This report was reviewed for medical and scientific accuracy by Kiron M. Das, MD, PhD, FRCP, FACP, Professor of Medicine, Molecular Genetics and Microbiology; Chief, Division of Gastroenterology/Hepatology, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Editorial

Edwin K. Kuffner Jr., MD, Attending Toxicologist, Rocky Mountain Poison and Drug Center, Denver, Colorado, Instructor, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado

For more than 50 years in the United States (U.S.), acetaminophen has demonstrated a remarkable safety profile in virtually all patient populations when used appropriately at therapeutic doses. Despite this safety profile, there has been concern for many years among healthcare providers about the safety of therapeutic doses of acetaminophen being used by alcoholic patients and patients who drink alcohol regularly.¹ Many clinicians practicing today do not realize that the concerns regarding alcohol and acetaminophen use are largely theoretical and not supported by current standards of evidence-based medicine.

Epidemiological concerns are related to the patterns of use and availability of both alcohol and acetaminophen. Acetaminophen, the most commonly recommended over-the-counter (OTC) analgesic and antipyretic is used by millions of Americans every day. In fact, in any given week, approximately 20% of adults in the U. S. will have taken some form of acetaminophen.² Alcohol is without question the most commonly used and abused drug in the U.S. with a lifetime risk for alcoholism in the U.S. between 5-10% and with approximately 60% of Americans drinking alcohol regularly, the public health consequences of an alcohol-acetaminophen drug-drug interaction are staggering.³

Pharmacological concerns are primarily related to the cytochrome P450 system, specifically CYP2E1, which is only involved in the metabolism of both acetaminophen and alcohol to a minor extent. The small amount of acetaminophen that is metabolized by CYP2E1 is converted to a toxic metabolite, n-acetyl-p-benzoquinoneimine (NAPQI). Following a therapeutic dose of acetaminophen, hepatic stores of glutathione easily detoxify the small amount of the toxic metabolite that is formed. Since chronic alcohol use can induce CYP2E1, it has been theorized that alcoholics and patients who drink alcohol regularly metabolize a greater percentage of acetaminophen via this otherwise minor pathway, generate more of the toxic metabolite (NAPQI), overwhelm the hepatic stores of glutathione, and develop hepatotoxicity. Although this is a compelling theory, the majority of pharmacokinetic and clinical studies conducted in humans do not support it.^4-8

Since theoretical concerns regarding the use of therapeutic doses of acetaminophen in alcoholic patients and patients who drink alcohol regularly continues to be a topic of interest amongst healthcare providers, we recently conducted two studies at the Rocky Mountain Poison and Drug Center aimed at answering the question: Can alcoholic patients develop hepatotoxicity from therapeutic doses of acetaminophen?

Discussed in this GI/Hepatology Express Report are the results of these two studies that have been recently published.

The first study is a systematic review of recent English literature between 1996 and 1999, which identified only 20 reports involving 25 patients containing enough information to even consider the possibility that an alcoholic patient who ingested less than or equal to 4 grams of acetaminophen per day would develop hepatotoxicity.⁹ Common weaknesses of these case reports included retrospective data collection that was often incomplete, suspected inaccuracies in the alcoholic patient's history with respect to the dose of acetaminophen ingested, acetaminophen levels that were more consistent with acute overdose than therapeutic dosing, and failure to exclude other common causes of hepatotoxicity and fulminant hepatic failure.

The second study reports the findings of a randomized, double blind, placebo controlled trial involving 201 alcoholic patients, which showed no evidence of liver injury following the administration of the maximal recommended adult daily dose of acetaminophen; 4 grams.¹⁰

Based upon critical review of the medical literature to date and applying current standards of evidence-based medicine, it appears that therapeutic doses of acetaminophen, up to the maximal recommended adult daily dose of 4 grams, are safe for alcoholic patients and patients who drink alcohol regularly.

Healthcare providers who do not discuss the issue of OTC analgesic and antipyretic use with alcoholic patients and patients who drink alcohol regularly and clinicians who continue to assert that this patient population should avoid acetaminophen, may actually be placing patients at risk. If alcoholic patients and patients who drink alcohol regularly are advised against acetaminophen use, they may use alternative OTC analgesics and antipyretics such as nonsteroidal anti-inflammatory drugs (NSAIDS) and aspirin. These medications can cause life-threatening toxicities at therapeutic doses in the form of gastric ulcers and gastrointestinal bleeding.^11-15 Based upon the available data, it now appears that acetaminophen when used appropriately up to the maximal daily recommended adult dose of 4 grams is the safest OTC analgesic and antipyretic for both alcoholic and non-alcoholic patients.

Acetaminophen is a Safe and Effective Analgesic When Used as Directed in Patients Who Regularly Drink Alcohol

A recent randomized clinical trial looking at the hepatic effect of maximal daily doses of acetaminophen in alcoholic patients presents the latest evidence-based data that supports the safety of acetaminophen as an effective analgesic when used as directed. In this trial of 201 patients, no evidence of liver injury was found in alcoholic patients who consumed ≤ 4 grams of acetaminophen per day.¹⁰ Other recent publications, including a systematic review⁹, put these results into perspective with earlier reports and concluded that acetaminophen is indeed safe for patients who regularly drink alcohol.

The controversy that currently exists about the safety of acetaminophen in patients who drink alcohol prompted a study analysis by Richard C. Dart MD, PhD, Director, Rocky Mountain Poison and Drug Center; Professor of Surgery, Pharmacy and Medicine, University of University of Colorado Health Sciences Center, Denver, Colorado.¹⁶ In 1998, the Food and Drug Administration (FDA) announced that all over the counter pain relievers and fever reducers must carry a warning on the label directing people who consume more than three alcoholic drinks a day to consult with a physician before using these products.¹⁷ Acetaminophen was included in this warning because of a series of retrospective case reviews and case reports suggesting that concomitant ingestion of acetaminophen and chronic alcohol consumption may cause liver damage.

A Basis of Concern Rooted in Theory and Anecdote

Clinical evidence demonstrates clearly that chronic alcohol consumption increases the risk of NSAID-associated gastrointestinal (GI) bleeding.¹⁸ However, the concern about the susceptibility of liver toxicity with alcohol and acetaminophen lies mainly on anecdotal and theoretical grounds.

As explained by Dr. Dart, a number of retrospective case reviews and case reports associate life-threatening fulminant hepatic failure with consumption of therapeutic doses of acetaminophen in alcoholic patients.¹ This has led many to theorize a reason for the putative damage.

After ingestion, about 5% of acetaminophen is metabolized in the liver to the active metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). The enzyme responsible for this transformation is CYP2E1 (a.k.a. P4502E1), an isozyme in the hepatic cytochrome P450 system. The remainder is conjugated to nontoxic forms of glucoronide and sulfate and excreted in the urine.

According to Dr. Dart, normal doses of acetaminophen (i.e. ≤ 4 grams/day) result in clinically insignificant levels of NAPQI because the metabolite is quickly detoxified in the liver. With an overdose of acetaminophen however, the amount of NAPQI is capable of overwhelming the hepatic glutathione detoxification mechanism, causing necrosis of liver cells and potentially fulminant hepatic failure, especially at high doses. Animal studies have shown that chronic administration of ethanol induces the activity of CYP2E1 and increases production of NAPQI when acetaminophen is ingested.¹⁹ Other studies have shown that animals that are chronically fed alcohol will suffer liver injury at a lower dose of acetaminophen than control animals if it is administered in a period of abstinence from alcohol.²⁰ This is the period in which the induction of CYP2E1 is still increased and acetaminophen metabolism is unimpeded by competition with alcohol. Animal studies demonstrate that concomitant administration of alcohol and acetaminophen decreases the production of NAPQI, with less liver damage as a result.

These observations, along with studies in humans showing that alcohol ingestion induces the activity of CYP2E1, have led some individuals to propose that the alcoholic patient may suffer injury with therapeutic doses of acetaminophen.¹ Dr. Dart points out, however, that the evidence concerning cytochrome induction in humans is not clear. He writes, "some reports indicate that alcoholic patients have increased elimination of paracetamol (acetaminophen), implying that cytochrome P450 may metabolize it at a greater rate.^21,22 However, the increase in metabolism does not increase the quantity of NAPQI produced."²³

Reports of Liver Damage Unsubstantiated

In his review⁹, Dr. Dart screened more than 2000 reports in the literature of acetaminophen toxicity, poisoning, or adverse events in humans and selected 27 studies involving alcohol.

The studies were divided into categories based on the strength of evidence. Class I data consisted of randomized, controlled clinical trials; Class II data consisted of prospective, non-randomized trials; and Class III data was made up of retrospective case reviews and case reports. Seven articles in Dr. Dart's review provided Class I or II data and 20 articles provided Class III data.

According to Dr. Dart, Class I data showed that repeated ingestion of a therapeutic dose of paracetamol over 48 hours by severely alcoholic patients "did not produce an increase in hepatic aminotransferase enzyme levels nor any clinical manifestations compared with a placebo group." Class II data showed that a 1-to-2 gram single dose of acetaminophen administered to alcoholic patients produced no adverse effect. Also included in this class are data showing that therapeutic doses of acetaminophen administered for periods up to 14 days in patients with overt liver disease (alcoholic, primary biliary, postnecrotic, or unspecified cirrhosis or alcoholic, acute viral, chronic active, or other infectious hepatitis) have produced no adverse effects.⁵ "In contrast," he writes, "Class III data...describe hepatic injury after repeated paracetamol ingestion with therapeutic intent, although usually not at therapeutic doses."

In his discussion, Dr. Dart explains that Class III data is weak and cannot be considered conclusive. For example, it is difficult to assess the cause of hepatic injury in the setting of alcohol abuse in a retrospective analysis. Fulminant hepatic failure may be caused by hepatitis or several other conditions²⁴, including exposure to organic compounds, natural products (mushrooms, herbs), and hypersensitivity reactions to drugs.

The most troubling aspect of the Class III data, however, lies in the unreliability of patient histories used to determine the dose of acetaminophen ingested. Dr. Dart writes, "the history of ingestion is often unknown or contradicts other clinical information provided. For example, the history may indicate a therapeutic dose, but the serum paracetamol is elevated to levels only produced by ingestion much larger than the history indicates."

In summary, Dr. Dart states that "all methodologically sound studies available indicate that therapeutic dosing of paracetamol to the alcoholic patient is not associated with hepatic injury" and notes "unless stronger evidence of a potentially dangerous interaction emerges, the use of paracetamol in the alcoholic patient is reasonable. During chronic treatment of pain, paracetamol may be preferred in the compliant alcoholic patients owing to the adverse effects associated with long-term use of nonsteroidal anti-inflammatory agents."

Randomized Controlled Trial Supports Safety of Acetaminophen and Alcohol Coadministration

Because of the lack of sufficient, high-quality, prospective data, Dr. Dart and his colleagues performed a randomized, double blind, placebo-controlled trial to determine if hepatic injury was associated with maximal therapeutic dosing of acetaminophen to chronic alcoholic abuse patients immediately following cessation of alcohol intake, the putative time of maximal vulnerability.¹⁰ In addition, the investigators assessed the effect of acetaminophen on subgroups of patients potentially malnourished and exposed to agents that induce the activity of P450 enzymes.

A total of 230 patients were selected from an alcohol detoxification center and randomized to receive 4 days treatment with acetaminophen (n = 118) or placebo (n = 112). Patients were excluded if their baseline aspartate or alanine transferase (AST or ALT) levels were greater than 120 U/L, ensuring that none of the patients who were randomized had liver impairment. Also excluded were patients who had a baseline international normalized ratio (INR = the ratio of the patient's clotting time to a mean reference value) greater than 1.5, a baseline serum acetaminophen level greater than 20 mg/L (the maximum therapeutic level), a positive serum pregnancy test, a history of ingesting more than 4 grams/day of acetaminophen for any of the four days preceding randomization, a history of acetaminophen allergy, or alcohol intoxication at the time of the first dose of study medication.

Over the course of the study, 16 patients withdrew from the acetaminophen arm and 13 withdrew from the placebo arm, all for reasons other than adverse events. Overall, 201 patients completed the study, 102 receiving acetaminophen and 99 receiving placebo.

A two-way ANOVA showed that there was a significant change in the liver enzyme concentrations over time for both groups combined, but no significant difference between groups.

Specifically, the mean AST level on day 4 was 38.0 U/L in the acetaminophen-treated group and 37.5 in the placebo-treated group. There were 4 patients in the acetaminophen-treated group and 5 in the placebo-treated group who developed an increase in their serum AST level to greater than 120 U/L, but it did not exceed 200 U/L in any patient. The mean INR on day 4 was 0.96 in the acetaminophen-treated group and 0.98 in the placebo-treated group. In addition, neither the alcoholic subjects with evidence of malnutrition nor those who were treated long-term with agents expected to induce the activity of the cytochrome P450 system showed evidence of increased AST or ALT levels or an increased INR.

The authors concluded that the repeated administration of the maximum recommended daily doses of acetaminophen in long-term alcoholics was not associated with evidence of liver injury.

Strengths and Limitations of the Study

The importance of this study is that it avoided the weaknesses of retrospective reports. The dose of acetaminophen was known and it was administered at a time of maximal CYP2E1 inhibition, soon after the subject-achieved sobriety.

The authors explain, "if subjects did not develop hepatic damage when they were not intoxicated with alcohol, it is unlikely that they would have developed a hepatotoxic reaction when they were intoxicated and protected against acetaminophen-induced hepatotoxic reaction. Also if subjects did not develop hepatic damage when their CYP2E1 was maximally induced, it is unlikely that they would have developed a hepatotoxic reaction as their CYP2E1 induction waned. Our subjects were at maximal vulnerability for developing a toxic reaction."

The authors admit to the limitation that the acetaminophen dose did not exceed the maximum therapeutic daily dose of 4 grams/day and was administered for only two days. In a real world situation, alcohol patients might be expected to take higher than recommended doses of acetaminophen for longer periods of time. The authors write, "although unlikely based on human CYP2E1-induction data, it is possible that administration of acetaminophen for a longer period than two days is required for alcoholic patients to manifest a hepatotoxic reaction. It is also possible that a hepatotoxic reaction from therapeutic dosing of acetaminophen is an idiosyncratic and rare event that would only be detected in a study with an extremely large sample size.

Another limitation is that the study also excluded subjects who had AST or ALT elevations greater than 120 U/L, leaving unanswered the question about how acetaminophen might affect alcoholic patients with existing liver impairment.

Despite these limitations, the randomized controlled trial by Dr. Dart and colleagues provides the strongest evidence to date for the safety of acetaminophen in patients who regularly consume alcohol.

Clinical Implications and Conclusions

The retrospective reports of acetaminophen hepatotoxicity in alcoholic patients, combined with the 1998 FDA warning have led many physicians to suggest to their patients that they avoid acetaminophen if they are drinking. As well, extensive coverage in the lay press has discouraged patients who drink alcohol from using acetaminophen.

According to Dr. Edwin Kuffner, attending physician at the Rocky Mountain Poison and Drug Center, and lead author of the AIM paper, this may lead to serious consequences.²⁵ Patients led away from acetaminophen would most likely take alternatives such as aspirin and NSAIDs, both of which are proven to increase the risk of life-threatening GI bleeding in alcoholic subjects.

The key message of these recent studies is that acetaminophen is safe and effective for patients who regularly drink alcohol when taken in recommended doses. Another consideration is that most people do not consume as much alcohol as the subjects in the above clinical trial, suggesting an even higher margin of safety for these individuals.

References

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22. Skinner MH, Matano R, Hazle W, et al. Acetaminophen Metabolism in Recovering Alcoholics. Meth Find Exp Clin Pharmacol 1990;12:513-515.
23. Critchley JA, Cregeen RJ, Balali-Mood M, et al. Paracetamol Metabolism in Heavy Drinkers. Br J Clin Pharmacol 1982;13:276P-277P.
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Disclosure
Kiron M. Das, MD, PhD, FRCP, FACP
Has no significant relationships to disclose.

Edwin K. Kuffner, Jr, MD
Has no significant relationships to disclose.

Bruce Wilson
Has no significant relationships to disclose.

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

This report is supported by an educational grant from McNeil Consumer and Specialty Pharmaceuticals.

Medical Writer
Bruce Wilson, Freelance Medical Writer, Millennium Medical Communications, Inc., Hampton, NH

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This GI/Hepatology Express Report(tm) does not include discussion of treatment and indications outside of current approved labeling. This GI/Hepatology Express Report(tm) was made possible through an unrestricted educational grant from McNeil Consumer and Specialty Pharmaceuticals.

(c) 2002 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education