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).

Clinical trials

In randomized clinical trials, oral ergotamine was found to be superior to placebo but inferior to oral sumatriptan. In contrast, rectal ergotamine was found to have higher efficacy than rectal sumatriptan. Intranasal dihydroergotamine was found to be superior to placebo but less effective than subcutaneous and intranasal sumatriptan.

A review of clinical trials indicates that dihydroergotamine as a single agent is not as effective as sumatriptan or phenothiazines for treatment of acute migraine, but when administered with an antiemetic, dihydroergotamine appears to be as effective as opiates, ketorolac, or valproate (03).

In a retrospective study of patients who had failed triptan therapy for treatment of headaches, 47% showed partial to complete response to dihydroergotamine nasal spray treatment (05).

In clinical trials, MAP0004, an orally inhaled dihydroergotamine, was effective in treating migraine irrespective of the time of treatment, even more than 8 hours after onset of migraine pain (22). In a phase 1, open-label, randomized, single-dose, 3-period, 3-way crossover study, INP104 (dihydroergotamine mesylate delivered by Precision Olfactory Delivery intranasal device) showed comparative bioavailability with intravenous dihydroergotamine and Migranal® and was well tolerated (17). These findings support further investigation of INP104 as an effective, well tolerated, and noninvasive treatment for acute episodic migraine.

Indications

The most common indication of dihydroergotamine is to abort or prevent an acute attack of migraine.

Off-label uses

	• 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.

Contraindications

Dihydroergotamine is contraindicated in patients who have:

• Previously shown hypersensitivity to the drug. • Peripheral arterial disease or coronary artery disease. • Cerebrovascular ischemia or hemiplegic migraine. • Reversible cerebral vasoconstriction syndrome • Uncontrolled hypertension. • Severely impaired renal or hepatic function.

Goals and duration of treatment

The aim is control of an acute migraine attack. The dose may be repeated every 15 minutes up to a maximum of 4 mg. Dihydroergotamine is effective in treating and aborting an episode of status migraine, particularly in children and adolescents who have failed to respond to other abortive therapies (08). Parenteral dihydroergotamine is reported to be as effective as or, in some studies, less effective than triptans for pain control but more effective than other drugs used in the treatment of migraine attacks (15).

An extensive review of various publications indicates that migraine patients likely to respond better to treatment with dihydroergotamine than with other agents include those with status migrainosus, migraine recurrence, medication-overuse headache, and chronic daily headache (10). The Canadian Headache Society conducted a systematic review of controlled clinical trials of interventions for migraine in emergency settings and weakly recommended dihydroergotamine based on a low level of evidence (13). Analysis of pooled data from randomized trials indicate that sumatriptan is less effective as acute therapy for migraine attacks with aura compared with attacks without aura whereas inhaled dihydroergotamine has similar efficacy for attacks with and without aura (07). This may influence the choice of an agent for acute migraine. Although dihydroergotamine is an old drug, its intravenous formulation is still clinically useful for patients with refractory migraine attacks not responsive to triptans (16).

Dosing

One mg dihydroergotamine in 1 mL solution.

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.

Interactions

Dihydroergotamine interacts with:

	• 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).

Adverse effects

Adverse effects of dihydroergotamine include:

	• 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.