lacosamide and Pain

Scant evidence is available on the use of intravenous pain treatment in acute exacerbations of trigeminal neuralgia. The aim of this descriptive study was to evaluate the effectiveness and security of intravenous lacosamide and phenytoin in the treatment of acute trigeminal neuralgia pain.. We reviewed patients who attended the emergency department of a tertiary hospital between 2012 and 2020 for exacerbations of trigeminal neuralgia pain and were treated with either intravenous phenytoin or lacosamide for the first time. Primary endpoints were pain relief and adverse effects during the hospital stay. A comparative analysis between both treatment groups was performed.. We studied 144 episodes in 121 patients (median age 61 years, 66.1% women). Trigeminal neuralgia etiology was secondary in 9.9%. Pain relief was observed in 77.8% of 63 patients receiving lacosamide infusions, and adverse effects in 1.6%. Pain relief was observed in 72.8% of 81 phenytoin infusions and adverse effects in 12.3%, all mild. No difference was observed in pain relief between groups, but the proportion of adverse effects was significantly different (p = 0.023). Statistically significant differences were also detected in readmissions within six months, time to readmission, and pain relief status at first follow-up visit.. Intravenous lacosamide and phenytoin can be effective and safe treatments for acute pain in trigeminal neuralgia. According to our series, lacosamide might be better tolerated than phenytoin and lead to lower readmissions and sustained pain relief.

Topics: Female; Humans; Lacosamide; Male; Middle Aged; Pain; Phenytoin; Retrospective Studies; Treatment Outcome; Trigeminal Neuralgia

Lacosamide (LCM), (SPM 927, (R)-2-acetamido-N-benzyl-3-methoxypropionamide, previously referred to as harkoseride or ADD 234037) is a member of a series of functionalized amino acids that were specifically synthesized as anticonvulsive drug candidates. LCM has demonstrated antiepileptic effectiveness in different rodent seizure models and antinociceptive potential in experimental animal models that reflect distinct types and symptoms of neuropathic as well as chronic inflammatory pain. Recent results suggest that LCM has a dual mode of action underlying its anticonvulsant and analgesic activity. It was found that LCM selectively enhances slow inactivation of voltage-gated sodium channels without affecting fast inactivation. Furthermore, employing proteomic affinity-labeling techniques, collapsin-response mediator protein 2 (CRMP-2 alias DRP-2) was identified as a binding partner. Follow-up experiments confirmed a functional interaction of LCM with CRMP-2 in vitro. LCM did not inhibit or induce a wide variety of cytochrome P450 enzymes at therapeutic concentrations. In safety pharmacology and toxicology studies conducted in mice, rats, rabbits, and dogs, LCM was well tolerated. Either none or only minor side effects were observed in safety studies involving the central nervous, respiratory, gastrointestinal, and renal systems and there is no indication of abuse liability. Repeated dose toxicity studies demonstrated that after either intravenous or oral administration of LCM the adverse events were reversible and consisted mostly of exaggerated pharmacodynamic effects on the CNS. No genotoxic or carcinogenic effects were observed in vivo, and LCM showed a favorable profile in reproductive and developmental animal studies. Currently, LCM is in a late stage of clinical development as an adjunctive treatment for patients with uncontrolled partial-onset seizures, and it is being assessed as monotherapy in patients with painful diabetic neuropathy. Further trials to identify LCM's potential in pain and for other indications have been initiated.

Topics: Acetamides; Animals; Anticonvulsants; Disease Models, Animal; Drug Evaluation, Preclinical; Epilepsy; Humans; Intercellular Signaling Peptides and Proteins; Lacosamide; Models, Biological; Nerve Tissue Proteins; Pain

Few new drugs have been developed for chronic pain. Drug development is challenged by uncertainty about whether the drug engages the human target sufficiently to have a meaningful pharmacodynamic effect. IMI2-PainCare-BioPain-RCT1 is one of four similarly designed studies that aim to link different functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics. This study focusses on biomarkers derived from nerve excitability testing (NET) using threshold tracking of the peripheral nervous system.. This is a multisite single-dose, subject and assessor-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD), and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from NET of large sensory and motor fibers and small sensory fibers using perception threshold tracking will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose with at least 1 week apart. Motor and sensory NET will be assessed on the right wrist in a non-sensitized normal condition while perception threshold tracking will be performed bilaterally on both non-sensitized and sensitized forearm skin. Cutaneous high-frequency electrical stimulation is used to induce hyperalgesia. Blood samples will be taken for pharmacokinetic purposes and pain ratings as well as predictive psychological traits will be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split across the two primary outcomes: strength-duration time constant (SDTC; a measure of passive membrane properties and nodal persistent Na. Measurements of NET using threshold tracking protocols are sensitive to membrane potential at the site of stimulation. Sets of useful indices of axonal excitability collectively may provide insights into the mechanisms responsible for membrane polarization, ion channel function, and activity of ionic pumps during the process of impulse conduction. IMI2-PainCare-BioPain-RCT1 hypothesizes that NET can serve as biomarkers of target engagement of analgesic drugs in this compartment of the nociceptive system for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.. This trial was registered 25/06/2019 in EudraCT ( 2019-000942-36 ).

Topics: Biomarkers; Double-Blind Method; Healthy Volunteers; Humans; Lacosamide; Multicenter Studies as Topic; Pain; Peripheral Nerves; Pregabalin; Randomized Controlled Trials as Topic; Tapentadol

IMI2-PainCare-BioPain-RCT2 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on specific compartments of the nociceptive system that could serve to accelerate the future development of analgesics. IMI2-PainCare-BioPain-RCT2 will focus on human spinal cord and brainstem activity using biomarkers derived from non-invasive neurophysiological measurements.. This is a multisite, single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Neurophysiological biomarkers of spinal and brainstem activity (the RIII flexion reflex, the N13 component of somatosensory evoked potentials (SEP) and the R2 component of the blink reflex) will be recorded before and at three distinct time points after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol), and placebo, given as a single oral dose in separate study periods. Medication effects on neurophysiological measures will be assessed in a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin), and in a non-sensitized normal condition. Patient-reported outcome measures (pain ratings and predictive psychological traits) will also be collected; and blood samples will be taken for pharmacokinetic modelling. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between the two primary endpoints, namely the percentage amplitude changes of the RIII area and N13 amplitude under tapentadol. Remaining treatment arm effects on RIII, N13 and R2 recovery cycle are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modelling are exploratory.. The RIII component of the flexion reflex is a pure nociceptive spinal reflex widely used for investigating pain processing at the spinal level. It is sensitive to different experimental pain models and to the antinociceptive activity of drugs. The N13 is mediated by large myelinated non-nociceptive fibers and reflects segmental postsynaptic response of wide dynamic range dorsal horn neurons at the level of cervical spinal cord, and it could be therefore sensitive to the action of drugs specifically targeting the dorsal horn. The R2 reflex is mediated by large myelinated non-nociceptive fibers, its circuit consists of a polysynaptic chain lying in the reticular formation of the pons and medulla. The recovery cycle of R2 is widely used for assessing brainstem excitability. For these reasons, IMI2-PainCare-BioPain-RCT2 hypothesizes that spinal and brainstem neurophysiological measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.. This trial was registered on 02 February 2019 in EudraCT ( 2019-000755-14 ).

Topics: Analgesics; Biomarkers; Brain Stem; Cross-Over Studies; Double-Blind Method; Healthy Volunteers; Humans; Lacosamide; Multicenter Studies as Topic; Pain; Pregabalin; Randomized Controlled Trials as Topic; Spinal Cord; Tapentadol

IMI2-PainCare-BioPain-RCT3 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics, by providing a quantitative understanding between drug exposure and effects of the drug on nociceptive signal processing in human volunteers. IMI2-PainCare-BioPain-RCT3 will focus on biomarkers derived from non-invasive electroencephalographic (EEG) measures of brain activity.. This is a multisite single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from scalp EEG measurements (laser-evoked brain potentials [LEPs], pinprick-evoked brain potentials [PEPs], resting EEG) will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose in separate study periods. Medication effects will be assessed concurrently in a non-sensitized normal condition and a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin). Patient-reported outcomes will also be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between LEP and PEP under tapentadol. Remaining treatment arm effects on LEP or PEP or effects on EEG are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modeling are exploratory.. LEPs and PEPs are brain responses related to the selective activation of thermonociceptors and mechanonociceptors. Their amplitudes are dependent on the responsiveness of these nociceptors and the state of the pathways relaying nociceptive input at the level of the spinal cord and brain. The magnitude of resting EEG oscillations is sensitive to changes in brain network function, and some modulations of oscillation magnitude can relate to perceived pain intensity, variations in vigilance, and attentional states. These oscillations can also be affected by analgesic drugs acting on the central nervous system. For these reasons, IMI2-PainCare-BioPain-RCT3 hypothesizes that EEG-derived measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.. This trial was registered 25/06/2019 in EudraCT ( 2019%2D%2D001204-37 ).

Topics: Biomarkers; Cross-Over Studies; Double-Blind Method; Electroencephalography; Healthy Volunteers; Humans; Lacosamide; Pain; Pain Measurement; Pregabalin; Tapentadol

Small fibre neuropathy is a common pain disorder, which in many cases fails to respond to treatment with existing medications. Gain-of-function mutations of voltage-gated sodium channel Nav1.7 underlie dorsal root ganglion neuronal hyperexcitability and pain in a subset of patients with small fibre neuropathy. Recent clinical studies have demonstrated that lacosamide, which blocks sodium channels in a use-dependent manner, attenuates pain in some patients with Nav1.7 mutations; however, only a subgroup of these patients responded to the drug. Here, we used voltage-clamp recordings to evaluate the effects of lacosamide on five Nav1.7 variants from patients who were responsive or non-responsive to treatment. We show that, at the clinically achievable concentration of 30 μM, lacosamide acts as a potent sodium channel inhibitor of Nav1.7 variants carried by responsive patients, via a hyperpolarizing shift of voltage-dependence of both fast and slow inactivation and enhancement of use-dependent inhibition. By contrast, the effects of lacosamide on slow inactivation and use-dependence in Nav1.7 variants from non-responsive patients were less robust. Importantly, we found that lacosamide selectively enhances fast inactivation only in variants from responders. Taken together, these findings begin to unravel biophysical underpinnings that contribute to responsiveness to lacosamide in patients with small fibre neuropathy carrying select Nav1.7 variants.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cells, Cultured; Humans; Lacosamide; Membrane Potentials; Middle Aged; Mutation; NAV1.7 Voltage-Gated Sodium Channel; Pain; Pain Measurement; Patch-Clamp Techniques; Small Fiber Neuropathy; Sodium Channel Blockers; Treatment Outcome; Young Adult

The efficacy and tolerability of oral lacosamide (200, 400, and 600 mg/day) was evaluated in patients with painful diabetic neuropathy in a double-blind, randomized, placebo-controlled trial. The primary target dose to be confirmed was lacosamide 400 mg/day. Efficacy was assessed by changes in pain scale scores from baseline, with changes over the last 4 weeks of the 12-week maintenance period regarded as the primary endpoint. Endpoint reductions in mean pain score were higher with all doses of lacosamide, reaching the level of significance with 400 mg/day (P = .05). Over the treatment period (titration + maintenance), pain relief was significantly higher than placebo with lacosamide 400 (P = .02) and 600 mg/day (P = .03). Lacosamide had an early-onset effect with significant reductions over placebo during the titration period. Nonparametric and mixed-model analysis approaches gave similar results, supporting significant efficacy at 400 mg/day. Secondary criteria such as Patient's Global Impression of Change, responder rates, and pain-free days provided additional support. Adverse events included dizziness, nausea, and headache. Incidence of cognitive and behavioral adverse events was low. This trial suggests that lacosamide has beneficial effects and may be a suitable treatment option for patients with diabetic neuropathic pain.. This study presents efficacy and safety results of a phase 3, double-blind, placebo-controlled trial of the anticonvulsant drug lacosamide in patients with painful diabetic neuropathy. Lacosamide treatment at a dose of 400 mg/day reduced diabetic neuropathic pain with a favorable safety and tolerability profile that may be suitable for patients with diabetes.

Topics: Acetamides; Analgesics, Non-Narcotic; Diabetic Neuropathies; Double-Blind Method; Female; Humans; Lacosamide; Male; Middle Aged; Pain; Pain Measurement; Statistics, Nonparametric; Time Factors

First-line treatment for trigeminal neuralgia (TN) is limited to carbamazepine and oxcarbazepine, and in refractory cases, alternatives are scarce. Lacosamide has been suggested as a valid option. In this study, we describe a series of patients who received oral lacosamide as treatment for TN after first-line drug failure.. In this retrospective descriptive cohort study, we included patients with refractory TN who attended a tertiary center between 2015 and 2021 and were prescribed oral lacosamide after first-line treatment failure. The primary endpoints were pain relief and adverse effects. We secondarily analyzed clinical outcomes and compared responders versus nonresponders in the search for potential predictors of response.. Eighty-six patients were included (mean age: 62 [SD 15.6] years; 54/86 [63%] female). The TN etiology was secondary in 16/86 (19%) patients. Concomitant continuous pain was present in 29/86 (34%) patients. The mean number of previous treatments was 2.7 [SD 1.5]. Pain relief was achieved in 57/86 (66%) cases, with 28/86 (33%) patients presenting adverse effects, all of which were mild. No statistically significant differences were observed between responders and nonresponders, but subtle clinical differences suggested potential predictors of response.. Lacosamide may be an effective and relatively safe treatment for refractory pain in TN patients after first-line treatment failure.

Topics: Cohort Studies; Female; Humans; Lacosamide; Male; Middle Aged; Pain; Retrospective Studies; Treatment Outcome; Trigeminal Neuralgia

Voltage-gated sodium (Na

Topics: Analgesics; Carbamazepine; Humans; Lacosamide; Pain; Protein Domains; Voltage-Gated Sodium Channel Blockers; Voltage-Gated Sodium Channels

The treatment of trigeminal neuralgia (TN) involves first- and second-generation anticonvulsants. However, side effects (SEs) impair compliance with treatment, especially in elderly patients. Lacosamide (LCM) is a third-generation anticonvulsant with a mechanism of action that is not completely clear. It has few SEs and has been considered in the treatment of neuropathic pain.. LCM was prescribed as a monotherapy for a 60-year-old female with TN who had proven refractory to previous treatments in terms of both the absence of any pain relief and the appearance of severe leukopenia. The treatment dosage was 100 mg twice daily. Pain relief was obtained after three weeks of treatment without any SEs. Currently, the patient takes a maintenance dosage of 100 mg/daily, remaining in a state of complete well-being.. LCM has shown evidence of a potential efficacy and a good safety profile in the treatment of this patient with TN.

Topics: Aged; Anticonvulsants; Female; Humans; Lacosamide; Middle Aged; Pain; Pain Management; Treatment Outcome; Trigeminal Neuralgia

The voltage-gated sodium channel Na

Topics: Acetamides; Analgesics; Animals; Cell Line; HEK293 Cells; Humans; Intercellular Signaling Peptides and Proteins; Lacosamide; Mice; Mice, Inbred C57BL; Mice, Transgenic; NAV1.7 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Pain; Protein Binding; Protein Interaction Mapping; Protein Transport; Receptors, N-Methyl-D-Aspartate; Receptors, Opioid; Sensory Receptor Cells; Synaptotagmin II; Vesicular Transport Proteins; Voltage-Gated Sodium Channel beta-3 Subunit

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease linked to mutations of the Nf1 gene. Patients with NF1 commonly experience severe pain. Studies on mice with Nf1 haploinsufficiency have been instructive in identifying sensitization of ion channels as a possible cause underlying the heightened pain suffered by patients with NF1. However, behavioral assessments of Nf1 mice have led to uncertain conclusions about the potential causal role of Nf1 in pain. We used the clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (CRISPR/Cas9) genome editing system to create and mechanistically characterize a novel rat model of NF1-related pain. Targeted intrathecal delivery of guide RNA/Cas9 nuclease plasmid in combination with a cationic polymer was used to generate allele-specific C-terminal truncation of neurofibromin, the protein encoded by the Nf1 gene. Rats with truncation of neurofibromin, showed increases in voltage-gated calcium (specifically N-type or CaV2.2) and voltage-gated sodium (particularly tetrodotoxin-sensitive) currents in dorsal root ganglion neurons. These gains-of-function resulted in increased nociceptor excitability and behavioral hyperalgesia. The cytosolic regulatory protein collapsin response mediator protein 2 (CRMP2) regulates activity of these channels, and also binds to the targeted C-terminus of neurofibromin in a tripartite complex, suggesting a possible mechanism underlying NF1 pain. Prevention of CRMP2 phosphorylation with (S)-lacosamide resulted in normalization of channel current densities, excitability, as well as of hyperalgesia following CRISPR/Cas9 truncation of neurofibromin. These studies reveal the protein partners that drive NF1 pain and suggest that CRMP2 is a key target for therapeutic intervention.

Topics: Acetamides; Animals; Calcium Channels, N-Type; CRISPR-Cas Systems; Female; Ganglia, Spinal; Genes, Neurofibromatosis 1; Intercellular Signaling Peptides and Proteins; Lacosamide; Male; Nerve Tissue Proteins; Neurofibromin 1; Neurons; Pain; Phosphorylation; Rats, Sprague-Dawley

The purpose of this study was to synthetize the focused library of 34 new piperazinamides of 3-methyl- and 3,3-dimethyl-(2,5-dioxopyrrolidin-1-yl)propanoic or butanoic acids as potential new hybrid anticonvulsants. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5-38 were prepared in a coupling reaction of the 3-methyl- or 3,3-dimethyl-2-(2,5-dioxopyrrolidin-1-yl)propanoic (1, 2) or butanoic acids (3, 4) with the appropriately substituted secondary amines in the presence of the N,N-carbonyldiimidazole reagent. The initial anticonvulsant screening was performed in mice (ip) using the 'classical' maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests as well as in the six-Hertz (6Hz) model of pharmacoresistant limbic seizures. The acute neurological toxicity was determined applying the chimney test. The broad spectra of activity across the preclinical seizure models in mice ip displayed compounds 7, 15, and 36. The most favorable anticonvulsant properties demonstrated 15 (ED50 MES=74.8mg/kg, ED50scPTZ=51.6mg/kg, ED50 6Hz=16.8mg/kg) which showed TD50=213.3mg/kg in the chimney test that yielded satisfying protective indexes (PI MES=2.85, PI scPTZ=4.13, PI 6Hz=12.70) at time point of 0.5h. As a result, compound 15 displayed comparable or better safety profile than clinically relevant AEDs: ethosuximide, lacosamide or valproic acid. In the in vitro assays compound 15 was observed as relatively effective binder to the neuronal voltage-sensitive sodium and L-type calcium channels. Beyond the anticonvulsant properties, 6 compounds diminished the pain responses in the formalin model of tonic pain in mice.

Topics: Analgesics; Animals; Anticonvulsants; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Injections, Intraperitoneal; Mice; Molecular Structure; Pain; Pain Measurement; Pentylenetetrazole; Piperazines; Pyrrolidinones; Seizures

Tetrodotoxin-resistant (TTX-r) sodium channels are key players in determining the input-output properties of peripheral nociceptive neurons. Changes in gating kinetics or in expression levels of these channels by proinflammatory mediators are likely to cause the hyperexcitability of nociceptive neurons and pain hypersensitivity observed during inflammation. Proinflammatory mediator, tumor necrosis factor-α (TNF-α), is secreted during inflammation and is associated with the early onset, as well as long-lasting, inflammation-mediated increase in excitability of peripheral nociceptive neurons. Here we studied the underlying mechanisms of the rapid component of TNF-α-mediated nociceptive hyperexcitability and acute pain hypersensitivity. We showed that TNF-α leads to rapid onset, cyclooxygenase-independent pain hypersensitivity in adult rats. Furthermore, TNF-α rapidly and substantially increases nociceptive excitability in vitro, by decreasing action potential threshold, increasing neuronal gain and decreasing accommodation. We extended on previous studies entailing p38 MAPK-dependent increase in TTX-r sodium currents by showing that TNF-α via p38 MAPK leads to increased availability of TTX-r sodium channels by partial relief of voltage dependence of their slow inactivation, thereby contributing to increase in neuronal gain. Moreover, we showed that TNF-α also in a p38 MAPK-dependent manner increases persistent TTX-r current by shifting the voltage dependence of activation to a hyperpolarized direction, thus producing an increase in inward current at functionally critical subthreshold voltages. Our results suggest that rapid modulation of the gating of TTX-r sodium channels plays a major role in the mediated nociceptive hyperexcitability of TNF-α during acute inflammation and may lead to development of effective treatments for inflammatory pain, without modulating the inflammation-induced healing processes.

Topics: Acetamides; Action Potentials; Animals; Cells, Cultured; Computer Simulation; Disease Models, Animal; Electron Transport Complex IV; Ganglia, Spinal; Lacosamide; Male; Models, Neurological; Nociceptors; p38 Mitogen-Activated Protein Kinases; Pain; Patch-Clamp Techniques; Rats, Sprague-Dawley; Sodium Channel Blockers; Sodium Channels; Tetrodotoxin; Tumor Necrosis Factor-alpha

Alterations in voltage-gated sodium channel (VGSC) function have been linked to chronic pain and are good targets for analgesics. Lacosamide (LCM) is a novel anticonvulsant that enhances the slow inactivation state of VGSCs. This conformational state can be induced by repeated neuronal firing and/or under conditions of sustained membrane depolarisation, as is expected for hyperexcitable neurones in pathological conditions such as epilepsy and neuropathy, and probably osteoarthritis (OA). In this study, therefore, we examined the antinociceptive effect of LCM on spinal neuronal and behavioural measures of pain, in vivo, in a rat OA model.. OA was induced in Sprague Dawley rats by intraarticular injection of 2 mg of monosodium iodoacetate (MIA). Sham rats received saline injections. Behavioural responses to mechanical and cooling stimulation of the ipsilateral hind paw and hindlimb weight-bearing were recorded. In vivo electrophysiology experiments were performed in anaesthetised MIA or sham rats, and we recorded the effects of spinal or systemic administration of LCM on the evoked responses of dorsal horn neurones to electrical, mechanical (brush, von Frey, 2 to 60 g) and heat (40°C to 50°C) stimulation of the peripheral receptive field. The effect of systemic LCM on nociceptive behaviours was assessed.. Behavioural hypersensitivity ipsilateral to knee injury was seen as a reduced paw withdrawal threshold to mechanical stimulation, an increase in paw withdrawal frequency to cooling stimulation and hind limb weight-bearing asymmetry in MIA-treated rats only. Spinal and systemic administration of LCM produced significant reductions of the electrical Aβ- and C-fibre evoked neuronal responses and the mechanical and thermal evoked neuronal responses in the MIA group only. Systemic administration of LCM significantly reversed the behavioural hypersensitive responses to mechanical and cooling stimulation of the ipsilateral hind paw, but hind limb weight-bearing asymmetry was not corrected.. Our in vivo electrophysiological results show that the inhibitory effects of LCM were MIA-dependent. This suggests that, if used in OA patients, LCM may allow physiological transmission but suppress secondary hyperalgesia and allodynia. The inhibitory effect on spinal neuronal firing aligned with analgesic efficacy on nociceptive behaviours and suggests that LCM may still prove worthwhile for OA pain treatment and merits further clinical investigation.

Topics: Acetamides; Analgesics; Animals; Disease Models, Animal; Lacosamide; Male; Osteoarthritis; Pain; Pain Measurement; Random Allocation; Rats; Rats, Sprague-Dawley; Treatment Outcome

Functional amino acids (FAAs) and alpha-aminoamides (AAAs) are two classes of antiepileptic drugs (AEDs) that exhibit pronounced anticonvulsant activities. We combined key structural pharmacophores present in FAAs and AAAs to generate a new series of compounds and document that select compounds exhibit activity superior to either the prototypical FAA (lacosamide) or the prototypical AAA (safinamide) in the maximal electroshock (MES) seizure model in rats. A representative compound, (R)-N-4'-((3''-fluoro)benzyloxy)benzyl 2-acetamido-3-methoxypropionamide ((R)-10), was tested in the MES (mice, ip), MES (rat, po), psychomotor 6 Hz (32 mA) (mice, ip), and hippocampal kindled (rat, ip) seizure tests providing excellent protection with ED(50) values of 13, 14, approximately 10 mg/kg, and 12 mg/kg, respectively. In the rat sciatic nerve ligation model (ip), (R)-10 (12 mg/kg) provided an 11.2-fold attenuation of mechanical allodynia. In the mouse biphasic formalin pain model (ip), (R)-10 (15 mg/kg) reduced pain responses in the acute and the chronic inflammatory phases.

Topics: Acetamides; Alanine; Amides; Amino Acids; Animals; Anticonvulsants; Benzylamines; Drug Evaluation, Preclinical; Lacosamide; Mice; Pain; Rats; Seizures; Structure-Activity Relationship; Treatment Outcome

Various mechanisms underlie the complexity of neuropathic pain (pain due to disease of the somatosensory system), with each mechanism bearing a different order of relevance from one person and pain state to the next. Successful treatment is contingent on sound knowledge of underlying mechanisms that may occur at peripheral, spinal and/or supraspinal sites. In particular, ion channels throughout the nervous system are known to play an intimate part in neuropathic pain, and thus stand as good targets for analgesic drugs. Agents that modulate voltage-gated sodium channel function can reduce action potential propagation along sensory neurones to reduce the transmission and perception of nociceptive signals. Lacosamide is a functionalised amino acid that affects voltage-gated sodium channels in a novel way by enhancing the slow inactivating 'braking' state of these channels. To validate lacosamide's inhibitory efficacy in vivo, we unilaterally ligated spinal nerves L5 and L6 in rats to induce a state of neuropathy, and on post-operative days 14-17 recorded evoked-responses of deep dorsal horn neurones before and after spinal or systemic lacosamide delivery. Lacosamide's effects on various measures in spinal nerve-ligated rats were compared to rats that underwent sham surgery. Our results show that neuropathy induced novel inhibitory effects of lacosamide on mechanical and electrical responses, and enhanced inhibitory effects on thermal responses after systemic or spinal administration, suggesting state-preference actions of lacosamide.

Topics: Acetamides; Action Potentials; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Evoked Potentials; Lacosamide; Lumbar Vertebrae; Male; Microelectrodes; Pain; Pain Measurement; Peripheral Nervous System Diseases; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Spinal Nerves; Time Factors

The etiology of osteoarthritis is multifactorial, with inflammatory, metabolic, and mechanical causes. Pain in osteoarthritis is initiated by mild intra-articular inflammation and degeneration of articular cartilage and subchondral bone. The principle of treatment with acetaminophen or non-steroidal anti-inflammatory drugs is to reduce pain and improve joint function. Recently, animal models for osteoarthritic pain behavior have been established. The most frequently used rat model for analyzing properties of drugs on the pathology of osteoarthritis is the injection of the metabolic inhibitor monosodium iodoacetate into the joint, which inhibits the activity of glyceraldehyde-3-phosphate dehydrogenase in chondrocytes. Here, we characterize the effect on pain behavior of lacosamide, a member of a family of functionalized amino acids that are analogues of endogenous amino acids and D-serine, in the monosodium iodoacetate rat model for osteoarthritis in comparison to diclofenac and morphine. Lacosamide (3, 10, and 30 mg/kg) was able to reduce secondary mechanical allodynia and hyperalgesia similarly to morphine (3 mg/kg). In contrast, diclofenac (30 mg/kg) was only effective in reducing secondary mechanical hyperalgesia. During the first week, pain is induced mainly by inflammation in the iodoacetate model, but afterwards inflammation plays only a minor role in pain. Lacosamide was able to inhibit pain at days 3, 7 and 14 after induction of arthritis. This shows that lacosamide is able to reduce pain behavior induced by multiple mechanisms in animals.

Topics: Acetamides; Analgesics; Animals; Disease Models, Animal; Iodoacetates; Lacosamide; Male; Osteoarthritis; Pain; Pain Measurement; Rats; Rats, Wistar

Chronic muscle pain is a problem with high prevalence in clinical practice and its pharmacological treatment is difficult. There is a lack of animal models which reliably predict analgesic activity of drugs on muscle pain. Here we used intramuscular injection of tumor necrosis factor-alpha (TNF) in rats as a model of muscle pain. In this model we tested the antihyperalgesic action of lacosamide in comparison to the analgesics pregabalin and gabapentin. Mechanical withdrawal thresholds to muscle pressure were measured with an algesimeter exerting pressure on the gastrocnemius muscles previously injected with TNF. Fore limb grip strength was measured with a digital grip force meter after TNF injection into the biceps brachii muscles. A complete reversal of hyperalgesia was seen with lacosamide at 30mg/kg. Significant effects were also seen for pregabalin at 30 and 100mg/kg and gabapentin at 100mg/kg. In biceps muscle hyperalgesia, a significant reversal of hyperalgesia was seen with lacosamide at 10mg/kg. Significant effects were also seen for pregabalin and gabapentin at 100mg/kg. We could thus demonstrate in a rat model for myalgia that lacosamide effectively reduces muscular hyperalgesia and is somewhat more potent than gabapentin and pregabalin.

Topics: Acetamides; Amines; Animals; Behavior, Animal; Cyclohexanecarboxylic Acids; Excitatory Amino Acid Antagonists; Gabapentin; gamma-Aminobutyric Acid; Hand Strength; Hyperalgesia; Lacosamide; Male; Muscular Diseases; Pain; Pregabalin; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factors

Lacosamide is a functionalized amino acid which was initially synthesized as an antiepileptic drug. In addition to its broad anti-seizure activity, lacosamide was shown to display efficacy in animal models for neuropathic pain and is currently in phase III clinical development for the treatment of epilepsy and neuropathic pain. In order to further profile its antinociceptive properties, the effects of lacosamide on inflammatory pain in the formalin test, the carrageenan model and the adjuvant-induced arthritis model were investigated. For the formalin test, mice received an intraplantar injection of formalin and the subsequent licking response was measured over 45 min. Lacosamide was administered 30 min before formalin. For the carrageenan model, mechanical and thermal hyperalgesia were assessed 3 h following an intraplantar injection of carrageenan. Lacosamide was administered to rats 30 min before pain threshold measurements. For the adjuvant-induced arthritis test rats received intraplantar injections of Freund's complete adjuvant into the right hindpaw which lead to the development of arthritic symptoms in all animals tested for antinociception. On day 11 after arthritis induction, mechanical hyperalgesia was assessed by the modified Randall Selitto paw pressure test following acute treatment with lacosamide. Lacosamide dose-dependently attenuated mechanical hyperalgesia following carrageenan injection and in rats suffering from Freund's complete adjuvant-induced arthritis. Moreover, thermal hyperalgesia induced by carrageenan as well as the formalin-induced licking response were dose-dependently attenuated by lacosamide. These results suggest lacosamide may be active against various forms of acute and chronic inflammatory pain in humans.

Topics: Acetamides; Animals; Arthritis; Carrageenan; Disease Models, Animal; Dose-Response Relationship, Drug; Formaldehyde; Hot Temperature; Hyperalgesia; Lacosamide; Male; Mice; Pain; Rats; Rats, Sprague-Dawley; Rats, Wistar; Reaction Time; Touch

Lacosamide was tested in the streptozotocin rat model of diabetic neuropathic pain in comparison to drugs which are commonly used in the treatment of diabetic neuropathic pain, i.e. antidepressants and anticonvulsants. In diabetic rats, lacosamide attenuated cold (10, 30 mg/kg, i.p.), warm (3, 10, 30 mg/kg, i.p.) and mechanical allodynia (30 mg/kg, i.p.). Streptozotocin-induced thermal and mechanical hyperalgesia were reduced by lacosamide at doses of 10 and 30 mg/kg, i.p. Morphine (3 mg/kg) showed similar efficacy on allodynia and hyperalgesia. Amitriptyline (10 mg/kg), venlafaxine (15 mg/kg), levetiracetam (180 mg/kg) and pregabalin (100 mg/kg) exhibited significant effects on thermal allodynia and mechanical hyperalgesia. Only treatment with amitriptyline (30 mg/kg, i.p.) produced full reversal of thermal allodynia comparable to lacosamide. Lamotrigine (45 mg/kg, i.p.) had no effect on both behavioral readouts. Lacosamide's potency and efficacy in reversing pain behavior might be due to its new, yet unknown mechanism of action.

Topics: Acetamides; Analgesics; Analgesics, Opioid; Animals; Anticonvulsants; Antidepressive Agents; Diabetic Neuropathies; Hyperalgesia; Lacosamide; Male; Pain; Pain Measurement; Physical Stimulation; Rats; Rats, Sprague-Dawley; Streptozocin

The effect of systemic administration of lacosamide, a newly developed anti-epileptic, on neuropathic pain-like behaviors was examined in rats after ischemic injury to the infraorbital nerve or spinal cord using a photochemical method. In rats with infraorbital nerve injury, lacosamide reduced mechanical hypersensitivity and the effect was markedly stronger in female than in male rats. In spinal cord injured female rats 10-20 mg/kg lacosamide dose-dependently alleviated the mechanical and cold allodynia-like behaviors without causing motor impairments or marked sedation. Administration of lacosamide twice daily at 20 mg/kg for 7 days totally alleviated the allodynia-like state in spinally-injured rats with no tolerance. Following treatment cessation the cold and the static allodynia reappeared but the effect on dynamic mechanical allodynia (brushing) was maintained until day 11. Lacosamide also produced hypothermia at antinociceptive doses in rats. It is suggested that this novel compound may be useful as an analgesic for treating central and trigeminal neuropathic pain. Furthermore, there may be a gender difference to the effect of lacosamide with female rats being more responsive to the treatments.

Topics: Acetamides; Animals; Anticonvulsants; Behavior, Animal; Body Temperature; Cold Temperature; Female; Lacosamide; Male; Pain; Pain Threshold; Peripheral Nervous System Diseases; Physical Stimulation; Psychomotor Performance; Rats; Rats, Sprague-Dawley; Skin Temperature; Spinal Cord Injuries; Trigeminal Neuralgia; Vocalization, Animal

The aim of the study is to establish if the putative anticonvulsant SPM 927 has an analgesic effect in human neuropathic pain and to assess its tolerability. This is an open label study of 25 adult human subjects with resistant neuropathic pain. Subjects were treated with SPM 927 in a dose-escalating scheme to 600 mg daily, if tolerated. Treatment was continued for 4 weeks then withdrawn without tapering. Pain scores were recorded using a 11-point Likert score and a categorical pain-rating scale. Laboratory parameters and, electrocardiographs (ECGs) were collected; side effects were noted. Of the 25 enrolled subjects, 12 completed the study according to the protocol. The remaining subjects dropped out due to adverse events (n=12) or withdrawn consent. Mean daily pain scores (Likert score) fell by 0.83 (95% CI -1.77, +0.11) at the end of maintenance and rose by 0.58 (95% CI -0.23, +1.40) after withdrawal of SPM 927. Similar changes were seen in the categorical pain-rating scores. There were decreases in the mean scores for shooting pain, paraesthesia, and allodynia, but much less change in the numbness and burning-pain scores. The most common side effects were nausea, dizziness, leukocytosis, and increased ALT. No consistent changes in ECG recordings or haemodynamic variables were observed. SPM 927 may have an analgesic effect in human neuropathic pain and was reasonably well tolerated in this study. These data support the continued clinical development of SPM 927 for neuropathic pain.

Topics: Adult; Amides; Analgesics; Confidence Intervals; Female; Humans; Male; Middle Aged; Mononeuropathies; Pain; Propane