Wrzosek Anna, Woron Jaroslaw, Dobrogowski Jan, Jakowicka-Wordliczek Joanna, Wordliczek Jerzy
1st Department of Anaesthesiology and Intensive Care, University Hospital, Kopernika 36, Krakow, Poland, 31-501.
Cochrane Database Syst Rev. 2015 Aug 31;8(8):CD010967. doi: 10.1002/14651858.CD010967.pub2.
Clonidine is a presynaptic alpha-2-adrenergic receptor agonist used for many years to treat hypertension and other conditions, including chronic pain. Adverse events associated with systemic use of the drug have limited its application. Topical use of drugs is currently gaining interest, as it may limit adverse events without loss of analgesic efficacy. Topical clonidine (TC) formulations have been investigated recently in clinical trials.
The objectives of this review were to assess the analgesic efficacy of TC for chronic neuropathic pain in adults and to assess the frequency of adverse events associated with clinical use of TC for chronic neuropathic pain.
We searched the Cochrane Register of Studies (CRS) Online (Cochrane Central Register of Controlled Trials (CENTRAL)), MEDLINE and EMBASE databases, reference lists of retrieved papers and trial registries, and we contacted experts in the field. We performed the most recent search on 17 September 2014.
We included randomised, double-blind studies of at least two weeks' duration comparing TC versus placebo or other active treatment in patients with chronic neuropathic pain.
Two review authors extracted data from the studies and assessed bias. We planned three tiers of evidence analysis. The first tier was designed to analyse data meeting current best standards, by which studies reported the outcome of at least 50% pain intensity reduction over baseline (or its equivalent) without use of the last observation carried forward or other imputation method for dropouts, reported an intention-to-treat (ITT) analysis, lasted eight weeks or longer, had a parallel-group design and included at least 200 participants (preferably at least 400) in the comparison. The second tier was designed to use data from at least 200 participants but in cases in which one of the above conditions was not met. The third tier of evidence was assumed in other situations.
We included two studies in the review, with a total of 344 participants. Studies lasted 8 weeks and 12 weeks and compared TC versus placebo. 0.1%. TC was applied in gel form to the painful area two to three times daily.Studies included in this review were subject to potential bias and were classified as of moderate or low quality. One drug manufacturer supported both studies.We found no top-tier evidence for TC in neuropathic pain. Second-tier evidence indicated slight improvement after the drug was used in study participants with painful diabetic neuropathy (PDN). A greater number of participants in the TC group had at least 30% reduction in pain compared with placebo (risk ratio (RR) 1.35, 95% confidence interval (CI) 1.03 to 1.77; number needed to treat for an additional beneficial outcome (NNTB) 8.33, 95% CI 4.3 to 50). Third-tier evidence indicated that TC was no better than placebo for achieving at least 50% reduction in pain intensity and on the Patient Global Impression of Change Scale. The two included studies could be subject to significant bias. We found no studies that reported other neuropathic pain conditions.The rate of adverse events did not differ between groups, with the exception of a higher incidence of mild skin reactions in the placebo group, which should have no clinical significance.
AUTHORS' CONCLUSIONS: Limited evidence from a small number of studies of moderate to low quality suggests that TC may provide some benefit in peripheral diabetic neuropathy. The drug may be useful in situations for which no better treatment options are available because of lack of efficacy, contraindications or adverse events. Additional trials are needed to assess TC in other neuropathic pain conditions and to determine how patients who have a chance to respond to the drug should be selected for treatment.
可乐定是一种突触前α-2肾上腺素能受体激动剂,多年来一直用于治疗高血压及其他病症,包括慢性疼痛。该药物全身用药相关的不良事件限制了其应用。目前局部用药受到关注,因为它可能在不损失镇痛效果的情况下限制不良事件。局部用可乐定(TC)制剂最近已在临床试验中得到研究。
本综述的目的是评估TC治疗成人慢性神经性疼痛的镇痛效果,并评估TC用于慢性神经性疼痛临床治疗相关不良事件的发生频率。
我们检索了Cochrane在线研究注册库(Cochrane对照试验中心注册库(CENTRAL))、MEDLINE和EMBASE数据库、检索论文的参考文献列表及试验注册库,并联系了该领域的专家。我们于2014年9月17日进行了最新检索。
我们纳入了至少为期两周的随机、双盲研究,比较TC与安慰剂或其他活性治疗对慢性神经性疼痛患者的疗效。
两位综述作者从研究中提取数据并评估偏倚。我们计划进行三个层次的证据分析。第一层旨在分析符合当前最佳标准的数据,即研究报告在未使用末次观察结转或其他针对失访的插补方法的情况下,疼痛强度较基线降低至少50%(或其等效值)的结果,报告意向性分析(ITT),持续8周或更长时间,采用平行组设计,且比较中纳入至少200名参与者(最好至少400名)。第二层旨在使用至少200名参与者的数据,但存在上述条件之一未满足的情况。在其他情况下采用第三层证据。
我们在综述中纳入了两项研究,共344名参与者。研究持续8周和12周,比较了TC与安慰剂。0.1%。TC以凝胶形式每日涂于疼痛部位两到三次。本综述纳入的研究存在潜在偏倚,质量被归类为中等或低等。两项研究均由同一家药品制造商资助。我们未发现TC治疗神经性疼痛的顶级证据。第二层证据表明,在患有疼痛性糖尿病神经病变(PDN)的研究参与者中使用该药物后有轻微改善。与安慰剂相比,TC组有更多参与者疼痛至少减轻30%(风险比(RR)为1.35,95%置信区间(CI)为1.03至1.77;为获得额外有益结果所需治疗人数(NNTB)为8.33,95%CI为4.3至50)。第三层证据表明,在疼痛强度至少降低50%以及在患者总体变化印象量表方面,TC并不比安慰剂更好。纳入的两项研究可能存在显著偏倚。我们未发现报告其他神经性疼痛病症的研究。除安慰剂组轻度皮肤反应发生率较高外,两组不良事件发生率无差异,而这一差异应无临床意义。
来自少数质量中等或低等研究的有限证据表明,TC可能对周围性糖尿病神经病变有一定益处。在因疗效不佳、禁忌证或不良事件而没有更好治疗选择的情况下,该药物可能有用。需要更多试验来评估TC在其他神经性疼痛病症中的效果,并确定应如何选择可能对该药物有反应的患者进行治疗。