Toms Laurence, Derry Sheena, Moore R Andrew, McQuay Henry J
Pain Research and Nuffield Department of Anaesthetics, University of Oxford, West Wing (Level 6), John Radcliffe Hospital, Oxford, Oxfordshire, UK, OX3 9DU.
Cochrane Database Syst Rev. 2009 Jan 21;2009(1):CD001547. doi: 10.1002/14651858.CD001547.pub2.
This is an updated version of the Cochrane review published in Issue 4, 1998. Combining drugs from different classes with different modes of action may offer opportunity to optimise efficacy and tolerability, using lower doses of each drug to achieve the same degree of pain relief. Previously we concluded that addition of codeine to paracetamol provided additional pain relief, but at expense of additional adverse events. New studies have been published since. This review sought to evaluate efficacy and safety of paracetamol plus codeine using current data, and compare findings with other analgesics evaluated similarly.
Assess efficacy of single dose oral paracetamol plus codeine in acute postoperative pain, increase in efficacy due to the codeine component, and associated adverse events.
We searched CENTRAL, MEDLINE, EMBASE, the Oxford Pain Relief Database in October 2008 for this update.
Randomised, double-blind, placebo-controlled trials of paracetamol plus codeine, compared with placebo or the same dose of paracetamol alone, for relief of acute postoperative pain in adults.
Two authors assessed trial quality and extracted data. The area under the "pain relief versus time" curve was used to derive proportion of participants with paracetamol plus codeine and placebo or paracetamol alone experiencing least 50% pain relief over four-to-six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated using 95% confidence intervals (CIs). Proportion of participants using rescue analgesia over a specified time period, and time to use of rescue analgesia, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected.
Twenty-six studies, with 2295 participants, were included comparing paracetamol plus codeine with placebo. Significant dose response was seen for the outcome of at least 50% pain relief over four-to-six hours, with NNTs of 2.2 (95% CI 1.8 to 2.9) for 800 to 1000 mg paracetamol plus 60 mg codeine, 3.9 (2.9 to 4.5) for 600 to 650 mg paracetamol plus 60 mg codeine, and 6.9 (4.8 to 12) for 300 mg paracetamol plus 30 mg codeine. Time to use of rescue medication was over four hours with paracetamol plus codeine and two hours with placebo. The NNT to prevent remedication was 5.6 (4.0 to 9.0) for 600 mg paracetamol plus 60 mg codeine over four to six hours. Adverse events increased of mainly mild to moderate severity with paracetamol plus codeine than placebo.Fourteen studies, with 926 participants, were included in the comparison of paracetamol plus codeine with the same dose of paracetamol alone. Addition of codeine increased proportion of participants achieving at least 50% pain relief over four-to-six hours by 10 to 15%, increased time to use of rescue medication by about one hour, and reduced proportion of participants needing rescue medication by about 15% (NNT to prevent remedication 6.9 (4.2 to 19). Adverse events were mainly mild to moderate in severity and incidence did not differ between groups.
AUTHORS' CONCLUSIONS: This update confirms previous findings that combining paracetamol with codeine provided clinically useful levels of pain relief in about 50% of patients with moderate to severe postoperative pain, compared with under 20% with placebo. New information for remedication shows that the combination extended the duration of analgesia by about one hour compared to treatment with the same dose of paracetamol alone. At higher doses, more participants experienced adequate pain relief, but the amount of information available for the 1000 mg paracetamol plus 60 mg codeine dose was small, and based on limited information.
这是1998年第4期发表的Cochrane系统评价的更新版本。将具有不同作用方式的不同类别药物联合使用，可能有机会优化疗效和耐受性，通过使用较低剂量的每种药物来达到相同程度的疼痛缓解。我们之前得出结论，对乙酰氨基酚加可待因可提供额外的疼痛缓解，但代价是会出现额外的不良事件。此后又发表了一些新的研究。本系统评价旨在利用当前数据评估对乙酰氨基酚加可待因的疗效和安全性，并将结果与其他以类似方式评估的镇痛药进行比较。
评估单剂量口服对乙酰氨基酚加可待因用于急性术后疼痛的疗效、可待因成分所致的疗效增加以及相关不良事件。
我们于2008年10月检索了Cochrane中心对照试验注册库（CENTRAL）、医学期刊数据库（MEDLINE）、荷兰医学文摘数据库（EMBASE）以及牛津疼痛缓解数据库，以进行此次更新。
对乙酰氨基酚加可待因的随机、双盲、安慰剂对照试验，与安慰剂或相同剂量的对乙酰氨基酚单独使用相比，用于缓解成人急性术后疼痛。
两位作者评估试验质量并提取数据。使用经过验证的公式，通过“疼痛缓解与时间”曲线下的面积，得出服用对乙酰氨基酚加可待因以及安慰剂或对乙酰氨基酚单独使用的参与者在四至六小时内疼痛缓解至少50%的比例。使用95%置信区间（CI）计算治疗获益所需人数（NNT）。收集在特定时间段内使用解救镇痛药的参与者比例以及使用解救镇痛药的时间，作为疗效的额外衡量指标。收集不良事件和退出试验的信息。
纳入了26项研究，共2295名参与者，将对乙酰氨基酚加可待因与安慰剂进行比较。在四至六小时内疼痛缓解至少50%这一结果上观察到显著的剂量反应，对于800至1000毫克对乙酰氨基酚加60毫克可待因，NNT为2.2（95%CI 1.8至2.9）；对于600至650毫克对乙酰氨基酚加60毫克可待因，NNT为3.9（2.9至4.5）；对于300毫克对乙酰氨基酚加30毫克可待因，NNT为6.9（4.8至12）。服用对乙酰氨基酚加可待因后使用解救药物的时间超过四小时，而服用安慰剂后为两小时。在四至六小时内，600毫克对乙酰氨基酚加60毫克可待因预防再次用药的NNT为5.6（4.0至9.0）。与安慰剂相比，对乙酰氨基酚加可待因导致的不良事件增加，主要为轻至中度严重程度。纳入了14项研究，共926名参与者，将对乙酰氨基酚加可待因与相同剂量的对乙酰氨基酚单独使用进行比较。添加可待因使在四至六小时内疼痛缓解至少50%的参与者比例增加了10%至15%，使使用解救药物的时间延长了约一小时，并使需要解救药物的参与者比例降低了约15%（预防再次用药的NNT为6.9（4.2至19））。不良事件主要为轻至中度严重程度，两组之间的发生率无差异。
本次更新证实了之前的研究结果，即与安慰剂组不到20%的患者相比，对乙酰氨基酚与可待因联合使用可为约50%的中重度术后疼痛患者提供临床上有用的疼痛缓解水平。关于再次用药的新信息表明，与相同剂量的对乙酰氨基酚单独治疗相比，联合用药使镇痛持续时间延长了约一小时。在较高剂量下，更多参与者获得了充分的疼痛缓解，但对于1000毫克对乙酰氨基酚加60毫克可待因剂量的可用信息量较少，且基于有限的信息。
