1 EFFECT OF MAROPITANT, ACEPROMAZINE AND ELECTROACUPUNCTURE IN THE PREVENTION OF NAUSEA AND VOMITING ASSOCIATED WITH ADMI NISTRATION 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
2 2012 Ronald Koh
3 To my family, especially my m om and d ad Rita Garnica and Koh Han C hew
4 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 t o 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 g uidance dedication and s upport this project could not have been comp leted. 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 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 h er 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.
5 I gratefully thank my family; d ad and mo m for nourishing my life and for encouraging me to achieve this academic work, and my brothers and sister who car ed about me while I am stud yi ng 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.
6 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 8 LIST OF FIGURES ................................ ................................ ................................ .......... 9 LIST OF ABBREV IATIONS ................................ ................................ ........................... 10 ABSTRACT ................................ ................................ ................................ ................... 11 C HAPTER 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 affer ents ................................ ................... 19 Higher centers of the brain ................................ ................................ ......... 19 Vestibular apparatus ................................ ................................ .................. 20 Conseque nces and Complications of Vomiting ................................ ................ 20 Pathophysiology of Opioid Induced Nausea and Vomiting ............................... 21 M orphine Induced Nausea and Vomiting ................................ ......................... 22 Antiemetics ................................ ................................ ................................ ............. 24 Serotonin receptor antagonists ................................ ................................ ........ 25 Dopamine receptor antagonists ................................ ................................ ....... 26 Histamine receptor a ntagonists ................................ ................................ ........ 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 ME THODS ................................ ................................ ................ 36 Research Design ................................ ................................ ................................ .... 36 Study Population ................................ ................................ ................................ ..... 36 Sample Size ................................ ................................ ................................ ............ 37 Experiment P rotocol ................................ ................................ ................................ 37 Pharmacological Treatments ................................ ................................ ............ 38 Electroa cupuncture T reatments ................................ ................................ ....... 39
7 Acupoint Descriptions ................................ ................................ ....................... 40 Recording of V omiting or Retching E vents ................................ ....................... 41 Assessment of N ausea and S edation ................................ .............................. 41 Rescue Treatment ................................ ................................ ............................ 41 Data Analysi s ................................ ................................ ................................ .......... 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 V omiting /R etching 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 ................................ ................................ ................................ ........... 5 4 4 DISCUSSION ................................ ................................ ................................ ......... 71 LIST OF REFERENCES ................................ ................................ ............................... 87 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 103
8 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 par ameters 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
9 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 a t lateral side of the pelvic limb. ................................ ..................... 45 2 4 Gallbladder 34 at lateral side of the pelvic limb. ................................ ................. 46 2 5 Bladder 20 and Bladder 21 at dorsola teral aspect of the spine. ......................... 46 2 6 Sham non acupoint at medial side of pelvic limb. ................................ ............... 47 3 1 The incidence of vomiting/retching (V/R) by treatment group ............................. 66 3 2 The comparative effectiveness of the six treatment groups o n the mean number of V/R events ................................ ................................ ........................ 66 3 3 The mean duration of V/R (mean SD minutes) for the six treatment groups ... 67 3 4 The incidence of signs of nausea for the six treatment groups before an d after morphine administration ................................ ................................ ............. 67 3 5 The mean score for signs of nausea for the six treatment groups before treatment (Time 0, as baseline) and after treatment (Time 20), as well as 10, 15 and 20 minutes after m orphine administration (Ti me 30, 35 and 40, respectively) ................................ ................................ ................................ ....... 68 3 6 The mean score for signs of nausea (mean SD) for the six treatment groups at Time 0 (before treatment, as baseline), Time 20 (after treatment), and 10, 15 and 20 minutes after morphine administration (Ti me 30, 35 and 40, respectively) ................................ ................................ ................................ 69 3 7 The sedation score s (mean SD) for the six treatment groups before (Time 0, as baseline) and after treatment (Time 20), as well as 10, 15 and 20 minutes after morphine administration (Ti me 30, 35 and 40, respectively) ......... 70
10 LIST OF ABBREVIATION S 5 HT 5 hydroxy tryptamine A PR Area postrema A SA Americ an Society of Anesthesiologists BCS Body score condition C NS Central nervous system C RTZ Chemoreceptor Trigger Zone C SF Cerebrospinal fluid D MV Dorsal motor nucleus of the vagus DVC Dorsal vagal complex E A Electroacupuncture E C CELL Enterochromaffin cell G I Gastrointestinal H Z Hertz I M Intramuscular I V Intravenous NTS Nucleus Tractus Solitarius PO Per os R PC Retrograde peristaltic contraction S C Subcutaneous V/R Vomiting or retching s Microsecond
11 Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science EFFECT OF MAROPITANT, ACEPROMAZINE AND ELECTROACUPUNCTURE IN THE PREVENTION OF NAUS EA AND VOMITING ASSOCIATED WITH ADMINISTRATION OF MORPHINE IN DOGS By Ronald Boon Wu Koh December 2012 Chair: Sheilah Robertson Major: Veterinary Medical Sciences The objective of th is study was to evaluate the antiemetic properties of maropitant, acepromazine and electroacupuncture (EA) in dogs receiving morphine as an anesthetic premedication. T he study population include d 222 male and female dogs of various breeds, aged from 0.60 to10.0 years of age, and weighing f ro m 1.90 to 55.0 kg scheduled for elective surgical procedures Dogs were randomly assigned to one of six treatment groups (37 dogs per group). Group I received saline ( placebo ) 0.10 m L /kg ( SC ) Group II received maropitant citrate 1.0 mg/kg (SC) and Group III received acepromazine maleate 0. 0 5 mg/kg (IM) 20 minutes before administration of morphine. Group IV underwent EA (2 100 Hz) at acupoint PC 6 and Group V received EA at acupoints PC 6, ST 36, GB 34, BL 20 and BL 21 for 20 minutes before administration of morphine. Group VI (sham) received EA at a non acupoint. All dogs received 0.5 mg/k g morphine IM Vomiting or retching (V/R) was recorded for 20 minutes after morphine administration; nausea and sedation were assessed before treatment as a baseline, before morphine administration, and 10, 15 and 20 minutes after morphine administration. The incidence of V/R and the number of V/R events was significantly
12 lower in Group II ( 37.8%; 21 events) and Group III ( 45.9%; 38 events) compared to Group I ( 75.7%; 88 events) and Group VI ( 86.5%; 109 events) ( p <0.0 5 ) Groups IV and V had a V/R incidence of 64.8% and 70.3%, respectively, and the number of V/R events were significantly lower in Groups IV (35 events) and V (34 events) than Groups I and VI ( p <0.0001) The incidence of signs of nausea was significantly lower in Groups III (8.1%) IV (18.9%) and V (10.8%) compared to the Groups I (29.7%), II (32.4%), and VI (40%) following morphine ( p <0.05) The severity of signs of nausea was significantly less in Groups III, IV and V compared to Groups I, II and VI ( p <0.05) In conclusion, maropi tant and acepromazine were effective in preventing morphine induced V/R. EA did not influence the incidence of V/R but was effective in reducing V/R events per dog Acepromazine and EA were effective in preventing signs of nausea induced by morphine.
13 CHAPTER 1 INTRODUCTION Background Pain management is an important and but challenging contemporary issue in veterinary medicine. It is now understood and accepted that uncontrolled pain is a major biologic stressor that can affect numerous aspects of physical and mental health in animals. 1 Continual p ain is detrimental to the general well being of any animal and can slow the overall recovery process. 2 Opioids have provided consistent and effective pain relief for many years and are still commonly used for pain management in daily veterinary practice, especially for management of postoperative pain in dogs. 3 5 However, opioids have been associated with many unwanted sid e effects in dogs, including sedation and vomiting. 6,7 Central nervous system ( CNS ) depression (i.e., sedation) is typically seen in dogs after systemic administration of various opioids, most notably morphine. 6 Sedation can be classified as an undesirable side effect when using opioids primarily for analgesia. C linically this side effect may be advantageous when opioids are used to facilitate handling and performing of diagnostic or therapeutic procedures. Opioids are often combined with tranquilizer s or sedative s such as phenot hiazine drugs or 2 adrenoceptor agonists to provide sedation and analgesia prior to induction of an esthesia or to produce neuroleptanalgesia. 3,6 Synergism occurs when these drugs are used together, thus providing more profound sedation and analgesia than that achieved with either drug given alone 6,8 Nausea and vomiting are the most common side effects in dogs after opioid administration, and is frequently associated with morphine hydromorphone and oxymorphone administration 7,9,10 Vomiting can lead to adverse sequelae, such as
14 aspiration of gastric content s esophagitis and resultant stricture, tension on suture lines, increased intracranial and intraocular pressure, and prolonged hospitalization. 11,12 Opioids have both emetic and antiemetic effects in dogs, cats, ferrets, and humans. 13 The emetic effect of opioids is due to interaction with opioid receptor s opioid receptors in the chemoreceptor trigger zone ( CRTZ ) of the brain. 14,15 It has also been shown that opioids manifest their emetogenic effects by increasing vestibular sensitivity to m ovement and decreasing t he motility of the gastrointestinal (GI) tract 16 T he antiemetic effect of opioids c and/or receptor mediated mechanism s in the emetic center of the brain. 14 ,15 Morphine, a full receptor agonist, is widely used as a preemptive and postoperative analgesic in dogs 4,17 Therapeutic doses of morphine for sedation or premedication (0.5 to 1.0 mg/kg) frequently cause na usea and vomiting or retching in dogs 7,10,13,18 20 Studies report that between 63 to 100% of dogs vomited after intravenous intramuscular, or subcutaneous injection of morphine. 7,10,19,21 Several agents that act on receptors in the CRTZ to block neurotransmission can be used to combat opioid induced nausea and vomiting as well as nausea and vomiting from a variety of other causes. 5 D 2 Dopaminergic antagonists, such as metoclopramide, are commonly used to protect against nausea and vomiting. 22,23 Other agents including NK 1 n eurokinin antagonist s (e. g. m aropitant), 5 HT 3 s erotonergic antagonists (e.g. ondansetron ) M 1 c holinergic antagonists (e.g. propantheline), 2 a drenergic antagonists (e.g. chlorpromazine), and H 1 histaminergic antagonists (e.g. meclizine) are also available for treatment (or prevention of) to prevent or treat nausea and vomiting in veterinary practice 22,23 Studies in dogs have shown that marop itant
15 which was approved as an antiemetic in dogs, is an effective antiemetic against both central and peripheral emetogens. 24,25 One study showed that m aropitant was effective in preventing nausea and vomiting induced by hydromorphone in dogs 26 To our knowledge there are no large scale studies reporting its efficacy against morphine induce d nausea and vom iting in dogs On the other hand use of n on pharmacological strategies as a supplementary tool in the management of nausea and vomiting are gaining prominence in human medicine In humans, there is a large body of clinical evidence that supports the effectiveness of acupuncture in preventing nausea and vomiting related to surgery 27 30 and chemotherapy 31 34 E lectr ical stimulation (electroacupuncture EA ) at acupunc ture point (acupoint) PC 6 significantly reduced the number of vomiting episodes induced by morphine and cyclophosphamide in ferretcs. 35,36 A cupuncture significantly reduced th e incidence of vasopressin induced retching and vomiting in dogs. 37 Other studies reported that acupuncture at acup oints PC 6, BL 20, BL 21, CV 12 or LIV 1 3 was effective in preventing vomiting induced by xylazine in dogs 38 40 In the acupuncture group s the incidence of vomiting in dogs receiving acupuncture at PC 6 (33.3%) BL 20 (16.7%) BL 21 (16.7% CV 12 (50%), or LIV 13 (16.7% ) was lower than th ose receiving non acupoint treatments ( ranges from 44 to 67% ) However, the se reports were published in a foreign language (Korean) therefore no t widely read Furthermore, a few stud ies have indicated that electro acupuncture of ST 36 and PC 6 improved gastric dysrhythmia and accelerated gastric emptying via vagal mechanisms in dogs 41,42 and enhanced migrating gastric motor complexes in humans 43 thereby reducing nausea
16 and vomiting. The effect of acupuncture has not been extensively assessed in dogs for controlling nausea and vomiting associated with opioid administration. Therefore, a randomized sham controlled study wa s conducted to assess the effect of maropitant, acepromazine and electro acupuncture on the incidence of vomiting in dogs after morphine administration prior to induction of general anesthesia. Outc ome assess ment s includ e d the incidence of vomiting or retching (V/R) the number of V/R events, time to onset of first V/R event and duration of V/R The s econd objective wa s to determine the incidence of signs of nausea the nausea score, and the sedation score in each treatment gro up We hypothesized that treatment with maropitant, acepromazine, and EA before morphine would prevent or decrease the incidence of V/R the number of V/R events and the severity of signs of nausea. We also hypothesized that dogs treated with EA would provide a greater degree of s edation compared to dogs treated with placebo, sham and maropitant Pathophysiology of Vomiting Definition s and Mechanisms T he physical act of vomiting can be divided into three components: nausea, retching and vomiting 23,44,45 Nausea is an unpleasant subjective experience that closely related to part of the emetic center in the medulla of the brain. 46 I t is difficult to recognize and detect nausea in dogs Common s igns associated with nausea in dogs are ptyalism, lip licking, swallowing, tachycardia, nervousness, restless ness hiding or seeking attention, s hivering, panting, and yawning which are triggered by general activation of the sympathetic and parasympathetic branches of the autonomic nervous system 23,47 Increased salivation stimulates swallowing, which stimulates relaxation of
17 the gastroesophageal sphincter. Bicarbonate rich saliva secreted by the salivary glands helps provide an alkaline buffer to prevent damage to the esophagus from the acidic contents of the stomach. 23,47 Retching is the rhythmic contractions of the diaphragm and abdominal muscles without expu lsion of gastric contents 47 These actions produce decreased intra thoracic pressure and increased intra abdominal pressure 48 Possible purp oses for retching include of the neural circuitry that creates a vomiting episode, empty ing of the proximal duodenal co ntents into the stomach, and facilitat ion of the movement of gastric contents into the esophagus by relaxing the lower esophage al sphincter 49 51 Vomiting is initiated by vigorous and coordinated contractions o f the diaphragm and the abdominal muscles resulting in ejection of stomach contents through the mouth. 47 Because vo miting can be easily quantified by frequency of occurrence and by the volume of emesis, it is a more objective measure than nausea. 52 Du ring retching and vomiting, animals adopt a characteristic posture presumably t o optimize compression of the stomach and to minimize strain on muscles that are not involved in vomiting. 53 Vomiting must be differentiated from regurgitation, dysphagia (difficulty swallowing), and various forms of esophageal dysfunction. Regurgitation is a passive expulsion of partially or completely undigested food or liq uid from the esophagus and/or stomach through the mouth without effort or muscular contractions (i.e., through gravity and body position). 54 Dysphagia is difficulty swallowing and involves active but ineffective muscular contractions and may produce movements that closely resemble retching, however, the process represents a dysfunctional movement of liquid and/or food into, not out of, the GI tract. 55
18 Anatomical Structures Related to Nausea and Vomiting Vomiting is a complex reflex act ion that can be triggered by b oth neural and humoral pathways and is ultimately mediated neurologically by activation of emetic center. 56,57 This is the ar ea that initiates, regulates, and organizes the vomiting reflex. Rather than being in a specific and discrete location, the emetic center is a collection of neurons distribut ed within the medulla oblongata 57 There are four main contributors which mediat e nausea and vomiting 48,57 The vomiting reflex can be initiated by the emetic center after receiving emetogenic stimuli directly or indirectly from (1) the chemoreceptor trigger zone, (2) the visceral vagal and sympathetic afferent pathways, (3) the higher centers of the brain, or (4) the vestibular apparatus in the CNS When activated, motor pathways descend from the emetic center and trigger multiple e fferent pathways that innervate different systems which contribute to vomiting 58,59 These motor impulses travel within the 5 th 7 th 9 th 10 th and 12 th cranial nerves to the upper gastrointestinal tract, within vagal and sympathetic nerves to the lower gastrointestinal tract, and within spinal nerves to the diaphragm and abdominal muscles. 59 Chemoreceptor trigger zone (CRTZ) The C R TZ has been identified within the area postrema (AP R ) region on the floor of the fourth ventricle 56 T he APR is directly connected to the nucleus tract us solitarius ( NTS ) and the dorsal motor nucleus of the vagus (DMV) that receives direct vagal afferent signals, specifically emetic signals arising from enterochromaffin (EC) c ells of the GI tract 57 However, the APR is not essential for vomiting induced by the activation of vagal nerve afferents 60 Additionally w hile the APR is richly vascularized it is not protected by the blood brain barrier 61 The APR capillary endothelium lacks tight
19 junctions and is not surrounded by glial cells and making it easily permeated by emetogenic substances regardless of their lip id solubility or molecular size 58 This allows the C R TZ to detect chemical stimuli in the circulating blood as well as in the cerebrospinal f luid (CSF) 60,62 Visceral v agal and s ympathetic a fferents The vagal and sympathetic afferent neurons originate from the GI tract, particularly the duodenum, as well as other areas such as the urinary and reproductive system, liver, pancreas, per itoneum, and cardiac vessels 48 T he vagal nerves primarily carry afferents from the s tomach and duodenum while the sympathetic nerves primarily carry afferents from the rest of the intestines 23 The GI wall contains mechanoreceptors and chemorecept ors which help to detect over distention of the intestinal wall (e.g., acidity, alkalinity, hypertonic fluids, temperature extremes, and irritants), respectively 57 Enterochromaffin (EC) cells, which are located in the intestinal mucosa respond to emetogenic substances within the GI tract or in the blood circulating to the GI tract 62 For example cytotoxic drugs that enter the GI tract damage the EC cells causing release of serotonin ( 5 hydroxy tryptamine, or 5 HT ), which stimulates the vagus nerve s via 5 HT 3 receptors resulting in activation of the CRTZ or direct stimulation of the emetic center The n eurotransmitter serotonin (5 hydroxy tryptamine, or 5 HT) which is released by d amaged EC ce lls, stimulates the vagus nerve via 5 HT 3 receptors resulting in activation of the CRTZ 57,62,63 Higher c enters of the b rain The higher brain centers i ncluding the cerebral cortex and the limbic system can contribute to stimulation of the emetic center Hydrocephalus, head traum a, increased intracranial pressure, inflammatory diseases, or neoplasia related to the brain can
20 trigger nausea and vomiting via direct stimulation of the emetic center 45 Connections between the C R TZ an d the higher brain centers have been postulated as an explanation for coordinated responses of anticipatory nausea and vomiting in humans 57,64 N ausea and vomiting can result from overstim ulation of the cerebral cortex or the limbic system in response to events or sensory stimuli, such as shock, fear, distress, excitement, pain, taste, or smell. 65 It is uncertain to what ex tent the limbic system initiates nausea and vomiting in animals, although some animals tend to show signs of nausea and may vomit when experiencing stress, fear or excitement 66 Vestibul ar a pparatus The vestibular apparatus detect s body motion and balance and has been directly implicated in creating emetogenic stimuli. 57 Vestibular stimulat ion passes through the CRTZ before activating the emetic center. 47 M otion sickness, inflammation of the labyrinth, or lesions i n the cerebellum results in nausea and vomiting via this pathway. 47 I n dogs it has been shown that motion within the semicircular canals is transduced to the vestibulocochlear neurons that ultimately synapses in the CRTZ, whereas in cats, it synapses in the emetic center. 56 Consequences and Complications of Vomiting Simple vomiting rarely causes problems, but on occasion, can lead to such serio us consequences as aspiration pneumonia which can progress to acute respiratory distress syndrome 67 Under normal circumstances, the gag reflex and coughing will prevent aspiration ; however, these protective reflexes are compromised in animals that are sedat ed or under anesthesia Additionally, profuse v omiting leads to dehydration, electrolyte depletion and disturbances in acid base balance, w hich may further complicat e the initial clinical situation or disease If vomiting is prolonged and
21 excessive, it can cause hypovolemic sh ock and severe life threatening a cid base and electrolyte disturbance s 68,69 Pathophysiology of Opioid Induced Nausea and Vomiting Opioid s are useful agents for treating pain of various etiologies; however, some of the ir side effects such as nausea and vomiting may result in limitations to their use. Morphine and hydromorphone are c ommonly used o pioid analgesics in veterinary medicine that and are known to have emetogenic effect s. They appear to produce vomiting more commonly than fentanyl, mepe ridine, buprenorphine, and butor phanol. 6 The emetic effects of most opioids are usually apparent within 5 10 minutes of intramuscular or subcutaneous administration 6 Opioids cause nausea and vomiting through multiple mechanisms, including direct stimulation of the C R TZ, inhibition of gut motility, and stimulation of the vestibular apparatus 6,70 The effects are mediated via interaction with specific opioid receptors ( and subtypes) in the brain and spinal cord and at peripheral sites 71 O pioid s stimulate and receptors at the level of the CRTZ which activates the emetic center 72 Opioids also activate the emetic center and CRTZ directly through th e stimulation of histamine (H 1 ) or dopamine (D 2 ) receptors found in these areas. 6 In the GI tract the emetic mechanism appears to be mediated by the a ctivation of and receptors in the digestive tract leading to reduced GI motility and transit time 73 In dog s morphine at a dose of 0.05 mg/kg (SC) cause d gastric relaxation and subsequently vomiting. 19 Opioids also create gastropare sis and ileus 74 The resulting g astric distention causes stimulat ion of the visceral mechanoreceptors in the gut wall which may result in vomiting 75 R etention of electrical slow waves in the longitudinal muscle of
22 bowel that fail to initiate action potentials and contraction of the circular muscle may also lead to decreased peristal tic waves and possibly gut distention (and stimulation of the mechanoreceptors ) 76 The vestibular apparatus is stimulated directly by most opioids, possibly through mediation of receptors on the vestibular epithelium ; however the mechanism by which this occu rs remains unclear 70 I ncreased of vestibular sensitivity is likely to cause nausea and vomiting in ambulatory patients. 70 M orphine Induced Nausea and Vomiting Morphine is the principal alkaloid derived from op ium and is the opioid agonist to which all other opioids are compared in terms of receptor binding, efficacy and clinical effects 17 Although other opioids are known to have greater analgesic potency to date, none is more effective than morphine at relieving pain 17 Morphine is a pure opioid agonist with a ffinity primarily at the receptor and, to a lesser degree, at the and receptors. 71 I t can cross the blood brain barrier and act on both peripheral and central opioid receptors. 6 Morphine produces the majority of its pharmacological effects by binding to satura ble stereospecific opioid receptors that are widely but unevenly distributed throughout the CNS and peripheral organs 77 These effects include analgesia, sedation, and some adverse effects such as respira tory depression nausea as well as vomiting, dysphoria, panting, bradycardia, salivation, hypothermia, and constipation in dogs 4,13,17 The recommended dose of morphine for pain management in dogs ranges from 0.05 to 2 mg/kg intravenously ( I V), intramuscularly (IM), or subcutaneously (SC) with a suggested dosing interval of 2 to 6 h ours 4,17 Vo miting may occur after IV, IM, SC, or epidural administration of morphine 10,20,78,79 The emetic effects of morphine usually
23 occur within 2 minutes of intrav enous administration (0.3 mg/kg ), 13 or within 5 minutes following intramuscular a dministration at a dose of 0.5 mg/kg 7 Studies have shown a high incidence of vomiting ( 6 of 6 dogs ) after IM administration of morphine (1 mg/kg) 80 Another study reported that 0 of 30 (0%) 9 of 30 (30%), and 24 of 30 (80%) dogs vomited following IM administration of morphine at dose s of 0, 0.22, and 1.10 mg/kg, respectively. 81 A m ore recent study reported that 5 of 8 (63%) dogs vomited after being given 1.0 mg/kg morphine IM. 82 Similarly, morphin e, SC, at 0.5 mg/kg caused 5 of 8 ( 63% ) of dogs to vomit and defecat e 20 The emetic effects of morphine are dose related. 7 It can have a biphasic action on the CNS to either induce or preven t emesis 13 Low dose s of morphine (e.g. 0.3 mg/kg IV ) have been shown to induce vomiting, whereas hi gher dose (e.g. 1 2 mg/kg, IV) reduce the incidence of vomiting in dogs 13 The dose dependent e metic and anti emetic effects of morphine are due to its low lipid solubility 83 L ow dose s of morphine reach the superficially located C R TZ, which is outside the blood brain barrier, in sufficiently high concentrations to act on the emetic recep tors and therefore cause vomiting Conversely, higher dose s allow eno ugh morphine to reach the emetic center located more deep l y in the medulla and within the blood brain barrier, where it blocks the emetic effects on the C R TZ. 13,21,83 Both the emetic and antiemetic effects of morphine on the C R TZ and emetic center respectively, can be antagonized by the opioid antagonists nalorphine and naloxone which can cross the blood brain barrier, demonstrating that activation of opioi d receptors may be necessary for vomiting 13,83 In addition, the emetic effect of morphine was prevent ed by ablation of the C R TZ in dogs 21
24 More recently, a study reported that the vasopressinergic pathway may be involve d in the nausea and vomiting effects of morphine 84 In ferrets, i ntravenous administration of morphine alone, but not ondansetron alone, was associated with a significant increase in plasma arginine vasopressin concentrations with 5 of 6 animals exhibit ing s igns of nausea and retching. The mechanism remains u nclear and f urther studies are needed to investigate the roles of vasopressin in nausea and vomiting related to morphine administration It is also well described that central ( intracerebroventricular ) or systemic administration of morphine delay s or inhibit s GI motility which i s frequently associated wit h vomiting events. 18,85,86 Several stud ies demonstrate that stimulation of central opioid receptor s delays gastric emptying and GI transit time in animals 18,70 This effect may be mediated via peripheral adrenergic pathway s 86 However, the mechanism of inhibitory effects of central opioid receptor stimulation on GI motility remains unclear. Antiemetics Several different neurotransmitters have been associated with neural signals that stimulat e nausea and vomit ing, including serotonin (5 HT 3 ), dopamine (D 2 ), histamine (H 1 ), acetylcholine (muscarinic M 1 ), and substance P (neurokinin NK 1 ) 87 There are differences among species (i.e. dogs, cats, and human s ) with respect to th e importance of various neurotransmitter receptor signal transductions 87 For example, D 2 dopamine receptor agonists ( i.e apomorphine ) readily induces vomiting in dogs, but not in cats 88 Conversely x ylazine, an 2 adrenergic agonist more re adily stimulate s vomiting in cats than in dogs 88,89 Successful antiemetic therapy involves blocking one or more of the
25 receptor s for these neurotransmitters thereby inhibiting the activation of the C R TZ and the emetic center. In the emetic center seroton ergic (5 HT 1 ), 2 adrenergic, and neurokinin (NK 1 ) receptors are considered the primary mediators, with dopamine rgic (D 2 ) receptors being a secondary mediator, for inducing vomiting. 6,56 In the CRTZ, dopamine rgic (D 2 ) serotonin ergic (5 HT 3 ), histamine rgic (H 1 H 2 ) neurokinin (NK 1 ) acet yl choline (M 1 ), and enkephalin (ENK ) receptors are important. 6,56 In the vestibular apparatus, acetylcholine (M 1 ) histamine (H 1 ) as well as N methyl D aspartate (NMDA) play a role, especially in motion sickness. 56 M ore recently, NK 1 have been shown to be involved in pathogenesis of motion sickness. 56 In the abdominal vagal afferents, s erotonin ergic (5 HT 3 ) receptor is the primary mediator for inducing vomiting through the emetic center or the NTS 56 Serotonin r eceptor a ntagonists A ctivation of the 5HT 3 receptor by serotonin plays a significant role in nausea and vomiting. 87 The 5HT 3 receptor is found both peripherally on vagal nerve terminals and centrally in the CRTZ 48,87 These receptors are normally stimulated by serotonin released from the EC cells of the GI mucosa in response to damage to the gastrointestinal tract by cytotoxic agents (e. g. chemotherapy agents or radiation therapy ), or by mechanical damage such as obstruction or surgical procedures on the intestinal 5HT 3 serotonergic antagonists block these receptors by preventing serotonin stimulation of the vagal afferents and the C R TZ 57 Several selective 5HT 3 re ceptor antagonists effectively inhibit vomiting induced by cisplatin and cyclophosphamide in dogs and ferret s 90,91 Ondansetron and dolasetron are members of this class of
26 antiemetic drugs and have been studied and used extensively in human medicine T hey seem to be safe antiemetic alternatives in veterinary medicine. 48,92 Ondansetron and dolasetron are effective in preventing and con trolling nausea and vomiting in dogs especially related to cancer chemotherapy 63,93 Side effects in dogs and cats have yet to be fully described 92,93 I n humans, these drugs have been reported to cause mild headaches, mild elevat ions in transaminase enzymes constipation, or diarrhea 94 Electrocardiographic al changes, including PR and QT prolongation and QRS widening have been reported in people 95,96 Dopamine r eceptor a ntagonists Dopamine is another neurotransmitter that stimulates vomiting via the CRTZ Activation of D 2 dopaminergic receptor s in the CRTZ mediate s vomiting due to apomorphine in dogs 88 Dopaminergic antagonists, such as metoclopramide, are effective antiemetics for many causes of vomiting Metoclopramide is known for its potent dopaminergic antagonism in the CNS similar to that of phenothiazines. It has additional prokinetic effects through the release of acetylcholine in GI smooth muscle, leading to enhanced gastric and upper intestinal motility, which may contribute to its overall antiemetic effects 87 In cats, stud ies show that dopamine injected into the cerebral ventricles induce s vomiting and that m etoclopramide is not effective in preventing this whereas s elective 2 adrenoceptor antagonists inhibit dopamine induced vomiting 97 This s ugges ts that activation of 2 adrenoceptors instead of dopamine receptors may play a major role in triggering vomiting in cats Unfortunately, dopaminergic antagonist s ha ve no selectivity for dopaminergic receptors in the CRTZ ; it
27 can produce sedative and extrapyramidal motor disturbances by acting on dopaminergic systems in other part of the CN S 87,92 Histamine r eceptor a ntagonists Both H 1 and H 2 histamine rgic receptors are found in the CRTZ, whereas histamine H 1 receptor are present in the vestibular nucleus 87 H istamine is involved in vomiting in response to vestibular st imulation that may be directed either through the CRTZ, or directly to the emetic center. 48 The effect of histaminergic nerve transmission on the stimulat ion of vomiting is more important in dogs than cats 87 Histaminergic antagonists block histamine re ceptors and thus intercept nerve transmission to these areas. H 1 a ntihistamine s also ha ve antimuscarinic activity which can help decrease vomiting caused by stimulation of the vestibular system and CRTZ 87 Histamine blocking drugs used to control vomiting include diphenhydramine, dimenhydrinate, promethazine, and meclizine. They are mainly used to control vomiting due to motion sickness. D iphenhydramine however, is found less effective in dogs than in human s in controlling vomiting 98 The most commonly seen adverse effects are anticholinergic effects (dry mouth, urinary retention), and CNS depression (lethargy, somnolence, and s edation) with diphenh ydramine and dimenhydrinate hav ing the greatest sedative effects. 92 Phenothi a zines At low dose s p henothiazines block stimulation of vomiting in the CR TZ because of their antidopaminergic and antihistaminergic effects. They also target 2 adrenergic receptors in the emetic center 56,87 At higher dose s they exert cholinergic actions at other CNS centers. 87 C hlorpromazi ne, prochlorperazine, and ace promazine are the most commonly used phenothiazines as antiemetics in veterinary medic ine
28 One consideration in selecting a phenothiazine is differences in their adverse effects, which correlate with varying degrees of anticholinergic, antihistaminic, and adrenergic blocking effects. Generally, acepromazine is more potent in sedation effe ct than other phenothiazine derivatives including chlorpromazine and produce s marked sedation at relatively low doses, but has moderate extrapyramidal effects 92 Prochlorperazine, on the other hand, is associated with less sedation and fewer anticholinergic effects, but may be associated with a greater incidence of extrapyramidal symptoms, including rigidity, tremors, weakness and restlessness when given at high d osages. 99 A side from their sedative effects, phenothiazine antiemetics can also cause hypotension due to the ir vasodilatory properties. 92 This effect is thought to be mediated by adrenergic inhibit ion and is not, therefore, recommended in dehydrated animals. Acepromazine is a w idely used sedative in veterinary medicine to induce marked sedation muscle relaxation and a decrease in spontaneous activity attributable principally to central dopaminergic antagonism 78 Acepromazine is not reversible and does not provide analgesia For these reasons, it is best administered in conjunction with opioid analgesics as part of a balanced regimen for painful diagnostic and surgical procedures. 78 In deed the combination of acepromazine and opioid produces excellent and balanced neuroleptanalgesia, which facili tates han dling of animals and reduce s the dose of injectable and inhalational anesthetics required to induce a nd maintain anesthesia 100 In addition to its sedative effects, acepromazine decrease s the incidence of vomiting produced by opioids in dogs 7 When it is administered 15 minutes before opioids, acepromazin e lowers the incidence of vomiting induced by opioids (i.e. morphine, hydromorph o ne and oxymorph o ne) b y approximately 30 40 % compared to
29 dogs receiving acepromazine 15 minutes after opioids 7 Dogs that are treated simultaneously with acepro mazine and opioids do not show a reduction in the incidence of vomiting. Cholinergic r eceptor a ntagonists Cholinergic receptors (muscarinic M 1 receptor s ) are present in several regions of the CNS including vestibular nuclei, the CRTZ, and nucleus tractus solitari e s (NTS) 101 They have been typically associated with motion sickness. 101,102 Cholinergic antagonists act via inhibition of muscarinic receptors and thus block cholinergic afferent pathway transmission from the GI tract, the vestibular system, and the CRTZ to the emetic center 87 Anticholinergics of this class include atropine, scopolamine, aminopentamide, propantheline, and isopropamide. Scopolamine has been shown to effectively treat motion sickness in humans, 103 but is less effective in dogs and cats 87 Cholinergic antagonists produce adverse effects that include xerostomia (dry mouth) sedation, visual distur bances, drowsiness, dysphoria, confusion, gastrointestinal ileus, and disorientation 92 Neurokinin 1 r eceptor a ntagonists Substance P (NK 1 ) the most potent agonist of the tachykinin neuro k inin 1 ( NK 1 ) receptor, plays a key role in the pathophysiology of nausea and vomiting 104 It is found in high concentrations in areas of the brain stem involved in vomiting including the emetic center and CRTZ 105,106 Recent studies have shown that the NK 1 recept or is also highly expressed in gastric motor efferents in the dorsal vagal complex ( DVC ) and activation of NK 1 recepto r s in this region result in gastric fundic relaxation in rats NK 1 receptor antagonists i nhibit the se receptors and abolish the fundic relaxation 107
30 Maropitant is the first drug of this class developed specifically to prevent vomiting in veterinary patients. 108 It is a lipophilic compound that is readily able to penetrate the blood brain barrier and bind to the NK 1 receptors located at the emetic center and CRTZ. 109 Maropitant NK 1 receptor complex blocks the co mmon final pathway of the neural and humoral pathways within the central emetic circuitry, and thus impedes or attenuates the stimulation of the emetic reflex 109 Maropitant ha s been shown to prevent acute vom iting associated with a wide range of clinical conditions, such as parvoviral enteritis, gastro enteritis resulting from dietary indiscretion, and pancreatitis 110 It was later established in field efficacy studies that maropitant is effective against acute and delayed vomiting in canine cancer patients undergoing ci splatin or doxorubicin chemotherapy 25,111,112 Maropitant also shows effectiveness in preventing vomiting caused by motion sickness in dogs and cats. 113,114 Adverse effects reported with maropitant include ataxia, anorexia, diarrhea, and injection site soreness 108 however m aropitant has a low acute toxicit y and is well tolerated in healthy dog s 92 Caution should also be taken when administer ing maropitant in dogs with hepatic dysfunction because cytochrome P450 isoenzymes are primarily responsibl e for the biotransformation of m aropitant 92,109 Maropitan t may increase the risk of arrhythmias in dogs with bradycardia or underlying heart diseas e. 108 P ain at the injection site has been frequently reported after subcutaneous administration and is thought to be related to the amount of maropitant that is not bound to the adjuvant compound sulphobutylether beta cycldextrin Study data suggest that refrigerat ing Cerenia may significantly reduce or eliminate pain associated with SC
31 injection 115 This is believed to be caused by reduced unbound maropitant in a chilled solution. 115 Acupuncture Acupuncture a branch of traditional Chinese medicine (TCM) and traditional Chinese veterinary medicine (TCVM) has been practice d as a medical modality to address various conditions, including GI disorders, in the Chinese community for thousands of years 116,117 Over time, acupuncture has spread to other Asian countries such as Vietnam Japan, and Korea. It remains a comprehensive form of healthcare for the treat ment of various diseases and for pain management in China and other Asian countries Its use and clinical benefits have also been do cumented in veterinary medicine 11 8 Like human acupuncture, v eterinary acupuncture also dates back thousands of years, at least to the reign of the Chinese Emperor Zhou mu, circa 900 BCE, 118 or to the earlier Shang Dynasty. 119 Ancient e quine acupuncture has provided important therapeutic foundations for mode rn veterinary acupuncture practice, including traditional Chinese medical doctrines of illnesses in animals and methods for acupuncture treatment. 118 In 1971 ever since James Reston, a reporter for the New York Times, wro te about his experience of receiving acupuncture treatment for pain relief after undergoing diplomatic trip to China 120 Since then, the American medical community has become increasingly interested in acupuncture and may researchers have initiated serious scientific investigations of its clinical benefits. Over the last millennia, this treatment modality h as spread throughout Europe, India, Africa, and Australia. In 1974, in cooperation with the
32 National Acupuncture Association (NAA), the International Veterinary Acupuncture Society (IVAS) was f oun ded in the United States. Th is organization promotes the practice of veterinary acupuncture and encourages addition of acupuncture into modern veterinary medical practices. Veterinary acupuncture has expanded dramatically since then. In 1997, the National Institutes of Health (NIH) created a 12 member panel to evaluate the scientific documentation on the clinical efficacy of acupuncture Th is panel s consensus statement indicated that acupuncture appeared to be clinically effective for 14 heath related pro blems in humans including nausea and vomiting related to pregnancy, surgery, and chemotherapy. 121 However, the panel concluded that many studies provided equivocal results because of issues with study design, sample size, failure to use appropriate controls, and other factors. In spite of these difficulties, the panel concluded that a cupuncture showed efficacy for three conditions : postoperative nausea and vomiting (PONV), chemotherapy associated nausea and vomiting, and postoperative dental pain. 121 The evidence was insufficient to evaluate treatment of other conditions for which acupuncture is used. The panel arrived at an conclusion that studie and more well designed, controlled studies are needed to determine the efficacy of acupuncture 121 Acupuncture treatment is administered by inserting fine gauge acupuncture needles into acupoints through skin, muscle, vessel s fascia, or other tissue. In addition to manual stimulation, e lectrical stimulation ( electroacupuncture EA ), laser generated light, and inje ctable agents (aquapuncture) has been developed to stimulate acupoints.
33 Manual acupuncture or dry n eedling, in which needles are left on the body for minutes, rank s as the most common form of veterinary acupuncture. EA entails attaching one end of an electrical lead to the shaft of an acupuncture needle and the other end to an electrical stimulator. The amplitude of the stimulus at different frequencies is adjusted depending on the patient s tolerance. Usually, the amplitude of the stimulation is increased until one of the needle electrodes shows a slight twitch, and then the amplitude is decreased sligh tly until the twitch disappears. The technique of aquapuncture is performed by instilling an appropriate volume of a sterile solution using a hypodermic needle and syringe into each of one or more acu points. Acupuncture for Nausea and Vomiting Acupuncture offers potential as a minimally invasive and safe antiemetic therapy in veterinary practice. Although the physiological mechanisms by which stimula tion of acu points affect nausea and vomiting remains largely unknown, mounting evidence from both clinical trials and retrospective studies suggests that th is practice is efficacious for nausea and vomiting associated with surgery or chemotherapy i n p eople 27 34 Acupoints that have been studied in human and animal models include Pericardium 6 (PC 6, in Chinese Nei guan ), Stomach 36 (ST 36, Zu san li ) Gall b ladder 34 (GB 34, Yang ling quan ), Bladder 10(BL 10), Bladder 11 (BL 11), Bladder 20 (BL 20, pi shu ), Bladder 21 (BL 21, wei shu ) Conception Vessel 12 (CV 12), and Liver 13 (LIV 13) 38 40,122,123 Among the se acupoints ST 36 and PC 6 are the 2 most commonly used acu points in the treatment of gastrointestinal disorders with PC 6 being the most scientifically investigated antiemetic acupoint. 124
34 Mechanisms The exact mechanism (s) by which acupuncture may control and prevent nau sea and vomiting has yet to be established. Several physiological mechanisms of acupuncture in general have been suggested 125 Proposed mechanisms include changes in neurotransmitters, along with mechanisms that af fect vagal modulation and gastric relaxation. The most probable m echanism of antiemetic action resulting from acupuncture stimulation may be attributed to the release of endogenous opioids and modulation of other neurotransmitters in the body 126 Many experimental studies have shown that acupuncture influences the endogenous opioid system, in particular release of endorphin from the hypothalamus into the cerebrospinal fluid 127 The release of endorphin is thought to be due to activation of fiber synapses within the dorsal horn where acupoint activated skin sensory fiber s end 128 endorphins are considered to have an antiemetic effect mediated via receptors. 129 Another proposed mechanism is th at acupuncture stimulates type and type afferent ne rves, which subsequently stimulate the spinal cord. These signals converge in several nuclei in the brain stem, such as the nucleus tractus solitarius (NTS ) and dorsal motor nucleus of the vagus (DMV ), which play an important role in the mediation of vomit ing 130 134 In addition to the NTS and DMV, acupuncture may also activate some other nuclei in the brain. EA at PC 6 activates neurons in the arcuate (ARC) nucleus and periaqueductal gray (PAG) and inhibits the a ctivity of the rostral ventrolateral medulla (RVLM) of the brain stem, suggesting the existence of a n ARC PAG RVLM neuronal pathway in mediating EA inhibition on visceral excitatory cardiovascular r eflexes 135 Although the study focuse d on the cardiovascular syste m similar mechanisms might be utilized to produce the
35 effects of EA on GI motor function as the PAG has been shown to be responsible for receptor agonist and neurotensin induced inhibition of intestinal transit 136 Acupuncture is also thought to have a direct influence on the smooth muscle of the GI tract. 125 EA at P C 6 reduced gastric tachyarrhythmia in induced motion sickness studies 137,138 enhanced the percentage of regular slow waves seen by electrogastrography 41 and suppressed retrograde peristaltic contractions and reduced vomiting episodes induced by vasopressin in dogs 37 Zou and colleagues speculate d that acupuncture may work through a somatovisceral reflex after they found EA at P C 6 inhibited the rate of transient lower esophageal sphincter relaxations triggered by gastric distension in human s and was not inhibited by naloxone 139 Recent functional magnetic resonance imaging (fMRI) studies reported that acupuncture may influence the cerebellar vestibular neuromatrix through the activation of the left superior fron tal gyrus, anterior cingulated gyrus, and dorsomedial nucleus of the thalamus, as well as nausea specific substrates in the cerebellum. 140,141 This did not occur with penetrating sham needling at a non acupuncture point.
36 CHAPTER 2 MATERIAL S AND METHODS Research Design This study used a randomized, sham and placebo controlled design, examining the effect of maropitant, acepromazine, si ngle acupoint EA and multiple acupoint EA for the prevention of nausea and vomiting or retching (V/R) associated with preanesthetic administration of morphine in dogs. This study was approved by the Institutional Animal Car e and Use Committee (IACUC) of the University of Florida (IACUC study #201207528 ). Study Population The target population included dogs at least six month s of age, of any breed, sex, and body weight that were presented to the Merial Shelter Medicine clinical program at the University of Florida College of Veterinary Medicine between July 2011 and August 2012 T hese dogs were scheduled t o receive morphine as part of their preanesthetic medication prior to induction of anesthesia for routine procedures such as castration, ovariohysterectomy (OHE), or dental cleaning T o avoid potential confounding variables, only dogs that were classified as American Societ y of Anesthesiologists (ASA) status I (healthy, no systemic disease) or status II (mild systemic disease; no functional limitations) were included in the study 142 Exclusion criteria include nausea, vomiting, inappetence, or diarrhea noted within the previous two days. Dogs receiving concurrent medications with potential for gastrointestinal irri t ation such as non steroidal anti inflammatory drugs or prednisolone, were excluded due to a potentially high er risk of nausea and vomiting 23 Any dog that had received another medication classified as antiemetics, acid reducers or coating agent s within two days
37 before the procedure were also disqualified from participation Dogs suspected to have one or more with a primary gastrointestinal disorder, such as gastric ulcers, inflammatory bowel disease, or pancreatitis, were d isqualif ied from participation. A ggressive dogs were also excluded from the study Sample Size The expected incidence of vo miting or retching in the placebo (saline) group of th is study was taken from data collected in a preliminary study (Robertson and colleagues unpublished data). I n that pilot study, which included 48 dogs and 3 treatment groups, m orphine administration (0.5 mg/kg, IM) produced vomiting in 65 % of dogs The efficacy of EA at PC 6 for 5 minutes reduced the incidence of vomiting following morphine by approximately 30 % Therefore, a 30 % or greater reduction in the incidence of vomiting /retching wa s determined to be a meaningful response to treatment in the current study On the basi s of a two sided type 1 error with sign ificance level = 0.05 and power of 0.8 it was determined that a sample size of at least 37 dogs in each group was needed to detect a reduction in the incidence of vomiting /retching of 30 % 143 Experiment P rotocol 222 dogs meeting the in clusion criteria were random ly assigned to one of si x treatment groups by use of a computer program 144 Group 1 was the placebo ( control ) group and rece ived saline. G roup 2 and 3 were treated with maropitant and acepromazine, respectively. G roup 4 received EA at a single acupoint, Pericardium 6 (PC 6). G roup 5 receiv ed EA at PC 6 and four additional acupoints: Stomach 36 (ST 36), Ga llbladder 34 (GB 34), Bladder 20 (BL 20 ) and Bladder 21 (BL 21). G roup 6 dogs were treated with sham non acupoint EA (sham control) Food was withheld for 8
38 hours prior to surgery but water was provided ad libitum until administration of morphine Prior to enrollment, each dog was weighed and examined to ensure that it was in good general health and fulfilled inclusion criteria Heart rate, respiratory rate, rectal temperature and body condition score was recorded. Each d og w as temporarily housed in a standard cage. Treatme nt s w ere administered starting at time 0 ( injectable treatments) or starting at time 0 (acupuncture treatments) At time 20 minutes dogs were injected with morphine and were observed for 20 minutes V omiting or retching including time to onset of first episode, number of episodes and duration up to 20 minutes were recorded D ogs were considered to have completed the study at time 40 (minutes) Video recordings were made of each dog before treatment (2 4 minutes), after treatment (2 4 minutes) and after morphine administration (20 minute video segment) and were later used for assessm ent of nausea and sedation by a blinded observer. At completion (Time 40) all dogs were anesthetized f or procedures as scheduled. The o verall methodology of the study is schematically shown in Figure 2 1 Pharmacological Treatments Dogs that served as the placebo group received saline solution ( 0.9% NaCl Hospira Inc., Lake Forest, IL, USA) Saline solution was administered by SC injection at a volume of 0.1 m L /kg. The volume of saline was selected to equal the volume per kilogram bodyweight of maropitant given at 1 mg / kg Maropitant ( M aropitant c itrate 10 mg/mL Cerenia, Pfizer Inc., New Y ork, USA ) was administered at a dosage of 1 mg/kg, SC Acepromazine ( A cepromazine m aleate 10 mg/kg, Phoenix Pharmaceutical Inc., St. Joseph, MO, USA ; diluted with sterile saline to a concentration of 1 mg/mL) was administered at recommended premedication dose of 0.05 mg/kg IM 8,92 Morphine
39 ( M orphine s ulphate 15 mg/m L Baxter Healthcare Corporation, Deerfield, IL, USA ) was administered at recommended premedication dose of 0.5 mg/kg, IM 8 All SC injections were made at a single site in the loose skin over the shoulder blades. All IM injections were made at a single site into the middle gluteal muscle (midway between the greater trochanter of the femur and the wing of th e ilium) 145 Electroa cupuncture T reatments Acupuncture entails insertion of sterile acupuncture needles at acupoints through skin, muscle, vessel, or fascia. 146 Acupuncture needles (0.5 inch in length and 0.22 mm in diameter ; 34 gauge Suzhou Shenlong M e dical Apparatus Co., Ltd., China ) were used in toy (less than 5 kg) small (5 10 kg) and medium (10 20 kg) sized dogs, whereas acupuncture needles one inch in length and 0.25 mm in diameter ( 32 g auge Suzhou Shenlong M e dical Apparatus Co., Ltd., China ) were used in large (20 40 kg) and giant (greater than 40 kg) dogs 147 Depending on the location of acupoints and the size of the dog, the needles were inserted to depths of 3 10 mm into acupoints PC 6 in Group 4 and PC 6, ST 36, GB 34, BL 20 and BL 21 in Group 5 on both sides of the body and then attached to an electrical stimulator (ITO ES 160 Electro Therapy Device, ITO Co., Ltd., OMS, Japan) PC 6, BL 20, and BL 21 were connected bilaterally; ST 36 was connected to GB 34 on each side. A low electrical current ( 6 .0 mA, 200 microsecond ( s ) ) with a frequency of 2 Hz for 10 minutes followed by 10 minutes at 100 Hz was applied After a total of 20 minute s EA was terminated and the needles w ere removed. All dogs were examined for local reactions at the site of needle insertion such as minor bleeding or swelling. All acupuncture treatments were performed by the
40 same certified veterinary acupuncturist throughout the study to avoid technique variability and bias Acupo int Description s In dogs, PC 6 is located on the medial side of the thoracic limb, 2 cun ( Chinese inches, which are proportional unit s ; 148 as a reference, the distance from the center of the elbow to the area just proximal to the carpus is 12 cun ) proximal to the transverse carpal crease of the carpus, in the groove between the flexor carpi radialis and the superficial digital flexor muscles (Figure 2 2 ) 147 ST 36 is located on the craniolateral aspect of the pelvic limb, 3 cun distal to the center of the stifle and 0.5 cun lateral to the cranial aspect of the tibial crest, in the belly of the cranial tibialis muscle (Figure 2 3 ) (as a reference, the distance from the center of the stifle to the lateral malleolus is 16 cun ) 147 GB 34 is located on the lateral side of the pelvic limb at the stifle, in a small depression cranial and distal to the head of th e fibula (Figure 2 4 ) 147 BL 20 and BL 21 are located on the dorsolateral aspect of the spine, 1.5 cun lateral to the caudal border of the dorsal spinous process of thoracic vertebrae T12 and T13, respectively (Figure 2 5 ; as a reference, the width of the last intercostal space is equal to one cun ). 147 The s ham non acupoint used in th is study wa s located on the caudomedial aspect of the pelvic limb, 3 cun proximal to the medial malleo lus of the tibia, in the thin fleshy tissue on the crania l border of the Achilles tendon (Figure 2 6 ; as a reference, on the medial side of the fore limb, it is 13 cun from the medial epicondyle of the tibia to the medial malleolus) This non acupoint is not on any acupuncture meridian and is at least 1 cun away from any neighbor ing acupoints. 147
41 Re cording of V omiting or Retching E vents A vomiting event was defined as reflex act that eject ed GI conte nts from the mouth via forceful and sustained contrac tions of the abdominal muscles R etching was defined as forceful abdominal contractions occurring w ithout expulsio n of GI contents from the mouth The number and timing of each discrete vomiting or retching event was recorded. The clinician, who performed the EA or administered test drugs and morphine was resp onsible for observ ing each dog for 20 minutes after morphine administration. Assessment of N ausea and S edation S igns of n ausea were defined as ptyalism, lip licking, swallowing, nervousness, restlessness, and panting. Each score for clinical signs of nausea was quantified by marking on a four point scale, ranging from 1 (none) to 4 (worst) ( Table 2 1 ). Sedation is defined as a reduction of anxiety, stress, irritability, or excitement by administration of a sedative agent or drug. The degree of sedation was quantified by marking on a five point scale, ranging from 1 ( normal ) to 5 (highly sedated) ( Table 2 2 ). Scores for nausea and sedation were recorded for each dog before treatment as a baseline, at T ime 20 before m orphine administration, and at T ime 30, 35, and 40 after morphine administration. Signs of nausea and sedation were assessed by a n observer who did not know the allocation of treatments and was not the treatment dispenser Rescue Treatment To ensure the welfare of the study dogs, a resc ue antiemetic protocol was devised. A ny dog that experience d five or more V/R events during the observation period following administration of morphine would receive maropitant at a dose of 1
42 mg/kg, SC. Additionally, fluid therapy or any additional treatme nt deemed necessary by the clinician would be initiated Data Analysis Statistical analyses were performed to evaluate for differences in vomiting/ retching nausea and sedation among placebo maropitant, acepromazine, single acupoint EA, multi acupoint EA, and sham non acupoint EA groups. A chi square test was used to detect the difference of categorical variables; whereas a Kruskal Wallis non parametric analysis of variance (ANOVA) was used to detect the difference of continuous variables. The data of the number of V/R events and the duration of V/R was tested with Kruskal Wallis test with post hoc testing by means of the Mann Whitney U test When the ANOVA test gave a significant difference, then the Bonferr oni test was used as a post hoc t est to correct for the number of comparisons performed in the study. There were a total six groups, yielding 15 sets of intergroup comparisons, thus, a corrected P value of 0.0033 (0.05 divided by 15) was considered statistically significant. The level of significance was set at P < 0.05 for ANOVA F or the Bonferroni correction, the level of significance was set at P < 0.0033. All statistical analyses were performed with a statistical software program ( NCSS 6.0.22 Kaysville, UT )
43 Table 2 1 Assessment scale for nausea 1 2 3 4 Lip licking or Swallowing N one N one N one Occasional Moderate Frequent Salivation Slightly increase d (may or may not see a few drops of saliva dripping from the tongue) Moderate increase (more saliva dripping from the tongue and slightly covering the lips) Excessive (saliva is dripping or the fur is soaked with slobber) Panting Mild/occasional panting Increased panting Panting most of the time Attitude/Mentation/ Posture Normal Mild restlessness or depressed; Siting, standing or lying down Moderate restlessness or depressed; Standing, walking or lying down; may bark occasionally Very Restless : pacing back & forth in the cage with/without barking Very Depressed : sitting with head extended/ pressing down, or lying down with head moving down & up sev eral times due to discomfort Table 2 2 Assessment scale for sedation. 1 2 3 4 5 Attitude, Mentation, Posture Alert, playful, or spontaneously inquisitive and tail wagging Awake & alert but qui e t & tail wagging, standing or sitting Tired, standing, sitting or sternal ly recumbent Drowsy, tranquil, recumbent but able to rise Very drowsy, sternal or lateral recumbent & reluctant to rise Response to noise Normal startle reaction (head turns toward noise or dog cringes) Reduced startle reaction (reduced head turn or cringing) Reduced startle reaction (reduced head turn or minimal cringing) Minimal startle reaction Absent startle reaction
44 Morphine 0.5 mg/kg, IM Observation 20 min observation for vomiting/retching assesment of sedation and nausea acore at Time 30, 35, and 40 Group 1 n=37 Saline, 0.5mL/kg, SC Group 2 n=37 Maropitant, 1.0mg/kg, SC Group 3 n=37 Acepromazine, 0.05mg/kg, IM Group 4 n=37 EA: PC6 2Hz for 10min; 100Hz for 10min Group 5 n=37 EA: PC6, BL20, BL21, ST36, GB34 2Hz for 10min; 100Hz for 10min Group 6 n=37 EA: Sham non acupoint 2Hz for 10min; 100Hz for 10min Study completed Figure 2 1 O verall methodology of the study Allocation 222 dogs meeting inclusion criteria were randomly divided into one of six groups assessment of nausea and sedation scores at Time 0 Time 0 000in Assessment of nausea and sedation scores Time 40 Time 20
45 Figure 2 2. Pericardium 6 (PC 6, red spot) at medial side of the thoracic limb. Figure 2 3. Stomach 36 (ST 36, red spot) at lateral side of the pelvic limb. C opyright 2007 by Chi Institute
46 Figure 2 4. Gallbladder 34 (GB 34, red spot) at lateral side of the pelvic limb. Figure 2 5. Bladder 20 and Bladder 21 (BL 20, red spot ; BL 21, yellow spot ) at dorsolateral aspect of the spine.
47 Figure 2 6. Sham non acupoint (red spot) at medial side of pelvic limb.
48 C HAPTER 3 RESULTS Animal Demographics Two hundred and twenty two dogs that met the inclusion criteria were included and all dogs completed the study. All 222 dogs were included in the analyses of the incidence of V/R, the number of V/R events, the onset time to V/R and the duration of V/R. Du e to technical problems, video footage of one dog in acepromazine group (Group III) was unavailable for analyses of nausea and sedation. After enrollment, and upon further examination, two dogs were considered to be painful ; one dog had proptosis of the left eye ; the other dog was non weight bearing on its left rear limb Heart murmurs were found in five dogs during physical examination; the murmur was graded as 3 out of 6 in four dogs; and as 5 out of 6 in one dog. A mass on the mammary gland, ve ntral neck, and perianal area was found in three other dogs. These eight dogs were not excluded from the study The characteristics of each treatment group are shown in Table 3 1 No significant differences were found between groups for sex, age, body wei ght, body temperature, heart rate, respiratory rate, ASA status, BCS, and planned procedure ( Table 3 2 ). Examples of brachycephalic breeds included Pug, Pekingese, Chihuahua, Cavalier King Charles s paniel Boxer, English bulldog, and Boston terrier M ixed breed dogs that were phenotypically brachycephalic, were also characterized as brachycephalic breeds T here was a difference in the distribution of BCS over the six groups, and this was further analyzed using Kruskal Wallis non parametric test to examine the influence of BCS on the duration of V/R and the number of V/R events. Results showed no evidence that BCS influenced the duration ( P =0.44) or number of
49 ( P =0.19) of V/R events Chi square test showed that the distribution of b rachycephalic dogs was different between the six groups ( P =0.03). Further test s (Kruskall Wallis and two factor ANOVA) w ere conducted to determine if being classed as a brachycephalic breed influence d the duration of V/R or the number of V/R events ; this was not found to have an impact on the duration ( P =0.63) or frequency ( P =0.92) of V/R. Finally, there was no difference in the planned procedure (i.e. castration, OHE, dental scaling, or mass removal) between the six groups. Clinical Safety Six dogs exp erienced five vomiting events or more; four dogs vomited six times, one dog vomited five times, and the remaining dog vomited nine times. A trace amount of frank blood was seen in the vomitus of th e dog that vomited nine times. All th e dogs were treated with the antiemetic maropitant, at a dose of 1 mg/kg subcutaneously No further vomiting was noted after rescue treatment. Dogs were subsequently treated with fluid therapy intravenously. Two dogs given maropitant exhibited transient p ain on injection. Vocalization, skin twitching, and scratching at the injection were noticed and the reaction was considered as mild or moderate 115 Erythematous skin was noted at t he inject ion site in one dog receiving maropitant. No other abnormalities were observed at the site of injection, and the pain and erythema resolved over 3 to 5 minutes without additional medication M ost dogs that recei ved EA treatment (groups 4, 5 and 6) exhibited mild responses such as flinching, struggling, or muscle quivering after the insertion of acupuncture needles but this quickly subsided Two dogs defecat ed and strained for approximately one minute after morphine administration. A side from vomiting, nausea,
50 and signs of transient pain on injection, no other abnormal clinical observations were noted during the stud y and no dog was withdrawn from the study Effects of Treatments on Vomiting or Retching Incidence of Vomiting/ Retching The incidence of V/R in dogs over the twenty minute evaluation period following morphine administration in the six treatment group is presented in Table 3 3. 28 of 37 (75.7%) treated with saline ( G roup 1) exhibited V/R at least once after morphine administration compared with 14 of 37 (37.8%) maropitant treated ( G roup 2) and 17 of 37 (45.9%) acepromazine treated ( G roup 3), dogs respectively. 24 of 37 (64.8%) of dogs receiving single acu point EA ( G roup 4) vomited or retched f ollowing morphine administration. V/R was observed in 26 of 37 (70.3%) dogs treated with multiple acu point EA ( G roup 5). In the sham non acu point EA ( G roup 6 ), 32 of 37 (86.5%) dogs experienced V/R after morphine administration. Based on the results, d ogs treated with maropitant had a significant ly l ower incidence of V/R tha n dogs receiving saline ( P =0.015) sham ( P <0.001), and multiple acu point EA ( P =0.005). S ignificantly fewer dogs in the acepromazine group experienced V/R compared with those in the saline treated ( P =0.009) and sham ( P <0.05) groups The incidence of V/R between maropitant and acepromazine groups was not significantly different ( P =0.48) The incidence of V/R in d ogs that received single acupoint or multiple acupoint was not significantly differen t compared with dogs treated with saline and sham non acupoint ( P >0.05). Finally the re was no significant difference in the incidence of V/R between saline treated and sham group ( P =0.24). A fter applying the Bonferroni correction for pairwise comparisons the difference between m aropitant saline and sham remained significant ( P < 0.0 0 33) Acepromazine was also showed a
51 significant reduction in incidence of V/R as compared to the sham group after Bonferroni correction ( P < 0.0 0 33) Figure 3 1 shows the incidence of V/R by treatment group. Number of V omiting /R etching Events Descriptive data for the number of V/R events for the six groups is given in Table 3 3. T here was a significant reduction in the mean number of V/R events in dogs treated with maropitant (0.57 0.90 P <0.001), acepromazine (1.03 1.40, P =0.01), single acu point EA (0.95 0.88, P =0.003), or multiple acu point EA (0.92 0.76, P =0.001) r elative to saline treated dogs (2.38 1.67). Similarl y, significantly fewer V/R events ( P <0.001) were observed in dogs treated with maropitant, acepromazine, single acu point EA, or multiple acu point EA compared to sham treated dogs (2.95 2.09) following morphine administration. All groups remained significant after Bonferroni correction for pairwise comparisons ( P <0.0033). Although d ogs receiving sham treatment had more V/R events than saline treated dogs the difference was not statistica lly significant ( P >0.05). The mean number of V/R events for dogs given maropitant did not differ significantly ( P > 0.05) from those of dogs treated with acepromazine, single acu point EA, or multi acu point EA after morphine administration. Finally, the numbe r of V /R events between single acu point EA and m ulti acu point EA treatments were not significantly different ( P > 0.05). Figure 3 2 shows the effect of the six treatment groups on the mean number of V /R events. Onset Time to Vomiting/Retching In the maropitant and acepromazine groups mean time to the first V/R event was 0.52 1.31 and 1.12 1.35 minutes respectively which was significantly shorter than
52 the onset to V/R t ime i n dogs that received saline ( 2. 02 1.41 minutes) acepromazine ( 2.08 1 .18 minutes ) and multi acu point EA ( 2.11 1.45 minutes ) ( P <0.05) D ogs receiving single acu point EA vomited or retched at an average time of 1.59 1.42 minutes after receiving morphine (Table 3 3) Duration of Vomiting/Retching The mean time to cessation of V/R for dogs treated with saline was 1.32 1.41 minutes and was significantly longer compared to dogs treated with maropitant (0.06 0.19 minutes ; P <0.001 ) and acepromazine (0.48 1.10 minutes ; P =0.003 ), respectively (Table 3 3) Saline treated dogs also had a significant ly longer mean duration of V/R than single acu point EA (0.20 0.46 minutes, P <0.001) and multi acu point EA (0.15 0.33 minutes, P <0.001), but did not differ significantly from dogs treated with sham non ac upoint (1.87 2 62 minutes, P >0.05). All groups remained significant after Bonferroni correction for pairwise comparisons ( P <0.0033). Dogs receiving maropitant had a slightly shorter duration of V/R than dogs treated with acepromazine, single point EA and multi point EA, but the differences were not statistically significant ( P >0.05). Furthermore, t he mean time to cessation of V/R between dogs given single acu point EA and multiple acu point EA did not differ significantly ( P >0.05). Figure 3 3 shows the mean duration of V/R for the six treatment groups. T he Bonferroni corrected pair wise comparisons showed th at maropitant and acepromazine were highly effective in preventing V / R compared to other groups with regard to the incidence, the number of events, and the duration of V/R. Moreover, EA (single and multiple points) was also effective for reducing the number of events and the duration of V/R
53 Effects of Treatments on Signs of Nausea and Sedation Signs of Nausea The incidence of signs of nausea for the six groups following morphine administration is shown in Table 3 4 8.1% of the acepromazine treated dogs experienced signs thought to be associated with nausea which was significantly lower compared to dogs trea ted with saline (29.7% ; P =0 .02 ) maropitant (32.4% ; P =0.0 09 ) and sham EA (40.5% ; P = 0.001 ). T he incidence of signs of nausea was significantly lower in the single acupoint EA (18.9% ; P =0.0 4 ) or multi acupoint EA (10.8% ; P =0.0 04 ) group s compared to the sham group after morphine administration. Dog s that received multi acupoint EA also ha d a significant ly lower incidence of signs of nausea than maropitant treated dogs ( P =0.03). W hen a Bonferroni correction for p airwise comparisons was applied only the acepromazine group had a significant ly lower incidence of signs of n ausea compared to the saline treated group ( P =0.0 033) Figure 3 4 shows the incidence of signs of nausea for the six treatment groups. T he baseline nausea scores at Time 0 for the six groups were similar (Table 3 4). There were no significant differences in the mean scores for nausea between baseline and post treatment times ( Time 20 ; Figure 3 5). The mean score s for nausea was significantly less in the acepromazine group as compared with the saline maropitant and sham group s during the first 1 0 minutes following morphine administration (Time 30; P =0.02, 0.008, and 0.0 01, respectively ). During the next 10 minutes (Time 35 and 40), a cepromazine treated dogs continued to show significantly lower nausea scores tha n dogs that received maropitant and sham treatment ( P <0.03 and 0.001 at Time 35; P <0.017 and 0.002 at Time 40, respectively) The mean nausea scores in the single acupoint EA group was significant lower compared to the sham group 10 (Time 30) and
54 20 (Time 40) minutes after morphine administration ( P =0.03 and 0.016, respectively). In the multiple acupoint EA group dogs had significantly l ower mean nausea scores than sham group 10 (Time 30) and 15 (Time 35) minutes after morphine administration. ( P =0.004 and 0.0 16 respectively). This group also had lower mean nausea scores than maropitant group at Time 30 ( P =0.03). A fter Bonferroni correct ion only dogs treated with acepromazine had s ignificant ly lower nausea scores during the 20 minutes after morphine administration as compared with dogs receiving sham treatment ( P <0.0033 at Time 30, 35, and 40) T he pooled mean scores of saline maropitant and sham groups after morphine administration were significantly higher compared to their baseline s at T ime 0 as well as the mean nausea scores at Time 20 ( P <0.05; Figure 3 6). They remained significant after Bonferroni correction. In contrast, the pooled mean nausea scores after morphine administration in acepromazine single acupoint EA and multi acupoint EA groups were neither significantly differs from their baselines nor their mean nausea scores at Time 20 Overall, results showed that acepromazine single acupoint EA and multi acupoint EA appeared to reduce the incidence of signs of nausea induced by morphine admiration D ogs treated with acepromazine single acupoint EA or multi acupoint EA were also less likely to show signs of nausea after morphine administration. S edation The mean sedation scores for the six groups are shown in Table 3 5 and Figu re 3 7 T he baseline sedation values at Time 0 recorded for the six groups were not equal The a cepromazine and single acupoint EA groups had significant ly higher mean sedation scores than the maropitant and sham groups ( P 0.05). However, t he mean sedation scores were not significant after Bonferroni correction for multiple comparisons.
55 After 20 minutes of treatment (Time 20), the mean sedation scores were significant ly greater in dogs that received acepromazine or EA (single acupoint or mu lti acupoint EA) compared to saline maropitant, and sham groups ( P <0.05). Acepromazine treated dogs also had significant ly higher mean sedation scores than both EA groups ( P <0.005). However, only the acepromazine group had s ignificant ly higher mean sedation scores as compared with saline maropitant, and sham groups a fter Bonferroni correction ( P <0.0033). There were no significant differences among saline maropitant, and sham group s ( P >0.05). Similarly, mean sedation scores in the EA single acupoin t or multi acupoint groups were not significantly different from each other ( P >0.05). At Time 30 (10 minutes after morphine), the mean sedation score in the acepromazine group remained significant ly higher compared to saline maropitant, and sham groups ( P <0.0001) A cepromazine group also had significant ly higher mean sedation scores than single acupoint EA ( P =0.02), but not multi acupoint EA group ( P >0.05). In the EA group s dogs receiving singl e acupoint or multi acupoint EA had significant ly higher mean sedation scores than saline and sham groups ( P <0.005) but not maropitant group ( P >0.05). Mean s edation scores in the acepromazine group remained significant ly higher as compared with saline maropitant, and sham groups after Bonferroni correction, ( P < 0.0033). At Time s 35 and 40 (15 and 20 minutes after morphine administration respectively), acepromazine group continued to have a significant ly higher mean sedation score than the saline maropitant, and sham groups ( P <0.005). Bonferroni correction showe d acepromazine group to be significant ly more sedated when
56 compared with saline and sham groups at Time 35 and 40 ( P <0.0033). Single acupoint EA group had significant higher mean sedation scores compared to sham group at Time 35 ( P =0. 04). M ulti acupoint EA group did not significant ly differ from saline maropitant, and sham groups 15 and 20 minutes after morphine administration in regard to the mean sedation scores ( P >0.05) Overall, the acepromazine group had a significant ly higher sedation score than other five groups 20 minutes after injection and during the observation period following morphine administration. EA groups ( single acupoint or multi acupoint E A) showed significant sedation after EA treatment as well as 10 minutes after morphine administration compared to saline maropitant, and sham groups
57 Table 3 1. Demographic characteristics of the six treatment groups Characteristics No. of Dogs Overall Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Sex Male Female 109 113 19 18 19 18 19 18 18 19 16 21 18 19 Body weight (kg) < 10 10 25 > 25 108 79 35 17 15 5 22 12 3 21 9 7 16 14 7 15 17 5 16 13 8 Breed Chihuahua Greyhound Dachshund American Pit B ull T errier Shih Tzu J ack Russell Terrier Beagle Labrador Retriever Maltese American Staffordshire Terrier Australian S hepherd Boston T errier Boxer Cavalier King Charles Spaniel German shepherd Mini ature Aus tralian Shepherd Pekingese Pomerian Rottweiler Other purebred Mix ed bre e d 17 11 10 7 7 5 4 4 3 2 2 2 2 2 2 2 2 2 2 18 116 4 2 1 0 4 1 0 0 1 0 0 0 1 0 0 0 1 0 0 5 17 5 1 3 0 2 1 2 1 1 0 1 1 1 1 0 0 1 0 1 2 13 4 3 0 1 0 2 0 0 1 0 0 0 0 1 1 0 0 0 0 2 22 0 0 3 2 0 1 1 0 0 0 0 1 0 0 0 0 0 2 1 3 23 1 3 2 2 1 0 1 2 0 1 1 0 0 0 0 1 0 0 0 2 20 3 2 1 2 0 0 0 1 0 1 0 0 0 0 1 1 0 0 0 4 21 Body Size Toy 33 6 5 5 5 5 7
58 Table 3 1. Continued. Characteristics No. of Dogs Overall Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Body Size Small Medium Large Giant 74 17 97 1 12 2 16 1 13 3 16 0 14 3 15 0 12 3 17 0 11 3 18 0 12 3 15 0 Brachycephalic Yes No 53 169 13 24 14 23 9 28 8 29 4 33 5 32 Body Score Condition (1 9 scale) 3 4 5 6 7 8 6 39 145 26 5 1 0 2 33 2 0 0 0 6 27 3 0 0 0 6 23 7 2 0 2 3 24 6 1 1 4 10 19 2 2 0 0 14 19 6 0 0 ASA I II 200 22 33 4 32 5 32 5 33 4 34 3 36 1 Surgery Procedure Castration Ovariohysterectomy (OHE) Others 104 110 8 18 18 1 17 18 2 19 18 0 16 19 2 16 19 2 18 18 1 Group 1 : Saline/ placebo ; Group 2 : Maropitant; Group 3 : Acepromazine; Group 4 : Single acupoint EA (PC 6); Group 5 : Multi acupoint EA (PC 6, ST 36, GB 34, BL 20, BL 21); Group 6 : Sham non acupoint.
59 Table 3 2. Baseline demographic characteristics and physiologic parameters of the six treatment groups Characteristics Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 P value Age (months) Mean SD SEM 25.68 15.9 2.62 29.86 26.40 4.34 28.14 20.78 3.42 28.86 22.37 3.68 29.05 27.54 4.53 28.16 20.87 3.43 0.98 Sex (%) Male Female 51.35 48.65 51.35 48.65 51.35 48.65 51.35 48.65 56.76 43.24 51.35 48.65 0.98 Body weight (kg) Mean SD SEM 13.56 10.51 1.73 10.88 8.84 1.45 12.47 10.32 1.70 15.50 11.16 1.84 15.69 9.26 1.52 14.75 9.89 1.63 0.26 Rectal Temperature ( F) Mean SD SEM 101.7 0.94 0.15 101.9 0.96 0.16 101.9 0.90 0.15 101.8 0.98 0.16 101.9 0.74 0.12 102.1 1.02 0.17 0.35 Heart Rate (bpm) Mean SD SEM 123.8 25.00 4.11 134 24.08 3.96 128.9 30.26 4.97 125.2 31.36 5.16 121.0 23.52 3.87 127.5 29.09 4.78 0.42 Respiratory Rate (bpm) Mean SD SEM 34.39 11.46 2.06 35.63 11.10 2.03 38.67 16.14 2.95 38.07 19.83 3.68 37.63 16.62 3.03 34.96 14.00 2.80 0.84 BCS (%) 3 4 5 6 7 8 0 5.41 89.19 5.41 0 0 0 16.22 75.68 8.11 0 0 0 16.22 59.46 18.92 5.41 0 5.41 8.11 64.86 16.22 2.70 2.70 10.81 27.03 51.35 5.41 5.41 0 0 32.43 51.35 16.22 0 0 0.06
60 Table 3 2. Continued. Characteristics Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 P value ASA (%) I II 89.19 10.81 86.49 13.51 86.49 13.51 89.19 10.81 91.89 97.30 97.30 2.70 0.63 Brachycephalic (%) Yes No 35.14 64.86 37.84 62.16 24.32 75.86 21.62 78.38 10.81 89.19 13.51 86.49 0.03 0.92 Procedure (%) OHE Castration Others 48.65 48.65 2.70 48.65 45.95 5.41 48.65 48.65 2.70 51.53 43.24 5.41 51.35 43.24 5.41 48.65 48.65 2.70 0.99 C orrelation is significant at the 0.05 level. Correlation between brachycephalic and frequency or duration of vomiting/retching. Table 3 3. Descriptive data of vomiting/retching (V/R) of the six treatment groups. Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 N o. of dogs 37 37 37 37 37 37 Vomiting & retching (%) 28 (75.7) 14 (37.8) 17 Â§ (45.9) 24 (64.8) 26 (70.3) 32 (86. 5 ) N o. of V/R events N o. of vomiting 83 17 35 34 33 104 N o. of retching 5 4 3 1 1 5 T otal no. 88 21 38 35 34 109 R ange 0 5 0 2 0 4 0 3 0 2 0 9 Mean SD 2.38 1.67 0.57 0.90 1.03 1.40 0.95 0.88 0.92 0.76 2.95 2.90 SEM 0.27 0.15 0.23 0.14 0.12 0.34
61 Table 3 3. Continued. Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 No. of V/R events 25 th Quartile 1.0 0.0 0.0 0.0 0.0 2.0 75 th Quartile 4.0 1.0 2.0 1.0 1.0 4.0 Onset Time to V/R (min) Mean SD 2.02 1.41 0.52 ** 1.31 1.12 ** 1.35 1.59 1.42 2.11 1.45 2.08 1.18 Range 0.34 7.03 0.41 6.44 0.32 5.42 1.06 5.13 1.55 7.02 0.47 4.40 Duration of V/R (min) Mean SD 1.32 1.41 0.06 0.19 0.48 1.10 0.20 0.46 0.15 0.33 1.87 2.62 SEM 0.23 0.03 0.18 0.07 0.05 0.43 25 th Quartile 0.0 0.0 0.0 0.0 0.0 0.72 75 th Quartile 1.75 0.0 0.45 0.0 0.0 1.80 Significant ly different from Group 1 ( P <0.05) Significant ly different from Group 6 ( P <0.05) Significant ly different from Group 1 ( Bonferroni adjusted P < 0.0 033 ) Â§ Significant ly different from Group s 6 ( Bonferroni adjusted P < 0.0 033 ) ** Significant ly different from Group 1, 5 and 6 ( P <0.05)
62 Table 3 4. Descriptive d ata of nausea scores for the six treatment groups. Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 No. of dogs 37 37 36 37 37 37 Incidence of signs of nausea (%) 29.7 32.4 8.1 18.9 10.8 40.5 Time 0 Mean SD 1.0 0.0 1.0 0.0 1. 1 0.2 1.0 0.2 1.0 0.0 1.1 0.2 SEM 0.0 0.0 0.0 0.0 0.0 0.0 25 th Quartile 1.0 1.0 1.0 1.0 1.0 1.0 75 th Quartile 1.0 1.0 1.0 1.0 1.0 1.0 Time 2 0 Mean SD 1. 1 0 .3 1. 1 0. 3 1. 1 0. 2 1. 1 0. 2 1. 1 0. 3 1. 1 0. 4 SEM 0.1 0.1 0.0 0.1 0.1 0.1 25 th Quartile 1.0 1.0 1.0 1.0 1.0 1.0 75 th Quartile 1 .0 1 .0 1.0 1.0 1.0 1 3 Time 30 Mean SD 1.4 0 6 1.5 0.7 1.1 0.3 1.2 0.5 1.1 0.4 1.6 0.9 SEM 0.1 0.1 0.0 0.1 0.1 0.1 25 th Quartile 1.0 1.0 1.0 1.0 1.0 1.0 75 th Quartile 2.0 2.0 1.0 1.0 1.0 2.0 Time 35 Mean SD 1.2 0 5 1.4 0.7 1.1 0.4 1.2 0.5 1.1 0.4 1.5 0.8 SEM 0.1 0.1 0.1 0.1 0.1 0.1 Time 35 25 th Quartile 1.0 1.0 1.0 1.0 1.0 1.0 75 th Quartile 1.0 1.0 1.0 1.0 1.0 2.0
63 Table 3 4. Continued. Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Time 40 Mean SD 1.1 0 3 1.3 0.7 1.0 0.4 1.1 0.5 1.1 0.4 14 0.8 SEM 0.1 0.1 0.1 0.1 0.1 0.1 25 th Quartile 1.0 1.0 1.0 1.0 1.0 1.0 75 th Quartile 1.0 1.0 1.0 1.0 1.0 2.0 Significant ly different from Group 1 ( P <0.05) Significant ly different from Group 2 ( P <0.05) Significant ly different from Group 6 ( P <0.05) Â§ Significant ly different form Group 6 ( B onferroni adjusted P <0.0 033 )
64 Table 3 5. Descriptive data of sedation scores for the six treatment groups. Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 No. of dogs 37 37 36 37 37 37 Time 0 Mean SD 1.1 0.3 1.1 0.2 1.2 0.5 1.3 0.5 1.2 0.4 1.1 0.2 SEM 0.1 0.0 0.1 0.1 0.1 0.0 25 th Quartile 1.0 1.0 1.0 1.0 1.0 1.0 75 th Quartile 1.0 1.0 1.0 1.0 1.0 1.0 Time 20 Mean SD 1.4 0.7 1.5 0.7 2.3 1.1 1.7 0.6 1.8 0.8 1.4 0.6 SEM 0.1 0.1 0.2 0.1 0.1 0.1 25 th Quartile 1.0 1.0 2.0 1.0 1.0 1.0 75 th Quartile 2.0 2.0 3.0 2.0 2.0 2.0 Time 30 Mean SD 2.5 0.8 2.8 0.9 3.4 0.8 2.9 0.9 3.0 1.0 2.6 0.8 SEM 0.1 0.1 0.1 0.1 0.2 0.1 25 th Quartile 2.0 2.0 3.0 3.0 2.0 2.0 75 th Quartile 3.0 3.0 4.0 3.0 4.0 3.0 Time 35 Mean SD 3.0 0.8 3.2 0.9 3.8 0.9 3.4 0.8 3.3 0.1 3.0 0.8 SEM 0.1 0.1 0.1 0.1 0.2 0.1 25 th Quartile 3.0 3.0 3.0 3.0 3.0 2.0
65 Table 3 5. Continued. Group 1 Group 2 Group 3 Group 4 Group 5 Group 6 Time 35 75 th Quartile 4.0 4.0 4.0 4.0 4.0 3.0 Time 40 Mean SD 3.1 0.8 3.2 1.0 3.9 1.0 3.5 0.9 3.5 1.1 3.1 1.0 SEM 0.1 0.2 0.2 0.2 0.2 0.2 25 th Quartile 3.0 3.0 3.0 3.0 3.0 2.0 75 th Quartile 4.0 4.0 5.0 4.0 4.0 4.0 Si gnificant ly different from Group 1 ( P <0.05) Significant ly different from Group 2 ( P <0.05) Significant ly different from Group 6 ( P < 0.05) Â§ Significant ly different from Group s 1, 2 and 6 ( B onferroni adjusted P <0.0 033 )
66 Figure 3 1. T he incidence of vomiting/ retching (V/R) by treatment group. I ndicates a s ignificant difference ( P <0.05) from placebo and sham I ndicates a s ignificant difference ( P <0.05) from multi acupoint EA group I ndicates significant difference after Bonferroni adjusted ( P <0.0 033 ) with placebo or sham. Figure 3 2 T he comparative effectiveness of the six treatment groups on the mean number of V /R events. I ndicates a s ignificant difference at P <0.05 and Bonferroni adjusted P <0.0 033 from placebo and sham. 0 10 20 30 40 50 60 70 80 90 100 Incidence of V/R (%) 0 1 2 3 4 5 6 Mean number of V/R events
67 Figure 3 3 T he mean duration of V/R (mean SD minutes) for the six treatment groups Indicates a s ignificant difference at P <0.05 and B onferroni adjusted P <0.0 033 from placebo and sham. Figure 3 4 T he incidence of signs of nausea fo r the six treatment groups before and after morphine administration I ndicates a s ignificant difference ( P <0.05) from placebo I ndicates a s ignificant difference ( P <0.05) from maropitant. I ndicates a s ignificant difference ( P <0.05) from placebo and sham. Â§ I ndicates significant difference after Bonferroni adjusted ( P <0.0 033 ) from sham. 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 Mean duration of V/R (minutes) 0 5 10 15 20 25 30 35 40 45 Incidence of nausea (%)
68 Figure 3 5 T he mean score for signs of nausea for the six treatment groups before treatment (Time 0, as baseline) and after treatment (Time 20), as well as 10, 15 and 20 minutes after morphine administration (Time 30, 35 and 40, respectively). I ndicates a s ignificant ( P <0.05) difference with placebo ; I ndicates a significant ( P <0.05) difference with maropitant; I ndicate s s ignificant differen ce from sham ( P <0.05) ; Â§ indicated s ignificant differen ce from Sham ( Bonferroni adjusted P <0.0 033 ) 0 0.5 1 1.5 2 2.5 3 Time 0 Time 20 Time 30 Time 35 Time 40 Mean score for nausea Placebo Maropitant Acepromazine Single-acupoint Multi-acupoint Sham nonacupoint
69 Figure 3 6 The mean score for signs of nausea (mean SD) for the six treatment groups at Time 0 (before treatment, as baseline ) Time 20 (after treatment), and 10, 15 and 20 minutes after morphine administration (Time 3 0, 35 and 40, respectively). I ndicates a significant ( P <0.05) difference with Time 0 and 20 I ndicates significant differences ( P < 0 .0 5 ) with baseline and Time 20 for the pooled variables after morphine administration. 0 0.5 1 1.5 2 2.5 3 Mean score for nausea Time 0 Time 20 Time 30 Time 35 Time 40 *
70 Figure 3 7 The sedation score s (mean SD) for the six treatment groups before (Time 0, as baseline) and after treatment (Time 20), as well as 10, 15 and 20 minutes after morphine administration (Time 30, 35 and 40, respectively). Acepromazine was significant ly different from the other five groups (P<0.05) after treatment (P<0.05 and Bonferroni corrected P<0.0033) Single acupoint EA and multi acupoint EA were significantly different from placebo maropitant and sham at Time 20 and remained significant ly different from placebo and sham at Time 30 (P<0.05). At Time 35, Single acupoint EA was significant ly different from sham (P<0.05). I nd icates significant difference from placebo and/or sham. 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 Time 0 Time 20 Time 30 Time 35 Time 40 Mean score of sedation Placebo Maropitant Acepromazine Single-acupoint Multi-acupoint Sham *
71 CHAPTER 4 DISCUSSION Nausea and vomiting are two of the undesirable side effects that frequently occur in animals after administration of opioids 6,7 Morphine hydromorphone and oxymorphone frequently induce nausea and vomiting in dogs when used as an analgesic or premedica nt 7,26 The purpose of the current study was to determine the effe ctiveness of maropitant, acepromazine, and electroacupuncture on prevention of nausea and vomiting associated with low or moderate dose of morphine administration in dogs. The primary findings of the present study demonstrate d that maropitant and acepromaz ine before administration of morphine significant ly reduced the incidence and number of episode s of retching or vomiting in dogs. EA also was effective in reducing the number of retching or vomiting events. Acepromazine and EA also reduced the incidence an d severity of signs of nausea in dog s induced by morphine administration. The incidence of vomiting o r retching following administration of morphine to dogs in this study is generally consistent with previously published research 7,13,20,21,81 Approximately 75% of dogs receiving saline and 86% receiving sham EA treatment vomited or retched after morphine administration demonstrating a high potential for morphi ne to induce vomiting in dogs. When morphine was administered at recommended premedication dose of 0.5 mg/kg (IM), the average time to the first vomiting episode was 2.20 1.41 and 2.08 1. 18 minutes for the saline and sham EA groups respectively was similar to previous studies 7,13 T he average time to cessation of vomiting or retching was significantly shorter in dogs treated with maropitant, acepr omazine and EA, suggesting these treatments influence the duration of vomiting or retching and hasten recove ry from the emetic effects of morphine. A total of t wenty
72 dogs defecated after morphine administration and this occurred in all treatment groups, an d may be attributed to duodenal contraction induced by stimulation of opioid receptors in the gut 149 Maropitant, a novel NK 1 receptor antagonist with approval for use in dogs, inhibit s the binding of substance P to NK 1 receptors, ther eby blocking t he final common pathway involved in activating the vomiting reflex in the CNS and is effective against vomiting induced by both peripheral and central stimuli 24,104,150 In laboratory studies, NK 1 receptor antagonists (GR205171 and GR203040) were highly effective in preventing and treating vomiting induced by morphine in ferrets. 151,152 NK 1 receptor antagonists (GR205171 and GR203040) were highly effective in preventing and treating vomiting induced by morphine in ferrets. Efficacy of maropitant on morphine induced vomiting in a dog has been demonstrated in a single case report, where it appeared to prevent vomiting in a dog after the injection of epidural morphine. 79 In addition a study showed that maropitant was completely effective in preventing vomiting, retching and nausea after premedication of hydromorphon e (IM) in dogs. 26 In the present study, we demonstrated that maropitant at a dose of 1 mg/kg, SC, was highly effective in the prevention of vomiting induced by IM morphine administration M aropitant reduced the percentage of dogs that vomited by approximately 38% compared to saline treatment and by 46% compared to sham treatment. The g roup of dogs receiving maropitant had the fewest vomiting events. S tudies have reported that the time taken to achieve maximum plasma concentrations of maropitant is shorter following SC administration (with a mean of 0.75 hours at 1 mg/ kg ) compared to 1 .9 hours for 2 mg/kg when given per os ( PO ) 109
73 Hence the injectable route provides a more rap id onset and is more appropriate for the prevention of vomiting associated with opioid premedication in a clinic al setting This study demonstrated that vomiting event s were significantly reduced after pre treatment with SC maropitant 20 minutes prior to m orphine administration Hay Craus showed that SC maropitant given one hour prior to hydromorphone protects against vomiting or retching in all nine dogs. 26 Maropitant has a plasma half life of approximately 8 hours after SC administration 109 but field studies show that the antiemetic eff ect of maropitant is maintained for approximately 24 hours after a single administration 25,112,153 T he emetic effects of most opioids are usually apparent within 5 10 minutes and cease within 30 minutes after a single IM administration 6,13 he nce, a single dose of maropitant was appropriate for prevention of vomiting in this study. The effic acy of maropitant in the current study along with a series of reports in dogs, where maropitant was effective in treating acute vomiting resulting from a variety of etiologies including non specific gastritis, dietary indiscretion uremia, motion sickness and chemotherapy demonstrat es that maropitant is a broad spectrum antiemetic 25,110 113,153,154 This proven broad spectrum efficacy is consistent with the efficacy of maropitant a gainst both peripherally or centrally acting emetogenic stimuli 24 In addition to its antiemetic effect, an i ntravenous bolus followed by a constant rate infusion of maropitant significantly decr eased the anesthetic requirements (minimum alveolar concentration) for sevoflurane during visceral stimulation of the ovary and ovarian li gament and noxious stimulation of the tail in dogs, suggesting a potential role for NK 1 antagonists for the manag em e n t of somatic or visceral pain. 155,156 NK 1 receptor s and the agonist substance P have been reported in pain pathways at the level of the
74 CNS and peripheral nervous system of rat s and cats 157,158 T herefore maropitant may be a good choice for perioperative use to prevent vomiting and enhance analgesia when opioids are used Phenothiazines, such as prochlorperazine, chlorpromazine, and acepromazine, antagonize D 2 dopaminergic, M 1 cholinergic, 2 adrenergic, and histaminergic receptors. 23,80,87 S tud ies have show n that a cepromazine ( IM ) adm inistered 15 minutes before morphine, hydromorphone and oxymorphone decreased t he incidence of vomiting 7 The results of the present study are consistent with other studies demonstrating that IM injection of acepromazine was effective in reducing the rate of morphine induced vomiting. It also effectively lowered the number of vomiting events in dogs that did vomit. Time to onset of the full effect s of acepromazine is approximately 15 20 minutes following IM injection 159 Valverde et al demonstrated that acepromazine needs to be administered prior to the opioid for the desired anti emetic effects. Dogs administered acepromazine 15 minutes before an opioid had the lowest incidence of vomiting (18%) when compared with dogs that received acepromazine and the opioid concurrently (45%), and those that received the opioid first (55%) Similarly results were found in the current study, in which dogs given acepromazine 20 minutes before morphine had significant ly less vomiting compared to dogs given placebo T he proportion of dog s that vomited in the current study (45.9%) was higher than those receiving the same dose of acepromazine in the study reported by V a lverde and others ( 25%). 7 The cause for this dif ference may be related to the sample size: 37dogs in the current study versus 8 dogs in the Valverde s study. 6 In the current study, a sample size of 37 dogs in each group provided a statistical power of 80% at the 5% two sided alpha
75 significance level Another explanation in respect of the slightly better effect of acepromazine against morphine induced vomiting in Valverde s study than the current study could be due to different injection sites were used in both studies I njections into different muscle groups have been reported to produce different concentration s of drugs in plasma and different clinical effects as a result of sequestration of drug in the fascial plane s between muscles 160,161 Grabinski and othe rs showed that peak plasma morphine levels were 1 8 times higher when injections were made into the deltoideus rather than the gluteal muscles. 160 Evans et al. demonstrated that IM injections of alphadalone/alphaxalone into the biceps femoris muscle group of cats were less effective than injections into the quadriceps muscle. 161 I n the current study acepromazine was injected into the middle gluteal muscle, whereas the location of IM injection used in the study of V a lverde et al. was not desc ribed Acupuncture is an ancient Chinese therapy that has gained much interest from the scientific medical community. It has been used to treat various GI problems including acute and chronic gastroenteritis, dysphagia diarrhea, constipation, nausea, vomiting, irritable bowel syndrome, visceral pain, and gastroduodenal ulcer s however some studies yielded mixed results in regard to its efficacy 162,163 According to the traditional Chinese medicine system, the acupoint PC 6 is the most important acupuncture point for nausea and vomiting in human s and ani mals 147,163 Other acupoints, such as BL 10 BL 11, BL 20, B L 21, ST 36, GB 34, LIV 13, and CV 12 also shown to have antiemetic effects. 38 40,122,123 However, none have been studied to the extent that PC 6 has In the current study, we investigate d the antiemetic activity of acupoint PC 6 alone in addition to a combin ation of five acupoints ( PC 6, BL 20, Bl 21,
76 ST 36, and GB 34) on morphine induced nausea and vomiting. Results showed EA was effecti ve i n r educing the number of vomiting episodes which is consistent with previous studies in dogs and ferrets 36,37,123 EA at a frequency of 2 Hz (10 minutes) followed by 100 Hz (10 minutes) at PC 6 alone produced an greater than 50% reduction in the number of vomiting events following morphine compared to saline and sham non acupoint treatments These findings were not significantly different to maropitant and acepromazine treatments. EA t reatments did not decrease the incidence of vomiting in this study. Furthermore, results of o ur study suggested that the antiemetic effects of PC 6 alone and the combination acupoints ( PC 6, ST 36, GB 34, BL 20 and BL 21 ) were similar under the same e lectrical stimulation settings It is reasonable to presume that the acupoints, ST 36, GB 34, BL 20 and BL 21, do not provide an additional antiemetic effect in dogs with morphine induced vomiting However, further study would be necessary to confirm this speculation by conducting study that evaluated the efficacy each of these acupoints in the prevention of vomiting under different circumstances such as chemo therapy GI ulcerations or parvoviral enteritis A number of studies have been conducted on the effect of acupuncture, electroacupuncture, and a quapuncture on vomiting in d ogs 37 40,123 EA (1 30 Hz) at PC 6 significantly reduced the incidence of vomiting associa ted with vasopressin in dogs. The emetic effect of vasopressin is thought to be mediated at the CRTZ. The antiemetic effect of PC 6 was abolished by naloxone, which is able to cros s the blood brain barrier and blocks both central and peripheral opioid rece ptors In contrast, t he antiemetic w as not antagonized by naloxone methiodide that does not cross the blood brain barrier and blocks only peripheral opioid receptors This s uggest s that the antiemetic effect of
77 acupuncture at PC 6 is mediated via the central opioid pathway. 37 Chen and others demonstrated that nausea and vomiting induced by vasopressin were prevented by EA at PC 6 with short pulse stimulation (pulse width of 300 microseconds, 2 mA) in dogs but was not effective in vagotomized dogs. This suggests that the antiemetic effect of EA stimulation is also medi ated via a vagal pathway. 123 The effects of EA on GI motility that have also been reported in dogs, may contribute to the overall antiemetic effectiveness of acupuncture. 42,43 EA at acupoints ST 36 and PC 6 enhance d gastric migrating motor complex es in dogs by reducing the length of phase I and increasing the length of phases II and III of the migrating myoelectrical complex. 43 The absence of phase III contractions has been found in conditions of bacterial overgrowth, nausea and vomiting, and intestin al pseudo obstruction. 164 Ouyang and others found EA stimulation to substantially accelerate gastric emptying of liq uid in dogs with gastroparesis. 42 The accelerating effect of EA on gastric emptying may be attributed to the improvement in gastric slow wave rhythmicity and antral contractile activity via the enhancement of vagal activity. 42 More recently, a Cochrane r eview concluded that acupuncture was effective in reducing the risk of post operative nausea and vomiting (PONV) in humans with minimal side effects, al though it was less than or equal to the effectiveness of antiemetic m edications. 28 Lee and Fan reviewed 40 studies involving 4858 participants and suggested that stimulation at P C 6 reduces the risk of PONV compared to sham treatment 28 P C 6 stimulation prevented postoperative nausea (Relative Risk ( RR ) 0.71, 95% C onfidence Intervals (CI) 0.61 to 0.83 ) vomiting ( RR 0.70, 95% CI 0.59 to 0.83 ) and need for antiemetic rescue ( RR 0.69, 95% CI 0.57 to 0.83 ) compared to sham
78 treatment There was no difference in the risk of postoperative nausea for P6 acupoint stimulation compared to antiemetic drugs Another Cochrane Review supported the use of acupuncture as a complementary therapy for acute nausea and vomiting in patients receiving chemotherapy 31 The stimulation of acupoints by all methods combined (manual acupuncture, electroacupuncture, and acupressure) with concomitant pharmacologic an tiemetics significantly reduced the incidence of acute nausea and vomiting (RR 0.82; 95% CI, 0.69 to 0.99; P = 0 .04) Following these reviews, human field trials continue to grow and support the effic acy of acupuncture for prevention of nausea and vomiting. Current research has focused on investigating the efficacy of combining acupuncture wit h standard antiemetic drugs. As an adjunct to standard antiemetic drug therapy, transcutaneous electrical acupoin t stimulation (TEAS) at PC 6 30 minutes before the induction of anesthesia significantly reduced the incidence of PONV by approximately 20% after craniotomy. 165,166 When combined with ondansetron for prophylaxis against PONV following laparoscopic surgery PC 6 stimulation significantly reduced subsequent vomiting ( seen in 8 % of patients ) compared with ondansetron or acupuncture alone where 18% of patients experienced PONV 167 Studies by White and colleagues further support these findings. 168,169 They reported that patients receiv ing the combination of PC 6 stimulation and ondansetron had a significant ly lower incidence of nausea (20 vs. 50%), vomiting (0 vs. 20%), and the need for rescue antiemetics (10 vs. 37%) compared with ondansetron alone after surgery. They also found that perioperative PC 6 stimulation ( an active device applied for 30 min utes before and for 72 h ours after surgery ) significantly increased complete responses (68%) as compared with stimulation for 30 minutes before surgery (43%) ; c omplete responses were defined
79 as no vomiting or retching or need for a rescue antiemetic to treat persistent nausea within the first 24 h a fter surgery 169 In addition to antiemetic effects, patients receiving acupuncture experienced less pain in the post anesthesia care unit, were better able to resume a normal diet after surgery, and the overall quality of recovery was significantly improved. 168 170 While pharmacological studies often use placebo pills solution s or injection s in the control groups, placebo control s for procedural interventions such as surgical operations and acupuncture are especially difficult to develop. Various sham techniques for acupuncture studies have been developed to confirm the effect of acupuncture at specific acupoints. These include: ( 1 ) the use of non invasive or non penetrating needling at the same acupoints; ( 2 ) the use of non acupoints without stimulation, which emphasizes the importance of both acupoints and effects o f electrical stimulation; ( 3 ) the use of the same stimulation at n on acupoints, which distinguishes between acupoints and non acupoints; and ( 4 ) the use of the same stimulation at other acupoints, which distinguishes between two different acupoints. 171,172 In the present study, sham EA was performed by inserting needles at a non acupoint to differentiate the physiologic effects (specific versus non specific) between an acupoint and a non acupoint. Our results demonstrated that EA at sham non acupoint had no preventative effect on the vomiting induced by morphine administration in dogs These data are consistent with most previously published studies 43,171,173,174 There has been much debate regarding the use of a penetrating or non penetrating sham procedure as a control. It has been shown that procedures which employ needle insertion can elicit neurobiological responses at various levels in the CNS including the brainstem,
80 thalamus, left cerebellum and the anterior cingulate cortex 175 Nevertheless our data suggest that penetration of a non acupoint along with electrical stimulation does not have antiemetic activity We therefore, determined that a non acupoint, which is located at 3 units proximal to the medial malleolus of the tibia on the caudomedial aspect of the pelvic limb (Figure 2 6) could reasonably serve as a credible and safe sham control in acupuncture trial s in dogs and may be useful in other species. EA has become the most utilized technique in acupuncture research in human and animal models because the frequency, intensity and duration of EA stimulation can be described and reproduc ed using simple electrical parameter s ( e.g. Hz, frequency) However, there are challenges in assessing the effi cacy of EA stimulation because different frequencies induce the release of different endogenous neuropeptides which may result in variable outcomes 176 Low frequency EA (2 5 Hz) was reported to accelerate the release of en k ephalin, endorphin and endomorphin in the central nervous system 176,177 Conversely, high f requency EA ( 100 Hz ) selectively increases the release of dynorphin. 176 In the present study, EA was performed at 2 Hz for 10 minutes followed by 100 Hz for another 10 minutes to maximize therapeutic effect b y stimulating release of all four opioid peptides 178 These frequency settings were effective for reducing the number of vomiting event s ; h owever, we did not measure endogenous neuropeptide s in this study. Th ere has also been much debate on the optimal duration of stimulation to prevent nausea and vomiting. In clinical practice, EA is commonly applied for 20 30 min. 147 T he present study suggest s that EA for 20 minutes at the settings used is effective in reducing the frequency of vomiting episodes associated with morphine administrati on. It is possible that using different stimulation protocols with
81 different duration and frequency could re sult in different outcome s Further clinical studies are warranted to investigate the optimal stimulation protocols for the prevention of vomiting i n veterinary practice However, stimulation time s of over 20 minutes may not be practical in a busy clinical setting N ausea may be include d by several mechanisms including direct stimulation of the CRTZ and/or the emetic center, reduced gastrointestinal motility, or enhanced vestibular sensitivity. 46,179 Most investigators believe that the neural system that is responsible for nausea is anatomically distinct from the neural circuits responsible for vomiting 180 although i t is usually assumed that nausea is a low level stimulus that if increased would result in vomiting. As nausea is highly subjective, it remains a clinical sign that is eas ily overlooked in veterinary practice. In human s nausea has been ranked the third mo st common unwanted side effect of anesthesia despite the availability of effective antiemetics 181,182 and ranked the most common (experienced by 73% of patients ) and troublesome side effect of chemotherapy 183 This indicates that the possible impact of nausea on veterinary patients may warrant more attention than perhaps it has received previously and that better strategies for assess ing nausea in animals are needed. A study by Chen et al. 123 demonstrated that EA at PC 6 significantly reduced nausea scores follo wing vasopressin administration in dogs Maropitant markedly reduce d signs of n ausea induced by cisplatin in dogs and xylazine in cats 25,114 However Rau et al did not find a significant reduction in the signs of nausea during prophylactic treatment with maropitant for doxorubicin chemotherapy. 111 In the present study t he incidence and the severity of signs of nausea in dogs receiving acepromazine
82 or EA at combined acupoints were significantly lower than in dogs treated with saline sham EA maropitant or single acupoint PC 6 EA ( P <0.05), although only the acepromazine versus sham group remained significant after Bonferroni correction ( P <0.0033). M aropitant, at a dose of 1 mg / kg, did not appear to protect dogs from signs of nausea caused by morphine in the present study. However, it is important to realize that nausea remains difficult to evaluate in dogs. Preventing and treating nausea is a n issue in veterinary practice as well as in human medicine because little is known about th is complex neural response This lack of information is largely due to the difficulty in recognizing and objectively measuring nausea in animals, as well as challenges in studying this phenomenon in animals using research tools, such as brain imaging techniques that have been used in humans 180 N o review to date has comprehensively assessed available nausea scales in terms of their reliability, validity and usefulness as clinical assessment tools. While v isual analog scale s (VAS) ha ve been commonly used to assess nausea in dogs and cats in veterinar y research studies 25,111,114 they produce d mixed results when used to assess reduction of nausea induced by emetogenic chemotherapy agent in dogs treated with maropitant. Using VAS requires investigators to convert what is a subjective sensation in an animal to a mark on a straight line provided on the assessment tool. It could potentially lead to bias because the scale could be subjectively graded by investigators as t here are differing opinions what nausea looks like in animals VAS is also limited to the measurement of one component (usually intensity) of a complex and multi dimensional phenomenon such as nausea and pain 184,185 Furthermore, it is extremely difficu lt to consistently and accurately place th e mark on a VAS line and then accurately
83 measure this making it difficult to analyze data obtained this way for use in research studies 186 Holton et al. reported that VAS used for assessment of pain in dogs yields a significant inter observer variability, even when four veterinary anesthesiologist s view ed the same animals at the same time. 185 In an attempt to make the grading scale more appropriate for nausea assessment in our study, we d eveloped a numerical (ordinal) rating scale (Table 2 1) to record the occurrence and severity of nausea in dogs This was based on signs suggestive of nausea used in previous studies such as salivation, swallowing, restlessness nervousness, and pacing 25,111,114 as well as the Veterinary cooperative oncology group common terminology ( VCOG CTCAE ) which is an objective grading system (from grade1 to 5) of adverse gastrointestinal events in dogs and cats 187 In the rating scale used in the current study, the behavioral and physiological observations were refined and assigned a score rang ing from 1 to 4. While this scale does provid e more specificity and objectiv ity than a VAS in the grading criteria for nausea, additional work is required to extend and validate assessment tools for nausea in dogs. Future investigation would include developing objective tools based on behavior and physiological measures in a similar way tha t acute pain scoring systems have been developed for dogs 188 A well developed nausea assessment tool would be valuable in clinical settings and at the same time provide detailed information needed for research studies, which could then be used to help support evidence based practices and compare the effectiveness of new antiemetics Sedation is a state characterized by central depression accompanied by drowsiness, where the patient is general ly unaware of its surroundings but responsive
84 to painful stimuli 100 In veterinary medicine sedation is often advantageous as it produces sedation and muscle relaxation for procedures such as venipuncture for intravenous therapy or blood sampling, induction of inhalant anesthesia, and diagnostic imaging. The primary met hod of sedation is the use of drugs including phenothiazine derivatives (acepromazine), benzodiazepines (diazepam and midazolam), butyrophenones (azaperone), opioids (butorphanol) or 2 adrenergic agoni sts (xylazine, medetomidine ). 5,100 Acepromazine at 0.05 mg/kg is frequently used as a sole sedative or as an anesthetic premedication to imp rove both induction and recovery in animals 5 Higher doses of acepromazine may provide greater sedati on but they also carry the risk of increase d s ide effects such as hypotension and extrapyramidal signs (such as involuntary muscle spasms motor restlessness, ataxia, and inappropriate aggression ) 5,159 Syncope and cardiovascular collapse has been reported in some strains of Boxer dogs following the use of even low doses of acepromazine and this may be d ue to orthostatic hypotension vasovagal syncope or Boxer cardiomyopathy 5 In addition to the use of pharmacological agents, acupuncture has been shown to have sedative and tranquilizing effects in human and animals. 147,189 196 The degree of mental depression or behavioral changes is related to alteration s in CNS activity caused by the release of opioid ne uropeptides. 195 Physiologically, there is a decrease in and wave activity on the electroencephalogram (EEG) during acupuncture treatments in rats 197 These effects are utilized in acupun cture treatment of anxiety stat e s, insomnia, epilepsy, addictions, and behavior problems. 190,198 Zheng and colleagues present evidence that EA markedly reduced the dose of midazolam infusion required to sedate critically ill patients. 199 A pilot study showed significant reduction in the dose of propofol
85 required for sedation in critically ill patients following EA. 189 In prospective studies, EA effectively reduced anxiety, discomfort, and demand for sedati ve drugs during colonoscopy and lithotripsy in human s 192,193,200 When acupuncture at GV20 or Yin tang was given concurrently with butorpha nol in dogs the mean spectral edge frequency 95 values, which is one of the electroencephalographic parameters, was significantly lower compared to dogs treated with butorphanol alone. 196 In the present study, acepromazine caused significant sedation in dogs and they remained highly sedated after morphine administration. The results are consistent with previous studies. 7 Although it was not as effective as acepromazine, sedation after treatment with EA at PC 6 alone or PC 6 combined with ST 36, GB 34, BL 20, and BL 21 was also apparent when compared to dogs treated with saline, sham EA or maropitant EA at a non acupoint did not show a significant sedative effect. The results suggest that EA at acupoints c ould be useful for producing sedation in animals Incorporating a cupuncture in to a sedative regimen could potentially allow a reduction in the dose of sedative agents and therefore may effectively reduce the risk of side effects of these drugs in patients. In conclusion, b ased on the results of this study, m aropitant has a potent antiemetic effect against morphine induced vomiting, where it effectively decreases the incidence of vomiting and reduces the number of vomiting episodes. However, it does not appear to effectively prevent signs of n ausea related to morphine administration In addition to its sedative effect, a cepromazine is effective not only in prevent ing vomiting but also in reducing the incidence of nausea induced by morphine Although EA was found to be ineffective in preventing the incidence of vomiting, it effectively reduced
86 vomiting episodes induced by morphine administration There appeared to be no difference between PC 6 alone or PC 6 combined with other acupoints in reducing signs of nausea F urthermore, d ogs receiving EA were less likely to show signs of nausea following morphine administration and EA also produced sedation. Further studies may provide information on the optimal EA frequency and treatment times for decreasing the incidence of vomiting. Future investigatio n should also focus on investigating the efficacy of acupuncture as an adjunct treatment to antiemetic drug therapy for improved antiemetic efficacy.
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103 BIOGRAPHICAL SKETCH Ronald Koh is a Chinese descendant, who was born and raised in Malaysia. He attended college in Taiwan and received his Doctor of Veterinary Medicine degree with honors from National Chung Hsing University College of Veterinary Medicine, Taichung, Taiwan, in 2006 After graduation, he practic ed in small animal medicine for two and a half years. At that time, he developed a special interest in internal medicine, oncology, and nutrition. He is also passionate about using acupunctur e, Chinese herbal and food therapy as integrative methods to treat and prevent diseases and cancers in animals. Ronald was admitted to the acupuncture internship program at the V eterinary M edical C enter at the University of Florida (UF) in 2009. He was later certified as a veterinary acupuncturist, herbalist and food therapist by the Chi Institute for Traditional Chinese Veterinary Medicine. After his internship, he continued to pursue graduate stu d ies in veterinary clinical sciences at UF under the supervi sion of Dr. Sheilah Robertson During his research study, h e spent most of his time work ing at the UF Merial Shelter Medicine His m f maropitant, acepromazine, and electroacupuncture on nausea and vomiting related to morphine administration in dogs. Over the years, he has owned dogs, cats, birds and fish, but currently there is just one cat at home. When not working, Ronald enjoys play ing with his cat, reading, listening to music, gardening, and exercise.