ORIGINAL CONTRIBUTION
ketorolac; meperidine; migraine
A
Randomized, Double-Blind, Comparative Study
of the Efficacy of Ketorolac Tromethamine Versus Meperidine in the Treatment of Severe Migraine From the Department of Surgery, Emergency Medicine
Gregory Luke Larkin, MD John E Prescott, MD, FACEP
Service, West Virginia University Health Sciences Center, Morgantown.
Study objective: Toevaluate the relative efficacy of ketorolac tromethamine and meperidine hydrochloride in the emergency department treatment of severe migraine. Design: Prospective, randomized, double-blind trial. Setting:
Receivedfor publication January 9, 1992. Revision received April 2, ] 992. Accepted for publication April 13, ] 992.
University hospital ED.
Participants: Patients presenting to the ED with an isolated diagnosis of common or classic migraine. Interventions: Subjects were randomized to receive a single intramuscular injection of either 30 mg ketorolac or 75 mg meperidine.
Measurements and main results: Of the 31 patients completing the trial, 15 received ketorolac and 16 received meperidine. The demographic characteristics of beth groups were comparable. At one hour, ketorolac was significantly less effective than meperidine in reducing headache pain (P= .02) and in improving clinical disability (P= .01). Ketorolac also was less effective at reducing nausea, photophobia, and the need for rescue medication (P< .05). Sustained headache relief was experienced by 44% of the patients treated with meperidine at 12- to 24-hour follow-up, compared with 13% of the patients treated with ketorolac (P= NS). No significant side effects were observed for either group. Conclusion: IM ketorolac tromethamine is less effective than meperidine in the ED treatment of severe migraine. [Larkin GL, Prescott JE: A randomized, double-blind, comparative study of the efficacy of ketorolac tromethamine versus meperidine in the treatment of severe migraine. Ann EmergMedAugust1992;21:919-924.]
AUGUST 1992 21:8
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919/ 37
KETOROLAC Larkin & Prescott
INTRODUCTION
MATERIALS AND METHODS
Migraine headache is an extremely common disorder affecting more than 8 million Americans and about 15% to 20% of the general population. ~,2 Treatment of the acute attack has traditionally included ergot derivatives or narcotics, although neither is ideal in the emergency setting. Ergots, for example, can lose their efficacy once the headache is already well established. 3 Moreover, ergot compounds are contraindicated in patients with severe neurologic symptoms, p e r i p h e r a l vascular disease, and coronary a r t e r y disease. They are also contraindicated in pregnancy, which is p a r t i c u l a r l y relevant because most migraine patients are women of childbearing age. Narcotic analgesics are often used instead of ergot p r e p a rations for the emergency department treatment of severe migraine; however, narcotics have well-known limitations of their own: sedation, nausea, r e s p i r a t o r y depression, u r i n a r y retention, hypotension, and, over time, addiction. In addition, narcotics may confound the neurologic examination and thereby obscure other differential diagnoses. The development of tolerance to narcotics and ergot alkaloids makes a p p a r e n t the need for alternative therapy, z To this end, various nonsteroidal anti-inflammatory analgesic preparations have been used orally to a b o r t acute migraine with some limited success. 4-9 However, giving oral medications to nauseated migraineurs is fraught with obvious p r o b lems. Recently, the availability of a p a r e n t e r a l nonsteroidal anti-inflammatory analgesic in the form of ketorolac tromethamine has afforded the vomiting patient with a nonnarcotic, nonsedating, p a r e n t e r a l alternative. Ketorolac (Toradol ®) is a new, p a r e n t e r a l analgesic indicated for the short-term management of pain. This drug has demonstrated efficacy superior or equal to the opiates in the treatment of renal colic and postoperative, dental, and cancer pain. x°-z5 We could find no previous reports of its efficacy in the treatment of pain from migraine headache. The purpose of this study was to compare the efficacy of meperidine, a s t a n d a r d t h e r a p y for severe migraine, with ketorolac in the ED treatment of acute migraine attacks.
This study was a p p r o v e d by the West Virginia University Institutional Review B o a r d for the protection of human subjects in biomedical research. Patients who were diagnosed by the attending emergency physician as having an acute attack of classic migraine (with aura) or common migraine (without aura) as defined by the International Headache Society 16 were considered for entry into the study. Eligible patients were enrolled if they met the exclusion criteria shown (Figure 1). Written informed consent was obtained from all eligible patients, and the principles of the Declaration of Helsinki and patient confidentiality were maintained throughout the study. Clinical evaluation included a thorough history, physical examination, and l a b o r a t o r y tests as deemed a p p r o p r i a t e by
Figure 1. Exclusion criteria for patients in the migraine study Age less than 18 or more than 60 years Risk of nonsteroida] or opiate intolerance Known or potential pregnancy* or breast-feeding First migraine, nonmigraine headache, or mild migraine~ headache Suspected substance abuse and/or previous treatment with meperidine Hepatic or renal dysfunction, cardiovascular disease, or other serious illness History of recent trauma or seizure Marked hyperpyrexia, hypertension, or orthostatic hypotension *Female patientsof childbearing age with an unreliable menstrual history. tMild migraine refersto a migraine that does not interfere with the capacityfor normal function (eg,working).
38/920
Table. Comparison of demographic characteristics among ketorolac and meperidine treatment groups Ketorolac (15)
Meperidine (16)
P
Sex (%) Male Female
3 (20) 12 (80)
4 (25) 12 (75)
31.5 -+4.4 18-51
33.8 _+5.0 19-55
.52
10 (67) 5 (33)
12 (75) 4 (25)
.70
1.0
Age (yr) Mean* Range
Migraine type (%) Common Classic (with aura)
Initial headache severity/ clinical disability (%) Grade 3--most severe (incapacitated or bedridden) 11 (73) Grade 2--marked (interferes with work, job, ete) 4 (27) Grade 1--mild (slightly impaired but able to work) 0
14 (87) 2 (13)
.39
0
Most common associated symptoms at presentation (%) Nausea Photophobia Sonophobia Vomiting Numbness or tingling Lightheadedness
Family history of migraine (%)
13 (87) 15 (100) 8 (53) 6 (40) 5 (33) 3 (20)
16 (100) 16 (100) 7 (44) 6 (38) 5 (31) 5 (31)
.26 1.0 .72 1.0 1.0 .69
10 (67)
8 (50)
.47
Medication taken before ED visit (%) None Acetaminophen Nonsteroidal anti-inflammatory analgesic (including aspirin) Codeine preparation Ergot preparation Sedatives Prophylactic medications t
3 (20.0) 4 (26.7)
2 (12.5) 5 (31.3)
.65 1.0
2 (13.3) 3 (20.0) 2 (13.3) 1 (6.7) 7 (46.7)
2 (12.5) 3 (18.8) 2 (12.5) 2 (12.5) 9 (56.3)
1.0 1.0 1.0 .61 .72
*Values are _+95% confidenceintervalsbasedon the standard deviationand the standard error of the mean. qncludes calcium channel blockers,~-blockers, and antidepressants.
ANNALS 0FEMERGENOYMEDICINE
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AUGUSTt992
KETOROLAC
Larkin & Prescott
the attending emergency physician. Physicians completed a headache history form on all patients detailing the onset, duration, intensity, location, and type of migraine. Precipitants, exacerbating and ameliorating factors, associated complaints, family history, prodromal aura, self-medication, and result of self-medication (both in the past and as pertains to the present headache) also were recorded. After giving informed consent, patients were assigned to one of the two treatment groups by a computer-generated random number. The subjects were randomized in a 1:1 fashion to receive a single IM dose of either 75 mg meperidine (Demerol ®) or 30 mg ketorolac (Toradol®). Both the investigator and patient were blinded as to the drug used. A nurse who was not involved in patient care except to give the injection was the only person who knew which medication the subject received. This nurse was considered to be a disinterested party and, by protocol, did not communicate information regarding the case to anyone for the duration of the study. Patients filled out questionnaires every 15 minutes to measure pain relief and any side effects experienced. Pain relief was recorded on a verbal analog scale from "no relief" to "complete pain relief." The scale included intermediate labels of "some relief but less than half better" and "marked relief/more than half better." Although less sensitive than a visual analog scale, the simple descriptive scale was easier for our photophobic patients to use. Blood pressure, pulse, and headache-associated nausea, vomiting, photophobia, phonophobia, and numbness were assessed on the same schedule as pain relief. The severity of the headache and the corresponding degree of clinical disability were graded on an analog scale both immediately before and one hour after treatment as follows: Figure 2.
grade 0, none (able to work and function normally); grade l , mild (working ability mildly impaired); grade 2, marked (working ability markedly impaired); grade 3, severe (total incapacitation, bedridden). Only patients with grade 2 or 3 disability were eligible for enrollment into the study. If little or no relief was afforded at the end of the 60minute trial, rescue medication (eg, analgesics and/or antinauseants) were offered to the patient. Any use of rescue medication was documented by the clinician, as were any adverse reactions or side effects. Treating physicians also recorded their impression of treatment efficacy after 60 minutes as poor, fair, good, or excellent. Patients received follow-up telephone calls the next day to establish the frequency of migraine relapse and side effects and to assess overall patient satisfaction. Figure 3.
Clinical disability: Baseline a n d one h o u r after treatment % Patients 1 )Or--
'°I
,o
NN
~
Grade 3
Grade 2
Grade 1
Grade 0
% Patients
% Patients
100
n
Meperidine
]
Ketorolac 60 Minutes
80
60
i¸7 ~
I
!iN
{
I Complete relief
AUGUST1992
Meperidine
0 Minutes
3oi-
o
Pain relief at 60 minutes
Ketorolac •[ ]
21:8
Marked Some (more than half better) (less than half better) Pain Relief
A N N A L S OF EMERGENCY M E D I C I N E
No relief
Grade 3 (severe)
Grade 2 (marked)
Grade 1 (mild)
Grade 0 (none)
Disability
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KETOROLAC Larkin & Prescott
Statistical analysis was carried out on the pain relief scores and the improvement in disability using the Wilcoxon r a n k sum or Mann-Whitney U test. All other comparisons were made using the Fisher's exact test. All P values r e p o r t e d are two-sided exact values calculated using Stat Xact ® software (Cytel Software Corp, Cambridge, Massachusetts).
RESULTS Thirty-three patients were enrolled in the trial; however, two were subsequently removed from the study because they failed to meet the exclusion criterion of first migraine attack. Thus, 31 patients were included in the analysis: 15 in the kctorolac group and 16 in the meperidine group. Comparison of demographic characteristics showed that both treatment groups were similar with respect to age, sex, type of migraine, clinical disability, family history, associated symptoms, duration of headache, and previous treatment (Table). No patients had re-entered the study. After one hour, patients treated with ketorolac r e p o r t e d a smaller reduction in pain than patients treated with meperidine (Figure 2). Two-sided analysis of the raw pain relief score data using the Wilcoxon r a n k sum test shows the difference in pain relief to be significant (P = .02). Assessment of clinical disability after 60 minutes revealed that there was significantly less improvement in the ketorolac group (P = .01). No patients treated with ketorolac indicated that they could r e t u r n to work unimpaired, but 25% (four of 16) of the meperidine group r e p o r t e d the complete absence of disability at 60 minutes (Figure 3). Fifty-three percent of the ketorolac group r e p o r t e d no improvement in disability grade during the study compared with 12.5% of the meperidine group (P = .001).
Figure 4. Migraine patients with photophobia versus time
No. Photot:)hobicPatients
0
15
30
Time(rain)
40/922
45
m
Ketorolac
~
Mepeddine
60
Ketorolac was also significantly less effective at reducing the most common symptom accompanying the headache, photophobia (P = .03) (Figure 4). Ketorolac did not reduce nausea as well as meperidine, but the difference was not statistically significant (P = . 10). The numbers of patients with other symptoms were too small for meaningful analysis. Eleven of 15 patients treated with ketorolac r e q u i r e d rescue medication after one hour, compared with six of 16 (37.5%; mid P = .05) who received meperidine. Of the patients who did not require rescue medication, five had r e b o u n d at 12- to 24-hour follow-up: two in the ketorolac group and three in the meperidine group (P = NS). Sustained headache relief at 12 to 24 hours was reported by seven (44%) of those who received meperidine and by two (13%) of those who received ketorolac as monotherapy (P = NS). Side effects of treatment were few. Increased nausea was r e p o r t e d by one patient in each group, and drowsiness was r e p o r t e d as a side effect in five patients: three from the ketorolac group and two from the meperidine group. Nonetheless, no patients left the trial before the end of the 60-minute observation period. There were no reported adverse reactions to either drug. The response to t h e r a p y was consistent between both common and classic migraine however, the sample size used was too small to allow stratification of these data.
DISCUSSION Although derangements in serotonin, endorphins, and prostaglandins have all been suggested to play a role in the pathogenesis of acute migraine headache, 17 no one mechanism adequately explains the response (or lack thereof) to different therapies. This confusion has led to a bewildering a r r a y of suboptimal treatment options. 18 Antinauseants, narcotics, and ergot compounds, for example, are s t a n d a r d therapy, yet they c a r r y with them well-known risks and undesirable side effects, is The results of this study demonstrate that 30 mg ketorolac is well tolerated in migraine patients and causes very few side effects; however, it was not as efficacious as 75 mg meperidine in relieving migraine headache pain and disability. Although our study used a small sample size and verbal analog scales, the differences in pain relief and clinical improvement between groups were consistent and statistically significant. We found the verbal pain relief scale easier for our patients to use than the more sensitive visual analog scale. This was p a r t i c u l a r l y true of patients experiencing scintillating scotomata or other visual disturbances. Measuring pain relief instead of pain ensured that all patients started at the same baseline and had the same degree of potential response. The use of a "pain relief" r a t h e r than a " p a i n " scale receives some support from the work of Huskisson, 19 who found it superior to subtracting pain scores after treatment from initial pain scores.
ANNALS OF EMERGENCY MEDICINE 21:8
AUGUST1992
KETOROLAC Larkin & Prescott
Previous studies using various nonsteroidal anti-inflammatory analgesics in the treatment of acute migraine r e p o r t e d good efficacy; 4-8 nevertheless, these data do not necessarily apply to our study with ketorolac. First, none of the p r i o r studies were conducted in controlled ED or hospital-based settings. In addition, the patients were neither monitored for compliance n o r controlled for ingestion of nonstudy drugs. Because the subjects in these previous studies were told to take the study medication at home at the first sign of headache, many nonmigraine headaches may have been included in the analyses. Our study, however, addressed only 12 migraines as defmed by stringent International Headache Society criteria. 16 Moreover, the headaches treated in our study were uniformly severe and disabling; the pain was not only refractory to treatments at home, but it caused the patients to seek relief in an ED. Last, photophobia, a r e p o r t e d l y strong indicator of attack severity, 2° was present in 100% of the study population. Our results show ketorolac to have only marginal efficacy when c o m p a r e d with meperidine in the treatment of acute migraine headache. A placebo control was not used because it was deemed inhumane to delay or withhold treatment from patients in acute pain. Surprisingly, our data are in m a r k e d contrast to other trials, which found ketorolac, at 30 mg or less, to deliver analgesia superior or equivalent to 100 mg of meperidine.Z°,n,13,15 F o r example, Brown et a115 stated that 100 mg of meperidine and 5 mg of ketorolac were indistinguishable in the treatment of pain after m a j o r oral surgery. Another comparative trial concluded that 10 mg of ketorolac was as efficacious as 100 mg of meperidine for the treatment of renal colic. 10 Although the migraine pain model studied is different than the aforementioned pain models, it is noteworthy that all the previous studies used higher doses of meperidine and lower doses of ketorolac than our study. It is unlikely, therefore, that doses of ketorolac of more than 30 mg would have been of significant benefit. Numerous studies have already demonstrated equivalent analgesic efficacy between 30 and 90 mg of ketorolac at one hour after treatment. 11,12,21-23 Similarly, there are no published data to suggest that 60-mg doses are superior to 30 mg at one hour after dosing. One possible reason for our study results showing ketorolac to be less effective than meperidine is that prostaglandins are not as important in migraine as serotonin (5-hydroxytryptamine) TM or other mediators. 24 The relative success of drugs that affect serotonin (eg, dihydroergotamine 25 and sumatriptan 26) and dopamine (eg, metoclopramide 27 and phenothiazines 28) suggests that ~-receptor agonists (eg, n a r cotics) are often unnecessary. Regrettably, many non-narcotic modalities provide inconsistent relief and have undesirable side effects of their own. Metoclopramide and the phenothiazines, for example, can induce acute dystonic reactions. In addition to e x t r a p y r a m i d a l reactions, phenothiazines can also cause neuroleptic malignant syndrome, which, although
AUGUST1992
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ANNALS OF EMERGENCY MEDICINE
rare, is fatal in 20% of cases. 29 Both sumatriptan and dihydroergotamine have demonstrated efficacy,25,26 but both can cause flushing, tingling, chest pain, and lightheadedness. Moreover, the vasoconstrictive effects of ergotamine can lead to claudication, angina, and in r a r e instances, myocardial infarction.30 Comparing ketorolac and other new therapies to s t a n d a r d narcotic analgesia is difficult because migraine trials are p a r t i c u l a r l y susceptible to large placebo effects. 31 In addition, the euphoric effects from narcotics may augment their analgesic effects. 31 We did not include suspected substance abusers or persons known to have been treated previously with meperidine in our study. Nevertheless, further studies comparing ketorolac with less-euphoric agents (eg, a narcotic agonist-antagonist) may be warranted. It is possible that the peak onset of action of meperidine is faster than ketorolac. This may explain, in p a r t , why meperidine is still widely used as a s t a n d a r d antimigraine t h e r a p y in many EDs. There are several limitations to the use of single-dose intramuscular analgesics as used in our study. F o r example, there is large interindividual variation in responsiveness to n a r cotics that demands dosage flexibility. Moreover, the optimal way to titrate narcotic analgesia is through the IV route. Ketorolac, however, is not currently a p p r o v e d for IV use in the United States. CONCLUSION
Although ketorolac tromethamine has been demonstrated to be superior to meperidine in several different pain models, it is not as efficacious as meperidine in the ED treatment of acute severe migraine. Meperidine was significantly better than ketorolac in several outcome measures, including improvement in migraineassociated pain, photophobia, and disability. Ketorolac, although well tolerated, was associated with more refractory migraine symptoms and a greater need for rescue medication, The authors thank Raymond Jackson, MD, FACEP,for his thoughtful editing of the manuscript.
REFERENCES 1. Waters WE: Headache, Clinical Epidemiolagy,vol 2. Littleton, Massachusetts, John Wright-PS6, 1986,p 37-39. 2. US Bureau ofthe Census:Statistical Abstract of the US, 1989,ed 109.Washington, BC, US National Center for Health Statistics, 1989,p 118. 3. Scheife RT, Hills JR: Migraine headaches: Signs, symptoms, biochemistry, and current therapy. Am J Hasp Pharm 1980;37:365. 4. Nestvold K, Kloster R, Partinen M, et al: Treatment of acute migraine attack: Naproxen and placebo compared. Cephalalgia 1985;5:115-119. 5. Havana-Kanniainen H: Treatment of acute migraine attack: Ibuprofen and placebo compared. Headache 1989;29:507-509. 6. Pradalier A, Rancurel G, Dordain 6, et al: Acute migraine attack therapy: Comparison of naproxen sodium and an ergotramine tartrate compound. Cephalalgia 1985;5:107-113.
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7. Hakkarainen H, Vapaatalo H, Gothoni G, et al: Tolfenamic acid is as effective as ergotamine during migraine attacks. Lancet 1979;2:326-328. 8. Sargent Jd, Baumel B, Peters K, et al: Aborting a migraine attack: Naproxen sodium vs ergotamine plus caffeine. Headache 1988;28:263-266. 9. Andersson PG, Hinge HH, Johansen 0, et al: Double-blind study of naproxen vs placebo in the treatment of acute migraine attacks. Cephalalgia 1989;9:29-32.
31. Tfelt-Hansen P, Olesen J: Methodological aspects of drug trials in migraine. Neuroepidemiology 1985;4:204-226.
Address for reprints: Gregory Luke Larkin, MD, Department of Emergency Medicine, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, Michigan 48073.
10. Oosterlinck W, Philip NH, Charig C, et al: A double-blind single dose comparison of intramuscular ketorolac tromethamine and pethidine in the treatment of renal colic. J Clin Pharmaco11990;30:336-341. 11. Fricke J, Angelocci D: The analgesic efficacy of IM ketorolac and meperidine for the control of postoperative dental pain (abstract). Clin Pharmacol Ther 1987;41:181. 12. Yee JP, Koshiver JE, AIIbon C, et al: Comparison of intramuscular ketorelac tromethamine and morphine sulfate for analgesia of pain after major surgery. Pharmacotherapy 1986;6:253-261. 13. Yee J, Bradley R, Stanski D, et el: A comparison of the analgesic efficacy of intramuscular ketorolac tromethamine and meperidine in postoperative pain (abstract). Clin Pharmaco! Ther 1986;39:237. 14. Carlson RW, Morrison RA, Shear HB, et el: A multiinstitutional evaluation of the analgesic efficacy and safety of ketorolac tromethamine, acetaminophen plus codeine, and placebo in cancer pain. Pharmacotherapy 1990;10:211-216. 15. Brown CB, Moodie JE, Evans SA, et al: Efficacy of intramuscular ketorolac tremetharnine and meperidine in pain following major oral surgery (abstract). Clin Pharmacol Thor 1988;.43:161. 16. Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8(suppl 7):19-28. 17. Lance JW: A concept of migraine and the search for the ideal headache drug. Headache 1990;3g(suppl):17-23. 18. Peroutka SJ: The pharmacology of current anti-migraine drugs. Headache 1990;30(suppl):5-1 1. 19. Huskisson EC: Measurement of pain. Lancet1974;2:1127-1131. 20. Dexter SL, Graham AN, Johnston ED, et el: Double-blind controlled study of paramax in the acute treatment of common and classical migraine. BrJ Clin Pract1985;39:388392. 21. Stanski DR., Cherry C, Bradley R, et el: Efficacy and safety of single doses of intramuscular ketorolac tromethamine compared with meperidine for postoperative pain. Pharmacotherapy 1990;10:40S-44S. 22. Brown CR, Moodie JE, Dickie 6, et ah Analgesic efficacy and safety of single-dose oral and intramuscular keterolac trometharnine for postoperative pain. Pharmacotherapy1990;10:59S-70S. 23. 0'Hara BA, Fragen RJ, Kinder M, ot al: Ketorolac tromethamine as compared with morphine for treatment of postoperative pain. Clin Pharmacol Ther1987;41:556-561. 24. Della Bella D, Carenzi F, Casacci B, et al: Endorphins in the pathogenesis of headache. Adv Neuro11982;33:75-79. 25. Cailaham M, Raskin N: A controlled study of dibydroergotamine in the treatment of acute migraine headache. Headache 1986;26:168-171. 28. Cady RK, Wendt JK, Kirchner JR, et el: Treatment of acute migraine with subcutaneous sumatriptan. JAMA 1991;265:2831-2835. 27. Tek DS, McClellan DS, Olshaker JS, et al: A prospective, double-blind study of meteclepramide hydrochloride for the control of migraine in the emergency department. Ann EmergMed 1990;19:1083+1087. 28. Stiell IG, Dufour D6, Moher D, et el: Methotrimeprazine versus meperidine and dimenhydrinate in the treatment of severe migraine: A randomized, controlled trial. Ann EmergMed1991;20:1201-1205. 29. Varia IM, Taska R: The neuroleptic malignant syndrome. Res Staff Physician 1985;31:83-85. 30. Magee R: Saint Anthony's fire revisited: Vascular problems associated with migraine reedication. Med J Aust 1991;154:145-149.
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ANNALS OF EMERGENCY MEDICINE
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AUGUST1992
ketorolac; meperidine; migraine
A
Randomized, Double-Blind, Comparative Study
of the Efficacy of Ketorolac Tromethamine Versus Meperidine in the Treatment of Severe Migraine From the Department of Surgery, Emergency Medicine
Gregory Luke Larkin, MD John E Prescott, MD, FACEP
Service, West Virginia University Health Sciences Center, Morgantown.
Study objective: Toevaluate the relative efficacy of ketorolac tromethamine and meperidine hydrochloride in the emergency department treatment of severe migraine. Design: Prospective, randomized, double-blind trial. Setting:
Receivedfor publication January 9, 1992. Revision received April 2, ] 992. Accepted for publication April 13, ] 992.
University hospital ED.
Participants: Patients presenting to the ED with an isolated diagnosis of common or classic migraine. Interventions: Subjects were randomized to receive a single intramuscular injection of either 30 mg ketorolac or 75 mg meperidine.
Measurements and main results: Of the 31 patients completing the trial, 15 received ketorolac and 16 received meperidine. The demographic characteristics of beth groups were comparable. At one hour, ketorolac was significantly less effective than meperidine in reducing headache pain (P= .02) and in improving clinical disability (P= .01). Ketorolac also was less effective at reducing nausea, photophobia, and the need for rescue medication (P< .05). Sustained headache relief was experienced by 44% of the patients treated with meperidine at 12- to 24-hour follow-up, compared with 13% of the patients treated with ketorolac (P= NS). No significant side effects were observed for either group. Conclusion: IM ketorolac tromethamine is less effective than meperidine in the ED treatment of severe migraine. [Larkin GL, Prescott JE: A randomized, double-blind, comparative study of the efficacy of ketorolac tromethamine versus meperidine in the treatment of severe migraine. Ann EmergMedAugust1992;21:919-924.]
AUGUST 1992 21:8
ANNALS OF EMERGENCY MEDICINE
919/ 37
KETOROLAC Larkin & Prescott
INTRODUCTION
MATERIALS AND METHODS
Migraine headache is an extremely common disorder affecting more than 8 million Americans and about 15% to 20% of the general population. ~,2 Treatment of the acute attack has traditionally included ergot derivatives or narcotics, although neither is ideal in the emergency setting. Ergots, for example, can lose their efficacy once the headache is already well established. 3 Moreover, ergot compounds are contraindicated in patients with severe neurologic symptoms, p e r i p h e r a l vascular disease, and coronary a r t e r y disease. They are also contraindicated in pregnancy, which is p a r t i c u l a r l y relevant because most migraine patients are women of childbearing age. Narcotic analgesics are often used instead of ergot p r e p a rations for the emergency department treatment of severe migraine; however, narcotics have well-known limitations of their own: sedation, nausea, r e s p i r a t o r y depression, u r i n a r y retention, hypotension, and, over time, addiction. In addition, narcotics may confound the neurologic examination and thereby obscure other differential diagnoses. The development of tolerance to narcotics and ergot alkaloids makes a p p a r e n t the need for alternative therapy, z To this end, various nonsteroidal anti-inflammatory analgesic preparations have been used orally to a b o r t acute migraine with some limited success. 4-9 However, giving oral medications to nauseated migraineurs is fraught with obvious p r o b lems. Recently, the availability of a p a r e n t e r a l nonsteroidal anti-inflammatory analgesic in the form of ketorolac tromethamine has afforded the vomiting patient with a nonnarcotic, nonsedating, p a r e n t e r a l alternative. Ketorolac (Toradol ®) is a new, p a r e n t e r a l analgesic indicated for the short-term management of pain. This drug has demonstrated efficacy superior or equal to the opiates in the treatment of renal colic and postoperative, dental, and cancer pain. x°-z5 We could find no previous reports of its efficacy in the treatment of pain from migraine headache. The purpose of this study was to compare the efficacy of meperidine, a s t a n d a r d t h e r a p y for severe migraine, with ketorolac in the ED treatment of acute migraine attacks.
This study was a p p r o v e d by the West Virginia University Institutional Review B o a r d for the protection of human subjects in biomedical research. Patients who were diagnosed by the attending emergency physician as having an acute attack of classic migraine (with aura) or common migraine (without aura) as defined by the International Headache Society 16 were considered for entry into the study. Eligible patients were enrolled if they met the exclusion criteria shown (Figure 1). Written informed consent was obtained from all eligible patients, and the principles of the Declaration of Helsinki and patient confidentiality were maintained throughout the study. Clinical evaluation included a thorough history, physical examination, and l a b o r a t o r y tests as deemed a p p r o p r i a t e by
Figure 1. Exclusion criteria for patients in the migraine study Age less than 18 or more than 60 years Risk of nonsteroida] or opiate intolerance Known or potential pregnancy* or breast-feeding First migraine, nonmigraine headache, or mild migraine~ headache Suspected substance abuse and/or previous treatment with meperidine Hepatic or renal dysfunction, cardiovascular disease, or other serious illness History of recent trauma or seizure Marked hyperpyrexia, hypertension, or orthostatic hypotension *Female patientsof childbearing age with an unreliable menstrual history. tMild migraine refersto a migraine that does not interfere with the capacityfor normal function (eg,working).
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Table. Comparison of demographic characteristics among ketorolac and meperidine treatment groups Ketorolac (15)
Meperidine (16)
P
Sex (%) Male Female
3 (20) 12 (80)
4 (25) 12 (75)
31.5 -+4.4 18-51
33.8 _+5.0 19-55
.52
10 (67) 5 (33)
12 (75) 4 (25)
.70
1.0
Age (yr) Mean* Range
Migraine type (%) Common Classic (with aura)
Initial headache severity/ clinical disability (%) Grade 3--most severe (incapacitated or bedridden) 11 (73) Grade 2--marked (interferes with work, job, ete) 4 (27) Grade 1--mild (slightly impaired but able to work) 0
14 (87) 2 (13)
.39
0
Most common associated symptoms at presentation (%) Nausea Photophobia Sonophobia Vomiting Numbness or tingling Lightheadedness
Family history of migraine (%)
13 (87) 15 (100) 8 (53) 6 (40) 5 (33) 3 (20)
16 (100) 16 (100) 7 (44) 6 (38) 5 (31) 5 (31)
.26 1.0 .72 1.0 1.0 .69
10 (67)
8 (50)
.47
Medication taken before ED visit (%) None Acetaminophen Nonsteroidal anti-inflammatory analgesic (including aspirin) Codeine preparation Ergot preparation Sedatives Prophylactic medications t
3 (20.0) 4 (26.7)
2 (12.5) 5 (31.3)
.65 1.0
2 (13.3) 3 (20.0) 2 (13.3) 1 (6.7) 7 (46.7)
2 (12.5) 3 (18.8) 2 (12.5) 2 (12.5) 9 (56.3)
1.0 1.0 1.0 .61 .72
*Values are _+95% confidenceintervalsbasedon the standard deviationand the standard error of the mean. qncludes calcium channel blockers,~-blockers, and antidepressants.
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the attending emergency physician. Physicians completed a headache history form on all patients detailing the onset, duration, intensity, location, and type of migraine. Precipitants, exacerbating and ameliorating factors, associated complaints, family history, prodromal aura, self-medication, and result of self-medication (both in the past and as pertains to the present headache) also were recorded. After giving informed consent, patients were assigned to one of the two treatment groups by a computer-generated random number. The subjects were randomized in a 1:1 fashion to receive a single IM dose of either 75 mg meperidine (Demerol ®) or 30 mg ketorolac (Toradol®). Both the investigator and patient were blinded as to the drug used. A nurse who was not involved in patient care except to give the injection was the only person who knew which medication the subject received. This nurse was considered to be a disinterested party and, by protocol, did not communicate information regarding the case to anyone for the duration of the study. Patients filled out questionnaires every 15 minutes to measure pain relief and any side effects experienced. Pain relief was recorded on a verbal analog scale from "no relief" to "complete pain relief." The scale included intermediate labels of "some relief but less than half better" and "marked relief/more than half better." Although less sensitive than a visual analog scale, the simple descriptive scale was easier for our photophobic patients to use. Blood pressure, pulse, and headache-associated nausea, vomiting, photophobia, phonophobia, and numbness were assessed on the same schedule as pain relief. The severity of the headache and the corresponding degree of clinical disability were graded on an analog scale both immediately before and one hour after treatment as follows: Figure 2.
grade 0, none (able to work and function normally); grade l , mild (working ability mildly impaired); grade 2, marked (working ability markedly impaired); grade 3, severe (total incapacitation, bedridden). Only patients with grade 2 or 3 disability were eligible for enrollment into the study. If little or no relief was afforded at the end of the 60minute trial, rescue medication (eg, analgesics and/or antinauseants) were offered to the patient. Any use of rescue medication was documented by the clinician, as were any adverse reactions or side effects. Treating physicians also recorded their impression of treatment efficacy after 60 minutes as poor, fair, good, or excellent. Patients received follow-up telephone calls the next day to establish the frequency of migraine relapse and side effects and to assess overall patient satisfaction. Figure 3.
Clinical disability: Baseline a n d one h o u r after treatment % Patients 1 )Or--
'°I
,o
NN
~
Grade 3
Grade 2
Grade 1
Grade 0
% Patients
% Patients
100
n
Meperidine
]
Ketorolac 60 Minutes
80
60
i¸7 ~
I
!iN
{
I Complete relief
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0 Minutes
3oi-
o
Pain relief at 60 minutes
Ketorolac •[ ]
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Marked Some (more than half better) (less than half better) Pain Relief
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No relief
Grade 3 (severe)
Grade 2 (marked)
Grade 1 (mild)
Grade 0 (none)
Disability
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Statistical analysis was carried out on the pain relief scores and the improvement in disability using the Wilcoxon r a n k sum or Mann-Whitney U test. All other comparisons were made using the Fisher's exact test. All P values r e p o r t e d are two-sided exact values calculated using Stat Xact ® software (Cytel Software Corp, Cambridge, Massachusetts).
RESULTS Thirty-three patients were enrolled in the trial; however, two were subsequently removed from the study because they failed to meet the exclusion criterion of first migraine attack. Thus, 31 patients were included in the analysis: 15 in the kctorolac group and 16 in the meperidine group. Comparison of demographic characteristics showed that both treatment groups were similar with respect to age, sex, type of migraine, clinical disability, family history, associated symptoms, duration of headache, and previous treatment (Table). No patients had re-entered the study. After one hour, patients treated with ketorolac r e p o r t e d a smaller reduction in pain than patients treated with meperidine (Figure 2). Two-sided analysis of the raw pain relief score data using the Wilcoxon r a n k sum test shows the difference in pain relief to be significant (P = .02). Assessment of clinical disability after 60 minutes revealed that there was significantly less improvement in the ketorolac group (P = .01). No patients treated with ketorolac indicated that they could r e t u r n to work unimpaired, but 25% (four of 16) of the meperidine group r e p o r t e d the complete absence of disability at 60 minutes (Figure 3). Fifty-three percent of the ketorolac group r e p o r t e d no improvement in disability grade during the study compared with 12.5% of the meperidine group (P = .001).
Figure 4. Migraine patients with photophobia versus time
No. Photot:)hobicPatients
0
15
30
Time(rain)
40/922
45
m
Ketorolac
~
Mepeddine
60
Ketorolac was also significantly less effective at reducing the most common symptom accompanying the headache, photophobia (P = .03) (Figure 4). Ketorolac did not reduce nausea as well as meperidine, but the difference was not statistically significant (P = . 10). The numbers of patients with other symptoms were too small for meaningful analysis. Eleven of 15 patients treated with ketorolac r e q u i r e d rescue medication after one hour, compared with six of 16 (37.5%; mid P = .05) who received meperidine. Of the patients who did not require rescue medication, five had r e b o u n d at 12- to 24-hour follow-up: two in the ketorolac group and three in the meperidine group (P = NS). Sustained headache relief at 12 to 24 hours was reported by seven (44%) of those who received meperidine and by two (13%) of those who received ketorolac as monotherapy (P = NS). Side effects of treatment were few. Increased nausea was r e p o r t e d by one patient in each group, and drowsiness was r e p o r t e d as a side effect in five patients: three from the ketorolac group and two from the meperidine group. Nonetheless, no patients left the trial before the end of the 60-minute observation period. There were no reported adverse reactions to either drug. The response to t h e r a p y was consistent between both common and classic migraine however, the sample size used was too small to allow stratification of these data.
DISCUSSION Although derangements in serotonin, endorphins, and prostaglandins have all been suggested to play a role in the pathogenesis of acute migraine headache, 17 no one mechanism adequately explains the response (or lack thereof) to different therapies. This confusion has led to a bewildering a r r a y of suboptimal treatment options. 18 Antinauseants, narcotics, and ergot compounds, for example, are s t a n d a r d therapy, yet they c a r r y with them well-known risks and undesirable side effects, is The results of this study demonstrate that 30 mg ketorolac is well tolerated in migraine patients and causes very few side effects; however, it was not as efficacious as 75 mg meperidine in relieving migraine headache pain and disability. Although our study used a small sample size and verbal analog scales, the differences in pain relief and clinical improvement between groups were consistent and statistically significant. We found the verbal pain relief scale easier for our patients to use than the more sensitive visual analog scale. This was p a r t i c u l a r l y true of patients experiencing scintillating scotomata or other visual disturbances. Measuring pain relief instead of pain ensured that all patients started at the same baseline and had the same degree of potential response. The use of a "pain relief" r a t h e r than a " p a i n " scale receives some support from the work of Huskisson, 19 who found it superior to subtracting pain scores after treatment from initial pain scores.
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Previous studies using various nonsteroidal anti-inflammatory analgesics in the treatment of acute migraine r e p o r t e d good efficacy; 4-8 nevertheless, these data do not necessarily apply to our study with ketorolac. First, none of the p r i o r studies were conducted in controlled ED or hospital-based settings. In addition, the patients were neither monitored for compliance n o r controlled for ingestion of nonstudy drugs. Because the subjects in these previous studies were told to take the study medication at home at the first sign of headache, many nonmigraine headaches may have been included in the analyses. Our study, however, addressed only 12 migraines as defmed by stringent International Headache Society criteria. 16 Moreover, the headaches treated in our study were uniformly severe and disabling; the pain was not only refractory to treatments at home, but it caused the patients to seek relief in an ED. Last, photophobia, a r e p o r t e d l y strong indicator of attack severity, 2° was present in 100% of the study population. Our results show ketorolac to have only marginal efficacy when c o m p a r e d with meperidine in the treatment of acute migraine headache. A placebo control was not used because it was deemed inhumane to delay or withhold treatment from patients in acute pain. Surprisingly, our data are in m a r k e d contrast to other trials, which found ketorolac, at 30 mg or less, to deliver analgesia superior or equivalent to 100 mg of meperidine.Z°,n,13,15 F o r example, Brown et a115 stated that 100 mg of meperidine and 5 mg of ketorolac were indistinguishable in the treatment of pain after m a j o r oral surgery. Another comparative trial concluded that 10 mg of ketorolac was as efficacious as 100 mg of meperidine for the treatment of renal colic. 10 Although the migraine pain model studied is different than the aforementioned pain models, it is noteworthy that all the previous studies used higher doses of meperidine and lower doses of ketorolac than our study. It is unlikely, therefore, that doses of ketorolac of more than 30 mg would have been of significant benefit. Numerous studies have already demonstrated equivalent analgesic efficacy between 30 and 90 mg of ketorolac at one hour after treatment. 11,12,21-23 Similarly, there are no published data to suggest that 60-mg doses are superior to 30 mg at one hour after dosing. One possible reason for our study results showing ketorolac to be less effective than meperidine is that prostaglandins are not as important in migraine as serotonin (5-hydroxytryptamine) TM or other mediators. 24 The relative success of drugs that affect serotonin (eg, dihydroergotamine 25 and sumatriptan 26) and dopamine (eg, metoclopramide 27 and phenothiazines 28) suggests that ~-receptor agonists (eg, n a r cotics) are often unnecessary. Regrettably, many non-narcotic modalities provide inconsistent relief and have undesirable side effects of their own. Metoclopramide and the phenothiazines, for example, can induce acute dystonic reactions. In addition to e x t r a p y r a m i d a l reactions, phenothiazines can also cause neuroleptic malignant syndrome, which, although
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rare, is fatal in 20% of cases. 29 Both sumatriptan and dihydroergotamine have demonstrated efficacy,25,26 but both can cause flushing, tingling, chest pain, and lightheadedness. Moreover, the vasoconstrictive effects of ergotamine can lead to claudication, angina, and in r a r e instances, myocardial infarction.30 Comparing ketorolac and other new therapies to s t a n d a r d narcotic analgesia is difficult because migraine trials are p a r t i c u l a r l y susceptible to large placebo effects. 31 In addition, the euphoric effects from narcotics may augment their analgesic effects. 31 We did not include suspected substance abusers or persons known to have been treated previously with meperidine in our study. Nevertheless, further studies comparing ketorolac with less-euphoric agents (eg, a narcotic agonist-antagonist) may be warranted. It is possible that the peak onset of action of meperidine is faster than ketorolac. This may explain, in p a r t , why meperidine is still widely used as a s t a n d a r d antimigraine t h e r a p y in many EDs. There are several limitations to the use of single-dose intramuscular analgesics as used in our study. F o r example, there is large interindividual variation in responsiveness to n a r cotics that demands dosage flexibility. Moreover, the optimal way to titrate narcotic analgesia is through the IV route. Ketorolac, however, is not currently a p p r o v e d for IV use in the United States. CONCLUSION
Although ketorolac tromethamine has been demonstrated to be superior to meperidine in several different pain models, it is not as efficacious as meperidine in the ED treatment of acute severe migraine. Meperidine was significantly better than ketorolac in several outcome measures, including improvement in migraineassociated pain, photophobia, and disability. Ketorolac, although well tolerated, was associated with more refractory migraine symptoms and a greater need for rescue medication, The authors thank Raymond Jackson, MD, FACEP,for his thoughtful editing of the manuscript.
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Address for reprints: Gregory Luke Larkin, MD, Department of Emergency Medicine, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, Michigan 48073.
10. Oosterlinck W, Philip NH, Charig C, et al: A double-blind single dose comparison of intramuscular ketorolac tromethamine and pethidine in the treatment of renal colic. J Clin Pharmaco11990;30:336-341. 11. Fricke J, Angelocci D: The analgesic efficacy of IM ketorolac and meperidine for the control of postoperative dental pain (abstract). Clin Pharmacol Ther 1987;41:181. 12. Yee JP, Koshiver JE, AIIbon C, et al: Comparison of intramuscular ketorelac tromethamine and morphine sulfate for analgesia of pain after major surgery. Pharmacotherapy 1986;6:253-261. 13. Yee J, Bradley R, Stanski D, et el: A comparison of the analgesic efficacy of intramuscular ketorolac tromethamine and meperidine in postoperative pain (abstract). Clin Pharmaco! Ther 1986;39:237. 14. Carlson RW, Morrison RA, Shear HB, et el: A multiinstitutional evaluation of the analgesic efficacy and safety of ketorolac tromethamine, acetaminophen plus codeine, and placebo in cancer pain. Pharmacotherapy 1990;10:211-216. 15. Brown CB, Moodie JE, Evans SA, et al: Efficacy of intramuscular ketorolac tremetharnine and meperidine in pain following major oral surgery (abstract). Clin Pharmacol Thor 1988;.43:161. 16. Headache Classification Committee of the International Headache Society: Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8(suppl 7):19-28. 17. Lance JW: A concept of migraine and the search for the ideal headache drug. Headache 1990;3g(suppl):17-23. 18. Peroutka SJ: The pharmacology of current anti-migraine drugs. Headache 1990;30(suppl):5-1 1. 19. Huskisson EC: Measurement of pain. Lancet1974;2:1127-1131. 20. Dexter SL, Graham AN, Johnston ED, et el: Double-blind controlled study of paramax in the acute treatment of common and classical migraine. BrJ Clin Pract1985;39:388392. 21. Stanski DR., Cherry C, Bradley R, et el: Efficacy and safety of single doses of intramuscular ketorolac tromethamine compared with meperidine for postoperative pain. Pharmacotherapy 1990;10:40S-44S. 22. Brown CR, Moodie JE, Dickie 6, et ah Analgesic efficacy and safety of single-dose oral and intramuscular keterolac trometharnine for postoperative pain. Pharmacotherapy1990;10:59S-70S. 23. 0'Hara BA, Fragen RJ, Kinder M, ot al: Ketorolac tromethamine as compared with morphine for treatment of postoperative pain. Clin Pharmacol Ther1987;41:556-561. 24. Della Bella D, Carenzi F, Casacci B, et al: Endorphins in the pathogenesis of headache. Adv Neuro11982;33:75-79. 25. Cailaham M, Raskin N: A controlled study of dibydroergotamine in the treatment of acute migraine headache. Headache 1986;26:168-171. 28. Cady RK, Wendt JK, Kirchner JR, et el: Treatment of acute migraine with subcutaneous sumatriptan. JAMA 1991;265:2831-2835. 27. Tek DS, McClellan DS, Olshaker JS, et al: A prospective, double-blind study of meteclepramide hydrochloride for the control of migraine in the emergency department. Ann EmergMed 1990;19:1083+1087. 28. Stiell IG, Dufour D6, Moher D, et el: Methotrimeprazine versus meperidine and dimenhydrinate in the treatment of severe migraine: A randomized, controlled trial. Ann EmergMed1991;20:1201-1205. 29. Varia IM, Taska R: The neuroleptic malignant syndrome. Res Staff Physician 1985;31:83-85. 30. Magee R: Saint Anthony's fire revisited: Vascular problems associated with migraine reedication. Med J Aust 1991;154:145-149.
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