Scientific Session II: Pharmacology

SCIENTIFIC SESSION II

Pharmacology

OR11

Novel targets for migraine therapy

P. J. Goadsby

Institute of Neurology, The National Hospital for Neurology

and Neurosurgery, London, UK

The 1990s might usefully be thought of as the decade of the

triptans. The isolation of a serotonin, 5-HT1-like receptor in

the cranial circulation by Humphrey and collaborators and its

speci®city in closing arterio-venous shunts, heralded a major

advance in migraine therapy. The development of the triptans

brought substantial bene®ts to many very disabled patients,

and pointed to neuroanatomical and pathophysiological

substrates for further developments. Some of these targets

have been tested and found wanting, while others show great

promise. Many will be tested over the next 5 years and

hopefully new, particularly non-vascular targets will be

found. Novel targets that do not have antimigraine effects:

a number of targets for acute antimigraine compounds have

been suggested by the model of neurogenic plasma protein

extravasation (PPE) in the rat. Some have been tested and

failed, notably substance P (neurokinin-1) antagonists,

endothelin antagonists and speci®c potent PPE blockers,

CP122 288 and 4991w93. Novel targets explored and as yet

unclear: Sumatriptan is a serotonin 5-HT1B/1D/1F agonist, so

two possibilities have been tested. Initial studies with 5-HT1F

receptor agonists suggested that they worked as antimigraine

agents but toxicity problems stopped that compound. Initial

studies with a 5-HT1D agonist were not successful but this

compound may not have been optimal. Nitric oxide (NO)

synthase inhibitors have been studied and worked in one

placebo-controlled trial. This observation bears repetition and

exploration with NO being a major possible target. Novel

targets to be explored: A number of targets can be adduced

from trigeminovascular anatomy and physiology; these

include calcitonin gene-related peptide (CGRP) antagonists,

which have the best rationale, excitatory amino acid receptor

antagonists, adenosine A1 receptor agonists and channel

modulators. The future is bright with a number of possible

targets that may deliver more effective, or safer options to the

many patients who seek adequate care of acute migraine.

OR12

IV LY293558, an AMPA/KA receptor antagonist,is effective in migraine

N. Ramadan1, C. Sang2, A. Chappell1, F. Vandenhende1,K. Johnson1, L. Phebus1, D. Bleakman1, P. Ornstein1,B. Arnold1, F. Freitag3, T. Smith4, S. Silberstein5

& S. Tepper6

1Eli Lilly & Co., Indianapolis, IN, USA, 2Massachusetts General

Hospital, Boston, MA, USA, 3Diamond Headache Clinic,

Chicago, IL, USA, 4Unity Health Research, Chester®eld,

MO, USA, 5Jefferson Headache Center, Philadelphia, PA, USA,6New England Center for Headache, Stamford, CT, USA

Background Glutamate hyperactivity is implicated in

migraine. LY293558 is an AMPA/KA receptor antagonist

with proven ef®cacy in preclinical models of migraine, and is

inactive in the rabbit saphenous vein model up to 10±4M.

Objective To test the ef®cacy and tolerability of LY293558

during migraine.

Methods Randomized, placebo-controlled, double-blind,

double-dummy, multicentre study of 1.2 mg/kg iv

LY293558 (LY), 6 mg sc sumatriptan (S) or placebo (Pl) to

treat an IHS-diagnosed moderate or severe migraine¡aura.

Severity of headache or associated symptoms (AS) was scored

as 0=no symptom, 1=mild, 2=moderate, 3=severe. Ef®cacy

measures were: response (R=% with headache mild or no

pain 2 h postdosing), pain free (PF=% without headache at

2 h), sustained response (SR=% with response at 2 h and no

rescue/recurrence from 2±24 h), sustained pain free (SPF=% pain free at 2 h and no rescue/recurrence from 2±24 h),

recurrence (RR=% responders/pain free with 2/3 headache

from 2±24 h), relief of AS (% with no symptom at 2 h, from a

2/3 baseline score). Adverse events (AEs) were recorded for

24 h. The study was conducted in accordance with IHC

Guidelines.

Results 44 patients (M:F=20 : 24; age [mean ¡ SD]

=40¡9 years) completed the study. Ef®cacy results are in

the table [*P=0.017 LY293558 vs placebo, **P<0.01 LY293558

or sumatriptan vs placebo; P>0.1 sumatriptan vs LY293558

for all comparisons (chi-square test)]. Two (15% of patients on

LY), eight (53% on S) and ®ve (31% on Pl) reported AEs

(P=0.037 LY vs S), which included chest/throat symptoms

(0% LY, 13% S, 0% Pl), disorientation (8% LY, 27% S, 6% Pl),

dizziness (15% LY, 27% S, 13% Pl), extremity heaviness/

tingling (0% LY, 33% S, 0% Pl), nervousness (0% LY, 7% S, 0%

Pl), sedation/drowsiness (15% LY, 33% S, 25% Pl), warm

feeling (8% LY, 33% S, 6% Pl), and visual symptoms (8% LY,

27% S, 6% Pl).

# Blackwell Science Ltd Cephalalgia, 2001, 21, 267±272 267

Conclusions This is the ®rst demonstration that an AMPA/

KA receptor antagonist is clinically effective in migraine.

Also, iv LY293558 was as effective and better tolerated than

sc sumatriptan. These observations combined with preclinical

evidence of no vasoconstriction of LY293558 provide

good evidence for the role of non-vasoactive AMPA/KA

antagonists in migraine.

OR13

GLUR5 antagonists as novel migraine therapies

K. W. Johnson1, D. K. Dieckman1, L. A. Phebus1,M. A. Kato®asc1, M. L. Cohen1, K. W. Schenck1, S. A. Filla1,P. L. Ornstein1, A. M. Ogden1, N. M. Ramadan1, K. Jarvie2,K. Ho2 & D. Bleakman1

1Neuroscience Research, Eli Lilly and Company, Indianapolis,

IN, USA, 2NPS/Allelix, Toronto, ON, Canada

Background L-glutamate activates neurons in the trigeminal

nucleus caudalis (TNC). Furthermore, non-NMDA ionotropic

glutamate receptors such as GluR5 are expressed in rat

trigeminal ganglion (TG), and GluR5 receptors play an

important role in central sensitization (CS). CS is implicated

in, and the trigeminal system is at the core of, migraine.

Therefore, we hypothesized that GluR5 receptor antagonists

would be effective in preclinical models of migraine.

Objectives (1) To test the potency and ef®cacy of GluR5

antagonists with varying degrees of af®nity and selectivity

for the GluR5/kainate receptor in the dural plasma protein

extravasation (PPE) and the c-fos models of migraine.

(2) To test these GluR5 receptor antagonists for their ability

to contract the rabbit saphenous vein (RSV) in vitro.

Methods GluR5 antagonists were synthesized in the Lilly

Research Laboratories. Ligand binding studies using recom-

binant human non-NMDA receptors expressed in HEK293

cell membranes were used to determine compound af®nity.

We evaluated parenterally administered compounds in the

PPE and the c-fos models induced by electrical stimulation

of male rats' TG. Fos protein in the TNC was measured in the

c-fos experiment. Ring preparations of RSV were suspended

in tissue baths and isometric contractions were recorded

following incremental increases in the concentration of the

test compound. Sumatriptan was used as a positive control

for the RSV studies.

Results LY293558, LY382884 and LY435735 dose-

dependently blocked protein extravasation in the PPE

model. The rank order of potency correlated with af®nity

for GluR5. In contrast, LY300168, a potent and selective

AMPA antagonist, did not block protein extravasation, even

at relatively high doses. LY293558 and LY435735 also blocked

c-fos expression in the TNC. LY293558 and LY382884 did not

contract the tissue in the RSV assay at concentrations up to

100 mM.

Conclusions The inhibitory effects of GluR5 antagonists in

the PPE and c-fos preclinical models of migraine suggest a

novel role for GluR5 antagonism in migraine therapy. The

lack of ef®cacy of the selective AMPA antagonist LY300168 in

PPE does not support a role for this mechanism in migraine.

The lack of activity of these compounds in the RSV provides

a therapeutic advantage of GluR5 antagonists over current

vasoactive migraine therapies. These pharmacological prop-

erties of GluR5 antagonists suggest that they could be used in

the treatment of acute migraine without a cardiovascular

liability.

OR14

Inhibition of trigeminal nociceptive afferents byadenosine A1 receptor activation: a novel approachtowards the design of new anti-migrainecompounds

P. P. Humphrey1,2, P. A. Bland-Ward2, A. M. Carruthers1,H. E. Connor2, W. Feniuk1,2, A. C. Honey2 & M. Thomas2

1Glaxo Institute of Applied Pharmacology, University of

Cambridge, Cambridge, UK, 2Headache Research Group, Glaxo

Wellcome R&D, Stevenage, UK

Introduction The discovery and development of sumatriptan

has revolutionized the acute treatment of migraine. The

antimigraine effects of sumatriptan are mediated via 5-HT1B

and 5-HT1D receptors. These receptors transduce their effects

via G proteins of the Gi type, and hence we have examined the

effects of agonists at other Gi protein-coupled receptor types

for their trigeminovascular actions. One such receptor is the

adenosine A1 receptor at which GR 79236 is a highly selective

agonist (1).

Methods The release of CGRP was measured by an ELISA

from rat trigeminal neurones cultured as described by Eckert

and colleagues (2). The effects of GR79236 on neurogenic

vasodilatation of meningeal arteries were measured in the

anaesthetized rat using intravital microscopy (3). The central

effects of GR 79236 were examined on noxious inputs from

the dura to the trigeminal nucleus caudalis (TNC) using an

in vivo electrophysiological model and protocol like that

reported by Cumberbatch and colleagues (4).

Results We have shown that A1 receptors are located on

human trigeminal neurones (5) and that GR79236

(10 nMx1 mM) inhibited CGRP release from rat trigeminal

neurones in culture by about 70%. In in vivo studies, GR79236

(1±10 mg/kg) inhibited neurogenically mediated vasodilata-

tion, which results from CGRP release from perivascular

trigeminal nerve terminals innervating the meningeal vascu-

lature. In separate experiments involving electrical stimula-

tion of the meninges, GR 79236 (10 and 30 mg/kg) also

Pl LY S

n

R (%)

PF (%)

SR (%)

SPF (%)

RR (%)

Photophobia relief (%)

Phonophobia relief (%)

Nausea relief (%)

16

4 (25)

1 (6)

1 (6)

0 (0)

1/2 (50)

1/14 (7)

1/11 (9)

1/9 (11)

13

6 (69)*

7 (54)**

9 (69)**

7 (54)**

0 (0)

9/13 (69)*

7/10 (70)**

8/10 (80)**

15

13 (86)*

9 (60)**

12 (80)**

9 (60)**

1/13 (8)

9/14 (64)**

7/11 (64)**

6/7 (86)**

# Blackwell Science Ltd Cephalalgia, 2001, 21, 267±272

268 Scienti®c Session II

markedly inhibited transmission centrally within the TNC.

All these effects were attributable to A1 receptor activation.

Conclusion We have shown that activation of A1 receptors

leads to inhibition of trigeminal neurones and their release of

CGRP both in vitro and in vivo. This suggests that agonists at

A1 receptors may be useful in the acute treatment of migraine.

Early indications from pilot clinical studies suggest that

GR 79236 does have an antimigraine action, which prob-

ably results from an inhibitory effect on nociceptive tri-

geminal neurones. The implications and insights gained from

pursuing this novel integrated approach to ®nding new

antimigraine drugs will be discussed.

References

1 Gurden MF et al. Br J Pharmacol 1993; 109:693±8.

2 Eckert SP et al. J Neurosci Meth 1997; 77:183±90.

3 Honey AC et al. Cephalalgia 2000; 20:419.

4 Cumberbatch MJ et al. Eur J Pharmacol 1997; 328:37±40.

5 Schindler M et al. Neurosci Lett 2001; 297:211±5.

OR15

Effect of adenosine (A1) receptor agonist GR79236on trigeminal nociception by blink re¯ex recordingsin healthy human subjects

N. J. Gif®n1, F. Kowacs1, V. Libri2, P. Williams2,P. J. Goadsby1 & H. Kaube1

1Headache Group, Institute of Neurology, London, UK,2Neurology Centre of Excellence in Drug, GlaxoSmithKline,

Greenford, UK

Introduction There are no good migraine models in humans,

although established models of trigeminovascular nocicep-

tion in animals exist. The recent development of a low-current

intensity trigeminally mediated blink re¯ex (BR) allows the

study of nociception speci®c transmission in the trigeminal

nucleus caudalis, believed to be pivotal in trigeminovascular

activation in migraine. Adenosine and its analogues are

antinociceptive in humans and animals. GR79236 is a highly

potent and selective adenosine A1-receptor agonist that has

been shown to have analgesic and anti-in¯ammatory actions

at doses with no cardiovascular effect and may have

therapeutic potential in migraine. We investigated the effect

of GR79236 on the nociceptive BR.

Methods 12 female healthy volunteers (20±36 years) were

randomized in a placebo-controlled double-blind crossover

study. Measurements: BRs were elicited by supraorbital nerve

stimulation with standard or nociception-speci®c electrodes.

Stimulation parameters: Monopolar square pulses, 300 ms,

10±15 mA for standard or 1.5±23pain sensation threshold

(1.43¡0.06 mA) for nociceptive re¯exes at random intervals

of 12±18 s. BR responses were recorded bilaterally from

infraorbital muscles (sampling frequency 2.5 kHz, 300 ms

sweeps and analysed of¯ine. Each measurement was based

on 25 sweeps. Areas under the curve (AUCs) of the R2

component of the BR were calculated from the recti®ed EMG,

before and 30 min after drug administration. Drugs: GR79236

(10 mg/kg) or placebo was administered IV over 15 min.

Primary end points: Median AUC at 30 min, modelled using

analysis of covariance with subject, period, treatment and

baseline AUC as terms in the model.

Results Comparison of the two groups showed a non-

signi®cant reduction of the ipsilateral nociceptive R2 after

GR79236 vs placebo of 17%(x567 [95% CI x1260±125.8]

mVms). However, there was a signi®cant reduction of the

contralateral nociceptive R2 (P<0.05) of 20%(x473 [95%

CI x786.6, x158.7] mVms).There were no signi®cant adverse

events attributable to GR79236.

Conclusion The contralateral BR is mediated via poly-

synaptic trigeminal connections. Although this pathway is

less well understood than the ipsilateral re¯ex, the results sug-

gest an inhibitory effect of the A1-receptor agonist GR79236

on trigeminal nociceptive pathways. The nociception-speci®c

electrode directly depolarises cutaneous ®bres and GR79236

may therefore act at second order trigeminal neurons in the

nucleus caudalis, or more rostrally, and thus crosses the

blood±brain barrier. This suggests that it may be effective in

primary headache disorders.

OR16

Characterization of the prostanoid receptor typesinvolved in mediating CGRP release fromtrigeminal neurones

D. W. Jenkins, W. Feniuk & P. P. Humphrey

Glaxo Institute of Applied Pharmacology, University

of Cambridge, Cambridge, UK

Objectives The neuropeptide, CGRP, is a potent vasodilator

that has been implicated in migraine. It is released into the

cephalic venous blood of migraineurs during attacks and

levels are normalised by the clinically effective antimigraine

agent, sumatriptan. The cyclooxygenase inhibitor, aspirin, is

also effective in treating acute migraine, particularly when

administered intravenously. This evidence, coupled with the

observation that prostaglandins can cause migraine-like

symptoms when injected into volunteers, suggests a role

for prostaglandins in migraine pathophysiology. In this

study, we have investigated the effects of prostaglandins on

CGRP release from cultured trigeminal neurones.

Materials and methods Primary cultures were derived from

adult rat trigeminal ganglia as previously described (1).

Neurones were grown for 4±6 days in the presence of nerve

growth factor (50 ng/mL) and cytosine-b-D-arabinofurano-

side (Ara-C; 20 mM). CGRP levels were measured after 30 min

using an enzyme immunometric assay (SPIbio, Massy,

France) and quanti®ed in pg/mL. To account for differences

in neuronal numbers between preparations, CGRP levels

following exposure to drug or vehicle (DMSO, 0.01%) were

compared to the baseline value obtained immediately before

stimulation in the same test well. All values are shown as

mean¡SE mean of at least 3 experiments, and drug

concentrations were all 1 mM. Statistical comparison was by

one-way analysis of variance followed by the Tukey test with


Pharmacology 269

P<0.05 being considered signi®cant. All experiments were

conducted in the presence of indomethacin (10 mM).

Results The average baseline CGRP concentration obtained

over 30 min was 106¡17 pg/mL that varied between 23 and

231 pg/mL (n=11 individual preparations) and no increase

in CGRP levels occurred in vehicle control wells (6.7¡8%).

Exposure to 1 mM PGE2, carbaprostacyclin (cPGI2) or PGD2

resulted in a signi®cant increase in CGRP levels of 199¡23%,

306¡41% and 150¡16%, respectively. In contrast, no CGRP

release was observed when cells were stimulated with PGF2a

(29¡24%), the thromboxane receptor agonist, U46619

(32¡26%), the EP3 receptor agonist, GR63799 (25¡5%), or

the EP3>EP1 receptor agonist, sulprostone (x6¡11%).

However, a signi®cant increase was observed in response

to the EP2 receptor agonist, butaprost (244¡23%), and the

EP3>EP2 receptor agonist, misoprostol (123¡14%).

Conclusion These data suggest that CGRP release from

trigeminal neurones can be stimulated by the activation of

either EP, IP or DP receptors, but not by FP or TP receptors.

Furthermore, the use of EP subtype speci®c agonists suggests

that the EP subtype involved may be the EP2 receptor.

Reference

1 Eckert et al. J Neurosci Meth 1997; 77:183±90.

OR17

Characterization of the effects of the CGRP receptorantagonist BIBN4096BS in SK-N-MC cells andisolated human cerebral, meningeal and coronaryarteries

L. Edvinsson1, R. Alm1, S. A. Kane3, R. Z. Rutledge3,K. S. Koblan3 & J. Longmore2

1Internal Medicine, Lund University, Lund, Sweden, 2Merck

Research Laboratories, The Neuroscience Research Centre,

Harlow, UK, 3Pharmacology, Merck Research Laboratories,

West Point, PA, USA

Intracranial and coronary blood vessels are innervated by

calcitonin gene-related peptide (CGRP) containing ®bres

originating in the sensory ganglion. During migraine attacks,

circulating levels of CGRP are elevated and administration of

the antimigraine drug sumatriptan has been shown to

normalize CGRP levels concomitant with headache relief. A

CGRP antagonist therefore may serve as a novel abortive

migraine treatment. Here we present data on a human cell

line and isolated human vessels for such an antagonist,

BIBN4096BS (1). On SK-N-MC membranes, radiolabelled

CGRP was displaced by both CGRP8-37 and BIBN4096BS,

yielding pKi values of 8.5 and 11.4, respectively. Functional

studies with SK-N-MC cells showed a CGRP-induced cAMP

production which was antagonised by both CGRP8-37 and

BIBN4096BS with pA2 values of 7.8 and 11.2, respectively.

Isolated human cerebral, meningeal and coronary arteries

were studied with a sensitive myograph technique. CGRP

induced a concentration-dependent relaxation which was

antagonized by both CGRP8-37 and BIBN4096BS in a

competitive manner. In the coronary arteries CGRP was

less potent as compared to the intracranial arteries;

BIBN4096BS was an effective antagonist also in this tissue.

In human omental arteries CGRP did not produce relaxation.

When compared to another CGRP antagonist, Compound 1

(2) BIBN4096BS was signi®cantly more potent. The clinical

effect on acute migraine attacks of the CGRP antagonists is

awaited with great interest.

Acknowledgement This study was supported by the

Swedish Medical Research Council (Grant 5958).

References

1 Doods H, Hallenmayer G, Dongmei W, Entzeroth M, Rudolf K,

Engel W, Eberlein W. Pharmacological pro®le of BIBN4096BS, the

®rst selective small molecule CGRP antagonist. Br J Pharmacol

2000; 129:420±3.

2 Edvinsson L, Sams A, Jansen-Olesen I, Tajti J, Kane SA et al.

Characterisation of the effects of a non-peptide CGRP receptor

antagonist in SK-N-MC cells and isolated human cerebral arteries.

Eur J Pharmacol. In press.

OR18

Intranasal sumatriptan is effective in the treatmentof acute cluster headache ± a double-blindplacebo-controlled crossover study

J. A. van Vliet2, A. Bahra1, V. Martin3, S. K. Aurora4,N. T. Mathew5 & P. J. Goadsby1

1Institute of Neurology, London, UK, 2Leiden University Medical

Centre, Leiden, Netherlands, 3Cincinnati Headache Center,

Cincinnati, OH, USA, 4Headache Center, Seattle, WA, USA,5Houston Headache Clinic, Houston, TX, USA

Cluster headache attacks reach a peak of pain intensity

quickly, and are short-lasting; therefore acute treatments need

to be fast acting. This study sought to determine if intranasal

sumatriptan is an effective treatment of acute cluster head-

ache. Patients with episodic and chronic cluster headache,

by IHS criteria, were recruited and after explanation and

obtaining informed consent were randomized to a double-

blind placebo-controlled two-period crossover study. Patients

were instructed to treat two attacks of at least moderate pain

severity, with at least a 12-h break, using intranasal

sumatriptan 20 mg or matching placebo. Patients recorded

the time of onset of the attack, time of treatment, headache

severity on a ®ve point scale (0-nil, 1-mild, 2-moderate,

3-severe, 4-very severe) at 5, 10, 15, 20 and 30 min after

treatment. The primary endpoint was the headache response

de®ned as: very severe, severe or moderate pain becomes

mild or nil, at 30 min. Secondary measures included pain free

rates, treatment of associated symptoms and adverse events.

The primary endpoint was analysed using a Multilevel

Analysis (1) approach with MLwiN (http://www.ioe.ac.uk/

multilevel) with P<0.05 as the level of signi®cance for testing.

In total, 118 patients were recruited; 97 males and 21 females.



Of these, 87 provided ef®cacy data on attack one and 81 on

attack two. Twenty-®ve provided no ef®cacy data because

their bout ended, and six were lost to follow-up. Six cycled

out of a cluster period between attack one and attack two.

Modelling the treatment outcome as a binomial where

response was determined by treatment, using the patient as

the level 2 variable, and considering period effect, sex, site

and cluster headache type as other variables of interest,

the effect of intranasal sumatriptan 20 mg was superior

to placebo at 30 min on the headache response endpoint

(P=0.01). For the ®rst attack the placebo response rate was

11/37 (30%) and the sumatriptan 20 mg rate 29/50 (58%);

for the second attack the rates were 15/45 (33%) and 18/36

(50%), respectively. There were no serious adverse events.

It can be concluded that intranasal sumatriptan 20 mg is

effective in the acute treatment of cluster headache when

compared to placebo. For cluster headache patients, these

data add a further evidence-based treatment to the manage-

ment portfolio of this disabling primary headache.

Reference

1 Snijders TAB, Bosker RJ. Multilevel analysis. In: An Introduction

to Basic and Advanced Multilevel Modelling, 1st edn. London:

Sage Publications, 1999.

OR19

Zolmitriptan nasal spray is effective, fast-actingand well tolerated during both short- andlong-term treatment

W. J. Becker1 & D. Lee2

1Foothills Medical Center, Calgary, AB, Canada, 2AstraZeneca,

Wilmington, DE, USA

Objectives Zolmitriptan nasal spray offers an alternative

formulation that may be advantageous for patients in terms of

rapid onset and convenience. The results of the ®rst clinical

study involving the nasal spray are presented, along with

results from a 1-year follow-up study. The objectives were

to determine the ef®cacy of zolmitriptan nasal spray com-

pared with zolmitriptan 2.5 mg oral tablet and placebo, and

to assess the long-term ef®cacy and tolerability of the

zolmitriptan 5 mg nasal spray.

Methods In the ®rst study, 1547 patients were randomized to

zolmitriptan nasal spray 0.5, 1.0, 2.5 or 5 mg, oral zolmitriptan

tablet 2.5 mg or placebo in a double-blind, double-dummy

manner for the treatment of 3 moderate or severe migraine

attacks. The primary end point was 2-h headache response

(reduction from moderate/severe pain at baseline to mild/

none). In the long term study, patients were initially

randomized to zolmitriptan nasal spray 0.5, 1.0, 2.5 or

5 mg. Once the optimal dose had been determined from

the dose-®nding study, patients were switched to the optimal

5 mg dose for the rest of the 1-year period.

Results 1371 patients were included in the ITT population of

the dose-ranging study. Each dose of zolmitriptan nasal spray

gave a signi®cantly greater 2-h headache response rate than

placebo. Response rates at 2-h for the 0.5, 1, 2.5 and 5 mg

doses were 41%, 55%, 59% and 70%, respectively, compared

with 30% for placebo (all P<0.001) and 61% for the 2.5 mg

tablet. The speed of onset following treatment with the nasal

spray was rapid. Within 15 min, a signi®cantly greater

headache response rate was seen with zolmitriptan 5 mg

nasal spray compared with placebo (11% vs 5% of attacks;

P<0.01). The ef®cacy of the nasal spray was examined in a

subgroup of patients with pretreatment nausea, i.e. those for

whom oral medication may not be optimal. In these patients,

42%, 49%, 58% and 68% of patients receiving nasal spray

doses of 0.5, 1, 2.5 and 5 mg, respectively, achieved a 2-h

headache response vs 31% for placebo and 57% for the tablet.

In the long term study, 783 patients took at least one dose of

zolmitriptan 5 mg nasal spray and treated a total of 10505

attacks. The nasal spray was consistently effective over time,

with 2-h headache response rates of 73%, 75%, 75% and 75%

for the periods 0±3, 4±6, 7±9 and 10±12 months, respectively.

Long-term use was well tolerated, with a low incidence of

adverse events that remained stable over the 12-month period

(24%, 20%, 23% and 22% of attacks for months 0±3, 4±6, 7±9

and 10±12, respectively).

Conclusions Zolmitriptan nasal spray has a rapid onset of

action and is highly effective in the treatment of migraine. The

nasal spray produces a consistent response and is well

tolerated with long-term use.

OR20

Ef®cacy of intramuscular droperidol formigraine treatment: a dose-response study

S. Silberstein1, W. B. Young1, J. E. Mendizabal2,J. F. Rothrock2 & A. S. Alam3

1Neurology, Thomas Jefferson University, Philadelphia, PA,

USA, 2Neurology, University of Alabama, Mobile, AL, USA,3Taylor Pharmaceuticals, Linolnshire, IL, USA

Objective To evaluate the ef®cacy and tolerability of 4

different doses of IM droperidol vs placebo for the acute

treatment of migraine with or without aura.

Background Droperidol, an adjunct during general anesthe-

sia, has been used to treat agitation, surgical pain in

combination with an opiate analgesic, and nausea and

vomiting. Two recent reports suggest that droperidol is

effective in selected migraine patients (1,2).

Design and methods Double-blind, placebo-controlled, ran-

domized, parallel group, 22-centre study. Patients had an IHS

migraine diagnosis and were randomized to one of four doses

of droperidol (0.1, 2.75, 5.5 or 8.25 mg) or placebo at clinic

visit 1. At migraine onset, patients returned to the clinic (visit

2) for treatment of a single moderate or severe attack via

intramuscular injection in the deltoid, thigh, or buttock

delivered as a 1-mL volume.

Results Of 537 screened patients, 305 patients received

treatment. Compared with placebo (57%), more patients in

the droperidol 2.75, 5.5 and 8.25 mg treatment groups

experienced a signi®cant reduction in headache by 2 h

(moderate or severe to none or mild; 87%, 81%, and 84%,


Pharmacology 271

respectively; primary outcome; P=0.0002). Onset of response

was assessed at multiple time points (secondary end point)

and was signi®cantly improved at 1 and 1.5 h with the

2.75- and 5.5-mg doses. The 8.25-mg group was statistically

superior to placebo at 0.5 h. Pain-free response rates were

signi®cantly greater than placebo at 1 h in the 2.75-mg

treatment group and more than 60% of patients receiving

droperidol were pain free at 2 h (placebo 30%). Headache

improvement >2 grade levels, fewer headache recur-

rences, less use of rescue medications, and fewer non-

headache-associated symptoms were signi®cantly associated

with droperidol doses >2.75 mg. AEs occurring in greater

than 5% of patients receiving droperidol included asthenia,

anxiety, akathisia, somnolence, and injection site reactions.

Most AEs were mild to moderate. Anxiety, akathisia, and

somnolence were present in 15±30% of patients with a dose

>2.75 mg (approximately 30% of these were of severe

intensity). There was no effect on standard clinical chemistry,

hematology, urinalysis, vital signs or ECG, or evidence of

adverse cardiovascular effects.

Conclusions Droperidol 2.75 IM is effective in treating acute

migraine headache with a 2-h headache response of over 80%

in patients with moderate to severe migraine. Higher doses

were no more effective, but produced more AEs.

References

1 Wang et al. Headache 1997; 37:377±82.

2 Mendizabal. Headache 1999; 10:55±7.



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Scientific Session II: Pharmacology