EFFECT OF MAROPITANT, ACEPROMAZINE AND ELECTROACUPUNCTURE IN THE PREVENTION OF NAUSEA AND VOMITING ASSOCIATED WITH ADMINISTRATION OF MORPHINE IN DOGS By RONALD BOON WU KOH A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2012 1 © 2012 Ronald Koh 2 To my family, especially my mom and dad, Rita Garnica and Koh Han Chew 3 ACKNOWLEDGMENTS Completing the project and writing this thesis has been both academically challenging and rewarding. Without the inspiration, support, encouragement, and guidance of the following people, this thesis would have never have been completed. I wish to express my deepest gratitude to the following individuals. I wish to express my special thanks of gratitude to Dr. Sheilah Robertson for giving me the opportunity to do this wonderful project. Without her excellent guidance, dedication and support, this project could not have been completed. I sincerely thank Dr. Huisheng Xie and his family for inspiration, support, and encouragement. His knowledge and experience in traditional Chinese veterinary medicine have been invaluable. I gratefully thank Drs. Natalie Isaza and Brian Gigangi for their invaluable contribution and support. I sincerely thank all members of UF Merial Shelter Medicine Program, with a special ‘Thank You’ to Melissa, Erika, Andrea, and Ali, without their generous help and patience, this research would not have been possible. I deeply thank Dr. Kirsten Cooke for accepting the invitation to join my committee advisory. I greatly appreciate her thoughtful feedback and enlightening questions that always encouraged me to think deeper and further. I am thankful for her keen view and dedication to my thesis. I gratefully acknowledge the American Association of Traditional Veterinary Chinese Medicine (AATCVM) for their gracious financial support for my project. I sincerely acknowledge Dr. Joe Hauptman for his excellent work on the statistical analysis of the data. 4 I gratefully thank my family; dad and mom for nourishing my life and for encouraging me to achieve this academic work, and my brothers and sister who cared about me while I am studying overseas. Extra special thanks must go to my most dear friend Tony Henninger for his care and support all the time. Last but not least, I sincerely thank everyone who contributed to my research but whom I have forgotten to mention in this acknowledgement. 5 TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................. 4 LIST OF TABLES ............................................................................................................ 8 LIST OF FIGURES .......................................................................................................... 9 LIST OF ABBREVIATIONS ........................................................................................... 10 ABSTRACT ................................................................................................................... 11 CHAPTER 1 INTRODUCTION .................................................................................................... 13 Background ............................................................................................................. 13 Pathophysiology of Vomiting ................................................................................... 16 Definitions and Mechanisms ............................................................................. 16 Anatomical Structures Related to Nausea and Vomiting .................................. 18 Chemoreceptor trigger zone (CRTZ) ......................................................... 18 Visceral vagal and sympathetic afferents ................................................... 19 Higher centers of the brain ......................................................................... 19 Vestibular apparatus .................................................................................. 20 Consequences and Complications of Vomiting ................................................ 20 Pathophysiology of Opioid-Induced Nausea and Vomiting ............................... 21 Morphine-Induced Nausea and Vomiting ......................................................... 22 Antiemetics ............................................................................................................. 24 Serotonin-receptor antagonists ........................................................................ 25 Dopamine-receptor antagonists ....................................................................... 26 Histamine-receptor antagonists ........................................................................ 27 Phenothiazines ................................................................................................. 27 Cholinergic-receptor antagonists ...................................................................... 29 Neurokinin-1-receptor antagonists ................................................................... 29 Acupuncture ............................................................................................................ 31 Acupuncture for Nausea and Vomiting ............................................................. 33 Mechanisms ..................................................................................................... 34 2 MATERIALS AND METHODS ................................................................................ 36 Research Design .................................................................................................... 36 Study Population ..................................................................................................... 36 Sample Size ............................................................................................................ 37 Experiment Protocol................................................................................................ 37 Pharmacological Treatments ............................................................................ 38 Electroacupuncture Treatments ....................................................................... 39 6 Acupoint Descriptions ....................................................................................... 40 Recording of Vomiting or Retching Events ....................................................... 41 Assessment of Nausea and Sedation .............................................................. 41 Rescue Treatment ............................................................................................ 41 Data Analysis .......................................................................................................... 42 3 RESULTS ............................................................................................................... 48 Animal Demographics ............................................................................................. 48 Clinical Safety ......................................................................................................... 49 Effects of Treatments on Vomiting or Retching ....................................................... 50 Incidence of Vomiting/Retching ........................................................................ 50 Number of Vomiting/Retching Events ............................................................... 51 Onset Time to Vomiting/Retching ..................................................................... 51 Duration of Vomiting/Retching .......................................................................... 52 Effects of Treatments on Signs of Nausea and Sedation........................................ 53 Signs of Nausea ............................................................................................... 53 Sedation ........................................................................................................... 54 4 DISCUSSION ......................................................................................................... 71 LIST OF REFERENCES ............................................................................................... 87 BIOGRAPHICAL SKETCH .......................................................................................... 103 7 LIST OF TABLES Table page 2-1 Assessment scale for nausea. ............................................................................ 43 2-2 Assessment scale for sedation. .......................................................................... 43 3-1 Demographic characteristics of the six treatment groups. .................................. 57 3-2 Baseline demographic characteristics and physiologic parameters of the six treatment groups. ............................................................................................... 59 3-3 Descriptive data of vomiting/retching (V/R) of the six treatment groups. ............ 60 3-4 Descriptive data of nausea scores for the six treatment groups. ........................ 62 3-5 Descriptive data of sedation scores for the six treatment groups. ...................... 64 8 LIST OF FIGURES Figure page 2-1 Overall methodology of the study. ...................................................................... 44 2-2 Pericardium-6 at medial side of the thoracic limb. .............................................. 45 2-3 Stomach-36 at lateral side of the pelvic limb. ....................................................