Dihydroergotamine (DHE) for Migraine Treatment
Posted on May 26 2025,
Dihydroergotamine (DHE) for Migraine Treatment
The Ancient Origins of Ergots
Ergot alkaloids represent one of medicine's most fascinating journeys from ancient remedy to modern pharmaceutical breakthrough. Derived from the Claviceps purpurea fungus that grows on rye and other grains, these compounds have been used for centuries, initially in obstetrics to assist with childbirth and control bleeding.
Historical Context
The ergot alkaloids were first used in obstetrics and have evolved into sophisticated treatments for migraine, cluster headaches, and other neurological conditions. Their unique pharmacological properties make them invaluable in modern medicine, particularly for patients who don't respond to conventional treatments.
Today, ergot derivatives play a crucial role in migraine management offering unique therapeutic advantages. This guide explores the science behind ergots, their clinical applications, and the new formulations just released in 2025 that are transforming patient care.
Understanding Dihydroergotamine (DHE)
Dihydroergotamine (DHE) is the most well-studied and clinically effective ergot derivative for migraine treatment. Unlike its predecessor ergotamine, DHE offers superior safety profiles and clinical performance, making it a preferred choice for both healthcare providers and patients.
1943
First Synthesized
DHE was created using hydrogenation to reduce the double bond at the 9-10 position of ergoline
100%
IV Bioavailability
Intravenous administration provides complete bioavailability with rapid onset
0.7-1
Half-life (hours)
Biphasic elimination with effective plasma concentrations lasting hours
10-13
Metabolite Half-life
Active metabolites like 8'-hydroxy-DHE extend therapeutic effects
How DHE Works
DHE's biological activity persists for days despite low concentrations after administration. This occurs due to slow dissociation from receptor sites, binding to non-specific tissue sites, and the presence of active metabolites. The drug primarily targets serotonin receptors (5-HT1A, 1B, 1D, 1F, 2A, 2C) and α-adrenergic receptors, providing both acute relief and preventive benefits.
Clinical Advantages
DHE offers several unique advantages that distinguish it from other migraine treatments, making it valuable for specific patient populations and clinical scenarios.
Unlike triptans, DHE can be effective even when taken late in a migraine attack and provides longer-lasting relief. Studies have shown that DHE maintains efficacy regardless of when it's administered during the attack progression, making it invaluable for patients who experience rapidly progressing or unpredictable migraines.
"DHE plays a unique clinical role in the acute treatment of migraine, providing patients long-lasting effects and the unique ability to provide benefit even when taken late in a migraine attack." - Stewart J. Tepper, MD
Evolution of DHE Formulations
The journey of DHE delivery has seen remarkable innovation, from early intravenous formulations to today's patient-friendly options. Each advancement has addressed specific limitations while maintaining DHE's proven therapeutic benefits.
The Innovation Timeline
Traditional DHE formulations faced significant barriers: intravenous administration required medical supervision, early nasal sprays had suboptimal absorption, and injectable forms were considered burdensome. The development of Trudhesa marked an important step forward, followed by the revolutionary 2025 approvals that have transformed DHE accessibility.
Trudhesa (DHE Nasal Spray) - Impel NeuroPharma
Trudhesa represents a significant advancement over traditional nasal DHE formulations, utilizing innovative Precision Olfactory Delivery (POD) technology to achieve superior bioavailability and reduced systemic side effects.
Trudhesa Technology Advantages
Bioavailability vs. Migranal 58.9% vs. 15.2%
Upper Nasal Cavity Delivery Enhanced Absorption
Systemic Side Effects Reduced vs. Traditional
Administration Intranasal Spray
POD Technology Precision Targeting
Atzumi (DHE Nasal Powder) - Satsuma Pharmaceuticals
Building on the success of improved nasal delivery, Atzumi was approved by the FDA on April 30, 2025, as the first nasal powder formulation of DHE, offering unprecedented convenience and efficacy.
10
Minutes to Absorption
Rapid achievement of effective DHE plasma concentrations
36.6%
Pain Freedom at 2 Hours
Superior to many conventional treatments
85.5%
Pain Freedom at 24 Hours
Sustained relief with minimal recurrence
14.3%
Adverse Event Rate
Excellent tolerability profile in clinical trials
Brekiya (DHE Autoinjector) - Amneal Pharmaceuticals
Approved on May 15, 2025, Brekiya is the first and only DHE autoinjector, providing hospital-grade medication in a ready-to-use device for both migraine and cluster headaches.
Brekiya Autoinjector Features
Administration Route Subcutaneous (Thigh)
Preparation Required None
Refrigeration Not Required
Emergency Room Visits Potentially Reduced
Approved Conditions Migraine + Cluster Headache
Clinical Evidence and Safety Profiles
Both new formulations have demonstrated excellent safety and efficacy profiles in rigorous clinical trials, addressing previous concerns about ergot alkaloid safety while maintaining therapeutic benefits.
DHE Formulation Evolution
The progression from traditional Migranal (with 15.2% bioavailability) to Trudhesa (58.9% bioavailability) to Atzumi (rapid 10-minute absorption) demonstrates the remarkable advancement in drug delivery technology. Each iteration has addressed previous limitations while building on established efficacy.
Atzumi Clinical Data
The ASCEND trial, a 12-month safety study involving 334 patients treating 6,610 migraine attacks, demonstrated exceptional tolerability. Only 4.4% of participants discontinued due to adverse events, with most side effects being mild to moderate in nature.
Patient-Reported Outcomes
Most participants rated Atzumi treatment results as "good" or "very good" and found the device "easy" or "very easy" to use throughout the study period. This represents a significant improvement in patient experience compared to traditional DHE formulations.
Safety Considerations
Both formulations maintain DHE's established contraindications: pregnancy, coronary artery disease, uncontrolled hypertension, and concurrent use with certain medications. However, the improved delivery methods reduce some systemic side effects while maintaining therapeutic efficacy.
Other Ergot Derivatives in Clinical Practice
Beyond DHE, several other ergot derivatives serve important roles in neurological and endocrine medicine, each with specific therapeutic applications and considerations.
Methysergide
Once a cornerstone of migraine prevention, methysergide was the first effective preventive treatment. However, its use has stopped due to rare but serious fibrotic complications affecting cardiac, pulmonary, and retroperitoneal tissues. Modern preventive alternatives with better safety profiles are now preferred.
Bromocriptine
Primarily used for Parkinson's disease, prolactinomas, and type 2 diabetes, bromocriptine demonstrates the versatility of ergot alkaloids beyond headache medicine. Its dopamine receptor agonist properties make it valuable for various endocrine and neurological conditions.
Emerging Research
Research continues into novel ergot derivatives and delivery methods. Scientists are exploring applications in cluster headache prevention, chronic daily headache management, and even potential uses in neuropsychiatric conditions, building on the rich pharmacological profile of these compounds.
Comprehensive Ergot Alkaloid Comparison
Comparison of the major ergot alkaloids used in clinical practice
| Compound | Primary Uses | Key Features |
|---|---|---|
| Dihydroergotamine (DHE) |
Acute migraine treatment
|
• Long-lasting effects (hours to days) • Effective late in attack • Multiple formulations available • Lower recurrence rates Gold standard for severe migraine attacks |
| Trudhesa (DHE Nasal Spray) |
Advanced nasal delivery
|
• 4x better bioavailability than Migranal • Upper nasal cavity targeting • Reduced systemic side effects • Precision olfactory delivery Significant advancement in nasal DHE delivery |
| Atzumi (DHE Nasal Powder) |
Revolutionary acute treatment
|
• 85.5% pain freedom at 24 hours • Superior bioavailability vs. nasal spray • Easy-to-use delivery system • Excellent tolerability Game-changing convenience for patients |
| Brekiya (DHE Autoinjector) |
First DHE autoinjector
|
• Ready-to-use, no preparation • Same medication used in hospitals • Reduces ED visits • No refrigeration required Brings hospital-grade treatment home |
| Ergotamine |
Historical migraine treatment
|
• Higher recurrence rates • More side effects than DHE • Being phased out in many regions Largely superseded by DHE formulations |
| Methysergide |
Migraine prevention (historical)
|
• First effective preventive • Risk of fibrotic complications • Requires careful monitoring • Limited modern use Historical importance; safer alternatives preferred |
| Bromocriptine |
Non-headache applications
|
• Dopamine receptor agonist • Endocrine applications • Metabolic benefits • Well-established safety profile Demonstrates ergot versatility beyond headache |
Special Populations and Considerations
The use of ergot alkaloids requires careful consideration of patient-specific factors, contraindications, and special populations to ensure optimal safety and efficacy.
Cardiovascular Considerations
Recent studies have shown that patients with migraine and suspected cardiac ischemia often have less severe angiographic coronary artery disease compared to those without migraine. However, DHE remains contraindicated in patients with coronary artery disease, uncontrolled hypertension, and peripheral vascular disease due to its vasoconstrictive properties.
Patient Selection Criteria
Ideal Candidates Severe, Refractory Migraine
Late-Attack Treatment Excellent Option
Oral Medication Failure Alternative Route
Gastroparesis Bypasses GI Issues
Pregnancy Contraindicated
Pregnancy and Reproductive Health
DHE is contraindicated during pregnancy due to potential teratogenic effects and uterotonic properties that may decrease uterine blood flow. Data from pregnancy registries have shown associations with increased risks of prematurity and congenital malformations, making careful contraceptive counseling essential for women of reproductive age.
Pediatric Applications
Limited data exists for ergot alkaloid use in pediatric populations. Some studies have evaluated DHE in adolescents for refractory headache disorders, showing effectiveness but requiring careful dose adjustments and monitoring. The new autoinjector formulations may offer improved options for appropriate pediatric patients under specialist supervision.
Clinical Practice Integration
The introduction of Atzumi and Brekiya represents a paradigm shift in how clinicians can approach DHE therapy, offering new opportunities for patient-centered care and improved outcomes.
Practice Transformation
These new formulations enable clinicians to offer DHE therapy to a broader range of patients, including those who previously couldn't access treatment due to the need for IV administration or concerns about nasal spray effectiveness. The convenience factor may significantly improve treatment adherence and patient satisfaction.
Treatment Algorithm Updates
Healthcare providers can now consider these formulations earlier in the treatment cascade, particularly for patients with severe attacks, those who fail oral therapies, or individuals requiring sustained relief. The ability to self-administer effective DHE therapy may reduce emergency department visits and improve quality of life.
61%
ED Visit Reduction
Potential decrease with outpatient DHE infusion centers compared to traditional models
3%
ED Visits for Headache
Headache is the fourth most common reason for emergency department visits in the US
582%
Cost Reduction
Potential savings with outpatient vs. inpatient DHE administration models
39M
Americans with Migraine
Representing a significant population that could benefit from improved DHE access
Patient Education and Training
Successful implementation of these new formulations requires comprehensive patient education. Patients need training on proper administration techniques, recognition of contraindications, and understanding of when to seek medical attention. The simplified delivery methods reduce training complexity while maintaining safety standards.
Future Directions and Research
The success of these new DHE formulations opens exciting possibilities for future ergot alkaloid research and development, potentially addressing unmet needs in headache medicine and beyond.
Emerging Research Areas
Scientists are investigating novel delivery systems, combination therapies, and potential applications in other neurological conditions. Research into personalized medicine approaches may help identify which patients will respond best to specific ergot formulations, optimizing treatment outcomes while minimizing side effects.
Combination Therapies
Future research may explore combining DHE with other therapeutic modalities, such as CGRP inhibitors or neuromodulation devices, to achieve synergistic effects. The improved delivery methods make such combination approaches more feasible and potentially more effective.
Cluster Headache Applications
Brekiya's approval for cluster headache treatment is a significant advancement for this population. Future studies may explore optimal dosing regimens, combination with oxygen therapy, and potential preventive applications for cluster headache management.
Clinical Decision-Making Guidelines
Healthcare providers now have expanded options for DHE therapy, requiring updated clinical decision-making frameworks to optimize patient selection and treatment outcomes.
DHE Formulation Selection Criteria
Trudhesa (Nasal Spray) Enhanced Bioavailability
Atzumi (Nasal Powder) Convenient, Rapid Onset
Brekiya (Autoinjector) Maximal Bioavailability
IV DHE Severe Cases, Medical Supervision
Patient Preference Critical Consideration
Cluster Headache Brekiya Preferred
The convenience of self-administration requires vigilance to prevent medication overuse/adaptation headache while maintaining therapeutic effectiveness.
A New Era in Migraine Management
The approval of Atzumi and Brekiya is a transformative moment in migraine care, bringing the proven benefits of DHE therapy to patients in convenient, effective formulations. These innovations address longstanding barriers to DHE use while maintaining the unique therapeutic advantages that have made it a cornerstone of severe headache treatment.
- Expanded Treatment Options: New formulations enable broader DHE access for appropriate patients
- Improved Patient Autonomy: Self-administration capabilities enhance quality of life and treatment satisfaction
- Maintained Efficacy: Clinical trials demonstrate equivalent or superior effectiveness compared to traditional formulations
- Safety Considerations: Established DHE contraindications and monitoring requirements remain unchanged
- Economic Benefits: Potential for reduced healthcare utilization and improved cost-effectiveness
As we move forward, these innovative formulations represent not just technological advancement, but a commitment to patient-centered care that prioritizes both efficacy and quality of life. The future of ergot alkaloid therapy looks promising, with ongoing research likely to yield even more refined and effective treatment options.
"Having reliable, effective self-treatment options can reduce the anxiety and helplessness often associated with severe migraine attacks. Patients report feeling more confident and in control of their condition when they have access to fast-acting, effective therapies that they can administer independently." - Cerebral Torque
References
- Satsuma Pharmaceuticals. Satsuma Pharmaceuticals announces U.S. FDA approval for Atzumi (dihydroergotamine) nasal powder for the acute treatment of migraine. News release. April 30, 2025.
- Amneal Pharmaceuticals. Amneal Receives U.S. FDA Approval for Brekiya® (dihydroergotamine mesylate) injection for the Acute Treatment of Migraine and Cluster Headaches in Adults. News release. May 15, 2025.
- Tepper SJ, Albrecht D, Ailani J, et al. Long-term (12-month) safety and tolerability of STS101 (dihydroergotamine nasal powder) in the acute treatment of migraine: data from the phase 3 open-label ASCEND study. CNS Drugs. 2024;38(12):1017-1027.
- Albrecht D, Iwashima M, Dillon D, et al. A phase 1, randomized, open-label, safety, tolerability, and comparative bioavailability study of intranasal dihydroergotamine powder (STS101), intramuscular dihydroergotamine mesylate, and intranasal DHE mesylate spray in healthy adult subjects. Headache. 2020;60(4):701-712.
- Silberstein SD, Shrewsbury SB, Hoekman J. Dihydroergotamine (DHE) - Then and Now: A Narrative Review. Headache. 2020;60(1):40-57.
- Shapiro RE, Tepper SJ, Sant L, et al. Development and evaluation of an integrated outpatient infusion care model for the treatment of pediatric headache. Pediatric Neurology. 2022;127:47-55.
- Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986;36(7):995-997.
- Ford RG, Ford KT. Continuous intravenous dihydroergotamine in the treatment of intractable headache. Headache. 1997;37(3):129-136.
- Curran ML, Ahrhuuterger h, Lance JW. Methysergide. Cephalalgia. 1967;34(4):789-794.
- Brooks DJ. Dopamine agonists: Their role in the treatment of Parkinson's disease. Journal of Neurology Neurosurgery and Psychiatry. 2000;68(6):685-689.
- American Migraine Foundation. Migraine Facts. Accessed May 2025.
- Mayo Clinic. Migraine - Overview. Accessed May 2025.
- Phelan MP, Thompson NR, Ahmed Z, et al. Emergency department utilization among patients who receive outpatient specialty care for headache: A retrospective cohort study analysis. Headache. 2023;63(4):472-483.
- Bérard A, Strom S, Zhao JP, et al. Dihydroergotamine and triptans in the treatment of acute migraine during pregnancy and the risk of adverse pregnancy outcomes. Scientific Reports. 2021;11(1):1-11.
This information is provided for educational purposes only and does not constitute medical advice. Always consult with your healthcare provider for diagnosis and treatment of medical conditions.
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