Ο University of Khartoum Faculty of Medicine Postgraduate Medical Studies Board Comparison between Morphine and Morphine plus Ketamine for postoperative pain relief after orthopaedic surgery By Dr. Sarah Mahmoud Nuri M.B.B.S, (University of Khartoum) A thesis submitted in partial fulfilment for the requirements of the degree of Clinical MD in anaesthesia & intensive care, May 2004 Supervisor Prof. Ali Ahmed Salama MBBS, DA, FFA Faculty of Medicine Neelain University To my mother ...... My grateful acknowledgement is made to Dr. Ali Ahmed Salama for his supervision, encouragement, and advice during the performance of this study. I'm also grateful to all orthopaedic registrars and house officers who helped me in collecting the data. I’m also grateful to Dr. Yassir Salih for his great help and support. I would like also to thank my family for their help and support. LIST OF ABBREVIATIONS CAMP Cyclic adenosine mono phosphate. PIP2 Phosphatidyl inositol di phosphate. IP3 Inositol tri phosphate. ADH Anti Diuretic Hormone. GF Glumerular Filtration. BP Blood Pressure. ECG Electro cadiogram. CBF Cerebral Blood Flow GI Gastro Intestinal CNS Central Nervous system ASA American Society of Anesthiologist VAS Visual analogue scale. NSAIDs Non steroidal anti infalammatory drugs. NMDA N-methyl- D- Aspartate GFR Glumerular filtration rate. EEG Electroencephalogram. ABSTRACT The aim of this study is detection of the efficacy of ketamine in low doses as a potent analgesic and it's ability to provide superior analgesia when added to morphine. It compared morphine with ketamine to morphine alone in Quasi experimental design of post surgical pain control . Also this study compared the incidence of morphine common side effects between the two groups. Eighty ASA class I and II patients undergoing elective orthopaedic surgery were administered either 10 mg of morphine \ 8 hourly or 10 mg of morphine plus 0.5 mg/ kg ketamine 8 hourly via intravenous route, pain relief and side effects were assessed 24 hours after surgery. The mean visual analogue scale (VAS) pain rating of patients receiving morphine with ketamine was lower than the (VAS) scores of patients receiving only morphine. There was no much difference in side effects between the two groups, they reported the same incidence of nausea, pruritis and urinary retention. There was higher incidence of dysphoria in morphine plus ketamine group but they reported a lower incidence of sedation. In conclusion I/V ketamine in combination with morphine provide superior post surgical pain relieve. ﻤﻠﺨﺹ ﺍﻷﻁﺭﻭﺤﺔ ﺍﻟﻬﺩﻑ ﻤﻥ ﻫﺫﻩ ﺍﻟﺩﺭﺍﺴﺔ ﺘﻘﻴﻴﻡ ﻓﻌﺎﻟﻴﺔ ﻋﻘﺎﺭ ﺍﻟﻜﺘﺎﻤﻴﻥ ﻓﻰ ﺠﺭﻋﺎﺕ ﺼﻐﻴﺭﺓ ﻜﻤﺅﺜﺭ ﻗﻭﻱ ﻟﺘﺴﻜﻴﻥ ﺍﻵﻻﻡ ﻭﻤﻘﺩﺭﺘﻪ ﻹﺤﺩﺍﺙ ﺘﺄﺜﻴﺭ ﺃﻗﻭﻯ ﻋﻨﺩ ﺇﻀﺎﻓﺘﻪ ﻟﻌﻘﺎﺭ ﺍﻟﻤﻭﺭﻓﻴﻥ. هﺬﻩ اﻟﺪراﺳﺔ اﻟﺘﺠﺮﻳﺒﻴﺔ أﺟﺮﻳﺖ ﻟﻤﻘﺎرﻧﺔ ﻣﻔﻌﻮل اﻟﻤﻮرﻓﻴﻦ وﻣﻔﻌﻮل اﻟﻤﻮرﻓﻴﻦ ﻣﻊ اﻟﻜﺘﺎﻣﻴﻦ ﻟﺘﺴﻜﻴﻦ ﺁﻻم ﻣﺎ ﺑﻌﺪ اﻟﻌﻤﻠﻴﺎت اﻟﺠﺮاﺣﻴﺔ. آﻤﺎ ﻗﺎرﻧﺖ هﺬﻩ اﻟﺪراﺳﺔ اﻵﺛﺎر اﻟﺠﺎﻧﺒﻴﺔ اﻟﻨﺎﺗﺠﺔ ﻣﻦ ﻋﻘﺎر اﻟﻤﻮرﻓﻴﻦ ﻓﻰ آﻼ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ. إﺷﺘﻤﻠﺖ هﺬﻩ اﻟﺪراﺳﺔ ﻋﻠﻰ 80 ﻣﺮﻳﺾ ﻓﻰ ﻗﺴﻢ ﺟﺮاﺣﺔ اﻟﻌﻈﺎم ﻣﻦ اﻟﻤﺠﻤﻮﻋﺔ اﻷوﻟﻰ واﻟﺜﺎﻧﻴﺔ ﺗ ﺒ ﻌ ﺎً ﻟﺘﺼﻨﻴﻒ اﻟﺠﻤﻌﻴﺔ اﻷﻣﺮﻳﻜﻴﺔ ﻹﺧﺘﺼﺎﺻﻲ اﻟﺘﺨﺪﻳﺮ. وﺗﻢ ﺗﻘﺴﻴﻢ اﻟﻤﺮﺿﻰ ﻟﻤﺠﻤﻮﻋﺘﻴﻦ. أﻋﻄﻴﺖ اﻟﻤﺠﻤﻮﻋﺔ اﻷوﻟﻰ ﻋﻘﺎر اﻟﻤﻮرﻓﻴﺖ(10 ﻣﻠﺠﻢ ﺑﺎﻟﻮرﻳﺪ آﻞ 8 ﺳﺎﻋﺎت) واﻟﻤﺠﻤﻮﻋﺔ اﻟﺜﺎﻧﻴﺔ أﻋﻄﻴﺚ ﻋﻘﺎر اﻟﻤﻮرﻓﻴﻦ زاﺋﺪ اﻟﻜﺘﺎﻣﻴﻦ (10ﻣﺞ ﻣﻮرﻓﻴﻦ + 0.5 ﻣﺞ آﺘﺎﻣﻴﻦ ﻟﻜﻞ آﺠﻢ ﻣﻦ وزن اﻟﻤﺮﻳﺾ آﻞ 8 ﺳﺎﻋﺎت) ﺑﺎﻟﻮرﻳﺪ وﻗﺪ ﺗﻢ ﺗﻘﻴﻴﻢ اﻷﻟﻢ واﻵﺛﺎر اﻟﺠﺎﻧﺒﻴﺔ ﻟﻠﻤﺮﺿﻰ ﻓﻰ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ ﺑﻌﺪ 24 ﺳﺎﻋﺔ. أﺛﺒﺘﺖ هﺬﻩ اﻟﺪراﺳﺔ أن ﻋﻘﺎر اﻟﻤﻮرﻓﻴﻦ زاﺋﺪ اﻟﻜﺘﺎﻣﻴﻦ ذو ﻓﻌﺎﻟﻴﺔ أﻗﻮى ﻋﻠﻰ إزاﻟﺔ اﻷﻟﻢ ﻣﻦ ﻋﻘﺎر اﻟﻤﻮرﻓﻴﻦ وﻻ ﻳﻮﺟﺪ إﺧﺘﻼف آﺒﻴﺮ ﺑﻴﻦ اﻵﺛﺎر اﻟﺠﺎﻧﺒﻴﺔ ﻟﻠﻤﻮرﻓﻴﻦ ﺑﻴﻦ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ ﺣﻴﺚ أن ﻣﻌﺪل اﻹﺳﺘﻘﻴﺎء واﻟﻬﺮش اﻟﺠﻠﺪي واﻟﺤﺒﺲ اﻟﺒﻮﻟﻲ آﺎن ﻣﺘﺴﺎوﻳﺎً ﺑﻴﻦ اﻟﻤﺠﻤﻮﻋﺘﻴﻦ. اﻣﺎ ﻣﻌﺪل اﻟﻬﻠﻮﺳﺔ ﻓﻜﺎن أﻋﻠﻰ ﻓﻰ اﻟﻤﺠﻤﻮﻋﺔ اﻟﺘﻰ أﻋﻄﻴﺖ ﻋﻘﺎر اﻟﻤﻮرﻓﻴﻦ زاﺋﺪ اﻟﻜﺘﺎﻣﻴﻦ وﻣﻌﺪل اﻻﺳﺘﺮﺧﺎء آﺎن أﻗﻞ ﻓﻰ اﻟﻤﺠﻤﻮﻋﺔ اﻟﺘﻰ أﻋﻄﻴﺖ ﻋﻘﺎر اﻟﻤﻮرﻓﻴﻦ زاﺋﺪ اﻟﻜﺘﺎﻣﻴﻦ. LIST OF FIGURES Page Fig. 1: Age distribution (morphine group) 43 Fig. 2: Age distribution (morphine + katamine group) 44 Fig. 3: Sex distribution (morphine group) 45 Fig. 4: Sex distribution (morphine + katamine group) 46 LIST OF TABLES Page Table 1: Mean score of dysphoria reported by patients receiving morphine or morphine plus ketamine 47 Table 2: Mean score of nausea reported by patients receiving morphine or morphine plus ketamine 48 Table 3: Mean score of pruritis reported by patients receiving morphine or morphine plus ketamine 49 Table 4: Mean score of sedation reported by patients receiving morphine or morphine plus ketamine 50 Table 5: Mean score of urine retention reported by patients receiving morphine or morphine plus ketamine 51 Table 6: Mean score of pain reported by patients receiving morphine or morphine plus ketamine 52 CONTENTS Page Dedication……………………………………………………………......I Acknowledgements……………………………………………...….....II Abbreviations …………………………………………….……….…...III English abstract ……………………………………………………...IV Arabic abstract ……………………………….....……………..…...VI List of tables …………..…..……………. …................…...…....….VII List of figures ………..………..…….……. ……................…....….VIII CHAPTER ONE Introduction ………………………………………………….……...….1 Literature review……………………………….…………….........…...6 Objectives…………………………………………………………......35 CHAPTER TWO Patients and Methods …………………………………..……....……36 CHAPTER THREE Results ………………………………………………………………..40 CHAPTER FOUR Discussion…………………………………...…………………………53 Conclusion ………………………………...……………………….…58 Recommandations …………………………………………...…..…..59 References ………………………………………………………...….60 Appendix (questionnaire)……………………………………………68 INTRODUCTION Why it's important to treat postoperative pain? Apart from the obvious humanitarian reasons for relieving unnecessary suffering from acute severe pain, pain relieve is a prerequisite for an active rehabilitation regimen after surgery. There is a number of potentially beneficial effects on the post operative course of optimal post operative pain relief. These include: Improved pulmonary function. Improved cardiovascular function. Improved gastrointestinal function. Fewer thromboembolic complications. Reduced mortality in high-risk patients. Improved postoperative metabolism. Fewer septic complications. Shorter convalescence after surgery. Reduced chronic post surgical pain. Improved arterial graft survival. Reduced health care costs.(1) Why there is a poor control of postoperative pain?: An editorial in the British Medical Journal in 1978 stated: (it’s an indictment of modern medicine that an apparently simple problem such as the relief of post operative pain remains largely unsolved).(2) What can anaesthetist do to prevent postoperative pain?: 1- Pre-emptive analgesia: Experimentally, it has been shown that nociceptive stimulation from the periphery, causes functional changes in the spinal cord which lead to enhancement and prolongation of the sensation of pain. It has also been shown that prior administration of analgesics may inhibit the development of the hyper excitability within the spinal cord. Unfortunately, however, in clinical practice, prior administration of analgesics (pre-emptive analgesia) has not been shown to have an important effect on postoperative pain.(3) 2- Relief of postoperative pain in the post anaesthesia period: Balanced analgesia: The principle of balanced analgesia regimen is to combine several therapeutic modalities to optimize pain relief, while minimizing unwanted effects.(4) First: For short term use NSAID: They seem largely safe, provided that, the patient has no history of allergy to any of the drugs, GI ulcers, bleeding problems, hypovolaemia or reduced renal function. Paracetamol is the safest drug in this category. Second: use regional or local analgesia whenever appropriate: For major abdominal, thoracic and orthopedic surgery the most effective method of relieving severe pain in the immediate post anesthetic period is by prolonging a segmental epidural analgesia used as part of an operative anaesthetic technique. A number of peripheral nerve blocks are very useful. Wound infiltration with local anesthetic solution can also be quite effective. Third: add an opioid analgesic. For immediate post anaesthesia period, an opioid analgesic will usually be needed for an optimal pain relief, in the majority of patients after surgery. This can be administered in the traditional way. After more extensive surgery three alternative regimens for opioid administration may have advantages: a. Nurse controlled continuous opioid infusion analgesia. b. Patient controlled intravenous opiod analgesia. c. Epidural analgesia with an opiod drug combined with low dose local anesthetic drug. Nurse controlled continuous opioid infusion analgesia: This technique is employed to provide analgesia in patients receiving artificial ventilation in intensive therapy unit (ITU). It has also been used in general surgical wards for provision of postoperative analgesia in spontaneously breathing patients. The dose rate is determined by the nurse on trial and error basis and a fixed infusion rate prescribed. However this carries great risk of producing ventilatory depression and can not be recommended in spontaneously breathing patients outside a high dependency unit or intensive therapy unit. Patient controlled opioid analgesia (PCA): The basis for controlled intravenous opioid analgesia is that the patient can best evaluate pain and pain relief, by this technique the problems of the fluctuation in intensity of postoperative pain, the variable pain sensitivity, and the variable pharmacokinetics of opioids between patients will be solved. Optimally balanced epidural analgesia: Choice of drug combination: It’s now well established that specific spinal analgesia can be obtained clinically by at least three separate mechanisms