Systemic administration of local anesthetic agents to relieve neuropathic pain Stable (no update expected for reasons given in 'What's new')



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.


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We collected efficacy and safety data from all published and unpublished trials.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.


Vidya Challapalli, Ivo W Tremont‐Lukats, Ewan D McNicol, Joseph Lau, Daniel B Carr


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.


Vidya Challapalli, Ivo W Tremont‐Lukats, Ewan D McNicol, Joseph Lau, Daniel B Carr

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

The role of lidocaine and its oral analogs to control neuropathic pain was unclear until recently. This lack of definition was due to the multifaceted nature of neuropathic pain, the statistical and clinical heterogeneity of many of the trials, and few study participants. These drugs can relieve pain in selected patients with neuropathic pain, compared with placebo. We found evidence suggesting that this analgesic effect is also clinically important.

Implications for research 

There should be greater emphasis on accruing patients with neuropathic pain caused by one disease, with well‐structured, consistent trials with active placebos or active drug controls to evaluate the efficacy of local anesthetic‐type drugs in the treatment of neuropathic pain from specific etiologies. Future trials should also explore subcutaneous infusions with lidocaine, and move to newer oral analogs with more specificity to sodium channel receptor subtypes and fewer adverse effects. In addition, we recommend that future trials include quality of life or global satisfaction endpoints (Rogers 2000; Turk 2003).

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