Wang Juan, Zhu Yuyou
a Department of Dermatology , the Affiliated Provincial Hospital of Anhui Medical University , Hefei , China.
b Department of Neurology , the Affiliated Provincial Hospital of Anhui Medical University , Hefei , China.
J Dermatolog Treat. 2017 Feb;28(1):65-77. doi: 10.3109/09546634.2016.1163315. Epub 2016 Nov 1.
Gabapentin, extended-release gabapentin (gabapentin ER), and gabapentin enacarbil (GEn), play an important role in relieving pain associated with postherpetic neuralgia (PHN). Although previous systematic reviews have assessed the efficacy and safety of gabapentin formulations for PHN, they have failed to take formulation differences and dose differences into account. Aiming at assessing the efficacy and safety of different doses of gabapentin formulations for PHN, this study performed a systematical review and meta-analysis of randomized controlled trials (RCTs).
Electronic databases (PubMed, EBSCO, Ovid MEDLINE, and Web of Science) were systematically searched by terms of "gabapentin [Title/Abstract] AND postherpetic neuralgia [Title/Abstract]" from the year 1966 to present. Efficacy measurements were changes in average daily pain (ADP) scores, sleep interference scores, at least 50% reduction in pain intensity, and changes in Patient/Clinician Global Impression of Change (PGIC/CGIC) from baseline to the end of treatment. Safety measures were the proportion of patients suffering from any adverse event, dizziness, somnolence, and peripheral edema. Outcomes for continuous data and dichotomous data were estimated with standard mean difference (SMD) and risk ratio (RR), respectively.
Seven RCTs encompassing 2041 randomized participants for efficacy assessment and 2050 randomized participants for safety assessment were identified. Gabapentin formulations in reducing ADP scores (the primary outcomes) were as follows: gabapentin 3600 mg/day, SMD: -0.86; 95% CI: -1.13, -0.58; p < 0.00001; gabapentin ER 1800 mg/day once daily, SMD: -0.21; 95% CI: -0.42, -0.01; p = 0.04; gabapentin ER 1800 mg/day twice daily, SMD: -0.25; 95% CI: -0.57, 0.06; p = 0.12; GEn 1200 mg/day, SMD: -0.43; 95% CI: -0.66, -0.20; p = 0.0002; GEn 2400 mg/day, SMD: -0.33; 95% CI: -0.62, -0.03; p = 0.03; GEn 3600 mg/day, SMD: -0.50; 95% CI: -0.79, -0.20; p = 0.0009. In addition, gabapentin from 1800 to 3600 mg/day doses could significantly improve sleep interference, at least 50% reduction in pain intensity and PGIC/CGIC, but highly increased the incidence of any adverse event, dizziness, somnolence and peripheral edema with an increasing dose. Gabapentin ER 1800 mg/day once daily treatment could not only effectively relieve PHN pain but also significantly increase the risk of adverse events, while twice daily treatment almost showed no significant pharmacological effect and adverse events. GEn at doses of 1200 mg/day and 2400 mg/day were safe in decreasing any adverse event (1200 mg/day, RR = 1.08, 95% CI: 0.91, 1.29, p = 0.38; 2400 mg/day, RR = 1.18, 95% CI: 0.98, 1.41, p = 0.08), dizziness (1200 mg/day, RR = 1.86, 95% CI: 0.58, 6.01, p = 0.30; 2400 mg/day, RR = 1.74, 95% CI: 0.95, 3.19, p = 0.07), and somnolence (1200 mg/day, RR = 1.22, 95% CI: 0.51, 2.91, p = 0.65; 2400 mg/day, RR = 1.30, 95% CI: 0.53, 3.22, p = 0.57). GEn 3600 mg/day could only increase the risk of any adverse event (RR = 1.23, 95% CI: 1.03, 1.47, p = 0.02) and dizziness (RR = 2.03, 95% CI: 1.13, 3.63, p = 0.02).
An increasing gabapentin dose may not provide a good pharmacological therapy, whereas it can increase the risk of adverse events. Gabapentin ER, 1800 mg/day once daily treatment is significantly effective in pain relief, following high incidence of adverse events, but twice daily treatment shows no significant differences in both efficacy and safety compared with placebo. GEn 1200 mg/day and 2400 mg/day doses are more effective and safe in treating PHN. The long-term efficacy and safety of different doses of gabapentin formulations remain to be determined.
加巴喷丁、缓释加巴喷丁（加巴喷丁 ER）和普瑞巴林酯（GEn）在缓解带状疱疹后神经痛（PHN）相关疼痛方面发挥着重要作用。尽管先前的系统评价评估了加巴喷丁制剂治疗 PHN 的疗效和安全性，但它们未考虑剂型差异和剂量差异。为评估不同剂量加巴喷丁制剂治疗 PHN 的疗效和安全性，本研究对随机对照试验（RCT）进行了系统评价和荟萃分析。
通过检索词“加巴喷丁 [标题/摘要] 且带状疱疹后神经痛 [标题/摘要]”，对电子数据库（PubMed、EBSCO、Ovid MEDLINE 和 Web of Science）进行系统检索，检索时间范围为 1966 年至今。疗效指标包括日均疼痛（ADP）评分变化、睡眠干扰评分、疼痛强度至少降低 50%，以及从基线到治疗结束时患者/临床医生总体印象变化（PGIC/CGIC）。安全性指标包括发生任何不良事件、头晕、嗜睡和外周水肿的患者比例。连续数据和二分数据的结果分别用标准均数差（SMD）和风险比（RR）进行估计。
共纳入 7 项 RCT，其中 2041 名随机参与者用于疗效评估，2050 名随机参与者用于安全性评估。加巴喷丁制剂降低 ADP 评分（主要结局）的情况如下：加巴喷丁 3600mg/天，SMD：-0.86；95%CI：-1.13，-0.58；p＜0.00001；加巴喷丁 ER 1800mg/天，每日 1 次，SMD：-0.21；95%CI：-0.42，-0.01；p = 0.04；加巴喷丁 ER 1800mg/天，每日 2 次，SMD：-0.25；95%CI：-0.57，0.06；p = 0.12；普瑞巴林酯 12,00mg/天，SMD：-（此处原文有误，应为0.43）；95%CI：-0.66，-0.20；p = 0.0002；普瑞巴林酯 2400mg/天，SMD：-0.33；95%CI：-0.62，-0.03；p = 0.03；普瑞巴林酯 3600mg/天，SMD：-0.50；95%CI：-0.79，-0.20；p = 0.0009。此外，1800 至 3600mg/天剂量的加巴喷丁可显著改善睡眠干扰、疼痛强度至少降低 50%以及 PGIC/CGIC，但随着剂量增加，任何不良事件、头晕、嗜睡和外周水肿的发生率显著增加。加巴喷丁 ER 1800mg/天每日 1 次治疗不仅可有效缓解 PHN 疼痛，还会显著增加不良事件风险，而每日 2 次治疗在疗效和不良事件方面几乎无显著差异。普瑞巴林酯 1200mg/天和 2400mg/天剂量在降低任何不良事件（1200mg/天，RR = 1.08，95%CI：0.91，1.29，p = 0.38；2400mg/天，RR = 1.18，95%CI：0.98，1.41，p = 0.08）、头晕（1200mg/天，RR = 1.86，95%CI：0.58，6.01，p = 0.30；2400mg/天，RR = 1.74，95%CI：0.95，3.19，p = 0.07）和嗜睡（1200mg/天，RR = 1.22，95%CI：0.51，2.91，p = 0.65；2400mg/天，RR = 1.30，95%CI：0.53，3.22，p = 0.57）方面是安全的。普瑞巴林酯 3600mg/天仅会增加任何不良事件（RR = 1.23，95%CI：1.03，1.47，p = 0.02）和头晕（RR = 2.03，95%CI：1.13，3.63，p = 0.02）的风险。
加巴喷丁剂量增加可能无法提供良好的药物治疗效果，反而会增加不良事件风险。加巴喷丁 ER 1800mg/天每日 1 次治疗在缓解疼痛方面显著有效，但不良事件发生率高，而每日 2 次治疗在疗效和安全性方面与安慰剂相比无显著差异。普瑞巴林酯 1200mg/天和 2400mg/天剂量在治疗 PHN 时更有效且安全。不同剂量加巴喷丁制剂的长期疗效和安全性仍有待确定。
