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Cancer pain management using opioids in renal or hepatic dysfunction

Issue: October 10, 2008

ByStephanie M. Harman, MD, FACP

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Many patients with cancer develop hepatic or renal dysfunction during the course of their illness. A 2007 study by Launay-Vaucher et al examined the prevalence of renal insufficiency in more than 4,500 patients with cancer and found an estimated 20% to have a creatinine clearance less than 60 mL/min. Some patients have comorbid organ dysfunction at the time of their cancer diagnosis as well. Both primary and secondary hepatic and renal dysfunction complicate the use of opioids for cancer pain due to the following key reasons:

• impaired clearance of the parent drug.
• production and accumulation of active metabolites.
• direct toxicity from the drug itself.

In 2005, Murphy examined the evidence for dosing strategies and mechanisms of toxicity for different analgesic medications in the setting of organ dysfunction. His review provided a framework to guide management, which will be presented here, highlighting the more common opioids used in cancer pain.

Opioids are metabolized by the liver, but excretion of the parent drug as well as the metabolites primarily relies on the kidney. Although opioids are commonly associated with adverse events such as constipation and nausea, their use in the setting of renal dysfunction leads to additional adverse events of neurotoxicity due to the accumulation of active metabolites. A phenomenon of “delayed toxicity” can occur where initially patients tolerate the opioid but later develop adverse events after multiple doses due to accumulation of the opioid metabolites, which often have different properties compared to the parent drug.

The most common offenders amongst the active metabolites are the glucuronidated metabolites, such as morphine-3-glucuronide and hydromorphone-3-glucuronide. These metabolites are primarily neuroexcitatory in nature, causing myoclonus, hyperalgesia, and/or delirium; in severe cases, patients can even develop seizures. These effects can be mediated by reducing the opioid dose, if possible, and rotating to a different opioid. The neuroexcitation also responds to benzodiazepine therapy, if the opioid dose needs to remain the same to maintain pain control. Clonazepam has been shown effective, but other benzodiazepines such as lorazepam or diazepam can be used as alternatives.

In hepatic dysfunction, the biotransformation of opioids is impaired, causing accumulation of the parent drug rather than the metabolites. This then leads to increased bioavailability and subsequent toxicities, including sedation and respiratory depression. There have been fewer studies on opioid use in hepatic dysfunction than renal dysfunction, but in general, long-acting or extended-release formulations should be used with caution in patients with severe hepatic impairment due to decreased overall metabolism by the liver.

Metabolism does vary between opioids so that some have better safety profiles than others. There are recommended doses for common opioids in both renal and hepatic dysfunction (see chart). Codeine, meperidine, and propoxyphene are not recommended for use in patients with renal or hepatic dysfunction, primarily due to the higher risk of central nervous system side effects from their specific metabolites. The accumulation of normeperidine, meperidine’s primary metabolite, has been associated with seizures and even death.

In summary, for the management of cancer pain in patients with renal or hepatic dysfunction:

1) Start low and go slow.
2) Use short-acting opioids initially before moving to extended-release formulations.
3) Monitor patients carefully for limiting side effects and changing status.

Stephanie Harman, MD, is a Palliative Care Physician at Stanford University Medical Center and Director its Inpatient Palliative Care service.

For more information:

• Abrahm, JL. A Physician’s Guide to Pain and Symptom Management in Cancer Patients. 2nd ed. Baltimore: The Johns Hopkins University Press: 2005.
• Davis, MP et al. Practical guide to opioids and their complications in managing cancer pain—what oncologists need to know. Oncology (Williston Park). 2007;21:1229-1238.
• Johnson, SJ. Opioid safety in patients with renal or hepatic dysfunction. Pain Treatment Topics 2007; November. http://pain-topics.org/opioid_rx/safety.php#RenalHepatic.
• Launay-Vaucher, V et al. Prevalence of renal insufficiency in cancer patients and implications for anticancer drug management. Cancer. 2007;110:1376-1384.
• Mercadante, S. Pathophysiology and treatment of opioid-related myoclonus in cancer patients. Pain. 1998;74:5-9.
• Murphy, EJ. Acute pain management pharmacology for the patient with concurrent renal or hepatic disease. Anaesth Intensive Care. 2005;33:311-322.