Dihydroergotamine

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 03.06.2021
Released 02.23.1999
Expires For CME 03.06.2024

Dihydroergotamine

Author: K K Jain MD†

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Dihydroergotamine

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Introduction

Historical note and terminology

Ergotamine, originally derived from a rye fungus (Claviceps purpurea) and isolated in 1918, was reported to be an effective antimigraine agent in 1925 in Switzerland (24). However, absorption of this compound is erratic by oral or rectal routes, and side effects such as nausea, vomiting, and peripheral vasoconstriction are common. Dihydroergotamine mesylate has been used as an acute migraine treatment since 1945, but tolerability of intravenous administration limited its use. Ergotism can result from prolonged, excessive use. The search for a safer compound led to the development of a dehydrogenated derivative of ergotamine, dihydroergotamine as an adrenolytic agent in 1943. This was first available, in the inconvenient form of intramuscular injection, for treatment of acute migraine. Further clinical trials were conducted for dihydroergotamine administration by nasal spray in the early 1990s. The nasal spray was approved by the United States Food and Drug Administration in 1998. There is renewed interest in dihydroergotamine, and the need for nonoral, noninjected delivery is now being pursued further (20).

Pharmacology

Dihydroergotamine is an ergotamine hydrogenated at position 9,10 as the mesylate salt and has a different pharmacologic profile from ergotamine.

Pharmacodynamics. Dihydroergotamine has the following properties:

	• It is an alpha-adrenergic antagonist.
	• It is an agonist at 5-HT1A, 5-HT1B, 5-HT1D, and 5-HT1F receptors resulting in a vasoconstricting effect through contraction of arterial smooth muscle. It also constricts venous capacitance vessels.
	• It interacts with 5-HT2 and dopamine receptors. In acute migraine treatment, its mechanisms of action involve constricting the pain-producing intracranial extracerebral blood vessels at the 5-HT1B receptors and inhibiting the trigeminal neurotransmission at the peripheral and central 5-HT1D receptors.
	• Dihydroergotamine-induced inhibition of the perivascular sensory CGRPergic outflow may facilitate its vasoconstrictor properties (06).
	• Efficacy of dihydroergotamine varies according to the route of administration. Efficacy of injectable formulations including subcutaneous, intramuscular, and intravenous is superior to nasal spray, whereas nasal spray is generally more effective than placebo, but less effective than sumatriptan (19).

Compared to ergotamine, dihydroergotamine has greater alpha-adrenergic antagonist activity, lower arterial vasoconstriction, and less dopaminergic agonism; it is less likely to induce vomiting.

Pharmacokinetics. Plasma concentrations of dihydroergotamine following a single subcutaneous injection rapidly reach peak levels and quickly decline, whereas vasoconstrictor activity lasts longer. Based on the information provided by the manufacturer, the important points relevant to nasal administration of dihydroergotamine as compared to intramuscular administration are:

	• Nasally administered dihydroergotamine becomes rapidly available in the systemic circulation, with peak plasma levels of 1 mg/mL achieved in 0.9 hour. The relative bioavailability versus intramuscular route is 38.4%.
	• Dihydroergotamine administered by the nasal route exhibits linear dose proportionality (1 to 4 mg).
	• Vasomotor phenomena, which could also affect the nasal mucosa during a migraine headache, do not modify the bioavailability.
	• Interindividual variations for bioavailability were greater with nasally administered dihydroergotamine than by the intramuscular route but comparable to the oral route.

Alternative methods of delivery of dihydroergotamine. The oral formulation of dihydroergotamine is quickly metabolized; therefore, injectable preparations have been developed. The following methods are alternatives to injection.

Pulmonary delivery. Levadex®, an orally inhaled, aerosol formulation of dihydroergotamine mesylate using a pressurized, metered dose inhaler for rapid absorption through lung alveoli, was developed to provide the antimigraine efficacy of dihydroergotamine with fewer systemic effects than the intravenous formulation (18). Phase 3 trials have shown its antimigraine efficacy and safety.

Inhaled dihydroergotamine is less likely to bind with other serotonergic, adrenergic, and dopaminergic receptors, resulting in fewer adverse effects, and is considered preferable to intravenous formulation (23). The only approved product is Migranal (inhaled dihydroergotamine mesylate).

Transdermal delivery. Drug delivery by microneedle transdermal patches is a recognized technique. Results of an animal experimental study suggest that polyvinylpyrrolidone microneedle patches loaded with dihydroergotamine is an alternative delivery method that enables painless self-administration with rapid onset and high bioavailability (21). The material used is biodegradable, and the pharmacokinetics of transdermal dihydroergotamine are comparable with subcutaneous administration of the drug.

Sublingual delivery. Experimental studies have shown that dihydroergotamine mesylate loaded maltodextrin-pullulan sublingual films provide faster onset of action and higher bioavailability than oral administration and can be considered as an alternative dosage form for dihydroergotamine for migraine therapy to overcome the limitation of orally absorbed dose, which may be cleared by first pass metabolism (04).

Special considerations

Pediatric. Safe and effective use in children has not been established. Dihydroergotamine is usually not recommended in children. A retrospective study of intravenous dihydroergotamine in hospitalized patients reported that it is an effective abortive medication for intractable pediatric migraine, but headache relief is only short-term with only modest long-term benefit (12). A retrospective study based on a chart review of hospitalized pediatric patients supports the use of repetitive intravenous dihydroergotamine as an abortive therapy for status migrainosus or chronic migraine, with no evidence of differential efficacy in these groups (25). Intravenous dihydroergotamine shortened the length of hospital stay, but long-term efficacy needs to be studied.

Geriatric. There are no age-related adverse effects for dihydroergotamine use in the elderly, but this population is likely to have myocardial ischemia, renal, or hepatic impairment, which are contraindications for the use of the drug.

Pregnancy. No evidence of teratogenicity exists in animal reproductive studies. Dihydroergotamine crosses the placenta in small amounts and the vasoconstrictive effect, which can lead to reduced placental flow, may cause fetal growth retardation. An increase in uterine muscle contractility may predispose to spontaneous abortion. A case control study of adverse events showed that other than for prematurity, risk of dihydroergotamine use during pregnancy was like that of triptan use but was smaller than the risk associated with the use of non-steroidal antiinflammatory drugs (02). Dihydroergotamine is excreted in the milk and may cause an adverse reaction in the fetus. Nursing during dihydroergotamine treatment is not recommended.

Anesthesia. No special precautions. Dihydroergotamine has been used to counteract the hypotensive complications of spinal anesthesia.

References

01: Bekan G, Tfelt-Hansen P. Is the generally held view that intravenous dihydroergotamine is effective in migraine based on wrong "general consensus" of one trial? A critical review of the trial and subsequent quotations. Headache 2016;56(9):1482-91. PMID 27595607
02: Berard A, Kori S. Dihydroergotamine (DHE) use during gestation and the risk of adverse pregnancy outcomes. Headache 2012;52(7):1085-93. PMID 22612391
03: Colman I, Brown MD, Innes GD, Grafstein E, Roberts TE, Rowe BH. Parenteral dihydroergotamine for acute migraine headache: a systematic review of the literature. Ann Emerg Med 2005;45:393-401. PMID 15795718
04: Esim O, Ozkan CK, Kurbanoglu S, et al. Development and in vitro/in vivo evaluation of dihydroergotamine mesylate loaded maltodextrin-pullulan sublingual films. Drug Dev Ind Pharm 2019;45(6):914-21. PMID 30714426
05: Fisher M, Gosy EJ, Heary B, Shaw D. Dihydroergotamine nasal spray for relief of refractory headache: a retrospective chart review. Curr Med Res Opin 2007;23(4):751-5. PMID 17407631
06: González-Hernández A, Lozano-Cuenca J, Marichal-Cancino BA, MaassenVanDenBrink A, Villalón CM. Dihydroergotamine inhibits the vasodepressor sensory CGRPergic outflow by prejunctional activation of α2-adrenoceptors and 5-HT1 receptors. J Headache Pain 2018;19(1):40.** PMID 29802544
07: Hansen JM, Goadsby PJ, Charles A. Reduced efficacy of sumatriptan in migraine with aura vs without aura. Neurology 2015;84(18):1880-5. PMID 25841032
08: Kabbouche MA, Powers SW, Segers A, et al. Inpatient treatment of status migraine with dihydroergotamine in children and adolescents. Headache 2009;49(1):106-9. PMID 19125879
09: Kellerman D, Kori S, Forst A, et al. Lack of drug interaction between the migraine drug MAP0004 (orally inhaled dihydroergotamine) and a CYP3A4 inhibitor in humans. Cephalalgia 2012;32(2):150-8. PMID 22174351
10: Morren JA, Galvez-Jimenez N. Where is dihydroergotamine mesylate in the changing landscape of migraine therapy. Expert Opin Pharmacother 2010;11(18):3085-93. PMID 21080856
11: Nagy AJ, Gandhi S, Bhola R, Goadsby PJ. Intravenous dihydroergotamine for inpatient management of refractory primary headaches. Neurology 2011;77(20):1827-32. PMID 22049203
12: Nelson GR, Bale JF, Kerr LM. Outcome and cost of inpatient hospitalization for intravenous dihydroergotamine treatment of refractory pediatric headache. Pediatr Neurol 2017;66:76-81. PMID 27847180
13: Orr SL, Aubé M, Becker WJ, et al. Canadian Headache Society systematic review and recommendations on the treatment of migraine pain in emergency settings. Cephalalgia 2015;35(3):271-84. PMID 24875925
14: Schenkat DH, Schulz LT, Johnson BD. Dihydroergotamine-induced vasospastic angina in a patient taking a calcium channel blocker. Ann Pharmacother 2011;45(7-8):e41. PMID 21693700
15: Schurks M. Dihydroergotamine: role in the treatment of migraine. Expert Opin Drug Metab Toxicol 2009;5(9):1141-8. PMID 19624283
16: Shafqat R, Flores-Montanez Y, Delbono V, Nahas SJ. Updated evaluation of IV dihydroergotamine (DHE) for refractory migraine: patient selection and special considerations. J Pain Res 2020;13:859-64. PMID 32431533**
17: Shrewsbury SB, Jeleva M, Satterly KH, Lickliter J, Hoekman J. STOP 101: A phase 1, randomized, open-label, comparative bioavailability study of INP104, dihydroergotamine mesylate (DHE) administered intranasally by a I123 precision olfactory delivery (POD® ) device, in healthy adult subjects. Headache 2019;59(3):394-409.** PMID 30659611
18: Silberstein S. MAP0004: dihydroergotamine mesylate inhalation aerosol for acute treatment of migraine. Expert Opin Pharmacother 2012;13(13):1961-8. PMID 22860628
19: Silberstein SD, Kori SH. Dihydroergotamine: a review of formulation approaches for the acute treatment of migraine. CNS Drugs 2013;27(5):385-94. PMID 23620146
20: Silberstein SD, Shrewsbury SB, Hoekman J. Dihydroergotamine (DHE) - then and now: a narrative review. Headache 2020;60(1):40-57. PMID 31737909
21: Tas C, Joyce JC, Nguyen HX, et al. Dihydroergotamine mesylate-loaded dissolving microneedle patch made of polyvinylpyrrolidone for management of acute migraine therapy. J Control Release 2017;268:159-65. PMID 29051065
22: Tepper SJ, Kori SH, Goadsby PJ, et al. MAP0004, orally inhaled dihydroergotamine for acute treatment of migraine: efficacy of early and late treatments. Mayo Clin Proc 2011;86(10):948-55. PMID 21964172
23: Tfelt-Hansen P. Is orally inhaled dihydroergotamine (DHE) equivalent in efficacy in migraine to intravenous DHE? Headache 2014;54(2):383. PMID 24512579
24: Tfelt-Hansen PC, Koehler PJ. History of the use of ergotamine and dihydroergotamine in migraine from 1906 and onward. Cephalalgia 2008;28(8):877-86. PMID 18460007
25: Theroux LM, Cappa R, Mendoza A, Mallawaarachchi I, Samanta D, Goodkin HP. Implementation of an intravenous dihydroergotamine protocol for refractory migraine in children. Headache 2020;60(8):1653-63. PMID 32853454
26: Tso AR, Patniyot IR, Gelfand AA, Goadsby PJ. Increased rate of venous thrombosis may be associated with inpatient dihydroergotamine treatment. Neurology 2017;89(3):279-83.** PMID 28615428

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Dihydroergotamine

Other Pertinent Drugs

Antimigraine drugs: ergotamine

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	• Use in breaking the cycle of chronic daily headache.
	• Repetitive intravenous dihydroergotamine is used for the treatment of chronic daily headache and transformed migraine complicated by overuse of analgesics and triptans. Intravenous dihydroergotamine is effective in patients with primary refractory headaches, and longer treatments produce a better outcome (11). The efficacy of intravenous dihydroergotamine based on a single controlled trial in 1986 was re-examined in subsequent randomized trials, but conclusions about efficacy based on the original trial were maintained despite the results of later trials that did not show superiority of intravenous dihydroergotamine over the placebo (01).
	• Reduction of cerebral edema in traumatic brain injury through a vasoconstricting effect.
	• Refractory cluster headache.
	• Status migrainosus precipitated by electroconvulsive therapy that is refractory to treatment with triptan medications.

	• Vasoconstrictors
	• Beta blockers
	• Nicotine
	• Antibiotics of macrolide class
	• The product label of dihydroergotamine warns against concomitant use of CYP3A4 inhibitors because of potential drug interactions. However, a study demonstrated that CYP3A4 inhibition by ketoconazole had little effect on pharmacokinetics of MAP0004, an oral inhalation formulation of dihydroergotamine (09).

	• Nasal irritation, congestion, and rhinitis.
	• Taste disorders.
	• Symptoms of peripheral vascular ischemia due to vasospasm.
	• Vasospastic angina may occur in patients receiving dihydroergotamine who have no underlying coronary artery disease (14).
	• In some patients, dihydroergotamine may aggravate headache.
	• Frequent use of ergotamine, 3 times or more per week, can lead to a state of dependency (physiologic and psychological). Ergotamine abuse and subsequent ergotamine-induced headache is well known, and withdrawal therapy may be required. Information processing is impaired by ergotamine abuse and can be improved but not normalized after withdrawal therapy. Caution is advised, and prolonged use of any ergot derivatives should be avoided.
	• Pleural and retroperitoneal fibrosis has been reported in patients with prolonged use of dihydroergotamine.
	• Benign reversible cerebral angiopathy has been reported in patients using ergot derivatives including dihydroergotamine for headache.
	• Ergot alkaloids are now known to induce serotonin syndrome (see clinical summary for serotonin syndrome).
	• In hospitalized patients with acute migraine, intravenous dihydroergotamine treatment may be associated with an increased risk of catheter-associated venous thrombosis (26). Ultrasound should be used for early detection because anticoagulation therapy is frequently required for management of this complication.

Dihydroergotamine

Dihydroergotamine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

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Questions or Comment?

Also in This Category

Primary headache associated with sexual activity

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Dihydroergotamine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Primary headache associated with sexual activity

Primary cough headache

Medications and substances causing headache

Headache in children: overview and treatment approaches

Alternating hemiplegia of childhood

Late-life migrainous accompaniments

Complex regional pain syndrome

Serotonin syndrome

This is an article preview.
Start a Free Account
to access the full version.