OVERVIEW

Migraine headaches are marked by repeated, paroxysmal attacks of moderate-to-severe throbbing, one-sided headaches which (without treatment) last 4 to 72 hours and are usually associated with symptoms of nausea and vomiting. Migraine headaches are typically exacerbated by motion, bright lights and loud noises. Migraines may be associated with focal neurological symptoms referred to as “aura” which are typically visual, but may be sensory or motor. Migraine headaches are common, affecting at least 18% of women and 6.5% of men in the United States. The pattern of paroxysmal headaches typically arises in adolescence or young adulthood and may be life-long. The headaches often interfere with daily activities and can be incapacitating, result in major time lost from work and precipitate multiple physician and emergency room visits. Patients with migraine may also be at increased risk for other vascular complications such as stroke and eclampsia.

The cause of migraine headaches is not fully understood, but appears to be related to arteriolar vasodilation and inflammation of the trigeminal nerve endings, perhaps caused by local release of vasoactive peptides. Serotonin activity appears to lessen the pain and symptoms of migraine and serotonin receptor agonists have been developed that have activity against acute migraine. However, the most convincing candidate mediator of migraines is the calcitonin gene related protein (CGRP), a neuropeptide with potent vasodilator and pain-signaling activities. CGRP is found throughout the central and peripheral nervous systems but is particularly active in trigeminal ganglia. Circulating levels of CGRP are elevated in patients with migraines, and the efficacy of migraine therapies such as serotonin receptor agonists and ergot alkaloids is associated with lowering of circulating CGRP levels. Antagonists of CGRP have become a focus of migraine headache prevention and therapy.

Therapy of migraine headache usually combines preventive treatments with early intervention for acute attacks. Early treatment approaches to migraine have included a number of different classes of medications, including analgesics such as aspirin, nonsteroidal antiinflammatory agents and opiates, barbiturates, antiemetics, ergot alkaloids, two types of serotonin receptor agonists (triptans and ditans), and oral, small molecule CGRP antagonists.

For mild migraine headaches, commonly used analgesics such as NSAIDS and aspirin are often effective. They are approved for therapy of headaches, but not specifically for migraine headaches. Opiate analgesics should be avoided. Other medications such as barbiturates and antiemetics are often used, but treat some of the other symptoms of migraine such as nausea and dizziness.

The ergot alkaloids are generally the first line of therapy for migraines. They are inexpensive and have been in use for many years. They do have side effects that can be severe. Currently available forms include ergotamine (Cafergot: year of approval, 1948) and dihydroergotamine (Migranal: 1946). They are used only for treatment of acute attacks.

The triptans which are specific agonists of the serotonin 5-HT_1B/D receptors, are perhaps the most reliable and most common used therapies for acute migraine. Triptans in current use include sumatriptan (Imitrex: 1997), zolmitriptan (Zomig: 1997), naratriptan (Amerge: 1998), rizatriptan (Maxalt: 1998), almotriptan (Almogran, Axert: 2001), frovatriptan (Frova: 2001), and eletriptan (Relpax: 2002). Most of these are now available in generic and less expensive forms.

The ditans are highly selective 5-HT_1F receptor agonists and lack the vasoconstrictive activity of the triptans. The sole ditan approved for use in migraine headache is lasmiditan (Reyvow: 2019). Lasmiditan has had limited clinical use and, because of its price and relatively modest degree of efficacy, is usually limited to patients in whom triptans are contraindicated or have failed to control severe migraine attacks.

The identification of CGRP as an important mediator of vasodilation and pain in patients with migraine led to development of potent and well tolerated small molecule, oral CGRP antagonists as agents to treat acute attacks as well as long acting, monoclonal antibodies to CGRP or its receptor to prevent episodic and chronic migraine. The small molecule CGRP receptor inhibitors include ubrogepant (Ubrelvy: 2019) and rimegepant (Nurtec-ODT: 2020). These agents (the “gepants”) are given by mouth at the time of onset of migraine and have not been approved for chronic use to prevent migraines. The monoclonal antibodies to CGRP include fremanezumab (Ajovy: 2018), galcanezumab (Emgality: 2018) and eptinezumab (Vyepti: 2019) and the CGRP receptor, erenumab (Aimovig: 2018). These agents are given subcutaneously once monthly or every three months and have been found to reduce the frequency of migraines but rarely to eliminate them completely. They are not effective in treatment of ongoing, acute migraine.

Other therapies for prevention of migraine are mostly used off label and have limited efficacy. These preventive agents include valproate, topiramate, various beta-blockers, candesartan, antidepressants, and botulinum toxin type A.

The ergot alkaloids, triptans and ditans rarely if ever cause liver injury, perhaps because they are used for a short time only and in low doses. The monoclonal antibody and small molecule antagonists to CGRP have had limited general use, but appear to be free of significant hepatotoxicity. Rare instances of clinically apparent liver injury have been described in patients taking zolmitriptan and rizatriptan.

General references on the safety and hepatotoxicity of the drugs used specifically for migraine are provided with this introductory section. References specific to the individual agents are provided in separate chapters on the general class of agents (ergot alkaloids and the triptans) or on the specific individual agent.

The following links are to individual drug records.

• Ergot Alkaloids: Ergotamine, Dihydroergotamine
• Monoclonal Antibodies: Eptinezumab, Erenumab, Fremanezumab, Galcanezumab
• Small Molecule CGRP Receptor Antagonists: Rimegepant, Ubrogepant
• Serotonin-1B/D (5-HT_1B/D) Receptor Agonists, Triptans: Almotriptan, Eletriptan, Frovatriptan, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan
• Serotonin-1F (5-HT_1F) Receptor Agonists, Ditans: Lasmiditan

ANNOTATED BIBLIOGRAPHY

References updated: 22 July 2021

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Expert review of hepatotoxicity published in 1999; drugs for migraine headache are not discussed).
• Larrey D, Ripault MP. Benzodiazepines. Hepatotoxicity of psychotropic drugs and drugs of abuse. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 455.

  (Review of hepatotoxicity of neuroleptic drugs, does not mention the drugs for migraine headache).
• Sibley DR, Hazelwood LA, Amara SG. Drugs affecting 5HT signaling. 5-Hydroxytryptamine (serotonin) and dopamine. In, Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 231-4.

  (Textbook of pharmacology and therapeutics).
• Geraud G, Compagnon A, Rossi A., COZAM Study Group. Zolmitriptan versus a combination of acetylsalicylic acid and metoclopramide in the acute oral treatment of migraine: a double-blind, randomised, three-attack study. Eur Neurol. 2002;47:88–98. [PubMed: 11844897]

  (Among 666 patients with migraine treated with either zolmitriptan or aspirin/metoclopramide, side effects of paresthesias and dizziness were more common with zolmitriptan; no mention of any hepatic side effects).
• 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;47:99–107. [PubMed: 11844898]

  (Among 733 patients with migraine treated with either eletriptan or ergotamine/caffeine, side effects were transient and predominately mild or moderate; “No clinically significant laboratory…abnormalities were recorded”).
• Snow V, Weiss K, Wall EM, Mottur-Pilson C., American Academy of Family Physicians. American College of Physicians-American Society of Internal Medicine. Pharmacologic management of acute attacks of migraine and prevention of migraine headache. Ann Intern Med. 2002;137:840–9. [PubMed: 12435222]

  (Guidelines for management of acute migraine and chronic prevention; recommends use of nasal dihydroergotamine or a triptan in patients whose migraines fail to respond to aspirin, acetaminophen or nonsteroidal antiinflammatory agents).
• Jamieson DG. The safety of triptans in the treatment of patients with migraine. Am J Med. 2002;112:135–40. [PubMed: 11835952]

  (Review of the safety of triptans in migraine therapy focusing on vascular risk, stroke, myocardial infarction and ischemic bowel disease; no mention of hepatotoxicity).
• Loj J, Solomon GD. Migraine prophylaxis: who, why, and how. Cleve Clin J Med. 2006;73:793–4. [PubMed: 16970133]

  (Preventive therapy of migraine has limited efficacy and may take 2-3 months to have an effect; the most commonly used agents are beta-blockers, calcium channel blockers, anticonvulsants, tricyclic antidepressants and selective serotonin reuptake inhibitors [SSRIs]).
• Whyte CA, Tepper SJ. Adverse effects of medications commonly used in the treatment of migraine. Expert Rev Neurother. 2009;9:1379–91. [PubMed: 19769452]

  (Extensive review of common side effects of medications used to treat migraine; nausea is the most common and dose limiting side effect of ergot alkaloids and can require antiemetics; 1-8% of patients who take triptans develop “triptan sensations with throat and chest tightness, numbness and tingling and hot/cold sensations which may vary with different forms”).
• Loder E. Triptan therapy in migraine. N Engl J Med. 2010;363:63–70. [PubMed: 20592298]

  (Review of the pathophysiology of migraine headache and the mechanism of action, efficacy, tolerance and safety of the serotonin receptor agonists [triptans]; no mention of ALT elevations of clinically apparent liver injury).
• Taylor FR. Acute treatment of migraine headaches. Semin Neurol. 2010;30:145–53. [PubMed: 20352584]

  (Review of diagnosis and acute management of migraine headaches).
• Drugs for migraine. Treat Guidel Med Lett. 2011;9:7–12. [PubMed: 21304447]

  (Concise review of current medications used for migraine; no discussion of hepatotoxicity).
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A, Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America: an analysis of published reports. Ann Hepatol. 2014;13:231–9. [PubMed: 24552865]

  (Among 176 reports of drug induced liver injury from Latin America published between 1996 and 2012, none were attributed to drugs for migraine headaches).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, none were attributed to the triptans or other drugs for migraine headaches).
• Edvinsson L. The CGRP pathway in migraine as a viable target for therapies. Headache. 2018;58 Suppl 1:33–47. [PubMed: 29697153]

  (Review of the calcitonin gene-related peptide [CGRP] and its receptor including their relationship to migraine headaches and development of small molecular inhibitors and monoclonal antibody therapies based upon their inhibition).
• Tepper SJ. History and review of anti-calcitonin gene-related peptide (CGRP) therapies: from translational research to treatment. Headache. 2018;58 Suppl 3:238–75. [PubMed: 30242830]

  (Review of the role of CGRP in pathogenesis of migraine headaches and the development of small molecules and monoclonal antibody antagonists of CGRP actions).
• Eptinezumab (Vyepti) for migraine prevention. Med Lett Drugs Ther. 2020;62(1599):85–7. [PubMed: 32555116]

  (Concise review of the mechanism of action, clinical efficacy, safety and costs of eptinezumab in relation to other drugs for migraine prevention shortly after its approval in the US, states that it is modestly effective and that adverse events include nasopharyngitis and hypersensitivity reactions [1-2%] including angioedema; no mention of ALT elevations or hepatotoxicity).
• Lasmiditan (Reyvow) and ubrogepant (Ubrelvy) for acute treatment of migraine. Med Lett Drugs Ther. 2020;62(1593):35–9. [PubMed: 32555120]

  (Concise review of the mechanism of action, clinical efficacy, safety and costs of ubrogepant and lasmiditan as therapy of acute migraine shortly after their approval for this indication in the US, mentions side effects of ubrogepant being nausea and somnolence but does not mention ALT elevations or hepatotoxicity).
• Rimegepant (Nurtec ODT) for acute treatment of migraine. Med Lett Drugs Ther. 2020;62(1597):70–2. [PubMed: 32555113]

  (Concise review of the mechanism of action, pharmacology, clinical efficacy, safety and cost of rimegepant shortly after its approval in the US as therapy of acute migraine in adults, mentions that it “was generally well tolerated in clinical trials; nausea was the most common adverse event [~2%]”).
• Drugs for migraine. Med Lett Drugs Ther. 2020;62(1608):153–60. [PubMed: 33434187]

  (Concise summary of the relative clinical efficacy, safety and costs of drugs to treat acute migraine headache [such as analgesics, opiates, triptans, ergots and oral CGRP receptor antagonists] and to prevent migraines [such as anticonvulsants, beta blockers, antidepressants and monoclonal antibodies to CGRP and its receptor]).
• Robbins MS. Diagnosis and management of headache: a review. JAMA. 2021;325:1874–85. [PubMed: 33974014]

  (Review of the diagnosis and management of headache including use of serotonin receptor agonists and calcitonin gene-related peptide antagonists for acute migraine attacks; no mention of ALT elevations or hepatotoxicity).