The analgesic evaluation of gabapentin for arthroscopy: a meta-analysis of randomized controlled trials


 Introduction:

The efficacy of gabapentin for pain management of arthroscopy remains controversial. We conduct a systematic review and meta-analysis to explore the influence of gabapentin versus placebo on the postoperative pain intensity of arthroscopy.
Methods

We search PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through April 2020 for randomized controlled trials (RCTs) assessing the effect of gabapentin versus placebo on pain control of arthroscopy. This meta-analysis is performed using the random-effect model.
Results

Five RCTs are included in the meta-analysis. Overall, compared with control group for arthroscopy, gabapentin remarkably decreases pain scores at 24 h (Std. MD=-0.68; 95% CI=-1.15 to -0.02; P = 0.21), analgesic consumption (Std. MD=-18.24; 95% CI=-24.61 to -11.88; P < 0.00001), nausea and vomiting (OR = 0.42; 95% CI = 0.21 to 0.84; P = 0.01), but has no obvious influence on pain scores at 6 h (Std. MD=-1.30; 95% CI=-2.92 to 0.31; P = 0.11) or dizziness (OR = 1.12; 95% CI = 0.56 to 2.24; P = 0.75).
Conclusions

Gabapentin is effective for pain control after arthroscopy.


Introduction
Arthroscopy has been extensively developed for the diseases of shoulder, knee and hip [1][2][3][4]. Moderate to severe pain commonly occurs after arthroscopic surgery, and results from insertion of arthroscopic instruments into the joint, bone removal, soft tissue dissection and distention [5][6][7][8][9]. Multimodal analgesia is developed to target the routes of nerves and various neurotransmitters to inhibit hyperalgesia and nociception [10]. It may also improve in ammatory and neurogenic conditions [11].
Gabapentin was used as an anti-epileptic drug and was subsequently applied for acute and chronic pain associated with different diseases such as post-herpetic neuralgia, diabetic neuropathy, trigeminal neuralgia and various headaches [12]. It acts through binding to the alpha 2-delta-subunit of voltagegated calcium channels and inhibiting the release of nociceptive neurotransmitters including glutamates, P-substance and norepinephrine from presynaptic afferent neurons [13]. The anti-hyperalgesic feature of gabapentin may focus on the reduction of pathologic postoperative pain [14]. In a systematic review, gabapentin was reported to reduce pain signi cantly and decrease the need to opioids [15]. In contrast, a systematic narrative review of 22 randomized clinical trial studies indicated that gabapentin as a single dose preemptive analgesia did not reduce pain and opioid consumption [16,17].
The application of gabapentin for the pain management of arthroscopy is not fully explored, and several studies reported the con icting results [18][19][20]. With accumulating evidence, we therefore perform a systematic review and meta-analysis of RCTs to explore the e cacy and safety of gabapentin in patients with arthroscopy.

Materials And Methods
Ethical approval and patient consent are not required because this is a systematic review and metaanalysis of previously published studies. The systematic review and meta-analysis are conducted and reported in adherence to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [21,22].

Search strategy and study selection
Two investigators have independently searched the following databases (inception to April 2020): PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases. The electronic search strategy is conducted using the following keywords: gabapentin, and arthroscopy. We also check the reference lists of the screened full-text studies to identify other potentially eligible trials.
The inclusive selection criteria are as follows: (i) study design is RCT; (ii) population are patients undergo arthroscopy; (iii) intervention treatments are pregabalin versus placebo.

Data extraction and outcome measures
We have extracted the following information: author, number of patients, age, female, body weight, duration of surgery and detail methods in each group etc. Data have been extracted independently by two investigators, and discrepancies are resolved by consensus. We also contact the corresponding author to obtain the data when necessary.
The primary outcomes are pain scores at 6 h and 24 h. Secondary outcomes include analgesic consumption, dizziness, nausea and vomiting.

Quality assessment in individual studies
Methodological quality of the included studies is independently evaluated using the modi ed Jadad scale [23]. There are 3 items for Jadad scale: randomization (0-2 points), blinding (0-2 points), dropouts and withdrawals (0-1 points). The score of Jadad Scale varies from 0 to 5 points. An article with Jadad score≤2 is considered to be of low quality. If the Jadad score≥3, the study is thought to be of high quality [24].

Statistical analysis
We estimate the standard mean difference (Std. MD) with 95% con dence interval (CI) for continuous outcomes (pain scores at 6 h and 24 h, analgesic consumption) and odd ratio (OR) with 95% CIs for dichotomous outcomes (dizziness, nausea and vomiting). The random-effects model is used regardless of heterogeneity. Heterogeneity is reported using the I 2 statistic, and I 2 > 50% indicates signi cant heterogeneity [22,25]. Whenever signi cant heterogeneity is present, we search for potential sources of heterogeneity via omitting one study in turn for the meta-analysis or performing subgroup analysis. All statistical analyses are performed using Review Manager Version 5.3 (The Cochrane Collaboration, Software Update, Oxford, UK).

Results
Literature search, study characteristics and quality assessment A detailed owchart of the search and selection results is shown in Figure 1. 261 potentially relevant articles are identi ed initially. Finally, ve RCTs that meet our inclusion criteria are included in the metaanalysis [18-20, 26, 27].
The baseline characteristics of the ve eligible RCTs in the meta-analysis are summarized in Table 1. The three studies are published between 2006 and 2016, and total sample size is 346. The doses of gabapentin include 300 mg, 600 mg, 800 mg before the surgery.
Among the ve studies included here, two studies report pain scores at 6 h [18,19], three studies report pain scores at 24 h [18][19][20], two studies report analgesic consumption [18,19], four studies report dizziness [18][19][20]26], as well as four studies report nausea and vomiting [18,19,26,27]. Jadad scores of the ve included studies vary from 3 to 5, and all ve studies are considered to be high-quality ones according to quality assessment.

Sensitivity analysis
Signi cant heterogeneity is observed among the included studies for pain scores at 6 h. There are just two included RCTs, so we do not perform sensitivity analysis via omitting one study in turn to detect the heterogeneity.

Discussion
Many methods have been developed to reduce postoperative pain after arthroscopic surgery, and include in ltration of local anesthetic, nerve block and interscalene block [28][29][30]. However, they are limited by procedural di culties and complications inherent in their invasive nature [31]. Non-steroidal antiin ammatory drugs and opioid drugs are commonly used for the postoperative pain control, but may lead to nausea, vomiting and gastrointestinal bleeding. Thus, multimodal analgesia is developed to reduce these opioid-related adverse effect [32].
Gabapentinoids were found to interact with other analgesics additively or synergistically to decrease in ammatory hyperalgesia, and decrease opioid consumption [33,34]. Gabapentin on postoperative pain was studied in different surgical interventions, and showed obvious decrease in pain intensity and opioid consumption in hysterectomy and spinal surgery [35]. In orthopedic and musculoskeletal surgeries, the pain intensity and opioid consumption at 24 h follow-up visit was signi cantly reduced among patients taking gabapentin [27,[36][37][38].
Arthroscopic surgery, as a minimally-invasive procedure, has been increasing, but only limited numbers of studies examining the effectiveness of gabapentin in arthroscopic surgeries [20,26,27]. Our metaanalysis suggests that gabapentin is associated with substantially reduced pain scores at 24 h and analgesic consumption for arthroscopy, but has no remarkable in uence on pain scores at 6 h.
The e cacy in administration of gabapentin as a preemptive analgesic reported may be caused by the differences in gabapentin dosages, the time of the administration of gabapentin, being a single dose or multiple doses, and anesthesia method. 600 mg dosage of gabapentin was more effective than 300 mg dosage and has the same effectiveness as higher dosages (900 and 1200 mg) in reducing pain intensity and total opioid consumption [39]. A meta-analysis of 1151 patients (614 patients taking gabapentin in 16 RCTs) included three categories according to the gabapentin dosages: A. a single dose of 1200 mg; B. a single dose less than 1200 mg; C. multiple dose of less than 1200 mg. The results revealed that patients with a single dose of gabapentin experienced signi cantly less pain than the placebo group, and gabapentin group results in signi cantly more sedation, but less vomiting and pruritus [40].
Gabapentin 2 hours preoperatively is recommended to administer because it can achieve the maximum plasma concentration 2-3 h after the injection. Since gabapentin has no hepatic metabolism and is excreted without change through the kidneys, gabapentin is well tolerant [18,41]. In this meta-analysis, gabapentin shows no increase in dizziness, but is associated with the decrease in nausea and vomiting, which may be derived from the reduction of analgesic consumption after the surgery. This meta-analysis has several potential limitations. Firstly, our analysis is based on ve RCTs, and all of them have a relatively small sample size (n < 100). Overestimation of the treatment effect is more likely in smaller trials compared with larger samples. Next, there is signi cant heterogeneity for pain scores at 6 h, which may be caused by different methods of gabapentin and operation procedures. Finally, it is not feasible to perform the meta-analysis of some important index such as pain scores at longer follow up time and perform the subgroup analysis based on dosages.

Conclusions
Gabapentin is effective and safe to relieve the pain after arthroscopy.  Figure 1 Flow diagram of study searching and selection process. Forest plot for the meta-analysis of pain scores at 6 h.
Page 13/14 Figure 3 Forest plot for the meta-analysis of pain scores at 24 h.

Figure 4
Forest plot for the meta-analysis of analgesic consumption.

Figure 5
Forest plot for the meta-analysis of dizziness.

Figure 6
Forest plot for the meta-analysis of nausea and vomiting.