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Update Review Report
Agenda item 6.1
Expert Committee on Drug Dependence
Geneva, 16‐20 June 2014
36th ECDD (2014) Agenda item 6.1 Tramadol
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36th ECDD (2014) Agenda item 6.1 Tramadol
This report has been drafted under the responsibility of the WHO Secretariat, Essential Medicines and Health Products, Policy Access and Rational Use Unit. The WHO Secretariat would like to thank the following people for their contribution in producing this critical review report: Dr Edmundus Pennings, the Netherlands (literature review and drafting), Dr Caroline Bodenschatz, Switzerland (editing) and Mr David Beran, Switzerland (questionnaire report drafting).
Page 3 of 39 36th ECDD (2014) Agenda item 6.1 Tramadol Page 4 of 39 36th ECDD (2014) Agenda item 6.1 Tramadol Contents Summary
1. Substance identification
International Nonproprietary Name (INN)
Service (CAS) Registry Number
Trade Names (hydrochloride salt; including combinational medicinal products)
WHO Review History
3. Ease of convertibility into controlled substances
4. General pharmacology
4.2. Routes of administration and dosage
6. Adverse reactions in humans
7. Dependence potential
8. Abuse potential
9. Therapeutic applications and extent of therapeutic use and epidemiology of medical use.................. 23 10. Listing on the WHO Model List of Essential Medicines
11. Marketing authorizations (as a medicine)
12. Industrial use
13. Non-medical use, abuse and dependence
14. Nature and magnitude of public health problems related to misuse, abuse and dependence........... 27 15. Licit production, consumption and international trade
16. Illicit manufacture and traffic and related information
17. Current international controls and their impact
18. Current and past national controls
19. Other medical and scientific matters relevant for a recommendation on the scheduling of the substance
Annex 1: Report on WHO Questionnaire for Review of Psychoactive Substances for the 36th ECDD:
Evaluation of 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 on the µ-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, tramadol dependence may occur when used for prolonged periods of time (more than several weeks to months). Dependence to tramadol may occur when used within the recommended dose range of tramadol but especially when used at supra-therapeutic doses. In many individuals with tramadol dependence, a substance abuse history is found.
Orally administered tramadol can produce opioid-like effects (both mentally and physically) but these effects are mild and not produced following parenteral administration. Tramadol is generally considered as a medicine with a low abuse potential relative to morphine, and this potential is associated with high dose oral tramadol.
At supra-therapeutic doses and rarely at therapeutic doses, intoxications may occur.
Symptoms of tramadol intoxication are similar to those of other opioid analgesics but may include serotonergic and noradrenergic components. Symptoms include central nervous system (CNS) depression and coma, tachycardia, cardiovascular collapse, seizures, and respiratory depression up to respiratory arrest. Fatal intoxications are rare and appear to be associated with large overdoses of tramadol and co-ingestion of other drugs (including alcohol).
Tramadol is used worldwide and is listed in many medical guidelines for pain treatment. It is mentioned as a step-2 analgesic in the WHO guidelines for cancer pain relief. Tramadol is also listed on several national essential medicines lists. It is, however, not listed on the WHO Model List of Essential Medicines (April 2013).
There is growing evidence of abuse of tramadol in some African and West Asian countries considering large seizures of such preparations in North and West Africa. Abuse of tramadol is reported by Egypt, Gaza, Jordan, Lebanon, Libya, Mauritius, Saudi Arabia and Togo.
Because of increasing rate of abuse, Egypt has up-scheduled tramadol in 2009.
Tramadol is widely available via the Internet without a prescription. Websites provide many user reports on the non-medicinal use of tramadol.
Legal status of tramadol differs internationally. In most countries, it is a prescription-only medicine.
C. Other Names ()-cis-(2-dimethylaminomethyl)-1-(3-methoxyphenyl)-cyclohexanol D. Trade Names (hydrochloride salt; including combinational medicinal products) Acema, Actidol, Acty, Acugesic, Adamon, Admadol, Adolonta, Altadol, Amadol, Amanda, Amdol, Ammitran, An-Tian, Ana-Q, Anadol, Analab, Analtram, Anangor, Anatram, Andalpha, Arodol, Arrestadol, Astradol, Atdol, Avdol, Axidol, Axytram, Bei Pin, Bestodol, Bing Ning, Biodalgic, Biodil, Biodol, Biomadol, Biotram, Biotrama, Biotrany, Boldol, Bolodol, Bramadol, By-madiol, Cadol, Calmador, Calmpain, Camadol, Cambidol, Camigesik, Cemadol, Centrasic, Ceparidin, CG-MAC, Cincro Plus, Citra, Cloq, Combitram, Contradoc, Contram, Contramal, Conzip, Cormadol, Corsadol, Cortram, Cosdol, Crispin, Cromatodol, Cruzac, Cuntrol, D.M.Dol, Da Ma Err, Damadol, Damed, Damol, Darol, Didol, Doctramado, Dolan, Dolana, Dolbest, Dolbis, Dolfi, Dolfre, Dolga, Dolgesik, Dolma, Dolmal, Dolmax, Dolmeri, Dolocap, Dolocet, Dolodol, Dolol, Dolomed, Dolonil, Doloran, Dolotral, Dolotram, Dolotramin, Dolotramine, Dolpain, Dolpar, Dolpaz, Dols, Dolsic, Dolstar, Dolta, Doltel, Dolwin, Dolzam, Domadol, Dorless, Drobit, Dromadol, Durodor, Durotram, E-Dol, Ecodolor, Eltram, Esgipyrin, Etigesic, Eufindol, Fada Tramadol, Febrex, Feng Tong Ding, Forgesic, Formador, Fortradol, Fraxidol, FS, Gelotradol, Gemadol, GenRX Tramadol, Getpar, Glimadol, Gudil, Haldotram, Haledol, Hetradol, Hua Jie Wei, Hua Qu, Hyperdol, Idol, Imadol, Indolpara, Ingesic Forte, Inodol, Iodol, Ivydol, Ixprim, Jetra, Jpdol, KAlma, Kamadol, Katrasic, Kdol-P, Kedol, Kevtram, Kontram, Lanalget, Le Shi Pu Kang, Leedol, Lexidol, Lucidol, Lumidol, M-Dol, Mabron, Madol, Madola, Mandolgin, Manol, Mapdol-P, Marodol, Medol, Meradol, Meridol, Metazac, Metracop, Microdol, Milador, Minidol, Mipro, Mobiya, Monoalgic, Monocrixo, Muaction, Nettram, Neutram, Nictram, Noax, Nobligan, Nomal, Nonalges, Nopidol, Notil, Novadol, Nufapotram, Nycodol, OC-Dol, Odel, Omodel, Ondol, OPI-OT, Opidol, Opigesic, Orasic, Oratram, Orchidol, Orozumadol, Osdol, Osmadol, Ospidol, Oxxalgan, Ozitram, Pacmadol, Painadol, Paindol, Paine, Painlax, Paratel-P, Patradol, Patral, Paxilfar, Paxmax, Pengesic, Penover, Pinorec, Plazadol, Poltram, Postadol, Predalgic, Prontalgin, Prontofort, Protradon, PTR, Qi Zhi, Qimaite, Qu Feng, Qu Ming, Qu Teng, Qu Tong Kang, Qutong, Racetram, Rajdol, Ralgen, Ralivia, Ramadol, Ramax, Redimol, Relidol, Ridil, Rofy, Rotamol, Rui Li Ping, Rybix, Ryzolt, Sayadol, Sefmal, Seminac, Sensitram, Servodol, Siatram, Sigmadol, Simatral, Simudol, Sintradon, Slovadol, Souladol, Soztram, Splint Forte, Sridol, Stemadol, Strom, Page 9 of 39 36th ECDD (2014) Agenda item 6.1 Tramadol Supridol, Surgidol, Sylador, T Dol, T-Long, Tacil, Tanadol, Tadol, Tai Mei Ding, Takadol, Takol, Talnex, Tamadol, Tamolan, Tamriv, Tamvrin, Taridol, Taxidol, Taz, TDL, TDX, Tecsadol, Temadol, Tendia, Teramadol, Theradol, Ti Ma Er, Tial, Timarol, Timasen, Tinlol, Tioner, Tiparol, Tlusic, TM-Plus, TMD, Tofdol, Tol-A, Tolma, Tong Ting, Topalgic, Toptra, Trabar, Trabilin, Trace, Traceta, Tracin-P, Tracine, Tractadol, Tradef, Tradol, Tradolan, Tradolgesic, Tradolor, Tradonal, Tradorec, Tradosik, Tradyl, Traflash, Tragesic, Tragesik, Trail, Trak, Tral-ac, Tralenil, Tralgiol, Tralgit, Tralic, Tralodie, Tram-Proxyvon, Trama, Tramabene, Tramabeta, Tramabit, Tramacalm, Tramacap, Tramacet, Tramache, Tramacip, Tramacon, Tramaconti, Tramactil Uno, Tramacur, Tramacure, Tramada, Tramader, Tramadex, Tramadin, Tramadis, Tramadoc, Tramadol, Tramadol, Tramadolo, Tramadolor, Tramadon, Tramadura, Tramaflam, Tramaflash, Tramaforte, Tramag, Tramagem, Tramagesic, Tramagetic, Tramagit, Tramahexal, Tramake, Tramakind, Tramaklosidol, Tramal, Tramalan, Tramalek, Tramalex, Tramalgic, Tramalgin, Tramalin, Tramamed, Tramamerck, Tramanil, Tramapine, Tramared, Tramasindol, Tramasol, Tramaspen, Tramastad, Tramatas, Tramataur, Tramatyrol, Tramazac, Trambax, Trambo, tramcod, Tramcontin, Tramdop, Tramed, Tramedif, Tramedo, Tramedphano, Tramelene, Tramest, Tramex, Tramgesic, Trami, Tramico, Tramisol, Tramium, Tramjet, Tramned, Tramnom, Tramo, Tramoda, Tramodin, Tramoflex, Tramol, Tramolin, Tramospas, Tramrot, Tramp, Tramplas, Tramquel, Tramrod, Tramsars, Tramtor, Tramundal, Tramundin, Tramy, Tranal, Tranat, Trandol, Trandy, Transic, Trany, Tranzen, Trapain, Trapalin, Trapsure, Trasedal, Trasic, Trasik, Travex, Travictol, Trawel, Traxdol, Trazac, Trazodec, TRD, Treat, Tremolo, Tremtec, Trexol, Tridol, Tridural, Trodon, Trofel, Trol, Troma, Tromar, Tromy, Tropidol, Trosic, Trugesic, Trumac, Trump, Trunal, Trydol, Tryme, Tussdol, Ubitdol, Ultracon, Ultram, Ultramex, Unidol, Unitrama, Unitramarim, Urgendol, Utramal, Vardol, Veeradol, Vegadol, Veldrol, Verdol, Vertram, Victadol, Winpain, Wintram, Woolmar, Xi Li Xi Meng, Xiang Yang, Xidol, Xtradol, Xtram, Xtrapel, Xymel, Yi Bang, Yi Nuo Xing, Yin Jia, Yu Tong, Zaledor, Zaldiar, Zamadol, Zamudol, Zentra, Zephanal, Zodol, Zotadol, Zumalgic, Zumatram, Zydol, Zytram
F. Physical properties Tramadol hydrochloride salt is a white crystalline powder and has a bitter taste.
G. WHO Review History Tramadol was pre-reviewed for the first time at the 28th meeting of the Committee in 1992. The Committee did not recommend critical review on the basis of its low abuse liability as indicated by human studies on its subjective effects and the absence of significant abuse. At the 32nd meeting in 2000, tramadol was again pre-reviewed. The Committee noted significant numbers of cases of withdrawal syndrome and dependence reported as adverse drug reactions, as well as its potential to produce dependence of the morphine type, and recommended critical review of tramadol. At its 33rd meeting in 2002, the Committee decided that the information was not sufficient to recommend Page 10 of 39 36th ECDD (2014) Agenda item 6.1 Tramadol international control of tramadol, but was adequate to recommend that WHO keep the drug under surveillance. Subsequently, tramadol was pre-reviewed at the 34th meeting in 2006. Considering that tramadol continued to show a low level of abuse, even following the major increase in the extent of its therapeutic use, the Committee concluded that there was not sufficient evidence to justify a critical review.
2. Chemistry A. Chemical Name (1RS,2RS)-2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol or (1RS,2RS)-2-(dimethylaminomethyl)-1-(m-methoxyphenyl)cyclohexanol
The commercially available product contains the racemic (1:1) mixture of the (1R,2R) and the (1S,2S) enantiomers, also designated as the (+) and the (-) enantiomer of cis-(2-dimethylaminomethyl)-1-(3-methoxyphenyl) cyclohexanol, respectively. The (1R,2R) and (1S,2S) enantiomers have the hydroxyl and dimethylaminomethyl group in cis-configuration55, and the methoxyphenyl group and the dimethylaminomethyl group in transconfiguration.
D. Synthesis Tramadol was first synthesized in 1962 by Grünenthal GmbH in Germany by coupling of the corresponding cyclohexanon with 3-methoxyphenylmagnesium bromide in a Grignard reaction.20;21 More recently, the chemical synthesis of tramadol and two of its metabolites has been described by the same coupling reaction using organolithium derivatives.5 E. Chemical description Tramadol shows structural resemblance with codeine. Both tramadol and codeine have a 3-methoxy group on the phenyl ring and share O-demethylation as a metabolic step, yielding metabolites with stronger µ-opioid agonist activity than the parent compound.
In addition, the dimethylaminomethyl moiety of tramadol resembles the methylated ring nitrogen of morphine and codeine, and forms an essential part of the pharmacophore that interacts with the µ-opioid receptor and monoamine transporters. N-demethylation yields metabolites that lack significant analgesic activity.43;82
G. Chemical identification Tramadol may be identified chemically by infrared spectroscopy, mass spectrometry, and nuclear magnetic resonance.99 Many analytical methods for the identification and quantification of tramadol and major metabolites in body fluids have been described in the literature (see Baselt 201112 and Smyj et al 201399). Gas and liquid chromatographic techniques are available.