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FRCR. Thesis Submit 2807400880 CLINICAL AND PHARMACOLOGICAL ASPECTS OF THE USE OF MORPHINE IN ADVANCED CANCER Peter John Hoskin B.Sc., M.B.,B.S., MRCP(UK), FRCR. Thesis submitted for the degree of Doctor of Medicine in the University of London 1 ProQuest Number: U553630 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 U553630 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 ABSTRACT The pharmacology of morphine has been studied with particular reference to Its use In chronic dosage In patients with advanced cancer and to explore the hypothesis that one of Its metabolites, norphine-6 ^ 1ucurcnide, which is a highly potent analgesic in animal models, may play an Important part In the analgesic action of morphine. In this work two different assays for morphine, morphine-3- glucuronlde (M3G) and marphlne-6 -glucuronide (M6G) have been compared; radioimmunoassay (RIA) and high performance liquid chromatography (HPLC). Basic pharmacokinetic parameters for morphine and morphine-6 - glucurcnlde have been established In healthy volunteers. Changes in both morphine and M 6G plasma concentrations were found to reflect changes in scores for drowsiness, relaxation and dry mouth after oral and intravenous adniinistration. In cancer patients receiving regular doses of oral morphine there was a mean absolute bioavailability of 34% which was not significantly different from that in healthy volunteers. No influence of impaired hepatic function due to metastases was seen on this or plasma clearance. A ratio of morphine:M6 G of between 1:6 and 1:9 was found (compared to a ratio of 1 : 1 1 in healthy volunteers), and the ratio of morphine:M3G was 1:55. The pharmacology of controlled release morphine tablets (MST- Ocntinus) has been investigated. No difference in bioavailability relative to aqueous morphine solution was found and when changing from oral morphine solution to MST no advantage in using a loading dose of aqueous morphine when initiating treatment with controlled release tablets was found. 2 Morphine, M3G and M 6G have been demonstrated In CSF, pleural fluid and ascitic fluid from cancer patients. Evidence for an enterohepatic circulation of morphine has been obtained by the demonstration of these substances in bile from cancer patients receiving regular morphine. Patterns of use of morphine in patients with cancer pain have been studied by both a retrospective review of drug use in a continuing care unit and a postal questionnaire to a cross section of medical practitioners. 3 CONTENTS Page ABSTRACT 2 ACKNCWLEJX3EMENTS 18 CHAPTER 1 INTRODUCTION 21 l.a) Morphine Pharmaceutical preparations l.a.l Morphine Sulphate 24 l.a. 2 Nepenthe 24 l.a.3 Controlled Release Preparations 25 l.a.4 Parenteral Preparations 25 l.a.5 Others 25 Clinical use l.a.6 General Aspects 26 l.a.7 Oral Administration 29 l.a.8 Rectal Administration 30 l.a.9 Parenteral Administration 30 1. a. 10 Equivalent parenteral:oral dose ratios 31 l.a. 11 Spinal Administration 32 l.a. 12 Buccal Administration 34 l.a. 13 Tolerance and Addiction 34 l.a. 14 Morphine Intolerance 38 4 Pharmacokinetics Page l.a.15 General Considerations 39 1. a. 16 Absorption 3 9 1. a. 17 Distribution 40 1. a. 18 Metabolism 42 l.a. 19 Excretion 47 l.a.20 Summary of Published Pharmacokinetic Parameters 49 Pharmacodynamics l.a.21 Clinical Efects of Morphine 55 l.a.22 Opioid Receptors 55 l.a.23 Active Metabolites 57 l.b Objectives 61 CHAPTER 2 METHODS 2.a Review of Morphine Assay Methods 2.a.l Early Methods 63 2.a.2 Radioisotope Tracer Methods 64 2.a.3 Fluorometric Assay 64 2.a.4 Gas Liquid Chromatography 65 2. a. 5 Radioimmunoassay 65 2.a .6 High Performance Liquid 68 Chromatography 5 2.b HPLC Assay for Morphine and Morphine Metabolites Page 2.b.l Extraction Technique 70 2.b.2 Chromatography 72 2.b.3 Development of Assay 78 2.c RIA Assay for Morphine 82 2.d RIA Assay for Morphine Metabolites 87 2.e Comparison of RIA with HPLC 2.e.l Introduction 92 2.e.2 HPLC vs HPLC 93 2.e.3 HPLC vs RIA 95 2.e.4 HPLC vs HPLC vs RIA 98 2.e.5 Differential RIA 100 2.e.6 Discussion 103 2.f Method of Blood Sampling 2.f .1 Introduction 104 2.f .2 Materials and Method 106 (i ) Sample Collection (ii) Assay Technique (iii) Statistical Analysis 2.f .3 Results 108 2.f.4 Discussion 111 6 CHAPTER 3 PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES WITH MORPHINE IN HEALTHY VOLUNTEERS Page a) Pharmacokinetics of Morphine after (i) IV Injection (ii) Oral Elixir, (iii) Controlled Release Tablet (MST), (iv) Buccal Tablet. 3.a.l Introduction 114 3.a.2 Patients and Method 115 3.a.3 Assay Method 117 3.a.4 Statistical Analysis 117 3.a.5 Results 118 3.a .6 Discussion 124 b) Pharmacokinetics of M6G after (i) IV Injection (ii) Oral Elixir (iii) Controlled Release Tablet (MST) (iv) Buccal Tablet 3.b.l Introduction 126 3.b.2 Patients and Method 126 3.b.3 Assay Method 126 3.b.4 Statistical Analysis 126 3.b.5 Results 129 3.b.6 Discussion 133 7 c) Concentration ^ Effect Relationships Page (i) Morphine (ii) M6G 3.C.1 Introduction 135 3.C.2 Method 135 3.C.3 Results 138 3.C.4 Discussion 141 CHAPTER 4 STUDIES ON THE BIQAVAILABILITY AND PHARMACOKINETICS OF MORPHINE IN PATIENTS WITH ADVANCED CANCER 4.a Bioavailability of Morphine in patients with advanced cancer: (i) Normal hepatic function (ii) Impaired hepatic function 4.a.l Introduction 143 4.a.2 Patients and method 144 4.a.3 Sanple analysis 145 4.a.4 Statistical analysis 145 4.a.5 Results 146 4.a .6 Discussion 156 8 4.b The relative bioavailability of oral Morphine Elixir and Controlled Release Morphine Tablets (MST-Continus) Page 4.b.l Introduction 159 4.b.2 Patients and Method 160 4.b.3 Sample analysis 161 4.b.4 Statistical Analysis 162 4.b.5 Results 163 (i) Patient Population 163 (ii) Individual profiles 163 (iii) Relative Bioavailability of Morphine 165 Snax anc* *max far Morphine 168 (v) Metabolite Data 170 (vi) Pain Scores 175 (vii) Steady State Samples 177 4.b.6 Discussion 179 4.c Evaluation of the use of a loading dose of morphine when starting Controlled Release Morphine Tablets. 4.C.1 Introduction 183 4.C.2 Method 184 4.C.3 Sample analysis 186 4.C.4 Statistical analysis 186 4.C.5 Results 187 4.C.6 Discussion 196 9 CHAPTER 5 STUDIES INTO THE DISTRIBUTION OF MORPHINE AND MORPHINE-6 -GLUCURONIDE IN PATIENTS WITH ADVANCED CANCER Page 5.a Evidence fear enterohepatic circulation of Morphine in man 5.a.l Introduction 199 5.a.2 Patients and Method 199 5.a.3 Analysis 2 0 0 5.a.4 Results 2 0 0 5.a.5 Discussion 203 5.b The passage of Morphine and M 6G across the blood-brain barrier into CSF 5.b.l Introduction 205 5.b.2 Patients and Method 206 5.b.3 Analysis 206 5.b.4 Results 206 5.b.5 Discussion 2 1 1 5.c The passage of morphine and M 6 G into malignant effusions 5.C.1 Introduction 214 5.C.2 Patients and Method 214 5.C.3 Analysis 215 5.C.4 Results 215 5.C.5 Discussion 217 10 CHAPTER 6 CLINICAL STUDIES ON THE USE OF OPIOID DRUGS IN PATIENTS WITH ADVANCED CANCER Page 6 .a Questionnaire study into the use and attitudes of medical staff to opioid drugs in advanced cancer. 6 .a.l Introduction 219 6 .a .2 Subjects and method 2 2 0 6 .a.3 Statistical analysis 2 2 1 6 .a.4 Results 2 2 2 6 .a.5 Discussion 238 6 .b Retrospective review of treatment patterns in a continuing care unit. 6 .b.l Introduction 242 6.b.2 Patients and Methods 242 6.b.3 Results 243 (i) Analgesic Use 243 (ii) Coanalgesic Use 250 (iii) Antiemetic Use 251 (iv) Antitumour Therapy 254 (v) Other Therapies 256 6.b.4 Discussion 257 11 CHAPTER 7 OONCLUSICNS Page 7.a Assay Methods 262 7.b Pharmacokinetics of morphine 263 7.c Morphine metabolites 264 7.b Controlled release morphine tablets 265 7.e Enterohepatic circulation of morphine 265 7.f Clinical use of opioid drugs in patients with advanced cancer. 266 7.g Future Studies 267 REFERENCES 270 APPENDIX 1 Raw data 284 APPENDIX 2 Questionnaire from Chapter 6 .a 303 APPENDIX 3 PUBLICATIONS 308 12 LIST OF TABLES Page l.a.l Alternative strong opioid drugs and analgesic equivalents 27 1.a.2 Published pharmaookinetic parameters of morphine 50 2.C.1 Cross reactivity of specific morphine antiserum 83 2.C.2 Recovery of morphine added to drug-free serum 8 6 2.d.l Cross reactivity of rabbit antiserum G/R/ 6 8 8 2.d.2 Cross reactivity of goat antiserum G/G/l 90 2.e. 1 Comparison of HPLC (Barts) with HPLC (Hackney) for morphine and M6G 94 2.e.2 Comparison of HPLC and RIA using the mean difference over two series of 150 samples 97 2.e.3 Comparison of values for M6G by differential RIA 101 2.e.4 Recovery data for RIA 102 2.f.1 Details of sample preparation in published reports 1975-1987 105 2.f.2 Details of sample preparation 107 2.f.3 Details of morphine administration in patients entered in to sampling study 109 3.a.l Pharmaookinetic parameters for morphine after IV administration 1 2 0 3.a.2 AUC and absolute bioavailability for morphine in healthy volunteers 1 2 1 3.a.3 C^ax and for morphine in healthy volunteers 122 3.a.4 Subject acceptability of the buccal morphine tablet 123 3.b.l AUC for M 6G and morphine:M6G ratios in healthy volunteers 130 3.b.2 and tmax for M6G in healthy volunteers
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