Approximately thirty-one million American adults have migraine, a syndrome which comes in attacks with moderate to severe head pain. Migraine is associated with nausea, vomiting and sensitivity to light and sound and is the second most common cause of disability in the world. Migraine is the most common cause of disability among young women.

Check out my article “What is Migraine?” on my website, www.doctormigraine.com.

Trudhesa has a new drug mechanism utilizing Dihydroergotamine (DHE) for acute treatment of migraine. Ergotamine has a long historical use in medicine. There is need for an improved delivery system of DHE in place of the currently available Migranal, which according to patients, “tastes bad” and “runs down the back of my throat” with use.

Read my mini book on Migraine. Click here.

This is an article by Britt Talley Daniel MD, member of the American Academy of Neurology, Migraine textbook author, Podcaster, YouTube video producer, and Blogger.

In October 2021, the FDA approved Trudhesa for acute treatment of Migraine with and without aura. Trudhesa delivers DHE to the upper nasal cavity which has increased arterial blood supply and provides more consistent and higher drug absorption.

Trudhesa utilizes POD® (short for Precision Olfactory Delivery) for delivery, which is designed to gently deliver medication to the ideal place in the nose for rapid absorption. DHE is a proven drug that has been used by specialists for years.

Further questions.

What is the history of ergotamine?

Although first used in the sixteenth century during child delivery in obstetrics, it was not used for the treatment of Migraine until the nineteenth century.

The British ENT surgeon, Edward Woakes, (1837-1912) first recommended ergot as a vasoconstricting agent for migraine and other neurogenic conditions associated with vasodilatation in 1868.

Woakes subscribed to the theory of vasodilatation by sympathetic deficit, presented in the early 1850s by Brown-Séquard and Claude Bernard. Dihydroergotamine.  (DHE) was introduced as an adrenolytic agent in 1943.

What is the use of DHE in neurology?

DHE has been used for Migraine since 1925 and is currently available parenterally as IV and IM and as a nasal spray. It is not absorbed well orally. DHE has a special place in treating the most common new patient diagnosis to a headache practice—medication overuse headache.

Migranal, the other DHE nasal spray, is said by patients “to taste bad” and “to run down the back of the throat,” problems addressed by the administration of Trudhesa to the upper nasal cavity.

The upper nasal space arterial vasculature is more permeable compared to the lower nasal cavity, which is less well suited to deliver drug absorption. These advantages allow for better consistency in dosing and absorption of drugs, as well as the potential for improved efficacy and faster time to onset of action – meaning patients may stand to achieve fast and lasting symptomatic relief.

Trudhesa bypasses the GI tract and potential absorption issues since 80% of patients develop gastroparesis during a migraine attack.

What does the Trudhesa device look like?

How is Trudhesa dosed?

Trudhesa comes as a spray which is 0.725 mg per actuation. For acute treatment of migraine one actuation, or spray, should be delivered to each nostril once. The patient may repeat the dose once after one hour. The patient should discard Trudhesa within 8 hours after use.

Maximum dose is four actuations/day and six actuations/week.

Considering patients with renal impairment, there is no limitation of Trudhesa dosing for mild to moderate renal impairment. Dosing is contraindicated for persons with severe renal impairment or severe hepatic impairment.

There currently is no approved use of Trudhesa for pediatric aged patients.

Trudhesa is self-administered by the patient and has some preliminary assembly. After assembly, the drug should be primed before first using by releasing four nasal sprays.  A patient should use Trudhesa immediately after priming.
The recommended dose of Trudhesa is 0.725 mg administered as two metered sprays into the nose (one spray of 0.725 mg into each nostril). The dose may be repeated, if needed, a minimum of 1 hour after the first dose.

A patient should not use more than two doses of Trudhesa within a 24-hour period or three doses within a 7-day period. A patient should discard Trudhesa within 8 hours once the vial has been opened or the product has been assembled. A consumer assembly video is available on www.TRUDHESA.com.

What are the contraindications/cautions for Trudhesa?

Listed situations are:

Hypersensitivity to the drug

Pregnancy

Coronary vasospasm

Uncontrolled hypertension

Peripheral arterial disease

Migraine with brainstem aura

Hemiplegic migraine

Recent vascular surgery

Sepsis

Prolonged daily use

Caution in elderly patients

Caution if there is coronary arterial disease risk

What are Trudhesa adverse reactions?

Serious reactions are:  coronary vasospasm, myocardial ischemia, myocardial ischemia, ventricular tachycardia, ventricular fibrillation, severe hypertension, cerebral ischemia, stroke, cerebral hemorrhage, subarachnoid hemorrhage, intestinal ischemia, peripheral vascular ischemia, gangrene, headache exacerbation.

Common reactions are:  rhinitis, nausea, taste changes, dizziness, vomiting, pharyngitis, somnolence, diarrhea, paresthesia.

There were no serious Trudhesa-related treatment-emergent adverse events (TEAEs) observed in the STOP 301 study and the majority of TEAEs were mild and transient in nature

Some of the most frequently reported Trudhesa-related TEAEs (≥2%) during the entire 52-week study period were nasal congestion (17.8%), nausea (6.8%), nasal discomfort (6.8%), abnormal olfactory test (6.8%) and vomiting (2.7%).5

What are drug interactions with Trudhesa?

Trudhesa is dihydroergotamine, an ergot alkaloid, which could interact with drugs possessing the CYP3A4 substrate or the 5-HT2B receptor.

What are the safety or monitoring issues?

Patients with coronary artery disease risk should have an ECG after their first dose.

What is Pregnancy and lactation advice for Trudhesa?

Pregnancy and lactation are both contraindicated with Trudhesa use.

What are the pharmacology issues with Trudhesa?

Trudhesa us metabolized exclusively in the liver via the CYP450A4 substrate.

The drug is excreted in the bile and feces principally while 2-7% are excreted via the urine.

The half-life of DHE is 10-12 hours.

The migraine process causes cerebral vasodilation and DHE activates vascular serotonin 5-HT1D receptors which constrict cranial and peripheral blood vessels.

DHE is not a controlled drug.

What about controlled drug studies and Trudhesa?

There was a Phase 3, open-label, pivotal safety study, called STOP 301 performed. This is the largest longitudinal study ever conducted with nasal DHE. 5,650 migraine attacks were treated over 24 or 52 weeks during the study.

The primary objective of the study was to assess the safety, tolerability, and effectiveness of Trudhesa. The drug was well tolerated and provided rapid, sustained, and consistent relief of migraine headache symptoms.

Unlike oral acute triptan treatment which needs to be given within one hour of the onset of the attack, Trudhesa was effective even late into the migraine attack.

What was the reported effectiveness of Trudhesa from the STOP 301 study?

In the STOP 301 study more than a third of patients (38%) had pain freedom, two-thirds (66%) had pain relief, and more than half (52%) had freedom from their most bothersome migraine symptom at two hours after their first dose of Trudhesa.

For one in six patients (16%), pain relief started as early as 15 minutes. Of patients who were pain free at two hours, 93 percent were still pain free at 24 hours, and 86 percent were still pain free through two days.

The great majority of patients (84%) reported that Trudhesa was easy to use and preferred it over their current therapy.

What have headache specialists said about Trudhesa?

Stephanie J. Nahas-Geiger, MD, MS Ed, Associate Professor in the Department of Neurology, and Program Director of the Headache Medicine Fellowship Program, Thomas Jefferson University stated: “Many of my patients need more from their migraine treatment, and Trudhesa offers a non-oral, fast-acting, reliable option that overcomes many current medication challenges.

“Its upper nasal delivery circumvents the GI tract and common phenomena associated with migraine, such as nausea and gastroparesis, which can impact the effectiveness of oral treatments. And, importantly, it is a self-administered, single dose that can be taken anytime during a migraine attack, so patients do not need to worry about missing the opportunity to benefit from using Trudhesa within a certain timeframe.

“I think patients will be very receptive to this treatment, because it pairs the long-proven benefits of DHE with a patient-friendly delivery system.”

What are medical reports on using DHE?

Tfelt-Hansen and P J Koehler wrote in Cephalgia  2008 Aug;28(8):877-86 on .” History of the use of ergotamine and dihydroergotamine in migraine from 1906 and onward.”

Abstract

Dale showed in 1906 in a seminal work that ergot inhibits the pressor effect of adrenaline. Stoll at Sandoz isolated ergotamine from ergot in 1918. Based on the belief that migraine was due to increased sympathetic activity, ergotamine was first used in the acute treatment of migraine by Maier in Switzerland in 1925.

In 1938 Graham and Wolff demonstrated the parallel decrease of temporal pulsations and headache after ergotamine. This inspired the vascular theory of Wolff: an initial cerebral vasoconstriction followed by an extracranial vasodilation.

Dihydroergotamine (DHE) was introduced as an adrenolytic agent in 1943. It is still in use parenterally and by the nasal route. Before the triptan era ergotamine and DHE had widespread use as the only specific antimigraine drugs.

From 1950 the world literature on ergotamine was dominated by two adverse events: ergotamine overuse headache and the rare overt ergotism. Recently, oral ergotamine, which has an oral bioavailability of < 1%, has been inferior to oral triptans in randomized clinical trials.

A European Consensus in 2000 concluded that ergotamine is not a drug of first choice. In an American review in 2003 it was suggested that ergotamine may be considered in the treatment of selected patients with moderate to severe migraine.

Rafia Shafqat, Yadira Flores-Montanez, Victoria Delbono, and Stephanie J Nahas wrote in J Pain Res. 2020 Apr 30;13:859-864 on “Updated Evaluation of IV Dihydroergotamine (DHE) for Refractory Migraine: Patient Selection and Special Considerations.”

Abstract

Dihydroergotamine (DHE) is an ergot alkaloid derivative of substances produced by rye fungus. Ergotamine was first used in the field of gynecology and obstetrics, then used for migraine treatment a few years later. DHE was developed as a derivative of ergotamine.

DHE, when compared to ergotamine, demonstrates greater alpha-adrenergic antagonist activity, lower arterial vasoconstriction, less dopaminergic agonism, and lower emetic potential. DHE can be delivered via several routes including intravenous (IV), intramuscular (IM), subcutaneous (SC), intranasal (IN), oral, and orally inhaled (although the latter two are not available in the USA and the last remains experimental only)

DHE can be used in an outpatient basis in infusion centers, emergency departments, and urgent care centers, as well as inpatient treatment for admitted patients. There are protocols for adults as well as pediatric migraine treatment.

DHE and other ergot alkaloids are considered contraindicated in pregnant women as they decrease uterine blood flow and increase uterine muscle contractility predisposing to spontaneous abortion. DHE during lactation is also not recommended as it can lead to gastrointestinal distress and weakness in infants; it can also suppress milk production

Caution should be taken before administering DHE in patients with cardiovascular risk factors. DHE is an older drug with an interesting history, yet it is still clinically useful today for patients with migraine attacks not responsive to triptans, who have a greater burden from migraine, and in refractory migraine.

Stewart J Tepper wrote in Headache in 2013 Sep;53 Suppl 2:43-53 on “Orally inhaled dihydroergotamine: a review.”

Abstract

Orally inhalable dihydroergotamine (iDHE), before the US Food and Drug Administration in 2013 for consideration for approval for acute treatment of episodic migraine in adults, is a user-friendly formulation of an older medication. Dihydroergotamine (DHE) has a heterogeneous receptor profile, central penetration, and persistent receptor binding that may account for its clinical prolonged benefits in acute treatment of migraine.

The same features may result in the ability of DHE to reverse central sensitization and allodynia and to maintain efficacy deep into attacks. These characteristics make DHE particularly useful in treating migraine upon awakening, prolonged migraine, and status migrainosus, menstrually related migraine, and for bridging patients out of medication-overuse headache/chronic migraine. The inhalable formulation has helpful pharmacokinetics, with a lower maximal serum concentration than intravenous DHE which may account for minimal nausea, and less binding to the potentially toxic serotonin2B receptor.

The inhaler itself is designed for delivery of reproducible aliquots of intrapulmonary DHE with only nominal need for patient coordination. The inhalable form allows for bypassing the gastrointestinal tract in the setting of migraine nausea or vomiting and reduces first-pass effect.

No drug-related serious adverse events were reported during the Phase 3 study of iDHE. Product taste and nausea were the most common side effects in both the Phase 3 regulatory trial and in the safety extension trial. Limitations for use of iDHE are those for any ergot or triptan, i.e., contraindication in the setting of vascular disease.

In addition, iDHE is metabolized by the cytochrome P450 3A4 liver enzymatic system. Inhalable DHE provides the promise of a new formulation of a valued medication with important clinical features, useful deep into attacks in a variety of situations.

Learn more about “Medication Overuse Headache” by reading the article in my website, www.doctormigraine.com.

P J Koehler, H Isler wrote in Cephalalgia in 2002 Oct;22(8):686-91 on “The early use of ergotamine in migraine. Edward Woakes' report of 1868, its theoretical and practical background and its international reception.”

Abstract

Although ergot had been used in obstetrics for several centuries, it was proposed for the treatment of migraine only in the 19th century. The British ENT-surgeon Edward Woakes (1837-1912) recommended ergot as a vasoconstricting agent for migraine and other neurogenic conditions associated with vasodilatation in 1868.

He subscribed to the theory of vasodilatation by sympathetic deficit, presented in the early 1850s by Brown-Séquard and Claude Bernard. Du Bois-Reymond proposed vasoconstriction by sympathetic overactivity as the cause of migraine in 1860; Brown-Séquard opposed this in favor of vasodilatation.

Vasodilatation due to sympathetic deficit in migraine was again supported by Möllendorf, with clinical evidence, in 1867. Woakes' paper of 1868 introduced ergot as a vasoconstrictor for the same condition. Reception abroad was prompt. A German version appeared in 1869, and Eulenburg cited Woakes in his textbook of 1871.

Eulenburg presented the use of ergot for migraine as a routine measure in the second edition of his textbook in 1878, and in a paper published in 1883. The method was internationally accepted, but it became popular only after the isolation of pure ergotamine in 1918, resulting in the first reliable compounds with stable properties and predictable effects.

Contrary to Woakes' theory, in the early 20th century ergot was used for migraine because of its well-documented adrenolytic properties, as migraine was by then again believed to be a sympathotonic and vasospastic condition.

Read my big book on Migraine. Click Here.

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Britt Talley Daniel MD