Published: October 2000

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Tramadol

Information on this subject has been updated. Read the most recent information.

Prescriber Update 20: 26-30
October 2000

Professor Stephan A. Schug MD FANZCA FFPMANZCA & Anita Lim BScDivision of Anaesthesiology, Faculty of Medical and Health Sciences, University of Auckland, Auckland

Tramadol (Tramal™) is a synthetic, centrally acting analgesic used parenterally and orally for the treatment of moderate to severe pain.  It was approved in New Zealand in 1997, but it is not currently funded.  Its potency is comparable to that of pethidine, but in severe pain morphine is possibly superior.
Respiratory depression and constipation are less common with tramadol and less pronounced than with other opioids.  However, respiratory depression can occur, in particular, after overdose and with impaired renal function.  Unlike other opioids, tramadol is not usually associated with the development of tolerance, physical dependence or psychological addiction.  In clinical trials the most common adverse reactions, in decreasing frequency, were nausea, dizziness, drowsiness, tiredness, fatigue, sweating, vomiting, dry mouth and postural hypotension.  Tramadol may possibly increase the risk of seizures in those with a history of epilepsy or those on medication, which lowers the seizure threshold, but it appears that tramadol does not induce idiopathic seizures except at very high doses.  Tramadol is contraindicated in users of MAO inhibitors as a safety precaution and, because of the risk of serotonin syndrome, should be used with caution in combination with SSRIs.
In overdose, tramadol induces significant neurological toxicity (seizures, coma, respiratory depression), but cardiovascular toxicity is mild.

Tramadol (Tramal™) is a synthetic, centrally-acting analgesic used parenterally and orally for the treatment of moderate to severe pain.  While tramadol was not granted marketing consent in New Zealand until 1997, and it is not currently listed in the Pharmaceutical Schedule, experience in other countries dates back more than 20 years.  In 1998, tramadol became the most used centrally-acting analgesic worldwide; outselling morphine in dollars turned over.¹ The success of tramadol is mainly a result of its favourable side effect profile, which differs significantly from that of other opioids.

Proven efficacy in a broad range of painful conditions

Tramadol has a dose-dependent efficacy that lies between that of codeine and morphine, with a parenteral potency comparable to that of pethidine, i.e. about 10-20% of the gold standard morphine.²  Oral bioavailability is high (85-100%) and permits easy conversion from the oral to the parenteral route and visa versa.  Surprisingly, the efficacy of tramadol is not associated with the usual serious opioid side effects which can often be dose-limiting.  Furthermore, unlike nonsteroidal anti-inflammatory drugs, tramadol has no serious adverse gastrointestinal effects, such as gastrointestinal bleeding.  Numerous clinical trials have proven its efficacy and safety over a broad range of painful conditions, both acute and chronic; however, in severe pain morphine may be superior to tramadol.³ It is this combination of safety with good efficacy that has made tramadol a unique addition to the analgesic armamentarium.

Dual mechanism may explain improved side effect profile

The novel way in which tramadol provides analgesia with fewer side effects may be explained by its dual mechanism of action, opioid and monoaminergic.  Its major metabolite O-desmethyl tramadol (M1) has a weak affinity at μ-opioid receptors as an agonist.  The monoaminergic activity comes through the two stereoisomers of tramadol itself, which act synergistically on serotonergic and noradrenergic mechanisms of pain transmission.  More specifically, tramadol enhances spinal pain inhibitory pathways by inhibiting neuronal re-uptake of serotonin (5-HT) and noradrenaline (NA), and stimulating 5-HT release.^4,5  This added monoaminergic component possibly allows tramadol’s efficacy to stretch over a wider range of painful pathologies than other opioids.

Constipation & respiratory depression: less likely, less pronounced

Respiratory depression with tramadol is less pronounced, and occurs less often, in comparison to equianalgesic doses of morphine.^3,6  In large clinical and post-marketing studies including over 21,000 patients, no clinically relevant respiratory depression was reported.⁷  However, respiratory depression can occur, in particular with overdose⁸ (as described in children⁹) or with impaired renal function,¹⁰ possibly due to retention of the active metabolite M1.

Another opioid side effect, which is reduced with tramadol use, is constipation.¹¹ Clinically this has proven to be a significant advantage with long-term therapy, but could also be beneficial in the prevention of ileus postoperatively.

Low dependence potential

The effects of long-term opioid intake on the development of tolerance, physical dependence and psychological addiction are reduced with tramadol use.  In an experimental setting, it was demonstrated that even experienced opioid users could not recognise tramadol in lower doses as an opioid,¹² whereas in higher doses they could recognise it, but did not “like” it, presumably due to its tricyclic-like properties. Hence, the incidence of abuse of tramadol is low in all post-marketing surveys; the FDA reports a rate of abuse in the range of 1 in 100,000 patient exposures.¹³  Furthermore, tramadol is not registered as a controlled drug in any country.  However, this does not mean that its use in “at-risk” patients should be encouraged.  Rare cases of withdrawal reactions after abrupt discontinuation of tramadol have also been reported.⁷

Other adverse effects: nausea, vomiting, sweating

The most common adverse events reported in clinical trials and post-marketing studies were, in decreasing order of frequency (range 7 to 1%): nausea, dizziness, drowsiness, tiredness, fatigue, sweating, vomiting, dry mouth and postural hypotension.⁷  Nausea, a well-documented opioid side effect, seems to occur with an incidence comparable to that in other opioids, while vomiting is less common. The incidence of nausea varied with route and setting of administration from 3% in controlled trials of oral medication, to 21% with IV use via patient controlled analgesia (PCA) pumps in the postoperative period.  Avoidance of early mobilisation after IV administration, initiation of oral treatment at low doses with gradual increase, and use of antiemetics (phenothiazines and/or 5-HT₃-antagonists) can reduce the incidence and severity of this side effect.

Sweating is a side effect specific to tramadol, due to its monoaminergic effects, and it can be quite distressing to a small number of patients.¹⁴ In rare situations, sweating may be severe enough to necessitate discontinuation.

Caution in epileptics & those on tricyclics, SSRIs, high dose opioids

The issue of possible tramadol-induced seizures has been discussed increasingly in international literature.  Overall, there is no good evidence that tramadol use by itself can induce idiopathic seizures, except possibly in excessive doses.¹⁵  However, tramadol should be used with caution in patients with a history of epilepsy and those on concomitant seizure threshold-lowering medication (e.g. tricyclics, selective serotonin re-uptake inhibitors, high dose opioids).

Tramadol contraindicated in patients on MAOIs

There are now a number of case reports, which suggest induction of a serotonin syndrome by combination of tramadol with SSRIs.^16,17  Such combinations may be used with caution.  Although no reports of drug interactions with MAO inhibitors have been published, the concomitant use of MAOIs with tramadol is contraindicated as a safety precaution.  Other relevant interactions between tramadol and concomitant medication have not been described.  Initial reports of an interaction between tramadol and coumarins with prolongation of INR could not be confirmed.¹⁸

Overdosage can induce seizures & respiratory depression

In overdose, tramadol produces significant neurologic toxicity such as seizures, coma and respiratory depression, while cardiovascular toxicity seems to be limited to mild tachycardia and hypertension.⁸ When seizures do occur with tramadol use, they are commonly of short duration and are easily treatable.  In one reported case of a seizure, the convulsions were induced by naloxone administration.⁸  Hence, although respiratory depression in overdose can be treated with the opioid antagonist, naloxone, reversal of all opioid poisoning should be conducted with low doses, repeated as clinically indicated, to avoid rebound effects including pain, hypertension, tachycardia and seizures.

Competing interests: Professor Schug has been and is involved in clinical research on tramadol, partially funded or supported by Grünenthal GmbH, Stolberg, Germany and CSL (New Zealand) Ltd., Auckland.

Correspondence to Professor Stephan Schug, Head, Division of Anaesthesiology, Faculty of Medical and Health Sciences, University of Auckland, PO Box 92019, Auckland, New Zealand. Phone 09 373 7599 ext 6401 fax 09 373 7556,  e-mail s.schug@auckland.ac.nz

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