Tramadol is an opioid analgesic used for the therapy of mild-to-moderate pain. Tramadol overdose can cause acute liver failure. Pharmacologic doses 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 generics) and are given once daily. Physical dependence can occur, and while the potential for abuse is less than with more typical opioid analgesics, tramadol is classified as a schedule IV drug and is provided under a risk evaluation and mitigation strategy (REMS). Common side effects are nausea, dizziness, dry mouth, sedation and headache. Tramadol may increase the risk of seizures. It is considered contraindicated in children below the age of 12 because of risk of respiratory depression, and prolonged use should be avoided in pregnancy because of the risk of infant withdrawal syndrome. Rare but potentially severe adverse events include seizures, severe respiratory depression, serotonin syndrome, addiction, abuse and withdrawal syndrome.


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.

Likelihood score: E* (unproven cause of liver injury in therapeutic doses but reported to cause liver injury with overdose).

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).

Drug Class: Opioids



Tramadol – Generic, Ultram®




Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 24 November 2020

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