Preventive Effects of Ramelteon on Delirium
A Randomized Placebo-Controlled Trial
重要点：せん妄予防に効果的な介入方法は見つかっていない。
目的：メラトニンアゴニストであるラメルテオンがせん妄予防に効果的であるかどうか調べる。
デザイン、設定、患者：4つの大学病院と1つの市中病院の集中治療室と一般病棟で行われた多施設、評価者盲検、プラセボコントロールの無作為化試験。該当する患者は65歳から89歳で新たに重症の医学的問題で入院し、薬物の経口投与が可能である人である。余命が48時間以内と考えられる患者は除外された。
介入：67人の患者が封筒法を使って無作為的にラメルテオン8mg(33人)の内服とプラセボの7日間眠前服用に割り振られた。
アウトカム：DSM-4で定義されたせん妄の発生率
結果：ラメルテオンはせん妄の発症リスクを有意に低下させ(3％vs32％、P=0.03)、相対危険度を下げた(95％CI、0.01-0.09)。リスクファクターを調整してなお、ラメルテオンはせん妄の発生率の低下と関係していた。せん妄の進展の累積時間はラメルテオン群で6.94、プラセボ群で5.74であった。log-rank検定での比較ではラメルテオン群はプラセボ群と比較して著明にせん妄の頻度が低かった。
結論：急性期病態で入院した高齢者へのラメルテオンの夜間投与はせん妄予防につながる。これらはせん妄に対するメラトニンの神経伝達物質としての役割によるものである。
Patients
Eligible patients were 65 to 89 years old, newly admitted due to serious medical problems, and able to take medicine orally. Patients were admitted via emergency departments to intensive care units or regular acute wards. Patients were excluded from the study if they had an expected stay or life ex- pectancy of less than 48 hours.
他にも認知機能障害を来たす疾患やリスパダールなどを内服している人は除外．
Intervention
The dosage of ramelteon was 8 mg/d, given as a single tab- let nightly, representing the standard dosage for the ap- proved indication of sleep disturbance.
Control
The placebo com- prised 330 mg of lactose powder. The placebo did not match the ramelteon active agent in appearance.
Outcomes
The primary outcome measure was incidence of de- lirium, defined according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition).1 Simultane- ously, we censored patients in whom delirium developed, using the DRS-R98 total score, with a cutoff score of 14.5, estab- lished for the Japanese population by investigating the reli- ability and validity of the Japanese version of the DRS-R98.
Randomization
Patients were randomized using the sealed envelope method in a rater-blind manner to receive either ramelteon or pla- cebo. For randomization, we referred to a random number table, with sequentially numbered, opaque, sealed enve- lopes used to conceal the allocation sequence.
Characteristics
ｎが少ないので有意差は出ていないが，ばらつきはそこそこある．
目隠し
よくわからない理屈でSingle blindになっている．
適切な評価
全員follow upされている．
その他の治療は同じか．
Nurses provided all patients equally with preven- tive care, such as avoidance of immobilization, adequate light- ing, noise reduction, on-time clocks and calendars, and regu- lar verbal communication.
Family members were not allowed to stay in hos- pitals after 8 PM, and study medication was given at 9 PM. There- fore, there was low likelihood of bias due to interactions with family members. Thus, neither nursing care nor family inter- actions could have been different in the ramelteon group.
すべての記載はないが，ステロイドや向精神病薬は差がなかったり除外されている．不眠時の頓服はレスリンかアタラックスが投与されている．その他の，せん妄予防はどちらもしている．まぁ差がないと考えて良さそう．
size
The incidence of delirium during hospital stays report- edly ranges between 3% and 56%.5 Although patients with risk factors for delirium (eg, old age and dementia) are increas- ingly encountered in general hospitals, we thought that 56% was too high an incidence of delirium during general hospital stays in Japan. We therefore assumed that the incidence of de- lirium in patients receiving placebo would be half the upper limit (ie, 28%) and the incidence in those receiving ramelteon would be the lower limit (3%). To enable detection of differ- ences, we set the statistical power as 1 − β = 80% and the sen- sitivity as α = 5%. Through power analysis, we consequently set the required number of patients at 32 patients per group.
Results
Ramelteon was associ- ated with a lower risk of delirium (3% vs 32%; P = .003), with a relative risk of 0.09 (95% CI, 0.01-0.69). No adverse events potentially attributable to the study drug were observed.
Figure 2 shows scattergrams of the highest total DRS-R98 score in each patient. Two patients with dementia in the placebo group with scores of 17 and 19 did not have a diagnosis of de- lirium according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition).1
Kaplan-Meier estimates of the time to development of de- lirium were 6.94 (95% CI, 6.82-7.06) days for ramelteon and 5.74 (5.05-6.42) days for placebo (Figure 3). Comparison by log- rank test showed that delirium developed significantly less of- ten among patients taking ramelteon than among those tak- ing placebo (χ2 = 9.83; P = .002).
使うか．
レスリン 25mg 18.1円，セロクエル 25mg 25.7円，ロゼレム 82.5円
リスパダール 1mg 錠剤 11.7円，液体 42.1円，セレネース 5mg 1A 56円
高いので使わない．そもそもプラセボと勝負してる論文の意味があるのか・・・．副作用が少ないことを推しているが・・・．