A systematic review of the relevant literature was conducted in PubMed, the Cochrane Library, Embase, Scopus, and the Web of Science up to December 2018. There were no restrictions on the year or type of publication. The references lists of the selected studies and review articles were reviewed for additional relevant articles. Additionally, to ensure identifying most of the relevant studies, key journals relevant to the topic were searched separately. SCI, neuropathic pain; PGB, and GBP were the search terms.

After removing duplicate records, two authors (ABa and ABe) independently reviewed the titles and abstracts of the articles that were included based on the inclusion criteria. Disagreements were resolved by discussion between the two researchers and, if necessary, by a third person (DM). The selected studies were included for analysis if the following criteria were met [21]: (1) the focus was on individuals with neuropathic pain due to SCI with no restriction to any specific age group; (2) PGB and GBP were compared with each other or with a placebo; (3) neuropathic pain was measured as an outcome [22]; (4) the study design was a randomized clinical trial, and [22] (5) was published in the English language. Observational studies, case reports, editorial comments, and studies on animals were excluded.

We used Cochrane Collaboration’s tool to assess the risk of potential bias in the selected studies. The quality of the included randomized controlled trials (RCTs) was assessed independently by two researchers (ABa and AA).

Two reviewers (ABe and RS) independently extracted data using a constructed data extraction form including study characteristics (design, longitude, and following study), participants’ characteristics (age, sex, and number of patients), dosage (primarily median and maximum), efficacy outcomes (pain, anxiety, sleep, and depression), and side effects. In case of a dispute, issues were solved by discussion and checking with the third person (MD). The primary efficacy outcome variables were the changes in pain score and secondary outcomes included sleep interference, depression, and anxiety. Safety outcomes, which included adverse events (AEs) and discontinuations, were also analyzed.

A meta-analysis was performed to compare the efficacy and safety of PGB vs. GBP and PGB vs. placebo. Meta-analysis for the GBP and placebo studies was not possible due to differences in the treatment received by the control group. For example, in one study the control group used a placebo while in another study an active placebo (di-phenhydramine) was used. Additionally, in one study, a different scale was used for measuring and reporting the perceived pain. We performed the analysis using RevMan ver. 5.3 software.

For continuous variables, weighted mean difference (MD) and a 95% confidence interval (CI) were used.

For dichotomous variables, risk ratio (RR) and a 95% CI were used. Statistical heterogeneity has been evaluated using the I² and chi-square tests. The random-effects method and the fixed-effect method were used for studies with significant heterogeneity and for those without heterogeneity, respectively.

The processes of literature search, removal of duplicates, and screening based on title, abstract, and full text is shown in Fig. 1. The 866 articles found in the initial search were narrowed down to 8 articles that were selected for further eligibility assessment. After checking for all inclusion and exclusion criteria, finally, eight articles [39–46] were included in this review. One head-to-head trial was excluded due to the fact that the type of disease was not specified [47].

Of eight studies included in the review, two studies compared PGB with GBP, three studies compared PGB with a placebo, and three studies compared GBP with a placebo. In head-to-head studies [45,46], a total of 58 patients with neuropathic pain due to SCI in two crossover groups of PGB and GBP entered the studies. Of 58 participants, 40 individuals (69%) completed the studies. In both studies [45,46], pain scores were measured by the visual analogue scale (VAS). Sleep quality, depression, and anxiety were secondary outcomes. The prescribed dosage was 150–600 mg/day, two times per day, for PGB and 300–3,600 mg/day, three times per day for GBP. In three RCTs, 377 patients in two groups (PGB and placebo) were compared with each other [41,43,44]. Pain scores were measured by the VAS and duration-adjusted average change. The nine-item medical outcomes study-sleep scale problems index and the hospital anxiety and depression scale were used to measure sleep quality, depression, and anxiety, respectively. In three other RCTs, GBP was compared with a placebo [39,40,42] and an active placebo (diphenhydramine) in patients. The VAS, numeric rating scale, and neuropathic pain scale were used to measure pain scores. In one study, depressive symptomatology was measured by the center for epidemiologic studies depression scale short form. Study characteristics are presented in Table 1 [39–46].

Quality assessment of these studies, using the Cochrane Collaboration’s tool, is presented in Fig. 2 [39–46].

PGB vs. GBP: There is no significant difference between two drugs in the reduction of pain scores (MD = −0.37, 95% CI: −1.67, 0.93; P > 0.05, Fig. 3) [45,46].

PGB vs. placebo: The meta-analysis demonstrated a significant effect of PGB in comparison to a placebo on the reduction of pain scores (standardized mean difference [SMD] = −0.40; 95% CI: −0.78, −0.01; P < 0.05). For secondary outcomes, PGB was more effective than a placebo for anxiety (MD = −0.68; 95% CI: −0.77, −0.59; P < 0.05), depression (MD = −0.99; 95% CI: −1.08, −0.89; P < 0.05), and sleep interference (MD = −1.08; 95% CI: −1.13, −1.02; P < 0.05, Fig. 4) [41,44].

GBP vs. placebo: In two studies [39,40,42], GBP was only effective in some aspects of neuropathic pain such as pain intensity, unpleasantness, and hot sensation. In one study [42], there was no significant difference between GBP and an active placebo (diphenhydramine) in terms of pain scores. Generally, GBP vs. a placebo was more effective.

PGB vs. GBP: Drowsiness and somnolence were the commonly reported AEs for PGB and GBP [45,46]. Patients in the PGB group experienced a greater number of AEs than in the GBP group. Seven patients in the PGB group and two patients in the GBP group had to discontinue their medication therapy due to AEs. No significant difference was observed in discontinuation due to AEs in the two treatment groups (RR = 3.00; 95% CI: 0.81, 11.15; P > 0.05, Fig. 5) [45,46].

PGB vs. placebo: Drowsiness, dizziness, edema, and peripheral edema were the most common AEs in the selected studies [41,43,44]. According to the analyses performed on the results reported by the studies, no significant difference was observed between PGB and the placebo for discontinuation due to AEs (RR = 1.39; 95% CI: 0.71, 2.70; P > 0.05), somnolence (RR = 2.23; 95% CI: 0.97, 5.14; P > 0.05), and peripheral edema (RR = 1.31; 95% CI: 0.32, 5.40; P > 0.05). However, there was a significant difference between PGB and the placebo for dizziness (RR = 2.23; 95% CI: 0.97, 5.14; P < 0.05, Fig. 6) [41,43,44]. GBP vs. a placebo: The most common AEs reported for GBP were dry mouth, drowsiness, fatigue, dizziness, constipation, edema, and vertigo [39,40,42]. Nonetheless, one of the selected studies showed no significant difference in AEs between the recipients of GBP and the placebo [39,40,42].