TRAMADOL Pre-Review Report - WHO

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

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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


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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


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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).


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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 generally considered a medicine with a lower abuse potential compared

to morphine, but abuse of tramadol can occur and does occur. 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. 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. Websites provide many user

reports on the non-medicinal use of tramadol.


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1. Substance identification

A. International Nonproprietary Name (INN)

Tramadol

B. Chemical Abstract Service (CAS) Registry Number

27203-92-5 (base)

36282-47-0 (hydrochloride salt)

22204-88-2 (hydrochloride salt)

C. Other Chemical Names

()-cis-(2-dimethylaminomethyl)-1-(3-methoxyphenyl)-cyclohexanol

D. Trade Names

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, K-

Alma, 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, Supridol, Surgidol, Sylador, T Dol, T-Long,


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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

E. Street Names

Chill pills, Oxyontin Lite, Trammies, Ultras

F. Physical Appearance

Tramadol hydrochloride salt is a white crystalline powder and has a bitter taste.

G. WHO Review History

Tramadol has been considered by the WHO five times: in 1992, 2000, 2002, 2006,

and 2014. This compound was first pre-reviewed at the 28th meeting of the

Committee (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 a significant numbers of cases of a 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


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information was not sufficient to recommend international control of tramadol, but

was adequate to recommend that WHO keep the drug under surveillance. Tramadol

was again 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. The Committee reviewed tramadol most

recently (the fifth time) at its 36th meeting in 2014, and based on the evidence

available regarding dependence, abuse and risks to public health recommended that

a critical review of tramadol was not warranted at that time. A pre-review of

tramadol was recommended based on information received by the WHO Secretariat

regarding the misuse of tramadol.

2. Chemistry

A. Chemical Name

IUPAC Name:

(1S,2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol

CA Index Name:

tramadol

B. Chemical Structure

(Image available from PubChem[1])

Free base:

Molecular Formula: C16H25NO2

Molecular Weight: 263.4 (base); 299.8 (hydrochloride salt)


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C. Stereoisomers

Tramadol has two chiral centers in the cyclohexane ring, Consequently, four

different stereoisomers exist: (1R,2R), (1S,2S), (1R,2S), and the (1S,2R)

stereoisomer.

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-configuration [2], and the methoxyphenyl group

and the dimethylaminomethyl group in trans- configuration.

D. Methods and Ease of Illicit Manufacturing

Tramadol was first synthesized in 1962 by Grunenthal GmbH in Germany by

coupling of the corresponding cyclohexanon with 3-methoxyphenylmagnesium

bromide in a Grignard reaction. [3, 4] The chemical synthesis of tramadol and two

of its metabolites has been described by the same coupling reaction using

organolithium derivatives. [5]

The National Centre for Biotechnology (NCBI) PubChem states that a Grignard

reaction of 2-(dimethylaminomethyl)cyclohexanone (obtained by Mannich reaction

of cyclohexanone, formaldehyde, and dimethylamine hydrochloride) and the

Grignard reagent of 3-bromoanisole yields tramadol as a cis/trans mixture (cis:trans

= 85:15). Tramadol (cis isomer) is separated from the reaction mixture by

crystallization of the hydrochloride salt. ... The trans isomer can be epimerized to

the cis isomer by strong acids. [1]

E. Chemical Properties

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. [6, 7]

Melting point: 180-181 °C

Boiling point: no data

Solubility: water soluble; methanol soluble

F. Identification and Analysis

Tramadol may be identified chemically by infrared spectroscopy, mass

spectrometry, and nuclear magnetic resonance. [8] Many analytical methods for the

identification and quantification of tramadol and major metabolites in body fluids

have been described in the literature (see Baselt 2011 and Smyj et al 2013 [8, 9]).

Gas and liquid chromatographic techniques are available.


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The enantiomeric separation of tramadol and metabolites by chiral chromatography

has also been described. [10, 11]

Most commercial opioid immunoassays do not significantly cross-react with

tramadol or its metabolites and do not detect tramadol.

3. Ease of Convertibility Into Controlled Substances

Based on its chemical structure, it is not likely that tramadol can be converted into a

controlled substance.

4. General Pharmacology

A. Routes of administration and dosage

Tramadol is marketed as the hydrochloride salt and is generally used in the oral

form (as tablets or capsules). Online sources indicate that it can be a parenteral

form (most typically, intravenous, although such as form could be used

subcutaneously or intramuscularly) in some countries (e.g., India), and a rectal form

(e.g., Bangladesh). Other online resources suggest that it is available in a variety of

other pharmaceutical formulations, such as sublingual drops, and an intranasal

form, although it is not clear if these are currently available marketed forms.

Tramadol is also available in combination with acetaminophen (paracetamol).

Immediate-release and extended-release oral formulations are available. The

following pharmaceutical formulations are available for oral use:

- 50 mg immediate-release (IR) tablets/capsules

- 50 mg; 100 mg; 150 mg; 200 mg; 300 mg; and 400 mg extended-release (ER)

tablets/capsules

- 37.5 mg tramadol combined with 325 mg acetaminophen tablets/capsules

- various doses of a combined IR + ER forms of tramadol capsules (i.e.,

variable release): 25 mg + 75 mg; 50 mg + 150 mg; 50 mg + 250 mg (IR +

ER, respectively)

The recommended daily dose is in the range of 100-400 mg. The maximum dose

should not exceed 400 mg per day. Normal-release forms may be given every 4-6

hours and the extended-release forms should be given every 24 hours. Extended-

release preparations are better tolerated and are dosed once daily.

B. Pharmacokinetics

Pharmacokinetic data are mainly from the electronic Medicines Compendium

(eMC) which contains Summaries of Product Characteristics (SPCs) checked and

approved by the European Medicines Agency. [12]


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Absorption

Tramadol is almost completely absorbed after oral (>90%), rectal and intramuscular

administration. Average bioavailability is 70%, irrespective of current food intake.

Peak plasma concentrations after oral, rectal and intramuscular administration are

reached in 1-2 hours, 3 hours, and 45 minutes, respectively. Extended-release

preparations produce a smoother plasma concentration profile and have lower

(about half) peak concentrations after 4 to 6 hours. [12, 13]

Peak plasma concentrations of tramadol after single dose oral administration (100

mg) are 0.31 +/- 0.08 mg/L. [12] Peak plasma concentrations of O-

desmethyltramadol usually are 15-25% those of tramadol.

The pharmacokinetics of oral and intravenous tramadol do not differ significantly

between adults and children.

Distribution

The distribution volume of tramadol is about 2.6-2.9 L/kg bodyweight, following a

100-mg intravenous dose. Plasma protein binding is approximately 20%.

Metabolism and elimination

Tramadol is extensively metabolised in the liver by demethylation, oxidation and

conjugation (sulphation and glucuronidation). [12] Twenty-three metabolites have

been identified. [14] Both O- and N-desmethyl metabolites are formed, including

di- and tri-desmethyl derivatives. O-demethylation occurs primarily by the hepatic

enzyme cytochrome P450 2D6 (CYP2D6) and N-demethylation by cytochrome

P450 3A4 (CYP 3A4). [15, 16]

The O-demethylation reaction, yielding the active metabolite O-

desmethyltramadol, depends on the activity of the enzyme CYP 2D6. This enzyme

displays genetic polymorphism. Slow metabolizers have relatively low plasma

concentrations of O-desmethyltramadol, whereas (ultra)rapid metabolizers have

relatively high plasma concentrations of this active metabolite. As such, CYP 2D6

activity affects tramadol’s analgesic activity. CYP 2D6 can be inhibited by a

number of medicines, including various antidepressants and oral contraceptives.

Concomitant therapy with such inhibitors may affect the analgesic effect of

tramadol.

Oral tramadol is eliminated in urine (90%) and the feces (10%). About 30% of an

oral dose is excreted unchanged in the urine, and about 60% in the form of free and

conjugated metabolites. [6, 9]

The elimination half-life of racemic tramadol is approximately 6 hours, irrespective

of the mode of administration, and about 8 hours for O- desmethyltramadol. [9]

Half-lives may be prolonged in people with decreased liver or kidney function. [12]

At therapeutic doses, tramadol shows linear pharmacokinetics. The analgesic effect

is dose dependent and serum concentrations of 0.1-0.3 mg/L are considered

effective. [12]


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C. Pharmacodynamics

Tramadol exists as the racemic (1:1) mixture of the (+) and (-)-enantiomer. It has a

multimodal mechanism of action as on the one hand the (+) and (-)-enantiomer act

on serotonin and noradrenaline reuptake, and on the other hand the O-desmethyl

metabolite of tramadol (called M1 or ODT) acts on the μ-opioid receptor. This

implies that the analgesic mechanism of action of tramadol includes both non-

opioid components, i.e., noradrenergic and serotonergic components, and opioid

components. [6, 7, 17] The (+)-enantiomer of tramadol contributes to analgesia by

inhibiting the reuptake of serotonin, the (-)-enantiomer by inhibiting the reuptake of

noradrenaline, and the O-desmethyl metabolite by binding with relative high

affinity (compared to tramadol) to the μ-opioid receptor (Table 1).

(+/-)-Tramadol binds with low affinity to the human μ-opioid receptor with an

affinity constant (Ki) of 2.4 μM.42 This affinity is approximately 4000-fold less

than that of morphine (Ki = 0.34 nM). The affinity of tramadol for the δ- and κ-

opioid receptors is even less (Table 1). The (+/-)-O-desmethyl metabolite (M1) of

tramadol, on the other hand, shows about 400-fold higher affinity for the μ-opioid

receptor (Ki = 5.4 nM) than the parent compound, but still with much lower affinity

than morphine. The affinity of M1 for the μ-opioid receptor is due to the (R) (+)-

enantiomer (Ki = 3.4 nM) and not the (S) (-)-enantiomer (Ki = 240 nM). The

affinity of the (R) (+)-enantiomer of M1 is one- tenth that of morphine for the μ-

opioid receptor, and about 700 times that of (+/-)- tramadol. The metabolite (+/-)-

M5 also has a higher affinity than (+/-)-tramadol for the μ- opioid receptor (Ki =

100 nM). However, animal studies indicate that M5 does not cross the blood-brain

barrier and does not contribute to the anti-nociceptive effect of tramadol. The

metabolites M2, M3, and M4 of tramadol have negligible affinity for the human μ-

opioid receptor. [6, 18]

Table 1. Affinity of tramadol and O-desmethyltramadol (M1) for opioid receptors and their

inhibition of monoamine uptake. Reproduced from Raffa et al (1992, 1993) [19] [20] and

Gillen et al (2000) [18].

Drug Ki (μmol/L)

opioid receptor affinity uptake inhibition

μ (human) μ (rat) δ κ noradrenaline serotonin

(+/-)-Tramadol 2.4 2.1 58 43 0.79 0.99

(+)-Tramadol 1.3 62 54 2.51 0.53

(-)-Tramadol 24.8 213 54 0.43 2.35

(+/-)-M1 0.0054

(+)-M1 0.0034

(-)-M1 0.24

Morphine 0.00062 0.00034 0.092 0.57 inactive inactive

Data refer to rat receptors or tissues, except for affinity data for the μ-opioid receptor which are from human and rat

receptors.


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In addition to its opioid activity, tramadol acts on serotonergic and noradrenergic

pathways, which is thought to act synergistically with tramadol’s effects on the μ–

opioid receptor. The fact that non-opioid mechanisms are involved in the analgesic

effect is supported by the observation that naloxone only partially (approx. 30%)

antagonized tramadol-induced analgesia and that quinidine (an inhibitor of hepatic

demethylation of tramadol into M1) inhibited tramadol-induced miosis but hardly

affected tramadol analgesia. [21] In addition, Desmeules et al (1996) found that

yohimbine (an alpha-2-adrenoceptor antagonist) was able to significantly reduce

the analgesic effect of tramadol in healthy volunteers (maximum decrease 67% and

97% at 2.8 h, by subjective and objective measures, respectively). [22] These data

suggest significant agonist activity (i.e., of O-desmethyltramadol) at the μ-opioid

receptor and the involvement of non-opioid mechanisms in tramadol analgesia.

Tramadol appears to act both as a serotonin releaser and as a serotonin reuptake

inhibitor, and as a reuptake inhibitor of noradrenaline in vitro. [6] (+)-Tramadol is

the enantiomer with highest activity as a serotonin releaser and reuptake inhibitor in

rat dorsal raphe nucleus brain slices. [23] The (+)-enantiomer is about four times

more potent than the (-)-enantiomer as serotonin reuptake inhibitor. [24] Besides,

tramadol is an effective blocker of noradrenaline reuptake in rat spinal cord

synaptosomes by blocking the noradrenaline transporter. [25] As a noradrenaline

reuptake inhibitor, (-)- tramadol is about ten times more potent than (+)-tramadol in

rat hypothalamic synaptosomes. [24]

Minami et al. (2007) reviewed the effects of tramadol on monoamine transporters

and G-protein coupled receptors. [26] They concluded that G-protein coupled

receptors and ligand-gated ion channels may also be targets for tramadol. It is,

however, not known if the actions of tramadol on these receptors are involved in

the analgesic effect of tramadol. [26]

In summary, the analgesic effect of tramadol appears to be produced in a

multimodal mechanism involving the μ-opioid system, the noradrenergic system,

and the serotonergic system. Tramadol appears to act a releaser and reuptake

inhibitor of serotonin, and as a reuptake inhibitor of noradrenaline, and its

metabolite (M1) is active as a μ-opioid receptor agonist. (+)-Tramadol is primarily

responsible for serotonin reuptake inhibition, (-)-tramadol for noradrenaline

reuptake inhibition, and the metabolite O-desmethyltramadol (M1) is primarily

responsible for the agonist activity on the μ-opioid receptor.

5. Toxicology

Carcinogenicity

Animal studies do not reveal a carcinogenic effect of tramadol. Reproductive and

developmental toxicity studies have been negative. In addition, mutagenicity studies do not

show evidence of a genotoxic risk to man. [27]


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Fatalities

Compared to the classical opioid analgesic morphine, tramadol is considered to be a

relatively safe analgesic (cases of fatal poisoning due to tramadol alone have been reported

in the literature over the years; [28-36]). More frequent are intoxications with co-ingestion

of other drugs or alcohol [29, 35-41] Symptoms following a tramadol intoxication are

similar to those of other opioids analgesics. These include central nervous system (CNS)

depression, including coma, nausea and vomiting, tachycardia, cardiovascular collapse,

seizures, and respiratory depression up to respiratory arrest. [12, 42, 43] Moreover, in

combination with serotonergic agents (in particular, selective serotonin reuptake inhibitors

and monoamine oxidase inhibitors) tramadol may induce the serotonin syndrome [44-50]

The hyperthermia in the serotonin syndrome is potentially fatal.

Respiratory depression

Opiates reduce the sensitivity of the respiratory center to carbon dioxide. This may result in

decreased tidal volume and decreased respiratory rate. Because of the μ-opioid agonist

activity of O-desmethyltramadol, tramadol may lower the respiratory rate and potentially

lead to severe respiratory depression. This has been observed in overdose cases of

tramadol. [51-53] However, at therapeutic doses tramadol is not likely to cause significant

respiratory depression. [6]

In healthy subjects, tramadol reduced the sensitivity to carbon dioxide, but did not reduce

the ventilatory response to hypoxia. [54] At therapeutic doses, tramadol produced less

respiratory depression, both in adults and in children, compared to morphine, pethidine,

and oxycodone. [55-59] In neonates undergoing surgery in Benin City (Nigeria), tramadol

provided adequate analgesia without significant complications. [60] Nevertheless, in

patients at risk for respiratory depression, the use of tramadol is contra-indicated. [12, 61]

Cases of tramadol-related respiratory depression have been described in the literature. [51-

53] Intravenous naloxone has been successfully used to reverse the opioid effects of

tramadol overdose [52, 62]

For example, a male patient with acute respiratory distress syndrome had a blood

concentration of 9.5 mg/L tramadol, without toxic levels of other drugs [53] The patient

presented with tachycardia, deep coma and bilaterally dilated pupils. He had mixed

respiratory and metabolic acidosis, and needed mechanical ventilation. Subsequently, he

developed multiple organ dysfunction and had seizures for two days.

A patient with pre-operative renal impairment developed a low respiratory rate (2- 3/min)

and narrow pupils after repeated administration of tramadol following renal surgery. [51]

Peak plasma concentrations of (+)-tramadol, (-)-tramadol, (+)-O- desmethyltramadol and (-

)-O-desmethyltramadol were 0.9 mg/L, 1 mg/L, 0.17 mg/L and 0.22 mg/L, respectively.

Genotyping revealed that the patient was a CYP2D6 ultra-rapid metaboliser which – in

conjunction with the renal impairment – may have resulted in lower renal clearance of the

O-desmethyl metabolite.

In a case series of deliberate tramadol self-poisonings, 19 patients (3.6%) had apnoea and

received respiratory support or naloxone. [63] The mean dose ingested by those

experiencing apnoea (2125 ± 1360 mg; range 200-4600 mg) was significantly higher than


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the dose ingested by those who did not experience apnoea (1383 ± 1088 mg; range 100-

6000 mg). Note, however, that this study lacked laboratory confirmation of tramadol-only

poisoning. [64]

Cardiac Effects

Electrocardiographic changes after tramadol overdoses may include QRS prolongation,

non-specific ST-segment and T-wave changes, first-degree atrioventricular block, atrial

fibrillation, prolonged corrected QT intervals, and ventricular dysrhythmias. Rarely,

cardiopulmonary arrest has occurred after tramadol overdose. [28, 39, 43, 65] Case reports

of cardiogenic shock [66, 67] associated with tramadol overdose have appeared in the

literature, but are relatively rare and may represent unusual clinical scenarios. These case

histories show that fatal or near-fatal intoxications are associated with supra-therapeutic

doses (overdoses) of tramadol and that intoxication at therapeutic doses is rare.

Seizures

Rarely, seizures occur at therapeutic doses of tramadol. Tramadol-related seizures appear

to be mainly associated with doses exceeding the maximum recommended dose of 400 mg

per day. [44, 62, 68-74] Seizure risks of up to 54% of cases (overdose or abuse) have been

found in some studies, with the risk related to the dose of tramadol ingested. Recurrent

seizures are not common and the usual outcome is full recovery. [75] ECG parameters are

not predictive for seizures. [76] Symptoms of seizures after tramadol ingestion have also

been reported in infants. [77, 78]

In a retrospective chart review of tramadol exposures reported to the California Poison

Control System (N = 190; co-ingestant cases excluded; study period January 1999 to July

2001), seizures ranked fourth in observed adverse effects. [62] Main symptoms were CNS

depression (27%), nausea and vomiting (21%), tachycardia (17%), and seizures (13.7%).

Ingested doses ranged from a few milligrams to 5000 mg. The lowest dose associated with

seizures was 200 mg and 85% of seizures developed within 6 hours of tramadol ingestion.

Of the 26 patients with seizures, 81% had one seizure, 3.8% had two seizures, and 11.5%

had multiple seizures. No patient developed status epilepticus. Seven out of 8 patients with

documented data responded to naloxone with improved mental status. One patient had

severe respiratory depression. Serious toxicity from tramadol exposures was rare.

In a surveillance study in the USA, seizure risk was associated with age 24-54 years, with

more than four tramadol prescriptions, and with a history of alcohol abuse, stroke or head

injury. [79]

Another retrospective study conducted in the USA used Poison Control Center data to

compare tapentadol and tramadol toxicity (217 and 8566 cases of sole ingestion,

respectively). [80] The most common clinical effects associated with tramadol were

drowsiness/lethargy (25.4%), tachycardia (16.5%), and seizures (14.6%).

Seizures induced by high doses of tramadol has been observed in rodents and appeared to

be comparable with the potential of codeine to induce seizures. [81] (+)-Tramadol and (–)-

tramadol were about equipotent in this respect, whereas metabolites, including (+)- M1 and

(-)-M1, were less potent than tramadol.


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6. Adverse Reactions in Humans

Adverse reactions of therapeutic use of tramadol include nausea and dizziness (> 10%),

drowsiness, fatigue, headache, increased sweating, vomiting, dry mouth, constipation (1-

10%), diarrhea, and cardiovascular dysregulation (palpitations, tachycardia, postural

hypotension - particularly after rapid intravenous administration) (0.1-1%). Respiratory

depression, epileptiform convulsions, tremor, bradycardia, hallucinations, and anxiety are

rare (0.01-0.1%). [12, 82, 83]

Physical dependence on tramadol may occur, and is addressed more fully in the next

section. [84-86] Withdrawal reactions can include restlessness, agitation, anxiety, sweating,

insomnia, hyperkinesia, tremor, paresthesias, and gastrointestinal symptoms, consistent

with opioid withdrawal symptoms. [86-89]

The incidence of adverse effects depends on the dose and the mode of administration. [6,

16] Sustained-release preparations show a better tolerability profile. [13] One report from

the USA has shown an increase in emergency department (ED) adverse event visits

associated with tramadol, more than doubling between 2005 and 2009, with relative

stability in the following years. [90] However, these absolute numbers were not corrected

for the number of prescriptions of tramadol, and rates of visits would be more informative.

Analysis of French pharmacovigilance data from the period 1987-2006 indicated that the

incidence of adverse reactions to the tramadol-paracetamol combination was 44.5 cases per

105 patient-years, which was significantly higher than for the dextropropoxyphene-

paracetamol combination (24.9) and the codeine-paracetamol combination (12.5). [91] The

relatively short pharmacovigilance period of the tramadol-paracetamol combination

(introduced in France in 2002) compared to the two other combinations (introduced in

1970 and 1985, respectively) may have biased the results.

7. Dependence Potential

A. Animal Studies

Animal studies showed that physical dependence on tramadol may develop, but this

is not consistently seen in all studies. [92] In rhesus monkeys, only mild to

moderate withdrawal symptoms were detected (see review [93]).

B. Human Studies

Tramadol can produce opioid physical dependence. Opioid-like withdrawal

symptoms have been demonstrated with chronic dosing (consistent with the need

for accumulation of the M1 metabolite in order to see opioid effects). Studies show

that tramadol physical dependence may occur when used daily for more than a few

weeks.

Human laboratory studies

In an early human laboratory study that enrolled non-dependent opioid users,

intramuscular tramadol was placebo-like at doses of 75 and 150 mg, while a 300


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mg dose was identified as morphine-like but was otherwise not associated with

typical abuse liability measures. [94]

In dependent opioid abusers, intramuscular tramadol was shown to act as a mild

opioid agonist, able to suppress opioid withdrawal symptoms, though statistically

not to a significant degree, comparable to hydromorphone. [95] In this study,

tramadol did not show opioid antagonist effects. In another human laboratory study

among 6 opioid-dependent subjects on methadone maintenance therapy,

intramuscular tramadol (100 and 300 mg) did not produce agonist activity (opioid-

like effects) nor antagonist activity (withdrawal symptoms). [96]

In prescription-opioid users with opioid dependence, extended-release tramadol 200

mg modestly attenuated withdrawal symptoms, whereas the 600 mg extended-

release preparation was ineffective and caused more use of breakthrough

withdrawal medication. [97] In the second part of this study, cessation of the 600

mg extended-release tramadol preparation (treatment for one week) produced mild

opioid withdrawal symptoms.

Precipitated withdrawal intensity was studied in a group of opioid-dependent adults

who were initially maintained on 60 mg (15 mg q.i.d.) subcutaneous morphine

maintenance, and then two different daily oral doses of tramadol (200 mg/day and

800 mg/day, respectively), with each tramadol dosing period lasting 4-weeks. [86]

Acute tramadol withdrawal effects were tested after intramuscular placebo,

naloxone, or hydromorphone. Naloxone caused withdrawal symptoms. The

intensity of these symptoms was positively related to both naloxone challenge dose

and tramadol maintenance dose. Magnitude of naloxone- induced antagonistic

effects during 800 mg/day tramadol maintenance was similar to the magnitude of

naloxone antagonism during the subcutaneous morphine maintenance.

Intramuscular hydromorphone challenge produced opioid-agonistic effects that

were not attenuated by either tramadol maintenance therapy. The results show that

chronic tramadol administration can produce dose-related opioid-like physical

dependence in opioid-dependent adults, but that it did not produce significant cross-

tolerance.

Clinical reports

In many cases of tramadol physical dependence, a history of substance abuse is

present. [98, 99] However, dependence does also occur in individuals without a

substance abuse history. [84, 100]

Zhang et al (2013) studied tramadol dependence in users without a history of

substance abuse. [101] According to the authors, tramadol became a drug of abuse

after its introduction in China as a non-controlled analgesic medicine. After being

placed under national control in 2007, tramadol use among drug abusers declined

from 13.3% in 2009 to 3.4% in 2011. However, use remained relatively high in

some regions. Therefore, the authors started a study to characterize tramadol-

dependent users spontaneously visiting an addiction unit (Medical Hospital,

Guangzhou, China) from July 2012 till January 2013. Twenty-three tramadol

dependent users were identified in the study period. The median dose was not


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clearly defined (described as from 750 mg per time to 2000 mg per time, with a

dose range from 100 mg to 10,000 mg). Prescription data in the general population

were not given and the prevalence of tramadol dependence cannot be derived from

this study.

In a German study (including a literature study, an analysis of two drug safety

databases, and questionnaires analyses), the low abuse and low dependence

potential of tramadol were re-confirmed. [102] From these two databases, the

incidence of abuse or dependence was calculated as 0.12 and 0.21 per million

defined daily doses (300 mg tramadol), respectively. The German expert group

found a low prevalence of abuse or dependence in clinical practice in Germany, and

concluded that tramadol has a low potential for misuse, abuse, and dependence in

Germany.

Analysis of the data from the Swedish pharmacovigilance system (spontaneous

reports) identified 104 cases of tramadol dependence (fulfilling DSM-IV criteria)

out of 550 tramadol-related reports of adverse drug reactions during the study

period (1995 to 2006). [99] This number of 104 cases corresponded to 0.48 cases

per million DDDs. Thirty percent of these cases had a documented history of

substance abuse and 39% had a documented history of illicit drug use in the last 10

years. Hospitalization was reported in 50% of the cases, mostly in a psychiatric or

dependence clinic.

Occasionally, withdrawal symptoms of tramadol dependence have been treated

effectively with buprenorphine-naloxone. [103]

Summary on dependence potential

In summary, the data on the dependence potential of tramadol show that tramadol

can produce physical dependence, but that physical dependence is associated with

the use of tramadol under chronic dosing conditions (i.e., over an extended period

of time – a matter of weeks). Several studies indicate that the incidence of tramadol

dependence may differ between countries and within different regions of countries,

which may be associated with the availability and prescription practice for

tramadol, and with the availability of alternative psychoactive substances for drug

abusers.

8. Abuse Potential

A. Animal Studies

Based on animal studies, tramadol is an atypical opioid analgesic with mild opioid-

like effects (see review [93]). Based on self-administration in monkeys, tramadol

has some abuse potential but less so than morphine. In one rat model of self-

administration under a fixed-ratio and progressive-ratio schedule, tramadol acted as

a weak reinforcer of self-administration compared to remifentanil and morphine.

[104] A second rat study that examined the pharmacological characteristics of

tramadol using self-administration and conditioned place preference procedures


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found effects consistent with the potential for physical dependence and abuse

potential. [92]

B. Human Studies

Human laboratory studies

Human studies show that tramadol has a low abuse potential relative to the

prototypic opioid morphine (see review [93]). Opioid-like effects can be produced

by oral administration of tramadol, but these are mild and not produced by

parenteral administration. [93] In agreement with this, volunteer non-dependent

opiate abusers (‘post- addicts’) were able to identify 300 mg tramadol, but not 75

mg and 100 mg, as an opioid-like substance when administered intramuscularly.

This dose of 300 mg tramadol did not produce significant liking scores, miosis, or

other morphine-like effects. [94]

A human drug discrimination study demonstrated the opioid activity of oral

tramadol. [105] Non-dependent subjects (n=8) were trained to discriminate between

placebo, hydromorphone (8 mg) and methylphenidate (60 mg). In the following

drug discrimination sessions, subjects identified orally administered tramadol as an

opioid drug. Lower doses of tramadol (50 mg and 100 mg) were generally

identified as placebo, whereas 200 mg and 400 mg tramadol were identified as

hydromorphone or opioid-like. The 400 mg dose of tramadol did not significantly

increase ratings of drug liking and ‘good’ effects, but did increase scores on a

stimulant scale. Such a profile fits with tramadol’s dual mechanism of action, i.e.,

its activity at the monoaminergic system and the activity of tramadol’s metabolite

M1 at the μ-opioid receptor. The authors concluded that this effect profile of

tramadol is consistent with a modest abuse liability for tramadol.

In contrast, oral tramadol appears to act as a reinforcer in non-dependent opioid

abusers, comparable to oxycodone. [106] In this laboratory study with 9

participants, both the 200 mg and the 400 mg tramadol dose increased ‘like drug’

effect and decreased pupil size, relative to placebo, and all subjects identified 400

mg tramadol as an opioid agonist on a Drug Identification Questionnaire. The time-

to-peak effect for miosis was substantially later for tramadol (i.e., 4 h) than for

oxycodone or codeine (i.e., 1–2.4 h). Next to this effect, tramadol functioned as a

reinforcer as the 400-mg dose was readily self-administered. The 200-mg dose

failed to significantly increase self-administration, which shows that self-

administration of tramadol is dose dependent. The authors concluded that oral

tramadol has reinforcing efficacy in non-dependent opioid abusers, confirming its

abuse potential in this population.

In a study that enrolled recreational drug users (n=22), 100 mg oral tramadol was

found to induce effects of ‘drug liking’ and ‘want to take again’. [107] The drug

ratings were comparable to those of 25 mg morphine but lagged behind those of

morphine in some subjects. These findings indicate that tramadol has abuse liability

in recreational drug users.


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Finally, a within subject study of 10 withdrawn drug users compared the acute

intramuscular effects of tramadol (100 mg), buprenorphine (0.6 mg), and placebo

[108]. In this study, tramadol produced acute subjective effects, and in general had

greater opioid-like effects than placebo, but less so than buprenorphine.

Clinical reports and post-marketing surveillance

A history of drug abuse is frequently detected among tramadol abusers. [99, 109,

110] Data indicate that there is a growing number of tramadol abusers, in particular

in some Middle East countries. [73, 111-113] For example, in a study from Iran, the

association of tramadol use and use of other psychoactive substances was

investigated in high school students (n=1894; response rate 95%). [112] Life-time

prevalence of tramadol misuse was 4.7% and lifetime tramadol misuse was

associated with last month alcohol use, cannabis use, and ecstasy use. Adjusted

odds ratios were 2.2 (CI: 1.1-4.4) for last-month alcohol use, 5.0 (CI: 1.5-21.6) for

cannabis use, and 8.9 (CI: 2.7-29.4) for ecstasy.

In an analysis of tramadol poisonings (n=401 from March 2008 to March 2009; 266

mild and excluded; 135 included in the study; confirmation by blood analyses) in

Iran, the investigators found 70 cases of intentional intoxications and 40 cases of

recreational abuse (euphoria intention). [73] A history of chronic tramadol abuse

was found in 34 cases.

In the United States, tramadol was introduced onto the market in 1994 as an

analgesic. Several post-marketing studies have been published since. Data from the

first post- marketing surveillance program, which started shortly after the

introduction of tramadol in that country, showed that the reported rate of tramadol

abuse (rated as positive, possible and alleged) was 1-3 cases per 100,000 patients in

the first three years (1995-1998). [114] The majority of abuse cases (97%)

concerned individuals with a history of substance abuse. Analysis of the

surveillance data over five years (1995 to 2000) indicated that nearly 40% of all

adverse reactions were withdrawal symptoms associated with chronic tramadol use.

[115] Most cases showed typical opiate withdrawal symptoms, but 12% of cases

presented as atypical (severe anxiety and panic attacks, paranoia, unusual sensory

phenomena, and hallucinations). The incidence of withdrawal symptoms (both

typical and atypical) was about 0.5-1 per 100,000 individuals in the period 1999-

2000 following a peak that was observed in 1996, i.e., one year after its

introduction in the United States. Reporting bias and non-representative sampling

of cases may have underestimated the true incidence of abuse. [116]

Further monitoring in the USA up to 2004 showed that the rates of abuse remained

stable, despite the introduction of new brands and new generic formulations. [110]

Again, this line of research/monitoring found that abuse was almost exclusively

(95%) in individuals with a history of substance abuse.

Using structured interviews (up to nine) over a 12-month period, the prevalence of

tramadol abuse was also assessed in patients with chronic non-cancer pain in a

prospective 3-arm study (11,352 subjects) conducted in the USA. [117] Patients

with an active substance abuse problem were excluded from the study, but patients


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with a history of abuse were included. Abuse (expressed as at least once during the

12-month follow-up) occurred in 2.7% of patients receiving tramadol, in 2.5% of

patients receiving NSAIDs, and in 4.9% of patients receiving hydrocodone. Using

more than one-time abuse as criterion of persistence, the abuse rates were 0.7% for

tramadol, 0.5% for NSAIDs, and 1.2% for hydrocodone. The abuse rates for

tramadol and NSAIDs were significantly less than the abuse rate for hydrocodone.

A report from the USA on emergency department (ED) visits for tramadol misuse

or abuse more than doubled between 2005 and 2010, with the majority of patients

having concurrent abuse of another substance. [118]

The German expert group mentioned before studied the abuse and dependence

potential of tramadol by analysis of animal and human studies, and of two drug

safety databases (WHO Vigibase and originator’s safety database). From these two

databases, the incidence of abuse or dependence was calculated as 0.12 and 0.21

cases per million defined daily doses (300 mg tramadol), respectively. The expert

group concluded that tramadol has a low potential for misuse, abuse, and

dependence, and that abuse or dependence has a low prevalence in clinical practice

in Germany. [102]

9. Therapeutic Applications and Extent of Therapeutic Use and

Epidemiology of Medical Use

Analgesia

Tramadol is used to treat moderate to severe pain (most countries) or moderate to

moderately severe pain (USA). It has a wide range of applications in both acute (e.g.,

postoperative, trauma) and chronic (cancer and non-cancer) pain (see reviews [6, 13, 16,

17, 102, 119]), and is available worldwide as a medicine.

Tramadol 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. [120] In chronic non-cancer pain,

tramadol may be appropriate when non-opioid analgesics are ineffective or contra-

indicated.

In general, the analgesic effect of tramadol monotherapy is modest. In meta-analyses,

tramadol showed no significant effect on pain relief in chronic nonspecific low back pain

[121], some effect (low quality evidence) in chronic low back pain [122], and a modest

effect (fair evidence) in chronic osteoarthritis [123-125]. Manchikanti et al. (2011) [124]

concluded that the evidence for tramadol in managing osteoarthritis pain (knee and

multiple joints) was fair, and that the evidence was poor in all other conditions of chronic

non-cancer pain.

A recent Cochrane review meta analysis by Wiffen [126], that looked at the use of

tramadol for chronic pain related to the presence of a malignant tumor, found limited and

low quality evidence that this medication produced pain relief. Similarly, another Cochrane

review meta-analysis carried out in 2017 found limited and low quality evidence

supporting the efficacy of tramadol in the treatment of neuropathic pain. [127] Another

recent systematic review and meta analysis of tramadol for neuropathic pain concluded


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with a weak recommendation for tramadol’s use as a second line agent. [128] However,

these reviews may speak less to the efficacy of tramadol for these conditions, and more to

the lack of high quality trials that can provide a database supporting the use of tramadol for

the treatment of chronic cancer or neuropathic pain.

In a review by a German expert committee (described above), the authors re-confirmed the

analgesic efficacy of tramadol with strong evidence from systematic reviews and

(inter)national guidelines on acute and chronic pain management. [102] The authors added

that tramadol monotherapy does not usually provide sufficient analgesia and that there is

little evidence from German medical guidelines for the use of opioids, including tramadol,

for more than three months in chronic non-cancer pain (see German guidelines [129]).

The treatment of opioid withdrawal

Reports on the use of tramadol for the treatment of opioid withdrawal have periodically

appeared in the literature. (See, for example, [130-133]) Tramadol is not indicated for this

condition. A recent randomized, controlled trial compared tramadol ER to clonidine and

buprenorphine for medically managed opioid withdrawal in 103 opioid dependent patients.

[134] In this study, tramadol was generally more effective than clonidine and comparable

to buprenorphine on treatment retention and withdrawal suppression, and interestingly did

not show the rebound withdrawal seen after buprenorphine treatment ended.

10. Listing on the WHO Model List of Essential Medicines

Tramadol is not listed on the WHO Model List of Essential Medicines (20th List) or the

WHO Model List of Essential Medicines for Children (6th List). [135]

However, it is listed in several national essential medicines lists (e.g., Algeria [2007],

Bhutan [2012], Botswana [2012], several provinces of China, Congo [2013], Cook Islands

[2007], Cote d'Ivoire, Croatia [2010], Dominican Republic [2005], Ecuador [2009], Egypt

[2006], Ethiopia [2015], Ghana [2010], Honduras [2009-11], India [2011], Iraq [2010],

Jamaica [2008], Jordan [2011], Maldives [2011], Montenegro [2011], Morocco [2008],

Myanmar, Namibia [2008], Peru [2010], Philippines [2008], Republic of Moldova [2009],

Rwanda [2010], Serbia [2008], Seychelles [2010], Slovakia [2010], Slovenia [2010], South

Africa [2006], Sri Lanka [2009], Sudan [2010], Tajikistan [2009], Thailand [2012], The

former Yugoslav Republic of Macedonia [2010], Timor-Leste [2004], Togo [2012],

Trinidad and Tobago [2010], Tunisia [2008], Ukraine [2010], United Republic of Tanzania

[2013], Vietnam [2008], Uruguay [2011]). [136]

11. Marketing Authorizations (as a Medicinal Product)

Marketing authorizations for tramadol as a medicine are held by many companies.

Examples (not limited) are: Accord Healthcare Ltd, Actavis UK Ltd, Aurobindo Pharma-

Milpharm Ltd, Beacon Pharmaceuticals, Beechmere Pharmaceuticals Ltd., Chiesi Ltd,

Concordia International, Consilient Health, Endo Ventures Ltd, Grunenthal GmbH,

Hameln Pharmaceuticals Ltd, Janssen Pharmaceuticals Inc, Johnson and Johnson, Kent

Pharmaceuticals Ltd, Lupin Ltd, Macleods Pharmaceuticals Ltd, Major Pharmaceuticals,

Meda Pharmaceuticals, Par Pharmaceutical Inc, Pliva Pharma Ltd, Prima Medika, Sandoz


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Pharmaceutical, Sun Pharma, Teva Pharmaceutical Industries Ltd, Watson Labs, Winthrop,

Zydus Pharmaceuticals Inc. [12]

12. Industrial Use

Industrial use of tramadol is not reported.

13. Non-Medical Use, Abuse and Dependence

Tramadol is advertising as being available via the Internet without a prescription, although

it is not known if these sites are actually providing tramadol. The website EROWID, and

other websites as well, provide user reports of the non-medicinal use of tramadol.

United States

Data from the post-marketing surveillance program in the USA, started shortly after the

introduction of tramadol, showed that the reported rate of tramadol abuse (rated as positive,

possible and alleged) was 1-3 cases per 100,000 patients in the first three years (1995-

1998). [114] Analysis of the surveillance data over five years (1995 to 2000) indicated that

an incidence of withdrawal symptoms (both typical and atypical) of about 0.5-1 per

100,000 individuals in the period 1999-2000 following the peak in 1996, i.e., one year after

its introduction in the United States. [115] Reporting bias and non- representative sampling

of cases may have underestimated the true incidence of abuse. [116] Further monitoring up

to 2004 showed that the rates of abuse remained stable, despite the introduction of new

brands and new generic formulations. [110] This study confirmed that abuse was found

almost exclusively (95%) in individuals with a history of substance abuse.

Iran

In Iran, tramadol was approved as an analgesic in 2002. As prescription rates increased so

did non-medical use. Analysis of fatal cases in Iran showed a steady increase in tramadol-

associated deaths (confirmed by toxicological analysis) in the period from 2005 to 2008.

Among the 20,000 toxicological analyses carried out during this period, 294 cases (1.5%)

showed tramadol exposure either alone (151 cases) or in combination (143 cases) with

other drugs (in particular, opioids, antidepressants, and benzodiazepines). [111] A history

of drug abuse was reported in 20% (60 cases) of these 294 cases.

During two months (April to May 2007), 114 cases of mixed tramadol intoxications (not

confirmed by chemical analysis) were identified among 5850 admissions to the Teheran

Poison Centre (Iran). [43] Co-ingestion of other substances (e.g., benzodiazepines) was

common and (attempted) suicide (81% of cases) was the main reason for the ingestion.

Seizures occurred in 35% of cases and two cases were fatal (tramadol dose 5 gram and 8.2

gram). These observations contributed to tramadol’s classification as a controlled

substance in Iran in 2007.

A survey study with 1894 grade 10 students found that the lifetime prevalence of tramadol

misuse was 4.7% [112] in the city of Ilam, Iran. In this study, a lifetime history of tramadol

misuse was associated with cannabis, alcohol, and ecstasy use in the month prior to the

survey.


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China

In China, abuse of tramadol led the Chinese State Food and Drug Administration to place

tramadol under national control in 2007. As a result, tramadol use among drug abusers fell

sharply from 13.3% in 2009 to 3.4% in 2011 but remained relatively high in the

Guangdong province in South China. [101] From a study among 23 tramadol abusers

spontaneously referred to the addiction unit of the Medical Hospital in Guangzhou during a

half-year study period (July up to December 2012), Zhang and Liu (2013) concluded that

tramadol has a high risk of dependence in this study population and that dependence may

be related to the use of high doses of tramadol for extended periods of time. This study

does not give an indication of the magnitude of tramadol misuse.

France

An analysis of different surveillance methods used to assess tramadol abuse in France

concluded that there was not a major public health issue with the use of this medication in

that country [137]. Notably, these different methods do find cases of misuse and abuse, as

well as physical dependence on tramadol.

Egypt

Tramadol misuse in Egypt has been a growing concern. [138] A report from The National

Council for Drug Control and Treatment (Egypt) noted that the proportion of people

seeking treatment for tramadol addiction has been steadily increasing between 2011

(38.7% of “total addicts” were “tramadol addicts”) and 2016 (71.1%). [139] It appears that

much of the tramadol being abused in Egypt is imported from India.

A study of 204 school students in Egypt found that 8.8% of them had a urine drug screen

positive for tramadol [140], and among those who admitted tramadol use, the most

common frequency of self-reported use was once per month. A study with focus groups of

Egyptian youth found tramadol was the most commonly used pharmaceutical drug. [141]

The absolute number of persons seeking treatment for tramadol addiction, as assessed by

hot line data, increased between 2011 and 2012 (3320 and 8313), as did the proportion of

all calls related to tramadol (38% and 39%) [142].

Germany

The German study mentioned before noted the low abuse and dependence potential of

tramadol after analysis of animal and human studies, and of two drug safety databases

(WHO Vigibase and originator’s safety database). From these two databases, the incidence

of abuse or dependence was calculated as 0.12 and 0.21 cases per million defined daily

doses (300 mg tramadol), respectively. The German expert group concluded that tramadol

has a low potential for misuse, abuse, and dependence, and that abuse or dependence has a

low prevalence in clinical practice in Germany. [102]

United Kingdom

Analysis of Office for National Statistics (ONS) drug poisoning databases (study period

2000-2011) in England and Wales revealed that the number of tramadol mentions on death

certificates increased from 87 in 2009 to 154 in 2011. [29, 143] In 35% of the cases

between 2000 and 2011, tramadol was mentioned as the only drug (297 cases). This


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increase was paralleled by an increase in the number of tramadol prescription items

dispensed, from 5.9 million Defined Daily Doses (DDDs) in September 2005 to 11.1

million in September 2012. [144] In 2012, the number of tramadol mentions on death

certificates in England and Wales was 175; this increased to a peak of 240 in 2014, but

then trended back down in 2015 and 2016 (with 208 and 184 deaths, respectively). [145]

Note that the mentioning of tramadol on a death certificate does not allow any conclusions

on the cause of death. Largely because of the increase in tramadol-mentions on death

certificates, the Advisory Council on Misuse of Drugs (ACMD) recommended in 2013 that

tramadol be controlled as a class C substance under the Misuse of Drugs Act 1971. [143]

A UK internet survey (n=7,360) of nonmedical use of tramadol found that 5% (326

respondents) had used tramadol in the past year. [146] While most tramadol was obtained

by prescription, there were 163 respondents who used tramadol for reasons other than pain

relief. These findings suggest there is a relatively small number of persons in the UK who

misuse tramadol. A large analysis of opioid prescription exposures between 2008 and 2012

found that the incidence of tramadol use disorder was stable. [144]

Columbia

An observational (retrospective) study of opioid misuse in hospitalized patients in

Medellin, Columbia found a relatively small number of persons with DSM-IV opioid

dependence (n=60). However, the most common diagnosis, in 37 of the 60, was tramadol.

[147]

Worldwide, other countries

The Uppsala Monitoring Centre (UMC) provided the WHO Secretariat with a summary

file (received August 23, 2017) of all adverse drug reactions (ADRs) that have been

reported to the UMC in connection with drug abuse or dependence of tramadol, during the

years 1984 to 2017. While sporadic reports appear in the early years, it was not until 1996

that some more consistency in these reports started to occur. The numbers by year are

presented in Table 2.

Table 2

Year Drug Abuse Drug Dependence

1996 3 60

1997 0 106

1998 1 15

1999 0 42

2000 119 101

2001 2 20

2002 120 53

2003 5 22

2004 1 21

2005 2 44

2006 15 31

2007 0 3

2008 25 83

2009 23 34


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2010 66 38

2011 32 54

2012 84 22

2013 38 28

2014 562 57

2015 280 28

2016 118 73

2017 23 32

TOTAL 1526 982

14. Nature and Magnitude of Public Health Problems Related to Misuse,

Abuse and Dependence

After scheduling tramadol in two USA states (Kentucky and Arkansas), the yearly trend of

an increased number of poison center calls concerning tramadol exposures was halted and

a decrease in the number of cases was reported. [148] From this study, no conclusions can

be drawn about the number of adverse tramadol exposures relative to the number of

legitimate prescription users. Additional data suggested that the number of people calling

the Kentucky Regional Poison Center decreased proportionately with the number of people

filling a prescription. [149] In other words, the decline in calls to the Kentucky Regional

Poison Center was associated with less prescribing tramadol.

There is growing abuse of tramadol in some African and West Asian countries, as

evidenced by large seizures of such preparations in North and West Africa. Abuse of

tramadol has become a serious problem in Egypt and abuse has also been reported by Iran,

Jordan, Lebanon, Libya, Mauritius, Saudi Arabia and Togo. [150] In 2010, an increase of

non-medical use (abuse) of tramadol in Gaza was reported. [113]

15. Licit Production, Consumption and International Trade

From the manufacturer’s records on the total amount of tramadol used, the total amount of

tramadol used worldwide in the period from 1990 to 2009 was calculated to be 11,758

million DDDs (1 DDD defined as 300 mg). [102]

16. Illicit Manufacture and Traffic and Related Information

There is evidence of increased trafficking in tramadol preparations to North and West

Africa, as indicated by recent large seizures of such preparations in this region. [150]

Egyptian authorities seized about 120 million tablets containing tramadol in 2011 and

about 320 million tablets in the first quarter of 2012. According to information available to

the International Narcotics Control Board (INCB), the preparations were smuggled into

Egypt mainly from China and India. Saudi Arabia also reported increasing amounts of

seizures of preparations containing tramadol. In Gaza, the number of drug arrests related to

tramadol was 591 out of 1204 arrests in 2009, and close to two and half million tramadol

pills were seized in 2009, compared to 550,000 in 2008. [113] In Benin, Ghana, Senegal


of 36

and Togo (West Africa), large amounts of tramadol preparations, totaling more than 132

tons of such preparations, were seized between February and October 2012. The

preparations had been concealed in sea containers sent from India and were intercepted by

the local law enforcement authorities. [150]

Data provided by the UNODC on global tramadol seizures was provided for this report

(July of 2017). These data showed a steady rise in seizures between 2007 (when 0.00545

kg were seized) and 2015 (when 111,846 kg were seized). Virtually all of the seizures in

2015 were associated with Benin (111,800 kg), but the pattern in seizures by country

varied on a year-by-year basis. Thus, for example, in 2014 total seizures were 25,079 kg,

which were predominantly Jordan (14,416 kg). In 2013, total seizures were 1271 kg, which

were predominantly Saudi Arabia (722 kg).

17. Current International Controls and Their Impact

Tramadol is not controlled under the 1961, 1971 or 1988 United Nations Conventions.

18. Current and Past National Controls

The legal status of tramadol differs internationally. In many countries, it is a prescription-

only medicine.

When tramadol was initially approved for use in the United States, it was not scheduled as

a controlled substance by the U.S. Drug Enforcement Administration. However, in 2014

the U.S. reclassified it as a Schedule 4 controlled substance.

Tramadol is under national control in Bahrein since 2000, in Mauritius since 2000, in

Australia since 2001, in Iran since 2007, in Sweden since 2008, in the Bolivarian Republic

of Venezuela since 2008, in Ukraine since 2008, in Egypt (up-scheduled in 2009), and in

Jordan and Saudi Arabia.

In China, the Food and Drug Administration has listed tramadol as a second category

psychoactive substance in 2007. [101]

In February 2013, the Advisory Council on Misuse of Drugs (ACMD) recommended that

tramadol is controlled as a Class C substance under the Misuse of Drugs Act 1971 in the

United Kingdom. [143]

19. Other Medical and Scientific Matters Relevant for a Recommendation on

the Scheduling of the Substance

None.


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Annex 1: Report on WHO Questionnaire for Review of Psychoactive

Substances for the 39th ECDD: Evaluation of Tramadol

Please refer to separate Annex 1 document published on ECDD website

TRAMADOL Pre-Review Report - WHO

Documents

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