Original article

Ibrahim Turkcuer,1 Mustafa Serinken,1 Cenker Eken,2 Atakan Yilmaz,3 Ömer Akdag,1 Emrah Uyanık,4 Cihan Kiray,1 Hayri Elicabuk1 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ emermed-2013-203044) 1

Department of Emergency Medicine, Pamukkale University Hospital, Denizli, Turkey 2 Department of Emergency Medicine, Akdeniz University Hospital, Antalya, Turkey 3 Emergency Services, Tekirdag State Hospital, Tekirdag, Turkey 4 Department of Emergency Medicine, Tekirdag State Hospital, Tekirdag, Turkey Correspondence to Professor M Serinken, Department of Emergency Medicine, Pamukkale University Hospital, PAU University, Kınıklı, Denizli 20020, Turkey; [email protected] Received 17 July 2013 Revised 22 November 2013 Accepted 23 November 2013 Published Online First 6 January 2014

ABSTRACT Objective Migraine is a common form of headache that is a major burden for patients who often seek emergency care. The goal of this study was to compare the effectiveness of intravenous non-steroidal antiinflammatory medication (dexketoprofen) with paracetamol (acetaminophen) in the treatment of an acute migraine attack. Materials and methods This prospective, randomised, double blind, controlled study was conducted in a tertiary care emergency unit. Study patients were randomised into two groups to receive either 50 mg of dexketoprofen trometamol or 1000 mg of paracetamol intravenously by rapid infusion in 150 mL of normal 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 measurement tool 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 years and 81% (n=162) were women. Median reduction in VAS score at 30 min was 56 (IQR 30–78.5) for the paracetamol group and 55 (IQR 34–75) for the dexketoprofen group, with a difference of 1 mm (95% CI −7 to 10) between the two groups. Conclusions Intravenous paracetamol and dexketoprofen appear to produce equivalent pain relief for migraine in the emergency department. ClinicalTrials.gov No NCT01730326.

INTRODUCTION

▸ 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. 182

Headache is one of the leading causes of emergency department (ED) presentations. Migraine is a common form of headache that is a major burden for patients who often seek emergency care. Recent studies suggest that adults with migraine suffer an average of 1.8 attacks per month, but the frequency and severity of episodes tend to vary individually. Migraine causes significant economic and social burdens, in common with other chronic disorders.1 2 ED treatment aims at rapid relief of pain with minimum side effects and prevention of further attacks that might cause re-admission to the ED. A Cochrane meta-analysis showed that oral forms of paracetamol,3 ibuprofen,4 diclofenac5 and sumatriptan, that seem to be more expensive than simple analgesics,6 are effective in treating the migraine attack. However, few studies have examined the effectiveness of parenteral drugs in migraine attacks. Some studies evaluating the effectiveness of parenteral metoclopramide and magnesium sulfate in

migraine attacks showed that these agents had insufficient effects. Although narcotic analgesics provide effective and rapid analgesia, they have side effects such as hypotension, nausea and vomiting, and drowsiness. In recent years, with the production of parenteral forms of non-steroidal anti-inflammatory drugs (NSAIDs), the analgesic efficacy of these drugs has become a topic of interest to researchers. In particular, an intravenous form of paracetamol has been introduced and, compared with other NSAIDs, is an effective drug in various types of pain7 8 with a wide safety margin and a low incidence of side effects. The goal of this study was to compare the effectiveness of intravenous dexketoprofen with paracetamol in the treatment of acute migraine attack.

MATERIALS AND METHODS Study design and setting This prospective, randomised, double blind, controlled study was conducted between March 2012 and November 2012 in a tertiary care hospital with an annual census of 57 000 patients. The local ethics committee approved the study.

Selection of participants Patients between 18 and 69 years of age who presented with a primary complaint of headache were accepted as candidates for the study. Patients who met the criteria of the International Classification of Headache Disorders for migraine without aura (see online supplementary appendix 1) and agreed to provide informed consent were enrolled in the study. Patients were enrolled in the study consecutively 24 h a day, 7 days a week. Triage staff, nurses and physicians were trained and informed before the study. The eligibility of patients was determined by 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 the study drugs; haemodynamic instability; vision problems; pain character or intensity different from former migraine attacks; and illiteracy. Furthermore, patients who had undergone renal transplantation and those with liver, kidney, cardiac or pulmonary insufficiency were excluded from the study.

Interventions Study patients were randomised into one of two groups to receive 50 mg of dexketoprofen trometamol (Arveles, IE Ulagay-Menarini, Turkey) or 1000 mg of paracetamol (Perfalgan, Bristol-Myers

Turkcuer I, et al. Emerg Med J 2014;31:182–185. doi:10.1136/emermed-2013-203044

Emerg Med J: first published as 10.1136/emermed-2013-203044 on 6 January 2014. Downloaded from http://emj.bmj.com/ on 27 June 2018 by guest. Protected by copyright.

Intravenous paracetamol versus dexketoprofen in acute migraine attack in the emergency department: a randomised clinical trial

Original article Statistical analyses

Methods of measurements

RESULTS

A 100 mm Visual Analogue Scale (VAS) (‘no pain’=0 and ‘worst pain’=100 mm), a standard 11 point Numeric Rating Scale (NRS) and the Verbal Rating Scale (VRS) (no pain, mild, moderate and severe) were used to measure the level of pain. Pain levels at baseline, and at 15 and 30 min after study drug administration were recorded. Patients were also asked about any additional drugs at the end of the study. Adverse effects such as allergic reaction, nausea and vomiting, dyspepsia and others reported by study subjects were recorded on the study form.

A total of 3510 patients were admitted to the ED with headache during the study period, and 444 were diagnosed with migraine. One hundred and ninety-eight patients were excluded from the study for various reasons (figure 1) and 46 did not give informed consent. Two hundred patients (100 in the paracetamol group and 100 in the dexketoprofen group) participated in the study and were included in the final analysis. All patients were administered the full dose and no patient was lost to follow-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 15 min was 30 (IQR 15–40) for the paracetamol group and 28 (IQR 18.5–40) for the dexketoprofen group. Median reduction in VAS score at 30 min was 56 (IQR 30–78.5) for the paracetamol group and 55 (IQR 34–75) for the dexketoprofen group (table 1). The difference in pain reduction scores between

Outcome measures The primary outcome measure was change in VAS, NRS and VRS scores at 15 and 30 min. Secondary outcome measures were the necessity for additional drugs after 30 min and adverse effects.

The 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 used to compare the effects of the two groups. The study was planned as an equivalence trial: an α value of 0.05 with 80% power, and 20 mm SD and with a 10 mm tolerance limit indicated that 69 patients were needed for each group. However, 100 patients were included in each group because of a different formula used for sample size initially. All the hypotheses were constructed as two tailed.

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

Turkcuer I, et al. Emerg Med J 2014;31:182–185. doi:10.1136/emermed-2013-203044

183

Emerg Med J: first published as 10.1136/emermed-2013-203044 on 6 January 2014. Downloaded from http://emj.bmj.com/ on 27 June 2018 by guest. Protected by copyright.

Squibb, USA) intravenously by rapid infusion in 150 mL of normal saline. Both solutions were identical in colour and appearance. A simple randomisation method was used for the study. An assistant, blind to the study, prepared the randomisation schedule using a computer. A potentially eligible patient for the study was assigned to a study number which was concealed in a sealed envelope. A study nurse prepared the study drug and a second nurse, blind to the study drug, administered it to the patient. At the end of 30 min, if the patient required additional treatement, fentanyl was administered as rescue medication at a dose of 1 μg/kg.

Original article

Variable

Paracetamol group

Visual Analogue Scale Baseline 90 (80–95.5) 15 min 59.5 (45.5–70) 30 min 25 (50–60) Visual Analogue Scale change from baseline 15 min 30 (15–40) 30 min 56 (30–78.5) Verbal Rating Scale Baseline 1 (1–1) 15 min 2 (2–2) 30 min 3 (2–3.5) Numeric Rating Scale Baseline 9 (7–10) 15 min 5 (4–7) 30 min 3 (1–5.5)

Dexketoprofen group

89 (77.5–95) 55 (47–66) 28 (11–49.5) 28 (18.5–40) 55 (34–75) 1 (1–1) 2 (2–2) 3 (2–3) 8 (7–9) 5 (4–6) 3 (1–4)

Values are median (IQR).

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 were similar to VAS (table 2). Thirty-three patients (33%) in the paracetamol group and 24 patients (24%) in the dexketoprofen group needed rescue medication (difference 9%, 95% CI −4.2% to 21.9%). No adverse effects were recorded that related to the study drugs.

DISCUSSION Our findings suggest that intravenous paracetamol and dexketoprophen appear to have similar efficacy in the treatment of migraine pain at 15 and 30 min in the ED. Migraine headache is a common and potentially exhausting disorder, commonly treated by emergency physicians. Migraine and other severe headaches are a common and major public health 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 pain but 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 intravenous paracetamol in migraine attacks. Intravenous acetaminophen differs from the available intravenous opioids and NSAIDs as it is not associated with the adverse effects (nausea and vomiting, and respiratory depression) seen after opioid use, or with platelet dysfunction, gastritis and renal toxicity that are related to NSAID use.8 9 Intravenous acetaminophen is rarely associated

Table 2 Pain outcome measures of the treatment groups

Variable Difference between baseline and 15 min (median (IQR)) Difference between baseline and 30 min (median (IQR))

184

with hepatotoxicity, and has been shown to be safe even with underlying liver conditions. However, intravenous acetaminophen is contraindicated in patients with severe hepatic impairment or severe active liver disease. Derry et al3 reported no adverse effects with oral paracetamol in acute migraine attacks. Treatment related adverse reactions may occur in ≥3% of patients treated with intravenous acetaminophen. The most common adverse reactions in adults are nausea and vomiting, headache and insomnia.10 However, none of these adverse reactions occurred in our study. Intravenous paracetamol has been shown to be effective in patients presenting to the ED with renal colic and mechanical low back pain and also in patients with postoperative pain.11–13 Although there are studies showing that oral paracetamol can be effective in migraine attacks, it is not suitable because of the delayed onset of action and oral intolerance due to nausea and vomiting, which are common in migraine attacks.14 15 Intravenous acetaminophen has a faster onset of action and results in more predictable pharmacokinetics than oral or rectal acetaminophen formulations.16 Sumatriptan is another alternative for migraine attacks, shown to be effective via the oral route in a Cochrane meta-analysis. The number of patients who had a pain free response at 2 h was 5.1 after 100 mg of sumatriptan but 3.1 for pain relief at 2 h with the same dose.6 However, adverse events were more common compared with placebo, with a number of needed to harm value of 7.1 with 100 mg of sumatriptan. However, adverse events were not found to be statistically significant for 50 and 25 mg doses according to this meta-analysis. Also, the oral form of sumatriptan is more expensive than parenteral forms of NSAIDs and paracetamol. Metoclopramide is relatively inexpensive and commonly used for migraine attacks in the ED. Although a meta-analysis by Colman et al17 found that metoclopramide was superior to placebo in migraine atttacks, the studies included in the meta-analysis had serious methodological limitations. Two studies, not included in this meta-analysis and with a better methodology, favoured metoclopramide, with borderline clinically significant pain reduction in migraine attacks.18 19 There are some limitations to the current study. Firstly, we investigated if paracetamol and dextketoprophen were equal in ceasing migraine attacks in the ED. However, we cannot conclude that both drugs are effective in ceasing migraine pain and superior to placebo with this methodological construction. Excluding patients in the last 6 h is also a limitation which may restrict the generalisability of the results. The 30 min interval also may be short in some instances. Outcomes such as recurrence of pain, readmission to the ED and length of ED stay were not measured in the present study. In conclusion, intravenous paracetamol and dexketoprofen appeared to produce equivalent pain relief for migraine in the ED. Contributors IT, OA, CK and HE collected the data. IT, MS, EU and AY served as scientific advisors. CE performed the statistical study.

Paracetamol group

Dexketoprofen group

Paracetamol vs dexketoprophen (median (95% CI))

Competing interests None.

30 (15–40)

28 (18.5–40)

0 (−5 to 5)

Provenance and peer review Not commissioned; externally peer reviewed.

56 (30–78.5)

55 (34–75)

1 (−7 to 10)

REFERENCES

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

1

Friedman BW, Solorzano C, Esses D, et al. Treating headache recurrence after emergency department discharge: a randomized controlled trial of naproxen versus sumatriptan. Ann Emerg Med 2010;56:7–17.

Turkcuer I, et al. Emerg Med J 2014;31:182–185. doi:10.1136/emermed-2013-203044

Emerg Med J: first published as 10.1136/emermed-2013-203044 on 6 January 2014. Downloaded from http://emj.bmj.com/ on 27 June 2018 by guest. Protected by copyright.

Table 1 Pain outcome measures of the treatment groups

Original article

3

4

5 6 7

8

9 10

Goldstein J, Silberstein SD, Saper JR, et al. Acetaminophen, aspirin, and caffeine in combination versus ibuprofen for acute migraine: results from a multicenter, double-blind, randomized, parallel-group, single-dose, placebo-controlled study. Headache 2006;46:444–53. Derry S, Moore RA, McQuay HJ. Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev 2010;11:CD008040. Rabbie R, Derry S, Moore RA, et al. Ibuprofen with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev 2010;10: CD008039. Derry S, Rabbie R, Moore RA. Diclofenac with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev 2012;2:CD008783. Derry CJ, Derry S, Moore RA. Sumatriptan (oral route of administration) for acute migraine attacks in adults. Cochrane Database Syst Rev 2012;2:CD008615. Smitherman TA, Burch R, Sheikh H, et al. The prevalence, impact, and treatment of migraine and severe headaches in the United States: a review of statistics from national surveillance studies. Headache 2013;53:427–36. Silvanto M, Munsterhjelm E, Savolainen S, et al. Effect of 3 g of intravenous paracetamol on post-operative analgesia, platelet function and liver enzymes in patients undergoing tonsillectomy under local anaesthesia. Acta Anaesthesiol Scand 2007;51:1147–54. Haas DA. An update on analgesics for the management of acute postoperative dental pain. J Can Dent Assoc 2002;68:476–82. Gilmore B, Michael M. Treatment of acute migraine headache. Am Fam Physician 2011;83:271–80.

Turkcuer I, et al. Emerg Med J 2014;31:182–185. doi:10.1136/emermed-2013-203044

11

12

13

14 15

16 17 18

19

Serinken M, Eken C, Turkcuer I, et al. Intravenous paracetamol versus morphine for renal colic in the emergency department: a randomized double-blind controlled trial. Emerg Med J 2012;29:902–5. Sinatra RS, Jahr JS, Reynolds LW, et al. Efficacy and safety of single and repeated administration of 1 gram intravenous acetaminophen injection ( paracetamol) for pain management after major orthopedic surgery. Anesthesiology 2005;102:822–31. Eken C, Serinken M, Elicabuk H, et al. Intravenous paracetamol versus dexketoprofen versus morphine in acute mechanical low back pain in the emergency department: a randomised double-blind controlled trial. Emerg Med J 2014;31: 177–81. Prior MJ, Codispoti JR, Fu M. A randomized, placebo-controlled trial of acetaminophen for treatment of migraine headache. Headache 2010;50:819–33. Freitag F, Diamond M, Diamond S, et al. Efficacy and tolerability of coadministration of rizatriptan and acetaminophen vs rizatriptan or acetaminophen alone for acute migraine treatment. Headache 2008;48:921–30. Bertolini A, Ferrari A, Ottani A, et al. Paracetamol: new vistas of an old drug. CNS Drug Rev 2006;12:250–75. Colman I, Brown MD, Innes GD, et al. Parenteral metoclopramide for acute migraine: a meta-analysis of randomised controlled trials. BMJ 2004;329:1369–73. Jones J, Pack S, Chun E. Intramuscular prochlorperazine versus metoclopramide as single-agent therapy for the treatment of acute migraine headache. Am J Emerg Med 1996;14:262–4. Cete Y, Bora B, Ertan C, et al. A randomized prospective placebo-controlled study of intravenous magnesium sulphate vs. metoclopramide in the management of acute migraine attacks in emergency department. Cephalalgia 2005;25:199–204.

185

Emerg Med J: first published as 10.1136/emermed-2013-203044 on 6 January 2014. Downloaded from http://emj.bmj.com/ on 27 June 2018 by guest. Protected by copyright.

2

Intravenous paracetamol versus dexketoprofen in acute migraine attack in the emergency department: a randomised clinical trial.

Migraine is a common form of headache that is a major burden for patients who often seek emergency care. The goal of this study was to compare the eff...
446KB Sizes 0 Downloads 0 Views