關鍵資訊
- 派醋甲酯 (Methylphenidate) 可能可減少兒童過動與衝動，並幫助其集中注意力。派醋甲酯也可能有助改善兒童日常行為，但無證據顯示會提升或降低其生活品質。
- 無證據顯示長期 (六個月以上) 使用派醋甲酯 (Methylphenidate) 可能會增加嚴重（危及生命）不良反應之風險。然而，派醋甲酯仍與睡眠障礙及食慾不振等不良反應之風險增加有關。
- 期許更多未來研究關注派醋甲酯 (Methylphenidate) 之不良影響，並加長整體研究介入時間。
什麼是注意力不足及過動症 (ADHD)？
注意力不足及過動症 (Attention Deficit Hyperactive Disorder,ADHD) 是兒童最常見的精神疾病之一。患有 ADHD 的兒童不僅很難集中注意力，也很常表現出過動（如煩躁，無法長時間靜坐）以及衝動（如做事不經思考）等行為。由於 ADHD 兒童很難聽從指示與集中注意力，因此較難有出色的學業/學校表現。而其行為問題也會影響他們與家人及朋友間的相處，除了較難相處融洽外，也可能會惹出更多麻煩 (或更多磨擦)。
如何治療 ADHD？
最常見的 ADHD 兒童及青少年治療藥物為派醋甲酯 (如利他能錠 Ritalin)。此藥為一種興奮劑，有助於提升部分大腦活動，如增加注意力。派醋甲酯除了口服藥物外，也可作為皮膚貼片使用，並且可分為速釋藥效，或緩釋藥效等類型。派醋甲酯常見不良反應為頭痛、腹痛以及睡眠障礙，有時也會導致嚴重不良反應，如心臟問題、幻覺或面部抽動。
我們想了解什麼？
藉由 ADHD 兒童之教師的量表評估結果，我們想了解派醋甲酯是否能改善其症狀 (如注意力不足、過動)，以及派醋甲酯是否會產生嚴重不良反應，如死亡、住院、殘疾。我們也想了解其他非嚴重不良反應，如睡眠障礙、食慾不振，以及影響兒童行為與生活品質的程度。
我們做了什麼？
我們檢索了 ADHD 兒童和青少年使用派醋甲酯的相關研究。研究受試者的年齡必須在 18 歲 (含) 以下，診斷患有 ADHD，且可能合併或患有其他疾病，或者正在服用其他藥物與接受行為治療。而他們必須有正常的 IQ（智商）。納入研究需確保受試者經過隨機分派，且實驗組為派醋甲酯，對照組為安慰劑（外觀和味道與派醋甲酯相同但不含活性成分的藥物）或無介入措施。我們比較與統整了納入研究之結果，並根據研究方法與規模等因素評估證據品質。
我們發現了什麼？
我們納入 212 篇文獻，共 16,302 位 ADHD 兒童與青少年。大多數研究主要在比較派醋甲酯與安慰劑；研究受試者人數多落在 70 人左右，規模較小，平均年齡為 10 歲（年齡範圍為 3 至 18 歲）；整體介入時間較短，平均 1 個月左右，其中時間最短之研究只持續了 1 天，最長為 425 天。而納入之多數研究皆在美國進行與完成。
根據 ADHD 兒童及青少年之教師的評分，相較安慰劑或無介入措施相比，派醋甲酯：
- 可能可改善 ADHD 症狀（21 項研究，1,728 名受試者）
- 可能不影響嚴重不良反應之風險（26 項研究，3,673 名受試者）
- 可能增加更多非嚴重不良反應（35 項研究，5,342 名受試者）
- 可能可改善行為（7 項試驗，792 名受試者）
- 可能不會影響生活品質（4 項試驗，608 名受試者）
證據的侷限性
基於以下幾個原因，我們對研究結果信心有限：(1)研究參與者可能知道受試者們正在接受哪種治療，因而影響研究結果之分析；(2)部分研究之結果並不完整，且不盡相同；(3)部分研究規模較小，並且各自使用不同的量表來測量與評估症狀；(4)多數研究介入時間較短，較難評估派醋甲酯的長期影響；(5)大約 41% 的研究為製藥商資助或部分資助。
這些證據的更新時效為何？
本文為 2015 年已發表之文獻回顧的更新。實驗證據資料收集至 2022 年 3 月。
The majority of our conclusions from the 2015 version of this review still apply. Our updated meta-analyses suggest that methylphenidate versus placebo or no-intervention may improve teacher-rated ADHD symptoms and general behaviour in children and adolescents with ADHD. There may be no effects on serious adverse events and quality of life. Methylphenidate may be associated with an increased risk of adverse events considered non-serious, such as sleep problems and decreased appetite. However, the certainty of the evidence for all outcomes is very low and therefore the true magnitude of effects remain unclear.
Due to the frequency of non-serious adverse events associated with methylphenidate, the blinding of participants and outcome assessors is particularly challenging. To accommodate this challenge, an active placebo should be sought and utilised. It may be difficult to find such a drug, but identifying a substance that could mimic the easily recognised adverse effects of methylphenidate would avert the unblinding that detrimentally affects current randomised trials.
Future systematic reviews should investigate the subgroups of patients with ADHD that may benefit most and least from methylphenidate. This could be done with individual participant data to investigate predictors and modifiers like age, comorbidity, and ADHD subtypes.
Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children and adolescents with ADHD find it difficult to pay attention and they are hyperactive and impulsive. Methylphenidate is the psychostimulant most often prescribed, but the evidence on benefits and harms is uncertain. This is an update of our comprehensive systematic review on benefits and harms published in 2015.
To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD.
We searched CENTRAL, MEDLINE, Embase, three other databases and two trials registers up to March 2022. In addition, we checked reference lists and requested published and unpublished data from manufacturers of methylphenidate.
We included all randomised clinical trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. The search was not limited by publication year or language, but trial inclusion required that 75% or more of participants had a normal intellectual quotient (IQ > 70). We assessed two primary outcomes, ADHD symptoms and serious adverse events, and three secondary outcomes, adverse events considered non-serious, general behaviour, and quality of life.
Two review authors independently conducted data extraction and risk of bias assessment for each trial. Six review authors including two review authors from the original publication participated in the update in 2022. We used standard Cochrane methodological procedures. Data from parallel-group trials and first-period data from cross-over trials formed the basis of our primary analyses. We undertook separate analyses using end-of-last period data from cross-over trials. We used Trial Sequential Analyses (TSA) to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the GRADE approach.
We included 212 trials (16,302 participants randomised); 55 parallel-group trials (8104 participants randomised), and 156 cross-over trials (8033 participants randomised) as well as one trial with a parallel phase (114 participants randomised) and a cross-over phase (165 participants randomised). The mean age of participants was 9.8 years ranging from 3 to 18 years (two trials from 3 to 21 years). The male-female ratio was 3:1. Most trials were carried out in high-income countries, and 86/212 included trials (41%) were funded or partly funded by the pharmaceutical industry. Methylphenidate treatment duration ranged from 1 to 425 days, with a mean duration of 28.8 days. Trials compared methylphenidate with placebo (200 trials) and with no intervention (12 trials). Only 165/212 trials included usable data on one or more outcomes from 14,271 participants.
Of the 212 trials, we assessed 191 at high risk of bias and 21 at low risk of bias. If, however, deblinding of methylphenidate due to typical adverse events is considered, then all 212 trials were at high risk of bias.
Primary outcomes: methylphenidate versus placebo or no intervention may improve teacher-rated ADHD symptoms (standardised mean difference (SMD) −0.74, 95% confidence interval (CI) −0.88 to −0.61; I² = 38%; 21 trials; 1728 participants; very low-certainty evidence). This corresponds to a mean difference (MD) of −10.58 (95% CI −12.58 to −8.72) on the ADHD Rating Scale (ADHD-RS; range 0 to 72 points). The minimal clinically relevant difference is considered to be a change of 6.6 points on the ADHD-RS. Methylphenidate may not affect serious adverse events (risk ratio (RR) 0.80, 95% CI 0.39 to 1.67; I² = 0%; 26 trials, 3673 participants; very low-certainty evidence). The TSA-adjusted intervention effect was RR 0.91 (CI 0.31 to 2.68).
Secondary outcomes: methylphenidate may cause more adverse events considered non-serious versus placebo or no intervention (RR 1.23, 95% CI 1.11 to 1.37; I² = 72%; 35 trials 5342 participants; very low-certainty evidence). The TSA-adjusted intervention effect was RR 1.22 (CI 1.08 to 1.43). Methylphenidate may improve teacher-rated general behaviour versus placebo (SMD −0.62, 95% CI −0.91 to −0.33; I² = 68%; 7 trials 792 participants; very low-certainty evidence), but may not affect quality of life (SMD 0.40, 95% CI −0.03 to 0.83; I² = 81%; 4 trials, 608 participants; very low-certainty evidence).
翻譯者：吳方瑜 (成功大學，學生)【本翻譯計畫由臺北醫學大學考科藍臺灣研究中心 (Cochrane Taiwan)、東亞考科藍聯盟 (EACA) 統籌執行。聯絡E-mail:cochranetaiwan@tmu.edu.tw】