tramadol pharmacology

Clin Pharmacokinet 2004; 43 (13): 879-923REVIEW ARTICLE 0312-5963/04/0013-0879/$31.00/0

2004 Adis Data Information BV. All rights reserved.

Clinical Pharmacology of TramadolStefan Grond and Armin Sablotzki

Department of Anesthesia, Martin-Luther-University, Halle-Wittenberg, Germany

ContentsAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8801. Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 881

1.1 Pharmaceutical Formulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8811.2 Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8811.3 Sustained-Release Preparations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8811.4 Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8841.5 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8841.6 Influence of Cytochrome P450 on Biotransformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8881.7 Stereoselective Pharmacokinetic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8891.8 Pharmacokinetic-Pharmacodynamic Modelling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8911.9 Effect of Age and Impaired Renal and Hepatic Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8921.10 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 893

2. Pharmacodynamic Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8932.1 Mechanism of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8932.2 Analgesic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8942.3 Effects on Respiration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8952.4 Haemodynamic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8952.5 Gastrointestinal Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8962.6 Effects on Immune System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 896

3. Therapeutic Efficacy in Acute Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8963.1 Postoperative Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 896

3.1.1 Oral Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8963.1.2 Rectal Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8973.1.3 Intramuscular Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8973.1.4 Intravenous Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9003.1.5 Patient-Controlled Analgesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9013.1.6 Regional Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 902

3.2 Other Acute Pain Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9023.2.1 Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9023.2.2 Abdominal Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9033.2.3 Labour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 903

3.3 Place of Tramadol in Acute Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9034. Chronic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 906

4.1 Cancer Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9064.1.1 Sustained-Release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 907

4.2 Chronic Non-Cancer Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9094.2.1 Sustained-Release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 910

4.3 Neuropathic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9104.4 Place of Tramadol in Chronic Pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 911

5. Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9126. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915

880 Grond & Sablotzki

Tramadol, a centrally acting analgesic structurally related to codeine andAbstractmorphine, consists of two enantiomers, both of which contribute to analgesicactivity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the µ opioid receptor. (+)-Tramadolinhibits serotonin reuptake and (–)-tramadol inhibits norepinephrine reuptake,enhancing inhibitory effects on pain transmission in the spinal cord. The comple-mentary and synergistic actions of the two enantiomers improve the analgesicefficacy and tolerability profile of the racemate.

Tramadol is available as drops, capsules and sustained-release formulations fororal use, suppositories for rectal use and solution for intramuscular, intravenousand subcutaneous injection. After oral administration, tramadol is rapidly andalmost completely absorbed. Sustained-release tablets release the active ingredi-ent over a period of 12 hours, reach peak concentrations after 4.9 hours and have abioavailability of 87–95% compared with capsules. Tramadol is rapidly distribut-ed in the body; plasma protein binding is about 20%.

Tramadol is mainly metabolised by O- and N-demethylation and by conjuga-tion reactions forming glucuronides and sulfates. Tramadol and its metabolites aremainly excreted via the kidneys. The mean elimination half-life is about6 hours.

The O-demethylation of tramadol to M1, the main analgesic effective metabo-lite, is catalysed by cytochrome P450 (CYP) 2D6, whereas N-demethylation toM2 is catalysed by CYP2B6 and CYP3A4. The wide variability in the pharmaco-kinetic properties of tramadol can partly be ascribed to CYP polymorphism. O-and N-demethylation of tramadol as well as renal elimination are stereoselective.Pharmacokinetic-pharmacodynamic characterisation of tramadol is difficultbecause of differences between tramadol concentrations in plasma and at the siteof action, and because of pharmacodynamic interactions between the two enanti-omers of tramadol and its active metabolites.

The analgesic potency of tramadol is about 10% of that of morphine followingparenteral administration. Tramadol provides postoperative pain relief com-parable with that of pethidine, and the analgesic efficacy of tramadol can furtherbe improved by combination with a non-opioid analgesic. Tramadol may proveparticularly useful in patients with a risk of poor cardiopulmonary function, aftersurgery of the thorax or upper abdomen and when non-opioid analgesics arecontraindicated.

Tramadol is an effective and well tolerated agent to reduce pain resulting fromtrauma, renal or biliary colic and labour, and also for the management of chronicpain of malignant or nonmalignant origin, particularly neuropathic pain. Tramadolappears to produce less constipation and dependence than equianalgesic doses ofstrong opioids.

Tramadol hydrochloride (tramadol), (1RS,2RS)- effects, particularly of respiratory depression, con-stipation and abuse potential,[2] and has never been a2-[(dimethylamino)methyl]- 1 -(3-methoxyphenyl)-scheduled drug.[3] Therefore it became the mostcyclohexanol hydrochloride, is a centrally actingfrequently prescribed opioid in Germany.analgesic that is structurally related to codeine and

morphine. It was first synthesised in 1962 and has The registration of tramadol in the UK (1994),been available for pain treatment in Germany since the US (1995) and then many other countries re-1977.[1] Tramadol has a low incidence of adverse quired extensive additional preclinical and clinical

2004 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2004; 43 (13)

Tramadol 881

research and increased international interest. Recent no available pharmacokinetic data on soluble tab-studies have confirmed the unique and unusual phar- lets, but rapid absorption, similar to that of drops,macodynamic profile of this opioid, which is attrib- can be expected.utable to tramadol being a racemate. Both enanti- Following a single oral dose of 100mg, Cmax isomers and their metabolites contribute to the analge- approximately 300 µg/L.[6-9,11] Plasma concentrationsic activity by means of different mechanisms.[4,5] and area under the concentration-time curve (AUC)These include binding to opioid receptors and block- increase linearly over the dose range 50–400mg.[7,10]

ade of both norepinephrine and serotonin reuptake. The extent of oral absorption of tramadol is almostThis duality of action has prompted the classifica- 100% and the bioavailability is 70% following ation of tramadol by the US FDA as a nontraditional single dose.[8,20-22] The difference between absorp-centrally acting analgesic. tion and bioavailability is attributed to the 20–30%

first-pass metabolism.[6,8,21,22] Following multiple1. Pharmacokinetic Properties oral administration of tramadol 100mg four times

daily, Cmax is 16% higher and AUC is 36% higherthan after a single 100mg dose, indicating that oral1.1 Pharmaceutical Formulationsbioavailability increases to approximately 90–100%

Tramadol is available in various pharmaceutical on multiple oral administration, possibly due to sat-forms. Ampoules contain 50mg (1mL) or 100mg urated first-pass hepatic metabolism.[12,23] The bio-(2mL) of tramadol in a solution for intravenous, availability of drops with ethanol is about the sameintramuscular or subcutaneous injection. Immedi- as that of drops without ethanol.[7] Oral administra-ate-release (IR) formulations, which normally re- tion of tramadol 100mg following a high-fat break-quire oral administration four to six times daily, are fast results in a 17% higher Cmax and a 10% highercapsules (50mg), soluble tablets (50mg to be dis- AUC than the corresponding values in fasted volun-solved in 50mL of water), drops (50mg = 0.5mL = teers.[24] This increase of the bioavailability by food20 drops or four actuations of the pump) and suppos- was not considered clinically relevant.[21,22]

itories (100mg). Several sustained-release (SR) for- After rectal administration of suppositoriesmulations have been developed, which provide the 100mg, tramadol absorption begins within a fewopportunity for administration only twice daily. SR minutes (0–22 minutes).[11] A Cmax of 294 µg/L istablets (100, 150 and 200mg) are based on a hydro- reached within 3.3 hours.[11] The absolute bioavaila-philic matrix system in which tramadol is evenly bility (77%) is higher than that after oral administra-distributed. On contact with the gastrointestinal flu- tion, probably due to a reduced first-pass metabol-id, the outer layer of the tablet swells gradually and ism after rectal administration.[11]

forms a retarding gel layer. SR capsules (100, 150 Tramadol is rapidly and almost completely ab-and 200mg) contain multiple pellets of 1mm in sorbed after intramuscular injection.[17] Cmax of 166diameter consisting of a neutral core layered with µg/L is reached 0.75 hours after intramuscular injec-tramadol and a membrane that controls the release. tion of 50mg.[17] Intramuscular injection and intra-In addition, a two-phase SR tablet contains 25mg of venous infusion over 30 minutes are bioequivalenttramadol for IR and 75mg of tramadol for SR. with respect to the extent of systemic availability.[17]

Cmax values of 355–369 µg/L are reached 0.9 and1.2 Absorption 1.1 hours after intramuscular injections of

100mg.[18] The pharmacokinetic properties of sub-The pharmacokinetic properties of tramadol arecutaneous tramadol, which is effective in post-summarised in table I. After oral administration,operative pain,[25] have not been examined.tramadol is absorbed almost completely and quite

rapidly after a lag time of 0.2 hours for drops[6,7] and1.3 Sustained-Release Preparations0.5 hours for capsules.[8] Peak plasma concentra-

tions (Cmax) are attained within 1.2 hours after oraladministration of drops[6,7] and within 1.6–1.9 hours SR tablets and capsules provide stable plasmaafter oral administration of capsules.[8,9] There are concentrations when administered at 12-hour inter-


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Table I. Pharmacokinetic properties of tramadol

Population Route and dose tmax Cmax AUC∞ t1/2β CL Reference(n) (mg) (h) (µg/L) (µg • h/L) (h) (mL/min)Volunteers (4) PO (100) 260 (4h) 2194 5.1 10

Volunteers (4) PO (200) 575 (3.5h) 4924 5.9

Volunteers (3) PO (300) 930 (4h) 8599 5.7

Volunteers (3) PO (400) 1220 (4.7h) 10 473 5.3

Volunteers (10) PO, capsules (100) 1.9 290 2488 5.1 710 8

Volunteers (8) PO, ethanol drops (100) 1.2 308 2390 5.5 742 6

Volunteers (12) PO, drops (50) 1.2 136 875 5.0 837 7

Volunteers (10) PR, suppository (100) 3.3 294 2933 5.7 11

Volunteers (18) PO (100) [single dose] 1.6 308 2649 5.6 110a 12

Volunteers (18) PO (100) [qid, 1 week]b 2.3 592 3679 6.7 73a

Volunteers (12) PO, capsules (100) 1.6 274 2177 5.9 13

Volunteers (12) PO, SR tablets (100) 4.9 141 2119 5.7

Volunteers (12) PO, capsules (100) [bid, 5 days]c 1.9 414 2970

Volunteers (12) PO, SR tablets (100) [bid, 5 days]d 3.5 293 2656

Volunteers (12) PO, SR capsules (50) 5.3 70 1039 6.0 14



Fasting (24) PO, SR capsules (200) 6.7 294 5293 7.2 15Nonfasting (24) PO, SR capsules (200) 7.0 305 5266 6.8Fasting (24) PO, IR capsules (200) 2.0 640 5826 6.1Fasting (24) PO, SR tablets (200) 4.5 375 5517 6.2Volunteers (24) PO, IR capsules (50) [qid, 3 days] 321 5167 16Volunteers (24) PO, SR capsules (100) [bid, 3 days] 274 5168Volunteers (10) IV (100) 409 (2h) 3709 5.2 467 8Volunteers (8) IV (100) 394 (2h) 3490 5.2 487 6Volunteers (10) IV (100) 418 (2h) 3775 5.7 447 11Volunteers (12) IV over 30 min (50) 0.52 287 1233 5.0 594 7Volunteers (12) IV over 30 min (50) 0.54 305 1332 5.5 596 17Volunteers (12) IM (50) 0.75 293 1353 5.5 613Volunteers (12) IM (100) 0.9 355 3160 18Volunteers (12) IM (100) 1.1 369 325065–75 years (12) PO, capsules (100) 2.0 324 2508 6.1 793 19>75 years (8) PO, capsules (100) 2.1 415 3854 7.0 491 19Renal insufficiencye (21) IV (100) 894 7832 10.8 280 19Hepatic impairmentf (12) PO, capsules (100) 1.9 433 7848 13.3 271 19

Continued next page

Tramadol 883

vals. SR tablets (100, 150 and 200mg) release 100%of the active ingredient over a 12-hour period invitro.[13] The absolute bioavailability of SR tablets is67.3% relative to the intravenous reference formula-tion, indicating bioequivalence of SR tablets and IRcapsules (95.1%, 90% CI 87.8, 103.0%).[13] Thetime to Cmax (tmax) of 4.9 ± 0.8 hours for the SRtablets (compared with 1.6 ± 0.5 hours for IR cap-sules), the Cmax of 141.7 ± 40.4 µg/L (274.1 ± 75.3µg/L) and the mean absorption time of 4.70 ± 0.90hours (1.09 ± 0.56 hours) reflect the slow-releaseproperties of the SR tablets (table I).[13]

At steady state (after 48 hours of twice-dailyadministration), bioavailability of the SR tablet is87.4% (90% CI 81.3, 94.0%) relative to IR capsulesadministered with the same regimen.[13] The peak-trough fluctuation in plasma concentrations atsteady state is reduced from 121% with the IRcapsule to 66% with the SR tablet.[13] The extent ofrelative bioavailability of tramadol SR tablets after alipid-rich meal (postprandial/fasting administration)is 105.1% (90% CI 99.0, 111.5%) and within therange of 80–125%.[13] Food intake has a slight influ-ence on rate of absorption, as shown by the shortertmax and higher Cmax, indicating that food causes aslight reduction in the retarding effect.[13]

The pharmacokinetic properties of SR capsulesare similar to those of SR tablets. Single doses of 50,100 and 200mg of tramadol as SR capsules produceplasma concentrations above half of Cmax (half-value duration) for 12.8, 12.9 and 13.0 hours, re-spectively.[14] There is a direct linear relationshipbetween the administered dosage and the achievedconcentration (table I).[14] Compared with with IRcapsules, bioavailability is only slightly diminished,whereas Cmax is markedly reduced and tmax in-creased (table I).[15] Compared with SR tablets200mg, SR capsules 200mg show 95% of the AUC,77% of the Cmax and 118% of the half-value dura-tion (table I), indicating enhanced retardation atalmost identical bioavailability.[15] Food intake hasno influence on plasma concentrations after admin-istration of tramadol 200mg as SR capsules.[15] Atsteady state (reached after approximately 48 hours),the bioavailability of the SR capsule 100mg every12 hours is 100% relative to IR capsules 50mg every6 hours.[16] The peak-trough fluctuation in plasma


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concentrations at steady state is reduced from 86% milk, and have been detected within 16 hours afterwith the IR capsule to 57% with the SR capsule.[16] administration.[22]

The two-phase tablet of tramadol (25mg IR plus1.5 Metabolism and Elimination75mg SR) produces a faster increase in plasma

concentration than an IR capsule of tramadol 50mg Tramadol is mainly excreted via the kidneys (ap-and an SR tablet of tramadol 100mg.[26] About 2.5 proximately 90%); the residual activity of a radioac-hours after administration of the two-phase tablet, tively labelled dose of tramadol was recovered in thethe concentrations become lower than those after the faeces.[30] In a study involving nine cholecystec-SR tablet of tramadol 100mg. tomised patients, only 1% of tramadol and its meta-

For subcutaneous, intramuscular or intrathecal bolites were eliminated via biliary excretion.[10] Atadministration, a tramadol depot system composed 30 minutes after intramuscular administration ofof monoolein and water has been developed.[27] In tramadol 50mg, tramadol concentrations in salivarats, intramuscular administration provides stable and urine considerably exceeded the plasma concen-pain relief for more than 10 hours.[27] Further inves- tration.[17] The Cmax in saliva and urine occurred attigations of this novel depot system will be of inter- nearly the same time as in plasma, and thereafter theest. plasma and saliva concentrations and the renal ex-

cretion rates decreased almost in parallel.[17] The1.4 Distribution saliva concentrations were 7- to 8-fold and the urine

concentrations 43- to 46-fold higher than the corre-Tramadol is rapidly distributed in the body, with sponding plasma concentrations.[17] The mean elimi-

a distribution half-life in the initial phase of 6 min- nation half-life is about 5–6 hours (table I).[6-12,17]

utes, followed by a slower distribution phase with a The mean total clearance of tramadol was 467 mL/half-life of 1.7 hours.[23] The high total distribution min (approximately 28 L/h) and 710–742 mL/minvolume of 306L after oral and 203L after parenteral (approximately 43–44 L/h) following intravenousadministration indicates high tissue affinity; plasma and oral administration, respectively.[6,8]

protein binding is about 20%.[8,23] After intravenous The main metabolic pathways of tramadol, N-injection of tramadol 100mg, plasma concentrations and O-demethylation (phase I reactions) and conju-of 612, 553, 483 and 409 µg/L were measured after gation of O-demethylated compounds (phase II re-0.25, 0.5, 1 and 2 hours.[8] In a rodent model, tram- actions), were described 20 years ago.[30] Elevenadol was particularly distributed into the lungs, metabolites were known, five arising by phase Ispleen, liver, kidneys and brain.[21] reactions (M1 to M5) and six by phase II reactions

Brain peak concentrations of tramadol occur 10 (glucuronides and sulfates of M1, M4 and M5).minutes after oral administration, and those of its Tramadol is metabolised much more rapidly in ani-major active metabolite O-desmethyl-tramadol mals than in humans: 1% and 25–30% of an oral(M1) 20–60 minutes after oral administration.[28] In dose, respectively, are excreted unchanged in themice, the ratio tramadol/M1 in plasma was 0.5–1.0 urine.[30] In all species, M1 and M1 conjugates, M5throughout the measurements, whereas the ratio in and M5 conjugates, and M2 are the main metabo-brain was about ten at 10 minutes and about two lites, whereas M3, M4 and M4 conjugates are onlyfrom 20 to 50 minutes.[28] In rats, the ratio tramadol/ formed in minor quantities (table II).[30] In a studyM1 in plasma was 0.5–1.5, whereas the ratio in brain where a 50mg oral dose of tramadol was given towas about 15 at 10 minutes and about 4–7 there- 104 volunteers, mean values for tramadol, M1 andafter.[28] There appears to be preferential brain ver- M2 excretion in 24-hour urine were 12%, 15% andsus plasma distribution of tramadol over M1 in mice 4% of the administered dose, respectively.[31] How-and rats. ever, great interindividual differences were observ-

Tramadol passes the placental barrier, with um- ed in two humans after oral administration of eitherbilical venous plasma concentrations being 80% of 1.06 or 1.25 mg/kg of 14C-labelled tramadol.[30] Onematernal concentration.[29] Very small amounts volunteer produced mainly M1, M5, M1 conjugates(0.1%) of tramadol and M1 are excreted in breast and M5 conjugates, whereas the other produced


Tram

adol

885

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Table II. Excretion of unchanged tramadol and its metabolites in the urine of humans, dogs and rats receiving oral tramadol, and metabolites found in human hepaticmicrosomes[30,31,33,34]

Analyte Chemical structure[30,33,34] Percentage of each analyte found

humana humanb dogc ratd humane humanf hepaticg rath dogi

Tramadol 25 32 1 0.9 12 >10 82 2 2M1 O-Desmethyl-tramadol 10 5 2 9 15 >10 5 13 6M2 N-Desmethyl-tramadol 2 31 5 17 4 >10 6 13 6M3 N,N-Didesmethyl-tramadol ND 0.8 2 10 5–10 ND 9 4M4 O,N,N-Tridesmethyl-tramadol 0.1 0.8 4 2 <2 <0.5 <2 <2M5 O,N-Didesmethyl-tramadol 13 6 10 14 5–10 <0.5 5 6M6 4-Hydroxycyclohexyl-tramadol 2–5 3 <2 3M7 4-Hydroxycyclohexyl-N-desmethyl- <2 ND <2 3

tramadolM8 4-Hydroxycyclohexyl-N,N-didesmethyl- <2 ND <2 <2

tramadolM9 4-Oxocyclohexyl-tramadol <2 ND <2 <2M10 Dehydrated tramadol <2 ND <2 <2M11 2-Formyl-1-(3- <2 ND <2 <2

methoxyphenyl)cyclohexanolM12 Tramadol glucuronide <2 NDM13 M1 glucuronide 2–5 ND 7 <2M14 M4 glucuronide <2 ND <2 <2M15 M5 glucuronide 2–5 ND 10 7M16 M6 glucuronide 2–5 ND <2 8M17 M7 glucuronide <2 ND <2 7M18 M8 glucuronide <2 ND ND <2M19 Tramadol sulfate <2 NDM20 M1 sulfate 2–5 NDM21 M4 sulfate 2–5 NDM22 M5 sulfate 5–10 NDM23 M6 sulfate <2 NDM24 M7 sulfate ND <2M25 Acetyl-M2 <2 <2M26 Dehydro-M3 <2 <2M27 Dehydro-M11 <2 <2M28 Alcoholic metabolite <2 <2M29 Carboxylic acid <2 <2M30 M29 glucuronide ND <2M31 Tramadol N-oxide ND 2 ND ND

Continued next page


mainly M2 (table II).[30] In contrast to the above-mentioned studies involving Caucasians, the bio-transformation of tramadol appears to be remark-ably reduced in African subjects.[32] In 10 Nigerianvolunteers, about 96% of tramadol was excretedunchanged in the urine after oral administration of100mg.[32] There is a need to investigate racialvariations in the metabolism of tramadol inmore detail.

In a recent study, a total of 23 metabolites, con-sisting of 11 phase I metabolites (M1 to M11) and12 conjugates (seven glucuronides, five sulfates),were profiled in the urine of male volunteers afteroral tramadol 100mg.[33] These metabolites wereformed via the following six metabolic pathways:O-demethylation, N-demethylation, cyclohexyl oxi-dation, oxidative N-dealkylation, dehydration andconjugation.[33] The previously known metabolites(M1 to M5)[30] were confirmed as major metabolicproducts (table II). Six additional phase I metabo-lites (M6 to M11) resulted from newly identifiedpathways and had not previously been reported.M12 to M18 were identified as glucuronides andM19 to M23 as sulfates, of which M13 to M15 andM20 to M23 had previously been reported as M1,M4 and M5 conjugates.[30] Additional phase I meta-bolites (M25 to M29) and phase II metabolites (M24and M30) have been identified in rats or dogs, butnot in humans (table II).[33,34]

The in vitro metabolism of tramadol has beenstudied in a human liver microsomal fraction incu-bated with tramadol 10 mg/L.[33] Unchanged tram-adol (82% of the sample) plus eight metabolites(M1, M2, M4, M5 and M6, plus M31, M32 andM33, which were not found in urine) were identified(table II).[33] Of the 26 identified metabolites inhumans, seven (M12, M19 to M23 and M33) havenot been found in the rat or dog.[34]

The metabolism of tramadol to M1 is slow inhumans (table III). After oral or rectal administra-tion of tramadol 100mg, the tmax of M1 is about 1.4hours longer than that of tramadol and the Cmax ofM1 is no more than 18–26% of that of tram-adol.[12,35] After multiple oral doses or administra-tion of SR capsules, the time to reach Cmax oftramadol and M1 was similar.[12,36] After single andmultiple oral administration of tramadol, the AUCfor M1 was about 25% of that of the parent com-


Tab

le I

I. C

ontd

Ana

lyte

Che

mic

al s

truc

ture

[30,

33,3

4]P

erce

ntag

e of

eac

h an

alyt

e fo

und

hum

ana

hum

anb

dogc

ratd

hum

ane

hum

anf

hepa

ticg

rath

dogi

M32

Hyd

roxy

-M1

ND

<1

ND

ND

M33

Deh

ydra

ted

M31

ND

<2

M13

or

M20

M1

conj

ugat

es15

812

11

M14

or

M21

M4

conj

ugat

es0.

80.

26

4

M15

or

M22

M5

conj

ugat

es15

633

14

Unk

now

n18

1125

20

aU

rine

(0–7

2h)

of h

uman

s (n

= 1

) af

ter

oral

tra

mad

ol 1

.25

mg/

kg.[3

0]

bU

rine

(0–7

2h)

of h

uman

s (n

= 1

) af

ter

oral

tra

mad

ol 1

.06

mg/

kg.[3

0]

cU

rine

(0–7

2h)

of d

ogs

(n =

3)

afte

r or

al t

ram

adol

10.

5 m

g/kg

.[30]

dU

rine

(0–7

2h)

of r

ats

(n =

5)

afte

r or

al t

ram

adol

30

mg/

kg.[3

0]

eU

rine

(0–2

4h)

of h

uman

s (n

= 1

04)

afte

r or

al t

ram

adol

50m

g.[3

1]

fU

rine

(4–1

2h)

of h

uman

s (n

= 3

) af

ter

oral

tra

mad

ol 1

00m

g.[3

3]

gH

uman

live

r m

icro

som

al f

ract

ion

incu

bate

d w

ith t

ram

adol

10

mg/

L.[3

3]

hU

rine

(0–2

4h)

of r

ats

(n =

4)

afte

r or

al t

ram

adol

50

mg/

kg.[3

4]

iU

rine

(0–2

4h)

of d

ogs

(n =

2)

afte

r or

al t

ram

adol

20

mg/

kg.[3

4]

ND

= n

ot d

etec

ted.

Tram

adol

887

2004 A

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Table III. Pharmacokinetic properties of M1 and tramadol after administration of tramadol

Study Population Administration Analyte tmax Cmax AUC∞ t1/2β CL(n) (h) (µg/L) (µg • h/L) (h) (mL/min)

Liao et al.[12] Volunteers (18) PO, 100mg (single dose) Tramadol 1.6 308 2649 5.6 110a

M1 3.0 55 722 6.7 188a

PO, 100mg (qid, 1 week)b Tramadol 2.3 592 3679 6.7 73a

M1 2.4 110 835 7.0 134a

Thurauf et al.[36] Volunteers (20) PO (SR capsules), 100mg Tramadol 4.8 160 1402c

M1 4.7 73 618c

PO (SR capsules), 200mg Tramadol 4.4 295 2599c

M1 5.4 143 1201c

Nobilis et al.[35] Volunteers (24) PR (suppositories)d, 100mg Tramadol 2.5 796e 9510f 9.1

M1 4.0 214e 3590f

PR (suppositories)d, 100mg Tramadol 2.7 879e 10 410f 8.5

M1 4.0 230e 3960f

Murthy et al.[37] Children (9) IV, 2 mg/kg Tramadol 0.19 1079 5738 6.4 6.1g

M1 4.9 64 1172 10.6

Children (5) Caudally, 2 mg/kg Tramadol 0.55 709 4774 3.7 6.6g

M1 6.4 40 556 5.4

a Renal clearance.

b Multiple doses, 100mg qid for 1 week.

c AUC12.

d Two different pharmaceutical formulations.

e nmol/L.

f AUC32 (µmol • h/L).

g mL/min/kg.

AUCx = area under the concentration-time curve from time zero to x hours; AUC∞ = area under the concentration-time curve from time zero to infinity; Cmax = maximum plasmaconcentration; CL = total clearance; IV = intravenous; PO = oral; PR = rectal; qid = four times daily; SR = sustained-release; tmax = time to maximum plasma concentration; t1/2β =terminal elimination half-life.


pound and the elimination half-life of M1 was 6.7 M1 production in microsomes prepared from theand 7.0 hours, respectively, which is not substantial- liver of a poor metaboliser was markedly re-ly different from that of tramadol.[12] duced.[43] After administration of tramadol 2 mg/kg,

the plasma concentration of (+)-M1 ranged fromThe pharmacokinetic properties of other metabo-10 to 100 µg/L in extensive metabolisers, whereas inlites have not been investigated in detail. It has beenpoor metabolisers plasma concentrations of (+)-M1reported that the biological half-lives of the metabo-were below or around the detection limit of 3 µg/lites are similar to that of the parent substance,L.[44] Furthermore, poor metabolisers had inferiordiminishing the likelihood of accumulation of meta-analgesic effects, because tramadol interacts with µbolites after multiple administration.[23] Like tram-opioid receptors predominantly by way of M1.[44]adol, all metabolites are almost completely excreted

via the kidneys; from a quantitative point of view, In a study of 104 healthy volunteers, poor meta-biliary excretion of these components is negligi- bolisers of sparteine exhibited a 5-fold higher tram-ble.[30] adol/M1 plasma concentration ratio than extensive

The N-oxide of tramadol is a prodrug for tram- metabolisers.[31] Furthermore, there was a highlyadol.[38] Although tramadol N-oxide has no direct significant correlation between sparteine oxidationpharmacodynamic effects, it produces dose-related and tramadol O-demethylation in extensive metabo-long-lasting antinociception in the mouse and rat.[39] lisers.[31]

Tramadol concentrations were essentially the same However, the biotransformation of tramadol var-after administration of either tramadol or tramadol ies within the phenotypic population of extensiveN-oxide to mice, suggesting complete conver- metabolisers depending on the genotype ofsion.[39] In contrast to the rapid attainment of Cmax CYP2D6.[45] In 13 children, there was only a modestand rapid decline in tramadol plasma concentration correlation between tramadol/M1 plasma concentra-after tramadol administration, tramadol concentration ratio and CYP2D6 activity, as determined bytions increase more gradually and were maintained dextromethorphan urinary metabolite ratio; how-for a longer period after administration of tramadol ever, when subjects were segregated based on theN-oxide.[39] Therefore, tramadol N-oxide could offer number of functional CYP2D6 alleles, a muchthe clinical benefits of an extended duration of ac- stronger relationship was observed for subjects withtion and a ‘blunted’ plasma concentration spike, two functional alleles, with essentially no relation-possibly leading to an improved adverse effect pro- ship evident in those individuals with one functionalfile.[39]

allele.[45] Further evaluation of these data suggestedthat the CYP2D6-mediated metabolite (M1) is

1.6 Influence of Cytochrome P450 formed to a lesser extent, and the formation of theon Biotransformation non-CYP2D6 product (M2) is more pronounced, in

subjects with one versus two functional alleles.[45]In vitro investigations suggest that the O-demethylation of tramadol to metabolite M1 is cat- The importance of the CYP2D6 genotype for thealysed by the liver enzyme cytochrome P450 (CYP) biotransformation of tramadol has been emphasised2D6, because this biotransformation is inhibited by by a study in Malaysian subjects.[46] Compared withquinidine, a selective CYP2D6 inhibitor.[40,41] In 5–10% of Caucasians, only 1% of Asians are homo-addition, good correlations were obtained between zygous for mutant CYP2D6 alleles such asM1 formation and dextromethorphan O-demethy- CYP2D6*3, *4 or *5, which results in no functionallase, a marker for CYP2D6, in human liver micro- protein being formed.[46] Despite this low frequencysome preparations.[41] The gene encoding for of poor metabolisers in the Asian population, theyCYP2D6 is known to show polymorphism and the carry a high frequency (51%) of the CYP2D6*10existence of different alleles results in functionally allele, which is relatively rare in Caucasian popula-different enzymes.[42] Phenotypically, 90–95% of tions.[46] This mutation leads to an unstable enzymeCaucasians are ‘extensive metabolisers’ and the re- with lower metabolic activity. Of 30 healthy Malay-mainder are ‘poor metabolisers’ of CYP2D6 probe sians, all being extensive metabolisers, those whosubstrates such as debrisoquine and sparteine. were homozygous for CYP2D6*10 had a longer


Tramadol 889

plasma half-life of tramadol than subjects in the The wide variability in the pharmacokineticheterozygous or normal groups (7.2, 10.0 and 12.1 properties of tramadol can partly be ascribed to CYPhours, respectively).[46] When these patients were polymorphism. Because fluctuations in the concen-screened for the presence of other alleles as well, the trations of tramadol and its pharmacodynamicallypharmacokinetic parameters were even better ex- active metabolites have impact on the therapeuticplained: tramadol half-lives were 6.6 hours for response and toxicity of tramadol, genotypic andCYP2D6*1/*1, 7.4 hours for CYP2D6*1/*9 and phenotypic characterisation of individuals andCYP2D6*1/*10, 7.5 hours for CYP2D6*1/*4 and populations becomes increasingly important to pre-CYP2D6*1/*5, 8.5 hours for CYP2D6*10/*10 and dict enzyme activity, individualise drug therapy andCYP2D6*10/*17 and 21.5 hours for CYP2D6*4/ thus maximise safety and efficacy.*10 and CYP2D6*5/*10.[46]

Investigations in human liver microsomes have 1.7 Stereoselectiveshown differences between the kinetics of O- and N- Pharmacokinetic Propertiesdemethylation.[41] Although M1 is the major metab-olite formed at low tramadol substrate concentra- Tramadol is administered as a racemic mixture oftions, M2 formation predominates at high substrate two enantiomers, (+)-tramadol and (–)-tramadol,concentrations.[41] The biphasic kinetics of both M1 that are essentially metabolised by the liver produc-and M2 formation indicate the participation of more ing (+)-metabolites and (–)-metabolites, respective-than one CYP isoform in these pathways of tram- ly. Several in vitro and in vivo studies have shownadol metabolism.[41] In the presence of low CYP2D6 that the metabolism and distribution of tramadol areconcentrations or when the O-demethylation of tra- stereoselective. So far, no study has investigatedmadol is inhibited, a metabolic switch in favour of whether interconversion of the enantiomers of tram-enhanced N-demethylation can be observed.[22,47] In adol or its metabolites occurs.vivo, however, there was no correlation between In vitro, O- and N-demethylation of tramadolCYP2D6 activity, determined by sparteine oxida- were both demonstrated to be stereoselective.[40]

tion, and tramadol N-demethylation.[31]The O-demethylation of tramadol, leading to M1,

In vitro, the N-demethylation of tramadol to me- was determined to be 2-fold greater for the (–)-tabolite M2 is catalysed by cDNA-expressed human enantiomer than for the (+)-enantiomer.[40] On theCYP2B6 and CYP3A4.[41] In addition, M2 forma- other hand, N-demethylation, leading to M2, wastion was inhibited by the CYP3A4 inhibitor trole- considerably faster after incubation of the (+)-enan-andomycin to 33–44% of control, and good correla- tiomer compared with the (–)-enantiomer.[40] Sincetions were obtained between M2 formation and (S)- O-demethylation is the preferred biotransformationmephenytoin N-demethylase, a marker for CYP2B6, of tramadol in most subjects, higher plasma concen-in human liver microsomes.[41] trations of (+)-tramadol and (–)-M1 compared with

(–)-tramadol and (+)-M1, respectively, can be ex-Based on the observations that CYP2D6 primari-pected in vivo.ly catalyses tramadol O-demethylation (M1 forma-

To study the stereoselectivity of renal clearance,tion), whereas CYP2B6 and CYP3A4 primarily cat-isolated kidneys of rats were perfused with tramadolalyse tramadol N-demethylation (M2 formation),and M1.[48] The renal clearance of the enantiomersCYP2D6 would be expected to participate in M5of both compounds was stereoselective, (–)-tram-formation from M2.[41] In addition, CYP2B6 andadol and (+)-M1 being preferentially eliminated. InCYP3A4 would be expected to participate in M1addition, the O-demethylation of tramadol was ster-metabolism to M5, and M2 metabolism to M3.[41]

eoselective in the kidneys, (–)-tramadol being pref-Additional studies, using M1 and M2 as substrates,erentially metabolised.[48]are required to fully elucidate the CYP isoforms

involved in M3 and M5 formation. Further in vitro The distribution of tramadol in the central ner-and in vivo studies should investigate the influence vous system of rats is also stereoselective.[49] At 1of CYP isoforms on the formation of the remaining hour after intraperitoneal administration of tramadoltramadol metabolites. 17 mg/kg, concentrations of (+)-tramadol were



higher than those of (–)-tramadol and concentrationsof (–)-M1 were higher than those of (+)-M1 inplasma, cerebrospinal fluid and cerebral cortex.[49]

Tramadol and M1 concentrations of both enanti-omers were the highest in cerebral cortex and thelowest in cerebrospinal fluid.[49] At 1 hour afterintraperitoneal administration of M1 5 mg/kg, theconcentrations of (+)-M1 were higher than those of(–)-M1 in plasma, cerebrospinal fluid and cerebralcortex, which was different from the results afterintraperitoneal administration of tramadol.[49] Theconcentrations of both enantiomers of M1 were thehighest in cerebral cortex and the lowest in cerebro-spinal fluid.[49] Following intravenous infusion of(+)-M1 or (–)-M1 in rats, the pharmacokinetics ofboth substrates were similar and could best be de-scribed by a two-compartment model.[50] There wasno pharmacokinetic interaction between the twocompounds.[51]

Following an intravenous infusion of tramadol100mg over 10 minutes to 12 human volunteers, atall times of the observation period (10 minutes to 24hours) plasma concentrations, AUC and eliminationhalf-life of (+)-tramadol were greater than those of(–)-tramadol (table IV).[52] On the other hand, (+)-M1 concentrations were lower than (–)-M1 concen-trations between 10 minutes and 8 hours after infu-sion, but greater at 12 and 24 hours.[52]

After oral administration of tramadol 200mg,tmax was identical for (+)-tramadol and (–)-tram-adol, as well as for (+)-M1 and (–)-M1 (table IV).[53]

The Cmax and AUC values of (+)-tramadol weregreater than those for (–)-tramadol, and those of (–)-M1 were greater than those of (+)-M1 (table IV).[53]

Another study investigated the stereoselectivepharmacokinetics of tramadol after multiple oraldoses of SR tablets 100mg.[54] (+)-Tramadol wasshown to be absorbed more completely, but elimi-nated more slowly. At steady state, the plasma con-centrations of (+)-tramadol were higher than thoseof (–)-tramadol at every sampling timepoint, andthose of (–)-M1 were higher than those of (+)-M1 atmost sampling timepoints. A time-dependent in-crease of the (+)/(–)-tramadol ratio and the (–)/(+)-M1 ratio was observed during the 32-hour samplingperiod. Although the (+)/(–)-tramadol ratios weresimilar among the 12 subjects (range 1.19–1.48), the(–)/(+)-M1 ratios were very different (range


Tab

le I

V.

Ste

reos

elec

tive

phar

mac

okin

etic

pro

pert

ies

of t

ram

adol

and

M1

afte

r ad

min

istr

atio

n of

tra

mad

ol

Ref

eren

ceP

opul

atio

nA

dmin

istr

atio

nA

naly

tet m

axC

max

AU

C∞

t1 /2β

CL

(n)

(h)

(µg/

L)(µ

g•

h/L)

(h)

(mL/

min

)C

ampa

nero

et

al.[5

2]V

olun

teer

s (1

2)IV

ove

r 30

min

, 10

0mg

(+)-

Tra

mad

ol18

155.

542

3a

(–)-

Tra

mad

ol13

484.

655

4a

(+)-

M1

515

9.1

1513

a

(–)-

M1

501

9.0

1500

a

Cec

cato

et

al.[5

3]V

olun

teer

s (3

0)P

O,

100m

g(+

)-T

ram

adol

1.8

323

2784

b

(–)-

Tra

mad

ol1.

829

022

27b

(+)-

M1

2.1

6169

7b

(–)-

M1

2.1

8176

1b

Liu

et a

l.[54]

Vol

unte

ers

(12)

PO

(S

R t

able

ts),

100

mg

(+)-

Tra

mad

ol4.

216

424

827.

8(b

id,

5 da

ys)

(–)-

Tra

mad

ol3.

414

419

116.

2(+

)-M

13.

818

162

(–)-

M1

3.4

2317

9a

mL/

h/kg

.b

AU

C36

.A

UC

36 =

are

a un

der

the

conc

entr

atio

n-tim

e cu

rve

from

tim

e ze

ro t

o 36

hou

rs;

AU

C∞

= a

rea

unde

r th

e co

ncen

trat

ion-

time

curv

e fr

om t

ime

zero

to

infin

ity;

bid

= t

wic

e da

ily;

CL

=to

tal

clea

ranc

e; C

max

= m

axim

um p

lasm

a co

ncen

trat

ion;

IV

= i

ntra

veno

us;

PO

= o

ral;

SR

= s

usta

ined

-rel

ease

; t m

ax =

tim

e to

max

imum

pla

sma

conc

entr

atio

n; t

1 /2β

= t

erm

inal

elim

inat

ion

half-

life.

Tramadol 891

0.89–1.90). It needs to be determined whether the M1 2 mg/kg was enough to achieve 100% anti-pharmacokinetic stereoselectivity of the enanti- nociception without respiratory depression. Anti-omers of M1 is caused by different levels of protein nociceptive response elicited by (+)-M1 could bebinding, different rates of renal clearance and/or adequately described by a standard pharmacokine-polymorphism of CYP2D6. tic-pharmacodynamic model. In addition, the results

indicated the development of tolerance for the anti-Analysis of the enantiomers of tramadol and itsnociceptive effects of (+)-M1. The administration ofmetabolites in the urine of volunteers has confirmeddoses of (+)-M1 higher than 2.5 mg/kg elicited dose-that a stereoselective metabolism of tramadol clear-dependent respiratory depression. However, dosesly occurs. After oral administration of tramadolof (–)-M1 up to 8 mg/kg showed neither anti-100mg, 16% of the dose was excreted within 30nociception nor respiratory effects.[50]hours in the urine as unchanged tramadol, 16% as

M1, 2% as M2 and 15% as M5.[55] For all com- The second pharmacokinetic-pharmacodynamicpounds, a time-dependent increase of the initial study investigated the interactions between (+)-M1enantiomeric ratio was observed during the study and (–)-M1 in rats.[51] The pharmacokinetic para-period.[55] The enantiomeric ratios [(+)/(–) for tram- meters of both enantiomers infused together wereadol; not determined if (+)/(–) or (–)/(+) for metabo- similar to those obtained when both compoundslites] were 1.22 for tramadol, 1.48 for M1, 2.29 for were administered alone; no pharmacokinetic inter-M2 and 2.19 for M5.[55] This is in good agreement action between (+)- and (–)-M1 was found. Al-with the results of other investigations, which also though (–)-M1 alone showed no antinociception,[50]

showed a higher excretion of the (+)-enanti- it caused potentiation of the antinociceptive effectomer.[56-58] In addition, a 4- to 5-fold higher excre- elicited by (+)-M1. This phenomenon has success-tion of the (–)-enantiomers of two phase II metabo- fully been modelled by using a noncompetitivelites, O-demethyl-tramadol glucuronide (M13) and interaction model, including an effect compartmentN,O-didemethyl-tramadol (M15), was observed to account for the opioid effect of (+)-M1 and anafter oral administration of tramadol 100 or 150mg indirect response model accounting for the releaseto volunteers.[58,59] of norepinephrine by (+)-M1 and inhibition of nore-

pinephrine reuptake by (–)-M1.[51,60]

1.8 Pharmacokinetic- In humans, no pharmacokinetic-pharmacody-Pharmacodynamic Modelling namic modelling has been performed so far. Two

studies investigated the analgesic effect of SR tram-Pharmacokinetic-pharmacodynamic studies areadol in 20 volunteers with an experimental painused to describe and predict the time course of the inmodel.[36,61] In both studies, the antinociceptive ef-vivo effect in different scenarios. For tramadol, in-fects did not correlate with changes in pharmaco-terpretation of the pharmacokinetic-pharmacody-kinetics. The authors concluded that these discrep-namic relationship is difficult because of: (i) a delayancies might be based on differences between tram-of effect resulting from transport from plasma toadol concentrations in plasma and at the site ofcentral nervous system; (ii) potential developmentaction.of tolerance; and (iii) pharmacodynamic interactions

among the two enantiomers of tramadol and its Another approach was the determination of ‘min-active metabolites.[50] So far, only two animal stud- imum effective’ plasma concentrations during intra-ies have investigated the pharmacokinetic-pharma- venous patient-controlled analgesia (PCA) for post-codynamic relationships of tramadol.[50,51] operative pain. Venous blood samples were taken

The first pharmacokinetic-pharmacodynamic immediately before a patient’s demand, i.e. at thestudy investigated the pharmacokinetic properties point in time at which the patient was just becomingand the antinociceptive and respiratory effects of the dissatisfied with analgesia.[62-64] The determinedtwo main metabolites of tramadol, (+)-M1 and (–)- mean minimum effective concentrations varied de-M1, in rats.[50] The pharmacokinetics of both com- pending on the study conditions, and were 298 µg/Lpounds were considered similar and were well in a study where patients received at least 5 µg/kgdescribed with multicompartment models. (+)- fentanyl intraoperatively,[64] 590 µg/L in a study



where patients received no opioids whatsoever be- analytical methods to quantify plasma concentra-sides tramadol[62] and 916 µg/L in a study where tions of each of the important and active compon-tramadol PCA was combined with a continuous ents, is required to allow better understanding ofinfusion of tramadol at 12 mg/h independent of the tramadol effects.demands.[63] The range of minimum effective con-

1.9 Effect of Age and Impaired Renal andcentrations was rather broad in all of these threeHepatic Functionstudies – 20–986 µg/L,[64] 65–2169 µg/L[62] and

272–1900 µg/L.[63] The relative parenteral opioid The pharmacokinetics of tramadol are not age-potency derived from minimum effective concentra- dependent (table I). Only one study has investigatedtions in postoperative pain treatment was calculated the pharmacokinetic properties of tramadol in chil-to be 0.05 : 1 for tramadol compared with mor- dren (table I).[37] After intravenous injection of tram-phine.[65]

adol 2 mg/kg in nine children aged 1–7 (median 2.4)The minimum effective concentrations of M1 (84 years, the mean plasma concentrations of tramadol

and 36 µg/L) were only 12–14% of those of tram- and M1 were only slightly higher than those inadol.[62,64] Plasma concentrations did not rise from adults.[37] None of the pharmacokinetic variablesthe initial to the final blood sample (tramadol, 250 calculated was significantly different from those invs 208 µg/L; M1, 30 vs 34 µg/L),[65] indicating that healthy adult volunteers.[37] As O-demethylation ofaccumulation or acute tolerance does not develop tramadol is carried out by CYP, which usuallyduring short postoperative use of tramadol. reaches adult levels by 1 year of age, it is not

During intravenous PCA using (+)-tramadol, tra- surprising that the M1/tramadol plasma concentra-madol racemate and (–)-tramadol, the mean plasma tion ratio after intravenous injection was similar toconcentrations of tramadol were 470, 590 and 771 that in adults.[37] The AUC value in five childrenµg/L, and those of M1 were 57, 84 and 96 µg/L, aged 6–12 (median 6.0) years after caudal adminis-respectively.[62] The finding that the minimum effec- tration was only 17% lower than after intravenoustive concentrations of tramadol and M1 in the (+)- injection, demonstrating that there is extensive sys-tramadol group were lower than those in the (–)- temic absorption of tramadol after caudal adminis-tramadol group confirms that (+)-tramadol or (+)- tration.[37]

M1 are more potent analgesics than the (–)-enanti- Only one study has investigated the pharmaco-omers.[62] Stereoselective analysis showed that the kinetic properties of tramadol in older subjectsconcentrations of (+)-tramadol and (+)-M1 were (table I).[19] There were no clinically relevant differ-lower in the tramadol racemate group than in the ences in pharmacokinetic properties between(+)-tramadol group; this finding suggests that a healthy adult volunteers aged <65 years and volun-potentiation in the analgesic effect elicited by (+)- teers aged >65–75 years. However, elimination maytramadol or (+)-M1 is caused by (–)-tramadol or (–)- be prolonged in patients >75 years of age.[19]

M1 in humans.[62]Since tramadol and its main pharmacologically

The concentrations described as ‘minimum ef- active metabolite M1 are eliminated both metaboli-fective’ in these studies,[62-64] however, are not really cally and renally, the terminal half-life may be pro-‘minimum effective’ because no quantitative data longed in hepatic or renal function disorders. How-are available for the roles of tramadol, M1 and other ever, the prolongation of the elimination half-life ismetabolites in the analgesic effect of tramadol.[62] In relatively slight, as long as one of the two excretionaddition, all studies demonstrated a great inter- and organs is virtually intact.[19] In patients with severeintraindividual variability in postoperative plasma liver cirrhosis, the elimination half-life of tramadolconcentrations and could not fix narrow analgesic was extended to a mean of about 13 hours; extremethreshold concentrations.[62] values reached up to 22 hours.[19] In addition, the

Proper pharmacokinetic-pharmacodynamic char- renal clearance of unchanged tramadol increases inacterisation of tramadol in humans, which implies patients with liver cirrhosis.[66] Since it is not yetthe administration of (+)-tramadol, (–)-tramadol, known whether patients with liver cirrhosis experi-(+)-M1 and/or (–)-M1 and use of enantioselective ence sufficient pain relief after recommended doses


Tramadol 893

of tramadol, and because of the potential for delayed Investigations on the interaction with carbamaze-elimination and accumulation, it appears advisable pine 400mg twice daily for 12 days as a typicalto consider alternative drugs in this setting until enzyme inducer showed that tramadol Cmax (51%),more information becomes available.[66] AUC (26%) and elimination half-life (54%) were

reduced.[19] Therefore, an increase in tramadol dos-In patients with renal failure whose creatinineage should be considered in patients with previousclearance was <5 mL/min the mean eliminationor concomitant carbamazepine treatment.half-life of tramadol was about 11 hours; extreme

values reached about 19 hours.[19] The administra- There is no interaction between tramadol andtion of tramadol 50mg four times daily on a coumarin anticoagulants.[68]

haemodialysis-free day resulted in a tmax of 3 hoursand an elimination half-life of 6.4 hours, both being 2. Pharmacodynamic Propertiescomparable to those in healthy subjects.[67] How-ever, total clearance (151 mL/min) and volume of

2.1 Mechanism of Actiondistribution (83L) were decreased, and thus the Cmaxincreased (478 µg/L).[67] Therefore, the doses and Tramadol has a weak affinity for the µ opioidintervals of tramadol should be adjusted in patients receptor. A second, non-opioid, mechanism is sug-with severe renal impairment. gested by: (i) lack of naloxone reversibility; (ii) lack

Dialysis appears not to have a significant effect of significant naloxone-induced withdrawal; (iii)on tramadol concentrations. The total amount of production of mydriasis (rather than miosis); andtramadol and M1 removed during a 4-hour dialysis (iv) attenuation of its antinociceptive or analgesicperiod (haemodialysis, intermittent or continuous effect by non-opioid (i.e. serotonin or adrenergic)haemofiltration, peritoneal dialysis) was <7% of the antagonists.[69]

administered dose.[10] However, a case report de- Tramadol possesses only a modest affinity for µscribed a 55% extraction ratio during haemodialysis opioid receptors and no affinity for δ or κ opioidand recommended that tramadol administration receptors.[4] The affinity of tramadol for µ opioidshould be performed after the session of haemodial- receptors is approximately 10-fold less than that ofysis.[67]

codeine and 6000-fold less than that of morphine, anaffinity that by itself does not seem sufficient to

1.10 Drug Interactions contribute to the analgesic action of tramadol (tableV). The metabolite M1 binds with about 300-fold

An interaction study with cimetidine, a typical higher affinity than the parent compound, but stillenzyme inhibitor, showed that previous administra- with much lower affinity than morphine.[60,70,71] Thetion of cimetidine 400mg twice daily for 3 days increase in subjective and objective pain thresholdsresulted in an increase of tramadol AUC (27%) and induced by tramadol is, in contrast to that of otherelimination half-life (20%),[19] an effect that was not opioids, only partially blocked by the opioid ant-considered to require dosage adjustment.[10] agonist naloxone.[72] Therefore, the activation of µ

Table V. Relative activity for inhibition of opioid receptor binding or monoamine uptake[5,73]

Drug Ki (µmol/L)

opioid receptor affinity uptake inhibition

µ δ κ norepinephrine serotonin

(±)-Tramadol 2.1 57.6 42.7 0.78 0.9

(+)-Tramadol 1.3 62.4 54.0 2.51 0.53

(–)-Tramadol 24.8 213 53.5 0.43 2.35

(+)-M1 0.0034

Morphine 0.00034 0.092 0.57 IA IA

Imipramine 3.7 12.7 1.8 0.0066 0.021

IA = inactive; Ki = inhibition constant.



opioid receptors appears to be only one of the com- phrine transporter function.[81] The effect onponents of the mechanism of action of tramadol. norepinephrine efflux was smaller than the effect on

norepinephrine uptake.[82] (–)-Tramadol is a moreIn addition to its opioid actions, tramadol inhibitspotent blocker of norepinephrine reuptake than isthe neuronal reuptake of norepinephrine and seroto-(+)-tramadol or M1.[82,83]nin (5-hydroxytryptamine, 5-HT).[4] These mono-

These findings led to the hypothesis that tram-amine neurotransmitters are involved in theadol produces its antinociception in animals andantinociceptive effects of descending inhibitoryanalgesia in humans by a multimodal mechanism.[69]pathways in the central nervous system. The α2-(+)-M1 acts as a µ opioid agonist, (+)-tramadoladrenoceptor antagonist yohimbine and the seroto-inhibits serotonin reuptake and (–)-tramadol inhibitsnin antagonist ritanserin block the antinociceptivenorepinephrine reuptake. The activity of the individ-effects of tramadol,[72] but not those of morphine.[4]

ual enantiomers at either the opioid or monoamineThe reuptake inhibition of the non-opioid systemuptake sites is low when compared with such refer-requires the same range of concentrations as theence compounds as morphine for the opioid sitesinhibition of the opioid system (table V), suggestingand imipramine for the uptake sites (table V).[69]that both mechanisms are active in vivo.

In rats, the measured effective dose to produceTramadol is a racemate of 50% (+)-enantiomer50% antinociception (ED50) of racemic tramadoland 50% (–)-enantiomer.[74] (+)-Tramadol has a 2-was lower than the theoretical value calculated if thefold higher affinity for the µ opioid receptor than thecontributions of the enantiomers were simply addi-racemate (table V).[5] Of the metabolites, (+)-M1 hastive.[5] Thus, combined as a racemate, the enanti-the highest affinity for the µ opioid receptor, beingomers of tramadol act in a synergistic manner andabout 700-fold more potent than (±)-tramadol.[73]

are more efficacious. It is of great interest that less-Another metabolite with a higher affinity than (±)-than-synergistic interactions have been observed fortramadol for the µ opioid receptor is (±)-M5.[73] Theadverse events, i.e. in the rotarod test and the colonicintravenous administration of M1, but not of M5,propulsive motility test.[5] The severity of adverseproduced strong antinociceptive effects.[71] How-events seen with the racemate is reduced becauseever, a pronounced effect was seen after direct ad-these effects predominate with one or the other ofministration of M5 into the brain ventricle, indicat-the enantiomers and, in part, they antagonise eaching that M5 does not penetrate the blood-brain barri-other.er because of its high polarity.[71] Therefore in vivo,

(+)-M1 appears to be responsible for the µ opioid-derived analgesic effect of tramadol. 2.2 Analgesic Effects

(±)-Tramadol inhibits the neuronal reuptake ofserotonin; the (+)-enantiomer is about 4-fold more In healthy volunteers undergoing experimentalpotent than the (–)-enantiomer.[75] In addition, (±)- pain, oral tramadol 100mg and intravenous tramadoltramadol and its (+)-enantiomer, but not the (–)- 2 mg/kg provided analgesia superior to that of place-enantiomer and M1, increase serotonin efflux.[76] bo.[84,85] Analgesia peaked at 3 hours and lasted forWhereas one study suggests that an enhancement of about 6 hours.[84] Tramadol-induced analgesia wasserotonin release contributes to its actions,[77] an- only partly antagonised by the opioid antagonistother study indicates that tramadol is only a seroto- naloxone.[84,86] The combination of naloxone and thenin reuptake blocker and not a serotonin releaser.[78] α2-adrenoceptor antagonist yohimbine abolishedFurthermore, the serotonergic pathway is responsi- the analgesic effects of tramadol.[72] Furthermore,ble for the antinociceptive effect of tramadol in the ondansetron, a selective 5HT3 receptor antagonist,formalin test, and this effect is mediated by 5-HT2 reduced the analgesic effects of tramadol in post-receptors.[79] operative pain.[87,88] These data point to the synergy

of monoaminergic modulation and opioid agonismTramadol enhances extraneuronal norepine-in tramadol-induced analgesia in humans.phrine levels in the spinal cord by competitive inter-

ference with the norepinephrine reuptake mecha- Tramadol interacts with µ opioid receptors pre-nism.[80] The site of interference is the norepine- dominantly by way of its metabolite (+)-M1.[44] In


Tramadol 895

extensive sparteine metabolisers, the analgesic ef- 2.3 Effects on Respirationfects of tramadol were superior to those in poor

Tramadol, as a µ opioid agonist, influences respi-metabolisers.[44] Therefore, the formation of (+)-M1ration but is unlikely to produce clinically relevantby CYP2D6 is important for the analgesic effect ofrespiratory depression at the recommended dosage.tramadol.In healthy volunteers, tramadol reduces total venti-

Three studies investigated the extent of analgesia latory CO2 sensitivity by acting at µ opioid receptorscontributed by the enantiomers of tramadol in in the brainstem,[93] but does not depress the hypoxichumans.[89-91] In healthy volunteers, oral (+)-tram- ventilatory response.[94] Furthermore, tramadol ex-adol was associated with an immediate rapid inhibited a minimum effect on respiration and breath-crease in the pain threshold that could be inhibited ing pattern when given as a 150mg bolus plus aby naloxone.[91] (–)-Tramadol and the racemate both subsequent 3-hour steady infusion of 250mg.[95]

induced antinociceptive effects of a similar magni- In spontaneously breathing anaesthetised pa-tude that were not affected by naloxone.[91] Follow- tients, tramadol 0.6 mg/kg had no effects on end-ing orthopaedic surgery, intravenous administration tidal CO2 concentration, minute volume and respira-of up to 150mg of (+)-tramadol, (–)-tramadol or the tory rate, whereas equianalgesic doses of oxycodoneracemate were superior to placebo, but inferior to or pethidine produced respiratory depression.[96,97]

morphine (up to 15mg).[90] Whereas (+)-tramadol In children under halothane anaesthesia, intravenousand morphine had the highest rate of adverse events, tramadol 1 or 2 mg/kg caused significantly lesstramadol racemate had the lowest rate.[90] In a ran- respiratory depression than intravenous pethidinedomised double-blind study, 98 patients recovering 1 mg/kg.[98]

from major gynaecological surgery were treatedwith intravenous PCA.[89] Of patients treated with 2.4 Haemodynamic Effects(+)-tramadol, racemate or (–)-tramadol, 67%, 48%

Tramadol has no clinically relevant haemodyna-and 38%, respectively, were considered respondersmic effects. In healthy volunteers, blood pressureregarding the primary criterion of efficacy, andand heart rate were only very slightly and transiently82%, 76% or 41% with respect to the secondaryelevated following intravenous tramadol 100mg.[99]

criterion. Nausea and vomiting were the most fre-A bolus of 150mg plus a subsequent 3-hour steadyquently reported adverse effects and were most of-infusion of 250mg did not have any clinically signif-ten seen with (+)-tramadol. Taking into accounticant effects on haemodynamics in volunteers, butboth efficacy and adverse events, the racematean increase in plasma epinephrine levels was not-seems to be superior to either enantiomer alone.[89,90]

ed.[95] During artificial ventilation with oxygen andLehmann performed multiple identical studies nitrous oxide before the start of surgery, intravenous

using different opioids in intravenous PCA and cal- tramadol 0.75 and 1.5 mg/kg caused a minor in-culated equipotent dose ratios from hourly opioid crease in systemic and pulmonary blood pres-consumption and retrospective pain score.[65] The sure.[100] Intravenous tramadol 0.6 mg/kg and oxy-equipotent dose ratio of tramadol compared with codone 0.04 mg/kg had no significant effect on heartmorphine was between 6.3 : 1 and 10.2 : 1.[65]

rate in spontaneously breathing patients duringIn a pooled analysis of 18 single-dose studies on halothane anaesthesia.[101]

oral tramadol, nine in dental extraction pain (1594 No major effects on heart rate, mean pulmonarypatients) and nine in postsurgical pain (1859 pa- artery pressure, pulmonary capillary wedge pres-tients), tramadol 50mg showed similar analgesic sure, stroke volume index and total peripheral resis-efficacy to codeine 60mg, and tramadol 100mg was tance were observed in 57 circulatory risk patientsthe optimal single dose for acute pain.[92] Because prior to major vascular surgery following equipotenttramadol has a higher oral bioavailability than mor- doses of morphine, fentanyl, alfentanil, tramadolphine, an equipotent dose ratio of 4 : 1 for oral and nalbuphine.[102] Furthermore, tramadol 50mgtramadol compared with oral morphine should be administered intravenously produced no significantexpected. change in heart rate and blood pressure in patients



with myocardial infarction or unstable angina after surgery blocked the enhancement of lung me-pectoris.[103] tastasis induced by surgery in rats.[111]

After surgery in cancer patients, analgesic doses2.5 Gastrointestinal Effects of tramadol, in contrast to morphine, returned the

surgery-induced depression of T lymphocyte proli-Tramadol, in contrast to other µ receptor ago- feration to basal levels.[112] In addition, tramadol

nists, has only a minor delaying effect on gastroin- enhanced the activity of natural killer cells.[112]

testinal transit. In healthy volunteers, tramadol 1mg/kg did not delay gastric emptying.[104] In another 3. Therapeutic Efficacy in Acute Painstudy, tramadol 1.25 mg/kg had a measurable but

Extensive studies reviewed previously[22,65] havesmaller inhibitory effect on gastric emptying com-demonstrated the analgesic efficacy and tolerabilitypared with morphine and codeine.[105] In a double-of orally, intramuscularly or intravenously adminis-blind crossover study of ten healthy volunteers, tra-tered tramadol in acute pain. Although tramadol hasmadol 50mg and placebo solutions were given fourbeen used in post-traumatic, obstetric, and renal ortimes daily for 10 days.[106] In this longer-termbiliary colic pain, most studies have investigatedstudy, tramadol had a minor delaying effect onpostoperative pain (table VI). In a meta-analysis thatcolonic transit but no effect on upper gastrointestinalincluded, for methodical reasons, only three of 36transit or gut smooth muscle tone.controlled trials on postoperative pain, an odds ratioIn patients with pancreatitis, orocecal transit timeof 0.4 (95% CI –0.60, 0.86) demonstrated the anal-was unchanged after 5 days of tramadol, but in-gesic efficacy of tramadol compared with placebocreased with morphine.[107] Gastrointestinal motilityand morphine.[113]was also evaluated after abdominal hysterectomies

in 50 patients who were randomised to receive3.1 Postoperative Paindouble-blinded postoperative 48-hour infusions of

morphine or tramadol.[108] Orocecal and colonic3.1.1 Oral Administrationtransit times increased after operation with bothA meta-analysis of published and unpublishedmorphine and tramadol, but gastric emptying was

data has demonstrated clear analgesic efficacy ofprolonged only with morphine. Whereas penta-single-dose oral tramadol.[142] In postsurgical pain,zocine causes spasm of the bile duct sphincter, tram-oral tramadol 50, 100 and 150mg had numberadol, buprenorphine and saline showed no such ef-needed to treat (NNT) of 7.1, 4.8 and 2.4, respec-fect.[109]

tively, compared with aspirin 650mg plus codeine60mg (3.6) and paracetamol (acetaminophen)2.6 Effects on Immune System650mg plus propoxyphene 100mg (4.0).[142] This

In rats, tramadol has an immunological profile means that one in every 2.4–7.1 patients woulddifferent from that of morphine, which is known to experience at least 50% pain relief with tramadol,suppress both natural killer cell activity and T lym- but would not have done so with placebo.phocyte proliferation at subanalgesic doses.[110] Tra- Two of these single-dose studies have been pub-madol significantly depressed T lymphocyte func- lished in detail, but present contradicting re-tion at analgesic doses, but did not modify the sults.[118,119] Oral tramadol 75 or 150mg was signifi-activity of natural killer cells, which mediate cantly more effective than placebo and a combina-cytotoxicity against tumour cells and are important tion of paracetamol 650mg and propoxyphenein immune defence against viral infection.[110] 100mg in 161 patients following caesarean sec-

Another study demonstrated immunostimulatory tion.[119] Stubhaug et al.,[118] however, found no dif-properties of tramadol.[111] In contrast to morphine, ference in analgesic efficacy between tramadol 50 ortramadol increased natural killer cell activity in nor- 100mg and placebo on the first day after total hipmal non-operated rats and was able to prevent sur- replacement in 144 patients, but significantly moregery-induced suppression of natural killer cell ac- emetic episodes after tramadol. The good test sensi-tivity.[111] Furthermore, tramadol given before and tivity of the latter study was confirmed by the active


Tramadol 897

control (paracetamol 1000mg plus codeine 60mg) paracetamol 16/1000 mg/day.[114] Prior to discharge,being superior to tramadol and placebo. Explana- the patients received pre-, intra- and postoperative-tions for the discrepancy between these two studies ly, either tramadol 100mg or fentanyl intravenously.are that baseline pain intensity was obviously higher Tramadol provided analgesic efficacy superior toin the study of Stubhaug et al.[118] and that pain that of fentanyl plus codeine/paracetamol. In afollowing hip surgery is somatic whereas pain fol- double-blind study of 91 gynaecological patients,lowing caesarean section also includes visceral pain. oral tramadol 100mg administered pre- and postop-Thus, a single oral dose of tramadol does not seem eratively provided similar analgesic efficacy com-to be adequate in severe pain following orthopaedic pared with oral naproxen 500mg administered pre-surgery. Multiple doses of oral tramadol 50–200mg, and postoperatively.[117] Well-being improved sig-however, provided effective analgesia on the day nificantly in the tramadol group compared with theafter prolapsed intervertebral disc repair in 80 pa- naproxen group. In another double-blind study,tients with severe pain, with no difference in pain postoperative administration of tramadol 50–100mgrelief or adverse events to oral pentazocine every 4–6 hours provided efficacy similar to that of50–200mg.[116] a combination of paracetamol/codeine 500/30mg or

paracetamol/dextropropoxyphene 325/32.5mg in 68The analgesic efficacy of oral single-dose tram-patients who underwent laparoscopic surgery.[115]adol can be increased by combination with a non-

opioid analgesic. A meta-analysis of seven random-3.1.2 Rectal Administrationised, double-blind, placebo-controlled trials com-The use of rectal tramadol administration waspared the combination of tramadol 75 or 112.5mg

investigated in only one study of 40 patients.[147]plus paracetamol 650 or 975mg with its components

There was no difference in pain scores at rest andin postoperative pain.[143] Combination analgesicsduring movement between tramadol suppositories(tramadol plus paracetamol) had significantly better100mg or paracetamol/codeine suppositories 1000/NNTs than the components alone and a similar rate20mg every 6 hours, but the incidence of nausea andof adverse events.vomiting was significantly higher in the tramadol-

Oral tramadol has also been demonstrated to be treated group (84% vs 31%).effective following surgery in children. Oral tram-adol 1.5 mg/kg provided postoperative analgesia 3.1.3 Intramuscular Administrationsuperior to that of placebo in 60 children undergoing Early studies in 1981 demonstrated the analgesicextraction of six or more teeth.[144] In another study, effects of single-dose intramuscular tramadol81 postsurgical patients 7–16 years of age received 50–100mg.[120,123] Several recent studies have con-oral tramadol 1 or 2 mg/kg for postoperative analge- firmed that repeated intramuscular administration ofsia when they were ready to convert from morphine tramadol can provide effective and well toleratedPCA to oral analgesics.[145] The 2 mg/kg group postoperative analgesia comparable to that ob-required approximately half as much rescue analge- tained with morphine, pentazocine and ketoro-sia as did the 1 mg/kg group. Adverse events were lac.[112,121,124,126,127] In contrast, multiple intramuscu-similar between the two treatment groups. In a sin- lar injections of codeine 60mg provided bettergle-blind study of children aged 11 years and older, analgesia than tramadol 50 or 75mg after cranioto-oral tramadol delivered the same analgesic efficacy my.[125] In addition, tramadol 75mg was associatedas oral diclofenac for post-tonsillectomy pain re- with increased sedation, nausea and vomiting.[125] Alief.[146] potential explanation for this discrepancy could be

that pain after craniotomy is less responsive to sero-Oral tramadol is a suitable analgesic in patientstonin and norepinephrine reuptake inhibition, whichundergoing day surgery, because the lack of respira-is part of the mechanism of action of tramadol.tory depressant effect allows its use after discharge

from hospital. In a double-blind, multicentre study, The intramuscular administration of tramadol111 patients were treated with oral tramadol 150mg also improved lung function in 20 patients100–400 mg/day after discharge from groin surgery receiving dipyrone 2g every 6 hours intravenouslyand 117 patients were treated with oral codeine/ following laparoscopic cholecystectomy[122] and in-


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Table VI. Controlled trials of tramadol in postoperative pain

Study Type of surgery Study design n Analgesic drug Dosage (mg/day) Analgesic efficacyOral administrationBamigbade et al.[114] Groin db 228 Tramadol 100–400 T > C/P

Codeine/paracetamol 16–64/1000–4000

Crighton et al.[115] Laparoscopy db 68 Tramadol 50–400 T = C/P = DP/P

Codeine/paracetamol 30–240/500–4000

Dextropropoxyphene/paracetamol 32.5–260/325–2600

Kupers et al.[116] Orthopaedic db 160 Tramadol 50 T = PE

Pentazocine 50

Peters et al.[117] Gynaecological db 91 Tramadol 150–200 T > N

Naproxen 750–1000

Stubhaug et al.[118] Orthopaedic db, sd 144 Tramadol 50 or 100 C/P > T = PL

Codeine/paracetamol 60/1000

Placebo

Sunshine et al.[119] Section db, sd 161 Tramadol 75 or 150 T > PR/P > PL

Propoxyphene/paracetamol 100/650

Placebo

Intramuscular administrationAlon et al.[120] General db, sd 60 Tramadol 50 T < B

Buprenorphine 0.3

Colletti et al.[121] Nasal nb 77 Tramadol 100–400 T = K

Ketorolac 30–90

de La Pena et al.[122] Laparoscopic db, sd 20 Tramadol 50 T > Pcholecystectomy

Placebo

Fassolt[123] General db, sd 75 Tramadol 100 T = PE

Pentazocine 30

Gritti et al.[124] Abdominal nb 70 Tramadol 100–600 T = M

Morphine 10–60

Jeffrey et al.[125] Craniotomy db 75 Tramadol 50 T < C

Tramadol 75

Codeine 60

Lanzetta et al.[126] Orthopaedic nb 48 Tramadol 100–400 T = K

Ketorolac 30–90

Magrini et al.[127] Various nb 50 Tramadol 300 T > PE

Pentazocine 90

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Table VI. Contd

Study Type of surgery Study design n Analgesic drug Dosage (mg/day) Analgesic efficacySacerdote et al.[112] Abdominal db, sd 30 Tramadol 100 T = M

Morphine 10

Intravenous administration

Bloch et al.[128] Thoracotomy db 89 Tramadol (+ morphine PCA) 150 + 350/24h T = ME > PL

Morphine epidural (+ morphine PCA) 2 + 0.2/h

Placebo (+ morphine PCA)

Dejonckheere et al.[129] Thyroidectomy db 80 Tramadol 1.5 mg/kg T > PP

Propacetamol 2000

Driessen et al.[130] Vaginal hysterectomy nb, sd 27 Tramadol 50 T < PE < B

Buprenorphine 0.3

Pentazocine 30

Houmes et al.[131] Gynaecological db 150 Tramadol 50–150 T = M

Morphine 5–15

Manji et al.[132] Cardiac nb 56 Tramadol 100–600 T = A

Alfentanil 12.5 µg/kg/h

Olle et al.[133] Abdominal hysterectomy db 76 Tramadol 400 T > K

Ketorolac 120

Putland and Laparoscopy db, sd 60 Tramadol 1.5 mg/kg T > KMcCluskey[134]

Ketorolac 10

Ranucci et al.[135] Cardiac db 60 Tramadol 200 T = K > PP

Ketorolac 60

Propacetamol 2000

Sellin et al.[136] Cardiac db 100 Tramadol 360–600 T = M

Morphine 24 + 2 prn

Stankov et al.[137] Urological db, sd 100 Tramadol 100 T < D

Dipyrone 2500

Striebel et al.[138] Vaginal hysterectomy db 60 Tramadol/dipyrone 400/5000 T/D = T/I

Tramadol/ibuprofen 400/585

Torres et al.[139] Abdominal hysterectomy db 151 Tramadol 100–400 T = D

Dipyrone 1000–8000

Tryba and Zenz[140] Orthopaedic db 60 Tramadol 50–100 T = M = CL

Morphine 5–10

Clonidine 0.15–0.3

Vickers and Paravicini[141] Abdominal db 523 Tramadol 100–650 T = M

Morphine 5–60

A = alfentanil; B = buprenorphine; C = codeine; CL = clonidine; D = dipyrone; db = double-blind; DP = dextropropoxyphene; I = ibuprofen; K = ketorolac; M = morphine; ME =morphine epidural; N = naproxen; nb = nonblind; P = paracetamol; PCA = patient-controlled analgesia; PE = pentazocine; PL = placebo; PP = propacetamol; PR = propoxyphene;prn = as needed; sd = single dose; T = tramadol; > indicates superior to; = indicates equivalent to; < indicates inferior to.


tramuscular administration of tramadol 100mg bolus of tramadol followed by an infusion was ascould improve postoperative immune suppres- effective as epidural morphine and avoided the ne-sion.[112] cessity of placing a thoracic epidural catheter.

The continuous intravenous infusion of tramadol0.25 mg/kg/h was also shown to be a simple and3.1.4 Intravenous Administrationwell tolerated procedure following urological sur-In an early study, a single intravenous bolusgery in children.[151]injection of tramadol 50mg was inferior to

Several studies have compared the efficacy ofbuprenorphine 0.3mg for pain relief after vaginalintravenous tramadol with that of non-opioidhysterectomy.[130] The authors suggested that tram-analgesics. A single dose of tramadol 1.5 mg/kgadol doses >50mg might be necessary in manyprovides a better quality of analgesia than that withpatients. In two other studies, two or three intra-propacetamol 2g during the first 6 hours after thy-venous bolus doses of tramadol 50mg provided ac-roidectomy.[129] In an observer-blind randomisedceptable analgesia, which was similar to the effectsstudy, single intravenous doses of tramadol 100mgof morphine 5mg.[131,140] In a double-blind random-produced less pain relief after abdominal or urologi-ised study involving 523 patients, the analgesic effi-cal surgery than intravenous dipyrone, which pos-cacy of tramadol (up to 650 mg/day) was comparedsesses spasmolytic effects.[137] Another study usedwith that of morphine (up to 60 mg/day) given asan intravenous loading dose immediately after abdo-repeated intravenous boluses as required to controlminal hysterectomy followed by intravenous main-pain following abdominal surgery.[141] Respondertenance infusion and on-demand boluses up to arates reached 72.6% with tramadol and 81.2% withmaximum of either dipyrone 8 g/day or tramadolmorphine, and the treatments were statistically equi-500 mg/day.[139] Both drugs showed similar efficacyvalent.for early pain, but tramadol caused nausea andIn two double-blind comparative studies, contin-vomiting more frequently. An intravenous bolus ofuous intravenous infusion of tramadol 12 mg/htramadol 1.5 mg/kg was more effective than ketoro-showed a trend towards better pain relief than withlac 10 mg/kg following laparoscopic sterilisation inintermittent intravenous bolus doses of tramadol60 patients.[134] No difference in either the incidence50mg following abdominal surgery.[148,149] Althoughor severity of nausea and vomiting was observedtotal consumption of tramadol was more than 30%between the two groups. In 76 women undergoinghigher with the continuous infusion, the rate ofabdominal hysterectomies, the intravenous injectionadverse events was not increased.[148,149] Two otherof tramadol 100mg every 6 hours provided morestudies demonstrated that continuous infusion ofeffective pain relief than that with ketorolac 30mg,tramadol, titrated to the patient’s requirements, pro-but was associated with a high incidence of post-vides adequate analgesia after cardiac surgery, com-operative vomiting.[133] A randomised trial wasparable with the effects of alfentanil or morphineaimed at investigating the effectiveness of intra-infusion.[132,136] In two recent studies, the addition ofvenous ketorolac 60mg, propacetamol 2g and tram-a tramadol infusion to morphine PCA improvedadol 200mg for the management of postoperativeanalgesia and reduced morphine requirements afterpain in early extubated cardiac surgical patients.[135]abdominal or thoracic surgery.[128,150] No differencesThere was a significantly higher rate of patients withwere found with regard to nausea or sedation aftersevere pain in the propacetamol group. Patientsabdominal surgery.[150] For the management of post-treated with tramadol had a higher arterial partialthoracotomy pain, 90 patients received, in additionpressure of CO2, which was not clinically relevantto morphine PCA, either intravenous tramadoland can be explained by the relatively high dose of(150mg bolus followed by infusion, total 450 mg/200mg.day), epidural morphine (2mg, then 0.2 mg/h) or

nothing.[128] Pain scores at rest and on coughing The infusion of a fixed combination of tramadolwere lower in the tramadol and epidural morphine and non-opioids, which is very popular in Germany,groups than in the placebo (only PCA morphine) has been investigated in only one controlledgroup. The authors concluded that an intraoperative study.[138] This study compared a tramadol/dipyrone


Tramadol 901

infusion (400mg/5g in 500mL) with a tramadol infu- Several studies have investigated the intravenousinjection of tramadol 0.5–3 mg/kg at induction ofsion (400mg in 500mL) in combination with rectalanaesthesia in children.[165-169] In adenoidectomyibuprofen 585mg.[138] In 60 patients recovering fromand/or tonsillectomy, pre-emptive tramadol pro-vaginal hysterectomy, satisfactory pain reductionvided posterior analgesia superior to that with place-occurred rather late, although 60% of the 500mLbo[165,167,169] or propacetamol.[166] Tramadol 3 mg/kgwas administered within 60 minutes. The authorswas inferior to pethidine 1.5 mg/kg and nalbuphineconcluded that neither regimen could be recommen-0.3 mg/kg in tonsillo-adenoidectomy,[169] and tram-ded for fast onset of adequate analgesia. Anotheradol 1 mg/kg was inferior to fentanyl 2 µg/kg/h infixed combination, tramadol 600mg and ketorolacpaediatric neurosurgery.[168]180mg diluted to a volume of 96mL and intra-

Intravenous tramadol is also effective in prevent-venously infused at a constant rate of 2 mL/h, wasing the pain of propofol injection.[170,171] The combi-investigated in 585 patients following major abdo-nation of tramadol with lidocaine for intravenousminal surgery.[152] Supplementary tramadolregional anaesthesia had only a limited benefit and100–300 mg/day was injected on request. The aver-cannot be recommended.[172-175]

age pain intensity (verbal numeric scale 0–10) wasbelow 3 at rest and below 4 on movement, whichwas interpreted as good quality of pain relief by the 3.1.5 Patient-Controlled Analgesiaauthors of this uncontrolled trial.[152] PCA allows the patients to self-administer small

bolus doses of a potent analgesic in a running intra-Intravenous tramadol reduces not only post-venous infusion.[176] Whenever the patients feel thatoperative pain but also postoperative shivering. Sev-pain relief is necessary, they can activate an elec-eral double-blind controlled studies demonstratetronically controlled infusion pump that dispenses athat intravenous tramadol 0.7–2.5 mg/kg can pre-preprogrammed amount of analgesic. A controlledvent the severity and prevalence of postanaestheticstudy of 20 patients undergoing gynaecological op-shivering in a dose-dependent manner.[132,153-156]

erations compared tramadol PCA (loading dose 3Tramadol 1 mg/kg was superior to pethidine 0.5mg/kg, demand dose 30mg, lock-out time 5 minutes,mg/kg.[153] Furthermore, intravenous tramadol re-concurrent infusion 5 mg/h) and tramadol continu-duced shivering during regional anaesthesia of ob-ous infusion (loading dose 3 mg/kg, continuousstetric patients in two controlled double-blind stud-infusion 0.35 mg/kg/h).[177] PCA ensured adjust-ies.[157,158]

ment of the medication to the individual demand,In an early double-blind study on the intraopera- whereas continuous infusion provided better analge-

tive use of tramadol, 65% of the patients receiving sia after sleeping periods.[177]

tramadol were aware of intraoperative music where- Table VII summarises the controlled trials ofas patients in the placebo group were amnesiac.[159] PCA with tramadol, demonstrating its feasibility inTherefore, tramadol was not recommended as the postoperative pain. Most studies compared tramadolsole agent for intraoperative analgesia. Several re- with other opioids, used a tramadol demand dose ofcent studies on the intraoperative use of tramadol in 10–50mg and investigated pain following abdomi-combination with volatile or intravenous anaesthet- nal or orthopaedic surgery. In the only placebo-ics have shown no clinically relevant lightening of controlled study of intravenous PCA, tramadol andanaesthetic depth.[160-164] Preoperative administra- morphine proved to be efficacious.[178] Of 180 pa-tion of morphine 10mg was more effective than tients recovering from abdominal surgery, 68%,tramadol 100mg as an intraoperative analgesic, but 75% and 18% of patients treated with tramadol,there was no difference in the postoperative pain morphine and placebo, respectively, were assessedtreatment.[160] Other studies demonstrated that intra- as responders. In five PCA studies comparing intra-venous tramadol administered at wound closure pro- venous tramadol and morphine, the equipotent dosevided postoperative analgesia superior to that with ratio was between 9 : 1 and 19 : 1.[160,179-182] An-placebo[161,162] and similar to that with intrave- other study compared tramadol and morphine vianous[163] or epidural[164] morphine. subcutaneous PCA following major orthopaedic



surgery in 40 patients.[25] Both drugs provided effec- compared with 58% with ketorolac, 50% withtive analgesia; the mean consumption in the first 24 clonixin and 55% with dipyrone.hours was 792mg of tramadol and 42mg of mor-

3.1.6 Regional Administrationphine. Whereas tramadol is associated more fre-

Only a few studies are available on epiduralquently with nausea and vomiting, morphine has a

tramadol,[194-197] a mode of administration for whichhigher risk of respiratory depression.[25,179-182]

tramadol is not registered. Two placebo-controlledDouble-blind PCA studies comparing tramadol studies demonstrated that epidural tramadol 50 and

with other opioids reported an equipotent dose ratio 100mg provided adequate postoperative analgesiaof 5 : 1 for tramadol : nalbuphine, 979 : 1 for tram- after caesarean delivery.[194,198] After abdominal sur-adol : fentanyl, 1.1–1.2 : 1 for tramadol : pethidine gery, epidural tramadol 100mg produced better painand 8 : 1 for tramadol : oxycodone.[63,183,184,190,191]

relief than tramadol 50mg or 10mL of 0.25% bupre-Several studies have investigated methods to re- norphine[196] and was not different from morphine

duce the rate of nausea during tramadol PCA. Ad- 4mg.[197] However, ineffective analgesia from epi-ministering the loading dose of tramadol during dural tramadol 50 and 100mg was reported in pa-surgery decreases the risk of nausea/vomiting and tients undergoing total knee replacement.[195]

improves the quality of tramadol PCA in the relief of Tramadol 1–2 mg/kg has also administered cau-postoperative pain.[192] A tramadol and droperidol dally in children for postoperative analgesia.[199-203]

combination is superior to tramadol alone for post- Caudal tramadol 2 mg/kg provided reliable post-operative PCA.[193] It provides a similar quality of operative analgesia similar to that with caudal mor-analgesia with less nausea and vomiting and without phine 0.03 mg/kg in children who were undergoingan increase in sedation. When ondansetron was ad- herniorrhaphy.[199] Although in two studies tramadolministered for antiemetic prophylaxis, the tramadol was less effective than caudal bupivacainerequirement during PCA was increased.[88]

0.2–0.25%,[200,203] one study reported comparableThe analgesic effect of tramadol in postoperative effects.[201] In another study, lower pain scores were

PCA can further be improved by a combination with seen with caudal bupivacaine 0.25% in the immedi-non-opioid analgesics. The combination of tramadol ate postoperative period, whereas caudal tramadoland dipyrone was superior to piritramide.[185] A fur- caused a significantly lower pain score in the latether study included 101 post-hysterectomy patients postoperative period.[202] The combination of bothwho, at the time of analgesia request, received tram- drugs improved the analgesic action of bupivacaineadol 100mg or dipyrone 1.2g alone, or combined in in only one[200] of three studies.[200,201,203]

1 : 1, 1 : 0.3 or 1 : 3 ratio.[187] After 15 minutes, they Prompted by the success of intra-articular mor-received the same treatment by PCA. When drugs phine, tramadol 10mg was used intra-articularlywere combined in a 1 : 1 ratio, synergy was present after arthroscopic knee surgery in a double-blindfor the analgesic effects, but also for adverse events; study and provided effective pain relief, althoughall other treatments were additive. Tramadol PCA in morphine 1mg was more effective.[204] Anothercombination with intravenous propacetamol 2g four study demonstrated that the admixture of tramadoltimes daily provided analgesia superior to that of 100mg with mepivacaine 1% for brachial plexustramadol monotherapy.[186] Another randomised block provided a pronounced prolongation of block-double-blind study compared PCA with tramadol ade without adverse effects.[205]

and PCA with a mixture of tramadol plus lysineacetylsalicylate (a soluble aspirin) in 50 adult pa- 3.2 Other Acute Pain Syndromestients who had undergone major orthopaedic sur-

3.2.1 Traumagery.[188] Total tramadol consumption was signifi-cantly less and patients were more alert in the aspirin Several reports describe positive experiencesgroup. One study of PCA has compared tramadol with tramadol for orthopaedic trauma,[206] winterwith non-opioid analgesics.[189] According to patient sports injuries[207] and use in the prehospital situa-global assessment, 72% of patients in the tramadol tion by ambulance paramedics.[208] A double-blindgroup assessed analgesia as excellent or very good, study found no difference in the efficacy of tramadol


Tramadol 903

100–200mg and morphine 5–20mg administered and neonates.[29,220-223] Intravenous tramadolintravenously for the management of pain in 105 50–100mg in the first stages of labour producedtrauma patients in the prehospital situation.[209] In a respiratory depression in only 7% of neonates, com-controlled trial, intravenous tramadol 1 mg/kg, pared with 31% in the pethidine group.[224] Thispropacetamol 20 mg/kg and diclofenac 1 mg/kg study is unusual with regard to the high rate ofwere equally efficacious for emergency analgesic respiratory depression in both groups. Tramadoltreatment of 131 patients.[210] In the piritramide suppositories have also been recommended for ob-group (0.25 mg/kg), significantly more adverse ef- stetrical analgesia.[225]

fects were noted.

3.3 Place of Tramadol in Acute Pain3.2.2 Abdominal PainParenteral tramadol in emergency department pa-

The treatment of acute pain is not only importanttients with abdominal pain in the right lower quad-for the well-being of patients, it also reduces the riskrant resulted in pain reduction without concurrentof complications such as pneumonia, cardiac infarc-normalisation of abdominal examination findingstion or thromboembolism and may improve the out-indicative of acute appendicitis.[211] Several control-come.[226] Besides regional analgesia, which is inva-led studies have demonstrated the efficacy of tram-sive and only suitable for selected patients, the ad-adol in colic pain.[212-216] In renal and biliary colicministration of opioids is the most commonpain, intravenous dipyrone 2.5g was superior toapproach to treat postoperative pain.tramadol 100mg and butylscopolamine 20mg.[214,215]

Tramadol provides adequate analgesia in acuteIn another study, tramadol 100mg was as effectivepain, being superior to placebo and comparable withas dipyrone 2.5g for ureteric colic.[216] In acute renalvarious opioid and non-opioid analgesics in the ma-colic pain, intravenous pethidine 50mg was superiorjority of studies (table VI and table VII). Therefore,to tramadol 50mg[212] and intramuscular ketorolactramadol can be recommended as a basic analgesic30mg was as effective as subcutaneous tramadol 1for the treatment of moderate-to-severe acutemg/kg.[213]

pain.3.2.3 Labour Intravenous infusion or intravenous PCA are in-Elbourne and Wiseman[217] searched the Coch- dicated in severe pain following surgery. Although

rane Library in 1997 and assessed 16 randomised intramuscular tramadol is effective, the injection istrials comparing the effects of different currently painful and systemic absorption might be delayed inused opioids administered intramuscularly in labour the early postoperative period; therefore, oral orfor women who requested systemic analgesia. They intravenous administration may be preferred. Dropsfound no evidence of a difference between pethidine or capsules are a good choice when enteral adminis-and tramadol in terms of pain relief, interval to tration is possible after surgery, particularly in daydelivery, or instrumental or operative delivery. case surgery. Further indications for systemic tram-There appeared to be more adverse effects such as adol include postanaesthetic shivering, post-trau-nausea, vomiting and drowsiness with pethidine. matic pain, labour pain and colic pain. In addition,

oral and intravenous tramadol appears to be an ef-Intramuscular tramadol 100mg, but not 50mg,fective and well tolerated analgesic agent in childrenprovided pain relief equivalent to that with pethidinewith postoperative pain. The good analgesic effects75mg.[218] With pethidine, adverse effects wereachieved by caudal administration can be explainedmore frequent and respiratory function of the neo-by extensive systemic absorption,[37] and no advan-nates was significantly lower. Another study foundtages over systemic administration can be expec-no differences in analgesic efficacy, incidence ofted.adverse effects, umbilical cord blood gases or Apgar

scores between tramadol 100mg and pethidine In contrast to the majority of studies (table VI and50mg.[219] Other authors confirmed that tramadol table VII), tramadol did not equal the analgesicresulted in analgesia equivalent to that with efficacy of other drugs in all circumstances. A singlepethidine without respiratory depression in mothers dose of tramadol was not different from placebo in a


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Table VII. Controlled trials of patient-controlled analgesia with tramadol in postoperative pain

Study Surgery [duration of PCA (h)] Drug n Loading dose Infusion Demand dose Mean Analgesic efficacy(mg) rate (mg) [lock-out cumulative (relative potency)

(mg/h) (min)] dose (mg)

Alon et al.[183] Abdominal hysterectomy (5) Tramadol 20 50 25 25 (30) 373 T = N (1 : 5)

Nalbuphine 20 10 5 5 (30) 73

Hackl et al.[63] Cholecystectomy (6) Tramadol 7 0 12 20 412 T = F (1 : 979)

Fentanyl 10 0 0.054 0.009 0.53

Lehmann et al.[184] Various (18) Tramadol 40 0 1.15 9.6 (1) 203 T = PE (1 : 1.2)

Pethidine 40 0 1.15 9.6 (1) 175

Likar et al.[185] Orthopaedic (24) Tramadol/dipyrone 18 164/1090 0 10/50 (6) 267/1335 T/D > PI

Tramadol/dipyrone 19 72/482 0 5/25 (6) 256/1275

Piritramide 21 7.5 0 1.5 (6) 44

Piritramide 20 4.5 0 0.75 (6) 37

Migliorini et al.[186] Orthopaedic (24) Tramadol 35 0 10 50 (15) 489 T < T/PP

Tramadol + 35 0 10 50 (15) 426propacetamol 2g qid

Montes et al.[187] Abdominal hysterectomy (24) Tramadol 21 100 0 20 (15) NR T/D (1 : 1) > T = D= T/D (1 : 0.3) =T/D (0.3 : 1)

Dipyrone 21 1200 0 240 (15) NR

Tramadol/dipyrone 20 50/600 0 10/120 (15) NR(1 : 1)

Tramadol/dipyrone 19 75/300 0 15/60 (15) NR(1 : 0.3)

Tramadol/dipyrone 20 25/900 0 5/180 (15) NR(0.3 : 1)

Naguib et al.[160] Laparoscopy (24) Tramadol 50 100 0 16 (5) 248 T = M (1 : 13)

Morphine 50 10 0 1.6 (5) 20

Ng et al.[179] Abdominal (48) Tramadol 19 0 0 10 (5) 9.8/h T = M (1 : 9)

Morphine 19 0 0 1 (5) 1.1/h

Pang et al.[180] Orthopaedic (48) Tramadol 40 285 0 30 (10) 868 T = M (1 : 19)

Morphine 40 13 0 1 (10) 46

Pang et al.[188] Orthopaedic (48) Tramadol 25 2.5 mg/kg 0 923 (T) T < T/AS

Tramadol/aspirin 25 1.25/12.5 mg/kg 0 614 (T)

Rodriguez et al.[189] Abdominal hysterectomy (24) Tramadol 40 30 15 15 (NR) NR T = K = D > CL

Continued next page

Tramadol 905

study of severe pain following orthopaedic sur-gery,[118] and tramadol was less effective than code-ine after craniotomy,[125] less effective than dipyroneafter abdominal urological surgery,[137] less effectivethan pethidine or nalbuphine after tonsillo-ade-noidectomy in children,[169] and less effective thanfentanyl in paediatric neurosurgery.[168] The discrep-ancy in the results can mainly be attributed to differ-ent baseline pain intensity, different type of pain,different criteria of efficacy, and different doses andpotencies of the active drug control. These resultsemphasise that the analgesic efficacy of tramadolshould be monitored, as that of any other opioid, andthat the dosage requires titration up to individualneed by repeated oral administration, repeated injec-tions, adaptation of a continuous infusion or intrave-nous PCA.

The analgesic efficacy of tramadol can be in-creased by combination with non-opioid analgesicssuch as paracetamol, dipyrone or ketoro-lac.[143,152,186-188] Following a suggestion of Krimmeret al.,[227] an infusion of a fixed combination oftramadol 300–400mg and dipyrone 2.5–5g in500mL of saline over 12–30 hours is frequently usedin Germany.[65] Despite the widespread applicationof this simple-to-use combination, which is usuallygiven in general wards without close supervision, nocontrolled studies investigating the risk/benefit ratioof such combinations are available. If tramadol atdosages of 400–600 mg/day provides no adequatepain relief, administration of a stronger opioid, suchas morphine, is necessary and useful.[150]

Nausea and vomiting are typical adverse effectswith opioids. Although some studies found that tra-madol is associated with an increasedrisk,[118,125,147,179,181] others reported no difference inthe incidence of nausea and vomiting between tram-adol and other opioids.[114,116,124,127,132,160] The rate ofpostoperative nausea and vomiting, however, de-pends only partly on the type of opioid; other majorfactors include dose, time and mode of opioid ad-ministration, pain intensity, type of surgery, type ofanaesthesia and history of motion sickness. The rateof nausea and vomiting can be reduced by prophy-lactic administration of antiemetics, but unfortu-nately droperidol has been withdrawn and ondanse-tron reduces the analgesic efficacy of tramadol.There is lack of evidence whether triflupromazine,


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dimenhydrinate, metoclopramide or other antiemet- Recently, tramadol was shown to have positiveics have a better risk/benefit ratio in combination effects on immune system function.[110,112,229] There-with tramadol. One study showed that nausea and fore, tramadol might be a better choice than mor-vomiting with tramadol occurred more frequently phine, particularly in patients with compromisedduring the 15 minutes after the initial injection of the immunity or cancer. Further studies are required toloading dose than during the PCA period, when confirm these preliminary results.boluses were infused over 2 minutes.[178] The au-

4. Chronic Painthors concluded that a slower injection could avoidsome nausea and vomiting. This hypothesis is in

Chronic pain requires regular administration ofagreement with personal experiences of many doc-analgesics. Only studies on the oral administrationtors, but has not been investigated. Another ap-of tramadol over a period of at least 1 week canproach to reduce the rate of postoperative nauseainvestigate its utility in the treatment of chronicand vomiting is to inject the first tramadol boluspain. Therefore, single-dose studies and studies onintraoperatively at wound closure.[162,163,192]

parenteral administration have not been included inTramadol demonstrates similar analgesia to thatthe following discussion. The controlled studiesof several non-opioid analgesics (table VI). Al-have been summarised in table VIII. In a meta-though it is associated with a higher risk of typicalanalysis, which, for methodical reasons, includedopioid adverse effects, such as nausea, it may proveonly two of six controlled trials on cancer pain andparticularly beneficial in patients in whom non-three of ten controlled trials on chronic non-canceropioid analgesics are not appropriate, including pa-pain, odds ratios of 0.49 (95% CI –0.36, 0.8) andtients predisposed to peptic ulcers, with haemor-0.57 (95% CI 0.23, 0.9), respectively, demonstratedrhagic disorders, hypertension and renal insufficien-the analgesic efficacy of tramadol compared withcy.[22]

placebo and morphine.[113]

The most important advantage of tramadol overmorphine and other opioids is its minimal effect on 4.1 Cancer Painrespiratory function.[25,97,131,141,179-182,191,228] There-fore, tramadol is a very good choice for children, in Three noncomparative studies have demonstra-day-surgery, in normal wards without close supervi- ted the efficacy of oral tramadol in cancersion, in labour pain and in traumatic pain. In addi- pain.[232,250,251] Of 30 patients with different malig-tion, tramadol improves lung function after lap- nant diseases, 86% had excellent or adequate painaroscopy[122] and thoracotomy;[128] in the latter study relief after the administration of tramadol up to 200it was similar to epidural morphine. Patients with an mg/day.[250] In another study, 51 cancer patientsincreased risk of respiratory dysfunction, such as the were treated with oral or intramuscular tramadol 300elderly, smokers, those with pre-existing cardiopul- mg/day for periods of 2 weeks to 14 months.[251]

monary disease and those after surgery of the thorax Eighty-three percent of patients with bone pain andor upper abdomen causing a decreased residual re- 62% of patients with visceral pain, but only 33% ofserve, are expected to benefit particularly from this patients with neuropathic pain, reported good anal-advantage. Further studies comparing equianalgesic gesia. In another open study, tramadol was used indoses of different opioids and carefully assessing 294 cancer patients in whom non-opioids aloneadverse events are needed to confirm the influence failed to provide sufficient analgesia.[232] As recom-of tramadol on postoperative convalescence in these mended by the WHO, tramadol was combined withsituations. non-opioid analgesics and co-analgesics where ap-

Another advantage of tramadol is its low gastro- propriate. Patients were treated with oral tramadol atintestinal inhibition.[108] Tramadol is, therefore, ex- 4-hour intervals at a dosage of between 250 and 600pected to improve gastrointestinal recovery from mg/day for an overall period of 8227 days (mean 28abdominal surgery and reduce the risk of post- days). If pain could not be controlled with the maxi-operative paralysis and ileus compared with other mum daily dosage of 600mg, a strong opioid wasopioids. started (70% of patients). Tramadol was stopped


Tramadol 907

because of adverse events in only 4% of patients. On fewer adverse effects. In a double-blind, random-78% of the treatment days, patients had no or only ised, crossover trial (2 × 4 days), 20 patients weremild pain. treated with oral solutions of tramadol (mean dosage

375 mg/day) and morphine (mean dosage 101 mg/The effectiveness and tolerability of tramadol inday).[235] Tramadol had the same efficacy but pro-the treatment of cancer pain has been confirmed induced less nausea and constipation than morphine.several studies comparing tramadol with morphineExamination of doses used revealed a tendency toor buprenorphine (table VIII). A nonrandomisedgreater tolerance development with morphine thanstudy compared 810 patients receiving high-dosagewith tramadol.[233,234]tramadol 300–600 mg/day for a total of 23 497 days

with 848 patients receiving low-dosage morphine To compare the analgesic effect and tolerability10–60 mg/day for a total of 24 695 days.[252] The of tramadol 300 mg/day and buprenorphine 0.6 mg/analgesic efficacy was good in 74% and 78% of day, 60 cancer patients were treated orally in apatients receiving tramadol and morphine, respec- controlled crossover trial (2 × 1 week).[230] Bupre-tively. Constipation, neuropsychiatric symptoms norphine and tramadol had a similar analgesic ef-and pruritus were observed more frequently with fect; the incidence of adverse effects such as consti-morphine. This lower rate of typical opioid adverse pation and respiratory depression was lower witheffects can be explained by the multiple modes of tramadol. Only one patient discontinued tramadolaction of tramadol. The recommended maximum compared with 18 using buprenorphine. The finaldose of tramadol is 400 mg/day. Tramadol, how- assessment was significantly in favour of tramadolever, is a pure agonist (with a low affinity) at µ as regards efficacy and patient acceptability.opioid receptors and no ceiling effect has been de-termined. The above data demonstrate that tramadol

4.1.1 Sustained-Releasedosages up to 600 mg/day are effective and well

SR formulations are given at intervals of 8–12tolerated in the treatment of cancer pain. Higherhours and are, therefore, of special interest for thedosages have not been investigated, although a fur-treatment of chronic pain. An open noncomparativether enhancement of the analgesic effects would bestudy proved the analgesic efficacy of SR tramadolexpected. They cannot be recommended because ofwith administration every 12 hours to patients witha potentially increasing risk of specific and nonspe-moderate-to-severe cancer pain.[253] Of 146 patients,cific adverse effects, such as seizures.62% completed the 6-week trial period; 20% discon-Osipova et al.[233] compared 98 patients receivingtinued because of adverse events, 9% because oftramadol (mean dosage 368 mg/day [stable doseinadequate pain relief, 3% because of both reasonsthroughout the study]) and 26 patients receiving SRand 6% because of other reasons. The number ofmorphine (mean dosage increased from 69 mg/daypatients with good and complete pain relief in-to 96 mg/day during the study) for relief of severecreased from 43% after week 1 to 71% after week 6cancer pain. Tramadol was effective and well toler-with daily dosages of tramadol up to 650mg. Mostated during a study period of 1–3 months in allpatients (86%) experienced adverse events duringpatients with moderate pain and in 89% of thethe study period. Nausea and vomiting were mostpatients with severe pain. Morphine produced excel-frequently reported, but were judged to be clearlylent to good analgesic efficacy in all patients, butrelated to the study medication in <25% of patients.was associated with more intense adverse effects.In a multicentre trial of 131 cancer patients over aSimilar results were observed by Tawfik et al.[234]

period of up to 6 months, levels of efficacy andinvestigating 32 patients being treated with tramadolacceptability were better with tramadol (one 100mg(mean dosage 217 mg/day) and 32 patients treatedSR tablet every 8–12 hours) than with buprenor-with SR morphine (mean dosage 50 mg/day) for upphine (one sublingual 0.2mg tablet every 6–8to 8 weeks. Adequate pain relief was obtained withhours).[231] Adverse reactions were reported in 25%tramadol in 58–88% and with morphine in 67–100%of patients taking tramadol and in 26% takingof the patients. Insufficient analgesia was more fre-

quent in the tramadol group, but tramadol caused buprenorphine. Serious symptoms arose more fre-


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Table VIII. Controlled trials of oral tramadol in chronic pain

Study Type of pain Study n Duration Analgesic drug Dosage Analgesic Adverse eventsdesign (mg/day) efficacy

Cancer painBono and Cuffari[230] Cancer db, co 60 2 × 1wk IR tramadol 300 T = B T < B

Buprenorphine 0.6

Brema et al.[231] Cancer no 131 1–6mo SR tramadol 200–300 T > B T = B

Buprenorphine 0.6–0.8

Grond et al.[232] Cancer no 1658 1–967d IR or SC tramadol 300–600 T = M T < M

IR morphine 10–60

Osipova et al.[233] Cancer no 124 4–12wk IR tramadol 368 T < M T < M

SR morphine 69–96

Tawfik et al.[234] Cancer db 64 8wk IR tramadol 217 T < M T < M

SR morphine 50Wilder-Smith et al.[235] Cancer db, co 20 2 × 4d IR tramadol 375 T = M T < M

IR morphine 101

Chronic painAdler et al.[236] Osteoarthritis db, 279 1mo SR tramadol 150–400 SR-T = IR-T SR-T = IR-T

IR tramadol 150–400Bird et al.[237] Osteoarthritis db, co 40 2 × 2wk IR tramadol 200 T > PE T < PE

Pentazocine 150Goroll[238] Chronic db 84 1wk IR tramadol prn T > TI/N NR

Tilidine/naloxone prnJensen and Osteoarthritis db 264 2wk IR tramadol 300 T > D T > DGinsberg[239]

Dextropropoxyphene 300Pavelka et al.[240] Osteoarthritis db, co 60 2 × 4wk IR tramadol 164 T = DI T > DI

Diclofenac 87Rauck et al.[241] Chronic db 390 4wk IR tramadol 244 T = P/C T = P/C

Paracetamol/codeine 1407/140Roth[242] Osteoarthritis db 63 13d IR tramadol + NSAID 250 T > PL NR

Placebo + NSAIDSchnitzler et al.[243] Low back db 254 4wk IR tramadol 200–400 T > PL T > PL

PlaceboSilverfield et al.[244] Osteoarthritis db 308 10d IR tramadol/paracetamol 150–300/ T/P > PL T/P > PL

+ NSAID 1300–2600Placebo + NSAID

Sorge and Stadler[245] Low back db 205 3wk SR tramadol 200 SR-T = IR-T SR-T = IR-T

Continued next page

Tramadol 909

quently in the buprenorphine group (19% vs10%).

4.2 Chronic Non-Cancer Pain

Several studies have demonstrated the effective-ness of oral tramadol in the treatment of chronic painof nonmalignant origin (table VIII). In a double-blind study involving 264 osteoarthritis patients,oral treatment with tramadol 300mg was comparedwith oral dextropropoxyphene 300mg.[239] Pain re-lief was superior with tramadol; at the end of thesecond week, 72% of tramadol-treated patients and53% of dextropropoxyphene-treated patients hadsymptom improvement during daily activities. Tra-madol was associated with a higher incidence ofadverse effects, especially nausea, dizziness andvomiting, which led to more withdrawals from thestudy. However, in view of reports of fatal over-doses with dextropropoxyphene,[254] the authorsconcluded that tramadol should be preferred forchronic pain.

Bird et al.[237] found lower pain scores and lessmorning stiffness in 40 patients with osteoarthritiswho received tramadol 200mg compared with thosetreated with pentazocine 150mg in a double-blindcrossover study (2 × 2 weeks). Adverse events werereported by 53% of patients taking tramadol and78% of those taking pentazocine. Patients ratedoverall efficacy higher for tramadol than for penta-zocine.

The analgesic efficacy of oral tramadol dropswas superior to that of tilidine/naloxone drops in adouble-blind study in patients with various chronicpain conditions.[238] Unfortunately, pain aetiologywas not mentioned in this report.

Another double-blind crossover study (2 × 4weeks) compared diclofenac and tramadol in 60patients with painful osteoarthritis.[240] The dosageof tramadol (50–100mg up to three times daily) anddiclofenac (25–50mg up to three times daily) couldbe individually titrated by the patients. Both tram-adol (mean dosage 164 mg/day) and diclofenac(mean dosage 87 mg/day) improved pain intensityand functional parameters, and there was no differ-ence between the groups. More patients reportedadverse events with tramadol than with diclofenac(20% vs 3%).


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4.2.1 Sustained-ReleaseIn a 4-week, double-blind study, tramadol wasIn experimental pain, SR tramadol was effectivecompared with a combination of paracetamol and

for 12 hours and produced fewer adverse effectscodeine in 390 patients >65 years of age who had athan the standard formulation, presumably becausevariety of malignant and nonmalignant pain condi-high peak concentrations did not occur.[36,61] Antions.[241] Patients were allowed to titrate the dosageopen noncomparative study investigated the effi-according to pain intensity. There was a tendencycacy of SR tramadol in 1893 patients with chronicfor better pain relief with tramadol (mean dosagepain.[257] Daily dosages of between 1 × 100mg and 3244 mg/day) than with paracetamol/codeine (mean× 100mg were administered for a period of 4 weeks.dosage 1407/140 mg/day), but the difference wasEfficacy was assessed as very good by 46% ofnot significant. Nausea, constipation, dizziness andpatients and good by 42% of patients.somnolence were the most common adverse events,

A randomised, double-blind study compared thewith no differences between the groups.analgesic efficacy and tolerability of tramadol SRIn a study of patients with chronic low back pain,tablets and IR capsules in patients with chronic low380 subjects were treated with tramadol up to 400back pain, of whom 103 received tramadol SR (2 ×mg/day.[243] Of these, 254 entered a double-blind100 mg/day) and 102 received tramadol IR (4 × 50study with tramadol 200–400 mg/day or placebo.mg/day) over 3 weeks.[245] There was no differenceThe discontinuation rate because of therapeutic fail-in pain relief between tramadol SR and IR (59% vsure was 21% in the tramadol group and 51% in the59% of patients with sufficient pain relief). Adverseplacebo group. There were better scores on theevents were reported at a similar rate in both groupsvisual analogue pain scale, the McGill Pain Ques-(54% vs 53%). These results confirmed the equiva-tionnaire and the Roland Disability Questionnairelence with regard to efficacy and tolerability ofamong tramadol patients compared with placebotwice daily administration of tramadol SR comparedpatients.with four-times-daily administration of tramadol IR.Roth[242] investigated the efficacy of tramadol inAnother study compared SR tablets once daily (1 ×63 osteoarthritis patients who experienced break-150–400 mg/day) with IR capsules (3 × 50mg up tothrough pain while taking a NSAID. In addition to4 × 100 mg/day) in 279 patients with osteoarthri-their stable daily NSAID regimen, patients weretis.[236] There was no difference between treatmentsrandomised to a 13-day double-blind phase of ad-and both produced good pain control and a similarjunctive therapy with tramadol 50–100mg every 4–6adverse event profile; 49% of SR tramadol recipi-hours as needed, or placebo. The time to exit froments and 52% of IR tramadol recipients withdrew,the study because of insufficient pain relief tendedmostly because of adverse events.to be longer in the tramadol group. Patients’ overall

Wilder-Smith et al.[246] compared analgesia andassessment and investigator’s rating of global im-adverse effects of tramadol (2 × 100 mg/day) andprovement were significantly better with tram-dihydrocodeine (2 × 60 mg/day), both in long-actingadol.formulations, in 60 osteoarthritis patients withIn 308 patients with osteoarthritis achieving inad-strong pain refractory to treatment with NSAIDs.equate pain relief from traditional NSAIDs or cyclo-During the treatment period of 1 month, theoxygenase (COX)-2-selective inhibitors, the addi-dihydrocodeine dosage was increased to 180 mg/tion of tramadol/paracetamol tablets to existing ther-day in five patients and the tramadol dosage to 300apy was investigated in a double-blind placebo-mg/day in two patients. The pain intensity at rest,controlled study.[244] Supplementation with one orbut not during movement, was significantly lowertwo tramadol/paracetamol (37.5/325mg) tablets fourwith tramadol. The frequency of defecation wastimes daily was superior to placebo on the patients’lower and stools were harder with dihydrocodeine.and physicians’ overall assessments.

Two studies demonstrated that a slower titration 4.3 Neuropathic Painrate of tramadol can improve its tolerability in pa-tients who previously discontinued therapy because For a long time, neuropathic pain has been con-of nausea and/or vomiting.[255,256] sidered to be unresponsive to opioids. Most authors


Tramadol 911

now agree that opioids may be effective on such A randomised, double-blind, placebo-controlled,pain provided that sufficient dosages are crossover study investigated tramadol in painfulachieved.[258,259] The monoaminergic effect of tram- polyneuropathy during two treatment periods of 4adol, although substantially weaker, is similar to that weeks’ duration.[249] After baseline observations, 45of the tricyclic antidepressants commonly used in patients were assigned to tramadol SR tablets (200neuropathic pain. Therefore, tramadol is an interest- mg/day titrated up to 400 mg/day) or placebo.ing alternative to strong opioids in the treatment of Thirty-four patients completed the study. Their rat-neuropathic pain. The antinociceptive efficacy of ings for pain (median 4 vs 6), paraesthesia (4 vs 6)tramadol was demonstrated in experimental models and touch-evoked pain (3 vs 5) were lower on tram-of neuropathic pain.[260,261] Several clinical studies adol than on placebo. Tramadol was associated withhave demonstrated the analgesic efficacy of tram- a higher rate of adverse events (82% vs 35%). Theadol in neuropathic pain, but more controlled trials investigators concluded that tramadol appears toare required. In postmarketing surveillance of SR relieve both ongoing pain symptoms and the keytramadol, 485 of 7710 documented patients had only neuropathic pain feature allodynia in polyneuropa-neuropathic pain.[262] Patients were treated over a thy.period of 4 weeks with a mean tramadol dosage of The above studies demonstrate that tramadol can205 mg/day; 83% reported excellent or good, 12% relieve neuropathic pain. Further crossover studiesadequate and 5% inadequate pain relief. would be useful to compare the efficacy of tramadol

with that of other opioids in different types of neuro-In an open study, 35 patients with postherpeticpathic pain. Of most importance are long-term stud-neuralgia were randomised to oral tramadol up toies demonstrating effectiveness and tolerability of600 mg/day or clomipramine up to 100 mg/day withtramadol over several months compared with an-or without levomepromazine 100 mg/day.[247] Tenticonvulsants, antidepressants or antiarrhythmics.patients on tramadol and 11 patients on

clomipramine completed the 6-week treatment4.4 Place of Tramadol in Chronic Painphase. Nine of ten patients in the tramadol group and

six of 11 patients in the clomipramine group rated Many patients with chronic pain are inadequatelytheir analgesia as excellent, good or satisfactory. treated and suffer needlessly. Opioids are oftenThe incidence of adverse events was similar in both withheld because of irrational fears of respiratorygroups (77% vs 83%). depression, dizziness, confusion, addiction and tol-

erance. However, adequate use of opioids accordingA total of 131 patients with painful diabeticto the guidelines of the WHO has been shown to beneuropathy were treated with oral tramadol or place-an efficacious, well tolerated and simple method forbo in a randomised, double-blind study over 42cancer pain relief until death.[264] Because of thesedays.[248] Tramadol, at an average dosage of 210 mg/good results, opioids are indicated not only in mostday, was significantly more effective, whereas nau-patients with cancer pain, but also in a subgroup ofsea, constipation and headache were reported morepatients with chronic pain of nonmalignant origin.frequently. Patients in the tramadol group scored

significantly better in physical and social function- The regular administration of oral analgesics ising ratings than patients in the placebo group. A the mainstay of cancer pain treatment.[265] Depen-total of 117 patients (56 former tramadol and 61 ding on pain intensity, analgesics are selected ‘byformer placebo) entered an open-label extension of the ladder’, switching from non-opioids (WHO stepup to 6 months and received tramadol 50–400 mg/ 1) to weak opioids (step 2) and then to strongday.[263] Mean pain relief scores (2.4 vs 2.2) were opioids (step 3). Analgesics are combined with co-similar after 30 days in the former placebo and analgesics (e.g. antidepressants, anticonvulsants,former tramadol groups, respectively, and were corticosteroids) to treat special pain conditions, ormaintained for the duration of the study. Four pa- with adjuvants (e.g. antiemetics, laxatives) againsttients discontinued therapy because of ineffective other symptoms. The effectiveness and feasibility ofpain relief; 13 patients discontinued because of ad- the WHO guidelines have been demonstrated inverse events. several clinical studies.[266,267]



The distinction between weak and strong opioids, Tramadol, particularly the SR formulation, mayalso be used for long-term treatment of chronic painmade by the WHO for practical purposes, is arbitra-of nonmalignant origin, either alone or in combina-ry and does not reflect pharmacological differences.tion with non-opioid analgesics. Many studies haveIn contrast with strong opioids, the weak opioidsdemonstrated its effectiveness in pain from osteoar-listed in the WHO guidelines[265] (codeine,thritis. Special advantages are expected in neuro-dihydrocodeine, dextropropoxyphene, standardisedpathic pain.opium and tramadol) have a maximum recommen-

ded dosage and are not scheduled in many countries.The maximum dosages were chosen from experi- 5. Tolerabilityence that higher dosages are associated with pro-gressively more adverse effects, notably nausea and Safety data for tramadol have recently been sum-vomiting, that outweigh any extra analgesic effect, marised by Cossmann et al.[270] They consideredbut have not been formally determined in clinical information from phase II to IV clinical studies andstudies. postmarketing surveillance studies, covering safety

data from a total of more than 21 000 patients. TheDue to lack of alternatives in many countries,most frequent adverse events were nausea (6.1%),codeine was regarded as the standard drug amongdizziness (4.6%), drowsiness (2.4%), tiredness/the weak opioids. Codeine is a prodrug of morphinefatigue (2.3%), sweating (1.9%), vomiting (1.7%)and has, therefore, the same efficacy and adverseand dry mouth (1.6%). Adverse events that occurredeffect profile as low doses of morphine. For thisin <1% but >0.1% of patients were somnolence,reason, there have been continuous demands tohypotension, flush, stomach upset, constipation,abolish WHO step 2 and to initiate early therapynausea plus vomiting, sedation, circulatory failure,with low doses of morphine.[268] However, the three-sleep disorder, pruritus, abdominal pain, diarrhoea,step analgesic ladder of the WHO has an importanttachycardia and local irritation. Other events occur-political and educational impact and should not bering in <0.1% of patients were not shown, becausealtered.[269]

more than 150 descriptive terms were in-Tramadol can be recommended as a well tolerat- volved.[270]

ed and efficacious drug for step 2 of the WHO The profile for single-dose or short-term (<24guidelines for cancer pain management. Compared hours) administration (6011 patients) is quite simi-with morphine, tramadol is more freely available lar, qualitatively and quantitatively, to that for long-and offers pain relief to many patients who would term administration (15 211 patients), as shown inotherwise receive no opioids at all or at a later time. figure 1.[270]

Furthermore, several comparative trials suggest that The incidence of most adverse events, in partic-tramadol has a better adverse effect profile than ularly nausea, was higher in controlled trials than inother opioids, although long-term studies comparing postmarketing surveillance studies (table IX). Thisequianalgesic dosages of tramadol and other opioids is not unexpected, because controlled studies areare required for confirmation. The incidence of nau- performed under more stringent conditions.[270] Insea can be reduced by antiemetics or careful dosage addition, most controlled studies involved post-titration. If cancer pain cannot be controlled by operative use and had been carried out in hospitals,adequate dosages of tramadol, morphine or other whereas the postmarketing surveillance studies werestrong opioids are required. all in outpatients.[270] The incidence of adverse

The oral administration of SR formulations has events depends also on the mode of administrationthe advantage of continuous pain relief and better (table IX). Following parenteral administration, rel-compliance. In many cancer patients, the combina- atively high initial plasma concentrations are at-tion of tramadol with non-opioid analgesics and tained, particularly when an injection is adminis-

tered too rapidly.adjuvants can improve efficacy and safety. Whenoral administration is not longer possible, tramadol Qualitatively, the profile of adverse effects ofcan be given subcutaneously. tramadol corresponds to that known for opioids,


Tramadol 913

Nausea

Dizziness

Drowsiness

Tiredness

Sweating

Vomiting

Dry mouth

Somnolence

Hypotension

Flush

Headache

Stomach upset

Nausea and vomiting

Sedation

Adverse event frequency (%)

Long-term (n = 15 211)

Short-term (n = 6011)

2 4 6 80

Fig. 1. Frequency of adverse events in clinical trials and postmarketing surveillance studies of tramadol (reproduced from Cossmann etal.,[270] with permission).

although there are some essential differences. Sever- respiratory depression after an infusion of tramadolal long-term trials have shown that the rate of 600mg following abdominal surgery.[273] He recov-constipation[232-235] and nausea [233,235] was lower for ered completely after repeated doses of naloxone.tramadol than for morphine. In postoperative pain, Although faster metabolism could be expected insome studies found that tramadol is associated with hyperthyroid patients, no explanation is availablean increased risk of nausea and vomit- for this mishap. Another patient with impaired renaling,[118,125,147,179,181] whereas others reported no dif- function became respiratory insufficient duringference between tramadol and other opi- treatment with tramadol 400 mg/day.[272] He alsooids.[114,116,124,127,132,160] Of particular significance, recovered completely following naloxone infusion.tramadol had less respiratory depressant potential A few cases of respiratory depression have beenthan morphine,[25,131,141,179-182] buprenorphine,[97,130] reported to the spontaneous reporting system ofoxycodone,[228] pethidine[98,191] and nalbuphine.[271] Grunenthal GmbH.[270] In the cases where the causeThe use of tramadol in postoperative pain, however, could be attributed to tramadol, mainly high paren-is not completely free from problems, as two case teral doses of up to 1000mg had been administered,reports describe respiratory depression.[272,273] A pa- or the patients had considerably compromised func-tient with undiagnosed hyperthyroidism developed tion.



Table IX. Incidence of adverse events with tramadol observed in controlled trials and postmarketing surveillance studies, classified by routeof administration (reproduced from Cossmann et al.,[270] with permission)

Adverse event Patients experiencing event (%)

short-term administration long-term administration

PO IM IV PCA PMSa PO PMSb

(n = 352) (n = 546) (n = 759) (n = 140) (n = 3536) (n = 799) (n = 13 129)

Nausea 3.1 17.8 16.2 20.7 4.2 21.4 4.8

Dizziness 1.7 2.9 3.2 6.4 4.4 18.7 4.6

Drowsiness 0.3 10.3 3.6 8.5 1.1

Tiredness 5.7 3.3 6.9 1.9 5.9 2.1

Sweating 1.1 4.6 3.6 15.0 0.8 7.9 0.8

Vomiting 2.6 7.0 6.2 11.4 0.5 9.6 1.0

Dry mouth 3.1 1.3 2.8 14.3 0.7 4.3 1.5

a Parenteral.

b Oral or parenteral.

IM = intramuscular; IV = intravenous; PCA = patient-controlled analgesia; PMS = postmarketing surveillance; PO = oral.

In their review, Cossmann et al.[270] presented Research Database identified 21 cases of idiopathicdata from the spontaneous reporting system reflect- seizures in 11 383 subjects.[276] Three patients wereing the time period 1977–93, in which more than exposed to tramadol, ten to other opioids, three toone billion single dose units were distributed. The both tramadol and other opioids, one to othermost frequently documented adverse effects in for- analgesics, and four to no analgesics. The risk ofmal studies, namely nausea, vomiting, dizziness, idiopathic seizures was similarly elevated in eachdrowsiness, tiredness, sweating and dry mouth, were analgesic exposure category compared with non-noted infrequently in spontaneous reports, since users, suggesting that the risk for patients takingthese adverse effects are usually recognised as typi- tramadol was not increased compared with othercal of opioids and described in the product informa- analgesics.[276]

tion.[270] There have been some spontaneous reportsTramadol has a low abuse potential and is notof allergic and anaphylactic reactions, but the inci-

classified as a controlled drug. Epidemiological datadence was lower than 0.1%, corresponding to thecollected in Germany over 14 years through thegenerally accepted knowledge that the incidence ofsubstance abuse warning system indicates that tram-these reactions is low with opioids. Most of theadol abuse is less common than abuse ofreports dealt with psychiatric disorders, mainly de-dihydrocodeine or codeine, despite much greater usependence and abuse, and central and peripheral ner-of tramadol.[3] Most of the patients were abusingvous system disorder, mainly seizures.other drugs or alcohol at the same time as abusingIn a cohort of 9218 adult tramadol users, fewertramadol.[3] After approval of tramadol as a non-than 1% had a presumed incident seizure.[274] Riskscheduled drug in 1995, a postmarketing surveil-was highest among those aged 25–54 years, thoselance programme was started in the US.[277] The datawith more than four tramadol prescriptions, andfor 3 years show that the reported rate of abuse hasthose with history of alcohol abuse, stroke, or headbeen low. Although a period of experimentationinjury. A case-control study among users was con-seemed to occur in the first 18 months after itsducted to validate incident seizure outcomes fromintroduction, which reached a peak rate of approxi-medical records.[274] Only eight cases were con-mately two cases per 100 000 patients exposed, thefirmed and all had cofactors associated with in-reported rate of abuse has significantly declined,creased seizure risk. Experimental data from ratsreaching levels of less than one case per 100 000confirm that a pre-existing lowered seizure thres-patients in the second 18 months. The overwhelm-hold increases the risk of tramadol-induceding majority of abuse cases (97%) have been foundseizures.[275] An evaluation of a General Practice


Tramadol 915

to occur among individuals with a history of sub- mulations for intramuscular, intravenous and subcu-stance abuse.[277] taneous injection are available. Tramadol has

proved to be an effective and well tolerated analge-Further evidence for the low abuse potential ofsic in the treatment of acute and chronic pain.tramadol comes from a double-blind placebo con-

trolled study in volunteers who were previous ad- Tramadol can be recommended as a basic analge-dicts.[278] Morphine 15 and 30mg produced typical sic for the treatment of moderate-to-severe acutesubjective effects, opioid identification and miosis. pain. The most frequent adverse event is nausea.Tramadol 75 and 150mg was not different from Tramadol is particularly useful in patients with poorplacebo. Although tramadol 300mg was identified cardiopulmonary function, including the elderly, theas an opioid, it produced no other morphine-like obese, smokers, and after surgery of the thorax oreffects and was not liked. These observations were upper abdomen, in situations with an increased riskconfirmed in a study involving volunteers enrolled of respiratory depression, including labour pain,in a methadone maintenance programme.[279] Tram- paediatric surgery, day-case surgery and generaladol 100 and 300mg neither produced morphine- wards without close supervision, in patients inlike effects nor precipitated a withdrawal syndrome; whom non-opioid analgesics need to be used withits subjective, behavioural and physiological effects caution and in patients with compromised immunitywere not different from those of placebo. or cancer.

Overdose of tramadol is associated with neuro- Tramadol can be recommended as an opioid forlogical toxicity; cardiovascular toxicity has not been step 2 of the WHO guidelines for cancer pain treat-reported.[280] Prospective data from seven poisons ment. Because IR preparations should be adminis-centres in the US indicate that the most common tered every 4 (up to 6) hours, SR preparations thatsymptoms of tramadol overdose are lethargy (30%), can be administered every 8–12 hours are preferred.nausea (14%), tachycardia (13%), agitation (10%), Tramadol can be combined with non-opioidseizures (8%), coma (5%), hypertension (5%) and analgesics or adjuvants. If tramadol at dosages up torespiratory depression (2%). In case reports describ- 600 mg/day is not adequate, morphine or othering tramadol toxicity, most patients received con- opioids of step 3 are required. Tramadol can also becomitant medications or alcohol.[281-285] recommended in the treatment of chronic pain of

nonmalignant origin, such as osteoarthritis or neuro-6. Conclusions pathic pain. Further crossover studies would be use-

ful to compare the efficacy of tramadol with that ofTramadol offers an important alternative to otherother opioids in different types of chronic pain. Ofopioids, because the complementary and synergisticmost importance are long-term studies aiming toactions of the two enantiomers (opioid and reuptakedemonstrate the effectiveness and tolerability of tra-inhibitor of norepinephrine and serotonin) enhancemadol over several months.its analgesic effects and improve its tolerability pro-

file. The analgesic efficacy of tramadol has beenAcknowledgementsdemonstrated in different acute and chronic pain

syndromes, being comparable with that of various The authors thank Grunenthal GmbH for providing dataother opioid and non-opioid analgesics. Unlike other on file on sustained-release tramadol. Dr S. Grond is the

principal investigator of several clinical studies fromopioids, tramadol has no clinically relevant effectsGrunenthal GmbH, Mundipharma GmbH and Janssen-Cilagon respiration, is associated with a low incidence ofGmbH, and presents clinical lectures on behalf of theseconstipation, shows positive effects on immune sys-companies.

tem function and has a low potential for abuse anddependence. In addition, tramadol is not scheduled

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