Treatment of familial erythermalgia with the association of lidocaine and mexiletine

Service de Dermatologie, CHU, 5, avenue Foch, 29200 Brest.
Annales de Dermatologie et de Vénéréologie (Impact Factor: 0.67). 05/2003; 130(4):429-33.
Source: PubMed

ABSTRACT Erythermalgia is a rare acrosyndrome characterized by reddening of the skin, local increase heat and pain. The disease is frequently resistant to treatment. Recently, Kuhnert et al. presented very favorable results using a combination of lidocaine and mexiletine. We used this treatment in 4 patients suffering from familial erythermalgia.
In a family exhibiting severe familial erythermalgia involving 5 members over 3 generations, we treated 4 patients aged 41, 39, 19 and 15 years. In these patients, the erythermalgia known since early childhood, progressed in the form of multiple flares (6 to 7/day) during the day and at night, lasting several hours and often accompanied by headaches. The impact of the disease on their quality of life was major. Only cold-water baths provided temporary relief, obliging them to live with their "feet in cold water". After they had been informed of the modalities of treatment and in the absence of any contraindication, notably cardiologic, 200 mg (100 mg in the youngest patient) of lidocaine were infused in 4 hours in a single intravenous injection on the first day. Mixelitine was introduced on the second day at the dose of 600 mg in 3 oral intakes (200 mg in the youngest patient). The painful paroxistic symptomatology rapidly improved and the flares had disappeared on the 3dr day, thus permitting the progressive reduction in analgesics and major improvement in quality of life. This beneficial effect persisted with oral mexiletine alone, 2 years after the infusion of lidocaine in the first patient treated (and one year after in the other patients).
Primary familial erythermalgia is highly resistant to treatment. The combined action of lidocain and mexiletine, usually well tolerated (class IB antiarrythmic), blocks the sodium channels. The mechanism of action of their analgesic effect is peripheral or central or even mixed. This benefit warrants confirmation in other forms of erythermalgia.

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    • "In comparison, gain-of-function mutations in the related SCN9A gene, which encodes NaV1.7, can result in primary erythromelalgia (PEM), either a familial or a sporadic chronic neuropathic pain syndrome (Dib-Hajj et al., 2005). Several publications have reported an analgesic effect of mexiletine in patients suffering from this monogenic pain disorder (Kuhnert et al., 1999; Legroux-Crespel et al., 2003; Dib-Hajj et al., 2005; Nathan et al., 2005; Choi et al., 2009). The apparent absence of pro-arrhythmic and other major adverse effects at analgesic doses of mexiletine points to a mode of action that preferentially affects pathological channels. "
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    ABSTRACT: Background and purposeThe non-selective sodium channel inhibitor mexiletine has been found to be effective in several animal models of chronic pain and became popular in the clinical setting as an orally available alternative to lidocaine. It remains unclear why patients with monogenic pain disorders secondary to gain-of-function SCN9a mutations benefit from a low systemic concentration of mexiletine, which usually does not induce adverse neurologic effects. The aim of this study was therefore to investigate the biophysical effects of mexiletine on the L858F primary erythromelalgia NaV1.7 mutation in vitro.Experimental approachHuman wildtype and L858F mutated NaV1.7 channels were expressed in HEK293A cells. Whole cell currents were recorded by voltage-clamp techniques to characterize the effect of mexiletine on channel gating properties.Key resultsWhile the concentration-dependent tonic block of peak currents by mexiletine was similar in wildtype (IC50 1.1±0.05 mM) and L858F channels (IC50 0.87±0.06 mM), phasic block was more pronounced in cells transfected with the L858F mutation. Moreover, mexiletine lead to a substantial shift in the pathologically hyperpolarized voltage-dependence of steady-state activation in L858F-mutated channels (+15.2 mV in V1/2, P<0.01) towards wildtype values and voltage-dependence of steady-state fast inactivation was shifted (-16.5 mV in V1/2, P<0.01) to more hyperpolarized potentials, leading to an overall reduction in window currents.Conclusion and implicationsMexiletine has a normalizing effect on pathological gating properties of the L858F gain-of-function mutation in NaV1.7, which might in part explain the beneficial effects of systemic treatment with mexiletine in patients with gain-of-function sodium channel disorders.
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