4Journal ofNeurology, Neurosurgery, and Psychiatry 1997;62:490-495

The efficacy of subcutaneous sumatriptan in thetreatment of recurrence of migraine headache

R E Cull, W H Price, A Dunbar

AbstractObjectives-To investigate the efficacy ofa second subcutaneous dose of6 mg suma-triptan in the treatment of recurrence ofheadache after successful treatment of amigraine attack with an initial 6 mg dose.Methods-In a prospective, randomised,placebo controlled, double blind, parallelgroup study, 803 patients were treated forone to three migraine attacks with severeor moderate headache with a subcuta-neous injection of 6 mg sumatriptan. Anysubsequent recurrence of migraineheadache was treated with a randomisedsecond injection of sumatriptan orplacebo. Recurrence was defined as aheadache of moderate or severe intensityoccurring 1-24 hours after the initial dosein a patient whose headache had beenrelieved by sumatriptan (reduction ofheadache severity from severe or moder-ate to mild or none after one hour).Results-Headache recurrence wasreported by 100%o-15% of patients. At eachattack, 6 mg sumatriptan given subcuta-neously was significantly (P < 0.0005)more effective than placebo at relievingrecurrent headache after one hour(84%/o-93% v 310/o%50% of patients);760/o-83% of patients reported headacherelief one hour after the initial dose ofsumatriptan. Sumatriptan was generallywell tolerated.Conclusions-Up to 15% of patients withmigraine experience significant recur-rence of headache after successful treat-ment with subcutaneous sumatriptan, andthis recurrence is effectively treated by afurther dose of subcutaneous sumatrip-tan.

(J Neurol Neorosurg Psychiatry 1997;62:490-495)

Departnent of ClinicalNeurosciences,Western GeneralHospital, Crewe Road,Edinburgh, EH4 2XU,UKR E CullW H PriceA DunbarCorrespondence to:Dr R E Cull, Department ofClinical Neurosciences,Western General Hospital,Crewe Road, Edinburgh,EH4 2XU, UK.Received 7 May 1996and in final revised form16 December 1996Accepted 23 December 1996

Keywords: sumatriptan; migraine; headache recur-rence; tolerability

The novel antimigraine drug sumatriptan is aselective 5-hydroxytryptamine 1 (5-HT,BlID)receptor agonist, and acts at 5-HT, receptors(probably 5-HT,B subtype) which mediatevasoconstriction of cranial blood vessels. 1 2The primary mechanisms of action of suma-

triptan may be related to these vasoconstric-tive effects, but the drug may also blockneurogenic inflammation and neural transmis-sion via activation of 5-HT, receptors on

trigeminal nerve terminals. '

In clinical trials, sumatriptan given subcuta-neously or orally is an effective and well toler-ated acute treatment for migraine.34 At least70% of patients report headache relief withinone hour after a subcutaneous injection of 6mg sumatriptan in comparison with 22%-31%of those on placebo,5-7 and efficacy is main-tained in long term use (up to one year) withno evidence of tachyphylaxis.89 However,these studies were designed to evaluate reliefof headache and other symptoms of migraine,and took no account of the severity of recur-rent headache or of the use of any additionalnon-study medication in the interveningperiod.

Although a second dose of sumatriptan afterone hour is not effective in treating patientswho do not respond to an initial dose,5-7 anappropriately timed second dose might be ofvalue in treating recurrence of headache. Thestudy reported here was designed to investi-gate prospectively the incidence of recurrenceof headache after subcutaneous sumatriptanand the efficacy of a further dose of subcuta-neous sumatriptan in treating the recurrentmigraine headache.

Patients and methodsSTUDY DESIGNThis was a randomised, placebo controlled,double blind, parallel group study carried outin 192 general practice centres and 12 hospitalcentres in the United Kingdom. The patientstreated themselves outside the clinic, and eachpatient remained in the study for three monthsor until three migraine attacks had beentreated, whichever was the sooner.The trial was conducted in accordance with

the Declaration of Helsinki 1964. Approvalwas obtained from the ethics committee ofeach of the participating hospitals and from anindependent central ethics committee for thegeneral practice centres. Patients gave theirwritten consent before entering the trial. Datawere collected on standardised forms and col-lected by Glaxo Wellcome study monitors.The database was held and analysed byStatistics and Data Management, GlaxoWellcome UK Ltd, Stockley Park West,Uxbridge, Middlesex.

SELECTION OF PATIENTSMen and women aged between 18 and 65years, who met the International HeadacheSociety's criteria for migraine with or withoutaura,9 were enrolled in the study. They had acurrent migraine history of at least six months

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491The efficacy ofsubcutaneous sumatriptan in the treatment of recurrence of migraine headache

(age at onset < 50 years), with between one

and four severe or moderately severe attacksper month and at least 24 hours of freedomfrom headache between attacks. Patients tak-ing prophylactic medications for migrainewere included if they had received this ther-apy, at a constant dose, for the previous threemonths and continued on the same prophylac-tic treatment regimen throughout the study.Patients were excluded if they had a history ofischaemic heart disease, uncontrolled hyper-tension (diastolic blood pressure > 95 mmHg), or other clinically concurrent medicalcondition, had hemiplegic migraine, were

pregnant or breast feeding, or were concur-

rently taking ergotamine, daily analgesic or

antiemetic therapy, monoamine oxidaseinhibitors, 5-HT reuptake inhibitors, or

lithium. Patients who had misused ergota-mines, alcohol, or other drugs were alsoexcluded.

TREATMENTSAt the first visit to the hospital or general prac-

tice centre (week 0), patients were given a

brief medical examination, and their migrainehistory and pertinent medical history were

recorded. Migraine diary cards were issuedand patients were asked to stop any ergota-mine or sumatriptan therapy, and to take no

ergotamines for the duration of the study. Theoccasional use of analgesics was permitted,provided that they were not taken within sixhours before the study medication.The patients were randomly allocated to

one of two treatment groups (groups A andB). Starting from week 2, patients in bothgroups took 6 mg sumatriptan subcutaneouslyat the onset of a migraine headache of moder-ate or severe intensity (dose 1). For the treat-ment of headache recurrence only (dose 2)group A took 6 mg sumatriptan subcuta-neously and group B took placebo. Patientsself administered study medication with a

modified Owen Mumford autoinjector.Headache intensity was graded by the patientson the diary cards as severe (grade 3), moderate(grade 2), mild (grade 1), or none (grade 0).Recurrence of headache was defined as a

headache of moderate or severe intensity thatoccurred between one and 24 hours after thefirst dose of sumatriptan in a patient whosemigraine headache was initially relieved bydose 1.

If relief of headache was inadequate(headache grade 3 or 2) one hour after dose 1or 2, patients could take rescue medication(not ergotamine containing drugs or commer-

cially available sumatriptan). Patients who hadtaken rescue medication after dose 1 for reliefof persistent or recurrent headache were

excluded from the analysis for that attack.Patients treated their next migraine attack withstudy medication provided that at least 24hours had elapsed since their last study treat-

ment. The maximum permitted dose of suma-triptan in 24 hours was two 6 mg injections.The patients returned to the clinic at four

week intervals for up to 14 weeks. At these fol-low up visits the diary cards and treatment

packs were checked for compliance with thestudy protocol. Patients who had treated threemigraine attacks were considered to have com-pleted the study.

EVALUATION OF EFFICACY, TOLERABILITY, AND

SAFETYThe primary end point of clinical efficacy wasthe relief of the recurrent headache (fromsevere or moderate to mild or none) at onehour after treatment with dose 2. Secondaryend points included relief of headache onehour after dose 1, the requirement for rescuemedication after two doses of study medica-tion, shifts in headache severity (time of dos-ing v one hour after dosing), and the patient'sglobal response to treatment. Global responsewas assessed at the final follow up visit whenthe patients graded their overall assessment ofthe treatment efficacy as ineffective, poor, rea-sonable, good, or excellent.The tolerability of sumatriptan was assessed

by monitoring adverse events in all patientstreated with study medication. An adverseevent was defined as any untoward clinicalevent that occurred during the trial, irrespec-tive of its relation to the study treatment.Investigators gave their opinion of the relationbetween the adverse event and the study drug(not related, unlikely to be, possibly, probably,or almost certainly related). Additional safetyassessments included heart rate and bloodpressure measurements, which were recordedbefore treatment (visit 1-week 0). A 12 leadECG was taken if a patient had an adverseevent involving cardiac symptoms (chest pain,tighmess) during the study and if the investi-gator considered this to be a useful supple-mentary investigation. The ECGs wereassessed by an independent cardiologist.

STATISTICAL METHODSThe percentage of patients with headacherelief one hour after treatment of a recurrentheadache with placebo was estimated to be20%. Data on 48 patients per treatment groupwere required to have a 90% chance of detect-ing a 30%-50% difference between sumatrip-tan and placebo for the treatment of aheadache recurrence using a two sided 5% sig-nificance level. Allowing for a 77% successrate with the first dose of sumatriptan for thetreatment of the initial migraine attack, and a30% incidence of headache recurrence amongthese patients, 208 patients per treatmentgroup were required. Sample size calculationswere based on the method for comparing twobinomial proportions described by Machinand Campbell.'0The two treatment groups were compared,

using the normal approximation to the biono-mial distribution, with regard to the propor-tions of patients with a recurrence, with reliefof headache recurrence, and needing rescuemedication. Comparisons between the twogroups in the patients' global response totreatment were made using the Wilcoxon ranksum test. Efficacy data for the first, second,and third migraine attacks were analysed sepa-rately, and all statistical tests were two sided.

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Table 1 Demographic and migraine characteristics of the study population

Group A Group BTotal population n = 443 n = 438

Men (n (%)) 85 (19) 70 (16)Women (n (%)) 358 (81) 368 (84)Age (y) (mean (SD)) 41 (10-8) 40-5 (10-3)Weight (kg) (mean (SD)) 68-9 (14-6) 69-2 (15-2)Migraine history (n (%))

Frequency:1-4 attacks/month 385 (87) 388 (89)1-4 attacks/week 58 (13) 49 (11)Daily 0 1

Type:Without aura 223 (50) 207 (47)With aura 75 (17) 74 (17)Both 145 (33) 157 (36)

Severity:Mild 2 (< 1) I (< 1)Moderate 101 (23) 97 (22)Severe 340 (77) 340 (78)

The safety data were not analysed statisti-cally. All patients who treated one or moreattacks with study medication were includedin the safety population. Adverse events thatoccurred on more than one occasion in anypatient were reported each time the eventoccurred.

(13%) were withdrawn. In group A, the mainreasons for withdrawal were patients asking towithdraw (23 patients, 5%), failure to returnfor follow up visits (22 patients, 5%), andadverse events (17 patients, 4%). In group B,20 patients (5%) withdrew because of adverseevents, 13 (3%) wished to withdraw, and 15(3%) did not return for follow up.More than 64% of patients in each group

treated three attacks during the study period.The total samples of patients with one, two,and three attacks were 400, 344, and 288respectively, in group A, and 400, 340, and285 respectively in group B.

INCIDENCE OF RECURRENCEOnly those patients whose recurrentheadaches met the defined criteria and whohad complied strictly with the assessmenttimetable and medication protocols wereincluded in the data analyses. Headache recur-rence during three attacks was experienced by14%-15% of those randomised to receive asecond dose of sumatriptan and by 10%-12%of those who were randomised to receiveplacebo (fig 1).

ResultsSTUDY POPULATIONA total of 924 patients were enrolled into thestudy, and 881 entered the treatment phase:433 patients were randomised to group A(sumatriptan for recurrence) and 438 wererandomised to group B (placebo for recur-rence). The two groups had similar demo-graphic and migraine characteristics (table 1),incidence of concomitant diseases, and med-ication. Most patients were women and experi-enced one to four severe or moderate attacksper month of migraine with or without aura.More patients in group A (22%) than in groupB (17%) had taken prophylactic medicationfor migraine in the three months before enter-ing the study. The most common drugs forprophylaxis were pizotifen and propranolol,which together accounted for 70% (group A)and 83% (group B) of the prophylactic drugsused. Other drugs used included clonidinehydrochloride and amitriptyline hydrochlo-ride.

During the course of the study 60 patientsin group A (14%) and 58 patients in group B

Figure 1 Incidence ofrecurrence of migraineheadache 1-24 hours afterinitial treatment with 6 mgsubcutaneous sumatriptan.Group A: 6 mgsumatriptan +6 mgsumatriptan (for recurrenceonly); group B: 6 mgsumatriptan + placebo (forrecurrence only).

Attack 1

c

EFFICACYTreatment of recurrenceAt one hour after treatment of a recurrence,relief ofheadache (from grade 3 or 2 to grade 1or 0) across the three attacks was reported by84%-93% of patients who took sumatriptanand by 31%-50% of those who took placebo(fig 2). For each of the three attacks there wasvery strong evidence of a true treatment differ-ence in favour of sumatriptan in the propor-tions of patients with headache relief one hourafter treatment of recurrence (P < 0 0005).For attack 1, the estimate of the true treatmentdifference was 34 percentage points (pp) infavour of group A (95% confidence interval15-52 pp). For attacks 2 and 3 the estimateand 95% confidence intervals were 54 (36-72)pp and 51 (33-70) pp respectively.

At each attack, subsequent rescue medica-

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2 Headache relief one hour after treatment ofIce of migraine headache with 6 mg subcutaneousiptan or placebo. Headache reliefwas defined as an in severity of headache from grade 3 or 2 to grade

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The efficacy of subcutaneous sumatriptan in the treatment of recurrence of migraine headache

Figure 3 Use of rescuemedication from one hourafter treatment of arecurrence of migraineheadache with 6 mgsubcutaneous sumatriptanor placebo.

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55% of patients in group B reported a total of912 adverse events. Table 2 shows the mostoften reported adverse events. Injection sitereactions occurred in 9%-i1% of treatments.Most events were mild to moderate in severity(84% in group A and 84% in group B), andmore than 96% had resolved at the time ofassessment.

Sixteen patients in group A (4%) and 19patients (5%) in group B withdrew from thestudy because of adverse events after begin-ning the study medication. The most commonreasons for withdrawal due to adverse eventswere nausea and tightness in the chest. Threeper cent of patients in each group reportedchest symptoms after sumatriptan. Fifteenpatients had 12 lead ECGs taken after suchsymptoms and all ECGs were assessed as nor-mal by the independent cardiologist.

tion was required by more patients who tookplacebo to treat headache recurrence than bythose who took sumatriptan (fig 3). For thefirst attack the difference between the twotreatment groups in this respect neared signifi-cance (P = 0-056).

Headache relief after the first dose sumatriptanMore than 76% of patients in both treatmentgroups obtained headache relief one hour afterdose 1 (6 mg sumatriptan given subcuta-neously) at each attack, and 41%-50% wereheadache free. These data are uncontrolledbut are in keeping with published placebo con-trolled studies.7 Most patients (75%-80%) didnot require rescue medication.

Patients' assessment of treatmentOf those patients who gave their opinion at theend of the study period, 80% in group A and78% in group B rated the efficacy of the treat-ment as good or excellent.

Tolerability and safetyA total of 402 patients in group A and 401patients in group B treated one or moreattacks with study medication. In total, 1033and 1025 attacks were treated in groups A andB respectively.

After treatment, 58% of patients in group Areported a total of 970 adverse events, and

Table 2 Mostfrequent adverse events* that occurred after the study medication had beenstarted

Percentage of attacks with adverse event

Group A Group B(6 mg sumatriptan + (6 mg sumatriptan +

Adverse event 6 mg sumatriptan) + placebo)

Nausea/vomiting 11 8Dizziness/vertigo 12 6Tingling 9 5Injection site reaction 4 5Feeling of heaviness 1 6Warm/hot sensation 2 4Paraesthesia 4 2Chest symptoms 3 3Fatigue/malaise 3 2Throat symptoms 3 2No of attacks treated 1033 1025Total No of adverse eventst 971 912No of patients with adverse events 235 (58%) 220 (55%)

*Events that occurred in > 3% of attacks in either group.tSome patients reported more than one symptom.

DiscussionThis study was designed prospectively toascertain, in a large clinical trial, the incidenceof recurrence of migraine headache after suc-cessful treatment with 6 mg subcutaneoussumatriptan. The definition of headacherecurrence used was precise and likely to be ofclinical relevance. The efficacy of a secondsubcutaneous dose of 6 mg sumatriptan forthe treatment of the recurrent headache wasalso assessed according to strictly defined cri-teria.The patient population entered into the

present study was similar in demographiccharacteristics to the general migraine popula-tion. Most patients were women, who had hadmigraine attacks for more than 15 years(median) and most attacks were of migrainewithout aura. Patients were severely affectedby their attacks, reporting one to four migraineattacks per month. The attacks were typicallysevere in intensity, and lasted from severalhours to several days. Although more patientsin group A (22%) had taken prophylacticmedication for migraine than in group B(17%), it is unlikely that this had any signifi-cant effect on severity or duration of headache.Recent studies have shown that pizotifen doesnot have a significant effect on severity ofattacks. I'The overall incidence of recurrence was

10%-15% after a single 6 mg dose of subcuta-neous sumatriptan during this study. This rateof recurrence is much lower than that reportedin earlier studies in which a precise definitionof recurrence was not used. Recurrence over48 hours was reported by 46% of patientswho administered 6 mg sumatriptan subcuta-neously themselves,7 and within 24 hours by38% of patients given subcutaneous injectionsof 6 mg sumatriptan by a physician.6 Patientsin these studies were asked only to recordwhether their headaches had returned duringthe specified period, with no attempt beingmade to verify that the returning headache wasa migraine, and no account was taken of theuse of rescue or non-study medication. It islikely, therefore, that the recurrent headachereported by some of the patients was a mild

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recovery phase headache which would notalways warrant further treatment. In the pre-sent study mild recurrent headache, after dose1, was reported by only 2%-4% of patients ineach attack. Including these mild recurrentheadaches in the analysis would therefore notgreatly effect the results of this study.

Sumatriptan is a drug with a relatively shorthalf life (about two hours) after subcutaneousadministration.'2 Plasma concentrations of thedrug decrease very rapidly after injection, andare low by five to seven hours after administra-tion. By contrast, a migraine attack may lastup to 72 hours. The recurrence of a trulymigrainous headache may therefore be theresult of the migraine attack outlasting theduration of the effect of the treatment.'3 Thisrecurrent headache should not be confusedwith rebound headache, which can occur inpatients who use medication very frequently,often daily, and in excessive doses. Suchpatients may develop drug induced headachewhich becomes worse with continuing medica-tion, but discontinuation of treatment can leadto the development of a drug withdrawalheadache.'4 15 Studies on the long term patternof use of sumatriptan have disclosed no evi-dence of any such dose escalation,'6 but occa-sional cases of rebound headache have beenreported in patients misusing sumatriptan-that is, taking regular daily doses.'7 18

Sumatriptan was effective in treating therecurrence of the migraine headache. Overthree attacks, 84%-93% of patients reportedheadache relief one hour after taking 6 mgsumatriptan subcutaneously to treat a recur-rence, in comparison with 31%-50% ofpatients who took placebo. The differencebetween the two treatment groups was highlysignificant (P < 0-0005). The response toplacebo was quite high, and this may berelated to the high expectancy of the patients,as both treatment groups took 6 mg subcuta-neous sumatriptan as dose 1 to treat the initialmigraine attack. In this study data were gath-ered from patients who had treated one, two,or three attacks. Although some patientstherefore may have contributed two or threesets of data, each attack was analysed sepa-rately.

This study was the first large scale trialundertaken in general practice with sumatrip-tan in which the patients self administered thedrug using an autoinjector. This method ofadministration proved to be very acceptable tothe patients. About 80% of patients in bothtreatment groups rated the efficacy of themedication as good or excellent, and morethan 80% said they would take the medicationagain. More than 800 patients treated one ormore migraine attacks with subcutaneoussumatriptan, but only one patient reported afaulty autoinjector, and only three were unableto self inject. The incidence of injection sitereactions was low, with reactions occurring inabout 10% of attacks-a level of incidencesimilar to that in earlier clinical trials of suma-triptan given with this autoinjector.7 Only twopatients withdrew from the study because ofreactions at the injection sites.

In conclusion, subcutaneous sumatriptangiven by the patients themselves with anautoinjector is an effective and well toleratedtreatment for migraine. A second 6 mg dosewas effective in relieving recurrence ofheadache, which was reported by a minority ofpatients. The efficacy of sumatriptan wasmaintained over treatment of up to threeattacks.

The study was supported by Glaxo Wellcome UK Ltd,Stockley Park West, Uxbridge, Middlesex, UB11 1 BT.The following doctors participated in the trial:

Dr AJ Hulme and Mr A Browning, (GlaxoWellcome Uk Ltd.)Aarons BM, Abbott RJ, Acharya HK, Adams RM, AitchisonWRC, Allen A, Anand H, Anand MS, Anderson EM,Anderson AMR, Arastu ZH, Arthur CP, Astles JG, AthertonMTC, Atkin M, Babinskyj RM, Ballantine DI, Barbour J,Barnard PD, Berger AB, Bhatia IL, Bhutani HC, Birrell DH,Blagden MD, Blewitt NJ, Boddie HG, Bradley JH, BraidwoodL, Bremner AD, Brown ID, Brown MM, Campbell AM,Campbell J, Came DR, Carpenter SF, Carr WD, Cartmel RM,Chalmers AJ, Chandra U, Chattopadhyay PK, Chauhdry MS,Cheridjian VE, Clark MC, Clark WIC, Cleleand PG,Coladangelo RC, Compson LJ, Corrighan GA, Costello FT,Counihan RG, Cowlard RJ, Cox MH, Cull RE, CuthbertsonPJR, Daengsvang PADC, Dalton PG, Davidson DLW, DaviesE, Davies GP, Davies EGL, Davis KJ, Debney FWD, DrakeLA, Duggal AN, Dunbar AP, Edgley JN, Evans EC, FaruqiMT, Fearns SN, Feld MS, Fell PJ, Flynn JF, Ford GC, GaleAN, Ganguli A, Gerg RK, Gibson DA, Glass J, Glover M,GodfreyJJ, Gordon DH, Gostling AC, GovesJR, Gowling GE,Graham RD, HamillJS, Handa Sk, Hanany WF, Harding MJ,Hargrave DC, Harries AI, Harries IG, Hartill SA, HaugneyMGJ, Hawker H, Hennessy TD, Herd EJ, Hewett MF, HirstAM, Horsfield P, Hudgson P, Hutchinson I, Hutchinson G,Hyatt-Williams R, Hyde JC, Jackson NR, Jackson EP, JafriSKA, Janikiewicz SMJS, Jefferson D, Jennings J, Johnson ML,Jones JP, Jones HHG, Jones DG, Kanungo SM, Khan MA,Kilgallon B, Krasner EB, Lakhani DN, Langridge DA,Lawrence RS, Lloyd RS, Loizou LA, Long RJ, Macauley SJ,MacIntosh NJ, MacLean MH, Mahamood K, Marazzi PJM,Marshall AH, Martin HM, Martin C, McGarrity C, McHattieAG, McInnes GK, McLaren GI, McWilliams JG, Messing HJ,Mitchell DG, Mittal VK, Mooney PN, Moore AC, MorganGF, Muggleton RJ, Multani SS, Mutch MW, Nagle PJ,Nahami GR, Nath BK, Nicholas ME, Nightingale MD, North-Coombes DP, Nutley PG, O'Horan P, Parkinson K, Parr-Burman SJ, Patel KS, Patel JA, Patel VA, Patel NH, PearceRLV, Pilpel JM, Plant NA, Prasad YN, Price E, Price WH,Ralphs GJG, Rees-Jones DI, Reid JJ, Rodger GN, RogersDCG, Rohatgi S, Rohatgi MK, Ruddock FS, Rummens IF,Sacks GE, Sadler SJ, Salter DHR, Samal K, Scott RJ, SelfridgeDI, Servant JB, Seth AK, Sharples PE, Shaw G, Sinclair NM,Smith F, Smye RA, Steiner NBM, Steiner RR, Stoy NS,Swales VS, Tandon PK, Tarrant PD, Thomas MJ, Thomas SJ,Thornton PW, Till RJW, TobiasJA, Trueman MD, Udal MS,VasanS, Vose MA,WlakerJA, Ward RJ, Warren KE, WebbEJ, Whiting AJ, Williams AP, Williams PH, Williams JAG,Willmott NJ, Wilson PST, Woo PYC, WoodJA, Wood N,Wood IHY, Wright MHG, WrightJ, Wyper DJ, Young BS,ZachariahJ.

1 Humphrey PPA, Fenuik W. Mode of action of the anti-migraine drug sumatriptan. Trends Pharmacol Sci 1991;12:444-6.

2 Hamel E, Fan E, Linville D, Ting V, VillemureJ, Chia LS.Expression of mRNA for the serotonin 5-hydroxytrypta-mine 1 Db Receptor subtype in human and bovine cere-bral arteries. Mol Pharmacol 1993;44:242-6.

3 Pilgrim AJ, Blakeborough P. The clinical efficacy of suma-triptan in the acute treatment of migraine. Reviews ofContemporary Pharmacotherapy 1994;5:295-309.

4 Simmons VE, Blakeborough P. The safety profile of suma-triptan in the acute treatment of migraine. Reviews ofContemporary Pharmacotherapy 1994;5:319-28.

5 Cady RK, WendtJK, KirchnerJR, SargentJD, RothrockJF, et al. Treatment of acute migraine with subcutaneoussumatriptan. JAMA 199 1;265:2831-5.

6 The Subcutaneous Sumatriptan International StudyGroup. Treatment of migraine attacks with sumatriptan.NEnglJ7Med 1991;325:316-21.

7 The Sumatriptan Auto-injector Study Group. Self-treat-ment of acute migraine with subcutaneous sumatriptanusing an auto-injector device. Eur Neurol 1991;31:323-31.

8 O'CallaghanJ, for the Study Group. Long-term efficacy ofsubcutaneous sumatriptan using a novel self-injector.Cephalalgzia 1993;13(suppl 13):161.

9 Headache Classification Committee of the InternationalHeadache Society. Classification and diagnostic criteriafor headache disorders, cranial neuralgias and facial pain.Cephalalgia 198;8(suppl 7):19-28.

10 Machin D, Campbell MJ. Statistical tables for the design ofclinicaltnials. Oxford: Blackwell Scientific, 1987.

11 Cleland PG, Barnes D, Elrington GM, Schapira AHV.Does Pizotifen prophylaxis improve migraine beyond the

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12 Fowler PA, Lacey LF, Thomas M, Keene ON, TannerRJN, Baber NS. The clinical pharmacology, pharmacoki-netics and metabolism of sumatriptan. Eur Neurol 1991;31:291-4.

13 Blau JN. Sumatriptan and the recurrence of migraine.Lancet 1992;340: 1110.

14 Mathew NT. Drug-induced headache. Neurol Clin 1990;8:903-12.

15 Mathew NT, Kurman R, Perez F. Drug-induced refractory

headache-clinical features and management. Headache1990;30:634-8.

16 Tansey MJB, Pilgrim AJ, Martin PM. Long-term experi-ence with sumatriptan in the treatment of migraine. EurNeurol 1993;33:310-5.

17 Catarci T, Fiacco F, Argentino C, Sette G, Cerbo R.Ergotamine-induced headache can be sustained by suma-triptan daily intake. Cephalalgia 1994;14:374-5.

18 Catarci T, Lenzi GL, Cerbo R, Fieschi C. Sumatriptan anddaily headache. J Neurol Neorosurg Psychiatry 1995;58:508.

HISTORICAL NOTES

Octave Landry's ascending paralysis and the Landry-Guillain-Barre-Strohl syndrome

Jean Baptiste Octave Landry de Theizillat (1826-65)was born in Limoges. He was greatly influenced instarting the study of medicine by his uncle, the neu-ropsychiatrist Dr de Thezillat. While still a traineephysician under Sandras and Gubler at the H6tel Dieuand Hopital Beaujon in 1852, he showed that muscularactivity, both active and passive, depended on afferentrelays derived from muscles: "sens de l'activite". Thisimportant notion foreshadowed by three years thesame conclusion reached by Duchenne and Bellion.

In 1859 he published the first volume of his Traitecomplet des paralysies. And, in the same year his famousmemoir on "ascending paralysis" recorded 10 patients,including five whom he had personally attended; threedied, two at the height of the illness, one some monthslater. He described three types of presentation: ascend-ing paralysis without sensory signs or symptoms;ascending paralysis with concomitant ascending anaes-thesia and analgesia; and a progressive generalised dis-order characterised by paralysis and sensory loss.

Landry described the illness that he called "ascendingparalysis",' in a 43 year old paver. After premonitoryfever, malaise, and pain in the limbs, on 1 June hewalked to hospital complaining of "weakness, formica-tions in the tips of his fingers and toes". There was nocramp, spinal pain or sphincter disturbance. Touchwas lost in the feet but was little impaired in the uppertwo thirds of the lower limbs; it was absent in the fingertips.The paralysis ascended, with formications and sen-

sory loss: "like a band around the affected parts". Hehad to be supported when standing by his bed. By thethird week his limbs were paralysed, he developed diffi-culty in breathing, chewing, and swallowing, accompa-nied by fever and coughing. Touch was lost in the feetand impaired in the finger tips, but, "pain and temper-ature sensation were not altered anywhere". The paverperished in the third week. The location of his illness

in the peripheral nerves remained undiscovered, forthe necropsy included histological examination only ofthe cord and soleus muscle. Gubler examined andcommented on the case drawing a parallel with diph-theritic paralysis; he mentioned exhaustion of the ner-vous system and permanent defects of innervation, buthaving come so close to the truth, curiously, failed toexamine the peripheral nerves.

Samuel Wilks furnished details of nine such cases ofascending paralysis, recorded in his book in thechapter on the spinal cord; but its peripheral neuralorigin was not suspected. Wilks thought "it might bedue to a reflex paralysis in which the cord is in no waystructurally altered, and therefore may at any timerecover . . . "2

Polyneuropathy is a recent name replacing Ernstvon Leyden's (1832-1910) term "multiple neuritis".3The first account was probably one of beriberi neuritisdescribed by Bontius in 1642.4 Robert Graves in 1843deserves credit for first implicating disease of theperipheral nerves as a cause of paralysis.5 While inParis in 1828 Graves observed the remarkable epi-demic of acute sensorimotor polyneuropathy, aetiolog-ically still obscure. Described by Auguste-FrancoisChomel,6 it was known as epidimie de Paris. Graves'account in 1843 is to be found in his ClinicalLectures.7

In 1876 Westphal referred to "Landry's ascendingparalysis". Five years after Landry's account LouisDumenil (1823-1890) provided the first account ofthe peripheral nerve pathology in four patients and insix published reports. His first was a 71 year old stonecutter afflicted by a Landry's type of neuropathy:

"a genuine atrophy of the medullary substance of theperipheral nerve tubes and related loss of transverse stria-tions of shrunken muscle fibres in the periphery."8

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