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Opioids in Patients with Renal or Hepatic Dysfunction

The use of opioids in geriatric patients and those with hepatic or renal insufficiency can present significant challenges for clinicians.
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Clinicians are often confronted with patients who have renal and/or hepatic dysfunction, including the elderly. These patients pose unique challenges related to opioid choice and dosing considerations. In this review, Dr. Carbonara provides the clinician with practical pharmacokinetic/ pharmacodynamic information from which to base rational treatment decisions.

Charles D. Ponte, PharmD, CDE, BCPS, FASHP, FCCP, FAPhA

In 2006, approximately 26% of Americans, or 76.5 million people, older than 20 years of age reported that they had suffered pain lasting more than 24 hours.1 Of those suffering from pain, 42% reported that the pain lasted longer than one year.1

The use of opioids for chronic non-malignant pain has become increasingly accepted. Based on the World Health Organization analgesic ladder for pain, opioids should be instituted for pain that is classified as moderate to severe or when non-opioid analgesics have failed to achieve optimal pain control.2 Opioids must be carefully managed for all patients to effectively control pain while minimizing adverse effects.

Renal Insufficiency

An estimated 37 to 50% of hemodialysis patients experience chronic pain, with 82% of that pain classified as moderate to severe.3,4 Patients may suffer from pain related to their primary renal condition, but often other factors contribute to their reports of pain. Patients with renal insufficiency experience pain that is multi-factorial, since co-morbidities such as vascular diseases and diabetes may lead to neuropathic pain, and arthritis may cause musculoskeletal pain.4

Opioids are often needed for effective pain control for these patients. The absorption, metabolism, and renal clearance of opioid analgesics are often quite complex requiring frequent dose adjustments and medication changes.3,4 The properties of the parent drug and its metabolites must be considered when selecting an opioid analgesic for this patient population.4,5 For example, meperidine is metabolized in the liver to the metabolite normeperidine—a CNS excitotoxin—and then excreted by the kidneys. In cases of renal insufficiency, normeperidine accumulates and may cause anxiety, tremors, myoclonus, and generalized seizures and is therefore not recommended for use in renal insufficiency.6 Unfortunately, the data on the pharmacokinetic and pharmacodynamic properties of some opioids is limited and sometimes conflicting—presenting additional challenges for clinicians.4 For example, oxymorphone—the only active metabolite of oxycodone—was found to have no pharmacodynamic effects in subjects with normal renal function but the cumulative effects of this metabolite in renal failure are not known.7 The author reported CNS toxicity and sedation with normal doses of oxycodone with renal failure,7 so that clinical experience is often necessary to determine the most appropriate opioid analgesics for patients.

Glomerular filtration rate (GFR) is one measure of the elimination of opioid analgesics from the body. The chemical properties of opioids (weak organic bases) may be altered by urine pH thus affecting the relationship between GFR and renal elimination. Nevertheless, GFR is sometimes used by clinicians to assist with opioid analgesics dose adjustments in patients with renal insufficiency.7 For example, the dose of morphine may be initiated at 75% of the normal dose for patients with a GFR of 20-50 mL/min.7

Table 1 provides general recommendations for common opioid use in patients with renal insufficiency.

Hepatic Insufficiency

Many patients suffering from liver failure may experience pain. The pain may have various causes, including pain from the stretching of the liver capsule or bone pain caused by metastatic liver cancer.8 Therefore, treatment with opioid analgesics is often needed for effective control of moderate to severe pain.

As the liver is primarily responsible for the metabolism of opioid drugs to their metabolites, the pharmacokinetic and pharmacodynamic properties must be carefully reviewed prior to initiating these agents in this patient population.5 Oxidation is the major metabolic pathway of most opioids with the exception of morphine and buprenorphine, and oxidation is decreased in patients with hepatic cirrhosis.8 This may result in decreased drug clearance, increased oral bioavailability, and decreased first-pass metabolism.8 These factors must be considered when selecting and dosing opioid analgesics.8 Morphine, although metabolized through glucoronidation, has also been shown to have decreased clearance and increased oral bioavailability in patients with liver cirrhosis.9

Decreases in drug metabolism with liver insufficiency can therefore lead to accumulation of the drug in the body with repeated administration and long-term use. Therefore, lower doses and longer administration intervals may be warranted.9

Table 2 provides general recommendations for common opioid use in patients with liver insufficiency.

Geriatric Patients

The incidence of painful conditions is quite high in geriatric patients yet their pain is often undertreated. The American Geriatric Foundation reports that approximately 25-50% of community-dwelling elders can expect to suffer pain and 71-83% of institutionalized elders report some type of pain.1 Therefore, geriatric patients represent another challenging population for pain management clinicians. Economic, emotional, and physiologic issues must all be carefully considered in this population. The assessment and management of pain in the elderly may often be difficult. Loss of sensory neurons may result in altered perception of pain, and pain assessment is often impacted by co-morbid conditions such as dementia.10

Altered pharmacokinetic and pharmacodynamic profiles pose an additional challenge for effective treatment of chronic pain in the elderly. Pharmacokinetic changes include delayed elimination of drugs due to hepatic and renal insufficiency, reduced receptor sites for drug binding, and reduced volume of distribution.10 There is often a narrow therapeutic index for opioid analgesics related to hepatic and renal insufficiency and an increased sensitivity to CNS drugs and so adverse effects must be carefully monitored.10,11 For example, in older patients, a longer duration of action has been observed following morphine administration due to a prolonged elimination of the drug from the plasma.6

The use of opioid analgesics for geriatric patients with moderate to severe, chronic, non-malignant pain is becoming increasingly accepted.12 It is important to recognize that in addition to the possibility of an increased sensitivity to CNS agents, geriatric patients should also be monitored for drug-drug and drug-disease interactions prior to the initiation of an opioid analgesic.11 For patients older than 70 years of age, doses should be initiated at 25 to 50% of the adult recommended started dose then slowly titrated upward to minimize adverse effects.6

Last updated on: December 20, 2011
First published on: May 1, 2008