Postherpetic neuralgia (PHN) is a sensory nervous system injury-based neuropathic pain, caused by the herpes zoster virus. PHN is a persistent burning and paroxysmal stimulation pain that lasts from several months to several years. It commonly occurs in the chest and back, but may also affect the whole body [
At present, most of the clinical applications on neuropathic pain patients consisted of the antiviral treatment of early-onset herpes zoster. For patients with persistent pain, a combination of multiple medications is used, including opioid analgesics (morphine and oxycodone [
Gabapentin, associated with PHN, was initially used as an antiepileptic drug. It possesses a central analgesic effect and also inhibits the ectopic discharge of the peripheral nerve after injury [
Some randomized controlled trials (RCTs) [
Data were retrieved electronically from PubMed, Embase, CNKI, the China Biomedical Database, and the Library of Clinical Database. Retrieval time began from inception to April 2017. The key words used were “gabapentin” and “postherpetic neuralgia.” The inclusion criteria from the study reference were used to retrieve the literature. The studies screened independently according to the standards of two reviewers.
The inclusion criteria were as follows: (1) study: RCTs, (2) research object: PHN patients, and (3) intervention measures: unlimited dosage of oral gabapentin or placebo. The exclusion criteria were as follows: (1) Non-RCTS, (2) study of poor balance between groups, (3) in vitro or animal trial, (4) use of other analgesics in addition to the conventional treatment, and (5) patients with other diseases, such as diabetes or AIDS, which might affect the treatment.
The Jadad Standard was used to evaluate the quality of included studies. (1) Randomization grouping: random sequence by random number table or computer (2 points); the tests are randomly assigned, but the methods for generating random sequences are not accounted for (1 point) quasi-random or semirandom trials (0 point); (2) randomization concealment: appropriate (2 points), unclear (1 point), and unused or inappropriate (0 point); (3) blind: appropriate (2 points), unclear (1 point), and inappropriate (0 point); (4) exit: described reasons and number of exits (1 point), reasons and number of exits are not described (0 point).
The primary outcomes were as follows: pain intensity (VAS or NRS), the influence degree of pain on sleep, and the most common incidence of adverse events (somnolence, dizziness, and peripheral edema).
Revman 5.3 software was used for the screening and meta-analysis of data. The data included the Chi2 test for heterogeneity and used
A total of 3485 relevant publications were identified by the initial electronic search. After reviewing the articles, 3474 studies were excluded, mainly because they were case reports or reviews or did not satisfy the inclusion criteria. Only 11 trials [
Flowchart of the trial selection for meta-analysis.
The trials involved 2376 participants, of whom 1424 were assigned to the gabapentin group and 952 to the placebo group. Most studies were conducted in the USA [
Summary of clinical trials included in meta-analysis.
Study | Design | Intervention (sample size and age) | Duration (week) | Primary endpoints | Secondary endpoints | Common AEs | Jadad score |
---|---|---|---|---|---|---|---|
Irving 2009 [ | Double-blind, randomized, placebo-controlled, parallel | 158 included in the ITT analysis: Gabapentin ER1800 mg, QD, PM (55) (71±10.3); BID, 600 mg AM, 1200 mg PM (52) (68±12.9) placebo (51) (69±11.5) | 5 | ADP scores | Dizziness, Somnolence, Nausea, Dry mouth, Headache, Fatigue, Gait disturbance, Peripheral edema, Upper respiratory tract infection | 5 | |
Wallace 2010 [ | Double-blind, randomized, placebo-controlled, multicenter, parallel | 400 included in ITT analysis: Gabapentin ER 1800 mg, QD (134) (68±11.8); BID (135) (66±13.2) placebo (131) (66±12.6) | 11 | ADP scores | | Dizziness, Headache, Somnolence, Peripheral edema | 5 |
Backonja 2011 [ | Double-blind, randomized, placebo-controlled, parallel | 101 included in ITT analysis: GEn1200 mg, BID (47) (65±12.32); placebo (54)(64±12.69) | 4 | ADP scores | Dizziness, Nausea, Headache, Diarrhea, Fatigue, PHN, Insomnia, Depression | 4 | |
Zhang 2013 [ | Double-blind, randomized, placebo-controlled, multicenter, parallel | 371 included in the ITT analysis: GEn 1200 mg, BID, (107) (61.7±12.58); GEn 2400 mg, BID, (82) (64.1±8.94); GEn 3600 mg, BID, (87) (61.3±15.41); Placebo (95) (61.7±12.77) | 14 | ADP scores | | Dizziness, Somnolence, Headache, Nausea, Constipation, Diarrhea, Fatigue, Nasopharyngitis, Edema peripheral, Arthralgia, Insomnia, Urinary tract infection, Back pain, Weight increase, Dry mouth, Hypertension, Nasal congestion, Vision blurred, Flatulence, Joint sprain, Tremor | 5 |
Rice 2001 [ | Double-blind, randomized, placebo-controlled, multicenter, parallel | 334 included in ITT analysis: Gabapentin 1800 mg (115) (74.8, 22.5–88.6); 2400 mg (108) (76.3, 36.1–90.8); Placebo (111) (74.9, 28.9–94.8) | 7 | ADP scores | Dizziness, Somnolence, Peripheral edema, Asthenia, Dry mouth, Diarrhea | 5 | |
Sang 2013 [ | Double-blind, randomized, placebo-controlled, multicenter, parallel | 450 included in the ITT analysis: gabapentin ER 1800 mg, QD (220) (65.3±13.3); Placebo (230) (65.9±11.1) | 10 | ADP scores | Dizziness, Somnolence, Headache, Nausea, Peripheral edema, Nasopharyngitis | 4 | |
Rowbotham 1998 [ | Double-blind, randomized, placebo-controlled, multicenter, parallel | 229 included in the ITT analysis: Gabapentin 3600 mg, TID (113) (73,40–90); placebo (116)(74,39-89) | 8 | ADP scores | Sleep interference, SF-MPQ, PGIC/CGIC, SF-36, POMS | Somnolence, Dizziness, Ataxia, Peripheral edema, Infection | 5 |
Gong 2008 [ | Double-blind, randomized, placebo-controlled, multicenter, parallel | 215 included in the ITT analysis: Gabapentin divided-doses 1800 mg (109) (67.49±11.55); Placebo (106) (65.25±12.11) | 6 | ADP scores | Dizziness, Somnolence, Amblyopia, Peripheral edema, Nausea, Vomiting, Nystaxis, Dysuria | 5 | |
Jin 2006 [ | Double-blind, randomized, placebo-controlled, parallel | 36 included in the ITT analysis: Gabapentin divided-does 2400 mg (18) (63±10.3); Placebo (18) (64.39±9.12) | 4 | ADP scores | Dizziness, Somnolence, Ataxia, Nausea, Vomiting | 5 | |
Xie 2009 [ | Double-blind, randomized, placebo-controlled, parallel | 50 included in the ITT analysis: Gabapentin divided-does 2400 mg (26); Placebo (24) | 4 | ADP scores | Dizziness, Somnolence, Anorexia, Insomnia | 4 | |
He 2008 [ | Double-blind, randomized, placebo-controlled, parallel | 32 included in the ITT analysis: Gabapentin divided-does 1200 mg (16) (74.1±12.2); Placebo (16) (72.69±11.7) | 4 | ADP scores | Dizziness, Somnolence, Week, Ataxia, Anorexia, Insomnia, Vertigo | 4 |
ITT: intent to treat; GEn: gabapentin enacarbil; gabapentin ER: gabapentin extended-release; QD: once daily; BID: twice daily; TID: three times daily; ADP: average daily pain scores; SF-MPQ: Short Form-McGill Pain Questionnaire; NPS: Neuropathic Pain Scale; PGIC/ CGIC: Patient/Clinical Global Impression of Change; BPI: The Brief Pain Inventory; POMS: the Profile of Mood States; SF-36: Short Form-36; QS: Quality Of Sleep.
Gabapentin was used to treat PHN. Gabapentin has three formulations: Gabapentin, gabapentin ER, and GEn. Gabapentin ER was usually taken 1800 mg/day [
Although the race, age, gender, frequency, and duration of drug administration may influence the outcome of the subgroup analysis of gabapentin, research about this matter is scarce. Instead, a subgroup analysis on the formulation of the drug (gabapentin ER, GEn, and gabapentin) was carried out.
Seven [
Change in average daily pain score from the baseline.
All the studies [
At least 50% reduction in pain intensity.
Five [
Reduction in sleep rating scores.
The effect model meta-analysis of data from eight [
PGIC.
All included studies [
Adverse event.
Our main results (Figures
According to our inclusion criteria, the quality of research is very high (Jadad ≥4); only four researches [
The results of the sensitivity analysis by changing the effect mode show that most of the results are relatively stable in addition to a small number of patients because of the side effect withdrawal of drug. If the analysis results show that P>0.05, I2 ≥50%, then the fixed effect model can be used for meta-analysis; if the analysis results show that P<0.05, I2 ≤50%, then the random effect model can be used for meta-analysis. The subgroup analysis can be used to analyze the sources of heterogeneity. If the measurement unit of data is inconsistent, then the SMD value is used to replace MD. The subgroup analysis showed that the sources of heterogeneity may be related to the formulations of gabapentin. In addition, the GEn group performed better than other drug formulations, indicating that its formulation is considerably safe. However, this conclusion should be demonstrated further, especially through the control of the gabapentin dosage administered to patients.
In addition, [
Moreover, Moore et al.[
Gabapentin can relieve pain in PHN significantly. To maximize the efficacy and reduce adverse events, the appropriate formulations of the drug should be thoroughly considered. The GEn group showed better results than the other groups, indicating that this is better than the other formulations in the treatment of PHN effectively and safely. However, the long-term clinical efficacy and safety in different formulations of gabapentin remains to be determined.
Nevertheless, our study has limitations. First, most of our references are English publications; therefore, we may have missed miss nonmainstream and gray research. Second, most of the studies are from the United States; hence, most of the participants are White, thereby limiting our research results to other races. Third, the long-term safety and efficacy of gabapentin therapy in PHN cannot be assessed because the studies included are only for short-term treatment regimes. Fourth, four studies [
Overall, our study shows that, compared with the placebo, gabapentin can significantly relieve pain in PHN patients and reduce the pain of sleep disorders. Moreover, PHN patients have good tolerance to gabapentin. Future research should explore the different dosages, durations, and frequencies of gabapentin administration in the treatment of PHN. These studies should also examine the therapeutic effect and safety of gabapentin when administered to different races. Finally, long-term follow-up should be included.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors declare that there are no conflicts of interest regarding the publication of this paper.
Meng Zhang and Cun-Xiang Gao contributed equally to this work.
The authors would like to express their thanks to all those who helped in the writing of this paper. The project is supported by the National Natural Science Fund (no. 81560175).