Among all included trials, preoperative pregabalin was associated with a significantly reduced incidence of PONV (Figure 2; RR = 0.53; 95% confidence interval [CI], 0.39–0.73, P = 0.0001; P for heterogeneity = 0.10; I2 = 40%), nausea (Figure 3; RR = 0.62; 95% CI, 0.46–0.83; P = 0.002; P for heterogeneity = 0.20; I2 = 24%), vomiting (Figure 4; RR = 0.68; 95% CI, 0.52–0.88; P = 0.003; P for heterogeneity = 0.77; I2 = 0%), and rescue antiemetic administration (Figure 5; RR = 0.63; 95% CI, 0.43–0.93; P = 0.02; P for heterogeneity = 0.11, I2 = 44%) within 24 hours when compared with controls.
Preoperative pregabalin administration was associated with a statistically significant reduction in opioid requirement (morphine equivalents, mg; mean difference = −8.3; 95% CI, −12.3 to −5.7; P for heterogeneity <0.001; I2 = 94%) within 24 hours of surgery compared with controls. In a metaregression model, opioid requirement was not a significant predictor of PONV (coefficient = 0.003; P = 0.17), nausea (coefficient = 0.002; P = 0.07), or vomiting (coefficient = 0.006; P = 0.79) at 24 hours. Metaregression was not performed for rescue antiemetic administration given a lack of available data.
Perioperative enhanced recovery protocols have increasingly introduced nonopioid alternatives to promote early patient recovery. Several of these medications serve multiple purposes through anxiolysis, reduction in postoperative inflammation, limitation of opioid administration, or prevention of PONV. This has created a larger niche for medications such as gabapentin and pregabalin, which have been repeatedly shown to reduce postoperative pain and reduce opioid requirements.39 Although gabapentin has also been vetted for its antiemetic potential, little has been published to date regarding the potential efficacy of the related drug, pregabalin. Based on our findings of the pooled analysis of included trials, preoperative administration of pregabalin is shown to reduce nausea, vomiting, and rescue antiemetic administration within 24 hours of surgery performed under general anesthesia.
The primary endpoints resulted in pooled analysis with low degrees of heterogeneity, which suggests that pregabalin consistently conveyed its antiemetic effect among alternative surgical subtypes, patient populations, and anesthetics. The effect was further tested among specific subgroups, and pregabalin was repeatedly shown to be associated with a similar postoperative antiemetic effect. Our results contrast those of a prior meta-analysis investigating the postoperative analgesic effects of pregabalin, which reported a reduction in PONV and nausea, but not vomiting.13 In addition, this prior review included multiple forms of anesthetics, including regional and sedation cases, as well as widely disparate dosing schedules. In our review, which was limited to cases involving general anesthesia, subgroup analysis aimed at controlling for anesthetic-based confounders, high-risk patient populations, and single-dose administration all yielded similar antiemetic efficacy for preoperative pregabalin.
Similar to gabapentin, the mechanism of action that underlies pregabalin’s antiemetic potential remains speculative. Effects are likely mediated through α2/δ subunits of voltage-sensitive calcium channels, which result in multiple downstream effects depending on the associated signaling pathway.40 Studies have shown that gabapentinoids may pre-empt nausea and vomiting through inhibition in the area postrema, decreased tachykinin neurotransmission, or reduction in postoperative inflammation.41–43 Others suggest that pregabalin’s role in prevention of PONV is a product of postoperative opioid reduction.13,14 Similar to prior studies, analysis in this review of postoperative opioid requirements resulted in a significant reduction in narcotic administration among those patients who received pregabalin compared with controls. Given metaregression did not show opioid administration was a significant predictor of subsequent PONV endpoints, we postulate that the true antiemetic mechanism of pregabalin is likely multifactorial in nature.
The potential side effect profile associated with pregabalin is largely linked to its unintended impact on the central nervous system. Several studies have linked the use of pregabalin to increased dizziness and sedation.13 Interestingly, our findings did not reconfirm these results. This may, in part, be attributable to the fact that this prior study included a number of regional and sedation cases where added sedating side effects would lead to a greater clinical impact when compared with general anesthesia. Our review did, however, find a significant association between administration of preoperative pregabalin and postoperative visual disturbance. Unfortunately, only 1 of the included studies reported directly on the length of postanesthesia care unit stay, which actually resulted in a reduction in length of stay in the pregabalin group.28 As a result, we cannot comment on the impact of any of these potential side effects on overall patient recovery. At least 1 prior study investigated the impact of escalating doses of preoperative pregabalin in ambulatory surgery. Those authors reported that when doses approach 300 mg, patients are at increased risk for postoperative sedation and prolonged recovery times.44 Unfortunately, too few studies are represented in this review to properly assess for the impact of individual dosing schedules on associated side effect profiles.
This review was limited to the use of preoperative pregabalin in adult patients for surgery performed undergoing general anesthesia. Our review was not designed to assess monitored anesthesia care with sedation, regional/neuraxial anesthetics, or pediatric populations. Other studies have been devoted to these topics separately.45–47 Additionally, it would be ideal to directly compare pregabalin with known antiemetics. To our knowledge, there are no available studies that address this area. Our results are limited to the initial 24 hours after surgery. Far too few studies directly reported on PONV endpoints in the postanesthesia care unit to allow for quantitative analysis. Furthermore, we are unable to comment on the effect of dosage of pregabalin on subsequent antiemetic potency given a paucity of available studies. Lastly, it is important to recognize that the included studies utilized PONV as secondary endpoints in their original trial design, which may limit interpretation of the results. This may be particularly true in the case of rescue antiemetic administration, where trial design and drug administration triggers may differ between trials. These considerations only further illustrate the importance of additional high-quality controlled studies in this promising area.
The results of this study support the inclusion of preoperative pregabalin not only for a growing indication to optimize analgesia, but also as part of an approach to prevent PONV. In an era where evidence-based multidisciplinary protocols are increasingly used, including nonopioid alternatives in an effort to provide multimodal analgesia, a drug such as pregabalin, which addresses several comorbid endpoints associated with general anesthesia, would be an ideal addition.
The authors thank Blair Anton, Associate Director for Informationist Services of the William H. Welch Medical Library, for literature search assistance.
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