Anaesth Intensive Care 2000; 28: 363-374

Reviews
TramadolPresent and Future
E. A. SHIPTON*
Department of Anaesthesiology and Pain Management, CH Baragwanath Hospital, University of the Witwatersrand, Johannesburg, South Africa

SUMMARY The atypical opioid, tramadol, has recently been introduced into Australia and New Zealand. Tramadols efficacy in a wide range of acute and chronic pain states, its multi-formulation availability, and its low serious side-effect potential at high doses and in prolonged therapy, combine to bestow on it a user-friendly profile, for short- and long-term use in hospitals and communities. This paper reviews the following: its formulation and routes of administration; its unique enantiomeric biochemistry and metabolism; its triple mechanisms of action; its pharmacokinetics and pharmacodynamics; its analgesic efficacy compared with other opioids; the indications for its clinical use in a variety of acute and chronic (including cancer) painful states; its specific use in the elderly, in paediatric and in obstetric patients; its adverse event (including drug interaction) and safety profile; its advantages in terms of its relative lack of respiratory depression, major organ toxicity and histamine release, and dependence and abuse potential. The review looks at new uses for this drug and what can be expected in this area in the future.
Key Words: ANALGESICS, OPIOID: tramadol, biochemistry, pharmacology, mechanisms of action

Among the atypical central-acting opioids is tramadol hydrochloride. Tramadol [tramadol hydrochloride:(1RS, 2RS)-2-[(dimethylamine) methyl-1(3 methoxyphenyl)-cyclohexanol HCl] is a synthetic 4-phenyl-piperidine analogue of codeine1. It is thus an aminocyclohexonol derivative2. It was synthesized by Drs Flick and Frankus at Grunenthal Research Laboratories in Aachen, Germany in 19623. It entered the West German market in 1977 as a 100 mg (2 ml) ampoule in 19772. It is the most widely sold opioid analgesic in the world and is registered and marketed in more than 100 countries3. It is the most recently introduced analgesic in many countries (e.g., Australia, New Zealand)4,5. Throughout the world, more than 50 million patients have received tramadol and hence a large pool of knowledge has been gathered concerning its behaviour both in terms of efficacy and safety2,4,5. Initially, it received a mixed reception, as there were reports of intraoperative awareness, convulsions and possible interactions with

coumarins2,6,7. Tramadol was considered to be a weak atypical opioid6. However, new evidence now clarifies both its analgesic mechanism and clinical application. PHARMACOKINETICS In terms of human pharmacokinetics, the oral absorption of tramadol in the upper small intestine is 95 to 100%, and the bioavailability is 70% following single doses (due to an approximately 30% first pass metabolism) and 90% in multiple dose studies with a steady state being reached in 36 hours2,8,9,10. After oral administration it is rapidly absorbed, with peak serum concentrations reached within two hours for capsules and five hours for sustained release tablets1,8. There is 1% placental transfer8 with 0.1% of the dose reaching breast milk2. Tramadol has a high tissue affinity with a volume of distribution of 306 and 203 litres after oral and intravenous (IV) administration, respectively8. Approximately 20% is protein-bound11. The elimination pharmacokinetics of tramadol are appropriately described by a twocompartment model, with a reported elimination half-life (T12E) of 5.1 (SD0.8) hours (h) for tramadol, and 9 h for the Metabolite 1 (M1) derivative after a single oral dose of 100 mg1,12. This explains the approximately twofold accumulation of the parent drug and its M1 derivative that is observed during multiple dose treatment with tramadol1.

*M.B.,. Ch.B., D.A., F.F.A., F.R.C.A.(Hon.), M.Med., D.Med.(Anaesth), Chairperson, Department of Anaesthesiology and Pain Management, CH Baragwanath Hospital, University of the Witwatersrand. Address for Reprints: Professor E. A. Shipton, 14 Montreuil Street, Montroux, Johannesburg 2195, South Africa. Accepted for publication on April 7, 2000. Anaesthesia and Intensive Care, Vol. 28, No. 4, August 2000

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mu-opioid receptors than the respective (-) enantiomers3. The opioid and 5-hydroxy tryptamine (5-HT or serotonin) reuptake inhibitory effect (increasing the central neuronal synaptic 5-HT levels and displacing stored 5-HT from nerve endings), is about four times more potent in the (+) enantiomer24. There is also a presynaptic stimulation of 5-HT release3,6,20,25,26. The noradrenaline (NA) reuptake inhibitory effect is in the (-) enantiomer, which also causes increased stimulation-evoked release by pre-synaptic autoreceptor activation2,3,20,25,27. By its ability to block these uptake mechanisms, tramadol elevates the central synaptic levels of noradrenaline and 5-HT, the former acting via alpha-2 adrenoceptor mechanisms, the latter via unknown receptors to reduce excitability of spinal nociceptive activity3. A recent study with rat brain cortical synaptosomes indicates that tramadol is a 5-HT uptake blocker28. The activity of tramadol is only partially reversed with naloxone (about 30%)29. 5-HT antagonists (rianserin), as well as alpha-2 adrenoceptor antagonists (yohimbine), will remove the remainder30,31. Tramadol achieves spinal modulation of pain through indirect activation of postsynaptic alpha-2 adrenoceptors, preventing impulses from reaching the brain8. There is strong evidence for a synergistic interaction between the mu-opioid receptors and the alpha-2 adrenoceptors3. As these are independent receptors sharing common effector mechanisms, a supra-additive inhibitory action results from the simultaneous activation of the two receptors3. The uptake inhibition in both the non-opioid and opioid systems takes place in the same concentration range (0.5-50 M)2. Thus, the overall analgesic action of tramadol results from multiple pharmacological mechanisms of opioid and nonopioid actions, such that the degree of pain relief is greater than the sum of the individual components of its action. The complementary and synergistic mode of action of these two enantiomers is both opioid and monoaminergic (extending the analgesic effect to both opioid sensitive and insensitive pain); this synergism results in a significant reduction in the sideeffect profile typically associated with opioids, thus enhancing the safety profile of tramadol1,3,8,32. The racemate seems to have superior efficacy and safety when compared to either enantiomer, (+) or (-)33. Using straightforward molecular modelling techniques, the preference of the enantiomers of tramadol and its metabolites for binding at the mu-opioid receptor and the noradrenaline-uptake transporter can be understood in light of the different
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Tramadol sustained release capsules (50, 100, 200 mg) have shown dose-linearity in healthy volunteers13. Statistical analysis of the Area Under the Curve (AUC, 0-infinity) and Cmax after logarithmic transformation yielded bioequivalence with or without concomitant food intake14. As a result of statistical analysis of AUCs (48-72 h) after logarithmic transformation, the bioavailability of the sustained release capsules was calculated as equivalent to that of the instant release capsules15. Eighty-six per cent of absorbed tramadol is metabolized in the liver and 90% of tramadol and its metabolites are excreted by the kidneys, with the residual in the faeces8,16,17. Less than 1% of tramadol is eliminated by biliary excretion2. The enantiomeric ratios of all the excreted analytes, tramadol, M1, M2 and M5 are found to be very different from 1.0, showing that a stereoselective metabolism of tramadol occurs16. Consequently, malfunction of either organ (liver or kidney) may affect plasma levels. In these situations, it is recommended that the total dose of tramadol be halved, but the dosage interval be increased (e.g., to 200 mg/day in 12-hourly divided doses in chronic renal failure, and to 50 mg every 12 hours with hepatic cirrhosis)2,8,18. Four hours of dialysis removes less than 7% of tramadol and M12. With drug-induced hepatic enzyme induction, its dose can be doubled8. The oral administration of tramadol is comparable to the intramuscular (IM) injection both in time to analgesic onset and to peak plasma levels1. The recommended oral daily dose is between 50 and 100 mg every four to six hours1. The duration of analgesia is about six hours after a single oral dose of 100 mg1. Tramadol is rapidly absorbed after IM injection, making the IM injection (50 mg) bioequivalent (with respect to the extent of systemic availability) to the 30-minute (50 mg) IV infusion19. The differences in the times of onset and duration of action expected due to the slightly slower absorption after IM injection are small and probably therapeutically irrelevant19.

PHARMACOLOGY (a) Mechanism of Action Tramadol possesses a weak affinity for the mu-opioid receptor, and even less for the kappa and delta5. This affinity is some 6000 times less than that of morphine, 100-fold less than dextropropoxyphene, 10-fold less than codeine, and equivalent to dextromethorphan2,20-23. The (+) enantiomer of tramadol and its metabolites bind more strongly to the

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three-dimensional arrangements of the pharmacophores in comparison to morphine and to noradrenaline3. (b) Metabolism Tramadol is metabolized by a polymorphic isoenzyme of the debrisoquine-type, cytochrome P450 2D6 (CYP2D6) or sparteine oxygenase1,3,4, to 11 metabolites. Of the 11 metabolites, five arise from phase I reactions (M1 to M5) and six by phase II conjugation reactions (glucuronides and sulphates of M1, M4, and M5)17. The phase I metabolites are mono-Ode(s)methyl-tramadol or M1 (the only pharmacologically active metabolite), mono-N-demethyl tramadol (M2), di-N-demethyl tramadol (M3), tri-N, O-demethyl tramadol (M4), and di-N,O-demethyl tramadol (M5)17,35. The M1 and M1-conjugates, M5 and M5-conjugates, and M2 are the main metabolites, whereas M3, M4, and M4-conjugates are formed only in minor quantities17, of which the active (analgesic) metabolite, mono-O-de(s)methyl tramadol (M1) predominates6. Both M1 and M5 bind to the opioid receptor3. M1 has a greater (200 fold) affinity for the mu-opioid receptor than does tramadol itself1,36, but clinically, plays the minor role in the production of analgesia (while M5 has no analgesic role)3. About one third of the dose is metabolized to the O-de(s)methylated metabolites ( +) and (-)M1 by CYP2D6 catalysation3. This enzyme exhibits genetic polymorphism. It is present in 93% of the population (extensive metabolizers of the drug sparteine) and absent in 7% (poor metabolizers or PMS)3. It can be inhibited by different drugs (e.g., quinidine)3. The selective O-de(s)methylation of tramadol via CYP2D6 can be used to study the contribution of the monoaminergic effect of tramadol and the opioid effect of (+)-M1 to the analgesic effect of tramadol. It has been concluded that (+)-M1 contributes to the analgesic effect of tramadol in experimental pain and probably also in clinical pain3. However, the analgesic effect of tramadol seems to depend on both the monoaminergic effects of tramadol itself and the opioid effect of (+)-M1, since the analgesic effect is reduced, but not completely abolished, in poor metabolizers that are unable to form ( +)-M1 from tramadol3. Tramadol has been found to reduce IV propofol injection pain37. A peripheral analgesic effect of tramadol is postulated37. (c) Preparations Available The drug is available in formulations suitable for oral, rectal, and parenteral (IM and IV) administration4,5. The marketed formulations of tramadol
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contain a racemic mixture of two enantiomers (50:50), each one displaying differing affinities for various receptors, yet each separately producing a dose-dependent central-mediated antinociception1,3. It is available as capsules (50 mg), oral drops (20 drops =50 mg), ampoules (100 mg preservative-free, with a shelf-life of five years), dispersable (50 mg) and sustained release tablets (100, 150, and 200 mg), or adult rectal suppositories (100 mg up to four times daily) and paediatric suppositories (15, 30 and 50 mg)2. The capsules (onset of action 20 to 40 min) and oral drops are administered three to four times daily and the sustained release tablets twice daily (onset of action 60 min)2. Intravenous injections should be given slowly over two to three minutes to minimize side-effects (such as transient haemodynamic instability) and in appropriate dosage titrated to pain severity and patient response2. ADVERSE EFFECTS Tramadol causes a minor delay in colonic transit, but has no effect on upper gastro-intestinal transit or gut smooth muscle tone38. Its intestinal action is mediated mainly peripherally through the enteric opioid and serotonergic systems2. It has no significant effect on the sphincter of Oddi or intrabiliary pressure, and has weak spasmolytic properties3. Constipation is thus reported to a lesser extent than with other opioids2. Adverse events of tramadol from different routes of administration are comparable2. Data from shortterm multiple dose studies show tramadol most commonly causes nausea, tiredness, vomiting, sweating, drowsiness and postural hypotension39. Hypotension and orthostatic hypotension occasionally occur after IV administration secondary to peripheral vasodilatation2. This can be limited by injecting the drug slowly over several minutes or limiting the size of the bolus dose2. Urinary retention occurs less commonly when compared to potent opioids2. An open phase IV study using all the formulations of tramadol in 7198 patients with over 100 different pain indications showed adverse events in 16.8% of patients (68.9% were slight, 22.1% were severe)40. The most common adverse events were: dizziness (5.3%), central nervous system effects/incoordination (7.1%); nausea (4.8%); autonomic system disorders (3.3%), dry mouth (2.2%) and sedation (2.4%)40. The incidence of nausea is lowest after oral administration and highest in PCA administration2. A post-marketing surveillance survey studied 7710 patients with acute and chronic pain, treated with sustained-release tramadol, in a mean (usually twice) daily dose of

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go slow principle). This results in a low incidence of side-effects and rapidly creates tolerance to them6,56,57. Nausea and vomiting can be treated with antiemetics (e.g., phenothiazine dopamine antagonists)6,58. The use of ondansetron fails to reduce the nausea associated with tramadol59. Concerning side-effects, the rank order is (-) enantiomer > (+) enantiomer > racemate, proving the racemate to be superior in this respect3. Like other opioids, tramadol may induce seizures, especially when used in the presence of proconvulsive drugs (such as monoamine oxidase inhibitors and the tricyclic and selective serotonin uptake inhibitor antidepressants) and it should be avoided in these cases and in epilepsy1,2,60,61. By increasing central nervous cathecholamines, tramadol may cause convulsions in susceptible patients, and should be used with caution in patients with head injuries2. The reported rate of convulsions with tramadol by the Committee on Safety of Medicines in the United Kingdom is 1 in 7000, with most cases involving interaction with proconvulsive agents or large IV tramadol doses6,62. Much of the toxicity in tramadol overdose appears attributable to the monoamine uptake inhibition rather than its opioid effects63. There is no risk of idiopathic convulsions with tramadol alone6,64. Agitation, tachycardia, confusion and hypertension suggest a possible mild serotonin syndrome63. A serotonin syndrome may occur with the concomitant administration of tramadol with sertraline34. In moderate overdose situations, cerebral depression, muscular spasms and opisthotonos without cardiovascular or respiratory depression can occur2. In acute toxicity studies, lethal dose (LD) 50 values of tramadol are estimated to be around 300-350 mg/kg body weight (rat, mouse, oral administration)65. After acute IV administration, the LD 50 values range from 50-100 mg/kg body weight65. In subacute and chronic toxicity studies, clinical signs of intoxication are mainly behavioural disorders and convulsions, beginning at dose levels of 25 mg/kg65. Reports of deaths involving tramadol alone with associated tissue concentrations are rare66. In each tissue or fluid (except urine), the tramadol concentration was found to be greater than the metabolites M1 and M266. Patients with acute porphyrias may, however, be at a greater risk for developing porphyric attacks when treated with tramadol, due to the highest level of porphyrin accumulation compared with other analgesics67. There has been failure to confirm the prolongation of the International Normalized Ratio (INR) due to the interaction of tramadol with coumarin anticoagulants7. There is a low magnitude and frequency of
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202.4 mg41. Adverse effects occurred in 5.9% of patients, most typically nausea, dizziness and muzziness41. The mean onset of analgesia was 35 minutes and the duration, an average of nine hours41. Over 80% of patients described the analgesic effect as good or very good41. A very recent post-marketing surveillance study of sustained-release tramadol (100, 150, and 200 mg) evaluated 3153 patients in acute and chronic pain42. Adverse events occurred in 6.5% of patients and included nausea (3.4%), dizziness (1.5%) and vomiting (1.1%). The mean daily dose was 236 mg (usually in two doses) with good or very good analgesia reported by 82.5% of patients42. Tramadol produces naloxone-reversible muscle rigidity at doses higher than the therapeutic dose43. The estimated incidence of anaphylactoid or anaphylactic reactions to tramadol is 1 in 700,00044. In cardiovascular risk patients, tramadol seems to offer some advantages due to its minor cardiovascular and respiratory side-effects45. The value of tramadol in pain states from ophthalmic origin has yet to be fully clinically established46. In all areas of practice, the adverse event profile of tramadol, in a dose-response fashion, is a mixture of opioid (dyspepsia, nausea, vomiting, tiredness, drowsiness) and monoaminergic (headache, dizziness, sweating, dry mouth) effects47,48. Tramadol is associated with a low incidence of cardiac depression, and significantly less dizziness and drowsiness than morphine4. Side-effects predominate in one or other of the enantiomers and partly antagonize each other, reducing the severity of side-effects seen in the racemic mixture2. By comparison to other strong analgesics, the incidence of adverse events is lower and many of these events can either be prevented or readily treated49-51. In children, the incidence of adverse events with tramadol is much less than in adults52. Tramadol has not been associated with clinically significant side-effects such as respiratory depression, constipation, or sedation5. Tolerance and psychological dependence have not been a problem in the long-term32. One of the more outstanding aspects of tramadol is the extremely low liability to produce clinically relevant respiratory depression, which is negligible in comparison with other opioids used for postoperative pain management53-55. Both tramadol and M1 do, however, depress laryngeal activity (the cough reflex)2. Particularly in the therapy of chronic pain, the commencement of dosage at a low level, with gradual increase, frequently prevents the onset of adverse events, especially in the elderly56. Therapy is best commenced at 50 mg three times daily, and gradually increasing until analgesia is achieved (the start low,

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withdrawal signs when daily treatment with tramadol is discontinued3. Tramadol fails to precipitate withdrawal in morphine-treated subjects or to attenuate withdrawal in morphine-deprived subjects3. It is hypothesized that minimal tolerance, reduced dependence and abuse liability occur because of a unique combination of pharmacological actions; namely, the low affinity and efficacy at the mu-opioid receptors, the slow onset of action and the blockade of noradrenaline reuptake3. The frequency of euphoria and dysphoria with tramadol are negligible11. It thus has pharmacodynamic and pharmacokinetic properties that are highly unlikely to lead to dependence1. Epidemiological data, controlled clinical studies and post-marketing surveillance studies have all confirmed extremely low liability for the development of tolerance and dependence1,3,68,69. Tramadol neither produced morphine-like effects nor precipitated a withdrawal syndrome in volunteers on a methadone maintenance program, and is not an attractive substance for abuse or as an opioid substitute2,70. Clinical studies tend to demonstrate no significant precipitated withdrawal signs and minimal dose escalation2. In the United States, the abuse potential is less than one in 100,0006,71. This may result in the greater acceptance of tramadol among health care professionals who have concerns about long-term treatment with morphine-like opioids3. CLINICAL USE (a) Acute Pain Tramadol has been well evaluated in all the surgical fields, including cardiothoracic72,73, orthopaedic49,74, general75-77 and paediatric surgery78-81. Tramadol has been varyingly described as having a potency ranging between 1/5 to 1/20 that of morphine6,27,74. It is thus a unique central-acting opioid analgesic with, in general, analgesic efficacy and potency comparable to pethidine22,32. Clinically, in the acute situation, tramadol compares favourably with a range of analgesic agents from paracetamol to morphine, in terms of both efficacy and adverse event occurrence. Analgesic intervention with oral tramadol is of proven value82. Comparative studies have generally shown tramadol to be more effective than oral agents such as nonsteroidal anti-inflammatory agents (NSAIDs), pentazocine, dextropropoxyphene and combination formulations containing paracetamol, although single-dose oral dextropropoxyphene 65 mg plus paracetamol 650 mg was found to have a similar analgesic efficacy to tramadol 100 mg4,49,83-85. In both in-patient and day-case studies, intraoperaAnaesthesia and Intensive Care, Vol. 28, No. 4, August 2000

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tive tramadol analgesia has not been associated with cardiorespiratory side-effects or accidental awareness, probably because tramadol does not antagonize the hypnotic effects of the volatile inhalational agents6,72,82,86-90. Tramadol does not cause clinically significant lightening of anaesthesia or recall of intraoperative music during moderately deep isoflurane/ nitrous oxide anaesthesia87,91. Parenteral administration has mainly been associated with postoperative pain management. Given intravenously, tramadol doses ranging from 50 to 400 mg produce analgesia2,8,32. Postoperatively, an initial intravenous loading dose of tramadol 3 mg/kg, followed by 50 mg every 10 to 20 minutes up to a maximum of 250 mg in the first hour, and 600 mg in 24 hours, may be given8. Its intravenous use has recently been compared to epidural morphine for immediate post thoracotomy pain, where a single IV bolus of tramadol was as effective as the epidural morphine bolus and infusion72. As a standard dose, tramadol 3 mg/kg, given at induction of anaesthesia, does not obtund the pressor response (for which a short-acting potent opioid should be used), because its onset time is relatively slow2,6,25,92. In contrast to postoperative bolus administration, this may allow the patient to awake pain-free with a low incidence of side-effects (nausea, dizziness)2,6. A 3 mg/kg IV dose appears to be the most suitable for acute pain of moderate to severe intensity and it causes minimal respiratory depression6,93,94. Tramadol has shown comparative efficacy when used as a continuous IV infusion75,95. A postintubation bolus of 1.0 mg/kg followed by a continuous infusion of tramadol (2.5 mg/ml at 15 ml/h titrated postoperatively up or down in 3 ml/h increments based on haemodynamic and respiratory criteria), has been compared with morphine infusion in a tramadol:morphine dose ratio of 16:1. Pain scores were not significantly different and patients receiving tramadol had significantly improved oxygen saturation and higher respiratory rates96. It has been suggested that after six hours of continuous infusion, the rate be reduced in order to prevent unnecessary over-administration75. Parenterally, tramadol has been found to be effective for moderately severe pain after a loading dose of 150-250 mg and up to 600 mg/day2. Postoperatively, intravenous and intramuscular tramadol has been used with good efficacy in moderate surgical pain53. Orally, in postsurgical pain, tramadol 50, 100, and 150 mg had numbers-neededto-treat (NNTs) for >50% maximal total pain relief (TOTPAR) of 7.1 (95% confidence intervals 4.6-18),

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titration to an individual loading dose) and incremental doses of 20 mg, IV tramadol PCA is effective in acute pain9,10. Intravenous PCA with tramadol or morphine was found to be equally efficacious in treating pain after laparoscopic cholecystectomy, but only after 90 minutes from the end of surgery110. In orthopaedics, following joint replacement therapy, no significant differences in pain scores or side-effects were found in patients given IM or oral tramadol compared to those receiving IV PCA piritramid111. Post-arthroscopy, intra-articular tramadol 10 mg is not as effective as morphine 1 mg112. After arthroscopic anterior cruciate ligament reconstruction, IM lornoxicam provided a useful alternative to IM tramadol for postoperative analgesia113. Tramadol 1.5 mg/kg IV offers little benefit clinically compared with fentanyl 1.5 g/kg IV when used at the induction of anaesthesia for day-case arthroscopic surgery114. In paediatric surgery, for moderate to severe pain in patients over the age of 12 months, tramadol has been used effectively in IM or IV doses of 1-2 mg/kg2,78,81. In one study, 21 infants (3-10 kg) received IV or oral tramadol (1 mg/kg) followed by a continuous IV infusion, without respiratory or cardiovascular side-effects115. In the paediatric setting, tramadol, especially in droplet form116, has real potential as a safe and effective agent for the treatment of moderate pain in children more than 12 months old. Tramadol drops 1.5 mg/kg given 30 minutes before multiple dental extractions in children aged four to seven years resulted in significantly better postoperative analgesia, measured up to 120 minutes postoperatively117. For hypospadias surgery, tramadol has also been used neuraxially (by caudal epidural) with a longer duration than that of bupivacaine6,118,119. In the neonate, however, further pharmacokinetic and clinical studies with tramadol are needed2. In labour, tramadol 100 mg IM has been found to be as effective as pethidine 75 mg IM, but with a superior safety profile without respiratory depression of the neonate53,105,120. The addition of an antiemetic to tramadol did not reduce the incidence or severity of nausea or vomiting121. Tramadol is considered to be non-mutagenic in vivo122. The battery of mutagenicity studies show no evidence of genotoxic risk to humans65. Reproductive and developmental toxicity investigations and carcinogenicity studies are without positive findings65. Tramadol is therefore unlikely to cause damage to germinal cells that could result in birth defects or neoplastic events122. Neuraxially, in epidural administration for pain
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4.8 (3.4-8.2) and 2.4 (2.0-3.1) respectively. This was comparable with aspirin 650 mg plus codeine 60 mg [NNT 3.6 (2.5-6.3)] and paracetamol 650 mg plus propoxyphene 100 mg [NNT 4.0 (3.0-5.7)]97. Although predominantly mild in nature, the most commonly reported side-effects were headache, nausea, vomiting, dizziness and somnolence47. These were significantly higher after dental surgery, possibly as a result of acute dosing of awake patients and rapid patient mobilization47. Following abdominal surgery, tramadol has been found to be similar in efficacy to morphine for postoperative pain relief98. After abdominal hysterectomy, 48 h postoperative infusions of tramadol and morphine showed equal analgesic efficacy99. No somatic or visceral sensitization was evident during the infusions99. After lower abdominal surgery, IV tramadol produces a significantly lower incidence of arterial hypoxaemia than IV morphine93. However, when used in combination with other central nervous system depressants (e.g., other opioids), respiratory changes may be seen2,3. Tramadol appears to lend itself particularly to use in the day-case surgical environment100. Its efficacy and safety is most appropriate for a combined preoperative, perioperative and postoperative sequence76,101-104. It provides analgesia with little or no anxiolysis when used as a premedicant2. In groin incision day-case surgery, intraoperative and postoperative tramadol gave superior pain relief when compared with intraoperative fentanyl and postoperative co-codamol2,6,88. Tramadol shows analgesic dose-response in postoperative and dental pain patients47. Oral tramadol is effective for the relief of acute dento-alveolar surgical pain, although the addition of tramadol to diclofenac results in no useful improvement in analgesia59,105,106. In day-case laparoscopic sterilization, patients receiving IV tramadol 1.5 mg/kg showed significantly less pain in the recovery room and at discharge when compared with IV ketorolac 10 mg107. For acute treatment of mild to moderate postoperative pain, frequent nausea and vomiting from tramadol 100 mg suppositories make these less suitable than paracetamol/ codeine suppositories108. Tramadol has also shown good efficacy in IV patient controlled analgesia (PCA)1,76,90 and in subcutaneous PCA74,109, with wide individual variation. Using a loading dose of 40 mg, demand doses of 20 mg and lock-out time of 5 min after major orthopaedic surgery, subcutaneous PCA resulted in good pain relief with a 20:1 dose ratio of tramadol: morphine74. After a loading dose of 200 mg (or

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after abdominal surgery, tramadol is a more effective analgesic than bupivacaine, but less effective than morphine105. Epidural tramadol has been given, without respiratory depression, for postoperative pain after caesarean section123. The mean time to first analgesic administration was 4.5 (3.1) h in patients receiving epidural tramadol 100 mg, compared to 6.6 (3.4) h in those receiving epidural tramadol 200 mg123. Tramadol is not, however, recommended for epidural use, due to lack of preclinical neurotoxicity data and the fact that doses required are similar to those of less invasive routes2. When administered intrathecally in rodents, the antinociceptive potency of tramadol followed a rank order of racemate > (+) enantiomer > (-) enantiomer3. Using an isobolic plot, a synergistic interaction of the isomers could be proven3. Tramadol 1 mg/kg IV has been successfully used to treat postoperative shivering124. Intravenous tramadol 0.25 mg/kg and 0.5 mg/kg is effective in treating intraoperative shivering during regional anaesthesia for caesarean section125. The admixture of tramadol 100 mg with mepivacaine 1% for brachial plexus block provides a pronounced prolongation of blockade without side-effects, supporting a peripheral analgesic effect of tramadol126. Tramadol is effective in the treatment of acute ureteric colic (1 mg/kg subcutaneously), acute trauma53,127 and pain from myocardial ischaemia53. However, following acute myocardial infarction, IV tramadol 50 mg or 100 mg results in a significant decrease in left ventricular stroke wall index (LVSWI) and cardiac index128. Although tramadol is usually associated with haemodynamic stability, transient haemodynamic effects have been seen after IV injection8. (b) Chronic Pain In the treatment of chronic pain, tramadol has been shown to be effective across a wide range of conditions, as might be predicted based on its modes of analgesic action6. Examples include chronic pancreatitis2, neuropathic pain (diabetic peripheral neuropathy, postherpetic neuralgia)129-131 and rheumatology (osteoarthritis, fibromyalgia)132-134. Tramadol is also effective when making use of differing routes (orally and intra-articularly)6,131-134. In the rat model, tramadol inhibits acute and chronic inflammation without affecting immune mechanisms135. Intraarticular tramadol 50 mg provided significantly better analgesia (a mean duration of five days) than placebo in the treatment of osteoarthritis of the ankle, knee and hip joints133. In the treatment of osteoarthritis, tramadol appears preferable to pentazocine and
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dextropropoxyphene84,136. The addition of tramadol 200 mg/day allows a significant reduction in naproxen dosage without compromising pain relief137 and it may have a role as adjunctive treatment for breakthrough pain in patients receiving NSAID therapy for osteoarthritis138. An open study has shown tramadol to be of use in the treatment of the restless legs syndrome, but controlled studies are needed139. In chronic painful conditions, its reduced constipating effect is an advantage when compared to other opioids6,140. The oral sustained release preparation improves patient compliance and reduces sideeffects6,141. In chronic low back pain, there is equivalence of efficacy and tolerability of twice daily tramadol 100 mg sustained release capsules and four times daily tramadol 50 mg capsules142. Tramadol has also proved effective in chronic pain of vascular origin (e.g., scleroderma)143. (c) Cancer Pain For the treatment of cancer pain, tramadol has been found to be efficacious over a wide range of cancer pain syndromes, with a better side-effect profile and tolerability compared with morphine, and it now occupies step II of the World Health Organisation ladder1,2. For Step I treatment, an NSAIDparacetamol can be used, adding or substituting tramadol for inadequate analgesia or NSAID intolerance2,144. Overall however, in the initial treatment, morphine has been more effective for severe cancer pain (which may reflect tramadols slower onset)2. In both cancer and non-cancer pain, tramadol was shown to have a comparable analgesic effect to morphine and other commonly used analgesic agents, while causing significantly fewer adverse events56,57,68,132,145-149. Its role in the long-term management of the various types of intractable pain remains to be more accurately described6.

CONCLUSION The advantages of tramadol over traditional opioids are the minimal potential for tolerance (and limited cross-tolerance with morphine), for addiction and for respiratory depression2. Even in healthy volunteers, it exhibits little effect on breathing and respiratory patterns150. Tramadol is a prescriptiononly medicine rather than a drug controlled by a Misuse of Drugs Act in most countries, conferring advantages for both inpatient and community use2,8,151. The most important side-effects of tramadol are nausea and vomiting, but their incidence and severity

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REFERENCES
1. Dayer P, Desmeules J, Collart L. Pharmacology of tramadol. Drugs 1997; 53 (Suppl 2):18-24. 2. Bamigbade TA, Langford RM. The clinical use of tramadol hydrochloride. Pain Reviews 1998; 5:155-182. 3. Schug SA, Dickenson AH, Strauburger W, et al. Current concepts on the mechanisms of action of tramadol. In: Abstract Booklet on Symposium Current concepts on the mechanisms of action of tramadol. 9th World Congress on Pain, Austria Center Vienna, 25 August 1999. 4. Lehmann KA. Tramadol in acute pain. Drugs 1997; 53 (Suppl 2):25-33. 5. Shipton EA. The Future. In: Shipton EA. PainAcute and Chronic. London: Arnold, 1999: 344-346. 6. Budd K, Langford R. Tramadol revisited. Br J Anaesth 1999; 82:493-495. 7. Boeijinga JK, Meegen van E, van den Ende R, Schook CE, Cohen AF. Lack of interaction between tramadol and coumarins. J Clin Pharmacol 1998; 38:966-970. 8. Duthie DJR. Remifentanil and tramadol. Br J Anaesth 1998; 81:51-57. 9. Stamer UM, Maier C, Grond S, Veh-Schmidt B, Klaschik E, Lehmann KA. Tramadol in the management of post-operative pain: a double-blind, placebo- and active drug-controlled study. Eur J Anaesthesiol 1997; 4:646-654. 10. Lehmann KA. Tramadol in the management of acute pain. Drugs 1994; 47 (Suppl 1):19-32. 11. Bono AV, Cuffari S. Effectiveness and tolerance of tramadol in cancer pain: a comparative study with respect to buprenorphine. Drugs 1997; 53 (Suppl 2):40-49. 12. Lintz W, Barth H, Osterloh G, Schmidt-Bothelt E. The bioavailability of enteral tramadol formulationsfirst communication: capsules. Arzneimittelforschung/Drug Research 1986; 36:1278-1283. 13. Schultz HU, Raber M, Schurer M, Amschler S, Momberger H. Pharmacokinetic properties of tramadol sustained release capsules. 1st communication: investigation of dose linearity. Arzneimittelforschung 1999; 49:582-587. 14. Raber M, Schultz HU, Schurer M, Bias-Imhoff U, Momberger H. Pharmacokinetic properties of tramadol sustained release capsules. 2nd Communication: investigation of relative bioavailability and food interaction. Arzneimittelforschung 1999; 49:588-593. 15. Raber M, Schultz HU, Schurer M, Krupp S, Momberger H. Pharmacokinetic properties of tramadol sustained release capsules. 3rd Communication: investigation of relative bioavailability under steady state conditions. Arzneimittelforschung 1999; 49:594-598. 16. Rudaz S, Veuthey JL, Desiderio C, Fanali S. Simultaneous stereoselective analysis by capillary electrophoresis of tramadol enantiomers and their main phase I metabolites in urine. J Chromatogr A 1999; 846:227-237. 17. Lintz W, Erlacin S, Frankus E, Uragg H. Biotransformation of tramadol in man. Arzneim-Forsch/Drug Research 1981; 31:1932-1943. 18. Tegeder I, Lotsch J, Gisslinger G. Pharmacokinetics of opioids in liver disease. Clin Pharmacokinet 1999; 37:17-40. 19. Lintz W, Beier H, Gerloff J. Bioavailability of tramadol after i.m. injection in comparison to i.v. infusion. Int J Clin Pharmacol Ther 1999; 37:175-183. 20. Raffa RB. A novel approach to the pharmacology of analgesics. Am J Med 1996; 101 (1A):40S-46S. 21. Raffa RB, Friederichs E. Opioid and non-opioid components
Anaesthesia and Intensive Care, Vol. 28, No. 4, August 2000

can often be reduced by intraoperative administration in the surgical patient, by slow dose titration for those with chronic pain and by the administration of a prophylactic antiemetic2,4. A recent study has shown that a slower titration rate improves tolerability in patients who previously discontinued therapy due to nausea and vomiting152. The rate of titration of tramadol rather than the target dose was found to be the major determinant of tolerablilty152. A slower rate of initiating tramadol therapy (50 mg increments every three days) also improves tolerability and leads to significantly fewer discontinuations due to dizziness or vertigo153. Tramadol is a central-acting analgesic which has been shown to have dose-related efficacy and to be well tolerated1. It appears to be a valuable addition to the analgesic armamentarium as a safe and effective agent across a wide spectrum of acute and chronic painful conditions. It has no major organ toxicity6,154. When compared to the NSAIDs, it does not aggravate hypertension, provoke asthma, gastrointestinal mucosal damage, renal impairment or congestive heart failure8,151,155. It is of particular value in treating the elderly and in day-case surgery6. When compared with other opioids, it does not induce significant respiratory depression, constipation, histamine release, cross-tolerance or have significant abuse potential8,151. It thus confers enhanced safety2. Tramadols lack of gastrointestinal side-effects and its reduced constipation effects (compared with other opioids) gives it great value for prolonged use2,140. Tramadols efficacy over a wide range of acute and chronic pain states, its multi-formulation availability, and its low serious side-effect potential at high doses and in prolonged therapy, combine to bestow on it a user-friendly profile, for short- and long-term use in hospitals and communities2. The unique composition of this agent, with its triple action accompanied by minimal side-effects, will promote further research in this area3. The time is ripe to undertake further steps in order to design the next generation of tramadol by fitting together all the knowledge that has been obtained by a subtle step-by-step follow up of this analgesic3. A series of compounds related to tramadol has been prepared by linking one of the N-methyls to the 3-position of the cyclohexane ring (Carson JR, 1999unpublished data). These 4-aryloctahydroisoindoles showed antinociceptive effects in rats and mice. They do not bind to the mu-opioid receptor, nor does their activity parallel their effects on monoamine reuptake. But meanwhile the time has come to take a new look at tramadol itself!

TRAMADOLPRESENT AND FUTURE

independently contribute to the mechanism of action of tramadol, an atypical opioid analgesic. J Pharmacol Exp Ther 1992; 260:275-285. Vickers MD, OFlaherty D, Szekely SM, Read M, Yoshizumi J. Tramadol: pain relief by an opioid without depression of respiration. Anaesthesia 1992; 47:291-296. Houmes RJM, Voets MA, Verkaaik A, Erdmann W, Lachmann B. Efficacy and safety of tramadol versus morphine for moderate and severe postoperative pain with special regard to respiratory depression. Anesth Analg 1992; 74:510-514. Grond S, Meuser T, Uragg H, Stahlberg HJ, Lehmann KA. Serum concentrations of tramadol enantiomers during patientcontrolled analgesia. Br J Clin Pharmacol 1990; 48:254-257. Raffa RB, Friederichs E. The basic science aspect of tramadol hydrochloride. Pain Reviews 1996; 4:249-271. Bamigbade TA, Davison C, Langford RM, Stamford JA. Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus. Br J Anaesth 1997; 79:352-356. Franceschini D, Lipartiti M, Giusti P. Effect of acute and chronic tramadol on [3H]-norepinephrine-uptake in rat cortical synaptosomes. Prog Neuropsychopharmacol Biol Psychiatry 1999; 23:485-496. Gobbi M, Mennini T. Release studies with rat brain cortical synaptosomes indicate that tramadol is a 5-hydroxytryptamine uptake blocker and not a 5-hydroxytryptamine releaser. Eur J Pharmacol 1999; 370:23-26. Collart L, Luthy C. Partial inhibition of tramadol antinociceptive effect by naloxone in man. Br J Clin Pharm 1993; 35:73P. Raffa RB, Nyak RK. The mechanisms of action and pharmacokinetics of tramadol hydrochloride. Rev Contemp Pharmacother 1993; 6:485-497. Desmeules JA, Piguet V, Collart L, Dayer P. Contribution of monoaminergic modulation to the analgesic effect of tramadol. Br J Clin Pharmacol 1996; 41:7-12. Bamigbade TA, Langford RM. Tramadol hydrochloride: an overview of its current use. Hosp Med 1998; 59:373-376. Grond S, Meuser T, Zech D, Hennig U, Lehmann KA. Analgesic efficacy and safety of tramadol enantiomers in comparison with the racemate: a randomised, double-blind study with gynaecological patients using intravenous patientcontrolled analgesia. Pain 1995; 62:313-320. Mason BJ, Blackburn KH. Possible serotonin syndrome associated with tramadol and sertraline coadministration. Ann Pharmacother 1997; 31:175-177. Poulsen L, Arendt Nielsen L, Brosen K, Sindrup SH. The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 1996; 60:636-644. Sevcik J, Neiber K, Driessen B, Illes P. Effects of the central analgesic tramadol and its main metabolite o-desmethyltramadol on rat locus coeruleus neurons. Br J Pharmacol 1993; 110:169-176. Pang WW, Huang PY, Chang DP, Huang MH. The peripheral analgesic effect of tramadol in reducing propofol injection pain: a comparison with lidocaine. Reg Anesth Pain Med 1999; 24:246-249. Wilder-Smith CH, Bettiga A. The analgesic tramadol has minimal effect on gastrointestinal motor function. Br J Clin Pharmacol 1997; 43:71-75. Cossmann M, Kohnen C. General tolerability and adverse profile of tramadol hydrochloride. Rev Contemp Pharmacother 1995; 6:513-531. Cossmann M, Wilsmann KM. Effects and side-effects of tramadol: an open phase IV study with 7198 patients. Therapiewoche 1987; 37:3475-3485.

371

22.

23.

24.

25. 26.

27.

28.

29. 30.

31.

32. 33.

34.

35.

36.

37.

38.

39.

40.

41. Anderson A, Kohnen C, Schwarzbald M. Pain treatment with prolonged-release tramadol. Results of a post-marketing surveillance study amongst practitioners. Kassenartz 1997; 37:38-46. 42. Nossol S, Schwarzbold M, Stadler T. Treatment of pain with sustained-release tramadol 100, 150, 200 mg: results of a postmarketing surveillance study. Int J Clin Pract 1998; 52:115-121. 43. Ossowska K, Wolfarth S. Muscle rigidity induced by the opioid analgesic tramadol, but not by the non-opioid flupurtine. Pol J Pharmacol 1994; 46:61-65. 44. Fischer MM, Harle DG, Baldo BA. Anaphylactoid reactions to narcotic analgesics. Clin Rev Allergy 1991; 9:309-318. 45. Ellmauer S, Dick W, Otto S, Muller H. Various opioids in cardiovascular risk patients: Comparative study of central and peripheral haemodynamic side effects. Anaesthetist 1994; 43:743-749. 46. Gaynes BI, Barkin RL. Analgesics in ophthalmic practice: a review of the oral non-narcotic agent tramadol. Optom Vis Sci 1999; 76:445-461. 47. McQuay HJ, Moore RA. Oral tramadol versus placebo, codeine, and combination analgesics. In: McQuay HJ, Moore RA, eds. An Evidence-Based Resource for Pain Relief. Oxford:Oxford University Press 1998; 22:138-146. 48. Cossmann M, Kohnen C, Langford R, McCartney C. Tolerance and safety of tramadol use: results of international studies and data from drug surveillance. Drugs 1997; 53 (Suppl 2):50-62. 49. Kupers R, Callebaut V, Debois V, Camu F, Verbogh C, Coppejars H, Adriansen H. Efficacy and safety of oral tramadol and pentazocine for post-operative pain following prolapsed intervertebral disc repair. Acta Anaesthesiol Belg 1995; 46:31-37. 50. Cossmann M, Kohnen C. General tolerability and adverse event profile of tramadol hydrochloride. Rev Contemp Pharmacother 1995; 6:513-531. 51. Cossmann D, Wilsmann KM. Wirking und Begleitwerkungen von Tramadol. Offene Phase-IV-Prufung mit 7198 Patienten. Therapiewoch 1987; 37:3475-3485. 52. Ratcliffe S, Repas C. A comparison of adverse effects of tramadol in children and adults. 3rd International Symposium of Paediatric Pain 1994:182. 53. Radbruch L, Grond S, Lehmann KA. A risk-benefit assessment of tramadol in the management of pain. Drug Saf 1996; 15:8-29. 54. Lee CR, Mc Tavish D, Sorkin EM. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 1993; 46:313-340. 55. Tarkkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and pethidine. Eur J Anaesthesiol 1998; 15:64-68. 56. Dalgin PH. Use of tramadol in chronic pain. Clin Geriatrics 1995; 3:1-6. 57. Price PM, Budd K. Tramadol in the treatment of spinal pain. Br J Med Econ 1995; 9:17-20. 58. Vickers MD. The efficacy of tramadol in the treatment of postoperative pain. Rev Contemp Pharmaccother 1995; 6:499-506. 59. Broome IJ, Robb HM, Raj N, Girgis Y, Wardall GJ. The use of tramadol following day-case surgery. Anaesthesia 1999; 54:289292. 60. Committee on Safety of Medicines/ Medicines Control Agency. Curr Probl Pharmacovig 1996; 22:11. 61. Bowdle TA. Adverse effects of opioid agonists and agonistantagonists in anaesthesia. Drug Saf 1998; 19:173-189. 62. Committee on Safety of Medicines/Medicines Control Agency. Curr Probl Pharmacovig 1995; 21:2.

Anaesthesia and Intensive Care, Vol. 28, No. 4, August 2000

372

E. A. SHIPTON
85. Collins SL, Edwards JE, Moore RA, McQuay HJ. Single dose dextropoxyphene in post-operative pain: a quantitative systematic review. Eur J Clin Pharmacol 1998; 54:107-112. 86. Coetzee JF, van Loggerenberg H. Tramadol or morphine administered during operation: a study of immediate postoperative effects after hysterectomy. Br J Anaesth 1998; 81: 737-741. 87. Coetzee JF, Maritz JS, Du Toit JC. Effect of tramadol on depth of anaesthesia. Br J Anaesth 1996; 76:415-418. 88. Bamigbade TA, Langford RM, Blower AL, et al. Pain control in day surgery: tramadol compared to standard analgesia. Br J Anaesth 1998; 80:558P-559P. 89. De Witte, Rietman GW, Vandenbroucke G, Deloof T. Postoperative effects of tramadol administered at wound closure. Eur J Anaesthesiol 1998; 15:190-195. 90. Stamer UM, Maier C, Grond S, Veh-Schmidt B, Klaschlik E, Lehmann LA. Tramadol in the management of post-operative pain: a double-blind, placebo- and active-controlled study. Eur J Anaesthesiol 1997; 14:646-654. 91. Bamigbade TA, Paes M , Gayles R, Foster JMG, Langford RM. Does tramadol lighten anaesthetic depth during isoflurane anaesthesia? Abstract. 8th World Congress on Pain, Vancouver, Aug 1996. Seattle:International Association for the Study of Pain 1997; 261. 92. Van den Berg AA, Halliday E. Attenuation of vasomotor responses to tracheal intubation. Comparison of tramadol, pethidine, nalbuphine and placebo. Br J Anaesth 1998; 80:A65. 93. Langford R, Bakhshi KN, Moylan S, Foster JMG. Hypoxaemia after lower abdominal surgery: comparison of tramadol and morphine. Acute Pain 1998; 1:7-12. 94. Trakkila P, Tuominen M, Lindgren L. Comparison of respiratory effects of tramadol and pethidine. Eur J Anaesthesiol 1998; 15:64-68. 95. Rodriquez MJ, de la Torre MR. Comparative study of tramadol versus NSAIDs as intravenous continuous infusion for postoperative pain. Curr Ther Res Clin Exp, 1993; 54:375-383. 96. Raff M. The comparison of continuous intravenous tramadol and morphine sulphate for postoperative analgesia. Acute Pain 1998; 1:7-10. 97. Moore RA, McQuay HJ. Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine, and combination analgesics. Pain 1997; 69:287-294. 98. Vickers MD, Paravicini D. Comparison of tramadol with morphine for post-operative pain following abdominal surgery. Eur J Anaesthesiol 1995; 12:265-271. 99. Wilder-Smith CH, Hill L, Wilkins J, Denny L. Effects of morphine and tramadol on somatic and visceral sensory function and gastrointestinal motility after abdominal surgery. Anesthesiology 1999; 91:639-647. 100. Coulthard P, Snowdon AT, Rood JP. The efficacy and safety of postoperative pain management with tramadol for day case surgery. Ambul Surg 1996; 4:25-29. 101. Makanday S, Wilson A. integrated clinical and statistical report for a randomised, double-blind, multicentre study to compare intravenous Zydol (tramadol)/ oral Zydol with intravenous fentanyl/co-codamol in day case patients following groin/testicular surgery. Clinical Research Report No. U9097-06-029. Searle, High Wycombe, United Kingdom 1997. 102. Melish DR, Minn F. Tramadol hydrochloride; efficacy compared to codeine sulphate, acetaminophen with dextropropoxyphene and placebo in dental extraction pain. Pain 1990; 40 (Suppl 5):41. 103. Thomson PJ, Rood JP. Investigation of pre-operative tramadol in the prevention of post-operative pain for day case surgery.
Anaesthesia and Intensive Care, Vol. 28, No. 4, August 2000

63. Spiller HA, Gorman SE, Villalobos D, et al. Prospective multicenter evaluation of tramadol exposure. J Toxicol Clin Toxicol 1997; 35:361-364. 64. Jick, Derby LE, Vasilakis C, Fife D. The risk of seizures associated with tramadol. Pharmacotherapy 1998; 18:607-611. 65. Matthiesen T, Wohrmann T, Coogan TP, Uragg H. The experimental toxicology of tramadol: an overview. Toxicol Lett 1998; 95:63-71. 66. Moore KA, Cina SJ, Jones R, Selby DM, Levine B, Smith ML. Tissue distribution of tramadol and metabolites in an overdose fatality. Am J Forensic Med Pathol 1999; 20:98-100. 67. Lambrecht RW, Gildemeister OS, Williams A, Pepe JA, Tortorelli KD, Bonkovsky HL. Effects of selected antihypertensives and analgesics on hepatic porphyrin accumulation: implications for clinical porphyria. Biochem Pharmacol 1999; 58:887-896. 68. Budd K. Chronic painchallenge and response. Drugs 1994; 47 (Suppl 1):33-38. 69. Gibson TP. Pharmacokinetics, efficacy, and safety of analgesia with a focus on tramadol HCL. Am J Med 1996; 101 (1A):47S53S. 70. Cami J, Lamas X, Farre M. Acute effects of tramadol in methadone-maintained volunteers. Drugs 1994; 47 (Suppl 1):39-43. 71. FDA Committee. FDC Reports (Pink Sheet) Prescription Pharmaceuticals and Biotechnology 1998; 60:4-5. 72. James MFM, Heijke SAM, Gordon PC. Intravenous tramadol versus epidural morphine for post-thoracotomy pain relief: a placebo-controlled double-blind trial. Anesth Analg 1996; 83:87-91. 73. Lomona J. Is tramadol a suitable analgesic for high risk patients after heart surgery? Br J Anaesth 1995; 74, Suppl 2:7. 74. Hopkins D, Shipton EA, Potgieter D, et al. The comparison of tramadol and morphine by subcutaneous PCA. Can J Anaesth 1998; 45:435-442. 75. Rud V, Fischer MV. Postoperative analgesia with tramadol: continuous infusion versus repetitive bolus administration. Anaesthetist 1994; 43:316-321. 76. Vickers MD, O Flaherty D, Szekely SM, Read M, Yoshizumi J. Tramadol: pain relief by an opioid without depression of respiration. Anaesthesia 1992; 47:291-296. 77. Canepa G, Di-Somma C, Ghia M, Vadala A, Real M, Cerruti S, Stasi M, Trezzi P. Post-operative analgesia with tramadol. Int J Clin Pharmacol Res 1993; 13:43-51. 78. Barsoum MW. Comparison of the efficacy and tolerability of tramadol, pethidine, and nalbuphine in children with postoperative pain. Clin Drug Invest 1995; 9:183-190. 79. Schaffer J, Pipenbrock S. Nalbuphine und tramadol zur postoperativen schmertzkampfung bei kindern. Anaesthetist 1986; 35:408-413. 80. Schaffer J, Hagemann H. Investigation of paediatric postoperative analgesia with tramadol. Fortschr Anaesth 1989; 3:42-45. 81. Bosenberg A, Ratcliffe S. The respiratory effects of tramadol in children under halothane anaesthesia. Anaesthesia 1998; 53:960-964. 82. McQuay HJ, Moore RA. Postoperative analgesia and vomiting, with special reference to day-case surgery: a systematic review. Health Technol Assess 1998; 2:1-236. 83. Sunshine A, Olsen NZ, Zighelboim I, De Castro A, Minn FL. Analgesic oral efficacy of tramadol hydrochloride in postoperative pain. Clin Pharm Ther 1992; 51:740-746. 84. Jensen EM, Ginsberg F. Tramadol versus dextropropoxyphene in the treatment of osteoarthritis. Drug Invest 1994; 8:211-218.

TRAMADOLPRESENT AND FUTURE

7th World Congress on Pain, Paris, 1993. Seattle:International Association for the Study of Pain Press 1994; 54. 104. Couthard P, Snowdon AT. The efficacy and safety of postoperative pain management with tramadol for day case surgery. Amb Surg 1996; 4:25-29. 105. Lewis KS, Han NH. Tramadol: a new acting central analgesic. Am J Health Syst Pharm 1997; 54:643-652. 106. Collins M, Young I, Sweeney P, et al. The effect of tramadol on dento-alveolar surgical pain. Br J Maxillofac Surg 1997; 35 (1):54-58. 107. Putland AJ, McCluskey A. The analgesic efficacy of tramadol versus ketorolac in day case laparoscopic sterilisation. Anaesthesia 1999; 54:382-385. 108. Pluim MA, Wegener JT, Rupreht J, Vulto AG. Tramadol suppositories are less suitable for post-operative pain relief than rectal acetaminophen/codeine. Eur J Anaesthesiol 1999; 16:473-478. 109. Alfonso Megido J, Valasco L. Utilidad clinica dela administracion de tramadol por via subcutanea. Cienc Pharm 1994; 4:22-24. 110. Naguib M, Seraj M, Attia M, Samarkandi AH, Seet M, Jaroudi R. Perioperative antinociceptive effects of tramadol. A prospective, randomised, double-blind comparison with morphine. Can J Anaesth 1998; 45:1168-1175. 111. Forst J, Wolff S, Thamm P, Forst R. Pain therapy following joint replacement. A randomised study of patient-controlled analgesia versus conventional pain therapy. Arch Orthop Trauma Surg 1999; 119:267-270. 112. Likar R, Mathiaschitz K, Burtscher M, Stettner H. Randomised, double-blind, comparative study of morphine and tramadol administered intra-articularly for postoperative analgesia following arthroscopic surgery. Clin Drug Invest 1995; 10:17-21. 113. Staunstrup H, Ovesen J, Larsen UT, Elbaek K, Larsen U, Kroner K. Efficacy and tolerability of lornoxicam versus tramadol in postoperative pain. J Clin Pharmacol 1999; 39:834-841. 114. Cagney B, Williams O, Jennings L, Buggy D. Tramadol or fentanyl analgesia for ambulatory knee arthroscopy. Eur J Anaesthesiol 1999; 16:182-185. 115. Rister M, Paul M. Management of pain in infants with opioid analgesics Abstract. 7th World Congress on Pain, Paris, Aug 1993. Seattle:International Association for the Study of Pain 1994; 96. 116. Payne KA, Roelofse JA, Shipton EA. Tears at bedtime. Br J Anaesth 1999; 83:359. 117. Roelofse JA, Payne KA. Oral tramadol: analgesic efficacy in children following multiple dental extractions. Eur J Anaesthesiol 1999; 16:441-447. 118. Prosser DP, Davis A, Booker PD, Murray A. Caudal tramadol for postoperative analgesia in paediatric hypospadias surgery. Br J Anaesth 1997; 79:293-296. 119. Batra YK, Prasad MK, Arya VK, Chari P, Yaddanapudi LN. Comparison of caudal tramadol vs bupivacaine for postoperative analgesia in children undergoing hypospadias surgery. Int J Clin Pharmacol Ther 1999; 37:238-242. 120. Viegas OAC, Khaw SB, Ratnam SS. Tramadol in labour pain in primiparous patients: a prospective comparative clinical trial. Eur J Obstet Gynecol Reprod Biol 1993; 49:131-135. 121. Kaintz C, Joura E, Obgeweser R, Plockinger B, Gruber W. Wirsamkeit und Vertraglichkeit von tramadol mit oder ohne Antiemetikum sonie von Pethidin zur geburtshilflichen Analgesie. Z Geburtshilfe Perinatol 1992; 196:78-82. 122. Volkner W. Chromosome aberration assay in bone marrow
Anaesthesia and Intensive Care, Vol. 28, No. 4, August 2000

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cells of the rat with tramadol hydrochloride. (Data on file: report no. FO-TP 1025). Aachen. FRG. Grunenthal GmbH 1994. 123. Siddik-Sayyid S, Aouad-Maroun M, Sleiman D, Sfeir M, Baraka A. Epidural tramadol for postoperative pain after Cesarean section. Can J Anaesth 1999; 46:731-735. 124. De Witte J, Deloof T, de Veylder J, Housemans PR. Tramadol in the treatment of postanaesthetic shivering. Acta Anaesthesiol Scand 1997; 41:506-510. 125. Chan AM, Ng KF, Tong EW, Jan GS. Control of shivering under regional anesthesia in obstetric patients with tramadol. Can J Anaesth 1999; 46:253-258. 126. Kaparal S, Gollmann G, Waltl B, et al. Tramadol added to mepivacaine prolongs the duration of an axillary brachial plexus blockade. Anesth Analg 1999; 88:853-856. 127. Nicolas TJA, Rigabert MM, Banon PV, Valdelvira NP, Perez AM. Intramuscular ketorolac compared with subcutaneous tramadol in the initial emergency treatment of renal colic. Arch Esp Urol 1999; 52:435-437. 128. Stankow S. Haemodynamic effects of tramadol and morphine in patients with acute myocardial infarction. Abstract. 7th World Congress on Pain, Paris, Aug 1993. Seattle: International Association for the Study of Pain Press 1995; 293. 129. Mackin GA. Medical and pharmacologic management of upper extremity neuropathic pain syndromes. J Hand Ther 1997; 10:96-109. 130. Gobel H, Stadler T. Treatment of pain due to postherpetic neuralgia with tramadol. Clin Drug Invest 1995; 10:208-214. 131. Harati Y, Gooch C, Swenson M, et al. Double-blind randomised trial of tramadol for the treatment of the pain of diabetic peripheral neuropathy. Neurology 1998; 50:18421846. 132. Roth S. Efficacy and safety of tramadol hydrochloride in breakthrough musculoskeletal pain attributed to osteoarthritis. J Rheumatol 1998; 25:45-54. 133. Budd K. The analgesic effect of tramadol hydrochloride when administered intra-articularly. Abstract. 8th World Congress on Pain. Vancouver, Aug 1996. Seattle: International Association for the Study of Pain Press 1997; 229. 134. Biasi G, Manca S, Manganelli S, Marcolongo R. Tramadol in the fibromyalgia syndrome: a controlled clinical trial versus placebo. Int J Clin Pharmacol Res 1998; 18:13-19. 135. Bianchi M, Rossini G, Sacerdote P, Panerai AE. Effects of tramadol on experimental inflammation. Fundam Clin Pharmacol 1999;13:220-225. 136. Bird HA, Hill J, Statford ME, Fenn GC, Wright V. A doubleblind cross-over study comparing the analgesic efficacy of tramadol with pentazocine in patients with osteoarthritis. J Drug Dev Clin Pract 1995; 7:181-188. 137. Schnitzer TJ, Kamin M, Olson WH. Tramadol allows reduction of naproxen dose among patients with naproxenresponsive osteoarthritis pain: a randomised, double-blind, placebo-controlled study. Arthritis Rheum 1999; 42:13701377. 138. Roth SH. Efficacy and safety of tramadol HCl in breakthrough osteoarthritis pain. J Rheumatol 1998; 25:1358-1363. 139. Lauerma H, Markkula J. Treatment of the restless legs syndrome with tramadol: an open study. J Clin Psychiatry 1999; 60:241-244. 140. Wilder-Smith CH, Hill L, Osler W, O Keefe S. Effect of tramadol and morphine on pain and gastrointestinal motor function in patients with chronic pancreatitis. Dig Dis Sci 1999; 44:1107-1116.

374

E. A. SHIPTON
148. Pavelka K, Peliskova Z. Intraindividual differences in pain relief and functional improvement in osteoarthritic patients receiving diclofenac or tramadol. Ann Rheum Dis 2000 (in press). 149. Rauck RL, Ruoff GE. Comparison of tramadol and acetaminophen with codeine for long term management in elderly patients. Curr Ther Res Clin Exp 1994; 55:1417-1431. 150. Mildh LH, Leino KA, Kirvela OA. Effects of tramadol and meperidine on respiration, plasma catecholamine concentrations, and haemodynamics. J Clin Anesth 1999; 11:310-316. 151. Katz WA. Pharmacology and clinical experience with tramadol in osteoarthritis. Drugs 1996; 52 (Suppl 3):39-47. 152. Petrone D, Kamin M, Olson W. Slowing the titration rate of tramadol HCl reduces the incidence of discontinuation due to nausea and/or vomiting: a double-blind randomised trial. J Clinic Pharm Therapeut 1999; 24:115-123. 153. Ruoff GE. Slowing the initial titration rate of tramadol improves tolerability. Pharmacotherapy 1999; 19:88-93. 154. Tolman KG. Hepatotoxicity of non-narcotic analgesics. Am J Med 1998; 105 (1B):13S-19S. 155. Ruoff GE. The impact of nonsteroidal anti-inflammatory drugs on hypertension: alternative analgesics for patients at risk. Clin Ther 1998; 20:376-387.

141. Nossol S. Treatment of pain with sustained-release tramadol. Int J Clin Pract 1998; 52:94-126. 142. Sorge J, Stadler T. Comparison of the analgesic efficacy and tolerability of tramadol 100 mg sustained-release tablets and tramadol 50 mg capsules for the treatment of chronic low back pain. Clin Drug Invest 1997; 14:157-164. 143. Guseva NG, Alekperov RT, Anikina NV. Effect of tramadol on vascular pains in patients with systemic scleroderma and other rheumatic diseases. Ter Arkh 1994; 66:20-24. 144. Schnitzer TJ. Non-NSAID pharmacologic treatment options for the management of chronic pain. Am J Med 1998; 195 (1B):45S-52S. 145. Osipova NA, Novilov GA. Analgesic effect of tramadol on cancer patients with chronic pain: a comparison with prolonged action morphine. Curr Ther Res Clin Exp 1991; 50:812-821. 146. Wilder-Smith CH, Schimke J, Osterwalde B, Senn HJ. Oral tramadol, a non-opioid agonist and monoamine reuptake blocker and morphine in strong cancer related pain. Ann Oncol 1994; 5:141-146. 147. Grond S, Zech D. Tramadola weak opioid in the relief of cancer pain: a double-blind comparison against sustained release morphine. Pain Clin 1992; 5:241-247.

Anaesthesia and Intensive Care, Vol. 28, No. 4, August 2000