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The Effect of Preoperative Pregabalin on Postoperative Nausea and Vomiting: A Meta-analysis

Grant, Michael C. MD*; Betz, Matthew DO*; Hulse, Matthew MD; Zorrilla-Vaca, Andres MD; Hobson, Deborah BSN*; Wick, Elizabeth MD*; Wu, Christopher L. MD*

doi: 10.1213/ANE.0000000000001404
Ambulatory Anesthesiology and Perioperative Management: Original Clinical Research Report
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BACKGROUND: Nonopioid adjuvant medications are increasingly included among perioperative Enhanced Recovery After Surgery protocols. Preoperative pregabalin has been shown to improve postoperative pain and limit reliance on opioid analgesia. Our group investigated the ability of preoperative pregabalin to also prevent postoperative nausea and vomiting (PONV).

METHODS: Our group performed a meta-analysis of randomized trials that report outcomes on the effect of preoperative pregabalin on PONV endpoints in patients undergoing general anesthesia.

RESULTS: Among all included trials (23 trials; n = 1693), preoperative pregabalin was associated with a significant reduction in PONV (risk ratio [RR] = 0.53; 95% confidence interval [CI], 0.39–0.73; P = 0.0001), nausea (RR = 0.62; 95% CI, 0.46–0.83; P = 0.002), and vomiting (RR = 0.68; 95% CI, 0.52–0.88; P = 0.003) at 24 hours. Subgroup analysis designed to account for major PONV confounders, including the exclusion trials with repeat dosing, thiopental induction, nitrous oxide maintenance, and prophylactic antiemetics and including high-risk surgery, resulted in similar antiemetic efficacy. Preoperative pregabalin is also associated with significantly increased rates of postoperative visual disturbance (RR = 3.11; 95% CI, 1.34–7.21; P = 0.008) compared with a control.

CONCLUSIONS: Preoperative pregabalin is associated with significant reduction of PONV and should not only be considered as part of a multimodal approach to postoperative analgesia but also for prevention of PONV.

Published ahead of print July 26, 2016.

From *The Johns Hopkins Medical Institutions, Baltimore, Maryland; Vanderbilt University Hospital, Nashville, Tennessee; and Hospital Universitario del Valle, Universidad del Valle, Valle del Cauca, Colombia.

Published ahead of print July 26, 2016.

Accepted for publication April 11, 2016.

Funding: None.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Michael C. Grant, MD, Department of Anesthesiology, The Johns Hopkins Medical Institutions Sheikh Zayed Tower, 8120 ACCM, 1800 Orleans St, Baltimore, MD 21287. Address e-mail to mgrant17@jhmi.edu.

Postoperative nausea and vomiting (PONV) remains a common and distressing comorbidity associated with the provision of anesthesia. Nausea and vomiting in the perioperative realm can lead to substantial delays in recovery, incur increased personnel and medication costs, and reduce overall patient satisfaction.1,2 Research in the area of PONV has expanded to introduce drugs that enhance γ-aminobutyric acid activity such as midazolam and gabapentin. Midazolam, formally utilized for its anxiolytic potential, has been associated with significant improvement in the incidence of PONV.3 Similarly, gabapentin has proven to be an attractive option in the perioperative period because of its ability to not only reduce postoperative opioid requirements and treat pain, but also reduce rates of PONV.4,5 The dual-purpose nature of these medications adheres directly to a multimodal therapeutic approach supported among numerous perioperative Enhanced Recovery After Surgery guidelines.6,7 As a result, individual Enhanced Recovery After Surgery protocols have begun to include these GABAergic adjuvants as potential alternatives in the PONV armamentarium.8,9

Pregabalin, a compound related in structure and mechanism to gabapentin, has well-documented anticonvulsant as well as analgesic properties. Although approved for the treatment of partial seizures, pregabalin has been administered for other indications such as fibromyalgia, diabetic neuropathy, and even acute postsurgical pain.10–14 Although gabapentin has been investigated as an agent for the prevention of PONV, no similar studies have been devoted to pregabalin.4,5 Our group conducted a formal review and meta-analysis of all available randomized controlled trials for the use of preoperative pregabalin in general anesthesia. We predicted that the administration of preoperative oral pregabalin would be associated with a reduced incidence of PONV.

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METHODS

Search Strategy

This study utilized the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. We searched MEDLINE, EMBASE, and CINAHL for all available studies from inception onward with updates to March 2015 (Supplemental Digital Content, Search Strategy, http://links.lww.com/AA/B436). In addition, individual citations were reviewed from included studies. Inclusion criteria included (1) population: studies involving adult (age >18 years) human patients undergoing surgery under general anesthesia; (2) intervention: preoperative oral pregabalin administered ≥30 minutes before surgical incision; (3) predefined outcomes: incidence of postoperative nausea, vomiting, PONV, and rescue antiemetic administration within 24 hours of surgery; and (4) design: randomized controlled trials published in English, full-text versions. No minimal sample size or dosing regimen was required for inclusion.

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Data Extraction

Two authors (MH, MB) screened the titles and abstracts of initial search results, extracted data, and assessed for risk of bias independently. Disagreements were resolved by a third reviewer (MCG). Demographic and clinical data, including PONV endpoints, were extracted from qualified studies and subsequently analyzed. A Jadad score15 was calculated for each individual trial, which is based on whether the trial was described with (a) appropriate randomization, (b) appropriate double blinding, and (c) complete account for participant withdrawals or dropouts. Elements are individually scored, and their sum (5 representing a perfect score) is the Jadad score.

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Analysis

The aim of the primary analysis is to examine the pooled effect of preoperative pregabalin on the overall incidence of nausea, vomiting, PONV, and rescue antiemetic requirement within 24 hours of the completion of surgery. Nausea and vomiting were defined as the number of patients per group who experienced at least 1 episode of the given endpoint. PONV was based on individual author definition and was most commonly defined as the number of patients who experienced both nausea and vomiting in the given timeframe. When scales or rubrics were utilized, any “nonzero” occurrence was considered an episode of either nausea or vomiting depending on the endpoint of interest. Rescue antiemetic administration was defined as the number of patients who required an additional antiemetic resulting from excessive nausea and vomiting and was defined by individual study parameters. Twenty-four hours was chosen as the primary endpoint based on both evidence of single-dose drug efficacy and preponderance of side effect reporting of included studies over that timeframe. In addition, the amount of opioids administered in the initial 24 hours was collected, converted to morphine equivalents using a previously described opioid conversion,13 and subsequently analyzed. Metaregression analysis was performed to evaluate the association between opioid administration and subsequent incidence of specific primary endpoints. Lastly, postoperative side effect data were collected within 24 hours including sedation, dizziness, headache, and visual disturbance when data were available. Individual author definitions were used for these endpoints.

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Subgroup Analysis

Subgroup analysis was also performed to assess the pooled effects of preoperative pregabalin on PONV endpoints. Specifically, we evaluated (1) all trials excluding those with repeat dosing to reduce confounding associated with subsequent postoperative medication administration; (2) all trials excluding those that utilized thiopental as an induction agent given its removal from the marketplace; (3) all trials excluding those that use nitrous oxide for maintenance anesthetic given its potential for increased PONV8; (4) all trials excluding those that use total IV maintenance anesthetic with propofol; (5) all trials excluding those that utilize known prophylactic antiemetics; and (6) all trials involving high PONV risk surgical procedures such as gynecologic, head and neck, and laparoscopic surgery.8

For dichotomous data, risk ratio (RR) was used to describe the size of the treatment effect, and for continuous data, mean difference was used. A random-effects model was used for all analyses. Heterogeneity was measured and expressed as I2, which describes the percentage of total variation across studies that is the result of heterogeneity rather than chance. I2 was calculated from basic results obtained from a typical meta-analysis as I2 = 100% × (Q − df)/Q, where Q is the Cochrane heterogeneity statistic. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity. Sensitivity analysis was performed using leave-one-out methodology when individual endpoints resulted in significant heterogeneity (P value for heterogeneity ≤0.05), and results were subsequently reported where applicable. Funnel plots of the incidence of various end points were used to assess for publication bias when >10 comparisons were available for a given endpoint. Publication bias was assessed by inspection of the funnel plot and by formal testing “funnel plot” asymmetry using the Egger test. Sensitivity analysis was performed excluding high risk of bias (Jadad score <4) studies, and any potential influence on outcome was subsequently reported in the results. Level of significance for all analyses was set at 0.05. All statistical analyses were performed with Review Manager (RevMan) 5.3 (The Cochrane Collaboration, 2014) and Stata version 13.0 (Stata, College Station, TX).

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RESULTS

Literature Identification

Figure 1.

Figure 1.

The initial search resulted in 723 studies (364 from MEDLINE, 321 from EMBASE, 38 from CINAHL) that met the inclusion criteria. After removing 267 duplicate studies, 456 potentially relevant articles were screened based on the abstract. After removing 407 abstracts that did not meet the inclusion criteria, the remaining 49 full-text articles were thoroughly reviewed. An additional 23 articles were excluded on the following basis: no data on outcomes of interest, pregabalin not utilized as the primary intervention, primarily regional anesthesia technique used, and nonplacebo-based control. Twenty-three randomized controlled trials (n = 1693) were included in the final analysis16–38 (Figure 1) comparing control (no pregabalin; n = 754) with pregabalin (n = 939).

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Study Characteristics

Table 1.

Table 1.

Table 1 summarizes characteristics of the studies including total patients, surgery type, medication timing, induction and maintenance anesthetics, and follow-up parameters. Within the 23 included trials, there are 28 comparisons of controls to pregabalin experimental arms given 5 trials involved the use of 3 arms (2 separate pregabalin experimental arms with differing medication doses16,23,31,32,35).

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Primary Outcomes

Figure 2.

Figure 2.

Figure 3.

Figure 3.

Figure 4.

Figure 4.

Figure 5.

Figure 5.

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.

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Sensitivity Analysis

After excluding trials with Jadad scored of <4 (Table 1), preoperative pregabalin was associated with a significant reduction in nausea (RR = 0.66; 95% CI, 0.47–0.86; P = 0.003; P for heterogeneity = 0.25; I2 = 21%) and vomiting (RR = 0.66; 95% CI, 0.51–0.86; P = 0.002; P for hetero geneity = 0.82; I2 = 0%) compared with controls. Given no studies that reported on PONV or rescue antiemetic administration resulted in Jadad score <4, no sensitivity analysis was performed for these endpoints. Funnel plots for nausea, vomiting, and PONV endpoints are included in Supplemental Digital Content (http://links.lww.com/AA/B436). None of these 3 endpoints resulted in evidence of significant publication bias based on the Egger test (PONV, bias = −0.76, P = 0.404; nausea, bias = −0.26, P = 0.747; and vomiting, bias = −0.57, P = 0.466).

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Subgroup Analysis

Table 2.

Table 2.

Table 2 further illustrates the pooled effect of trials involving preoperative pregabalin excluding trials with repeat dosing, excluding trials with nitrous oxide administration, excluding trials with thiopental induction, excluding trials with total IV maintenance anesthetic, and excluding trials that utilized another known prophylactic antiemetic medication. As shown, preoperative pregabalin was noted to significantly reduce PONV, nausea, vomiting, and rescue antiemetic administration within the first 24 hours of surgery compared with the control across all subgroups. Analysis of the pooled effects of preoperative pregabalin in trials involving high nausea-provoking risk procedures yielded similar results.

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Opioid Requirements

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.

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Pregabalin Side Effects

Table 3.

Table 3.

Table 3 shows the results of the pooled analysis of potential side effects associated with pregabalin administration. Preoperative pregabalin was not associated with increased incidence of sedation, dizziness, or headache compared with the control. However, pregabalin administration was associated with a significant increase in postoperative visual disturbance (RR = 3.11; 95% CI, 1.34–7.21; P = 0.008; P for heterogeneity = 0.30, I2 = 16%) compared with controls.

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DISCUSSION

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.

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DISCLOSURES

Name: Michael C. Grant, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Name: Matthew Betz, DO.

Contribution: This author helped conduct the study and write the manuscript.

Name: Matthew Hulse, MD.

Contribution: This author helped conduct the study and write the manuscript.

Name: Andres Zorrilla-Vaca, MD.

Contribution: This author helped analyze the data and write the manuscript.

Name: Deborah Hobson, BSN.

Contribution: This author helped design the study and conduct the study.

Name: Elizabeth Wick, MD.

Contribution: This author helped design the study and conduct the study.

Name: Christopher L. Wu, MD.

Contribution: This author helped design the study, conduct the study, and write the manuscript.

This manuscript was handled by: Tong J. Gan, MD.

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ACKNOWLEDGMENTS

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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