Advancing Migraine Treatment: Exploring the Applications of DHE in the Upper Nasal Space

This article is sponsored by Impel Pharmaceuticals.

As neurologists and healthcare professionals dedicated to providing optimal care for people living with migraine, it’s crucial to stay informed of the latest advancements in treatment options. Migraine is a varied and complex disorder, characterized by a broad spectrum of symptoms associated with neurological, vascular, autonomic, and gastrointestinal (GI) dysfunction. Migraine attacks are phasic, where symptoms may be present before initiation of an attack, during an attack, immediately after an attack or in between attacks. This complex pathophysiology and heterogeneity require a multi-pronged treatment approach tailored to each person’s unique symptoms.

This article delves into the applications of dihydroergotamine (DHE) in treating migraine attacks, particularly its efficacy when delivered to the upper nasal space. We will explore how this delivery method may provide benefits beyond those of older formulations, discuss the types of migraine that may benefit most from DHE, and review recent safety data on DHE delivered to the upper nasal space that can provide helpful context to physicians considering this treatment option for their patients.

Understanding DHE

DHE, a semi-synthetic ergot alkaloid, has long been recognized as an effective option for treating migraine. DHE exhibits anti-migraine activity through various mechanisms with its affinity for multiple receptor subtypes. However, it is erratically absorbed through the gut, which limits this molecule to non-oral routes of administration.

Intravenous (IV) DHE is especially effective for acutely treating migraine, however it requires healthcare personnel to administer and has been associated with unwanted side effects such as nausea, vomiting, muscle cramps and diarrhea. Subcutaneous (SC)/intramuscular (IM) injections are also available, but can be challenging to self-administer and are not acceptable for people with needle phobia.

Intranasal DHE options have been available for nearly two decades and were a welcomed improvement for the important patient-centric considerations of convenience and acceptability. However, earlier DHE nasal sprays used rudimentary delivery systems which limited bioavailability and resulted in variable pharmacokinetics (creating therapeutic challenges such as unpredictable clinical response or adverse events).

Improving DHE Delivery: Targeting the Upper Nasal Space

Recent advances revealed the potential of delivering DHE to the upper nasal space as an innovative approach for migraine treatment. This novel delivery method capitalizes on the unique characteristics of the highly vascularized upper nasal cavity, bypassing the first-pass metabolism and ensuring greater bioavailability compared to nasal sprays that deliver DHE to the lower nasal space. This allows for more consistent and predictable therapeutic effects.

By utilizing intranasal devices specifically designed for upper nasal delivery, DHE can be conveniently administered by people themselves for consistent outcomes. Exploratory results from a 24-week study where 4,515 migraine attacks were treated with Trudhesa® (DHE mesylate delivered to the upper nasal space via Precision Olfactory Delivery [POD®] technology) showed:

• Rapid Onset: The upper nasal space facilitates quicker and more consistent absorption compared to the lower nasal space. With Trudhesa, some patients saw relief in as early as 15 minutes, with more than half of people free from their most bothersome symptom at 2 hours.
• Sustained Benefits: One dose of Trudhesa resulted in some patients experiencing pain freedom for 2 days, with 86% of those who were pain free at 2 hours remaining pain free for 48 hours. Importantly, 85% of the attacks treated didn’t require a second dose when Trudhesa was first used, and those who got relief once were likely to experience it treating subsequent attacks.
• No Dosing Window Limitation: Many oral medications need to be taken within the first 60 minutes of a migraine attack to be most effective. Trudhesa was just as effective if taken early or if taken more than 4 hours from migraine onset, which could help with reducing patients’ anxiety of having to take their medicine in a short window to get relief – an all-too-common experience among people living with migraine that can be extremely debilitating in itself.
• Reduced Systemic Side Effects: Upper nasal DHE delivery provides similar plasma exposure to IV DHE, but without the initial high peak plasma concentrations, minimizing systemic exposure and potential side effects associated with higher doses required in other routes.

In addition to these efficacy considerations, the self-administered nature of Trudhesa empowers people to take control of their treatment. By eliminating the need for healthcare provider administration, patients can conveniently manage their migraine attacks with greater autonomy.

Determining Ideal Candidates for Trudhesa

For clinicians and patients, the ultimate goal of treatment is rapid and complete resolution of migraine pain and its associated symptoms. DHE effectively treats migraine with and without aura, providing flexibility so that people can depend on it time and time again – even when taken late into an attack. Consider Trudhesa for the following scenarios:

• Migraine with Nausea/Vomiting: Studies reveal that 80% of people with migraine experience gastroparesis (delayed emptying of the stomach) during and between attacks; 73% experience nausea and 29% experience vomiting during attacks. Additionally, nausea experienced early in the course of a migraine attack produces aversion to ingesting anything by mouth[i]. These and other types of GI motility symptoms can make it difficult to take oral medications, and can also affect the rate and efficiency of their absorption. Given that Trudhesa is noninvasive and does not need to be taken orally, it may be good option when a person with migraine also experiences GI symptoms.
• Wake with Migraine[ii]: Early morning is the most common time for migraine headaches to occur. Since many acute therapies only work when taken early in the course of an attack, people who wake up with full-blown migraine symptoms require flexibility in their treatment options – DHE is proven to be effective late into an attack, and can provide pain freedom for up to two days with one dose.
• Triptan-Resistant Migraine[iii]: Only one-third of people are pain free at 2 hours after using a triptan[iv], and a quarter of people do not respond to triptans at all[v]. DHE encompasses the mechanism of action of triptans, ditans, and CGRP inhibitors, which may make it especially effective in those who are triptan-resistant.
• Menstrual Migraineⁱⁱⁱ: Menstrual migraine affects a significant subset (about 20% to 25%) of women and girls with the disease. Migraine attacks occurring with menses tend to be more severe and refractory to treatment than those experienced at other times. Additionally, more than 50% of people who experience menstrual migraine struggle with headache recurrence. DHE has been shown to reduce the risk of migraine recurrence.
• Migraine with Allodyniaⁱⁱⁱ: Allodynia is the experience of pain from stimuli that aren’t normally painful (e.g., a person with migraine saying, “my hair hurts”) – an often-overlooked aspect of migraine that affects up to 70% of patients. Unlike triptans, experimental models have suggested that DHE may work in the presence of allodynia.
• Severe/Prolonged Migraineⁱⁱⁱ: Migraine accompanied by extreme pain, or that has persisted despite multiple acute treatments (such as status migrainosus), leaves patients with very few treatment options, which is why IV DHE has long been a staple for treating prolonged migraine in infusion centers, emergency departments and inpatient settings. Delivering DHE to the upper nasal space provides the same bioavailability as IV DHE, but with at-home convenience and a lower risk of unwanted side effects.
• Adding-on to oral CGRP Therapies and Other Acute Treatments: While DHE cannot be used within 24 hours of triptan administration, it can be combined or used as a rescue treatment with gepants, NSAIDs, simple and combination analgesics, anti-emetics and other acute therapies. Patients taking preventive treatment for migraine, including CGRP antagonists (monoclonal antibodies or gepants), can use DHE for breakthrough attacks.

Safety of Trudhesa: Considerations for Providers

Data presented at the 2023 American Academy of Neurology (AAN) and American Headache Society (AHS) annual meetings suggested Trudhesa is safe to use when co-administered with commonly prescribed migraine medications:

• Drug-Drug Interactions (DDIs) with Oral Gepants: One analysis suggested that no DDIs of clinical concern are theoretically predicted if Trudhesa and gepants are co-administered within recommended clinical doses given their differing mechanisms of action, though potential pharmacodynamic DDIs cannot be completely excluded. Additionally, while first-pass metabolism may limit the bioavailability of orally administered drugs, as Trudhesa is administered via the upper nasal space, it bypasses the GI and hepatic first-pass metabolism. These differing routes of administration may further reduce the potential for interaction.
• Concomitant Use with Preventive CGRP, Erenumab, and Triptans: A recent analysis of a small subgroup from the pivotal, Phase 3 STOP 301 trial found that concomitant use of Trudhesa and erenumab, a preventive CGRP antagonist, is well tolerated with the majority of adverse events being mild or moderate and considered unrelated to treatment. Meanwhile, another analysis in a small population found that no significant safety concerns emerged consequent to off-protocol concomitant use of triptans and Trudhesa during the STOP 301 trial.
• Initial Real-World Evidence: Preliminary real-world findings from an assessment of medical and pharmacy claims data for people living with migraine who were treated with Trudhesa in the U.S. suggest that concomitant preventive (with the exception of the anti-CGRP monoclonal antibody class) and acute medication use generally decreases in those taking Trudhesa. Importantly, an increase in antinausea medications was not observed following Trudhesa use, whereas these medications are commonly used with DHE administered via IV.

To learn more about this migraine treatment option, ask your health care provider or visit Trudhesa.com. 

Important Safety Information

Serious or potentially life-threatening reductions in blood flow to the brain or extremities due to interactions between dihydroergotamine (the active ingredient in Trudhesa) and strong CYP3A4 inhibitors (such as protease inhibitors and macrolide antibiotics) have been reported rarely. As a result, these medications should not be taken together.

Indication

Trudhesa is used to treat an active migraine headache with or without aura in adults. Do not use Trudhesa to prevent migraine when you have no symptoms. It is not known if Trudhesa is safe and effective in children.

Do not use Trudhesa if you:

• Have any disease affecting your heart, arteries, or blood circulation
• Are taking certain anti-HIV medications known as protease inhibitors (such as ritonavir or nelfinavir)
• Are taking a macrolide antibiotic such as clarithromycin or erythromycin
• Are taking certain antifungals such as ketoconazole or itraconazole
• Have taken certain medications such as triptans or ergot-type medications for the treatment or prevention of migraine within the last 24 hours
• Have taken any medications that constrict your blood vessels or raise your blood pressure
• Have severe liver or kidney disease
• Are allergic to ergotamine or dihydroergotamine

 Before taking Trudhesa, tell your doctor if:

• You have high blood pressure, chest pain, shortness of breath, heart disease; or risk factors for heart disease (such as high blood pressure, high cholesterol, obesity, diabetes, smoking, strong family history of heart disease or you are postmenopausal, or male over 40); or problems with blood circulation in your arms, legs, fingers, or toes.
• You have or had any disease of the liver or kidney.
• You are taking any prescription or over-the-counter medications, including vitamins or herbal supplements.
• You are pregnant, planning to become pregnant or are nursing, or have ever stopped medication due to an allergy or bad reaction.
• This headache is different from your usual migraine attacks.

The use of Trudhesa should not exceed dosing guidelines and should not be used on a daily basis.

Serious cardiac (heart) events, including some that have been fatal, have occurred following the use of dihydroergotamine mesylate, particularly with dihydroergotamine for injection, but are extremely rare.

You may experience some nasal congestion or irritation, altered sense of taste, sore throat, nausea, vomiting, dizziness, and fatigue after using Trudhesa.

Contact your doctor immediately if you experience:

• Numbness or tingling in your fingers and toes
• Severe tightness, pain, pressure, heaviness, or discomfort in your chest
• Muscle pain or cramps in your arms or legs
• Cold feeling or color changes in 1 or both legs or feet
• Sudden weakness
• Slurred speech
• Swelling or itching

The risk information provided here is not comprehensive. To learn more, talk about Trudhesa with your healthcare provider or pharmacist. The FDA-approved product labeling can be found at www.trudhesa.com or 1-800-555-DRUG. You can also call 1-833-TRUDHESA (1-833-878-3437) for additional information.

POD and TRUDHESA are registered trademarks of Impel Pharmaceuticals Inc. All other trademarks, registered or otherwise, are the property of their respective owner(s).

References 

1. Arca KN, Cai J, Wang F et al. Migraine and gastroparesis. Curr Neurol Neurosci Rep 2022:22(12)813-821.
2. Fox AW, Davis RL. Migraine chronobiology. Headache. 1998; 38: 436- 441.
3. Silberstein SB, Shrewsbury SB, Hoekman J. Dihydroergotamine (DHE) – Then and Now: A Narrative Review. Headache. 2016;60(1):40-57.
4. Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: a meta-analysis of 53 trials. Lancet. 2001;358(9294):1668–1675.
5. Diener HC, Limmroth V. Advances in pharmacological treatment of migraine. Expert Opin Investig Drugs. 2001;10(10):1831–1845.

*The contents of this article are intended for general informational purposes only and do not constitute professional medical advice, diagnosis, or treatment. Always seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. The writer does not recommend or endorse any specific course of treatment, products, procedures, opinions, or other information that may be mentioned. Reliance on any information provided by this content is solely at your own risk.