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Tramadol

A Preliminary Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in Acute and Chronic Pain States

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Abstract

Synopsis

Tramadol is a centrally acting analgesic which possesses opioid agonist properties and activates monoaminergic spinal inhibition of pain. It may be administered orally, rectally, intravenously or intramuscularly. In patients with moderate to severe postoperative pain, intravenous or intramuscular tramadol has generally proved to be of equivalent potency to pethidine (meperidine) and one-fifth as potent as nalbuphine. Intravenous tramadol 50 to 150mg was equivalent in analgesic efficacy to morphine 5 to 15mg in patients with moderate pain following surgery; however, when administered epidurally tramadol was one-thirtieth as potent as morphine. Tramadol has demonstrated efficacy in a few studies in the short term treatment of chronic pain of various origins. Orally administered tramadol was found to be an effective analgesic in step 2 of the World Health Organization’s guidelines for the treatment of patients with cancer pain.

Tramadol is well tolerated in short term use with dizziness, nausea, sedation, dry mouth and sweating being the principal adverse effects. Respiratory depression has been observed in only a few patients after tramadol infusion anaesthesia. When used for pain relief during childbirth, intravenously administered tramadol did not cause respiratory depression in neonates. The tolerance and dependence potential of tramadol during treatment for up to 6 months appears to be low, although the possibility of dependence with long term use cannot be entirely excluded.

Thus, evidence to date of the analgesic effectiveness of tramadol combined with a low respiratory depressant effect and low dependence potential in short term use, suggests that the drug may become a useful alternative to the opioid analgesics currently available for the treatment of patients with moderately severe acute or chronic pain.

Pharmacodynamic Properties

Tramadol is a centrally acting analgesic which acts at opioid receptors and also appears to modify transmission of pain impulses by inhibition of monoamine reuptake. Tramadol has demonstrated analgesic activity in a number of animal models. In healthy volunteers with experimentally induced pain, oral tramadol exhibited analgesic activity similar to that of dextropropoxyphene and was more effective than flupirtine or dipyrone (metamizole) but less effective than tilidine. The duration of analgesia with orally administered tramadol was 3 to 6 hours, with maximum pain relief reported at 1 to 4 hours post-dose. Intravenous tramadol 2 mg/kg was as effective as pethidine (meperidine) 1 mg/kg.

In healthy volunteers, intravenous tramadol produced a slight dose-dependent respiratory depression. Tramadol administered intravenously to postoperative patients either produced no change in partial pressure of CO2 or a clinically nonsignificant increase. Tramadol 0.5 to 2 mg/ kg produced a nonsignificant increase in end-tidal CO2 whereas morphine 0.143 mg/kg elicited a significant increase. After intravenous administration tramadol tended to produce transient changes in heart rate and blood pressure in the first 5 to 10 minutes postinjection. The respiratory depressant and haemodynamic effects elicited by tramadol are unlikely to be clinically significant at the recommended parenteral dosage. Epidemiological data suggest that tramadol has a low abuse potential. It appears from tolerance and physical dependence tests in animals and humans that tramadol has a low physical dependence potential. However, during long term treatment the possibility of physical dependence cannot be entirely excluded.

Pharmacokinetic Properties

After oral administration as capsules or tablets, tramadol appears in the plasma within 15 to 45 minutes, reaching peak plasma concentrations at a mean of 2 hours. The absolute oral bio-availability of tramadol is approximately 68% after single doses and increases to 90 to 100% on multiple administration. Tramadol has a high tissue affinity with apparent volumes of distribution of 306 and 203L after oral and intravenous administration, respectively, in healthy volunteers.

Tramadol undergoes hepatic metabolism, with approximately 85% of an oral dose being metabolised in young healthy volunteers. Only 1 metabolite, O-demethyl tramadol, is pharmacologically active. The mean elimination half-life of tramadol following oral or intravenous administration is 5 to 6 hours. Approximately 90% of an oral dose is excreted via the kidneys. The elimination half-life is increased approximately 2-fold in patients with impaired hepatic or renal function. On coadministration with the hepatic enzyme inducer carbamazepine, the elimination half-life of tramadol is decreased.

Therapeutic Efficacy

The analgesic efficacy of oral, parenteral or rectal tramadol has been established in large multicentre phase IV trials with 73 to 94% of patients obtaining satisfactory pain relief depending on the cause of pain. In postoperative pain states using patient-controlled analgesia (PCA), intravenously administered tramadol was equivalent to pethidine, one-fifth as potent as nalbuphine and one-thousandth as potent as fentanyl. Tramadol administered epidurally was one-thirtieth as potent as morphine in patients following abdominal surgery, and was superior in analgesic efficacy to bupivacaine. Intravenous tramadol 50 to 150mg was equivalent in analgesic efficacy to morphine 5 to 15mg in the treatment of patients with moderate, but not severe, postoperative pain. In other postoperative pain states the analgesic effect of intramuscular tramadol 50mg was similar to that of pentazocine 30mg, nefopam 20mg, and dipyrone 1500mg but less effective than nicomorphine 10mg and buprenorphine 0.3mg. Following surgery in paediatric patients, tramadol was as effective and one-fifth as potent as nalbuphine, both administered intramuscularly. In most studies the peak analgesic effect of intramuscularly administered tramadol occurred in 1 to 2 hours and analgesia lasted for 5 to 6 hours. Orally administered tramadol 50mg was equivalent to pentazocine 50mg in the relief of pain in patients following osteosynthesis.

In obstetric analgesia intramuscular tramadol 50 to 150mg was generally found to be equivalent to intramuscular pethidine 50 to 100mg and tramadol 100mg was equivalent to morphine 10mg. In the short term treatment of various chronic pain states intramuscular tramadol 50 and 100mg was equivalent to pentazocine 30mg but less effective than pentazocine 60mg and oral tramadol 50mg was more effective than tilidine 50mg. A daily dose of tramadol 250mg to 600mg administered orally was found to be an effective analgesic in step 2 of the World Health Organization’s guidelines for the treatment of patients with cancer pain. Tramadol appeared to be equivalent to sustained release morphine in the treatment of moderate cancer pain but was generally less effective in severe pain.

Tramadol was not found to be a suitable analgesic for use in balanced anaesthesia because of problems with increased intraoperative awareness.

Tolerability

The most common adverse effects associated with tramadol administration are dizziness, nausea, sedation, dry mouth and sweating with an incidence ranging from 2.5 to 6.5%. No clinically relevant respiratory depression has been reported after recommended doses of the drug. In higher than recommended doses after infusion as a supplement to anaesthesia, tramadol caused respiratory depression requiring naloxone in a few patients. In one study tramadol, administered intravenously for pain relief during childbirth, caused respiratory depression in neonates although this was significantly less than that caused by pethidine. The incidence of other opioid-related adverse effects, such as constipation, appears to be low with tramadol.

Dosage

Tramadol is available for oral, parenteral and rectal use. Tramadol dose should be titrated according to the pain intensity and the response of the individual patient, with 50 to 100mg 4 times daily usually providing adequate pain relief. A total daily dose of 400mg is usually sufficient. Intravenous injections should be administered slowly to reduce the potential for adverse events, particularly nausea. Based on pharmacokinetic data, caution should be observed in patients with renal or hepatic dysfunction as the potential for delayed elimination and accumulation of the drug exists. In these patients the dosage interval should be extended. Tramadol may be used in children at a dosage of 1 to 2 mg/kg.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    C. Rhoda Lee, Donna McTavish & Eugene M. Sorkin

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  1. C. Rhoda Lee
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  2. Donna McTavish
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Various sections of the manuscript reviewed by: E. Alon, Institut für Anästhesiologie, Universitätsspital, Zürich, Switzerland; S.S. Bloomfield, Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA; R.J. Fragen, Department of Anesthesia, Northwestern University Medical School, Chicago, Illinois, USA; T.J. Gal, University of Virginia, Health Sciences Center, Charlottesville, Virginia, USA; I. Jurna, Institut für Pharmakologie und Toxikologie der Universität des Saarlandes, Homburg/Saar, Federal Republic of Germany; Ch. Kainz, 2nd Department of Obstetrics and Gynecology, University of Vienna Medical School, Vienna, Austria; V. Kayser, Institut National de la Santé et de la Recherche Médicale, Paris, France; B. Lachmann, Department of Anesthesiology, Erasmus University, Rotterdam, The Netherlands; K.A. Lehmann, Institut für Anaesthesiologie und Operative Intensivmedizin der Universität zu Köln, Köln, Federal Republic of Germany; N.A. Osipova, Department of Anaesthesiology and Reanimation, P.A. Herzen Research Institute of Oncology, Moscow, Russia; J. Sawynok, Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada; J. Schäffer, Abteilung Anästhesiologie II, Medizinische Hochschule Hannover, Hannover, Federal Republic of Germany; T. Suvonnakote, Department of Obstetrics and Gynaecology, Siriraj Hospital, Bangkok, Thailand; J.A. Vale, West Midlands Poisons Unit, Dudley Road Hospital, Birmingham, England; M.D. Vickers, Department of Anaesthetics, University of Wales College of Medicine, Cardiff, Wales.

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Lee, C.R., McTavish, D. & Sorkin, E.M. Tramadol. Drugs 46, 313–340 (1993). https://doi.org/10.2165/00003495-199346020-00008

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