Pharmacokinetics of a New,Once-Daily,Sustained-release Pregabalin Tablet in Healthy Male Volunteers

PurposeA new sustained-release (SR) pregabalin formulation (YHD1119) designed for once-daily dosing has recently been developed to improve patient adherence. This study aimed to compare the pharmacokinetics of pregabalin SR and immediate-release (IR) formulations after multiple oral doses and to assess the effect of food on the pharmacokinetic profile of the pregabalin SR formulation after a single dose in healthy individuals.MethodsTwo clinical trials were conducted: a randomized, open-label, multiple-dose, 2-treatment, 2-period crossover study to evaluate the steady-state pharmacokinetic properties of SR treatment (pregabalin SR 300 mg once daily for 3 days) and IR treatment (pregabalin IR 150 mg twice daily for 3 days) under fed conditions and a randomized, open-label, single-dose, 2-treatment, 2-period, crossover study to evaluate the effect of food intake on the pharmacokinetic properties of the pregabalin SR formulation. Plasma concentrations of pregabalin were measured using LC-MS/MS. The AUC and C_max for pregabalin were calculated using noncompartmental method and compared between treatments in each study.FindingsThirty-one individuals in the bioequivalence study and 23 in the food effect study completed the pharmacokinetic sampling. The geometric mean ratios of C_max,ss and AUC_0–τ between the SR and IR formulations were 1.1642 (90% CI, 1.1043–1.2272) and 0.9704 (90% CI, 0.9372–1.0047), respectively. The geometric mean ratios of C_max and AUC_0–last between the SR formulation in the fed state and in the fasted state were 1.6514 (90% CI, 1.3820-1.9732) and 1.7899 (90%CI, 1.4499-2.2097), respectively.ImplicationsThe bioavailability of the pregabalin SR 300 mg formulation is increased if taken with a high-fat meal. Once-daily pregabalin SR 300 mg is bioequivalent to twice-daily pregabalin IR 150 mg under fed conditions at steady state. The pregabalin SR formulation is expected to improve patient adherence. ClinicalTrials.gov identifiers: NCT02783183 (bioequivalence study) and NCT03191136 (food effect study).     

Pregabalin does not decrease acute pain or postoperative nausea and vomiting after hysterectomy: a meta-analysis

ObjectiveHysterectomy is associated with severe postoperative pain. The relative efficacy of pregabalin compared with other treatments for post-hysterectomy pain is unclear.MethodsWe searched the PubMed, Cochrane Library, and Web of Science databases for studies that compared the use of pregabalin and placebo for reducing pain in patients undergoing hysterectomy.ResultsThis meta-analysis showed that pregabalin had limited pain-relieving effects at 2, 6, 24, and 48 hours after hysterectomy compared with placebo. Pregabalin significantly reduced postoperative nausea and vomiting. However, there was no significant difference in postoperative sedation or visual disturbances between patients treated with pregabalin and placebo.ConclusionsPregabalin is not clinically superior to placebo in terms of reducing pain intensity and morphine consumption in patients undergoing hysterectomy. However, the limitations of this meta-analysis mean that more high-quality randomized controlled trials are necessary to verify our pooled results.     

Pregabalin for Alcohol Dependence: A Critical Review of the Literature

Introduction

Alcohol dependence represents a severe pathological disorder associated with a significant rate of morbidity and mortality. To date, limited pharmacological agents exist to treat this disorder, and there is a growing interest for new therapies. In this context, pregabalin represents a promising strategy. Pregabalin, like gabapentin, selectively binds to the ??²??subunit of voltage-gated calcium channels, inhibiting release of excessive levels of excitatory neurotransmitters. The main focus of this review is the clinical use of pregabalin in alcoholic patients, but the authors also reported some data about chemistry, pharmacology, and pharmacokinetics of this drug.

Methods

The authors conducted a PubMed search of clinical human studies published in English from January 2000 to August 2012 using the following search terms: pregabalin alcohol dependence, pregabalin alcohol withdrawal, pregabalin alcoholism.

Results

The search revealed a total of five studies: two trials for the treatment of alcohol relapse and three articles for the management of alcohol withdrawal syndrome with pregabalin. The critical review of the literature suggests that pregabalin could be a novel and effective treatment option for the management of alcohol relapse in detoxified patients, whereas until now there have been mixed results for the treatment of alcohol withdrawal syndrome. In particular, pregabalin showed a greater beneficial effect on patients with comorbid conditions such as alcoholism and generalized anxiety disorders. The exact mechanism of action of pregabalin in the management of alcoholism is not well understood but it is thought to be due mainly to the modulation of neurotransmitters such as glutamate and norepinephrine by inhibiting activity-dependent calcium influx in nerve terminals.

Conclusion

Pregabalin, within a dosage of 150?C450 mg/day, showed beneficial effects for alcohol relapse prevention and contrasting results for the treatment of the withdrawal syndrome. Its use appears to be safe and well tolerated.     

Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo-controlled trial with pregabalin

This was a multicenter, double-blind (DB), placebo-controlled, randomized discontinuation trial to evaluate the efficacy of pregabalin monotherapy for durability of effect on fibromyalgia (FM) pain. The trial included a 6-week open-label (OL) pregabalin-treatment period followed by 26-week DB treatment with placebo or pregabalin. Adults with FM and 40-mm score on 100-mm pain visual analog scale (VAS) were eligible. During OL weeks 1-3, patients received escalating dosages of pregabalin to determine their optimal dosages. During OL weeks 4-6, patients received their optimal fixed dosages (300, 450, 600mg/d). To be randomized, patients must have had 50% decrease in pain VAS and a self-rating of "much" or "very much" improved on Patient Global Impression of Change (PGIC) at the end of OL. Double-blind treatment was with placebo or the patient's optimal fixed dosage of pregabalin. Primary outcome was time to loss of therapeutic response (LTR), defined as <30% reduction in pain (from OL baseline) or worsening of FM. A total of 1051 patients entered OL; 287 were randomized to placebo, 279 to pregabalin. Time to LTR was longer for pregabalin versus placebo (P<.0001). Kaplan-Meier estimates of time-to-event showed half the placebo group had LTR by Day 19; half the pregabalin group still had not lost response by trial end. At the end of DB, 174 (61%) placebo patients met LTR criteria versus 90 (32%) pregabalin patients. Pregabalin was well tolerated, though 178 (17%) discontinued during OL for treatment-related adverse events (AE), and more pregabalin than placebo patients discontinued for AEs during DB. In those who respond, pregabalin demonstrated durability of effect for relieving FM pain.     

A randomized,double-blind,placebo-controlled trial and open-label extension study to evaluate the efficacy and safety of pregabalin in the treatment of neuropathic pain associated with human immunodeficiency virus neuropathy

The objective of these studies was to assess the efficacy and safety of pregabalin in the treatment of human immunodeficiency virus (HIV)–associated neuropathic pain. Patients with HIV-associated distal sensory polyneuropathy (DSP) were randomized to treatment with flexible-dose pregabalin (150–600 mg/day) or placebo for 17 weeks in a single-blind, placebo lead-in, randomized, double-blind, parallel-group, placebo-controlled multinational trial. The primary efficacy outcome was the change in mean pain score on an 11-point numeric rating scale (NRS) from baseline to study endpoint. Participants who completed this trial were invited to participate in a 6-month open-label extension study with pregabalin. Of the 377 patients enrolled in the randomized controlled trial (pregabalin, n = 183; placebo, n = 194), 68.4% completed treatment. In the open-label extension, 217 patients were treated and 59.4% completed treatment. Both studies were terminated by the sponsor after a preplanned interim analysis indicated trial futility. At endpoint, the change from baseline in least-squares mean NRS pain scores in the intent-to-treat population was −2.04 for pregabalin versus −2.11 for placebo (P = .709). There were no significant differences between the pregabalin and placebo groups in the secondary efficacy measures. Incidence of adverse events was lower than seen in previous pregabalin studies. Overall, this trial did not show pregabalin to be more efficacious than placebo in treating HIV-associated DSP. Studies such as these, which fail to support their primary hypotheses, may be important in informing the methodology of future trials, especially when novel approaches to limit variability in the control group are included.     

Pregabalin und postoperative Hyperalgesie

Numerous studies support the theory that pregabalin causes an antihyperalgesic effect, which could be potentially beneficial in a perioperative setting. By binding to calcium channels pregabalin reduces the release of excitatory neurotransmitters and therefore inhibits central sensitization. Animal studies clearly demonstrated the antihyperalgesic potency of pregabalin but human experiments are, however, inconclusive. Clinical studies with quantitative sensory testing have not yet been published. Although strongly supported by theoretical considerations the routine preoperative application of pregabalin for the prevention of hyperalgesia cannot be recommended due to the lack of clinical studies. Future studies should incorporate secondary hyperalgesia and allodynia as primary parameters.     

加巴喷丁与普瑞巴林治疗带状疱疹后神经痛的效果比较

目的观察加巴喷丁和普瑞巴林治疗带状疱疹后神经痛(post-herpetic neuralgia,PHN)的效果以及对患者睡眠的影响。方法 60例PHN患者按随机数字表法分为加巴喷丁组和普瑞巴林组各30例,分别给予加巴喷丁900 mg/d口服和普瑞巴林150 mg/d口服,疗程均为28天。观察治疗前后疼痛和睡眠的改善情况及药物不良反应。结果两组患者治疗后各时点与治疗前相比疼痛评分随时间下降,睡眠时间增加(P<0.05);普瑞巴林组治疗后各时点的疼痛视觉模拟评分(Visualanalogue scale,VAS)低于加巴喷丁组(P<0.05),24小时睡眠时间大于加巴喷丁组(P<0.05);两组未出现严重的药物不良反应,普瑞巴林组嗜睡发生率明显低于加巴喷丁组(P<0.05),其余不良反应发生率两组间比较差异均无统计学意义(P>0.05)。结论普瑞巴林治疗PHN更安全有效,优于加巴喷丁。     

Costs and health resources utilization following switching to pregabalin in individuals with gabapentin-refractory neuropathic pain: a post hoc analysis

Purpose: To analyze the changes in pain severity and associated costs resulting from resource utilization and reduced productivity in patients with gabapentin‐refractory peripheral neuropathic pain who switched to pregabalin therapy in primary care settings in Spain. Patients and Methods: This is a post hoc analysis of a 12‐week, multicentre, noninterventional cost‐of‐illness study. Patients were included in the study if they were over 18 years of age and had a diagnosis of chronic, treatment‐refractory peripheral neuropathic pain. The analysis included all pregabalin‐naïve patients who had previously shown an inadequate response to gabapentin and switched to pregabalin. Severity of pain before and after treatment with pregabalin, alone or as an add‐on therapy, was assessed using the Short‐Form McGill Pain Questionnaire (SF‐MPQ) and its related visual analogue scale (VA). Healthcare resource utilization, productivity (including lost‐workday equivalents [LWDE]), and related costs were assessed at baseline and after pregabalin treatment. Results: A total of 174 patients switched to pregabalin had significant and clinically relevant reductions in pain severity (mean [SD] change on SF‐MPQ VA scale, ?31.9 [22.1]; P < 0.05 vs. baseline; effect size, 1.87). Reduction in pain was similar with both pregabalin monotherapy and add‐on therapy. Significant reductions in healthcare resource utilization (concomitant drug use [in pregabalin add‐on group], ancillary tests, and unscheduled medical visits) were observed at the end of trial. Additionally, there were substantial improvements in productivity, including a reduction in the number of LWDE following pregabalin treatment (?18.9 [26.0]; P < 0.0001). These changes correlated with substantial reductions in both direct (?652.9 ± 1622.4 €; P < 0.0001) and indirect healthcare costs (?851.6 [1259.6] €; P < 0.0001). Conclusions: The cost of care in patients with gabapentin‐refractory peripheral neuropathic pain appeared to be significantly reduced after switching to pregabalin treatment, alone or in combination with other analgesic drugs, in a real‐life setting.     

Pregabalin: a novel gamma-aminobutyric acid analogue in the treatment of neuropathic pain, partial-onset seizures, and anxiety disorders

BACKGROUND: The US Food and Drug Administration (FDA) approved pregabalin in December 2004 for the treatment of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. Pregabalin is the first drug approved in the United States and in Europe for both conditions. In June 2005, pregabalin was approved as an adjunctive treatment in adults with partial-onset seizures. The FDA currently is considering the approval of pregabalin as adjunctive therapy in adults with generalized anxiety disorder (GAD) or social anxiety disorder (SAD). OBJECTIVES: The goals of this review were to summarize the pharmacology, pharmacokinetics, efficacy, and tolerability of pregabalin; review its approved uses in the management of neuropathic pain and refractory partial-onset seizures; and investigate its potential use in patients with GAD or SAD. METHODS: Relevant English-language literature was identified through a search of MEDLINE (1993-June 2006) and International Pharmaceutical Abstracts (2000-June 2006). The search terms included pregabalin, Lyrica, S-(+)-3 isobutyl-gaba, PN, DPN, diabetic peripheral neuropathy, PHN, postherpetic neuralgia, partial seizures, epilepsy, generalized anxiety disorder, and CI-1008. RESULTS: In 4 clinical trials in a total of 1068 patients with diabetic peripheral neuropathy, the patients receiving pregabalin 300 to 600 mg/d had significantly greater improvement in mean pain scores than placebo recipients (P < or = 0.01). Patients with postherpetic neuralgia receiving pregabalin 450 to 600 mg/d had significantly greater improvement in relief of pain and pain-related sleep interference than placebo recipients (P < or = 0.002). Patients with refractory partial-onset seizures who received pregabalin 150 to 600 mg/d (divided into 2 or 3 doses) concomitantly with antiepileptic drugs had significantly fewer seizures than placebo recipients (P < or = 0.001). In the 3 studies that evaluated the efficacy of pregabalin in patients with GAD or SAD, the patients receiving pregabalin 200 to 600 mg/d (divided into 2 or 3 daily doses) had a significantly greater reduction in mean pain scores on the Hamilton Anxiety Scale than placebo recipients (P < or = 0.01). Across all the reviewed clinical trials, the most commonly reported adverse effects (AEs) were those affecting the central nervous system, including somnolence (< or =50%), dizziness (< or =49%), and headache (< or =29%). AEs resulted in withdrawal from the study in < or =32% of patients. CONCLUSIONS: Pregabalin appears to be an effective therapy in patients with diabetic peripheral neuropathy, postherpetic neuralgia, and adults with refractory partial-onset seizures. The available data suggest that pregabalin may be beneficial as an adjunctive therapy in adult patients with GAD or SAD.     

Safety and efficacy of pregabalin in patients with central post-stroke pain

Pregabalin has demonstrated efficacy in several forms of neuropathic pain, but its long-term efficacy in central post-stroke pain (CPSP) is unproven. We evaluated the efficacy and safety of pregabalin versus placebo in patients with CPSP. A 13-week, randomized, double-blind, multicenter, placebo-controlled, parallel group study of 150 to 600 mg/day pregabalin was conducted in patients aged ?18 years with CPSP. The primary efficacy endpoint was the mean pain score on the Daily Pain Rating Scale over the last 7 days on study drug up to week 12 or early termination visit. Secondary endpoints included other pain parameters and patient-reported sleep and health-related quality-of-life measures. A total of 219 patients were treated (pregabalin n = 110; placebo n = 109). A mean pain score at baseline of 6.5 in the pregabalin group and 6.3 in the placebo group reduced at endpoint to 4.9 in the pregabalin group and 5.0 in the placebo group (LS mean difference = -0.2; 95% CI = -0.7, 0.4; P = 0.578). Treatment with pregabalin resulted in significant improvements, compared with placebo, on secondary endpoints including MOS-sleep, HADS-A anxiety, and clinician global impression of change (CGIC) P < 0.05. Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 9 (8.2%) of pregabalin patients versus 4 (3.7%) of placebo patients. Although pain reductions at endpoint did not differ significantly between pregabalin and placebo, improvements in sleep, anxiety, and CGIC suggest some utility of pregabalin in the management of CPSP.     

A Cost-Utility Analysis of Pregabalin Versus Duloxetine for the Treatment of Painful Diabetic Neuropathy

ABSTRACT

The objective of the current study was to determine the cost-utility of pregabalin versus duloxetine for treating painful diabetic neuropathy (PDN) using a decision tree analysis. Literature searches identified clinical trials and real-world studies reporting the efficacy, tolerability, safety, adherence, opioid usage, health care utilization, and costs of pregabalin and duloxetine. The proportions of patients reported in the included studies were used to determine probabilities in the decision tree model. The base-case model included the Food and Drug Administration (FDA)-approved doses of pregabalin (300 mg/day) and duloxetine (60 mg/day), whereas “real-world” sensitivity analyses explored the effects over a range of doses (pregabalin 75–600 mg/day, duloxetine 20–120 mg/day). A 6-month time horizon and a US third-party payer perspective were chosen for the study. Outcomes from the model were expressed as cost per quality-adjusted life-year (QALY). In the base-case model, duloxetine cost less and was more effective than pregabalin (incremental cost ?$187, incremental effectiveness 0.011 QALYs). Results from two real-world sensitivity analyses indicated that duloxetine cost $16,300 and $20,667 more per additional QALY than pregabalin. Using a decision tree model that incorporated both clinical trial and real-world data, duloxetine was a more cost-effective option than pregabalin in the treatment of PDN from the perspective of third-party payers.     

Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: A randomized,double‐blind study

Seven published, randomized, placebo‐controlled clinical trials with pregabalin have shown robust efficacy for relief of neuropathic pain from DPN and PHN. An investigation of the efficacy and safety of twice daily pregabalin enrolled 395 adults with painful DPN for ≥1 year in a 12‐week, double‐blind, placebo‐controlled trial. Patients were randomized to placebo, 150, 300, or 600mg/day pregabalin (n=96, 99, 99, and 101). Primary efficacy measure was change from baseline in endpoint mean pain score from patients’ daily pain diaries. Secondary efficacy measures included pain‐related sleep‐interference scores, Patient and Clinical Global Impressions of Change (PGIC, CGIC), and the EuroQOL Health Utilities Index (EQ‐5D). Statistically significant reduction in pain was observed in patients receiving pregabalin 600mg/day, and 46% of patients treated with 600mg/day pregabalin reported ≥50% improvement in mean pain scores from baseline (vs 30% of placebo patients, p=0.036). Number needed to treat to achieve such response was 6.3. Pregabalin 600mg/day was significantly superior to placebo in improving pain‐related sleep‐interference scores (p=0.003), PGIC (p=0.021), and CGIC (p=0.009). (Neither pregabalin 150 nor 300mg/day separated from placebo on these measures, largely because of an atypically large placebo response in one country representing 42% of patients.) All pregabalin dosages were superior to placebo in improving EQ‐5D utility scores (all p≥0.0263 vs placebo). Pregabalin was well tolerated at all dosages; adverse events were generally mild to moderate. Number needed to harm (discontinuation because of adverse events) was 10.3 for pregabalin 600mg/day.     

A Randomized,Controlled Trial of Oxycodone Versus Placebo in Patients With PostHerpetic Neuralgia and Painful Diabetic Neuropathy Treated With Pregabalin

The aim of this randomized double-blind, placebo-controlled, parallel-group study was to evaluate the efficacy, safety, and tolerability of pregabalin in combination with oxycodone or placebo, in patients with either postherpetic neuralgia (PHN) or painful diabetic neuropathy (PDN). After a 7-day washout period, 62 patients were randomized to receive either oxycodone mixture 10 mg/day or placebo mixture for 1 week. Patients were then started on open-label pregabalin (75, 150, 300 and 600 mg/day) according to a forced titration dosing regimen, while continuing the same dosage of oxycodone or placebo for 4 weeks. The primary efficacy measure was a decrease in the pain-intensity score of at least 2cm and a pain score <4cm measured using a 10-cm visual analogue scale (VAS) following pregabalin dosage escalation and treatment for 4 weeks. Secondary efficacy measures included sleep interference and the Neuropathic Pain Scale. There were similar levels of overall efficacy between pregabalin/oxycodone and pregabalin/placebo groups in relieving PHN and PDN related pain.PerspectivePeripheral neuropathic pain presents commonly in clinical practice, and 2 of its most prevalent types are PHN and PDN. Currently available treatments provide some degree of pain relief in ～40-60% of patients, leaving the remainder with unremitting pain. Although this study supports the effectiveness of pregabalin in the treatment of PHN or PDN, it also shows that the addition of a low dose of oxycodone at 10mg/day does not enhance the pain-relieving effects of pregabalin.     

Comparison of Medication Adherence and Healthcare Costs between Duloxetine and Pregabalin Initiators among Patients with Fibromyalgia

Objective: To examine and compare medication adherence and direct healthcare costs between duloxetine and pregabalin initiators among patients with fibromyalgia. Methods: A retrospective analysis of commercially insured fibromyalgia patients aged 18 to 64 was conducted among those who initiated duloxetine or pregabalin between January 1, 2006 and December 31, 2006. The first initiation date was defined as the index date. All patients included had continuous enrollment in the 12‐month pre‐ and post‐index periods. Each individual was classified in the duloxetine or pregabalin cohort based on the initiating agent. The pregabalin cohort was constructed via propensity scoring controlling for differences in demographics, pre‐index clinical and economic characteristics, and pre‐index treatment patterns. Medication adherence (ie, medication possession ratio [MPR] and proportion of patients with MPR ≥ 80%) and healthcare costs over the 12 months post‐index period were examined between cohorts. Results: The study cohorts included 3,711 duloxetine and 4,111 pregabalin patients with the mean age of 51 years. The common comorbidities included neuropathic pain other than diabetic peripheral neuropathic pain, low back pain, cardiovascular disease, headache, and osteoarthritis. Over 80% of the duloxetine or pregabalin initiators used opioids. Controlling for demographics, pre‐index clinical and economic characteristics, and prior medication history, duloxetine patients had significantly higher MPR (0.7 vs. 0.5, P < 0.05), higher proportion of patients with MPR ≥ 80% (46.5% vs. 26.4%, P < 0.05), but significantly lower total healthcare costs ($19,378 vs. $27,045, P < 0.05) over the 12 months post‐index period than pregabalin patients. Conclusion: Fibromyalgia patients on duloxetine had significantly higher medication adherence, but significantly lower direct healthcare costs than those on pregabalin.