lacosamide and Neuralgia

Epilepsy is one of the most common brain disorders, affecting more than 50 million people worldwide. Although its treatment is currently symptomatic, the last generation of anti-seizure drugs is characterized by better pharmacokinetic profiles, efficacy, tolerability and safety. Lacosamide is a third-generation anti-seizure drug that stands out due to its good efficacy and safety profile. It is used with effectiveness in the treatment of partial-onset seizures with or without secondary generalization, primary generalized tonic-clonic seizures and off-label in status epilepticus. Despite scarcely performed until today, therapeutic drug monitoring of lacosamide is proving to be advantageous by allowing the control of inter and intra-individual variability and promoting a successful personalized therapy, particularly in special populations. Herein, the pharmacology, pharmacokinetics, and clinical data of lacosamide were reviewed, giving special emphasis to the latest molecular investigations underlying its mechanism of action and therapeutic applications in pathologies besides epilepsy. In addition, the pharmacokinetic characteristics of lacosamide were updated, as well as current literature concerning the high pharmacokinetic variability observed in special patient populations and that must be considered during treatment individualization.

Topics: Animals; Anticonvulsants; Epilepsy; Humans; Lacosamide; Neuralgia

Most of the clinical practice guidelines consulted agree that tricyclics, dual (venlafaxine/duloxetine) antidepressants, gabapentin/pregabalin antiepileptic drugs, lidocaine 5% patches and capsaicin 8% patches are the first-line drugs in the treatment of peripheral neuropathic pain, being tramadol and some strong opioids (morphine, oxycodone and tapentadol) second-line drugs treatment. Moreover, the prevalence of neuropathic pain refractory to treatment is about 1.5% of the population, so that an estimated 50% of patients not responding to prescribed treatment. There are other antiepileptic drugs who not have neuropathic pain indication by regulatory agencies, such as lamotrigine, topiramate or oxcarbazepine, but are used in routine clinical practice off-label.. Following a literature search, we reviewed the use of lacosamide in neuropathic pain, both in various animal models and in different human studies.. Treatment with lacosamide in neuropathic pain of various etiologies could be considered as an effective alternative for patients who do not respond or not tolerate standard treatments. However, most of the available evidence, except phase II/III clinical trials in diabetic neuropathic pain, corresponds to open and observational studies without a control group, and low number of patients; but the favorable results invite to investigate further the usefulness of lacosamide in neuropathic pain.. Lacosamida y dolor neuropatico, una revision.. Introduccion. La mayor parte de las guias de practica clinica consultadas coinciden en señalar que los antidepresivos triciclicos, duales (venlafaxina/duloxetina), antiepilepticos gabapentina/pregabalina, apositos de lidocaina al 5% y parches de capsaicina al 8% constituyen los farmacos de primera linea en el tratamiento del dolor neuropatico periferico, y el tramadol y algunos opioides potentes (morfina, oxicodona y tapentadol) son farmacos de segunda linea. Por otra parte, la prevalencia de dolor neuropatico refractario al tratamiento se acerca al 1,5% de la poblacion, de forma que se calcula que un 50% de los pacientes no responde al tratamiento prescrito. Existen otros antiepilepticos que no tienen indicacion en el dolor neuropatico por las agencias reguladoras, como la lamotrigina, el topiramato o la oxcarbacepina, pero se utilizan en la practica clinica habitual fuera de indicacion. Desarrollo. Tras una busqueda bibliografica, se realizo una revision sobre el empleo de la lacosamida en el dolor neuropatico, tanto en distintos modelos animales como en diferentes estudios en humanos. Conclusiones. El tratamiento con lacosamida en el dolor neuropatico de diferentes etiologias podria considerarse como una alternativa efectiva para los pacientes que no respondan o no toleren los tratamientos estandares. Sin embargo, la mayor parte de la evidencia disponible, a excepcion de los ensayos clinicos en fase II/III realizados en el dolor neuropatico diabetico, corresponde a estudios abiertos y observacionales, sin grupo control y con bajo numero de pacientes, pero los resultados favorables obtenidos invitan a seguir investigando la utilidad de la lacosamida en el dolor neuropatico.

Topics: Acetamides; Anticonvulsants; Humans; Lacosamide; Neuralgia

Antiepileptic drugs have been used in pain management since the 1960s; some seem to be especially useful for neuropathic pain. Lacosamide is an antiepileptic drug that has recently been investigated for neuropathic pain relief, although it failed to get approval for painful diabetic peripheral neuropathy from either the Food and Drug Administration or the European Medicines Agency.. To evaluate the analgesic efficacy and adverse effects of lacosamide in the management of chronic neuropathic pain or fibromyalgia.. We searched the Cochrane Neuromuscular Disease Group Specialized Register (2011, Issue 4), CENTRAL (2011, Issue 3), MEDLINE (January 2000 to August 2011) and EMBASE (2000 to August 2011) without language restriction, together with reference lists of retrieved papers and reviews.. We included randomised, double-blind studies of eight weeks duration or longer, comparing lacosamide with placebo or another active treatment in chronic neuropathic pain or fibromyalgia.. Two review authors independently extracted data for efficacy and adverse events and examined issues of study quality, including risk of bias assessments. Where possible, we calculated numbers needed to treat to benefit from dichotomous data for effectiveness, adverse events and study withdrawals.. We included six studies; five (1863 participants) in painful diabetic neuropathy (PDN) and one (159 participants) in fibromyalgia. All were placebo-controlled and titrated to a target dose of 200 mg, 400 mg or 600 mg lacosamide daily, given as a divided dose. Study reporting quality was generally good, although the imputation method of last observation carried forward used in analyses of the primary outcomes is known to known to impart major bias where, as here, adverse event withdrawal rates were high. This, together with small numbers of patients and events for most outcomes at most doses meant that most results were of low quality, with moderate quality evidence available for some efficacy outcomes for 400 mg lacosamide.There were too few data for analysis of the 200 mg dose for painful diabetic neuropathy or any dose for fibromyalgia.In painful diabetic neuropathy, lacosamide 400 mg provided statistically increased rates of achievement of "moderate" and "substantial" benefit (at least 30% and at least 50% reduction from baseline in patient-reported pain respectively) and the patient global impression of change outcome of "much or very much improved". In each case the extra proportion benefiting above placebo was about 10%, yielding numbers needed to treat to benefit compared with placebo of 10 to 12. For lacosamide 600 mg there was no consistent benefit over placebo.There was no significant difference between any dose of lacosamide and placebo for participants experiencing any adverse event or a serious adverse event, but adverse event withdrawals showed a significant dose response. The number needed to treat to harm for adverse event withdrawal was 11 for lacosamide 400 mg and 4 for the 600 mg dose.. Lacosamide has limited efficacy in the treatment of peripheral diabetic neuropathy. Higher doses did not give consistently better efficacy, but were associated with significantly more adverse event withdrawals. Where adverse event withdrawals are high with active treatment compared with placebo and when last observation carried forward imputation is used, as in some of these studies, significant overestimation of treatment efficacy can result. It is likely, therefore, that lacosamide is without any useful benefit in treating neuropathic pain; any positive interpretation of the evidence should be made with caution if at all.

Topics: Acetamides; Analgesics; Anticonvulsants; Diabetic Neuropathies; Female; Fibromyalgia; Humans; Lacosamide; Male; Middle Aged; Neuralgia

The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain recently sponsored the development of evidence-based guidelines for the pharmacological treatment of neuropathic pain. Tricyclic antidepressants, dual reuptake inhibitors of serotonin and norepinephrine, calcium channel alpha(2)-delta ligands (ie, gabapentin and pregabalin), and topical lidocaine were recommended as first-line treatment options on the basis of the results of randomized clinical trials. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in certain clinical circumstances. Results of several recent clinical trials have become available since the development of these guidelines. These studies have examined botulinum toxin, high-concentration capsaicin patch, lacosamide, selective serotonin reuptake inhibitors, and combination therapies in various neuropathic pain conditions. The increasing number of negative clinical trials of pharmacological treatments for neuropathic pain and ambiguities in the interpretation of these negative trials must also be considered in developing treatment guidelines. The objectives of the current article are to review the Neuropathic Pain Special Interest Group guidelines for the pharmacological management of neuropathic pain and to provide a brief overview of these recent studies.

Topics: Acetamides; Amines; Analgesics; Analgesics, Opioid; Anesthetics, Local; Antidepressive Agents; Cyclohexanecarboxylic Acids; Evidence-Based Medicine; Gabapentin; gamma-Aminobutyric Acid; Humans; Lacosamide; Neuralgia; Practice Guidelines as Topic; Pregabalin; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors

Neuropathic pain remains a condition that is difficult to treat and with which therapeutic failure is not uncommon. The need for new and effective drugs to treat neuropathic pain remains strong.. The available preclinical and clinical data for the pain relieving effect of lacosamide have been examined using the papers published and referenced on Medline between 1990 and present.. It is hoped that readers will gain an insight into the use of this novel analgesic agent in human clinical pain.. The data relating to the pain relieving effect of lacosamide are sparse. The majority of the published human data relate to the use of lacosamide for the treatment of painful diabetic neuropathy where the extent of pain relief produced has not been deemed sufficient to warrant an application for a product license for this indication. That said, it is suggested that there remains merit in further investigation of this drug for other neuropathic pain conditions.

Topics: Acetamides; Analgesics; Animals; Diabetic Neuropathies; Female; Humans; Lacosamide; Male; Neuralgia; Rats

Lacosamide is a novel chemical entity with anticonvulsant and analgesic properties that is being developed to treat epilepsy and neuropathic pain conditions. Lacosamide has shown efficacy in many animal models of chronic pain and in several short- and long-term Phase II/III clinical trials in humans with diabetic neuropathic pain. The mechanism of action of lacosamide differs from other drugs used to treat neuropathic pain in that it selectively enhances sodium channel slow inactivation without affecting fast inactivation, and may modulate collapsin-response mediator protein 2. The pharmacokinetic properties of lacosamide include a fast rate of absorption, little or no interaction with cytochrome P450 isoenzymes, limited effect of age and gender on plasma levels and low potential for drug-drug interactions.

Topics: Acetamides; Analgesics; Animals; Clinical Trials as Topic; Diabetic Neuropathies; Humans; Lacosamide; Neuralgia

Neuropathic pain is a common pain condition that has a major negative impact on health-related quality of life. However, despite decades of research, it remains difficult to treat neuropathic pain. Lacosamide is a sodium-channel blocker that is efficacious in animal models of neuropathic pain. In humans, its effect in neuropathic pain is inconclusive, based on inconsistent results and very large placebo responses. Previous trials have not used patient stratification or looked for predictors for response.. This study will be conducted as a multicenter, randomized, double-blind, placebo-controlled, parallel, phase 2, proof-of-concept, phenotype-stratified study. The study will enroll 108 patients with peripheral neuropathic pain who will be randomized to a 12-week treatment with lacosamide or placebo up to 400 mg/day in a 2:1 ratio. The primary objective is to compare the change in the mean value of the patients' daily ratings of average pain intensity from baseline to the last week of treatment in patients with and without the irritable nociceptor phenotype in the per-protocol population. A supportive objective is to compare the effect of lacosamide with that of placebo in the two phenotypes. Secondary and tertiary outcomes include the Patient Global Impression of Change, pain relief, presence of 30% and 50% pain reduction, sleep disturbance, depression, and anxiety.. We will examine the concept of individualized therapy based on phenotyping, and expect that this study will provide important information on the usefulness of lacosamide in the treatment of peripheral neuropathic pain.. ClinicalTrials.gov, NCT03777956 . Registered on 18 December 2018.

Topics: Analgesics; Clinical Trials, Phase II as Topic; Denmark; Double-Blind Method; Female; Humans; Lacosamide; Male; Multicenter Studies as Topic; Neuralgia; Pain Measurement; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome; Voltage-Gated Sodium Channel Blockers

Although different treatments are available for neuropathic pain, these patients are often refractory, which makes it necessary to test treatments that, as they have proven useful in other pathologies, could be effective in neuropathic pain.. The study made use of the medical records of patients who had been treated with lacosamide for neuropathic pain in different hospitals in the central area of the peninsula and who fulfilled similar characteristics in terms of refractoriness to other standard treatments, in a follow-up that lasted at least six months, or who had had to stop treatment with that drug for some reason or another. A sample of 114 patients (61 males and 53 females) with a mean age of 60.5 years was obtained from the data.. The most common causes of neuropathic pain were: diabetic polyneuropathy (31.6%), post-herpes neuralgia (22.8%), trigeminal neuralgia (17.5%), suboccipital and lumbar-radicular neuralgia (both 12.3%). Effectiveness was good/very good in most patients, with the mean score on the visual analogue scale after six months dropping from 7.7 to 4.8. No serious side effects were reported in any of the patients, but in 12 and 10 patients no recordings were made beyond six months, due to ineffectiveness and intolerance to the treatment, respectively.. Treatment with lacosamide in neuropathic pain due to different causes could be considered an effective and well-tolerated alternative for patients who fail to respond to standard treatments.. Efectividad de la lacosamida en el tratamiento del dolor neuropatico refractario: estudio observacional abierto.. Introduccion. Aunque se dispone de diferentes tratamientos para el dolor neuropatico, en muchas ocasiones estos pacientes son refractarios, lo que hace necesario probar tratamientos que, por su utilidad en otras patologias, podrian ser eficaces en el dolor neuropatico. Pacientes y metodos. Se recogieron las historias clinicas de pacientes que hubieran sido tratados con lacosamida para el dolor neuropatico, en diferentes hospitales de la zona centro peninsular, y que cumplieran unas caracteristicas similares en cuanto a refractariedad a otros tratamientos estandares, en un seguimiento de al menos seis meses, o que hubiesen tenido que suspender el tratamiento con dicho farmaco por cualquier motivo. Se obtuvo una muestra de 114 pacientes, 61 varones y 53 mujeres, con una edad media de 60,5 años. Resultados. Las causas de dolor neuropatico mas frecuentes fueron: polineuropatia diabetica (31,6%), neuralgia postherpetica (22,8%), neuralgia del trigemino (17,5%), neuralgia suboccipital y lumbociatalgia (un 12,3% en ambas). La eficacia fue buena/muy buena en la mayoria de los pacientes, con un descenso medio en la escala analogica visual tras seis meses de 7,7 a 4,8. No se registraron efectos secundarios graves en ningun paciente, pero en 12 y 10 pacientes no hubo registro mas alla de seis meses, por ineficacia e intolerancia al tratamiento, respectivamente. Conclusiones. El tratamiento con lacosamida en el dolor neuropatico de diferentes causas podria considerarse como una alternativa efectiva y bien tolerada para aquellos pacientes que no respondan a los tratamientos estandares.

Topics: Acetamides; Adult; Aged; Aged, 80 and over; Female; Humans; Lacosamide; Male; Middle Aged; Neuralgia; Retrospective Studies; Young Adult

Topics: Anticonvulsants; Humans; Lacosamide; Neuralgia; Off-Label Use

We report the outcome of a pilot, open-label study that tested the potential of lacosamide (200 mg/bi.d) as an effective and safe symptomatic treatment against acute painful oxaliplatin-induced peripheral neurotoxicity (OXAIPN). Lacosamide was introduced in 18 colorectal cancer patients with evidence of clinically significant acute, painful OXAIPN after infusion of the third course (T1) of oxaliplatin-based chemotherapy (FOLFOX4) and was maintained until completion of all 12 courses (T4). The OXA-Neuropathy Questionnaire (OXA-NQ) was used to record the severity of acute OXAIPN; the PI-NRS estimated the severity of neuropathic pain, while the chronic OXAIPN was graded with TNSc. The EuroQOL (EQ-5D) instrument was also applied. The Patient Global Impression of Change (PGIC) scale measured the lacosamide-attributed perception of change. LCM-responders were considered those with ≥50% reduction in PI-NRS and OXA-NQ scores at T4, compared to T1. Patients experienced on T1 a median number of acute OXAIPN symptoms of 4 and had a median neuropathic pain severity score of 6, which was strongly related to lower quality of life, according to EQ-VAS (P < .001). At T4, 12 patients (66.7%) were classified as responders. A significant clinical improvement was documented in the severity of acute OXAIPN and neuropathic pain in relation to lacosamide (P < .001) at T4 compared to T1, which was associated with improved EQ-VAS scores (P < .001). Twelve patients scored PGIC ≥5 (lacosamide-attributed) at T4. There were no incidences of early drop-outs for safety reasons. Lacosamide appears to be an effective and well-tolerated symptomatic treatment against acute, painful OXAIPN.

Topics: Acute Disease; Aged; Antineoplastic Agents; Colorectal Neoplasms; Female; Humans; Lacosamide; Male; Middle Aged; Neuralgia; Neurotoxicity Syndromes; Outcome Assessment, Health Care; Oxaliplatin; Peripheral Nervous System Diseases; Pilot Projects; Prospective Studies; Voltage-Gated Sodium Channel Blockers

Inspired by the traditional Chinese herbal pair of Polygala tenuifolia-Acori Tatarinowii for treating epilepsy, 33 novel substituted cinnamic α-asaronol esters and analogues were designed by Combination of Traditional Chinese Medicine Molecular Chemistry (CTCMMC) strategy, synthesized and tested systematically not only for anticonvulsant activity in three mouse models but also for LDH inhibitory activity. Thereinto, 68-70 and 75 displayed excellent and broad spectra of anticonvulsant activities with modest ability in preventing neuropathic pain, as well as low neurotoxicity. The protective indices of these four compounds compared favorably with stiripentol, lacosamide, carbamazepine and valproic acid. 68-70 exhibited good LDH1 and LDH5 inhibitory activities with noncompetitive inhibition type, and were more potent than stiripentol. Notably, 70, as a representative agent, was also shown as a moderately positive allosteric modulator at human α1β2γ2 GABA

Topics: Allosteric Regulation; Animals; Anisoles; Anticonvulsants; Carbamazepine; Cinnamates; Dioxolanes; Drug Design; Drugs, Chinese Herbal; Esters; Humans; L-Lactate Dehydrogenase; Medicine, Chinese Traditional; Mice; Molecular Structure; Neuralgia; Polygala; Receptors, GABA-A; Structure-Activity Relationship; Valproic Acid

Early hyperexcitability activity of injured nerve/neuron is critical for developing sympathetic nerve sprouting within dorsal root ganglia (DRG) since lacosamide (LCM), an anticonvulsant, inhibits Na. Lacosamide (50 mg/kg) was daily injected intraperitoneally into rats subjected to chronic compression DRG (CCD), an animal model of neuropathic pain that exhibits sympathetic nerve sprouting, for the 1st 7 days after injury. Mechanical sensitivity was tested from day 3 to day 18 after injury, and then DRGs were removed off. Immunohistochemical staining for tyrosine hydroxylase (TH) was examined to observe sympathetic sprouting, and patch-clamp recording was performed to test the excitability and Na. Early systemic LCM treatment significantly reduced TH immunoreactivity density in injured DRG, lowered the excitability level of injured DRG neurons and increased paw withdrawal threshold. These effects on reducing sympathetic sprouting, inhibiting excitability and suppressing pain behaviour were observed 10 days after the end of early LCM injection. In vitro 100 μmol/L LCM instantly reduced the excitability of CCD neurons via inhibiting Na. All the findings suggest, for the first time, that early administration of LCM inhibited sympathetic sprouting and then alleviated neuropathic pain.. Early LCM administration inhibited sympathetic sprouting within DRG in CCD rats via reducing hyperexcitability of neurons. Early LCM administration suppressed neuropathic pain in CCD rats.

Topics: Animals; Disease Models, Animal; Ganglia, Spinal; Lacosamide; Male; Neuralgia; Neurons; Rats; Rats, Sprague-Dawley; Tyrosine 3-Monooxygenase; Voltage-Gated Sodium Channel Blockers

Anticonvulsant drugs such as pregabalin (PGB) and lacosamide (LCM), exhibit potent analgesic effects in diabetic neuropathy; however, their possible role/mechanisms in paclitaxel (PTX)-induced peripheral neuropathy have not been elucidated, which is the aim of the present study. Neuropathic pain was induced in rats by injecting PTX (2 mg/kg, i. p) on days 0, 2, 4 and 6. Forty eight hours after the last dose of PTX, rats were treated orally with 30 mg/kg/day of either PGB or LCM for 21 days. Both therapies improved thermal hyperalgesia and cold allodynia induced by PTX. Interestingly, LCM therapy showed no motor impairment that was observed upon using PGB, as demonstrated using rotarod test. Treatment with PGB or LCM restored the sciatic nerve content of the depleted total antioxidant capacity (TAC) and nerve growth factor (NGF), and lessened the elevated contents of nuclear factor kappa B p65 (NF-kB p65), tumor necrosis factor-α (TNF-α), and active caspase-3. On the molecular level, the drugs reduced the protein expression of Notch1 receptor, phosphorylated p38 mitogen-activated protein kinase (p-p38-MAPK), and the trajectory interleukin-6/phosphorylated janus kinase 2/phosphorylated signal transducer and activator of transcription 3 (IL-6/p-JAK2/p-STAT3). Therefore, the current study demonstrated a pivotal role for LCM in the management of PTX-induced peripheral neuropathy similar to PGB, but without motor adverse effects via the inhibition of oxidative stress, inflammation and apoptosis, as well as IL-6/JAK/STAT pathway and Notch1 receptor over-expression.

Topics: Animals; Hyperalgesia; Lacosamide; Male; Neuralgia; Paclitaxel; Pregabalin; Rats, Wistar; Receptors, Notch; Sciatic Nerve; Signal Transduction; STAT3 Transcription Factor; Tumor Necrosis Factor-alpha

Topics: Acetamides; Diagnosis, Differential; Humans; Lacosamide; Laryngeal Nerves; Male; Middle Aged; Neuralgia

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

The functionalized amino acid, lacosamide ((R)-2), and the α-aminoamide, safinamide ((S)-3), are neurological agents that have been extensively investigated and have displayed potent anticonvulsant activities in seizure models. Both compounds have been reported to modulate voltage-gated sodium channel activity. We have prepared a series of chimeric compounds, (R)-7-(R)-10, by merging key structural units in these two clinical agents, and then compared their activities with (R)-2 and (S)-3. Compounds were assessed for their ability to alter sodium channel kinetics for inactivation, frequency (use)-dependence, and steady-state activation and fast inactivation. We report that chimeric compounds (R)-7-(R)-10 in catecholamine A-differentiated (CAD) cells and embryonic rat cortical neurons robustly enhanced sodium channel inactivation at concentrations far lower than those required for (R)-2 and (S)-3, and that (R)-9 and (R)-10, unlike (R)-2 and (S)-3, produce sodium channel frequency (use)-dependence at low micromolar concentrations. We further show that (R)-7-(R)-10 displayed excellent anticonvulsant activities and pain-attenuating properties in the animal formalin model. Of these compounds, only (R)-7 reversed mechanical hypersensitivity in the tibial-nerve injury model for neuropathic pain in rats.

Topics: Acetamides; Alanine; Analgesics; Animals; Anticonvulsants; Benzylamines; Cells, Cultured; Cerebral Cortex; Disease Models, Animal; Female; Formaldehyde; Lacosamide; Male; Membrane Potentials; Mice; Neuralgia; Neurons; Patch-Clamp Techniques; Rats, Sprague-Dawley; Seizures; Tibial Nerve; Voltage-Gated Sodium Channel Blockers; Voltage-Gated Sodium Channels

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

Lacosamide is a novel anti-epileptic drug that enhances the slow- and not fast-inactivating state of voltage-gated sodium channels. Lacosamide has demonstrated analgesic efficacy in several animal studies but preclinical studies on neuropathic pain models are rare, and recent clinical trials showed no superior analgesic effects.. Here, we examine whether an acute or chronic administration of lacosamide (3-60 mg/kg, i.p.) attenuates pain behaviour induced by spinal nerve ligation (SNL). To validate the inhibitory efficacy of lacosamide on voltage-gated sodium channels, sodium currents in naïve and SNL-injured dorsal root ganglion (DRG) neurons were recorded using whole-cell patch clamping.. Lacosamide only marginally attenuated thermal hyperalgesia, but not tactile allodynia when applied once 7 or 14 days after SNL and showed no analgesic effect when applied daily for 19 days. In naïve neurons, 100 μmol/L lacosamide inhibited sodium channel currents by 58% and enhanced the slow inactivation (87% for lacosamide vs. 47% for control). In contrast, lacosamide inhibited sodium currents in injured DRG neurons by only 15%, while the effects on slow inactivation were diminished. Isolated currents from the NaV 1.8 channel subtype were only marginally changed by lacosamide.. The reduced effectiveness of lacosamide on voltage-gated sodium channel currents in injured DRG neurons may contribute to the reduced analgesic effect observed for the SNL model.

Topics: Acetamides; Action Potentials; Analgesics; Animals; Ganglia, Spinal; Hyperalgesia; Lacosamide; Ligation; Male; Neuralgia; Neurons; Rats; Rats, Wistar; Sodium Channel Blockers; Sodium Channels; Spinal Nerves

Topics: Acetamides; Adult; Aged; Anticonvulsants; Drug Evaluation; Female; Humans; Lacosamide; Male; Middle Aged; Neuralgia; Retrospective Studies; Salvage Therapy; Treatment Outcome; Voltage-Gated Sodium Channel Blockers

N-Benzyl 2-acetamido-2-substituted acetamides, where the 2-substituent is a (hetero)aromatic moiety, are potent anticonvulsants. We report the synthesis and whole animal pharmacological evaluation of 16 analogues where the terminal 2-acetyl group was removed to give the corresponding primary amino acid derivatives (PAADs). Conversion to the PAAD structure led to a substantial drop in seizure protection in animal tests, demonstrating the importance of the N-acetyl moiety for anticonvulsant activity. However, several of the PAADs displayed notable pain-attenuating activities in a mouse model.

Topics: Acetamides; Amino Acids; Animals; Anticonvulsants; Disease Models, Animal; Drug Evaluation, Preclinical; Male; Mice; Mice, Inbred Strains; Molecular Structure; Neuralgia; Seizures; Structure-Activity Relationship

Lacosamide is a new antiepileptic drug with a novel mechanism of action, as it selectively promotes the slow inactivation of voltage-dependent sodium channels without affecting fast inactivation. There are studies in the literature regarding its effectiveness in controlling neuropathic pain.. We describe the use of intravenous lacosamide in the treatment of three patients with neuropathic pain: a woman with neuropathic pain in the first branch of the right trigeminal nerve during the acute phase of herpes zoster, a woman with central pain secondary to Dejerine-Roussy syndrome due to a malignant brain tumour, and a man with facial pain due to infiltration of the trigeminal nerve by a secondary lymphoma of the central nervous system. In the three cases, the administration of intravenous lacosamide has led to a considerable improvement in pain. The lacosamide dose has been 200 mg/day with excellent tolerability.. Lacosamide can be an effective and well-tolerated alternative in the treatment of neuropathic pain and, moreover, its intravenous use can achieve pain control faster or be suitable when it is not tolerated orally.

Topics: Acetamides; Adult; Anticonvulsants; Female; Herpes Zoster; Humans; Lacosamide; Lymphoma; Magnetic Resonance Imaging; Male; Middle Aged; Neuralgia; Thalamic Diseases; Treatment Outcome

Pharmacological management remains the primary method to treat epilepsy and neuropathic pain. We have advanced a novel class of anticonvulsants termed functionalized amino acids (FAAs). In this study, we examine FAA derivatives from which the terminal acetyl moiety was removed and termed these compounds primary amino acid derivatives (PAADs). Twenty-seven PAADs were prepared; the central C(2) R-substituent was varied, including C(2) stereochemistry, and the compounds were tested in rodent models of seizures and neuropathic pain. C(2)-Hydrocarbon N-benzylamide PAADs were potent anticonvulsants and excellent anticonvulsant activity (mice, ip; rat, po) was observed for C(2) R-substituted PAADs in which the R group was ethyl, isopropyl, or tert-butyl, and the C(2) stereochemistry conformed to the d-amino acid configuration ((R)-stereoisomer). These values surpassed the activities of several clinical antiepileptic drugs. The C(2) (R)-ethyl and C(2) (R)-isopropyl PAADs also displayed excellent activities in the mouse (ip) formalin neuropathic pain model. Significantly, unlike the FAA structure-activity relationship, PAAD anticonvulsant activity increased upon substitution of a methylene unit for a heteroatom in the R-substituent that was one atom removed from the C(2) site, suggesting that these PAADs function by a different pathway than FAAs.

Topics: Amino Acids; Analgesics; Animals; Anticonvulsants; Convulsants; Electroshock; Formaldehyde; Male; Mice; Neuralgia; Pentylenetetrazole; Rats; Rats, Sprague-Dawley; Seizures; Stereoisomerism; Structure-Activity Relationship

Recently, we reported that select N'-benzyl 2-substituted 2-amino acetamides (primary amino acid derivatives (PAADs)) exhibited pronounced activities in established whole animal anticonvulsant (i.e., maximal electroshock seizure (MES)) and neuropathic pain (i.e., formalin) models. The anticonvulsant activities of C(2)-hydrocarbon N'-benzyl 2-amino acetamides (MES ED(50) = 13-21 mg/kg) exceeded those of phenobarbital (ED(50) = 22 mg/kg). Two additional studies defining the structure-activity relationship of PAADs are presented in this issue of the journal. In this study, we demonstrated that the anticonvulsant activities of (R)-N'-benzyl 2-amino-3-methylbutanamide and (R)-N'-benzyl 2-amino-3,3-dimethylbutanamide were sensitive to substituents at the 4'-N'-benzylamide site; electron-withdrawing groups retained activity, electron-donating groups led to a loss of activity, and incorporating either a 3-fluorobenzyloxy or 3-fluorophenoxymethyl group using a rationally designed multiple ligand approach improved activity. Additionally, we showed that substituents at the 4'-N'-benzylamide site of (R)-N'-benzyl 2-amino-3-methoxypropionamide also improved anticonvulsant activity, with the 3-fluorophenoxymethyl group providing the largest (∼4-fold) increase in activity (ED(50) = 8.9 mg/kg), a value that surpassed phenytoin (ED(50) = 9.5 mg/kg). Collectively, the pharmacological findings provided new information that C(2)-hydrocarbon PAADs represent a novel class of anticonvulsants.

Topics: Amino Acids; Analgesics; Animals; Anticonvulsants; Butyrates; Male; Mice; Neuralgia; Pain Measurement; Propionates; Rats; Rats, Sprague-Dawley; Seizures; Stereoisomerism; Structure-Activity Relationship

Pain and paresthesias are the most common symptoms of chemotherapy induced painful neuropathy (CIPN). Current treatment and preventive strategies of CIPN are ineffective, and the neuropathy may lead to discontinuation of anti-tumor therapy. Here we used experimental vincristine-induced neuropathy in rats to evaluate the disease modifying potential of lacosamide using a sustained release formulation and the acute treatment effects of a rapid release formulation. Pain behavior was assessed by withdrawal responses to von Frey hairs, acetone drops, the Randall-Selitto device, and to radiant heat. Neuropathy was assessed using electrophysiological recordings. Preventive lacosamide treatment (30 mg/kg subcutaneously b.i.d. for 17 days) was well tolerated, and pharmacokinetic analysis revealed a peak plasma concentration 2 h post-injection with a plasma half-life of approximately 3 h. Rats treated with lacosamide, in contrast to vehicle treated rats, did not develop vincristine-induced cold allodynia. Neurophysiology showed a delayed F-wave latency in vehicle treated rats, which was not present in lacosamide treated animals. We could thus demonstrate a protective disease modifying potency of lacosamide in an animal model of CIPN. Lacosamide may be a promising candidate for preventive treatment of CIPN in patients receiving chemotherapy with vinca alkaloids or platinum drugs.

Topics: Acetamides; Animals; Lacosamide; Male; Neuralgia; Neuroprotective Agents; Pain Measurement; Rats; Rats, Sprague-Dawley; Vincristine

Topics: Acetamides; Analgesics; Clinical Trials as Topic; Data Interpretation, Statistical; Diabetic Neuropathies; Humans; Lacosamide; Models, Statistical; Neuralgia; Pain Measurement; Patient Dropouts; Treatment Outcome; United States; United States Food and Drug Administration

Pain is the most common physical symptom of cancer patients, with most patients experiencing more than one site of pain. Current treatments lack full efficacy. Based on the need for new approaches in that field the effect of systemic administration of lacosamide (SPM 927, (R)-2-acetamido-N-benzyl-3-methoxypropionamide, previously referred to as harkoseride or ADD 234037), a member of a series of functionalized amino acids that were specifically synthesized as anticonvulsive drug candidates, was examined in rats in a tumor-induced bone cancer pain model and in a chemotherapy-induced neuropathic pain model. Lacosamide inhibited tactile allodynia (20, 40 mg/kg, i.p.), thermal hyperalgesia (30 mg/kg) and reduced weight-bearing differences (40 mg/kg) in the rat model of bone cancer pain induced by injection of MRMT-1 cells into the tibia. Morphine (5 mg/kg, s.c) was effective inhibiting tactile allodynia and weight bearing but could not reduce thermal hyperalgesia. In the vincristine-induced neuropathic pain model, lacosamide attenuated thermal allodynia, on the cold plate (4 degrees C), at 10 and 30 mg/kg, and in the warm (38 degrees C) and hot plate (52 degrees C) even at 3 mg/kg. Tactile allodynia and mechanical hyperalgesia were inhibited by lacosamide at 10 and 30 mg/kg. In contrast to lacosamide, morphine (3 mg/kg, s.c.) had no effect on mechanical hyperalgesia. Lacosamide is effective as an analgesic in a bone cancer pain model as well as chemotherapy-induced neuropathic pain model in animals and even reduced hyperalgesia where morphine did not (3 or 5 mg/kg, s.c.).

Topics: Acetamides; Amines; Analgesics; Animals; Antineoplastic Agents, Phytogenic; Bone Neoplasms; Cyclohexanecarboxylic Acids; Female; Gabapentin; gamma-Aminobutyric Acid; Lacosamide; Neuralgia; Pain, Intractable; Rats; Rats, Sprague-Dawley; Vincristine