Teresa Leon

The efficacy and safety of pregabalin in the treatment of neuropathic pain associated with chronic lumbosacral radiculopathy

&NA; We evaluated the efficacy of pregabalin in patients with chronic lumbosacral radiculopathy. This randomized, controlled, withdrawal trial included five phases: screening (4–18 days); run‐in (4–10 days) to screen out placebo responders; single‐blind (28 days) to identify pregabalin responders; double‐blind to randomize responders to pregabalin or placebo (35 days); and final study medication taper (7 days). The primary endpoint was time to loss of response (LOR) during the double‐blind phase (≥1‐point increase in pain, discontinuation, or rescue‐medication use). In the single‐blind phase, 58% of patients had ≥30% pain reduction. In the double‐blind phase, pregabalin (n = 110) and placebo (n = 107) groups did not differ significantly in time to LOR. Adverse events caused the discontinuation of 9.9% and 5.6% of pregabalin‐treated and placebo‐treated patients, respectively. Most patients with chronic lumbosacral radiculopathy responded to pregabalin therapy; however, time to LOR did not significantly differ between pregabalin and placebo. Considering the results of all phases of the study, it is difficult to draw definitive conclusions from it, suggesting a need for further work to understand the clinical potential of pregabalin treatment for lumbosacral radiculopathy.

Association of subjective anxiety, depression, and sleep disturbance with quality-of-life ratings in adults with epilepsy

Purpose:  To determine the relative contributions of subjective anxiety, depression, sleep disturbance, and seizure‐related variables to quality‐of‐life scores in adults with epilepsy, and the interrelationships among these factors.

Pregabalin for the treatment of generalized anxiety disorder: a novel pharmacologic intervention

Pregabalin is the first anxiolytic pharmacologic alternative for the treatment of generalized anxiety disorder (GAD) to be introduced in more than 10 years. GAD is a significant psychiatric condition with lifetime prevalence rates ranging between 5.7 and 6.4%. It causes significant impairment in quality of life and functional abilities equivalent to those associated with major depression. Randomized, controlled trials confirm that pregabalin is superior to placebo and comparable with lorazepam, alprazolam and venlafaxine for the treatment of patients with moderate-to-severe GAD. The onset of anxiolytic activity for pregabalin is apparent within 1 week following initiation of treatment, which is more rapid than that obtained with paroxetine and venlafaxine. Additionally, pregabalin has demonstrated potential for the prevention of relapse of GAD. Recently, the efficacy, safety and tolerability of pregabalin were also shown in a placebo-controlled study with elderly patients. Safety and tolerability profiles are favorable, with transient dizziness and somnolence of mild-to-moderate severity being the most commonly reported adverse events. Pregabalin has minimal potential for drug–drug interactions and does not provoke a clinically significant withdrawal response. Furthermore, pregabalin has low potential for abuse and dependence, unlike other classes of medications used for the treatment of GAD. Clinicians may consider the use of pregabalin in lieu of benzodiazepines as an alternative therapy for their patients with GAD.

An International, Randomized, Double-blind, Placebo-controlled, Phase III Trial of Pregabalin Monotherapy in Treatment of Patients with Fibromyalgia

Objective. To evaluate the efficacy and safety of pregabalin monotherapy versus placebo for symptomatic pain relief and improvement of patient global assessment in patients with fibromyalgia (FM) enrolled from countries outside the United States. Methods. This international, multicenter, double-blind, placebo-controlled trial randomly assigned 747 patients with FM to placebo or 300, 450, or 600 mg/day pregabalin twice daily for 14 weeks. Primary efficacy measures were endpoint mean pain scores and Patient Global Impression of Change (PGIC). Secondary outcomes included assessments of sleep and function. Results. Patients in the 450 mg/day pregabalin group showed significant improvements versus placebo in endpoint mean pain score (−0.56; p = 0.0132), PGIC (73% improved vs 56% placebo; p = 0.0017), and function [Fibromyalgia Impact Questionnaire (FIQ) total score −5.85; p = 0.0012]. PGIC was also significant for 600 mg/day pregabalin (69% improved; p = 0.0227). Results for these endpoints were nonsignificant for pregabalin at 300 mg/day and for pain and FIQ score at 600 mg/day. Early onset of pain relief was seen, with separation from placebo detected by Week 1 in all pregabalin groups. All pregabalin doses demonstrated superiority to placebo on the Medical Outcomes Study-Sleep Scale Sleep Disturbance subscale and the Sleep Quality diary. Dizziness and somnolence were the most frequently reported adverse events. Conclusion. Pregabalin demonstrated modest efficacy in pain, global assessment, and function in FM at 450 mg/day, and improved sleep across all dose levels, but it did not provide consistent evidence of benefit at 300 and 600 mg/day in this study. Pregabalin was generally well tolerated for the treatment of FM. (Clinical trial registry NCT00333866).

A comparison of pregabalin, lamotrigine, and placebo as adjunctive therapy in patients with refractory partial-onset seizures.

PURPOSE This study assessed the comparative efficacy of pregabalin for refractory partial seizures. METHODS Four-hundred and thirty-four patients with partial seizures were randomized to pregabalin, lamotrigine, or placebo as adjunctive therapy for 17 weeks of double-blind treatment. In phase I (11 weeks), pregabalin was titrated over 1 week and lamotrigine over 5 weeks to fixed dosages of 300mg/day for both. In phase II (6 weeks), patients not yet seizure-free were increased to pregabalin 600mg/day or lamotrigine 400mg/day. RESULTS During phase I, there was a nonsignificant trend toward a greater reduction in seizures with pregabalin versus placebo and lamotrigine. Across the 17 weeks of treatment, pregabalin showed a median percentage reduction from baseline in seizure frequency of -20.0% (p=.001) versus placebo, and -9.7% (p=.080) versus lamotrigine. The responder rate (> or =50% reduction in seizure frequency) for pregabalin exceeded that of placebo (36% vs 21%; p=.007) and lamotrigine (36% vs 24%; p=.04). Adverse events were consistent with the known safety profiles of pregabalin and lamotrigine. DISCUSSION Pregabalin was demonstrated to be noninferior to lamotrigine in the treatment of refractory partial seizures. Overall conclusions were complicated by an unusually large and heterogeneous placebo response.

Relationships among pain and depressive and anxiety symptoms in clinical trials of pregabalin in fibromyalgia.

Background Fibromyalgia, as defined by the American College of Rheumatology, is characterized by widespread pain lasting for at least 3 months, with pain in at least 11 out of 18 tender points when palpated with digital pressure. Objective The authors investigated the relationship between changes in pain and symptoms of anxiety and depression, using data from pregabalin clinical trials. Method Results from three double-blind, placebo-controlled trials of pregabalin monotherapy in fibromyalgia (8–14 weeks) were pooled, and baseline to end-point changes in pain and Hospital Anxiety and Depression Scale (HADS) scores were analyzed. Path-analysis evaluated the association between improvements in anxiety and depression and pain relief. Results Baseline HADS scores indicated moderate-to-severe anxiety in 38% of patients and moderate-to-severe depressive symptoms in 27%. The improvement in pain was not related to baseline levels of anxiety or depression. The correlation between changes in pain and depressive or anxiety symptoms was low-to-moderate. Pathanalysis showed that most of the pain relief observed with pregabalin treatment was a direct analgesic effect and was not explained by improvement in mood. Conclusion Response to treatment of pain in the pregabalin trials did not depend on baseline levels of anxiety or depressive symptoms, and pregabalin improved pain in fibromyalgia patients with or without depressive or anxiety symptoms. Changes in the level of anxiety or depression had a low-tomoderate impact on pain reduction. Pain reduction with pregabalin treatment appeared to result mostly from a direct treatment effect, rather than an indirect effect mediated through improvement in anxiety or depressive symptoms.

Pregabalin add-on therapy using a flexible, optimized dose schedule in refractory partial epilepsies: a double-blind, randomized, placebo-controlled, multicenter trial.

Purpose:  To evaluate the efficacy and safety of pregabalin (PGB) as adjunctive therapy, using a flexible‐dosing schedule in Korean patients with refractory partial‐onset seizures.

Add-on treatment with pregabalin for partial seizures with or without generalisation: pooled data analysis of four randomised placebo-controlled trials.

Pooled data analysis was performed on individual data from 807 pregabalin- and 367 placebo-treated patients with treatment-resistant partial seizures with or without generalization from four placebo-controlled studies evaluating the short-term efficacy, safety and tolerability of add-on pregabalin 150-600 mg/day. Short-term add-on treatment with pregabalin resulted in statistically significant reductions from baseline in seizure frequency and statistically significantly higher responder rates over placebo (OR 5.93 [95% CI 4.10, 8.57]). Its overall tolerability was good, with an OR of withdrawing from the study due to any reason of 1.71 (95% CIs 1.24, 2.35). The most commonly reported AEs were dizziness and somnolence, however, they were most pronounced during the first week of treatment, followed by a sharp fall in incidences across all dosing groups to <5% from Week 2 and onwards. Weight gain, reported by 5.4-17.1% of patients across pregabalin dosing groups, appeared to be dose-related, but it led to study withdrawal in only 0.74% (6 out of 810) pregabalin-treated subjects. Our analysis suggests that pregabalin has a robust efficacy and good tolerability demonstrated in a study population more treatment-refractory compared to the one enrolled into short-term studies of other new antiepileptic drugs.

Pregabalin or placebo used adjunctively with levetiracetam in refractory partial-onset epilepsy: a post hoc efficacy and safety analysis in combined clinical trials.

Abstract Objective: Some patients with epilepsy require treatment with >1 adjunctive antiepileptic drug (AED) to achieve adequate seizure remission. The purpose of this analysis was to evaluate the efficacy and safety of adding adjunctive pregabalin to an AED regimen that included levetiracetam in patients with refractory partial-onset epilepsy. Research design and methods: Data from the pregabalin and placebo arms of two placebo-controlled, double-blind, randomized studies of pregabalin in patients who received adjunctive treatment with levetiracetam in addition to ≥1 other AEDs were pooled for this post hoc analysis. Patients (aged ≥18 years) had ≥4 partial-onset seizures and no 28-day period free of seizures during baseline. Efficacy outcomes included Response Ratio (RRatio), change from baseline in seizure frequency, proportion of patients with ≥50% reduction in seizure frequency, and 28-day seizure-freedom rate. Safety was evaluated using adverse events (AEs). Results: In total, 138 patients were included in the analysis (placebo, n = 47; pregabalin, n = 91). Pregabalin was significantly better than placebo for difference in least squares mean of the RRatio (−16.4; 95% confidence interval [CI]: −28.5, −4.5; p = 0.0085), median of the difference in percentage change from baseline in seizure frequency (−22.3; 95% CI: −40.1, −7.2; p = 0.0095), and proportion of 50% responders (36.3 vs. 17.0; odds ratio, 3.2; 95% CI: 1.3, 8.3; p = 0.018), but not 28-day seizure-freedom rate (7 [7.7%] vs. 2 [4.3%]; p = 0.353). The most common AEs when adding pregabalin were dizziness/vertigo, fatigue, somnolence, blurred vision, and increased weight that were not proportional to the number of concomitant AEDs. Conclusions: In this population of patients with refractory partial-onset seizures, adding pregabalin to an AED regimen with levetiracetam produced further seizure reductions. The safety profile of pregabalin in patients receiving levetiracetam and ≥1 other AEDs did not appear to be compromised by the number of concomitant AEDs.

Erratum to “Add-on treatment with pregabalin for partial seizures with or without generalisation: Pooled data analysis of four randomised placebo-controlled trials” [Seizure: European Journal of Epilepsy 18 (2009) 184–192]

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