Orally Inhaled Dihydroergotamine

Table 1.  Pharmacokinetic profiles of dihydroergotamine formulations.

	INH DHE (0.88 mg; four inhalations)	IV DHE (1 mg)	SC/IM DHE (1 mg)	NS DHE (1 mg)
Tmax (min)	9.5–12	1–6	15–30	30–60
Cmax (µg/l)	4.3	>10	2.9–4.4	1.02
AUC (µg/l/h)	7.5	9.7	13.6	5.1
T1/2 (h)	9.5–12	9–15	10–23	10
Bioavailability (%)	77	100	100	40

AUC: Area under the curve; DHE: Dihydroergotamine; IM: Intramuscular; INH: Orally inhaled; IV: Intravenous; NS: Nasal spray; SC: Subcutaneous.
Data taken from [2,12,14,18,20,22,24,39,40]

Authors and Disclosures

Eric P Baron^†1 & Stewart J Tepper<sup>1

1</sup>Cleveland Clinic Neurological Institute, Department of Neurology, Center for Headache & Pain, Center for Regional Neurology, 9500 Euclid Avenue/T33, Cleveland, OH 44195, USA

^†Author for correspondence
Tel.: +1 330 225 8886 n Fax: +1 330 273 2533 barone2@ccf.org

Sidebar

Executive Summary

Introduction

• Dihydroergotamine (DHE) is a semisynthetic ergot alkaloid derived from the fungus Claviceps purpurea.

• DHE has broader neuroreceptor activity compared with the selective serotonin receptor activity of triptans.

• Clinically, some patients who respond poorly to triptans may respond better to DHE given its wider receptor binding profile.

• Orally inhaled DHE (INH DHE) appears to be as effective as intravenous (IV) DHE, with a better side effect profile.

• INH DHE will help eliminate difficulties associated with administration of standard IV, intramuscular (IM), subcutaneous (SC) or nasal spray (NS) formulations of DHE.

DHE pharmacology

• Agonism at 5-HT _1B receptors constricts the pain-producing intracranial vasodilation in the meninges.

• Agonism at 5-HT _1D receptors inhibits trigeminal peptide release, modulates central trigeminal nucleus caudalis nociceptive signaling and inhibits nausea and vomiting in the nucleus tractus solitarius.

• Triptans act as selective agonists only at 5-HT _1B and 5-HT _1D (and some at 5-HT _1F) receptors.

• DHE acts at the same serotonin receptors as triptans, in addition to multiple other serotonin receptor subtypes, as well as dopaminergic and adrenergic receptors.

• The central effects of DHE may reverse central sensitization, which is usually less responsive to triptans.

• DHE undergoes extensive hepatic metabolism.

DHE in clinical use

• DHE is useful in those with prominent nausea and vomiting, status migrainosus, prolonged migraine, menstrual migraine, refractory cluster headache, high migraine recurrence, migraine upon awakening when allodynia is present and triptans are typically less effective and when bridging a patient out of medication overuse headache.

• Standard forms of DHE include IV, SC, IM and NS routes, with IV DHE being the most effective.

• Lack of familiarity with protocols of various forms of DHE, difficulty with use, unsatisfactory outcomes in the outpatient setting, premedication requirements with antiemetics for IV administration, SC/IM self-injection, NS use with poor results and side effects such as nausea and vomiting have limited the use of DHE in its standard forms.

• INH DHE is an easy-to-use formulation of a well understood and needed acute medication that differs significantly from triptans and extends the clinical armamentarium for home treatment of acute migraine attacks.

Orally inhaled DHE pharmacokinetics

• INH DHE is delivered by a novel inhaler delivery system (TEMPO ®) that uses a breath-triggered, synchronized mechanism and provides significantly increased drug delivery compared with conventional pressurized metered-dose inhalers.

• With IV DHE, there is a higher initial peak of medication than with INH DHE, and this initial peak is linked to adverse events, especially nausea and transiently increased headache. The INH DHE does not have this initial peak, but levels off at plasma levels similar to where IV DHE levels off. Thus, efficacy is comparable but without the initial spike of C _max , and pretreatment with antiemetics is unnecessary with INH DHE.

Orally inhaled DHE efficacy

• INH DHE is statistically superior to placebo at 2 h for pain relief, phonophobia-free, photophobia-free and nausea-free outcome measures.

• In Phase III trials, INH DHE caused no adverse events leading to discontinuation, had no drug-related serious adverse events and provided class I evidence for efficacy and tolerability in treating acute migraine and its associated features of nausea, photophobia and phonophobia.

Side effects

• In general, side effects for any form of DHE may include myalgias, cramps, paresthesias, itching, dizziness, weakness in extremities, nausea, vomiting, abdominal pain, tachycardia, palpitations, bradycardia and edema.

Contraindications

• Contraindications of INH DHE are the same as triptans and other forms of DHE: cerebral, coronary and peripheral arterial disease, Prinzmetal's variant angina, renal or hepatic failure, uncontrolled hypertension, sepsis, hypersensitivity reactions and basilar and hemiplegic migraine.

• An electrocardiogram or functional cardiac evaluation should be checked in patients with risk factors for undiagnosed coronary artery disease such as men aged 40 years or older, hyperlipidemia, tobacco abuse, hypertension, postmenopausal women, obesity, diabetes and family history of premature heart disease.

• DHE is contraindicated with other vasoconstrictors such as triptans within 24 h.

• DHE has been classified by the US FDA as category X and is contraindicated in pregnancy, as well as in breast-feeding mothers.

• DHE should not be used with concomitant potent CYP3A4 inhibitors such as protease inhibitors and macrolide antibiotics, as it is metabolized through this liver pathway.

Conclusion

• INH DHE is a promising new option for patients with headache, especially migraine and cluster, who typically respond poorly to triptans, cannot tolerate standard forms of DHE, have limited availability to treatment options or have difficulty with their use.

• DHE appears to be superior to IV DHE in terms of tolerability, while providing similar efficacy.