Pre- Review Report: Preparations of codeine listed in Schedule lll of the 1961 Single Convention on Narcotic Drugs Acetyldihydrocodeine Codeine Dihydrocodeine Ethlymorphine Nicocodine Nicodicodine Norcodeine Pholcodine Expert Committee on Drug Dependence Forty-second Meeting Geneva, 21-25 October 2019 This report contains the views of an international group of experts, and does not necessarily represent the decisions or the stated policy of the World Health Organization 42nd ECDD (2019): Preparations of codeine © World Health Organization 2019 All rights reserved. This is an advance copy distributed to the participants of the 42nd Expert Committee on Drug Dependence, before it has been formally published by the World Health Organization. The document may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means without the permission of the World Health Organization. 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Page 2 of 40 42nd ECDD (2019): Preparations of codeine Contents Acknowledgements ............................................................................................................................ 5 Executive Summary ............................................................................................................................ 6 1. Substance identification ................................................................................................................... 8 2. Chemistry........................................................................................................................................11 B. Chemical Structure ........................................................................................................................ 12 C. Stereoisomers ................................................................................................................................ 15 D. Methods and Ease of Illicit Manufacturing ................................................................................... 16 A. Chemical Properties ...................................................................................................................... 16 B. Identification and Analysis ............................................................................................................ 18 3. Ease of Convertibility Into Controlled Substances ............................................................................19 4. General Pharmacology ...................................................................................................................19 A. Routes of administration and dosage............................................................................................ 19 C. Pharmacokinetics .......................................................................................................................... 20 D. Pharmacodynamics ....................................................................................................................... 23 5. Toxicology .......................................................................................................................................25 6. Adverse Reactions in Humans .........................................................................................................26 7. Dependence Potential .....................................................................................................................27 A. Animal Studies ............................................................................................................................... 27 E. Human Studies .............................................................................................................................. 27 8. Abuse Potential ...............................................................................................................................27 A. Animal Studies ............................................................................................................................... 27 F. Human Studies .............................................................................................................................. 28 9. Therapeutic Applications and Extent of Therapeutic Use and Epidemiology of Medical Use ............28 10. Listing on the WHO Model List of Essential Medicines ....................................................................29 11. Marketing Authorizations (as a Medicinal Product) ........................................................................30 12. Industrial Use ..................................................................................................................................30 13. Non-Medical Use, Abuse and Dependence ......................................................................................30 14. Nature and Magnitude of Public Health Problems Related to Misuse, Abuse and Dependence .......31 15. Licit Production, Consumption and International Trade ..................................................................31 16. Illicit Manufacture and Traffic and Related Information ..................................................................32 17. Current International Controls and Their Impact .............................................................................32 18. Current and Past National Controls .................................................................................................32 Page 3 of 40 42nd ECDD (2019): Preparations of codeine 19. Other Medical and Scientific Matters Relevant for a Recommendation on the Scheduling of the Substance .......................................................................................................................................34 References........................................................................................................................................ 35 Page 4 of 40 42nd ECDD (2019): Preparations of codeine Acknowledgements This document was produced for the WHO Expert Committee on Drug Dependence (ECDD) under the overall direction of the WHO Secretariat led by Dr Gilles Forte (Division of Access to Medicines, Vaccines, and Pharmaceuticals). The document was written by Professor Kim Wolff under the technical direction of Dr Dilkushi Poovendran (Division of Access to Medicines, Vaccines, and Pharmaceuticals). The report was edited by Professor Jason White. The member state questionnaire was produced under the technical direction of Ms Judith Sprunken (Division of Access to Medicines, Vaccines, and Pharmaceuticals). The WHO Secretariat would also like to thank the European Monitoring Centre for Drugs and Drug Addiction (EMCCDA), International Narcotics Control Board (INCB), United Nations Office of Drugs and Crime (UNODC), and Member States for providing relevant information for the review of substances. Page 5 of 40 42nd ECDD (2019): Preparations of codeine Executive Summary Preparations listed in Schedule lll of the 1961 Single Convention on Narcotic Drugs include a variety of compounds: acetyldihydrocodeine, codeine, dihydrocodeine, ethlymorphine, nicocodicine (nicocodeine), nicodicodeine (nicodicodeine), norcodeine and pholcodine. The Schedule also includes these compounds when formulated with one or more other ingredients containing not more than 100 milligrams of the drug per dosage and with a concentration of not more than 2.5 per cent in undivided preparations The preparations are all opioids (derived from a natural opiate or of a synthetic origin); one norcodeine is a non-active metabolite. Some such as nicocodine and nicodicodine (nicodicodeine) were discovered in 1904, and acetyldihydrocodeine in Germany in 1914. Most if not all have been marketed as antitussive medicines (cough suppressants), and to provide analgesia for mild to moderate pain (acetyldihydrocodeine, ethylmorphine, nicocodine, nicodicodine). Pholcodine helps suppress unproductive coughs and acts as a mild sedative effect, but little or no analgesic effects. Some, notably acetyldihydrocodeine (a very close relative derivative of Thebacon), nicocodine, an ester of codeine closely related to dihydrocodeine and nicodicodine are not commonly used. Norcodeine is the N-demethylated a metabolite of codeine and has relatively little opioid activity in its own right. Whereas codeine and dihydrocodeine either alone or compounded with paracetamol or a nonsteroidal anti-inflammatory drug such as aspirin or ibuprofen are commonly used worldwide. In the main, preparations listed in Schedule lll are administered orally. Both codeine