Leopoldino Amanda O, Machado Gustavo C, Ferreira Paulo H, Pinheiro Marina B, Day Richard, McLachlan Andrew J, Hunter David J, Ferreira Manuela L
Institute of Bone and Joint Research, The Kolling Institute, Sydney Medical School, The University of Sydney, Reserve Road St Leonards, Sydney, New South Wales, Australia, 2065.
Cochrane Database Syst Rev. 2019 Feb 25;2(2):CD013273. doi: 10.1002/14651858.CD013273.
Paracetamol (acetaminophen) is vastly recommended as the first-line analgesic for osteoarthritis of the hip or knee. However, there has been controversy about this recommendation given recent studies have revealed small effects of paracetamol when compared with placebo. Nonetheless, past studies have not systematically reviewed and appraised the literature to investigate the effects of this drug on specific osteoarthritis sites, that is, hip or knee, or on the dose used.
To assess the benefits and harms of paracetamol compared with placebo in the treatment of osteoarthritis of the hip or knee.
We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, AMED, CINAHL, Web of Science, LILACS, and International Pharmaceutical Abstracts to 3 October 2017, and ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP) portal on 20 October 2017.
We included randomised controlled trials comparing paracetamol with placebo in adults with osteoarthritis of the hip or knee. Major outcomes were pain, function, quality of life, adverse events and withdrawals due to adverse events, serious adverse events, and abnormal liver function tests.
Two review authors used standard Cochrane methods to collect data, and assess risk of bias and quality of the evidence. For pooling purposes, we converted pain and physical function (Western Ontario and McMaster Universities Osteoarthritis Index function) scores to a common 0 (no pain or disability) to 100 (worst possible pain or disability) scale.
We identified 10 randomised placebo-controlled trials involving 3541 participants with hip or knee osteoarthritis. The paracetamol dose varied from 1.95 g/day to 4 g/day, and the majority of trials followed participants for three months only. Most trials did not clearly report randomisation and concealment methods and were at unclear risk of selection bias. Trials were at low risk of performance, detection, and reporting bias.At 3 weeks' to 3 months' follow-up, there was high-quality evidence that paracetamol provided no clinically important improvements in pain and physical function. Mean reduction in pain was 23 points (0 to 100 scale, lower scores indicated less pain) with placebo and 3.23 points better (5.43 better to 1.02 better) with paracetamol, an absolute reduction of 3% (1% better to 5% better, minimal clinical important difference 9%) and relative reduction of 5% (2% better to 8% better) (seven trials, 2355 participants). Physical function improved by 12 points on a 0 to 100 scale (lower scores indicated better function) with placebo and was 2.9 points better (0.95 better to 4.89 better) with paracetamol, an absolute improvement of 3% (1% better to 5% better, minimal clinical important difference 10%) and relative improvement of 5% (2% better to 9% better) (7 trials, 2354 participants).High-quality evidence from eight trials indicated that the incidence of adverse events was similar between groups: 515/1586 (325 per 1000) in the placebo group versus 537/1666 (328 per 1000, range 299 to 360) in the paracetamol group (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.92 to 1.11). There was less certainty (moderate-quality evidence) around the risk of serious adverse events, withdrawals due to adverse events, and the rate of abnormal liver function tests, due to wide CIs or small event rates, indicating imprecision. Seventeen of 1480 (11 per 1000) people treated with placebo and 28/1729 (16 per 1000, range 8 to 29) people treated with paracetamol experienced serious adverse events (RR 1.36, 95% CI 0.73 to 2.53; 6 trials). The incidence of withdrawals due to adverse events was 65/1000 participants in with placebo and 77/1000 (range 59 to 100) participants with paracetamol (RR 1.19, 95% CI 0.91 to 1.55; 7 trials). Abnormal liver function occurred in 18/1000 participants treated with placebo and 70/1000 participants treated with paracetamol (RR 3.79, 95% CI 1.94 to 7.39), but the clinical importance of this effect was uncertain. None of the trials reported quality of life.Subgroup analyses indicated that the effects of paracetamol on pain and function did not differ according to the dose of paracetamol (3.0 g/day or less versus 3.9 g/day or greater).
AUTHORS' CONCLUSIONS: Based on high-quality evidence this review confirms that paracetamol provides only minimal improvements in pain and function for people with hip or knee osteoarthritis, with no increased risk of adverse events overall. Subgroup analysis indicates that the effects on pain and function do not differ according to the dose of paracetamol. Due to the small number of events, we are less certain if paracetamol use increases the risk of serious adverse events, withdrawals due to adverse events, and rate of abnormal liver function tests.Current clinical guidelines consistently recommend paracetamol as the first-line analgesic medication for hip or knee osteoarthritis, given its low absolute frequency of substantive harm. However, our results call for reconsideration of these recommendations.
对乙酰氨基酚（扑热息痛）被广泛推荐为髋或膝骨关节炎的一线镇痛药。然而，鉴于近期研究显示与安慰剂相比，对乙酰氨基酚的效果甚微，这一推荐引发了争议。尽管如此，以往研究并未系统地回顾和评估文献，以探究该药物对特定骨关节炎部位（即髋或膝）或所用剂量的影响。
评估对乙酰氨基酚与安慰剂相比，在治疗髋或膝骨关节炎中的利弊。
我们检索了截至2017年10月3日的Cochrane对照试验中央注册库、MEDLINE、Embase、AMED、CINAHL、科学引文索引、拉丁美洲和加勒比地区卫生科学数据库以及国际药学文摘，并于2017年10月20日检索了ClinicalTrials.gov和世界卫生组织国际临床试验注册平台（ICTRP）入口。
我们纳入了比较对乙酰氨基酚与安慰剂治疗髋或膝骨关节炎成人患者的随机对照试验。主要结局包括疼痛、功能、生活质量、不良事件以及因不良事件导致的退出、严重不良事件和肝功能检查异常。
两位综述作者采用标准的Cochrane方法收集数据，并评估偏倚风险和证据质量。为了合并分析，我们将疼痛和身体功能（西安大略和麦克马斯特大学骨关节炎指数功能）评分转换为0（无疼痛或残疾）至100（最严重疼痛或残疾）的通用量表。
我们确定了10项随机安慰剂对照试验，涉及3541名髋或膝骨关节炎患者。对乙酰氨基酚的剂量从1.95克/天到4克/天不等，大多数试验仅对参与者随访了三个月。大多数试验未明确报告随机化和隐藏方法，存在选择偏倚风险不明的情况。试验在实施、检测和报告偏倚方面风险较低。在3周或3个月的随访中，有高质量证据表明对乙酰氨基酚在疼痛和身体功能方面没有提供临床上重要的改善。安慰剂组疼痛平均减轻23分（0至100量表，分数越低疼痛越轻），对乙酰氨基酚组更好3.23分（更好5.43分至更好1.02分），绝对减轻3%（更好1%至更好5%，最小临床重要差异9%），相对减轻5%（更好2%至更好8%）（7项试验，2355名参与者）。身体功能在0至100量表上安慰剂组改善了12分（分数越低功能越好），对乙酰氨基酚组更好2.9分（更好0.95分至更好4.89分），绝对改善3%（更好1%至更好5%，最小临床重要差异10%），相对改善5%（更好2%至更好9%）（7项试验，2354名参与者）。八项试验的高质量证据表明，两组不良事件发生率相似：安慰剂组为515/1586（每1000人325例），对乙酰氨基酚组为537/1666（每1000人328例，范围299至360）（风险比（RR）1.01，95%置信区间（CI）0.92至1.11）。由于置信区间较宽或事件发生率较低，关于严重不良事件、因不良事件导致的退出以及肝功能检查异常率的风险，确定性较低（中等质量证据），表明结果不精确。安慰剂治疗的1480人中17人（每1000人11例）和对乙酰氨基酚治疗的1729人中28人（每1000人16例，范围8至29）发生严重不良事件（RR 1.36，95%CI 0.73至2.53；6项试验）。因不良事件导致的退出发生率在安慰剂组为每1000名参与者65例，对乙酰氨基酚组为每1000名参与者77例（范围59至100）（RR 1.19，95%CI 0.91至1.55；7项试验）。安慰剂治疗的参与者中每1000人有18例肝功能异常，对乙酰氨基酚治疗的参与者中每1000人有70例（RR 3.79，95%CI 1.94至7.39），但这种影响的临床重要性尚不确定。没有试验报告生活质量。亚组分析表明，对乙酰氨基酚对疼痛和功能的影响不因对乙酰氨基酚剂量（3.0克/天或更低与3.9克/天或更高）而有所不同。
基于高质量证据，本综述证实对乙酰氨基酚对髋或膝骨关节炎患者的疼痛和功能仅提供了极小的改善，总体不良事件风险并未增加。亚组分析表明，对疼痛和功能的影响不因对乙酰氨基酚剂量而有所不同。由于事件数量较少，我们对使用对乙酰氨基酚是否会增加严重不良事件、因不良事件导致的退出以及肝功能检查异常率的风险不太确定。鉴于其实际伤害的绝对发生率较低，当前临床指南一致推荐对乙酰氨基酚作为髋或膝骨关节炎的一线镇痛药物。然而，我们的结果呼吁重新考虑这些推荐。
