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Tramadol

A Review of its Use in Perioperative Pain

Summary

Abstract

Tramadol is a synthetic, centrally acting analgesic agent with 2 distinct, synergistic mechanisms of action, acting as both a weak opioid agonist and an inhibitor of monoamine neurotransmitter reuptake. The 2 enantiomers of racemic tramadol function in a complementary manner to enhance the analgesic efficacy and improve the tolerability profile of tramadol.

In several comparative, well designed studies, oral and parenteral tramadol effectively relieved moderate to severe postoperative pain associated with surgery. Its overall analgesic efficacy was similar to that of morphine or alfentanil and superior to that of pentazocine. Tramadol provided effective analgesia in children and in adults for both inpatient and day surgery.

Tramadol was generally well tolerated in clinical trials. The most common adverse events (incidence of 1.6 to 6.1%) were nausea, dizziness, drowsiness, sweating, vomiting and dry mouth. Importantly, unlike other opioids, tramadol has no clinically relevant effects on respiratory or cardiovascular parameters at recommended doses in adults or children. Tramadol also has a low potential for abuse or dependence.

Conclusions: The efficacy of tramadol for the management of moderate to severe postoperative pain has been demonstrated in both inpatients and day surgery patients. Most importantly, unlike other opioids, tramadol has no clinically relevant effects on respiratory or cardiovascular parameters. Tramadol may prove particularly useful in patients with poor cardiopulmonary function, including the elderly, the obese and smokers, in patients with impaired hepatic or renal function, and in patients in whom nonsteroidal anti-inflammatory drugs are not recommended or need to be used with caution. Parenteral or oral tramadol has proved to be an effective and well tolerated analgesic agent in the perioperative setting.

Pharmacodynamic Profile

Tramadol is a synthetic, centrally acting analgesic agent with 2 distinct, synergistic mechanisms of action. It is both a weak opioid agonist with selectivity for the μ-receptor and a weak inhibitor of the reuptake of noradrenaline (norepi-nephrine) and serotonin (5-hydroxytryptamine; 5-HT). This dual mechanism of action may be attributed to the 2 enantiomers of racemic tramadol. The (+)-enantiomer has a higher affinity for the μ-receptor and is a more effective inhibitor of 5-HT reuptake, whereas the (−)-enantiomer is a more effective inhibitor of noradrenaline reuptake and increases its release by autoreceptor activation.

In healthy volunteers, oral tramadol 100mg provided superior analgesia compared with placebo. The peak analgesic effect occurred 1 to 4 hours after drug administration, with analgesia persisting for 3 to 6 hours.

Tramadol is extensively metabolised in the liver, with the O-desmethyl (M1) metabolite of tramadol having an ≈200-fold higher affinity for opioid receptors than the parent drug. The O-desmethylation of tramadol is dependent on the cytochrome P450 enzyme CYP2D6 sparteine-oxygenase (deficient in ≈8% of Caucasians). Studies in healthy volunteers deficient in this enzyme (poor tramadol metabolisers) provided evidence for the possible contribution of the M1 metabolite to the analgesic effects of tramadol, with reduced analgesia in poor metabolisers compared with extensive metabolisers.

The two enantiomers of tramadol act synergistically to provide analgesia. In both clinical and animal studies, the (+)-enantiomer provided similar analgesia to that of racemic tramadol and superior analgesia compared with the (−)-enantiomer. However, racemic tramadol showed an improved tolerability profile compared with the (+)-enantiomer in these studies.

Several comparative, double-blind studies, in both adults and children, indicated that unlike other opioids (such as morphine, pethidine, oxycodone and nalbuphine) postoperative tramadol was not associated with clinically relevant respiratory depression. In addition, although one study demonstrated a statistically significant increase in both systolic and diastolic blood pressure, these were not considered clinically relevant. There were also no clinically relevant effects on heart rate with tramadol and it reduced shivering in postoperative patients.

Pharmacokinetic Profile

Tramadol is rapidly absorbed following single or multiple oral 100mg doses in adult volunteers. The mean absolute bioavailability of tramadol was ≈68% and increased to >90% with multiple doses and with intramuscular administration. Food intake had no clinically relevant effects on its bioavailability. In healthy adult volunteers administered a lOOmg single oral dose of tramadol, the maximum plasma concentration (Cmax) was 308 μg/L at 1.6 hours and with a single intramuscular dose was 193 μg/L attained at 0.75 hours. Cmax for the M1 metabolite after a single oral 100mg dose was 55 μg/L and was reached in ≈3 hours. Tramadol has a high tissue affinity, with an apparent volume of distribution after parenteral administration of ≈260L.

Tramadol undergoes extensive first-pass metabolism in the liver, with ≈10 to 30% of an oral dose excreted unmetabolised in healthy volunteers. Both tramadol and its metabolites are primarily excreted via the kidneys (90%). The terminal elimination half-life (t½β) value for tramadol after a single oral (100mg) or parenteral (50mg) dose was ≈5.5 hours. t½β values for the M1 metabolite following oral single or multiple 100mg doses were 6.69 and 6.98 hours, respectively. t½β is increased ≈2-fold in patients with renal or hepatic impairment. Concomitant administration with carbamazepine, an inducer of hepatic enzymes, reduced the t½β of tramadol by ≈50%.

Clinical Efficacy

The analgesic efficacy of intravenous, intramuscular and oral tramadol has been established in several randomised, double-blind, parallel-group, comparative studies in adult patients with moderate to severe acute postoperative pain, and in a limited number of studies in paediatric patients.

Parenteral or oral tramadol effectively relieved moderate to severe postoperative pain associated with several types of surgery (including abdominal, orthopaedic and cardiac surgery), reducing pain intensity by 46.8 to 57.6% within 4 to 6 hours (assessed using a 100mm or 100-point visual analogue scale). There is also a dose-dependent reduction in the severity and prevalence of postoperative shivering with tramadol treatment.

The overall analgesic efficacy with tramadol was comparable to that achieved using equianalgesic doses of parenteral morphine or alfentanil. Intramuscular tramadol also provided similar efficacy compared with intramuscular ketorolac in postoperative patients.

Concomitant use of intravenous tramadol 50 or 100mg with dipyrone 25 or 50mg (a nonsteroidal anti-inflammatory drug; NSAID) using patient controlled analgesia provided better analgesia than intravenous piritramide 0.75 or 1.5mg (an opioid agent). A continuous infusion of tramadol 10 mg/h with concomitant oral propacetamol 2g 4 times daily achieved superior analgesic efficacy compared with tramadol monotherapy.

In children, intramuscular tramadol 2 mg/kg as required provided analgesia similar to that of intramuscular pethidine 1 mg/kg or nalbuphine 0.1 mg/kg following lower abdominal surgery. Furthermore, a single caudal injection of tramadol 2 mg/kg provided similar analgesia 3 to 12 hours postoperatively to that of caudal bupivacaine 2 mg/kg (a local anaesthetic) or tramadol 2 mg/kg with concomitant bupivacaine 2 mg/kg, although at the 3-hour time point bupivacaine provided superior analgesia.

Tramadol provided effective postoperative pain relief in patients after day surgery (including groin and gynaecological surgery). The majority of these studies involved complex treatment regimens, with the concomitant administration (pre-, intra-and/or postoperatively) of several other analgesic agents (both opioids and NSAIDs). In a large multicentre study, perioperative intravenous and oral tramadol 100mg provided superior analgesic efficacy for the first 24 hours compared with a combination of intraoperative fentanyl 100μg and postoperative oral codeine 16mg/paracetamol 1000mg. Tramadol 100mg (administered intra-and post-operatively) also provided similar analgesic efficacy compared with naproxen sodium 500mg in 91 patients. Furthermore, intravenous tramadol 1.5 mg/kg, administered at the induction of anaesthesia, provided superior pain relief compared with intravenous ketorolac 10mg in 60 patients after laparoscopic surgery.

Results from early studies investigating the intraoperative use of tramadol were controversial, with reports of increased recall of intraoperative events following its use. However, several recent studies using volatile or intravenous anaesthetic techniques, in both inpatients and day surgery patients, have not shown any clinically significant lightening of anaesthesia depth sufficient to cause accidental awareness while undergoing surgery.

Tolerability

In general, tramadol was well tolerated in clinical trials. The most common adverse events with single or multiple dose oral or parenteral administration of tramadol were nausea (6.1% of patients), dizziness (4.6), drowsiness (2.4), tiredness (2.3), sweating (1.9), vomiting (1.7) and dry mouth (1.6). Adverse events occurred in ≈15% of patients. Unlike other opioids, notably morphine, tramadol did not cause clinically relevant respiratory depression at recommended therapeutic doses. The incidence of seizures in patients receiving tramadol is estimated to be <1%.

The risk of dependence or abuse with tramadol is low (0.7 to 1.5 cases of abuse per 100 000 individuals). The most common symptoms associated with an overdose were lethargy (30% of patients), nausea (14%), tachycardia (13%), agitation (10%), seizures (8%), coma (5%), hypertension (5%) and respiratory depression (2%). Naloxone treatment reversed sedation and apnoea in 50% of patients. No serious cardiotoxicity was observed with tramadol overdose.

Dosage and Administration

Tramadol is recommended for the management of acute or chronic moderate to severe pain. In adults and adolescents, the usual dosage is 50 to 100mg every 4 to 6 hours as required, with a maximum dosage of 400 mg/day. It may be administered orally or parenterally, although only an oral formulation is available in the US. Dosage adjustments may be required in patients with renal or hepatic impairment and in those >75 years of age. Recommendations for the use of tramadol in paediatric patients may vary between individual countries. For example, tramadol is not recommended for use in children <12 years of age in the UK or in those <16 years of age in the US, whereas in Germany some formulations are approved for use in children aged ≥1 year.

Tramadol is not recommended in patients receiving monoamine oxidase inhibitors and is contraindicated in cases of acute intoxication with alcohol, hypnotics, centrally acting analgesics, opioids or psychotropic drugs. The risk of seizure with tramadol administration may be enhanced in patients receiving monoamine oxidase inhibitors, neuroleptics, other drugs that reduce the seizure threshold, patients with epilepsy or patients otherwise at risk of seizure. Tramadol should be used with caution in patients with increased intracranial pressure and when treating patients with respiratory depression or if concomitant central nervous system depressant agents are being administered. When used with concomitant carbamazepine, dosages of tramadol may require adjustment.

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Correspondence to Lesley J. Scott.

Additional information

Various sections of the manuscript reviewed by: S.R. Abel, Indiana University Medical Centre, Indianapolis, Indiana, USA; S.S. Bloomfield, University of Cincinnati, Cincinnati, Ohio, USA; J.E. Caldwell, Department of Anesthesia, University of California, San Francisco, California, USA; K.A. Lehmann, Institute of Anaesthesiology and Intensive Care Medicine, University of Cologne, Cologne, Germany; L. Radbruch, Institute of Anaesthesiology and Intensive Care Medicine, University of Cologne, Cologne, Germany; K. Szymanski, Indiana University Medical Centre, Indianapolis, Indiana, USA; P. Tarkkila, Department of Anaesthesia, Helsinki University Centre Hospital, Helsinki, Finland; C.H. Wilder-Smith, Gastrointestinal Unit and Nociception Research Group, Berne, Switzerland.

Data Selection

Sources: Medical literature published in any language since 1993 on tramadol, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand) and Medline. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘tramadol’ or ‘CG-315’ or ‘CG-315E’ or ‘U-26225A’. Medline search terms were ‘tramadol’. Searches were last updated 26 May 2000.

Selection: Studies in patients with perioperative moderate to severe pain who received tramadol. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Tramadol, analgesia, pain, pharmacodynamics, pharmacokinetics, therapeutic use.

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Scott, L.J., Perry, C.M. Tramadol. Drugs 60, 139–176 (2000). https://doi.org/10.2165/00003495-200060010-00008

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Keywords

  • Morphine
  • Tramadol
  • Ketorolac
  • Analgesic Efficacy
  • Dipyrone