Lacosamide in painful diabetic neuropathy: an 18-week double-blind placebo-controlled trial. Lacosamide in painful diabetic peripheral neuropathy: a phase 2 double-blind placebo-controlled study. Efficacy and safety of lacosamide in painful diabetic neuropathy. Efficacy and safety of lacosamide in diabetic neuropathic pain: an 18-week double-blind placebo-controlled trial of fixed-dose regimens. Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Efficacy and safety of pregabalin 600 mg/d for treating painful diabetic peripheral neuropathy: a double-blind placebo-controlled trial. Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy: a 52-week multicenter placebo-controlled double-blind parallel group study. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study.
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. 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. 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. 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. This was a 6-week, randomized, double-blind, multicenter study evaluating the efficacy of pregabalin in the treatment of painful diabetic neuropathy. Two hundred forty-six men and women with painful diabetic neuropathy received pregabalin (150 or 600 mg/day by mouth) or placebo. The primary efficacy variable was mean pain score at the end of treatment. Efficacy results indicate that pregabalin 600 mg/day significantly decreased mean pain score to 4.3 (vs 5.6 for placebo, P = .0002) and increased the proportion of patients who had a > or =50% decrease from baseline pain (39% vs 15% for placebo, P = .002). Pregabalin also significantly reduced sleep interference, past week and present pain intensity, sensory and affective pain scores, and bodily pain and decreased by > or =50% the number of patients describing their pain as gnawing, sickening, fearful, and punishing-cruel. More patients receiving pregabalin 600 mg/day than placebo showed improvement, as rated on the Clinical and Patient Global Impression of Change scales, 73% vs 45% and 85% vs 47%, respectively. Pregabalin 150 mg/day was essentially no different from placebo. Dizziness was the most common side effect. These study results show pregabalin 600 mg/day to be safe and effective in reducing the pain and other associated symptoms of painful diabetic neuropathy.
                Painful diabetic peripheral neuropathy is a challenging neuropathic pain syndrome. This randomized controlled trial demonstrates that pregabalin, a new drug that interacts with the alpha2-delta protein subunit of the voltage-gated calcium channel, is an efficacious and safe treatment for the pain of this condition. Pregabalin, an alpha2-delta ligand with analgesic, anxiolytic, and anticonvulsant activity, has been evaluated for treatment of neuropathic pain. The authors assessed the efficacy and tolerability of pregabalin (75, 300, 600 mg/day) vs placebo in patients with diabetic peripheral neuropathy (DPN).
                Patients with a 1- to 5-year history of DPN and average weekly pain score of > or =4 on an 11-point numeric pain-rating scale were enrolled in a 5-week, double-blind, multicenter, placebo-controlled study. Patients (n = 338) were randomized to receive one of three doses of pregabalin or placebo TID. Pregabalin 600 mg/day was titrated over 6 days; lower doses were initiated on day 1.
                Patients in the 300- and 600-mg/day pregabalin groups showed improvements in endpoint mean pain score (primary efficacy measure) vs placebo (p = 0.0001). Improvements were also seen in weekly pain score, sleep interference score, patient global impression of change, clinical global impression of change, SF-McGill Pain Questionnaire, and multiple domains of the SF-36 Health Survey. Improvements in pain and sleep were seen as early as week 1 and were sustained throughout the 5 weeks. Responders (patients with > or =50% reduction in pain compared to baseline) were 46% (300 mg/day), 48% (600 mg/day), and 18% (placebo). Pregabalin was well tolerated with a low discontinuation rate. The most common adverse events were dizziness and somnolence.
                In patients with diabetic peripheral neuropathy, pregabalin demonstrated early and sustained improvement in pain and a beneficial effect on sleep, which were confirmed by positive patient global impression. Pregabalin was well tolerated at all doses. Recent consensus guidelines recommend pregabalin as a first-tier treatment for painful diabetic peripheral neuropathy (DPN). We evaluated the efficacy of pregabalin 600 mg/d (300 mg dosed BID) versus placebo for relieving DPN-associated neuropathic pain, and assessed its safety using objective measures of nerve conduction (NC).
                In this randomized, double-blind, placebo-controlled trial, the primary efficacy measure was endpoint mean pain score (MPS) from daily pain diaries (11-point scale). NC velocity and sensory and motor amplitudes were assessed at baseline, endpoint, and end of follow-up (2 weeks post-treatment). At each timepoint, the median-motor, median-sensory, ulnar-sensory, and peroneal-motor nerves were evaluated. Secondary efficacy measures included weekly MPS and proportion of responders (patients achieving >or=50% reduction in MPS from baseline to endpoint). After 1-weeks' dosage escalation, pregabalin-treated patients received 300 mg BID for 12 weeks.
                Eighty-two patients received pregabalin and 85 placebo. Mean durations were 10 years for diabetes and approximately 5 years for painful DPN. Pregabalin-treated patients had lower MPS than controls (mean difference, -1.28; p <.001). For all four nerves, 95% CIs for median differences in amplitude and velocity from baseline to endpoint and baseline to follow-up included 0 (ie, no significant difference vs. placebo). Significant pain improvement among pregabalin-treated patients was evident at week 1 and sustained at every weekly timepoint. More pregabalin-treated patients (49%) than controls (23%) were responders (p <.001).
                Pregabalin 600 mg/d (300 mg BID) effectively reduced pain, was well tolerated, and had no statistically significant or clinically meaningful effect on NC in patients with painful DPN. The purpose of this study was to evaluate the efficacy of fidarestat, a novel aldose reductase (AR) inhibitor, in a double-blind placebo controlled study in patients with type 1 and type 2 diabetes and associated peripheral neuropathy.
                A total of 279 patients with diabetic neuropathy were treated with placebo or fidarestat at a daily dose of 1 mg for 52 weeks. The efficacy evaluation was based on change in electrophysiological measurements of median and tibial motor nerve conduction velocity, F-wave minimum latency, F-wave conduction velocity (FCV), and median sensory nerve conduction velocity (forearm and distal), as well as an assessment of subjective symptoms.
                Over the course of the study, five of the eight electrophysiological measures assessed showed significant improvement from baseline in the fidarestat-treated group, whereas no measure showed significant deterioration. In contrast, in the placebo group, no electrophysiological measure was improved, and one measure significantly deteriorated (i.e., median nerve FCV). At the study conclusion, the fidarestat-treated group was significantly improved compared with the placebo group in two electrophysiological measures (i.e., median nerve FCV and minimal latency). Subjective symptoms (including numbness, spontaneous pain, sensation of rigidity, paresthesia in the sole upon walking, heaviness in the foot, and hypesthesia) benefited from fidarestat treatment, and all were significantly improved in the treated versus placebo group at the study conclusion. At the dose used, fidarestat was well tolerated, with an adverse event profile that did not significantly differ from that seen in the placebo group.
                The effects of fidarestat-treatment on nerve conduction and the subjective symptoms of diabetic neuropathy provide evidence that this treatment alters the progression of diabetic neuropathy. To evaluate the efficacy and safety of 6 weeks of venlafaxine extended-release (ER) (75 mg and 150-225 mg) treatment in patients with painful diabetic neuropathy. This multicenter, double-blind, randomized, placebo-controlled study included 244 adult outpatients with metabolically stable type 1 or 2 diabetes with painful diabetic neuropathy. Primary efficacy measures were scores on the daily 100 mm Visual Analog Pain Intensity (VAS-PI) and Pain Relief (VAS-PR) scales. Secondary efficacy measures included the Clinical Global Impressions-Severity of Illness and the Clinical Global Impressions-Improvement, Patient Global Rating of Pain Relief, and percentage of patients achieving 50% reduction in pain intensity. Baseline pain intensity was 68.7 mm (moderately severe). At week 6, the percentage reduction from baseline in VAS-PI was 27% (placebo), 32% (75 mg), and 50% (150-225 mg; P < 0.001 vs placebo). Mean VAS-PR scores in the 150-225 mg group were significantly greater than placebo at week 6 (44 vs 60 mm; P < 0.001). The number needed to treat (NNT) for 50% pain intensity reduction with venlafaxine ER 150-225 mg was 4.5 at week 6. Nausea and somnolence were the most common treatment-emergent adverse events. Seven patients on venlafaxine had clinically important ECG changes during treatment. Venlafaxine ER appears effective and safe in relieving pain associated with diabetic neuropathy. NNT values for higher dose venlafaxine ER are comparable to those of tricyclic antidepressants and the anticonvulsant gabapentin.
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.