Impact of Pregabalin on Acute and Persistent Postop Pain
Impact of Pregabalin on Acute and Persistent Postop Pain
In this systematic review and meta-analysis, we found that the perioperative administration of pregabalin was associated with a statistically significant reduction in pain scores at rest (MD of 0.81 at 2 h and 0.38 at 24 h), pain scores during movement (MD of 0.58 at 2 h, and 0.47 at 24 h), and opioid consumption (MD of 2.09 mg ME at 2 h, and 8.27 mg ME at 24 h) after surgery compared with placebo. The incidence of opioid-related side-effects (PONV and pruritus) was significantly reduced with pregabalin administration by 38% and 51%, respectively, relative to placebo at 24 h after surgery. The administration of pregabalin was associated with a significantly higher incidence of sedation (46% increase), dizziness (33% increase), and visual disturbance (3.5 times more likely) relative to placebo. Of note, pregabalin-treated patients achieved hospital discharge criteria 14 h earlier than controls. Although we were not able to reach a definitive conclusion regarding preoperative anxiety due to the wide CIs of the non-statistically significant pooled results, six of the 10 studies investigating preoperative anxiety reported significantly lower anxiety with pregabalin. Similarly for persistent pain, we were not able to reach a conclusion regarding the incidence at 3 months, while at 6 and 12 months, there was limited information suggesting a possible benefit. The only two studies investigating neuropathic pain reported a benefit from pregabalin administration.
The optimal dose or frequency of administration of pregabalin is unclear. In the included studies, the individual dose of pregabalin administered before surgery ranged from 50 to 300 mg. Our analyses suggested that the opioid-sparing effect of pregabalin seemed to be limited to doses 100–150 and 300 mg but not ≤75 mg at 2 h after surgery, whereas at 24 h, no statistically significant differences were detected between the three dose levels. These doses are lower than the lowest effective daily dose of 225 mg suggested in an earlier meta-analysis.
Pregabalin has an elimination half-life estimated to range from 5.5 to 6.7 h which is independent of the dose and frequency of administration. With nearly half the included trials studying single dosing while the other half using multiple dosing, we investigated whether the frequency of administration impacts the analgesic efficacy of pregabalin. While the opioid-sparing effect was statistically significant with both single and multiple dosing of pregabalin ≤75–300 mg, the reduction in pain scores seemed to be limited in general to multiple dosing. The further reduction in pain scores with multiple dosing over single dosing however was modest and likely not clinically relevant. In fact, there were no statistically significant differences between single and multiple dosing with regard to opioid consumption and pain scores, except for pain scores on movement with the ≤75 mg dose. These results might suggest that for acute pain outcomes, there is no significant benefit of repeated dosing of pregabalin compared with a single preoperative dose. This agrees with the results of the only study that prospectively compared single dose of pregabalin 150 mg vs three perioperative doses and reported no difference in acute pain outcomes between the groups.
In a previous meta-analysis, Clarke and colleagues investigated the incidence of persistent pain at 3–6 months after surgery and, pooling results from two studies, reported an odds ratio (95% CI) of 0.09 (0.02–0.52) with pregabalin compared with control. More recently, Chaparro and colleagues investigated the incidence of persistent pain at 3 months after surgery and found a reduction in this incidence with pregabalin after pooling the results of four studies [RR (95% CI)=0.70 (0.51, 0.95)]. However, the authors stated that these positive results in favour of pregabalin were mainly due to one positive study, while the other three studies showed no benefit. This positive overall result is likely due to the use of the fixed effect model in that review. We however used a random effects model, which we deemed more appropriate, given the clinical heterogeneity of the studies, and including six studies, we found the data insufficient to reach a conclusion about pain at 3 months due to the wide CIs of the pooled results. While we found a statistically significant reduction in the incidence of persistent pain at 6 months [RR (95% CI)=0.31 (0.10, 0.92) and 12 months [0.47 (0.23, 0.97)], each of these two analyses included only two studies, with one of them having a high risk of bias. Only two studies investigated neuropathic pain, with both studies reporting a benefit from pregabalin administration; however, one of those studies had a high risk of bias. The optimum pregabalin regimen needed for affecting chronic pain is not clear. Most of the studies studying the impact of pregabalin on chronic pain used multiple doses starting before operation and extending to several days after operation. Studies comparing the impact of single vs multiple dosing of pregabalin on the incidence of chronic post-surgical pain are lacking.
Overall, pregabalin produced a clinically relevant opioid sparing of 25% at 24 h. The impact on pain scores was less pronounced with 19% and 16% reduction in the mean pain scores at rest and on movement at 24 h, and therefore might not be clinically relevant. Pregabalin-induced opioid sparing was however associated with a reduction in opioid-related side-effects such as PONV and pruritus. However, these benefits were at the expense of increased risk of sedation and dizziness. The available data allowed only limited assessment of the impact of sedation on patients' recovery. For instance, only four studies reported on the duration of PACU stay, and this did not seem to be impacted by pregabalin. Furthermore, interestingly, the duration of hospital stay was reduced with pregabalin administration, but this was only reported in five of the included studies.
Since type of surgery and type of anaesthesia can influence postoperative analgesic outcomes, we included both in addition to pregabalin dosing in the meta-regression models. In fact, both were significant predictors of some of the outcomes in our analysis. For instance, type of surgery was a significant predictor of pain scores at rest at 2 and 24 h. This agrees with previous studies showing that type of surgery is a significant predictor of postoperative analgesic outcomes. The type of anaesthesia also predicted 2 h pain scores on movement and 24 h opioid consumption, likely due to the analgesic effect of regional anaesthesia in the early postoperative period.
There are several limitations to this review:
Multiple areas for future research have been identified. Large studies with adequate power are needed to compare the efficacy and side-effect profile of different doses of pregabalin. Studies are also needed to assess the efficacy and side-effects of single vs multiple dosing of pregabalin. In addition, further investigation is needed to assess the ideal pregabalin regimen for the reduction in persistent pain in surgical patients. Those studies should focus on surgeries associated with a high risk of chronic post-surgical pain. Studies also need to specifically address neuropathic pain and make a distinction between different types of persistent pain.
In conclusion, this systematic review and meta-analysis confirms previous meta-analyses suggesting that the perioperative administration of pregabalin is associated with a significant reduction in opioid consumption after surgery. In this review, we also found a significant reduction in pain scores with pregabalin administration. The impact on opioid consumption seemed to be more pronounced, while the reduction in pain scores was only modest. Other new findings from our review are the fact that the analgesic effect of pregabalin seemed to be associated with much lower doses than previously reported. Furthermore, our review suggested that overall there was no difference in acute pain outcomes between single and multiple dosing of pregabalin. Neuropathic pain might be reduced with pregabalin, but available data are sparse. Consistent with previous meta-analyses, sedation, dizziness, and visual disturbance occurred more commonly in pregabalin-treated patients.
Discussion
In this systematic review and meta-analysis, we found that the perioperative administration of pregabalin was associated with a statistically significant reduction in pain scores at rest (MD of 0.81 at 2 h and 0.38 at 24 h), pain scores during movement (MD of 0.58 at 2 h, and 0.47 at 24 h), and opioid consumption (MD of 2.09 mg ME at 2 h, and 8.27 mg ME at 24 h) after surgery compared with placebo. The incidence of opioid-related side-effects (PONV and pruritus) was significantly reduced with pregabalin administration by 38% and 51%, respectively, relative to placebo at 24 h after surgery. The administration of pregabalin was associated with a significantly higher incidence of sedation (46% increase), dizziness (33% increase), and visual disturbance (3.5 times more likely) relative to placebo. Of note, pregabalin-treated patients achieved hospital discharge criteria 14 h earlier than controls. Although we were not able to reach a definitive conclusion regarding preoperative anxiety due to the wide CIs of the non-statistically significant pooled results, six of the 10 studies investigating preoperative anxiety reported significantly lower anxiety with pregabalin. Similarly for persistent pain, we were not able to reach a conclusion regarding the incidence at 3 months, while at 6 and 12 months, there was limited information suggesting a possible benefit. The only two studies investigating neuropathic pain reported a benefit from pregabalin administration.
The optimal dose or frequency of administration of pregabalin is unclear. In the included studies, the individual dose of pregabalin administered before surgery ranged from 50 to 300 mg. Our analyses suggested that the opioid-sparing effect of pregabalin seemed to be limited to doses 100–150 and 300 mg but not ≤75 mg at 2 h after surgery, whereas at 24 h, no statistically significant differences were detected between the three dose levels. These doses are lower than the lowest effective daily dose of 225 mg suggested in an earlier meta-analysis.
Pregabalin has an elimination half-life estimated to range from 5.5 to 6.7 h which is independent of the dose and frequency of administration. With nearly half the included trials studying single dosing while the other half using multiple dosing, we investigated whether the frequency of administration impacts the analgesic efficacy of pregabalin. While the opioid-sparing effect was statistically significant with both single and multiple dosing of pregabalin ≤75–300 mg, the reduction in pain scores seemed to be limited in general to multiple dosing. The further reduction in pain scores with multiple dosing over single dosing however was modest and likely not clinically relevant. In fact, there were no statistically significant differences between single and multiple dosing with regard to opioid consumption and pain scores, except for pain scores on movement with the ≤75 mg dose. These results might suggest that for acute pain outcomes, there is no significant benefit of repeated dosing of pregabalin compared with a single preoperative dose. This agrees with the results of the only study that prospectively compared single dose of pregabalin 150 mg vs three perioperative doses and reported no difference in acute pain outcomes between the groups.
In a previous meta-analysis, Clarke and colleagues investigated the incidence of persistent pain at 3–6 months after surgery and, pooling results from two studies, reported an odds ratio (95% CI) of 0.09 (0.02–0.52) with pregabalin compared with control. More recently, Chaparro and colleagues investigated the incidence of persistent pain at 3 months after surgery and found a reduction in this incidence with pregabalin after pooling the results of four studies [RR (95% CI)=0.70 (0.51, 0.95)]. However, the authors stated that these positive results in favour of pregabalin were mainly due to one positive study, while the other three studies showed no benefit. This positive overall result is likely due to the use of the fixed effect model in that review. We however used a random effects model, which we deemed more appropriate, given the clinical heterogeneity of the studies, and including six studies, we found the data insufficient to reach a conclusion about pain at 3 months due to the wide CIs of the pooled results. While we found a statistically significant reduction in the incidence of persistent pain at 6 months [RR (95% CI)=0.31 (0.10, 0.92) and 12 months [0.47 (0.23, 0.97)], each of these two analyses included only two studies, with one of them having a high risk of bias. Only two studies investigated neuropathic pain, with both studies reporting a benefit from pregabalin administration; however, one of those studies had a high risk of bias. The optimum pregabalin regimen needed for affecting chronic pain is not clear. Most of the studies studying the impact of pregabalin on chronic pain used multiple doses starting before operation and extending to several days after operation. Studies comparing the impact of single vs multiple dosing of pregabalin on the incidence of chronic post-surgical pain are lacking.
Overall, pregabalin produced a clinically relevant opioid sparing of 25% at 24 h. The impact on pain scores was less pronounced with 19% and 16% reduction in the mean pain scores at rest and on movement at 24 h, and therefore might not be clinically relevant. Pregabalin-induced opioid sparing was however associated with a reduction in opioid-related side-effects such as PONV and pruritus. However, these benefits were at the expense of increased risk of sedation and dizziness. The available data allowed only limited assessment of the impact of sedation on patients' recovery. For instance, only four studies reported on the duration of PACU stay, and this did not seem to be impacted by pregabalin. Furthermore, interestingly, the duration of hospital stay was reduced with pregabalin administration, but this was only reported in five of the included studies.
Since type of surgery and type of anaesthesia can influence postoperative analgesic outcomes, we included both in addition to pregabalin dosing in the meta-regression models. In fact, both were significant predictors of some of the outcomes in our analysis. For instance, type of surgery was a significant predictor of pain scores at rest at 2 and 24 h. This agrees with previous studies showing that type of surgery is a significant predictor of postoperative analgesic outcomes. The type of anaesthesia also predicted 2 h pain scores on movement and 24 h opioid consumption, likely due to the analgesic effect of regional anaesthesia in the early postoperative period.
There are several limitations to this review:
Heterogeneity: We combined different types of surgery, different pregabalin doses, different anaesthetic types, and different regimens (single and multiple dosing) in our main analysis, which created heterogeneity within that analysis. It has been suggested that this is expected and inevitable in a meta-analysis, and that any amount of heterogeneity is acceptable, provided that the predefined eligibility criteria for the meta-analysis are sound and the data are correct. In order to investigate the efficacy of different dosing regimens of pregabalin and the efficacy of pregabalin in different types of surgery and with different anaesthetic techniques, we performed a number of sensitivity and subgroup analyses and meta-regressions. However, results from these analyses should be regarded as observational in nature, may be biased and limited by the small number of studies included in some of the subgroups, and should therefore be interpreted with caution. While included trials might have allocated treatment randomly, their inclusion in this review is not random. Furthermore, while we used a random effects meta-analysis due to the clinical heterogeneity, this method weighs the studies more equally than a fixed effect meta-analysis. To exclude a small study effect on the results of our analysis, we compared the results of the fixed and random effects model on our primary outcomes and those yielded comparable results further strengthening the internal validity of our findings.
Risk of bias in individual studies: Limiting the review to RCTs limits the potential for bias. Our risk of bias assessment indicated that most included studies had a low risk of bias. Furthermore, our sensitivity analysis excluding the few studies with unclear or high risk of bias did not affect our conclusions. Another limitation was the inconsistency of reporting outcomes among the studies, and the lack of response from some authors with regard to data that we requested. However, the results of our review were consistent in the various sensitivity analyses. Some important clinically relevant outcomes such as the duration of PACU stay and of hospital stay were only rarely reported.
Multiple areas for future research have been identified. Large studies with adequate power are needed to compare the efficacy and side-effect profile of different doses of pregabalin. Studies are also needed to assess the efficacy and side-effects of single vs multiple dosing of pregabalin. In addition, further investigation is needed to assess the ideal pregabalin regimen for the reduction in persistent pain in surgical patients. Those studies should focus on surgeries associated with a high risk of chronic post-surgical pain. Studies also need to specifically address neuropathic pain and make a distinction between different types of persistent pain.
In conclusion, this systematic review and meta-analysis confirms previous meta-analyses suggesting that the perioperative administration of pregabalin is associated with a significant reduction in opioid consumption after surgery. In this review, we also found a significant reduction in pain scores with pregabalin administration. The impact on opioid consumption seemed to be more pronounced, while the reduction in pain scores was only modest. Other new findings from our review are the fact that the analgesic effect of pregabalin seemed to be associated with much lower doses than previously reported. Furthermore, our review suggested that overall there was no difference in acute pain outcomes between single and multiple dosing of pregabalin. Neuropathic pain might be reduced with pregabalin, but available data are sparse. Consistent with previous meta-analyses, sedation, dizziness, and visual disturbance occurred more commonly in pregabalin-treated patients.
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