Treatment of familial erythermalgia with the association of lidocaine and mexiletine
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. "
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.British Journal of Pharmacology 05/2014; 171(19). DOI:10.1111/bph.12788 · 4.99 Impact Factor
Article: Erythromelalgia[Show abstract] [Hide abstract]
ABSTRACT: No treatment is consistently effective in the management of patients with erythromelalgia. There is a dearth of adequate studies examining the response of erythromelalgia to therapy. Most recommendations are suggested based on case reports, small case series, and anecdotal reports. The management of erythromelalgia is difficult and frequently involves a multidisciplinary approach. An approach to management of individuals with erythromelalgia includes patient education, learning to avoid episodes relieving discomfort of the episodes, controlling secondary and underlying factors, and use of drugs used to control erythromelalgia.Current Treatment Options in Cardiovascular Medicine 07/2002; 4(3):207-222. DOI:10.1007/s11936-002-0002-8
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ABSTRACT: We characterized the beta-adrenoceptor-blocking property of mexiletine, a class Ib antiarrhythmic drug, on Chinese hamster ovary (CHO) cells stably expressing cloned human beta1-, beta2-, and beta3-adrenoceptors. In radioligand binding experiments, mexiletine (10 microM-1 mM) concentration-dependently displaced the specific binding of [125I]cyanopindolol to human beta1- and beta2-adrenoceptors in the membrane fraction of the cells. High concentration (100 microM-1 mM) of mexiletine partially displaced the specific binding of [125I]cyanopindolol to human beta3-adrenoceptor. On the other hand, high concentration (300 microM and 1 mM) of lidocaine, another class Ib antiarrhythmic drug, partially displaced the specific binding of [125I]cyanopindolol to human beta1-adrenoceptor, whereas it did not affect the specific binding of [125I]cyanopindolol to human beta2- and beta3-adrenoceptors. Mexiletine (5, 50, and 500 microM) reduces basal adenosine 3',5'-cyclic monophosphate (cAMP) level and isoprenaline-induced cAMP accumulation on CHO cells stably expressing cloned human beta1- and beta2-adrenoceptors. Lidocaine (10 and 100 microM and 1 mM) tend to reduce basal cAMP level on CHO cells stably expressing cloned human beta1-adrenoceptors, whereas the drug did not reduce the isoprenaline-induced cAMP accumulation on CHO cells stably expressing cloned human beta1-, beta2-, and beta3-adrenoceptors. Mexiletine and lidocaine have no effect on forskolin (0.1, 1, and 3 microM)-induced cAMP accumulation. These results demonstrate that mexiletine blocks the binding of agonists to beta1- and beta2-adrenoceptors, and thereby attenuates the agonist-induced cAMP accumulation, and that the action of mexiletine as an antagonist of beta1- and beta2-adrenoceptors is independent of its antiarrhythmic property.Biochemical Pharmacology 04/2004; 67(5):815-22. DOI:10.1016/j.bcp.2003.09.044 · 4.65 Impact Factor