Cost-effectiveness of add-on therapy with pregabalin in patients with refractory partial epilepsy

PURPOSE: To estimate the cost-effectiveness of pregabalin as add-on therapy in patients with refractory partial epilepsy. METHODS: We developed a model to estimate clinical and economic outcomes over 1 year in a hypothetical cohort of patients with refractory partial epilepsy assumed alternatively to receive add-on therapy with pregabalin (300 mg/day) or no add-on therapy. For each patient in the model, we estimated the occurrence of seizure and side effects, using techniques of stochastic simulation. We assigned health-state utilities to each day of follow-up based on whether or not seizure or side effects were predicted to occur. Patients could discontinue therapy due to lack of efficacy or side effects. Outcomes included expected numbers of days without seizure ("seizure-free [SF] days"), quality-adjusted life-years (QALYs), and costs of therapy. Cost-effectiveness was assessed alternatively in terms of incremental cost per SF day gained and incremental cost per QALY gained. RESULTS: Add-on therapy with pregabalin was estimated to result in an average gain of 23.8 SF days over one year; the estimated additional cost of therapy was $678. Incremental cost (mean, 95% CI) per SF day gained was $28.45 ($27.25, $29.44); corresponding estimates of incremental cost per QALY gained were $52,893 ($49,249, $56,983). CONCLUSIONS: In patients with refractory partial epilepsy, the cost-effectiveness of pregabalin 300 mg/day compares favorably with published estimates of cost-effectiveness for other add-on antiepileptic drugs.     

加巴喷丁添加治疗难治性部分性癫痫疗效及安全性的Meta分析

目的 初步评价加巴喷丁添加治疗难治性部分性癫痫的疗效及安全性.方法 采用RevMan5.0软件对纳入文献的相关数据进行Meta分析.结果 加巴喷丁组发作频率减少及增加的比例与安慰剂组相比,差异均具有统计学意义.发作频率减少≥50％的OR为2.17,95％ CI为1.53 ～ 3.07；50％≤发作频率减少＜75％的OR为1.87,95％ CI为1.02～3.44；发作频率减少≥75％的OR为2.16,95％CI为1.16 ～4.03.发作频率增加的OR为0.57,95％CI为0.40～0.81.加巴喷丁组因不良反应退出的比例及部分不良反应发生率与安慰剂组相比,差异具有统计学意义.结论 加巴喷丁添加治疗难治性部分性癫痫的疗效高于安慰剂,部分不良反应发生率高于安慰剂.     

Efficacy and tolerability of pregabalin in partial epilepsy

Pregabalin, the most recently approved antiepileptic drug, is a structural analog of GABA with a favorable pharmacokinetic profile. Pregabalin binds to the alpha2-delta subunit of a neuronal voltage-gated calcium channel and is believed to exert its anticonvulsant effect by modulating the release of specific neurotransmitters from hyperexcited presynaptic neurons. Animal models of epilepsy have suggested that this drug will be efficacious against partial-onset and generalized tonic-clonic seizures. Four pivotal, add-on clinical trials conducted in patients with partial-onset seizures demonstrated that pregabalin at daily doses of 150-600 mg is efficacious and associated with dose-dependent adverse events. Meta-analyses of efficacy and tolerability indicated that pregabalin is an efficacious and relatively well-tolerated antiepileptic drug.     

Progabide for refractory partial epilepsy: a controlled add-on trial

Progabide, an experimental GABA-ergic antiepileptic drug, was given in a placebo-controlled double-blind cross-over trial to 19 adult patients with chronic partial epilepsy refractory to previous high-dose antiepileptic drug therapy. A mean daily dose of 32 mg/kg (range, 16 to 63) of progabide did not significantly change the seizure frequency. In patients with a therapeutic response, progabide led to an increase in the plasma concentration of phenytoin and phenobarbital. Comedication with carbamazepine was associated with a poor response to progabide. Side effects were mild except for a several-fold increase of SGOT and SGPT, which required withdrawal of progabide in one patient. Progabide does not seem to be the drug urgently needed for failures of previous high-dose drug therapy.     

Evidence for sustained efficacy of levetiracetam as add-on epilepsy therapy

PURPOSE: To evaluate the long-term clinical usefulness of levetiracetam (LEV, Keppra((R))(1)) as add-on therapy in patients with refractory epilepsy. METHODS: Data for all 1422 patients with refractory epilepsy treated with LEV during the development program were analyzed for changes in seizure frequency per week, seizure freedom, and adverse events. RESULTS: Median percent reduction from baseline in seizure frequency per week over the whole treatment period was 39.6%, and no decrease over time was observed within each cohort exposed to LEV for durations ranging from 6 to 54 months. The median treatment period was 399 days (range 1-8 years). The proportion of responders during the first 3 months of LEV treatment was 39.2%. This proportion remained stable at 6 months (36.1%). Overall, 38.6 and 20.1% of patients had reductions in seizure frequency of at least 50 and 75%. Sixty-five (4.6%) patients were seizure-free over their entire treatment period, compared with 167 (11.7%) and 126 (8.9%) during their last 6 and 12 months of follow-up. Ninety-seven (19.8%) of 491 patients who received only one other antiepileptic drug (AED) in addition to LEV were seizure-free during their last 6 months. The proportion of patients who reduced their number of concomitant AEDs was 14.4% (205 patients), while 5.5% (79 patients) were treated with LEV only at the end of follow-up. Accidental injury (28.0%), infection (26.6%), headache (25.8%), somnolence (23%), asthenia (22.6%), and dizziness (18.9%) were among the most common adverse events. CONCLUSION: LEV offers sustained efficacy in patients with refractory partial seizures, and its long-term tolerability is similar to that seen in the short-term placebo-controlled trials.     

Erectile dysfunction associated with pregabalin add-on treatment in patients with partial seizures: five case reports

Sexual dysfunction has been reported in both men and women with epilepsy. Associated factors are diverse but include, among others, antiepileptic drugs. We present the cases of 5 men who reported mild to moderate erectile dysfunction or impotence for the first time when treated with the new antiepileptic drug pregabalin as add-on therapy.     

Long-term efficacy and tolerability of topiramate as add-on therapy in refractory partial epilepsy: An observational study

Purpose:   To evaluate the long-term efficacy and tolerability of topiramate (TPM) as add-on therapy in patients with refractory partial epilepsy.
Methods:   This is a retrospective, single-center, long-term observational study. Patients fulfilling the criteria of medical intractability proposed by Berg et al. were entered into the study if they were newly prescribed TPM as add-on therapy between January 2000 and June 2002. The usual starting dosage of TPM was 50 mg/day and optimal-dose adjustments were made according to individual clinical responses. Efficacy and tolerability were analyzed every year during 5-year follow-up in the "intention-to-treat (ITT) population." Retention rate was estimated by Kaplan-Meyer analysis.
Results:   A total of 125 patients were included in the study and 107 patients (85.6%) were followed for 5 years. Retention rate was 87.2% at 1 year and 64% at 5 years. At the end of 5 years, the median seizure frequency reduction rate was 69.0% and responder rate was 43.2% in the ITT population. Cumulative seizure-free rate (SFR) was 30.4% and the terminal 1-year SFR was 12.8% in the ITT population (20.0% in completers) at 5-year follow-up. Adverse events (AEs) occurred in 39.2% of patients, including significant AEs leading to antiepileptic drug (AED) withdrawal in 14.4%. The most common AEs were anorexia (16.0%), weight loss (10.4%), and gastrointestinal symptoms (8.8%). Concomitant AEDs were reduced in 25.0% of the completers.
Discussion:   Low-dose and slow-dose escalation of TPM in add-on therapy for patients with refractory partial epilepsy is effective and well tolerated in long-term, individualized clinical practice.     

Open study of pranlukast add-on therapy in intractable partial epilepsy

Innovative treatments of epileptic seizures are needed to improve the outcome of epilepsy. We studied the effect of pranlukast on seizure outcome in patients with intractable partial epilepsy. An open study was conducted to evaluate the clinical efficacy of 24-week pranlukast add-on therapy in 50 patients with intractable partial seizures. Serum concentrations of matrix metalloproteinase (MMP)-9 were determined using Biotrak Activity Assay System. Cytokines in cerebrospinal fluid (CSF) were measured by the BioPlex (BioRad) system and soluble TNF receptor1 (sTNFR1) in CSF was measured by the ELISA. Surface markers of lymphocytes in CSF were examined by cell-sorter. Seizure-free rate (SFR) was 13.6%, responder rate (RR) was 47.7%, and aggravation rate (AR) was 18.2% at the 13–24 week period after starting pranlukast. In patients with increased serum MMP-9 before pranlukast therapy (baseline), comparison of paired serum levels showed a significant decrease after pranlukast therapy. Baseline CSF levels of IL-1β and IL-6 were elevated in patients compared with disease controls. Of four patients with paired data, three (including a responder to pranlukast) showed decreased pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), and four showed decreased sTNFR1, after pranlukast treatment, and only a responder had markedly decreased frequency of CD8+ T cells in CSF. Pranlukast reduces seizure frequencies probably by pleiotropic effects including normalization of MMP-9 in sera, reduced leakage of pro-inflammatory cytokines into CNS, and inhibition of extravasation of leucocytes from brain capillaries. Further investigations by double-blind control study and animal models are warranted.     

添加拉莫三嗪治疗儿童部分性癫的疗效观察

目的 探讨添加拉莫三嗪治疗儿童部分性癫的临床疗效及耐受性.方法 观察42例部分性癫患儿添加拉莫三嗪治疗后疗效、不同发作类型的有效率及发作频率的改变.结果 添加拉莫三嗪治疗后,患儿月发作频率减少38.1%,简单部分性发作有效率68.4%,部分性发作转为全面性发作有效率66.7%,复杂部分性发作有效率72.7%,总有效率69.0%.治疗前后比较差异有统计学意义(P＜0.05).不良反应轻微.结论 拉莫三嗪添加治疗儿童部分性癫具有良好的临床疗效及耐受性.     

Aromatase inhibitors as add-on treatment for men with epilepsy

Manipulation of neurosteroids to treat epilepsy has been an area of active research. The effect of testosterone on brain excitability and seizure threshold has been mixed; the estradiol metabolite of testosterone increases brain excitability, while the reduced metabolite of testosterone, 3alpha-androstanediol, decreases brain excitability, likely through an action at the gamma-amino butyric acid A receptor. Therefore, the metabolites of testosterone produce opposite effects on brain excitability in seizure models. Aromatase is the enzyme for the conversion of testosterone to 17beta-estradiol. Aromatase inhibitors could decrease brain excitability by decreasing local estradiol levels and therefore, could be beneficial for the treatment of epilepsy. Aromatase inhibitors are US Food and Drug Administration-approved and have a long history of safe use in menopausal women with breast cancer. This review presents the results of using anastrazole in an open-label, add-on manner in a small group of men with epilepsy in order to improve seizures. The results suggested some effect on reduction of seizures and no side effects. Testosterone levels did increase, but not to above the normal range. Letrozole used in a single case was also beneficial for seizures. It was concluded that aromatase inhibitors may be a useful adjunct to the treatment of epilepsy, but habituation to the treatment may be limiting. Many men with epilepsy have low testosterone, and aromatase inhibition may be helpful in restoring levels to normal. Modulation of reproductive hormones by aromatase inhibition as well as enhancement of the 3alpha-androstanediol pathway may be an avenue of epilepsy treatment that would not produce sedative side effects, which is often a limiting factor with standard antiseizure medications. A further interesting result is that elevated follicle stimulating hormone and luteal stimulating hormone levels were associated with seizure reduction, suggesting that they may be a biomarker for a beneficial effect of aromatase inhibition on brain excitability.     

A neurobehavioral approach for treatment of complex partial epilepsy: efficacy.

This is a retrospective study of the efficacy of a short-term comprehensive multidisciplinary neurobehavioral treatment approach for complex partial epilepsy. Eleven patients were treated intensively for five consecutive days followed by 6 months of weekly telephone contact and an additional 6 months of monitoring of seizure logs and journals. Data was analysed at least 24 months after initiation of treatment. Pre-treatment seizure frequency ranged from 1 to 15 per month. Post-treatment seizure frequency was zero per month for the nine patients who experienced less than four seizures per month prior to treatment and less than two per month for the other two patients. Additional benefits of the treatment program were improved levels of professional achievement in the arts and computer sciences and reduction of medication dosages.     

Losigamone add-on therapy in partial epilepsy: a placebo-controlled study

OBJECTIVES: To evaluate the efficacy and tolerability of losigamone (LSG). PATIENTS AND METHODS: Double-blind, placebo-controlled add-on study with 3x500 mg LSG/die for the treatment of chronic partial seizures in 203 patients (99 treated with LSG, 104 on placebo). RESULTS: The median percent change of seizures was 14.9% (LSG) versus 6.7% (placebo) (P=0.004). Seizure frequency was decreased by more than 50% in 22.3% (LSG) and 14.6% (placebo) of patients (P=0.13). Mean percent change of seizures was best in patients with only one additional anticonvulsant drug (LSG versus placebo, P=0.004). Adverse events (usually CNS-related side effects of mild to moderate intensity) were reported in 59.6% (LSG) and 37.5% (placebo) of patients. CONCLUSIONS: LSG proved to be an effective and well tolerated anticonvulsant drug for the treatment of chronic partial seizures.     

Comparison of add-on valproate and primidone in carbamazepine-unresponsive patients with partial epilepsy

PurposeEvaluation of the efficacy of add-on valproate (VPA) or primidone (PRM) in patients with partial epilepsy unresponsive to carbamazepine (CBZ).MethodsThe trial was prospective and open. Patients, aged 8–58 years, with partial epilepsy who did not become seizure free on CBZ were randomized to either VPA add-on or PRM add-on. The baseline period and the evaluation period were both 3 months. Proportions of patients with different degrees of reduction in seizure frequency were determined.ResultsSignificantly more patients on VPA (51% of 68 patients) achieved a greater than 50% seizure reduction than on PRM (34% of 68 patients). There was no significant difference in percentage seizure free (26% and 16%, respectively) or in percentage treatment withdrawals due to adverse effects.ConclusionOur results indicated that the efficacy of the CBZ/VPA combination tends to be greater than the efficacy of the CBZ/PRM combination.     

氟桂利嗪剂量递增法治疗难治性癫痫部分性发作的疗效观察

目的：研究氟桂利嗪作为添加剂，采用剂量递增法治疗难治性癫痫部分性发作的疗效和安全性。方法：对1997年1月至2000年1月收治的43例难治性部分性发作患者（男25例，女18例，年龄8－56岁），进行氟桂利嗪添加治疗的开放性自身对照研究，原服用的抗癫痫药种类和剂量不变，氟桂利嗪剂量递增给药方法为：8－12岁儿童，第1周口服5mg/d，以后每周增加5mg/d；成人第1周口服10mg/d，以后每周增加10mg/d；至第4周时，儿童以20mg/d、成人以40mg/d维持量给药，分2次口服，连续观察半年。结果2年失访，3例因不能耐受的副反应，在剂量递增期间退观察。38例完成氟桂利嗪剂量递增添加治疗。总有效率为63％，其中单纯部分性发作（SPS）有效率75％，38例完成氟桂利嗪剂量递增添加治疗。总有效率为63％，其中单纯部分性发作（SPS）有效率为75％，复杂部分性发作（CPS）为62％，继发性全身性发作（SGS）为56％。同添加治疗前比较，总的发作频率减少69％，其中SPS为73％，GPS为66％，SGS为57％。脑电图呈中度或重度异常的患者比例，由76％下降到47％，治疗前后的心电图及肝、肾、血、尿等化检验检查均无明显变化。16例患者出现轻度副反应，但未影响治疗。结论：氟桂利嗪作为添加剂，用剂量递增法治疗难治性癫痫部分性发作，疗效确切，安全性较高。     

Vigabatrin as first add-on treatment in carbamazepine-resistant epilepsy patients

Numerous clinical reports and several controlled clinical trials have confirmed that vigabatrin is both effective and well-tolerated as an add-on treatment for patients with drug-resistant epilepsy. This report presents the results of a study of 40 patients (22 women and 18 men), aged I960 years (mean 37 years), with partial seizures (with or without secondary generalization) and receiving carbamazepine, 600-1800 mg/day. Vigabatrin was given as first add-on drug at a dose of 2-3 g/day for an average of 6 months, in order to assess the clinical response before considering other anti-epilepsy drugs. There was a significant decrease in seizure frequency, from a median of 13 seizures/month at baseline, to 3 seizures/month during the last month on vigabatrin (p<0.01). Seven patients became seizure-free (17.5%). The most common adverse events experienced during the study were drowsiness, diplopia/blurred vision, and were already present before vigabatrin treatment. In conclusion, vigabatrin is effective as a first add-on therapy for partial epilepsy, refractory to carbamazepine monotherapy, and appears to be a worthy clinical alternative to other drug combinations.     

Lamotrigine in add-on therapy: assessment of efficacy in drug resistant epilepsy

The authors presented the results of treatment with lamotrigine (LTG, Lamictal) in 13 patients with drug resistant epilepsy (add-on therapy). There were 8f, 5m. aged 16-60 years, mean age 28.8 years. Generalized seizures occurred in 8 patients (62%). In this group there was 1 patient (aged 16 years) with the Lennox-Gastaut syndrome and 1 patient (aged 20 years) with valproate resistant juvenile myoclonic epilepsy. Complex partial seizures and complex partial with secondary generalization occurred in 5 patients (38%). Before LTG addition mean seizure frequency was from 3/month to several times/day. The mean duration of epilepsy was 16.6 years. The 8 patients were treated with CBZ and VPA, one with PHT and VPA, one CBZ and VGB. Monotherapy with VPA was introduced in 3 patients. After 6 months of treatment with LTG the efficacy was evaluated. 12 patients took LTG with VPA, 1 LTG with CBZ. Complete reduction of seizures was achieved in 3 cases (23%), at least 50% reduction in 3 patients (23%), reduction below 50% in 4 patients (31%). In 3 cases (23%) the results of treatment were negative (increase or no change in seizure frequency). Beneficial psychotropic effect was observed in 9 patients (69%). Adverse effects occurred in 2 patients (15%). Headache, vertigo, sleepness were observed in one case. Rash occurred in 1 patient (treated with LTG and VPA). After 6 months 3 patients were excluded from the study because of negative effects of treatment. LTG is helpful and well tolerated in drug-resistant epilepsy.     

An open-label, add-on study of pregabalin in patients with partial seizures: A multicenter trial in Greece

Introduction

Pregabalin efficacy and safety as an adjunctive treatment for partial seizures was evaluated using an open-label, flexible-dose.

Study design

In 98 adults with refractory partial epilepsy taking 1–3 anti-epileptic drugs with ≥2 seizures during an 8-week baseline period.

Methods

Pregabalin was increased to ≤600 mg/day during a 9-week dose optimization period with dosage maintained for 12 additional weeks. Primary endpoint was the percentage change in partial seizure frequency between the 8-week baseline and 12-week observation period.

Results

Pregabalin treatment was associated with a significant reduction in partial seizure frequency: median percent change in partial seizure frequency from baseline to 12 weeks was −33% and −22% in patients with a baseline seizure frequency of ≤3 and >3 per 28 days, respectively. The 50% and 75% responder rates were 41.94% (95% CI: 31.91–51.96) and 30.11% (95% CI: 20.78–39.43), respectively. Nineteen percent of subjects were seizure-free throughout the last 12 weeks. Pregabalin administration resulted in a significant reduction in anxiety (mean reduction in Hospital Anxiety and Depression Scale scores of 1.68 units, 95% CI: −2.60 to −0.76). Most patients were much improved or very much improved on Patient Global Impression of Change (53.8%) and Clinical Global Impression of Change (53.8%). The most frequently self-reported adverse events (AEs) were mild or moderate somnolence (20.4%) and dizziness (5.1%) with a low AE discontinuation rate (5.1%).

Conclusions

The efficacy and side-effect profile of pregabalin were similar to previous pregabalin double-blind, controlled studies. Additionally, pregabalin, as an add-on treatment for partial epilepsy, exhibits significant anti-anxiety properties.     

Seizure-free days observed in randomized placebo-controlled add-on trials with levetiracetam in partial epilepsy

PURPOSE: We examined the effect of adjunctive levetiracetam (LEV; 1,000 to 3,000 mg/day) on the number of seizure-free days gained per quarter in adult patients with refractory partial-onset epilepsy. METHODS: The treatment effect was studied in a meta-analysis using individual patient data of a subpopulation of patients (n = 846) emerging from the three randomized, double-blind, placebo-controlled, phase III trials (n = 904). RESULTS: Adding LEV effectively increased the number of days without seizures by 5.19 days per quarter [95% confidence interval (CI), 3.63-6.76; p = 0.0001; titration and stable dose periods]. CONCLUSIONS: LEV adjunctive treatment shows a clear benefit in terms of seizure-free days gained for patients with refractory epilepsy. This gain is significant for the pooled and for each LEV dose compared with placebo.