ORIGINAL C O N T R I B U T I O N hydroxyzine; ketorolac; meperidine ; migraine

Ketorolac Versus Meperidine and Hydroxyzine in

the Treatment of Acute Migraine Headache:

A Randomized, Prospective, Double-Blind Trial

From the Departments of Emergency Medicine* and Preventive Medicine, 1" University of Illinois College of Medicine at Peoria; and St Francis Medical Center, + - Peoria, Illinois.

Received for publication April 21, 1992. Accepted for publication May 11, 1992.

Presented at the Society for Academic Emergency Medicine Annual Meeting in Toronto, Ontario, Canada, May 1992.

Carlos Duarte, MD *~

Frank Dunaway, MO**

Lanuy Turner, MD, FACEP ~ Jean Aldag, PhD t

Richard Frederick, MD, FACEP**

Study objective: To compare the effectiveness of IM ketorolac with that of meperidine and hydroxyzine in the treatment of acute migraine headache.

Design: Prospective, randomized, double-blind trial.

Sett ing: Urban emergency department with an annual census of 42,000 patients,

P a r t i c i p a n t s : Forty-seven adult patients with migraines enrolled on 50 visits.

In te rvent ions : Patients were randomly assigned to receive a single injection of either 60 mg ketorolac (group 1) or 100 mg meperidine and 50 mg hydroxyzine (group 2). Pain assessment was made Using both visual-analog and verbal descriptor scales.

Results: At 60 minutes, 15 patients (60%)from group 1 (25)and 14 patients (56%) from group 2 (25) reported a great deal of complete relief (P= .77) Sixty-minute mean pain relief scores (3.35 versus 3.37) were different (P= .76). Nine patients (36%) from group 1 and seven patients (28%) from group 2 required additional analgesi a (P= .76)

Conclus ion: Ketorolac is as effective as meperidine and hydroxyzine for the treatment of acute migraine headache.

[Duarte C, Dunaway F, Turner L, Aldag J, Frederick R: Ketorolac versus meperidine and hydroxyzine in the treatment of acute migraine headache: A randomized, prospective, double-blind trial. Ann Emerg Med September 1992;21:1116-1121 .]

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KETOROLAC Duarte et al

I N T R O D U C T I O N Migraine headache is a common disease that affects an esti- mated 23 million Americans. 1 Many of these patients experi- ence incapacitating pain and present to the emergency depar t - ment seeking prompt and effective relief. Tradit ionally, paren te ra l narcotics have been the mainstay of t reatment despite their potential for abuse and addict ion; Langemark and Olesen calculated that 13 migraineurs per 1 million peo- ple become dependent on narcotics. 2

Numerous drugs have been advocated for use in the t reat- ment of acute migraine. 3-7 Nonsteroidal ant i - inf lammatory drugs have been researched extensively and found to be superior to placebo and as effective as some s tandard refer- ence drugs. 8 Although the etiology of migraine headaches remains controversial , platelet aggregation with subsequent release of vasoactive substances9o lo as well as prostaglandin synthesis n have been implicated. The inhibit ion of these mechanisms may account for the usefulness of nonsteroidal ant i -f lammatory drugs in migraine management, u

Ketor01ac, a new nonsteroidal ant i - f lammatory drug with potent analgesic and ant i - inf lammatory proper t ies , is the first drug of its class available in pa ren te ra l form in the United States that is approved for IM treatment of moderate- to-severe pain. 12 Most clinical tr ials with ketorolac have focused on the t reatment of postoperat ive pain, in which ketorolac was found to be as effective as morphine or meper id ineJ 3 Recently, ketorolac was compared with dihydroergotamine and metoclopramide in the t reatment of acute migraine headache. 14

Our study was a double-bl ind, randomized clinical t r ial comparing IM ketorolac with the IM combination of meperi- dine and hydroxyzine, one drug regimen adminis tered in our ED for the t reatment of acute migraine headache.

M A T E R I A L S A N D M E T H O D S All patients aged 18 years or older presenting to St Francis Medical Center ED diagnosed as migraine with and without aura , as defined by the In ternat ional Headache SocietyJ 5 were eligible for enrollment. Exclusion cri ter ia included first migraine, allergy or sensitivity to the study drugs, known in t racran ia l masses, t raumat ic etiology, gastritis, peptic ulcer disease, bleeding dyscrasias, pregnancy, and nursing mothers. The study protocol was reviewed and approved by the hospital 's insti tutional review board .

After a complete history and physical examination, Written informed consent was obtained from eligible study par t ic ipants . Init ial assessment of pain intensity was made using a 10-cm horizontal visual-analog scale with the words "pain-free" and "most severe pain ever experienced" at either end of the scale. A new unmarked scale was used for each reassessment of pain so that previous marks would not influence decisions regarding present pain intensity.

Patients were randomly assigned to receive a single IM injection into the left deltoid of either 60 mg ketorolac

t romethamine or the combination of 100 mg meperidine and 50 mg hydroxyzine, as p repa red by the pharmacy. The study medications ar r ived premixed at the ED in identical syringes containing a 2.0-mL total volume of either ketorolac (30 mg/mL) or meperidine (100 mg/mL) and hydroxyzine (50 mg/mL). The contents of each syringe remained bl inded to the emergency physicians, nurses, and patients until the study was completed.

At 30 and 60 minutes after the injection, assessment of pain intensity and pain relief was made using the 10-cm visual-analog scale described above and a verbal descriptor scale, respectively. The verbal descr iptor scale consisted of a vertical list of five phrases ("complete relief," "great deal of relief," "some relief," "small amount of relief," and "no relief") whereby patients marked the most appropr ia te phrase. Informat ion regarding adverse effects and need for addi t ional analgesia were noted. If necessary, patients were medicated with a drug chosen at the discretion of the treat- ing physician after the conclusion of the study period. All patients were given the option of withdrawing from the study at any time.

Statistical analysis was performed; the two outcome vari- ables were the propor t ion of patients achieving "complete" or "great deal" of relief and pain-intensity scores of the visual-analog scale assessment. Differences between the mean values of the ketorolac and meperidine/hydroxyzine groups were analyzed for significance using a two-tailed unpa i red Student 's t-test. Pearson 's ~2 was used to compare propor t ions between groups. The mean values for each group, as determined by the visual-analog scale, were ana- lyzed using the Mann-Whitney U test. Results were consid- ered statistically significant for a value of P < .05.

R E S U L T S During a 12-month per iod, 49 patients were enrolled in the study represent ing 52 separate ED visits. Two cases were subsequently excluded due to incomplete records and volun- ta ry withdrawal from the study before receiving medication. The final analysis, therefore, consisted of 50 cases of ED visits by 47 patients, of whom three patients were enrolled twice.

Table. Patient demographic characteristics

Meperidine! Ketorolac Hydroxyzine

Group Group Characteristic (N=25) (N=25) P

Age (yr) 34.9 __ 10.1 34.4 + 12.3 .86 Female (%) 80.0 80.8 1.00 Duration of headache (hr) 41.4+_38.1 16.5+_20.5 .03 Type of headache (%) ,53

Common 76.8 68.(1 Classic 24.0 32.0

Initial pain score (cm) 7.74 _+ i.84 8.28 _+ 1.65 .33

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Of the 50 cases, 25 were randomized into the ketorolac group, and 25 were randomized into the meperidine/hydrox- yzine group. At entry, there were no significant differences in age, sex, type of headache, or initial pain score (Table). The ketorolac group tended to have a longer dura t ion of headache at time of enrollment than the meperidine/hydroxy- zinc group.

Analysis of the pain-intensity scores of the ketorolac group and the meperidine/hydroxyzine group revealed no signifi- cant differences at 30 minutes (5.04 versus 5.63, P = .40) or at 60 minutes (3.35 Versus 3.37, P = .76). The temporal pro- gression of pain-intensity scores was nearly identical for both groups (Figure 1). Our sample size of 25 cases per group could detect an effect size of .80 with a statistical power of 80%.

The dis tr ibut ion of pain relief scores tended to skew toward improved pain relief from 30 minutes to 60 minutes in both groups (Figures 2 and 3). Complete or a great deal of relief was obtained in six patients in the ketorolac group (24%) and five patients in the meperidine/hydroxyzine group (20%) at 30 minutes (P = .73) (Figure 2). At the con- clusion of the study, 15 patients of the ketorolac group (60%) and 14 patients of the meperidine/hydroxyzine group (56%) had achieved complete or a great deal of relief from their headache pain (P =.77) (Figure 3). After 30 minutes, more patients in the ketorolac group (24%) had no relief than those in the meperidine/hydroxyzine group (8%); by 60 minutes, however, three patients from the ketorolac group had obtained at least a small amount of relief, whereas those in the meperidine/hydroxyzine group still had obtained no relief (Figures 2 and 3).

All of the patients in the ketorolac group and four of five patients in the meperidiue/hydroxyzine group who repor ted a small amount of pain relief required addit ional analgesia, as did all five patients from both groups who had obtained

: Figure 1. Visual-analog scale

Severity of pain (cm)

;I • Meperidine/Hydroxyzine • Ketororae

~ ~ _ 8,28 +- 1.65

.63 -+ 2.78

5.04 -+- 2.59

I I 30 60

Time (min)

no pain relief. There was no significant difference between the propor t ion of patients from either group who required addit ional analgesia at the conclusion of the study per iod (36% versus 28%, P = .76).

Classification and analysis of subgroups of patients with classic migraine versus common migraine were not possible due to a limited number of patients. Of patients with classic migraine, three of eight from the meperidine/hydroxyzine group and three of six from the ketorolac group required addit ional analgesia.

Adverse effects were repor ted more often in the meperi- dine/hydroxyzine group than in the ketorolac group (48% versus 28%, P = . 15). Of the 19 patients report ing adverse affects, nausea and drowsiness were most common. Nausea was present in four patients in the meperidine/hydroxyzine and in three patients in the ketorolac group. Drowsiness was repor ted in seven patients in the meperidine/hydroxyzine group and in two patients in the ketorolac group.

One of the three patients, a 39-year-old woman who was enrolled twice into the study, received meperidine/hydroxy- zinc on her first visit and ketorolac on her second visit. On her first visit, she complained of "numbness all over" 60 minutes after meperidine/hydroxyzlne administrat ion, which resolved soon after receiving 5 mg proch!orperazine IV for inadequate headache relief. On her second visit, she complained of dizziness five minutes after ketorolac adminis- t ra t ion while arising from a supine position; this resolved immediately when replaced supine and did not recur.

An "anxiety a t tack" was repor ted by a 4 l -year-old woman with a history of panic attacks approximately 90 minutes after ketorolac administrat ion and approximately 30 minutes after 10 mg prochlorperazine IV for inadequate headache relief. Although it is unclear whether this adverse affect was due to either ketorolac or prochlorperazine, the

Figure 2. Verbal descriptor scale at 30 minutes

% of Patients

-- [ ] Meperidine/Hyd roxyzine Ketorolac

10 (40%) 9

Complete Great Deal Some Smarl Amount Amount of Pain Relief

None

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KETOROLAC Duarte et al

patient's symptoms resolved spontaneously during observa- tion, and she was discharged from the ED in good condition without headache pain.

D I S C U S S I O N Management of the acute migraine headache is difficult and challenging for the emergency physician, in part because there is no consistently successful therapy. Numerous medi- cations have been advocated for treatment of migraine symptoms as well as migraine causes, including analgesics, antiemetics, sedatives, and, more specifically acting drugs such as the ergot derivatives or, more recently, sumatriptanA 6

Current theory of migraine pathophysiology includes the pronounced dilatation of intracranial extracerebral blood vessels with subsequent transudation of plasma and neuronal substances, including serotonin and prostaglandins, that produce a sterile perivascular inflam- mation. 7,n,15-ia In addition, platelet activation, mediated in part by prostaglandins, with subsequent aggregation and release of Vasoactive substances, has been observed during acute migraine attacks.9,19 The end result is the perception of pain, with the associated symptoms of nausea, vomiting, anxiety, phonophobia, and photophobia.

Oral nonsteroidal anti-inflammatory drugs have been used in the management of acute migraine for more than 20 years and have proven to be as effective as some antimigraine drugs. 8 Decreased prostaglandin synthesis by cyclo-oxyge- nase inhibition to produce anti-inflammatory and analgesic properties is thought to be a determinant of nonsteroidal anti-flammatory drug effectiveness. 8 In comparison trials versus placebo, nonsteroidal anti-flammatory drugs such as naproxen, ibuprofen, flufenamic acid, pirprofen, and diclofenac have all been found to be significantly superior

Figure 3. Verbal descriptor scale at 60 minutes

% of Patients 100~

k .50 I-.-

10 10 (4o%) (40%)

• Mepe ridin e/Hyd roxyzine

Ketorolac

Complete Great Deal Some Small Amount Amount of Pain Relief

None

to placebo regarding headache severity and duration as well as in the need for escape medication. 20-24

In a recent trial, ketorolac was compared with the combi- nation of dihydroergotamine and metoclopramide and found to be inferior regarding pain relief and improvement in dis- abilityA 4 Several limitations, however, impede these conclu- sions. The study used very small sample sizes, and the physi- cian administering the medication was not blinded to its contents. In addition, ketorolac was administered IM, whereas the dihydroergotamine compound was given IV, which further compromised the blind design. This would also allow a more rapid onset of action for the dihydroergo- tamine compound (peak plasma level, two to 11 minutes after IV injection 25) than for ketorolac (peak plasma level, 45 to 50 minutes after IM injectionl3), a difference that might have allowed the dihydroergotamine group sufficient time to improve while the ketorolac group had not yet reached optimal drug response.

The results of our study suggest that ketorolac is as effec- tive in relieving acute migraine headache as is the combina- tion of meperidine/hydroxyzine. Patients from both groups entered the study with similar headache pain and completed the study having attained nearly identical lowered pain intensities, with similar proportions of patients having obtained adequate headache relief. Slightly more patients in the ketorolac group required escape medication than those in the meperidine/hydroxyzine group, although the differ- ence was not significant. Almost twice as many adverse effects were reported by the meperidine/hydroxyzine group, mostly related to drowsiness. In the ketorolac group, the incidence of drowsiness was low, which is a desirable effect for patients treated in the ED.

It is unclear why there was an overall longer duration of headache reported by the ketorolac group; these prolonged headaches did not appear to affect the final outcomes as the two drug group scores were similar at the conclusion of the study. However, it certainly is possible that these prolonged and intuitively more-difficuh-to-treat headaches would result in fewer patients achieving adequate pain relief. In such a scenario, these patients may have achieved better pain relief if they had presented to the ED earlier compared with the patients in the meperidine/hydroxyzine group.

Limitations of this study were the small sample size and the small differences between the mean pain scores. Using the visual-analog scale, we could detect no significant differ- ences between treatment groups. In addition, if the small differences detected by the verbal descriptor scale were real, an impractical sample size of more than 1,500 patients per group would be needed to detect these differences.

Ketorolac tromethamine is the first nonsteroidal anti- flammatory drug to be approved for parenteral (IM) use in the United States for control of pain. It is a powerful anal- gesic with effects that have been shown to be peripheral rather than central acting; 26 as such, it presents a potential- ly beneficial and more attractive alternative to narcotics in

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the control of moderate-to-severe pain. i3 Ketorolac is one of the most potent analgesic nonsteroidal anti-flammatory drugs; it has demonstra ted potency 800 times that of aspir in and twice that of naproxen in animal studies. 13,26 The efficacy of ketorolac in human beings has been tested in single-dose, double-blind clinical tr ials , usually with postoperat ive discomfort as the pain model in which ketorolac has been found to be as effective as morphine,27, 28 buprenorphine , 29 or meperidine. 30

Overall , fewer adverse effects have been repor ted with ketorolac than with ei ther morphine or meperidine, lz The most commonly repor ted adverse effects are somnolence, pain at injection site, sweating, gastrointestinal pain, and nausea. 12 Most of these are similar to the adverse effects reported from the use of other nonsteroidal ant i - f lammatory drugs. Other, less frequently repor ted side effects include diarrhea, dizziness, headache, and edema.31 Ketorolac also has been noted to cause a prolongation of bleeding time, although no clinical significance has been demonstrated. 32

Ketorolac has been shown to have several advantages over narcotic analgesics. Compared with morphine, ketoro- lac does not produce resp i ra tory depression: 33 Ketorolac 'als0 has no significant effects on mental or physical perfor- mances in contrast to buprenorphine , which caused signifi- cant psychomotor impairment in volunteer subjects. 34

Fur thermore , as ketorolac does not bind to opiate recep- tors, it has been found to lack addictive potential.13, 30 It has been proposed that the use of a non-narcotic paren te ra l analgesic like ketorolac could improve medical staff efficiency and reduce hospital costs due to the elimination of controlled- substance d is t r ibut ion systems that are routinely used for narcotics. 35

CONCLUSION Ketorolac is as effective as the combination of meperidine/ hydroxyzine for the t reatment of acute migraine headache. The overall pain rel ief and its rate of change over time are very similar for each drug regimen. Ketorolac is well tolerated by patients. Therefore, ketorolac, a new injectable nonsteroidal anti-flammatory drug, should be considered an al ternative to the potential ly addictive narcotics for the t rea tment of acute migraine headaches.

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2. Langemark M, Olesen J: Drug abuse in migraine patients. Pain1984;19:81-86.

3. Kunkel R: Pharmacologic management of migraine headaches. RationalDrug Therapy 1987121:1-6.

4. 01esen J: A review of current drugs for migraine. J Neural 1991 ;238:S23-$27.

5. Kudrow L: Treatment of idiopathic headache without frustration or failure. Emerg Med Rap 1990111:33-42.

6. Beekett B: Contemporary management of migraine: Pen~ 1. Am Pharmacy 1990;NS30:51-58.

7. Saper J: Migraine, migraine variants, and related headaches. Otolaryngol C/in Nor, Am 1989122:1115-1130.

8. Pradalier A, Ciapin A, Dry J: Treatment review: Non-steroidal anti-inflammatory dru in the treatment long-term prevention of migraine attacks. Headache 1988;28:560-557.

9. Wachowicz B: Platelet activation: Its possible role in the migraine mechanism. Adv Neural 1982;33:243-252.

10. Diamond S, Freitag F: Do non-steroidal anti-inflammatory agents have a role in the treatment of migraine headaches? Drugs 1989137:755-760.

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12. Abramowicz M (ed): Ketorolac tremetharnine. MedLett1990;32:79-81.

13. Buekley M, Brogden R: Ketorolac: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potentiaE Drugs 1990;39:86-109.

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76. Saxena P, Den Boer M: Pharmacology of antirnigraine drugs. J Neurol1991;238:S28- $35.

17. Rowland LP (ad): Merritt's Textbook of Neurology, ed 8. Philadelphia, Lea & Febiger, 1989, p 773-780.

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19. Ha/rosen H: Pratelets and prostaglandins. Cephalalgia 1986;6(suppl 4):33-42.

26. Andersson P, Hinge H, Johansan D, et el: Double-blind study of naproxen vs placebo in the treatment of acute migraine attacks. Cephalalgia 198919:29-32.

21. Havanka-Kanniainen H: Treatment of acute migraine attack: Ibuprofen and placebo compared. Headache 1989129:507-509.

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23. Guidotti M, Zanasi S, 6aragiola U: Pirprofen in the treatment of migraine and episodic headache attacks: A placebo-controlled crossover clinical trial. J IntMedRes 1989;17:48-54.

24. Massiou H, Serrurier D, Laserre O, et al: Effectiveness of oral diclofenac in the treatment of common migraine attacks: A double-blind study versus placebo. Cephalalgia 1991;11:59-63.

25. Raskin N: Headache. New York, Churchill Livingstone, 1988, p 151-153.

26. Rooks WH, Tomolonis A J, Maloney P J, at al: The analgesic and anti-inflammatory profile of (±)-5-benzoyl-1, 2-dihydro-3H-pyrrolo(1,2a) pyrrole-l-earboxylic acid (RS- 37619). Agents Actions 1982112:684-690.

27. O'Hara DA, Fragen R J, Kinzer M, et al: Ketorolac tromethamine as compared with morphine sulfate for treatment of postoperative pain. Clin Pharmacol Therap 1987141:556-561.

28. Yea JP, Koshiver JE, AIIbon CA, et at: Comparison of intramuscular ketorolae tromethamine and morphine sulfate for analgesia of pain after major surgery. Pharmacetherapy 198816:263-261.

29. CenadelI-Carafi J, Morene-Londono A, Gonzelez-Caudevilla B: Ketorolac, a new nen-opioid analgesic: A single-blind trial versus buprenorphine in pain after orthopaedic surgery. CurrMedResOpinien 1991;12:343-349,

30. Oosterlinck W, Philip NG, Charig C, et ah A double-blind single dose comparison of intramuscular ketorolac trometharnine and pathidine in the treatment of renal colic. J Clin Pharmaco/1996;30:336-341.

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32. Conrad K, Fagan T, Mackie M, et al: Effects of ketorelac tromethamine on hemostasis in volunteers, C/in Pharmacol Therap 1988;43:542-546.

33. Brandon Bravo L, Mattie H, Spierdijk J, et ah The effects on ventilation of ketorolac in comparison with morphine. EurJ Clin Pharmaco11988;35:491-494.

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34, MacDonald FC, Gough K J, Nicoll R, et al: Psychomotor effects of ketorolac in comparison with buprenorphine and diclofenac. Br J Clin Pharmaco11989;27:453-459.

35. Koffar H, Hildebrand J, Connell M: Potential for nonnarcotic analgesics to save personnel costs associated with controlling injectable morphine and meperidine. Am J Hosp Pharm 1990;47:1084-1088.

The authors are indebted to the ED staff of nurses and physicians at St Francis Medical Center for assistance in completing this study, as well as to Jackie Duarte for preparing this manuscript.

Address for reprints: Richard Frederick, MD, FACEP 530 Northeast Glen Oak Avenue St Francis Medical Center Peoria, Illinois 61637

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