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

Stephen D. Silberstein, MD; Stephen B. Shrewsbury, MBChB; John Hoekman, PhD

Disclosures

Headache. 2020;60(1):40-57. 

In This Article

Abstract and Introduction

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 ClinicalTrials.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.

Introduction

Ergotamine has historically been used to treat migraine since the middle ages, and as a pharmaceutical since 1926,[1] but is limited by poor tolerability (nausea, vomiting, and cardiovascular effects), thus attempts were made to synthesize compounds with the same efficacy but reduced safety concerns. Dihydroergotamine (DHE) was synthesized by Stoll and Hofmann in 1943 and was the 45th experimental modification hence the original intravenous (IV) formulation was branded as D.H.E. 45®. This modified molecule is more potent than ergotamine as an alpha-adrenergic antagonist (but less potent as an arterial vasoconstrictor), from which it is derived and causes less nausea and vomiting.[2] DHE was originally envisaged as an antihypertensive agent, but it was later shown to be highly effective in treating migraine at the Mayo Clinic.[3] DHE has a chemical structure similar to many naturally occurring neurotransmitters (eg, epinephrine, norepinephrine, dopamine, and serotonin) and as a result binds to a broad range of receptors (Figure 1).[4] DHE was approved in 1946 as one of the first drugs of the post-World War II era and continues to be a choice today for acute migraine, status migrainosus, and cluster headaches. DHE is erratically absorbed through the gut with absorption ranging from 10 to 60% and extremely poor oral bioavailability (0.07–0.14%),[5] and therefore this molecule is limited to non-oral routes of administration. IV administration of DHE is especially effective for treating acute migraine and has a high response rate. Other routes of administration such as nasal delivery (Migranal) have been approved but report 32% bioavailability[6] and variable pharmacokinetics (PK) that create therapeutic challenges (eg, unpredictable clinical response or adverse events). Thus, an unmet need exists for more effective and consistent delivery of DHE that provides improved safety, tolerability, and ease of use while retaining its efficacy. In the last decade, an orally inhaled version of DHE (suspended in hydrofluoroalkane [HFA] propellant), MAP0004 showed promise with a successful clinical development program but failed to overcome manufacturing issues so has never been approved. Now, with renewed interest in the disease, at least 3 companies are developing nasally delivered options of DHE while other non-oral, non-injected products are also in development.

Figure 1.

The molecular structures of (A) ergotamine (tartrate) and (B) dihydroergotamine (mesylate).

This narrative review will highlight the development of non-oral, non-injected DHE programs for acute migraine and summarize the status of the 5 programs in development (3 nasal, 2 in late stage clinical, 1 microneedle patch, and 1 sublingual film) and the 1 oral inhalation formulation. These are the currently, or recently active, development programs identified for DHE which attest to the considerable interest in this 70-year old molecule.

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