Tramadol is an opioid analgesic used for the therapy of mild-to-moderate pain. Tramadol overdose can cause acute liver failure. Pharmacologic use of tramadol has not been associated with cases of clinically apparent drug induced liver disease.
Tramadol is a synthetic codeine analog that acts as a weak opioid agonist in addition to mildly inhibiting serotonin and norepinephrine reuptake. Tramadol is effective against mild-to-moderate pain, but is not as effective as standard opioids and not recommended for severe pain. Tramadol was approved for use in the United States in 1995 and is currently widely used, with more than 18 million prescriptions written yearly. Tramadol is available in 50 mg tablets in multiple generic forms and under the brand name Ultram. It is also available as tablets of 37.5 mg in combination with acetaminophen (325 mg) both generically and under the brand name Ultracet. The usual dose in adults is initially 25 mg daily, with titration based on effect and tolerance to 50 to 100 mg every 4 to 6 hours as needed for pain, but not to exceed 400 mg daily. Extended release formulations in capsules of 100, 200 and 300 mg are also available (Conzip) and are given once daily. Physical dependence is uncommon, and the potential for abuse is less than with more typical opioid analgesics for which reason tramadol is not classified as a scheduled drug. Common side effects are nausea, dizziness, dry mouth, sedation and headache. Tramadol may increase the risk of seizures.
Serum aminotransferase levels can be elevated in a small proportion of patients receiving tramadol, particularly with high doses. Intentional and accidental overdoses of tramadol can cause respiratory arrest as well as acute liver failure, several fatal instances of which have been reported. In these cases, however, the liver injury may have been caused by shock, hypoxia or ischemia secondary to the respiratory arrest. Liver injury attributed to tramadol overdose has also been associated with hyperammonemia, lactic acidosis and hepatic steatosis, suggestive of direct mitochondrial injury. In some situations, acute liver failure after tramadol overdose may be related to acetaminophen taken separately or in combination with tramadol. Clinically apparent idiosyncratic liver injury with recommended doses of tramadol has not been reported and must be rare, if it occurs at all.
Mechanism of Injury
The mechanism of hepatotoxicity from overdoses of tramadol is not known, but is likely due to direct hepatocellular injury, either as a result of ischemia or mitochondrial toxicity. Tramadol is metabolized by the liver, predominantly by CYP 2D6 and 3A4 to its active form and it can result in troublesome drug-drug interactions.
Outcome and Management
The minor enzyme elevations that occur with tramadol use are usually mild, asymptomatic and self-limited, resolving even with continuation of therapy. Cases of acute liver failure due to tramadol overdose require intensive medical management and can be fatal. In acute overdoses, there may be interaction with other agents capable of causing liver injury (particularly acetaminophen).
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REPRESENTATIVE TRADE NAMES
Tramadol – Generic, Ultram®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 05 December 2012
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Leppert W. Tramadol as an analgesic for mild to moderate cancer pain. Pharmacol Rep 2009; 61: 978-92. PubMed Citation (Review of mechanism of action, pharmacology, efficacy and safety of tramadol in mild-to-moderate cancer pain; side effects occur in 1-6% of patients, but serious adverse effects are very rare; hepatotoxicity and ALT abnormalities are not discussed).
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