Pharmacy & Therapeutics- July 2008 - (Page 407) CONTINUING EDUCATION CREDIT algesics and over-the-counter (OTC) anti-inflammatory drugs before seeking care from a health care professional. Monotherapy with aspirin (ASA) may also benefit some patients, although the doses required are not always tolerated in patients with concurrent GI symptoms. Aspirin’s mechanism of action is probably similar to that of other NSAIDs that act on the anti-inflammatory response in migraine.40,41,51 Clinical trials of aspirin have been conducted in patients with mild-tosevere migraine in both monotherapy versus placebo and in comparison trials with sumatriptan succinate (Imitrex, GlaxoSmithKline) and ibuprofen. Studies with 900 to 1,000 mg reported benefits when compared with placebo51–54 and similar efficacy when compared with sumatriptan 50 mg and ibuprofen 400 mg, although more pain-free effects were reported in one trial with sumatriptan.55,56 Most of these studies used effervescent formulations that are not available in the U.S., thereby making the role of aspirin in the treatment of acute migraine attacks unclear. Aspirin, therefore, should probably be reserved as a second-line or third-line choice.53–56 The combination of aspirin and metoclopramide (Reglan, Baxter) has also demonstrated efficacy and may offer improved tolerability over aspirin alone.52,53 Combination therapy with the simple analgesics APAP and ASA, with caffeine added to enhance absorption and to possibly potentiate activity, may also be used in acute migraine.41,42,46 In clinical trials involving two tablets of this combination, patients with mild-to-moderate migraine reported relief of headache intensity and of migraine-associated symptoms (e.g., nausea and vomiting),57–59 and similar or greater efficacy, compared with other simple analgesics, was also observed.57–61 Higher or more frequent doses of this combination have not been studied. In addition to the potential for medication-overuse headache (see page 408), the caffeine in these products can lead to insomnia, restlessness, and palpitations.46,62,63 These combination analgesics may have a place in mild-to-moderate migraine, but their role in moderate-to-severe migraine is not supported by clinical trials. Nonsteroidal Anti-inflammator y Drugs NSAIDs have been effective in the abortive therapy of mildto-severe migraine in both placebo-controlled64–75 and comparison trials with other abortive agents, including the triptans (see Table 1).76–83 Numerous agents have been studied at various doses, with trials showing improvements in pain-free periods and reductions in pain intensity and in migraineassociated symptoms (e.g., nausea, vomiting, and sensory disturbances).64–83 The proposed mechanism of action is achieved via antiinflammatory effects on vasoactive peptide–induced inflammation, which may occur during migraine.41,42 The use of NSAIDs in combination with caffeine or other abortive agents, including triptans, may offer additive benefits in some patients.84,85 The properties of NSAIDs, including drug interactions and adverse drug reactions, are well documented elsewhere. NSAID-induced GI side effects may be problematic in migraine patients who experience nausea and vomiting, thus limiting their utility in these patients, although the addition of metoclopramide may improve tolerabilty.52,86 The role of NSAIDs in the abortive management of migraine is appropriate in patients with infrequent, mild-to-severe attacks who experience minimal GI symptoms.41,42,46 Barbiturate Analgesics Barbiturate combination products containing butalbital, an intermediate-acting barbiturate, have been used for years for migraine (see Table 1). Butalbital is available in various combinations products with APAP (Fioricet, Watson) or ASA (Fiorinal, Watson) with or without the addition of codeine. Barbiturates cause central nervous system (CNS) depression and confusion, and they can affect cognition and may cause paradoxical excitation.87 Although butalbital has a long history of use in migraine patients, no data are available that support its utility. Use of this agent has also resulted in abuse and dependency problems, often leading to medication-overuse headache in patients. Products containing this barbiturate have been banned in Eastern Europe and in non-Western countries, and expert panels throughout the world have pointed to its potential for abuse.88–90 Although butalbital continues to be considered an abortive therapy in migraine, patients who are using barbiturates on a regular basis should be evaluated and provided with an alternative therapy.87–91 Opioid Analgesics Similar to the barbiturate combinations, opioid analgesics in the abortive management of migraine should be limited or avoided altogether because of similar concerns with overuse, abuse, tolerance, and the risk of medication-overuse headache. The mechanism and pharmacological profile of these agents is described elsewhere. Various opiate products are often used in combination with acetaminophen or aspirin (see Table 1).92–94 Although some trials support the use of opioids in migraine,95–97 the use of alternative therapies is suggested because of concerns about medication-overuse headache.75,95,99 Butorphanol (Stadol, Apothecon), a mixed opioid agonist/ antagonist, has been used extensively in acute migraine. It has a high potential for abuse and should be restricted or avoided as an abortive agent.100,101 More recent data report the concept of opioid-induced hyperalgesia, which may be unique in patients with migraine. This event supports the lack of utility of these agents and an escalation of their use in some patients.102 The role of opioidcontaining analgesics should be restricted in most migraine patients, although their short-term use may be justified in women with intractable menstrual migraine, women who are pregnant, elderly patients, or patients with severe and debilitating head pain who are intolerant of or unresponsive to other agents. If opioid analgesics are used, they should be vigilantly monitored by patients, their family members, and their health care professionals.102,103 Isometheptene/Dichloralphenazone/Acetaminophen (Midrin) Another analgesic combination with a history of use as a migraine abortive agent is the combination drug Midrin (Excellium). Midrin is composed of isometheptene, a mild vasoconstrictor; dichloralphenazone, a mild sedative; and acetamin- Vol. 33 No. 7 • July 2008 • P&T® 407
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