REGULATORY STRATEGIES FOR PROMOTING THE SAFE USE OF PRESCRIPTION OPIOIDS AND THE POTENTIAL IMPACT OF OVERREGULATION Wissenschaftliche Prüfungsarbeit zur Erlangung des Titels „Master of Drug Regulatory Affairs“ der Mathematisch-Naturwissenschaftlichen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn vorgelegt von Dr. Katja Bendrin aus Torgau Bonn 2020 Betreuer und Erster Referent: Dr. Birka Lehmann Zweiter Referent: Dr. Jan Heun REGULATORY STRATEGIES FOR PROMOTING THE SAFE USE OF PRESCRIPTION OPIOIDS AND THE POTENTIAL IMPACT OF OVERREGULATION Acknowledgment │ page II of VII Acknowledgment I want to thank Dr. Birka Lehmann for her willingness to supervise this work and for her support. I further thank Dr. Jan Heun for assuming the role of the second reviewer. A big thank you to the DGRA Team for the organization of the master's course and especially to Dr. Jasmin Fahnenstich for her support to find the thesis topic and supervisors. Furthermore, thank you Harald for your patient support. REGULATORY STRATEGIES FOR PROMOTING THE SAFE USE OF PRESCRIPTION OPIOIDS AND THE POTENTIAL IMPACT OF OVERREGULATION Table of Contents │ page III of VII Table of Contents 1. Scope.................................................................................................................................... 1 2. Introduction ......................................................................................................................... 2 2.1 Classification of Opioid Medicines .................................................................................................. 2 2.2 Opioid Receptors and Mode of Action ........................................................................................... 3 2.3 Need for Opioid Medicines ............................................................................................................. 4 2.3.1 WHO Analgesic Ladder ............................................................................................................... 5 2.3.2 WHO Essential Medicines List .................................................................................................... 6 2.3.3 Adverse Events of Opioid Medicines .......................................................................................... 6 2.4 Consequences of Unmanaged Pain ................................................................................................ 8 3. International Control and Availability of Opioid Medicines for Pain Management................... 9 3.1 International Control by Drug Control Treaties .............................................................................. 9 3.2 Availability of Opioids for Treatment ........................................................................................... 10 3.3 The Prevalence of Opioid-Related Harms Increases Worldwide .................................................. 12 4. Regulatory Barriers to Opioid Accessibility ........................................................................... 13 4.1 Europe .......................................................................................................................................... 16 4.1.1 Germany ................................................................................................................................... 16 4.1.2 United Kingdom ........................................................................................................................ 20 4.1.3 Poland ....................................................................................................................................... 24 4.2 North America .............................................................................................................................. 26 4.2.1 Canada ...................................................................................................................................... 27 4.3 Oceania ......................................................................................................................................... 31 4.3.1 Australia .................................................................................................................................... 31 4.4 Asia ............................................................................................................................................... 36 4.4.1 Japan ......................................................................................................................................... 37 4.4.2 India .......................................................................................................................................... 40 4.5 Africa ............................................................................................................................................. 44 4.5.1 South Africa .............................................................................................................................. 44 4.5.2 Rwanda ..................................................................................................................................... 47 5. Alternatives to Opioids, Novel Approaches, and their Regulatory Status............................... 54 5.1 Cannabis as Opioid Substitute ...................................................................................................... 54 5.2 Novel Non-opioids ........................................................................................................................ 54 5.3 Gene Therapy ............................................................................................................................... 55 6. Discussion and Conclusion ................................................................................................... 56 6.1 Implementation of the UN Single Convention 1961 into National Legislations ........................... 56 6.2 Availability of Clinical Guidelines for the Use of Opioids in Pain Management ........................... 59 6.3 Are Prescription Opioids the Drivers of Opioid Crises? ................................................................ 61 6.4 Addressing the Problematic Availability and Use of Opioids through Regulatory Measures ...... 62 7. Summary ............................................................................................................................ 64 8. References .......................................................................................................................... 66 9. Appendices ......................................................................................................................... 77 REGULATORY STRATEGIES FOR PROMOTING THE SAFE USE OF PRESCRIPTION OPIOIDS AND THE POTENTIAL IMPACT OF OVERREGULATION List of Tables │ page IV of VII List of Tables Table 1: Classification of Opioids............................................................................................................. 3 Table 2: Average Consumption of Narcotic Drugs in the Selected Countries, 2006-2008 and 2016-2018 ............................................................................................................................................................... 15 Table 3: Comparison of the National Control Acts for the Regulation of Opioids in Germany, UK, Poland, Canada, Australia, India, Japan, South Africa and Rwanda ................................................................... 50 List of Figures Figure 1: The WHO Cancer Pain Ladder for Adults ................................................................................. 5 Figure 2: Availability of Opioids for Pain Management ......................................................................... 12 REGULATORY STRATEGIES FOR PROMOTING THE SAFE USE OF PRESCRIPTION OPIOIDS AND THE POTENTIAL IMPACT OF OVERREGULATION List of Abbreviations │ page V of VII List of Abbreviations ACDA Act on Counteracting Drug Addiction art Article ARTG Australian Register of Therapeutic Goods ATC Anatomical Therapeutic Chemical AWMF Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e.V.) BfArM Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel) BMG Federal Ministry of Health (Bundesministerium für Gesundheit) BtM Narcotics (Betäubungsmittel) BtMG German Narcotic Drugs Act (Betäubungsmittelgesetz) BtMVV Narcotic Drugs Prescription Ordinance (Betäubungsmittelverschreibungsverordnung) CBD Cannabidiol CBN Central Bureau of Narcotics CDC Centers for Disease Control and Prevention CDSA Controlled Drugs and Substances Act CDSCO Central Drugs Standard Control Organisation CHM Commission on Human Medicines CIOMS Council for International Organizations of Medical Sciences CNCP Chronic non-cancer pain CND Commission on Narcotic Drugs CNS Central nervous system CP Caudate putamen DDD Defined daily dose (The DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults) DOP Delta (δ) OPiate receptor e.g. For example (lat. "exempli grazia") EML Essential Medicines List EWG Expert Working Group FDA Food and Drug Administration GABA Gamma-aminobutyric acid GPM Good Pain Management HIV Human immunodeficiency virus HPRG Health Products Regulation Group REGULATORY STRATEGIES FOR PROMOTING THE SAFE USE OF PRESCRIPTION OPIOIDS AND THE POTENTIAL IMPACT OF OVERREGULATION List of Abbreviations │ page VI of VII HRH Human resources for health IASP Association for the Study