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:

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:

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

Contraindications

Dihydroergotamine is contraindicated in patients who have:

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:

Adverse effects

Adverse effects of dihydroergotamine include: