Earn CME/CE in your profession:

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.


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]

Article Details

Article Author

Michelle Ngo

Article Editor:

Prasanna Tadi


7/4/2022 8:25:48 PM



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 : a journal of neurology. 2000 Jan;     [PubMed PMID: 10611116]


Migraine Headache Agents 2012;     [PubMed PMID: 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. Frontiers in physiology. 2014;     [PubMed PMID: 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. The journal of headache and pain. 2017 Dec;     [PubMed PMID: 28389966]


Silberstein SD,McCrory DC, Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache. 2003 Feb;     [PubMed PMID: 12558771]


Anderson JR,Drehsen G,Pitman IH, Effect of caffeine on ergotamine absorption from rat small intestine. Journal of pharmaceutical sciences. 1981 Jun;     [PubMed PMID: 7252810]


Diener HC,Jansen JP,Reches A,Pascual J,Pitei D,Steiner TJ, 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. European neurology. 2002;     [PubMed PMID: 11844898]


Lipton RB,Diener HC,Robbins MS,Garas SY,Patel K, Caffeine in the management of patients with headache. The journal of headache and pain. 2017 Oct 24     [PubMed PMID: 29067618]


Ergot Alkaloids 2012;     [PubMed PMID: 31643724]


Mathew NT, Dosing and administration of ergotamine tartrate and dihydroergotamine. Headache. 1997;     [PubMed PMID: 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 : an international journal of headache. 1983 Mar;     [PubMed PMID: 6406071]


Antonaci F,Ghiotto N,Wu S,Pucci E,Costa A, Recent advances in migraine therapy. SpringerPlus. 2016;     [PubMed PMID: 27330903]


Lipton RB, Ergotamine tartrate and dihydroergotamine mesylate: safety profiles. Headache. 1997;     [PubMed PMID: 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 progressi in medicina. 1991 Jul-Aug;     [PubMed PMID: 1947404]


Aabech J,Jensen FB,Engell HC, [Ergotism in migraine. Peripheral vascular complications in 14 patients with migraine]. Ugeskrift for laeger. 1989 Aug 14;     [PubMed PMID: 2773132]


Jost WH,Schimrigk K, [Ergotamine-induced rectal lesions in asymptomatic patients]. Wiener klinische Wochenschrift. 1994;     [PubMed PMID: 8197748]


Meyler WJ, Side effects of ergotamine. Cephalalgia : an international journal of headache. 1996 Feb;     [PubMed PMID: 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. Romanian journal of internal medicine = Revue roumaine de medecine interne. 2019 Mar 1;     [PubMed PMID: 30954974]


Wooltorton E, Risk of stroke, gangrene from ergot drug interactions. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2003 Apr 15;     [PubMed PMID: 12695387]


Wells KE,Steed DL,Zajko AB,Webster MW, Recognition and treatment of arterial insufficiency from cafergot. Journal of vascular surgery. 1986 Jul;     [PubMed PMID: 3723691]


Ibraheem JJ,Paalzow L,Tfelt-Hansen P, Low bioavailability of ergotamine tartrate after oral and rectal administration in migraine sufferers. British journal of clinical pharmacology. 1983 Dec;     [PubMed PMID: 6419759]


Skowronski GA,Tronson MD,Parkin WG, Successful treatment of ergotamine poisoning with sodium nitroprusside. The Medical journal of Australia. 1979 Jul 14;     [PubMed PMID: 502953]


Glazer G,Myers KA,Davies ER, Ergot poisoning. Postgraduate medical journal. 1966 Sep;     [PubMed PMID: 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;     [PubMed PMID: 31213753]


Demaagd G, The pharmacological management of migraine, part 1: overview and abortive therapy. P     [PubMed PMID: 19750119]


Öztürk V, Acute Treatment of Migraine. Noro psikiyatri arsivi. 2013 Aug;     [PubMed PMID: 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;     [PubMed PMID: 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. The journal of headache and pain. 2011 Oct;     [PubMed PMID: 21779789]