ORIGINAL CONTRIBUTION

chlorpromazine;
dihydroergotamine;
lidocaine;
migraine headache

A Comparative Trial of Three Agents in the

Treatment of Acute Migraine Headache

Study objectives: A study was conducted to evaluate the relative effi- Robert Bell, MD, FRCP(C)
cacy of three non-narcotic agents, chloropromazine, lidocaine, and dihy- David Montoya, MD, FRCP(C)
droergotamine, in the treatment of migraine headache in an emergency Asphaq Shuaib, MD, FRCP(C)
department setting. Mary Ann Lee, MD, FRCP(C)
Calgary, Alberta, Canada
Design: The trial was randomized and single blinded.
Setting: The study was conducted in two university-affiliated EDs.
Type of participants: All patients had an isolated diagnosis of common From the Department of Clinical
Neurosciences, University of Calgary,
or classic migraine. Foothills Hospital; and the Department of
Interventions: Patients were pretreated with 500 mL (IV) normal saline Emergency Medicine, University of
before r a n d o m i z a t i o n . S t u d y drugs as a d m i n i s t e r e d were d i h y - Calgary General Hospital, Calgary,
droergotamine 1 mg IV repeated after 30 minutes if the initial response Alberta, Canada.
was inadequate; lidocaine 50 mg IV at 20-minute intervals to a m a x i m u m
total dose of 150 mg as required; or chloropromazine 12.5 mg IV repeated Received for publication December 28,
at 20-minute intervals to a total m a x i m u m dose of 37.5 mg as required. 1988. Revisions received October 16,
Patients were asked to grade headache severity on a ten-point scale before 1989, and April 16, 1990. Accepted for
and one hour after the initiation of therapy. Follow-up by phone was publication April 26, 1990.
sought the following day.
Measurements and main results: Of 76 patients completing the trial, 24 Presented at the Canadian Royal College
were r a n d o m i z e d to receive chloropromazine, 26 to receive dihy- of Physicians Annual Meeting in ©ttawa,
droergotamine, and 26 to receive lidocaine. Reduction in mean headache Canada, September 1988.
i n t e n s i t y was ~significantly better among those treated w i t h chloro-
promazine (P < .005). Persistent headache relief was experienced by 16 of Address for reprints: Robert B Bell, MD,
the chloropromazine-treated patients (88.9%) contacted at 12 to 24 hours FRCP(C), Department of Neurology &
follow-up compared with ten of the dihydroergotamine-treated patients Neurological Sciences, Stanford University
(52.6%) and five of the lidocaine-treated group (29.4%). School of Medicine, Stanford, California
94305-5235.
Conclusion: The relative effectiveness of these three antimigraine thera-
pies appears to favor chloropromazine in measures of headache relief, inci-
dence of headache rebound, and patient satisfaction with therapy. [Bell R,
Montoy~a D, Shuaib A, Lee MA: A comparative trial of three agents in the
t r e a t m e n t of a c u t e m i g r a i n e headache. A n n Emerg M e d O c t o b e r
1990;19:1079-1082.]

INTRODUCTION
Migraine headache is a common disorder that affects approximately 20%
of the populationJ The management of these patients in the emergency
department presents a therapeutic challenge in attempting to provide ade-
quate relief without hospitalization, minimizing time spent in the ED, pro-
viding a low rate of rebound of headache on discharge, and avoiding poten-
tial for drug abuse. Narcotic analgesics have traditionally been the main-
stay of t r e a t m e n t , but because of the t r a n s i e n t nature of the ED
population, there is significant potential for drug abuse and iatrogenic drug
addiction. Recently, there has been attention focused on alternative ap-
proaches to therapy for acute management of migraine headache, and sev-
eral agents have been suggested as useful. 2-9 The relative efficacies of these
non-narcotic therapies, however, have not been demonstrated.
This study was designed to compare the results of treatment with three
agents in the management of acute established migraine in the EDs of two
University of Calgary-affiliated hospitals. Either dihydroergotamine (DHE),
ehloropromazine (CPZ), or lidocaine (LID) was given parenterally to con-
senting migraine patients presenting to the ED. Results of therapy were

19:10 October 1990 Annals of Emergency Medicine 1079/25

MIGRAINE HEADACHE
Bell et al
assessed at 60 m i n u t e s after initia-
tion of t r e a t m e n t . Because the poten-
tial for r e b o u n d headache subsequent
to t h e r a p y has n o t been a d e q u a t e l y
e v a l u a t e d in the l i t e r a t u r e , p a t i e n t s
in this s t u d y were also followed at 24
hours after treatment.
METHODS
Ninety-five adult patients present-
ing to the EDs of the Foothills or Cal-
gary G e n e r a l H o s p i t a l c o n s e n t e d to
participate in this study, w h i c h was
a p p r o v e d by t h e C o n j o i n t M e d i c a l
Ethics C o m m i t t e e , Faculty of Medi-
cine, at t h e U n i v e r s i t y of Calgary.
The chief c o m p l a i n t was headache,
and all p a t i e n t s were given a diag-
nosis of migraine headache by the at-
tending e m e r g e n c y physician.
Migraine headache was defined as
either c o m m o n , characterized by re-
c u r r e n t a t t a c k s of h e a d a c h e l a s t i n g
hours or days, associated with gastro-
i n t e s t i n a l d i s t u r b a n c e , and h a v i n g
some features of pulsatile character,
photophobia, sonophobia, uni-
l a t e r a l i t y , and p o s i t i v e f a m i l y his-
tory; or classic, exhibiting recurrent
a t t a c k s of h e a d a c h e as in c o m m o n
m i g r a i n e b u t p r e c e d e d by a motor,
sensory, or visual aura. Exclusion cri-
teria were n o n m i g r a i n e headache, age
less than 18 or m o r e than 60 years,
s u b s t a n c e abuse, n e u r o l o g i c or sei-
zure disorder, a l c o h o l abuse, allergy
or s e n s i t i v i t y , p r e g n a n c y or b r e a s t
feeding, p e r i p h e r a l v a s c u l a r disease,
coronary vascular disease, hyperten-
sion, or hepatic or renal failure.
After giving informed w r i t t e n con-
sent, p a t i e n t s w e r e r a n d o m i z e d to
one of three t r e a t m e n t groups in a
single-blind fashion w i t h only the pa-
t i e n t being b l i n d e d to the therapy.
Because of the disparate toxicity pro-
files of the three study agents and the
perceived need to m o r e closely focus
p a t i e n t m o n i t o r i n g to e x p e c t e d ad-
verse effects, the attending physician
and nursing staff were not blinded.
All patients had an IV line started
and received a 500-mL bolus of nor-
m a l s a l i n e . T h e p a t i e n t s t h e n re-
c e i v e d e i t h e r 1 m g DHE, 12.5 m g
CPZ, or 50 mg LID; all drugs were
administered intravenously. The
study protocol altowed this initial
dosage to be repeated once at 30 min-
utes for a total m a x i m u m dose of 2
m g DHE, t w i c e at 2 0 - m i n u t e inter-
vals for a t o t a l m a x i m u m dose of
37.5 mg CPZ, and twice at 20-min-
u t e i n t e r v a l s for a t o t a l m a x i m u m
26/1080
TABLE 1. Pattern of headache response
CPZ DHE LID
No. % No. % No. %
Complete relief 8 33.3 6 23.1 2 7.7
No change 2 8.3 5 19.2 6 23.1
Headache worse ••• 3 11.5 3 11.5
Headache worse or no change 2 8.3 8 30.8 9 34.6*
•P < .05.
TABLE 2. Effect of treatment on headache severity
CPZ DHE LID
Pretreatment median
intensity score 8.5O 7.50 8.0O
(range, 6 - 1 0 ) (range, 4 - 1 0 ) (range, 5 - 1 0 )
Post-treatment
median score 1.75 4.75 4.00"
Change in severity 6.75 (79.5%) 2.75 (36.7%) 4.00 (50.0%)t
*P < .05, tp < .005.
dose of 150 mg LID. During therapy, sided Fisher's exact test. C o m p a r i s o n
an IV d r i p of n o r m a l s a l i n e w a s of m e d i a n p o s t - t r e a t m e n t h e a d a c h e
m a i n t a i n e d at 75 mL/hr. Drug dosage scores and changes in severity (Table
was d e t e r m i n e d by reference to exist- 2) w e r e m a d e w i t h t h e t w o - s i d e d
i n g l i t e r a t u r e on t h e s e a g e n t s in M a n n - W h i t n e y test. M e d i a n r a t h e r
h e a d a c h e m a n a g e m e n t and by their than m e a n scores were used to pro-
reported toxicity profiles. 4-11 v i d e a m o r e a c c u r a t e r e f l e c t i o n of
P a t i e n t s were asked to judge the c e n t r a l t e n d e n c y because the head-
s e v e r i t y of t h e i r h e a d a c h e b e f o r e ache scores were not on an absolute
t r e a t m e n t on a scale of 1 to 10, w i t h scale and did not follow a n o r m a l dis-
10 d e n o t i n g t h e w o r s t h e a d a c h e . tribution.
They were then asked to reassess the Follow-up data (Table 3) were also
severity of their headache after trcat- analyzed w i t h the two-sided Fisher's
ment. exact test.
D a t a were subjected to t h r e e - w a y Failure to respond to the assigned
analysis w i t h the Kruskal-Wallis test therapy or any deterioration gave the
(for analysis of scores) and the X2 test attending p h y s i c i a n the option to ter-
(for analysis of categorical variables). m i n a t e the s t u d y and use w h a t e v e r
This analysis revealed that the three therapy was d e e m e d appropriate. An-
groups were statistically different. As t i e m e t i c s were n o t used u n l e s s ne-
a result, sequential two-sided Mann- cessitated by protracted vomiting.
W h i t n e y U and Fisher's exact tests All patients w h o could be reached
were applied to the data. received telephone follow-up the
Sequential analysis revealed that n e x t day for q u e s t i o n s designed to
the LID and DHE groups were not d e t e r m i n e the p r e s e n c e of recrudes-
s t a t i s t i c a l l y d i f f e r e n t (except w h e n c e n c e of h e a d a c h e and o v e r a l l sat-
c o m p a r e d for side effects; P < .05) isfaction with the administered
and were therefore grouped for com- therapy.
p a r i s o n to the CPZ group. Where a
statistically significant difference RESULTS
was e n c o u n t e r e d , g r o u p i n g d i d n o t N i n e t y patients were entered into
take place. the trial; 19 were s u b s e q u e n t l y ex-
T h e p a t t e r n of h e a d a c h e response c l u d e d due to i n c o m p l e t e records,
(Table 1) was analyzed w i t h the two- e a r l y s e l f - d i s c h a r g e , or r e q u e s t for
Annals of Emergency Medicine 19:10 October 1990

TABLE 3. Twenty-four-hour fo]low-~zp
CPZ
No. % Iio.
No. patients contacted 18 75.0
24-hour relief 16 88.9
Would use again 12 66.7
Side effects 4 22.2*
Follow-up on 54 of 76 patients (71.1%).
*Minor, ?severe gastrointestinal, ¢ineffective.
§P < .05.
withdrawal from the trial. Of the 76
patients completing the trial, 24 were
randomized to the CPZ group, 26 to
the DHE group, and 26 to the LID
group. There were 60 women and 16
men. Eighty-four percent of patients
had a history of migraine headaches,
and 43% had a family history of mi-
graine headaches. Forty-two percent
had both histories.
All groups had comparable pre-
treatment median headache scores
and ranges. Initial median headache
intensities were 8.50 for CPZ, 7.50
for DHE, and 8.00 for LID (Table 2).
More than 30% of the patients
who received DHE or LID had head-
aches that remained unchanged or
worsened, whereas only two patients
(8.3%) who received CPZ noted no
i m p r o v e m e n t , and none worsened
(Table 1) (P < .05). Also, 33% of pa-
tients in the CPZ group received
complete relief from their therapy
c o m p a r e d w i t h 23% in the DHE
group and only 7.7% in the LID
group.
After therapy, the median head-
ache intensity was 1.75 for CPZ, 4.75
for DHE, and 4.00 for LID; this repre-
sented a decrease in severity of head-
ache of 79.5%, 36.7%, and 50%, re-
spectively (Table 2; P < .005).
Follow-up was obtained from 54
patients (71.1%). Eighteen received
CPZ, 19 received DHE, and 17 re-
ceived LID. Patients receiving addi-
tional therapies were segregated only
on the basis of the study drug re-
ceived. Persistent relief of headache
at the 24-hour follow-up was re-
ported by 16 patients (88.9%) receiv-
ing CPZ, ten receiving DHE (52.6%},
and five receiving LID (29.4%). Addi-
tional medication (outside the treat-
ment protocol) was needed by 20.8%
of the patients (five) allocated to
CPZ, whereas 50% of the DHE group
19:10 October 1990
DHE LID
% No. % Of the three agents we studied,
19 73.1 17 65.5
10 52.6 5 29.4
5 26.3 5 29.4
11 57.9t§ 5 29.4*5
(13) and 42.3% of the LID group (11)
needed something else (Table 3; P <
.05). All patients requiring additional
medication received narcotics, with
the exception of three patients in the
DHE group who received CPZ. All
patients were discharged with relief
of their headaches.
When questioned as to whether
they would like to receive the same
medication for future migraine head-
aches, a positive response was re-
ceived in 66.7% of those in the CPZ
group, whereas only 26.3% of the
DHE group and 29.4% of the LID
group said they would take it again (P
< .01). In the majority of cases, pa-
tients refused to receive LID again
because they felt that it had been in-
effective, whereas those rejecting
DHE did so because of the severe gas-
trointestinal side effects (reported in
11 of 19 cases)(P < .01).
DISCUSSION
The identification of pharmaco-
therapies that are efficacious in the
m a n a g e m e n t of acute migraine is
complicated by the absence of a com-
plete understanding of the patho-
physiologic basis of this condition.
As a result, the current use of many
i n t e r v e n t i o n s f r e q u e n t l y m a y be
more the result of coincidence or the
p e r c e p t i v e o b s e r v a t i o n of a n t i -
m i g r a i n e effects after the use of
agents in other disciplines and condi-
tions than it is a rational attack
based on scientific principle. Physi-
cians dispensing migraine therapy
should carefully compare old with
new therapies to ensure the greatest
efficacy and safety, fewest side ef-
fects, and most infrequent rate of
headache recurrence after discharge.
The growing potential for abuse of
narcotic analgesics in an EDpopula-
tion will continue to influence the
Annals of Emergency Medicine
trend toward alternative therapies,
all of which should be subjected to
clinical comparisons before they be-
come standard parts of the anti-
migraine armamentarium.
DHE and CPZ are routinely used in
migraine management; LID has only
recently been suggested to have ther-
apeutic potential, z-7
DHE has long been used for acute
migraine headache, but only recently
have c o m p a r a t i v e or c o n t r o l l e d
studies been conducted that support
its effectiveness.4, ~J Unfortunately,
these trials have been unable to ad-
dress the potential importance of an-
tiemetics given concurrently with
the putative primary therapy.
DHE given parenterally offers the
advantages of being a safe alternative
to narcotics, with few side effects
and relative ease of administration.
The mechanism of action of DHE in
migraine is believed to reside in the
ability of its metabolites to bind to
central monoaminergic recep-
tors. 6,12,13 This is consistent with
current theories of the modes of ac-
tion of drugs effective in migraine. 13
Ergotamines are contraindicated in
pregnancy, peripheral vascular dis-
ease, coronary vascular disease, hy-
pertension, and hepatic and renal
failure. Their major limiting adverse
effect is the production of nausea and
vomiting, which frequently necessi-
tates the additional use of antiemetic
agents, m a n y of which may have
their own effects on migraine. DHE
offers such advantages over other er-
gots as less-frequent nausea, less po-
tential for vasospasm, and main-
tained efficacy several hours after the
onset of headache. 6
CPZ has become a frequently ad-
ministered therapy for acute mi-
graine, largely as a result of clinical
trials recently published.6,s, 14 The
mechanism for its effect on migraine
is incompletely understood but is
thought to result from its powerful
antiemetic effect mediated by the
chemoreceptor trigger zone in the
reticular formation, by its ability to
alter the perception of pain, and per-
haps by its ability to alter mediators
of v a s o r e g u t a t o r y s y s t e m s in the
brainstem.S, 14 Several adverse effects,
particularly postural hypotension,
seizures, and dystonic reactions, nray
complicate its use.
LID has recently been reported to
be effective in the treatment of acute
1081/27
MIGRAINE HEADACHE
Bell et al
migraine i n anecdotal reports and is
r e c o m m e n d e d in some standard ref-
erences, although a clinical trial
d e m o n s t r a t i n g its effectiveness has
not been conducted.6, m The mode of
a c t i o n of LID i n m i g r a i n e is u n -
known. Its m e m b r a n e - s t a b i l i z i n g ef-
fects m a y i n h i b i t the release from
p l a t e l e t s of v a s o a c t i v e s u b s t a n c e s
k n o w n to m e d i a t e the sterile inflam-
matory response in migraine. LID is
widely used as a local anesthetic and
an a n t i a r r h y t h m i c agent, particularly
i n t r e a t i n g v e n t r i c u l a r arrhythmias.
It has few undesirable cardiovascular
effects except in p a t i e n t s w i t h se-
verely c o m p r o m i s e d cardiac func-
tion. The m a i n adverse effects act on
the central nervous system. Perioral
paresthesias, feelings of dissociation,
m i l d d r o w s i n e s s , or a g i t a t i o n are
dose related and are not dangerous.
T h e r e s u l t s of this trial d e m o n -
strate that in our population, CPZ
was the m o s t efficacious t r e a t m e n t
in t e r m s of n u m b e r of patients re-
lieved, degree of relief, and p a t i e n t
satisfaction with the treatment. The
ability of agents to prevent recrudes-
cence of headache after ED discharge
is of p a r t i c u l a r i m p o r t a n c e and has
not been addressed in previous
studies. Residual hangover some-
t i m e s identified w i t h CPZ was n o t
identified here as a significant prob-
lem. Of the three t r e a t m e n t groups,
those receiving CPZ were most satis-
fied w i t h t h e t r e a t m e n t t h e y re-
ceived.
Side effects were not a l i m i t i n g fac-
tor in any t r e a t m e n t group. Postural
h y p o t e n s i o n experienced in previous
studies of CPZ was largely avoided
by preloading w i t h fluids and main-
taining fluid infusion throughout
t r e a t m e n t . The i n c i d e n c e of n a u s e a
and v o m i t i n g in patients treated with
DHE suggests that it may be advis-
able to pretreat p a t i e n t s w i t h anti-
emetics. However, m a n y antiemetics
have a n t i m i g r a i n e effects, and the ef-
fectiveness of therapy in these cir-
c u m s t a n c e s m a y n o t be attributed to
28/1082
DHE alone. LID was relatively free of
adverse effects but was also a m u c h
less effective therapy.
C o m p a r i n g these t r e a t m e n t s w i t h
standard t r e a t m e n t with narcotics is
difficult because of the lack of clini-
cal trials of narcotic therapy in mi-
graine. One study has reported a 29%
response rate to narcotics, considera-
bly less than the best responses seen
in our study, a Recent trials compar-
ing DHE with narcotics and CPZ
w i t h n a r c o t i c s have s u p p o r t e d the
usefulness of those agents.S, 9
It should be cautioned that the re-
s p o n s e to t r e a t m e n t w i t h t h e s e
agents does not in any way confirm a
diagnosis of vascular headache; we
have experience with headache origi-
n a t i n g from a large frontal glioblas-
toma that responded to CPZ dramati-
cally.
M a n y difficulties are i n h e r e n t in
studying the response of migraine to
treatment. In addition to the absence
of a s c i e n t i f i c r a t i o n a l e for use of
m a n y of the c o m m o n l y used agents,
there is also a large placebo response
in migraine therapies. Because of the
r e c o g n i z e d effectiveness of several
c o m m o n l y used medications, there is
a reluctance for patients to enroll in a
trial that m a y place t h e m in a pla-
cebo group. D e s p i t e t h e s e l i m i t a -
tions, we believe that effective com-
parative a s s e s s m e n t s m a y be made
and that therapies with the most sat-
isfactory risk-to-benefit profiles may
be identified. The result of compara-
tive trials does n o t negate the effec-
tiveness of any one drug in an indi-
v i d u a l p a t i e n t . We have, however,
been u n a b l e to identify any features
of the headache or demographic fea-
tures of affected patients that would
allow us to favor one therapy over
another.
CONCLUSION
This comparative study of the rela-
tive effectiveness of three n o n - n a r -
cotic a n t i m i g r a i n e therapies reports
greater satisfaction w i t h CPZ t h a n
Annals of Emergency Medicine
w i t h DHE or LID. Therapy w i t h CPZ
also p r o d u c e d less r e c r u d e s c e n c e
of headache after discharge. F u t u r e
trials should determine the influence
of fluid loading in migraine therapies.
The authors thank Dr Gordon Fick for
providing assistance with statistical anal-
ysis and Corinne Siegers for patient fol-
low-up. The contributions of ED staff and
physicians at the Foothills Hospital, Cal-
gary, are also gratefully acknowledged.
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