Orally Inhaled Dihydroergotamine: A Review

Abstract

Orally inhalable dihydroergotamine (iDHE), before the US Food and Drug Administration in 2013 for consideration for approval for acute treatment of episodic migraine in adults, is a user-friendly formulation of an older medication. Dihydroergotamine (DHE) has a heterogeneous receptor profile, central penetration, and persistent receptor binding that may account for its clinical prolonged benefits in acute treatment of migraine. The same features may result in the ability of DHE to reverse central sensitization and allodynia and to maintain efficacy deep into attacks. These characteristics make DHE particularly useful in treating migraine upon awakening, prolonged migraine and status migrainosus, menstrually related migraine, and for bridging patients out of medication-overuse headache/chronic migraine. The inhalable formulation has helpful pharmacokinetics, with a lower maximal serum concentration than intravenous DHE which may account for minimal nausea, and less binding to the potentially toxic serotonin2B receptor. The inhaler itself is designed for delivery of reproducible aliquots of intrapulmonary DHE with only nominal need for patient coordination. The inhalable form allows for bypassing the gastrointestinal tract in the setting of migraine nausea or vomiting, and greatly reduces first-pass effect. No drug-related serious adverse events were reported during the Phase 3 study of iDHE. Product taste and nausea were the most common side effects in both the Phase 3 regulatory trial and in the safety extension trial. Limitations for use of iDHE are those for any ergot or triptan, ie, contraindication in the setting of vascular disease. In addition, iDHE is metabolized by the cytochrome P450 3A4 liver enzymatic system. Inhalable DHE provides the promise of a new formulation of a valued medication with important clinical features, useful deep into attacks in a variety of situations.

Targeting Inhaled Therapy beyond the Lungs

“…This is apparently an effective strategy since dihydroergotamine is now under development for the same purpose (Levadex; Allergan, Irvine, Calif., USA) [71]. Other agents that act in the CNS have been explored more recently, including those to treat agitation in schizophrenia (Loxapine; Alexza, Mountain View, Calif., USA) [72] and drugs used for pain relief [73].…”

Ergot Use and Overuse: A Pharmacoepidemiology Retrospective Cohort Study

“…However, ergots may be helpful for patients with migraine more difficult to treat, in particular for triptan nonresponders. Orally inhaled DHE could also be a possible alternative to triptans in the future, if oral drugs are usually vomited …”

Journal Club: Exacerbation of headache during dihydroergotamine for chronic migraine does not alter outcome

“…An alternative way to obviate the occurrence of nausea during DHE administration is by using nasally and orally inhalable DHE preparations; the former is available commercially while the latter is currently undergoing clinical trials. 8,9 Inhalable DHE administrations have lower nausea effect and this has been explained as a consequence of reduced maximal serum concentrations compared to the IV form. 9 …”

“…8,9 Inhalable DHE administrations have lower nausea effect and this has been explained as a consequence of reduced maximal serum concentrations compared to the IV form. 9 …”