Analgesics in Patients with Hepatic Impairment

Abstract

The physiological changes that accompany hepatic impairment alter drug disposition. Porto-systemic shunting might decrease the first-pass metabolism of a drug and lead to increased oral bioavailability of highly extracted drugs. Distribution can also be altered as a result of impaired production of drug-binding proteins or changes in body composition. Furthermore, the activity and capacity of hepatic drug metabolizing enzymes might be affected to various degrees in patients with chronic liver disease. These changes would result in increased concentrations and reduced plasma clearance of drugs, which is often difficult to predict. The pharmacology of analgesics is also altered in liver disease. Pain management in hepatically impaired patients is challenging owing to a lack of evidence-based guidelines for the use of analgesics in this population. Complications such as bleeding due to antiplatelet activity, gastrointestinal irritation, and renal failure are more likely to occur with nonsteroidal anti-inflammatory drugs in patients with severe hepatic impairment. Thus, this analgesic class should be avoided in this population. The pharmacokinetic parameters of paracetamol (acetaminophen) are altered in patients with severe liver disease, but the short-term use of this drug at reduced doses (2 grams daily) appears to be safe in patients with non-alcoholic liver disease. The disposition of a large number of opioid drugs is affected in the presence of hepatic impairment. Certain opioids such as codeine or tramadol, for instance, rely on hepatic biotransformation to active metabolites. A possible reduction of their analgesic effect would be the expected pharmacodynamic consequence of hepatic impairment. Some opioids, such as pethidine (meperidine), have toxic metabolites. The slower elimination of these metabolites can result in an increased risk of toxicity in patients with liver disease, and these drugs should be avoided in this population. The drug clearance of a number of opioids, such as morphine, oxycodone, tramadol and alfentanil, might be decreased in moderate or severe hepatic impairment. For the highly excreted morphine, hydromorphone and oxycodone, an important increase in bioavailability occurs after oral administration in patients with hepatic impairment. Lower doses and/or longer administration intervals should be used when these opioids are administered to patients with liver disease to avoid the risk of accumulation and the potential increase of adverse effects. Finally, the pharmacokinetics of phenylpiperidine opioids such as fentanyl, sufentanil and remifentanil appear to be unaffected in hepatic disease. All opioid drugs can precipitate or aggravate hepatic encephalopathy in patients with severe liver disease, thus requiring cautious use and careful monitoring.

Population Pharmacokinetics of Fentanyl in the Critically Ill*

“…Like many liphophilic drugs, fentanyl redistributes to the peripheral tissues and accumulates when infused over a longer period of time, leading to a longer half-time than is the case with shorter infusions. Our results suggest clinicians should be especially cautious when using a fentanyl infusion or multiple boluses in the setting of liver dysfunction or congestive heart failure, supporting recommendations outlined in a recent review (32), which highlighted the need for data regarding the pharmacokinetics of continuously infused fentanyl in cirrhotic patients. Similar to severe liver disease, congestive heart failure was also a risk factor for reduced fentanyl clearance in our study, a novel finding suggesting judicious dosing is warranted in the setting of heart failure.…”

Effect of Experimentally Induced Hepatic and Renal Failure on the Pharmacokinetics of Topiramate in Rats

“…In addition, the observed significant increase in AUC 0- ∞ in CCl 4 -treated rats could be related to portal-systemic shunting, which occurs frequently in advanced liver disease. This complication may substantially decrease drug metabolism and result in a significant decrease in nonrenal clearance [17]. In accordance with our findings, Brockmöller and coworkers investigated possible changes in the pharmacokinetics of levetiracetam in patients with liver cirrhosis.…”

Cardiopulmonary Bypass Ischemic Hepatitis Reported in Five Patients

“…Inadequate anticoagulation due to the quality of heparin and protamine, etc). Sufentanil was used in all patients, but the pharmacokinetics of phenylpiperidine opioids such as fentanyl, sufentanil, and remifentanil appear to be unaffected by hepatic disease [11] .…”