title: Systemic administration of local anesthetic agents to relieve neuropathic pain.
abstract: 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 (Keats 1951; Gilbert 1951; De Clive-Lowe 1958; Bartlett 1961). 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 (Boas 1982; Lindblom 1984; Petersen 1986; Dunlop 1988; Bach 1990; Awerbuch 1990). 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.
  
  
  
  To evaluate pain relief and adverse effect rates between systemic local anesthetic-type drugs and other control interventions.
  
  
  
  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.
  
  
  
  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.
  
  
  
  We collected efficacy and safety data from all published and unpublished trials.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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Notes
  2017
  A restricted search in June 2017 did not identify any potentially relevant studies likely to change the conclusions. Therefore, this review has now been stabilised following discussion with the authors and editors. If appropriate, we will update the review if new evidence likely to change the conclusions is published, or if standards change substantially which necessitate major revisions.
  
  2019
  We performed another restricted search in September 2019 but did not identify any potentially relevant studies likely to change the conclusions. Therefore, this review has now been stabilised following discussion with the authors and editors, and we will reassess the review for updating in 2020. If appropriate, we will update the review sooner if new evidence likely to change the conclusions is published, or if standards change substantially which necessitate major revisions.
  
  2020
  We performed another restricted search in September 2020 but again did not identify any potentially relevant studies likely to change the conclusions. This area of research is not active and therefore this review has now been stabilised following discussion with the authors and editors; we will reassess the review for updating in 2025. If appropriate, we will update the review sooner if new evidence likely to change the conclusions is published, or if standards change substantially which necessitate major revisions.
authors.forename: V
authors.initials: V
authors.lastname: Challapalli
authors.forename: I W
authors.initials: IW
authors.lastname: Tremont-Lukats
authors.forename: E D
authors.initials: ED
authors.lastname: McNicol
authors.forename: J
authors.initials: J
authors.lastname: Lau
authors.forename: D B
authors.initials: DB
authors.lastname: Carr
mesh_terms: D000284:Administration, Oral; D018686:Anesthetics, Intravenous / Q000008:administration & dosage; D000779:Anesthetics, Local / Q000008:administration & dosage*; D005424:Flecainide / Q000008:administration & dosage; D006801:Humans; D008012:Lidocaine / Q000008:administration & dosage* / Q000031:analogs & derivatives; D008801:Mexiletine / Q000008:administration & dosage; D009422:Nervous System Diseases / Q000150:complications*; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D016032:Randomized Controlled Trials as Topic; D016677:Tocainide / Q000008:administration & dosage
chemical_list: D018686:Anesthetics, Intravenous; D000779:Anesthetics, Local; D008801:Mexiletine; D016677:Tocainide; D008012:Lidocaine; D005424:Flecainide