Toupin April Karine, Bisaillon Jacinthe, Welch Vivian, Maxwell Lara J, Jüni Peter, Rutjes Anne Ws, Husni M Elaine, Vincent Jennifer, El Hindi Tania, Wells George A, Tugwell Peter
Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.
Cochrane Database Syst Rev. 2019 May 27;5(5):CD005522. doi: 10.1002/14651858.CD005522.pub3.
Tramadol is often prescribed to treat pain and is associated physical disability in osteoarthritis (OA). Due to the pharmacologic mechanism of tramadol, it may lead to fewer associated adverse effects (i.e. gastrointestinal bleeding or renal problems) compared to non-steroidal anti-inflammatory drugs (NSAIDs). This is an update of a Cochrane Review originally published in 2006.
To determine the benefits and harms of oral tramadol or tramadol combined with acetaminophen or NSAIDs in people with osteoarthritis.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase databases, as well as the US National Institutes of Health and World Health Organization trial registries up to February 2018. We searched the LILACS database up to August 2015.
We included randomized controlled trials (RCTs) that evaluated the effect of tramadol, or tramadol in combination with acetaminophen (paracetamol) or NSAIDs versus placebo or any comparator in people with osteoarthritis.
We used standard methodologic procedures expected by Cochrane.
We included 22 RCTs (11 more than the previous review) of which 21 RCTs were included in meta-analyses for 3871 participants randomized to tramadol alone or tramadol in combination with another analgesic and 2625 participants randomized to placebo or active control. Seventeen studies evaluated tramadol alone and five evaluated tramadol plus acetaminophen. Thirteen studies used placebo controls and eleven studies used active controls (two trials had both placebo and active arms). The dose of tramadol ranged from 37.5 mg to 400 mg daily; all doses were pooled. Most trials were multicenter with a mean duration of two months. Participants were predominantly women with hip or knee osteoarthritis, with a mean age of 63 years and moderate to severe pain. There was a high risk of selection bias as only four trials reported both adequate sequence generation and allocation concealment. There was a low risk for performance bias as most studies blinded participants. There was a high risk of attrition bias as 10/22 trials showed incomplete outcome data. Most of the trials were funded by the pharmaceutical industry.Moderate quality evidence (downgraded due to risk of bias) indicated that tramadol alone and in combination with acetaminophen had no important benefit on pain reduction compared to placebo control (tramadol alone: 4% absolute improvement, 95% confidence interval (CI) 3% to 5%; 8 studies, 3972 participants; tramadol in combination with acetaminophen: 4% absolute improvement, 95% CI 2% to 6%; 2 studies, 614 participants).Fifteen out of 100 people in the tramadol group improved by 20% (which corresponded to a clinically important difference in pain) compared to 10/100 in the placebo group (5% absolute improvement). Twelve out of 100 people improved by 20% in the tramadol in combination with acetaminophen group compared to 7/100 in the placebo group (5% absolute improvement).Moderate quality evidence (downgraded due to risk of bias) indicated that tramadol alone and in combination with acetaminophen led to no important benefit in physical function compared to placebo (tramadol alone: 4% absolute improvement, 95% CI 2% to 6%; 5 studies, 2550 participants; tramadol in combination with acetaminophen: 4% absolute improvement, 95% CI 2% to 7%; 2 studies, 614 participants).Twenty-one out of 100 people in the tramadol group improved by 20% (which corresponded to a clinically important difference in physical function) compared to 16/100 in the placebo group (5% absolute improvement). Fifteen out of 100 people improved by 20% in the tramadol in combination with acetaminophen group compared to 10/100 in the placebo group (5% absolute improvement).Moderate quality evidence (downgraded due to risk of bias) indicated that, compared to placebo, there was a greater risk of developing adverse events with tramadol alone (risk ratio (RR) 1.34, 95% CI 1.24 to 1.46; 4 studies, 2039 participants) and tramadol in combination with acetaminophen compared to placebo (RR 1.91, 95% CI 1.32 to 2.76; 1 study, 308 participants). This corresponded to a 17% increase (95% CI 12% to 23%) with tramadol alone and 22% increase (95% CI 8% to 41%) with tramadol in combination with acetaminophen.The three most frequent adverse events were nausea, dizziness and tiredness. Moderate quality evidence (downgraded due to risk of bias) indicated that there was a greater risk of withdrawing from the study because of adverse events with tramadol alone compared to placebo (RR 2.64, 95% CI 2.17 to 3.20; 9 studies, 4533 participants), which corresponded to a 12% increase (95% CI 9% to 16%).Low quality evidence (downgraded due to risk of bias and inconsistency) indicated that there was a greater risk of withdrawing from the study because of adverse events with tramadol in combination with acetaminophen compared to placebo (RR 2.78, 95% CI 1.50 to 5.16; 2 studies, 614 participants), which corresponded to a 8% absolute improvement (95% CI 2% to 19%).Low quality evidence (downgraded due to risk of bias and imprecision) indicated that there was a greater risk of developing serious adverse events with tramadol alone compared to placebo (110/2459 participants with tramadol compared to 22/1153 participants with placebo; RR 1.78, 95% CI 1.11 to 2.84; 7 studies, 3612 participants), which corresponded to a 1% increase (95% CI 0% to 4%). There were no serious adverse events reported in one small study (15 participants) of tramadol with acetaminophen compared to placebo.
AUTHORS' CONCLUSIONS: Moderate quality evidence indicates that compared to placebo, tramadol alone or in combination with acetaminophen probably has no important benefit on mean pain or function in people with osteoarthritis, although slightly more people in the tramadol group report an important improvement (defined as 20% or more). Moderate quality evidence shows that adverse events probably cause substantially more participants to stop taking tramadol. The increase in serious adverse events with tramadol is less certain, due to the small number of events.
曲马多常用于治疗疼痛，且与骨关节炎（OA）患者的身体残疾有关。由于曲马多的药理机制，与非甾体抗炎药（NSAIDs）相比，它可能导致较少的相关不良反应（如胃肠道出血或肾脏问题）。这是对2006年首次发表的Cochrane系统评价的更新。
确定口服曲马多或曲马多联合对乙酰氨基酚或NSAIDs治疗骨关节炎患者的益处和危害。
我们检索了Cochrane对照试验中心注册库（CENTRAL）、MEDLINE和Embase数据库，以及美国国立卫生研究院和世界卫生组织的试验注册库，检索截止至2018年2月。我们检索了LILACS数据库，检索截止至2015年8月。
我们纳入了随机对照试验（RCTs），这些试验评估了曲马多或曲马多联合对乙酰氨基酚（扑热息痛）或NSAIDs与安慰剂或任何对照物相比，对骨关节炎患者的疗效。
我们采用了Cochrane预期的标准方法程序。
我们纳入了22项RCTs（比之前的综述多11项），其中21项RCTs被纳入荟萃分析，3871名参与者被随机分配至单独使用曲马多或曲马多联合另一种镇痛药组，2625名参与者被随机分配至安慰剂或活性对照组。17项研究评估了单独使用曲马多，5项研究评估了曲马多联合对乙酰氨基酚。13项研究使用了安慰剂对照，11项研究使用了活性对照（两项试验同时设有安慰剂和活性组）。曲马多的剂量范围为每日37.5mg至400mg；所有剂量均进行了汇总。大多数试验为多中心试验，平均持续时间为两个月。参与者主要为患有髋部或膝部骨关节炎的女性，平均年龄为63岁，疼痛程度为中度至重度。由于只有4项试验报告了充分的随机序列产生和分配隐藏，因此存在较高的选择偏倚风险。由于大多数研究对参与者进行了盲法处理，因此存在较低的实施偏倚风险。由于22项试验中有10项显示结局数据不完整，因此存在较高的失访偏倚风险。大多数试验由制药行业资助。
中等质量证据（因偏倚风险而降级）表明，与安慰剂对照相比，单独使用曲马多以及曲马多联合对乙酰氨基酚在减轻疼痛方面没有重要益处（单独使用曲马多：绝对改善率4%，95%置信区间（CI）3%至5%；8项研究，3972名参与者；曲马多联合对乙酰氨基酚：绝对改善率4%，95%CI 2%至6%；2项研究，614名参与者）。
曲马多组中每100人中有15人改善了20%（这相当于临床上重要的疼痛差异），而安慰剂组中每100人中有10人（绝对改善率5%）。曲马多联合对乙酰氨基酚组中每100人中有12人改善了20%，而安慰剂组中每100人中有7人（绝对改善率5%）。
中等质量证据（因偏倚风险而降级）表明，与安慰剂相比，单独使用曲马多以及曲马多联合对乙酰氨基酚在身体功能方面没有重要益处（单独使用曲马多：绝对改善率4%，95%CI 2%至6%；5项研究，2550名参与者；曲马多联合对乙酰氨基酚：绝对改善率4%，95%CI 2%至7%；2项研究，614名参与者）。
曲马多组中每100人中有21人改善了20%（这相当于临床上重要的身体功能差异），而安慰剂组中每100人中有16人（绝对改善率5%）。曲马多联合对乙酰氨基酚组中每100人中有15人改善了20%，而安慰剂组中每100人中有10人（绝对改善率5%）。
中等质量证据（因偏倚风险而降级）表明，与安慰剂相比，单独使用曲马多发生不良事件的风险更高（风险比（RR）1.34，95%CI 1.24至1.46；4项研究，2039名参与者），曲马多联合对乙酰氨基酚与安慰剂相比发生不良事件的风险更高（RR 1.91，95%CI 1.32至2.76；1项研究，308名参与者）。这相当于单独使用曲马多增加了（95%CI 12%至23%）17%，曲马多联合对乙酰氨基酚增加了（95%CI 8%至41%）22%。
最常见的三种不良事件是恶心、头晕和疲劳。中等质量证据（因偏倚风险而降级）表明，与安慰剂相比，单独使用曲马多因不良事件退出研究的风险更高（RR 2.64，95%CI 2.17至3.20；9项研究，4533名参与者），这相当于增加了（95%CI 9%至16%）12%。
低质量证据（因偏倚风险和不一致性而降级）表明，与安慰剂相比，曲马多联合对乙酰氨基酚因不良事件退出研究的风险更高（RR 2.78，95%CI 1.50至5.16；2项研究，614名参与者），这相当于绝对改善率增加了（95%CI 2%至19%）8%。
低质量证据（因偏倚风险和不精确性而降级）表明，与安慰剂相比，单独使用曲马多发生严重不良事件的风险更高（曲马多组2459名参与者中有110人，安慰剂组1153名参与者中有22人；RR 1.78，95%CI 1.11至2.84；7项研究，3612名参与者），这相当于增加了（95%CI 0%至4%）1%。在一项关于曲马多联合对乙酰氨基酚与安慰剂的小型研究（15名参与者）中，未报告严重不良事件。
中等质量证据表明，与安慰剂相比，单独使用曲马多或曲马多联合对乙酰氨基酚可能对骨关节炎患者的平均疼痛或功能没有重要益处，尽管曲马多组中报告有重要改善（定义为20%或更多）的人数略多。中等质量证据表明，不良事件可能导致更多参与者停止服用曲马多。由于事件数量较少，曲马多导致严重不良事件增加的情况不太确定。
