Triptans are undoubtedly efficacious in migraine, yet there remain many patients who benefit little from triptans but respond exquisitely well to DHE. In fact, it is estimated that up to a third of patients fail to achieve adequate pain relief with oral triptans and require additional treatments. Migraine pathophysiology involves a multitude of complex processes, and many unrecognized pathways are likely present throughout the brainstem, cortex and cerebral vasculature. Triptans act as selective agonists at serotonin (5-hydroxytryptamine [5-HT]) receptors 5-HT1B, 1D (and some at 5-HT1F). It is the agonism at 5-HT1B receptors that constricts the pain-producing intracranial vasodilatation in the meninges, and 5-HT1D receptors that inhibit trigeminal peptide release and modulate central trigeminal nucleus caudalis nociceptive signaling, as well as likely inhibit nausea and vomiting in the nucleus tractus solitarius.[8,9]
Dihydroergotamine has a broader spectrum of activity than triptans, including effects at dopaminergic and adrenergic receptors, as well as 5-HT1A/1B/1D/1F/2A/2C/3/4 subtypes.[2,10] This wider spectrum of receptor interaction likely accounts for the additional efficacy of DHE observed in many patients when triptans fail.
The broad spectrum of receptor activity is also the reason for the additional side effects sometimes encountered with DHE compared with triptans, such as nausea and vomiting (D2, 5-HT3 and muscarinic), nausea and dysphoria (5-HT1A), peripheral vasoconstriction (α-adrenergic and 5-HT2A), and dizziness (adrenergic and 5-HT2c).[2,12] DHE tends to produce less headache recurrence than triptans, possibly due to tighter receptor binding and strong sequestration by tissues, which is why DHE is often more efficacious in patients with prolonged and frequent migraine recurrence.[2,7,13] Central effects of DHE may also reverse central sensitization, which is usually less responsive to triptans in prolonged migraine.[14–17]
Dihydroergotamine undergoes extensive hepatic metabolism. The major metabolite is 8β-hydroxydihydroergotamine and is active. A further oxidation step produces 8β,10β-dihydroxydihydroergotamine, which is also active, and other metabolites are also formed. Therefore, the elimination of DHE is biphasic.[18,19]
Future Neurology. 2011;6(3):327-333. © 2011 Future Medicine Ltd.
Cite this: Orally Inhaled Dihydroergotamine - Medscape - May 01, 2011.