The Efficacy of Gabapentin/Pregabalin in Improving Pain After Tonsillectomy: A Meta-Analysis

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1 The Laryngoscope VC 2015 The American Laryngological, Rhinological and Otological Society, Inc. The Efficacy of Gabapentin/Pregabalin in Improving Pain After Tonsillectomy: A Meta-Analysis Se Hwan Hwang, MD, PhD; In Joon Park, MD; Young Jin Cho, MD; Yeon Min Jeong, MD; Jun Myung Kang, MD, PhD Objectives/Hypothesis: Gabapentin and pregabalin are useful for treating neuropathic pain because of their antiallodynic and antihyperalgesic properties, which may be beneficial in managing acute postoperative pain. The goal of this metaanalysis was to perform a systematic review of the literature on the effect of gabapentinoids on postoperative pain following tonsillectomy, and its adverse effects in patients. Data Sources: MEDLINE, SCOPUS, and Cochrane database. Methods: Two authors independently searched the databases from their inception of article collection to May Included in the analysis were studies that compared preoperative gabapentinoid administration (gabapentinoids groups) with a placebo or pain control agent (control group) during a 24-hour postoperative period, the outcomes of interest being postoperative pain intensity; rescue analgesic consumption; or adverse effects such as sedation, nausea and vomiting, dizziness, and headache. Results: The pain score reported by the physician during the first 8 hours, as well as the need for analgesics during 24 hours postoperatively, were significantly decreased in the gabapentinoids group versus the control group. Additionally, there was no significant difference between gabapentinoids and control groups for adverse effect during 24 hours postoperatively. In the subgroup analyses (gabapentin and pregabalin) regarding pain-related measurements, two subgroups showed the similar effect on reducing the postoperative pain severity. Conclusion: Preoperative administration of gabapentinoids could provide pain relief without side effects in patients undergoing tonsillectomy. However, considering the insufficient evaluation of efficacy of gabapentinoids according to the high heterogeneity in some parameters, further clinical trials with robust research methodology should be conducted in order to confirm the results of this study. Key Words: Gabapentin, pregabalin, tonsillectomy, pain, analgesics, systematic review, meta-analysis. Level of Evidence: NA. Laryngoscope, 126: , 2016 INTRODUCTION Postoperative pain and swallowing difficulty following tonsillectomy remain one of the most difficult pain states to manage in otolaryngology. 1,2 Many therapeutic modalities ranging from nonsteroidal antiinflammatory drugs (NSAIDs) to systemic opioids, acetaminophen, and tramadol have been used for posttonsillectomy pain control in patients. 3,4 However, NSAIDs increase the risk of postoperative bleeding. Opioids increase the risk of nausea and vomiting, as well as the ominous risk of respiratory depression in patients with sleep-disordered breathing. Acetaminophen alone provides less pain relief From the Department of Otolaryngology Head and Neck Surgery, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea Editor s Note: This Manuscript was accepted for publication August 12, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Jun Myung Kang, MD, PhD, Department of Otolaryngology Head and Neck Surgery, Bucheon St. Mary s Hospital, College of Medicine, The Catholic University of Korea, 2 Sosa-dong, Wonmi-Gu, Bucheon, Gyeonggi-Do, Republic of Korea, entkjm@catholic.ac.kr DOI: /lary than opioids and requires more rescue analgesia. 5 Therefore, it is necessary to develop an effective approach to control posttonsillectomy pain by combining treatment modalities that can block different pain mechanisms. 6 Gabapentin and pregabalin, referred to as gabapentinoids, are structural analogues of gamma-amino butyric acid, which is an anti convulsant drug that possibly achieves its effects via voltage-dependent calcium channels. 7 The results of several recent studies in posttonsillectomy pain using gabapentinoids preemptively as an analgesic adjuvant are encouraging regarding the effects of gabapentinoids on postoperative pain and opioid consumption. 8 However, there is currently insufficient evidence in the literature to fully support the use of gabapentinoids for managing posttonsillectomy pain. This review aims to assess the evidence on the efficacy of gabapentinoids for improving the patient experience of tonsillectomy. MATERIALS AND METHODS Search Strategy and Selection of Studies Studies published in English prior to May 2015 were identified on MEDLINE, Scopus, and the Cochrane Register of Controlled Trials using the following search terms: tonsillectomy, 357

2 Fig. 1. Diagram of selection of studies. adenotonsillectomy, gabapentin, pregabalin, pain, analgesics, and opioid. Two independent literature reviewers screened all abstracts and titles for candidate studies and discarded studies that were not related to the preoperative administration of gabapentinoids. The full text of studies that were potentially relevant to the topic was obtained if a decision for inclusion could not be made from the abstract alone. Randomized controlled trials that met the following inclusion criteria were eligible for review: the trials studied patients receiving the tonsillectomy procedure (cold or thermal) without age limitation and any route of gabapentinoids administration. Studies were excluded if, in addition to tonsillectomy, patients underwent procedures such as nasal and otologic surgery or if multiple reports were based on the same trial data. In cases where there were missing or incomplete data, attempts were made to obtain further details directly from the authors. Studies were excluded from the analysis if outcomes of interest were not clearly reported with quantifiable data or if it was not possible to extract and calculate the appropriate data from the published results. According to the PRISMA statement, the 27-item checklist and flow diagram were used to perform transparent and complete reporting of meta-analyses (Supp. Table and Fig. 1). Data Extraction and Risk of Bias Assessment Data from eligible studies were extracted using standardized forms and were independently checked by the two reviewers. Outcomes analyzed were postoperative pain (swallowing or resting pain scores after leaving the operation room), 2,6,8 12 postoperative (24 hours) analgesic requirements (either doses or percentage of patient receiving postoperative opioids or nonopioids analgesics), 2,6,8 10,12,13 time to first analgesic administration (opioids or nonopioids analgesics administered with a defined pain intensity target), 9 11 time to first oral uptake, 2,5,12,13 the occurrence of postoperative nausea and vomiting (incidence or percentage of patients), 2,6,8 13 dizziness, 6,8,12 and headache, 6,8,12 or sedation (sedation scores). 2,11 These outcomes were compared between the preoperative gabapentinoids group, in which there was intravenous and oral administration, and the control group, in which there was no treatment or use of opioids during the 24-hour postoperative period. The influence of gabapentinoids on pain and sedation was analyzed separately after patients left the operation room. From the enrolled studies, we abstracted data regarding patient number, grading scale used, amount of analgesics taken, time to first analgesic administration, incidence or percentage of adverse effects, and the P value recorded as comparison between the preoperative gabapentinoid group and the control group. The risk of bias for each study was evaluated using the Cochrane risk of bias tool. Statistical Analysis The meta-analysis of selected studies was performed with R statistical software (R Foundation for Statistical Computing, Vienna, Austria). When original data were expressed as continuous variables, meta-analysis was performed using the standardized mean difference (SMD). The SMD is used as a summary statistic to standardize the results of the studies to a uniform scale when the studies all assess the same outcome but measure it in a variety of ways. The common representation of the SMD is Cohen s d, which suggests that a larger effect size indicates that a treatment is more clinically effective. An effect size (SMD) between 2 means of around is considered a small effect (possibly clinically nonsignificant), an effect size of around is considered a medium effect, and an effect size of or greater is considered a large and clinically significant effect. 14 This method was chosen to assess postoperative pain and analgesic requirements, time to first analgesic administration, and postoperative sedation. In all other cases, outcome incidence analysis was performed using the odds ratio (OR). A funnel plot and Egger s test were used simultaneously to detect publication bias. Additionally, the Duval and Tweedie trim-andfill method was used to adjust for missing studies and to correct the overall effect size according to publication bias. Sensitivity analyses were performed to estimate the influence of each study on the overall meta-analysis results. RESULTS Nine studies comprising of 588 participants were reviewed in this study. The results of bias assessment and study characteristics are described in Table I. Publication bias was not assessed because the number of trials included was insufficient to properly assess a funnel plot or to perform more advanced regression-based assessments. 358

3 TABLE I. Summary of Studies Included in the Meta-Analysis. Study (year) Sample Size Comparison/Age Range Outcome Measure Analyzed Judgment of Risk of Bias Amin (2011) 70 Preoperative gabapentin vs. control Child (46 years) Yeganeh 60 Preoperative gabapentin vs. control (2012) Child and adult (1025 years) Amin 80 Preoperative gabapentin vs. control (2014) Child (46 years) Fatthallah 60 Preoperative gabapentin vs. control (2012) Adult (1931 years) Mathiesen 88 Preoperative pregabalin vs. control (2011) Adult (1850 years) Mohamed 144 Preoperative gabapentin vs. control (2014) Child (4 8 years) Park (2015) 48 Preoperative gabapentin vs. control Adult (> 18 years) Jeon (2009) 58 Preoperative pregabalin vs. control Child and adult (> 15 years) Postoperative analgesic requirement (mg) Time to first analgesia (minutes) Adverse effect (nausea and vomiting) Postoperative analgesic requirement (mg) Adverse effect (dizziness, headache, and nausea and vomiting) Postoperative analgesic requirement (mg) Time to first analgesia (minutes) Adverse effect (nausea and vomiting) Time to first analgesia (minutes) Adverse effect (sedation and nausea and vomiting) Postoperative analgesic requirement (mg)incidence of analgesic requirements Adverse effect (sedation score and nausea and vomiting) Incidence of analgesic requirements Adverse effect (nausea and vomiting) Postoperative analgesic requirement (mg) Adverse effect (dizziness; headache, nausea, and vomiting) Postoperative analgesic requirement (mg) Adverse effect (dizziness; headache, nausea, and vomiting) Administration of Gabapentinoid Versus Control (Resting or Swallowing Pain) The postoperative resting pain at 2 (SMD ; confidence interval (CI) 95% [20.83 to 20.26]), 4 (SMD ; CI [21.21 to 20.35]), and 8 hours (SMD ; CI [23.83 to 20.60]) was statistically lower in the gabapentinoids group than that in the control group. However, there was no significant difference between both groups in the postoperative pain at 12 (SMD ; CI [20.61 to 0.17]) and 24 hours (SMD ; CI [20.59 to 0.39]). Significant interstudy heterogeneity was found at all periods (024 hours; I 2 > 50%) (Table II and II-I). The postoperative swallowing pain at 2 (SMD ; CI [20.75 to 20.36]), 4 (SMD ; CI [21.33 to 20.54]), and 8 hours (SMD ; CI [23.84 to 20.96]) was statistically lower in the gabapentinoids group versus the control group. However, there was no significant difference between both groups in the postoperative pain at 12 (SMD ; CI [20.87 to 0.12]) and 24 hours (SMD ; CI [20.83 to 0.43]). Significant interstudy heterogeneity was found at all periods (024 hours; I 2 > 50%), except swallowing pain at 2 hours (Table III and III-I). The effect size and its CI provide information to assess the clinical usefulness of the treatment. The CI describes the uncertainty inherent in this estimate and describes a range of values within which the true effect actually lies. The relatively narrow CI means that the effect size is known precisely. By contrast, the wider CI could make the uncertainty greater, although there may still be enough precision to make decisions about the utility of the treatment. In this study, small enrolled studies and high heterogeneity (more than 60%) of the results obtained by all studies could cause the relatively wide CI of these SMDs. 15 Additionally, the overall analysis did not take into account the administration agent (gabapentin vs. pregabalin). This could be reflected in the high heterogeneity of the results. Consequently, subgroup analyses were indicated. Analysis of efficacy according to the administration agent in postoperative periods showed that this factor could not influence the analyzed outcomes (Table IV). Administration of Gabapentinoid Versus Control (Postoperative Analgesic Requirements and Time to First Analgesic Administration) The incidence of analgesic requirements (Log OR ; CI [21.90 to 20.93]) and the amount of analgesic requirements (SMD ; CI [21.40 to 359

4 TABLE II. Preoperative Gabapentinoid Versus Control in Postoperative Pain. Study Gabapentin total Control total Weight Effect size, 95% CI Standard Mean Difference of Resting Pain at 2 Hours (A) Amin (2011) % [21.38, 20.40] Yeganeh (2012) % [20.63, 0.38] Yeganeh (2012) % [21.26, 20.21] Amin (2014) % [20.53, 0.34] Amin (2014) % [ ] Fatthallah (2012) % [20.76, 0.49] Mathiesen (2011) % [20.78, 0.06] Mathiesen (2011) % [21.41, 20.51] Park (2015) % [22.27, 20.97] Jeon (2009) % [20.64, 0.39] Total (95% CI) % [20.83, 20.26] Heterogeneity: I %; Test for overall effect: Z (P ) Standard Mean Difference of Resting Pain at 4 Hours (B) Amin (2011) % [22.40, 21.28] Amin (2014) % [21.02, 20.13] Amin (2014) % [22.13, 21.12] Fatthallah (2012) % 0.00 [20.62, 0.62] Mathiesen (2011) % [ ] Mathiesen (2011) % [21.18, 20.31] Park (2015) % [21.29, 20.12] Jeon (2009) % [20.77, 0.27] Total (95% CI) % [21.21, 20.35] Heterogeneity: I %; Test for overall effect: Z (P ) Standard Mean Difference of Resting Pain at 8 Hours (C) Amin (2011) % [23.33, 22.03] Amin (2014) % [23.29, 22.08] Amin (2014) % [25.76, 24.01] Park (2015) % [21.29, 20.12] Jeon (2009) % [ ] Total (95% CI) % [23.83, 20.60] Heterogeneity: I %; Test for Overall Effect: Z (P ) Total: Number of participants per group; the resting pain at 2 (A), 4 (B), and 8 (C) hours from leaving operation room ]) during the postoperative period (024 hours) was significantly lower in the gabapentinoids group than in the control group. The time to first analgesic administration (SMD ; CI [0.26 to 2.48]) was significantly longer in the gabapentinoids group versus the control group. Significant interstudy heterogeneity was found in the amount of analgesic requirements and time to first analgesic administration in comparison with the control or opioids groups (I 2 > 50%) (Table V). Regarding the issue of heterogeneity in the included studies, Park s study 12 was a single outlying trial in the amounts of analgesic requirements during the postoperative period and Amin s study 10 was a single outlying trial in the time to first analgesic administration. The noticeable things were that the SMD of Park et al. and Amin et al. were much larger than those of the summed SMD in the amount of analgesic requirements (28.71 vs ) and the time to first analgesic administration (3.03 vs. 1.37), respectively. Excluding these studies in each meta-analysis caused the I 2 test to drop below 50%, but there was no significant change in the results. This possibly means that these studies were substantive sources of the overall observed heterogeneity. These results showed that gabapentinoids could reduce the postoperative analgesic requirements during the postoperative period (024 hours), despite partial heterogeneity. Administration of Gabapentinoid Versus Control (Adverse Effect) The incidence of postoperative nausea and vomiting (Log OR ; CI [20.87 to 20.10]) during the postoperative period (024 hours) was significantly lower in the gabapentinoids group than in the control group. The 360

5 TABLE II-I. Preoperative Gabapentinoid Versus Control in Postoperative Pain. Study Gabapentin total Control total Weight Effect Size, 95% CI Standard Mean Difference of Resting Pain at 12 hours (D) Amin (2011) % [20.83, 20.11] Yeganeh (2012) % 0.40 [20.12, 0.91] Yeganeh (2012) % 0.53 [0.02, 1.05] Amin (2014) % [20.91, 20.02] Amin (2014) % [21.45, 20.52] Park (2015) % [21.05, 0.10] Jeon (2009) % [20.67, 20.36] Total (95% CI) % [20.61, 0.17] Heterogeneity: I %; Test for Overall Effect: Z (P ) Standard Mean Difference of Resting Pain at 24 hours (E) Yeganeh (2012) % 0.49 [20.03, 1.00] Yeganeh (2012) % 0.74 [0.22, 1.27] Mathiesen (2011) % [20.82, 0.03] Mathiesen (2011) % [21.08, 20.21] Park (2015) % [21.37, 20.20] Jeon (2009) % 0.00 [20.52, 0.52] Total (95% CI) % [20.59, 0.39] Heterogeneity: I %; Test for Overall Effect: Z (P ) Total: Number of participants per group; the resting pain at 12 (D) and 24 Hours (E) from leaving operation room). degree of sedation during the postoperative period (024 hours; SMD ; CI [20.17 to 0.38]) was not significantly larger in the gabapentinoids group compared to the control group. The incidence of dizziness (Log OR ; CI [21.04 to 0.22]) and headache (Log OR ; CI [20.39 to 0.68]) showed no significant difference between the gabapentinoids group and the control group. Significant interstudy heterogeneity was not found on these measurements (I 2 < 50%) (Table VI). Therefore, these results showed that the selective studies were not biased and that gabapentinoids could not increase the postoperative adverse effect during the postoperative period (024 hours). Sensitivity Analyses Sensitivity analyses evaluated the differences in the pooled estimates by repeating the meta-analyses with a different study omitted each time. All results were consistent with the above outcomes. DISCUSSION Because posttonsillectomy pain is a universal complaint among patients and remains a considerable clinical problem, pain assessment and control after tonsillectomy must be included in the routine posttonsillectomy management of patients. 16 The visual analog scale (VAS) is a subjective pain assessment scale, which allows patients to mark a point along a scale that best represents their level of pain. It can be speculated that measuring VAS scores on movement such as swallowing would be more informative than measuring them only at rest. 17 Additionally, the frequency or the amount of analgesics used following tonsillectomy can be adopted as an objective criterion for the assessment of pain. 18,19 For the time period in the evaluation of gabapentinoid effect, most of the enrolled studies measured the treatment effect within postoperative 24 hours. However, the only small studies including small number of patients evaluated the long-term effects related to pain control (more than 24 hours), which were insufficient for metaanalysis and decreased the applicability of the related results. Therefore, this study used both approaches to assess the extent of postoperative pain during swallowing or resting in the first 24 hours after surgery. Gabapentin, via voltage-dependent calcium channels in the spinal cord and brain, may attenuate central sensitization and eventually decrease postoperative pain. Several reports have indicated that preoperative administration of gabapentin may play a role in the treatment of postoperative pain after different surgical procedures, such as abdominal and vaginal hysterectomy, breast surgery for cancer, lumbar discectomy and spinal fusion, laparoscopic cholecystectomy, and tonsillectomy. 16 In this study, we used a detailed time category to reflect the time-dependent change of the effect of gabapentinoid on postoperative pain. Although there have been a variety of clinical studies in a variety of settings (different timing and duration of drug administration, with dosages ranging from 300 mg to 1,800 mg per day), most trials regarding tonsillectomy performed a preoperative single administration of gabapentin for 361

6 TABLE III. Preoperative Gabapentinoid Versus Control in Postoperative Pain. Study Gabapentin total Control total Weight Effect Size, 95% CI Standard Mean Difference of Swallowing Pain at 2 hours (A) Amin (2011) % [21.38, 20.40] Yeganeh (2012) % [20.63, 0.38] Yeganeh (2012) % [21.26, 20.21] Amin (2014) % [20.53, 0.34] Amin (2014) % [ ] Fatthallah (2012) % [20.84, 0.40] Mathiesen (2011) % [21.08, 20.22] Mathiesen (2011) % [21.24, 20.36] Park (2015) % [21.62, 20.42] Jeon (2009) % [21.06, 0.00] Total (95% CI) % [20.75, 20.36] Heterogeneity: I %; Test for overall effect: Z (P < ) Standard Mean Difference of Swallowing Pain at 4 hours (B) Amin (2011) % [22.40, 21.28] Amin (2014) % [21.02, 20.13] Amin (2014) % [22.13, 21.12] Fatthallah (2012) % [20.82, 0.43] Mathiesen (2011) % [ ] Mathiesen (2011) % [21.24, 20.36] Park (2015) % [21.97, 20.71] Jeon (2009) % [21.02, 0.03] Total (95% CI) % [21.33, 20.54] Heterogeneity: I %; Test for overall effect: Z (P < ) Standard Mean Difference of Swallowing Pain at 8 hours (C) Amin (2011) % [23.33, 22.03] Amin (2014) % [23.29, 22.08] Amin (2014) % [25.76, 24.01] Park (2015) % [22.01, 20.75] Jeon (2009) % [21.02, 0.03] Total (95% CI) % [23.84, 20.96] Heterogeneity: I %; Test for overall effect: Z (P ) Total: Number of participants per group; the swallowing pain at 2 (A), 4 (B), and 8 hours (C) from leaving operation room. treating posttonsillectomy pain. Additionally, many studies have found that gabapentin in a single dose of 1,200 mg or less can prevent the potential risk of adverse effects. 20 Therefore, this study included studies with narrow inclusion criteria (preoperative oral or intravenous administration methods and single dosage from 300 mg to 1,200 mg). Our results showed that the postoperative pain (in resting and during swallowing) during the postoperative period (28 hours), as well as the frequency and amount of analgesics taken during the postoperative period (024 hours), were statistically decreased in the gabapentin group compared with the control group. Moreover, the time to first analgesic administration was significantly longer in the gabapentin group than in the control group. Moreover, the SMD for the measurements regarding pain and analgesics intake were mostly greater than 0.8, which meant that these effect sizes were clinically significant during the postoperative periods. 14 Gabapentin was reported to have a more beneficial effect on the evoked pain during movement than on the pain at rest in previous studies. 2,21 In this study, the effect sizes of pain during swallowing were larger than those of pain at rest, although a difference of two effect sizes was not significant. It could mean that the potency of decreasing movement-related pain following surgical procedures with gabapentin would be beneficial in tonsillectomy cases. However, the decreased beneficial effect of gabapentin on pain during the postoperative period (12 24 hours) could be explained by pharmacodynamics characteristic that the elimination half-life of gabapentin, when administered as monotherapy, is between approximately 5 and 8 hours. 20 Based on our results, preoperative administration of gabapentin after 362

7 TABLE III-I. Preoperative Gabapentinoid Versus Control in Postoperative Pain. Study Gabapentin total Control total Weight Effect Size, 95% CI Standard Mean Difference of Swallowing Pain at 12 hours (D) Amin (2011) % [20.83, 0.11] Yeganeh (2012) % 0.40 [20.21, 0.91] Yeganeh (2012) % 0.51 [0.02, 1.05] Amin (2014) % [20.91, 20.02] Amin (2014) % [21.45, 20.52] Park (2015) % [22.01, 20.75] Jeon (2009) % [20.92, 0.13] Total (95% CI) % [20.87, 0.12] Heterogeneity: I %; Test for overall effect: Z (P ) Standard Mean Difference of Swallowing Pain at 24 hours (E) Yeganeh (2012) % 0.49 [20.03, 1.00] Yeganeh (2012) % 0.74 [0.22, 1.27] Mathiesen (2011) % [20.60, 0.24] Mathiesen (2011) % [20.97, 20.11] Park (2015) % [22.22, 20.93] Jeon (2009) % [20.72, 0.32] Total (95% CI) % [20.83, 0.43] Heterogeneity: I %; Test for overall effect: Z (P ) Total: Number of participants per group; the swallowing pain at 12 Hours (D) and 24 hours (E) from leaving operation room. TABLE IV. Subgroup Analysis of the Effects of Administration Agent on the Postoperative Pain. Effect Size 2 hours 4 hours 8 hours 12 hours 24 hours Overall results (resting pain score) [20.83, 20.26] I % P Gabapentin (pain score) [20.62, 20.12] I % P Pregabalin (pain score) [21.64, 20.24] I % P Overall results (swallowing pain score) [20.75, 20.36] I % P < Gabapentin (pain score) [20.67, 20.20] I % P Pregabalin (pain score) [21.05, 20.51] I % P < [21.21, 20.35] I % P [21.57, 20.14] I % P [20.91, 20.37] I % P < [21.33, 20.54] I % P < [21.58, 20.31] I % P [21.18, 20.55] I % P < [23.83, 20.60] I % P [24.45, 20.72] I % P [21.29, 20.12] P [23.84, 20.96] I % P [24.40, 20.91] I % P [22.00, 20.74] P < [20.61, 0.17] I % P [20.63, 0.27] I % P [21.04, 0.10] P [20.87, 0.12] I % P [20.67, 0.23] I % P [22.00, 20.74] P < [20.59, 0.39] I % P [20.01, 0.83] I % P [20.84, 20.30] I % P < [20.07, 2.63] I % P [20.20, 0.89] I % P [21.51, 0.05] I % P

8 TABLE V. Preoperative Gabapentinoid Versus Control in Postoperative Pain Control. Study Gabapentin total Control total Weight Effect Size, 95% CI Standard Mean Difference of the Amounts of Analgesic Requirements (A) Amin (2011) % [21.24, 20.27] Yeganeh (2012) % [20.82, 0.20] Yeganeh (2012) % [22.31, 21.13] Amin (2014) % [21.22, 20.31] Amin (2014) % [21.60, 20.66] Mathiesen (2011) % [21.20, 20.34] Mathiesen (2011) % [21.18, 20.31] Park (2015) % [210.55, 26.88] Jeon (2009) % [21.40, 20.32] Total (95% CI) % [21.40, 20.10] Heterogeneity: I %; Test for overall effect: Z (P ) Standard Mean Difference of Time to First Analgesic Administration (B) Amin (2011) % 1.06 [0.56, 1.56] Amin (2014) % 1.06 [0.59, 1.53] Amin (2014) % 3.03 [2.38, 3.67] Fatthallah (2012) % 0.35 [20.27, 0.98] Total (95% CI) % 1.37 [0.26, 2.48] Heterogeneity: I %; Test for overall effect: Z (P ) Odds Ratio of the Incidence of Analgesic Requirements (C) Mathiesen (2011) % [22.32, 20.53] Mathiesen (2011) % [22.36, 20.56] Mohamed (2014) % [22.11, 20.62] Total (95% CI) % [21.90, 20.93] Heterogeneity: I %; Test for overall effect: Z (P < ) Total: Number of participants per group; the amounts of analgesic requirements (A), time to first analgesic administration (B), and the incidence of analgesic requirements (C). tonsillectomy had a large effect on both pain at rest and during swallowing; hence, it could reduce the analgesic requirements. Because of the emetic nature of tonsillectomy, postoperative nausea and vomiting can occur in up to 70% of patients and may contribute to dehydration or disruption of the surgical site if severe retching or vomiting occurs. 11,16 In this meta-analysis, there was a low incidence of postoperative nausea and vomiting in the gabapentinoids group in comparison to the control group. Although studies on safety issues regarding gabapentin have demonstrated adverse effects, such as nausea and vomiting, these studies were usually performed in patients with long-term gabapentin use. Many studies using only a single oral dose reported no significant adverse effects associated with gabapentin. 22 However, the administration of opioids has an additive effect on the incidence of nausea and vomiting. These facts could explain the positive effect of gabapentin on emesis because of effective pain control and reduced analgesic requirements, including opioids. Gabapentin is well tolerated and has few side effects and minor interactions with other drugs. In a few studies, gabapentin resulted in side effects related to the central nervous system, which includes increased dizziness, headache, and sedation. 22 In this meta-analysis, the incidence of dizziness and headache in the gabapentin group was low, and the degree of sedation, as well as incidences of adverse events, were similar to the control group. This is in accordance with data from previous studies in which single- and low-dose gabapentin was used during anesthesia. 20 These results could suggest that the effects of single- and low-dose gabapentin are relatively unimportant with respect to the adverse effects. Subgroup analyses (gabapentin and pregabalin) regarding pain scores were applied in order to decrease the heterogeneity and to identify factors influencing the results. Both gabapentin and pregabalin were effective in postoperative pain control. These results showed that preoperative gabapentin and pregabalin administration both reduced the incidence and severity of postoperative pain, as well as the need for analgesics in patients undergoing tonsillectomy. Despite the subgroup analyses, it was not possible to decrease the heterogeneity for gabapentin. These results would originate from the different dose of gabapentin, pain medications, and dosage of adjunctive medications. 364

9 TABLE VI. Preoperative Gabapentinoid Versus Control in the Adverse Effects. Study Gabapentin total Control total Weight Effect Size, 95% CI Standard Mean Difference of the Degree of Sedation (A) Fatthallah (2012) % 0.33 [20.30, 0.95] Mathiesen (2011) % 0.05 [0.59, 1.53] Mathiesen (2011) % 0.05 [0.59, 1.53] Total (95% CI) % 0.10 [20.17, 0.38] Heterogeneity: I %; Test for overall effect: Z (P ) Odds Ratio of the Incidence of Dizziness (B) Yeganeh (2012) % [21.43, 0.79] Yeganeh (2012) % [21.87, 0.48] Park (2015) % [22.27, 0.85] Jeon (2009) % 0.03 [21.29, 1.35] Total (95% CI) % [21.04, 0.22] Heterogeneity: I %; Test for overall effect: Z (P ) Odds Ratio of the Incidence of Headache (C) Yeganeh (2012) % 0.42 [20.62, 1.47] Yeganeh (2012) % 0.28 [20.76, 1.31] Park (2015) % [21.47, 0.85] Jeon (2009) % 0.10 [20.94, 1.14] Total (95% CI) % 0.14 [20.39, 0.68] Heterogeneity: I %; Test for overall effect: Z (P ) Odds Ratio of the Incidence of Postoperative Nausea and Vomiting (D) Amin (2011) % 0.47 [20.89, 1.83] Yeganeh (2012) % [21.43, 1.03] Yeganeh (2012) % [22.00, 0.32] Amin (2014) % [21.37, 1.32] Amin (2014) % [21.48, 1.37] Fatthallah (2012) % [23.23, 1.74] Mathiesen (2011) % [21.43, 0.55] Mathiesen (2011) % 2069 [21.74, 0.36] Mahmoud (2014) % [21.79, 20.32] Park (2015) % 2.53 [20.42, 5.47] Jeon (2009) % [24.55, 1.61] Total (95% CI) % [20.87, 20.10] Heterogeneity: I %; Test for overall effect: Z (P ) Total: Number of participants per group; the degree of sedation (A) and the incidence of dizziness (B), headache (C), and postoperative nausea and vomiting (D). In our study, only randomized controlled trials were also included for improving the quality of the underlying studies in the meta-analysis, despite several trials (case series or case-controlled trials) presenting the various results related to the effect of gabapentinoid. Although the results of this study offer evidence for the use of preoperative gabapentinoid at a single dose of 1,200 mg or less in ameliorating patient s morbidity, larger trials, duration of treatment, and standardized dosing represent some areas in which further study is needed. However, the short-term dosing, limited side effect risk, and lack of drug interactions make this an easy adjunctive pain control option with effectiveness in both movement-evoked pain and pain at rest, while decreasing opioid usage and possibly side effects related to their use. CONCLUSION This meta-analysis showed that the systemic administration of gabapentin before tonsillectomy could decrease posttonsillectomy pain efficiently without adverse effects. It can also decrease analgesic consumption and the time to the beginning of analgesic intake. However, the duration of the treatment and standardized dosing require further investigation, and larger trials need to be included. BIBLIOGRAPHY 1. Bameshki AR, Razban M, Khadivi E, Razavi M, Bakhshaee M. The effect of local injection of epinephrine and bupivacaine on post-tonsillectomy pain and bleeding. Iran J Otorhinolaryngol 2013;25: Mathiesen O, Jorgensen DG, Hilsted KL, et al. Pregabalin and dexamethasone improves post-operative pain treatment after tonsillectomy. Acta Anaesthesiol Scand 2011;55:

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