This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Non-Injectable Naloxone for the Prevention of Opioid Overdose Deaths McDonald, Rebecca Silvia Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 25. Sep. 2021 NON-INJECTABLE NALOXONE FOR THE PREVENTION OF OPIOID OVERDOSE DEATHS Rebecca McDonald Addictions Department Institute of Psychiatry, Psychology and Neuroscience Thesis submitted to King’s College London for the degree of Doctor of Philosophy (PhD) May 2017 1 2 Abstract Background and Aims: Naloxone is the standard treatment for reversal of opioid overdoses. Due to risk of needle-stick injury, licensed injectable naloxone products are not well suited for layperson administration or take-home naloxone distribution. The aims of this thesis are threefold: Aim 1) assess the effectiveness and limitations of take-home naloxone provision (any naloxone formulation); Aim 2) compare the pharmacokinetic profiles of non-injectable naloxone formulations; Aim 3) identify non-injectable formulations that provide early naloxone exposure similar to a 0.4mg intramuscular dose. Methods: Primary and secondary data analyses were conducted in two stages. The first stage involved evidence syntheses (including two systematic reviews), with secondary data retrieval from the peer-reviewed literature and international patent applications. The second stage involved pharmacokinetic data analysis of two clinical trials (n=12 and 38 healthy volunteers; open-label randomized cross-over design) of concentrated intranasal naloxone formulations (1mg/0.1mL–16mg/0.4mL range). Results: Re Aim 1: Take-home naloxone meets the Bradford Hill criteria. The intervention is effective at reducing opioid overdose mortality and has a low rate of adverse events. Re Aim 2: Improvised nasal kits using non-concentrated spray (1mg/ml per nostril) have low bioavailability of FIM ≤ 10% (relative to intramuscular administration). Concentrated intranasal spray (≥10mg/ml; administered as ≤0.2mL per nostril) has good bioavailability of FIM = 26-57%. Re Aim 3: Relative to the 0.4mg intramuscular reference, a 2mg/0.1mL nasal spray provided equal naloxone exposure in the first 10-minutes post-dosing and then exceeded blood levels for two hours. Conclusions: Take-home naloxone distribution to opioid users should be introduced as standard of care for the community-based prevention of overdose-related deaths and injury. In the presence of licensed alternatives, continued off-label use of improvised nasal kits is not justified. If approved by relevant regulatory agencies, the 2mg/0.1mL naloxone nasal spray could offer greater acceptability and suitability for take-home naloxone provision. 3 Table of Contents ABSTRACT .................................................................................................................. 3 TABLE OF CONTENTS ................................................................................................ 4 TABLE OF FIGURES ................................................................................................. 11 TABLE OF TABLES.................................................................................................... 12 ACKNOWLEDGEMENTS ........................................................................................... 14 ABBREVIATIONS ....................................................................................................... 15 PREFACE .................................................................................................................. 16 CHAPTER 1 THE DISCOVERY OF NALOXONE ....................................................... 24 1.1 WHAT IS NALOXONE? ............................................................................................. 25 1.1.1 The early development of naloxone ............................................................ 25 1.1.2 The predecessors of naloxone and more recent alternatives ...................... 28 1.1.3 Regulatory approval .................................................................................... 29 1.1.4 Inclusion in the WHO Model List of Essential Medicines ............................. 29 1.2 PHARMACOKINETICS ............................................................................................... 30 1.2.1 Absorption................................................................................................... 30 1.2.2 Distribution .................................................................................................. 31 1.2.3 Metabolism ................................................................................................. 31 1.2.4 Excretion ..................................................................................................... 32 1.3 PHARMACODYNAMICS ............................................................................................. 32 1.3.1 Opioid-induced respiratory depression ........................................................ 32 1.3.2 How does naloxone reverse opioid overdose? ............................................ 34 1.3.3 Duration of action ........................................................................................ 35 1.3.4 Naloxone dosing ......................................................................................... 36 1.4 THE SHIFT FROM INTRAVENOUS TO INTRAMUSCULAR NALOXONE ADMINISTRATION ...... 37 CHAPTER 2 TWENTY YEARS OF TAKE-HOME NALOXONE .................................. 39 2.1 INTRODUCTION ....................................................................................................... 40 4 2.2 METHODS .............................................................................................................. 41 2.2.1 Literature search ......................................................................................... 41 2.2.2 Data extraction and evidence synthesis ...................................................... 41 2.3 RESULTS ................................................................................................................ 42 2.3.1 1996-2001 circa: Conception and early implementation .............................. 42 2.3.2 2001-2006 circa: Modest progress amidst legal and safety concerns .......... 47 2.3.3 2006-2011 circa: Identification of legal pathways for THN ........................... 48 2.3.4 2011-2016 circa: Emergence of stronger data and expansion..................... 52 2.4 DISCUSSION ........................................................................................................... 58 2.4.1 Statement of principal findings .................................................................... 58 2.4.2 Strengths and weaknesses of the chapter................................................... 58 2.4.3 Questions for future research ...................................................................... 59 2.5 CONCLUSION .......................................................................................................... 59 CHAPTER 3 BRADFORD HILL ANALYSIS OF TAKE-HOME NALOXONE ............... 62 3.1 INTRODUCTION ....................................................................................................... 63 3.2 METHODS .............................................................................................................. 64 3.2.1 Identification of eligible studies .................................................................... 64 3.2.2 Analysis ...................................................................................................... 68 3.3 RESULTS ................................................................................................................ 70 3.3.1 Consideration according to the original Bradford Hill criteria ....................... 70 3.3.2 Consideration according to additional feasibility and implementation criteria .................................................................................................................. 76 3.4 DISCUSSION ........................................................................................................... 81 3.4.1 Statement of principal findings .................................................................... 81 3.4.2 Strengths and weaknesses of the chapter................................................... 81 3.4.3 Possible mechanisms and