Orally Inhaled Dihydroergotamine

Reviving and Improving a Classic

Eric P Baron; Stewart J Tepper


Future Neurology. 2011;6(3):327-333. 

In This Article

Dihydroergotamine in Clinical Use

Other than the NSAID analgesics, ergotamine and DHE remained the only available acute-specific migraine therapies for many years, until sumatriptan, the first of the triptans, was released in 1991 in Europe and 1993 in the USA. However, physicians have long known that headache, particularly migraine and cluster, often respond well to DHE when other acute treatments, such as the triptans, fail. A summary outlining when DHE is likely to provide greater efficacy than the triptans is available and includes those with prominent nausea and vomiting who cannot tolerate oral medications, status migrainosus, prolonged migraine (as in menstrual migraine), refractory cluster headache, high migraine recurrence, migraine upon awakening when allodynia is present and triptans are typically less effective and when bridging a patient out of medication overuse headache.[1]

Dihydroergotamine is available in the USA in nasal spray (NS), subcutaneous (SC), intramuscular (IM) and IV formulations. Oral DHE is not used in the USA, because it has such a poor bioavailability of <1%,[2] but, as previously noted, is available in Europe. An extensive review of the literature and evidence regarding DHE confirmed that SC, IV, IM and NS routes are all well tolerated and efficacious in treating migraine.[2,20]

The IV form is the most potent and is felt to provide the most clinical benefit, with complete headache freedom having been reported in up to 90% of patients with refractory migraine, chronic daily headache and refractory cluster headache after 48–72 h of repetitive administration.[10] Peak plasma levels occur in 1–2 min with IV DHE, 24 min with IM or SC DHE and 30–60 min with NS DHE.[2]

Similar efficacy has been reported for IM and SC DHE;[10] they are easier to use in the outpatient setting and nausea is less commonly reported.[10,21] Notably, SC DHE 1 mg was similar in benefit at 4 h to SC sumatriptan 6 mg, but resulted in fewer recurrences than sumatriptan when directly compared.[13,20] However, SC and IM DHE are limited by delayed onset, variable absorption and patient reluctance for parenteral self administration.

The most convenient form available in the USA at the time of writing is NS DHE, although its utility is quite limited, due to lower efficacy, nasal stuffiness and poor patient adherence leading to inconsistent therapeutic doses.[22] Regardless, NS DHE was given to patients with one or more triptan failures and greater than 40% responded, again suggesting that DHE is a useful choice in triptan nonresponders or poor responders.[11]

The American Academy of Neurology Practice Parameter Guidelines state that DHE is safe and effective at up to 3 mg/day and 20 mg/week,[23] and this is much higher than the US prescribing information recommended maximum dose of 6 mg/week.

Unfortunately, a general lack of familiarity with protocols, difficulty with use or unsatisfactory outcomes in the outpatient setting requiring premedication with antiemetic for IV administration, SC/IM self-injection, NS use with poor results and side effects such as nausea and vomiting have limited the use of DHE in its standard forms, especially the most useful IV formulation. Furthermore, when the triptans became available for treatment of cluster and migraine headache, use of DHE continued to decline. This was both because of the problems of DHE formulations compared with the convenience of triptan formulations, but also because DHE and triptans are contraindicated for administration within 24 h of each other.

However, the crucial and often forgotten role of DHE in headache management has recently been revived by a new orally inhaled formulation of DHE (INH DHE), MAP0004 (Levadex™, MAP Pharmaceuticals, CA, USA). INH DHE provides an improved tolerability and side effect profile, but similar efficacy to the highly therapeutic IV DHE, and ultimately will provide a much needed additional treatment option for those who respond poorly to triptans or do not have the availability or convenience of receiving other forms of DHE. INH DHE is an easy to use formulation of a well understood and needed acute medication that differs significantly from triptans and extends the clinical armamentarium for home treatment of acute migraine attacks.


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