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.
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.
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%).
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.
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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