Orally Inhaled Dihydroergotamine

Reviving and Improving a Classic

Eric P Baron; Stewart J Tepper


Future Neurology. 2011;6(3):327-333. 

In This Article

Orally Inhaled Dihydroergotamine


Dihydroergotamine in an orally inhaled form has completed Phase III trials. The novel delivery system consists of an inhaler (TEMPO®; MAP Pharmaceuticals), which uses a breath-triggered, synchronized mechanism and is shown to provide significantly increased drug delivery compared with conventional pressurized metered-dose inhalers.[24]

Phase I trial data of the safety, pharmacokinetics and tolerability of DHE in healthy subjects reported that an inhaled dose of four actuations (0.88 mg) provides similar, but slightly lower, systemic exposure compared with a 1.0-mg IV dose based upon area under the curve values.[24] Specifically, the measured area under the curve of four inhaled actuations was 77% of the systemic levels of the standard 1.0-mg IV dose, suggesting a 23% lower systemic exposure.[24] The mean concentration of IV DHE at 10 min post-dose was approximately tenfold higher compared with four actuations of INH DHE, but approximately equal at 2 h.[24]

Nausea and headache were both absent to minimal after four actuations of INH DHE, and this observation has been consistent in subsequent studies. These observations suggest that the lower Cmax of INH DHE leads to the same therapeutic migraine receptor interactions as IV DHE, while providing an initial lower overall systemic exposure and subsequently avoiding interactions at receptors associated with the typical side effects of IV DHE. Therefore, Phase I trials concluded that INH DHE was well tolerated with similar, but improved, pharmacokinetics and less side effects compared with IV DHE.[24]

The important distinction is that 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 Cmax, pretreatment with antiemetics would be unnecessary with the INH DHE.

Concerns regarding the pulmonary delivery, pharmacokinetics, safety and tolerability profiles of INH DHE in this Phase I study were addressed in a group of asthmatic patients in a later study.[22] Subsequently, in the Phase III regulatory and safety extension study of INH DHE, not available at the time of writing, both asthmatic and nonasthmatic patients were given INH DHE for home usage as needed for acute treatment of migraine across 1 year, and pulmonary function tests were monitored. The pharmacokinetics of DHE in its various forms are outlined in Table 1.


In a Phase II trial of 69 adult migraine patients in the as-treated population, INH DHE was shown to provide a statistically significant onset of pain relief for moderate-to-severe migraine within 10 min, sustained pain relief rates for up to 48 h, low incidence of adverse events and relief from nausea, photophobia and phonophobia compared with placebo.[22,25]

A Phase III trial (FREEDOM-301) confirmed prior studies of efficacy and tolerability. This was a randomized, double-blind, placebo-controlled, multicenter study of INH DHE in 903 adults with episodic acute migraine.[26] Patients were randomized to receive either placebo or INH DHE in a 0.63-mg emitted dose (1.0-mg nominal dose; 0.5-mg systemic equivalent) for acute migraine, and instructed to treat at moderate-to-severe levels of pain.

The coprimary end points consisted of patient-assessed pain relief and resolution of photophobia, phonophobia and nausea at 2 h post-treatment.[26] INH DHE was superior to placebo in all four of these end points; pain relief (58.7 vs 34.5%; p < 0.0001), free from phonophobia (52.9 vs 33.8%; p < 0.0001), free from photophobia (46.6 vs 27.2%; p < 0.0001) and free from nausea (67.1 vs 58.7%; p = 0.0210). In addition, more patients were pain free at 2 h after treatment with INH DHE than with placebo (28.4 vs 10.1%; p < 0.0001).[26]

In their conclusion, the authors reported that INH DHE caused no adverse events leading to discontinuation, had no drug-related serious adverse events and the study was determined to provide class I evidence for INH DHE's efficacy and tolerability in treating acute migraine and its associated features of nausea, photophobia and phonophobia.[26]

Side Effects & Contraindications

In the FREEDOM-301 trial, reported side effects that were increased with INH DHE compared with placebo included product taste (6.4 vs 1.7%), nausea (4.5 vs 2%), cough (2.5 vs 1.2%) and vomiting (2 vs 0.7%). Triptan-type sensations in the INH DHE group such as chest discomfort (1%), chest pain (0%) and paresthesias (0.5%) were infrequent and comparable with placebo.[26] In general, side effects for any form of DHE may include myalgias, cramps (especially in the legs), paresthesias, itching, dizziness, weakness in extremities, nausea, vomiting, abdominal pain, tachycardia, palpitations, bradycardia and edema.

There are rare reports of complications involving retroperitoneal, pleural, pericardium and cardiac ostia and valvular fibrosis, which are assumed to be serotonergic-related idiosyncratic reactions with activation at the 5-HT1B receptors. However, for the most part, these rare cases have been primarily associated with concurrent use of high-dose prophylactic ergotamine, ergot-derived anti-Parkinson's medication or methysergide, rather than with DHE alone.[2,12,27,28]

Pleuropulmonary side effects have been associated with older, rarely used ergot derivatives such as bromocriptine, pergolide and cabergoline. Some of these side effects are known to be potentially reversible and may include pleural thickening and effusion, interstitial pneumonitis and pulmonary infiltrates and fibrosis.[29–32] Pleural involvement occurs more frequently than parenchymal involvement, and a literature search (Medline, 1966–2007) did not reveal any cases of severe pulmonary hypertension attributable to cabergoline or other dopamine agonists in the same family.[29] However, a rare case of pleural effusion with severe pulmonary hypertension was reported in a man with Parkinson's disease who had been treated with cabergoline for 1 year, and symptoms disappeared 10 months after the drug was stopped.[29] Therefore, INH DHE has raised some theoretical concern for pleuropulmonary adverse effects, although the current data have not shown their occurrence, and in fact, INH DHE was shown to be safe and effective in adult asthmatics.[22]

Recently, the ergot fibrotic complications of cardiac valvular insufficiency associated with use of ergot anti-Parkinson's medications have been found to remit or stabilize with time. After discontinuation of the ergot, valve abnormalities regressed in approximately a third of patients with significant multivalvular regurgitation and in approximately half of the patients with monovalvular regurgitation; no progression was observed in the remaining patients.[33]

In addition, in an INH DHE receptor study, concentrations were insufficient to interact with cardiovascular (5-HT2B and β1) and pulmonary (β2, adenosine, muscarinic and leukotriene) receptors compared with IV DHE.[12] This suggests that INH DHE may not pose a significant risk for fibrotic complications.

The contraindications for INH DHE are the same as with other forms of DHE and are similar to the triptans. These include cerebral, coronary and peripheral arterial disease, Prinzmetal's variant angina, renal or hepatic failure, uncontrolled hypertension, sepsis and hypersensitivity reactions. Basilar and hemiplegic migraine have generally been felt to be contraindications for the use of triptans (and DHE), although this theoretical concern originates from the older vascular theory of migraine, which is why these patients were excluded from early triptan trials. With the current neurovascular theory of migraine, migraine auras and neurologic symptoms likely do not represent arterial vasospasm, but rather spreading cortical depression affecting the cortical neurons.[34] In fact, multiple case studies have demonstrated triptans to be safe in these patients.[35–38] The use of triptans and DHE has been cautioned in migraine with prolonged aura for these same reasons.[10] 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 and triptans vasoconstrict via their 5-HT1B effects, and there are some 5-HT1B receptors in coronary arteries.

As previously noted, DHE is contraindicated with other vasoconstrictors such as triptans within 24 h. This is because of theoretical synergy at the 5-HT1B receptors.

Dihydroergotamine has been classified by the US FDA as category X and is contraindicated in pregnancy, as well as in breast-feeding mothers. It should not be used with concomitant potent CYP3A4 inhibitors such as protease inhibitors and macrolide antibiotics, as it is metabolized through this liver pathway.


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