Alternative Agents for Dihydroergotamine Mesylate in Management of Cluster Headaches and Acute Migraines

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Headaches are multifactorial and a common occurrence among the general population, with a subset of patients experiencing more severe forms, such as cluster headaches or migraines. Patients with these conditions often require pharmacological interventions for prophylactic treatment, as well as transitional and acute management of symptoms.

Cluster headaches (CH) present as a unilateral severe pain in the orbital, supraorbital, and/or temporal area that may last 15 to 180 minutes per episode; these episodes tend to occur frequently over the course of weeks to months, with a remission period of undetermined time and are known as episodic cluster headaches (eCH). Chronic cluster headaches (cCH) can occur and are considered episodes that either do not have a remission period or the remission period lasts <3 months. Migraines present as four symptom-distinct overlapping phases that culminate into an episode that lasts between 4 to 72 hours, with moderate-to-severe pain levels, and can be considered episodic (≤14 days per month) or chronic (>15 days per month). Migraines and cluster headaches have different pathologies but are pharmacologically managed in a similar fashion^1,2.

Dihydroergotamine (DHE) is a synthetic ergot alkaloid that is commonly used as a refractory treatment for CH and acute migraines. This medication inhibits neuronal input in the trigeminocervical complex and is generally well-tolerated. Treatment efficacy of DHE is limited to intravenous (IV), subcutaneous (SC), intramuscular (IM), suppository insertion, or nasal delivery due to poor oral bioavailability³.

First line agents commonly used for acute CH include SC or intranasal sumatriptan and intranasal zolmitriptan; these agents have been shown to effectively relieve CH pain (<15 minutes) and resolve CH episodes (<30 minutes). DHE may be used as an abortive treatment following first-line agent use but does not significantly reduce length or frequency of attacks and shows benefit in only reducing the intensity of CH pain. First line agents for CH prophylaxis include oral verapamil and topiramate, with an optional adjunctive therapy of corticosteroids (i.e., prednisolone) for transitional management till primary treatment takes effect. Refractory prophylactic management includes oral lithium and IM or IV DHE; DHE is recommended to be given as an adjunctive second-line therapy due to lack of monotherapy treatment efficacy in CH².

Acute migraine management consists of first-line agents such as triptans (oral and intranasal) and non-steroidal anti-inflammatory drugs (NSAIDs). Triptans are typically used in the outpatient setting for abortive treatment, with multiple formulations available to individualize treatment based upon time of migraine onset, severity (rapid or progressive onset), and pattern of migraine attacks¹. Second-line treatment following refractory primary migraine abortive management includes antidopaminergics (i.e., chlorpromazine, prochlorperazine, promethazine), metoclopramide, IV NSAIDs, and additional triptan use (if not previously used for initial treatment). DHE is shown to reduce pain of acute migraine episode but must be administered in conjunction with antiemetic due to heightened risk of nausea when given as an IV bolus¹.

A 2021 systemic review and meta-analysis of acute treatments for episodic migraines provided limited data available regarding DHE efficacy in comparison to commonly utilized medications for migraine management, with the majority of reported studies citing treatment efficacy over placebo only⁴. One older study (c. 1990) included an active comparator analysis of DHE, chlorpromazine, and lidocaine on treatment efficacy and risk of adverse events (AEs) for acute migraine treatment in the emergency department. Chlorpromazine was shown to significantly reduce migraine pain severity when compared to lidocaine and DHE (79.5%, 50%, and 36.7%, respectively; p<0.005). Additionally, DHE was significantly associated with severe gastrointestinal AEs when compared to minor AEs experienced with chlorpromazine and lidocaine use (p<0.05)⁵. Trials evaluating DHE use compared to placebo (N= 15) reported significantly more freedom from pain and sustained pain relief, as well as increased risk of gastrointestinal AEs⁴. Additional studies evaluating DHE use with other anti-migraine agents were not identified. 

Overall, the use of DHE in CH and migraines lacks high-quality data to support its use, as seen with the European Academy of Neurology guidelines on cluster headache management. Expert consensus is the basis for DHE use in acute and prophylactic CH management due to lack of sufficient clinical trials evaluating its treatment efficacy. Table 1 includes all treatment recommendations for cluster headache management^6,7.

Table 1

Alternative Agents for Dihydroergotamine Mesylate
Cluster Headache Management
Medication	Dosing	Clinical Pearls
Acute
Sumatriptan	6 mg SC 20 mg intranasal spray	Mild to moderate chest symptoms and distal paresthesia
	1st line for acute attack
Zolmitriptan	5 or 10 mg intranasal spray	Unpleasant taste, somnolence
	Beneficial for patients with moderate pain and long-lasting attacks
Lidocaine (4%)	4 intranasal sprays; 0.5 to 0.8 mL of nasal drops	Unpleasant taste
	Beneficial in patients with contraindications to triptans
Octreotide	100 mcg SC	Gastrointestinal disturbance, injection site reaction
	Last-line due to lack of evidence of treatment efficacy
Prophylactic
Verapamil	≤960 mg daily	Constipation, arrhythmia, fatigue, bradycardia; no serious AEs reported with daily dose <720 mg Requires ECG monitoring
	1st choice for eCH and cCH
Lithium	Serum concentration 0.7 to 1.2 mmol/L	Nausea, dizziness, tremor, polyuria Requires serum concentration, thyroid, and kidney function monitoring
	Avoid use in short bouts of eCH
Topiramate	≤200 mg daily	Paresthesia, depression, drowsiness, dizziness; tolerable in doses <100 mg/day Monitor for mood changes
	Treatment for eCH and cCH
Galcanezumab	300 mg SC monthly	Injection site pain
	Option for eCH only
Transitional
GON injection	Ipsilateral to pain	Mild local discomfort at injection site
	Option for eCH only
Prednisolone	High-dose IV or PO	Increased serum glucose
	Only recommended for short-term use
Frovatriptan	2.5 to 5 mg daily	Dizziness, drowsiness
	Limited observed clinical use
Abbreviations: ECG, electrocardiogram

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For acute migraine treatment in the emergency department (ED), DHE is commonly given as 0.5 to 1 mg IM or IV for treatment-refractory migraines following first-line medication use. Per the American Headache Society guidelines, antidopaminergic medications are recommended as second-line therapy over DHE alone and may be used in combination with DHE for improved treatment efficacy; antidopaminergic agents include prochlorperazine, metoclopramide, and chlorpromazine^8-10.  Table 2 includes all treatment recommendations for acute management of migraines that are treatment refractory and require emergency intervention.

Table 2

Alternative Agents for Dihydroergotamine Mesylate
Acute Migraine Management in ED
Medication	Dosing	Clinical Pearls
Chlorpromazine	0.1 mg/kg to 25 mg IV or IM	Antidopaminergics
Prochlorperazine	10 mg IV or IM; 25 mg PR
Promethazine	25 mg IM (caution IV use)
	Commonly used as adjunctive therapy
Metoclopramide	10 mg IV	Drowsiness, dizziness, akathisia
Sumatriptan	6 mg SC; 10 or 20 mg intranasal	Mild to moderate chest symptoms and distal paresthesia
Ketorolac	30 mg IM or IV	May be used in combination with triptans
Diclofenac	75 mg IM
Sodium valproate	300 to 1200 mg IV	-
Abbreviations: IV, intravenous; IM, intramuscular; PR, per rectum

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References:

1. Aguilar-Shea AL, Membrilla Md JA, Diaz-de-Teran J. Migraine review for general practice. Aten Primaria. 2022;54(2):102208. doi:10.1016/j.aprim.2021.102208
2. Suri H, Ailani J. Cluster Headache: A Review and Update in Treatment. Curr Neurol Neurosci Rep. 2021;21(7):31. Published 2021 May 5. doi:10.1007/s11910-021-01114-1
3. Silberstein SD, Shrewsbury SB, Hoekman J. Dihydroergotamine (DHE) - Then and Now: A Narrative Review. Headache. 2020;60(1):40-57. doi:10.1111/head.13700
4. VanderPluym JH, Halker Singh RB, Urtecho M, et al. Acute Treatments for Episodic Migraine in Adults: A Systematic Review and Meta-analysis. JAMA. 2021;325(23):2357-2369. doi:10.1001/jama.2021.7939
5. Bell R, Montoya D, Shuaib A, Lee MA. A comparative trial of three agents in the treatment of acute migraine headache. Ann Emerg Med. 1990;19(10):1079-1082. doi:10.1016/s0196-0644(05)81507-0
6. May A, Evers S, Goadsby PJ, et al. European Academy of Neurology guidelines on the treatment of cluster headache. Eur J Neurol. 2023;30(10):2955-2979. doi:10.1111/ene.15956
7. Brandt RB, Doesborg PGG, Haan J, Ferrari MD, Fronczek R. Pharmacotherapy for Cluster Headache. CNS Drugs. 2020;34(2):171-184. doi:10.1007/s40263-019-00696-2
8. Orr SL, Friedman BW, Christie S, et al. Management of Adults With Acute Migraine in the Emergency Department: The American Headache Society Evidence Assessment of Parenteral Pharmacotherapies. Headache. 2016;56(6):911-940. doi:10.1111/head.12835
9. Kazi F, Manyapu M, Fakherddine M, Mekuria K, Friedman BW. Second-line interventions for migraine in the emergency department: A narrative review. Headache. 2021;61(10):1467-1474. doi:10.1111/head.14239
10. Gelfand AA, Goadsby PJ. A Neurologist's Guide to Acute Migraine Therapy in the Emergency Room. Neurohospitalist. 2012;2(2):51-59. doi:10.1177/1941874412439583

 

 

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