MEXILETINE FOR TREATMENT OF CHRONIC PAINFUL DIABETIC NEUROPATHY

doi:10.1016/S0140-6736(88)90999-3

The Lancet

Volume 331, Issues 8575–8576, 9 January 1988, Pages 9-11

https://doi.org/10.1016/S0140-6736(88)90999-3 Get rights and content

Abstract

Sixteen of nineteen patients completed a randomised double-blind crossover trial to assess the effect of oral mexiletine (10 mg/kg bodyweight daily) on the symptoms and signs of chronic painful diabetic neuropathy. The median age of the sixteen patients was 50 years (range 30-64). Assessment with a five-item clinical symptom scale showed significant improvement during the mexiletine phase compared with the placebo phase. Pain was reduced during mexiletine but not during placebo, as assessed by a visual analogue rating scale. Mexiletine treatment had no effect on tendon reflexes, vibration threshold levels, beat-to-beat variation in heart rate during deep breathing, and postural blood pressure response. Mild side-effects were seen in three of the sixteen patients during mexiletine treatment.

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Citation Excerpt :
Mexiletine [1-methyl-2-(2,6-xylyloxy)ethylamine hydrochloride] is a Class 1b antiarrhythmic that is structurally related to lidocaine; it blocks multiple NaV-type channels, including NaV1.2 [186], NaV1.4 [187], NaV1.5 [188], NaV1.7 [189], as well as tetrodotoxin-resistant Na+ currents (presumably mediated by NaV1.8 and/or NaV1.9; [138]) in DRG neurons [186]. Early reports suggested that orally administered mexiletine could possibly improve neuropathic pain associated with idiopathic sensorimotor polyneuropathy, chemotherapy administration, diabetes [190,191], and erythromelalgia [192,193]. Subsequent reports also suggested that oral mexiletine could improve pain symptoms in some, but perhaps not all, patients with NaV1.7-linked erythromelalgia [189,194,195].
Neuropathic pain arises from injury to the nervous system. Conditions associated with neuropathic pain are diverse, and lesions and/or pathological changes in the central nervous system (CNS) or peripheral nervous system (PNS) can frequently, but not always, be identified. It is difficult to treat, with patients often on multiple, different classes of medications, all with appreciable adverse side effect profiles. Consequently, there is a pressing need for the development of new medications. The development of such therapeutics is predicated on a clear understanding of the relevant molecular and cellular processes that contribute to the development, and maintenance, of the neuropathic pain state. One proposed mechanism thought to contribute to the ontogeny of neuropathic pain is altered expression, trafficking, and functioning of ion channels expressed by primary sensory neurons. Here, we will focus on three voltage-gated ion channel families, Ca_V, HCN, and Na_V, first reviewing the preclinical data and then the human data where it exists.
Fentanyl produces an anti-hyperalgesic effect through the suppression of sodium channels in mice with painful diabetic neuropathy
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Correspondingly, the percentage of large-soma DRG neurons expressing TTX-S Nav1.2, Nav1.3, Nav1.7, and TTX-R Nav1.9 significantly increased in diabetic animals, suggesting that these alterations may underlie the increased sodium currents in diabetic rats. In fact, some sodium channel blockers, such as lidocaine and mexiletine, effectively prevent the tactile allodynia associated with diabetes-induced neuropathy under clinical diabetic neuropathic pain conditions (Viola et al., 2006; Wolff et al., 2010; Dejgard et al., 1988; Oskarsson et al., 1997) and in rodent models of painful diabetic neuropathy (Kamei et al., 1995; Suzuki et al., 2011). In this regard, interestingly, the sodium channel openers fenvalerate and veratridine antagonized the anti-hyperalgesic effect of fentanyl in diabetic mice, but had no effect on the antinociception induced by fentanyl in non-diabetic mice.
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The published literature was systematically searched to identify randomized, controlled trials of all available pharmacologic treatments for pDPN (recommended or nonrecommended) reporting predefined efficacy and safety outcomes. Bayesian fixed-effect mixed treatment comparison methods were used to assess relative therapeutic efficacy and harms.
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MEXILETINE FOR TREATMENT OF CHRONIC PAINFUL DIABETIC NEUROPATHY

Abstract

Lancet

Am J Med

Pain

Pain

J Chromatogr

Pain

Imipramine treatment of painful diabetic neuropathy

JAMA

Symptomatic treatment of penpheral diabetic neuropathy with Carbarnarepine (Tegretol) Double-blind, cross-over trial

Diabetologia

Continuous subcutaneous insulin infusion in the management of painful diabetic neuropathy

Diabetes Care