Dihydroergotamine (DHE) – Is there a place for its use?
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Medical University of Warsaw, Poland
J Pre Clin Clin Res. 2018;12(4):149–157
Nowadays, dihydroergotamine (DHE) is sporadically used as a vasoconstrictor in the treatment of acute migraine. The importance of this drug in medicine has significantly decreased in the recent years. Limitations on the use of dihydroergotamine are due to the high toxicity and increased the risk of severe adverse events after prolonged theraphy. The Committee for Medicinal Products for Human Use of the European Medicines Agency recommends limiting the use of drugs that contain ergotamine derivatives due to the potential risk of ischemic vascular events, fibrosis and ergotism. However, ergot alcaloids preparations are not recommended for use in the prophylaxis of migraine pain, although it is still a good alternative for people with status migrainosus, migraine recurrence or chronic daily headache that do not respond to the classical theraphy. In clinical practice, DHE can be used as a rescue medication to treat migraine attacks involving aura or without aura, as well as for the acute treatment of cluster headache episodes. The effectiveness of DHE in alleviating migraine headache was assessed in multiple clinical studies. This review describes the pharmacodynamic and pharmacokinetic properties of DHE in an expanded view and its role in modern therapy based on available clinical trials. Most clinical data confirm that the drug is still an important element of contemporary migraine therapy, especially in cases when conventional medicine fails.

Kamilla Blecharz-Klin   
Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland
1. Morren JA, Galvez-Jimenez N. Where is dihydroergotamine mesylate in the changing landscape of migraine therapy? Expert Opin Pharmacother. 2010; 11(18): 3085–93.
2. Becker WJ. Cluster headache: conventional pharmacological management. Headache. 2013; 53(7): 1191–6.
3. Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the american headache society evidence assessment of migraine pharmacotherapies. Headache. 2015; 55(1): 3–20.
4. Müller-Schweinitzer E. Alpha-adrenoceptors, 5-hydroxytryptamine receptors and the action of dihydroergotamine in human venous preparations obtained during saphenectomy procedures for varicose veins. Naunyn Schmiedebergs Arch Pharmacol. 1984; 327(4): 299–303.
5. Lesage AS, Wouters R, Van Gompel P, Heylen L, Vanhoenacker P, Haegeman G, Luyten WH, Leysen JE. Agonistic properties of alniditan, sumatriptan and dihydroergotamine on human 5-HT1B and 5-HT1D receptors expressed in various mammalian cell lines. Br J Pharmacol. 1998; 123(8): 1655–65.
6. Hanoun N, Saurini F, Lanfumey L, Hamon M, Bourgoin S. Dihydroergotamine and its metabolite, 8’-hydroxy-dihydroergotamine, as 5-HT1A receptor agonists in the rat brain. Br J Pharmacol. 2003; 139(2): 424–34.
7. Schaerlinger B, Hickel P, Etienne N, Guesnier L, Maroteaux L. Agonist actions of dihydroergotamine at 5-HT2B and 5-HT2C receptors and their possible relevance to antimigraine efficacy. Br J Pharmacol. 2003; 140(2): 277–84.
8. Dahlöf C, Maassen Van Den Brink A. Dihydroergotamine, ergotamine, methysergide and sumatriptan – basic science in relation to migraine treatment. Headache. 2012; 52(4): 707–14.
9. Masterson CG, Durham PL. DHE repression of ATP-mediated sensitization of trigeminal ganglion neurons. Headache. 2010; 50(9): 1424–39.
10. Silberstein SD, McCrory DC. Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache. 2003; 43(2): 144–66.
11. Kelley NE, Tepper DE. Rescue therapy for acute migraine, part 1: triptans, dihydroergotamine, and magnesium. Headache. 2012; 52(1): 114–28.
12. Suzuki K, Aimi T, Ishihara T, Mizushima T. Identification of approved drugs that inhibit the binding of amyloid β oligomers to ephrin type-B receptor 2. FEBS Open Bio. 2016; 6(5): 461–8.
13. Silberstein SD, Kori SH. Dihydroergotamine: a review of formulation approaches for the acute treatment of migraine.CNS Drugs. 2013; 27(5): 385–94.
14. Little PJ, Jennings GL, Skews H, Bobik A. Bioavailability of dihydroergotamine in man. Br J Clin Pharmacol. 1982; 13(6): 785–90.
15. Barthel W. [Venous tonus-modifying effect, pharmacokinetics and undesired effects of dihydroergotamine]. Z Gesamte Inn Med. 1984; 39(17): 417–28.
16. van der Kuy PH, Lohman JJ, Hooymans PM, Ter Berg JW, Merkus FW. Bioavailability of intranasal formulations of dihydroergotamine. Eur J Clin Pharmacol. 1999; 55(9): 677–80.
17. Saper JR, Silberstein S. Pharmacology of dihydroergotamine and evidence for efficacy and safety in migraine. Headache. 2006; 46 Suppl 4: S171–81.
18. Shrewsbury SB, Kori SH, Miller SD, Pedinoff A, Weinstein S. Randomized, double-blind, placebo-controlled study of the safety, tolerability and pharmacokinetics of MAP0004 (orally-inhaled DHE) in adult asthmatics. Curr Med Res Opin. 2008; 24(7): 1977–85.
19. Cook RO, Shrewsbury SB, Ramadan NM. Reduced adverse event profile of orally inhaled DHE (MAP0004) vs IV DHE: potential mechanism. Headache. 2009; 49(10): 1423–34.
20. Silberstein S. MAP0004: dihydroergotamine mesylate inhalation aerosol for acute treatment of migraine. Expert Opin Pharmacother. 2012; 13(13): 1961–8.
21. Wyss PA, Rosenthaler J, Nüesch E, Aellig WH. Pharmacokinetic investigation of oral and i.v. dihydroergotamine in healthy subjects. Eur J Clin Pharmacol. 1991; 41(6): 597–602.
22. Aellig WH. Investigation of the venoconstrictor effect of 8’ hydroxydihydroergotamine, the main metabolite of dihydroergotamine, in man. Eur J Clin Pharmacol. 1984; 26(2): 239–42.
23. Buck M. Intravenous Dihydroergotamine (DHE) for the Treatment of Refractory Migraines. Pediatric Pharmacotherapy. 2007; 13(7): 1–4.
24. Pradalier A, Lantéri-Minet M, Géraud G, Allain H, Lucas C, Delgado A. The PROMISE study: PROphylaxis of MIgraine with SEglor (dihydroergotamine mesilate) in French primary care. CNS Drugs. 2004; 18(15): 1149–63.
25. Hämäläinen ML, Hoppu K, Santavuori PR. Oral dihydroergotamine for therapy-resistant migraine attacks in children. Pediatr Neurol. 1997; 16(2): 114–7.
26. Patniyot IR, Gelfand AA. Acute Treatment Therapies for Pediatric Migraine: A Qualitative Systematic Review. Headache. 2016; 56(1): 49–70.
27. Ford RG, Ford KT. Continuous intravenous dihydroergotamine in the treatment of intractable headache. Headache. 1997; 37(3): 129–36.
28. Magnoux E, Zlotnik G. Outpatient intravenous dihydroergotamine for refractory cluster headache. Headache. 2004; 44(3): 249–55.
29. Kabbouche MA, Powers SW, Segers A, LeCates S, Manning P, Biederman S, Vaughan P, Burdine D, Hershey AD. Inpatient treatment of status migraine with dihydroergotamine in children and adolescents. Headache. 2009; 49(1): 106–9.
30. Charles JA, von Dohln P. Outpatient home-based continuous intravenous dihydroergotamine therapy for intractable migraine. Headache. 2010; 50(5): 852–60.
31. Tepper SJ. Orally inhaled dihydroergotamine: a review. Headache. 2013; 53 Suppl 2: 43–53.
32. Mathew PG, Krel R, Buddhdev B, Ansari H, Joshi SG, Spinner WD, Klein BC. A retrospective analysis of triptan and dhe use for basilar and hemiplegic migraine. Headache. 2016 Apr 8. doi: 10.1111/head.12804. [Epub ahead of print].
33. El-Chammas K, Keyes J, Thompson N, Vijayakumar J, Becher D, Jackson JL. Pharmacologic treatment of pediatric headaches: a meta-analysis. JAMA Pediatr. 2013; 167(3): 250–8.
34. Silver S, Gano D, Gerretsen P. Acute treatment of paediatric migraine: a meta-analysis of efficacy. J Paediatr Child Health. 2008; 44(1–2): 3–9.
35. Whyte CA, Stillman MJ, Tepper SJ. Dihydroergotamine and its use in migraine with posterior fossa symptoms. Headache. 2010; 50(9): 1419–23.
36. Tfelt-Hansen PC. Relatively slow and long-lasting antimigraine effect of dihydroergotamine is most likely due to basic pharmacological attributes of the drug: a review. Cephalalgia. 2013; 33(13): 1122–31.
37. Mayans L, Walling A. Acute Migraine Headache: Treatment Strategies. Am Fam Physician. 2018; 97(4): 243–251.
38. Colman I, Brown MD, Innes GD, Grafstein E, Roberts TE, Rowe BH. Parenteral dihydroergotamine for acute migraine headache: a systematic review of the literature. Ann Emerg Med. 2005; 45(4): 393–401.
39. EMA. Overall summary of the scientific evaluation of dihydroergotamine containing medicinal products (Annex I, II) http: // Library/Referrals_document/Ergot_derivatives-containing_products.
40. Bérard A, Kori S. Dihydroergotamine (DHE) use during gestation and the risk of adverse pregnancy outcomes. Headache. 2012; 52(7): 1085–93.
41. Wang H, Looper ML, Johnson ZB, Rorie RW, Rosenkrans CF Jr. Involvement of signaling pathways in bovine sperm motility, and effect of ergot alkaloids. In Vitro Cell Dev Biol Anim. 2009; 45(8): 483–9.
42. Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A, Sándor PS; European Federation of Neurological Societies. EFNS guideline on the drug treatment of migraine--revised report of an EFNS task force. Eur J Neurol. 2009; 16(9): 968–81.
43. Pradalier A, Lutz G, Vincent D. Transient global amnesia, migraine, thalamic infarct, dihydroergotamine, and sumatriptan. Headache. 2000; 40(4): 324–7.
44. Bachner EJ1, Konsens RM, Priem L, King T, Froimson AI. Reversible vasospasm in association with the use of heparin and dihydroergotamine. Clin Orthop Relat Res. 1992; (283): 261–4.
45. Padon A, Ostadian M, Wright C, Pohl J, Crisp D, Easley D. Dihydroergotamine-associated intestinal ischemia in a child with cyclic vomiting syndrome. J Pediatr Gastroenterol Nutr. 2006; 42(5): 573–5.
46. Kelley BJ, Samples S, Kunkel R. PRES following administration of DHE in a patient with unsuspected pheochromocytoma. Headache. 2008; 48(8): 1237–9.
47. Tfelt-Hansen PC, Diener HC. Use of dihydroergotamine (DHE) should be restricted to no more than twice a week. Headache. 2014; 54(9): 1523–5.
48. Kori S, Kellerman DJ, Voloshko P, Haugen G. Effects of a supratherapeutic dose of investigational orally inhaled dihydroergotamine (MAP0004) on QT interval: a randomized, double-blind, active- and placebo-controlled crossover study in healthy volunteers. Clin Ther. 2012; 34(9): 1920–8.
49. Beau-Salinas F, Jonville-Béra AP, Cissoko H, Bensouda-Grimaldi L, Autret-Leca E. Drug dependence associated with triptans and ergot derivatives: a case/non-case study. Eur J Clin Pharmacol. 2010; 66(4): 413–7.
50. Kozma CM, Reeder CE. Comparison of the economic, clinical, and humanistic attributes of dihydroergotamine and sumatriptan. Clin Ther. 1995; 17(2): 315–9.
51. Orr SL, Aubé M, Becker WJ, Davenport WJ, Dilli E, Dodick D, Giammarco R, Gladstone J, Leroux E, Pim H, Dickinson G, Christie SN. Canadian Headache Society systematic review and recommendations on the treatment of migraine pain in emergency settings. Cephalalgia. 2015; 35(3): 271–84.
52. Payne K, Kozma CM, Lawrence BJ. Comparing dihydroergotamine mesylate and sumatriptan in the management of acute migraine. A retrospective cost-efficacy analysis. Pharmacoeconomics. 1996; 10(1): 59–71.
53. 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): 1079–82.
54. Queiroz LP, Weeks RE, Rapoport AM, Sheftell FD, Baskin SM, Siegel SE. Early and transient side effects of repetitive intravenous dihydroergotamine. Headache. 1996; 36(5): 291–4.
55. Nagy AJ, Gandhi S, Bhola R, Goadsby PJ. Intravenous dihydroergotamine for inpatient management of refractory primary headaches. Neurology. 2011; 77(20): 1827–32.
56. Raina M, Chelimsky G, Chelimsky T. Intravenous dihydroergotamine therapy for pediatric abdominal migraines. Clin Pediatr (Phila). 2013; 52(10): 918–21.
57. Lambru G, Shanahan P, Matharu M. Exacerbation of SUNCT and SUNA syndromes during intravenous dihydroergotamine treatment: A case series. Cephalalgia. 2015; 35(12): 1115–24.
58. Eller M, Gelfand AA, Riggins NY, Shiboski S, Schankin C, Goadsby PJ. Exacerbation of headache during dihydroergotamine for chronic migraine does not alter outcome. Neurology. 2016; 86(9): 856–9.
59. Nelson GR, Bale JF, Kerr LM. Outcome and Cost of Inpatient Hospitalization for Intravenous Dihydroergotamine Treatment of Refractory Pediatric Headache. Pediatr Neurol. 2017; 66: 76–81.
60. Aurora SK, Rozen TD, Kori SH, Shrewsbury SB. A randomized, double blind, placebo-controlled study of MAP0004 in adult patients with migraine. Headache. 2009; 49(6): 826–37.
61. Aurora SK, Silberstein SD, Kori SH, Tepper SJ, Borland SW, Wang M, Dodick DW. MAP0004, orally inhaled DHE: a randomized, controlled study in the acute treatment of migraine. Headache. 2011; 51(4): 507–17.
62. Tepper SJ, Kori SH, Borland SW, Wang MH, Hu B, Mathew NT, Silberstein SD. Efficacy and safety of MAP0004, orally inhaled DHE in treating migraines with and without allodynia. Headache. 2012; 52(1): 37–47.
63. Winner P, Ricalde O, Le Force B, Saper J, Margul B. A double-blind study of subcutaneous dihydroergotamine vs subcutaneous sumatriptan in the treatment of acute migraine. Arch Neurol. 1996; 53(2): 180–4.
64. Saadah HA. Abortive headache therapy with intramuscular dihydroergotamine. Headache. 1992; 32(1): 18–20.
65. Silberstein SD, Young WB, Hopkins MM, Gebeline-Myers C, Bradley KC. Dihydroergotamine for early and late treatment of migraine with cutaneous allodynia: an open-label pilot trial. Headache. 2007; 47(6): 878–85.
66. Andersson PG, Jespersen LT. Dihydroergotamine nasal spray in the treatment of attacks of cluster headache. A double-blind trial versus placebo. Cephalalgia. 1986; 6(1): 51–4.
67. Tulunay FC, Karan O, Aydin N, Culcuoglu A, Guvener A. Dihydroergotamine nasal spray during migraine attacks. A double-blind crossover study with placebo. Cephalalgia. 1987; 7(2): 131–3.
68. Jenzer G, Bremgartner MF. [Dihydroergotamine as a nasal spray in the therapy of migraine attacks. Efficacy and tolerance]. Schweiz Rundsch Med Prax. 1990; 79(31–32): 914–7.
69. Ziegler D, Ford R, Kriegler J, Gallagher RM, Peroutka S, Hammerstad J, Saper J, Hoffert M, Vogel B, Holtz N, et al. Dihydroergotamine nasal spray for the acute treatment of migraine. Neurology. 1994; 44(3 Pt 1): 447–53.
70. Touchon J, Bertin L, Pilgrim AJ, Ashford E, Bès A. A comparison of subcutaneous sumatriptan and dihydroergotamine nasal spray in the acute treatment of migraine. Neurology. 1996; 47(2): 361–5.
71. Treves TA, Kuritzky A, Hering R, Korczyn AD. Dihydroergotamine nasal spray in the treatment of acute migraine. Headache. 1998; 38(8): 614–7.
72. Boureau F, Kappos L, Schoenen J, Esperanca P, Ashford E. A clinical comparison of sumatriptan nasal spray and dihydroergotamine nasal spray in the acute treatment of migraine. Int J Clin Pract. 2000; 54(5): 281–6.
73. Weintraub J. Repetitive dihydroergotamine nasal spray for treatment of refractory headaches: an open-label pilot study. Curr Med Res Opin. 2006; 22(10): 2031–6.
74. Fisher M, Gosy EJ, Heary B, Shaw D. Dihydroergotamine nasal spray for relief of refractory headache: a retrospective chart review. Curr Med Res Opin. 2007; 23(4): 751–5.
75. Saadah HA. Abortive headache therapy in the office with intravenous dihydroergotamine plus prochlorperazine. Headache. 1992; 32(3): 143–6.
76. Belgrade MJ, Ling LJ, Schleevogt MB, Ettinger MG, Ruiz E. Comparison of single-dose meperidine, butorphanol, and dihydroergotamine in the treatment of vascular headache. Neurology. 1989; 39(4): 590–2.
77. Klapper JA, Stanton JS. Ketorolac versus DHE and metoclopramide in the treatment of migraine headaches. Headache. 1991; 31(8): 523–4.
78. Klapper JA, Stanton JS. The emergency treatment of acute migraine headache: a comparison of intravenous dihydroergotamine, dexamethasone, and placebo. Cephalalgia. 1991; 11: 159–160.
79. Haugh MJ, Lavender L, Jensen A, Giuliano R. An office-based double-blind comparison of dihydroergotamine vs dihydroergotamine/metoclopramide in the treatment of acute migraine. Headache. 1992; 32: 251.
80. Klapper JA, Stanton J. Current emergency treatment of severe migraine headaches. Headache. 1993; 33(10): 560–2.
81. Linder SL.Treatment of childhood headache with dihydroergotamine mesylate. Headache. 1994; 34(10): 578–80.
82. Winner P, Dalessio D, Mathew N, Sadowsky C, Turkewitz LJ, Sheftell F, Silberstein SD, Solomon S. Concomitant administration of antiemetics is not necessary with intramuscular dihydroergotamine. Am J Emerg Med. 1994; 12(2): 138–41.
83. Scherl ER, Wilson JF. Comparison of dihydroergotamine with metoclopramide versus meperidine with promethazine in the treatment of acute migraine. Headache. 1995; 35(5): 256–9.
84. Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus intramuscular dihydroergotamine and metoclopramide for acute treatment of migraine headache. Headache. 2001; 41(10): 976–80.
85. Callaham M, Raskin N. A controlled study of dihydroergotamine in the treatment of acute migraine headache. Headache. 1986; 26(4): 168–71.
86. González-Espinosa LE, Gómez-Viera N, Olivera-Leal I, Reyes-Lorente R. [Treatment of acute attack of migraine with sumatriptan]. Rev Neurol. 1997; 25(147): 1672–5.
87. Hoffman L, Mayzell G, Pedan A, Farrell M, Gilbert T. Evaluation of a monthly coverage maximum (drug-specific quantity limit) on the 5-HT1 agonists (triptans) and dihydroergotamine nasal spray. J Manag Care Pharm. 2003; 9(4): 335–45.
88. Carleton SC, Shesser RF, Pietrzak MP, Chudnofsky CR, Starkman S, Morris DL, Johnson G, Rhee KJ, Barton CW, Chelly JE, Rosenberg J, Van Valen MK. Double-blind, multicenter trial to compare the efficacy of intramuscular dihydroergotamine plus hydroxyzine versus intramuscular meperidine plus hydroxyzine for the emergency department treatment of acute migraine headache. Ann Emerg Med. 1998; 32(2): 129–38.
89. Charles JA, Jotkowitz S. Observations of the “carry-over effect” following successful termination of chronic migraine in the adolescent with short-term dihydroergotamine, dexamethasone and hydroxyzine: a pilot study. J Headache Pain. 2005; 6(1): 51–4.
90. Hoernecke R, Doenicke A. [Treatment of migraine attacks: combination of dihydroergotamine tartrate and paracetamol in comparison with individual drugs and placebo]. Med Klin (Munich). 1993; 88(11): 642–8.
91. Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus intramuscular dihydroergotamine and metoclopramide for acute treatmentof migraine headache. Headache. 2001; 41(10): 976–80.