注意力缺陷過動症患童服藥順從性研究與OROS MPH及IR MPH療效暨安全性比較評估

Drug compliance research in ADHD children and Efficacy and safety evaluation of OROS MPH compared with IR MPH in NTUH ADHD children

沈欣怡(Hsin-Yi Shen)

指導教授 ： 高純琇

共同指導教授 ： 高淑芬(Shur-Fen Gau)

國立臺灣大學/醫學院/臨床藥學研究所/碩士(2004年)

https://doi.org/10.6342/NTU.2004.01556

摘要

研究背景：
在台灣唯一用以治療注意力缺失過動症（ADHD）之中樞神經興奮劑，為立即釋放型 methylphenidate（IR MPH）。由於其半衰期短，一天三次的給藥頻率對於ADHD患童而言相當不便。國外既有之第一代長效劑型MPH，藥效只能維持八小時，且療效不如傳統劑型；新一代的口服滲透壓釋放劑型（OROS MPH），其安全性與療效在國外的研究已被證實。ADHD患童的服藥順從性在國外有進行少數的研究，但目前並無國內相關資料；此外，國內患童對於長效劑型MPH的反應也有待評估。
研究目的:
1. 探討台灣地區ADHD患童的服藥順從性及其與家庭關係之關連。
2. 比較評估 OROS MPH與IR MPH 用於ADHD患童之療效與安全性。
研究方法: 共分成兩部分進行
1. 由台大兒童心理衛生中心、高雄長庚兒童醫院、及赤子心基金會，利用門診填寫或寄發問卷的方式請ADHD患童家長填答。資料收集部分包含基本資料與孩子服藥順從性評估、中文版親子關係量表（PBI-C）、中文版孩童與親少年社會適應量表（SAICA-C）家庭行為部分、家庭關懷度量表（APGAR）、及中國人健康問卷（CHQ）。問卷資料主要利用general linear model 及邏輯式迴歸分析加以分析。
2. 在台大兒童心理衛生中心進行一隨機分配、以IR MPH為對照組之OROS MPH臨床試驗，受試者為6-15歲過去有服用MPH經驗之ADHD患童，試驗期間為28天。在試驗用藥前及試驗用藥後的第6, 13, 20及第27天，由學校老師及家長透過柯氏兒童行為量表（老師版與父母版）評估孩子過去一星期之症狀表現；此外，學校老師還需於試驗開始用藥前及試驗進行後第13及第27天填寫SKAMP量表，家長需於試驗用藥前及試驗用藥後第27天，藉由HSQ評估孩子傍晚專心程度及由SAICA量表評估患童社會適應情形。整體治療效果之評估由家長與醫師在試驗28天結束後共同決定。患童的食慾、睡眠品質與其他副作用評估則在試驗用藥前與試驗進行兩週及四週時利用BSEQ作評估。研究結果主要採用general linear model及linear mixed model進行變異數分析。
結果:
1. 自民國92年十一月至民國93年三月共回收問卷375份。其中有307位正在服藥的案例，家長認為孩子「總是」與「經常」可以按時服藥者佔82.8%，一天中不能按時服藥的時段填答比例最高者為中午（63.4%），而忘記吃(72.7%)是不能按時服藥最主要的原因。年齡以及一天三次的服藥頻率是服藥順從性不佳的主要危險因子。藉由量表來評估家庭關係與親子互動，結果顯示當孩子服藥順從性較差時，父母對孩子的關懷程度較低，患童和母親之間的互動較不足，和父母相處的問題也較多。
2. 自民國93年二月到四月間自願參與試驗的受試者共64位，兩組受試者在性別、年齡等人口統計資料的分佈與未服藥前各症狀評估的嚴重程度皆沒有統計上顯著差別。兩治療組在接受一個月治療之後，OROS MPH組與IR MPH組在每個星期與未服藥時相較，兩組間改善的分數並無差異；利用linear mixed model觀察一個月中隨著週數而改變的平均量表分數，OROS MPH組在注意力不集中、過動/衝動、對立反抗行為及教室中行為舉止等症狀評估次項目之斜率都較IR MPH組大。在社會適應評估方面OROS MPH組比起IR MPH組，在學校態度、同儕關係、與同儕相處的問題、手足互動、與父母間的問題等部分都有顯著的進步。副作用的評估方面，兩組在各項副作用的發生比例並無顯著差異；若利用linear mixed model分析兩組患童量表分數隨時間的變化，OROS MPH 在食慾減低部分隨著時間，嚴重程度較IR MPH輕微。
結論:
研究結果顯示，一天多次的給藥模式是造成ADHD患童服藥順從性不佳的重要危險因子，而服藥順從性又與家庭關係及親子互動間有密切的關連。在一天一次OROS MPH和一天三次IR MPH的比較上看到相似的療效及安全性。藉由一天一次的給藥模式以改善服藥順從性，相信治療本身對於即將邁入青少年等低服藥順從性危險群患童及其家屬，會有更大的助益。

關鍵字

口服滲透壓釋放劑型MPH ； 服藥順從性 ； 注意力缺陷過動症

並列摘要

Background:
Immediate-released methylphenidate (IR MPH), the only CNS stimulant available for attention-deficit/hyperactivity disorder (ADHD) in Taiwan, has a short half-life, which needs 3 times a day dosing to maintain the effect throughout daytime. The first generation sustained-release formulation of MPH has an only 8 hours effect and has been be less effective when compared with IR MPH due to acute tolerance. A new generation Once-daily Osmotic Release Oral System (OROS) MPH provides a 12-hour effect with ascending profile of pharmacokinetics, which has been proved to have similar efficacy to IR MPH thrice daily and has been approved by FDA in 2000. No study has been done to investigate the patterns and impact of the compliance of IR MPH and efficacy of OROS in Taiwanese or other Asian populations. The objectives of this study are to identify the determinants of IR MPH compliance among children with ADHD, to examine the association of IR MPH compliance on family interaction, parent-child relationship, and parental mental status, and to evaluate the efficacy and safety of once-daily OROS MPH as compared with thrice daily IR MPH among ADHD children.

Methods:
This study consisted of two parts: Part I: compliance survey, and part II: OROS MPH clinical trial.
Part I: This study was a cross-sectional questionnaire survey on compliance to IR MPH. The sample consisted of 375 ADHD children (329 boys, 46 girls), who were recruited from National Taiwan University Hospital (n = 218), Chung-Gung hospital (n = 56), and ADHD Educational Foundation (n=101 ) from November 2003 to March 2004. Parents reported on the measures of demographics, children’s compliance to IR MPH, the Chinese version of Parental Bonding Instrument (PBI-C), the Family APGAR, the Home Behaviors subscale of the Chinese version of Social Adjustment for Children and Adolescent (SAICA-C), and the Chinese Health Questionnaire (CHQ).
Part II: The second part was a randomized clinical trial comparing the efficacy and safety of OROS MPH (n = 32) with trice daily dosing IR MPH (n = 32) among 64 ADHD children aged 6-15 yeas, who were recruited from February 2004 to April 2004. The study period was 28 days. The outcome measures covered the domains of ADHD symptoms at home and school settings, social functioning, and side effects. On study days 1, 6, 13, 20, 27, the ADHD symptoms in the previous week were evaluated by the school teacher and parent using the Conner’s Teacher and Parent Rating Scale-Revised: Short Form (CTRS-R:S and CPRS-R:S). The SKAMP Rating Scale scores were also evaluated by school teachers on study days 1, 13 and 27. The Home Situation Questionnaire was answered by parents on study days 1 and 27. The SAICA-C and Peer Interaction Items were rated by parents and school teachers on study days 1 and 27. Global assessments of treatment effects were determined by parents and the investigator at the end of the treatment. The side effects were evaluated globally at baseline, and after 2 and 4 weeks of treatment by the parents using the Barkley’s Side Effect Rating Scale. Mixed model and generalized linear model were used to conduct analysis of variance.
Results:
Part I: Among 375 ADHD children, 307 were taking IR MPH during study period, 82.8% of their parents thought their child always or often took IR-MPH according to instruction. The main reason for not regularly taking IR-MPH was forget to take medication (72.7%). Poor compliance was most prevalent at noon time (63.4%). Increased age and thrice daily dosing of IR MPH were the major determinants for poor compliance. Compared to their counterparts, parents of children with poor compliance appeared to have less affection and warmth toward their children, and their children were less likely to have interactions with mothers and more severe problems with parents.
Part II: There were no difference between the two treatment groups in demographics and baseline severity in ADHD. Both groups demonstrated significantly reductions in the ADHD core symptoms and inappropriate behaviors after the treatment. Compared to the IR MPH group, the OROS MPH group had greater improvement of symptoms over time in terms of all dimensions related to the ADHD symptoms. Regarding the four domains of social functioning, the OROS MPH group had a significant improvement in school relationships, peer relationships, and sibling relationships, and a decline in problems with parents, while these were not observed in the IR MPH group. The rates of adverse effects showed no significant difference between the two groups, except that the OROS MPH group had a less impact on appetite over time. The majority of the OROS MPH group (68.8%) were more satisfied with OROS MPH than IR MPH, which was used before this clinical trial.

Conclusions:
Findings from this study indicate that multi-dosing regimen decreases the drug compliance in ADHD children, and poor compliance is associate with adverse parent-child relationship. Similar efficacy and safety profile of once-daily OROS MPH to thrice daily IR MPH implies that OROS MPH is effective and acceptable to Taiwanese population. Accordingly, once-daily dosing regimen may improve treatment efficacy and enhance parent-child relationship among families with ADHD children, which is particularly important for ADHD children who are older and with more severe symptoms, due to a strong relation of good drug compliance to improvement in clinical outcomes.

並列關鍵字

drug compliance ； Attention deficit hyperactivity disorder ； OROS methylphenidate

參考文獻

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