What is Dihydroergotamine (DHE)?
First introduced in the U.S. in 1945 as a treatment for migraine, DHE is still considered the gold standard treatment for refractory migraine attacks. DHE has long been recommended as a first-line acute treatment option for migraine attacks and may offer clinical advantages over other therapeutics for many patients.
Mechanisms of Action
Dihydroergotamine is believed to exert its anti-migraine effects via a unique multi-modal mechanism of action that result from interactions with both serotonergic and adrenergic-type receptors. Thus, DHE has been referred to as a seroto-adrenergic modulator (SAM). Its multi-modal mechanism of action differentiates DHE from other migraine treatments, including triptans.
Similar to other migraine therapeutics with serotonergic effects, such as those in the triptan class, DHE is an agonist of 5-HT1B and 5-HT1D receptors. As a result of its 5-HT1B agonist activity, DHE causes vasoconstriction. The effect of its 5HT1D agonist activity is a reduction in vasodilation mediated by inhibition of calcitonin gene-related peptide (CGRP) release, a pro-inflammatory, vasoactive peptide with a well-established causative role in migraine. DHE’s effects via 5-HT1D receptors also result in inhibition of pain signal transmission within the trigeminovascular system, the activation and sensitization of which plays a key role in migraine pathophysiology. Following binding to 5-HT1B/1D receptors, DHE slowly dissociates, potentially contributing to its long-lived anti-migraine effects, which can last from many hours to days following dosing.
In addition to exerting anti-migraine effects through serotonergic receptors, DHE also interacts with adrenergic receptors to modulate nociception (or pain-signaling) pathways. DHE reverses central sensitization of central trigeminovascular neurons and produces anti-inflammatory effects via modulation of the MAP kinase / phosphatase system.
How DHE Relieves Migraine
Causes
Vasoconstriction
Inhibits Pain Signal Transmission
Reverses Central Sensitization
Produces Anti-Inflammatory Effects
Reduces
Vasodilation
The combination of DHE’s vasoconstrictive, anti-nociceptive and anti-inflammatory effects may result in improved anti-migraine effects and treatment outcomes for many patients who inadequately respond to other treatments, for example, those with recurrent or prolonged migraine and those experiencing allodynia.
Existing DHE Dosage Forms
Intravenous
Intravenous DHE, while effective, has invasive administration requirements, and must generally be administered by a healthcare provider, typically in the hospital or clinic setting, requires specialized equipment and may often result in side effects, in particular, nausea and vomiting.
Injectable
Similarly, intramuscular (IM) and/or subcutaneous (SC) injections are invasive, require administration via injection by the patient, caregiver or healthcare provider. Patients typically prefer non-injectable therapies.
Liquid Nasal Sprays
DHE liquid nasal sprays have complex, time-consuming and difficult administration, as well as high variability and slow absorption that may result in inconsistent and sub-optimal clinical performance. DHE liquid nasal spray products require assembly, priming, and administration of 4 sprays (2 per nostril 15 minutes apart) to deliver a full dose of DHE.
Due to DHE’s low oral bioavailability, there are no approved oral DHE products in the United States.
Although DHE is commercially available in injectable (for intravenous, subcutaneous or intramuscular administration) and liquid nasal spray formulation products, none of these treatment options offer the combination of consistent delivery, ease-of-use, convenience, limited side effects, and reliable efficacy.
Sources
1. Tepper, Mayo Clin Proc 2011
2. Winner, Arch Neurology 1996
3. Tepper, Headache 2012
4. Fisher, Curr Med Res Opin 2007
5. Saper, Headache 2006