Effects of Ketamine on Postoperative Pain After Remifentanil-Based Anesthesia for Major and Minor Surgery in Adults: A Systematic Review and Meta-Analysis

SYSTEMATIC REVIEW published: 17 August 2018 doi: 10.3389/fphar.2018.00921 Frontiers in Pharmacology | www.frontiersin.org 1August 2018 | Volume 9 | Article 921 Edited by: Milica S. Prostran, University of Belgrade, Serbia Reviewed by: Robert L. Barkin, Rush University Medical Center, United States Dragana Srebro, University of Belgrade, Serbia *Correspondence: Jose A. Moral-Munoz [email protected] Specialty section: This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology Received: 17 April 2018 Accepted: 26 July 2018 Published: 17 August 2018 Citation: García-Henares JF, Moral-Munoz JA, Salazar A and Del Pozo E (2018) Effects of Ketamine on Postoperative Pain After Remifentanil-Based Anesthesia for Major and Minor Surgery in Adults: A Systematic Review and Meta-Analysis. Front. Pharmacol. 9:921. doi: 10.3389/fphar.2018.00921 Effects of Ketamine on Postoperative Pain After Remifentanil-Based Anesthesia for Major and Minor Surgery in Adults: A Systematic Review and Meta-Analysis Juan F. García-Henares1, Jose A. Moral-Munoz2,3*, Alejandro Salazar3,4,5 and Esperanza Del Pozo6 1Hospital Marina Salud, Dénia, Alicante, Spain, 2Department of Nursing and Physiotherapy, University of Cádiz, Cádiz, Spain, 3Institute of Research and Innovation in Biomedical Sciences of the Province of Cadiz (INiBICA), University of Cádiz, Cádiz, Spain, 4Preventive Medicine and Public Health Area, University of Cádiz, Cádiz, Spain, 5The Observatory of Pain (External Chair of Pain), University of Cádiz, Cádiz, Spain, 6Department of Pharmacology, Faculty of Medicine, Institute of Neurosciences, Biomedical Research Institute Granada, University of Granada, Granada, Spain Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been postulated as an adjuvant analgesic for preventing remifentanil-induced hyperalgesia after surgery. This systematic review and meta-analysis aims to assess the effectiveness of ketamine [racemic mixture and S-(+)-ketamine] in reducing morphine consumption and pain intensity scores after remifentanil-based general anesthesia. We performed a literature search of the PubMed, Web of Science, Scopus, Cochrane, and EMBASE databases in June 2017 and selected randomized controlled trials using predefined inclusion and exclusion criteria. To minimize confounding and heterogeneity, studies of NMDA receptor antagonists other than ketamine were excluded and the selected studies were grouped into those assessing minor or major surgery. Methodological quality was evaluated with the PEDro and JADA scales. The data were extracted and meta-analyses were performed where possible. Twelve RCTs involving 156 adults who underwent minor surgery and 413 adults who underwent major surgery were included in the meta-analysis. When used as an adjuvant to morphine, ketamine reduced postoperative morphine consumption in the first 24 h and postoperative pain intensity in the first 2 h in the minor and major surgery groups. It was also associated with significantly reduced pain intensity in the first 24 h in the minor surgery group. Time to the first rescue analgesia was longer in patients who received ketamine and underwent major surgery. No significant differences in the incidence of ketamine-related adverse effects were observed among patients in the intervention group and controls. This systematic review and meta-analysis show that low-dose (≤0.5 mg/kg for iv bolus or ≤5µg/kg/min for iv perfusion) of ketamine reduces postoperative morphine consumption and pain intensity without increasing the incidence of adverse effects. Keywords: remifentanil, ketamine, minor surgery, mayor surgery, NMDA antagonist, meta-analysis García-Henares et al. Ketamine on Postoperative Pain INTRODUCTION Management of chronic postsurgical pain remains a challenge for anesthesiologists and surgeons. Approximately 240 million surgical procedures are performed worldwide each year, and an estimated 12% of patients still report moderate to intense pain 1 year after surgery (Fletcher et al., 2015). Inadequately treated pain could be considered an adverse postoperative effect, as it can lead to longer hospital stays, higher costs, and lower patient satisfaction (Shipton, 2014). Acute postoperative pain is also a risk factor for the development of chronic postsurgical pain (Perkins and Kehlet, 2000), and the relationship appears to be directly proportional, with more intense or longer-lasting pain linked to a higher incidence of chronic pain (Mion and Villevieille, 2013; Pozek et al., 2016; Reddi, 2016). Remifentanil is a widely used general anesthesia thanks to its pharmacodynamic and pharmacokinetic properties (Kim et al., 2015). Its potency as an opioid agonist combined with a short elimination half-life without accumulating with prolonged infusion allows anesthesiologists to maintain hemodynamic stability during surgery without risk of delayed awakening. Intraoperative remifentanil infusion has, however, been associated with opioid-induced hyperalgesia (Joly et al., 2005; Fletcher and Martinez, 2014). The N-methyl-D-aspartate (NMDA) receptor is believed to play an important role in the pathophysiology of opioid-induced hyperalgesia (Mao et al., 1995; Mayer et al., 1999; Williams et al., 2001; Ossipov et al., 2005; Angst and Clark, 2006; Mao, 2006). Ketamine is a non-competitive NMDA receptor antagonist (Mion and Villevieille, 2013) authorized by the U.S. Food and Drug Administration as an anesthetic drug and it is used in multimodal analgesia regimens to improve postoperative pain control (Chou et al., 2016). The classic anesthetic effect of ketamine is described as a dose-dependent central nervous system (CNS) depression that leads to a dissociative state characterized by profound analgesia and amnesia but not necessarily loss of consciousness (Kohrs and Durieux, 1998). The use of low subanesthetic doses of ketamine (no more than 1 mg/kg iv bolus or 20 µg/kg/min continuous infusion) as an adjuvant to morphine in postoperative multimodal analgesia regimens (Schmid et al., 1999) is supported by several lines of evidence: (i) the mechanism of action of ketamine and the importance of the NMDA neurotransmission system in nociceptive processing (Bell et al., 2015); (ii) evidence that ketamine potentiates the analgesic effects of opioids, suggesting that it could reduce acute postoperative pain and minimize opioid consumption (Carstensen and Möller, 2010; Song et al., 2013); and (iii) the low toxicity of subanesthetic doses of ketamine (Michelet et al., 2007). In addition, recent studies have attributed additional antihyperalgesic, neuroprotective, antidepressant, and anti-inflammatory effects to ketamine based on its interaction with multiple other receptors, such as AMPA, kainate, gamma-aminobutyric acid (GABA), opiate, muscarinic, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels (Zanos et al., 2018). The isomer S(+)-ketamine (also named Esketamine) is reported to be twice as potent as the racemic mixture as an anesthetic (Zanos et al., 2018). Despite these seemingly “ideal” qualities of ketamine, however, contradictory results have been reported for the efficacy of ketamine in multimodal perioperative analgesia regimens. We wondered if there was clinical evidence supporting the use of perioperative ketamine to improve postoperative pain after remifentanil-based anesthesia in adults. To our knowledge, only two meta-analyses, each analyzing 14 randomized controls trials (RCTs), have been conducted (Liu et al., 2012; Wu et al., 2015) and they reported conflicting findings One of the analyses found no significant evidence that NMDA antagonists prevented remifentanil-associated hyperalgesia (Wu et al., 2015), while the other one showed that ketamine significantly reduced postoperative pain and cumulative morphine consumption (Wu et al., 2015). This benefit was also found in a meta-analysis of the addition of ketamine to morphine in patient-controlled analgesia devices (Assouline et al., 2016). The contradictory results could be partly due to the fact that the meta-analyses did not distinguish between different types of surgery. The aim of this systematic review and meta-analysis was to evaluate the influence of perioperative ketamine within a multimodal analgesia regimen in adults undergoing surgery, distinguishing between minor and major procedures and excluding studies of NMDA antagonists other than ketamine to minimize confounding and heterogeneity. MATERIALS AND METHODS We performed a systematic review of the literature in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Eligibility Criteria An initial database search was undertaken to identify RCTs examining the use of perioperative low-dose ketamine in remifentanil-based general anesthesia for major or minor surgery. Only studies that were performed in adults and used morphine as a postoperative analgesic were eligible for inclusion. RCTs reporting on postoperative cumulative morphine consumption, pain intensity, pain outcomes, and adverse opioid or ketamine effects were considered. TABLE 1 | Search strategies and results in each bibliographic database. Database Search Query Results PubMed ((“Remifentanil” [Supplementary Concept]) AND “Ketamine”[Mesh]) AND “Hyperalgesia”[Mesh] 19 Cochrane Remifentanil AND Ketamine AND Hyperalgesia Refined by: Document Types: Trials 36 Web of science TS=(Remifentanil AND Ketamine AND Hyperalgesia) Refined by: Databases: Core Collection AND Document Types: Clinical Trials 57 Scopus TITLE-ABS-KEY (Remifentanil AND Ketamine AND Hyperalgesia) Refined by: Document Types: Articles 58 Frontiers in Pharmacology | www.frontiersin.org 2August 2018 | Volume 9 | Article 921 García-Henares et al. Ketamine on Postoperative Pain TABLE 2 | Details of the selected studies. Author Year Sample size (K/control) Ketamine protocol Remifentanil infusion rate Procedure N20 Anesthesia maintenance Postoperative analgesia Aubrun et al. 2008 45/45 0.5 mg/kg iv before surgical incisión + 5 mg/ml postoperative PCA 0.5 µg/kg/min Gynecological surgery NO Propofol Morphine PCA Ganne et al. 2005 30/31 0.15 mg/kg iv + 2µg/kg/min 0.25 µg/kg/min ENT surgery NO Propofol Morphine PCA+ Paracetamol 1 g/6 h+ methylprednisolone 2 mg/kg/dia Guignard et al. 2002 25/25 0.15 mg/kg iv + 2µg/kg/min 0.25 µg/kg/min Open colorrectal surgery NO Desfluorane Morphine PCA Hadi et al. 2013 30/15 1 µg/kg/min (±1µg/kg/min postoperative) 0.2 µg/kg/min Lumbar microdiscectomy Yes Sevofluorane Morphine PCA Hadi et al. 2010 15/15 1 µg/kg/min 0.2 µg/kg/min Spinal fusion YES Sevofluorane Morphine Pump Jaksch et al. 2002 15/15 0.5 mg/kg iv + 2µg/kg/min 0.5 µg/kg/min Arthroscopic ACL repair NO Propofol Morphine PCA Joly et al. 2005 24/25 0.5 mg/kg iv +5µg/kg/min+ 2µg/kg/min postoperative infusion 0.4 µg/kg/min Abdominal surgery NO Desfluorane Morphine PCA Leal et al. 2015 28/28 5 µg/kg/min 0.4 µg/kg/min Laparoscopic cholecystectomy NO Isoflourane Morphine PCA Lee et al. 2014 20/20 0.3 mg/kg+ 3µg/kg/min 4 ng/ml Laparoscopic cholecystectomy NO Sevofluorane Morphine PCA Sahin et al. 2004 17/16 0.5 mg/kg iv 0.1 µg/kg/min Lumbar disk operation YES Desfluorane Morphine PCA Van Elstraete 2004 20/20 0.5 mg/kg iv + 2µg/kg/min 0.25 µg/kg/min Tonsillectomy NO Propofol Morphine i.v. Yalcin et al. 2012 30/30 0.5 mg/kg 0.4 µg/kg/min Total abdominal hysterectomy NO Desfluorane Morphine PCA Information Sources and Search A search of the PubMed, Web of Science, Scopus, and Cochrane databases was performed in June 2017. Only articles written in English or Spanish were included. The search queries used for each database are shown in Table 1. Study Selection Two reviewers (JFGH and JAMM) independently performed the search and assessed the suitability of the articles for inclusion. In the event of disagreement, the reviewers discussed the discrepancies and decided whether or not to include the article. If they were unable to reach an agreement, a third reviewer (AS) was involved. In a pre-selection phase, the abstracts of all the articles retrieved by the literature search were screened for eligibility. Potentially eligible studies were then assessed in depth by examining the full text prior to inclusion. Data Collection Process Relevant data from selected articles were extracted and recorded in a purpose-designed spreadsheet by a single author (JFGH) using a standardized procedure. The authors of one original article that met the inclusion criteria but had some missing information on means and standard deviation were contacted twice by e-mail, but they did not reply (Hong et al., 2011). The information extracted by JFGH was independently reviewed by two authors (JAMM and AS). Data Items The following data were extracted from each study: study design, study population, ketamine and remifentanil regimens, description of the intervention or control and experimental groups, type of surgical procedure, postoperative analgesia strategies, follow-up period, and outcome measures (Table 2). Primary endpoints were cumulative morphine consumption (mg) in the first 24 h and pain intensity at 0, 2, 4, 12, and 24 h. Pain intensity was statistically standardized on a 0–10 cm visual analog scale (VAS). Due to the small number and heterogeneous nature of the articles selected, there were only two secondary endpoints: time to the first rescue analgesia and presence of ketamine or opioid adverse effects. Patient satisfaction and psychotic adverse effects in minor surgery were excluded from the meta-analysis as we were unable to obtain the missing data from the authors. Frontiers in Pharmacology | www.frontiersin.org 3August 2018 | Volume 9 | Article 921 García-Henares et al. Ketamine on Postoperative Pain Risk of Bias The methodological quality of the RCTs was analyzed using the PEDro (Maher et al., 2003) and Jadad (Clark et al., 1999) scales. The PEDro scale is an 11-item scale that assesses (i) notification of selection criteria, (ii) allocation of subjects to groups at random, (iii) concealment of allocation, (iv) similarity among groups at baseline in relation to the most important prognostic indicators, (v) blinding of participants, (vi) blinding of researchers/therapists, (vii) blinding of researchers measuring at least one key outcome, (viii) proportion of initial participants that contribute measures to the key results, (ix) compliance of the intervention assigned by the participants, (x) presentation of statistical comparisons between the groups, and (xi) presentation of specific measures and variability of the key results. One point is assigned to each criterion, except for (i), which is not included in the final score. The total possible score thus ranges from 0 to 10. Scores of 9 to 10 indicate excellent quality, 6to 8 good quality, 4 to 5 fair quality, and <4 poor quality (Gordt et al., 2018). With the Jadad scale, studies receive a score of 0–5 points (with higher scores representing higher methodological quality) depending on whether they (i) are described as randomized or doubled blind, (ii) use an appropriate randomization sequence or blinding procedure, and (iii) provide detailed information on withdrawals and dropouts. As studies of low methodological quality may overestimate treatment benefits (Moher et al., 1998), we only included studies with a PEDro score of 6 or higher (Clark et al., 1999) and a Jadad score of 3 or higher (Kang et al., 2018; Annex 1 in Supplementary Material). Statistical Analysis The 12 RCTs were grouped into 16 subgroups according to effect size and type of surgery (major or minor) (Table 3). A study could belong to more than one group if it reported more than one effect size or it analyzed both major and minor surgery. Studies could also appear more than once in the same subgroup if they performed comparisons with different groups under the same conditions. The effect sizes considered were pain intensity measured on a 10-point VAS, where 0 indicated no pain and 10 indicated the worst possible pain; morphine consumption (mg); time to first rescue with analgesia (minutes); incidence of postoperative nausea and vomiting (PONV); and incidence of ketamine-related adverse events. All the RCTs compared the administration of ketamine and morphine (intervention group) vs. morphine only (control group). A meta-analysis was carried out in each subgroup to compare the effect size between the intervention and control group. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) were used for continuous variables (VAS, morphine consumption, and time to first rescue analgesia), while relative risk (RR) and 95% CIs were used for the incidence of PONV and psychotic events (anxiety, visual disturbances, impairment of cognitive functioning or florid psychotics symptoms like delirium or hallucinations). The significance level was set at p<0.05. Heterogeneity was determined using the Dersimonian and Laird test and the Cochran Q statistic. A fixed-effects model was used for studies with homogeneity and a random-effects model was used when there was significant heterogeneity. The latter accounts for variability due to differences between studies. The results of the meta-analyses are shown in forest plots. The plots show the differences between the intervention and control groups for mean values, and RRs, showing overall measures, together with the corresponding confidence intervals. Publication bias was analyzed (only in subgroups with three or more studies) using the Begg test (Z statistic) and the Egger test (t statistic). Finally, a sensitivity analysis was carried out to study the contribution of each study to the overall effect estimate. The analyses were carried out using the statistical software program EPIDAT 3.1. (Table 3). RESULTS Study Selection The preliminary search identified 170 articles including 15 RCTs potentially responding to the inclusion criteria (Figure 1). Two of the RCTs were excluded because morphine was not used for postoperative analgesia (Launo et al., 2004; Choi et al., 2015) and one was excluded because the manuscript was written in Chinese (Launo et al., 2004). Twelve RCTs involving 569 adults were therefore included in the systematic review. The effects of ketamine and remifentanil-induced hyperalgesia have been analyzed in two relatively recent meta-analyses: one by Liu et al. (2012) in 2012 and another by Wu et al. (2015) in 2015. Compared with Liu et al. (2012), we studied five additional RCTs and excluded seven (Liu et al., 2012), while compared with Wu et al. (2015), we studied four additional RCTs and excluded six (Wu et al., 2015). The studies were excluded because they included children, NMDA receptor antagonists other than ketamine (magnesium sulfate and amantadine), or postoperative opioids other than morphine. Study Characteristics The 12 RCTs were published between 2002 and 2015 (Table 2) and had been conducted in six countries: France (Moher et al., 1998; Clark et al., 1999; Maher et al., 2003; Launo et al., 2004; Ganne et al., 2005; Joly et al., 2005; Yu et al., 2005; Choi et al., 2015; Gordt et al., 2018; Kang et al., 2018), Austria (Jaksch et al., 2002), Jordan (Hadi et al., 2010, 2013), Brazil (Leal et al., 2015), Korea (Lee et al., 2014), and Turkey (Sahin et al., 2004; Yalcin et al., 2012). Nine RCTs involving 413 patients were assigned to the major surgery group while three involving 156 patients were assigned to the minor surgery group. Although all 12 RCTs used morphine to control postoperative pain, the administration regimens varied. Eight studies administered morphine via a patient-controlled analgesia system (Schmid et al., 1999; Jaksch et al., 2002; Sahin et al., 2004; Joly et al., 2005; Hadi et al., 2010, 2013; Kim et al., 2014; Lee et al., 2014; Roeckel et al., 2016; one of these also used paracetamol, Ganne et al., 2005) and two did not specify the type of pump (Reddi, 2016) or infusion system used (Van Elstraete et al., 2004). Frontiers in Pharmacology | www.frontiersin.org 4August 2018 | Volume 9 | Article 921 García-Henares et al. Ketamine on Postoperative Pain TABLE 3 | Characteristics of subgroups included in the meta-analysis. Subgroup Trials included Effect size Heterogeneity test Model Publication bias* 1Van Elstraete et al.,−30 min 2004 Leal et al.,−30 min 2015 Van Elstraete et al.,−1 h 2004 Leal et al.,−1 h 2015 Van Elstraete et al.,−2 h 2004 Leal et al.,−2 h 2015 VAS 0–2 h Minor surgery Heterogeneity Q=225.2737; df =5; p<0.001 Random effects No bias Z=1.5029; p=0.1329 T= −1.3473; p=0.2492 2Assouline et al.,−1 h (2002) Jaksch et al.,−2 h (2002) Aubrun et al., 0–30 min (2008) VAS 0–2 h Major surgery Homgeneity Q=1.1184; df =2; p=0.5717 Fixed effects No bias Z<0.001; p>0.999 T=1.2596; p=0.4272 3Van Elstraete et al., 2004 Leal et al., 2015 VAS4 h Minor surgery Heterogeneity Q=14.7884; df =1; p=0.001 Random effects – 4Joly et al., 2005 Ganne et al., 2005 Aubrun et al., 2008 VAS 4 h Major surgery Heterogeneity Q=21.5624; df =2; p<0.001 Random effects No bias Z<0.001; p>0.999 T= −0.6603; p=0.6285 5Van Elstraete, 2004 Hadi et al., 2013 Hadi et al., 2013 Leal et al., 2015 VAS 12 h Minor surgery Heterogeneity Q=104.3763; df =3; p<0.001 Random effects Bias Z=1.6984; p=0.0894 T= −7.5979; p=0.0169 6Joly et al., 2005 Ganne et al., 2005 Aubrun et al., 2008 VAS 12 h Major surgery Heterogeneity Q=81.4968; df =2; p<0.001 Random effects No bias Z=1.0445; p=0.2963 T=2.0911; p=0.2840 7Van Elstraete, 2004 Hadi et al., 2013 Hadi et al., 2013 Leal et al., 2015 VAS 24 h Minor surgery Heterogeneity Q=197.5201; df =3; p<0.001 Random effects No bias Z=1.6984; p=0.0894 T= −2.1538; p=0.1641 8Joly et al., 2005 Ganne et al., 2005 Aubrun et al., 2008 VAS 24 h Major surgery Heterogeneity Q=71.2937; df =2; p<0.001 Random effects No bias Z=1.0445; p=0.2963 T=3.5866; p=0.1731 9Van Elstraete, 2004 Hadi et al., 2013 Hadi et al., 2013 Leal et al., 2015 Morphine consumption minor surgery Heterogeneity Q=118.7848; df =3; p<0.001 Random effects Bias Z=1.6984; p=0.0894 T= −16.5343; p=0.0036 10 Sahin et al., 2004 Ganne et al., 2005 Aubrun et al., 2008 Hadi et al., 2010 Guignard et al., 2002 Yalcin et al., 2012 Morphine consumption major surgery Heterogeneity Q=326.9692; df =5; p<0.001 Random effects Bias Z=1.5029; p=0.1329 T= −5.3088; p=0.0061 11 Van Elstraete, 2004 Hadi et al., 2013 Hadi et al., 2013 Time to first rescue analgesia Minor surgery Heterogeneity Q=105.1229; df =2; p<0.001 Random effects Bias Z=1.0445; p=0.2963 T=419.7603; p=0.0015 12 Jaksch et al., 2002 Guignard et al., 2002 Sahin et al., 2004 Joly et al., 2005 Time to first rescue analgesia Major surgery Heterogeneity Q=225.8723; df =3; p<0.001 Random effects No bias Z=0.3397; p=0.7341 T=3.6662; p=0.0670 13 Van Elstraete, 2004 Hadi et al., 2013 Hadi et al., 2013 Leal et al., 2015 PONV Minor surgery Heterogeneity Q=3.9975; df =3; p=0.2617 Random effects No bias Z= −0.3397; p=0.7341 T= −0.2830; p=0.8038 (Continued) Frontiers in Pharmacology | www.frontiersin.org 5August 2018 | Volume 9 | Article 921 García-Henares et al. Ketamine on Postoperative Pain TABLE 3 | Continued Subgroup Trials included Effect size Heterogeneity test Model Publication bias* 14 Guignard et al., 2002 Jaksch et al., 2002 Joly et al., 2005 Ganne et al., 2005 Aubrun et al., 2008 PONV Major surgery Homogeneity Q=1.7537; df =4; p=0.7809 Fixed effects No bias Z=0.7348; p=0.4624 T=1.0131; p=0.3856 15** Van Elstraete, 2004 Hadi et al., 2013 Hadi et al., 2013 Leal et al., 2015 Psychotic events minor surgery – – – 16 Jaksch et al., 2002 Aubrun et al., 2008 Psychotic events major surgery Homogeneity Q=0.1108; df =1; p=0.7393 Fixed effects – *Results not shown for subgroups with only two studies. PONV, postoperative nausea and vomiting; VAS, visual analog scale. **Results not shown for subgroup 15, which was not included in the meta-analysis. FIGURE 1 | Flow diagram of the different phases of the systematic review. Synthesis of Results We were unable to assess the incidence of psychotic events in minor surgery (subgroup 15) by meta-analysis because only one of the studies yielded a result other than 0. The characteristics of the 16 subgroups are shown in Table 3, together with the results of the heterogeneity and publication bias tests. Subgroups 2, 14, and 16 were homogeneous and the rest were heterogeneous. Risk of publication bias was detected in subgroups 5, 9, 10, and 11, and their results should, therefore, be interpreted with caution. The results of the meta-analysis are summarized in Table 4. Frontiers in Pharmacology | www.frontiersin.org 6August 2018 | Volume 9 | Article 921 García-Henares et al. Ketamine on Postoperative Pain TABLE 4 | Meta-analysis results. Subgroup Results Forest plot Study nMean difference (95% CI) Weight (%) VAS 0–2 h Minor surgery Van Elstraete, −30 min (2004) 40 −7.83 (−9.65; −6.0027) 16.7362 Van Elstraete, −1 h (2004) 40 −23.5538 (−28.752218.3553) 9.3902 Van Elstraete, −2 h (2004) 40 3.6858 (2.667; 4.7038) 18.1041 Leal, −2 h (2015) 56 0.5411 (0.0078; 1.0744) 18.6037 Leal, −30 min (2015) 56 −1.2014 (−1.7706; 0.6323) 18.5768 Leal, −1 h (2015) 56 −0.9581 (−1.5112; −0.4051) 18.5890 Random effects 288 −3.1549 (−5.4066; −0.9033) VAS 0–2 h Major surgery Jaksch, −1 h (2002) 30 −0.4071 (−1.1302; 0.3159) 21.0181 Jaksch, −2 h (2002) 30 −0.7381 (−1.4778; 0.0015) 20.0857 Aubrun, 0–30 min (2008) 90 −0.8615 (−1.2935; 0.4296) 58.8962 Fixed effects 150 −0.7412(−1.0727; −0.4098) VAS 4 h Minor surgery Van Elstraete, 2004 40 −2.1788 (−2.9612; 1.3964) 31.8379 Leal et al., 2015 56 −0.3301 (−0.8575; 0.1973) 34.5329 Random effects 96 −1.2309 (−3.0421; 0.5802) VAS 4 h Mayor surgery Joly et al., 2005 49 −1.7351 (−2.3922; 1.0781) 31.7254 Ganne et al., 2005 61 0.2193 (−0.2841; 0.7228) 33.6892 Aubrun et al., 2008 90 −0.6174 (−1.0403; 0.1945) 34.5854 Random effects 200 −0.6901 (−1.6751; 0.2948) (Continued) Frontiers in Pharmacology | www.frontiersin.org 7August 2018 | Volume 9 | Article 921 García-Henares et al. Ketamine on Postoperative Pain TABLE 4 | Continued Subgroup Results Forest plot Study nMean difference (95% CI) Weight (%) VAS 12 h Minor surgery Van Elstraete, 2004 40 −0.6143 (−1.2485; 0.0199) 27.2404 Hadi et al., 2013 30 −12.7851 (−16.0984; −9.4719) 19.7066 Hadi et al., 2013 30 −4.9236 (−6.3604; −3.4869) 25.6965 Leal et al., 2015 56 0.5562 (0.0224; 1.0901) 27.3564 Random effects 156 −3.7999 (−6.5450; −1.0548) VAS 12 h Major surgery Joly et al., 2005 49 2.3720 (1.6410; 3.1029) 32.8124 Ganne et al., 2005 61 0.5523 (0.0408; 1.0637) 33.5299 Aubrun et al., 2008 90 −1.4282 (−1.8910; −0.9653) 33.6576 Random effects 200 0.4828 (−1.5621; 2.5276) VAS 24 h Minor surgery Van Elstraete, 2004 40 −2.6816 (−3.5357; −1.8275) 26.1858 Hadi et al., 2013 30 −15.8746 (−19.9546; −11.7946) 22.5099 Hadi et al., 2013 30 −8.4976 (−10.7637–6.2315) 25.9533 Leal et al., 2015 56 2.4906 (1.7926; 3.1886) 26.2510 Random effects 156 −5.7507 (−10.8028; −0.6986) VAS 24 h Major surgery Joly et al., 2005 49 2.5823 (1.8239; 3.3407) 32.6371 Ganne et al., 2005 60 0.4164 (−0.0951; 0.9279) 33.5812 Aubrun et al., 2008 90 −1.1166 (−1.5609; −0.6724) 33.7817 Random effects 199 0.6054 (−1.3021; 2.5130) (Continued) Frontiers in Pharmacology | www.frontiersin.org 8August 2018 | Volume 9 | Article 921 García-Henares et al. Ketamine on Postoperative Pain TABLE 4 | Continued Subgroup Results Forest plot Study nMean difference (95% CI) Weight (%) Morphine consumption minor surgery Van Elstraete, 2004 40 −1.0657 (−1.7280; −0.4033) 35.1136 Hadi et al., 2013 30 −19.3089 (−24.2468; −14.3710) 22.1079 Hadi et al., 2013 30 −48.2743 (−60.5101; −36.0385) 7.5228 Leal et al., 2015 56 −0.1003 (−0.6244; 0.4239) 35.2556 Random effects 156 −8.3099 (−12.0904; −4.5295) Morphine consumption major surgery Sahin et al., 2004 33 1.0361 (0.3091; 1.7631) 17.3244 Ganne et al., 2005 61 0.6916 (0.1748; 1.2083) 17.4153 Aubrun et al., 2008 90 2.6299 (2.0657; 3.1942) 17.3974 Hadi et al., 2010 30 −7.3485 (−9.3408; 5.3561) 16.2113 Guignard et al., 2002 50 −12.5382 (−15.0574; −10.0190) 15.5224 Yalcin et al., 2012 53 −10.4428 (−12.5024; −8.3831) 16.1292 Random effects 317 −4.0644 (−7.0110; −1.1178) Time to first rescue analgesia minor surgery Van Elstraete, 2004 40 0.3305 (−0.2935; 0.9545) 34.1311 Hadi et al., 2013 30 14.6007 (10.8376; 18.3638) 32.9752 Hadi et al., 2013 30 15.1306 (11.2358; 19.0254) 32.8937 Random effects 100 9.9044 (−1.6756; 214845) Time to first rescue analgesia mayor surgery Jaksch et al., 2002 30 −1.2545 (−2.0374; −0.4716) 25.8794 Guignard et al., 2002 50 8.85487.0329; 10.6767 25.3153 Sahin et al., 2004 33 −2.6495 (−3.5847; −1.7143) 25.823 Joly et al., 2005 49 19.9587 (15.9676; 23.9497) 22.9816 Random effects 162 5.8196 (0.2130; 11.4261) (Continued) Frontiers in Pharmacology | www.frontiersin.org 9August 2018 | Volume 9 | Article 921