Nervenheilkunde 2018; 37(01/02): 60-67
DOI: 10.1055/s-0038-1642079
Kopfschmerz
Schattauer GmbH

Kopfschmerz bei Medikamentenübergebrauch

Primärer oder sekundärer Kopfschmerz?Medication overuse headachePrimary or secondary headache?
Z. Katsarava
1   Klinik Für Neurologie, Stiftung Evangelisches Krankenhaus Unna
,
S. Nägel
2   Neurologische Klinik und Westdeutsches Kopfschmerzzentrum, Universitätsklinikum Essen
› Author Affiliations
Further Information

Publication History

eingegangen am: 01 December 2017

angenommen am: 20 December 2017

Publication Date:
30 March 2018 (online)

Zusammenfassung

Es ist ein durch die Internationale Kopfschmerzgesellschaft akzeptierter Konsens,dass die häufige Einnahme von Akutmedikation zur Zunahme oder Chronifizierung von episodischen Kopfschmerzen führen kann.Dieser Kopfschmerz wird als Medikamentenübergebrauchskopfschmerz(MÜKS) bezeichnet.Definiert ist der MÜKS als ein Kopfschmerz,der an mindestens 15 Tagen pro Monat bei Patienten, die seit über 3 Monaten Akuttherapeutika im Übermaß einnehmen,auftritt. Die kritische Einnahmegrenze liegt für Triptane, Opioide und Kombinationsanalgetikabei 10 Tagen, für einfache Analgetikabei 15 Tagen pro Monat. Das Konzept fußt auf der Annahme, dass Menschen mit Migräne oder einem Kopfschmerz vom Spannungstyp ein besonders vulnerables trigeminalesSchmerzsystem haben, welches auf Schmerzmittelübergebrauchmit Sensitisierung der Schmerzverarbeitung und Chronifizierung des Kopfschmerzes reagiert. Der MÜKS wirddeswegen als sekundärer Kopfschmerz betrachtet.Das Mittel der Wahl zur Behandlungist nach aktueller Lehrmeinung eine Entzugsbehandlung.Diesem Konzept wird aber widersprochen.Die Gegner argumentieren,dass die häufige Schmerzmitteleinnahme lediglichbei einem Teil der Kopfschmerzpatientenzur Chronifizierung führt und man sich beidiesen nicht sicher sein kann, dass die Zunahme der Kopfschmerzfrequenz tatsächlich dieFolge des Schmerzmittelgebrauches ist, sondern,dass der übermäßige Schmerzmittelgebrauchdie Folge der häufigeren/chronifizierten Kopfschmerzen ist. Weiter wird argumentiert,die Verläufe würden sich nicht infolge derEntzugsbehandlung, sondern als Konsequenz einer multimodalen Therapie inklusive medikamentöser Prophylaxe und psychologischerund edukativer Betreuung bessern. Deswegensei der MÜKS keine eigene Entität. Durch dieDiagnose eines MÜKS stigmatisiere man dieBetroffenen, enthalte ihnen die nötigenSchmerzmedikamente vor und lasse sie unnötigleiden. In dieser Übersichtsarbeit beleuchtendie Autoren den aktuellen Stand der Literaturund stellen die Argumente für und gegenden MÜKS dar.

Summary

It is consented by the International Headache Society that the frequent intake of acute medicationcan induce an increase or chronification of preexisting episodic primary headache disorders. This headache type is called medication overuse headache (MOH). MOH is defined as a headache on more than 15 daysper month in patients who take too many acute medications for at least 3 months. The critical border for his intake is 10 days per month for triptans, opioids and combined analgesics and 15 days per month for simple analgesics. This concept is based on the assumptionthat patients with migraine or tension-type headache have a specifically vulnerable trigeminal pain system which responds to the overuse of analgesics with asensitisation of the pain processing and withchronification of headache. MOH is therefore regarded as a secondary headache. Treatment of choice is withdrawal therapy according to current guidelines. This is, however, often debated. Often, frequent intake of analgesics induces chronification only in a part of headache patients, and even in these patientsone cannot be sure that the increase of headache frequency really is the consequenceof the frequent analgesic intake; thefrequent intake of analgesics can more over be the consequence of frequent headache. Furthermore, the so-called withdrawal therapyis not the cause of improvement in theseheadache patients, but the multimodal therapy including medication prophylaxis and psychological and educational advice. Therefore, MOH is not a separate entity. Due to thediagnosis of MOH, patients undergo stigmatisation, they do not revceive necessarypain medication and suffer unnecessarily. Inthis review, the published literature is presented and the arguments pro and con MOH are discussed.

 
  • Literatur

  • 1 Peters GA, Horton BT. Headache: with special reference to the excessive use of ergotamine preparations and withdrawal effects. Proc Staff Meet Mayo Clin 1951; 26 (09) 153-61.
  • 2 Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Headache Classification Committee of the International Headache Society. Cephalalgia 1988; 08 Suppl (Suppl. 07) 1-96.
  • 3 Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004; 24 Suppl (Suppl. 01) 9-160.
  • 4 Olesen J, Bousser M-G, Diener H-C, Dodick D, First M, Goadsby PJ. et al. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia 2006; 26: 742-6.
  • 5 Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 2013; 33: 629-808.
  • 6 Scher AI, Rizzoli PB, Loder EW. Medication overuse headache: An entrenched idea in need of scrutiny. Neurology 2017; 89: 1296-304.
  • 7 Stovner LJ, Andree C. Prevalence of headache in Europe: a review for the Eurolight project. J Headache Pain 2010; 11: 289-99.
  • 8 Straube A, Pfaffenrath V, Ladwig KH, Meisinger C, Hoffmann W, Fendrich K. et al. Prevalence of chronic migraine and medication overuse headache in Germany—the German DMKG headache study. Cephalalgia 2010; 30: 207-213.
  • 9 Castillo J, Muñoz P, Guitera V, Pascual J. Epidemiology of Chronic Daily Headache in the General Population. Headache 1999; 39: 190-6.
  • 10 Colás R, Muñoz P, Temprano R, Gómez C, Pascual J. Chronic daily headache with analgesic overuse: epidemiology and impact on quality of life. Neurology 2004; 62: 1338-42.
  • 11 Park J-W, Moon H-S, Kim J-M, Lee K-S, Chu MK. Chronic daily headache in Korea: prevalence, clinical characteristics, medical consultation and management. J Clin Neurol 2014; 10: 236-43.
  • 12 Prencipe M, Casini AR, Ferretti C, Santini M, Pezzella F, Scaldaferri N. et al. Prevalence of headache in an elderly population: attack frequency, disability, and use of medication. J Neurol Neurosurg Psychiatry 2001; 70: 377-81.
  • 13 Lantéri-Minet M, Auray J-P, El Hasnaoui A, Dartigues J-F, Duru G, Henry P. et al. Prevalence and description of chronic daily headache in the general population in France. Pain 2003; 102: 143-9.
  • 14 Westergaard ML, Glümer C, Hansen EH, Jensen RH. Prevalence of chronic headache with and without medication overuse: associations with socioeconomic position and physical and mental health status. Pain 2014; 155: 2005-13.
  • 15 Katsarava Z, Schneeweiss S, Kurth T, Kroener U, Fritsche G, Eikermann A. et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004; 62: 788-90.
  • 16 Meskunas CA, Tepper SJ, Rapoport AM, Sheftell FD, Bigal ME. Medications Associated with Probable Medication Overuse Headache Reported in a Tertiary Care Headache Center Over a 15-Year Period. Headache 2006; 46: 766-72.
  • 17 Reuter U, Salomone S, Ickenstein GW, Waeber C. Effects of chronic sumatriptan and zolmitriptan treatment on 5-HT1 receptor expression and function in rats. Cephalalgia 2004; 24: 398-407.
  • 18 Tohyama Y, Yamane F, Fikre Merid M, Blier P, Diksic M. Effects of serotine receptors agonists, TFMPP and CGS12066B, on regional serotonin synthesis in the rat brain: an autoradiographic study. J Neurochem 2002; 80: 788-98.
  • 19 Dobson CF, Tohyama Y, Diksic M, Hamel E. Effects of acute or chronic administration of anti-migraine drugs sumatriptan and zolmitriptan on serotonin synthesis in the rat brain. Cephalalgia 2004; 24: 2-11.
  • 20 De Felice M, Ossipov MH, Wang R, Dussor G, Lai J, Meng ID. et al. Triptan-induced enhancement of neuronal nitric oxide synthase in trigeminal ganglion dural afferents underlies increased responsiveness to potential migraine triggers. Brain 2010; 133: 2475-88.
  • 21 Green AL, Gu P, De Felice M, Dodick D, Ossipov MH, Porreca F. Increased susceptibility to cortical spreading depression in an animal model of medication-overuse headache. Cephalalgia 2014; 34: 594-604.
  • 22 Srikiatkhachorn A, Anthony M. Platelet serotonin in patients with analgesic-induced headache. Cephalalgia 1996; 16: 423-6.
  • 23 Srikiatkhachorn A, Tarasub N, Govitrapong P. Effect of chronic analgesic exposure on the central serotonin system: a possible mechanism of analgesic abuse headache. Headache 2000; 40: 343-50.
  • 24 Srikiatkhachorn A, Anthony M. Serotonin receptor adaptation in patients with analgesic-induced headache. Cephalalgia 1996; 16: 419-22.
  • 25 Srikiatkhachorn A, Puangniyom S, Govitrapong P. Plasticity of 5-HT serotonin receptor in patients with analgesic-induced transformed migraine. Headache 1998; 38: 534-9.
  • 26 Rossi C, Pini LA, Cupini ML, Calabresi P, Sarchielli P. Endocannabinoids in platelets of chronic migraine patients and medication-overuse headache patients: relation with serotonin levels. Eur J Clin Pharmacol 2008; 64: 1-8.
  • 27 Cupini LM, Costa C, Sarchielli P, Bari M, Battista N, Eusebi P. et al. Degradation of endocannabinoids in chronic migraine and medication overuse headache. Neurobiol Dis 2008; 30: 186-9.
  • 28 Ayzenberg I, Obermann M, Nyhuis P, Gastpar M, Limmroth V, Diener HC. et al. Central sensitization of the trigeminal and somatic nociceptive systems in medication overuse headache mainly involves cerebral supraspinal structures. Cephalalgia 2006; 26: 1106-14.
  • 29 Ferraro D, Vollono C, Miliucci R, Virdis D, De Armas L, Pazzaglia C. et al. Habituation to pain in “medication overuse headache”: a CO2 laserevoked potential study. Headache 2012; 52: 792-807.
  • 30 Schmidt-Wilcke T, Leinisch E, Straube A, Kämpfe N, Draganski B, Diener HC. et al. Gray matter decrease in patients with chronic tension type headache. Neurology 2005; 65: 1483-6.
  • 31 Riederer F, Gantenbein AR, Marti M, Luechinger R, Kollias S, Sándor PS. Decrease of gray matter volume in the midbrain is associated with treatment response in medication-overuse headache: possible influence of orbitofrontal cortex. J Neurosci 2013; 33: 15343-9.
  • 32 Ferraro S, Grazzi L, Mandelli ML, Aquino D, Di Fiore D, Usai S. et al. Pain processing in medication overuse headache: a functional magnetic resonance imaging (fMRI) study. Pain Med 2012; 13: 255-62.
  • 33 Fumal A, Laureys S, Di Clemente L, Boly M, Bohotin V, Vandenheede M. et al. Orbitofrontal cortex involvement in chronic analgesic-overuse headache evolving from episodic migraine. Brain 2006; 129: 543-50.
  • 34 Di Lorenzo C, Coppola G, Currà A, Grieco G, Santorelli FM, Lepre C. et al. Cortical response to somatosensory stimulation in medication overuse headache patients is influenced by angiotensin converting enzyme (ACE) I/D genetic polymorphism. Cephalalgia 2012; 32: 1189-97.
  • 35 Di Lorenzo C, Di Lorenzo G, Sances G, Ghiotto N, Guaschino E, Grieco GS. et al. Drug consumption in medication overuse headache is influenced by brain-derived neurotrophic factor Val66Met polymorphism. J Headache Pain 2009; 10: 349-55.
  • 36 Cargnin S, Viana M, Ghiotto N, Bianchi M, Sances G, Tassorelli C. et al. Functional polymorphisms in COMT and SLC6A4 genes influence the prognosis of patients with medication overuse headache after withdrawal therapy. Eur J Neurol 2014; 21: 989-95.
  • 37 Zeeberg P, Olesen J, Jensen R. Probable medication-overuse headache: the effect of a 2-month drug-free period. Neurology 2006; 66: 1894-8.
  • 38 Bigal ME, Lipton RB. Excessive acute migraine medication use and migraine progression. Neurology 2008; 71: 1821-1828.
  • 39 Diener HC. And. Headache associated with chronic use of substances. In: Olesen J. (ed.) The headaches. 2nd ed.. New York: Williams & Wilkins; 1999: 871-878.
  • 40 Limmroth V, Katsarava Z, Fritsche G, Przywara S, Diener H-C. Features of medication overuse headache following overuse of different acute headache drugs. Neurology 2002; 59: 1011-4.
  • 41 Créac’h C, Radat F, Mick G, Guegan-Massardier E, Giraud P, Guy N. et al. One or several types of triptan overuse headaches?. Headache 2009; 49: 519-28.
  • 42 Hagen K, Vatten L, Stovner LJ, Zwart J-A, Krokstad S, Bovim G. Low socio-economic status is associated with increased risk of frequent headache: a prospective study of 22 718 adults in Norway. Cephalalgia 2002; 22: 672-9.
  • 43 Katsarava Z, Dzagnidze A, Kukava M, Mirvelashvili E, Djibuti M, Janelidze M. et al. Primary headache disorders in the Republic of Georgia: prevalence and risk factors. Neurology 2009; 73: 1796-803.
  • 44 Ayzenberg I, Katsarava Z, Sborowski A, Chernysh M, Osipova V, Tabeeva G. et al. The prevalence of primary headache disorders in Russia: a countrywide survey. Cephalalgia 2012; 32: 373-81.
  • 45 Kavuk I, Weimar C, Kim BT, Gueneyli G, Araz M. One-year prevalence and socio-cultural aspects of chronic headache in Turkish immigrants and German natives. Cephalalgia 2006; 26: 1177-1181.
  • 46 Ashina S, Serrano D, Lipton RB, Maizels M, Manack AN, Turkel CC. et al. Depression and risk of transformation of episodic to chronic migraine. J Headache Pain 2012; 13: 615-24.
  • 47 Sarchielli P, Corbelli I, Messina P, Cupini LM, Bernardi G, Bono G. et al. Psychopathological comorbidities in medication-overuse headache: a multicentre clinical study. Eur J Neurol 2016; 23: 85-91.
  • 48 da Silva Jr A, Costa EC, Gomes JB. Chronic headache and comorbibities: A two? phase, population-based, cross-sectional study. Headache 2010; 50: 1306-1312.
  • 49 Cevoli S, Sancisi E, Grimaldi D, Pierangeli G, Zanigni S, Nicodemo M. et al. Family history for chronic headache and drug overuse as a risk factor for headache chronification. Headache 2009; 49: 412-8.
  • 50 Hagen K, Linde M, Steiner TJ, Stovner LJ, Zwart J-A. Risk factors for medication-overuse headache: an 11-year follow-up study. The Nord-Trøndelag Health Studies. Pain 2012; 153: 56-61.
  • 51 Schramm SH, Moebus S, Lehmann N, Galli U, Obermann M, Bock E. et al. The association between stress and headache: A longitudinal population-based study. Cephalalgia 2015; 35: 853-863.
  • 52 Chai NC, Scher AI, Moghekar A, Bond DS, Peterlin BL. Obesity and headache: part I– a systematic review of the epidemiology of obesity and headache. Headache 2014; 54: 219-34.
  • 53 Hedenrud T, Babic N, Jonsson P. Medication overuse headache: Self-perceived and actual knowledge among pharmacy staff. Headache 2014; 54: 1019-1025.
  • 54 Rossi P, Di Lorenzo C, Faroni J, Cesarino F, Nappi G. Advice alone vs. structured detoxification programmes for medication overuse headache: a prospective, randomized, open-label trial in trans-formed migraine patients with low medical needs. Cephalalgia 2006; 26: 1097-105.
  • 55 Rossi P, Faroni JV, Tassorelli C, Nappi G. Advice alone versus structured detoxification programmes for complicated medication overuse headache (MOH): a prospective, randomized, open-label trial. J Headache Pain 2013; 14: 10.
  • 56 Diener HC, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ. TOPMAT-MIG-201 (TOP-CHROME) Study Group. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia 2007; 27: 814-23.
  • 57 Dodick DW, Turkel CC, DeGryse RE, Aurora SK, Silberstein SD, Lipton RB. et al. OnabotulinumtoxinA for Treatment of Chronic Migraine: Pooled Results From the Double-Blind, Randomized, Placebo-Controlled Phases of the PREEMPT Clinical Program. Headache 2010; 50: 921-36.
  • 58 Diener HC, Dodick DW, Aurora SK, Turkel CC, DeGryse RE, Lipton RB. et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 2 trial. Cephalalgia 2010; 30: 804-14.
  • 59 Aurora SK, Dodick DW, Turkel CC, DeGryse RE, Silberstein SD, Lipton RB. et al. OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial. Cephalalgia 2010; 30: 793-803.
  • 60 Grande RB, Aaseth K, Benth JŠ, Lundqvist C, Russell MB. Reduction in medication-overuse headache after short information. The Akershus study of chronic headache. Eur J Neurol 2011; 18: 129-37.
  • 61 Kristoffersen ES, Straand J, Vetvik KG, Benth JŠ, Russell MB, Lundqvist C. Brief intervention for medication-overuse headache in primary care. The BIMOH study: a double-blind pragmatic cluster randomised parallel controlled trial. J Neurol Neurosurg Psychiatry 2015; 86: 505-12.
  • 62 Krause SJ, Stillman MJ, Tepper DE, Zajac D. A prospective cohort study of outpatient interdisciplinary rehabilitation of chronic headache patients. Headache 2017; 57: 428-40.
  • 63 Katsarava Z, Fritsche G, Muessig M, Diener HC, Limmroth V. Clinical features of withdrawal headache following overuse of triptans and other headache drugs. Neurology 2001; 57: 1694-8.
  • 64 Diener HC, Limmroth V. Medication-overuse headache: a worldwide problem. Lancet Neurol 2004; 03: 475-483.
  • 65 Mathew NT. Amelioration of ergotamine withdrawal symptoms with naproxen. Headache 1987; 27: 130-3.
  • 66 Diener HC, Evers S, Fritsche G. Kopfschmerz bei Übergebrauch von Schmerz-und Migränemitteln. Leitlinien für Diagnostik und Therapie in der Neurologie Herausgegeben von der Kommission “Leitlinien “der Deutschen Gesellschaft für Neurologie. Stuttgart: Thieme; 2012: 731-8.
  • 67 Gaul C, van Doorn C, Webering N, Dlugaj M, Katsarava Z, Diener H-C. et al. Clinical outcome of a headache-specific multidisciplinary treatment program and adherence to treatment recommendations in a tertiary headache center: an observational study. J Headache Pain 2011; 12: 475-83.
  • 68 Suhr B, Evers S, Bauer B, Gralow I, Grotemeyer KH, Husstedt IW. Drug-induced headache: longterm results of stationary versus ambulatory withdrawal therapy. Cephalalgia 1999; 19: 44-9.
  • 69 Tassorelli C, Jensen R, Allena M, De Icco R, Sances G, Katsarava Z. et al. A consensus protocol for the management of medication-overuse headache: Evaluation in a multicentric, multinational study. Cephalalgia 2014; 34: 645-55.
  • 70 Bøe MG, Mygland A, Salvesen R. Prednisolone does not reduce withdrawal headache: a randomized, double-blind study. Neurology 2007; 69: 26-31.
  • 71 Rabe K, Pageler L, Gaul C, Lampl C, Kraya T, Foerderreuther S. et al. Prednisone for the treatment of withdrawal headache in patients with medication overuse headache: a randomized, double-blind, placebo-controlled study. Cephalalgia 2013; 33: 202-7.
  • 72 Chiang C-C, Schwedt TJ, Wang S-J, Dodick DW. Treatment of medication-overuse headache: A systematic review. Cephalalgia 2016; 36: 371-86.
  • 73 Baumgartner C, Wessely P, Bingöl C, Maly J, Holzner F. Longterm prognosis of analgesic withdrawal in patients with drug-induced headaches. Headache 1989; 29: 510-4.
  • 74 Diener HC, Dichgans J, Scholz E, Geiselhart S, Gerber WD, Bille A. Analgesic-induced chronic headache: long-term results of withdrawal therapy. J Neurol 1989; 236: 9-14.
  • 75 Schnider P, Aull S, Baumgartner C, Marterer A, Wöber C, Zeiler K. et al. Long-term outcome of patients with headache and drug abuse after inpatient withdrawal: five-year follow-up. Cephalalgia 1996; 16: 481-5.
  • 76 Grazzi L, Andrasik F, D’Amico D, Leone M, Usai S, Kass SJ. et al. Behavioral and pharmacologic treatment of transformed migraine with analgesic overuse: outcome at 3 years. Headache 2002; 42: 483-90.
  • 77 Williams DR, Stark RJ. Intravenous lignocaine (lidocaine) infusion for the treatment of chronic daily headache with substantial medication overuse. Cephalalgia 2003; 23: 963-71.
  • 78 Zidverc-Trajkovic J, Pekmezovic T, Jovanovic Z, Pavlovic A, Mijajlovic M, Radojicic A. et al. Medication overuse headache: clinical features predicting treatment outcome at 1-year follow-up. Cephalalgia 2007; 27: 1219-25.
  • 79 Evers S, Suhr B, Bauer B, Grotemeyer KH, Husstedt IW. A retrospective long-term analysis of the epidemiology and features of drug-induced headache. J Neurol 1999; 246: 802-9.
  • 80 Pini LA, Cicero AF, Sandrini M. Long-term follow-up of patients treated for chronic headache with analgesic overuse. Cephalalgia 2001; 21: 878-83.
  • 81 Fritsche G, Eberl A, Katsarava Z, Limmroth V, Diener HC. Drug-induced headache: long-term follow-up of withdrawal therapy and persistence of drug misuse. Eur Neurol 2001; 45: 229-35.
  • 82 Tribl GG, Schnider P, Wöber C, Aull S, Auterith A, Zeiler K. et al. Are there predictive factors for long-term outcome after withdrawal in drug-induced chronic daily headache?. Cephalalgia 2001; 21: 691-6.
  • 83 Tfelt-Hansen P, Krabbe A. Ergotamine abuse. Do patients benefit from withdrawal? Cephalalgia 1981; 01: 29-32.
  • 84 Katsarava Z, Manack A, Yoon M-S, Obermann M, Becker H, Dommes P. et al. Chronic migraine: classification and comparisons. Cephalalgia 2011; 31: 520-9.
  • 85 Diener HC. Headache associated with chronic use of substances. In: Olesen J. (ed) The headaches. Boston: Raven Press; 1993: 721-727.
  • 86 Buse DC, Silberstein SD, Manack AN, Papapetropoulos S, Lipton RB. Psychiatric comorbidities of episodic and chronic migraine. J Neurol 2013; 260: 1960-9.
  • 87 Lampl C, Thomas H, Tassorelli C, Katsarava Z, Laínez JM, Lantéri-Minet M. et al. Headache, depression and anxiety: associations in the Eurolight project. J Headache Pain 2016; 17: 59.
  • 88 Scher AI, Lipton RB, Stewart WF, Bigal M. Patterns of medication use by chronic and episodic headache sufferers in the general population: results from the frequent headache epidemiology study. Cephalalgia 2010; 30: 321-8.
  • 89 Schramm SH, Moebus S, Özyurt MKugumcu, Geisel MH, Obermann M, Yoon M-S. et al. Use of aspirin combinations with caffeine and increasing headache frequency: a prospective populationbased study. Pain 2015; 156: 1747-54.
  • 90 Silberstein SD, Dodick DW, Bigal ME, Yeung PP, Goadsby PJ, Blankenbiller T. et al. Fremanezumab for the preventive treatment of chronic migraine. N Engl J Med 2017; 377: 2113-22.