retroperitoneal fibrosis. Medication-overuse headache is another potential complication of ergot derivative overuse that may warrant similar care and monitoring, as with the analgesics.128,129,133,142–147 Potential drug interactions with the ergot derivatives include triptan use within 24 hours and other agents with serotonergic properties, including some antidepressants. Inhibitors of the cytochrome CYP 450 3A4 metabolic pathway (e.g., various antifungal agents, antibiotics, and macrolides) may increase their effects and potentiate toxicity.121,127,129 The ergot alkaloids are alternatives in the abortive treatment of migraine, but the emergence of the triptan class of migraine-specific agents has limited their use.35,36,91 Serotonergic Drugs Disturbances in serotonin (5-HT) regulation appear to be part of the pathogenesis of migraine, including neuropeptide release and inflammatory responses. The 5-HT receptor system involves numerous receptor subtypes, including 5-HT1, with additional subtypes (5-HT1d,1a, 1f,1b,1e). Agonist activity at these receptors, specifically the 5-HT1b/1d receptors, has been proposed as beneficial in migraine treatment, and two serotonergic drug classes—the ergotamine derivatives and the 5-HT receptor agonists (triptans)—have demonstrated efficacy.116–126 Ergot Alkaloids The ergot alkaloids were the first specific agents indicated for the abortive management of migraine.128,129 In recent years, 408 P&T® • July 2008 • Vol. 33 No. 7
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