Postoperative pain has a significant impact on recovery profile and hospital stay of patient. Though there are various drugs and modalities available to manage postoperative pain opioid are the mainstay in managing pain. Analgesic regimens aim for earlier mobilization and rehabilitation by decreasing the complications due to analgesic agents that occur after patients are discharged. Opioid-sparing drugs such as ketamine may be of value in adjuvant treatment for obtaining better analgesia with fewer side effects. Ketamine also has off-label usage as an adjuvant in certain circumstances such as treating neuropathic pain, acute postoperative pain, and refractory pain due to cancer. Researchers recently reported that opioids not only provide analgesia but may also cause hyperalgesia. Subsequently perioperative opioid usage may lead to an increase in postoperative pain and needs for opioids¹. Acute analgesic tolerance to opioid agents may be attenuated with N-methyl-D-aspartate antagonists², and they prevent the rebound hyperalgesia that occurs after opioid usage. Decreased opioid consumption and prolonged analgesia may be achieved with a ketamine and opioid combination³. Researchers have reported that these features of ketamine provide its successful use in treating postoperative pain and have suggested that ketamine can decrease sensitization of the spinal cord during postoperative periods⁴. However, ketamine usage in the outpatient setting is limited because of the psychotomimetic effects of the drug⁵. Researchers have suggested that postoperative pain can be prevented more effectively and the recovery period after ambulatory surgery may be decreased by preemptive multimodal procedures consisting of centrally and peripherally acting analgesic agents⁶. The aim of this study is to assess and compare the benefits of low dose ketamine and low dose fentanyl on post-operative analgesia in laparoscopic abdominal surgery in adults.

 Pain n in laparoscopic abdominal surgery has a multiple etiology. Pneumoperitoneum increases the intra-abdominal pressure intraoperatively and causes irritation of the diaphragm, which may increase postoperative pain. The irritating effect of CO2, use of electro cautery intraoperatively, and contact of bile with the peritoneal cavity may lead to significant postoperative pain. Innervation of the visceroperitoneal organs of the upper abdomen is provided by the vagus nerve,⁸ the spinal nerves of T5-T12,⁹ and the phrenic nerve (C3-C5).¹⁰ These nerves are closely related with visceroperitoneal nociception. Thus, researchers have suggested that central sensitization is maintained segmentally and heterosegmentally. Multiple afferent nociception blockade may be necessary to attain preemptive analgesia in upper abdominal surgery. However, reduced postoperative pain and decreased opioid consumption after ketamine application have been reported in previous studies.¹¹

In major abdominal surgeries, multimodal analgesia (particularly spinal and supraspinal types) has been preferred for years.¹² Ketamine as an adjunct to epidural and IV analgesics seems to be a useful treatment modality.¹³ In a study, a decrease in bupivacaine/morphine consumption up to 25% and improved pain ratings until 48 hours postoperatively were reported in renal surgery after a bolus ketamine dose of 0.5mg/kg and an infusion of 500mg/kg/h.¹⁴

In one study in 2009, effects of intraoperative low dose ketamine on remifentanil induced hyperalgesia in gynecologic surgery with sevoflurane anesthesia¹⁵. The VAS scores and morphine requirements of the ketamine group were significantly lower than those of the control at the postanesthetic care unit and at the ward for 24 hours postoperatively. The extubation time was delayed in ketamine compared with Control. Gui-Feng et al¹⁶ investigated the adjuvant effect of intraoperative and postoperative low-dose ketamine administration to remifentanil consumption in patient-controlled analgesia (PCA) for lower limb fracture.and concluded that low-dose ketamine can relieve postoperative pain and moderately decrease remifentanil consumption for PCA, with no obvious side effects of ketamine.

In another study, Florentino Fernandes Mendes, Ana Luft and Claudio Telöken evaluated in a double blind randomized trial the analgesic and adverse effects of S(+)-ketamine in a patients undergoing laparoscopic cholecystectomy¹⁷ where it was compared with the placebo group, there were no differences in the pain scores, rescue opioids requirements, and opioid-related adverse effects in the PACU and at 24-h postoperatively. Parikh, et al¹⁸, found that during the first 12 hrs. after surgery, the VAS pain score was significantly low and post-operative morphine use was significantly low if small dose of ketamine given before skin incision and as continuous infusion throughout the surgery. Haryalchi et al¹⁹, concluded that taking the preemptive dosage of ketamine (0.2 mg/kg) before cesarean could act as a probably model for decreasing opioid consumption. Kaur, et al²⁰ found out that intraoperative infusion of low-dose ketamine resulted in effective analgesia in first 6 h of the postoperative period, which was evident from reduced pain scores and reduced opioid requirements (P = 0.001). Kim et al²¹, concluded that low-dose ketamine at 2 μg/kg/min following bolus 0.5 mg/à significantly reduced the total amount of fentanyl consumption during the 48 h after lumbar spinal fusion surgery without increasing adverse effects. Guillou et al²² concluded that small doses of ketamine were a valuable adjunct to opioids in surgical intensive care unit patients after major abdominal surgery. Cengiz et al²³, studied low dose ketamine for acute post-operative pain in total knee replacement surgery and found that low-dose ketamine infusion prolonged the time to first analgesic request. It also reduced postoperative cumulative morphine consumption at 1, 3, 6, 12, and 24 hours postsurgery. Postoperative VAS scores were also significantly lower in the ketamine group than placebo, at all observation times. Incidences of side effects were similar in both study groups. Subramaniam et al²⁴ did a systematic review of 37 trials and concluded that small dose ketamine has been shown to a useful and safe additive to standard practice opioid analgesia in 54% of studies. Both systemic and epidural ketamine have shown their beneficial opioid sparing effects. In a Cochrane review from 2010, Bell et al²⁵ reviewed 37 randomized controlled trials of adult surgical patients who received perioperative ketamine or placebo and found that 27 of the 37 trials demonstrated that ketamine reduced analgesic requirements and/or pain scores. Ketamine should be considered as an additive in the surgical population with large opioid requirements, such as major abdominal surgery

AIMS AND OBJECTIVES

Primary Objective

1. To compare the effects of intraoperative low dose ketamine and low dose fentanyl on postoperative analgesia as measured by requirement of opioid analgesics in adults undergoing laparoscopic abdominal surgery.

Secondary Objective

1.      Comparison of intraoperative analgesic efficacy of ketamine with fentanyl.

2.      To assess the effect of intraoperative low dose ketamine infusion on VAS score in post-operative period

3.      To assess the presence of side effects of ketamine postoperatively with intraoperative low dose ketamine infusion

4.      To assess perioperative hemodynamic stability between study groups.

BIBLIOGRAPHY

1.      Bell RF, Dahl JB, Moore RA, et al. Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand. 2005;49:1405–1428

2.      Vuyk J,  Sitsen E, Reekers M, Intravenous Anaesthetic, ch 30, Miller’s Anaesthesia 8e;847

3.      Guignard B, Coste C, Costes H, et al. Supplementing desflurane-remifentanil anesthesia with small-dose ketamine reduces perioperative opioid analgesic requirements. Anesth Analg. 2002;95:103–108

4.      Kakinohana M, Higa Y, Sasara T, et al. Addition of ketamine to propofol-fentanyl anaesthesia can reduce post-operative pain and epidural analgesic consumption in upper abdominal surgery. Acute Pain. 2004;5:75–79.

5.      Badrinath S, Avramov MN, Shadrick M, et al. The use of a ketamine-propofol combination during monitored anesthesia care. Anesth Analg. 2000;90:858–862.

6.      White PF. The role of non-opioid analgesic techniques in the management of pain after ambulatory surgery. Anesth Analg. 2002;94:577–585.

7.      Karcioglu M, Davarci I, Tuzcu K, Bozdogan YB, Turhanoglu S, Aydogan A, and Temiz M; Addition of Ketamine to Propofol-Alfentanil Anesthesia May Reduce Postoperative Pain in Laparoscopic Cholecystectomy; Surg Laparosc Endosc Percutan Tech 2013;23:197–202

8.      Segawa H, Mori K, Kasai K, et al. The role of the phrenic nerves in stress response in upper abdominal surgery. Anesth Analg. 1996;82:1215–1224

9.      Schuligoi R, Jocic M, Heinemann A, et al. Gastric acid-evoked c-fos messenger RNA expression in rat brainstem is signaled by capsaicin-resistant vagal afferents. Gastroenterology. 1998;115: 649–6604.

10.   Ilkjaer S, Nikolajsen L, Hansen TM, et al. Effect of i.v. ketamine in combination with epidural bupivacaine or epidural morphine on postoperative pain and wound tenderness after renal surgery. Br J Anaesth. 1998;81:707–712

11.  Papaziogas B, Argiriadou H, Papagiannopoulou P, et al. Preincisional intravenous low-dose ketamine and local infiltration with ropivacaine reduces postoperative pain after laparoscopic cholecystectomy. Surg Endosc. 2001;15:1030–1033

12.  Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg. 1993;77:1048–1056. 14.

13.   Berti M, Baciarello M, Troglio R, et al. Clinical uses of lowdose ketamine in patients undergoing surgery. Curr Drug Targets. 2009;10:707–715. 15.

14.  Kararmaz A, Kaya S, Karaman H, et al. Intraoperative intravenous ketamine in combination with epidural analgesia: postoperative analgesia after renal surgery. Anesth Analg. 2003;97:1092–1096.

15.  Boo Hwi Hong, Wang Yong Lee, Yoon Hee Kim, Seok Hwa Yoon, and Won Hyung Lee. Effects of intraoperative low dose ketamine on remifentanil induced hyperalgesia in gynecologic surgery with sevoflurane anesthesia. Korean J Anesthesiol 2011; 61: 238-24

16.  Gui-feng. D, Jin-ping Z, Song W, Bin T and Shi-gang Z. Remifentanil combined with low-dose ketamine for postoperative analgesia of lower limb fracture: a double-blind, controlled study. Chinese Journal of Traumatology 2009; 12(4):223-227

17.  Mendes FF, Luft A, Telöken C (2011) Analgesia with Low-Dose S(+)-ketamine in Laparoscopic Cholecystectomy: A Randomized, DoubleBlind, Placebo-Controlled Clinical Trial. J Anesthe Clinic Res 2:133

18.  Parikh B, Shah V, Maliwad J. Preventive analgesia: Effect of small dose of ketamine on morphine requirement after renal surgery. Journal of Anaesthesiology Clinical Pharmacology. 2011;27(4):485.

19.  Haryalchi K, Sharami S, Faraji R, Asgharnia M, Salamat F, Hashemi S, et al. The effect of low-dose ketamine (preemptive dose) on postcesarean section pain relief. Journal of Basic and Clinical Reproductive Sciences. 2014;3(2):97.

20.  Kaur, S., Saroa, R., & Aggarwal, S. (2015). Effect of intraoperative infusion of low-dose ketamine on management of postoperative analgesia. Journal of Natural Science, Biology, and Medicine, 6(2), 378–382.

21.  Kim SH, Kim SI, Ok SY, Park SY, Kim M-G, Lee S-J, et al. Opioid sparing effect of low dose ketamine in patients with intravenous patient-controlled analgesia using fentanyl after lumbar spinal fusion surgery. Korean Journal of Anesthesiology. 2013;64(6):524.

22.  Guillou, N, Tanguy, M, Seguin, P,  Branger, B,  Campion, JP, Malledant, Y. The Effects of Small-Dose Ketamine on Morphine Consumption in Surgical Intensive Care Unit Patients After Major Abdominal Surgery. Anesthesia & Analgesia. 97(3):843-847, September 2003.

23.  Cengiz P, Gokcinar D, KarabeyoglDu I, Topcu H, Cicek GS and  Gogus N. Intraoperative Low-Dose Ketamine Infusion Reduces Acute Postoperative Pain Following Total Knee Replacement Surgery, A Prospective, Randomized Double-Blind Placebo-Controlled Trial. Journal of the College of Physicians and Surgeons Pakistan 2014, Vol. 24 (5): 299-303

24.  K. Subramaniam, B. Subramaniam, and R. A. Steinbrook, “Ketamine as adjuvant analgesic to opioids: a quantitative and qualitative systematic review,” Anesthesia and Analgesia, vol. 99, no. 2, pp. 482–495, 2004.

25.  Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for acute postoperative pain. Cochrane Database Syst Rev. 2006;1:CD004603

26.  Nimmo WS, Todd GJ; Fentanyl by constant rate I.V. infusion for postoperative analgesia, BJA:British Journal of Anaesthesia, Volume 57, issue 3, 1 March 1985, Pages 250-254.