Pain Management

Efficacy of Low-Dose Ibuprofen in Acute Migraine Treatment: Systematic Review and Meta-Analysis Chuthamanee Suthisisang, Nalinee Poolsup, Wararat Kittikulsuth, Phutsadee Pudchakan, and Pichamon Wiwatpanich

igraine is a chronic neurologic disorder characterized by recurrent episodes of headache and associated symptoms (eg, nausea, sensitivity to light and noise) that typically last from 4 to 72 hours.1 According to the prevalence estimates of migraine from 25 populationbased studies between 1991 and 2004, the prevalence of migraine in adult populations ranges from 0.7% to 22%, with the highest prevalence in both men and women between the ages of 25 and 55 years.2 In the US, migraine is a leading cause of absenteeism, resulting in $13–17 billion in productivity losses each year.2,3 Treatment of migraine includes both nonpharmacologic and pharmacologic methods for acute episodes and for prophylaxis. Pharmacologic treatment of migraine attacks primarily aims at alleviating head pain and symptoms accompanying migraine, avoiding headache recurrence, restoring the patient’s ability to function, and minimizing the use of rescue medications.4,5 These goals are usually achieved with administration of analgesics and nonsteroidal antiinflammatory drugs (NSAIDs), opioids, ergotamines, and triptans. Among the NSAIDs, aspirin, naproxen sodium, ibuprofen, tolfenamic acid, and the combination of acetaminophen and aspirin plus caffeine

M

BACKGROUND: Nonsteroidal antiinflammatory drugs such as aspirin and ibuprofen have been shown to be effective in treating migraine. OBJECTIVE:

To evaluate the efficacy of low-dose ibuprofen for treatment of acute migraine attack.

METHODS:

Clinical trials were identified through electronic searches (MEDLINE, EMBASE, EBM review, and the Cochrane Library) up to November 2006 and historical searches of relevant articles. Studies were included if they (1) were doubleblind, randomized, placebo-controlled trials that evaluated ibuprofen tablets in moderate or severe migraine attacks in patients greater than 16 years of age, (2) evaluated at least one migraine attack, and (3) reported headache relief, pain-free, sustained pain-free, or relief of other migraine-associated symptoms at 2 hours. The MeSH search terms used were migraine disorders, headache, vascular headache, ibuprofen, adult, and clinical trial. This was followed by a key word search using migraine, cephalalgia, and cephalgia as key words. The reference lists of relevant articles were also scanned to identify possible published trials. There was no language restriction. Two authors extracted data independently. Disagreements were resolved through discussion.

RESULTS: Ibuprofen 200 and 400 mg were more effective than placebo in reducing pain intensity and eliminating pain (pain-free) within 2 hours in adults with moderate or severe migraine attacks. For the 200 mg dose, the number needed to treat was 8 (95% CI 5 to 20) for headache relief and 13 (95% CI 8 to 50) for painfree. The risk ratios for headache relief and pain-free were 1.89 (95% CI 1.45 to 2.46; p < 0.0001) and 2.15 (95% CI 1.24 to 3.73; p = 0.0063), respectively, for ibuprofen 400 mg. The 24-hour sustained pain-free outcome with ibuprofen was no better than with placebo. Ibuprofen 400 mg increased the chance of relief in photophobia and phonophobia by 30% (95% CI 8 to 57; p < 0.01) and 49% (95% CI 23 to 81; p < 0.0001), respectively. CONCLUSIONS: The available evidence suggests that ibuprofen 200 and 400 mg are

effective in reducing headache intensity and rendering patients pain-free at 2 hours. Photophobia and phonophobia improved with 400 mg dosing. Due to the limited data and the shortcomings of the available evidence, further studies are needed. KEY WORDS: acute migraine, ibuprofen.

Ann Pharmacother 2007;41:1782-91. Published Online, 18 Sept 2007, www.theannals.com, DOI 10.1345/aph.1K121 A For Our Patients summary of this article is available at www.ForOurPatients.info

Author information provided at the end of the text.

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have demonstrated the most consistent evidence of efficacy in the management of acute migraine.6,7 However, use of over-the-counter (OTC) drugs, including NSAIDs, for migraine relief has been controversial.8 Migraine pathophysiology involves a combination of events, including the cortical spreading depression (CSD) and the release of inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide, which have direct effect on perivascular nociceptors. CSD also triggers the complex mechanisms of afferent and efferent trigeminal vascular events by stimulating the release of calcitonin gene-related peptide (CGRP) from the trigeminovascular system. PGE2 has also been shown to stimulate CGRP release from the primary cultures of adult rat trigeminal neurons.9 Therefore, NSAIDs that inhibit PGE2 synthesis are effective in treating acute migraine attack. Ibuprofen is an effective inhibitor of cyclooxygenase, resulting in the inhibition of prostaglandin synthesis. Although evidence from clinical studies suggests that ibuprofen provides better headache relief than does placebo in the treatment of migraine headache,10-18 it is not yet known whether ibuprofen offers clinical benefits to achieve the desired outcomes in acute migraine therapy as recommended by the International Headache Society (IHS). To the best of our knowledge, there has been no previously published systematic review and meta-analysis of ibuprofen treatment of acute migraine attacks. We therefore undertook a meta-analysis to evaluate the efficacy of lowdose ibuprofen in an attempt to determine its therapeutic benefit in the treatment of acute migraine attacks. Methods IDENTIFICATION OF STUDIES

Reports of randomized controlled trials of ibuprofen were identified through a systematic search of MEDLINE, EMBASE, EBM review, and the Cochrane Library. The bibliographic databases were searched from their inceptions to November 2006. The MeSH search terms used were migraine disorders, headache, vascular headache, ibuprofen, adult, and clinical trial. This was followed by a key word search using migraine, cephalalgia, and cephalgia as key words. The reference lists of relevant articles were also scanned to identify possible published trials. There was no language restriction.

hours, sustained pain-free, or relief of migraine-associated symptoms. DATA EXTRACTION

Data were extracted independently by 2 authors. Disagreements were resolved through discussion. The data abstracted were the year of publication, study location, study design, patient characteristics, number of patients, treatment regimen, outcome measures, and adverse effects. In the studies that assessed various doses of ibuprofen, only the data regarding doses of 200 and 400 mg were abstracted and analyzed. The methodological quality of a study was assessed using the scale developed by Jadad et al.19 A study with a score of at least 3 out of 5 points was considered high quality. STATISTICAL ANALYSIS

Efficacy was estimated based on headache relief at 2 hours, no pain (pain-free) at 2 hours, sustained pain-free, and relief of migraine-associated symptoms. The data from each study were analyzed on an intent-to-treat basis. Headache relief rate was defined as the proportion of patients in whom headache severity decreased from moderate or severe (grade 2, 3) to mild or no headache (grade 0, 1), according to the IHS criteria. Pain-free rate was defined as the proportion of patients who became pain-free after 2 hours postdose. Sustained pain-free rate was the percentage of patients without any recurrence of headache within 24 hours of initial dose. Relief of accompanying migraine symptoms, namely nausea, photophobia, and phonophobia, was estimated based on the proportion of patients with such symptoms reduced to none. Adverse events rate was assessed based on the number of patients who experienced any adverse effects. Treatment effects and adverse effects were expressed as risk ratio (RR), risk difference, and number needed to treat (NNT), as well as 95% confidence interval. The analysis was performed using StatsDirect 2.5.7 (StatsDirect Ltd., Cheshire, UK). The level of significance was set at p less than 0.05. A random effects model, inverse variance weighted method, was used in the pooling of treatment effects.20 Interstudy heterogeneity was tested using the Qstatistic and quantified using the I-square statistic.21 Possible publication bias was detected using the method formulated by Egger et al.22

STUDY SELECTION

The studies were included in the meta-analysis if they (1) were double-blind, randomized, placebo-controlled trials that evaluated ibuprofen tablets in moderate or severe migraine attacks in patients older than 16 years of age, (2) evaluated at least one migraine attack, and (3) reported efficacy in terms of headache relief at 2 hours, pain-free at 2 www.theannals.com

Results STUDY CHARACTERISTICS

We identified 13 published trials that evaluated ibuprofen treatment of acute migraine.10-18,23-26 All were published in English. Of these, one trial compared ibuprofen with

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acetaminophen.10 Two evaluated the effectiveness of ibuprofen–arginine24 and liquigel ibuprofen26 against placebo. Two other studies reported as outcome measures the duration of migraine attacks, the duration of pain, the severity of migraine attacks,11,12 migraine index, and the severity of nausea.12 One trial included patients suffering from mild-to-moderate migraine or episodic tension-type headache and reported headache response defined as a minimum decrease of headache intensity by 50% on a 10cm visual analog scale 1 hour after treatment.13 Two trials evaluated ibuprofen for acute treatment of pediatric migraine.23,25 The remaining 5 trials met our inclusion criteria for meta-analysis.14-18 Among these, one study evaluated both 200 and 400 mg ibuprofen.14 Table 1 lists the characteristics of the excluded trials and the reasons for exclusion.10-13,23-26 Characteristics of the included trials are presented in Table 2.14-18 No evidence of publication bias was found in our meta-analysis. EFFICACY

Ibuprofen 200 mg

Only one study compared ibuprofen 200 mg versus placebo; 437 patients were evaluated.14 Ibuprofen was superior to placebo in reducing and eliminating pain at 2 hours. The mean number of patients who need to be treated for one patient to achieve headache relief was 8 (95% CI 5 to 20). The corresponding number for pain-free was 13 (95% CI 8 to 50). There were no significant differences between ibuprofen and placebo regarding the relief of nausea, photophobia, and phonophobia (Table 3). Ibuprofen 400 mg

Pain Relief. A total of 1353 patients were involved in the 4 trials of ibuprofen that reported the results in terms of the proportion of patients whose pain intensity reduced from severe or moderate to mild or none 2 hours after treatment.14-17 As expected, ibuprofen 400 mg was more effective than placebo (RR 1.89; 95% CI 1.45 to 2.46; p < 0.0001) (Table 3, Figure 1). The pooled risk difference corresponded to the mean NNT of 4 (95% CI 3 to 7). Pain-Free. Four studies involving a total of 2161 patients provided poolable data regarding the percentage of patients who became pain-free at 2 hours.14,16-18 Pain-free rate was better with ibuprofen than with placebo (RR 2.15; 95% CI 1.24 to 3.73; p = 0.0063). On average, treating 9 patients with ibuprofen 400 mg would result in 1 patient who becomes pain-free within 2 hours. Sustained Pain-Free. The proportion of patients with the absence of recurrent migraine attack was reported in 3 trials.15-17 In these studies, ibuprofen was no better than placebo in reducing the risk of headache recurrence within 24 hours after the initial dose (RR 3.26; 95% CI 0.48 to 22.08). 1784

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Relief of Migraine-Associated Symptoms. Ibuprofen did not relieve nausea more effectively than placebo. However, the relief of photophobia and phonophobia was increased by 30% (95% CI 8 to 57) and 49% (95% CI 23 to 81), respectively, with ibuprofen. SAFETY

Adverse events were recorded by the patients after use of study medication. Four trials reported the number of patients who experienced any adverse events that could be transformed to adverse events rate.14,16-18 Ibuprofen caused no more adverse events than did placebo (RR 0.94, 95% CI 0.80 to 1.10). The adverse events commonly associated with ibuprofen were nausea, vomiting, dyspepsia, dry mouth, dizziness, and somnolence. Discussion This is the first systematic review and meta-analysis to evaluate the efficacy of ibuprofen tablets in the treatment of migraine attacks in adults. The doses of 200 and 400 mg were chosen because they are the ones approved for OTC availability in the US.3 We excluded any formulations of ibuprofen other than conventional tablets. These formulations (eg, ibuprofen arginine tablet and ibuprofen liquigel) are usually aimed at improving the amount and rapidity of drug absorption, which is crucial for effective treatment of migraine episodes. However, pooling the results of such formulations with those of the conventional tablet may distort the true effects of conventional ibuprofen. In clinical trials of drugs in migraine, it is recommended that the proportion of patients pain-free at 2 hours be used as a primary efficacy measure. It is clinically relevant and reflects patients’ expectations.27 Only 4 of the 5 trials included in our meta-analysis reported this outcome. Headache relief at 2 hours, sustained pain-free, and time to meaningful relief can be used as secondary efficacy measures. Despite the IHS recommendation and its limited clinical relevance, headache relief (or headache response) has been commonly used as the primary endpoint in many trials in migraine. As migraine is often associated with ancillary symptoms including nausea, photophobia, and phonophobia, it is also important that drugs used for migraine attack be effective against these symptoms.27 Four trials included in our meta-analysis reported the primary efficacy measure in terms of headache relief at 2 hours postdose. The secondary efficacy measures included the proportion of patients who became pain-free at 2 hours postdose, the percentage of patients without any recurrence of migraine attack within 24 hours after drug intake, and the percentage of patients with the relief of migraine-associated symptoms at 2 hours after initial treatment. We

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Nebe (1995)13

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IBU 200 mg, aspirin, or placebo for 3 headache episodes

IBU 1200 mg or placebo for 6 migraine attacks

IBU 800 mg or placebo for 5 migraine attacks

IBU 400 mg or acetaminophen 900 mg at the onset of each migraine attack and then every 4–6 h

Treatment

DB, PC

DB, PC

DB, CO

single dose of IBU liquigel 200, 400, 600 mg, or placebo

single dose of IBU 7.5 mg/kg or placebo

single dose of IBU– arginine 400 mg or placebo for 2 migraine attacks

DB, three-way single dose of CO acetaminophen 15 mg/kg, IBU 10 mg/kg, or placebo for 3 migraine attacks

DB, threefold CO

DB, CO

DB, CO

DB, CO

Design

evaluated liquigel IBU

included children and evaluated liquid IBU

faster-absorbed formulation, IBU– arginine, used

included children and evaluated liquid IBU

included pts. with mild-to-moderate migraine or episodic tension-type headache and reported headache response defined as a minimum decrease of headache intensity by 50% on a 10-cm VAS at 1 h after treatment

reported as outcome measures the duration of migraine attacks, severity of headache, migraine index, severity of nausea

reported as outcome measures the duration and severity of migrane attacks, the duration of pain

compared IBU vs acetaminophen

Reasons for Exclusion

Results

2 pts. taking IBU reported drowsiness and weakness; 3 pts. taking acetaminophen reported nausea, aggravation of vomiting, dyspepsia

Adverse Effects

at 2 h, IBU more effective than placebo in providing pain relief and pain-free state; pain relief rates for IBU 200, 400, 600 mg, and placebo groups were 64%, 72%, 72%, and 50%, respectively; the respective numbers for pain-free rates were 25.3%, 27.7%, 29.3%, and 13.4%

pain relief rate at 2 h higher with IBU than placebo (76% vs 53%; p = 0.006); no significant differences between groups regarding pain-free rate and headache recurrence rate

headache relief rate at 2 h higher with IBU than placebo (76% vs 53%; p = 0.006); no significant differences between groups regarding pain-free rate and headache recurrence rate

at 2 h, IBU more effective than placebo in reducing pain intensity by 2 grades (OR 2.9; 95% CI 1.0 to 8.1) and aborting migraine (OR 3.5; 95% CI 1.0 to 11.9); IBU superior to acetaminophen in aborting migraine at 2 h (OR 2.2; 95% CI 1.1 to 4.0)

IBU superior to aspirin; headache responses 31% and 15% in IBU and aspirin groups, respectively (p = 0.02)

IBU significantly reduced duration of migraine attacks (10.3 ± 15 h vs 15.7 ± 12 h; p = 0.002), severity of headache (1.78 ± 0.51 vs 2.33 ± 0.52; p < 0.001), nausea (0.82 ± 0.59 vs 1.22 ± 0.78; p = 0.01)

no significant differences among the 4 groups with respect to overall adverse events; incidences with IBU 200, 400, 600 mg, and placebo groups were 5.5%, 8.8%, 8%, and 7%, respectively

NR

NR

no significant difference in the number of adverse events reported

NR

3 pts. reported stomach discomfort or pain during IBU period, 1 reported stomach pain during placebo period

IBU superior to placebo; mean duration of migraine IBU well tolerated; no marked adverse attacks and mean duration of pain were 4.9 ± 2.9 h effects reported vs 11.2 ± 8.6 h (p < 0.001) and 4.6 ± 2.8 h vs 11.0 ± 8.4 h (p < 0.001), respectively

IBU significantly better than acetaminophen in reducing severity (p < 0.05) and duration (p < 0.01) of headache

CO = crossover; DB = double-blind; IBU = ibuprofen; NR = not reported; PC = placebo-controlled; VAS = visual analog scale.

US

US

Lewis (2002)25

Kellstein (2000)26

40

Italy

Sandrini (1998)24

84

66

Hamalainen Finland (1997)23

65

25

Norway

Kloster (1992)12

30

27

UK

Pearce (1983)10

Pts., N

HavankaFinland Kanniainen (1989)11

Country

Reference

Table 1. Characteristics of Excluded Studies

Efficacy of Low-Dose Ibuprofen in Acute Migraine

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India

US

Treatment

Pts., N

Inclusion Criteria

Outcome Measures

DB, P

single dose of IBU 200 mg, IBU 400 mg, or placebo

660 age ≥18 y primary IBU 200 mg = 216 history of migraine with at least headache relief at 2 h IBU 400 mg = 223 moderate pain intensity on the scale pain intensity difference from placebo = 221 that met the IHS diagnostic criteria baseline at 2 h for migraine with or without aura secondary fulfillment of the criteria for migraine severity differences from baseline administration of a semistructured for migraine-associated diagnostic headache interview symptoms from 0.5–6 h migraine attack frequency of ≥1 absence of migraine-associated episode every 2 mo but ≤6 symptoms at 2 and 6 h episodes/mo in the year before headache relief at 6 h study entry pain intensity differences from basehistory of treatment of previous line and pain relief from 0.5–6 h migraines with OTC medications pain-free at 2 and 6 h ability to differentiate a migraine pt. rating of overall impression headache from an interval time-interval weighted sum of the (tension-type) headache pain intensity difference from if a woman, postmenopausal or using baseline (SPID) an effective form of birth control for time-interval weighted sum of the at least 3 mo before study entry pain relief scores (TOTPAR) rescue rate at 6 h vomiting within 6 h DB, P ROF 25 mg, IBU 400 mg, or 124 age >16 y primary placebo for 1 mo or after ≥2 IBU = 40 at least a 12 mo history of migraine headache relief at 2 h attacks ROF = 42 with or without aura according to secondary placebo = 42 IHS criteria absence of migraine-associated ≤6 migraine attacks/mo symptoms 24 h sustained pain-free DB-CO single dose of effervescent 882 age 18–65 y primary aspirin 1000 mg, IBU 400 mg, IBU = 212 met IHS diagnostic criteria for headache relief at 2 h for effervesor sumatriptan 50 mg taken aspirin = 222 migraine with or without aura cent aspirin vs placebo within 6 h of headache onset sumatriptan = 226 history of migraine of ≥1 y and secondary placebo = 222 between 1 and 6 attacks/mo headache relief at 2 h pain-free at 2 h improvement in nausea, vomiting, photophobia, and phonophobia at 2 h use of escape medication within 2 h 24-h headache recurrence time to recurrence

Location Design

yes

yes

yes

ITT Analysis

IBU vs placebo = 18.4% (39/212) vs 20.3% (45/222)

5 pts. (12.5%) in the IBU group had abdominal pain; data were not reported for the placebo group

IBU vs placebo = 33.7% (148/439) vs 37.1% (82/221)

Adverse Events

DB = double-blind; DB-CO = double-blind, crossover; IBU = ibuprofen; IHS = International Headache Society; ITT = intent-to-treat; OTC = over-the-counter; P = parallel; ROF = rofecoxib. (continued on page 1787)

4

5

Quality Score

Misra (2004)15

Codispoti (2001)14

Reference

Table 2. Characteristics of Randomized Controlled Trials of Ibuprofen in Acute Migraine Treatment

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1559 AAC = 669 IBU = 669 placebo = 221 single 2-tablet dose for each of the 3 treatment groups: AAC, IBU 200 mg, or placebo DB, P US 4 Goldstein (2006)18

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AAC = combination of acetaminophen 250 mg, aspirin 250 mg, and caffeine 65 mg; DB = double-blind; IBU = ibuprofen; IHS = International Headache Society; ITT = intent-to-treat; P = parallel; PAR = pain relief; ROF = rofecoxib.

AAC = 9.7% IBU = 5.1% placebo = 5.5% yes

ROF 25 mg = 32.0% ROF 50 mg = 37.8% IBU = 28.1% placebo = 27.8% yes

≥18 y old primary met IHS criteria headache relief at 2 h 1–8 migraine attacks/mo in the 6 mo secondary prior to enrollment pain free at 2 h 24-h sustained pain relief 24-h sustained pain-free presence of associated symptoms, functional disability, quality-oflife ≥18 y old primary met IHS criteria weighted sum of PAR scores at 2 h good general health secondary history of migraine attack at least weighted sum of PAR scores at 4 h once every 2 mo, but ≤6 times time to meaningful PAR monthly, during the prior 12 mo pain intensity difference from baseline 4-h weighted sum of pain intensity differences from baseline proportion of pts. with pain reduced to mild or none proportion of pts. with pain reduced to none single dose of ROF 25 mg or 783 ROF 50 mg or IBU 400 mg or ROF 25 mg = 194 placebo ROF 50 mg = 196 IBU = 199 placebo = 194 Asia, DB, P Europe, Latin America, US 5 Saper (2006)17

Outcome Measures Inclusion Criteria Pts., N Treatment Location Design Reference

Quality Score

Table 2. Characteristics of Randomized Controlled Trials of Ibuprofen in Acute Migraine Treatment (contiued)

ITT Analysis

Adverse Events

Efficacy of Low-Dose Ibuprofen in Acute Migraine

therefore included headache relief at 2 hours, pain-free at 2 hours, 24-hour sustained painfree, and relief of migraine-associated symptoms as the measures of efficacy in our metaanalysis. Based on such measures, our results indicate the efficacy of ibuprofen 200 and 400 mg in providing headache relief and pain-free in adults with moderate-to-severe migraine headache. Ibuprofen was effective in reducing headache intensity and aborting pain within 2 hours of drug intake. However, it was no better than placebo in preventing the recurrence of migraine within 24 hours after treatment. This could be explained by the short half-life of ibuprofen, which is approximately 2 hours. The effect on the recurrence of migraine, however, may need further investigation, as interstudy variation among the included studies was very large. As seen in Figure 1, the pooled result regarding this measure was influenced by Diener et al.’s16 study, in which the sample size was large and no significant difference was found, compared with other trials that reported the same outcome. Besides, Diener et al. used a threefold crossover design and did not provide separate data for each treatment period. Regarding the efficacy of ibuprofen in terms of pain relief at 2 hours, the mean NNT of ibuprofen 400 mg (NNT = 4) was found to be in the same range as that of low-dose oral triptans (NNT = 2– 6).28 Therefore, ibuprofen 400 mg can offer a benefit comparable to that of triptans. Ibuprofen NNT for pain-free effect at 2 hours was comparable to the NNTs of sumatriptan 50 mg, naratriptan 2.5 mg, and the combination of aspirin 900 mg and metoclopramide 10 mg. However, eletriptan and rizatriptan were more effective than ibuprofen regarding this outcome. Our results revealed that ibuprofen 400 mg was effective for treating acute migraine attack and, due to its short half-life, it should be repeatedly administered every 4–6 hours to sustain pain relief throughout 24 hours. However, the strength of recommendation based on the efficacy of ibuprofen 400 mg in alleviating pain intensity at 2 hours may be reduced due to significant interstudy heterogeneity (I2 = 65.3%). This could be partly explained by the differences in the proportion of patients with severe migraine headache (29–82%),14-17 ibuprofen dissolution rate from different brands, and patient ethnicity.15,17 Our results are consistent with those reported in studies of pediatric migraine in which head-

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ache clinical improvement, generally defined when the patients’ headaches decline by at least 50%, was increased by 50% (95% CI 20 to 90) with ibuprofen compared with placebo.29 Ibuprofen 200 mg offered no advantages over placebo regarding the relief of nausea, photophobia, and phonophobia. At the dose of 400 mg, it significantly relieved photophobia and phonophobia, but not nausea. This outcome is directly assumed from the role of prostaglandin in stimulating CGRP release from the trigeminal neurons,9 which further increases the activation of second-order neu-

rons in the trigeminocervical complex and higher brain centers contributing to associated symptoms of photophobia, phonophobia, and nausea. Inhibition of prostaglandin synthesis by NSAIDs or cyclooxygenase-2 inhibitors indirectly alleviates this phenomenon and could thus reduce these associated symptoms, especially at higher doses. No significant difference in the risk of adverse events was observed between ibuprofen and placebo. The commonly reported adverse events were abdominal pain, nausea, and vomiting, which usually occur during a migraine.

Table 3. Comparison of Responses with Ibuprofen and Placebo Crude Rate Reference Ibuprofen 200 mg Codispoti (2001)14 pain relief at 2 h pain-free at 2 h relief of nausea relief of photophobia relief of phonophobia Ibuprofen 400 mg Pain relief at 2 h Codispoti (2001)14 Misra (2004)15 Diener (2004)16 Saper (2006)17 POOLED RESULTS

Pain-free at 2 h Codispoti (2001)14 Diener (2004)16 Saper (2006)17 Goldstein (2006)18 POOLED RESULTS

Sustained pain-free Misra (2004)15 Diener (2004)16 Saper (2006)17 POOLED RESULTS

Relief of nausea Codispoti (2001)14 Relief of photophobia Codispoti (2001)14 Diener (2004)16 POOLED RESULTS

Relief of phonophobia Codispoti (2001)14 Diener (2004)16 POOLED RESULTS

Ibuprofen

Placebo

RR (95% CI)

NNT (95% CI)

RD (95% CI)

90/216 34/216 51/128 45/210 47/198

62/221 17/221 38/122 32/212 34/204

1.49a (1.14 to 1.94) 2.05b (1.19 to 3.54) 1.28 (0.91 to 1.80) 1.42 (0.95 to 2.14) 1.42 (0.96 to 2.11)

0.14a (0.05 to 0.22) 0.08a (0.02 to 0.14) 0.09 (–0.03 to 0.20) 0.06 (–0.01 to 0.14) 0.07 (–0.007 to 0.15)

91/223 22/40 127/212 109/199 349/674

62/221 4/42 68/222 57/194 191/679

1.45 (1.12 to 1.90) 5.78 (2.36 to 15.10) 1.96 (1.57 to 2.46) 1.86 (1.46 to 2.41) 1.89c,d (1.45 to 2.46)

0.13 (0.04 to 0.21) 0.45 (0.26 to 0.62) 0.29 (0.20 to 0.38) 0.25 (0.16 to 0.35) 0.27c (0.15 to 0.38)

4 (3 to 7)

31/223 70/212 45/199 188/669 334/1303

17/221 28/222 10/194 51/221 106/858

1.81 (1.04 to 3.15) 2.62 (1.77 to 3.90) 4.39 (2.32 to 8.40) 1.22 (0.94 to 1.60) 2.15e,f (1.24 to 3.73 )

0.06 (0.004 to 0.12) 0.20 (0.13 to 0.28) 0.17 (0.11 to 0.24) 0.05 (–0.02 to 0.11) 0.12g (0.05 to 0.20)

9 (5 to 20)

17/40 172/212 34/199 223/451

3/42 182/222 5/194 190/458

5.95 (2.08 to 18.11) 0.99 (0.90 to 1.08) 6.63 (2.75 to 16.19) 3.26h (0.48 to 22.08 )

0.35 (0.18 to 0.52) –0.008 (–0.08 to 0.06) 0.15 (0.09 to 0.21) 0.15 (–0.01 to 0.30)

50/122

38/122

38/210 92/141 130/351 50/206 86/124 136/330

1.32 (0.94 to 1.85)

0.10 (–0.02 to 0.22)

32/212 68/138 100/350

1.20 (0.78 to 1.84) 1.32 (1.08 to 1.64) 1.30a,i (1.08 to 1.57)

0.03 (–0.04 to 0.10) 0.16 (0.04 to 0.27) 0.09 (–0.04 to 0.22)

34/204 59/128 93/332

1.46 (0.99 to 2.15) 1.50 (1.21 to 1.89) 1.49c,j (1.23 to 1.81)

0.08 (–0.002 to 0.15) 0.23 (0.11 to 0.35) 0.15 (–0.007 to 0.30)

8 (5 to 20) 13 (8 to 50)

NNT = number-needed-to treat; RD = risk difference; RR = risk ratio. a p < 0.01. b p < 0.05. c p < 0.0001. d Q-statistic for heterogeneity = 8.65, df = 3 (p = 0.03), I2 = 65.3%. e p = 0.0063. f Q-statistic for heterogeneity = 18.75, df = 3 (p = 0.0003), I2 = 84%. g p = 0.0015. h Q-statistic for heterogeneity = 41.57, df = 2 (p < 0.0001), I2 = 95%. i Q-statistic for heterogeneity = 0.18, df = 1 (p = 0.67). j Q-statistic for heterogeneity = 0.02, df = 1 (p = 0.88).

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Efficacy of Low-Dose Ibuprofen in Acute Migraine

It is worth noting that only published trials were included and only 5 studies were combined in the meta-analysis. We used the Egger method22 to detect possible publication bias and found no evidence of bias with regard to the pooling of pain relief and pain-free data at 2 hours. For the pooling of other outcomes, the number of studies was too few to allow such testing. There were some limitations of the individual studies included in the meta-analysis. One study involved a small number of patients.15 Another was crossover in design and did not provide separate data on each treatment

period.16 Even though the crossover design allows robust estimates of intraindividual consistency of response, a period effect may occur in such design.27 This may introduce a bias in favor of ibuprofen. In addition, despite the fact that relevant clinical outcomes recommended by the IHS were used, there were still inconsistencies in descriptions of the outcomes adopted by individual trials. For example, 24 hour sustained pain-free was defined in one trial as the absence of recurrent migraine attack within 24 hours, while it was described in other studies as the absence of recurrence of headache and lack of re-

Figure 1. Efficacy of ibuprofen 400 mg versus placebo in acute migraine attack.

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quirement of antimigraine medication for 24 hours. To ensure that our meta-analysis included quality studies, the quality of each study’s design was assessed with respect to randomization, double-blinding, and withdrawals and dropouts.19 All of the included trials were of high quality. We also analyzed all study results on an intent-to-treat basis. With regard to interstudy heterogeneity, this may be due to the differences in study design and sample size, populations, and treatments (Table 2). For example, some trials evaluated single doses of ibuprofen for single migraine attack,14,16-18 while another estimated the effects of ibuprofen after 2 or more migraine attacks.15 Since the number of included studies was too few to allow proper subgroup analysis to explore between-study heterogeneity, our results should be used with caution. In essence, ibuprofen 200 and 400 mg may be effective only in patients over 16 years of age with moderate-to-severe migraine attacks and no more than 6–8 attacks per month. Given the limited evidence and shortcomings of the published data, large, high-quality, randomized controlled trials that evaluate ibuprofen against placebo and other active treatments are needed. The efficacy parameters should be consistently measured and reported as recommended by the IHS. Conclusions The available evidence indicates that ibuprofen 200 and 400 mg are effective in reducing moderate or severe pain to mild or no pain and rendering patients pain-free within 2 hours. Ibuprofen is not effective in providing a sustained pain-free outcome during 24 hours. Ibuprofen 200 mg is no more effective than placebo in alleviating nausea, photophobia, and phonophobia. Both photophobia and phonophobia improved only with ibuprofen 400 mg. Adverse events were as frequently reported with ibuprofen as with placebo. Further high-quality and consistent trials comparing ibuprofen versus placebo and other active comparators are warranted to better define its usefulness in the treatment of acute migraine. Chuthamanee Suthisisang PhD, Associate Professor, Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand Nalinee Poolsup PhD, Assistant Professor, Department of Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon-Pathom, Thailand Wararat Kittikulsuth BPharm, Lecturer, Department of Pharmacology, Faculty of Pharmacy, Mahidol University Phutsadee Pudchakan BPharm, Pharmacist, Department of Pharmacology, Faculty of Pharmacy, Mahidol University Pichamon Wiwatpanich BPharm, Pharmacist, Department of Pharmacology, Faculty of Pharmacy, Mahidol University Reprints: Dr. Suthisisang, Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, 10400, Thailand, fax 66(0)26-448700, [email protected]

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References 1. Headache Classification Committee for the International Headache Society. The international classification of headache disorders: second edition. Cephalalgia 2004;24(suppl 1):1-151. 2. Lipton RB, Bigal ME. Migraine: epidemiology, impact, and risk factors for progression. Headache 2005;45(suppl 1):S3-13. 3. Wenzel RG, Sarvis CA, Krause ML. Over-the-counter drugs for acute migraine attacks: literature review and recommendations. Pharmacotherapy 2003;23:494-505. 4. Landy S. Migraine throughout the life cycle. Treatment through the ages. Neurology 2004;62(suppl 2):S2-8. 5. Krymchantowski AV. Acute treatment of migraine. Breaking the paradigm of monotherapy. BMC Neurol 2004;4:4. DOI 10.1186/1474-2377- 4-4 6. Snow V, Weiss K, Wall EM, Mottur-Pilson C; for the American Academy of Family Physicians and the American College of Physicians–American Society of Internal Medicine. Pharmacologic management of acute attacks of migraine and prevention of migraine headache. Ann Intern Med 2002;137:840-9. 7. Silberstein SD. Migraine. Lancet 2004;363:381-91. 8. Tonore TB, King DS, Noble SL. Do over-the-counter medications for migraine hinder physician? Curr Pain Headache Rep 2002;6:162-7. 9. Jenkins DW, Feniuk W, Humphrey PP. Characterization of the prostanoid receptor types involved in mediating calcitonin gene-related peptide release from cultured rat trigeminal neurones. Br J Pharmacol 2001;134:1296-302. 10. Pearce I, Frank GJ, Pearce JM. Ibuprofen compared with paracetamol in migraine. Practitioner 1983;227:465-7. 11. Havanka-Kanniainen H. Treatment of acute migraine attack: ibuprofen and placebo compared. Headache 1989;29:507-9. 12. Kloster R, Nestvold K, Vilming ST, et al. A double-blind study of ibuprofen versus placebo in the treatment of acute migraine attacks. Cephalalgia 1992;12:169-71. 13. Nebe J, Heier M, Diener HC, et al. Low-dose ibuprofen in self-medication of mild to moderate headache: a comparison with acetylsalicylic acid and placebo. Cephalalgia 1995;15:531-5. 14. Codispoti JR, Prior MJ, Fu M, et al. Efficacy of nonprescription doses of ibuprofen for treating migraine headache. A randomized controlled trial. Headache 2001;41:665-79. 15. Misra UK, Jose M, Kalita J, et al. Rofecoxib versus ibuprofen for acute treatment of migraine: a randomized placebo controlled trial. Postgrad Med J 2004;80:720-3. 16. Diener HC, Bussone G, de Liano H, et al. Placebo-controlled comparison of effervescent acetylsalicylic acid, sumatriptan and ibuprofen in the treatment of migraine attacks. Cephalalgia 2004;24:947-54. 17. Saper J, Dahlof C, So Y, et al. Rofecoxib in the acute treatment of migraine: a randomized controlled clinical trial. Headache 2006;46:264-75. 18. Goldstein J, Silberstein SD, Saper JR, Ryan RE, Lipton RB. Acetaminophen, aspirin, and caffeine in combination versus ibuprofen for acute migraine: results from a multicenter, double-blind, randomized, parallelgroup, single-dose, placebo-controlled study. Headache 2006;46:444-53. 19. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12. 20. Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F. Methods for meta-analysis in medical research. London: John Wiley & Sons, Ltd., 2000. 21. Higgin JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analysis. BMJ 2003;327:557-60. 22. Egger M, Davey SG, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34. 23. Hamalainen ML, Hoppu K, Valkeila E, Santavuori P. Ibuprofen or acetaminophen for the acute treatment of migraine in children: a doubleblind, randomized, placebo-controlled, crossover study. Neurology 1997; 48:103-7.

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Efficacy of Low-Dose Ibuprofen in Acute Migraine 24. Sandrini G, Franchini S, Lanfranchi S, et al. Effectiveness of ibuprofen–arginine in the treatment of acute migraine attacks. Int J Clin Pharmacol Res 1998;18:145-50. 25. Lewis DW, Kellstein D, Dahl G, et al. Children’s ibuprofen suspension for the acute treatment of pediatric migraine. Headache 2002;42:780-6. 26. Kellstein DE, Lipton RB, Geetha R, et al. Evaluation of a novel solubilized formulation of ibuprofen in the treatment of migraine headache: a randomized, double-blind, placebo-controlled, dose-ranging study. Cephalalgia 2000;20:233- 43. 27. International Headache Society Clinical Trials Subcommittee. Guidelines for controlled trials of drugs in migraine: second edition. Cephalalgia 2000;20:765-86. 28. Oldman AD, Smith LA, McQuay HJ, Moore A. Pharmacological treatments for acute migraine: quantitative systematic reviews. Pain 2002; 97:247-57. 29. Damen L, Bruijn JK, Verhagen AP, Berger MY, Passchier J, Koes BW. Symptomatic treatment of migraine in children: a systematic review of medical trials. Pediatrics 2005;116:e295-e302.

Eficacia de Ibuprofeno en Dosis Baja en el Tratamiento de Migraña Aguda; Revisión Sistemática y Meta-Análisis C Suthisisang, N Poolsup, W Kittikulsuth, P Pudchakan, y P Wiwatpanich Ann Pharmacother 2007;41:1782-91. EXTRACTO TRASFONDO: Se ha demostrado que los antiinflamatorios no-esteroidales (AINEs), tales como la aspirina y el ibuprofeno, son efectivos en el tratamiento de migraña. Realizamos este meta-análisis con el propósito de evaluar la respuesta en pacientes que recibieron ibuprofeno para un ataque de migraña. OBJETIVO: Evaluar la eficacia de ibuprofeno en dosis baja en el tratamiento de migraña aguda. MÉTODO: Se identificaron estudios clínicos a través de búsquedas computadorizadas (MEDLINE, EMBASE, revisión de EMB, y la biblioteca Cochrane) hasta noviembre de 2006 y de búsquedas históricas de artículos relevantes. Se incluyeron los estudios si (1) eran dobleciegos, aleatorios, controlados con placebo, y evaluaban el uso de ibuprofeno en tableta en el tratamiento de ataques de migraña moderados a severos en adultos, (2) evaluaban al menos un ataque de migraña, y (3) reportaban alivio del dolor de cabeza, libre de dolor, libre de dolor sostenido, o alivio de los síntomas asociados a la migraña en 2 horas. Los autores extrajeron la información independientemente. Los desacuerdos se resolvieron a través de discusión. RESULTADOS: Ibuprofeno 200 mg y 400 mg fue más efectivo que placebo en reducir la intensidad del dolor y en proveer alivio completo del dolor en 2 horas en adultos con ataque de migraña moderado a severo. Para la dosis de 200 mg, los números necesarios para tratar para alivio de dolor de cabeza fue de 8 (95% CI 5 y 20) y 13 (95% CI 8 y 50) para libre de dolor. La razón de riesgo para alivio del dolor de cabeza y libre de dolor fueron 1.89 (95% CI 1.45 y 2.46, p< 0.0001) y 2.15 (95% CI 1.24 y 3.73, p = 0.0063), respectivamente, para ibuprofeno 400mg. El alivio sostenido libre de dolor en 24 horas con ibuprofeno no fue mejor que con placebo. Ibuprofeno 400 mg aumentó la razón de riesgo de alivio en fotofobia y fotofobia por un 30% (95% CI 8% y 57%, p < 0.01) y 49% (95% CI 23% y 81%, p < 0.0001), respectivamente. CONCLUSIONES: La evidencia disponible sugiere que ibuprofeno 200 mg y 400 mg son efectivos en reducir la intensidad del dolor de cabeza y

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lograr alivio completo en 2 horas. La fotofobia y fotofobia mejoraron con la dosis de 400 mg. Más estudios son necesarios debido a lo limitado de la información y limitaciones de la evidencia disponible. Traducido por Giselle Rivera-Miranda

Efficacité de Faibles Doses d’Ibuprofène pour le Traitement Aiguë de la Migraine: Revue Systématique et Méta-Analyse C Suthisisang, N Poolsup, W Kittikulsuth, P Pudchakan, et P Wiwatpanich Ann Pharmacother 2007;41:1782-91. RÉSUMÉ INTRODUCTION: Les MAINS, tel que l’aspirine et l’ibuprofène, ont démontré leur efficacité dans le traitement de la migraine. Une métaanalyse a été effectuée pour évaluer l’efficacité de l’ibuprofène pour traiter une crise de migraine. OBJECTIF: Évaluer l’efficacité de faibles doses d’ibuprofène pour le traitement aiguë de la migraine. DEVIS EXPÉRIMENTAL: Une revue de diverses banques de données électroniques (MEDLINE, EMBASE, EBM review, et la bibliothèque de Cochrane) a permis d’identifier les études cliniques publiées jusqu’à novembre 2006. Les bibliographies de ces études ont aussi été inspectées pour identifier des études supplémentaires. Pour être sélectionnées, les études devaient (1) être des essais comparatifs au placebo, à double insu et à répartition aléatoire évaluant l’effet de l’ibuprofène en comprimé administré chez l’adulte pour les crises migraineuses d’intensité modérée ou sévère, (2) évaluer au moins une crise migraineuse, et (3) rapporter les résultats en termes de soulagement du mal de tête, d’absence de douleur 2 ou 24 heures après l’administration, ou de soulagement des symptômes associés à la migraine 2 heures après l’administration. Deux auteurs ont procédé à la sélection des données de façon indépendante et les divergences ont été résolues par discussion. RÉSULTATS: Cinq études, pour un total de 1569 patients (200 mg: 216; 400 mg: 674; placébo: 679), répondaient aux critères de sélection des études. Des doses de 200 et 400 mg d’ibuprofène se sont avérées plus efficaces que le placebo pour soulager totalement ou réduire l’intensité de la douleur 2 heures après l’administration. Pour la dose de 200 mg, le nombre d’individus à traiter pour réduire la douleur était de 8 (95% IC 5 à 20) et il était de 13 (95% CI 8 à 50) pour obtenir un soulagement total. Les ratios de risque pour la réduction de la douleur et le soulagement étaient de 1.89 (95% IC 1.45 à 2.46; p < 0.0001) et 2.15 (95% IC 1.24 à 3.73; p = 0.0063), respectivement pour une dose de 400 mg d’ibuprofène. Le nombre d’individus à traiter pour obtenir une réduction de la douleur avec la dose de 400 mg était de 4 (95% IC 3 à 7). L’absence de douleurs 24 heures après l’administration d’une dose de 400 mg n’était pas supérieure au placébo. Des doses de 400 mg sont respectivement 30% (95% CI 8 à 57; p < 0.01) et 49% (95% CI 23 à 81; p < 0.0001) plus efficaces que le placébo pour soulager la photophobie et la phonophobie. CONCLUSIONS: Les évidences actuellement disponibles suggèrent que des doses de 200 et 400 mg d’ibuprofène sont efficaces pour réduire l’intensité ou soulager les maux de tête 2 heures après l’administration. Les doses de 400 mg améliorent aussi la photophobie et la phonophobie. Cependant, plus d’études seront nécessaires pour confirmer ces observations, compte tenu du nombre limité d’études présentement disponibles et des limitations de celles-ci.

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