TRAMADOL Pre-Review Report Agenda Item 5.3 Expert Committee on Drug Dependence Thirty-ninth Meeting Geneva, 6-10 November 2017 39th ECDD (2017) Agenda item 5.3 Tramadol Page 2 of 36 39th ECDD (2017) Agenda item 5.3 Tramadol Contents Acknowledgements.................................................................................................................................. 5 Summary...................................................................................................................................................... 6 1. Substance identification ....................................................................................................................... 7 A. International Nonproprietary Name (INN).......................................................................................................... 7 B. Chemical Abstract Service (CAS) Registry Number .......................................................................................... 7 C. Other Chemical Names ................................................................................................................................................... 7 D. Trade Names ....................................................................................................................................................................... 7 E. Street Names ....................................................................................................................................................................... 8 F. Physical Appearance ....................................................................................................................................................... 8 G. WHO Review History ....................................................................................................................................................... 8 2. Chemistry ................................................................................................................................................... 9 A. Chemical Name .................................................................................................................................................................. 9 B. Chemical Structure ........................................................................................................................................................... 9 C. Stereoisomers ................................................................................................................................................................... 10 D. Methods and Ease of Illicit Manufacturing ........................................................................................................ 10 E. Chemical Properties ...................................................................................................................................................... 10 F. Identification and Analysis ........................................................................................................................................ 10 3. Ease of Convertibility Into Controlled Substances ...................................................................... 11 4. General Pharmacology ........................................................................................................................ 11 A. Routes of administration and dosage ................................................................................................................... 11 B. Pharmacokinetics .......................................................................................................................................................... 11 C. Pharmacodynamics ....................................................................................................................................................... 13 5. Toxicology ................................................................................................................................................ 14 6. Adverse Reactions in Humans ........................................................................................................... 17 7. Dependence Potential .......................................................................................................................... 17 A. Animal Studies ................................................................................................................................................................. 17 B. Human Studies................................................................................................................................................................. 17 8. Abuse Potential ...................................................................................................................................... 19 A. Animal Studies ................................................................................................................................................................. 19 B. Human Studies................................................................................................................................................................. 20 9. Therapeutic Applications and Extent of Therapeutic Use and Epidemiology of Medical Use .............................................................................................................................................................. 22 10. Listing on the WHO Model List of Essential Medicines .............................................................. 23 11. Marketing Authorizations (as a Medicinal Product) ................................................................. 23 12. Industrial Use ......................................................................................................................................... 24 13. Non-Medical Use, Abuse and Dependence ..................................................................................... 24 Page 3 of 36 39th ECDD (2017) Agenda item 5.3 Tramadol 14. Nature and Magnitude of Public Health Problems Related to Misuse, Abuse and Dependence ............................................................................................................................................. 27 15. Licit Production, Consumption and International Trade ......................................................... 27 16. Illicit Manufacture and Traffic and Related Information ........................................................ 27 17. Current International Controls and Their Impact ...................................................................... 28 18. Current and Past National Controls ................................................................................................ 28 19. Other Medical and Scientific Matters Relevant for a Recommendation on the Scheduling of the Substance ..................................................................................................................................... 28 References ................................................................................................................................................ 29 Annex 1: Report on WHO Questionnaire for Review of Psychoactive Substances for the 39th ECDD: Evaluation of Tramadol ............................................................................................... 36 Page 4 of 36 39th ECDD (2017) Agenda item 5.3 Tramadol Acknowledgements This report has been drafted under the responsibility of the WHO Secretariat, Department of Essential Medicines and Health Products, Teams of Innovation, Access and Use and Policy, Governance and Knowledge. The WHO Secretariat would like to thank the following people for their contribution in producing this review report: Professor Eric C. Strain, Maryland, United States (literature review and drafting), Ms. Dilkushi Poovendran, Geneva, Switzerland (questionnaire analysis and report drafting) and Dr. Stephanie Kershaw, Adelaide, Australia (review report editing, questionnaire analysis and report drafting). Page 5 of 36 39th ECDD (2017) Agenda item 5.3 Tramadol Summary Tramadol is a centrally acting analgesic with a multimode of action. It acts on serotonergic and noradrenergic nociception, while its metabolite O-desmethyltramadol acts as a mu agonist on the opioid receptor. Its analgesic potency is claimed to be about one tenth that of morphine. Tramadol is used to treat both acute and chronic pain of moderate to (moderately) severe intensity. Tramadol monotherapy does not usually provide adequate analgesia. In chronic non-cancer pain, there is little evidence for the use of tramadol for more than three months. Tramadol is considered to be a relatively safe analgesic. The main adverse reactions to tramadol therapy are nausea, dizziness, and vomiting, particularly at the start of the therapy. At therapeutic doses, tramadol does not cause clinically relevant respiratory depression. Tramadol is contra-indicated, however, in patients with diminished respiratory function. Tramadol is generally considered as a medicinal drug with a low potential for dependence relative to morphine. Nevertheless, physical dependence of the opioid type can occur with tramadol when used for a sustained period of time. Physical dependence on tramadol may occur when used within the recommended dose range of tramadol. In many individuals with tramadol misuse, a substance abuse history is found. Orally administered tramadol can produce opioid-like effects (both mentally and physically). Tramadol is