Is Tramadol (tramadol hydrochloride) nephrotoxic, causing impaired renal function?

From the Guidelines

Tramadol is not recommended for patients with renal insufficiency (GFR <30 mL/min/1.73 m2) and ESRD due to the risk of accumulation of the drug and its metabolites, which can lead to increased toxicity 1.

Key Considerations

• Tramadol is metabolized primarily by the liver, with its metabolites being excreted through the kidneys 1.
• Dosage adjustments are necessary for patients with existing kidney impairment, as the drug and its metabolites can accumulate in these individuals 1.
• For patients with severe renal impairment, alternative opioids such as methadone, which is excreted fecally, may be considered 1.
• Opioids primarily eliminated in urine, such as fentanyl, oxycodone, and hydromorphone, should be carefully titrated and frequently monitored for risk of accumulation of the parent drug or active metabolites 1.

Clinical Implications

• Tramadol should be avoided in patients with renal insufficiency or ESRD, unless there are no alternatives 1.
• Clinicians should perform more frequent clinical observation and opioid dose adjustment in patients with renal or hepatic impairment who receive opioids 1.
• Adequate hydration should be maintained during tramadol therapy to support kidney health.
• Patients on long-term tramadol therapy, especially those with pre-existing kidney disease, the elderly, or those taking other medications that might affect kidney function, should be closely monitored for signs of kidney injury or impairment 1.

From the FDA Drug Label

Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. In patients with creatinine clearances of less than 30 mL/min, dosing reduction is recommended (see DOSAGE AND ADMINISTRATION).

The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose

Renal Impaired, Tramadol c c 4.23 (54) 10.6 (31) CLcr10-30 mL/min M1 c c c 11.5 (40) 100 mg SD i.v Renal Impaired, CLcr<5mL/min 100 mg SD i.v

Special Populations Renal Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1

Tramadol is not directly nephrotoxic. However, impaired renal function can affect the excretion of tramadol and its active metabolite, M1, leading to increased plasma concentrations and potentially increased risk of adverse effects.

• Dosing reduction is recommended in patients with creatinine clearances of less than 30 mL/min 2.
• The drug label does not provide direct evidence of tramadol being nephrotoxic, but rather highlights the importance of renal function in the excretion of tramadol and its metabolites 2 2.

From the Research

Tramadol Nephrotoxicity

• Tramadol can be nephrotoxic, particularly with high doses or chronic administration 3.
• Renal impairment can reduce the elimination of tramadol and its metabolites, leading to accumulation and toxicity 4, 5.
• Studies have shown that tramadol can cause renal injury, including inflammation, necrosis, and tubular degeneration 3.
• Mitochondrial dysfunction and oxidative stress are involved in the mechanism of tramadol-induced renal injury 3.
• Tramadol should be used with caution and in reduced doses in patients with renal impairment 4, 5.
• There have been cases of transient acute kidney injury associated with tramadol ingestion, which may not require aggressive intervention 6.
• The incidence of new outpatient tramadol prescriptions has decreased after the publication of the 2016 Centers for Disease Control and Prevention Opioid Guideline 7.

Key Findings

• Tramadol can cause renal injury and should be used with caution in patients with renal impairment.
• High doses or chronic administration of tramadol can lead to nephrotoxicity.
• Mitochondrial dysfunction and oxidative stress are involved in the mechanism of tramadol-induced renal injury.
• Tramadol should be dosed correctly based on kidney function to minimize the risk of nephrotoxicity.

Clinical Implications

• Healthcare providers should be aware of the potential nephrotoxicity of tramadol and use it with caution in patients with renal impairment.
• Patients with renal impairment should be monitored closely for signs of nephrotoxicity when taking tramadol.
• Tramadol should be used at the lowest effective dose and for the shortest duration necessary to minimize the risk of nephrotoxicity.