論文抄録

The effects of oral Magnesium (Mg) pyrrolidone carboxylic acid were evaluated in 20 patients affected by menstrual migraine, in a double-blind, placebo controlled study. After a two cycles run-in period, the treatment (360 mg/day of Mg or placebo) started on the 15th day of the cycle and continued till the next menses, for two months. Oral Mg was then supplemented in an open design for the next two months. At the 2nd month, the Pain Total Index was decreased by both Placebo and Mg, with patients receiving active drug showing the lowest values (P less than 0.03). The number of days with headache was reduced only in the patients on active drug. Mg treatment also improved premenstrual complaints, as demonstrated by the significant reduction of Menstrual Distress Questionnaire (MDQ) scores. The reduction of PTI and MDQ scores was observed also at the 4th month of treatment, when Mg was supplemented in all the patients. Intracellular Mg++ levels in patients with menstrual migraine were reduced compared to controls. During oral Mg treatment, the Mg++ content of Lymphocytes (LC) and Polymorphonucleated cells (PMN) significantly increased, while no changes in plasma or Red Blood Cells were found. An inverse correlation between PTI and Mg++ content in PMN was demonstrated. These data point to magnesium supplementation as a further means for menstrual migraine prophylaxis, and support the possibility that a lower migraine threshold could be related to magnesium deficiency

文献 PubMed−ID

PMID: 1860787

エビデンスレベル

㈵ b

文献タイトル (日本語)

月経時片頭痛のマグネシウム予防：細胞内マグネシウムへの効果

目的

Mg が月経時片頭痛予防薬として有効かどうか決定すること．

研究デザイン

無作為二重盲検プラセボ対照試験（ randomized double-blind, placebo controlled study ）

対象患者

28 歳〜 36 歳（平均年齢 30.3 歳）の月経時片頭痛患者 24 人とコントロール 15 人（平均年齢 27.8 歳）

介入

導入期（ run-in period ）　 2m
Mg 360mg/ 日またはプラセボを 2m 内服

主要評価項目とそれに用いた統計学的手法

頭痛日記で発作持続時間 ,発作の重症度を記録
月経前徴候（ premenstrual syndrome）をMenstrual Distress Questionnaire(MDQ)を用いて記録
治療前 ,2ヵ月後,4ヵ月後に採血し Mg 血中濃度を測定
student's t-testを用いて検討

結果

頭痛日数は Mg 内服群のみで減少．
2 例が副作用で脱落（下痢 , 頭痛）

結論

Mg は月経時片頭痛予防薬の選択肢のひとつとして有効と考えられた．片頭痛域値低下が Mg 欠乏と関係している可能性がある．

備考

Publication Types:
・Clinical Trial
・Controlled Clinical Trial

MeSH Terms:

作成者

井尻珠美

論文抄録

In order to evaluate the prophylactic effect of oral magnesium, 81 patients aged 18-65 years with migraine according to the International Headache Society (IHS) criteria (mean attack frequency 3.6 per month) were examined. After a prospective baseline period of 4 weeks they received oral 600 mg (24 mmol) magnesium (trimagnesium dicitrate) daily for 12 weeks or placebo. In weeks 9-12 the attack frequency was reduced by 41.6% in the magnesium group and by 15.8% in the placebo group compared to the baseline (p < 0.05). The number of days with migraine and the drug consumption for symptomatic treatment per patient also decreased significantly in the magnesium group. Duration and intensity of the attacks and the drug consumption per attack also tended to decrease compared to placebo but failed to be significant. Adverse events were diarrhea (18.6%) and gastric irritation (4.7%). High-dose oral magnesium appears to be effective in migraine prophylaxis
 

文献 PubMed−ID

PMID: 8792038

エビデンスレベル

Ib

文献タイトル (日本語)

マグネシウム経口投与による片頭痛予防：多施設前向き無作為二重盲検プラセボ対照試験の結果

目的

Mg 経口投与が片頭痛予防薬として効果的かどうか決定すること．

研究デザイン

多施設前向き 無作為二重盲検プラセボ対照試験（ prospective, multicenter, placebo-controlled and doubleblind randomized study ）

対象患者

国際頭痛学会の診断基準を満たす 18-65歳（平均発作回数3.6回/月） の片頭痛患者 60 人．

介入

導入期；　 4 ｗの後
Mg 600mg(24 mmol)あるいはプラセボ経口投与　 試験期間 12w

主要評価項目とそれに用いた統計学的手法

頭痛頻度，頭痛日数，持続時間，程度，頓挫薬消費量など

結果

9-12週において発作回数は導入期と比較しMg群で41.6%，プラセボ群で15.8%減少した．Mgはプラセボと比較して有意に発作回数を減少させた(p<0.05)．また頓挫薬消費量もMg群でプラセボに比較し減少した．
副作用として下痢が 18.6%にみられた．

結論

Mg 600mg 内服は片頭痛予防として有効と考えられた．

コメント

副作用としての下痢が高頻度に出現．

備考

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

MeSH Terms:
・Adolescent
・Adult
・Aged
・Double-Blind Method
・Female
・Human
・Magnesium/therapeutic use*
・Male
・Middle Aged
・Migraine/drug therapy*
・Prognosis

Substances:
・Magnesium

作成者

井尻珠美，竹島多賀夫

文献 PubMed−ID

PMID: 12786918

エビデンスレベル

Ib

文献タイトル (日本語)

小児の頻回片頭痛における酸化マグネシウム経口投与による予防療法： 無作為二重盲検プラセボ対照試験

目的

酸化マグネシウム経口投与 が小児の片頭痛予防薬として効果的かどうか決定すること．

研究デザイン

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

研究期間

1997 年 6 月から 2000 年 1 月（ June 1997 and January 2000 ）

対象患者

最近の 4 週間に少なくとも 1 度頭痛発作のあった中等度〜重症の小児（ 3 歳〜 17 歳）片頭痛患者 118 人

介入

16 週間　 酸化マグネシウム 9 mg/kg / 日もしくはプラセボを内服

主要評価項目とそれに用いた統計学的手法

Primary outcome; 頭痛日数・程度
Secondary mesures;随伴症状・頭痛の程度

結果

ITT 解析において 酸化マグネシウム群は有意に頭痛頻度を減少させた (P=.0037) が，プラセボ群とは差がなかった (P=.88) ．頭痛の程度は酸化マグネシウム群は治療前と差がなかったが，プラセボより有意に低下していた (P=.0029) ．

結論

今回の結果からは小児片頭痛患者において 酸化マグネシウム内服がプラセボより片頭痛予防効果があるとは明確にいえないが，頭痛日数を減少させる可能性があると考えられた ．

コメント

比較的うまくデザインされた中規模の RCT．
さらに対象を増やして追試が必要．

備考

Publication Types:
・Clinical Trial
・Randomized Controlled Trial

MeSH Terms:
・Administration, Oral
・Adolescent
・Child
・Child, Preschool
・Comparative Study
・Double-Blind Method
・Female
・Human
・Magnesium Oxide/administration & dosage
・Magnesium Oxide/therapeutic use*
・Male
・Migraine/prevention & control*
・Recurrence
・Support, Non-U.S. Gov't
・Treatment Outcome

Substances:
・Magnesium Oxide

作成者

井尻珠美，竹島多賀夫

論文抄録

OBJECTIVE: To assess whether, in children, oral magnesium oxide reduces migrainous headache frequency, severity, and associated features compared to placebo. BACKGROUND: There is no single, safe, widely well-tolerated, and effective prophylactic treatment for all children and adolescents with frequent migrainous headache. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group trial. METHODS: This study was conducted between June 1997 and January 2000 using 7 selected Northern California Kaiser Permanente sites. We recruited children of ages 3 to 17 years who reported a 4-week history of at least weekly, moderate-to-severe headache with a throbbing or pulsatile quality, associated anorexia/nausea, vomiting, photophobia, sonophobia, or relief with sleep, but no fever or evidence of infection. Subjects were randomly assigned to receive either magnesium oxide (9 mg/kg per day by mouth divided 3 times a day with food) (n = 58) or matching placebo (n = 60) for 16 weeks. The number of headache days (days with at least one headache) during each of eight 2-week intervals was chosen to be the primary outcome variable. RESULTS: Of those enrolled, 86 (73%) completed the study (42 received magnesium oxide and 44 placebo); 74 of 192 eligible subjects declined to participate. Baseline information on demographic factors, health status, and headache history was similar comparing the 2 groups. By intention-to-treat analysis, we found a statistically significant decrease over time in headache frequency in the magnesium oxide group (P =.0037) but not in the placebo group (P =.086), although the slopes of these 2 lines were not statistically significantly different from each other (P =.88). The group treated with magnesium oxide had significantly lower headache severity (P =.0029) relative to the placebo group. CONCLUSIONS: This study does not unequivocally determine whether oral magnesium oxide is or is not superior to placebo in preventing frequent migrainous headache in children, but treatment with the active agent did lead to a significant reduction in headache days. Larger trials involving this safe, appealing complementary therapy are needed  

論文抄録

The migraine prophylactic effect of 10 mmol magnesium twice-daily has been evaluated in a multicentre, prospective, randomized, double-blind, placebo-controlled study. Patients with two to six migraine attacks per month without aura, and history of migraine of at least 2 years, were included. A 4-week baseline period without medication was followed by 12 weeks of treatment with magnesium or placebo. The primary efficacy end-point was a reduction of at least 50% in intensity or duration of migraine attacks in hours at the end of the 12 weeks of treatment compared to baseline. With a calculated total sample size of 150 patients, an interim analysis was planned after completing treatment of at least 60 patients, which in fact was performed with 69 patients (64F, 5M), aged 18-64 years. Of these, 35 had received magnesium and 34 placebo. The number of responders was 10 in each group (28.6% under magnesium and 29.4% under placebo). As determined in the study protocol, this was a major reason to discontinue the trial. With regard to the number of migraine days or migraine attacks there was no benefit with magnesium compared to placebo. There were no centre-specific differences, and the final assessments of treatment efficacy by the doctor and patient were largely equivocal. With respect to tolerability and safety, 45.7% of patients in the magnesium group reported primarily mild adverse events like soft stool and diarrhoea in contrast to 23.5% in the placebo group  

文献 PubMed−ID

PMID: 8902254

エビデンスレベル

Ib

文献タイトル (日本語)

Mg の片頭痛予防療法− 無作為二重盲検プラセボ対照試験

目的

Mg が片頭痛 - 予防薬として効果的かどうか決定すること．

研究デザイン

多施設無作為二重盲検プラセボ対照試験（ Randomized, a multicentre, prospective, double-blind, placebo-controlled study ）

対象患者

試験前の 3 ヶ月間に 2 〜 6 回の頭痛発作が見られた 18 歳〜 60 歳の前兆のない片頭痛患者 115 人．

介入

観察期（導入期 run-in period ）； 4 ｗ
引き続き Mg （ Magnesium-u-aspartate-hydrochloride-trihydrate ）　 20mmol またはプラセボを内服　１２ w

主要評価項目とそれに用いた統計学的手法

頭痛程度・持続時間が 50 ％以上の減少した人の割合を導入期と 12w 後で比較検討

結果

頭痛日数・発作回数は Mg とプラセボの間で差は見られなかった．
有害事象は Mg 群で 45.7 ％，プラセボ群で 23.5 ％であった．重篤なものはなく， Mg 群では軟便・下痢が主であった．

結論

片頭痛予防療法としての Mg 経口投与は無効であった．

備考

Publication Types:
・Clinical Trial
・Clinical Trial, Phase III
・Multicenter Study
・Randomized Controlled Trial

MeSH Terms:
・Adolescent
・Adult
・Aspartic Acid/administration & dosage*
・Aspartic Acid/adverse effects
・Dose-Response Relationship, Drug
・Double-Blind Method
・Drug Administration Schedule
・Female
・Human
・Male
・Middle Aged
・Migraine/drug therapy*
・Prospective Studies
・Treatment Outcome

Substances:
・Aspartic Acid

作成者

井尻珠美，竹島多賀夫

論文抄録

STUDY OBJECTIVE: We test the hypothesis that intravenous magnesium sulfate is an effective adjunctive medication for treatment of acute migraine. METHODS: In this randomized, double-blind, placebo-controlled trial, adults presenting to 2 urban emergency departments with headache meeting International Headache Society criteria for acute migraine received either 20 mg of intravenous metoclopramide plus 2 g of intravenous magnesium sulfate or 20 mg of intravenous metoclopramide plus a placebo of intravenous saline solution at 15-minute intervals for a maximum of 3 doses or until pain relief occurred. At 0, 15, 30, and 45 minutes, patients recorded pain intensity using a standard visual analog scale (VAS). The primary study end point was the between-group difference in pain improvement when initial and final VAS scores were compared. RESULTS: Of 44 patients enrolled (21 randomized to metoclopramide plus magnesium and 23 to metoclopramide plus placebo), 42 (95%) were women. Baseline features were comparable in both groups. Each group experienced a more than 50-mm improvement in VAS score during the study. However, this improvement was smaller in the magnesium group for the primary end point (16-mm difference favoring placebo [95% confidence interval (CI) -2 to 34 mm]), as was the proportion with normal functional status at their final rating (36% absolute difference also favoring placebo [95% CI 7% to 65%]). Using a 50% reduction in pain to dichotomize VAS scores, the number needed to harm with magnesium plus metoclopramide versus metoclopramide alone is 4 patients (95% CI 2 to 36). CONCLUSION: Although this result was unexpected, our data suggest that the addition of magnesium to metoclopramide may attenuate the effectiveness of metoclopramide in relieving migraine. Countertherapeutic cerebral vasodilatation caused by magnesium is a plausible, although unproven, explanation for this finding. Because of the preponderance of women in our trial, these data may not be generalizable to men
 

文献 PubMed−ID

PMID: 11719739

エビデンスレベル

Ib

文献タイトル (日本語)

救急診療における片頭痛の付加的治療としての硫酸マグネシウム静注 無作為臨床試験

目的

硫酸マグネシウム静注 が片頭痛頓挫薬として効果的かどうか決定すること．

研究デザイン

無作為二重盲検プラセボ対照試験（ Randomized, double-blind, placebo-controlled trial ）

対象患者

片頭痛患者 44 人．

介入

20mg metoclopramide+2g magnesium sulfate iv(21 人 ) もしくは
20mg metoclopramide+placebo(saline solution) iv(23 人 )

主要評価項目とそれに用いた統計学的手法

治療前後でＶＡＳを用いて痛みの改善度を比較
95% CI を算出

結果

VAS の結果には両群で有意な差はみられなかった

結論

硫酸 マグネシウムは救急時の片頭痛治療には無効であった．
片頭痛急性期治療時に硫酸マグネシウムをメトクロプロマイドに追加すると，メトクロプロマイドの効果を減弱するかもしれない．

コメント

いつくかの追試が必要．

備考

Publication Types:
・Clinical Trial
・Randomized Controlled Trial

MeSH Terms:
・Adult
・Comparative Study
・Double-Blind Method
・Drug Therapy, Combination
・Emergency Service, Hospital*
・Female
・Hospitals, Teaching
・Hospitals, Urban
・Human
・Infusions, Intravenous
・Magnesium Sulfate/administration & dosage*
・Magnesium Sulfate/adverse effects
・Male
・Metoclopramide/administration & dosage*
・Metoclopramide/adverse effects
・Migraine/drug therapy*
・Pain Measurement

Substances:
・Metoclopramide
・Magnesium Sulfate

作成者

井尻珠美，竹島多賀夫

論文抄録

OBJECTIVE: To study the efficacy and tolerability of 1 g of intravenous magnesium sulfate as acute treatment of moderate or severe migraine attacks. BACKGROUND: Migraine is a common disorder in which not only the pain but also the accompanying symptoms such as nausea and vomiting reduce activity and productivity of sufferers. Many drugs used for the treatment of acute migraine attacks have many side effects, are not well tolerated, are ineffective in some patients, or cannot be used during pregnancy or in patients with ischemic heart disease. Magnesium deficiency has been proposed to play a role in the pathophysiology of migraine, and recently treatment of migraine with magnesium has gained considerable interest. METHODS: This was a randomized, single-blind, placebo-controlled trial including 30 patients with moderate or severe migraine attacks. Fifteen patients received 1 g intravenous magnesium sulfate given over 15 minutes. The next 15 patients received 10 mL of 0.9% saline intravenously. Those in the placebo group with persisting complaints of pain or nausea and vomiting after 30 minutes also received 1 g magnesium sulfate intravenously over 15 minutes. The patients were assessed immediately after treatment, and then 30 minutes and 2 hours later. Intensity of pain, accompanying symptoms, and side effects were noted. RESULTS: All patients in the treatment group responded to treatment with magnesium sulfate. The pain disappeared in 13 patients (86.6%); it was diminished in 2 patients (13.4%); and in all 15 patients (100%), accompanying symptoms disappeared. In the placebo group, a decrease in pain severity but persisting nausea, irritability, and photophobia were noted in 1 patient (6.6%). Accompanying symptoms disappeared in 3 patients (20%) 30 minutes after placebo administration. All patients initially receiving placebo were subsequently given magnesium sulfate. All of these patients responded to magnesium sulfate. In 14 patients (93.3%), the attack ended; in 1 patient (6.6%), pain intensity decreased; and in all 15 patients (100%), accompanying symptoms disappeared. Both the response rate (100% for magnesium sulfate and 7% for placebo) and the pain-free rate (87% for magnesium sulfate and 0% for placebo) showed that magnesium sulfate was superior to placebo. Twenty-six patients (86.6%) had mild side effects which did not necessitate discontinuing treatment during magnesium sulfate administration. CONCLUSION: Our results show that 1 g intravenous magnesium sulfate is an efficient, safe, and well-tolerated drug in the treatment of migraine attacks. It is possible that magnesium sulfate could be used in a broader spectrum of patients than other drugs commonly used for attack treatment. In view of these results, the effect of magnesium sulfate in acute migraine should be examined in large-scale studies

文献 PubMed−ID

PMID: 11251702

エビデンスレベル

Ib

文献タイトル (日本語)

片頭痛急性期発作における硫酸マグネシウム静注療法の効果

目的

硫酸マグネシウム静注 が中等度〜重度片頭痛発作頓挫薬としての有効性・忍容性を調査すること．

研究デザイン

無作為単純盲検プラセボ対照試験（ randomized, single-blind, placebo-controlled trial ）

対象患者

少なくとも 1 年以上の病歴を持つ 20 歳〜 57 歳 ( 平均年齢 35 歳 ) の片頭痛患者 30 人 ．

介入

group 1(15人)：硫酸マグネシウム1g静注
group 2(15人)：プラセボ（生理食塩水10ml）静注 ,その後症状改善がなければ硫酸マグネシウム1gを投与

主要評価項目とそれに用いた統計学的手法

投与直後・投与後 30分,2時間後に頭痛の程度,随伴症状,副作用を評価

結果

硫酸マグネシウム投与群では 15人中13人(86.6%)で頭痛・随伴症状消失を認め,残る二人も症状軽減がみられ,24時間以内の再発もなかった．プラセボ群は3人で随伴症状軽減があったが,頭痛の程度は変わらず,全例硫酸マグネシウムを続いて投与された．これらの患者で14人は頭痛消失,残る一人も症状軽快した．
硫酸マグネシウム投与群はプラセボ群と比較して頭痛・随伴症状改善とも有意に改善がみられた（ p<.0001）．
有害事象は重篤なものはなかった．

結論

片頭痛急性期発作における硫酸マグネシウム 1g 静注療法は 有効かつ安全性であったが，さらなる大規模試験がなされるべきである．

備考

Publication Types:
・Clinical Trial
・Randomized Controlled Trial

MeSH Terms:
・Acute Disease
・Adult
・Analgesics/administration & dosage
・Analgesics/therapeutic use*
・Female
・Human
・Infusions, Intravenous
・Magnesium Sulfate/administration & dosage
・Magnesium Sulfate/therapeutic use*
・Male
・Middle Aged
・Migraine/classification
・Migraine/drug therapy*
・Single-Blind Method

Substances:
・Analgesics
・Magnesium Sulfate

作成者

井尻珠美

論文抄録

A deficit of mitochondrial energy metabolism may play a role in migraine pathogenesis. We found in a previous open study that high-dose riboflavin was effective in migraine prophylaxis. We now compared riboflavin (400 mg) and placebo in 55 patients with migraine in a randomized trial of 3 months duration. Using an intention-to-treat analysis, riboflavin was superior to placebo in reducing attack frequency (p = 0.005) and headache days (p = 0.012). Regarding the latter, the proportion of patients who improved by at least 50%, i.e. "responders," was 15% for placebo and 59% for riboflavin (p = 0.002) and the number-needed-to-treat for effectiveness was 2.3. Three minor adverse events occurred, two in the riboflavin group (diarrhea and polyuria) and one in the placebo group (abdominal cramps). None was serious. Because of its high efficacy, excellent tolerability, and low cost, riboflavin is an interesting option for migraine prophylaxis and a candidate for a comparative trial with an established prophylactic drug
 

文献 PubMed−ID

PMID: 9484373

エビデンスレベル

Ib

文献タイトル (日本語)

片頭痛予防療法における高容量リボフラビンの有効性： 無作為対照試験

目的

片頭痛予防に対するリボフラビンの有効性を検証する．

研究デザイン

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

研究期間

1995 年 3 月から 1996 年 7 月

対象患者

少なくとも 1 年以上の病歴があり，月に 2 〜 8 回の発作をおこしており，鎮痛剤やエルゴタミンの濫用がなく，重篤な器質的・精神的疾患を有さない IHS の診断基準を満たす 18 歳〜 65 歳の片頭痛患者 55 人

介入

観察期（導入期 run-in period ）；　 1 ヶ月
その後 3ヶ月間　28人がリボフラビン400mg内服，26人はプラセボ内服．

主要評価項目とそれに用いた統計学的手法

発作頻度， 頭痛重症度，持続時間，薬剤使用量，消化器症状

結果

ビタミン B2 群の発作頻度 は，導入期に比し ，治療第４ヶ月目 ( 治療３ヶ月目 ) に統計的有意に減少  (p = 0.0001) ．頭痛重症度，持続時間，薬剤使用量，消化器症状にも差がみられた．プラセボとの比較では，ビタミン B2 は発作頻度を有意に減少させ (p=0.005) ，さらに頭痛日数も有意に短縮させた（ p=0.012 ）．
頭痛日数について，有効者（最低 50% 改善した患者）の割合は，リボフラビンで 59% ，偽薬で 15% であった（ p=0.002 ）．
副作用は 3 件であり，重篤なものはみられなかった．

結論

ビタミン B2 は，効果が高く，認容性も良く，低価格であることより片頭痛予防に有望である．

コメント

比較的うまくデザインされた RCT．
研究およびレポートの質は高い．

備考

Publication Types:
・Clinical Trial
・Randomized Controlled Trial

MeSH Terms:
・Adolescent
・Adult
・Comparative Study
・Dose-Response Relationship, Drug
・Female
・Human
・Male
・Middle Aged
・Migraine/physiopathology
・Migraine/prevention & control*
・Placebos
・Riboflavin/therapeutic use*
・Severity of Illness Index
・Time Factors

Substances:
・Placebos
・Riboflavin

作成者

井尻珠美，竹島多賀夫

論文抄録

Seventeen patients who ate fresh leaves of feverfew daily as prophylaxis against migraine participated in a double blind placebo controlled trial of the herb: eight patients received capsules containing freeze dried feverfew powder and nine placebo. Those who received placebo had a significant increase in the frequency and severity of headache, nausea, and vomiting with the emergence of untoward effects during the early months of treatment. The group given capsules of feverfew showed no change in the frequency or severity of symptoms of migraine. This provides evidence that feverfew taken prophylactically prevents attacks of migraine, and confirmatory studies are now indicated, preferably with a formulation controlled for sesquiterpene lactone content, in migraine sufferers who have never treated themselves with this herb  

文献 PubMed−ID

PMID: 3929876

エビデンスレベル

Ib

文献タイトル (日本語)

ナツシロギクの片頭痛予防効果

目的

ナツシロギクが片頭痛予防薬として効果的かどうか決定すること．

研究デザイン

二重盲検プラセボ対照試験（ double-blind, placebo-controlled study ）

研究施設

London Migraine Clinic

対象患者

2 年以上の病歴があり月に 8 回以上の発作をおこしている片頭痛患者 17 人．

介入

8 人は乾燥 feverfew 約 60 ｍｇ， 9 人はプラセボ内服を 4-6m 継続

主要評価項目とそれに用いた統計学的手法

頭痛カードに頭痛の程度・頻度・随伴症状・使用頓挫薬・持続時間などを記録

結果

プラセボ群は内服前に比し著明な頭痛の程度・頻度・嘔気嘔吐の増悪あり． Feverfew 群は 内服前と比べ 頭痛程度・頻度に変化はなく，プラセボ群と比較しても有意に発作頻度・随伴症状を改善した．

結論

Feverfew は片頭痛予防薬として有効と考えられた．

備考

Publication Types:
・Clinical Trial
・Randomized Controlled Trial

MeSH Terms:
・Adult
・Blood Pressure/drug effects
・Body Weight
・Clinical Trials
・Double-Blind Method
・Ergotamine/therapeutic use
・Female
・Human
・Middle Aged
・Migraine/prevention & control*
・Nausea
・Plants, Medicinal*
・Sesquiterpenes/therapeutic use*
・Support, Non-U.S. Gov't
・Tanacetum parthenium
・Vomiting

Substances:
・Sesquiterpenes
・Ergotamine

作成者

井尻珠美

論文抄録

The use of feverfew (Tanacetum parthenium) for migraine prophylaxis was assessed in a randomised, double-blind, placebo-controlled crossover study. After a one-month single-blind placebo run-in, 72 volunteers were randomly allocated to receive either one capsule of dried feverfew leaves a day or matching placebo for four months and then transferred to the other treatment limb for a further four months. Frequency and severity of attacks were determined from diary cards which were issued every two months; efficacy of each treatment was also assessed by visual analogue scores. 60 patients completed the study and full information was available in 59. Treatment with feverfew was associated with a reduction in the mean number and severity of attacks in each two-month period, and in the degree of vomiting; duration of individual attacks was unaltered. Visual analogue scores also indicated a significant improvement with feverfew. There were no serious side-effects
 

文献 PubMed−ID

PMID: 2899663

エビデンスレベル

Ib

文献タイトル (日本語)

片頭痛予防療法におけるナツシロギク 無作為二重盲検プラセボ対照試験

目的

ナツシロギクが片頭痛予防薬として効果的かどうかを決定すること．

研究デザイン

無作為二重盲検プラセボ対照試験（ Randomised double-blind placebo-controlled trial ）

対象患者

24 歳〜 72 歳の片頭痛患者 72 人．

介入

観察期（導入期 run-in period ）；　 placebo 1 ヶ月
feverfew １カプセル（平均 82 ｍｇ）もしくはプラセボを 4 ヶ月間内服．

主要評価項目とそれに用いた統計学的手法

頭痛持続時間，頭痛程度，悪心・嘔吐， VAS

結果

Feverfew 内服群は平均頭痛回数，頭痛程度，嘔吐の減少と関係しており， VAS を有意に改善した．持続時間には差はみられなかった．
重篤な副作用はみられなかった．

結論

Feverfew は片頭痛予防薬として有効と考えられた．

コメント

研究およびレポートの質は高い．

備考

Publication Types:
・Clinical Trial
・Randomized Controlled Trial

MeSH Terms:
・Adult
・Aged
・Clinical Trials
・Double-Blind Method
・Female
・Human
・Male
・Middle Aged
・Migraine/prevention & control*
・Plants, Medicinal
・Random Allocation
・Sesquiterpenes/therapeutic use*
・Tanacetum parthenium

Substances:
・Sesquiterpenes

作成者

井尻珠美，竹島多賀夫

論文抄録

Tanacetum parthenium (feverfew), is a well-known herb for the prophylactic treatment of migraine. The primary objective was to show a dose-response of a new stable extract (MIG-99) reproducibly manufactured with supercritical CO2 from feverfew (T. parthenium). Furthermore, the study should provide data on the safety and tolerability of MIG-99. In a randomized, double-blind, multicentre, controlled trial with an adaptive design, the clinical efficacy and safety of three dosages of MIG-99 (2.08 mg; 6.25 mg; 18.75 mg t.i.d.) were compared with placebo. The patients (n = 147) suffered from migraine with and without aura according to International Headache Society (IHS) criteria and were treated with one of the study medications for 12 weeks after a 4-week baseline period. The primary efficacy parameter was the number of migraine attacks during the last 28 days of the treatment period compared with baseline. Secondary endpoints were total and average duration and intensity of migraine attacks, mean duration of the single attack, number of days with accompanying migraine symptoms, number of days with inability to work due to migraine as well as type and amount of additionally taken medications for the treatment of migraine attacks. The design of the study included a pre-planned adaptive interim analysis for patients with at least four migraine attacks within the baseline period. With respect to the primary and secondary efficacy parameter, a statistically significant difference was not found between the overall and the confirmatory intention-to-treat (ITT) sample in the exploratorily analysed four treatment groups. The frequency of migraine attacks for the predefined confirmatory subgroup of patients (n = 49) with at least four migraine attacks during the baseline period decreased in a dose-dependent manner (P = 0.001). The highest absolute change of migraine attacks was observed under treatment with 6.25 mg t.i.d. (mean +/- SD = -1.8 +/- 1.5 per 28 days) compared with placebo (-0.3 +/- 1.9; P = 0.02). Overall, 52 of 147 (35%) patients reported at least one adverse event (AE). The incidence of AEs in the active treatment groups was similar to that in the placebo group, and no dose-related effect was observed in any safety parameter. MIG-99 failed to show a significant migraine prophylactic effect in general. Accordingly, in the ITT analysis a dose-response relationship could not be observed. MIG-99 was shown to be effective only in a small predefined subgroup of patients with at least four attacks during the 28-day baseline period where the most favourable benefit-risk ratio was observed with a dosage of three capsules of 6.25 mg MIG-99 extract per day. Because of the low number of patients, these findings need to be verified in a larger sample. The incidence of AEs was similar for all treatment groups
 

文献 PubMed−ID

PMID: 12230594

エビデンスレベル

Ib

文献タイトル (日本語)

片頭痛予防療法におけるナツシロギクの有効性と安全性　多施設 無作為二重盲検プラセボ対照用量反応試験

目的

ナツシロギクが片頭痛予防薬として効果的かつ安全かどうかを決定すること．

研究デザイン

多施設 無作為二重盲検プラセボ対照試験（ double-blind, multicentre, randomized placebo-controlled dose-response study ）

対象患者

国際頭痛学会の診断基準を満たす 片頭痛患者 147 人

介入

観察期（導入期 run-in period ）； 4 ｗ　の後
feverfew から抽出した MIG-99 （ 2.08 mg; 6.25 mg; 18.75 mg ）もしくはプラセボを 12 週間内服．

主要評価項目とそれに用いた統計学的手法

primary efficacy parameter ； 片頭痛発作数を基線と比較
secondary outcome measures　；　導入期よりも頭痛日数 50% 以上減少

結果

ITT 解析（ n = 49 ）において feverfew 内服群は 平均発作頻度はプラセボと比較して有意に減少した（ P ＝ 0.001 ）．
MIG- 99 6.25mg内服群で片頭痛発作が最も減少した．
副作用は容量と相関しなかった．

結論

ITT 解析で feverfew はプラセボと比較して片頭痛予防薬として有効と考えられた．
ITT 解析 では用量反応関係はみられなかった．

コメント

患者数を増やして追試が必要．

備考

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

MeSH Terms:
・Adolescent
・Adult
・Aged
・Comparative Study
・Dose-Response Relationship, Drug
・Double-Blind Method
・Female
・Human
・Male
・Middle Aged
・Migraine/drug therapy
・Migraine/physiopathology
・Migraine/prevention & control*
・Phytotherapy/methods*
・Plant Extracts/adverse effects
・Plant Extracts/therapeutic use
・Statistics, Nonparametric
・Tanacetum parthenium*/adverse effects

Substances:
・Plant Extracts

作成者

井尻珠美，竹島多賀夫

論文抄録

OBJECTIVE: To determine the efficacy for migraine prophylaxis of a compound containing a combination of riboflavin, magnesium, and feverfew. BACKGROUND: Previous studies of magnesium and feverfew for migraine prophylaxis have found conflicting results, and there has been only a single placebo-controlled trial of riboflavin. DESIGN/METHODS: Randomized double-blind placebo-controlled trial of a compound providing a daily dose of riboflavin 400 mg, magnesium 300 mg, and feverfew 100 mg. The placebo contained 25 mg riboflavin. The study included a 1-month run-in phase and 3-month trial. The protocol allowed for 120 patients to be randomized, with a preplanned interim analysis of the data after 48 patients had completed the trial. RESULTS: Forty-nine patients completed the 3-month trial. For the primary outcome measure, a 50% or greater reduction in migraines, there was no difference between active and "placebo" groups, achieved by 10 (42%) and 11 (44%), respectively (P=.87). Similarly, there was no significant difference in secondary outcome measures, for active versus placebo groups, respectively: 50% or greater reduction in migraine days (33% and 40%, P=.63); or change in mean number of migraines, migraine days, migraine index, or triptan doses. Compared to baseline, however, both groups showed a significant reduction in number of migraines, migraine days, and migraine index. This effect exceeds that reported for placebo agents in previous migraine trials. CONCLUSION: Riboflavin 25 mg showed an effect comparable to a combination of riboflavin 400 mg, magnesium 300 mg, and feverfew 100 mg. The placebo response exceeds that reported for any other placebo in trials of migraine prophylaxis, and suggests that riboflavin 25 mg may be an active comparator. There is at present conflicting scientific evidence with regard to the efficacy of these compounds for migraine prophylaxis
 

文献 PubMed−ID

PMID: 15447697

エビデンスレベル

Ib

文献タイトル (日本語)

リボフラビン，マグネシウム，ナツシロギク合剤の片頭痛予防効果

目的

リボフラビン，マグネシウム，ナツシロギク合剤が 片頭痛 - 予防薬として効果的かどうか決定すること．

研究デザイン

無作為二重盲検プラセボ対照試験（ Randomized double-blind placebo-controlled trial ）

研究施設

Two suburban hospital-based headache clinics

対象患者

国際頭痛学会の診断基準を満たし，罹病期間が 1 年以上，月に 2 〜 8 回発作のある 18 ‐ 65 歳の片頭痛患者 49 人．

介入

導入期 run-in period ；　 1 ヶ月
その後 Mg 300mg, 　ビタミン B2 400mg ， feverfew 100mg の合剤もしくはビタミン B2 25mg を含有したプラセボを 3 ヶ月間投与した．

主要評価項目とそれに用いた統計学的手法

primary outcome measure ；導入期よりも 頭痛回数 50 ％以上減少
secondary outcome measures ； 50 ％以上頭痛日数 50 ％以上減少

結果

Mg, 　ビタミン B2 ， feverfew 合剤とプラセボ に頭痛の頻度，程度に差はなかった．しかし内服前と比較すると両群において有意に頭痛改善がみられた．

結論

Mg, 　ビタミン B2 ， feverfew 合剤の効果はもとより， ビタミン B2 25mg での片頭痛予防効果が示された．

コメント

ビタミン B2 少量で有効と考えられた報告（今までと矛盾）．
追試が必要．

備考

Publication Types:
・Clinical Trial
・Randomized Controlled Trial

MeSH Terms:
・Comparative Study
・Double-Blind Method
・Drug Combinations
・Female
・Humans
・Magnesium/therapeutic use*
・Male
・Migraine/prevention & control*
・Phytotherapy*
・Plant Preparations/therapeutic use*
・Riboflavin/therapeutic use*
・Tanacetum parthenium*
・Treatment Outcome

Substances:
・Drug Combinations
・Plant Preparations
・Magnesium
・Riboflavin

作成者

井尻珠美，竹島多賀夫

論文抄録

Naproxen sodium, a potent inhibitor of prostaglandin biosynthesis and platelet aggregation, was studied for efficacy in migraine prophylaxis in a randomized, double-blind, placebo-controlled, crossover trial. On naproxen treatment, 52% of the patients had no severe headaches, whereas 19% had no severe headaches during placebo. Naproxen sodium was much better than placebo when patients' diaries were reviewed for severity of attacks, nausea, vomiting, activity reduction, duration of headache, and decreased use of therapeutic medication. The degree of platelet inhibition did not correlate with efficacy in preventing headache. Naproxen sodium can be recommended as a drug of first choice for migraine prevention.
 

文献 PubMed−ID

PMID: 4022376

エビデンスレベル

Ib

文献タイトル (日本語)

ナプロキセンによる好結果の片頭痛予防療法

目的

ナプロキセン (Anaprox) が片頭痛予防薬として有効かどうかを決定する．

研究デザイン

a randomized, double-blind, placebo-controlled, crossover trial

対象患者

罹病期間が 1 年以上，月に 2 回以上発作のある片頭痛患者 49 人．

介入

run-in period ；　 2w
Period ㈵ ； 8w ナプロキセン 275mg 錠を一日二回内服またはプラセボ内服
Wash out ；　 2w
Period ㈼ ； 8w　 ナプロキセン 275mg 錠を一日二回内服またはプラセボ内服

主要評価項目とそれに用いた統計学的手法

頭痛の程度，持続時間，随伴症状，副作用

結果

ナプロキセン群は 52％に重度の頭痛がみられず，プラセボ群では19％でありプラセボと比較して有意に発作を抑制することが可能であった．
副作用はプラセボと差がなかった．

結論

ナプロキセンは片頭痛予防薬として第一選択にしうる薬剤である．

備考

Publication Types:
・Clinical Trial
・Randomized Controlled Trial

MeSH Terms:
・Adult
・Female
・Humans
・・Male
・Middle Aged
・Migraine/prevention & control*
・Naproxen/therapeutic use*

Substances:
・Naproxen

作成者

井尻珠美

論文抄録

318 patients satisfying the Ad Hoc Committee's criteria for common or classical migraine were entered into an 8 week single-blind placebo recording phase to establish, by diary cards, the frequency and severity of their attacks. 176 patients completed this and had records indicating 4-8 episodes in the 8 week period, with sufficient severity to reduce activity and/or work; these patients were randomized by a predetermined code, into three double-blinded groups: naproxen sodium 550 mg bid (60 patients), pizotyline 0.5 mg tid (59 patients), or placebo (57 patients). The patients were followed at monthly intervals for 12 weeks, with 25 dropping out (3 on naproxen sodium, and 2 each on pizotyline and placebo because of "side effects;" the remaining 18 because of noncompliance or reasons unrelated to therapy). Approximately 25% of patients in each of the 3 groups complained of side effects. Statistical analysis showed that both naproxen sodium and pizotyline were better than placebo, and of overall equivalent (i.e. equal) efficacy in the prophylaxis of migraine. In some respects, naproxen sodium was slightly more effective than pizotyline in the first month of treatment.  

文献 PubMed−ID

PMID: 2074163

エビデンスレベル

Ib

文献タイトル (日本語)

片頭痛予防療法におけるナプロキセンとピゾチリン，プラセボ比較試験

目的

片頭痛予防におけるナプロキセン ， ピゾチリン ， プラセボの効果と副作用を比較する

研究デザイン

A randomized double-blind placebo controlled trial

対象患者

罹病期間 1年以上の18歳〜45歳の片頭痛患者176人

介入

8w　導入期（プラセボ使用）の後
ナプロキセン 550mg錠一日二回 ， ピゾチリン 0.5mg一日三回 ， またはぷラセボのいずれかを内服　 12w

主要評価項目とそれに用いた統計学的手法

頭痛カードに頭痛発作の始まった時刻・頻度・程度・持続時間を記録

結果

ナプロキセン ， ピゾチリンともにプラセボより有効であり ， 効果はほぼ同等であったが ， 始めの 4週間はナプロキセンの方がピゾチリンよりもやや有効であった．
副作用で 25人が脱落 ， 各群の約 25％に副作用の訴えあり ， 群間に差はみられなかった．

結論

ナプロキセン ， ピゾチリンは片頭痛予防効果がある

備考

Publication Types:
・Clinical Trial
・Randomized Controlled Trial

MeSH Terms:
・Adolescent
・Adult
・Comparative Study
・Double-Blind Method
・Female
・Humans
・Male
・Middle Aged
・Migraine/prevention & control*
・Naproxen/adverse effects
・Naproxen/therapeutic use*
・Pizotyline/adverse effects
・Pizotyline/therapeutic use*

Substances:
・Pizotyline
・Naproxen

作成者

井尻珠美

論文抄録

From previous research with migraine patients we know that there are abnormalities of platelet aggregation and adhesiveness. These abnormalities suggest that possibly platelet antagonists might prevent migraine attacks. Dipyridamole and aspirin are both platelet antagonists and are the two drugs used in this double blind study. The patients were randomly assigned to 4 treatment groups; 1 Dipyridamole, 2. Aspirin, 3. Dipyridamole plus Aspirin, and 4. Placebo. These were 40 patients in each group(160 total). These patients had either classical or common migraine, were male or female, and the age group was 21-65. No pregnant female were used. All patients had at least 3 migraine attacks per month prior to entry into the study. The patients received the study medication for 8 weeks following a 4 weeks washout period during which no prophylactic medication for migraine was used. The results show that the group of patients taking the combination of dipyridamole and aspirin had the greater decrease in both headache frequency and headache index. The dipyridamole group and the aspirin group had better results than the placebo group. The improvement in the 3 group receiving the actual test medication had better in the second month, than they did in the first month. This leads one to the conclusion that perhaps if the protocol for this study called for 3 months testing rather than 2, the results would be even better. Platelets are the smallest element found in the blood. In normal blood there are usually between 200,000 to 400,000. This number is dependent upon a negative feedback mechanism which is modulated by thrompopoietin. The platelets are removed from the blood stream by the spleen and the liver after they have passed their normal life span, which is usually found to be from 8 to 10 days. Platelets contain granules. There are two types of granules contain ADP(adenosine dephosphate) ATP, 5HT, mucopolysacarides, adrenalin, and calcium. The other type of granule is the alpha granule which contains lysomal enzymes and possibly fibrinogen.  

文献 PubMed−ID

PMID: 7346693

エビデンスレベル

㈵ b

文献タイトル (日本語)

片頭痛予防療法：新たなアプローチ

目的

血小板抑制作用を有するジピリダモルとアスピリンの片頭痛予防効果を検討

研究デザイン

Randomized double blind study

対象患者

月に 3回以上発作のある21歳から65歳までの片頭痛患者160人

介入

4wのwashout period（予防薬内服なし）の後
1. 　ジピリダモル300mg+プラセボ
2.　アスピリン1300mg+プラセボ
3.　ジピリダモル300mg+アスピリン1300mg
4.　プラセボ
各 40人ずつ8w

主要評価項目とそれに用いた統計学的手法

頭痛発作頻度，程度，持続時間，ＡＤＬの程度，使用頓挫薬，副作用

結果

ジピリダモル +アスピリン群が頭痛頻度・インデックスをより減少させた．ジピリダモルとアスピリン単独群は内服前後で差はなかったがプラセボよりは結果が良かった．4週間後よりも8週間後の方が効果が高かった．
副作用は各群とも多くはなく，差はみられなかった．

結論

ジピリダモル +アスピリンは有効に思われたが統計学的有意差はなし．試験期間が3ヶ月であればさらに良い結果が得られたかもしれない．

コメント

期間を延長してのトライアルを要する．

備考

MeSH Terms:
・Adult
・Aged
・Aspirin/administration & dosage
・Aspirin/therapeutic use
・Dipyridamole/administration & dosage
・Dipyridamole/therapeutic use
・Double-Blind Method
・Drug Therapy, Combination
・Female
・Humans
・Male
・Middle Aged
・Migraine/physiopathology
・Migraine/prevention & control*
・Platelet Adhesiveness/drug effects
・Random Allocation

Substances:
・Aspirin
・Dipyridamole

作成者

井尻珠美

論文抄録

A prospective double-blind trial of aspirin prophylaxis demonstrated a reduction of more than 50% in headache frequency in 9 of 12 migraine patients. Response to aspirin did not correlate with age, duration of headache history, family history, or platelet ultrastructure. There is some evidence that response to aspirin is associated with raised platelet aggregation. This pilot study indicates that aspirin is effective in migraine prophylaxis  

文献 PubMed−ID

PMID : 82144

エビデンスレベル

㈼ b

文献タイトル (日本語)

片頭痛におけるアスピリン予防療法

目的

血小板凝集抑制作用を有するアスピリンは片頭痛予防に有効かを検討する．

研究デザイン

A double-blind crossover trial

対象患者

月に一回以上発作のある 18歳〜53歳の片頭痛患者12人

介入

アスピリン 650mg錠またはプラセボを一日二回内服を3ヶ月ずつ

主要評価項目とそれに用いた統計学的手法

頭痛頻度，頭痛の程度，使用頓挫薬，血小板凝集能を評価．
アスピリン内服時の頭痛頻度がプラセボより 50％以上減少したものを有効とした．

結果

アスピリン内服にて 12人中9人（75%）が有意に頭痛頻度減少がみられた（p<0.0001）．副作用がみられたものは少数であった．

結論

アスピリン 1300mg内服は片頭痛予防に有効であった．

備考

Publication Types:
・Clinical Trial
・Controlled Clinical Trial

MeSH Terms:
・Adolescent
・Adult
・Aspirin/administration & dosage
・Aspirin/therapeutic use*
・Clinical Trials
・Comparative Study
・Double-Blind Method
・Female
・Humans
・Male
・Middle Aged
・Migraine/blood
・Migraine/epidemiology
・Migraine/prevention & control*
・Placebos
・Platelet Aggregation/drug effects
・Prospective Studies
・Research Support , U.S. Gov't, Non-P.H.S.
・Research Support , U.S. Gov't, P.H.S.
・Time Factors

Substances:
・Placebos ・
Aspirin

作成者

井尻珠美

論文抄録

OBJECTIVE: To investigate the effectiveness of rofecoxib in the prevention of perimenstrual migraine. BACKGROUND: Nonsteroidal anti-inflammatory drugs have demonstrated benefit in reducing the frequency and intensity of menstrual migraine when administered perimenstrually. Anti-inflammatory drugs, however, may not be well tolerated and can produce gastrointestinal irritation. Rofecoxib, a selective cyclooxygenase-2 inhibitor, has anti-inflammatory and analgesic properties, and a significantly improved gastrointestinal tolerability profile. METHODS: A pilot study was conducted in which patients with a history of menstrually associated migraine and experiencing at least one migraine monthly during the perimenstrual period were enrolled. Patients who completed a baseline diary for the first month were randomized to receive either rofecoxib 25 mg or 50 mg daily for 10 days, starting 5 days before menstrual flow. Headaches experienced during this 10-day period were recorded in the patient's diary. Patients continued rofecoxib for 2 consecutive menstrual cycles. Mean migraine frequency, intensity, and duration as well as patient's level of functioning during the 2 cycles were compared with baseline.   RESULTS: Fourteen patients completed baseline and rofecoxib dosing for 2 menstrual cycles. Mean migraine frequency decreased from 5.6 to 2.6 migraines per menstrual cycle (P=.005). Eight (57%) of 14 patients had a > or = 50% reduction in headache frequency. No significant improvement in headache intensity, duration, and functional impairment were observed. Both doses of rofecoxib were well tolerated with no statistical difference in patient response between the doses. CONCLUSION: Rofecoxib at a perimenstrual daily dose of 25 or 50 mg demonstrated a significant reduction in frequency of perimenstrual migraine. A double-blind, placebo-controlled trial of rofecoxib in the prevention of perimenstrual migraine is warranted

文献 PubMed−ID

PMID : 14756855

エビデンスレベル

IIa

文献タイトル (日本語)

月経関連片頭痛の予防における Rofecoxib ：オープン，パイロット試験

目的

月経関連片頭痛の予防療法におけるロフェコキシブの効果を調査する．

研究デザイン

オープン試験

研究施設

Headache Wellness Center , Greensboro , NC 27401 , USA

対象患者

月経期に少なくとも 1 回の片頭痛を経験する患者を登録．

介入

ベースラインとして，最初の 1 ヶ月のダイアリをつけた後，ランダム化して月経期の 5 日前から 25mg 又は 50mg のロフェコキシブを 10 日間連日投与した．
この 10 日間，頭痛日記を記録．
連続した 2 ヶ月を rofecoxib を投与

主要評価項目とそれに用いた統計学的手法

2 つの月経サイクルで平均の片頭痛頻度，強度と持続期間，生活支障度をベースラインの観察期と比較

結果

14 例の患者が， 2 つの月経周期の間試験を完了．
平均の片頭痛頻度は，１回の月経周期につき 5.6 回から 2.6 回に有意に減少（ P=.005 ）した．
14 例中 8 例（ 57% ）は，頭痛頻度が 50% 以上減少した．
片頭痛発作時の頭痛強度，持続期間，生活支障度の改善は観察されなかった．
ロフェコキシブの 2 つの用量間には有意差がなく，どちらの用量でも忍容性は良好であった． 

結論

Rofecoxib 25 または 50mg は月経期片頭痛を観察期と比較して有意に減少させた．
プラセボを用いた 2 重盲検試験が必要である．

コメント

オープン試験 ， プラセボを用いた試験が必要．

作成者

竹島多賀夫