Despite advancements in risk factor identification and developments in the area of prevention, postoperative nausea and vomiting (PONV) remains a common occurrence after general anesthesia with estimated rates of PONV as high as 80% in certain high-risk settings.1,2 Aside from the distress associated with nausea and vomiting, occurrence of PONV can lend significant morbidity to seemingly innocuous procedures.3,4 Although PONV is often regarded as a necessary circumstance of surgery, efforts have been forged to eliminate its occurrence even in the highest-risk populations.5–7 Multimodal approaches to the prevention of PONV have been borne of this collective enterprise, but a great deal of work remains.
Originally developed as an anticonvulsant, gabapentin is perhaps best known for its utility within the chronic pain armamentarium to obviate neurogenic pain.8 More recently, it has been extensively studied as a non-opioid alternative to reduce morphine requirements as part of a multimodal approach to address postoperative pain.9,10 Given success in this arena, gabapentin has been increasingly introduced into “fast-track” bundles and enhanced recovery after surgery protocols to prevent unwanted side effects associated with opioid alternatives.11,12 Interestingly, gabapentin was serendipitously noted to also mitigate the effects of chemotherapy-induced nausea,13,14 a result that later led to reports of efficacy in the areas of hyperemesis gravidarum,15 postdural puncture emesis,16 and ultimately PONV.17
Although others have investigated the use of preoperative gabapentin and its ability to attenuate PONV, previous analyses have been limited by inclusion of studies wherein nausea and vomiting were secondary end points, inviting critiques regarding the insufficient power and increased heterogeneity.18,19 In this light, our group first performed a meta-analysis of all available trials investigating the preoperative administration of gabapentin wherein PONV was the primary end point of interest. Our secondary analysis aimed at addressing further weaknesses levied against previous studies regarding either elimination of certain surgical subpopulations18,19 or lack of overall quantitative review20 by performing a comprehensive review of all studies involving the use of preoperative gabapentin where the PONV end points of nausea and vomiting were reported.
In this study, we used the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. We searched MEDLINE, EMBASE, and CINAHL for all available studies from inception onward, with updates to January 2015 (Supplemental Digital Content 1, Search Strategy, https://links.lww.com/AA/B338). 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 gabapentin administered ≥30 minutes before surgical incision, (3) predefined outcomes: incidence of postoperative nausea, vomiting, nausea and vomiting, or provision of rescue antiemetics within the first 24 hours, and (4) design: randomized controlled trials published in English, full-text versions. No minimal sample size or dosing regimen was required for inclusion.
Two authors screened the titles and abstracts of initial search results, extracted data, and assessed for risk of bias independently. Disagreements were resolved by group consensus. Demographic and clinical data, including PONV end points, were extracted from qualified studies and subsequently analyzed. Risk of bias was assessed using the Cochrane Collaboration tool, which considers the following domains: adequacy of sequence generation, allocation concealment, blinding of participants, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other potential sources of bias. A Jadad score was also calculated for each individual trial by using previously described methodology.21 Individual analyses were performed both including and excluding high risk of bias (Jadad scale <3) studies, and any potential influence on outcome was subsequently reported in the results.
Analysis I: Trials Designed to Investigate the Primary End Point of PONV
The aim of the primary analysis was to examine the pooled effect of preoperative gabapentin on the overall incidence of PONV, nausea, vomiting, and rescue antiemetic requirement within 24 hours of the completion of surgery among trials originally intended to investigate PONV as the primary end point of the intervention. Twenty-four hours was chosen as the primary end point based on evidence of single-dose antiemetic efficacy over that time frame from previous review.20
Analysis II: All Trials Involving Preoperative Gabapentin Irrespective of the Primary End Point
A separate analysis was performed to assess the pooled postoperative effects of preoperative gabapentin for all included trials regardless of the primary end point of interest. Meta-analyses were performed to assess the effect of gabapentin on the incidence of nausea and vomiting within 24 hours of surgery when reported. In addition, we examined postoperative side effects within 24 hours, including dizziness, headache, excessive sedation/somnolence, and dry mouth, when data were available. Individual author definitions were used for these end points.
Further subgroup analysis was also performed to assess the pooled effects of preoperative gabapentin on PONV end points. Specifically, we evaluated (1) trials excluding repeat dosing to reduce confounding associated with subsequent postoperative medication administration, (2) trials excluding the use of thiopental as an induction agent given its removal from the marketplace and previous findings that gabapentin had less efficacy in the presence of propofol,18 (3) trials using nitrous oxide for maintenance of anesthesia given its potential for increased PONV,6 (4) trials specific to surgery subtype, (5) trials involving high PONV risk surgical procedures such as gynecologic, head and neck, and laparoscopic surgery,6 and (6) antiemetic efficacy of individual 1-time doses of gabapentin in an attempt to establish optimal dosing based on available data.
For dichotomous data, risk ratio (RR) was used to describe the size of the treatment effect, and, for continuous data, weighted mean difference was used. A random-effects model was used for all analyses. Given multiple outcomes, the level of significance was set at 0.01 for the primary outcomes of analysis I. Level of significance for other analyses was set at 0.05. All statistical analyses were performed with Review Manager (RevMan) 5.3 (The Cochrane Collaboration, 2014). Heterogeneity was measured and expressed as I2, which describes the percentage of total variation across the studies that is attributable to heterogeneity rather than chance. I2 was calculated from the 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. Where significant heterogeneity was observed (P value for heterogeneity ≤0.05), sensitivity analysis was conducted using the leave-one-out analysis as previously described.18 Individual studies were excluded from the model, and the influence of the exclusion of that study on the model parameters was assessed.
The initial search resulted in 795 studies (330 from MEDLINE, 376 from EMBASE, and 89 from CINAHL) that met the inclusion criteria. After removing 276 duplicate studies, 519 potentially relevant articles were screened based on the abstract. After removing 429 abstracts that did not meet the inclusion criteria, the remaining 90 full-text articles were thoroughly reviewed. An additional 46 articles were excluded on the following basis: no data on outcomes of interest, gabapentin not used as primary intervention, primarily regional anesthesia technique used, and study retraction. Forty-four randomized controlled trials (n = 3489) were included in the final analysis (Fig. 1) comparing control (no gabapentin; n = 1692) with gabapentin (n = 1809).
Table 1 summarizes the characteristics of the studies, including total patients, surgery type, medication timing, induction and maintenance anesthetics, and follow-up variables. Studies designed specifically to assess PONV as the primary end point are highlighted in gray (8 trials; n = 838). Supplemental Digital Content 2 (https://links.lww.com/AA/B339) provides an outline of the Cochrane risk of bias tool for these included trials. In total, there are 47 comparisons of placebo controls to gabapentin experimental arms, 4 comparisons of a drug in the control arm with a combination of that drug and gabapentin in the experimental arm, and 3 comparisons of an active placebo (or vitamin) to gabapentin.
Analysis I: Studies with PONV as the Primary Outcome
Among trials designed to assess PONV as the primary end point, preoperative gabapentin was associated with a significantly reduced incidence of PONV (Fig. 2; RR = 0.60; 99% confidence interval [CI], 0.47–0.76, P < 0.0001; I2 = 0%), nausea (Fig. 3; RR = 0.34; 99% CI, 0.17–0.65; P < 0.0001; I2 = 0%), vomiting (Fig. 4; RR = 0.34; 99% CI, 0.16–0.73; P = 0.0002; I2 = 0%), and rescue antiemetic administration (Fig. 5; RR = 0.52; 99% CI, 0.34–0.78; P < 0.0001; I2 = 0%) within 24 hours when compared with controls. According to these results, the number needed to treat (NNT) to prevent PONV is 4.1. The NNT to prevent nausea is 4.9, NNT to prevent vomiting is 6.1, and NNT to prevent rescue antiemetic administration is 4.8.
Analysis II: Evaluation of All Included Studies Regardless of Primary End Point
Table 2 shows the effect of preoperative gabapentin on PONV end points within 24 hours of surgery. The meta-analysis of these trials indicated that there was a significant reduction in nausea (RR = 0.76; 95% CI, 0.67–0.85; P < 0.0001; I2 = 0%; 42 studies of 2349 patients) and vomiting (RR = 0.67; 95% CI, 0.56–0.80; P < 0.0001; I2 = 0%; 36 studies of 2024 patients) end points compared with controls.
Table 2 further illustrates the pooled effect of trials involving preoperative gabapentin excluding trials with repeat dosing, thiopental induction, and nitrous oxide administration. As shown in Table 2, there was similar antinausea and antivomiting efficacy in all subgroup analyses. Analysis of the pooled effects of preoperative gabapentin in trials involving abdominal, hysterectomy, and high-risk procedures yielded similar results.
Dosing of Gabapentin and Nausea and Vomiting Efficacy
Escalating 1-time doses of preoperative gabapentin were all associated with significant reductions in PONV (Table 3) aside from 1-time 1200 mg gabapentin, which resulted in a nonsignificant reduction in nausea (P = 0.10) compared with control. One-time 300 mg gabapentin administration resulted in significant heterogeneity (P < 0.0001; I2 = 85%), which resolved when the study by Pandey et al.32 was excluded based on sensitivity analysis (I2 = 1%).
Gabapentin Side Effects and Associated Gabapentin Dosing
Table 4 shows the results of the pooled analysis of potential side effects associated with gabapentin administration. Preoperative gabapentin was not associated with increased incidence of headache, dizziness or lightheadedness, or dry mouth compared with control. However, gabapentin administration was associated with a significant increase in postoperative sedation or somnolence (RR = 1.56; 95% CI, 1.16–2.11; P = 0.003; P for heterogeneity = 0.003, I2 = 44%) compared with controls. When the study by Pandey et al.32 was excluded based on sensitivity analysis, gabapentin usage was still associated with a significant increase in sedation/somnolence compared with controls although the significant heterogeneity resolved (RR = 1.22; 95% CI, 1.02–1.47; P = 0.03; I2 = 0%).
When individual dosing regimens were reviewed, whereas pooled analysis of studies involving gabapentin dosing of 300 mg (RR = 2.91; 95% CI, 0.19–43.70; P = 0.44; P for heterogeneity = 0.005; I2 = 87%), 600 mg (RR = 1.30; 95% CI, 0.94–1.81; P = 0.11; P for heterogeneity = 0.55; I2 = 0%), and 900 mg (RR = 3.85; 95% CI, 0.51–24.96; P = 0.20; P for heterogeneity = 0.13; I2 = 56%) resulted in no statistically significant sedation, preoperative gabapentin dosing of 1200 mg resulted in significant postoperative sedation (RR = 1.42; 95% CI, 1.04–1.95; P = 0.03; P for heterogeneity = 0.99; I2 = 0%) compared with controls.
Although others have reported on the potential postoperative antiemetic effect of preoperative gabapentin, findings have been limited to isolated surgical settings such as abdominal surgery and hysterectomy,18,19 and reviews have been associated with significant heterogeneity. This has likely been due in large part to evaluation of studies where nausea and vomiting were secondary end points of included trials. Our review was tailored to address these limitations by evaluating the pooled effects of preoperative gabapentin among studies designed to investigate PONV as the primary end point. On the basis of the findings of the pooled analysis of involved trials, preoperative administration of gabapentin is shown to reduce postoperative nausea, vomiting, and rescue antiemetic requirements. Further analysis of all included trials that reported on PONV end points (primary or secondary) also resulted in a significant reduction in the incidence of PONV, nausea, vomiting, and rescue antiemetic requirement. This represents pooled data from the largest cohort of trials to date and suggests a significant role for preoperative gabapentin not only for alleviating postoperative pain but also for preventing PONV.
Reservation over the wide-spread adoption of the use of preoperative gabapentin is related to its central nervous system effects, namely potential excessive sedation and dizziness in the immediate postoperative period.65 Although our study did not show an association between gabapentin and various side effects, including dizziness/lightheadedness, headache, and dry mouth, we do report significant incidences of excessive postoperative sedation and somnolence. It is worth noting that, although a further analysis of sedation based on dosing schedule suggested the greatest impact with doses ≥1200 mg, these data should be interpreted with caution. Given the wide ranges of the associated CIs at smaller doses, we cannot entirely exclude these doses from causing similar rates of postoperative sedation. Unfortunately, only 2 studies reported directly on postanesthesia care unit (PACU) length of stay,31,60 and although neither study showed an association between gabapentin administration and prolonged PACU duration, there simply are not enough data available to make this assertion. Therefore, we cannot reliably comment on the significance of the observed postoperative somnolence effect or its clinical implication.
The majority of the primary end points of interest in the included studies involved the ability of preoperative gabapentin to both reduce postoperative pain scores and minimize the need for opioid rescue medications. Although the true mechanism mediating this effect is unknown, it is believed to be through action on the alpha2/delta subunit of voltage-sensitive calcium channels, thereby further inhibiting the downstream voltage-activated sodium channels and ultimate nociceptive signaling pathways.9,10 Interestingly, although upward titration of dosing appears to maximize pain-related efficacy in chronic pain such as diabetic neuropathy and postherpetic neuralgia, similar findings have not been consistently shown in the acute postoperative setting. At least 2 previous studies have reported a ceiling effect associated with a 1-time preoperative dose of either 600 or 900 mg, respectively.37,54 Above these thresholds, patients did not report improved pain scores compared with smaller doses. This phenomenon may be attributed to the proposed kinetics of gabapentin, whereby a saturable transport system may provide a dose-dependent absorption rather than a proportional one.66 In light of this potential ceiling effect of analgesia, coupled with our data that failed to show increased antiemetic efficacy with larger 1-time dosing of gabapentin, it would be reasonable for providers to consider moderate (600 mg) dosing schedules for preoperative gabapentin administration.
The actual mechanism by which gabapentin preempts nausea and vomiting remains a topic of debate. Previous studies have implicated a reduction in calcium signaling in the area postrema67,68 as well as a decreased tachykinin neurotransmission.69,70 Some have suggested a reduction in perioperative inflammation, thus reducing ileus and subsequent PONV.71 Still others explain the role of the drug in multimodal analgesia, thereby reducing perioperative opioid requirements and resulting in incidence of associated nausea and vomiting. A moderator analysis performed in a previous systematic review appears to refute this latter most theory,18 but it seems reasonable to conclude that some combination of the mechanisms above may be true.
This review was limited to preoperative gabapentin associated with general anesthesia in adults. Our review was not designed to assess the monitored anesthesia care with sedation, regional/neuraxial anesthetics, or pediatric populations. Other studies have been devoted to these topics separately.72–75 We also are unable to comment on the efficacy of administration of gabapentin in the immediate postoperative period although other studies suggest further benefit postoperatively as well.76 In addition, we cannot determine the efficacy of gabapentin on postdischarge PONV.77 There are limited numbers of studies that directly compare the known antiemetics and gabapentin on their ability to prevent PONV.26,28,62,78 Although previous results in this area favorably compare gabapentin with more traditional antiemetics, we cannot make overt statements regarding noninferiority compared with established antiemetics such as 5-hydroxytryptamine (5-HT),3 histaminic, or natural killer (NK)1 antagonists. Last, too few studies reported on PACU lengths of stay to reliably comment on the effect of potential excessive sedation in the postoperative period. This further alludes to the importance of additional high-quality controlled studies in this promising area.
Notably, our initial results among all included studies regarding overall nausea and sedation exhibited significant levels of heterogeneity. This effect was reversed after the exclusion of a single study.32 The disparate effect of this study was addressed in a previous review18 and is likely the result of using PONV as a secondary end point of the individual trial. Aside from heterogeneity, inclusion of this single trial did not affect the measure of our overall results.
The results of this study support the inclusion of preoperative gabapentin as part of the approach to prevent PONV. This conclusion is based not only on a meta-analysis of preoperative gabapentin with trials designed to investigate PONV as the primary end point but also on the review of the quantitative effect in trials regarding nausea and vomiting as secondary end points. In an era when comprehensive evidence-based protocols are being designed to both limit reliance upon opioids and maximize recovery, we would recommend the use of gabapentin to effectively improve both postoperative analgesic and antiemetic end points.
Name: Michael C. Grant, MD.
Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.
Attestation: Michael C. Grant approved the final manuscript and is the archival author. He attests to the integrity of the original data and the analysis reported in this manuscript.
Name: HeeWon Lee, MD.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: HeeWon Lee approved the final manuscript.
Name: Andrew J. Page, MD.
Contribution: This author helped conduct the study and write the manuscript.
Attestation: Andrew J. Page approved the final manuscript.
Name: Deborah Hobson, BSN.
Contribution: This author helped design the study and conduct the study.
Attestation: Deborah Hobson approved the final manuscript.
Name: Elizabeth Wick, MD.
Contribution: This author helped design the study and conduct the study.
Attestation: Elizabeth Wick approved the final manuscript.
Name: Christopher L. Wu, MD.
Contribution: This author helped design the study, conduct the study, and write the manuscript.
Attestation: Christopher L. Wu approved the final manuscript. He attests to the integrity of the original data and the analysis reported in this manuscript.
This manuscript was handled by: Tong J. Gan, MD, MHS, FRCA.
The authors would like to thank Blair Anton, Associate Director for Informationist Services of the William H. Welch Medical Library, for literature search assistance.
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