The preemptive effects of oral pregabalin on perioperative pain management in lower limb orthopedic surgery: a systematic review and meta-analysis

Background To systematically review the literature and provide a comprehensive understanding of the preemptive effects of oral pregabalin on perioperative pain management in lower limb orthopedic surgery. Method We searched three electronic databases for randomized controlled trials comparing the results of preoperative pregabalin and placebo in patients undergoing lower limb orthopedic surgery. Data analyses were conducted using RevMan 5.4. Results Twenty-one randomized controlled trials met our inclusion criteria. The cumulative opioid consumption within 24 and 48 h postoperatively in the pregabalin group was significantly less than that in the placebo group. The pooled static pain intensity at all time points within the first day was significantly lower in the pregabalin group than in the placebo group. Lower dynamic pain intensity at 48 h was detected in the pregabalin group than in the placebo group. Meanwhile, pregabalin led to a lower incidence of nausea but appeared to be associated with a higher incidence of dizziness and sedation. Subgroup analyses showed that no difference was detected between subgroups stratified by dosing regimen or pregabalin dose in the results of opioid consumption, pain intensity and incidence of complications. Conclusion This meta-analysis supports the use of pregabalin preoperatively in patients undergoing lower limb orthopedic surgery. However, it was wary of the resulting increase in dizziness and sedation. There is no evidence to support the continued use of pregabalin postoperatively or using more than 150 mg of pregabalin per day. Trial registration: This study was registered on 09 November 2021 with INPLASY (registration number: INPLASY2021110031). Supplementary Information The online version contains supplementary material available at 10.1186/s13018-022-03101-9.

of life [2]. Considering the increased opioid consumption and its adverse effects as well as the complications caused by poor postoperative pain control, multimodal analgesia has been recommended in pain management [5,6].
Pregabalin can reduce the release of excitatory neurotransmitters and the excitability of synapses by inhibiting calcium influx through high-voltage gated channels [7,8]. It has been proven that pregabalin can exert its analgesic effect by reducing the hyperexcitability of dorsal horn neurons caused by tissue damage rather than reducing pain transmission from the injury site [9,10]. Considering its analgesic properties, preoperative administration of pregabalin has been widely used in perioperative pain management, and its analgesic effectiveness in procedures (such as spinal surgery) has been confirmed by existing meta-analyses [3,11].
Pregabalin has been used in lower limb orthopedic surgery for more than 10 years, and several previous randomized trials have explored its effect on perioperative pain management [12][13][14][15]. However, there is no official consensus as to whether pregabalin is effective in perioperative pain management for patients undergoing lower limb orthopedic surgery. A meta-analysis is warranted.
In this analysis, we aim to conduct a meta-analysis to compare the cumulative opioid consumption, pain intensity and incidence of complications after surgery between the pregabalin group and the placebo group to provide recommendations for surgeons and anesthesiologists.

Inclusion and exclusion criteria
This meta-analysis was performed following the PRISMA guidelines (www. prisma-state ment. org) and was registered on 10 November 2021 with INPLASY (registration number: INPLASY2021110031) (Details were displayed in Additional file 1: Appendix 1). The studies were selected based on the PICO criteria. Studies comparing the outcomes of cumulative opioid consumption, pain intensity or complication incidence following preoperative administration of oral pregabalin and placebo in patients undergoing lower limb orthopedic surgery were included in the current analysis.

Search strategy
The PubMed, EMBASE, and Cochrane Library databases were systematically searched (search trials are displayed in Additional file 2: Appendix 2). No restrictions on the publication status or language were applied.
Studies were assessed by two of the authors independently, and data were extracted with a standard data extraction form. The risk of bias was assessed for the included studies based on the Cochrane risk-of-bias criteria. Any disagreement was resolved through discussion.

Statistical analysis
The primary outcomes in this analysis were defined as the cumulative opioid consumption, static pain intensity and dynamic pain intensity. For opioid consumption, the reported data were converted to the oral morphine equivalent dose. For pain intensity, the data of VAS (0, no pain; 10, worst imaginable pain) were pooled. The secondary outcomes included the incidence of complications, such as nausea, vomiting, dizziness and sedation. Mean differences (MD) with a 95% CI were calculated using the inverse variance method for continuous variables, and risk ratios (RR) with a 95% CI were calculated using the Mantel-Haenszel analysis method for dichotomous variables. Heterogeneity was assessed using the Chi 2 and I 2 tests, and an I 2 of > 50% was identified as substantial heterogeneity. Sensitivity analysis was performed for variables presenting with substantial heterogeneity by sequentially excluding individual studies. Subgroup analysis was conducted by stratifying studies according to dosing regimen (receiving pregabalin preoperatively only vs receiving pregabalin both pre-and postoperatively) and pregabalin dose (> 150 mg/day vs ≤ 150 mg/ day). We used the Chi 2 test to test for subgroup interactions. Analysis was undertaken using RevMan 5.4 (The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark) with a significance threshold of P < 0.05.

Study quality assessment
In the current analysis, we defined the trials as high quality when selection bias was graded as low risk, with the others as low or unclear. When selection bias was assessed as high risk, trials were graded as low quality. Trials were defined as moderate quality if they did not meet the above criteria. Sixteen trials were graded as high quality [12-14, 16-18, 20-23, 25, 27, 28, 30-32], and five trials were graded as moderate quality [15,19,24,26,29]. The details of the quality assessment are displayed in Fig. 2.

Cumulative opioid consumption at 24 h and 48 h postoperatively
The reported opioid consumption was uniformly converted to the oral morphine equivalent dose. Patients who received pregabalin preoperatively had significantly lower opioid consumption than patients receiving placebo at 24 h after surgery (MD − 34.47, 95% CI [− 52.32, − 16.63], P = 0.0002), and substantial heterogeneity was observed (I 2 = 84%). For the results at 48 h after surgery, a similarly lower morphine equivalent dose was detected in patients receiving pregabalin than in those receiving placebo (MD − 46.69, 95% CI [− 75.11, − 18.28], P = 0.001). High heterogeneity was also seen (I 2 = 68%) (Fig. 3). Sensitivity analyses were performed for the results, and no individual studies detected a significant influence on the pooled results of morphine consumption within 24 and 48 h (details are displayed in Additional file 3: Appendix 3).
Two trials included in this study reported the outcomes of chronic neuropathic pain assessed by the Leeds Assessment of Neuropathic Symptoms and Signs pain scale (LANSS) [13,17]. Quantitative analysis of chronic pain was not performed because of the paucity of data.

Subgroup analyses
To compare the effectiveness of pregabalin in patients taking various dosing regimens, subgroup analyses were performed. A minimum of two comparisons per subgroup were available in the current analysis. There was no statistically significant difference in the results of cumulative opioid consumption within 24 h (test for subgroup differences, P = 0.30) in the subgroups of patients receiving pregabalin only before surgery or in patients receiving pregabalin both before and after surgery. Similarly, no significant difference between subgroups was shown in the results of static pain intensity at 24 h and incidence of complications. Details are displayed in Table 2.
To further explore the effect of pregabalin dose in patients undergoing lower limb orthopedic surgery, post hoc subgroup analyses were conducted in studies stratified by pregabalin dose (> 150 mg/day vs ≤ 150 mg/day). A minimum of two arms per subgroup was available in the current analysis. There was no statistically significant difference in opioid consumption within 24 h (test for subgroup differences, P = 0.62) between subgroups. Comparable results between subgroups were also detected in static pain intensity at 24 h (test for subgroup differences, P = 0.30), dynamic pain intensity at 24 h (test for subgroup differences, P = 0.72) and incidence of complications. Details are displayed in Table 3.

Discussion
The main findings of the current analysis were that the use of pregabalin preoperatively in patients undergoing lower limb orthopedic surgery appeared to be associated with lower morphine consumption at 24 h and 48 h. Similarly, decreased static pain intensity within 24 h and dynamic pain intensity at 48 h were detected in patients taking pregabalin. Compared with placebo, the use of pregabalin was associated with a reduction in the incidence of nausea but an increase in dizziness. No evidence was found with subgroup analyses to support the continued use of pregabalin postoperatively or using more than 150 mg of pregabalin per day. To our knowledge, this was the first meta-analysis focused on the efficacy of pregabalin in perioperative pain management in patients undergoing lower limb orthopedic surgery. The primary outcomes in the current analysis were pain intensity and cumulative opioid consumption. A small reduction in the pain intensity at rest, as described in existing research [33], was detected in patients receiving pregabalin at all time points within the first day after surgery. Similar outcomes of pain intensity on movement at 48 h were also found. In addition, lower heterogeneity was noted among the studies. All the aforementioned outcomes confirm the analgesic effectiveness of pregabalin in patients undergoing lower limb orthopedic surgery, which has been known to induce hyperalgesia [34]. The test for subgroup differences was not significant, suggesting that altered pregabalin dose or dosing regimen does not affect the analgesic effectiveness of pregabalin.
Significantly lower morphine consumption within 24 h and 48 h was observed in patients receiving pregabalin, indicating that preoperative pregabalin could effectively reduce opioid consumption postoperatively. A similar result was also detected in a study by Lee et al. [24], who reported that pregabalin led to a reduction in fentanyl consumption during the first or the second days after surgery. Considering the reduction in pain intensity, the opioid-sparing effect of pregabalin can be regarded as a manifestation of analgesic effectiveness. Substantial heterogeneity was observed in the results, and sensitivity analyses were performed by subsequently excluding individual studies. However, no individual studies detected a significant influence on these pooled results, suggesting that the results were stable. Subgroup analyses were conducted on morphine consumption within 24 h by stratifying studies according to the pregabalin dose and dosing regimen. The heterogeneity persisted in each subgroup, suggesting that variations in pregabalin dose and dosing regimen could not explain the heterogeneity in opioid consumption. Although we converted the reported data to the oral morphine equivalent dose uniformly, the variations in the types of opioids and their routes of administration may be the possible source of heterogeneity in opioid consumption. Other possible explanations may be the various surgical sites, incision lengths, surgical experiences, perioperative analgesic regimens, and patient factors. However, it was impossible to perform subgroup analyses with regard to the aforementioned items because of the paucity of data. Additionally, the test for subgroup differences (stratified by pregabalin dose and dosing regimen) was not significant, suggesting that an increased pregabalin dose or long-term dosing regimen seemed to be ineffective in further reducing the consumption of opioids.
Recently, perioperative pain management has sought to reduce the incidence of opioid-related adverse effects [33]. In the current analysis, a lower incidence of nausea was observed in patients receiving pregabalin, indicating that pregabalin can reduce the incidence of opioidrelated adverse effects through its opioid-sparing effect. The incidence of dizziness and sedation, however, was significantly higher in the pregabalin group, which is considered to be an adverse effect associated with pregabalin [35]. Hence, we should use pregabalin with caution. Moreover, the test for subgroup differences regarding the results of dizziness stratified by pregabalin dose was not significant, indicating that pregabalin had no dose effect on the incidence of dizziness. These results are contrary to the outcomes of previous research, which reported that the adverse effects of pregabalin are dose-dependent [36]. The difference in results may be due to the variations in the types of surgery. Moreover, considering the indirect comparisons that existed in our current analysis, we cannot exclude a possible dose effect of pregabalin on adverse effects. Hence, considering that there is no detectable difference in the results of pregabalin's analgesic effect and opioid-sparing effect between subgroups stratified by pregabalin dose, we recommend that the use of pregabalin does not exceed 150 mg per day.
Only two trials that reported the incidence of chronic neuropathic pain were identified in this analysis. Formal meta-analysis was not performed because of the paucity of data. Buvanendran et al. [17] reported a lower incidence of chronic neuropathic pain in patients receiving pregabalin. However, no significant reduction in the incidence of chronic neuropathic pain was noted in the study by Yadeau et al. [13]. At present, no clear evidence has been proposed with regard to the beneficial effects of pregabalin on the prevention of chronic neuropathic pain. More research that focuses on chronic neuropathic pain is needed to solve this problem.