Actions of Non-Steroidal Anti-Inflammatory Drugs in Sheep
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ACTIONS OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS IN SHEEP by Elizabeth McCaulI Welsh B.V.M.S. , M.R.C.V.S. A thesis submitted for the degree of Doctor of Philosophy in the Faculty of Veterinary Medicine of the University of Glasgow Department of Veterinary Pharmacology August, 1993. ProQuest Number: 11007781 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 11007781 Published by ProQuest LLC(2018). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 GLASGOW UNIVERSITY LIBRARY i To my parents and Chris. CONTENTS Acknowledgements iv Declaration v Summary vi List of figures ix List of tables xii Abbreviations xvii Chapter 1- General Introduction 1 Chapter 2- General Materials and Methods 24 Chapter 3- The antinociceptive effects of non-steroidal anti-inflammatory drugs in sheep: 1 Clinical pain 36 3 .1 -Introduction 37 3.2- Materials and methods 47 3.3- Results 53 3.4- Discussion 98 Chapter 4- The antinociceptive effects of non-steroidal anti-inflammatory drugs in sheep: 2 Experimental pain 112 4.1-Introduction 113 4.2- Materials and methods 120 4.3- Results 123 4.4- Discussion 141 Chapter 5- The Pharmacokinetics of flunixin meglumine and carprofen (racemate) 150 iii 5.1- Introduction 151 5.2- Materials and methods 154 5.3- Results 159 5.4- Discussion 173 Chapter 6- Methods of lameness measurement 179 6.1- Introduction 180 6.2- Materials and methods 187 6.3- Results 192 6.4- Discussion 209 Chapter 7- General Discussion 218 References 226 ACKNOWLEDGEMENTS This work was generously funded by the Agricultural and Food Research Council. I would like to thank Dr. A. M. Nolan for her enthusiastic supervision of this work, and for her constant support and guidance. I would like to thank Dr. Q. A. McKellar for allowing the research to be carried out in his department, and also the technical staff in the Department of Veterinary Pharmacology for their assistance. In particular, I would like to thank Mr P. Baxter, Mrs A. Galbraith and Mrs M. Michael for their assistance with the HPLC analysis, and Mr I. Gibson for his help in constructing the tourniquet. I am indebted to Dr. G. Gettinby of the Department of Statistics and Modelling Science, University of Strathclyde, for his patience and encouragement whilst helping me with statistical methods. I wish to express my thanks to Dr. G. Fishwick and Dr. J. Parkins, Department of Animal Husbandry, University of Glasgow, The Institute of Animal Physiology and Genetics Research, Roslin, Mr J. Blair, Barrhead and Mr I. Lamont, Lochwinnoch for allowing me access to their flocks of sheep. I would like to thank Messrs. A. McFadyen, C. McFadyen, M. Williamson and the staff at Cochno Farm for managing the sheep used in the present study, and in addition, I would like to mention 'Meg' without whom, on occasion, the sheep may never have been gathered. I am grateful to Mr A. Hudd and Mr B. Robb for skilfully constructing the thermal device used in these experiments, and to Mr. G. Baxter for his helpful advice with the mechanical device. I would like to thank Ms. M. Ritchie, Ms. M. Thompson and Mr B. Wilson, who anaesthetised and operated on the sheep at IAPGR, for their unending cooperation and also Mr C. Blair for his assistance in taking the measurements. V DECLARATION The contents of this thesis are the work of the author. The thesis has not been submitted previously to any university for the award of a degree. The following publications are based on the work contained in this thesis: Welsh, E. W. , Baxter, P. , Nolan, A. M. 1992. Pharmacokinetics of carprofen administered intravenously to sheep. Research in Veterinary Science. 53, 264-266. Welsh, E. M. , McKellar, Q. A ., Nolan, A. M. 1993. The pharmacokinetics of flunixin meglumine in the sheep. Journal of Veterinary Pharmacology and Therapeutics. 16, 181- 188. Welsh, E. W. , Gettinby, G. , Nolan, A. M. 1993. Comparison of a visual analogue scale and a numerical rating scale for assessment of lameness, using sheep as a model. American Journal of Veterinary Research. 54, 976-983. vi SUMMARY Mechanical and thermal stimuli were used to determine threshold responses in normal experimental sheep which were familiar with both test procedures. The average control response threshold to noxious thermal and mechanical stimulation was 54.5°C and 3.2 Newtons (N), respectively. The effects of 2 non-steroidal anti-inflammatory drugs (NSAIDs), flunixin meglumine and carprofen, were investigated using the 2 test systems. Neither drug was shown to influence thresholds to noxious stimulation over a 6 hour period in normal sheep. Thresholds to noxious mechanical stimulation were .recorded from normal farm sheep which were unfamiliar with the testing procedure. The average response threshold in these sheep was significantly greater than that recorded from experimental sheep (mean, 4.9N), but fell over a period of 3 days to a similar level recorded from experimental sheep (mean, 3.IN). Thresholds to noxious mechanical stimulation in farm sheep which were unfamiliar with the testing procedure, and which had been suffering from footrot for a period of not less than 1 week, were not significantly different from normal farm sheep (mean, 4.7N). In addition, when these sheep were tested over a period of 3 days, thresholds did not fall in the manner described for normal sheep (mean, 4.6N). However, administration of flunixin meglumine, 1.0 mg/kg, IV, once daily for 3 days in sheep suffering from footrot caused a significant reduction in thresholds to noxious mechanical stimulation in sheep suffering from footrot on the third and fourth days after treatment had been initiated. Thresholds to noxious mechanical and thermal stimulation were assessed in sheep undergoing anaesthesia and abdominal surgery, and the effects of flunixin meglumine, carprofen and buprenorphine, a partial opioid agonist, on thresholds investigated. Induction of anaesthesia was achieved by injection of thiopentone or ketamine, IV, and anaesthesia was maintained by administration of halothane in oxygen and nitrous oxide. After thiopentone induction, thermal and mechanical thresholds were not shown to change after a 20 minute period of general anaesthesia alone, and similarly, thresholds to noxious mechanical stimulation were not significantly different from control values after induction of anaesthesia with either thiopentone or ketamine in sheep which underwent abdominal surgery. However, after thiopentone induction, thresholds to noxious thermal stimulation were significantly lower than control values 45, 60 and 120 minutes post- operatively. Intra-operative injection of flunixin meglumine (1.0 mg/kg, IV) and buprenorphine (10 |ig/kg, IV) prevented the development of post-operative thermal vii hyperalgesia, while carprofen (4.0 mg/kg, IV), not only prevented the development of hyperalgesia in the immediate post-operative period, but also caused a significant increase in thresholds to noxious thermal stimulation 60 minutes post-operatively. Thresholds to noxious thermal stimulation were unchanged in the post-operative period in sheep anaesthetised with ketamine which subsequently had undergone abdominal surgery under halothane anaesthesia. Thresholds to noxious mechanical stimulation were investigated during peripheral limb ischaemia, induced by application of a pneumatic tourniquet to the forelimb of sheep. During limb ischaemia, mechanical thresholds fell to below control values, and immediately prior to tourniquet deflation, were significantly lower than those recorded pre-inflation (3.IN vs 1.7N). Injection of flunixin meglumine (1.0 mg/kg, IV) and carprofen (0.7 mg/kg, IV) 1 hour prior to tourniquet inflation attenuated the fall in mechanical thresholds recorded after injection of saline (5 ml (0.9 %), IV) 1 hour before inflation. Similarly, administration of fentanyl (5 jLig/kg, IV), a fi-opioid agonist, prevented the reduction in thresholds observed during tourniquet inflation. Thresholds to noxious mechanical and thermal stimulation were assessed for a period of 120 minutes after intradermal injection of saline (0.9 %, 100 fil) or the irritant carrageenan (0.0625 %, 100 p.1). Flunixin meglumine (2.0 mg/kg, IV), carprofen (4.0 mg/kg, IV) or saline (5 ml (0.9 %), IV) was administered at 120 minutes, and subsequently, thresholds to noxious stimulation were investigated for a further 4 hours. Intradermal injection of carrageenan did not cause a clearly defined change in thresholds to noxious mechanical stimulation, but thresholds to thermal stimulation were significantly lower than control values 120 minutes after injection of the irritant (group mean, 52.4°C vs 49.3°C). Thresholds to noxious thermal stimulation remained significantly lower than control values after administration of saline, IV, for a further 60 minutes. However, after administration of either NSAID, thresholds were no longer significantly different from control values. Pharmacokinetic analyses of plasma levels of flunixin meglumine and carprofen (0.7 and 4.0 mg/kg) following intravenous injection in sheep was carried out. The decline of flunixin meglumine in plasma was best described by a tri-exponential equation, after injection of both 1.0 and 2.0 mg/kg, with elimination half-lives of 221.7 and 205.8 minutes, respectively. The decline of carprofen in plasma was best described by a bi exponential equation, after injection of both 0.7 and 4.0 mg/kg, with elimination half- lives of 25.8 and 32.3 hours, respectively.