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Tramadol - the Highs and Lows

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Prescriber Update 35(4): 49-51
December 2014

Key Messages

Tramadol is a centrally-acting synthetic analgesic with a dual mechanism of action - binding at µ-opioid receptors and inhibiting noradrenaline and serotonin re-uptake.
The most notable side effects of tramadol include serotonin syndrome/toxicity, seizures (including lowered seizure threshold), respiratory depression, increased intracranial pressure and anaphylactoid reactions.
Common adverse reactions include nausea, vomiting, constipation, dizziness, autonomic nervous effects (mainly dry mouth, perspiration), headache, sedation, asthenia (weakness) and fatigue.
Tramadol is metabolised primarily by CYP2D6. CYP2D6 polymorphisms may affect the metabolism of tramadol alone as well as form the basis for interactions (eg, warfarin).

Tramadol is a centrally-acting synthetic analgesic used for the relief of moderate to severe pain. Tramadol and its principal metabolite O-desmethyltramadol (M1) have opioid-like effects since they bind to µ-opioid receptors distributed throughout the central nervous system (CNS). The binding affinity of tramadol for µ-opioid receptors is approximately 6,000-fold less than morphine and approximately 20-fold less for M1¹. In addition to its opioid actions, tramadol also inhibits the neuronal re-uptake of noradrenaline (NA) and serotonin (5-HT). The data sheet provides more information on tramadol (www.medsafe.govt.nz/Medicines/infoSearch.asp).

Key characteristics of Tramadol

Dependence and opioid effects

The dual mechanism of action may reduce the risk of opioid-associated adverse reactions and the potential for tolerance, dependence or abuse. However, a risk still remains so caution is recommended when prescribing. Tramadol must not be used for opioid withdrawal treatment as it cannot suppress opioid withdrawal symptoms. In addition, tramadol is contraindicated in patients with acute intoxication due to alcohol, hypnotics, analgesics, opioids or psychotropic drugs².

Tramadol should be administered with caution in patients at risk of respiratory depression and in patients with increased intracranial pressure, head injury, shock or a reduced level of consciousness of uncertain origin².

The µ-opioid receptors are found throughout the CNS and are also found in the intestinal tract. Although less pronounced than with true opiate analgesics, tramadol may also cause constipation due to reduced gut motility³. Other commonly reported adverse reactions associated with tramadol use include nausea and vomiting, dizziness, autonomic nervous effects (dry mouth, perspiration/sweating), headache, sedation, asthenia (weakness) and fatigue².

Seizures

Tramadol, both alone or in combination with other medicines, may lower the threshold for seizures and is contraindicated in patients with uncontrolled epilepsy ⁴. The Centre for Adverse Reactions Monitoring (CARM) has received a total of 19 reports of convulsions, grand mal convulsions or convulsions aggravated associated with the use of tramadol since 2000. The convulsions were life-threatening in two cases and 14 patients required hospitalisation. The patients recovered in all cases except one where the outcome was unknown. In the majority of cases symptom onset was within 12 hours of the start of tramadol administration.

Serotonin Syndrome/Toxicity

As tramadol inhibits re-uptake of NA and 5-HT, use with other serotonergic agents increases the risk of serotonin syndrome/ toxicity. Tramadol should be used with caution in patients requiring selective serotonin re-uptake inhibitors (SSRIs), serotonin-noradrenaline re-uptake inhibitors (SNRIs) and tricyclic antidepressants. Use of tramadol is contraindicated in patients also taking monoamine oxidase inhibitors (MAOIs) and those who have taken MAOIs within the last 14 days².

CARM has received six reports since 2000 where tramadol use may have contributed to serotonin syndrome/toxicity. In four of these reports the patient required hospitalisation. Concomitant medicines included paroxetine, citalopram, fentanyl, methylene blue, fluoxetine, sibutramine and sertraline (some patients were taking more than one contributing medicine). If serotonin syndrome/toxicity is suspected, prompt withdrawal of the serotonergic medicines is recommended.

Serotonin syndrome/ toxicity usually occurs after initiating or increasing the dose of a serotonergic medicine. A serotonin syndrome/toxicity reminder is available at: www.medsafe.govt.nz/profs/PUArticles/SerotoninSyndromeToxicityReminder.htm.

Interactions

Tramadol is metabolised to its principal active metabolite M1, through O-demethylation by cytochrome p450 (CYP) isoenzyme 2D6 (CYP2D6). Poor metabolisers of medicines via CYP2D6 may therefore get less benefit from tramadol use due to reduced formation of the active metabolite^3,5.

The isoenzymes CYP3A4 and CYP2B6 are involved in the metabolism of tramadol via N-demethylation to a secondary metabolite M2¹. The addition of a CYP3A4 inhibitor may also inhibit the metabolism of tramadol and reduce the therapeutic response (eg, erythromycin, itraconazole).

Six reports of an interaction between oral tramadol and warfarin have been submitted to CARM since 2000. An elevated international normalised ratio (INR) was described in four reports, with onset occurring up to seven days after tramadol was commenced in patients stabilised on warfarin. In five cases, the patients developed haemorrhage-related symptoms, such as melaena, anaemia and purpura. The mechanism for this interaction has not been fully elucidated, but may be due to CYP2D6 polymorphism, which subsequently increases competition for CYP3A4 metabolism (involved in metabolism of R-warfarin)⁶. Caution should be exercised if tramadol and warfarin are used concurrently².

CNS depressants such as alcohol, opioids, anaesthetic agents, phenothiazines and sedative hypnotics may potentiate the sedating effects of tramadol, and should therefore be used with caution and in reduced doses².

Overdose

Although some evidence suggests there is less risk of respiratory depression with tramadol, the symptoms of tramadol overdose are similar to other centrally acting analgesics and include coma, convulsion, respiratory depression, respiratory arrest and cardiovascular collapse¹. Seizures may also occur with overdose.

Tramadol Dosing Guidelines

Tramadol is currently available as drops, capsules and tablets for oral use and solution for intramuscular or intravenous injection. Sustained release tablets and immediate release capsules are fully funded in the community. The dose of tramadol should be titrated to the severity of the pain and the clinical response of the individual, taking into account patient-specific factors.

Maximum daily dose in adults and children over 12 years of age:

Injectable tramadol 600mg per day (post-operative pain only); normally 400mg per day
Oral tramadol 400mg per day
Paediatric (2 years and older) recommended dose 1-2mg/kg up to a maximum daily dose to the lesser of 8mg/kg/day or 400mg per day
Elderly (75 years and older) 300mg per day

As tramadol is metabolised by the liver and excreted by the kidneys doses should be reduced in patients with hepatic or renal impairment.

Healthcare professionals are encouraged to report any adverse events, including events associated with tramadol, to CARM. Reports may be submitted on paper or electronically ( http://carm.otago.ac.nz/).

References

;Grond S and Sablotzki A. 2004. Clinical Pharmacology of Tramadol. Clinical Pharmacokinetics 43(13): 879-923.
bioCSL (NZ) Limited. 2013. Tramal Data Sheet April 2013. URL: www.medsafe.govt.nz/profs/datasheet/t/TramalcapSRtabinjoraldrops.pdf (accessed 6 October 2014).
Shipton EA. 2000. Tramadol - Present and Future. Anaesthesia and Intensive Care 28(4): 363-374.
Kaye K. 2004. Trouble with Tramadol. Australian Prescriber 27: 26-27.
Zahari Z and Ismail R. 2014. Influence of Cytochrome P450, Family 2, Subfamily D, Polypeptide 6 (CYP2D6) Polymorphisms on Pain Sensitivity and Clinical Response to Weak Opioid Analgesics. Drug Metabolism and Pharmacokinetics 29(1): 29-43.
Hedenmalm K, Lindh JD, Sawe J et al. 2004. Increased liability of tramadol-warfarin interaction in individuals with mutations in the cytochrome P₄₅₀ 2D6 gene. European Journal of Clinical Pharmacology 60 (5): 369-372.