Safe Usage of Analgesics in Patients with Chronic Liver Disease: A Review of the Literature
Pain management in patients with chronic liver disease poses unique challenges for clinicians. Many of the commonly used over-the-counter and prescription pain relievers like acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), and opiates are metabolized through the liver. Adverse events from analgesics are all too common, potentially fatal, and often avoidable in patients with chronic liver disease, especially in those with cirrhosis or hepatitis.
Unfortunately there currently are no definitive practice guidelines about treating the pain patient with chronic liver disease. This article examines some of the most commonly used analgesics, and the misconceptions as well as false impressions clinicians have regarding their usage in the chronic liver disease population.
Why the Liver Matters
According to the Centers for Disease Control and Prevention (CDC), 101,000 Americans were discharged from hospitals with chronic liver disease as their primary diagnosis in 2010.1 The American Liver Foundation (ALF) also reported that 30 million Americans were living with chronic liver disease in 2010, or roughly 1 in 10 people.2 When these numbers are taken together, one begins to see the scope of the disease.
Chronic liver disease and cirrhosis alter the metabolism and effect of drugs by different mechanisms that could potentially have hazardous side effects. There are three main pathways of drug metabolism by the liver:
- Oxidation, reduction of the cytochrome P 450 (CYP450) system
- Conjugation to glucuronic acid, sulfate, acetate, glycine, glutathione, or a methyl group
- Biliary excretion and elimination3
Acetaminophen (Tylenol, generic) is the most commonly prescribed over-the-counter analgesic and antipyretic medication in the US. Acetaminophen overdose is the most common cause of fulminant liver failure.4 Therefore, it is not surprising that the majority of pain practitioners are hesitant to recommend acetaminophen to patients with any form of liver disease. In a study conducted by Rossi et al, 40% of physician respondents reported that they would not recommend the use of acetaminophen in patients with compensated cirrhosis, and 23% would not recommend it in patients with chronic hepatitis.5
Acetaminophen can cause hepatic toxicity through two mechanisms. When ingested, the large majority of acetaminophen is metabolized in the liver by glucuronidation and sulfonation to nontoxic metabolites, which are then excreted with bile and urine. The remaining amount (<10%) is metabolized via the CYP450 pathway to acetaminophen’s hepatotoxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI). Once formed, it is primarily glutathione that is responsible for the detoxification of NAPQI and protection against oxidative damage. Glutathione is produced primarily in the liver. Evidence of hepatic damage isn’t seen until 70% of glutathione stores are depleted, as can occur with doses greater than 4 grams per 24 hours of acetaminophen.6
In considering acetaminophen treatment in patients with chronic liver disease, the main variables to be concerned about are: what affect liver disease has on CYP2E1 levels, the patient’s probable glutathione stores, and the half life of acetaminophen itself.
Several studies have demonstrated that CYP450 enzymatic action is either normal or reduced in patients with liver disease.7-10 Naturally, one could conclude from this that normal or even reduced levels of NAPQI would be seen in these patients at therapeutic doses. However, there have been mixed results concerning levels of glutathione in patients with liver disease. It was discovered in several studies that patients with chronic liver disease had reduced plasma and hepatic glut-athione levels.11-13 Two other studies demonstrated that patients with liver disease either had mildly decreased or slightly increased levels of glutathione,14,15 Even at mildly decreased levels, risk of hepatic damage is minimal, as damage isn’t seen until glutathione stores decrease below 30%. It is at this level that binding of hepatic NAPQI is seen.16,17
The half-life of acetaminophen is prolonged in patients with chronic liver disease. However, a study by Benson showed that repeated maximal dosing did not lead to accumulation in patients with chronic stable liver disease (CSLD).18 In that study, 20 patients with CSLD were given 4 grams per day of acetaminophen for 13 days without signs of toxicity. When compared to normal patients, Forrest et al demonstrated similar levels of cysteine and mercapturic acid conjugates, suggesting intact detoxification of NAPQI.19
Maximum Dosage Examined
In 2006, the American Liver Foundation (ALF) issued recommendations that patients not exceed 3 grams a day of acetaminophen for any "prolonged period of time."20 They pointed to a study that reported aspartate aminotransferase (AST) levels were elevated in healthy patients receiving 4 grams per day for 14 days.21 The ALF noted no issue with short-term use of 4 gram dosing.
Burns et al recommended that for patients with chronic active alcohol ingestion and cirrhosis, acetaminophen may be used at a maximum of 2 grams per day, which is one-half the recommended daily dose (well below toxicity levels).6 In addition, the 2013 American Chronic Pain Association stated that although the maximum recommended adult dose for acetaminophen is 4 grams per day, and 3 grams per day in older persons, patients can have asymptomatic elevations in liver enzymes at 2 grams per day of acetaminophen. Some healthcare professionals encourage patients to stay well below the 4 grams per day cutoff, even in patients without chronic liver disease or other concerns.22
In January 2011, the FDA released recommendations that manufacturers of prescription products that contain acetaminophen limit the per tablet (capsule) dose to 325 mg to reduce the risk of liver toxicity. The FDA additionally made it a requirement that manufacturers of prescription combination products include boxed label warnings of potential liver injury.4 This change did not alter the dosing schedule for prescribers. The change did ensure that at the typical upper dosing schedule for combination pain products (2 tablets every 4 hours), that the total daily dose of acetaminophen wouldn’t exceed the recommended maximum of 4 grams per 24 hours. These changes were designed to make accidental overdoses by patients less likely.