Intravenous paracetamol versus dexketoprofenin acute migraine attack in the emergencydepartment: a randomised clinical trialIbrahim Turkcuer,1 Mustafa Serinken,1 Cenker Eken,2 Atakan Yilmaz,3 Ömer Akdag,1

Emrah Uyanık,4 Cihan Kiray,1 Hayri Elicabuk1

▸ Additional material ispublished online only. To viewplease visit the journal online(http://dx.doi.org/10.1136/emermed-2013-203044)1Department of EmergencyMedicine, Pamukkale UniversityHospital, Denizli, Turkey2Department of EmergencyMedicine, Akdeniz UniversityHospital, Antalya, Turkey3Emergency Services, TekirdagState Hospital, Tekirdag, Turkey4Department of EmergencyMedicine, Tekirdag StateHospital, Tekirdag, Turkey

Correspondence toProfessor M Serinken,Department of EmergencyMedicine, Pamukkale UniversityHospital, PAU University,Kınıklı, Denizli 20020, Turkey;mserinken@hotmail.com

Received 17 July 2013Revised 22 November 2013Accepted 23 November 2013Published Online First6 January 2014

▸ http://dx.doi.org/10.1136/emermed-2012-201670▸ http://dx.doi.org/10.1136/emermed-2014-203566

To cite: Turkcuer I,Serinken M, Eken C, et al.Emerg Med J 2014;31:182–185.

ABSTRACTObjective Migraine is a common form of headache thatis a major burden for patients who often seek emergencycare. The goal of this study was to compare theeffectiveness of intravenous non-steroidal anti-inflammatory medication (dexketoprofen) withparacetamol (acetaminophen) in the treatment of anacute migraine attack.Materials and methods This prospective,randomised, double blind, controlled study wasconducted in a tertiary care emergency unit. Studypatients were randomised into two groups to receiveeither 50 mg of dexketoprofen trometamol or 1000 mg ofparacetamol intravenously by rapid infusion in 150 mL ofnormal saline. Pain reduction was measured at baseline,and after 15 and 30 min, using a Visual Analogue Scale(VAS)) as the primary outcome. VAS is a measurementtool ranging from 0 (no pain) to 100 mm (worst pain).Results 200 patients were included in the final analysis.Mean (SD) age of the study subjects was 30.1±11 yearsand 81% (n=162) were women. Median reduction in VASscore at 30 min was 56 (IQR 30–78.5) for theparacetamol group and 55 (IQR 34–75) for thedexketoprofen group, with a difference of 1 mm (95% CI−7 to 10) between the two groups.Conclusions Intravenous paracetamol anddexketoprofen appear to produce equivalent pain relieffor migraine in the emergency department.ClinicalTrials.gov No NCT01730326.

INTRODUCTIONHeadache is one of the leading causes of emergencydepartment (ED) presentations. Migraine is acommon form of headache that is a major burdenfor patients who often seek emergency care. Recentstudies suggest that adults with migraine suffer anaverage of 1.8 attacks per month, but the frequencyand severity of episodes tend to vary individually.Migraine causes significant economic and socialburdens, in common with other chronic disorders.1 2

ED treatment aims at rapid relief of pain withminimum side effects and prevention of furtherattacks that might cause re-admission to the ED.A Cochrane meta-analysis showed that oral forms

of paracetamol,3 ibuprofen,4 diclofenac5 and suma-triptan, that seem to be more expensive thansimple analgesics,6 are effective in treating themigraine attack. However, few studies have exam-ined the effectiveness of parenteral drugs inmigraine attacks.Some studies evaluating the effectiveness of par-

enteral metoclopramide and magnesium sulfate in

migraine attacks showed that these agents had insuf-ficient effects. Although narcotic analgesics provideeffective and rapid analgesia, they have side effectssuch as hypotension, nausea and vomiting, anddrowsiness. In recent years, with the production ofparenteral forms of non-steroidal anti-inflammatorydrugs (NSAIDs), the analgesic efficacy of thesedrugs has become a topic of interest to researchers.In particular, an intravenous form of paracetamolhas been introduced and, compared with otherNSAIDs, is an effective drug in various types ofpain7 8 with a wide safety margin and a low inci-dence of side effects.The goal of this study was to compare the effect-

iveness of intravenous dexketoprofen with para-cetamol in the treatment of acute migraine attack.

MATERIALS AND METHODSStudy design and settingThis prospective, randomised, double blind, con-trolled study was conducted between March 2012and November 2012 in a tertiary care hospital withan annual census of 57 000 patients. The localethics committee approved the study.

Selection of participantsPatients between 18 and 69 years of age who pre-sented with a primary complaint of headache wereaccepted as candidates for the study. Patients whomet the criteria of the International Classificationof Headache Disorders for migraine without aura(see online supplementary appendix 1) and agreedto provide informed consent were enrolled in thestudy. Patients were enrolled in the study consecu-tively 24 h a day, 7 days a week. Triage staff, nursesand physicians were trained and informed beforethe study. The eligibility of patients was determinedby a physician.Exclusion criteria were: receiving analgesic in the

past 6 h; known or a strong possibility of pregnancy;lack of informed consent; known allergy to thestudy drugs; haemodynamic instability; vision pro-blems; pain character or intensity different fromformer migraine attacks; and illiteracy. Furthermore,patients who had undergone renal transplantationand those with liver, kidney, cardiac or pulmonaryinsufficiency were excluded from the study.

InterventionsStudy patients were randomised into one of twogroups to receive 50 mg of dexketoprofen trometa-mol (Arveles, IE Ulagay-Menarini, Turkey) or1000 mg of paracetamol (Perfalgan, Bristol-Myers

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Squibb, USA) intravenously by rapid infusion in 150 mL ofnormal saline. Both solutions were identical in colour andappearance.

A simple randomisation method was used for the study. Anassistant, blind to the study, prepared the randomisation sched-ule using a computer. A potentially eligible patient for the studywas assigned to a study number which was concealed in a sealedenvelope. A study nurse prepared the study drug and a secondnurse, blind to the study drug, administered it to the patient. Atthe end of 30 min, if the patient required additional treatement,fentanyl was administered as rescue medication at a dose of1 μg/kg.

Methods of measurementsA 100 mm Visual Analogue Scale (VAS) (‘no pain’=0 and ‘worstpain’=100 mm), a standard 11 point Numeric Rating Scale(NRS) and the Verbal Rating Scale (VRS) (no pain, mild, moder-ate and severe) were used to measure the level of pain. Painlevels at baseline, and at 15 and 30 min after study drug admin-istration were recorded. Patients were also asked about any add-itional drugs at the end of the study. Adverse effects such asallergic reaction, nausea and vomiting, dyspepsia and othersreported by study subjects were recorded on the study form.

Outcome measuresThe primary outcome measure was change in VAS, NRS andVRS scores at 15 and 30 min. Secondary outcome measureswere the necessity for additional drugs after 30 min and adverseeffects.

Statistical analysesThe study data were analysed using SPSS V.15.0, Medcalc 11.Because the data were not normally distributed, median (IQR)for numeric data and frequency for categorical data were used.The difference in pain reduction stores with 95% CI was usedto compare the effects of the two groups. The study wasplanned as an equivalence trial: an α value of 0.05 with 80%power, and 20 mm SD and with a 10 mm tolerance limit indi-cated that 69 patients were needed for each group. However,100 patients were included in each group because of a differentformula used for sample size initially. All the hypotheses wereconstructed as two tailed.

RESULTSA total of 3510 patients were admitted to the ED with headacheduring the study period, and 444 were diagnosed with migraine.One hundred and ninety-eight patients were excluded from thestudy for various reasons (figure 1) and 46 did not giveinformed consent. Two hundred patients (100 in the paraceta-mol group and 100 in the dexketoprofen group) participated inthe study and were included in the final analysis. All patientswere administered the full dose and no patient was lost tofollow-up (figure 1).

Mean age of the study subjects was 30.1±11 years, and 81%(n=162) were women. Median reduction in VAS score at 15min was 30 (IQR 15–40) for the paracetamol group and 28(IQR 18.5–40) for the dexketoprofen group. Median reductionin VAS score at 30 min was 56 (IQR 30–78.5) for the paraceta-mol group and 55 (IQR 34–75) for the dexketoprofen group(table 1). The difference in pain reduction scores between

Figure 1 Patient flow chart. CAD,coronary artery disease; DM, diabetesmellitus; ED, emergency department;HT, hypertension.

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two groups was 0 (95% CI −5 to 5) at 15 min and 1 (95% CI−7 to 10) at 30 min. Pain reductions by VRS and NRS weresimilar to VAS (table 2).

Thirty-three patients (33%) in the paracetamol group and 24patients (24%) in the dexketoprofen group needed rescue medi-cation (difference 9%, 95% CI −4.2% to 21.9%). No adverseeffects were recorded that related to the study drugs.

DISCUSSIONOur findings suggest that intravenous paracetamol and dexketo-prophen appear to have similar efficacy in the treatment ofmigraine pain at 15 and 30 min in the ED.

Migraine headache is a common and potentially exhaustingdisorder, commonly treated by emergency physicians. Migraineand other severe headaches are a common and major publichealth problem, particularly among reproductive aged women.7

Women also comprised the majority of subjects in our study.Treatment in the ED is important, not only in curing the painbut also in rapidly returning patients to their daily life.

There are many alternative treatments for acute migraine,such as triptans, narcotic analgesic and intravenous NSAIDs.However, there are insufficient data for the use of intravenousparacetamol in migraine attacks. Intravenous acetaminophendiffers from the available intravenous opioids and NSAIDs as itis not associated with the adverse effects (nausea and vomiting,and respiratory depression) seen after opioid use, or with plate-let dysfunction, gastritis and renal toxicity that are related toNSAID use.8 9 Intravenous acetaminophen is rarely associated

with hepatotoxicity, and has been shown to be safe even withunderlying liver conditions. However, intravenous acetamino-phen is contraindicated in patients with severe hepatic impair-ment or severe active liver disease.

Derry et al3 reported no adverse effects with oral paracetamolin acute migraine attacks. Treatment related adverse reactionsmay occur in ≥3% of patients treated with intravenous acet-aminophen. The most common adverse reactions in adults arenausea and vomiting, headache and insomnia.10 However, noneof these adverse reactions occurred in our study.

Intravenous paracetamol has been shown to be effective inpatients presenting to the ED with renal colic and mechanicallow back pain and also in patients with postoperative pain.11–13

Although there are studies showing that oral paracetamol can beeffective in migraine attacks, it is not suitable because of thedelayed onset of action and oral intolerance due to nausea andvomiting, which are common in migraine attacks.14 15

Intravenous acetaminophen has a faster onset of action andresults in more predictable pharmacokinetics than oral or rectalacetaminophen formulations.16

Sumatriptan is another alternative for migraine attacks, shownto be effective via the oral route in a Cochrane meta-analysis.The number of patients who had a pain free response at 2 h was5.1 after 100 mg of sumatriptan but 3.1 for pain relief at 2 hwith the same dose.6 However, adverse events were morecommon compared with placebo, with a number of needed toharm value of 7.1 with 100 mg of sumatriptan. However,adverse events were not found to be statistically significant for50 and 25 mg doses according to this meta-analysis. Also, theoral form of sumatriptan is more expensive than parenteralforms of NSAIDs and paracetamol.

Metoclopramide is relatively inexpensive and commonly usedfor migraine attacks in the ED. Although a meta-analysis byColman et al17 found that metoclopramide was superior toplacebo in migraine atttacks, the studies included in themeta-analysis had serious methodological limitations. Twostudies, not included in this meta-analysis and with a bettermethodology, favoured metoclopramide, with borderline clinic-ally significant pain reduction in migraine attacks.18 19

There are some limitations to the current study. Firstly, weinvestigated if paracetamol and dextketoprophen were equal inceasing migraine attacks in the ED. However, we cannot con-clude that both drugs are effective in ceasing migraine pain andsuperior to placebo with this methodological construction.Excluding patients in the last 6 h is also a limitation which mayrestrict the generalisability of the results. The 30 min intervalalso may be short in some instances. Outcomes such as recur-rence of pain, readmission to the ED and length of ED staywere not measured in the present study.

In conclusion, intravenous paracetamol and dexketoprofenappeared to produce equivalent pain relief for migraine in theED.

Contributors IT, OA, CK and HE collected the data. IT, MS, EU and AY served asscientific advisors. CE performed the statistical study.

Competing interests None.

Ethics approval The study was approved by the Ministry of Health of TurkeyGeneral Directorate of Pharmaceuticals and Pharmacy.

Provenance and peer review Not commissioned; externally peer reviewed.

REFERENCES1 Friedman BW, Solorzano C, Esses D, et al. Treating headache recurrence after

emergency department discharge: a randomized controlled trial of naproxen versussumatriptan. Ann Emerg Med 2010;56:7–17.

Table 1 Pain outcome measures of the treatment groups

Variable Paracetamol group Dexketoprofen group

Visual Analogue ScaleBaseline 90 (80–95.5) 89 (77.5–95)15 min 59.5 (45.5–70) 55 (47–66)30 min 25 (50–60) 28 (11–49.5)

Visual Analogue Scale change from baseline15 min 30 (15–40) 28 (18.5–40)30 min 56 (30–78.5) 55 (34–75)

Verbal Rating ScaleBaseline 1 (1–1) 1 (1–1)15 min 2 (2–2) 2 (2–2)30 min 3 (2–3.5) 3 (2–3)

Numeric Rating ScaleBaseline 9 (7–10) 8 (7–9)15 min 5 (4–7) 5 (4–6)30 min 3 (1–5.5) 3 (1–4)

Values are median (IQR).

Table 2 Pain outcome measures of the treatment groups

VariableParacetamolgroup

Dexketoprofengroup

Paracetamol vsdexketoprophen(median (95% CI))

Difference betweenbaseline and 15 min(median (IQR))

30 (15–40) 28 (18.5–40) 0 (−5 to 5)

Difference betweenbaseline and 30 min(median (IQR))

56 (30–78.5) 55 (34–75) 1 (−7 to 10)

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