lacosamide and Pain--Postoperative

Chronic pain affects the life of millions of people. Current treatments have deleterious side effects. We have advanced a strategy for targeting protein interactions which regulate the N-type voltage-gated calcium (CaV2.2) channel as an alternative to direct channel block. Peptides uncoupling CaV2.2 interactions with the axonal collapsin response mediator protein 2 (CRMP2) were antinociceptive without effects on memory, depression, and reward/addiction. A search for small molecules that could recapitulate uncoupling of the CaV2.2-CRMP2 interaction identified (S)-lacosamide [(S)-LCM], the inactive enantiomer of the Food and Drug Administration-approved antiepileptic drug (R)-lacosamide [(R)-LCM, Vimpat]. We show that (S)-LCM, but not (R)-LCM, inhibits CRMP2 phosphorylation by cyclin dependent kinase 5, a step necessary for driving CaV2.2 activity, in sensory neurons. (S)-lacosamide inhibited depolarization-induced Ca influx with a low micromolar IC50. Voltage-clamp electrophysiology experiments demonstrated a commensurate reduction in Ca currents in sensory neurons after an acute application of (S)-LCM. Using constellation pharmacology, a recently described high content phenotypic screening platform for functional fingerprinting of neurons that uses subtype-selective pharmacological agents to elucidate cell-specific combinations (constellations) of key signaling proteins that define specific cell types, we investigated if (S)-LCM preferentially acts on certain types of neurons. (S)-lacosamide decreased the dorsal root ganglion neurons responding to mustard oil, and increased the number of cells responding to menthol. Finally, (S)-LCM reversed thermal hypersensitivity and mechanical allodynia in a model of postoperative pain, and 2 models of neuropathic pain. Thus, using (S)-LCM to inhibit CRMP2 phosphorylation is a novel and efficient strategy to treat pain, which works by targeting specific sensory neuron populations.

Topics: Acetamides; Animals; Behavior, Animal; Intercellular Signaling Peptides and Proteins; Lacosamide; Nerve Tissue Proteins; Neuralgia; Pain, Postoperative; Peripheral Nerve Injuries; Phosphorylation; Rats; Rats, Sprague-Dawley; Sensory Receptor Cells

Neuropathic pain is a condition that is still not well understood, although it affects a significantly high percentage of the population. The main problem lies in the fact that it can become a fairly disabling pathology. The most frequent treatment is based essentially on two drugs: gabapentin and pregabalin. Other pharmaceuticals, such as antidepressants, opioids or N-methyl-D-aspartate receptor antagonists can also be employed in combination with the primary drugs. All the same, treatment remains unsatisfactory. Furthermore, it must be borne in mind that there may be patients who are allergic to the two main drugs.. We report the case of a 36-year-old female with neuropathic pain secondary to surgery to correct a neurinoma in the brachial plexus, who could not be treated with gabapentin or pregabalin because of a personal history of allergy to these substances. Treatment with another drug (lacosamide), however, was very effective and displayed a very good response.. Lacosamide is a third-generation antiepileptic drug that has been proven to be effective, safe and with few side effects. It has been considered a good therapeutic option for the treatment of neuropathic pain in patients who are allergic to pregabalin.. Lacosamida como alternativa en el tratamiento del dolor neuropatico posquirurgico en una paciente alergica.. Introduccion. El dolor neuropatico es una entidad que no se conoce bien. Afecta a un porcentaje significativo de la poblacion. Su principal problema radica en que puede llegar a ser una patologia bastante invalidante. El tratamiento principal se basa fundamentalmente en dos farmacos: gabapentina y pregabalina. Otros farmacos, como los antidepresivos, los opioides o los antagonistas de receptores de N-metil D-aspartato tambien pueden utilizarse en combinacion con los farmacos principales. A pesar de esto, el tratamiento es poco satisfactorio. Ademas, debe considerarse que pueden existir pacientes que presenten alergia a los dos farmacos principales. Caso clinico. Mujer de 36 años, afecta de dolor neuropatico secundario a una cirugia de neurinoma del plexo braquial, cuyo tratamiento con gabapentina o pregabalina no era posible por tener antecedentes personales de alergia. Sin embargo, el tratamiento con otro farmaco (lacosamida) resulto muy efectivo, al presentar muy buena respuesta. Conclusion. La lacosamida es un farmaco antiepileptico de tercera generacion, eficaz, seguro y con pocos efectos secundarios. Se ha considerado una buena opcion terapeutica para el tratamiento del dolor neuropatico en pacientes alergicos a la pregabalina.

Topics: Acetamides; Adult; Amines; Analgesics; Anticonvulsants; Brachial Plexus Neuropathies; Contraindications; Cyclohexanecarboxylic Acids; Drug Hypersensitivity; Female; Gabapentin; gamma-Aminobutyric Acid; Humans; Lacosamide; Magnetic Resonance Imaging; Neuralgia; Neurofibroma; Pain, Postoperative; Peripheral Nervous System Neoplasms; Pregabalin