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9 Articles in Volume 13, Issue #9
Perioperative Pain Plan: Why is it Needed
A Case for Spinal Cord Stimulation Therapy—Don’t Delay
History of Pain: The Nature of Pain
Safe Usage of Analgesics in Patients with Chronic Liver Disease: A Review of the Literature
PROP Versus PROMPT: FDA Speaks
Editor's Memo: Long-Acting Opioids: More Than a Labeling Issue
Use of Long-term Muscle Relaxants
PAINWeek Highlights: Coping Skills, Insomnia, and Opioid Abuse Deterrence
Letters to The Editor

Safe Usage of Analgesics in Patients with Chronic Liver Disease: A Review of the Literature

Pain management in patients with chronic liver disease (CLD) 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. Articles reviews most commonly used analgesics and usage in patients with CLD.

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:

  1. Oxidation, reduction of the cytochrome P 450 (CYP450) system
  2. Conjugation to glucuronic acid, sulfate, acetate, glycine, glutathione, or a methyl group
  3. Biliary excretion and elimination3

Pain Medications

Acetaminophen

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.

In consideration of these findings, normal recommended doses of acetaminophen can be safely given for short-term use to patients who suffer from CSLD, provided they do not drink alcohol or take medications that could increase CYP activity. For long-term treatment, it is prudent to limit total daily dosing in CSLD patients to 2 to 3 grams per day, until additional studies can demonstrate safety.3 These patients were not shown to have elevated CYP450 level, nor significantly reduced glutathione levels. While it is true that these patients may metabolize acetaminophen more slowly than their healthy counterparts, no evidence of toxic accumulation has been seen to date.

NSAIDs

Since salicin was first extracted from the bark of the willow tree, to its first documented use in treating fever in 1827, NSAIDs have been one of the most popular drug classes—with 30 million people worldwide using NSAIDs daily.7 Acetylsalicylic acid (ASA, aspirin) and its main metabolite, sodium salicylate, were both synthesized in 1899 by Felix Hoffman as part of Bayer Corporation. However, it was not until 1971 that it was discovered that aspirin acts as an inhibitor of cyclooxygenase (COX), preventing the transformation of arachidonic acid to various prostaglandins. Two COX isoforms have since been identified—COX-1 and COX-2.

COX-1 forms prostaglandins that are important in protecting the gastric mucosa, in ensuring proper platelet function, and in maintaining renal function. In contrast, COX-2 is almost undetectable under normal physiologic conditions. However during periods of inflammation, COX-2 expression can increase by up to a factor of 80. The older NSAIDs are non-selective, inhibiting both COX-1 and COX-2, while newer agents were designed to selectively inhibit COX-2.

The metabolism of NSAIDs is governed largely by the hepatic CPY450 enzymes. As discussed previously, patients with CSLD have been shown to have either normal or reduced levels of CYP450.7-10 When considering treatment of patients with chronic liver disease, and those with cirrhosis in particular, it is important to consider the increased risk for portal hypertension, esophageal varices, renal insufficiency, and hepatorenal syndrome, as well as their associated complications. Patients with chronic liver disease have a reduced ability to metabolize many drugs, and an impaired ability to synthesize hepatic albumin, which would increase serum levels of the NSAID—putting the patient at increased risk for complications.

The coagulopathies common with advanced liver disease, particularly cirrhosis, are compounded by NSAIDs’ inhibition of thromboxane and resultant decreased platelet aggregation. This is troubling when one considers that these patients are at increased risk for esophageal varices as well as the gastrointestinal (GI) ulcers already inherent with NSAID use. One study showed that patients were 2.8 times as likely to have used NSAIDs in the week prior to a GI bleed than those who did not use NSAIDs.23

The effect of NSAIDs on renal function is well documented. NSAIDs reduce prostaglandins responsible for maintaining renal perfusion. Cirrhotic patients with portal hypertension are dependent on prostaglandins to counteract the renin-angiotensin-aldosterone system, maintain glomerular filtration rate (GFR), and prevent sodium retention. One study demonstrated cirrhotic patients treated with indomethacin showed a 19% decrease in GFR and a 29% increase in serum creatinine.24

One additional concern is what effect NSAIDs have on a practitioner’s ability to effectively manage patients with ascites. All non-selective NSAIDs reduce the effectiveness of diuretics in patients with ascites, impairing free water clearance and worsening ascites and edema. However, in a study comparing the selective COX-2 inhibitor celecoxib (Celebrex) and naproxen (Aleve), a significant reduction in natriuretic response to furosemide was seen with naproxen but not with celecoxib.25

Selective COX-2 inhibitors have been shown to be effective pain relievers. When compared to non-selective NSAIDs, selective COX-2 inhibitors have shown less renal and GI adverse events. They have been shown to cause a decrease in GFR, but to a lesser extent than non-selective NSAIDs,26 as well as potential cardiac complications. At this time there are no long-term studies examining the effects of COX-2 inhibitors in cirrhotic patients.

The bottom line: NSAIDs have been shown to increase the risk of variceal and other upper GI bleeding, renal failure, and diuretic resistant ascites. They should therefore be avoided in all patients with cirrhosis. While selective COX-2 NSAIDs are associated with less side effects, they reduce GFR and further long-term prospective studies are needed to better assess their safety. Therefore, while they may be a safe analgesic option in the future, it is currently recommended that they be avoided in these patients.

Opioids

Opiates are the mainstay of pain management in most patients with severe pain. Unfortunately, they could also be the worst agent to use in patients with liver disease. Most opioids are metabolized by one or more of the CYP450 isozymes, and this typically results in multiple metabolites. However, there are a few opioids that are only minimally metabolized by CYP450 and, thus, may be safer options for patients with chronic liver disease. These include hydromorphone, oxymorphone, and tapentadol.27

Morphine, an opiate that has been in use since 1827, can be detrimental in patients with chronic liver disease. The clearance of morphine is highly impaired in cirrhotic patients and could cause deleterious side effects, including encephalopathy.3 Since morphine is highly metabolized through the first-pass system, primary glucuronidation, its oral bioavailability becomes enormous in cirrhotic patients. There are two systems that metabolize morphine that are both equally affected in patients with end-stage liver disease: CYP pathway and glucuronidation.

In one study, patients with a history of hepatic encephalopathy were given morphine. They found that after oral intake, the plasma concentrations of its metabolites M3G and M6G were much lower than the control group and hence morphine had about two times more bioavailability. Morphine metabolites, M3G and M6G, are cleared by the kidney, which in most cirrhotic patients is also poorly functioning.28 Other opiates like oxycodone and hydrocodone have been less studied and may have less harmful effects. However, codeine is transformed to its active form, morphine, and has variable concentrations in the plasma.

Two opiates that have less toxicity in chronic liver disease patients are fentanyl and hydromorphone based on two reasons:

  1. Shorter half-life (1-3 hours) than other opiates
  2. Chronic liver disease patients, many of whom have renal disorders as well, don’t require adjustments based on GFR.3

Hepatitis C virus (HCV) infection is the most common chronic bloodborne infection in the United States; approximately 3.2 million persons are chronically infected.29 HCV is also the most common cause of chronic liver disease and the most common cause of an indication for a liver transplant in the US.30 Intravenous illicit drug use is by far the most common mode of transmission of the HCV. Many of these patients are also on long-term methadone maintenance for treatment of opioid addiction,31 but methadone is also commonly used as a low-cost pain medication. Its mechanism of action is by binding to the µ-opioid receptor, and is metabolized by the isoenzymes CYP3A4, CYP2B6 and CYP2D6. One study at a methadone maintenance program observed patients who had HCV and were former injection drug users. Many of the patients had persistent elevated liver enzymes. Compared to the general population with HCV, there was no significant elevation of liver enzymes in methadone patients. Methadone intake should be restricted in patients with concomitant alcoholism because it decreases the metabolism of methadone, which inevitably increases plasma levels.32

Combination Products

Acetaminophen and NSAIDs are often added to opioid medications. There are a wide variety of combination analgesics like opioid/NSAIDs or opioid/acetaminophen that are on the market that are used for chronic and acute pain syndromes. Brand names like Percocet (oxycodone/acetaminophen), Vicodin (hydrocodone/acetaminophen) and Vicoprofen (hydrocodone/ibuprofen) are well known even to the layperson.

In 2003, the combination product hydrocodone/acetaminophen was the most prescribed medication in the United States, with over 89 million prescriptions dispensed.33 The proposed pharmacology behind this synergy is the fact that anti-inflammatory medications, besides providing their own analgesia, induce sensitization of the nociceptors that allow opiates to produce an effective response at a lesser dose. Effects of combination medications have been well published in chronic pain and acute pain post-operatively. Many different organizations and societies are proponents of prescribing combination medications. For instance, The American Geriatrics Society recommends using combination analgesics in patients with chronic problems like hypertension and coronary artery disease. Due to their great analgesic effect, "opioid/acetaminophen combinations are recommended in the WHO analgesic ladder for moderate to severe forms of pain."34 However, much is not known regarding negative effects of combination analgesics and there still needs to be much research done to shed light upon synergistic side-effects.35

With regards to liver toxicity, a retrospective analysis based upon insurance claims of hospitalization related to hepatotoxicity found no significant increase in hepatotoxicity-related hospitalizations in patients who were taking combination drugs as compared to opioids alone.36

In 2009 there was a committee meeting by the FDA advisory team that wanted to eliminate any prescription acetaminophen combination drugs. There was an overwhelming number of cases of acute liver failure caused by acetaminophen, of which 63% was due to acetaminophen/opioid combination medications. The committee voted to recommend removal of acetaminophen-containing drugs. (However, as noted, the final FDA guidelines changed the recommended maximum dose to 325 mg/capsule of acetaminophen and there were no elimination of combination drugs from the market).

In a review article by Michna et al in 2009, publications provided to the committee were not randomized controlled trials and, thus, absolute risk and rate could not be estimated from the studies. There were no concrete studies that eliminated confounding variables like baseline liver functions, other medications that could have potentiated acetaminophen toxicity, and reference groups.37

Neuropathic Agents

Patients with CSLD frequently suffer from painful neuropathic pain as a result of concomitant conditions such as diabetes and long-standing alcoholism. The anticonvulsant medications, such as gabapentin and pregabalin (Lyrica) are not hepatically metabolized and frequently used to treat neuropathic pain.3 These agents may be started at a low dose and gradually titrated up. Practitioners should be mindful of unwanted side effects of dizziness, sedation, and nausea. Additionally, as these agents are excreted by the kidneys, lower dosing adjustments will be required in patients with concomitant renal insufficiency.

Carbamazepine is hepatically metabolized and known to cause hepatic toxicity,38 and therefore should be avoided in CSLD patients. Tricyclic antidepressants (nortriptyline, amitriptyline and imipramine) are also frequently used off-label in the treatment of neuropathic pain. These agents rely heavily on hepatic first-pass metabolism. CSLD patients should be started on a low dose nightly and gradually titrated as tolerated. CSLD patients will require a lower maintenance dose compared to the healthy population. Practitioners should watch for sedation as well as anticholinergic side effects.3

Conclusion

Treating chronic pain patients with chronic liver disease presents a clinical challenge to the medical professional. Unfortunately there are no concrete guidelines regarding the usage of OTC or prescription pain medications in patients with chronic liver disease. This literature review revealed that the preferred opiates in liver disease are hydromorphone and fentanyl, since they have a shorter half-life and have less harmful side effects on the renal system. Neuropathic pain may be safely treated with anticonvulsants and tricyclic antidepressants, with dose adjustments and monitoring for side effects.

With regards to OTC medications, normal recommended doses of acetaminophen can be safely given to patients who suffer from CSLD in the short term. Long-term dosing should be limited to 2 to 3 grams per day with regular liver function test monitoring. Patients should not be using any type of NSAIDs due to an associated increased risk of bleeding, renal impairment, and the development of diuretic-resistant ascites.

Last updated on: November 21, 2013
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