Cooper Tess E, Wiffen Philip J, Heathcote Lauren C, Clinch Jacqui, Howard Richard, Krane Elliot, Lord Susan M, Sethna Navil, Schechter Neil, Wood Chantal
Cochrane Pain, Palliative and Supportive Care Group, Pain Research Unit, Churchill Hospital, Churchill Hospital, Oxford, Oxfordshire, UK, OX3 7LE.
Cochrane Database Syst Rev. 2017 Aug 5;8(8):CD012536. doi: 10.1002/14651858.CD012536.pub2.
BACKGROUND: Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as importantWe designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents.As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (that is pain lasting three months or longer) can occur in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) relating to genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and for other unknown reasons.Antiepileptic (anticonvulsant) drugs, which were originally developed to treat convulsions in people with epilepsy, have in recent years been used to provide pain relief in adults for many chronic painful conditions and are now recommended for the treatment of chronic pain in the WHO list of essential medicines. Known side effects of antiepileptic drugs range from sweating, headache, elevated temperature, nausea, and abdominal pain to more serious effects including mental or motor function impairment. OBJECTIVES: To assess the analgesic efficacy and adverse events of antiepileptic drugs used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews as well as online clinical trial registries. SELECTION CRITERIA: Randomised controlled trials, with or without blinding, by any route, treating chronic non-cancer pain in children and adolescents, comparing any antiepileptic drug with placebo or an active comparator. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods if data were available. We assessed the evidence using GRADE and created two 'Summary of findings' tables. MAIN RESULTS: We included two studies with a total of 141 participants (aged 7 to 18 years) with chronic neuropathic pain, complex regional pain syndrome type 1 (CRPS-I), or fibromyalgia. One study investigated pregabalin versus placebo in participants with fibromyalgia (107 participants), and the other study investigated gabapentin versus amitriptyline in participants with CRPS-I or neuropathic pain (34 participants). We were unable to perform any quantitative analysis.Risk of bias for the two included studies varied, due to issues with randomisation (low to unclear risk), blinding of outcome assessors (low to unclear risk), reporting bias (low to unclear risk), the size of the study populations (high risk), and industry funding in the 'other' domain (low to unclear risk). We judged the remaining domains of sequence generation, blinding of participants and personnel, and attrition as low risk of bias. Primary outcomesOne study (gabapentin 900 mg/day versus amitriptyline 10 mg/day, 34 participants, for 6 weeks) did not report our primary outcomes (very low-quality evidence).The second study (pregabalin 75 to 450 mg/day versus placebo 75 to 450 mg/day, 107 participants, for 15 weeks) reported no significant change in pain scores for pain relief of 30% or greater between pregabalin 18/54 (33.3%), and placebo 16/51 (31.4%), P = 0.83 (very low-quality evidence). This study also reported Patient Global Impression of Change, with the percentage of participants feeling "much or very much improved" with pregabalin 53.1%, and placebo 29.5% (very low-quality evidence).We downgraded the evidence by three levels to very low for one of two reasons: due to the fact that there was no evidence to support or refute the use of the intervention, or that there were too few data and the number of events was too small to be meaningful. Secondary outcomesIn one small study, adverse events were uncommon: gabapentin 2 participants (2 adverse events); amitriptyline 1 participant (1 adverse event) (6-week trial). The second study reported a higher number of adverse events: pregabalin 38 participants (167 adverse events); placebo 34 participants (132 adverse events) (15-week trial) (very low-quality evidence).Withdrawals due to adverse events were infrequent in both studies: pregabalin (4 participants), placebo (4 participants), gabapentin (2 participants), and amitriptyline (1 participant) (very low-quality evidence).Serious adverse events were reported in both studies. One study reported only one serious adverse event (cholelithiasis and major depression resulting in hospitalisation in the pregabalin group) and the other study reported no serious adverse events (very low-quality evidence).There were few or no data for our remaining secondary outcomes (very low-quality evidence).We downgraded the evidence by three levels to very low due to too few data and the fact that the number of events was too small to be meaningful. AUTHORS' CONCLUSIONS: This review identified only two small studies, with insufficient data for analysis.As we could undertake no meta-analysis, we were unable to comment about efficacy or harm from the use of antiepileptic drugs to treat chronic non-cancer pain in children and adolescents. Similarly, we could not comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life.We know from adult randomised controlled trials that some antiepileptics, such as gabapentin and pregabalin, can be effective in certain chronic pain conditions.We found no evidence to support or refute the use of antiepileptic drugs to treat chronic non-cancer pain in children and adolescents.
背景:疼痛是全球儿童和青少年时期的常见特征,对许多年轻人来说,这种疼痛是慢性的。世界卫生组织(WHO)关于儿童持续性疼痛药物治疗的指南承认,儿童疼痛是世界上大多数地区高度重视的主要公共卫生问题。过去,疼痛在很大程度上被忽视,常常得不到治疗,但随着时间的推移,人们对儿童疼痛的看法发生了变化,现在疼痛缓解被视为很重要的事情。我们设计了一组关于慢性非癌性疼痛和癌性疼痛的七项综述(涉及抗抑郁药、抗癫痫药、非甾体抗炎药、阿片类药物和对乙酰氨基酚),以便回顾在儿童和青少年中使用药物干预治疗儿童疼痛的证据。作为当今世界发病的主要原因,慢性病(及其相关疼痛)是一个主要的健康问题。慢性疼痛(即持续三个月或更长时间的疼痛)可发生在儿科人群中,其病理生理分类多种多样(伤害性、神经性或特发性),与遗传疾病、神经损伤疼痛、慢性肌肉骨骼疼痛和慢性腹痛以及其他不明原因有关。抗癫痫(抗惊厥)药物最初是为治疗癫痫患者的惊厥而开发的,近年来已被用于为成年人缓解多种慢性疼痛病症的疼痛,现在被推荐用于治疗WHO基本药物清单中的慢性疼痛。抗癫痫药物已知的副作用范围从出汗、头痛、体温升高、恶心和腹痛到更严重的影响,包括精神或运动功能损害。 目的:评估用于治疗出生至17岁儿童和青少年慢性非癌性疼痛的抗癫痫药物的镇痛效果和不良事件,适用于任何情况。 检索方法:我们通过Cochrane在线研究注册库检索了Cochrane对照试验中心注册库(CENTRAL),通过Ovid检索了MEDLINE,并通过Ovid检索了Embase,检索时间从数据库建立至2016年9月6日。我们还检索了检索到的研究和综述的参考文献列表以及在线临床试验注册库。 选择标准:随机对照试验,无论是否采用盲法,通过任何途径,治疗儿童和青少年慢性非癌性疼痛,将任何抗癫痫药物与安慰剂或活性对照进行比较。 数据收集与分析:两位综述作者独立评估研究的纳入资格。如果有可用数据,我们计划使用二分数据来计算风险比和需治疗人数以获得一个额外事件,使用标准方法。我们使用GRADE评估证据并创建了两个“结果总结”表。 主要结果:我们纳入了两项研究,共有141名参与者(年龄7至18岁),患有慢性神经性疼痛、1型复杂性区域疼痛综合征(CRPS-I)或纤维肌痛。一项研究在纤维肌痛参与者中比较了普瑞巴林与安慰剂(107名参与者),另一项研究在CRPS-I或神经性疼痛参与者中比较了加巴喷丁与阿米替林(34名参与者)。我们无法进行任何定量分析。两项纳入研究的偏倚风险各不相同,原因包括随机化问题(低至不明确风险)、结果评估者的盲法(低至不明确风险)、报告偏倚(低至不明确风险)、研究人群规模(高风险)以及“其他”领域的行业资助(低至不明确风险)。我们将序列生成、参与者和人员的盲法以及失访的其余领域判断为低偏倚风险。主要结局一项研究(加巴喷丁900毫克/天与阿米替林10毫克/天,34名参与者,为期6周)未报告我们的主要结局(极低质量证据)。第二项研究(普瑞巴林75至450毫克/天与安慰剂75至450毫克/天,107名参与者,为期15周)报告,普瑞巴林组疼痛缓解30%或更高的疼痛评分与安慰剂组相比无显著变化,普瑞巴林组为18/54(33.3%),安慰剂组为16/51(31.4%),P = 0.83(极低质量证据)。该研究还报告了患者总体变化印象,普瑞巴林组感觉“有很大改善或非常有改善”的参与者百分比为53.1%,安慰剂组为29.5%(极低质量证据)。由于以下两个原因之一,我们将证据降级三级至极低:没有证据支持或反驳该干预措施的使用,或者数据太少且事件数量太少以至于无意义。次要结局在一项小型研究中,不良事件不常见:加巴喷丁2名参与者(2次不良事件);阿米替林1名参与者(1次不良事件)(为期6周的试验)。第二项研究报告的不良事件数量较多:普瑞巴林38名参与者(167次不良事件);安慰剂34名参与者(132次不良事件)(为期15周的试验)(极低质量证据)。两项研究中因不良事件导致的退出情况都很少见:普瑞巴林(4名参与者)、安慰剂(4名参与者)、加巴喷丁(2名参与者)和阿米替林(1名参与者)(极低质量证据)。两项研究均报告了严重不良事件。一项研究仅报告了1例严重不良事件(普瑞巴林组的胆石症和重度抑郁症导致住院),另一项研究未报告严重不良事件(极低质量证据)。我们其余次要结局的数据很少或没有(极低质量证据)。由于数据太少且事件数量太少以至于无意义,我们将证据降级三级至极低。 作者结论:本综述仅确定了两项小型研究,数据不足以进行分析。由于我们无法进行荟萃分析,因此无法评论使用抗癫痫药物治疗儿童和青少年慢性非癌性疼痛的疗效或危害。同样,我们无法对其余次要结局发表评论:照顾者总体变化印象;急救镇痛需求;睡眠时间和质量;治疗的可接受性;身体功能;以及生活质量。我们从成人随机对照试验中了解到,一些抗癫痫药物,如加巴喷丁和普瑞巴林,在某些慢性疼痛病症中可能有效。我们没有发现证据支持或反驳使用抗癫痫药物治疗儿童和青少年慢性非癌性疼痛。
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