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- cacy of three non-narcotic agents, chloropromazine, lidocaine, and dihy- droergotamine, in the treatment of migraine headache in an emergency department setting.

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

or classic migraine. Interventions: Patients were pretreated with 500 mL (IV) normal saline

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 ihy- droergotamine 1 mg IV repeated after 30 minutes if the initial response was inadequate; lidocaine 50 mg IV at 20-minute intervals to a max imum total dose of 150 mg as required; or chloropromazine 12.5 mg IV repeated at 20-minute intervals to a total max i mum dose of 37.5 mg as required. Patients were asked to grade headache severity on a ten-point scale before and one hour after the initiation of therapy. Follow-up by phone was sought the following day.

Measurements and main results: Of 76 patients completing the trial, 24 were randomized to receive chloropromazine, 26 to receive dihy- droergotamine, and 26 to receive lidocaine. Reduction in mean headache in tens i ty was ~ significantly better among those treated wi th chloro- promazine (P < .005). Persistent headache relief was experienced by 16 of the chloropromazine-treated patients (88.9%) contacted at 12 to 24 hours follow-up compared with ten of the dihydroergotamine-treated patients (52.6%) and five of the lidocaine-treated group (29.4%).

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 acute migra ine headache. Ann Emerg Med Oc tober 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- s tay of t r ea tment , but because of the t rans ien t na ture 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

Robert Bell, MD, FRCP(C) David Montoya, MD, FRCP(C) Asphaq Shuaib, MD, FRCP(C) Mary Ann Lee, MD, FRCP(C) Calgary, Alberta, Canada

From the Department of Clinical Neurosciences, University of Calgary, Foothills Hospital; and the Department of Emergency Medicine, University of Calgary General Hospital, Calgary, Alberta, Canada.

Received for publication December 28, 1988. Revisions received October 16, 1989, and April 16, 1990. Accepted for publication April 26, 1990.

Presented at the Canadian Royal College of Physicians Annual Meeting in ©ttawa, Canada, September 1988.

Address for reprints: Robert B Bell, MD, FRCP(C), Department of Neurology & Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305-5235.

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 in i t ia- t ion of t rea tment . Because the poten- t ial for rebound headache subsequent to the rapy has not been adequate ly eva lua ted in the l i te ra ture , pa t i en t s in this s tudy were also followed at 24 hours after t rea tment .

METHODS Ninety-f ive adul t pa t ients present-

ing to the EDs of the Foothil ls or Cal- gary Genera l Hosp i t a l consen ted to par t ic ipate in this study, which was approved by the C o n j o i n t Med ica l Ethics Commi t tee , Facul ty of Medi- cine, at the 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 pa t i en t s were given a diag- nosis of migraine headache by the at- tending emergency physician.

Migraine headache was defined as ei ther common, character ized by re- cur ren t a t t acks of headache las t ing hours or days, associated with gastro- i n t e s t i n a l d i s tu rbance , and hav ing some features of pulsat i le character, p h o t o p h o b i a , s o n o p h o b i a , u n i - l a t e ra l i t y , and pos i t i ve f a m i l y his- tory; or classic, exhibi t ing recurrent a t tacks of headache as in c o m m o n migra ine but preceded by a motor , sensory, or visual aura. Exclusion cri- teria were nonmigra ine headache, age less than 18 or more than 60 years, subs tance abuse, neuro logic or sei- zure disorder, a lcohol abuse, al lergy or s ens i t i v i t y , p r e g n a n c y or b reas t feeding, per iphera l vascu la r disease, coronary vascular disease, hyperten- sion, or hepat ic or renal failure.

After giving informed wr i t t en con- sent, p a t i e n t s were 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 s ingle-bl ind fashion wi th only the pa- t i en t being b l inded to the therapy. Because of the disparate toxic i ty pro- files of the three s tudy agents and the perceived need to more closely focus pa t i en t m o n i t o r i n g to expected ad- verse effects, the a t tending physic ian and nurs ing staff were not blinded.

All pat ients had an IV line started and received a 500-mL bolus of nor- m a l s a l i ne . T h e p a t i e n t s t h e n re- c e ived e i t h e r 1 m g DHE, 12.5 mg CPZ, or 50 mg LID; all drugs were a d m i n i s t e r e d i n t r a v e n o u s l y . T h e s tudy p r o t o c o l a l towed th is i n i t i a l dosage to be repeated once at 30 min- utes for a total m a x i m u m dose of 2 mg DHE, twice at 20 -minu te inter- vals for a to ta l m a x i m u m dose of 37.5 mg CPZ, and twice at 20-min- u te i n t e rva l s for a to ta l m a x i m u m

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

Pretreatment median intensity score

Post-treatment median score

Change in severity

*P < .05, tp < .005.

CPZ DHE LID

8.5O 7.50 8.0O

(range, 6-10) (range, 4 -10) (range, 5-10)

1.75 4.75 4.00"

6.75 (79.5%) 2.75 (36.7%) 4.00 (50.0%)t

dose of 150 mg LID. During therapy, an IV d r ip of n o r m a l s a l i n e was ma in ta ined at 75 mL/hr. Drug dosage was de te rmined by reference to exist- ing l i t e r a t u r e on t h e s e a g e n t s in headache m a n a g e m e n t and by thei r reported toxici ty profiles. 4-11

Pa t ien t s were asked to judge the s e v e r i t y of t h e i r h e a d a c h e before t rea tment on a scale of 1 to 10, wi th 10 d e n o t i n g the w o r s t h e a d a c h e . They were then asked to reassess the severi ty of their headache after trcat- ment.

Da ta were subjec ted to th ree -way analysis wi th the Kruskal-Wall is test (for analysis of scores) and the X 2 test (for analysis of categorical variables). This analysis revealed that the three groups were s ta t i s t ica l ly different. As a result , sequent ia l two-sided Mann- W h i t n e y U and Fisher ' s exact tes ts were applied to the data.

Sequen t i a l ana lys i s r evea led tha t the LID and DHE groups were not s t a t i s t i c a l l y d i f fe ren t (except w h e n compared for side effects; P < .05) and were therefore grouped for com- par i son to the CPZ group. Where a s t a t i s t i c a l l y s i g n i f i c a n t d i f f e rence was encoun t e r e d , g roup ing d id no t take place.

The pa t t e rn of headache response (Table 1) was analyzed wi th the two-

sided Fisher 's exact test. Compar ison of m e d i a n p o s t - t r e a t m e n t headache scores and changes in severi ty (Table 2) we re m a d e w i t h t he t w o - s i d e d M a n n - W h i t n e y tes t . M e d i a n r a the r than mean scores were used to pro- v ide a more accu ra t e r e f l ec t ion of cen t ra l t endency because the head- ache scores were not on an absolute scale and did not follow a normal dis- t r ibut ion.

Fol low-up data (Table 3) were also analyzed wi th the two-sided Fisher 's exact test.

Failure to respond to the assigned therapy or any deter iora t ion gave the a t tending phys ic ian the opt ion to ter- m i n a t e the s tudy and use wha teve r therapy was deemed appropriate. An- t i eme t i c s were no t used unless ne- cessi tated by protracted vomit ing.

Al l pat ients who could be reached r e c e i v e d t e l e p h o n e f o l l o w - u p t h e nex t day for ques t ions designed to de t e rmine the presence of recrudes- cence of h e a d a c h e and overa l l sat- i s f a c t i o n w i t h t h e a d m i n i s t e r e d therapy.

RESULTS Nine ty pat ients were entered into

the trial; 19 were subsequen t ly ex- c luded due to i n c o m p l e t e records , ea r ly se l f -d ischarge , or r eques t for

26/1080 Annals of Emergency Medicine 19:10 October 1990

TABLE 3. Twenty-four-hour fo]low-~zp

CPZ DHE LID

No. % Iio. % No. %

No. patients contacted 18 75.0 19 73.1 17 65.5

24-hour relief 16 88.9 10 52.6 5 29.4

Would use again 12 66.7 5 26.3 5 29.4

Side effects 4 22.2* 11 57.9t§ 5 29.4*5

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 improvement , and none worsened (Table 1) (P < .05). Also, 33% of pa- t ients in the CPZ group received complete relief from their therapy compared wi th 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

(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 management 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 in te rven t ions f requent ly may 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 an t i - migraine effects after the use of agents in other disciplines and condi- tions than it is a rational at tack 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

trend toward alternative therapies, all of which should be subjected to clinical comparisons before they be- come standard parts of the anti- migraine armamentarium.

Of the three agents we studied, 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 compara t i ve or con t ro l l ed 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 c e n t r a l m o n o a m i n e r g i c r ecep- 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, many 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 vasoreguta tory sys tems in the brainstem.S, 14 Several adverse effects, part icularly postural hypotension, seizures, and dystonic reactions, nray complicate its use.

LID has recently been reported to be effective in the treatment of acute

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MIGRAINE HEADACHE Bell et al

migraine in anecdotal reports and is recommended in some standard ref- e rences , a l t h o u g h a c l i n i c a l t r i a l demons t ra t ing its effectiveness has not been conducted.6, m The mode of ac t i on of LID in m i g r a i n e is un - known. Its membrane-s tabi l iz ing ef- fects may i n h i b i t the release from p l a t e l e t s of va soac t i ve s u b s t a n c e s known to media te the sterile inflam- matory response in migraine. LID is widely used as a local anesthetic and an ant iar rhythmic agent, particularly in t reat ing vent r icu la r arrhythmias. It has few undesirable cardiovascular effects except in pa t i en t s wi th se- vere ly c o m p r o m i s e d cardiac func- tion. The main adverse effects act on the central nervous system. Perioral paresthesias, feelings of dissociation, m i l d d rows iness , or ag i t a t i on are dose related and are not dangerous.

The resul t s of this trial demon- strate that in our populat ion, CPZ was the most efficacious t rea tment in terms of n u m b e r of pat ients re- lieved, degree of relief, and pat ient satisfaction with the treatment. The abili ty of agents to prevent recrudes- cence of headache after ED discharge is of par t icular impor tance and has n o t b e e n a d d r e s s e d in p r e v i o u s s tudies . Res idua l hangove r some- t imes ident if ied wi th CPZ was not identified here as a significant prob- lem. Of the three t rea tment groups, those receiving CPZ were most satis- f ied w i t h the t r e a t m e n t t hey re- ceived.

Side effects were not a l imi t ing fac- tor in any t rea tment group. Postural hypotension experienced in previous studies of CPZ was largely avoided by preloading wi th fluids and main- t a i n i n g f lu id i n f u s i o n t h r o u g h o u t t rea tment . The incidence of nausea and vomit ing in patients treated with DHE suggests that it may be advis- able to pretreat pa t ients wi th anti- emetics. However, many ant iemetics have ant imigraine effects, and the ef- fect iveness of therapy in these cir- cumstances may not be attr ibuted to

DHE alone. LID was relatively free of adverse effects but was also a much less effective therapy.

Compar ing these t rea tments wi th standard t rea tment 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 w i t h na rco t i c s and CPZ wi th narcot ics have suppor ted 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- na t ing from a large frontal glioblas- toma that responded to CPZ dramati- cally.

Many difficulties are inheren t in studying the response of migraine to t reatment . In addition to the absence of a sc ient i f ic r a t iona le for use of many of the commonly used agents, there is also a large placebo response in migraine therapies. Because of the recognized effect iveness of several commonly used medications, there is a reluctance for patients to enroll in a trial that may place them in a pla- cebo group. Desp i t e these l i m i t a - tions, we believe that effective com- parative assessments may be made and that therapies with the most sat- isfactory risk-to-benefit profiles may be identified. The result of compara- tive trials does not negate the effec- t iveness of any one drug in an indi- v idua l pa t ient . We have, however, been unable to identify any features of the headache or demographic fea- tures of affected patients that would allow us to favor one therapy over another.

C O N C L U S I O N This comparative study of the rela-

tive effectiveness of three non-nar- cotic an t imigra ine therapies reports greater sat isfaction wi th CPZ than

wi th DHE or LID. Therapy wi th 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. Future trials should determine the inf luence 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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9. Belgrade MJ, Ling LJ, Schleevogt MB, ct ah Comparison of single dose meperidine, butorphanol and dihydroergotamine in the treatment of vascular headache. Neurology 1989;39:590-592. 10. Lance WJ: Head and facial pain, in Johnson RT (ed): Current Therapy in Neurological Dis- eases. St Louis, CV Mosby, 1985, p 82. 11. Gilman AG, Goodman LS, Rall TW, et al: The Pharmacological Basis of Therapeutics, ed 7. New York, MacMillan, 1985. 12. Muller-Schweinitzer E: Pharmacological ac ~ tions of the main metabolites of dihy- droergotalnine. Eur / Clin Pharmacol 1985;26: 699-705. 13. Raskin NH: Pharmacology of migraine. Ann Rev PharmacoI Toxicol 1981~21:463-478. 14. Iserson KV: Parenteral chloropromazine treatment of nrigraine. Ann Emerg Med 1983; 12:756W58.

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