lacosamide and Diabetic-Neuropathies

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

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

To review the pharmacology, pharmacokinetics, efficacy, and safety of lacosamide, a new agent for use as adjunctive treatment in partial-onset seizures and a potential agent for treatment of neuropathic pain.. A MEDLINE search (1966-July 2009) was conducted using the key words lacosamide, harkoseride, SPM-927, ADD-234037, epilepsy, anticonvulsant, and neuropathic pain. Bibliographies of all articles retrieved were also reviewed.. All studies including humans and published in English with data describing lacosamide for the adjunctive treatment of partial-onset seizures and for treatment of neuropathic pain were reviewed.. Lacosamide is a functionalized amino acid molecule that selectively enhances the slow inactivation of voltage-gated sodium channels and interacts with the collapsin-response mediator protein-2. With its bioavailability of approximately 100%, minimal protein binding, and few drug-drug interactions, lacosamide has a favorable pharmacokinetic profile. Recent data suggest that lacosamide may have a role as adjunctive treatment of partial-onset seizures. Open-label studies showed a 14-47% reduction in seizure frequency, while placebo-controlled trials demonstrated a 26-40% reduction in seizure frequency. The 50% responder rates ranged from 32.7% to 41.2% with varying doses of lacosamide. Although lacosamide use is not approved by the Food and Drug Administration for treatment of neuropathic pain, studies demonstrated reductions of 2.01-3.60 in pain scale scores. The most common adverse effects, occurring in greater than 10% of subjects in the clinical trials, include arthralgia, ataxia, blurred vision, diplopia, dizziness, fatigue, headache, injection site pain (only in intravenous studies), nausea, tremor, upper respiratory tract infection, and vomiting.. Lacosamide is an effective agent for adjunctive treatment of refractory partial-onset seizures. Its exact role in the treatment of neuropathic pain needs to be determined.

Topics: Acetamides; Analgesics; Anticonvulsants; Chemotherapy, Adjuvant; Diabetic Neuropathies; Epilepsies, Partial; Humans; Lacosamide; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Seizures

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

To evaluate efficacy and safety of lacosamide compared with placebo in painful diabetic polyneuropathy.. Diabetic patients with at least moderate neuropathic pain were randomized to placebo or lacosamide 400 (in a slow or standard titration) or 600 mg/day over 6-week titration and 12-week maintenance periods. Primary efficacy criterion was intra-individual change in average daily Numeric Pain Rating Scale score from baseline to the last 4 weeks.. For the primary end point, pain reduction was numerically but not statistically greater with lacosamide compared with placebo (400 mg/day, P = 0.12; 600 mg/day, P = 0.18). Both doses were significantly more effective compared with placebo over the titration (P = 0.03, P = 0.006), maintenance (P = 0.01, P = 0.005), and entire treatment periods (P = 0.03, P = 0.02). Safety profiles between titration schemes were similar.. Lacosamide reduced neuropathic pain and was well tolerated in diabetic patients, but the primary efficacy criterion was not met, possibly due to an increased placebo response over the last 4 weeks.

Topics: Acetamides; Diabetic Neuropathies; Humans; Lacosamide; Placebo Effect; Treatment Outcome

This open-label follow-on trial aimed to investigate long-term safety and efficacy of lacosamide in patients with painful diabetic neuropathy.. After 1-week baseline period, lacosamide 100mg/day was started. Each week, based on pain and safety assessments, doses were escalated by 100mg/day to an optimal level, up to a maximum of 400mg/day. Patients then entered the 20-week maintenance period (dose adjusted as needed). Thereafter, patients could opt to continue lacosamide up to about 2.5 years (extension period).. Of the 69 enrolled patients, 47 (68%) completed the 20-week maintenance period and elected to continue into the extension period; 37/69 (54%) patients were in the extension period for more than one year and 34/69 (49%) continued until study termination. The modal lacosamide dose in most patients (54%) was 400mg/day. Headache, upper respiratory tract infection, arthralgia, sinusitis, nasopharyngitis, and back pain were the most frequently reported adverse events (10% of patients). Significant reductions from baseline in Likert pain scores began during dose titration and were sustained throughout the study. Significant improvements were also seen in Neuropathic Pain Scale, Quality of Life scores, and Patient's Global Impression of Change assessment. Of 34 patients at study termination, 32 (90%) elected to continue with lacosamide treatment in another long-term open-label trial (NCT00235443).. The long-term safety profile and sustained efficacy of lacosamide observed in this trial support its continued development for treatment of painful diabetic neuropathy.

Topics: Acetamides; Administration, Oral; Aged; Analgesics; Anticonvulsants; Diabetic Neuropathies; Dizziness; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Lacosamide; Male; Middle Aged; Nausea; Pain Measurement; Patient Satisfaction; Peripheral Nerves; Quality of Life; Stroke; Time; Treatment Outcome

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

The aims of this multicenter, randomized, placebo-controlled, double-blind trial were to confirm the efficacy of lacosamide at a daily dose of 400 mg/d and to explore the efficacy, safety, and tolerability of lacosamide 200 mg/d and 600 mg/d in the treatment of painful diabetic neuropathy.. The trial consisted of a 2-week run-in period, a 6-week titration phase, and a 12-week maintenance phase, during which patients received placebo or fixed doses of lacosamide 200, 400, or 600 mg/d. No back titration was allowed during the trial. The primary efficacy criterion was the change in Likert pain score from baseline to the average over the last 4 weeks of the maintenance phase in the intent-to-treat population.. The lacosamide 400 mg/d group demonstrated statistically significant improvement in Likert pain score over placebo for the primary efficacy measure. At the end of treatment, 58% of patients in the lacosamide 400 mg/d treatment group achieved at least a 2-point or 30% reduction in Likert pain score, compared with 46% of placebo-treated patients. The lacosamide 200 mg/d group separated from placebo, but failed to show statistical significance for any of the primary or secondary outcome measures. The lacosamide 600 mg/d group was significantly more efficacious than placebo in the observed cases but not in the intent-to-treat population. This was probably secondary to a relatively high-premature withdrawal rate due to adverse events that occurred during the titration phase in that group. Overall lacosamide at daily doses of 200 to 400 mg was well tolerated, with 8% of patients discontinuing due to an adverse event from the 200 mg/d group and 23% from the 400 mg/d group compared with 9% in the placebo group. Discontinuations due to adverse events were highest in the 600 mg/d group (40%). The most common adverse events consisted of dizziness, nausea, tremor, headache, and fatigue. Somnolence, cognitive and behavioral side effects, weight change, and edema were notably low.. Safety and efficacy analyses indicated that lacosamide 400 mg/d provided an optimal balance between efficacy and side effects in patients with painful diabetic neuropathy.

Topics: Acetamides; Adult; Aged; Aged, 80 and over; Analgesics; Comorbidity; Diabetic Neuropathies; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Female; Fibromyalgia; Humans; Incidence; Lacosamide; Male; Middle Aged; Pain Measurement; Placebo Effect; Treatment Outcome; United States

Peripheral diabetic neuropathy affects between 20% and 45% of patients with diabetes.. To ascertain the effect of lacosamide on pain associated with peripheral diabetic neuropathy.. One hundred nineteen patients with a 1 to 5-year history of pain attributed to diabetic neuropathy and a score of > or =4 on the Likert pain scale entered the multicenter, randomized, double-blind, placebo-controlled trial. Lacosamide (N=60) titrated from 100 to 400 mg/d or maximum tolerated dose and placebo (N=59) were the trial interventions. Primary efficacy criterion was change in pain score on the 11-point Likert pain scale. Secondary assessments included Short-Form McGill Pain and Short-Form-36 Quality of Life Questionnaires, sleep/activity interference, pain intensity, Patient and Clinical Global Impression of Change, and Profile of Mood. Patients receiving at least 1 dose of medication underwent safety evaluation.. Ninety-four patients (lacosamide 46; placebo 48) completed the trial. Lacosamide had significantly (P=0.039) better pain relief versus placebo (primary outcome). Improvements were also seen in secondary outcome measures. Adverse events occurred in 52 lacosamide and 44 placebo patients. Common adverse events, occurring in > or =5% of patients, were headache (lacosamide 18%, placebo 22%), dizziness (lacosamide 15%, placebo 8%), and nausea (lacosamide 12%, placebo 7%). Five lacosamide and 3 placebo patients withdrew for adverse events.. Lacosamide seems to attenuate pain in diabetic neuropathy in doses up to 400 mg/d and improves quality of life issues.

Topics: Acetamides; Aged; Analgesics; Diabetic Neuropathies; Double-Blind Method; Drug Eruptions; Electrocardiography; Female; Gastrointestinal Diseases; Headache; Heart; Humans; Lacosamide; Male; Middle Aged; Pain Measurement; Quality of Life; Treatment Outcome

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

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