U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

Cover of StatPearls

StatPearls [Internet].

Show details


; .

Author Information and Affiliations

Last Update: July 4, 2023.

Continuing Education Activity

The combination of ergotamine and caffeine is a medication used in the management and treatment of acute migraines. It is in the ergot alkaloid class of drugs. This article outlines the indications, action, and contraindications for Ergotamine/caffeine as a valuable agent in the treatment of acute migraines. This article will highlight the mechanism of action, adverse event profile, and other key factors, including dosing, pharmacokinetics, monitoring, and relevant interactions pertinent for members of the interprofessional healthcare team in the care of patients with acute migraines and related conditions.


  • Identify the indications for ergotamine/caffeine administration.
  • Describe the mechanism of action of ergotamine/caffeine.
  • Summarize the adverse effects and contraindications of ergotamine/caffeine.
  • Explain the importance of implementing a multidisciplinary approach in the delivery of care for patients with migraine headaches.
Access free multiple choice questions on this topic.


Ergotamine/caffeine, also known as ergotamine tartrate, is FDA approved to terminate or prevent vascular headaches such as migraines, variations of migraines, or cluster headaches. Since this is a migraine-specific agent, it is for use in patients who present with more severe symptoms and whose migraines have not responded to NSAIDs or combination analgesics. Additionally, because there are other medication options for the acute treatment of migraines that have fewer side effects, it is recommended that clinicians weigh the options and only prescribe ergotamine/caffeine to patients with attacks greater than 48 hours or frequent headache recurrence. Ergotamine/caffeine is also indicated for autonomic failure because it improves seated blood pressure and presyncopal symptoms; this is not an FDA approved indication.[1][2][3]

Mechanism of Action

Although the cause of migraine headaches is not entirely understood, the thinking is that arteriolar vasodilation and inflammation of the trigeminal nerve due to the release of local vasoactive peptides, such as 5-hydroxytryptamine (5-HT) and calcitonin gene-related protein (CGRP) plays a role. CGRP is a neuropeptide that can be found in the central and peripheral nervous systems and has pain-signaling and vasodilator functions. Patients with migraines have elevated levels of circulating CGRP, and migraine medications, such as the ergot alkaloids, are associated with lowering these CGRP levels.[2][4] Ergotamine has a complex mechanism of action that involves a variety of receptors, including 5-HT-1B/1D, dopamine, and alpha-adrenoreceptors. By activating 5HT-1B and 5HT-1D receptors on intracranial blood vessels, ergotamine induces vasoconstriction and relief of migraine headaches. Ergotamine also inhibits norepinephrine uptake and stimulates alpha-adrenergic receptors at therapeutic doses, leading to prolonged vasoconstriction. Blood flow to the extremities thus becomes reduced.[5]

Caffeine may work synergistically with ergotamine by also constricting cerebral vasculature or enhancing its GI absorption. The vasoconstrictive effects of caffeine are due to its antagonistic properties at adenosine A1, A2A, and A2B receptors. Implications point to adenosine receptors in vasodilation. The mechanism of caffeine's rate-accelerating effect appears to be due to its ability to increase ergotamine's water solubility and decrease gastric pH. Caffeine also has numerous physiologic effects that may influence improvement in migraine symptoms such as enhancing mood, alertness, and exercise performance.[6][7][8]


Ergotamine/caffeine has several various formulations, including aerosol, oral, and suppository, though the aerosol form is slowly being withdrawn from the market. It is available in 1 mg (ergotamine)+100 mg (caffeine) tablets under multiple brand names. It is also available as 2 mg rectal suppositories or a 2 mg sublingual form. Ergotamine/caffeine should be administered orally or sublingually for a slowly developing migraine that does not present with early-onset nausea and for treating cluster headaches. At the first sign of a migraine, the patient can place one 2 mg tablet under the tongue, and another tablet should be taken at 30-minute intervals following the initial tablet, if necessary. For severe and rapid onset migraines with nausea and/or vomiting, ergotamine should be administered via rectal suppository in combination with caffeine, as this is the most effective form.[9][10][11] 

Adverse Effects

Because ergotamine is not specific for the 5HT-1 serotonin receptors, it can cause a broad range of side effects. A common side effect of ergotamine and caffeine use is nausea and vomiting after both oral and parenteral administration, most likely due to a direct impact on CNS emetic centers. Cramps, insomnia, and transient lower limb muscle pain can also occur.[12] Other adverse effects of ergotamine tartrate that are related to excessive dosage or chronic usage include ischemia, overuse headache, acroparesthesia, and ergotism.[13] Bocchia et al. reported a case of chronic intoxication (ergotism), similar to the effects of ingesting Claviceps purpurea-infected rye, after ergotamine tartrate administration. The patient had been administered ergotamine rectally for her chronic migraine and showed signs of cerebral and leg ischemia due to vasospasm of the carotid and femoral arteries. Stopping the drug led to complete remission of the symptoms.[14] Aabech et al. also reported 14 cases of severe ischemia in the extremities due to ergotism.[15] Ergotamine-induced rectal lesions, though rare, can also be a complication that warrants alternative routes of administration if ergotamine use will be long-term.[16] Reports also exist of myocardial infarction and fibrotic changes as adverse effects.[17] Perez et al. reported a case of a patient with an ST-segment elevation myocardial infarct due to chronic ergotamine use, though these events are very rare.[18]


Ergotamine tartrate/caffeine is contraindicated in patients with peripheral vascular disorders, coronary artery disease, stroke, uncontrolled hypertension, impaired renal or hepatic function, sepsis, and pregnancy due to its vasoconstrictor effect. Additionally, because ergotamine metabolism occurs through cytochrome P450 (CYP) 3A4 in the liver, it is contraindicated in patients taking medications that are CYP 3A4 inhibitors since these would slow the metabolism of ergotamine and cause toxic effects such as stroke, gangrene, or death. Such CYP 3A4 inhibitors include grapefruit juice, heparin, tacrolimus, cyclosporine, ampicillin, macrolide antibiotics, antifungals, protease inhibitors, and antidepressants.[19][20]


Bioavailability of ergotamine/caffeine is about 5% or less through oral and rectal administration. One study estimated that the maximal possible bioavailability for tablets was 2% and for suppositories was 5%.[21] The elimination half-life is 2 to 2.5 hours, and clearance is approximately 0.68 L/h/kg. Ergotamine/caffeine should be administered as a 2 mg dose initially, and if symptoms persist, continue with 1 to 2 mg every 30 minutes. However, the maximum dosage should be 6 mg per attack and 10 mg weekly.[9]


Ergotamine poisoning and overdose symptoms are rarely seen in today’s clinical practice because newer, safer anti-migraine medications such as triptans are used more widely due to fewer side effects. However, intoxication symptoms could still manifest in sensitive patients taking it for migraine relief. In such cases, treatment involves the initial withdrawal of the drug, which could relieve symptoms. One study also noted that sodium nitroprusside administered intravenously, along with low molecular weight Dextran and Heparin, was successful in treating ergotamine poisoning.[22][14][23] 

Enhancing Healthcare Team Outcomes

It is important to approach headache treatment from a multidisciplinary perspective by employing various strategies to treat and educate patients about handling their pain to enhance the quality of life. Pharmacists, neurologists, psychologists, and physical therapists all play an important role in managing patient headaches and reducing the risk of medication overuse. Pharmacotherapy may be acute or preventative, and the prescriber must be fully aware of the possible side effects of ergotamine and what adverse reactions it could have if taken with other drugs. Since the introduction of more selective drugs with fewer side effects, such as the triptans, physicians must also exercise sound clinical judgment and effective communication with the healthcare team to evaluate the various medication options. Numerous authors have compared the efficacy and safety of triptans versus ergot alkaloids for the treatment of acute migraines and came to mixed conclusions. Thus, the physician needs to discuss with the pharmacy team what options might be best for individual patients.[24][25][26] 

Psychologists can carry out education and cognitive behavioral therapy for migraine patients, including self-management, handling medication, and lifestyle education. Physical therapists play a supplementary role in preventing headache episodes because of the common coexistence of neck pain with headaches. Additionally, various types of relaxation training can be effective treatments in preventing migraines. Due to the pervasive nature of migraines and the complexity of their treatment, it is valuable to utilize a multidisciplinary approach to achieve the most effective outcomes for the patient.[27][28] [Level V]

Review Questions


Tfelt-Hansen P, Saxena PR, Dahlöf C, Pascual J, Láinez M, Henry P, Diener H, Schoenen J, Ferrari MD, Goadsby PJ. Ergotamine in the acute treatment of migraine: a review and European consensus. Brain. 2000 Jan;123 ( Pt 1):9-18. [PubMed: 10611116]
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Jul 22, 2021. Migraine Headache Agents. [PubMed: 31643527]
Arnold AC, Ramirez CE, Choi L, Okamoto LE, Gamboa A, Diedrich A, Raj SR, Robertson D, Biaggioni I, Shibao CA. Combination ergotamine and caffeine improves seated blood pressure and presyncopal symptoms in autonomic failure. Front Physiol. 2014;5:270. [PMC free article: PMC4109567] [PubMed: 25104940]
Hou M, Xing H, Cai Y, Li B, Wang X, Li P, Hu X, Chen J. The effect and safety of monoclonal antibodies to calcitonin gene-related peptide and its receptor on migraine: a systematic review and meta-analysis. J Headache Pain. 2017 Dec;18(1):42. [PMC free article: PMC5383797] [PubMed: 28389966]
Silberstein SD, McCrory DC. Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache. 2003 Feb;43(2):144-66. [PubMed: 12558771]
Anderson JR, Drehsen G, Pitman IH. Effect of caffeine on ergotamine absorption from rat small intestine. J Pharm Sci. 1981 Jun;70(6):651-7. [PubMed: 7252810]
Diener HC, Jansen JP, Reches A, Pascual J, Pitei D, Steiner TJ., Eletriptan and Cafergot Comparative Study Group. Efficacy, tolerability and safety of oral eletriptan and ergotamine plus caffeine (Cafergot) in the acute treatment of migraine: a multicentre, randomised, double-blind, placebo-controlled comparison. Eur Neurol. 2002;47(2):99-107. [PubMed: 11844898]
Lipton RB, Diener HC, Robbins MS, Garas SY, Patel K. Caffeine in the management of patients with headache. J Headache Pain. 2017 Oct 24;18(1):107. [PMC free article: PMC5655397] [PubMed: 29067618]
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Feb 10, 2018. Ergot Alkaloids. [PMC free article: PMC547852] [PubMed: 31643724]
Mathew NT. Dosing and administration of ergotamine tartrate and dihydroergotamine. Headache. 1997;37 Suppl 1:S26-32. [PubMed: 9009471]
Ekbom K, Krabbe AE, Paalzow G, Paalzow L, Tfelt-Hansen P, Waldenlind E. Optimal routes of administration of ergotamine tartrate in cluster headache patients. A pharmacokinetic study. Cephalalgia. 1983 Mar;3(1):15-20. [PubMed: 6406071]
Antonaci F, Ghiotto N, Wu S, Pucci E, Costa A. Recent advances in migraine therapy. Springerplus. 2016;5:637. [PMC free article: PMC4870579] [PubMed: 27330903]
Lipton RB. Ergotamine tartrate and dihydroergotamine mesylate: safety profiles. Headache. 1997;37 Suppl 1:S33-41. [PubMed: 9009472]
Bocchia M, Baldini GG, Bertola G, Zorzoli C. [Risks related to the use of ergotamine in the therapy of hemicrania. Description of a case]. Recenti Prog Med. 1991 Jul-Aug;82(7-8):390-3. [PubMed: 1947404]
Aabech J, Jensen FB, Engell HC. [Ergotism in migraine. Peripheral vascular complications in 14 patients with migraine]. Ugeskr Laeger. 1989 Aug 14;151(33):2067-70. [PubMed: 2773132]
Jost WH, Schimrigk K. [Ergotamine-induced rectal lesions in asymptomatic patients]. Wien Klin Wochenschr. 1994;106(6):171-3. [PubMed: 8197748]
Meyler WJ. Side effects of ergotamine. Cephalalgia. 1996 Feb;16(1):5-10. [PubMed: 8825693]
Pérez Baztarrica GE, Armijos Carrion LP, Abarca Real JH, Paredes Lima WA, Giler Saltos OP, Porcile R. Acute coronary syndrome with elevation of ST associated with ergotamine abuse. Rom J Intern Med. 2019 Mar 01;57(1):69-71. [PubMed: 30954974]
Wooltorton E. Risk of stroke, gangrene from ergot drug interactions. CMAJ. 2003 Apr 15;168(8):1015. [PMC free article: PMC152687] [PubMed: 12695387]
Wells KE, Steed DL, Zajko AB, Webster MW. Recognition and treatment of arterial insufficiency from cafergot. J Vasc Surg. 1986 Jul;4(1):8-15. [PubMed: 3723691]
Ibraheem JJ, Paalzow L, Tfelt-Hansen P. Low bioavailability of ergotamine tartrate after oral and rectal administration in migraine sufferers. Br J Clin Pharmacol. 1983 Dec;16(6):695-9. [PMC free article: PMC1428366] [PubMed: 6419759]
Skowronski GA, Tronson MD, Parkin WG. Successful treatment of ergotamine poisoning with sodium nitroprusside. Med J Aust. 1979 Jul 14;2(1):8-9. [PubMed: 502953]
Glazer G, Myers KA, Davies ER. Ergot poisoning. Postgrad Med J. 1966 Sep;42(491):562-8. [PMC free article: PMC2465954] [PubMed: 5919182]
Miljković S, Smajlović D, Tirić Campara M, Jurina R, Duranović Vinković L, Janković SM, Begović B, Ćeranić M. The first comparative double-blind trial on efficacy and safety of ergotamine based five-component combination and sumatriptan in migraine without aura. Hippokratia. 2018 Jan-Mar;22(1):17-22. [PMC free article: PMC6528700] [PubMed: 31213753]
Demaagd G. The pharmacological management of migraine, part 1: overview and abortive therapy. P T. 2008 Jul;33(7):404-16. [PMC free article: PMC2740949] [PubMed: 19750119]
Öztürk V. Acute Treatment of Migraine. Noro Psikiyatr Ars. 2013 Aug;50(Suppl 1):S26-S29. [PMC free article: PMC5353074] [PubMed: 28360580]
Larsson B, Carlsson J, Fichtel A, Melin L. Relaxation treatment of adolescent headache sufferers: results from a school-based replication series. Headache. 2005 Jun;45(6):692-704. [PubMed: 15953302]
Gaul C, Visscher CM, Bhola R, Sorbi MJ, Galli F, Rasmussen AV, Jensen R. Team players against headache: multidisciplinary treatment of primary headaches and medication overuse headache. J Headache Pain. 2011 Oct;12(5):511-9. [PMC free article: PMC3173636] [PubMed: 21779789]

Disclosure: Michelle Ngo declares no relevant financial relationships with ineligible companies.

Disclosure: Prasanna Tadi declares no relevant financial relationships with ineligible companies.

Copyright © 2024, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Bookshelf ID: NBK555953PMID: 32310413


  • PubReader
  • Print View
  • Cite this Page

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

  • Transdermal Medications.[StatPearls. 2024]
    Transdermal Medications.
    Khan S, Sharman T. StatPearls. 2024 Jan
  • Hydroxocobalamin.[StatPearls. 2024]
    Ramezanpour Ahangar E, Annamaraju P. StatPearls. 2024 Jan
  • Zinc.[StatPearls. 2024]
    Rabinovich D, Smadi Y. StatPearls. 2024 Jan
  • Opioid Analgesics.[StatPearls. 2024]
    Opioid Analgesics.
    Cohen B, Ruth LJ, Preuss CV. StatPearls. 2024 Jan
  • Azilsartan.[StatPearls. 2024]
    Hardin MD, Jacobs TF. StatPearls. 2024 Jan
See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...