Extra-Strength Acetaminophen Can Cause Liver Inflammation in People without Liver Disease

[Guest guest]

Extra-Strength Acetaminophen Can Cause Liver Inflammation in People without

Liver Disease

http://www.hivandhepatitis.com/hep_b/news/2006/071406_c.html

It is well known that the pain-reliever acetaminophen (found in Tylenol and many

other products marketed to treat aches and pains, colds, flu, etc.) can cause

liver toxicity. It is often assumed that this primarily occurs in individuals

with pre-existing liver disease, or when healthy people take an overdose of the

drug or use it with alcohol.

A new study in the July 2006 Journal of the American Medical Association,

however, showed that 4 grams of acetaminophen -- the maximum recommended dose of

Extra-Strength Tylenol -- can cause liver enzyme elevations even in healthy

people who use the drug as directed. ALT elevation is a sign of liver

inflammation, and may precede more serious liver damage or liver failure.

Watkins, MD, from the University of North Carolina at Chapel Hill and

colleagues conducted the study after observing an unexpectedly high rate of

alanine aminotransferase (ALT) elevation among participants in a clinical trial

of a new hydrocodone/acetaminophen combination pill. They sought to characterize

the incidence and magnitude of ALT elevations in healthy individuals receiving 4

g acetaminophen daily, either alone or in combination with various opioids.

The study included 145 healthy adult volunteers (aged 18-45 years) treated at

two U.S. inpatient clinical pharmacology units. Participants were hospitalized

so that they could be carefully observed and their diets could be controlled;

they were not taking any other medications when they entered the study. Subjects

were randomly assigned to one of five arms, all of whom received study drugs

orally every 6 hours for up to 14 days:

2 tablets containing a combination of 7.5 mg oxycodone and 500 mg

acetaminophen (Percocet) plus 2 placebo tablets;

2 tablets containing 2 mg hydromorphone (Dilaudid) plus 2 " caplets "

containing 500 mg acetaminophen (Extra-Strength Tylenol);

2 tablets containing 15 mg morphine tablets plus 2 Extra-Strength Tylenol

caplets;

2 placebo tablets plus 2 Extra-Strength Tylenol caplets

4 placebo tablets

Each of the first four arms received a total of 4 g daily acetaminophen, the

maximum recommended daily dosage. Liver function was measured daily for the

first 8 days, then at 1- or 2-day intervals.

Results

In the four acetaminophen arms, 39% of participants (range 31%-44% in the

various groups) had a maximum ALT level greater than 3 times the upper limit of

normal (x ULN).

In these four arms combined, 25% (range 19%-37%) experienced ALT > 5 x ULN,

and 8% (range 4%-15%) had ALT > 8 x ULN; the highest observed level was 16 x

ULN.

Despite these elevations, no participants in any of the arms experienced

symptoms of liver dysfunction.

ALT elevations were observed equally often in the arm that received

acetaminophen only, without opioids.

None of the 39 participants assigned to the all-placebo arm had a maximum ALT

level > 3 x ULN.

The risk of ALT elevation was significant higher in the four treatment arms

compared with the all-placebo arm (P < 0.001).

The risk did not differ significantly across the four acetaminophen arms,

though it trended higher in the hydromorphone arm.

Compared with placebo, treatment with acetaminophen was associated with a

markedly higher median maximum ALT (ratio of medians 2.78; 95% CI 1.47-4.09; P <

0.001).

Aspartate aminotransferase (AST) elevations were generally smaller, but

followed a similar pattern; there were no abnormalities or consistent trends in

total bilirubin or alkaline phosphatase levels.

Trough (lowest level between doses) acetaminophen concentrations did not

exceed therapeutic limits in any participant.

After acetaminophen was discontinued, ALT continued to increase for up to

four days; drug concentrations often decreased to undetectable levels before ALT

elevation resolved.

ALT normalized after stopping acetaminophen, but this took as long as 11

days.

Conclusion

The researchers concluded that ongoing daily use of 4 g acetaminophen in healthy

adults is associated with ALT elevation, and that concurrent treatment with

opioids does not seem to increase this effect. They noted that the incidence of

ALT elevation in this study of healthy adults is higher than previously reported

in similar studies.

" A clinically important observation was that ALT elevations occurred in the

absence of plasma acetaminophen concentrations that would traditionally be

considered hepatotoxic, " the authors wrote. " Indeed, at the time of the highest

ALT elevation, acetaminophen concentrations were frequently near or below the

limits of assay detection. Plasma acetaminophen concentrations would therefore

be of limited value in determining whether ALT elevations were due to

therapeutic doses of acetaminophen. " They recommended that a patient's history

of acetaminophen use should be considered when diagnosing the cause of elevated

ALT, even in the absence of measurable serum acetaminophen concentrations.

This study adds to the evidence that acetaminophen's margin of safety (the

difference between a safe and a toxic dose) is small, and that even recommended

doses may cause problems for some individuals. In this study, baseline medical

and demographic characteristics generally did not predict who would experience

ALT elevation while taking acetaminophen, but Hispanic volunteers had a somewhat

higher risk.

Although acetaminophen is generally regarded as safe for most people, some

experts have called for increased regulation of the drug -- which is the leading

cause of liver failure in the U.S. (often due to suicide attempts) -- as is

already done in the United Kingdom.

7/14/06

Reference

P B Watkins, N Kaplowitz, J T Slattery, and others. Aminotransferase Elevations

in Healthy Adults Receiving 4 Grams of Acetaminophen Daily: A Randomized

Controlled Trial. Journal of the American Medical Association 296(1): 87-93.

July 5, 2006.

[Guest guest]

Extra-Strength Acetaminophen Can Cause Liver Inflammation in People without

Liver Disease

http://www.hivandhepatitis.com/hep_b/news/2006/071406_c.html

It is well known that the pain-reliever acetaminophen (found in Tylenol and many

other products marketed to treat aches and pains, colds, flu, etc.) can cause

liver toxicity. It is often assumed that this primarily occurs in individuals

with pre-existing liver disease, or when healthy people take an overdose of the

drug or use it with alcohol.

A new study in the July 2006 Journal of the American Medical Association,

however, showed that 4 grams of acetaminophen -- the maximum recommended dose of

Extra-Strength Tylenol -- can cause liver enzyme elevations even in healthy

people who use the drug as directed. ALT elevation is a sign of liver

inflammation, and may precede more serious liver damage or liver failure.

Watkins, MD, from the University of North Carolina at Chapel Hill and

colleagues conducted the study after observing an unexpectedly high rate of

alanine aminotransferase (ALT) elevation among participants in a clinical trial

of a new hydrocodone/acetaminophen combination pill. They sought to characterize

the incidence and magnitude of ALT elevations in healthy individuals receiving 4

g acetaminophen daily, either alone or in combination with various opioids.

The study included 145 healthy adult volunteers (aged 18-45 years) treated at

two U.S. inpatient clinical pharmacology units. Participants were hospitalized

so that they could be carefully observed and their diets could be controlled;

they were not taking any other medications when they entered the study. Subjects

were randomly assigned to one of five arms, all of whom received study drugs

orally every 6 hours for up to 14 days:

2 tablets containing a combination of 7.5 mg oxycodone and 500 mg

acetaminophen (Percocet) plus 2 placebo tablets;

2 tablets containing 2 mg hydromorphone (Dilaudid) plus 2 " caplets "

containing 500 mg acetaminophen (Extra-Strength Tylenol);

2 tablets containing 15 mg morphine tablets plus 2 Extra-Strength Tylenol

caplets;

2 placebo tablets plus 2 Extra-Strength Tylenol caplets

4 placebo tablets

Each of the first four arms received a total of 4 g daily acetaminophen, the

maximum recommended daily dosage. Liver function was measured daily for the

first 8 days, then at 1- or 2-day intervals.

Results

In the four acetaminophen arms, 39% of participants (range 31%-44% in the

various groups) had a maximum ALT level greater than 3 times the upper limit of

normal (x ULN).

In these four arms combined, 25% (range 19%-37%) experienced ALT > 5 x ULN,

and 8% (range 4%-15%) had ALT > 8 x ULN; the highest observed level was 16 x

ULN.

Despite these elevations, no participants in any of the arms experienced

symptoms of liver dysfunction.

ALT elevations were observed equally often in the arm that received

acetaminophen only, without opioids.

None of the 39 participants assigned to the all-placebo arm had a maximum ALT

level > 3 x ULN.

The risk of ALT elevation was significant higher in the four treatment arms

compared with the all-placebo arm (P < 0.001).

The risk did not differ significantly across the four acetaminophen arms,

though it trended higher in the hydromorphone arm.

Compared with placebo, treatment with acetaminophen was associated with a

markedly higher median maximum ALT (ratio of medians 2.78; 95% CI 1.47-4.09; P <

0.001).

Aspartate aminotransferase (AST) elevations were generally smaller, but

followed a similar pattern; there were no abnormalities or consistent trends in

total bilirubin or alkaline phosphatase levels.

Trough (lowest level between doses) acetaminophen concentrations did not

exceed therapeutic limits in any participant.

After acetaminophen was discontinued, ALT continued to increase for up to

four days; drug concentrations often decreased to undetectable levels before ALT

elevation resolved.

ALT normalized after stopping acetaminophen, but this took as long as 11

days.

Conclusion

The researchers concluded that ongoing daily use of 4 g acetaminophen in healthy

adults is associated with ALT elevation, and that concurrent treatment with

opioids does not seem to increase this effect. They noted that the incidence of

ALT elevation in this study of healthy adults is higher than previously reported

in similar studies.

" A clinically important observation was that ALT elevations occurred in the

absence of plasma acetaminophen concentrations that would traditionally be

considered hepatotoxic, " the authors wrote. " Indeed, at the time of the highest

ALT elevation, acetaminophen concentrations were frequently near or below the

limits of assay detection. Plasma acetaminophen concentrations would therefore

be of limited value in determining whether ALT elevations were due to

therapeutic doses of acetaminophen. " They recommended that a patient's history

of acetaminophen use should be considered when diagnosing the cause of elevated

ALT, even in the absence of measurable serum acetaminophen concentrations.

This study adds to the evidence that acetaminophen's margin of safety (the

difference between a safe and a toxic dose) is small, and that even recommended

doses may cause problems for some individuals. In this study, baseline medical

and demographic characteristics generally did not predict who would experience

ALT elevation while taking acetaminophen, but Hispanic volunteers had a somewhat

higher risk.

Although acetaminophen is generally regarded as safe for most people, some

experts have called for increased regulation of the drug -- which is the leading

cause of liver failure in the U.S. (often due to suicide attempts) -- as is

already done in the United Kingdom.

7/14/06

Reference

P B Watkins, N Kaplowitz, J T Slattery, and others. Aminotransferase Elevations

in Healthy Adults Receiving 4 Grams of Acetaminophen Daily: A Randomized

Controlled Trial. Journal of the American Medical Association 296(1): 87-93.

July 5, 2006.