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    Home » Lacosamide for Painful Small Fiber Neuropathy Due to Voltage-Gated Sodium Channel Mutations
    ABSTRACT & COMMENTARY

    Lacosamide for Painful Small Fiber Neuropathy Due to Voltage-Gated Sodium Channel Mutations

    April 1, 2019
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    Keywords

    Neuropathy

    pain

    lacosamide

    By Jennifer Langsdorf, MD

    Assistant Professor of Neurology, Peripheral Neuropathy Center, Weill Cornell Medical College

    Dr. Langsdorf reports no financial relationships relevant to this field of study.

    SYNOPSIS: The results of this randomized trial showed significant neuropathic pain score reduction with the use of lacosamide in patients with Nav1.7 mutations.

    SOURCE: de Greef BTA, Hoeijmakers JGJ, Geerts M, et al. Lacosamide in patients with Nav1.7 mutations-related small fibre neuropathy: A randomized controlled trial. Brain 2019;142:263-275.

    Small fiber neuropathy can be associated with intense itching and burning pain and skin sensitivity that can affect physical functioning, sleep, and quality of life. Current medications for small fiber neuropathy pain provide some relief. However, pain control often can be difficult to obtain and may require trials of multiple different medications. New approaches to treatment of neuropathic pain are needed.

    Some patients with small fiber neuropathy have been found to have mutations in voltage-gated sodium channels, particularly in SCN9A, which encodes for Nav1.7. These sodium channels are found in dorsal root ganglion neurons and peripheral sensory neurons and have an essential role in the sensation of pain through effects on neuronal excitability. Variant Nav1.7 sodium channels have been identified that can produce either gain of function or loss of function and thereby cause either pain hypersensitivity or congenital indifference to pain. Gain-of-function mutations in voltage-gated sodium channels are associated with small fiber neuropathy. Lacosamide is a modified amino acid that acts on Nav1.3, Nav1.7, and Nav1.8 voltage-gated sodium channels. It is FDA approved for treatment of partial seizures. Trials also have been done showing some effect on neuropathic pain in diabetic small fiber neuropathy. Lacosamide is thought to preferentially bind to Nav channels in the inactivated state. de Greef et al evaluated the potential effectiveness of lacosamide for treatment of neuropathic pain in patients with genetically confirmed mutations in SCN9A, which encodes for Nav1.7.

    In this study, 24 subjects with Nav1.7 mutation-related small fiber neuropathy entered a randomized, placebo-controlled, crossover design study. Patients with pure small fiber neuropathy in combination with SCN9A variant were eligible. Pure small fiber neuropathy was diagnosed based on typical clinical symptoms in combination with diminished epidermal nerve fiber density in skin biopsy and/or abnormal temperature threshold testing. The primary endpoint was a one-point average pain score reduction compared to baseline. The pain scores were recorded using the Pain Intensity Numerical Rating Scale (PI-NRS). The PI-NRS is an 11-point scale ranging from zero to 10, with zero meaning no pain and 10 correlating to the worst pain possible.

    The patients were randomized to start with either lacosamide or placebo. An initial titration period of three weeks was followed by an eight-week treatment period and ended with a two-week tapering period. After a washout period of at least two weeks, the same eight-week study periods took place with the different treatment during the crossover phase. The dose of lacosamide during the treatment period was 200 mg twice daily. The starting dose was 50 mg twice daily for one week, followed by an increase to 100 mg twice daily the second week and 150 mg twice daily the third week. An electrocardiogram was performed at the study onset.

    Pain scores were recorded twice each day in the morning and evening at fixed time points using the PI-NRS. For each subject, a baseline mean on-treatment pain score was calculated. The primary endpoint was at least a one-point improvement (score reduction) on the average PI-NRS compared to baseline. Secondary outcomes included the proportion of patients having an average pain improvement on the PI-NRS of two points or more, the daily sleep interference scale (DSIS), Neuropathy Pain Scale (NPS), Patient Global Impression of Change (PGIC), Small-Fiber Neuropathy Symptoms Inventory Questionnaire, and the 36-item Short Form Health Survey.

    At study completion, 24 patients had received lacosamide and 23 patients received placebo. One patient dropped out during the washout period. Results showed that in 58.3% of patients receiving lacosamide, the mean average pain score on the PI-NRS decreased by at least one point compared to 21.7% in the placebo group (odds ratio, 5.65).

    The PGIC reflects the patient’s belief in the efficacy of treatment. The PGIC showed significant differences between the two groups. In the lacosamide group, 33.3% reported their general condition improved vs. 4.3% in the placebo group (P = 0.0156). Additionally, a significant decrease in daily sleep interference was demonstrated by improvements in DSIS scores on lacosamide (P = 0.0484). The NPS showed significant improvement with lacosamide on surface pain intensity, one item in the NPS scale (P = 0.004).

    Generally, lacosamide was well tolerated. Two serious adverse events occurred on lacosamide: one patient reported diplopia and one patient reported vomiting. Other minor adverse events included dizziness, nausea, and headache.

    COMMENTARY

    In this study, lacosamide improved neuropathic pain in small fiber neuropathy associated with SCN9A mutations with a response rate of about 50% to 60%. This is comparable to the response rates to currently available medications for neuropathic pain. Positive effects on sleep quality and general well-being also were reported. For patients with SCN9A voltage-gated sodium channel mutations, lacosamide may be a useful treatment option for neuropathic pain. Its use in other small-fiber neuropathies remains to be investigated.

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    Neurology Alert

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    Neurology Alert (Vol. 38, No. 8) - April 2019
    April 1, 2019

    Table Of Contents

    Measurement of Brain Vital Signs in Concussed Athletes

    Lacosamide for Painful Small Fiber Neuropathy Due to Voltage-Gated Sodium Channel Mutations

    Cholecystokinin as a Biomarker Linking Metabolic Function to Alzheimer’s Disease

    Witness Observations in Diagnosing Transient Loss of Consciousness

    Vasculitic Neuropathy: Improving Diagnostic Accuracy

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    Financial Disclosure: Neurology Alert’s Editor in Chief Matthew Fink, MD; Peer Reviewer M. Flint Beal, MD; Executive Editor Leslie Coplin; Editor Jonathan Springston; Editorial Group Manager Terrey L. Hatcher; and Accreditations Manager Amy M. Johnson, MSN, RN, CPN, report no financial relationships relevant to this field of study.

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