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.