SciELO - Scientific Electronic Library Online

vol.13 issue3Transcutaneous electrical nerve stimulation for temporomandibular joint dysfunctionDepressive disorder and fibromyalgia: association to early life stress. Case report author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand




Related links


Revista Dor

Print version ISSN 1806-0013

Rev. dor vol.13 no.3 São Paulo July/Sept. 2012 



Methysergide to prevent migraine and cluster headache and the possibility of retroperitoneal fibrosis. Case reports*



Daniela Lino MacedoI; Priscila Amorim SoaresII; Denise da Silva FreitasIII; Ariovaldo Alberto da Silva JuniorIV; Rodrigo Santiago GomezV; Antonio Lucio TeixeiraVI

INeurologist by the Federal University of Minas Gerais (UFMG); Resident (R4) of Neurophysiology, University of São Paulo, Ribeirão Preto. Ribeirão Preto, SP, Brazil
IIResident in Neurology, Clinicas Hospital, Federal University of Minas Gerais (UFMG). Belo Horizonte, MG, Brazil
IIINeurologist and Fellow in Neuromuscular and Electroneuromyography, Federal University of Minas Gerais (UFMG). Belo Horizonte, MG, Brazil
IVNeurologist; Master in Neurology, Federal Fluminense University and Doctor in Neurosciences, Federal University of Minas Gerais (UFMG). Belo Horizonte, MG, Brazil
VNeurologist and Preceptor of Neurology Medical Residence, Federal University of Minas Gerais (UFMG). Belo Horizonte, MG, Brazil
VINeurologist and Psychiatrist; Associate Professor and Preceptor of Neurology Medical Residence, Clinicas Hospital, Federal University of Minas Gerais (UFMG). Belo Horizonte, MG, Brazil

Correspondence to




BACKGROUND AND OBJECTIVES: Methysergide is a drug with proven efficacy to prevent both migraine and cluster headache, although it may predispose to fibrosis (< 1%). This study aimed at reporting two cases of primary and difficult to control headache, satisfactorily treated with methysergide, which had to be withdrawn due to suspicion of retroperitoneal fibrosis (RF).
CASE REPORTS: Methysergide was successfully used to prevent migraine and cluster headache in a 69-year old male and in a 58-year old female, respectively, both refractory to first and second line drugs. After 24 months for the first case, and 30 months for the second case, of continuous methysergide, signs and symptoms suggesting RF were observed, such as asymmetric painless lower limbs edema in the migraine patient, and abdominal pain, sexual dysfunction and lower limbs edema in the cluster headache patient. In spite of the early negative screening for retroperitoneal edema made with normal abdominal ultrasound and CT, in the second, since signs and symptoms were progressing, we decided for methysergide withdrawal and decrease, respectively. There has been total resolution of symptoms approximately one week after such approach.
CONCLUSION: Methysergide is a good option for refractory cases, but should be used with caution. Withdrawing the drug every six months for approximately 4 to 8 weeks decreases the incidence of RF, in addition to clinical observation of signs and symptoms suggesting this side-effect.

Keywords: Cluster headache, Headache, Retroperitoneal fibrosis.




Chronic migraine affects approximately 2% of the world population1. It impairs patients' quality of life (QL) and results in major losses for society. In the United States, direct and indirect migraine costs are estimated in more than 20 billion dollars per year2.

Diagnostic criteria for chronic migraine, reviewed in 2006 are3: a) headache more than once or twice a month, for at least three months; b) patient has at least five headache attacks meeting the criteria of migraine without aura;  c) headache eight or more days per month for at least three months meeting c1 and/or c2 criteria, such as: c1a) headache with at least two of the following characteristics: unilateral, pulsatile, severe to moderate, triggered or worsened by routine activities; c1b) at least one characteristic during pain crisis: nausea and/or vomiting photophobia and phonophobia; c2) treated or relieved by triptans or ergot before the onset of migraine-related symptoms; and d) no drug abuse and headache not attributed to other causes.

Treatment of both chronic and episodic migraine may be divided into abortive (in the acute phase) and preventive (as prophylaxis). According to the Consensus of the Brazilian Headache Society4 and to the Guidelines of the American Consortium for Headache5, preventive migraine treatment is indicated in the following circumstances: recurrent migraine interfering with patients' routine in spite of treatment during the acute phase; frequent pain crises; contraindication, failure, poor tolerance or abuse of abortive drugs; special migraine subtypes (hemiplegic, basilar, with prolonged aura, with frequent and atypical aura and migrainous infarction).

Drugs for migraine prevention are6: a) first line: betablockers (atenolol and propanolol), tricyclic antidepressants (amitriptyline and nortriptyline) and calcium channel blockers (flunarizine); b) second line: antiepileptics (valproic acid and topiramate); c) third line: methysergide and pizotifen and d) fourth line: chlorpromazine and quetiapine.

Another chronic headache of major clinical importance due to its high morbidity is cluster headache. It is considered so disabling that some patients even attempt to commit suicide if the disease is not effectively managed7. Similar to migraine, this is a primary headache, however of short duration and associated to autonomic activation. According to the Headache Classification Subcommittee of the International Headache Society, cluster headache diagnostic criteria are8: a) at least five attacks meeting criteria from b to d; b) severe unilateral, orbital supraorbital and/or temporal pain lasting from 15 to 180 minutes if not treated; c) presence of at least one autonomic symptom at pain site: conjunctival injection, tearing, nasal congestion, rhinorrhea, ptosis, eyelid edema, miosis or forehead sweating; and d) frequency from one episode in alternate days to eight episodes per day. In its chronic form, attacks occur for more than one year without remission or with a remission period shorter than 14 days.

Episodic and chronic cluster headaches are similarly treated. Subcutaneous sumatriptan and inhalational oxygen are first line treatment for cluster headache. Other drugs with some evidence of efficacy are ergot, lidocaine and octretide7,9. The prophylactic treatment should start as early as possible, since patients have typically one to eight daily pain attacks and repeated abortive drugs could imply toxicity. Verapamil is the preventive treatment of choice for cluster headaches. Other effective options are glucocorticoids, lithium, topiramate and methysergide7,9.

So, methysergide (1-methyllysergic acid butanolamide) is a drug used to prevent both migraine and cluster headaches.

This is a semi-synthetic ergot alkaloid similar in structure to methylergonovine. It is 5HT2 receptor antagonist and agonist of some 5HT1 sub-types (5TH10 present in blood and cranial vessels; 5HT1D present in trigeminal nerve terminations)10-12. Methysergide acts both directly and through its active metabolite, methylergonovine or methylergometrine, which is probably the substance responsible for its prolonged anti-migraine effect. Its oral bioavailability is approximately 13% as a function of its fast conversion to methylergometrine. Methysergide and methylergometrine half-life is 60 and 220 minutes, respectively11,13. Methylergometrine has also dopaminergic activity14.

Methysergide was the first drug used to preventively treat migraine. Between 1948 and 1953, serotonin, serum vasoconstrictor factor, was identified, isolated and synthesized. In the 1950s and 1960s, its association to migraine was progressively established by some studies10,11,15-17. The search for some serotonin receptors antagonist with good tolerability has led to the synthesis of methysergide, which was introduced in the clinical practice in 1959 by Italian neurologist Federigo Sicuteri, from the Department of Clinical Pharmacology, University of Florence18. In line with Wolff, he also stated that local release of substances such as serotonin, histamine, bradykinin, among others, would lead to increased arterial tone, participating on the pathophysiology of some chronic headaches, such as migraine and cluster headache.

Since then, several studies indicating methysergide to prevent migraine and cluster headache were developed, showing the effectiveness of this drug19-22.

Approximately 20% to 45% of patients experience methysergide side-effects and approximately 10% of them discontinue its use. Most common side-effects, present in more than 5% of patients are sleepiness, nausea, vomiting, weight gain, epigastric pain, psychiatric disorders, peripheral arterial insufficiency and peripheral edema. In 24% to 35% of cases, symptoms are developed when the dose is higher than 8 mg/day11. Although uncommon, fibrosis is the most feared side-effect. Its incidence was estimated in 1% by a study23, differently from the incidence posteriorly found of 1/500011.

This study aimed at reporting two cases of primary chronic headache (1 patient with migraine and one patient with cluster headache), refractory to first line drugs, who obtained an adequate control after using methysergide, which was withdrawn due to suspicion of retroperitoneal fibrosis (RF).



Case 1: Female patient, 69 years old, diagnosed with chronic and difficult to treat migraine since her 15 years of age. She had already used propanolol, amitriptyline, nortriptyline, valproic acid and topiramate. Methysergide (1 mg/day) was started with satisfactory migraine control. After 24 months of continuous methysergide use, painless asymmetric lower limbs edema, more severe to the left, was observed. Lower limbs duplex scan was normal. Abdominal ultrasound (US) could not show the iliac vein and the possibility of retroperitoneal fibrosis was raised. Abdominal CT was also normal. In spite of negative RF screening, persistence of clinical signs has encouraged methysergide withdrawal. There has been total lower limbs edema resolution one week after drug withdrawal.

Case 2: Male patient, 58 years old, with episodic cluster headache poorly controlled with first line drugs. Methysergide (1 mg) at every 12 hours was started, with adequate control of cluster headache attacks and with patient reporting significant QL improvement after the introduction of the drug. After 30 months of continuous use, he complained of diffuse abdominal pain irradiating to left testicular region, in addition to sexual dysfunction with   complaint of "dry" orgasm and symmetric lower limbs edema. At investigation, lower limbs duplex scan, abdominal US and spermogram were normal. Similar to case 1, in spite of negative RF screening, signs and symptoms were progressing, which has encouraged methysergide withdrawal two months after initial patient's complaints. Seven days after methysergide dose decrease to 1 mg/day, clinical changes were totally resolved.



RF is an uncommon, insidious and nonspecific disease, thus being difficult to treat. Approximately 2/3 of cases are idiopathic. Most common secondary causes are drugs, retroperitoneal infections, aortic aneurysm and neoplasias24. It is more prevalent among males, except when its etiology is related to prolonged methysergide use, when it becomes more frequent among females25. Most common early symptom is pain, which may be abdominal, lumbar, clamping, continuous and not exacerbated by movement or palpation. Pain characteristics tend to change if the ureter is involved, for example. Lower limbs edema, probably secondary to extrinsic lymphatic and venous system compression, is also a common sign, as well as the presence of deep vein thrombosis. Scrotal edema, varicocele and hydrocele are also very frequent consequences, possibly secondary to the involvement of gonadal vessels. Less common symptoms, and in general associated to more advanced cases are: dysuria, oliguria, uremia-related complaints, lameness and intestinal ischemia26,27.

Imaging exams are critical for RF diagnosis and handling and may even, in some situations, differentiate secondary from idiopathic cases. Abdominal US is in general the first exam for being more accessible and for easily showing urinary tract changes, which is the region most earlier affected by RF. However, CT with contrasts is the exam of choice, since it defines fibrosis extension and helps identifying secondary causes. MRI is equally valuable with the advantage of not needing contrast. CT and MRI are important to define fibrosis extension and to show simultaneous changes which may suggest secondary causes26,28.

Fibrosis was firstly associated to methysergide in 196510,29. Authors have described three RF cases in patients under methysergide. There has been no direct causal relationship between methysergide and RF in these patients, but no other cause for such change was found. Since findings were insufficient to support drug withdrawal, authors proposed the discontinuation of the drug for three months at every year of regular use, in addition to periodic renal function and uremia follow up.

One year later, a study23 with 27 RF cases, 14 of them with diagnosis confirmed by biopsy and 13 of them by additional workup which has identified variable treatment duration from 9 to 54 months and doses from 2 to 28 mg10.

The incidence of pleural and cardiac RF is 1:5000 patients treated with methysergide11. It decreases with drug withdrawal. Studies11,30 have evaluated drug withdrawal for four weeks at every year of use and have observed reduction of cases of fibrosis. No case was observed with its periodic withdrawal. Current orientation is to give an interval of 4 to 8 weeks at every six months of use, in addition to periodic exams and renal function to be able to diagnose early RF cases.



Methysergide is effective for patients with headache refractory to first line drugs; however its chronic use should be done with caution, always valuing signs and symptoms suggesting early RF symptoms.



1. Castillo J, Munõz P, Guitera V, et al. Epidemiology of chronic daily headache in the general population. Headache. 1999;39(3):190-6.         [ Links ]

2. Stewart WF, Ricci JA, Chee E, et al. Lost productive time and cost due to common pain conditions in the US workforce. JAMA. 2003;290(18):2443-54.         [ Links ]

3. Olesen J, Bousser MG, Diener HC, et al. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia. 2006;26(6):742-6.         [ Links ]

4. Consenso da Sociedade Brasileira de Cefaléia. Recomendações para o tratamento profilático da migranea. Arq Neuropsiquiatr. 2002;60(1):159-69.         [ Links ]

5. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review) report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;55(6):754-62.         [ Links ]

6. Saper JR, Dodick D, Gladastone JP. Management of chronic daily headache: challenges in clinical practice. Headache. 2005;45(Suppl 1):S74-85.         [ Links ]

7. May A. Cluster headache: pathogenesis, diagnosis, and management. Lancet. 2005;366(9488):843-55.         [ Links ]

8. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headaches Disorders: 2nd ed. Cephalagia. 2004;24(Suppl 1):9-160.         [ Links ]

9. Matharu MS, Levy MJ, Meeran K, et al. Subcutaneous octreotide in cluster headache: randomized placebo-controlled double-blind crossover study. Ann Neurol. 2004;56(4):488-94.         [ Links ]

10. Koehler PJ, Tfelt-Hansen PC. History of methysergide in migraine. Cephalalgia. 2008;28(11):1126-35.         [ Links ]

11. Silberstein SD. Methysergide. Cephalalgia. 1998;18:421-35        [ Links ]

12. Moreira Filho PF, Silberstein SD. Advances in migraine prevention. Einstein. 2004;2(Supl 1):87-94        [ Links ]

13. Bredberg U, Eyjolfdottir GS, PaaIzow L, et al. Pharmacokinetics of methysergide and its metabolite methylergometrine in man. Eur J CIin Pharmacol. 1986;30(1):75-7.         [ Links ]

14. Herrman WM, Horowski R, Dannehl K, et al. Clinical effectiveness of Iisuride hydrogen maleate: a double-blind trial versus methysergide. Headache. 1977;17(1):54-60.         [ Links ]

15. Tfelt-Hansen PC, Koehler PJ. One hundred years of migraine research: major clinical and scientific observations from 1910 to 2010. Headache. 2011;51(5):752-78.         [ Links ]

16. Ostfeld AM, Chapman LF, Goodell H, et all. Studies in headache; summary of evidence concerning a noxious agent active locally during migraine headache. Psychosom Med. 1957;19(3):199-208.         [ Links ]

17. Wolff HG, Ostfeld AM, Chapman LF, et al. Studies in headache: a summary of evidence implicating a locally active chemical agent in migraine. Trans Amer Neurol Ass 81st meeting, 1956. p. 356.         [ Links ]

18. Sicuteri F. Prophylactic and therapeutic properties of 1-methyllysergic acid butanolamide in migraine. Int Arch Allergy Appl Immunol. 1959;15:300-7.         [ Links ]

19. Southwell N, Williams JD, MacKenzie I. Methysergide in the prophylaxis of migraine. Lancet. 1964;1(7332):523-4.         [ Links ]

20. Pedersen E, Møller CE. Methysergide in migraine prophylaxis. Clin Pharmacol Ther. 1966;7(4):520-6.         [ Links ]

21. Ekbom K, Hardebo JE. Cluster headache aetiology, diagnosis and management. Drugs. 2002;62(1):61-6.         [ Links ]

22. Dodick DW, Capobianco DJ. Treatment and management of cluster headache. Current Pain and Headache Reports. 2001;5(1):83.         [ Links ]

23. Graham JR, Suby HI, LeCompte PR, et al. Fibrotic disorders associated with methysergide. N Engl J Med. 1966;274(7):359-68.         [ Links ]

24. Hanley PC, Shub C, Lie JT. Constrictive pericarditis associated with combined idiopathic retroperitoneal and mediastinal fibrosis. Mayo Clin Proc. 1984;59(5):300-4.         [ Links ]

25. Koep L, Zuidema GD. The clinical significance of retroperitoneal fibrosis. Surgery. 1977;81(3):250-7.         [ Links ]

26. Vaglio A, Salvarani C, Buzio C. Retroperitoneal fibrosis. Lancet 2006;367(9506):241-51.         [ Links ]

27. Kermani TA, Crowson CS, Achenbach SJ, et al. Idiopathic retroperitoneal fibrosis: a retrospective review of clinical presentation, treatment, and outcomes. Mayo Clin Proc. 2011;86(4):297-303.         [ Links ]

28. Moussavian B, Horrow MM. Retroperitoneal fibrosis. Ultrasound Q. 2009;25(2):89-91.         [ Links ]

29. Utz DZ, Rooke ED, Spittell JA Jr, et al. Retroperitoneal fibrosis in patients taking methysergide. JAMA. 1965;191:983-5.         [ Links ]

30. Bana DS, MacNeaI PS, LeCompte PM, et al. Cardiac murmurs and endocardial fibrosis associated with methysergide therapy. Am Heart J. 1974;88(5):640-55.         [ Links ]



Correspondence to:
Denise da Silva Freitas, M.D.
Departamento de Neurologia do Hospital das Clínicas da UFMG.
Rua Alfredo Balena, 110/3º Ala Oeste – Santa Efigênia
30130-100 Belo Horizonte, MG.
Phone: (31) 3409-9417

Submitted in February 15, 2012.
Accepted for publication in June 21, 2012.



* Received from Headache Outpatient Setting, Neurology Service, Clinicas Hospital, Federal University of Minas Gerais (UFMG). Belo  Horizonte, MG.

Creative Commons License All the contents of this journal, except where otherwise noted, is licensed under a Creative Commons Attribution License