A Comparison of Multimodal Analgesic Approaches in Institutional Enhanced Recovery After Surgery Protocols for Colorectal Surgery: Pharmacological Agents

Abstract

Introduction:

Enhanced Recovery After Surgery (ERAS^®) protocols are the cornerstone of improved recovery after colorectal surgery. Their implementation leads to reduced morbidity and shorter hospital stays while attenuating the surgical stress response. Multimodal analgesia is an important part of ERAS protocols. We compared and contrasted protocols from 15 institutions to test our hypothesis that there is a fundamental consensus among them.

Materials and Methods:

ERAS protocols for open and laparoscopic colorectal surgery were compared from 15 different healthcare facilities. We examined each institution's approach to multimodal analgesia related to the use of oral and intravenous analgesics. Preoperative, intraoperative, and postoperative management was examined.

Results:

All but three protocols used preoperative multimodal analgesics, with acetaminophen, celecoxib, and gabapentin being the most common. Intraoperative recommendations included the use of ketamine, lidocaine, magnesium, and ketorolac. Some protocols advocated for the use of opiates, while others aimed to minimize total opioid dose. In the postoperative period, the three most utilized agents were acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids.

Conclusions:

There were many similarities and some significant differences among ERAS protocols examined. Acetaminophen was the most widely used nonopioid agent and along with NSAIDs offers a benefit with respect to postoperative analgesia, opioid-sparing effects, earlier ambulation, and reduction in postoperative ileus. Gabapentin was widely used as it may reduce opioid consumption within the first 24 hours postoperatively. Lidocaine infusion was recommended if there were contraindications to or failure of epidural anesthesia. Ketamine is frequently recommended due to its analgesic, antihyperalgesic, antiallodynic, and antitolerance properties. Differences in approaches may be due to both institutional- and provider-level factors.

Introduction

The development of Enhanced Recovery After Surgery (ERAS^®) pathways has contributed to improved postoperative recovery of surgical patients. The evidence-based treatments in ERAS protocols aim to preserve normal physiology in the postoperative period, hasten mobility after surgery, and lessen surgical stress. The overall goal is to reduce morbidity, expedite recovery, and decrease hospital length of stay.^1,2 The foundation of analgesia in ERAS pathways remains a multimodal approach, combining both regional anesthesia and pharmacological agents, with the goal of reducing opioid dosing and their unwanted side effects such as respiratory depression, ileus, nausea and vomiting, urinary retention, hyperalgesia, immune suppression, tolerance, and postoperative delirium, among others.³ Both oral and intravenous (IV) opioid-sparing analgesics have been successfully used in the perioperative setting, including gabapentinoids, nonsteroidal anti-inflammatory drugs (NSAIDs), lidocaine, ketamine, acetaminophen, and alpha-2 agonists. Nonetheless, even though there is an overall agreement regarding the use of multiple nonopioid agents in ERAS pathways, there exists some variability in the dosing, frequency, and types of drugs recommended by each institutional protocol. These differences may be multifactorial and driven by institutional- or provider-level factors. In addition, even though protocolizing each patient's management can lead to better overall patient outcomes, it is also important to take into consideration individual patient characteristics and specifics of the procedure.

In this study, we compare and contrast existing ERAS protocols from major hospitals, with a specific emphasis on pharmacologic analgesics used for open and laparoscopic colorectal surgery. Our hypothesis is that there will be fundamental consensus among ERAS protocols evaluated in regard to multimodal analgesic approach and some notable differences.

Materials and Methods

ERAS protocols for open and laparoscopic colorectal surgery were obtained from 15 different healthcare facilities. Five protocols were downloaded from the website of American Society for Enhanced Recovery (ASER). The remaining 10 were obtained through direct contact or through Google search. Protocols were acquired for the following institutions: Banner Health, Brigham and Women's Hospital, Cooper University, Chicago University, Dartmouth, Duke, Johns Hopkins, Mayo Clinic Phoenix, Mayo Clinic Rochester, McGill University, Stanford, University California San Francisco, University of Alabama, University of Virginia, and North Shore Hospital in Auckland, New Zealand. Institutional IRB approval was not required as the study did not involve human subjects.

A comparison was made with regard to the multimodal analgesic approaches, noting the similarities and differences within the preoperative, intraoperative, and postoperative periods and any opioid recommendations. Included in the postoperative period are any recommendations made for pain management in the post-anesthesia care unit (PACU) or successive postoperative days. Medication type, dosing, and duration were all reviewed.

Results

As expected, the protocols were overall similar in terms of oral and IV medications that were utilized. However, there were some interesting differences among all 15 protocols and no two were exactly alike. Some protocols were very specific in outlining the medications, dosing, and duration, while others only recommended type or class of drug to be used. The multimodal analgesic approaches were compared and contrasted within the preoperative, intraoperative, and postoperative phases of care, with results outlined in Table 1.

Table 1.

Comparison of Multimodal Analgesic Approaches for Enhanced Recovery After Surgery Protocols

	Preoperative	Intraoperative	Postoperative
Protocol 1	No recommendation	Remifentanil 0.2–0.4 mcg/kg/min	Acetaminophen 1 g Q6H PO/IV Etoricoxib 60–90 mg PO QD Tramadol SR 100 mg PO Q12H Tramadol^a 50–100 mg Oxycodone^a 10 mg PO Oxycodone^a 1 mg IV
Protocol 2	No recommendation	Lidocaine^b 1.5 mg/kg bolus, then 2 mg/kg/h Ketorolac	PCA Acetaminophen 650 mg PO Q6H PRN Celecoxib 200 mg PO BID
Protocol 3	No recommendation	IV opioids Ketorolac Acetaminophen	IV opioids
Protocol 4	Gabapentin 300 mg PO Celecoxib 200 mg PO	No recommendation	Gabapentin 300 mg PO TID × 12 doses Acetaminophen 1 g Q6H × 4 doses Ketorolac 30 mg IV Q6H Hydromorphone 0.5 mg IV Q2H IV meds fail → PCA Oxycodone 5 mg Q4H (POD1)
Protocol 5	Gabapentin 600 mg PO Acetaminophen 975 mg PO	Ketorolac 15 mg at end of case Ketamine 4 mcg/kg/min in chronic pain Lidocaine^b 1.5 mg/kg/h No IV opioids after induction without attending approval	Gabapentin 100 mg TID Acetaminophen 650 mg PO Q6H × 48 hours
Protocol 6	48-Hour acetaminophen preload Gabapentin 600 mg PO Celecoxib 400 mg PO Acetaminophen 1 g PO	Ketorolac Acetaminophen	Ketorolac QID × 48 hours Acetaminophen QID × 48 hours Tramadol 100 mg Q4H PRN Rescue narcotics
Protocol 7	Gabapentin^c 900 mg PO Diclofenac^c 75 mg PO Acetaminophen^c 1 g PO	Ketamine Lidocaine	PCA POD #0, then switch to Oxycodone 5–10 mg PRN Ketorolac IV × 24 hours, then naproxen^c × 5 days Scheduled tramadol Scheduled acetaminophen^c ± low-dose ketamine infusion
Protocol 8	Gabapentin^d Celecoxib^d Acetaminophen	Lidocaine 1.5 mg/kg/h Ketamine 0.5 mg/kg IBW Ketamine infusion if opioid tolerant Dexamethasone 0.1 mg/kg max dose (8 mg) Fentanyl	Fentanyl 50 mcg IV Q10 minutes max five doses If inadequate → Hydromorphone 0.4 mg IV max two doses If inadequate → PCA
Protocol 9	Gabapentin 600 mg PO Celecoxib 400 mg PO Acetaminophen 1 g PO	Ketamine 10–30 mg before incision Ketorolac^e 15–30 mg at end of case	Avoid excessive opioids
Protocol 10	Gabapentin 600 mg PO Celecoxib 200 mg PO Acetaminophen 975 mg PO	Ketamine infusion Lidocaine infusion Magnesium infusion	48 Hours of lidocaine infusion Celecoxib (scheduled) Acetaminophen (scheduled) PO opioids only
Protocol 11	Gabapentin^f 100–900 mg PO Celecoxib^g 400 mg PO Acetaminophen 1 g PO	Lidocaine^b 1.5 mg/kg/h Ketorolac^h Acetaminophenⁱ	IV Ketorolac^a Acetaminophen preferred to opioids
Protocol 12	Gabapentin^j 600 mg PO Celecoxib^k 400 mg PO Acetaminophen 1 g PO	Ketorolac 15 mg Ketamine 10–20 mg	Acetaminophen 1 g PO QID/BID Ketorolac 15 or 30 mg IV for four doses Ibuprofen 400–600 mg PO Q6H (begin after ketorolac) Oxycodone^l 5–10 mg PO Q4H
Protocol 13	Gabapentin 600 mg PO Diclofenac^m 100 mg PO Acetaminophen 1 g PO	Morphine/hydromorphone to titrate to respiratory rate of 12 before extubation Ketamine infusion 2 mcg/kg/min if opioid tolerant	Morphine/hydromorphone IV (PACU) Can start PCA (PACU) Gabapentin 600 mg PO QHS Acetaminophen 1 g IV/PO Q6H Ketorolac 15 mg IV Q6H or Diclofenac 50 mg PO TID If opioid tolerant, continue ketamine infusion
Protocol 14	Gabapentin 600 mg PO Celecoxib 200 mg PO Acetaminophen 1 g Midazolam 1–2 mg	Hydromorphone 0.5–1 mg Ketamine 30 mg or 0.5 mg/kg IBW	Fentanyl IV PRN (PACU) Hydromorphone IV PRN (PACU) Hydromorphone PCA Gabapentin 300 mg TID Acetaminophen 1 g
Protocol 15	Gabapentin 600 mg PO Celecoxib 200 mg PO Acetaminophen 1 g PO	Lidocaine^b 1.5 mg/kg/h Magnesium 4 g Ketorolac 30 mg Hydromorphone^a	While NPO Acetaminophen 1 g IV Q8H × 2 doses Ketorolac 30 mg IV Q6H Lidoderm patch 1–2 Q24H Hydromorphone^a IV Q3H PRN Oral intake resumed Tramadol 50 mg PO Q4H Acetaminophen 1 g PO Q8H Gabapentin 100 mg PO TID Ibuprofen 400 mg PO Q6H Hydromorphone^a 2 mg PO Q4H

For breakthrough pain.

If regional anesthesia is contraindicated or unsuccessful.

Unless contraindicated.

Based on age, type of surgery, and renal function.

Clear with surgeon.

Male <65 years old 900 mg, >65 years old 600 mg, >75 years old 300 mg; Female <65 years old 600 mg, >65 years old 300 mg, >75 years old or Asian >65 years old 100 mg.

Hold for chronic real failure.

At surgeon's and anesthesiologist's discretion.

When IV Ketorolac is contraindicated.

Age-based recommendations: 600 mg if age <60, 300 mg if age 60–69, no gabapentin if age ≥70.

Not for use with patients with true sulfa allergy, acute GI bleed, history of GI bleed within 6 months, or acute/chronic renal failure.

Start 24 hours after intrathecal opioid dose.

If eGFR >60.

BID, two times a day; eGFR, estimated globular filtration rate; IBW, ideal body weight; GI, gastrointestinal; IV, intravenous; NPO, Non per os; PACU, post-anesthesia care unit; PCA, patient-controlled analgesia; PO, per os; PRN, as needed; QID, four times a day; TID, three times a day.

Preoperative

The protocols had a high level of agreement with regard to the pharmacological agents used in the preoperative period. All but three protocols utilized pharmacological analgesics in this phase of care. Gabapentin, acetaminophen, and celecoxib were the most commonly used analgesics. Twelve of the protocol pathways used gabapentin, 11 used acetaminophen, 9 used celecoxib, and 2 used diclofenac. No protocol used a single agent, while 10 protocols used a combination of gabapentin, acetaminophen, and an NSAID. Two protocols used gabapentin with either celecoxib or acetaminophen.

The proposed route of administration for all of these medications was by per os (PO). Dosing for gabapentin ranged from 100 to 900 mg with age being the determining factor for dosing adjustments. Celecoxib dosing was either 200 or 400 mg with each occurring in four protocols, and one protocol did not indicate a dose. Diclofenac doses were either 75 or 100 mg. Some contraindications cited for holding celecoxib or diclofenac included acute and/or chronic renal failure, current or prior history of a gastrointestinal bleed, and true sulfa allergy. Preoperative acetaminophen was part of 10 protocols reviewed and dosing was 1 g in all but one, which used 975 mg instead. One protocol called for a 48-hour acetaminophen preload before surgery.

Intraoperative

Intraoperative analgesics were recommended as boluses before incision, infusions, or just before end of procedure. Medications used included acetaminophen, ketorolac, lidocaine, ketamine, magnesium, and various opioids. Acetaminophen was part of only three protocols, with one calling for it only when ketorolac was contraindicated. Ketorolac was included in eight protocols with dosing ranging from 15 to 30 mg. Some protocols left the decision to administer ketorolac at the discretion of the surgeon or anesthesiologist or stated that it must be discussed with the surgeon before administration. A lidocaine infusion was part of six protocols and was usually only recommended if a patient had not received any type of regional anesthesia whether from unsuccessful placement or contraindications. The preferred rate of infusion was 1.5 mg/kg/h in all but one protocol, which recommended a 1.5 mg/kg bolus, followed by an infusion of 2 mg/kg/h. Ketamine was found in eight protocols and was given as either a bolus before incision or as an infusion. Three of the four reviewed protocols that supported ketamine infusions cited opioid tolerance and chronic pain as indications for an infusion. Magnesium was supported in only two protocols.

The use of intraoperative opioids differed widely. Five protocols advocated for the use of parenteral narcotics. One protocol recommended a remifentanil infusion of 0.2–0.4 mcg/kg/min, while another protocol used hydromorphone or morphine to titrate a patient's respiratory rate to 12 before extubation. Three institutions specifically state to minimize the use of opioids, while another leaves it to the discretion of the anesthesiologist.

Postoperative

The postoperative period had the most variability between protocols. It also is where many protocols explicitly provided the most detail. Gabapentin, celecoxib, and acetaminophen were the only three drugs used in both the preoperative and postoperative settings. Postoperative gabapentin dosing ranged from 100 to 300 mg three times a day (TID) or 600 mg every bedtime (QHS) (before bedtime). Celecoxib was only seen in two protocols with dosing of 200 mg two times a day (BID).

Acetaminophen was the most commonly used medication for postoperative pain, with 12 institutions incorporating it into their protocol. Doses were either 650 mg or 1 g every 4 to 6 hours either IV or PO. Ketorolac was the second most common nonopioid analgesic. It was found in seven protocols with IV doses of 15–30 mg every 6 hours (Q6H). Some of the supported administration limits for ketorolac included four doses, 24-hour, and 48-hour time frames. One protocol gave the option of using 50 mg diclofenac instead of ketorolac. There was one institution that utilized a 48-hour lidocaine infusion for postoperative analgesia. It should be noted that this is complimentary to an opioid-only spinal anesthetic. Another protocol considered a ketamine infusion in the postoperative period as well. Tramadol was supported in four protocols with doses of 50–100 mg and could be scheduled or used for breakthrough pain.

The nine protocols with opioids as part of postoperative pain management varied widely in approach. Six of the eight protocols using opioids included patient-controlled analgesia (PCA). PCA as standard for treating postoperative pain was found in three protocols. Others indicated PCA if IV medications failed or at provider's discretion. Hydromorphone was in five protocols and administered in a PCA, IV, or PO. IV doses encountered were 0.4 or 0.5 mg every 2 hours (Q2H), 3 hours (Q3H), or as needed. The lone PO dose was 2 mg every 4 hours (Q4H). Two protocols used scheduled oxycodone Q4H in doses of 5–10 mg, while two others used it as needed (PRN) or for breakthrough pain. Fentanyl was found in two protocols with it being used to treat pain in the PACU. Morphine was mentioned in several protocols as an alternative to hydromorphone.

Discussion

There were many commonalities among the 15 protocols, with the highest consensus in the preoperative period. Intraoperative and postoperative periods differed more in respect to type of medication and dosing. The most frequently suggested medications were gabapentin, NSAIDs, acetaminophen, lidocaine, and ketamine.

The single most commonly used medication was acetaminophen. Both oral and IV formulations have been studied and shown to be safe additions to a multimodal pain management regimen. Analgesic effects may be more rapid with IV administration, but currently there is limited evidence that IV acetaminophen is superior to oral formulations.^4–6 The combination of acetaminophen and an NSAID has been shown to offer superior analgesia compared with either drug alone.⁷

Six of the 11 nonopioid medications utilized within the 15 protocols were a type of NSAID. When accounting for all phases of care, NSAIDs were included in every protocol. Regarding the use of NSAIDs, there is a clear benefit concerning improvement in postoperative pain scores, opioid-sparing effects, earlier ambulation, and reduction in postoperative ileus.^8–11 Celecoxib is commonly used because it is a selective inhibitor of the cyclooxygenase 2 enzyme, thus averting the potential adverse effects of gastrointestinal bleeding and platelet dysfunction.¹² IV ketorolac has been shown to be beneficial in terms of analgesia and reduction of ileus in combination with morphine PCA for laparoscopic colorectal surgery.^9–11 However, there has been concern regarding the safety of using NSAIDs in colorectal surgery as they may have deleterious effects on anastomotic healing.^11,13,14 Although the evidence pertaining to an increased risk of anastomotic leaks in patients receiving NSAIDs is inconclusive, it is currently recommended that for patients undergoing a bowel anastomosis, NSAIDs should be used with caution.

Gabapentin was not only most commonly used in the preoperative phase but it was also used postoperatively in several pathways. It was originally indicated as an anticonvulsant, but has gained popularity as an analgesic agent. The authors could not find any evidence-based results on the effects of gabapentin in colorectal surgery. However, in other types of surgeries, including abdominal hysterectomy and cholecystectomy, the use of gabapentin significantly reduced opioid consumption within the first 24 hours postoperatively.¹⁵ Other evidence suggests that there are no convincing data for the use of gabapentin in acute postoperative pain, especially when added to a multimodal regimen.¹⁶

The administration of gabapentin can lead to excessive sedation and dizziness in some patients.¹⁷

The use of lidocaine within the reviewed protocols was primarily recommended if there were contraindications to or failure of epidural anesthesia. Lidocaine possesses analgesic, anti-inflammatory, and antihyperalgesic properties.¹⁸ Systemic lidocaine has been shown to reduce postoperative ileus, post-operative nausea and vomiting (PONV), opioid consumption, pain intensity, and hospital length of stay.^19–21 Potential risks associated with its use are arrhythmia and hypotension, but there have been no significant systemic toxicities or adverse effects noted with its use.²²

Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist that can decrease perioperative pain and opioid use. In addition to its analgesia, ketamine possesses antihyperalgesic, antiallodynic, and antitolerance properties.²³ Administration of ketamine includes boluses as well as subanesthetic dose infusions. Ketamine has been shown to reduce pain scores, opioid consumption, and PONV with minimal side effects.^24–26 However, there is insufficient evidence on the effectiveness of ketamine in colorectal surgical patients, and further studies are needed to elucidate its role in ERAS pathways.

Multimodal analgesia plays an important role in ERAS protocols. The multimodal approach consists of using a combination of medications that decrease pain through different receptor pathways. This provides superior analgesia while minimizing side effects that can cause discomfort and delay the recovery process. For maximal analgesic efficacy and truly enhanced recovery, it is of most benefit to commence multimodal analgesia early and sustain it throughout the perioperative period. Our study demonstrates that there are some variations in the approach to multimodal analgesia among different institutions, although each protocol advocates for several nonopioid interventions. Differences in approaches may be guided by known side effects, lack of definitive outcomes and dosing data, institutional pharmacy formulary restrictions, institutional culture, and resources. Limitations of this study include the fact that only 15 colorectal ERAS protocols were examined, which is a relatively small sample, given significantly more existing ERAS programs. In addition, we did not examine any protocols from Europe, and only one protocol from a non-North American institution was examined. By examining each protocol, it is not possible to determine why one approach was favored over another. Nevertheless, our study points out some important similarities and differences and lays the framework for further efforts to standardize multimodal analgesic approaches in colorectal surgery.

Footnotes

Disclosure Statement

Richard D. Urman received research funding and consulting fees from Mallinckrodt, Inc. The article is not under consideration for publication elsewhere and it has never been partially published. There were no sources of financial support. ERAS^® is a registered trademark of the ERAS^® Society.

References

Rahbari

, Zimmermann

, Schmidt

, Koch

, Weigand

, Weitz

. Meta-analysis of standard, restrictive and supplemental fluid administration in colorectal surgery. Br J Surg, 2009; 96:331–341.

Gustafsson

, Scott

, Schwenk

, Demartines

, Roulin

, Francis

, McNaught

, MacFie

, Liberman

, Soop

, Hill

, Kennedy

, Lobo

, Fearon

, Ljungqvist

; Enhanced Recovery After Surgery Society. Guidelines for perioperative care in elective colonic surgery: Enhanced Recovery After Surgery (ERAS^®) Society recommendations. Clin Nutr, 2012; 31:783–800.

Rawlinson

, Kang

, Evans

, Khanna

. A systematic review of enhanced recovery protocols in colorectal surgery. Ann R Coll Surg Engl, 2011; 93:583–588.

McEvoy

, Scott

, Gordon

, Grant

, Thacker

JKM

, Wu

, Gan

, Mythen

, Shaw

, Miller

; Perioperative Quality Initiative (POQI) I Workgroup. American Society for Enhanced Recovery (ASER) and Perioperative Quality Initiative (POQI) joint consensus statement on optimal analgesia within an enhanced recovery pathway for colorectal surgery: Part 1-from the preoperative period to PACU. Perioper Med (Lond), 2017; 6:8.

Jibril

, Sharaby

, Mohamed

, Wilby

. Intravenous versus oral acetaminophen for pain: Systematic Review of Current Evidence to Support Clinical Decision-Making. Can J Hosp Pharm, 2015; 68:238–247.

Fenlon

, Collyer

, Giles

, Bidd

, Lees

, Nicholson

, Dulai

, Hankins

, Edelman

. Oral vs intravenous paracetamol for lower third molar extractions under general anaesthesia: Is oral administration inferior?. Br J Anaesth, 2013; 110:432–437.

Ong

, Seymour

, Lirk

, Merry

. Combining paracetamol (acetaminophen) with nonsteroidal antiinflammatory drugs: A qualitative systematic review of analgesic efficacy for acute postoperative pain. Anesth Analg, 2010; 110:1170–1179.

Sim

, Cheong

, Wong

, Lee

, Liew

. Prospective randomized, double-blind, placebo-controlled study of pre- and postoperative administration of a COX-2-specific inhibitor as opioid-sparing analgesia in major colorectal surgery. Colorectal Dis, 2007; 9:52–60.

Chen

, Ko

, Wen

, Wu

, Chou

, Yien

, Kuo

. Opioid-sparing effects of ketorolac and its correlation with the recovery of postoperative bowel function in colorectal surgery patients: A prospective randomized double-blinded study. Clin J Pain, 2009; 25:485–489.

10.

Chen

, Wu

, Mok

, Chou

, Sun

, Chen

, Chan

, Yien

, Wen

. Effect of adding ketorolac to intravenous morphine patient-controlled analgesia on bowel function in colorectal surgery patients—A prospective, randomized, double-blind study. Acta Anaesthesiol Scand, 2005; 49:546–551.

11.

Schlachta

, Burpee

, Fernandez

, Chan

, Mamazza

, Poulin

. Optimizing recovery after laparoscopic colon surgery (ORAL-CS): Effect of intravenous ketorolac on length of hospital stay. Surg Endosc, 2007; 21:2212–2219.

12.

Prabhakar

, Mancuso

, Owen

, Lissauer

, Merritt

, Urman

, Kaye

. Perioperative analgesia outcomes and strategies. Best Pract Res Clin Anaesthesiol, 2014; 28:105–115.

13.

Forrest

, Camu

, Greer

, Kehlet

, Abdalla

, Bonnet

, Ebrahim

, Escolar

, Jage

, Pocock

, Velo

, Langman

, Bianchi

, Samama

, Heitlinger

; POINT Investigators. Ketorolac, diclofenac, and ketoprofen are equally safe for pain relief after major surgery. Br J Anaesth, 2002; 88:227–233.

14.

Wattchow

, De Fontgalland

, Bampton

, Leach

, McLaughlin

, Costa

. Clinical trial: The impact of cyclooxygenase inhibitors on gastrointestinal recovery after major surgery—A randomized double blind controlled trial of celecoxib or diclofenac vs. placebo. Aliment Pharmacol Ther, 2009; 30:987–998.

15.

Arumugam

, Lau

, Chamberlain

. Use of preoperative gabapentin significantly reduces postoperative opioid consumption: A meta-analysis. J Pain Res, 2016; 9:631–640.

16.

Fabritius

, Geisler

, Petersen

, Nikolajsen

, Hansen

, Kontinen

, Hamunen

, Dahl

, Wetterslev

, Mathiesen

. Gabapentin for post-operative pain management—A systematic review with meta-analyses and trial sequential analyses. Acta Anaesthesiol Scand, 2016; 60:1188–1208.

17.

Tiippana

, Hamunen

, Kontinen

, Kalso

. Do surgical patients benefit from perioperative gabapentin/pregabalin? A systematic review of efficacy and safety. Anesth Analg, 2007; 104:1545–1556, table of contents.

18.

Wright

, Durieux

, Groves

. A brief review of innovative uses for local anesthetics. Curr Opin Aanaesthesiol, 2008; 21:651–656.

19.

Sun

, Li

, Wang

, Yun

, Gan

. Perioperative systemic lidocaine for postoperative analgesia and recovery after abdominal surgery: A meta-analysis of randomized controlled trials. Dis Colon Rectum, 2012; 55:1183–1194.

20.

Marret

, Rolin

, Beaussier

, Bonnet

. Meta-analysis of intravenous lidocaine and postoperative recovery after abdominal surgery. Br J Surg, 2008; 95:1331–1338.

21.

McCarthy

, Megalla

, Habib

. Impact of intravenous lidocaine infusion on postoperative analgesia and recovery from surgery: A systematic review of randomized controlled trials. Drugs, 2010; 70:1149–1163.

22.

Patel

, Lutz

, Panchagnula

, Bansal

. Anesthesia and perioperative management of colorectal surgical patients—Specific issues (part 2). J Anaesthesiol Clin Pharmacol, 2012; 28:304–313.

23.

Vadivelu

, Schermer

, Kodumudi

, Belani

, Urman

, Kaye

. Role of ketamine for analgesia in adults and children. J Anaesthesiol Clin Pharmacol, 2016; 32:298–306.

24.

Laskowski

, Stirling

, McKay

, Lim

. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth, 2011; 58:911–923.

25.

Sami Mebazaa

, Mestiri

, Kaabi

, Ben Ammar

. Clinical benefits related to the combination of ketamine with morphine for patient controlled analgesia after major abdominal surgery. Tunis Med, 2008; 86:435–440.

26.

Zakine

, Samarcq

, Lorne

, Moubarak

, Montravers

, Beloucif

, Dupont

. Postoperative ketamine administration decreases morphine consumption in major abdominal surgery: A prospective, randomized, double-blind, controlled study. Anesth Analg, 2008; 106:1856–1861.