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Preoperative use of pregabalin for acute pain in spine surgery

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Introduction
Spine surgeries are associated with moderate to extreme pain at hospital discharge, thus hampering recovery. [1,2] Appropriate pain control is a prerequisite to promoting early mobilization and functional recovery after spine surgery. Morphines are recommended as the first choice for management of post-surgery pain, but they are associated with many adverse effects. [3,4] Recently, a greater emphasis has been placed on the administration of nonopioid analgesic drugs as part of multimodal anesthesia schedules for relieving pain and reducing morphine-related complications. For surgery, operation-induced neuroplastic changes may induce sensitization and cause postoperative hyperalgesia or allodynia. Therefore, an optimal multimodal analgesic regimen, including antihyperalgesic drugs to attenuate central sensitization, may have beneficial effects for pain control after surgery.
Pregabalin is an anticonvulsant agent that can bind to the alpha2delta subunit of presynaptic voltage-gated calcium channels, thus reducing the calcium influx into presynaptic terminals. However, the efficacy of perioperative pregabalin in spinal surgery has not been determined. A previous metaanalysis has compared gabapentinoids (gabapentin and pregabalin) versus placebo for pain control in lumbar surgery. However, only 2 studies were included in a previous metaanalysis that compared pregabalin versus placebo for pain control after lumbar surgery. [5] Therefore, we searched for relevant studies and performed a meta-analysis comparing pregabalin versus placebo for reducing pain intensity in spinal surgery.

Materials and methods
This systematic review was reported according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.

Search strategies
The following databases were searched in September 2016 without restriction of regions or publication types: PubMed (1950-September 2016), EMBASE (1974-September 2016), Web of Science (1950-September 2016), and Cochrane Library (September 2016 Issue 3) (Supplement file 1, http://links.lww. com/MD/B595). The Mesh terms and their combinations used in the search were as follows: "analgesia" OR "pain management" OR "anesthetic agents" OR "lumbar surgery" OR "spinal surgery" OR "lumbar spine surgery" AND "pregabalin" [Mesh terms]. The reference lists of related reviews and original articles were searched for any relevant studies, including randomized controlled trials (RCTs) involving adult humans. Only articles originally written in English or translated into English were considered. When multiple reports describing the same sample were published, the most recent or complete report was used. Since this is a meta-analysis, no ethics committee or institutional review board approval was necessary for the study.

Inclusion criteria and study selection
Patients: adult human subjects (age>18 years) prepared for lumbar surgery (lumbar infusion, lumbar laminectomy, or lumbar discectomy); intervention: perioperative pregabalin as an intervention group; comparison: placebo; outcomes: visual analog scale (VAS) with rest or mobilization at 12 hours, 24 hours, and 48 hours and complications (nausea, sedation, dizziness, headache, and visual disturbances); Study design: RCTs. Two independent reviewers screened the title and abstracts of the identified studies after removing the duplicates of the search results. Any disagreements about the inclusion or exclusion of a study were solved by discussion or consultation with an expert. The reliability of the study selection was determined by Cohen's kappa test, and the acceptable threshold value was set at 0.61. [6,7] 2.3. Data abstraction and quality assessment A specific extraction was conducted to collect the following data from the included trials: patients' general characteristics, country, the sample size of the control group and intervention group, the preoperative and postoperative dose, and the timing and frequency of pregabalin use. Outcomes such as VAS score with rest or mobilization at 12 hours, 24 hours, and 48 hours and complications (nausea, sedation, dizziness, headache, and visual disturbances) were abstracted and recorded in a sheet. Postoperative pain intensity was measured by a 100-point VAS. When the numerical rating scale (NRS) was reported, it was converted to a VAS. Additionally, a 10-point VAS was converted to a 100-point VAS. [8] Data in other forms (i.e., median, interquartile range, and mean ± 95% confidence interval [CI]) were converted to the mean ± standard deviation (SD) according to the Cochrane Handbook. [9] If the data were not reported numerically, we extracted these data using "GetData Graph Digitizer" software from the published figures. All the data were extracted by 2 independent reviewers, and disagreements were resolved by discussion. The methodological quality of all included trials was independently assessed by 2 reviewers on the basis of the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0 (http://www.cochrane-handbook.org/).

Outcome measures and statistical analysis
Continuous outcomes (VAS with rest or mobilization at 12 hours, 24 hours, and 48 hours) were expressed as the weighted mean differences (WMD) and respective 95% CI. Dichotomous outcomes (the occurrence of nausea, sedation, dizziness, headache, and visual disturbances) were expressed as the risk ratio (RR) with 95% CI. Statistical significance was set at P < 0.05 to summarize the findings across the trials. The metaanalysis was calculated by Stata software, version 12.0 (Stata Corp., College Station, TX). Statistical heterogeneity was tested using the chi-squared test and I 2 statistic. When there was no statistical evidence of heterogeneity (I 2 < 50%, P > 0.1), a fixedeffects model was adopted; otherwise, a random-effect model was chosen. Publication bias was tested using funnel plots. Publication bias was assessed by the funnel plot and quantitatively assessed by Begg's test. Subgroup analysis was conducted according to the dose of pregabalin (<300 mg/d or ≥300 mg/ d). We considered there to be no publication bias if the funnel plot was symmetrical and the P value was > 0.05. In addition, we calculated the number needed to harm (NNH) to examine the risk versus benefits of pregabalin therapy regarding complications. [10] 3. Results

Search results and quality assessment
In the initial research, a total of 316 papers were identified from the electronic databases (PubMed = 121, Embase = 98, Web of Science = 75, Cochrane Library = 22). The number of articles after duplicates had been removed by Endnote X7 software was 255. After screened the abstracts and title of these 255 studies, 243 papers were excluded because they were irrelevant or did not meet the criteria. One study compared celecoxib, pregabalin, extended-release oxycodone, and acetaminophen as a multimodal anesthesia versus intravenous morphine for lumbar fusion surgery. [11] Another study compared gabapentin versus pregabalin with no control group in patients after lumbar disc herniation surgery. [12] Both studies were excluded. Finally, 10 clinical studies with 535 patients (pregabalin group = 294, control group = 241) were included in the meta-analysis. [13][14][15][16][17][18][19][20][21][22] The flow diagram for the included studies can be seen in Fig. 1. Two studies administered pregabalin with 2 different doses, and we thus divided the population into 2 arms. [15,19] The general characteristic of the included studies can be seen in Table 1. The quality assessment of the included studies is summarized in Figs. 2 and 3. Only 2 studies did not describe the random sequence generation procedure; the remaining 8 clinical trials performed appropriate random sequence generation. The quality of the remaining studies was all low risk.  Table 1 The general characteristic of the included studies.    Fig. 4). Funnel plot and Begg's test were performed, and the results indicated that there was no publication bias between the included studies in terms of VAS score with rest at 12 hours, 24 hours, and 48 hours (Fig. 5).

Subgroup analysis
Subgroup analyses were conducted according to a low dose of pregabalin (<300 mg/d) and a high dose of pregabalin (≥300 mg/ d). The detailed results can be seen in Table 2. The pooled results indicated that a high dose of pregabalin can reduce the VAS score with rest at 12 hours, 24 hours, and 48 hours with a significant difference (P < 0.05). Both low doses of pregabalin and high doses of pregabalin can reduce the cumulative morphine consumption at 24 hours and 48 hours (P < 0.05).

Discussion
The current meta-analysis demonstrated that the use of pregabalin is associated with reduced pain scores at 12 hours,    was that pregabalin can reduce the occurrence of nausea after spine surgery. However, pregabalin could also increase the occurrence of dizziness and had an NNH of 25.7, which means that of 25.7 patients who receive pregabalin, 1 will suffer from dizziness. These results are contradict with a previous meta-analysis that compared gabapentinoids versus placebo for managing pain after total knee arthroplasty. In the meta-analysis, the results indicated that no evidence to support the routine use of pregabalin after total knee arthroplasty. [23] Eipe et al [24] included 43 clinical studies in a meta-analysis and found that pregabalin use is small in magnitude and is primarily restricted to surgical procedures associated with pronociceptive mechanisms. Furthermore, pregabalin was most likely to demonstrate efficacy in conditions associated with chronic pain. Choi et al [14] reported that the occurrence of chronic pain after spine surgery was approximately 20%, and this incidence is lower than the 32% following discectomy and up to 85% observed after amputation. [25][26][27] If the theory proposed by Eipe et al [24] is correct, then the lower incidence of chronic pain after spine surgery may explain why pregabalin failed to demonstrate efficacy in patients undergoing spine surgery.
In a previous meta-analysis of the use of gabapentinoids in the management of postoperative pain after lumbar spinal surgery, the findings suggested that both gabapentin and pregabalin were efficacious in reducing postoperative pain. [5] However, only 2 studies were included in the meta-analysis to compare pregabalin versus placebo for spinal surgery. Dong et al [28] performed a  meta-analysis of the use of pregabalin for reducing pain after TKA and found that pregabalin was effective in reducing pain intensity after TKA. Morphine-related complications were also compared between the pregabalin and control groups. Although a reduction in the incidence of postoperative nausea following spine surgery was observed, this effect was limited (number needed to treat = 8.4). The reduction of the occurrence of nausea may have mainly been due to reductions in the cumulative morphine consumption. Grant et al [29] conducted a meta-analysis and found that preoperative pregabalin was associated with a significant reduction in PONV; however, postoperative analgesia did not improve correspondingly. There were no significant differences in sedation, headache, dizziness, or visual disturbances between the 2 groups. Several studies have linked the use of pregabalin to increased dizziness and sedation. [30] The NNH for dizziness is 25.7 and is lower than that of other complications. This suggests that the complication of dizziness is the least commonly observed complication regarding pregabalin administration.
There were a total of 5 limitations refer to this study: (1) 10 RCTs with relatively small sample size, which might have influence on the precision of the final results; (2) the follow-up for

Conclusion
In conclusion, this is the first meta-analysis to compare the preoperative use of pregabalin versus a placebo for the management of pain after spine surgery. Some analgesic efficacy and opioid-sparing effects were observed with the administration of pregabalin. Additionally, a significant decrease in the risk of nausea was associated with the use of pregabalin. Because the sample size and the number of included studies were limited, a multicenter RCT is needed to identify the effects of pregabalin for reducing acute pain after spine surgery.