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DRUG RECORD

 

MIGRAINE HEADACHE AGENTS

OVERVIEW
Migraine Headache Agents

 

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 loss 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.

 

Therapy of migraine headache usually combines preventive treatments with early intervention for acute attacks.  A great number of medications are used for migraine headaches including nonsteroidal antiinflammatory agents, opiate and nonopiate analgesics, barbiturates, antiemetics, ergot alkaloids, and serotonin receptor agonists.  Medications used specifically for migraine headaches and discussed here are the ergot alkaloids and the more recently developed serotonin receptor agonists (triptans).  The ergot alkaloids have been in use for many years, and currently available forms include ergotamine (Cafergot: year of approval, 1948) and dihydroergotamine (Migranal: 1946).  The triptans include sumatriptan (Imitrex: 1997), zolmitriptan (Zomig: 1997), naratriptan (Amerge: 1998), rizatriptan (Maxalt: 1998), almotriptan (Almogran, Axert: 2001), frovatriptan (Frova: 2001), and eletriptan (Relpax: 2002).


The ergot alkaloids and triptans rarely cause liver injury, perhaps because they are used for a short time only and in low doses.  Rare instances of clinically apparent liver injury have been described in patients taking zolmitripan and rizatriptan.  The references on hepatotoxicity of the drugs used specifically for migraine are listed together after this introductory section.  The agents are discussed after each overview section [ergot alkaloids and triptans]:

 

The following links are to individual drug records.
  • Ergot Alkaloids: Ergotamine, Dihydroergotamine
  • Triptans: Almotriptan, Eletriptan, Frovatriptan, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan

 

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REFERENCES
Migraine Headache Agents

 

References updated: 24 February 2016

  1. 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; ergotamine and triptans are not discussed).

  2. 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 ergotamine or the triptans).

  3. Sanders-Bush E, Mayer SE. 5-Hydroxytryptamine (Serotonin): receptor agonists and antagonists. In, Brunton LL, Lazo JS, Parker KL, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 11th ed. New York: McGraw-Hill, 2006, pp. 297-315.  (Textbook of pharmacology and therapeutics).

  4. Fisher PE, Silk DB, Menzies-Gow N, Dingle M. Ergotamine abuse and extra-hepatic portal hypertension. Postgrad Med J 1985; 61: 461-3. PubMed Citation  (Ergotamine abuse can lead to arteriospasm as well as venous complications; 48 year old woman developed hemiparesis after taking ergotamine 6 mg daily for 3 months which resolved on stopping, but she later presented with esophageal varices, believed to be due to splenic and portal vein thromboses).

  5. Deviere J, Reuse C, Askenasi R. Ischemic pancreatitis and hepatitis secondary to ergotamine poisoning. J Clin Gastroenterol 1987; 9: 350-2. PubMed Citation  (29 year old man with suicidal ergotamine overdose presented with hypotension, hypoxia and acidosis and then developed marked ALT [4200 U/L] and amylase [2940 U/L] elevations 2 to 3 days later, resolving rapidly without jaundice; compatible with ischemic injury).

  6. Block GA, Goldstein J, Polis A, Reines SA, Smith ME. Efficacy and safety of rizatriptan versus standard care during long-term treatment for migraine. Rizatriptan Multicenter Study Groups. Headache 1998; 38: 764-71. PubMed Citation  (Among 1831 patients treated for up to 12 months and experiencing 46,773 migraine attacks, pain relief was achieved in 2 hours in 80-90% on rizatriptan and 70% on standard care; side effects were similar and there were “no meaningful differences in the incidences of drug related laboratory adverse events”).

  7. O'Quinn S, Davis RL, Gutterman DL, Pait GD, Fox AW. Prospective large-scale study of the tolerability of subcutaneous sumatriptan injection for acute treatment of migraine. Cephalalgia 1999; 19: 223-31. PubMed Citation  (Among 12,339 patients in an open-label study of sumatriptan injections for migraine attacks, 4.1% had a serious adverse event, but only 20 [0.2%] were considered related to sumatriptan and none were hepatic).

  8. Heywood J, Bomhof MA, Pradalier A, Thaventhiran L, Winter P, Hassani H. Tolerability and efficacy of naratriptan tablets in the acute treatment of migraine attacks for 1 year. Naratriptan Long-Term Study Group. Cephalalgia 2000; 20: 470-4. PubMed Citation  (Among 417 patients with 15,301 migraine attacks in an open-label study of naratriptan, the most common side effects were nausea, salivation and drowsiness [2-3%] and no mention of hepatitis or liver related adverse events).

  9. 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 Citation  (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).

  10. 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 Citation  (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”).

  11. 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 Citation  (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).

  12. Jamieson DG. The safety of triptans in the treatment of patients with migraine. Am J Med 2002; 112: 135-40. PubMed Citation  (Review of the safety of triptans in migraine therapy focusing on vascular risk, stroke, myocardial infarction and ischemic bowel disease; no mention of hepatotoxicity).

  13. Redondo Cerezo E, Espinosa Aguilar MD, Nogueras López F, Martín-Vivaldi Martínez R. [Zolmitriptan-induced hepatotoxicity]. Gastroenterol Hepatol 2003; 26: 664. Spanish. PubMed Citation  (48 year old woman developed jaundice and itching one week after taking three doses of zolmitriptan for a severe bout of migraine [bilirubin 4.3 mg/dL, ALT 331 U/L, Alk P 530 U/L], resolving spontaneously and no rechallenge).

  14. Ashcroft DM, Millson D. Naratriptan for the treatment of acute migraine: meta-analysis of randomised controlled trials. Pharmacoepidemiol Drug Saf 2004; 13: 73-82. PubMed Citation  (Metaanalysis of 10 trials of naratriptan for acute migraine with 4499 participants found lower rates of adverse effects with naratriptan compared  to other triptans, but specifics of side effects were not provided; no mention of ALT elevations or liver injury).

  15. Deixler E, Helmke K. [Extrahepatic cholestasia during therapy with Zolmitriptan (AscoTop)]. Z Gastroenterol 2005; 43: 1045-9. German. PubMed Citation  (62 year old man developed recurrent, fluctuating jaundice and abdominal pain 6 months after starting zolmitriptan [3-4 times weekly] for migraine [bilirubin 7.8 mg/dL, ALT 690 U/L, Alk P 218 U/L], which recurred after cholecystectomy, but resolved within a month of stopping zolmitriptan: Case 1).

  16. Loj J, Solomon GD. Migraine prophylaxis: who, why, and how. Cleve Clin J Med 2006; 73: 793-4, 797, 800-1 passim. PubMed Citation  (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]).

  17. Chen LC, Ashcroft DM. Meta-analysis examining the efficacy and safety of almotriptan in the acute treatment of migraine. Headache 2007; 47: 1169-77. PubMed Citation  (Metaanalysis of 8 controled trials of almotriptan for acute migraine with 4995 participants; no mention of ALT elevations or hepatotoxicity).

  18. Chen LC, Ashcroft DM. Meta-analysis of the efficacy and safety of zolmitriptan in the acute treatment of migraine. Headache 2008; 48: 236-47. PubMed Citation  (Metaanalysis of 24 controled trials of almotriptan for acute migraine with 15,408 participants; no mention of ALT elevations or hepatotoxicity).

  19. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, none were attributed to agents used to treat migraine headaches).

  20. Whyte CA, Tepper SJ. Adverse effects of medications commonly used in the treatment of migraine. Expert Rev Neurother 2009; 9: 1379-91. PubMed Citation  (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”).

  21. Loder E. Triptan therapy in migraine. N Engl J Med 2010; 363: 63-70. PubMed Citation  (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).

  22. Taylor FR. Acute treatment of migraine headaches. Semin Neurol 2010; 30: 145-53. PubMed Citation  (Review of diagnosis and acute management of migraine headaches).

  23. Berenson F, Vasconcellos E, Pakalnis A, Mao L, Biondi DM, Armstrong RB.
    Long-term, open-label safety study of oral almotriptan 12.5 mg for the acute
    treatment of migraine in adolescents. Headache 2010; 50: 795-807. PubMed Citation  (Among 319 adolescents with migraine headache treated with almotriptan for 12 months, "minor changes (increases and decreases) in mean values for hematology, serum, chemistry and urinalysis parameters were observed, but there were no consistent trends").

  24. Drugs for migraine. Treat Guidel Med Lett 2011; 9: 7-12. PubMed Citation  (Concise review of current medications used for migraine; no discussion of hepatotoxicity).

  25. Fernandez-Atutxa A, Vergara M, Gil M, Dalmau B, Miquel M, Sanchez-Delgado J, Casas M. [Rizatriptan-induced liver toxicity. Report of a case]. Gastroenterol Hepatol 2013; 36: 261-3. Spanish. PubMed Citation   (17 year old girl with migraines developed jaundice [bilirubin 7.1 mg/dL, ALT 9729 U/L, Alk P normal] two weeks after taking a 10 mg tablet of rizatriptan).

  26. 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 Citation  (Among 176 reports of drug induced liver injury from Latin America published between 1996 and 2012, none were attributed to drugs for migraine headaches).

  27. 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: 1340-1352.e7. PubMed Citation  (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).

 

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