Anesthetic therapy for acute pain relief after laparoscopic cholecystectomy: systematic review

1 Federal University of Rio de Janeiro, Department of Surgery, Anesthesiology Service, Rio de Janeiro, RJ, Brazil. 2 State University of Rio de Janeiro, Department of General Surgery, Anesthesiology Service, Center for Teaching and Training in Pain, Rio de Janeiro, RJ, Brazil. Jesus Anesthetic therapy for acute pain relief after laparoscopic cholecystectomy: systematic review. 2 Rev Col Bras Cir 45(4):e1885 reviewer, following the steps for the design of a systematic review6. For the search of the scientific productions, we used the following combination of “Descritores em Ciências da Saúde” (DeCS) and Medical Subject Headings (MeSH) terms, in English, Portuguese and Spanish: “postoperative pain” (“dor pós-operatória”, “dolor postoperatorio”) AND “laparoscopic cholecystectomy” (“colecistectomia laparoscópica”, “colecistectomía laparoscópica”) AND analgesia. The inclusion criteria were papers indexed in the Medical Literature Analysis and Retrieval System Online (Medline), Scopus, Web of Science and Latin American and Caribbean Literature in Health Sciences (LILACS) databases, in the 2012 to 2016 five-year interval, published in Portuguese, English or Spanish, resulting from randomized controlled studies. In addition, we chose studies with adults/elders between 18 and 65 years of age, non-pregnant, submitted to elective laparoscopic cholecystectomy. We excluded works on surgical considerations (instillation of local anesthetics, amount of infused carbon dioxide, etc.), open cholecystectomy, literature reviews, and case reports. There were 800 articles, 136 in Medline, 306 in Scopus, 349 in Web of Science and nine in LILACS. We performed the search in unpublished, in progress and gray literature data sources through a research in the Clinical Trials website and in the Brazilian Registry of Clinical Trials. We used the terms "postoperative pain" AND "laparoscopic cholecystectomy" and "analgesia", with 46 articles found in Clinical Trials and none in the Brazilian Registry of Clinical Trials. After the search, we sent all references to EndNote® online for organization of study and deletion of duplicates. There were 846 articles, of which 173 were duplicates, remaining 673 in the first selection. We then read the title and Abstract, prioritizing the sensitivity in detriment of the specificity in order to make a selection of these references6. This was done by a pair of reviewers, independently. The article was considered when at least one of the reviewers judged it as eligible. This process resulted in 145 articles that could be submitted to a complete reading. If there was disagreement between the reviewers, these were resolved either by consensus between the reviewers or by consulting a third reviewer. There were 109 rejected articles and 36 were accepted to compose the definitive set (Figure 1). All articles that met the eligibility criteria for the systematic review had their methodological quality evaluated individually, minimizing biases and maximizing internal and external validity6. To that end, we assessed adequate randomization (allocation sequence generation), guaranteed allocation, blinding scheme (participants, team involved in conducting the study, outcome assessors), intention-to-treat analysis, loss of followup, as well as other sources of bias, such as early termination of the study due to benefit. Figure 1. Flowchart illustrating the article search strategy. Jesus Anesthetic therapy for acute pain relief after laparoscopic cholecystectomy: systematic review. 3 Rev Col Bras Cir 45(4):e1885 We organized the articles1-3,7-38 included in this systematic review and described in table 1. Through the convergence of the findings that answered the question of the study, we grouped the evidence according to the available therapeutic strategies for the control of acute pain after elective LC with the necessary comments to the discussion. RESULTS AND DISCUSSION In total, we identified 36 controlled and randomized clinical trials, including 2526 patients (Table 1). NSAIDs/COX-2 inhibitors Many studies have been done evaluating the risk-benefit of several NSAIDs/COX-2 inhibitors. The majority of the studies reviewed showed a reduction in the acute pain scores and the need for opioids in the postoperative period of LC, with adverse effects not found and/or not analyzed. There is no substantial superiority between the NSAIDs/COX-2 inhibitors available, and it is up to the anesthesiologist to decide which medication to use, according to the options available. However, their use is recommended as a key element within a Table 1. Interventions, evaluation of acute pain, need for postoperative opioid and adverse effects in the included studies. First author/year Number of patients/groups Intervention Effects Adverse effects Acute Pain Need for opioids NSAIDs/COX inhibitor Anil et al., 20161 60/2 Dexketoprofen trometamol (vs. diclofenac) ǂ § ǂ Fleckenstein et al., 20157 103/2 Etoricoxib (vs. placebo) ǂ ǂ ǂ Shuying et al., 20148 120/3 Parecoxib before anesthetic induction (vs. parecoxib after gallbladder removal or vs. placebo) + § ǂ Gautam et al., 20149 120/4 Etoricoxib with methylprednisolone/etoricoxib/ methylprednisolone (vs. placebo) + + ǂ Kouroukli et al., 201310 180/3 Lornoxicam/parecoxib (vs. placebo) + ǂ drugs/ § vs. placebo ǂ Gousheh et al., 201311 30/2 Paracetamol (vs. placebo) + ǂ Ureña-Frausto et al., 201312 56/4 Ketoprofen and tramadol (vs. ketorolac) + § ǂ Ekmekci et al., 201213 40/2 Tramadol and dexketoprofen (vs. tramadol) + § ǂ NMDA receptor antagonist Ozhan et al., 201514 60/2 Ketamine (vs. placebo) ǂ § + Yadav et al., 201515 66/2 Flupirtine (vs. placebo) + ǂ + Kocman et al., 201316 60/3 Magnesium sulfate (vs. placebo) + ǂ ǂ Leal et al., 201317 40/2 Ketamine (vs. placebo) ǂ ǂ ǂ Karcioglu et al., 201318 40/2 Ketamine (vs. placebo) + § + Jesus Anesthetic therapy for acute pain relief after laparoscopic cholecystectomy: systematic review. 4 Rev Col Bras Cir 45(4):e1885 First author/year Number of patients/groups Intervention Effects Adverse effects Acute Pain Need for opioids Singh et al., 201319 80/4 Ketamine (vs. placebo) + § + Nesek-Adam et al., 201220 80/2 Ketamine and diclofenac (vs. placebo) + ǂ ǂ Olgun et al., 201221 60/2 Magnesium sulfate (vs. placebo) + § + Gabapentin/Pregabalin Gurunathan et al., 201522 100/4 Pregabalin/celecoxib/pregabalin and celecoxib (vs. placebo) ǂ ǂ + Bekawi et al., 201423 90/3 Pregabalin (vs. Gabapentin or vs. placebo) + § + Sarakatsianou et al., 201324 50/3 Pregabalin (vs. placebo) + § + Balaban et al., 201225 90/3 Pregabalin (vs. diclofenac) + § + Miscellaneous Bakan et al., 20152 80/2 Dexmedetomidine and lidocaine (vs. remifentanyl) + ǂ + Dereli et al., 201526 60/4 Esmolol (vs. placebo) + § + Delfino et al., 201527 50/2 Phenylephrine (vs. placebo) ǂ § ǂ Akelma et al., 201428 48/3 Esmolol/ lidocaine (vs. remifentanyl) + § ǂ Ortiz et al., 20143 80/4 Propofol (vs. isoflurane, vs. desflurane and vs. sevoflurane) ǂ ǂ Lee et al., 201329 90/3 Nefopam and fentanyl (vs. fentanyl) + ǂ Park et al., 201230 42/2 Dexmedetomidine (vs. placebo) + ǂ Lopez-Alvarez et al., 201231 60/2 Esmolol (vs. ketamine and remifentanyl) + § ǂ Peripheral blockades Elamin et al., 201532 80/2 TAP block (vs. no blockade) + ǂ ǂ Basaran, 201533 76/2 TAP block (vs. no blockade) + § ǂ Pandey et al., 201534 60/2 Epidural blockade with levobupivacaine and clonidine (vs. ropivacaine and clonidine) + ǂ + Bathia et al., 201435 60/3 Subcostal TAP block (vs. posterior TAP block) + § ǂ Petersen et al., 201236 80/2 TAP block with ropivacaine (vs. placebo TAP block) + § ǂ Opioids Choi et al., 201537 54/2 Oxycodone (vs. fentanyl) + ǂ ǂ Hwang et al., 201438 81/2 Oxycodone (vs. fentanyl) + ǂ + Legends: Not investigated; + Significant effect in the treated group; ǂ Non-significant effect in the treated group; § Opioid reduction in the postoperative period. Studies of degree of recommendation A level of evidence 1B. Jesus Anesthetic therapy for acute pain relief after laparoscopic cholecystectomy: systematic review. 5 Rev Col Bras Cir 45(4):e1885 multimodal therapy, mainly because of its analgesic benefits and the rarity and low importance of its adverse effects. Some options are presented in the text and serve as a scientific basis for conduct. Intravenous (IV) parecoxib 40mg used 30-45 minutes prior to anesthetic induction was associated with less postoperative pain and opioid consumption when compared with its administration after gallbladder removal or with placebo8. The use of oral (VO) lornoxicam 8mg showed analgesic efficacy similar to parecoxib 40mg IV and better than placebo when given in three doses (30 minutes before surgery and 12 and 24 hours after). The need for opioids in the postoperative period was similar between lornoxicam and parecoxib10. The administration of methylprednisolone 125mg IV and etoricoxib 120mg VO one hour before surgery was more effective in reducing the consumption of opioids, without a higher incidence of adverse effects. However, only the associated use showed better postoperative pain scores9. The use of etoricoxib 120mg VO on the morning of surgery and for three days after surgery did not show superiority to placebo in reducing the cumulative dose of opioid after LC or in perioperative pain scores7. Ketorolac 1mg/kg IV on induction bolus showed worse scores of acute pain and greater need for rescue opioids compared with groups in which drugs were given 60 minutes before surgery in continuous infusion. These groups were ketoprofen 100mg IV followed by 2mg/kg/24h; ketoprofen 50mg IV associated with tramadol 50mg IV, followed by 1mg/kg/24h and 0.1mg/kg/h, respectively, in addition to one group using twice the dose of attack and maintenance of the previous group. The latter group receiving ketoprofen 100mg IV associated with tramadol 100mg IV with maintenance of 2mg/ kg/24h and 0.2mg/kg/h, respectively, needed less opioids in the postoperative period in relation to the other groups12. 


INTRODUCTION
T he inadequate treatment of postoperative pain in laparoscopic cholecystectomy (LC) can lead to negative consequences, such as late mobilization, with consequent delay in discharge, development of chronic pain and increased treatment costs 1 .
In recent years, multimodal analgesia has been recommended to combine additive and synergistic effects of different analgesics, with less adverse effects and more effective analgesia [1][2][3] . Systematic  4 . The other study recommended a single preoperative dose of dexamethasone, local anesthetics in the incisions (at the beginning or at the end of the surgery, depending on the anesthesiologist's preference), and continued treatment with non-steroidal antiinflammatory drugs (NSAIDs)/COX-2 during the first three to four days, reserving the opioids for when other analgesic techniques fail 5 .
The objective was to identify the best therapeutic strategy available to the anesthesiologist for treatment of acute postoperative pain of patients submitted to elective laparoscopic cholecystectomy. reviewer, following the steps for the design of a systematic review 6 . For the search of the scientific productions, we used the following combination of "Descritores em Ciências da Saúde" (DeCS) and Medical Subject Headings (MeSH) terms, in English, Portuguese and Spanish: "postoperative pain" ("dor pós-operatória", "dolor postoperatorio") AND There were 846 articles, of which 173 were duplicates, remaining 673 in the first selection. We then read the title and Abstract, prioritizing the sensitivity in detriment of the specificity in order to make a selection of these references 6 . This was done by a pair of reviewers, independently. The article was considered when at least one of the reviewers judged it as eligible. This process resulted in 145 articles that could be submitted to a complete reading. If there was disagreement between the reviewers, these were resolved either by consensus between the reviewers or by consulting a third reviewer.
There were 109 rejected articles and 36 were accepted to compose the definitive set ( Figure 1). All articles that met the eligibility criteria for the systematic review had their methodological quality evaluated individually, minimizing biases and maximizing internal and external validity 6 . To that end, we assessed adequate randomization (allocation sequence generation), guaranteed allocation, blinding scheme (participants, team involved in conducting the study, outcome assessors), intention-to-treat analysis, loss of followup, as well as other sources of bias, such as early termination of the study due to benefit. We organized the articles 1-3,7-38 included in this systematic review and described in

RESULTS AND DISCUSSION
In total, we identified 36 controlled and randomized clinical trials, including 2526 patients (Table 1).

NSAIDs/COX-2 inhibitors
Many studies have been done evaluating the risk-benefit of several NSAIDs/COX-2 inhibitors.
The majority of the studies reviewed showed a reduction in the acute pain scores and the need for opioids in the postoperative period of LC, with adverse effects not found and/or not analyzed.
There is no substantial superiority between the NSAIDs/COX-2 inhibitors available, and it is up to the anesthesiologist to decide which medication to use, according to the options available. However, their use is recommended as a key element within a  There was no difference in postoperative adverse effects and opioid consumption 16 .
The use of flupirtine 200mg VO two hours before surgery was superior to placebo for acute postoperative pain, but there was no difference in opioid consumption. Nonetheless, there was a higher incidence of sedation in the group studied 15 .

Gabapentin/Pregabalin
In general, the use of gabapentin/ pregabalin in patients undergoing LC also showed lower scores of acute pain and need for opioid in the postoperative period, but several studies have shown adverse effects that may limit their use, such as sedation, delayed extubation and dizziness.
Administration of pregabalin 150mg or 300 mg VO an hour before surgery decreased pain intensity and opioid consumption after LC compared with placebo. There was a higher degree of sedation on the Ramsay scale in the 300mg pregabalin group 25 .
This dose, on the night before surgery and one hour before surgery, when compared with placebo, also obtained these positive analgesic results, albeit associated with delayed extubation time, as well as with increased incidence of post-operative dizziness 24 .
The isolated use of pregabalin 150mg VO or in combination with celecoxib 400mg one hour before surgery did not provide lower pain scores or need for opioid when compared with placebo.
The pregabalin group presented more dizziness and somnolence 22 . The use of gabapentin 1200mg VO two hours before surgery, followed by the same dose 12 hours postoperatively and every eight hours for two days, and pregabalin 150mg VO in the same administration scheme, reduced the need for opioids in patients undergoing LC when compared with placebo. The pregabalin group showed lower pain scores when compared with the other groups.
Non-placebo interventions resulted in a greater degree of dizziness and drowsiness 23 .

Miscellaneous
Interventions that could not be amassed in the previous groups were considered miscellaneous. Regarding its use by patient-controlled analgesia, oxycodone 1mg IV per bolus showed similar effects for pain relief compared with fentanyl 10mcg IV, but showed a higher incidence of postoperative nausea and vomiting 38 .
Despite the viability of the various strategies for acute pain relief in patients undergoing LC, some studies have not investigated the adverse effects of interventions, only efficacy in postoperative analgesia and the need for opioids. This can be explained by the rarity of their occurrences, difficulty in evaluation, or because they were not the objective of these studies 4 .
The heterogeneity of the review studies may have led to weaknesses in the discussion. Nevertheless, this systematic review of the literature has contributed to teaching and professional practice with the theoretical enrichment of the analgesic tools available for LC therapy, as well as to alert the team to consider the adverse effects of the implemented interventions. Our study did not consider surgical strategies in the treatment of acute pain relief of patients undergoing LC, but these should be valued in the search for a better analgesic strategy.

CONCLUSION
There is no consensus as to the best analgesic strategy to be implemented in the acute postoperative pain of laparoscopic cholecystectomy, which requires its applicability in an individualized way, based on the scientific evidence found in the literature.