Bell Rae F, Eccleston Christopher, Kalso Eija A
Regional Centre of Excellence in Palliative Care, Haukeland University Hospital, Bergen, Norway.
Cochrane Database Syst Rev. 2017 Jun 28;6(6):CD003351. doi: 10.1002/14651858.CD003351.pub3.
This is an update of a review first published in 2003 and updated in 2012.Ketamine is a commonly used anaesthetic agent, and in subanaesthetic doses is also given as an adjuvant to opioids for the treatment of refractory cancer pain, when opioids alone or in combination with appropriate adjuvant analgesics prove to be ineffective. Ketamine is known to have psychomimetic (including hallucinogenic), urological, and hepatic adverse effects.
To determine the effectiveness and adverse effects of ketamine as an adjuvant to opioids for refractory cancer pain in adults.
For this update, we searched MEDLINE (OVID) to December 2016. We searched CENTRAL (CRSO), Embase (OVID) and two clinical trial registries to January 2017.
The intervention considered by this review was the addition of ketamine, given by any route of administration, in any dose, to pre-existing opioid treatment given by any route and in any dose, compared with placebo or active control. We included studies with a group size of at least 10 participants who completed the trial.
Two review authors independently assessed the search results and performed 'Risk of bias' assessments. We aimed to extract data on patient-reported pain intensity, total opioid consumption over the study period; use of rescue medication; adverse events; measures of patient satisfaction/preference; function; and distress. We also assessed participant withdrawal (dropout) from trial. We assessed the quality of the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation).
One new study (185 participants) was identified by the updated search and included in the review. We included a total of three studies in this update.Two small studies, both with cross-over design, with 20 and 10 participants respectively, were eligible for inclusion in the original review. One study with 20 participants examined the addition of intrathecal ketamine to intrathecal morphine, compared with intrathecal morphine alone. The second study with 10 participants examined the addition of intravenous ketamine bolus in two different doses to ongoing morphine therapy, compared with placebo. Both of these studies reported reduction in pain intensity and reduction in morphine requirements when ketamine was added to opioid for refractory cancer pain. The new study identified by the updated search had a parallel group design and 185 participants. This placebo-controlled study examined rapid titration of subcutaneous ketamine to high dose (500 mg) in participants who were using different opioids. There were no differences between groups for patient-reported pain intensity.Pooling of the data from the three included trials was not appropriate because of clinical heterogeneity.The study examining intrathecal drug administration reported no adverse events related to ketamine. In the study using intravenous bolus administration, ketamine caused hallucinations in four of 10 participants. In the rapid dose escalation/high-dose subcutaneous ketamine study, there was almost twice the incidence of adverse events in the ketamine group, compared to the placebo group, with the most common adverse events being needle site irritation and cognitive disturbance. Two serious adverse events (bradyarrhythmia and cardiac arrest) thought to be related to ketamine were also reported in this trial.For all three studies there was an unclear risk of bias overall. Using GRADE, we judged the quality of the evidence to be very low due to study limitations and imprecision due to the small number of participants in all comparisons.
AUTHORS' CONCLUSIONS: Current evidence is insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids for the relief of refractory cancer pain. The evidence was of very low quality, meaning that it does not provide a reliable indication of the likely effect, and the likelihood that the effect will be substantially different is high. Rapid dose escalation of ketamine to high dose (500 mg) does not appear to have clinical benefit and may be associated with serious adverse events. More randomised controlled trials (RCTs) examining specific low-dose ketamine clinical regimens in current use are needed.
这是一篇综述的更新版，该综述首次发表于2003年，2012年进行过更新。氯胺酮是一种常用的麻醉剂，在亚麻醉剂量下也可作为阿片类药物的辅助药物，用于治疗难治性癌痛，当单独使用阿片类药物或与适当的辅助镇痛药联合使用无效时。已知氯胺酮具有拟精神作用（包括致幻作用）、泌尿系统和肝脏不良反应。
确定氯胺酮作为阿片类药物辅助剂治疗成人难治性癌痛的有效性和不良反应。
本次更新时，我们检索了截至2016年12月的MEDLINE（OVID）。我们检索了截至2017年1月的CENTRAL（CRSO）、Embase（OVID）和两个临床试验注册库。
本综述考虑的干预措施是，与安慰剂或活性对照相比，将通过任何给药途径、任何剂量给予的氯胺酮添加到通过任何途径、任何剂量给予的现有阿片类药物治疗中。我们纳入了每组至少有10名参与者并完成试验的研究。
两位综述作者独立评估检索结果并进行“偏倚风险”评估。我们旨在提取关于患者报告的疼痛强度、研究期间阿片类药物总消耗量、急救药物的使用、不良事件、患者满意度/偏好的测量、功能和痛苦的数据。我们还评估了试验参与者的退出（失访）情况。我们使用GRADE（推荐分级评估、制定和评价）评估证据质量。
更新后的检索确定了一项新研究（185名参与者）并纳入本综述。本次更新我们共纳入了三项研究。两项小型研究均采用交叉设计，分别有20名和10名参与者，符合纳入原始综述的条件。一项有20名参与者的研究，将鞘内注射氯胺酮添加到鞘内注射吗啡中，并与单独鞘内注射吗啡进行比较。第二项有10名参与者的研究，将两种不同剂量的静脉注射氯胺酮推注添加到正在进行的吗啡治疗中，并与安慰剂进行比较。这两项研究均报告称，将氯胺酮添加到阿片类药物中治疗难治性癌痛时，疼痛强度降低，吗啡需求量减少。更新后的检索确定的新研究采用平行组设计，有185名参与者。这项安慰剂对照研究在使用不同阿片类药物的参与者中，研究了将皮下氯胺酮快速滴定至高剂量（500mg）的情况。患者报告的疼痛强度在组间无差异。由于临床异质性，对三项纳入试验的数据进行合并并不合适。研究鞘内给药的研究报告未发现与氯胺酮相关的不良事件。在使用静脉推注给药的研究中，氯胺酮导致10名参与者中的4名出现幻觉。在快速剂量递增/高剂量皮下氯胺酮研究中，氯胺酮组的不良事件发生率几乎是安慰剂组的两倍，最常见的不良事件是注射部位刺激和认知障碍。该试验还报告了两例被认为与氯胺酮相关的严重不良事件（缓慢性心律失常和心脏骤停）。对于所有三项研究，总体偏倚风险均不明确。使用GRADE，我们判断证据质量非常低，原因是研究存在局限性且由于所有比较中的参与者数量较少而导致结果不精确。
目前的证据不足以评估氯胺酮作为阿片类药物辅助剂缓解难治性癌痛的益处和危害。证据质量非常低，这意味着它不能提供可能效果的可靠指示，而且效果可能有很大差异的可能性很高。将氯胺酮快速滴定至高剂量（500mg）似乎没有临床益处，且可能与严重不良事件相关。需要更多的随机对照试验来研究目前使用的特定低剂量氯胺酮临床方案。
