Dihydroergotamine (DHE) – Then and Now: A Narrative Review

Abstract

Objective.-To provide a narrative review of clinical development programs for non-oral, non-injectable formulations of dihydroergotamine (DHE) for the treatment of migraine.Background.-Dihydroergotamine was one of the first "synthetic drugs" developed in the 20th century for treating migraine. It is effective and recommended for acute migraine treatment. Since oral DHE is extensively metabolized, it must be given by a non-oral route. Intravenous DHE requires healthcare personnel to administer, subcutaneous/intramuscular injection is challenging to self-administer, and the approved nasal spray formulation exhibits low bioavailability and high variability that limits its efficacy. Currently there are several attempts underway to develop non-oral, non-injected formulations of DHE.Method.-A systematic search of MEDLINE/PubMed and Clini calTr ials.gov databases, then narrative review of identified reports, focusing on those published in the last 10 years. Results.-Of 1881 references to DHE from a MEDLINE/PubMed search, 164 were from the last 10 years and were the focus of this review. Further cross reference was made to ClinicalTrials.gov for 19 clinical studies, of which some results have not yet been published, or are studies that are currently underway. Three nasal DHE products are in clinical development, reawakening interest in this route of delivery for migraine. Other routes of DHE administration have been, or are being, explored.Conclusion.-There is renewed appreciation for DHE and the need for non-oral, non-injected delivery is now being addressed.

Implementation of an Intravenous Dihydroergotamine Protocol for Refractory Migraine in Children

“…Another study by Raskin that year reported benefit with IV DHE administered repetitively for intractable migraine 3 . This treatment protocol, featuring IV DHE in an initial test dose of 0.5 mg with 10 mg metoclopramide, then increasing to 1.0 mg DHE administered every 8 hours for 2 days, became the basis for many protocols used in clinical practice today, including our institutional protocol 2,3 . Of note, unlike many of the current protocols it inspired, Raskin’s original treatment protocol included substantial ongoing treatment after completion of IV DHE.…”

“…Repetitive administration of intravenous (IV) dihydroergotamine (DHE) offers a potential benefit for the up to one third of pediatric migraine patients who do not respond to outpatient treatments 1 . This medication emerged in the 1940s, designed to improve upon the significant side effects and cardiovascular risk associated with ergotamine, a historical migraine treatment whose documented use dates back to the middle ages 2 . The increased α‐adrenergic antagonist effect, decreased vasoconstrictive properties, and less severe nausea and vomiting observed with DHE led to its successful application in the treatment of status migrainosus 2 .…”

“…This medication emerged in the 1940s, designed to improve upon the significant side effects and cardiovascular risk associated with ergotamine, a historical migraine treatment whose documented use dates back to the middle ages 2 . The increased α‐adrenergic antagonist effect, decreased vasoconstrictive properties, and less severe nausea and vomiting observed with DHE led to its successful application in the treatment of status migrainosus 2 . Due to its inconsistent absorption and limited bioavailability in an oral formulation, DHE is primarily administered intravenously, typically in an inpatient setting over the course of several days.…”

Nasal Delivery of Acute Medications for Migraine: The Upper Versus Lower Nasal Space

“…Injections may also represent a problem for those patients who are averse to needles [19]. Advantages of inhaled delivery include at-home administration, non-invasiveness, and easy self-administration as well as avoidance of drug degradation in the GI tract and first-pass metabolism (similar to injection), which allows for enhanced bioavailability and reduction of systemic side effects without the use of a needle [22,23].…”

Dihydroergotamine affects spatial behavior and neurotransmission in the central nervous system of Wistar rats

“…Current indications for DHE cover mainly acute migraine management. Although some new drugs, such as triptanes, were introduced to therapy, dihydroergotamine still occurs in recommendations [8][9][10]. There are also data supporting the use of DHE in menstrual migraine, migraine with central sensitization and cutaneous allodynia, medication-overuse headache, migraine recurrence, and migrainous state [11].…”