㈼-2-10 AF

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エビデンスレベル

文献タイトル (日本語)

片頭痛急性期治療における tolfenamic acidとカフェインの有効性を評価する

研究デザイン

Double-blind randomized cross-over study

Department of Clinical Pharmacology, University of Helsinki , Finland . Department of Neurology, University of Turku , Turku , Finland . Tokola, Medica Pharmaceutical Co Ltd, Helsinki , Finland .

49名の片頭痛患者（男性3名，女性46名）

Tolfenamic acid（200mg），カフェイン（100mg），メトクロプラミド（10mg），ｔolfenamic acid＋カフェイン（200mg＋100mg），ｔolfenamic acid＋メトクロプラミド（200mg＋10mg），プラセボを対象患者に投与．計482回の片頭痛発作を評価．

荒木治子／竹島多賀夫

OBJECTIVE: To assess the effectiveness of the nonprescription combination of acetaminophen, aspirin, and caffeine in alleviating migraine headache pain. DESIGN: Three double-blind, randomized, parallel-group, single-dose, placebo-controlled studies. SETTING: Private practice, referral centers, and general community. PATIENTS: Migraineurs with moderate or severe headache pain who met International Headache Society diagnostic criteria for migraine with aura or without aura. The most severely disabled segment of migraineurs, including those whose attacks usually required bed rest, or who vomited 20% or more of the time, were excluded. Of the 1357 enrolled patients, 1250 took study medication and 1220 were included in the efficacy-evaluable data set. INTERVENTION: Two tablets of the nonprescription combination of acetaminophen, aspirin, and caffeine or placebo taken orally as a single-dose treatment of 1 eligible acute migraine attack. Main Outcome Measures: Pain intensity difference from baseline; percentage of patients with pain reduced to mild or none. RESULTS: Significantly greater reductions in migraine headache pain intensity 1 to 6 hours after dose were seen in patients taking the acetaminophen, aspirin, and caffeine combination than in those taking placebo in each of the 3 studies. Pain intensity was reduced to mild or none 2 hours after dose in 59.3% of the 602 drug-treated patients compared with 32.8% of the 618 placebo-treated patients (P< .001; 95% confidence interval [CI], 55%-63% for drug, 29%-37% for placebo); at 6 hours after dose, 79% vs 52%, respectively, had pain reduced to mild or none (P<.001; 95% CI, 75%-82% vs 48%-56%). In addition, by 6 hours after dose, 50.8% of the drug-treated patients were pain free compared with 23.5% of the placebo-treated patients (P<.001; 95% CI, 47%-55% for drug, 20%-27% for placebo). Other migraine headache characteristics, such as nausea, photophobia, phonophobia, and functional disability, were significantly improved 2 to 6 hours after treatment with the acetaminophen, aspirin, and caffeine combination compared with placebo (P< or =.01). CONCLUSIONS: The nonprescription combination of acetaminophen, aspirin, and caffeine was highly effective for the treatment of migraine headache pain as well as for alleviating the nausea, photophobia, phonophobia, and functional disability associated with migraine attacks. This drug combination also has an excellent safety profile and is well tolerated.

アセトアミノフェン，アスピリン，カフェインの片頭痛治療における有効性と安全性

Three double-blind, randomized, placebo-controlled trials

Department of Neurology, Albert Einstein College of Medicine, Montefiore Headache Unit, Bronx ,

1220名の片頭痛患者

618名の対象患者にアセトアミノフェン，アスピリン，カフェイン（ AAC），602名の患者にはプラセボを投与．

ベースラインとの比較で，片頭痛強度の減少を認めた患者の割合を評価．

AAC投与群において有意に頭痛強度の改善を認めた．
投与 2時間後での頭痛強度改善率は，AAC投与群で59.3%，プラセボ群で32.8%とAAC群にて有意に高値であった（P<.001）.また，投与6時間後での頭痛強度改善率は，AAC投与群で50.8%，プラセボ群で23.5%とAAC群にて有意に高値であった（P<.001）.
随伴症状においても投与 2〜６時間でAAC群で有意に改善度が高かった（P<=.01）.

Publication Types:
• Clinical Trial
• Randomized Controlled Trial

MeSH Terms:
• Acetaminophen/therapeutic use*
• Adult
• Analgesics/therapeutic use*
• Aspirin/therapeutic use*
• Caffeine/therapeutic use*
• Double-Blind Method
• Drug Therapy, Combination
• Female
• Human
• Male
• Migraine/diagnosis
• Migraine/drug therapy*
• Pain Measurement
• Severity of Illness Index
• Support, Non-U.S. Gov't
• Treatment Outcome

Substances:
• Analgesics
• Acetaminophen
• Aspirin
• Caffeine

荒木治子／竹島多賀夫

OBJECTIVE : To examine the benefits of acetaminophen, aspirin, and caffeine (AAC) in the treatment of severe, disabling migraine attacks, in a population of migraine sufferers for whom over-the-counter (OTC) medications are appropriate.
BACKGROUND : Subjects (n = 1220) who met the International Headache Society criteria for migraine with or without aura were included in three independent clinical studies.
DESIGN/METHODS : Post-hoc analysis of 172 subjects who met the criteria for severe, disabling migraine reported a history of migraine attacks characterized by at least severe pain and severe disability, and treated attacks with severe pain and at least severe disability. Subjects who usually vomited with 20% or more of their migraine attacks, and those with incapacitating disability (subjects who required bed rest for more than 50% of their attacks) were not eligible for enrollment.
RESULTS : From 1 h and continuing through 6 h postdose, the proportion of responders was significantly greater (p< or =0.01) for AAC than placebo. The pain intensity difference from baseline was significantly greater (p< or =0.05) for AAC than placebo from 0.5 h through 6 h. The proportion of subjects reporting improvement in functional disability, photophobia, and phonophobia was significantly greater for AAC than placebo from 2 h through 6 h postdose. CONCLUSIONS : The nonprescription combination of AAC was well tolerated and effective.

重度片頭痛発作におけるアセトアミノフェン，アスピリン，カフェインの治療．

Randomized, double-blind， placebo-controlled study

San Francisco Headache Clinic , CA , USA .

172名の重症片頭痛患者

89名にはAAC( アセトアミノフェン 500mg，アスピリン500mg，カフェイン130mg) 治療を， 83名にはプラセボを投与

頭痛と随伴症状の強度をスコア化し，治療前のベースラインと治療 0.5〜6時間後での比較評価．

治療 0.5〜6時間後においてはプラセボ郡に比してAAC群にてより効果が得られやすく，その差は優位であった（P<0.01）．治療2〜6時間後においては，随伴症状の改善度もAAC群において有意に高かった．

よくデザインされた RCT．

Publication Types:
• Clinical Trial
• Randomized Controlled Trial

MeSH Terms:
• Acetaminophen/administration & dosage
• Acetaminophen/therapeutic use*
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Aspirin/administration & dosage
• Aspirin/therapeutic use*
• Caffeine/administration & dosage
• Caffeine/therapeutic use*
• Comparative Study
• Double-Blind Method
• Drug Combinations
• Drug Utilization
• Drugs, Non-Prescription/therapeutic use*
• Female
• Human
• Hyperacusis/drug therapy
• Hyperacusis/etiology
• Male
• Middle Aged
• Migraine/drug therapy*
• Nausea/drug therapy
• Nausea/etiology
• Photophobia/drug therapy
• Photophobia/etiology
• Severity of Illness Index

Substances:
• Drug Combinations
• Drugs, Non-Prescription
• Acetaminophen
• Aspirin
• Caffeine

荒木治子／竹島多賀夫

This retrospective study sought to examine the benefits of the nonprescription combination of acetaminophen, aspirin, and caffeine (AAC; Excedrin Migraine, Bristol-Myers Squibb Company, New York , New York ) for the treatment of menstruation-associated migraine compared with migraine not associated with menses. Data were derived from 3 double-masked, randomized, placebo-controlled, single-dose trials enrolling subjects who met the International Headache Society's diagnostic criteria for migraine with or without aura. Subjects with incapacitating disability (attacks requiring bed rest >50% of the time) and those who usually experienced vomiting > or =20% of the time were excluded. Retrospective analysis of the 1220 subjects included in the efficacy-evaluable data set indicated that 185 women treated menstruation-associated migraine, 781 women treated migraine not associated with menses, and 1 woman provided no information regarding menstrual status. At baseline and at 0.5, 1, 2, 3, 4, and 6 hours postdose, subjects assessed the intensity of headache pain, functional disability, nausea, photophobia, and phonophobia. Pain intensity, nausea, photophobia, and phonophobia were rated on a 4-point scale ranging from 0 = none to 3 = severe; functional disability was rated on a 5-point scale ranging from 0 = none to 4 = incapacitating. For both menstruation-associated migraine and migraine not associated with menses, the proportion of subjects with pain intensity reduced to mild or none (responders) was significantly greater with AAC than with placebo at all postdose time points from 0.5 through 6 hours (P< or =0.05), with no statistically significant difference in treatment effect between menstruation-associated migraine and migraine not associated with menses at any postdose time point. Migraine characteristics such as photophobia, phonophobia, and functional disability were significantly improved in AAC-treated subjects at all time points from 1 through 6 hours (P< or =0.01) in both the menstruating and nonmenstruating groups. Significant relief from nausea was experienced in both menstruation-associated migraine and migraine not associated with menses, but relief appeared earlier in the AAC nonmenstruating subjects (2 hours postdose, P< or =0.01) than in the menstruating subjects (6 hours postdose, P< or =0.05). Beginning at 3 hours postdose, significantly fewer subjects treated with AAC required rescue medication (P< or =0.05) for menstruation-associated migraine (AAC 6%, placebo 15%) and migraine not associated with menses (AAC 7%, placebo 14%). The most commonly used rescue medications in both the menstruating and nonmenstruating groups were nonsteroidal anti-inflammatory drugs, prescription combination analgesics/narcotics, and prescription migraine preparations. AAC was well tolerated in both menstruation-associated migraine and migraine not associated with menses; in general, adverse experiences were similar in both groups. The proportion of subjects who had 1 or more adverse experiences was significantly higher among those receiving AAC than among those receiving placebo (menstruation-associated migraine: AAC 26.4%, placebo 12.6%, P = 0.025; nonmenstruation-associated migraine: AAC 18.6%, placebo 11.4%, P = 0.005). Adverse experiences were similar in type and severity to those previously associated with single doses of acetaminophen, aspirin, or caffeine. Thus the nonprescription combination of AAC was highly effective in treating the pain, disability, and associated symptoms of both menstruation-associated migraine and migraine not associated with menses.

月経関連性の片頭痛におけるアセトアミノフェン，アスピリン，カフェインの治療効果

3 double-masked, randomized, placebo-controlled study

Jefferson Headache Center , Philadelphia , Pennsylvania , USA .

1995年8月〜1996年6月

1220名の片頭痛患者（967名の女性と253名の男性）
そのうち 967名の女性片頭痛患者を対象とした（185名の月経関連性の片頭痛患者と， 781名の月経非関連性の片頭痛患者）．

月経関連性の片頭痛患者は 85名にAAC，100名にプラセボを投与，非関連性の片頭痛患者は385名にAAC，396名にプラセボを投与．
AAC投与量はアセトアミノフェン 500mg，アスピリン500mg，カフェイン130mg．
治療前ベースラインと内服後 0.5，1，2，3，4，6時間での頭痛と随伴症状をスコア化して比較評価した．

月経関連性の片頭痛患者と月経非関連性の片頭痛患者ではどちらのクループにおいても，頭痛強度の改善が得られた患者数はプラセボに比して AACの方が有意に高値であった．(治療0.5〜６時間においての有意差はP<0.05．)
また，随伴症状も AACにおいて有意に改善率が高かった．(治療1〜６時間においての有意差はP<0.01．)

大規模でよくデザインされた RCT．

Publication Types:
• Clinical Trial
• Multicenter Study
• Randomized Controlled Trial

MeSH Terms:
• Acetaminophen/adverse effects
• Acetaminophen/therapeutic use*
• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Analgesics, Non-Narcotic/adverse effects
• Analgesics, Non-Narcotic/therapeutic use*
• Anti-Inflammatory Agents, Non-Steroidal/adverse effects
• Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
• Aspirin/adverse effects
• Aspirin/therapeutic use
• Caffeine/adverse effects
• Caffeine/therapeutic use
• Central Nervous System Stimulants/adverse effects
• Central Nervous System Stimulants/therapeutic use*
• Drug Therapy, Combination
• Female
• Human
• Menstruation*
• Middle Aged
• Migraine/drug therapy*
• Migraine/etiology
• Retrospective Studies
• Support, Non-U.S. Gov't

Substances:
• Analgesics, Non-Narcotic
• Anti-Inflammatory Agents, Non-Steroidal
• Central Nervous System Stimulants
• Acetaminophen
• Aspirin
• Caffeine

荒木治子／竹島多賀夫

OBJECTIVE : To compare the efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine suppositories with sumatriptan suppositories in the treatment of 2 consecutive migraine attacks of moderate or severe intensity in a multicenter, randomized, crossover study.
BACKGROUND : A fixed combination of indomethacin, prochlorperazine, and caffeine is the most commonly used drug for the acute treatment of migraine in Italy . No studies have been published comparing the efficacy of this combination with sumatriptan, the most widely prescribed of the triptans.
METHODS : One hundred twelve patients with migraine with or without aura according to the diagnostic criteria of the International Headache Society were randomized to treat 2 migraine attacks with a fixed combination of indomethacin, prochlorperazine, and caffeine and 2 migraine attacks with sumatriptan. Both drugs were rectally administered in a single dose for each attack. Patients were asked to take study medication as soon as possible at the onset of a headache.
RESULTS : Of the 112 patients, 88 were compliant to the protocol. More attacks became pain-free at 2 hours postdose (primary end point) on the combination than on sumatriptan (49% versus 34%; P<.01), while there was no difference in the relief of headache at 2 hours postdose (71% versus 65%). The combination was statistically superior to sumatriptan in the time to a pain-free response (a higher percentage of attacks became pain-free from 0.5 hours postdose to 5 hours postdose), in alleviation of nausea, and in a sustained pain-free response (pain-free at 2 hours postdose with no use of rescue medication or relapses within 48 hours). Moreover, a significant consistent response was achieved for the combination compared with sumatriptan across (higher percentage of patients pain-free at 2 hours postdose in the first, second, third, and fourth treated attack) and within patients (pain-free in 2 of 2 treated attacks in 35% of patients taking the combination and 20% of patients on sumatriptan). Both drugs were well-tolerated.
CONCLUSIONS : This study, analyzed according to the more recent guidelines for controlled trials in migraine, showed that a fixed combination of indomethacin, prochlorperazine, and caffeine is significantly more effective than sumatriptan in the acute treatment of migraine attacks. It is notable that the combination is less expensive than sumatriptan per unit dose.

インドメタシン，プロルクロマジン，カフェインの併用療法と，スマトリプタンの片頭痛急性期治療における効果の比較．

Multicenter, randomized, crossover study

Neurology Division I, Spedali Civili di Brescia , Italy

112名の片頭痛患者

2回の片頭痛発作にインドメタシン 25mg，プロルクロマジン4mg，カフェイン75mgの併用療法を行い，他の2回の片頭痛発作にスマトリプタン25mgを使用し，効果を評価．

Primary　end　point：治療2時間後の頭痛消失

112名の患者のうち，88名が研究を遂行できた．
2時間後の頭痛消失はスマトリプタン34%に比して併用療法では49%と有意に多かった（P<.01）．しかし，頭痛軽減の観点では両者に差は認めなかった（併用療法71%，スマトリプタン65%）.

Publication Types:
• Clinical Trial
• Multicenter Study
• Randomized Controlled Trial

MeSH Terms:
• Acute Disease
• Adult
• Anti-Inflammatory Agents, Non-Steroidal/therapeutic use
• Antiemetics/therapeutic use
• Caffeine/therapeutic use*
• Central Nervous System Stimulants/therapeutic use
• Comparative Study
• Cross-Over Studies
• Drug Combinations
• Female
• Human
• Indomethacin/therapeutic use*
• Male
• Migraine/drug therapy*
• Prochlorperazine/therapeutic use*
• Recurrence
• Research Design
• Serotonin Agonists/therapeutic use
• Sumatriptan/therapeutic use*
• Suppositories
• Treatment Outcome

Substances:
• Anti-Inflammatory Agents, Non-Steroidal
• Antiemetics
• Central Nervous System Stimulants
• Drug Combinations
• Serotonin Agonists
• Suppositories
• Sumatriptan
• Indomethacin
• Caffeine
• Prochlorperazine

荒木治子／竹島多賀夫

OBJECTIVE : A phase II, randomized, double-blind, crossover study was designed to evaluate the efficacy of 100-mg diclofenac sodium softgel (formulated using ProSorb technology) with or without 100-mg caffeine versus placebo in migraineurs during migraine attacks.
BACKGROUND : Diclofenac has been demonstrated to be an effective migraine treatment in several placebo-controlled studies. A rapidly absorbed softgel of diclofenac has been shown to be effective in the rapid relief of acute pain, and may have advantages in migraine treatment. In addition, caffeine has consistently been shown to increase both the efficacy and speed of onset of concurrently administered analgesics. The ability of caffeine to both enhance and accelerate analgesic effects has been documented with a variety of different medications (ie, aspirin, acetaminophen, ibuprofen, and ergotamine).
METHODS : The 3-period crossover study was designed to compare diclofenac softgel 100 mg, diclofenac softgel 100 mg plus caffeine 100 mg, and placebo in the acute treatment of migraine. Subjects treated one moderate or severe attack with each study medication. The primary efficacy parameter was the percentage of subjects with headache relief at 60 minutes as defined by a reduction of headache severity from moderate or severe at baseline to absent or mild compared with placebo. Though the sample size estimate required that 72 subjects treat 3 separate attacks, 51 subjects treated 1 migraine attack, 44 treated 2 attacks, and 39 treated 3 attacks.
Results.： In the placebo group, 6 (14%) of 43 subjects reported headache relief at 60 minutes versus 12 (27%) of 45 subjects in the diclofenac softgel group, and 19 (41%) of 46 subjects in the diclofenac softgel plus caffeine group. Differences were statistically significant for the diclofenac softgel plus caffeine group versus placebo (odds ratio, 4.2; 95% confidence interval, 1.3 to 13.7). Rescue medication was used by 27 (63%) of 43 subjects treated with placebo, 15 (33%) of 45 subjects treated with diclofenac softgel, and 14 (30%) of 46 subjects treated with diclofenac softgel plus caffeine. This result is highly statistically significant (chi22= 11.56, P=.003). Both the diclofenac plus caffeine (P <.03) and diclofenac only (P <.03) groups were significantly different from the placebo group in terms of the visual analog scale score at 60 minutes.
CONCLUSIONS : The major finding of the present study is that diclofenac softgel plus caffeine produces statistically significant benefits relative to placebo at 60 minutes. Diclofenac softgel alone did not differ significantly from placebo, perhaps due to limits in sample size. Nonsignificant trends support the analgesic adjuvant benefit of caffeine when added to diclofenac softgels

前兆のない片頭痛におけるジクロフェナクナトリウムソフトゲル 100mgとカフェイン100mgの併用とジクロフェナクナトリウムソフトゲル100mg単剤使用の効果の比較

Randomized, double-blind, crossover study

Burlingame , Calif. 94010 , USA

前兆のない片頭痛と診断された 18〜60歳の患者

治療 1時間後の頭痛改善度（中等度以上の頭痛が軽度になるか消失するか）

プラセボ群では 60分後の頭痛改善率が14%であったのに対し，ジクロフェナクソフトゲル群では27%，ジクロフェナク＋カフェイン群では41%と有意に高値であった（ジクロフェナク＋カフェイン群ｖｓプラセボ群でオッズ比4.2，95%ＣＩ　1.3〜13.7）．また，プラセボ群では63%が，ジクロフェナクソフトゲル群では33%，ジクロフェナク＋カフェイン群では30%がrescue medicationを必要とし，これも統計的な有意差を認めた.
ジクロフェナク単独使用群（ P<．03）はプラセボ群よりも優位に有効性が高いことが示された.

Publication Types:
• Clinical Trial
• Randomized Controlled Trial

MeSH Terms:
• Adolescent
• Adult
• Analgesics/administration & dosage
• Anti-Inflammatory Agents, Non-Steroidal/administration & dosage*
• Caffeine/administration & dosage*
• Common Migraine/drug therapy*
• Comparative Study
• Cross-Over Studies
• Diclofenac/administration & dosage*
• Double-Blind Method
• Drug Combinations
• Female
• Gels
• Human
• Male
• Middle Aged

Substances:
• Analgesics
• Anti-Inflammatory Agents, Non-Steroidal
• Drug Combinations
• Gels
• Diclofenac
• Caffeine

荒木治子／竹島多賀夫

1) Hakkarainen H, Parantainen J, Gothoni G, Vapaatalo H. Tolfenamic 　 acid and caffeine: a useful combination in migraine. Cephalalgia. 　 1982 Dec;2(4):173-7
論文抄録	Tolfenamic acid is a fenamate which inhibits prostaglandin (PG) biosynthesis and may act as a PG antagonist as well. Caffeine and metoclopramide are used in combination with analgesics and ergotamine in the treatment of migraine attacks, but controlled clinical studies on fixed combinations with analgesics are rare. The effects of orally given tolfenamic acid(200 mg), caffeine (100 mg), metoclopramide (10 mg), tolfenamic acid + caffeine (200 mg +100 mg), tolfenamic acid + metoclopramide (200 mg + 10 mg) and placebo were studied in 49 migraine patients (3 men, 46 women) in a double-blind randomized cross-over study comprising 482 migraine attacks. The patients were allowed to take either one or two capsules of each preparation for an attack. Additional drugs were allowed after 3 h. Parameters characterizing the effects and side-effects of the drugs were registered. Tolfenamic acid and its combinations were found to be effective in the treatment of acute migraine, but caffeine and metoclopramide alone did not differ from placebo. Combination with metoclopramide was better than tolfenamic acid alone as judged by the smaller dose needed and the intensity of attack. Between tolfenamic acid alone and its caffeine combination there were no statistically significant differences. o A nalgesic combinations,
文献 PubMed−ID	PMID: 6984358
エビデンスレベル	㈵ b
文献タイトル (日本語)	Tolfenamic acidとカフェインの片頭痛における治療
目的	片頭痛急性期治療における tolfenamic acidとカフェインの有効性を評価する
研究デザイン	Double-blind randomized cross-over study
研究施設	Department of Clinical Pharmacology, University of Helsinki , Finland . Department of Neurology, University of Turku , Turku , Finland . Tokola, Medica Pharmaceutical Co Ltd, Helsinki , Finland .
対象患者	49名の片頭痛患者（男性3名，女性46名）
介入	Tolfenamic acid（200mg），カフェイン（100mg），メトクロプラミド（10mg），ｔolfenamic acid＋カフェイン（200mg＋100mg），ｔolfenamic acid＋メトクロプラミド（200mg＋10mg），プラセボを対象患者に投与．計482回の片頭痛発作を評価．
結果	Tolfenamic acidとの併用療法では片頭痛急性期治療として有効性は高かったが，カフェイン，メトクロプラミドの単独療法ではその効果にプラセボとの差は認められなかった． Tolfenamic acid単独とカフェイン併用では統計学的には差はなかった．副作用は 482名中で軽度のものが47名に認められた．副作用の出現には各治療薬間での差はなかった．副作用としての嘔気出現はほんの7%にすぎなかった．
結論	NSAIDｓである tolfenamic acidはメトクロプラミドやカフェインと併用することにより片頭痛急性期治療において有効性を発揮する．カフェイン，メトクロプラミドともに単独での効果は低い．
コメント	中規模の RCT．IHS基準より以前の研究であり，対象の診断や均一性に関して情報が少ない．
備考１	Publication Types: • Clinical Trial • Randomized Controlled Trial MeSH Terms: • Adult • Anthranilic Acids/administration & dosage* • Anti-Inflammatory Agents, Non-Steroidal/administration & dosage* • Caffeine/administration & dosage* • Comparative Study • Drug Combinations • Female • Human • Metoclopramide/administration & dosage • Middle Aged • Migraine/drug therapy* • Prostaglandin Antagonists/administration & dosage* • Pyridoxine/administration & dosage • Random Allocation Substances: • Anthranilic Acids • Anti-Inflammatory Agents, Non-Steroidal • Drug Combinations • Prostaglandin Antagonists • tolfenamic acid • Metoclopramide • Caffeine Pyridoxine
備考２	PM: 6984358
作成者	荒木治子／竹島多賀夫

3) Lipton RB, Stewart WF, Ryan RE Jr, Saper J, Silberstein S, Sheftell 　 F. Efficacy and safety of acetaminophen, aspirin, and caffeine in 　 alleviating migraine headache pain: three double-blind, randomized, 　 placebo-controlled trials. Arch Neurol. 1998 Feb;55(2):210-7.
論文抄録	OBJECTIVE: To assess the effectiveness of the nonprescription combination of acetaminophen, aspirin, and caffeine in alleviating migraine headache pain. DESIGN: Three double-blind, randomized, parallel-group, single-dose, placebo-controlled studies. SETTING: Private practice, referral centers, and general community. PATIENTS: Migraineurs with moderate or severe headache pain who met International Headache Society diagnostic criteria for migraine with aura or without aura. The most severely disabled segment of migraineurs, including those whose attacks usually required bed rest, or who vomited 20% or more of the time, were excluded. Of the 1357 enrolled patients, 1250 took study medication and 1220 were included in the efficacy-evaluable data set. INTERVENTION: Two tablets of the nonprescription combination of acetaminophen, aspirin, and caffeine or placebo taken orally as a single-dose treatment of 1 eligible acute migraine attack. Main Outcome Measures: Pain intensity difference from baseline; percentage of patients with pain reduced to mild or none. RESULTS: Significantly greater reductions in migraine headache pain intensity 1 to 6 hours after dose were seen in patients taking the acetaminophen, aspirin, and caffeine combination than in those taking placebo in each of the 3 studies. Pain intensity was reduced to mild or none 2 hours after dose in 59.3% of the 602 drug-treated patients compared with 32.8% of the 618 placebo-treated patients (P< .001; 95% confidence interval [CI], 55%-63% for drug, 29%-37% for placebo); at 6 hours after dose, 79% vs 52%, respectively, had pain reduced to mild or none (P<.001; 95% CI, 75%-82% vs 48%-56%). In addition, by 6 hours after dose, 50.8% of the drug-treated patients were pain free compared with 23.5% of the placebo-treated patients (P<.001; 95% CI, 47%-55% for drug, 20%-27% for placebo). Other migraine headache characteristics, such as nausea, photophobia, phonophobia, and functional disability, were significantly improved 2 to 6 hours after treatment with the acetaminophen, aspirin, and caffeine combination compared with placebo (P< or =.01). CONCLUSIONS: The nonprescription combination of acetaminophen, aspirin, and caffeine was highly effective for the treatment of migraine headache pain as well as for alleviating the nausea, photophobia, phonophobia, and functional disability associated with migraine attacks. This drug combination also has an excellent safety profile and is well tolerated.
文献 PubMed−ID	PMID: 9482363
エビデンスレベル	㈵ b
文献タイトル (日本語)	アセトアミノフェン，アスピリン，カフェインの片頭痛治療における有効性と安全性
目的	片頭痛発作軽減におけるアセトアミノフェン，アスピリン，カフェインの効果と安全性を評価する
研究デザイン	Three double-blind, randomized, placebo-controlled trials
研究施設	Department of Neurology, Albert Einstein College of Medicine, Montefiore Headache Unit, Bronx ,
対象患者	1220名の片頭痛患者
介入	618名の対象患者にアセトアミノフェン，アスピリン，カフェイン（ AAC），602名の患者にはプラセボを投与．
主要評価項目とそれに用いた統計学的手法	ベースラインとの比較で，片頭痛強度の減少を認めた患者の割合を評価．
結果	AAC投与群において有意に頭痛強度の改善を認めた．投与 2時間後での頭痛強度改善率は，AAC投与群で59.3%，プラセボ群で32.8%とAAC群にて有意に高値であった（P<.001）.また，投与6時間後での頭痛強度改善率は，AAC投与群で50.8%，プラセボ群で23.5%とAAC群にて有意に高値であった（P<.001）. 随伴症状においても投与 2〜６時間でAAC群で有意に改善度が高かった（P<=.01）.
結論	AACによる片頭痛急性期治療は，頭痛強度および随伴症状の改善に高い有効性と安全性をもつ.
備考１	Publication Types: • Clinical Trial • Randomized Controlled Trial MeSH Terms: • Acetaminophen/therapeutic use* • Adult • Analgesics/therapeutic use* • Aspirin/therapeutic use* • Caffeine/therapeutic use* • Double-Blind Method • Drug Therapy, Combination • Female • Human • Male • Migraine/diagnosis • Migraine/drug therapy* • Pain Measurement • Severity of Illness Index • Support, Non-U.S. Gov't • Treatment Outcome Substances: • Analgesics • Acetaminophen • Aspirin • Caffeine
備考２	PM: 9482363
作成者	荒木治子／竹島多賀夫

4) Goldstein J, Hoffman HD, Armellino JJ, Battikha JP, Hamelsky SW, 　 Couch J, Blumenthal H, Lipton RB. Treatment of severe, disabling 　 migraine attacks in an over-the-counter population of migraine 　 sufferers: results from three randomized, placebo-controlled studies 　 of the combination of acetaminophen, aspirin, and caffeine. 　 Cephalalgia. 1999 Sep;19(7):684-91
論文抄録	OBJECTIVE : To examine the benefits of acetaminophen, aspirin, and caffeine (AAC) in the treatment of severe, disabling migraine attacks, in a population of migraine sufferers for whom over-the-counter (OTC) medications are appropriate. BACKGROUND : Subjects (n = 1220) who met the International Headache Society criteria for migraine with or without aura were included in three independent clinical studies. DESIGN/METHODS : Post-hoc analysis of 172 subjects who met the criteria for severe, disabling migraine reported a history of migraine attacks characterized by at least severe pain and severe disability, and treated attacks with severe pain and at least severe disability. Subjects who usually vomited with 20% or more of their migraine attacks, and those with incapacitating disability (subjects who required bed rest for more than 50% of their attacks) were not eligible for enrollment. RESULTS : From 1 h and continuing through 6 h postdose, the proportion of responders was significantly greater (p< or =0.01) for AAC than placebo. The pain intensity difference from baseline was significantly greater (p< or =0.05) for AAC than placebo from 0.5 h through 6 h. The proportion of subjects reporting improvement in functional disability, photophobia, and phonophobia was significantly greater for AAC than placebo from 2 h through 6 h postdose. CONCLUSIONS : The nonprescription combination of AAC was well tolerated and effective.
文献 PubMed−ID	PMID: 10524663
エビデンスレベル	㈵ b
文献タイトル (日本語)	重度片頭痛発作におけるアセトアミノフェン，アスピリン，カフェインの治療．
目的	重度片頭痛発作におけるアセトアミノフェン，アスピリン，カフェイン（ AAC）の有効性を評価する．
研究デザイン	Randomized, double-blind， placebo-controlled study
研究施設	San Francisco Headache Clinic , CA , USA .
対象患者	172名の重症片頭痛患者
介入	89名にはAAC( アセトアミノフェン 500mg，アスピリン500mg，カフェイン130mg) 治療を， 83名にはプラセボを投与
主要評価項目とそれに用いた統計学的手法	頭痛と随伴症状の強度をスコア化し，治療前のベースラインと治療 0.5〜6時間後での比較評価．
結果	治療 0.5〜6時間後においてはプラセボ郡に比してAAC群にてより効果が得られやすく，その差は優位であった（P<0.01）．治療2〜6時間後においては，随伴症状の改善度もAAC群において有意に高かった．
結論	重度片頭痛発作に対し， AAC治療は安全かつ有効であることが示唆された．
コメント	よくデザインされた RCT．
備考１	Publication Types: • Clinical Trial • Randomized Controlled Trial MeSH Terms: • Acetaminophen/administration & dosage • Acetaminophen/therapeutic use* • Adolescent • Adult • Aged • Aged, 80 and over • Aspirin/administration & dosage • Aspirin/therapeutic use* • Caffeine/administration & dosage • Caffeine/therapeutic use* • Comparative Study • Double-Blind Method • Drug Combinations • Drug Utilization • Drugs, Non-Prescription/therapeutic use* • Female • Human • Hyperacusis/drug therapy • Hyperacusis/etiology • Male • Middle Aged • Migraine/drug therapy* • Nausea/drug therapy • Nausea/etiology • Photophobia/drug therapy • Photophobia/etiology • Severity of Illness Index Substances: • Drug Combinations • Drugs, Non-Prescription • Acetaminophen • Aspirin • Caffeine
備考２	PM: 10524663
作成者	荒木治子／竹島多賀夫

5) Silberstein SD, Armellino JJ, Hoffman HD, Battikha JP, Hamelsky 　 SW, Stewart WF, Lipton RB. Treatment of menstruation-associated 　 migraine with the nonprescription combination of acetaminophen, 　 aspirin, and caffeine: results from three randomized, placebo- 　 controlled studies. Treatment of menstruation-associated migraine 　 with the nonprescription combination of acetaminophen, aspirin, and 　 caffeine: results from three randomized, placebo-controlled studies.
論文抄録	This retrospective study sought to examine the benefits of the nonprescription combination of acetaminophen, aspirin, and caffeine (AAC; Excedrin Migraine, Bristol-Myers Squibb Company, New York , New York ) for the treatment of menstruation-associated migraine compared with migraine not associated with menses. Data were derived from 3 double-masked, randomized, placebo-controlled, single-dose trials enrolling subjects who met the International Headache Society's diagnostic criteria for migraine with or without aura. Subjects with incapacitating disability (attacks requiring bed rest >50% of the time) and those who usually experienced vomiting > or =20% of the time were excluded. Retrospective analysis of the 1220 subjects included in the efficacy-evaluable data set indicated that 185 women treated menstruation-associated migraine, 781 women treated migraine not associated with menses, and 1 woman provided no information regarding menstrual status. At baseline and at 0.5, 1, 2, 3, 4, and 6 hours postdose, subjects assessed the intensity of headache pain, functional disability, nausea, photophobia, and phonophobia. Pain intensity, nausea, photophobia, and phonophobia were rated on a 4-point scale ranging from 0 = none to 3 = severe; functional disability was rated on a 5-point scale ranging from 0 = none to 4 = incapacitating. For both menstruation-associated migraine and migraine not associated with menses, the proportion of subjects with pain intensity reduced to mild or none (responders) was significantly greater with AAC than with placebo at all postdose time points from 0.5 through 6 hours (P< or =0.05), with no statistically significant difference in treatment effect between menstruation-associated migraine and migraine not associated with menses at any postdose time point. Migraine characteristics such as photophobia, phonophobia, and functional disability were significantly improved in AAC-treated subjects at all time points from 1 through 6 hours (P< or =0.01) in both the menstruating and nonmenstruating groups. Significant relief from nausea was experienced in both menstruation-associated migraine and migraine not associated with menses, but relief appeared earlier in the AAC nonmenstruating subjects (2 hours postdose, P< or =0.01) than in the menstruating subjects (6 hours postdose, P< or =0.05). Beginning at 3 hours postdose, significantly fewer subjects treated with AAC required rescue medication (P< or =0.05) for menstruation-associated migraine (AAC 6%, placebo 15%) and migraine not associated with menses (AAC 7%, placebo 14%). The most commonly used rescue medications in both the menstruating and nonmenstruating groups were nonsteroidal anti-inflammatory drugs, prescription combination analgesics/narcotics, and prescription migraine preparations. AAC was well tolerated in both menstruation-associated migraine and migraine not associated with menses; in general, adverse experiences were similar in both groups. The proportion of subjects who had 1 or more adverse experiences was significantly higher among those receiving AAC than among those receiving placebo (menstruation-associated migraine: AAC 26.4%, placebo 12.6%, P = 0.025; nonmenstruation-associated migraine: AAC 18.6%, placebo 11.4%, P = 0.005). Adverse experiences were similar in type and severity to those previously associated with single doses of acetaminophen, aspirin, or caffeine. Thus the nonprescription combination of AAC was highly effective in treating the pain, disability, and associated symptoms of both menstruation-associated migraine and migraine not associated with menses.
文献 PubMed−ID	PMID: 10321417
エビデンスレベル	㈵ b
文献タイトル (日本語)	月経関連性の片頭痛におけるアセトアミノフェン，アスピリン，カフェインの治療効果
目的	月経関連性の片頭痛におけるアセトアミノフェン，アスピリン，カフェインの治療効果を評価する．
研究デザイン	3 double-masked, randomized, placebo-controlled study
研究施設	Jefferson Headache Center , Philadelphia , Pennsylvania , USA .
研究期間	1995年8月〜1996年6月
対象患者	1220名の片頭痛患者（967名の女性と253名の男性）そのうち 967名の女性片頭痛患者を対象とした（185名の月経関連性の片頭痛患者と， 781名の月経非関連性の片頭痛患者）．
介入	月経関連性の片頭痛患者は 85名にAAC，100名にプラセボを投与，非関連性の片頭痛患者は385名にAAC，396名にプラセボを投与． AAC投与量はアセトアミノフェン 500mg，アスピリン500mg，カフェイン130mg．治療前ベースラインと内服後 0.5，1，2，3，4，6時間での頭痛と随伴症状をスコア化して比較評価した．
結果	月経関連性の片頭痛患者と月経非関連性の片頭痛患者ではどちらのクループにおいても，頭痛強度の改善が得られた患者数はプラセボに比して AACの方が有意に高値であった．(治療0.5〜６時間においての有意差はP<0.05．) また，随伴症状も AACにおいて有意に改善率が高かった．(治療1〜６時間においての有意差はP<0.01．)
結論	AACは月経関連性および非関連性の片頭痛患者において高い有効性を示す．
コメント	大規模でよくデザインされた RCT．
備考１	Publication Types: • Clinical Trial • Multicenter Study • Randomized Controlled Trial MeSH Terms: • Acetaminophen/adverse effects • Acetaminophen/therapeutic use* • Adolescent • Adult • Aged • Aged, 80 and over • Analgesics, Non-Narcotic/adverse effects • Analgesics, Non-Narcotic/therapeutic use* • Anti-Inflammatory Agents, Non-Steroidal/adverse effects • Anti-Inflammatory Agents, Non-Steroidal/therapeutic use • Aspirin/adverse effects • Aspirin/therapeutic use • Caffeine/adverse effects • Caffeine/therapeutic use • Central Nervous System Stimulants/adverse effects • Central Nervous System Stimulants/therapeutic use* • Drug Therapy, Combination • Female • Human • Menstruation* • Middle Aged • Migraine/drug therapy* • Migraine/etiology • Retrospective Studies • Support, Non-U.S. Gov't Substances: • Analgesics, Non-Narcotic • Anti-Inflammatory Agents, Non-Steroidal • Central Nervous System Stimulants • Acetaminophen • Aspirin • Caffeine
備考２	PM: 10321417
作成者	荒木治子／竹島多賀夫

6) Di Monda V, Nicolodi M, Aloisio A, Del Bianco P, Fonzari M, Grazioli 　 I, Uslenghi C, Vecchiet L, Sicuteri F. Efficacy of a fixed combination 　 of indomethacin, prochlorperazine, and caffeine versus sumatriptan 　 in acute treatment of multiple migraine attacks: a multicenter, 　 randomized, crossover trial. Headache. 2003 Sep;43(8):835-44
論文抄録	OBJECTIVE : To compare the efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine suppositories with sumatriptan suppositories in the treatment of 2 consecutive migraine attacks of moderate or severe intensity in a multicenter, randomized, crossover study. BACKGROUND : A fixed combination of indomethacin, prochlorperazine, and caffeine is the most commonly used drug for the acute treatment of migraine in Italy . No studies have been published comparing the efficacy of this combination with sumatriptan, the most widely prescribed of the triptans. METHODS : One hundred twelve patients with migraine with or without aura according to the diagnostic criteria of the International Headache Society were randomized to treat 2 migraine attacks with a fixed combination of indomethacin, prochlorperazine, and caffeine and 2 migraine attacks with sumatriptan. Both drugs were rectally administered in a single dose for each attack. Patients were asked to take study medication as soon as possible at the onset of a headache. RESULTS : Of the 112 patients, 88 were compliant to the protocol. More attacks became pain-free at 2 hours postdose (primary end point) on the combination than on sumatriptan (49% versus 34%; P<.01), while there was no difference in the relief of headache at 2 hours postdose (71% versus 65%). The combination was statistically superior to sumatriptan in the time to a pain-free response (a higher percentage of attacks became pain-free from 0.5 hours postdose to 5 hours postdose), in alleviation of nausea, and in a sustained pain-free response (pain-free at 2 hours postdose with no use of rescue medication or relapses within 48 hours). Moreover, a significant consistent response was achieved for the combination compared with sumatriptan across (higher percentage of patients pain-free at 2 hours postdose in the first, second, third, and fourth treated attack) and within patients (pain-free in 2 of 2 treated attacks in 35% of patients taking the combination and 20% of patients on sumatriptan). Both drugs were well-tolerated. CONCLUSIONS : This study, analyzed according to the more recent guidelines for controlled trials in migraine, showed that a fixed combination of indomethacin, prochlorperazine, and caffeine is significantly more effective than sumatriptan in the acute treatment of migraine attacks. It is notable that the combination is less expensive than sumatriptan per unit dose.
文献 PubMed−ID	PMID: 12940804
エビデンスレベル	㈵ b
文献タイトル (日本語)	インドメタシン，プロルクロマジン，カフェインの併用療法と，スマトリプタンの片頭痛急性期治療における効果の比較．
目的	中等度以上の片頭痛発作に対するインドメタシン，プロルクロマジン，カフェインの併用療法と，スマトリプタンの効果を比較評価する．
研究デザイン	Multicenter, randomized, crossover study
研究施設	Neurology Division I, Spedali Civili di Brescia , Italy
対象患者	112名の片頭痛患者
介入	2回の片頭痛発作にインドメタシン 25mg，プロルクロマジン4mg，カフェイン75mgの併用療法を行い，他の2回の片頭痛発作にスマトリプタン25mgを使用し，効果を評価．
主要評価項目とそれに用いた統計学的手法	Primary　end　point：治療2時間後の頭痛消失
結果	112名の患者のうち，88名が研究を遂行できた． 2時間後の頭痛消失はスマトリプタン34%に比して併用療法では49%と有意に多かった（P<.01）．しかし，頭痛軽減の観点では両者に差は認めなかった（併用療法71%，スマトリプタン65%）.
結論	インドメタシン，プロルクロマジン，カフェインの併用療法は片頭痛急性期治療において，スマトリプタンよりも有効であることが示された．また，これらの併用はスマトリプタンよりも安価であることが利点でもあるといえる．
備考１	Publication Types: • Clinical Trial • Multicenter Study • Randomized Controlled Trial MeSH Terms: • Acute Disease • Adult • Anti-Inflammatory Agents, Non-Steroidal/therapeutic use • Antiemetics/therapeutic use • Caffeine/therapeutic use* • Central Nervous System Stimulants/therapeutic use • Comparative Study • Cross-Over Studies • Drug Combinations • Female • Human • Indomethacin/therapeutic use* • Male • Migraine/drug therapy* • Prochlorperazine/therapeutic use* • Recurrence • Research Design • Serotonin Agonists/therapeutic use • Sumatriptan/therapeutic use* • Suppositories • Treatment Outcome Substances: • Anti-Inflammatory Agents, Non-Steroidal • Antiemetics • Central Nervous System Stimulants • Drug Combinations • Serotonin Agonists • Suppositories • Sumatriptan • Indomethacin • Caffeine • Prochlorperazine
備考２	PM: 12940804
作成者	荒木治子／竹島多賀夫

7) Peroutka SJ, Lyon JA, Swarbrick J, Lipton RB, Kolodner K, Goldstein 　 J. Efficacy of diclofenac sodium softgel 100 mg with or without 　 caffeine 100 mg in migraine without aura: a randomized, double- 　 blind, crossover study. Headache. 2004 Feb;44(2):136-41
論文抄録	OBJECTIVE : A phase II, randomized, double-blind, crossover study was designed to evaluate the efficacy of 100-mg diclofenac sodium softgel (formulated using ProSorb technology) with or without 100-mg caffeine versus placebo in migraineurs during migraine attacks. BACKGROUND : Diclofenac has been demonstrated to be an effective migraine treatment in several placebo-controlled studies. A rapidly absorbed softgel of diclofenac has been shown to be effective in the rapid relief of acute pain, and may have advantages in migraine treatment. In addition, caffeine has consistently been shown to increase both the efficacy and speed of onset of concurrently administered analgesics. The ability of caffeine to both enhance and accelerate analgesic effects has been documented with a variety of different medications (ie, aspirin, acetaminophen, ibuprofen, and ergotamine). METHODS : The 3-period crossover study was designed to compare diclofenac softgel 100 mg, diclofenac softgel 100 mg plus caffeine 100 mg, and placebo in the acute treatment of migraine. Subjects treated one moderate or severe attack with each study medication. The primary efficacy parameter was the percentage of subjects with headache relief at 60 minutes as defined by a reduction of headache severity from moderate or severe at baseline to absent or mild compared with placebo. Though the sample size estimate required that 72 subjects treat 3 separate attacks, 51 subjects treated 1 migraine attack, 44 treated 2 attacks, and 39 treated 3 attacks. Results.： In the placebo group, 6 (14%) of 43 subjects reported headache relief at 60 minutes versus 12 (27%) of 45 subjects in the diclofenac softgel group, and 19 (41%) of 46 subjects in the diclofenac softgel plus caffeine group. Differences were statistically significant for the diclofenac softgel plus caffeine group versus placebo (odds ratio, 4.2; 95% confidence interval, 1.3 to 13.7). Rescue medication was used by 27 (63%) of 43 subjects treated with placebo, 15 (33%) of 45 subjects treated with diclofenac softgel, and 14 (30%) of 46 subjects treated with diclofenac softgel plus caffeine. This result is highly statistically significant (chi22= 11.56, P=.003). Both the diclofenac plus caffeine (P <.03) and diclofenac only (P <.03) groups were significantly different from the placebo group in terms of the visual analog scale score at 60 minutes. CONCLUSIONS : The major finding of the present study is that diclofenac softgel plus caffeine produces statistically significant benefits relative to placebo at 60 minutes. Diclofenac softgel alone did not differ significantly from placebo, perhaps due to limits in sample size. Nonsignificant trends support the analgesic adjuvant benefit of caffeine when added to diclofenac softgels
文献 PubMed−ID	PMID: 14756851
エビデンスレベル	㈵ b
文献タイトル (日本語)	前兆のない片頭痛におけるジクロフェナクナトリウムソフトゲル 100mgとカフェイン100mgの併用とジクロフェナクナトリウムソフトゲル100mg単剤使用の効果の比較
目的	ジクロフェナクナトリウムソフトゲル 100mg単剤とカフェイン100mg併用での片頭痛治療における効果をプラセボと比較する.
研究デザイン	Randomized, double-blind, crossover study
研究施設	Burlingame , Calif. 94010 , USA
対象患者	前兆のない片頭痛と診断された 18〜60歳の患者
主要評価項目とそれに用いた統計学的手法	治療 1時間後の頭痛改善度（中等度以上の頭痛が軽度になるか消失するか）
結果	プラセボ群では 60分後の頭痛改善率が14%であったのに対し，ジクロフェナクソフトゲル群では27%，ジクロフェナク＋カフェイン群では41%と有意に高値であった（ジクロフェナク＋カフェイン群ｖｓプラセボ群でオッズ比4.2，95%ＣＩ　1.3〜13.7）．また，プラセボ群では63%が，ジクロフェナクソフトゲル群では33%，ジクロフェナク＋カフェイン群では30%がrescue medicationを必要とし，これも統計的な有意差を認めた. ジクロフェナク単独使用群（ P<．03）はプラセボ群よりも優位に有効性が高いことが示された.
結論	急性期治療開始 60分後の段階では，ジクロフェナク＋カフェインの併用療法がプラセボに比して有意に有効であった．一方で，ジクロフェナク単独使用による治療ではプラセボと有意な差は得られなかった．今後，対象例数を増やしての検討が必要である．
コメント	中規模な RCT．
備考１	Publication Types: • Clinical Trial • Randomized Controlled Trial MeSH Terms: • Adolescent • Adult • Analgesics/administration & dosage • Anti-Inflammatory Agents, Non-Steroidal/administration & dosage* • Caffeine/administration & dosage* • Common Migraine/drug therapy* • Comparative Study • Cross-Over Studies • Diclofenac/administration & dosage* • Double-Blind Method • Drug Combinations • Female • Gels • Human • Male • Middle Aged Substances: • Analgesics • Anti-Inflammatory Agents, Non-Steroidal • Drug Combinations • Gels • Diclofenac • Caffeine
備考２	PM: 14756851
作成者	荒木治子／竹島多賀夫