Brain (2000), 123, 9-18
`
`REVIEW ARTICLE
`Ergotamine in the acute treatment of migraine
`A review and European consensus
`
`P. Tfelt-Hansen, 1 P. R. Saxena,2 C. Dahlof,4 J. Pascual,5 M. Uiinez, 6 P. Henry, 7 H.-C. Diener, 8
`J. Schoenen,9 M. D. Ferrari3 and P. J. Goadsby 10
`
`1Department of Neurology, Glostrup Hospital, Copenhagen,
`Denmark, 2Department of Pharmacology, Erasmus
`University Medical Centre, Rotterdam, 3Department of
`Neurology, Leiden University Medical Centre, The
`Netherlands, 4Gothenburg Migraine Clinic, Goteborg,
`Sweden, 5Service of Neurology, University Hospital
`Marques de Valdecilla, Santander, 6Hospital General
`Universitario, Valencia, Spain, 7 CHU Hospital Pellegrin
`Service de Neurologie, Bordeaux, France, 8Neurologische
`Klinik and Poliklinik, University of Essen, Germany,
`9Departments of Neurology and Neuroanatomy, University
`of Liege, Belgium, 10The National Hospital for Neurology
`and Neurosurgery, Queen Square, London, UK
`
`Summary
`Ergotamine has been used in clinical practice for the acute
`treatment of migraine for over 50 years, but there has been
`little agreement on its place in clinical practice. An expert
`group from Europe reviewed the pre-clinical and clinical
`data on ergotamine as it relates to the treatment of
`migraine. From this review, specific suggestions for the
`patient groups and appropriate use of ergotamine have
`
`Correspondence to: Professor Peter J. Goadsby, Institute of
`Neurology, Queen Square, London WCJN 3BG, UK
`E-mail: peterg@brain. ion. ucl. ac. uk
`
`been agreed. In essence, ergotamine, from a medical
`perspective, is the drug of choice in a limited number of
`migraine sufferers who have infrequent or long duration
`headaches and are likely to comply with dosing restrictions.
`For most migraine sufferers requiring a specific anti(cid:173)
`migraine treatment, a triptan is generally a better option
`from both an efficacy and side-effect perspective.
`
`Keywords: migraine; headache; acute treatment; serotonin pharmacology; 5-HTrnnD receptors
`
`Introduction
`Ergotamine burst onto the medical scene during the Middle
`Ages when mass poisoning by ergotamine occurred
`throughout Europe due to eating bread contaminated with
`the sclerotia of the mushroom Claviceps purpurea, which
`is a parasite on rye, wheat, barley and other cultivated
`grains, climaxing in St Anthony's Fire. Due to its remarkable
`uterotonic and vasoconstrictor effects, ergotamine was
`used to precipitate childbirth and to control post-partum
`haemorrhage, first mentioned clearly by John Stearns m
`1808 in a letter published in the Medical Repository of
`New York (Thoms, 1931). The evolution of the use of
`ergot derivatives in obstetric practice is covered elsewhere
`(Moir, 1974). An extract of ergot was used in clinical
`practice by Eulenberg (1883), and ergotamine itself was
`
`© Oxford University Press 2000
`
`first isolated by Stoll (1918) and has been used in the
`acute treatment of migraine since 1926 (Maier, 1926), with
`no alternative specific acute anti-migraine treatment for
`decades. Remarkably, despite widespread use, there is little
`consensus as to its place in practice. In this review, we
`attempt to set out information concerning ergotamine and
`then make conclusions concerning its use based on current
`evidence. The American Academy of Neurology has
`published recommendations on crgotaminc use (Quality
`Standards Subcommittee of the American Academy of
`Neurology, 1995), but here we sought to provide detailed
`evidence for our position. Most clinicians feel ergotamine
`has some place in treating acute migraine, and we have
`attempted a consensus to present the core of its role.
`
`

`

`10
`
`P Tfelt-Hansen et al.
`
`Table 1 Receptor profile of ergotamine compared with dihydroergotamine and sumatriptan
`
`Receptor type
`
`pKi value on human cloned receptors in radioligand-binding assay"
`
`5-HT1A
`5-HTrn
`5-HTm
`5-HT1E
`5-HT1p
`5-HT2A
`5-HT28
`
`5-HT2c
`5-HT3
`5-HT4
`5-HTsA
`5-HTsB
`5-HT6
`5-HT7
`cx1 adrenoceptor
`cx2 adrenoccptor
`~ 1 adrenoceptor
`~2 adrenoceptor
`Dopamine D1
`Dopamine D2
`
`Ergotamine
`
`7.89b
`7.88b
`8.36b
`6.22d
`6.77d
`7.69c
`8.17 (pEC50, pig,
`functional/
`7.25 (pig, native)°
`ND
`ND
`7.26b
`8.50 (pKct, rat)g
`ND
`7.49 (pKct, rat)g
`8.00 (?)h
`8.20 (?)h
`ND
`ND
`ND
`8.50 n)h
`
`Dihydroergotamine
`
`9.3oc
`9.22°
`8.6oc
`6.22c
`6.96c
`8.54c
`7.70 (pEC50, pig, ND
`functionall
`7.43 (pig)°
`< 5.0 (pIC50, mouse)°
`6.52 (guinea pig)°
`7.34b
`ND
`6.78b
`7.] 7b
`8.00 (rat)°
`8.00 (rat)°
`5.27c
`< 5.0 (plC50)"
`5.32 (rat)"
`8.2] C
`
`Sumatriptan
`
`6.43c
`7.82c
`8.46c
`5.80c
`7.86c
`< 5.0 (pIC50)°
`
`< 5.0 (pIC50, pig)°
`< 5.0 (pIC50, mouse)°
`< 5.0 (pICso, guinea pig)°
`5.50b
`ND
`5.3 I b
`6.51 b
`< 5.0 (pIC50, rat)"
`< 5.0 (pIC50, rat)°
`< 5.0 (pIC50)c
`< 5.0 (pIC50)"
`< 5.0 (pIC 50, rat)"
`< 5.0 (pIC50)"
`
`"Unless otherwise stated; ? = species and test not specified; ND = not determined. hp J. Pauwels, personal communication to P.R.S.;
`cLeysen et al., 1996; dAdham et al., 1993; cHoyer, 1998; fG!usa and Roos, 1996; gHoyer et al., 1994; hLeysen and Gommeren, 1984.
`
`Pharmacology of ergotamine
`Receptor binding profile and mode of action
`The ergot alkaloids have a complex mode of action that
`involves interaction with a variety of receptors. Indeed, as
`shown in Table 1 (Leysen and Gommeren, 1984; Hoyer,
`1988; Adham et al., 1993; Hoyer et al., 1994; Glusa and
`Roos, 1996; Ley sen et al., 1996), both ergotamine and
`dihydroergotamine have affinities for 5-HT (5-hydroxy(cid:173)
`tryptamine), dopamine and noradrenaline receptors.
`In
`contrast, sumatriptan and the newer triptans are much more
`selective, showing high affinity for 5-HTrn and 5-HTrn
`receptors and a moderate affinity for 5-HT1A and 5-HTIF
`receptors (Goadsby, 1998).
`The cx-adrenoceptor-blocking property of ergotamine, first
`described by Dale (Dale, 1906), is textbook knowledge
`(Hoffman and Lefkowitz, 1996). However, this property is
`often overemphasized, since it is observed only with high
`doses used in some animal experiments and bears no relevance
`to therapeutic use in humans. In lower therapeutically relevant
`concentrations, ergotamine acts as an agonist at cx-adreno(cid:173)
`ceptors, 5-HT (particularly 5-HTrn11n) and dopamine D2
`receptors (MUller-Schweinitzer and Weidmann, 1978; Saxena
`and Cairo-Rawlins, 1979; Mtiller-Schweinitzer, 1992; De
`Vries et al., 1998; Villalon et al., 1999). In addition, there is
`evidence that both ergotamine and dihydroergotamine can
`activate novel, as yet uncharacterized receptors (De Vries
`etal., 1998).
`
`Effects on blood vessels
`The most important and conspicuous pharmacological effect
`of ergot alkaloids is undeniably the vasoconstrictor action
`(Mi.iller-Schweinitzer
`and Weidmann,
`1978; Mtiller(cid:173)
`Schweinitzer, 1992). Extensive studies in animals show that
`this vasoconstrictor effect is particularly marked within the
`carotid vascular bed and the selectivity extends to the
`arteriovenous anastomotic part; blood flow to a number of
`tissues, including that to the brain, is little affected (Johnston
`and Saxena, 1978; De Vries et al., 1998). Similar
`vasoconstrictor effects on cephalic arteriovenous anastomoses
`are also observed with sumatriptan as well as with other
`triptans (Saxena and Fe1rnri, 1996).
`In humans, ergotamine can constrict several isolated blood
`vessels, including the pulmonary (C011ijo et al., 1997),
`cerebral (Mi.iller-Schweinitzer, 1992), temporal (0stergaard
`et al., 1981) and coronary (MaassenVanDenBrink et al.,
`1998) arteries. The drug seems to be more active on large
`arteries ( conducting vessels) than on mterioles (resistance
`vessels). Basal cerebral (Andersen et al., 1987; Dixon et al.,
`1997) or myocardial (Gnecchi-Ruscone et al., 1998) blood
`flow may not change, although ergotamine does affect
`coronary vasodilator reserve (Gnecchi-Ruscone et al., 1998).
`Arterial blood pressure is moderately increased in therapeutic
`doses (Bulow et al., 1986; Dixon et al., 1997). An important
`feature of ergotamine and dihydroergotamine, as illustrated
`in Fig. 1 (Maassen VanDenBrink et al., 1998), is that their
`
`

`

`C
`
`0 ..,
`0
`!'l
`
`~
`
`....
`C
`0
`0
`cii
`
`-
`
`C
`
`0
`
`~ 0
`
`150
`
`100
`
`50
`
`0
`
`T T i T I
`
`t-•- -♦----·
`
`T...--.a.-+- -+-
`
`,-
`
`,-
`
`--O--o_,..
`-
`===•=•='-==rl
`
`0
`
`15
`45
`60
`75
`90
`30
`Time after first wash (min)
`
`Fig. 1 Persistent contractile response by ergots, but not triptans,
`on human isolated coronary arteries. Filled triangles =
`ergotamine; filled diamonds = dihydroergotamine; filled circles =
`sumatriptan; open squares = zolmitriptan; stars = rizatriptan;
`open triangles = naratriptan; open circles = avitriptan. All drugs
`were administered once at a concentration twice their EC 50. Data
`are displayed as mean ± standard error of the mean
`(MaasscnVanDenBrink et al., 1998).
`
`effects in isolated human coronary arteries are resistant to
`repeated wash. This appears to be due mainly to slow
`diffusion from the receptor biophase and, therefore, their
`effects last far longer than can be expected from plasma
`concentrations (Bulow et al., 1986; Tfelt-Hansen and
`Johnson, 1993).
`
`Other effects
`Ergotamine and dihydroergotamine have been reported to
`inhibit dural plasma extravasation after stimulation of the
`trigeminal ganglion in rats (Buzzi and Moskowitz, 1991;
`Buzzi et al., 1991). In addition, as has been demonstrated
`for dihydroergotamine (Goadsby and Edvinsson, 1993;
`Hoskin et al., 1996), ergotamine derivatives may block the
`trigeminovascular pathway centrally. Ergotamine also has a
`prominent uterotonic action (Graves, 1996).
`
`Pharmacokinetics of ergotamine
`Oral absorption of ergotamine is 60-70%, and the concunent
`administration of caffeine improves both the rate and extent
`of absorption. Due to high first-pass metabolism, ergotamine
`has a very low bioavailability from oral administration.
`There is considerable subject variability with respect to
`bioavailability and lack of consistency in the clinical response
`over multiple
`attacks. Compared with
`intravenous
`bioavailability ( 100% ), oral bioavailability of ergotamine is
`< 1 % (Sanders et al., 1983; Ibraheem et al., 1983), rectal
`bioavailability is 1 ~3% and intramuscular bioavailability
`is 47% (Tfelt-Hansen and Johnson, 1993). Ergotamine is
`metabolized in the liver by largely undefined pathways; 90%
`of the metabolites are excreted in the bile and the elimination
`half-life is 2 h (Tfelt-Hansen and Johnson, 1993). An inter(cid:173)
`action with erythromycin may dramatically increase the oral
`bioavailability of ergotamine (Francis et al., 1984), and
`ergotism is a reported complication of co-administration with
`
`Ergotamine in clinical practice
`
`11
`
`clarithromycin (Horowitz et al., 1996) and ritonavir (Liaudet
`et al., 1999). Since the same cytochrome P450 enzyme
`metabolizes a number of other drugs, including bromocriptine,
`dexamethasone, ethinyloestradiol, ketoconazole, nifedipine,
`omeprazole and verapamil (Christians et al., 1996), this
`interaction may extend to these drugs as well.
`
`Ergotamine formulations
`Most formulations of ergotamine are not very useful due to
`an inappropriate amount of ergotamine or compounding with
`other drugs, such as caffeine, chlorcyclizine or meprobamate.
`Ergotamine is marketed as aerosol (which is slowly being
`withdrawn), oral and suppository formulations. In some
`countries, ergotamine can be used alone in an oral formulation,
`or particularly in the very useful inhalational form, but most
`often the suppository formulation is compounded and contains
`1 ~2 mg of ergotamine with caffeine.
`
`Clinical studies with ergotamine
`Ergotamine is a relatively old drug and thus did not undergo
`a controlled clinical trial programme as would be expected
`of a modern drug. Nevertheless, oral ergotamine has been
`used over the past 30 years as the standard comparative drug
`in controlled trials of other medicines, although the number
`of good clinical trials incorporating this widely used drug is
`not large. A recent review (Dahlof, 1993) stated that 'there
`is little evidence that it is significantly more effective than
`placebo' and further 'the recommended doses of ergotamine
`cannot be justified'. Despite the limited number of studies
`with contemporary methodology that involve ergotamine
`(The International Headache Society Committee on Clinical
`Trials in Migraine, 1991 ), there is evidence for the efficacy
`of ergotamine in the literature, and this will be summarized
`briefly here.
`
`Randomized controlled clinical trials with
`ergotamine
`A summary of 18 controlled double-blind trials of oral
`ergotamine, or oral ergotamine plus caffeine, is given in
`Table 2. In 10 trials (Ostfeld, 1961; Ryan, 1970; Waters,
`1970; Hakkarainen et al., 1979; Kinnunen et al., 1988;
`Sargent et al., 1988; Friedman et al., 1989; Cartelli et al.,
`1996; McNeely and Goa, 1999; Reches and Eletriptan
`Steering Committee, 1999) ergotamine was compared with
`placebo, whereas in eight other trials ergotamine served as
`the standard comparative drug (Adams et al., 1971; Yuill
`et al., 1972; Hakkarainen et al., 1978, 1980; Pradalier et al.,
`1985; The Multinational Oral Sumatriptan and Cafergot
`Comparative Study Group, 1991; Treves et al., 1992; Le
`Jeunne et al., 1999) without placebo control. The initial dose
`of ergotamine varied from 1 to 5 mg, and in several trials
`repeated intake of test drugs was used (Table 2). The reported
`
`

`

`12
`
`P Tfelt-Hansen et al.
`
`Table 2 Double-blind randomized trials with pure oral ergotamine (Erg) or an ergotamine compound with caffeine (ErgC)
`in the treatment of migraine attacks.
`
`Trial
`
`Drug
`
`Initial (maximum)
`dosage (mg)
`
`Study
`design
`
`No. of
`attacks
`treated"
`
`No. of patients
`(no. evaluated)
`
`Result of trial
`
`Ostfeld, I 961
`
`Waters, 1970
`
`Ryan, 1970
`
`Yuill et al., 1972
`
`Hakkarainen et al., 1979
`
`Hakkarainen et al., 1978
`
`Hakkarainen et al., I 980
`
`Pradalier et al., 1985
`
`5
`
`2-3
`
`2 (6)
`2 (6)
`
`2 (6)
`130 (130)
`2 (6)
`130 (390)
`1
`200
`500
`
`co
`
`co
`
`co
`
`co
`
`co
`
`co
`
`co
`
`co
`
`Pa
`
`7b
`
`2
`
`2
`
`7
`
`7
`
`6
`
`44
`
`88 (79)
`
`48
`
`54
`
`38
`
`20
`
`25
`
`25
`
`114 (95)
`
`More than 50% headache relief: Erg (70%)
`> Pl (39%)
`Benefited based on clinical interview: Erg
`(5 I% )/Pl (58%)
`Escape medication: ErgC (22/48) = Ergs
`(22/46) > Pl (33/46)
`
`Mean headache duration: ErgC > Isome
`
`Headache intensity<l: IsomC (2.8) > ErgC
`(3.3). Nausea<l: IsomC (1.1) > ErgC (2.0)
`Mean duration of attack in h: Erg
`(3.8) = Tfa (3.2) = ASA (4.2) > Pl (7.1)
`Preference: all drugs > Pl
`
`Mean of attack prevented: Erg (3.6) =
`DextC (2.6) > Pl (1.1)
`
`Attack not prevented: Erg (53%) = DextC
`(59%) > Pl (82%)
`
`Erg
`Pl
`Erg
`Pl
`ErgC
`Ergs
`Pl
`ErgC
`IsomC
`ErgC
`IsomCc
`Erg
`Tfa
`ASA
`Pl
`Erg
`Dextce
`ASA
`Erg
`DcxtCc
`ASA
`Erger
`Napxs
`
`ErgC
`Napxs
`Pl
`Erger
`Pirp
`Pl
`
`ErgCf
`Pl
`
`ErgC
`Sum
`
`Erg
`Napxs
`
`I (3)
`100 (200)
`500 (1500)
`I (2)
`100 (200)
`500 (1000)
`2 (4)
`825 (1375)
`
`2 (3)
`825 (1100)
`
`2 (5)
`200 (500)
`
`2 (6)
`
`2
`JOO
`
`2 (4)
`750 ( 1750)
`
`ErgC
`CASA+M
`ErgC
`Diclo
`Pl
`
`ErgC
`Diclo
`Pl
`
`ErgC
`Elc
`Ele
`Pl
`
`900 + 10
`2 (6)
`50 (150)
`
`2 (5)
`50 (200)
`
`2 (4)
`40 (80)
`80 (160)
`
`Sargent et al., 1988
`
`Kinnunen et al., 1988
`
`Friedman et al., 1989
`
`The Multinational Oral
`Sumatripan and Cafergot
`Comparative Study
`Group, 1991
`Treves et al., 1992
`
`Le Jeunne et al., 1997
`
`Cartelli et al., 1996
`
`McNeely and Goa, 1999
`
`Reches and Eletriptan
`Steering Committee,
`1999
`
`Pa
`
`6
`
`169 (122)
`
`co
`
`67 (61)
`
`(104)
`
`580 (577)
`
`79 (7P)
`
`268
`
`63
`
`423
`
`2
`
`3
`
`6
`
`3
`
`Pa
`
`Pa
`
`Pa
`
`Pa
`
`co
`
`Pa
`
`Pa
`
`For test drug taken within 2 h: N apxs >
`ErgC for headache relief. Later intake of
`test drug, NSg
`Relief of headache at I h: Napxs > Pl,
`ErgC = Pl. Overall efficacy: ErgC > Pl,
`Napxs = Pl
`Escape medication: ErgC (18/59) = Pirp
`(18/58) > Pl (32/60). Dnration of attacks in
`h: ErgC (6.5) > Pl (10.5) but versus Pirp
`NS. For most parameters, ErgC vs Pirp NS
`Mean improvement from baseline on a
`5-point headache scale after 2 h: ErgC
`(1.0) > Pl (0)11
`Headache rclicfL Sum (66%) > ErgC
`(48%)
`
`N apxs > Erg for overall efficacy rating of
`treatments on a 6-point scale (none to
`excellent) .Improvement of headache:
`Napxs = Erg
`Headache reliefi CASA + M (54%)
`> ErgC (36%)
`Diclo > Pl (-15 mm mean difference for
`changes on a VAS scale after 1 h). Diclo
`> ErgC (-11. 9 mm mean difference)
`ErgC = Pl (-2.8 mm mean difference)
`Diclo > Pl (-9 mm mean difference for
`changes on VAS scale after 2 h). Diclo =
`ErgC (-3.6 mm mean difference). ErgC =
`Pl (-5.4 mm mean difference).
`Headache reliefi: Ele 80 (68%) > Ele 40
`(58%) > ErgC (33%) > Pl (21%)
`
`The table is modified from Tfclt-Hanscn and Johnson (1993). ASA = aspirin; CASA -,.. M = calcium carbasalatc (equivalent to 900 mg of ASA) plus
`metoclopramide; DextC = dcxtropropoxyphene compound; Diclo = diclofenac; Erg = ergotamine; ErgC = ergotamine compound with caffeine (I mg of
`ergotamine + 100 mg of caffeine); Ergs = ergostine ( + caffeine); Ele = eletriptan; IsornC = isometheptene compound; Napxs = naproxcn sodium;
`Pirp = pirprofen; Sum = sumatriptan; Tfa = tolfenamic acid; Pl = placebo; CO = crossover; Pa = parallel group; NS or = = no statistical significant
`difference; > = more effective than. "Maximum number of attacks treated; bapproximately one-quarter of patients did not have migraine (74); conly dose
`of isometheptcne given (for other components, see reference); <lverbal scale : I = very mild, 2 = mild, 3 = moderate, 4 = severe, 5 = very severe; conly
`doses for dextropropoxyphene [65 mg of the chloride (9) or JOO mg of the napsylate (10)] are indicated (for other components, sec references); fcontains
`other components in addition to caffeine, see references; gstudy conclusions weakened by the lack of use of double dummy technique; hpatients refractory
`to ergot therapy were excluded; ia decrease from severe or moderate headache to no or mild headache.
`
`

`

`parameters for efficacy were not all validated and varied
`considerably, from benefit based on a clinical interview
`(Waters, 1970) to use of changes on a verbal headache scale
`(Yuill et al., 1972; Friedman et al., 1989; The Multinational
`Oral Sumatriptan and Cafergot Comparative Study Group,
`1991). Methodological flaws in some of these trials include
`the lack of clearly stated inclusion criteria, no reporting of
`the baseline criteria and randomization procedures, unusual
`design of some of the crossover trials with a variable
`number of attacks per patient, and superiority claims without
`appropriate statistics.
`Ergotamine (1-5 mg) was superior to placebo for some
`parameters in seven trials (Ostfeld, 1961; Ryan, 1970;
`Hakkarainen et al., 1979; Kinnunen et al., 1988; Sargent
`et al., 1988; Friedman et al., 1989; Reches and Eletriptan
`Steering Committee, 1999) and no better than placebo in
`three studies using a dose of 2-3 mg (Waters, 1970; Cortelli .
`et al., 1999; McNeely and Goa, 1999). In two comparative
`trials, ergotamine was superior
`to aspirin
`(500 mg)
`(Hakkarainen et al., 1978, 1980), and was inferior to an
`isometheptene compound in one trial (Yuill et al., 1972) and
`superior to it in another trial (Adams et al., 1971). As shown
`in Table 2,
`the drugs, such as ergocristine, tolfenamic
`acid, dextropropoxyphene, naproxen sodium, pirprofen and
`diclofenac, were generally found to be comparable with
`ergotamine, although there is one recent study of diclofenac
`which showed superiority of this drug (Cartelli et al., 1999).
`Exceptions are sumatriptan (100 mg orally) which was
`superior to 2 mg of ergotamine plus 200 mg of caffeine (The
`Multinational Oral Sumatriptan and Cafergot Comparative
`Study Group, 1991 ), the combination of calcium carbasalate
`(equivalent to 900 mg of aspirin) and metoclopramide
`(10 mg), which was superior to a rather small dose of 1 mg
`of ergotamine plus 100 mg of caffeine (Le Jeunne et al.,
`1999), and eletriptan at 40 and 80 mg doses which were
`superior to 2 mg of ergotamine plus caffeine (Reches and
`Eletriptan Steering Committee, 1999).
`These trials of ergotamine, some of them placebo(cid:173)
`controlled, suggest that oral ergotamine is efficacious in the
`treatment of migraine but they do not quantify the benefit
`effectively. Thus no uniform picture of the utility of oral
`ergotamine emerges from these trials. Early use of ergotamine
`in migraine treatment was
`tried
`in
`two of the
`trials
`(Hakkarainen et al., 1978, 1980) in which the drugs were
`administered as soon as the patients felt the onset of an
`attack. The results from this strategy are not convincing. The
`use of escape medication is a clinically relevant efficacy
`parameter (The International Headache Society Committee
`on Clinical Trials in Migraine, 1991 ), and this was used by
`31 % (Kinnunen et al., 1988), 44% (The Multinational Oral
`Sumatriptan and Cafergot Comparative Study Group, 1991)
`and 46% (Ryan, 1970) of patients treated with ergotamine. No
`clinical trial data are available on within-subject consistency,
`which from results of pharmacokinetic studies and from
`clinical practice is probably poor compared with the use of
`triptans (Kramer et al., 1998; Pfaffenrath et al., 1998).
`
`Ergotamine in clinical practice
`
`13
`
`Non-oral routes of administration
`Other routes of administration of ergotamine, which from a
`kinetic point of view should be more efficacious, have
`scarcely been investigated. In one trial, inhaled ergotamine
`(maximum dose of 1.8 mg) was found to be superior to
`sublingual ergotamine (maximum dose of 2 mg) which was
`no better than a sublingual placebo (Crooks et al., 1964). In
`a double-blind placebo-controlled study, a suppository of
`ergotamine (2 mg) was no better than placebo, whereas
`ketoprofen (100 mg as a suppository) was superior to placebo
`(Kangasniemi and Kaaja, 1992). In a recent randomized,
`crossover, double-blind trial including 251 patients, so far
`published only on the Internet (1998), ergotamine plus
`caffeine suppositories (2 and 100 mg, respectively) were
`superior to 25 mg sumatriptan suppositories, with response
`rates of 73 and 63% respectively, after 2 h. Headache
`recun-ence
`(see below) occurred more
`frequently
`in
`sumatriptan-
`(22%)
`than
`in ergotamine-
`(11 % ) treated
`patients. However, significantly more patients prefened
`sumatriptan suppositories ( 44%) than prefen-ed ergotamine
`suppositories (36% ), due to more side-effects after the latter.
`Full publication of this study will be of great interest.
`
`Headache recurrence with ergotamine
`Headache recurrence can be defined as a return or worsening
`of the headache and associated migraine symptoms within
`24-72 h after an initial medication-induced amelioration. It
`is a major issue for all acute migraine treatments, but has
`only been recognized during the clinical trial programme
`with subcutaneous sumatriptan (Visser et al., 1996c).
`Recognition was triggered by the often dramatic contrast of
`an excellent initial improvement, which was followed by a
`rapid and very disappointing return of the headache after
`10-12 h. Subsequently, it has been observed that headache
`recurrence is common to all acute migraine treatments
`(Ferrari, 1998), including ergotamine (The Multinational Oral
`Sumatriptan and Cafergot Comparative Study Group, 1991),
`although some treatments are better than others in this regard.
`The mechanism of headache recurrence is unknown, but
`breakthrough of a temporarily suppressed migraine generator
`seems more likely than a new attack (Weiller et al., 1995;
`Visser et al., 1996a, b, c). A longer drug plasma half-life
`does not reduce the incidence of headache recurrence, but
`may delay the time to renmence (Visser et al., 1996a).
`Where the risk of headache recurrence has been studied in
`sumatriptan users, it seems to be a patient-dependent rather
`than an attack-dependent phenomenon. About one-third of
`migraine patients using sumatriptan, especially those with
`long attacks of 2-3 days, will consistently experience
`headache recurrence in each successfully treated attack, while
`patients with shorter attacks experience headache renmence
`only rarely (Visser et al., 1996b, c).
`A major point of discussion, even among the authors of
`the present review, is whether headache recurrence rates
`
`

`

`14
`
`P. Tfelt-Hansen et al.
`
`differ between drugs, and whether any differences have
`clinical implications. The general perception is that, when
`effective, ergotamine carries a lower risk of headache
`recurrence than the triptans. However, the questions arise as
`to whether this impression is correct, whether such a
`comparison can actually be made and whether this also
`implies that patients who experience headache recurrence on
`triptans will not do so on ergotamine. The initial response,
`since a patient has to respond first in order to be at risk for
`headache recurrence, and the use of analgesics for early
`treatment of recurring headache must be taken into account.
`In addition, the time at which recurrence occurs must be
`considered, since headache is usually only monitored up to
`24 h, although in an early direct comparison of rates of
`recurrence at 48 h after dosing, a significant difference (P =
`0.009), reported to be 41 % for oral sumatriptan 100 mg and
`30% for patients treated with Cafergot (ergotamine 1 mg
`plus caffeine, two tablets), was noted (The Multinational
`Oral Sumatriptan and Cafergot Comparative Study Group,
`1991). It is important to bear in mind that headache recurrence
`is assessed in a non-randomized population (responders to
`treatment), and therefore an imbalance in the baseline clinical
`characteristics cannot be excluded. As a result, simple
`comparison of headache recurrence may be misleading.
`Instead of reporting response and recurrence rates separately,
`overall efficacy might be better ascertained with a composite
`measure which includes all the factors mentioned above.
`Ideally, one would like to know how many patients require
`only one dose of medication to treat a migraine attack
`effectively. This could be assessed with the so-called
`'complete response', which is the proportion of patients who
`become pain-free within 2 h after drug administration and
`do not experience headache recurrence nor use analgesics in
`the subsequent 24-72 h (sustained relief).
`
`Side-effect issues with ergotarnine use
`Ergotamine has a low degree of receptor selectivity which
`increases the risk of experiencing a drug-induced side-effect
`(see above). Ergotamine often causes nausea and vomiting in
`a migraine sufferer and these are major clinical disadvantages
`given the high prevalence of these symptoms during the
`migraine attack. Nausea and vomiting occur in -10% of
`patients after oral administration of ergotamine and in about
`twice that number after parenteral administration. Nausea is
`most probably caused by a direct effect on CNS emetic centres.
`
`General side-effects
`Weakness in the legs has been reported, and occasionally severe
`muscle pains have occurred in the extremities following
`ergotamine use. Numbness and tingling of the fingers and toes
`are other reminders of the ergotism that this alkaloid may cause.
`Localized oedema and itching may occur in an occasional
`hypersensitive patient. Most of these effects are not alarming
`
`and ordinarily do not necessitate intem1ption of ergotamine
`therapy.
`In doses used in the treatment of migraine, the rectal
`administration of ergotamine produces little change in blood
`pressure but does cause a slowly progressing increase in
`peripheral arterial constriction that persists for up to 24 h
`(Bulow et al., 1986).
`
`Cardiovascular side-effects
`Ergotamine usually induces bradycardia even when the blood
`pressure is not increased (Hoffman and Lefkowitz, 1996). This
`is due predominantly to increased vagal activity, but a reduction
`in sympathetic tone (by a central as well as peripheral
`presynaptic action) and direct myocardial depression may also
`be involved (Saxena and Cairo-Rawlins, 1979; Hoffman and
`Lefkowitz, 1996). Ergotamine can produce coronary
`vasoconstriction, often with associated ischaemic changes and
`angina! pain in patients with coronary artery disease (Galer
`et al., 1991). In contrast to triptans, the contractile effect of
`ergotamine in the human isolated coronary artery is long(cid:173)
`lasting and persists even after repeated washings (Fig. 1)
`(Maassen VanDenBrink et al., 1998). Similarly, administration
`of ergotamine (0.25 mg) intravenously caused a reduction in
`coronary microcirculatory blood flow as measured by PET
`(Gnecchi-Ruscone etal., 1998) where, by contrast, sumatriptan
`produced no such change (Lewis et al., 1997).
`Ergotamine doses that produce peripheral vasoconst:riction
`can also damage the capillary endothelium. The mechanism of
`this toxic action is not clearly understood. Vascular stasis,
`thrombosis and gangrene are prominent features of ergot
`poisoning. The propensity of ergotamine to cause gangrene
`appears to parallel its vasoconstrictor activity (Peroutka, 1996).
`
`Uterine effects
`Ergotamine increases the motor activity of the uterus. After
`small doses, contractions are increased in force or frequency,
`or both, but are followed by a normal degree of relaxation. As
`the dose is increased, contractions become more forceful and
`prolonged, resting tonus is markedly increased, and sustained
`contracture can result (Graves, 1996).
`
`Contraindications
`Ergotamine is contraindicated in women who are or may
`become pregnant, since the drugs may cause foetal harm.
`Ergotamine is also contraindicated in patients with peripheral
`vascular disease, coronary heart disease, uncontrolled
`hypertension, stroke, impaired hepatic or renal function, and
`sepsis. Based on the theoretical additive pharmacological
`effects of the drugs, ergotamine should not be taken within 6 h
`of the use of triptans, and similarly triptans should not be
`administered within 24 h of ergotamine. It also is recommended
`that ergotamine should not be used in complicated migraine
`
`

`

`Ergotamine in clinical practice
`
`15
`
`Table 3 Recommendations for the use of ergotamine
`
`Recommendation
`
`Limitations and comments
`
`Which patients?
`• Patients requiring migraine-specific
`therapy
`• Patients established on ergotamine
`
`Special cases
`• Patients with very long attacks
`• Patients with frequent headache
`recurrence
`
`Frequency of dosing:
`I/week or 6/month
`
`Dose per attack:
`single dose (0.5-2 mg)
`
`Preferred route: rectal
`
`• When a migraine-specific therapy is indicated, a triptan is a better choice than ergotamine for
`most patients
`• Patients established on ergotamine who are responding satisfactorily, with no contraindications
`to its use and with no signs of dose escalation, should not usually be switched to a triptan
`
`• Attacks lasting > 48 h may be usefully treated with ergotamine
`• Headache recurrence is probably less likely with ergotamine
`
`• A major problem with ergotamine is ergotamine-induced headache and rebound headache
`associated with frequent use. This can be limited by restricting ergotamine consumption and
`encouraging use of a preventative medication as headache becomes more frequent.
`• May be modified to four consecutive doses for menstrual migraine
`• May be modified for use in cluster headache
`
`Ergotamine should be dosed at one time as early as practicable in the attack at a dose that
`produces a response with as few side-effects as possible. It is useful to test this dose for
`tolerability for nausea between attacks
`Although still useful orally, ergotamine is generally better used, provided it is acceptable to the
`patient, by the rectal route because of improved absorption. Where it is available, the ergotamine
`puffer is preferred to the oral route for the same reasons
`
`(Peroutka, 1996), migraine with prolonged aura, basal migraine
`or familial hemiplegic migraine.
`
`Daily headache and ergotamine overuse
`It seems likely that any medication used for the treatment of
`migraine attacks can be misused by being taken daily or almost
`daily (Diener and Tfelt-Hansen, 1993; Kaube et al., 1994;
`Limmroth eta!., 1999). The problem with ergotamine overuse
`with rebound headache was recognized by Graham in the late
`1940s (Wolfson and Graham, 1949) and further clarified by
`Peters and Horton (Peters and Horton, 1951) and Friedman and
`colleagues (Friedman et al., 1955). Why some patients are
`more prone to develop abuse and daily headache than others is
`unclear. Genetic and psychological factors seem to be involved.
`Analgesic abuse as a major cause of chronic daily headache
`was recogni