Intravenous dexketoprofen vs placebo for migraine attack in the emergency department: A randomized,placebo-controlled trial

Abstract

Objective

Migraine is a leading headache etiology that frequently presents to the emergency department (ED). In the present study, we aimed to determine the efficacy of dexketoprofen in aborting migraine headaches in the ED.

Methods

This prospective, randomized, double-blind study was conducted in an ED of a tertiary care hospital using allocation concealment. Patients were allocated into two arms to receive the study drug; 50 mg dexketoprofen in 50 ml saline and 50 ml saline as placebo. Change in pain intensity was measured by the visual analog scale at baseline, both at 30 and 45 minutes after the study medication was administered. Rescue medication requirement and pain relapse were also recorded by a telephone follow-up at 48 hours.

Results

A total of 224 patients (112 in each group) were included into the final analysis. Mean age of the study participants was 37 ± 11 (SD) and 25% (n = 56) of them were male. The median pain improvement at 45 minutes for patients receiving dexketoprofen was 55 (IQR: 49 to 60) and 30 (IQR: 25 to 35) for those receiving placebo. The mean difference between the two groups at 45 minutes was 21.4 (95% CI: 14.4. to 28.5). Rescue drugs were needed in 22.3% of patients who received dexketoprofen compared to 55.4% in patients who received placebo (dif: 33.1%; 95% CI: 20% to 45%). There were no adverse events reported in either group during the study period.

Conclusion

Intravenous dexketoprofen is superior to placebo in relieving migraine headaches in the ED. It may be a suitable therapy with minimum side effects in patients presenting with a migraine headache to the ED.

Introduction

Migraine is a leading headache etiology that frequently presents to the emergency department (ED). Nearly 5.2 million patients reported that headache or migraine headache was one of their three chief reasons for the ED visit (1) and ER management of migraine has an annual cost of $700 million (2). While patients presenting with a headache pattern similar to former migraine attacks generally do not require diagnostic testing in the ED, they do expect rapid and effective management of their headache.

Sumatriptan, dopamine antagonists such as metoclopramide, prochlorperazine and chlorpromazine, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are the most common drugs used via diverse routes for mitigating migraine headaches in the ED.

All of these drugs have demonstrated effectiveness in decreasing migraine pain with various side effects (3–5). Narcotic analgesics are frequently administered for pain in the ED with potent effects but also with common side effects such as nausea, vomiting, hypotension and drowsiness. A meta-analysis reported meperidine, an opioid, to be less potent than dihidrorgotamin and comparable to ketorolac (6).

Dopamine antagonists have also been widely used in stopping migraine headaches but with potential extra-pyramidal side effects. Metoclopramide, one the most common drugs used in migraine headache therapy, has heterogeneous results compared to placebo but not for active comparators (7–9).

Parenteral NSAIDs are medications that have few side effects with a growing involvement in pain management in the ED setting. In the present study, we aimed to determine the efficacy of intravenous (IV) dexketoprofen in ceasing migraine headaches in ED.

Material and methods

Study design and setting

This prospective randomized, double-blind, placebo-controlled trial was conducted between May 2014 and August 2014 in a tertiary care hospital with an annual census of 331,000 patients. The study was approved by the local and central (ministry of health) ethics committees with a clinicaltrial.gov ID of NCT02159547.

Selection of participants

Patients between 18 and 65 years old who presented with headache, had a pain score of greater than 30 mm on the visual analog scale (VAS), and met the criteria of the International Classification of Headache Disorders for migraine, were accepted to the study. Patients were enrolled in the study consecutively 24 hours a day and seven days a week. The eligibility of each patient was determined by residents, trained on the migraine criteria before the study, working in the ED with attending physicians and residents scheduled 24 hours a day and seven days a week.

Receiving an analgesic within the last six hours, possible or known pregnancy, active peptic ulcer disease, allergy to dexketoprofen, renal failure, hemodynamic instability, additional symptoms (abdominal pain, vertigo, etc.) and denying to give informed consent were the exclusion criteria for the study.

Randomization and interventions

A Web-based computerized randomization model with eight blocks was used to achieve a randomization schedule. The hospital pharmacist prepared the study drugs in accordance with the randomized eight blocks and sent them to the ED for study administration. Allocation concealment was ensured through the use of a central pharmacist and identical study supplies. Since the study drugs were identical in color and appearance, the patient, study nurse and treating physician(s) were blinded to the treatment allocation.

The eligible patients were enrolled to the study consecutively. After a patient was enrolled in the study, the study nurse administered the study drug and recorded the drug number to a standardized study form.

Study patients were randomized into two arms to receive either 50 mg dexketoprofen trometamol (Arveles, IE Ulagay-Menarini, Turkey) within a 50 ml normal saline solution or 50 ml normal saline as placebo. Each study medication was administered by rapid infusion.

Methods of measurements

A 100 mm VAS (0 = no pain and 100 mm = worst pain) was used to measure pain intensity. The clinically significant difference in VAS has been defined in the medical literature as 13 mm (10). Pain intensity was measured at baseline, then 30 and 45 minutes after medication administration.

Outcome measures

The primary outcome measure was change in pain intensity at 30 and 45 minutes after medication administration as measured by the VAS. Rescue medication, fentanyl, need and adverse effects were also recorded at the end of the study. Persistence or recurrence of the pain after ED discharge or re-attendance to another health care facility because of migraine was also recorded by a 48-hour telephone follow-up. Relapse of pain was questioned for patients discharged from the ED with a pain-free situation and persistence of pain was questioned in patients discharged without a pain-free condition.

Statistical analysis

The study data were analyzed by MedCalc, SPSS and Confidence Interval Analysis software. The numeric data were expressed by mean ± standard deviation (SD) or median (interquartile range (IQR)) and categorical data by rates. Because of the baseline, 30-minute and 45-minutes VAS values were not distributed normally, VAS values for these time points were expressed as median and IQR. However, VAS differences for the 30- and 45-minute point between two groups that distributed normally were presented both as median (IQR) and mean ± SD. Assessment of normality was performed using the Kolmogorov-Smirnov test. The study was designed as an equivalence trial that was calculated to need 104 patients per group with an alpha critical value of 0.05, 95% power, 10 mm tolerance limit and standard deviation of 20 mm. All the hypotheses were constructed as two tailed and a 95% confidence interval (CI) was used for expressing the study data. All the analyses were performed according to the intention to treat analysis.

Results

A total 3786 patients presented with headache during the study period and 416 (11%) were eligible for the study. From the eligible patient group, 156 (37.5%) patients were excluded for various reasons and 36 (8.7%) patients refused to provide written informed consent (Figure 1). Finally, 112 patients in the intervention group and 112 patients in placebo group were randomized and allocated to study arms. All the patients allocated to a study arm received the study medications and were included into the final analysis with no loss to follow-up at 45 minutes but not at 48 hours for telephone follow-up (Figure 1). Metoclopramide was administered to one patient in the intervention group and diclofenac to one patient in placebo group within the 30-minute period after the study medication was administered. However, both patients were included into the final analysis.

Figure 1.

Patient flowchart.

Mean age of the study participants was 37 ± 11 and 25% (n = 56) of them were male, and the baseline pain scores indicated severe pain (median VAS: 80 (IQR: 70–90)) vs 80 (IQR: 70–100), respectively). Mean pain improvement for dexketoprofen at 30 minutes was 38.9 ± 26 (95% CI: 34 to 43.7) and was 22.4 ± 20.5 (18.6 to 26.2) for placebo. The mean difference between the two groups at 30 minutes was 16.5 (10.3 to 22.7). Mean pain improvement at 45 minutes for the dexketoprofen group was 53.2 ± 28.1 (47.8 to 58.4) and 31.7 ± 25.1 (27 to 36.4). The mean difference between the two groups at 45 minutes was 21.4 (14.4. to 28.5) (Tables 1 and 2).

Table 1.

Change in pain intensity at 30 and 45 minutes for each study arm.

Variable	Dexketoprofen group	Placebo group
VAS
Median with IQR
Baseline	80 (70–95)	80 (70–100)
30 minutes	35 (20–60)	55 (40–75)
45 minutes	17 (0–74.5)	45 (40–50)
Change from baseline (VAS)
Median differences with 95% CI
30 minutes	38 (33 to 43)	20 (18 to 25)
45 minutes	55 (49 to 60)	30 (25 to 35)

IQR: interquartile range; VAS: visual analog scale; CI: confidence interval.

Table 2.

Differences of pain improvements between groups.

Variable	Dexketoprofen group Mean ± SD	Placebo group Mean ± SD	Dexketoprofen vs placebo Mean (95% CI)	p value
Differences from baseline to 30 minutes	38.9 ± 26	22.4 ± 20.5	16.5 (10.3 to 22.7)	<0.0001
Differences from baseline to 45 minutes	53.2 ± 28.1	31.7 ± 25.1	21.4 (14.4 to 28.5)	<0.0001

SD: standard deviation; CI: confidence interval.

Rescue medication requirement was 22.3% in the dexketoprofen group, 55.4% in the placebo group (dif: 33.1%; 95% CI: 8% to 52%). The median length of ED stay was 60 minutes (IQR: 60–90)) in the dexketoprofen group and 90 minutes (IQR: 60–90) in the placebo group (p = 0.01). There were no adverse events reported in either group during the study period.

A total of 183 patients were reached by telephone follow-up at 48 hours. There was no difference between the two groups when compared for a persistent headache, relapse of pain or re-attendance to a health care facility (Table 3).

Table 3.

Comparison of study arms for rescue drug need and pain condition after emergency department discharge.

Variable	Dexketoprofen % (n)	Placebo % (n)	Difference (95% CI)
Rescue drug need	22.3 (25)	55.4 (62)	33.1 (8 to 52)
Persistent pain	25 (23)	28.6 (26)	3.6 (−24 to 30)
Headache relapse	15.2 (14)	14.3 (13)	0.9 (−32 to 32)
Re-attendance to health care facility	5.4 (5)	11 (10)	5.6 (−48 to 41)

SD: standard deviation; CI: confidence interval.

Discussion

This study showed that a novel intravenous NSAID, dexketoprofen, is superior to placebo in treating a migraine attack and rescue medication need. A current study by Turkcuer et al. reported similar findings for dexketoprofen in aborting migraine headaches in the ED (11). Turkcuer et al. compared dexketoprofen to paracetamol in patients who presented with a migraine headache to the ED with a lack of placebo arm and they reported pain improvement of 53.2 ± 28.1 mm 45 minutes after treatment. Their results also showed that dexketoprofen and paracetamol are not superior to each other in these patients.

The present study also showed that dexketoprofen is superior to placebo for rescue medication requirement (22.3% vs 55.4%). Turkcuer et al. reported the rescue medication requirement in patients treated with dexketoprofen to be 24%, which is lower than the paracetamol group rescue medication requirement of 33%, but this was statistically insignificant.

As within the same group of drug with dexketoprofen, ketorolac has also been shown to be superior to placebo in acute migraine headaches according to a Cochrane meta-analysis (5). Derry et al. reported the number-needed-to treat (NNT) value of 50 mg oral diclofenac potassium over placebo for pain-free status at two hours as 6.2 with mild and transient adverse effects. Another systematic review by Taggart et al. compared ketorolac with active comparators, meperidine and sumatriptan (12). Although the sample size is small, meperidine, an opioid, is not superior to ketorolac according to the meta-analysis by Taggart et al. And also a small study reported ketorolac to be superior when compared to sumatriptan in the emergency setting (13).

Although adverse effects related to the gastrointestinal system are of concern in patients administered NSAIDs, the present study and the study by Turkcuer et al. reported no side effects to dexketoprofen. In a study with intramuscular diclofenac sodium (n = 24) in patients with a migraine headache, one patient reported having epigastric discomfort and one patient had worsening of nausea relieved quickly with symptomatic treatment (14). A well-known intravenous NSAID, ketorolac, was reported to have no side effects in two studies (15,16) and two studies reported nausea and drowsiness (17,18). Nausea and vomiting are common side effects that are related to migraine rather than NSAIDs. Dexketoprofen and NSAIDs are relatively safe drugs for ED administration in migraine attacks.

Dexketoprofen also seems to shorten the length of ED stays in migraine patients by approximately 30 minutes compared to placebo.

Limitations

There are some limitations to this study. Although there was a protocol violation in two patients, one in each group, by administering an additional drug, the final analysis was performed according to an intention-to-treat analysis. There are also some patients that were lost to follow-up at 48 hours after the ED discharge. Change in pain intensity was measured at 30 and 45 and minutes; a 60-minute pain measurement might be a goal of this study rather than 45 minutes. There was also no standard abortive therapy administered to patients during the study; however, the study period was brief and physicians were free to administer a rescue drug at the end of the 45 minutes.

There were also 41 patients who were not reached at the end of 48 hours, which might limit the accuracy of pain relapse and persistent pain after ED discharge. All adverse events might not be detected regarding the sample size.

Another limitation is not being able to compare the results with other acute treatments, given that most acute trials follow International Headache Society (IHS) clinical trial guidelines and use pain-free and sustained pain-free outcomes.

Conclusion

Intravenous dexketoprofen is a faster and more effective treatment than placebo for safely decreasing pain in the ED treatment of patients with migraine headaches. It decreases the need for rescue therapy and reduces the length of ED stay; however, it has no benefit in reducing follow-up symptoms. Dexketoprofen should be a safe and effective option for stopping acute migraine headache in the emergency setting.

Clinical implications

Dexketoprofen is superior to placebo in ceasing migraine headache in the emergency department (ED).

Dexketoprofen shortens length of stay for migraine attack in the ED.

Dexketoprofen is a relatively safe drug with no side effects.