Systemic administration of local anesthetic agents to relieve neuropathic pain

 

Abstract

Background

Lidocaine, mexiletine, tocainide, and flecainide are local anesthetics which give an analgesic effect when administered orally or parenterally. Early reports described the use of intravenous lidocaine or procaine to relieve cancer and postoperative pain. Interest reappeared decades later when patient series and clinical trials reported that parenteral lidocaine and its oral analogs tocainide, mexiletine, and flecainide relieved neuropathic pain in some patients. With the recent publication of clinical trials with high quality standards, we have reviewed the use of systemic lidocaine and its oral analogs in neuropathic pain to update our knowledge, to measure their benefit and harm, and to better define their role in therapy.

Objectives

To evaluate pain relief and adverse effect rates between systemic local anesthetic-type drugs and other control interventions.

Search methods

We searched MEDLINE (1966 through 15 May 2004), EMBASE (January 1980 to December 2002), Cancer Lit (through 15 December 2002), Cochrane Central Register of Controlled Trials (2nd Quarter, 2004), System for Information on Grey Literature in Europe (SIGLE), and LILACS, from January 1966 through March 2001. We also hand searched conference proceedings, textbooks, original articles and reviews.

Selection criteria

We included trials with random allocation, that were double blinded, with a parallel or crossover design. The control intervention was a placebo or an analgesic drug for neuropathic pain from any cause.

Data collection and analysis

We collected efficacy and safety data from all published and unpublished trials. We calculated combined effect sizes using continuous and binary data for pain relief and adverse effects as primary and secondary outcome measurements, respectively.

Main results

Thirty-two controlled clinical trials met the selection criteria; two were duplicate articles. The treatment drugs were intravenous lidocaine (16 trials), mexiletine (12 trials), lidocaine plus mexiletine sequentially (one trial), and tocainide (one trial). Twenty-one trials were crossover studies, and nine were parallel. Lidocaine and mexiletine were superior to placebo [weighted mean difference (WMD) = -11; 95% CI: -15 to -7; P < 0.00001], and limited data showed no difference in efficacy (WMD = -0.6; 95% CI: -7 to 6), or adverse effects versus carbamazepine, amantadine, gabapentin or morphine. In these trials, systemic local anesthetics were safe, with no deaths or life-threatening toxicities. Sensitivity analysis identified data distribution in three trials as a probable source of heterogeneity. There was no publication bias.

Authors' conclusions

Lidocaine and oral analogs were safe drugs in controlled clinical trials for neuropathic pain, were better than placebo, and were as effective as other analgesics. Future trials should enroll specific diseases and test novel lidocaine analogs with better toxicity profiles. More emphasis is necessary on outcomes measuring patient satisfaction to assess if statistically significant pain relief is clinically meaningful.

 

Plain language summary

Systemic administration of local anesthetic agents to relieve neuropathic pain

Intravenous lidocaine and oral derivatives relieve pain from damage to the nervous system (neuropathic pain). In early reports, intravenous lidocaine and its oral analogs mexiletine and tocainide relieved neuropathic pain, a type of pain caused by disease in the nervous system. However, the evidence was conflicting. The authors reviewed all randomized studies comparing these drugs with placebo or with other analgesics and found that: local anesthetics were superior to placebo in decreasing intensity of neuropathic pain; limited data showed no difference in efficacy or adverse effects between local anesthetics and carbamazepine, amantadine, gabapentin or morphine; local anesthetics had more adverse effects than placebo; and local anesthetics were safe.

 

摘要

背景

全身性給予局部麻醉劑緩解神經性疼痛的療效

局部麻醉劑如Lidocaine, mexiletine, tocainide 及flecainide，以口服或腸道外投予時具有止痛效果。在早年有報告指出靜脈投予lidocaine 或 procaine能緩解癌症及術後的疼痛。數十年後，當病人及許多臨床試驗報告腸道外投予lidocaine及其口服衍生物tocainide, mexiletine及flecainide能緩解某些病人的神經痛，又再度引起了人們的興趣。為了增進我們的知識，評估其效益及傷害，並對其在治療上的角色有更好的定位，我們以近期一些已發表的高品質標準之臨床試驗來回顧全身性投予lidocaine及其口服衍生物在治療神經性疼痛上的使用。

目標

評估全身性使用局部麻醉型藥物與其他控制性介入在疼痛緩解及不良反應上的差異

搜尋策略

我們尋找了MEDLINE (1966 through 15 May 2004), EMBASE (January 1980 to December 2002), Cancer Lit (through15 December 2002), Cochrane Central Register of Controlled Trials (2nd Quarter,2004), System for Information on Grey Literature in Europe (SIGLE), 及LILACS等資料庫自1966年一月到2001年三月之資料。也一一翻閱了研討會會議紀錄、教科書、原始著作及回顧性文章等資料。

選擇標準

我們將雙盲(double blinded)、平行(parallel)或交叉(crossover)設計的隨機分配(random allocation)試驗都包含在內。控制性介入(control intervention)包括安慰劑或任何用於控制神經性疼痛的止痛劑。

資料收集與分析

我們收集所有已發表及未發表臨床試驗中療效及安全性的資料。我們將試驗中有關疼痛緩解的連續及二元變項的數據合併後計算出效應值(effect size)，並視為主要結果測量；不良反應部分也以同樣方式來計算，但視為次要結果測量。」

主要結論

32個對照臨床試驗符合納入條件；2篇為重複的文章。治療藥物包括靜脈投予的lidocaine (16 個試驗)， mexiletine (12個試驗)， 先用lidocaine 隨後用 mexiletine (1個試驗)， 以及 tocainide (1個試驗)。21個試驗為交叉性研究(crossover studies)，9個為平行(parallel)研究。Lidocaine 及 mexiletine優於安慰劑[weighted mean difference (WMD) = −11; 95% CI: −15 to −7; P <0.00001]，有限的數據顯示lidocaine 及 mexiletine與carbamazepine, amantadine, gabapentin 或 morphine相較下，在療效(WMD = −0.6; 95% CI: −7 to 6)或不良反應上並無差異。在這些試驗中，全身性給予局部麻醉劑是安全的，沒有死亡或是危及生命的毒性發生。敏感度分析找出三個試驗為造成異質性的可能來源。分析中並未發現發表偏倚(publication bias)。

作者結論

在治療神經性疼痛的對照臨床試驗中，Lidocaine 及其口服衍生物與安慰劑相較下是安全的藥物，療效則與其他止痛劑相當。未來的試驗應該針對特定疾病並以毒性等級更安全的新一代Lidocaine衍生物進行測試。要評估疼痛緩解具有統計顯著意義時是否也具有臨床上的意義，則有必要多瞭解病人用藥後滿意度的測量。

翻譯人

本摘要由三軍總醫院洪乃勻翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

靜脈投予lidocaine及其口服衍生物能緩解神經系統損傷引起的疼痛(神經性疼痛)。 在早年的報告中，靜脈投予lidocaine及其口服衍生物mexiletine 及 tocainide能緩解神經性疼痛 (一種神經系統疾病導致的疼痛類型)。然而，其證據卻是互有衝突。作者回顧了所有將這些藥品與安慰劑或是其他止痛劑做比較的隨機研究發現：局部麻醉劑在降低神經性疼痛的強度優於安慰劑；有限的數據顯示局部麻醉劑與carbamazepine, amantadine, gabapentin 或 morphine相較下，在療效與不良反應上並無差異；局部麻醉劑的不良反應比安慰劑多；局部麻醉劑是安全的。