1) Bender WI. ACE inhibitors for prophylaxis of migraine headaches.
　 Headache 1995; 35(8):470-471.

片頭痛患者 17 例 I
nternational Headache Society 基準で診断
月 2 回以上片頭痛発作がある，中等症〜重症の片頭痛患者
年齢： 18-59 歳．

ACE 阻害剤投与（大部分は enalapril, 　一部 lisinopril ）
平均投与量 16.4 mg (range 10 to 25 mg).
治療期間 3ヶ月—3年

著効 10 例，中等度改善 6 例，軽度改善 1 例
主要な副作用は咳，（ 3 例でこのため中止， 1 例は薬剤継続）
他は特に副作用なし

OBJECTIVE: To determine the efficacy of an angiotensin converting enzyme inhibitor in the prophylaxis of migraine. DESIGN: Double blind, placebo controlled, crossover study. SETTING: Neurological outpatient clinic. PARTICIPANTS: Sixty patients aged 19-59 years with migraine with two to six episodes a month. INTERVENTIONS: Treatment period of 12 weeks with one 10 mg lisinopril tablet once daily for one week then two 10 mg lisinopril tablets once daily for 11 weeks, followed by a two week wash out period. Second treatment period of one placebo tablet once daily for one week and then two placebo tablets for 11 weeks. Thirty participants followed this schedule, and 30 received placebo followed by lisinopril. MAIN OUTCOME MEASURES: Primary end points: number of hours with headache, number of days with headache, number of days with migraine. Secondary end points: headache severity index, use of drugs for symptomatic relief, quality of life and number of days taken as sick leave, acceptability of treatment. RESULTS: In the 47 participants with complete data, hours with headache, days with headache, days with migraine, and headache severity index were significantly reduced by 20% (95% confidence interval 5% to 36%), 17% (5% to 30%), 21% (9% to 34%), and 20% (3% to 37%), respectively, with lisinopril compared with placebo. Days with migraine were reduced by at least 50% in 14 participants for active treatment versus placebo and 17 patients for active treatment versus run-in period. Days with migraine were fewer by at least 50% in 14 participants for active treatment versus placebo. Intention to treat analysis of data from 55 patients supported the differences in favour of lisinopril for the primary end points. CONCLUSION: The angiotensin converting enzyme inhibitor, lisinopril, has a clinically important prophylactic effect in migraine

Ib

PM:11141144

アンギオテンシン変換酵素阻害剤（リシノプリル）による片頭痛の予防的治療：無作為プラシーボ対照交叉試験

片頭痛の予防でアンギオテンシン変換酵素阻害剤の有効性を測定すること．

二重盲検，プラシーボ対照，交叉検査

ノルウェー科学技術大学，神経内科外来（ Norway）

1998.4−1999.12

60例の片頭痛患者，19-59才
1ヵ月につき2〜6回の発作．

1週間１日１回10mgリシノプリル・タブレット1錠，
その後 11週間，１日１回10mgリシノプリル・タブレット２錠，による12週の治療期間
2週ウオッシュアウト期間
1週間１日１回プラシーボ・タブレット1錠，
その後 11週間，１日１回プラシーボ・タブレット２錠，による12週の治療期間
30人の参加者はこのスケジュール．他の30例はプラセボの12週後にリシノプリルを投与

プライマリーエンドポイント：頭痛時間数，頭痛日数，片頭痛日数．
副次エンドポイント：頭痛重症度インデックス，急性期治療薬の使用， QOLと病気休暇日数，治療の許容性

試験を完了した 47人の参加者において，それぞれ，頭痛時間，頭痛日数，片頭痛日数と頭痛重症度インデックスはプラシーボと比較してリシノプリルで20%（95%信頼区間：５−36%），17%（５−30%），21%（９−34%）と20%（3-37%）と有意に減少した．
14人の参加者で片頭痛日数が，実薬はプラシーボと比較比して少なくとも50%減少した．また，ランイン期間との比較では17人の患者で50%以上減少していた．
55例のITT解析でも，プライマリーエンドポイントを指標としてリシノプリルが臨床的に意義があることを支持した．
（１２ W：頭痛日数ITT＝16；CI，5-27，片頭痛日数２２；CI，11-33)

アンギオテンシン変換酵素阻害剤（リシノプリル）は，臨床的に有意な片頭痛予防効果がある

よくデザインされた良質な RCT，

BMJ322019.pdf

竹島多賀夫

Treatment with ACE inhibitors has shown to be effective in the prophylaxis of migraine attacks. The aim of this study was to explore whether among hospitalized hypertensive patients use of ACE inhibitors may reduce the risk of headache caused by nitrates. To this end, we used the GIFA database, that includes patients admitted to academic medical centres throughout Italy . We studied 1537 patients (mean age 75 +/- 10 years) receiving treatment with nitrates during a hospital stay and diagnosed with hypertension. Headaches that had a probable or definite causal relation with nitrates use based on the Naranjo algorithm were considered for this analysis. Of the total enrolled sample, 762 patients (50%) used ACE inhibitors during hospital stay. Headache caused by nitrates was recorded in 12/762 (1.6%) ACE inhibitor users and in 24/775 (3.2%) other participants (P = 0.049). After adjusting for potential confounders, ACE inhibitors use was associated with a significantly lower risk of headache (OR 0.43; 95% Confidence Intervals: 0.20-0.90). This result was confirmed if ACE inhibitors use was compared with use of other antihypertensive agents (OR 0.44; 95% CI 0.20-0.95). In conclusion, this study suggests that among hypertensive subjects use of ACE inhibitors is associated with a reduced risk of headache caused by nitrates

PM:14616932

III

高血圧患者における ACE阻害薬使用と硝酸塩による頭痛の関連：
イタリアのグループによる高齢者の薬剤疫学研究結果（ GIFA）．

入院治療中の高血圧患者において， ACE阻害薬の使用が硝酸塩に起因する頭痛の危険度を減らす可能性があるかどうかを検討する．

このために，我々はイタリア中でアカデミックな医療センターに入院する患者を含む GIFAデータベースを使用した．
入院中に硝酸塩治療を受け，高血圧症と診断されている 1537人の患者（平均年齢75 +/-10年）を検討．
Naranjoアルゴリズムを用いて，硝酸塩使用と頭痛の因果関係を検討した． 登録者のうち 762人（50%がACE阻害薬を使用していた．

イタリア， GIFAデータベース登録施設，

The study periods:
May 1 to June 30 and September 1 to December 31, 1988 ;
May 15 to June 15, 1991 ;
May 1 to June 30 and September 1 to October 31 in 1993, 1995, 1997.

入院中に硝酸塩治療を受け，高血圧症と診断されている 1537人の患者（平均年齢75 +/-10年）．
（ Iinitial sample：28 411；高血圧の診断＋経口，舌下，経皮硝酸塩の処方：n=1555，明らかに硝酸塩誘発性頭痛を有するものなどを除外）  

なし

OR

硝酸塩に起因する頭痛は， ACE阻害薬使用者では12/762（1.6%），他の対象者では24/775（3.2%）であった（P = 0.049）．
他の潜在的な背景因子を調整すると ACE阻害薬使用は，頭痛リスクを低下OR 0.43;95% CI：0.20-0.90)させた．
ACE阻害薬使用群と他の降圧剤使用群で比較した場合にも同様の結果が得られた．（OR： 0.44;95% CI 0.20-0.95).

高血圧患者において， ACE阻害薬の使用が硝酸塩に起因する頭痛のリスク減少と関係している．

片頭痛に対する効果を直接みているわけではないが，硝酸製剤で片頭痛様頭痛が誘発されることを考慮すれば重要な文献として記載すべき．

Cephalalgia23901.pdf

竹島多賀夫

INTRODUCTION: Since a few case reports have demonstrated some beneficial effects of angiotensin converting enzyme (ACE) inhibitors in migraine prevention, we were interested in studying the impact of ACE inhibitors and angiotensin II receptor antagonists (Ang II) on the consumption of specific abortive migraine drugs and, therefore, indirectly on the frequency of migraine attacks. METHODS: Data from a large prescription database involving 95 patients initiating a specific abortive migraine drug (ergotamine or a triptan) and subsequently treated with either an ACE inhibitor or angiotensin receptor antagonist (index group: ACE/Ang II) or diuretic (reference group) were analysed. The effects of ACE/Ang II inhibition as well as diuretic therapy on reducing the frequency of migraine attacks were assessed by measuring the mean consumption of abortive migraine drug use, in DDDs per month ('therapeutic intensity'), before, during and after ACE/Ang II or diuretic therapy. A 'therapeutic fluctuation intensity estimate' of abortive migraine drug use for all patients was likewise calculated. RESULTS: On an individual level, the therapeutic intensity (TI) fluctuation estimate, 'during' relative to 'before' ACE diuretic therapy, was significantly larger for the ACE/Ang II group (62% reduction) than for the diuretic group (24% reduction) (p = 0.02). For patients who continued abortive migraine drug use during and after ACE/Ang II or diuretic therapy, a significantly larger reduction in this estimate was observed during ACE/Ang II inhibition (68.9%) compared to during diuretic therapy (10.5% increase) (p = 0.004). The TI fluctuation estimate, after relative to 'during', had increased by 50.3% after ACE/Ang II inhibition and had reduced by 22.2% after diuretic treatment (p = 0.1). CONCLUSIONS: A clear reduction in the TI of abortive migraine drug use during the use of ACE inhibitors as compared to diuretic treatment was observed. Our findings may indirectly support a positive effect of ACE/Ang II inhibition on the frequency and severity of migraine attacks, as observed in other studies and reports

PM:14971122

III

ACE阻害薬療法による頓用片頭痛治療薬の使用の減少— 予備的研究

ACE阻害薬とアンギオテンシンII受容器拮抗薬（Ang II）が
特異的片頭痛急性期治療薬の使用に及ぼす影響を調査する．また，間接的には片頭痛発作の頻度に対する影響を調査する．

処方データベースを検索

95人の片頭痛患者：
特異的な頓挫性の片頭痛薬（エルゴタミンまたは triptan）を始めていて，その後に，ACE阻害薬かアンギオテンシン受容体拮抗剤を処方された患者（インデックス・グループ：ACE/Ang II）
あるいは利尿剤（基準群）を処方された患者．

ACE/Ang II群と利尿剤群の間で，毎月の急性期片頭痛治療薬の使用量と片頭痛発作の頻度を比較した．
全患者の急性期片頭痛治療薬による『治療変動強度推定値』を算出．

各個人の治療の強度（ TI）変動推定値は，「治療前」と「治療後」の比較では，ACE/Ang II群は62%の減少，利尿剤群では24%の減少で，ACE/Ang II群の減少が有意に大きかった（p = 0.02）．
ACE/Ang IIまたは利尿剤による治療中及び治療後も，急性期片頭痛治療薬使用を続けた患者（継続的に頓用薬を使用している患者）を解析すると，このTI推定値はACE/Ang II治療群は68.9%の減少，利尿剤治療群は10.5%の増加（p = 0.004）．
ACE/Ang II群の治療中止後はTIが50.3%増加し，利尿剤治療群は22.2%減少した（p = 0.1）．

ACE阻害薬/ Ang IIの投与により，利尿剤を投与した場合と比較して急性期片頭痛治療薬の使用強度が有意に減少した．
また，間接的には ACE阻害薬/ Ang IIの投与により片頭痛の発作頻度と重症度を軽減する可能性を支持する．  

急性期治療薬の消費量を検討：実際的な研究である．

竹島多賀夫

PM:12558774

III

前兆のある片頭痛のエナラプリルによる予防

1例報告

Department of Neurology and Rehabilitation
Institute of Neuropsychiatry，University of Palermo
（ Italy）

68歳，女性，1998年に20年来の頭痛で受診
年に 6回頭痛発作，前兆のある片頭痛

高血圧のために enalapril 10 mgを内服（片頭痛治療を意図していない）

高血圧のために enalapril 10 mgを内服開始後頭痛発作が消失．
1年後のfollowでも完全に片頭痛発作が抑制されていた．  

前兆のある片頭痛の治療は ,未解決の問題も多い．片頭痛予防両方におけるACE阻害薬の有用性は，その有利な副作用プロフィールも考慮してさらに調査されなければならない．

Headache43170.pdf

竹島多賀夫

CONTEXT: There is a paucity of effective, well-tolerated drugs available for migraine prophylaxis.
OBJECTIVE: To determine whether treatment with the angiotensin II receptor blocker candesartan is effective as a migraine-prophylactic drug.
DESIGN AND SETTING: Randomized, double-blind, placebo-controlled crossover study performed in a Norwegian neurological outpatient clinic from January 2001 to February 2002. PATIENTS: Sixty patients aged 18 to 65 years with 2 to 6 migraine attacks per month were recruited mainly from newspaper advertisements.
INTERVENTIONS: A placebo run-in period of 4 weeks was followed by two 12-week treatment periods separated by 4 weeks of placebo washout. Thirty patients were randomly assigned to receive one 16-mg candesartan cilexetil tablet daily in the first treatment period followed by 1 placebo tablet daily in the second period. The remaining 30 received placebo followed by candesartan.
MAIN OUTCOME MEASURES: The primary end point was number of days with headache; secondary end points included hours with headache, days with migraine, hours with migraine, headache severity index, level of disability, doses of triptans, doses of analgesics, acceptability of treatment, days of sick leave, and quality-of-life variables on the Short Form 36 questionnaire.
RESULTS: In a period of 12 weeks, the mean number of days with headache was 18.5 with placebo vs 13.6 with candesartan (P =.001) in the intention-to-treat analysis (n = 57). Some secondary end points also favored candesartan, including hours with headache (139 vs 95; P<.001), days with migraine (12.6 vs 9.0; P<.001), hours with migraine (92.2 vs 59.4; P<.001), headache severity index (293 vs 191; P<.001), level of disability (20.6 vs 14.1; P<.001) and days of sick leave (3.9 vs 1.4; P =.01), although there were no significant differences in health-related quality of life. The number of candesartan responders (reduction of > or =50% compared with placebo) was 18 (31.6%) of 57 for days with headache and 23 (40.4%) of 57 for days with migraine. Adverse events were similar in the 2 periods.
CONCLUSION: In this study, the angiotensin II receptor blocker candesartan provided effective migraine prophylaxis, with a tolerability profile comparable with that of placebo.  

PMID: 12503978

Ib

アンギオテンシンＩＩ受容体遮断薬による片頭痛の予防的治療：ランダム化比較試験

アンギオテンシンＩＩ受容体遮断薬カンデサルタンが片頭痛 - 予防薬として効果的かどうか決定すること．

無作為二重盲検プラセボ対照交差試験（ Randomized, double-blind, placebo-controlled crossover study ）

ノルウェーの神経内科外来診療所（ a Norwegian neurological outpatient clinic ）

2001 年 1 月から 2002 年 2 月（ January 2001 to February 2002. ）

月に 2 〜 6 回の発作をおこしている 18 歳〜 65 歳の片頭痛患者 60 人．主として新聞広告により募集した

プライマリーエンドポイントは頭痛日数． 2 次エンドポイントは頭痛時間，片頭痛日数，片頭痛時間，頭痛重症度インデックス，生活支障度， triptan の服用量，鎮痛薬の服用量，治療の許容性，病気休暇日数， SF-36 による QOL 指標が含まれていた．

比較的うまくデザインされた中規模の RCT．
研究およびレポートの質は高い．
いつくかの追試と，他の予防薬との比較試験が必要．

Publication Types:
* Clinical Trial
* Randomized Controlled Trial

MeSH Terms:
* Adult
* Angiotensin II/antagonists & inhibitors*
* Benzimidazoles/therapeutic use*
* Cross-Over Studies
* Double-Blind Method
* Human
* Middle Aged
* Migraine/prevention & control*
* Receptors, Angiotensin/antagonists & inhibitors*
* Severity of Illness Index
* Support, Non-U.S. Gov't
* Tetrazoles/therapeutic use*
* Treatment Outcome
 
Substances:
* Benzimidazoles
* Receptors, Angiotensin
* Tetrazoles
* Angiotensin II
* candesartan

RefMan−TT文献＃43342
全文；　 JAMA289065.pdf  

竹島多賀夫

Triptans are usually administered for migraine, but cannot be given to patients with malfunctioning cardiac or cerebral vascular systems, which commonly accompany hypertension. This article focuses on 8 cases in which treatment with candesartan was successful in reducing both the incidence and severity of headache in hypertensive patients with migraine. The cases reported in this article showed a mean improvement in Migraine Disability Assessment score from 29.4 to 9 points and in blood pressure from 154.9/90.4 to 129.5/81.9mmHg, suggesting that candesartan is an extremely attractive option for the treatment of migraine. Although recent studies have reported the efficacy of candesartan for treating migraine, there has been no description of its potential advantages over other prophylactic drugs. The present study included patients who could not tolerate triptans for whom triptans were contraindicated, several patients for whom other migraine prophylactic drugs showed little or no effect, and one patient for whom candesartan was prescribed initially for hypertension, but was also found to be therapeutic for migraines. Thus candesartan is considered to be a unique, attractive choice of prophylactic agent for migraine complicated by hypertension

PM:15253110

V

高血圧患者の片頭痛治療のカンデサルタンの有効性

症例報告 8例

青山病院，東京医科歯科大

8例の片頭痛患者；triptansが禁忌，他の片頭痛予防薬が無効．
高血圧にカンデサルタンが処方されたケース  

N/A

MIDAS

前例で MIDASスコアが改善した．

カンデサルタンは高血圧症を伴う片頭痛の予防の選択になりうる

良質な症例報告，ケース選択基準は不明確．

竹島多賀夫