Population pharmacokinetics of pregabalin in healthy subjects and patients with post-herpetic neuralgia or diabetic peripheral neuropathy

AIM

Pregabalin, a chemical analogue of the mammalian neurotransmitter γ-aminobutyric acid, has been approved in many countries for partial-onset seizures, generalized anxiety disorder and various other pain disorders, including neuropathic pain associated with post-herpetic neuralgia and diabetic peripheral neuropathy and fibromyalgia. The aim of this study was to develop a population pharmacokinetic model and quantify the influence of covariates on the parameters.

METHODS

This pregabalin population pharmacokinetic analysis was conducted on data from 14 clinical trials involving healthy subjects, subjects with impaired renal function and patients with post-herpetic neuralgia or diabetic peripheral neuropathy (n = 616). The data analysis was performed using nonlinear mixed effects modelling methodology as implemented by NONMEM.

RESULTS

A one-compartment model with first-order absorption and elimination adequately described pregabalin pharmacokinetics. The model indicated that pregabalin apparent clearance (CL/F) was proportional to estimated creatinine clearance (CL_cr). The pregabalin systemic exposure in patients with lower renal function who received pregabalin 150 mg twice daily was almost equal to that of patients with normal renal function administered pregabalin 300 mg twice daily. The systemic exposure stratified by lower or normal renal function was similar between patients with post-herpetic neuralgia and diabetic peripheral neuropathy.

CONCLUSION

The developed model identified CL_cr and ideal body weight as clinically influential covariates on CL/F and volume of distribution, respectively. This study indicates that renal function accounts for variability in the apparent clearance of pregabalin which is consistent with what is known about the elimination of this drug.     

D-二聚体与2型糖尿病周围神经病变相关性分析

目的　分析D-二聚体（D-D）与2型糖尿病性周围神经病变（DPN）相关性。方法　对2018年11月至2020年11月在郑州大学附属洛阳中心医院内分泌科住院符合条件的937例2型糖尿病（T2DM）患者进行回顾性横断面研究,根据有无DPN分为DPN组和无DPN组,并收集其一般资料及临床指标等,组间比较采用t检验,计数资料组间比较用卡方检验;通过统计学分析D-D与DPN相关性。结果　无DPN组男367例,女253例,年龄（53.49±12.40）岁;DPN组男194例,女123例,年龄（58.02±10.88）岁。与无DPN组相比,DPN组更高龄（P=0.001）,病程更长（P<0.001）,更高的糖化血红蛋白（HbA1c）（P=0.012）、肌酐（Cr）（P<0.001）、低密度脂蛋白胆固醇（LDL-C）（P=0.024）、D-二聚体（D-D）（P<0.001）,以及更高比例的高血压（P=0.013）。将单因素中有意义的指标纳入多因素logistic分析模型中,结果发现：DPN与年龄［比值比（OR）：1.021,95%置信区间（CI）：1.006～1.035,P=0.004］、DM病程（OR：1.029,95%CI：1.006～1.053,P=0.013）、HbA1c（OR：1.155,95%CI：1.063～1.256,P=0.001）、Cr（OR：1.009,95%CI：1.001～1.016,P=0.025）、LDL-C（OR：1.221,95%CI：1.049～1.422,P=0.010）、D-D（OR：1.001,95%CI：1.000～1.002,P=0.004）有关。结论　D-D可能是DPN发生发展的危险因素。     

Pharmacologic management of diabetic peripheral neuropathic pain

Introduction: Diabetic peripheral neuropathic pain (DPNP) is a debilitating and distressing complication that occurs in patients with diabetes mellitus. This article provides an overview of diabetic peripheral neuropathy focusing on DPNP.

Areas covered: This article reviews the diagnosis, pathogenesis, prevention and treatment of diabetic neuropathy and neuropathic pain. A comprehensive and systematic Medline search of the published literature for treatment of diabetic peripheral neuropathy was done from 1965 to December 2012. Studies not in English language were excluded.

Expert opinion: Neuropathic pain is difficult to treat, and patients rarely experience complete pain relief. Despite several pharmacological agents being used in the treatment of DPNP, only duloxetine and pregabalin have evidence-based support for controlling DPNP.     

The safety and efficacy of pregabalin for treating subjects with fibromyalgia and moderate or severe baseline widespread pain

Objective To evaluate pregabalin’s efficacy (≤12 weeks) for pain relief and sleep improvement in patients with fibromyalgia (FM) and moderate-to-severe baseline pain.

Research design and methods Data were pooled from five randomized, double-blind, placebo-controlled, phase III clinical trials of pregabalin (300–450 mg/day) for FM treatment. Subjects, aged?≥18 years, had moderate (≥4–<7) or severe (≥7–10) mean baseline pain scores. Analyses included mixed effects repeated measures (MMRM), baseline observation carried forward (for parameters without enough data points for MMRM), or logistic regression.

Clinical trial registration Study number/ClinicalTrials.gov number: A0081056/NCT00645398, A0081077/NCT00230776, A0081100/NCT00333866, A0081208/NCT00830167.

Main outcomes measures Endpoints included mean change in pain and sleep quality scores (Weeks 8 and 12), patient-reported outcomes, and adverse events (AEs).

Results Baseline demographic characteristics were comparable between pregabalin and placebo in both baseline pain severity groups. Mean?±?SD baseline pain severity scores were equivalent between pregabalin and placebo within moderate (5.8?±?0.8) or severe pain (7.9?±?0.7) subgroups. All subjects reported reduced pain and improved sleep quality through Weeks 8 and 12, with larger effects observed with pregabalin over placebo and with baseline severe over moderate pain (all p?<?0.01). Pregabalin was generally well tolerated, AE findings were consistent with previously published trials, and AE profiles were similar between moderate and severe baseline pain subgroups. Limitations of this pooled analysis included differences in individual trial designs (e.g., dosing schedules, racial distribution, exclusion criteria that did not enroll mild severity patients).

Conclusions Pregabalin was efficacious through 12 weeks for reducing pain and improving sleep quality in FM patients with baseline moderate or severe pain, with larger effects in the baseline severe pain subgroup. AEs were consistent with pregabalin’s known safety profile and did not differ between moderate and severe pain subgroups.     

The efficacy of pregabalin in patients with moderate and severe pain due to diabetic peripheral neuropathy

Objective To compare the therapeutic response to pregabalin in patients with moderate or severe painful diabetic peripheral neuropathy (pDPN).

Research design and methods Data were pooled from 11 placebo-controlled trials to evaluate the efficacy of pregabalin flexible or fixed dose (150, 300 or 600?mg/day) in pDPN patients with mean baseline pain scores of ≥4 to <7 (moderate) or ≥7 to ≤10 (severe). Last observation carried forward imputation was used.

Study number/ClinicalTrials.gov identifier 1008-014/-, 1008-029/-, 1008-040/-, 1008-131/-, 1008-149/-, 1008-000-155/-, A0081030/NCT00156078, A0081060/NCT00159679, A0081071/NCT00143156, A0081081/NCT00301223, A0081163/NCT00553475.

Main outcome measures Pregabalin-mediated change in pain, pain-related sleep interference (PRSI) and patient global impression of change (PGIC) were compared versus placebo and between moderate and severe pain cohorts. Adverse events (AEs) were reported.

Results At baseline, 1816 patients had moderate pain (pregabalin, n?=?1189) and 1119 patients had severe pain (pregabalin, n?=?720). Pregabalin significantly reduced pain scores at endpoint compared with placebo when patients of all pain levels were combined (all doses; p?<?0.05). In the moderate and severe pain cohorts, pregabalin treatment (300, 600?mg/day or flexible) significantly reduced mean pain scores at endpoint compared with placebo (p?<?0.01). Pain reduction was greatest in patients with severe baseline pain compared with moderate baseline pain (pregabalin 300, 600?mg/day or flexible; p?<?0.0001). Pregabalin improved PRSI and PGIC in the moderate and severe cohorts compared with placebo. The greatest improvement in PRSI also occurred in the severe cohort. Treatment-emergent AEs, most commonly dizziness, somnolence and peripheral edema, occurred more frequently in patients treated with pregabalin compared with placebo.

Conclusions Pregabalin was effective in pDPN patients with both moderate and severe baseline pain. Patients with severe pain exhibited greater improvements in pain and PRSI than patients with moderate pain. Pain severity may, in part, predict therapeutic response to pregabalin.     

硫辛酸与盐酸丁咯地尔联合治疗糖尿病周围神经病变疗效观察

目的观察硫辛酸联用盐酸丁咯地尔治疗糖尿病周围神经病变的疗效。方法将68例2型糖尿病合并周围神经病变的患者随机分为2组,治疗组36例,予以硫辛酸注射液600mg加入生理盐水250mL中静脉滴注,每日1次,盐酸丁咯地尔0.1g加入生理盐水250mL中静脉滴注,每日1次,治疗2周;对照组32例,予以甲钴胺500μg加入生理盐水250mL中静脉滴注,每日1次,治疗2周。结果治疗组有效率为94.4,对照组有效率为79.1,两组比较有显著性差异(P<0.05),且两组的神经传导速度均提高,治疗组神经传导速度提高更明显(P<0.05)。结论硫辛酸联用盐酸丁咯地尔为治疗糖尿病周围神经病变比较理想的组合。     

前列地尔联合甲钴胺辅治糖尿病周围神经病变的疗效观察

目的观察前列地尔联合甲钴胺辅治糖尿病周围神经病变(DPN)的临床疗效。方法将DPN患者80例随机分成治疗组42例和对照组38例。在控制血糖基础上,对照组给予甲钴胺500μg肌内注射,每天1次,连续14d;治疗组在对照组治疗基础上加用前列地尔10μg+生理盐水100ml静脉滴注,每天1次,连续14d。观察2组临床疗效及治疗前后神经传导速度。结果治疗组总有效率为97.6%高于对照组的65.8%,差异有统计学意义(P<0.05)。2组治疗后正中神经和腓总神经运动传导速度(MCV)及感觉传导速度(SCV)均快于治疗前(P<0.05);且治疗组治疗后正中神经和腓总神经MCV及SCV均快于对照组(P<0.05)。结论前列地尔联合甲钴铵辅治DPN,对神经传导速度及症状、体征的改善均有良好作用,且无明显不良反应,值得推广应用。     

糖尿病神经病变患者血清抗神经节苷脂抗体与代谢、免疫的关系

目的 探讨糖尿病神经病变（DPN）患者血清抗神经节苷脂抗体anti-GS-Ab)与代谢、免疫的关系。方法 受试者分为三组，DPN组，糖尿病无神经病变组（DM组）和正常对照组（N组），每组30例，采用固相酶联免疫吸附法测定各组anti-GS-Ab同时测定糖化血红蛋白（HbA1c)，白介素-1β（IL-1β），肿瘤坏死因子α（TNF-α），一氧化氮（NO）《超氧化物歧化酶（SOD）和神经传导速度。结果 DPN组anti-GS-IgM-Ab,anti-GS-IgG-Ab的阳性率分别为45.67%及20%，显著高于N组及DM组，DPN组anti-GS-Ab与糖尿病神经病变临床分级（DPNC），TNF-α，IL-1β，HbA1c和NO呈显著正相关，而与SOD呈显著负相关；对anti-GS-Ab有显著作用的因素依次为DPNC，IL-1β；对HbA1c有显著作用的因素依次为IL-1β，anti-GS-Ab,TNF-α，NO；对TNF-α有显著作用的因素为HbA1c。结论 DPN患者体内存在代谢紊乱，细胞因孔子分泌失调，自由基清除障碍，这些因素与anti-GS-Ab增多密切相关且相互影响，提示anti-GS-Ab可作为一项了解DPN自身免疫状况的指标，对DPN的诊断及病情判断有参考价值。     

α-硫辛酸联合甲钴胺治疗2型糖尿病周围神经病变的临床研究

目的观察α-硫辛酸(LA)联合甲钴胺对2型糖尿病周围神经病变的治疗效果。方法选择2008年4月—2012年12月在该科住院的2型糖尿病伴有周围神经病变患者82例,随机分成两组。A组40例给予LA和甲钴胺联合治疗,B组42例给予单用甲钴胺治疗,疗程均为15 d。观察两组治疗前后的临床症状及神经传导速度(NCV)。结果 A组治疗总有效率(85.0%)高于B组(69.0%)(P0.05);两组治疗后临床症状及神经传导速度均有明显改善(均P0.05),但A组的疗效优于B组(P0.05);两组均未见明显药物不良反应。结论α-硫辛酸联合甲钴胺治疗能有效改善2型糖尿病周围神经病变的症状和神经传导速度,可以推广应用临床治疗。     

3种方案治疗糖尿病周围神经病变的成本-效果分析

目的:探讨不同药物治疗方案对糖尿病周围神经病变所产生的经济效果。方法:运用成本-效果分析法对3种治疗糖尿病周围神经病变方案进行回顾性分析。114例病人随机分为三组,A组采用甲钴胺注射液联合使用葛根素注射液;B组甲钴胺注射液联合使用羟苯磺酸钙胶囊口服;C组甲钴胺注射液肌注。结果A、B、C三组总有效率分别为92.11%、89.47%和68.42%。三组疗效比较A、B组与C组差异有显著性(P<0.05),成本-效果比分别为72.88、53.52和52.44。敏感度分析成本-效果比为68.04、52.26和51.09。故从药物经济学角度看B组治疗方案较理想。结论:B组方案治疗糖尿病周围神经病变高效、经济,为最佳方案。     

丁咯地尔联合弥可保治疗糖尿病周围神经病变的疗效观察

目的观察丁咯地尔联合弥可保治疗糖尿病周围神经病变的临床疗效。方法将52例糖尿病周围神经病变患者随机分为观察组26例给予丁咯地尔联合弥可保治疗,和对照组26例给予弥可保治疗,比较两组的疗效及治疗前后神经症状及体征评分的变化情况。结果观察组的总有效率达92.3%,明显高于对照组73.1%,经卡方检验,差异有统计学意义,P<0.05;两组治疗后神经症状及体征评分均较治疗前明显降低,且观察组神经症状及体征评分较对照组降低更明显,差异有统计学意义,P<0.05。结论丁咯地尔联合弥可保治疗糖尿病周围神经病变疗效显著,优于单用弥可保治疗的疗效,且安全性好,值得临床推广和应用。     

Emerging drugs for diabetic peripheral neuropathy and neuropathic pain

Introduction: Diabetic sensorimotor polyneuropathy (DSPN) is a common complication of diabetes.

Areas covered: In this review, the authors discuss the emerging drugs for DSPN, which aim either at improving alleviation of neuropathic pain or addressing the putative mechanisms underlying diabetic neuropathy.

Expert Opinion: Current treatment does not address the sensory deficits and pathogenesis underlying DSPN, so there is an unmet need for treatment options targeting the natural history of the condition. Some of these pathogenetic therapies have demonstrated clinically relevant improvements in neuropathic endpoints in recent randomised controlled trials. Since any effective analgesic monotherapy is known to induce a clinically meaningful response in only some 50% of the patients, there remains a substantial unmet need in patients with neuropathic pain. Advanced knowledge in the neurobiology of neuropathic pain and improved phenotypic profiling have led to a burst of research into novel pharmaceutical approaches. An array of promising molecular entities have reached the clinical stage of development, which should improve our therapeutic armamentarium in the fight against DSPN and neuropathic pain in the foreseeable future.     

普瑞巴林用于糖尿病痛性神经病变的疗效和安全性

目的:研究普瑞巴林用于糖尿病痛性神经病变的疗效和安全性。方法:52例糖尿病痛性神经病变患者随机分2组,对照组服用羟考酮控释片,试验组服用普瑞巴林胶囊,用药2周。评估治疗前后疼痛缓解程度和不良反应的发生情况。结果:对照组和试验组的有效率分别为56.0%和77.8%(P<0.05),试验组的镇痛效果优于对照组。治疗期间未见严重并发症。结论:普瑞巴林治疗糖尿病痛性神经病变疼痛安全有效。     

依达拉奉联合依帕司他治疗糖尿病周围神经病变的疗效观察

目的:探讨依达拉奉联合依帕司他治疗糖尿病周围神经病变(diabetic peripheral neuropathy,DPN)的临床疗效.方法:将87例糖尿病周围神经病变患者随机分为两组,治疗组采用依达拉奉联合依帕司他治疗,对照组采用甲钴胺治疗.观察临床疗效及肌电图变化.结果:治疗组总有效率明显高于对照组(P＜0.05),治疗组感觉神经传导速度及运动神经传导速度均明显高于对照组(P＜0.05).结论:依达拉奉联合依帕司他治疗糖尿病周围神经病变效果优于甲钴胺.     

通心络胶囊联合依帕司他治疗糖尿病周围神经病变45例临床观察

目的观察通心络胶囊联合依帕司他治疗糖尿病周围神经病变(DPN)的疗效。方法选取2型糖尿病周围神经病变患者90例,随机分为对照组及治疗组各45例,两组患者在糖尿病病程、周围神经病变程度、HbA1c、降糖措施及营养神经等基础治疗方面具有可比性。对照组服用依帕司他(50mg,3次/日),治疗组在对照组基础上加服通心络胶囊(3粒,3次/日),3个月为1疗程。比较两组治疗前后临床疗效及正中神经、腓总神经运动神经传导速度(MCV)及感觉神经传导速度(SCV)变化情况。结果治疗组与对照组总有效率比较有统计学意义(P<0.05),治疗组治疗前后正中神经及腓总神经MCV及SCV比较有统计学意义(P<0.05),对照组治疗前后正中神经MCV及SCV比较有统计学意义(P<0.05),对照组治疗前后MCV及SCV比较无统计学意义(P>0.05)。结论通心络胶囊联合依帕司他治疗糖尿病周围神经病变可提高疗效,尤其在改善下肢周围神经病变方面意义显著,联合用药未增加不良反应。     

甲钴胺联合前列地尔治疗2型糖尿病周围神经病变的疗效与安全性

目的评价甲钴胺联合前列地尔治疗2型糖尿病周围神经病变的临床疗效和安全性。方法 70例患者随机分为治疗组和对照组(各35例);在综合治疗基础上,治疗组给予甲钴胺注射液联合前列地尔注射液;对照组仅给予前列地尔注射液,4周为1个疗程。观察治疗前后2组的神经症状评分、神经体征评分、肌电图神经传导速度变化;观察药物不良反应。结果 2组均能有效降低神经症状和体征评分,增加神经传导速度,均无明显不良反应;但治疗组疗效明显优于对照组(P<0.05)。结论甲钴胺联合前列地尔治疗糖尿病周围神经病变,安全有效。     

The effect of pregabalin on pain-related sleep interference in diabetic peripheral neuropathy or postherpetic neuralgia: a review of nine clinical trials

Abstract

Objective:

Postherpetic neuralgia and painful diabetic peripheral neuropathy are common chronic neuropathic pain conditions associated with sleep disturbances. Pregabalin is indicated in the treatment of neuropathic pain. The objective of this review is to summarize the efficacy and safety of pregabalin in painful diabetic peripheral neuropathy and postherpetic neuralgia and the effect of pregabalin on sleep interference in these patients.     

安诺治疗仪联合腺苷钴胺治疗糖尿病周围神经病变的临床观察

目的：观察安诺治疗仪联合腺苷钴胺治疗糖尿病周围神经病变的临床疗效。方法将90例糖尿病周围神经病变患者随机分为治疗组和对照组各45例。治疗组给予安诺治疗仪联合腺苷钴胺治疗,对照组单用腺苷钴胺治疗。2组疗程均为14d,比较治疗后2组临床疗效和周围神经传导速度的变化。结果治疗2周后,治疗组总有效率为88．9％明显高于对照组的57．8％,差异有统计学意义（P＜0．05）。2组治疗前尺神经、腓神经的运动传导速度（MNCV）、感觉传导速度（SNCV）比较差异无统计学意义（P＞0．05）;治疗后2组MNCV、SNCV均高于治疗前,且治疗组高于对照组,差异均有统计学意义（P＜0．05）。结论安诺治疗仪联合腺苷钴胺治疗糖尿病周围神经病变疗效肯定,值得临床推广应用。     

杏丁治疗糖尿病周围神经病变的临床观察

目的 研究杏丁对糖尿病周围神经病变的治疗效果。方法 将糖尿病病人随机分成两组，杏丁治疗组(80例应用杏丁注射液20m1配入0．85％生理盐水中)，对照组(40例应用复方丹参注射液10m1配入0．85％生理盐水中)。治疗期为21d。观察病人肢端末梢的感觉变化情况及体感诱发的变化情况。结果 杏丁治疗组病人总有效74例(92．5％)，有效31例(38．75％)，显效43例(53．7％)，无效6例(7．1％)。结论 杏丁对糖尿病周围神经病变病人有恢复神经传导速度、减轻病人肢端末梢麻木、疼痛等治疗作用。     

普瑞巴林用于化疗诱导的周围神经病理性疼痛的疗效

目的观察普瑞巴林治疗化疗诱导的外周神经病理性疼痛的疗效及安全性。方法肿瘤化疗后出现周围神经病理性疼痛患者42例随机分为两组。A组20例,每日给予普瑞巴林300mg加甲钴胺治疗;B组22例,仅给予甲钴胺治疗。持续治疗4周。采用视觉模拟评分(VAS)进行疼痛评估,计算疼痛下降指数;比较两组的疗效及不良反应。结果治疗4周后,A组治疗有效率为75.0%,明显高于B组的40.9%(P<0.05)。两组不良反应均较轻。结论在甲钴胺治疗的基础上,兼用普瑞巴林更能有效缓解化疗诱导的周围神经病理性疼痛,不良反应少。