RE: Acetaminophen-more

[Guest guest]

Here's the abstract of the study mentioned.

NOTE: Be *careful* of the info from <http://www.citizen.org>

It is interesting how that article deviates from the abstract,

and does not mention that the effects were not detectable when

the use of acetaminophen was discontinued.

The article *assumes* that an elevated ALT level is some type of

indicator of liver disease.

Here's some *reliable* info about ALT levels:

http://hepatitis-central.com/hcv/labs/lft.html

" ALT = amino alanine transferase "

" Some points:

•These tests have meaning, but they generally cannot be interpreted

without clinical info. They are probably most useful to track, or

follow a particular problem, but even then they often " bounce around "

greatly.

•These numbers are not linear.

•These numbers do not always detect all liver disease. Some pts with

severe advanced liver disease will have normal or nearly normal enzyme

levels.

Are these numbers indicative of liver funtion? Not really. Unfortunately,

they are often called " liver function tests " or " LFT's " , but in actuality,

they do not measure function per se.

Then how is liver function measured? Other tests including:albumin

& bilirubin, & prothrombin time are more truely measures of function,

but clinical factors must be considered as well. "

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http://www.cumc.columbia.edu/dept/gi/labtests.html

" ALT is an enzyme produced in hepatocytes, the major cell type in

the liver. ALT is often inaccurately referred to as a liver

function test, however, its level in the blood tells little about

the function of the liver. The level of ALT in the blood (actually

enzyme activity is measured in the clinical lab) is increased in

conditions in which hepatocytes are damaged or die. As cells are

damaged, ALT leaks out into the bloodstream. All types of hepatitis

(viral, ETOHic, drug-induced, etc.) cause hepatocyte damage that

can lead to elevations in the serum ALT activity. The ALT level

is also increased in cases of liver cell death resulting from

other causes, such as shock or drug toxicity. The level of ALT

may correlate roughly with the degree of cell death or inflammation,

however, this is not always the case. An accurate estimate of

inflammatory activity or the amt cell death can only be made by

liver bx. "

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http://www.mayoclinic.com/health/elevated-liver-enzymes/HQ01011

" A lab report of elevated liver enzymes is common. It doesn't

indicate a specific disease. However, it may be due to a liver

disorder, even if you don't have any sxs of liver problems. To

determine the underlying cause of elevated liver enzymes, your

doctor may recommend further testing....Liver enzymes help maintain

a variety of chemical & metabolic processes that occur in the liver.

Normally, only very small amts of these enzymes are present in

your blood..... "

" Common causes of elevated liver enzymes include:

-Meds, such as certain nonsteroidal anti-inflammatory drugs,

cholesterol-lowering meds, antibiotics & anti-seizure meds

-Drinking too much ETOH

-Obesity

-Diabetes

-Elevated triglycerides

-Infection, such as viral hepatitis & mononucleosis

-Autoimmune disorders of the liver & bile ducts, such as autoimmune

hepatitis & primary sclerosing cholangitis & primary biliary cirrhosis

-Metabolic liver disease, such as hemochromatosis & 's disease

-Excessive use of vitamin supplements & certain herbal supplements

-Tumors of the liver or bile ducts

Tx of elevated liver enzyme depends on the underlying cause. "

Dianne Kiyomoto, RD

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" Aminotransferase Elevations in Healthy Adults Receiving 4 Grams of

Acetaminophen Daily: A Randomized Controlled Trial "

B. Watkins, MD; Neil Kaplowitz, MD; T. Slattery, PhD;

Connie R. Colonese, MS; Salvatore V. Colucci, MS; W. ,

PhD; C. , MD

JAMA. 2006;296:87-93. (JAMA Vol. 296 No. 1, July 5, 2006)

Context

During a clinical trial of a novel hydrocodone/acetaminophen

combination, a high incidence of serum alanine aminotransferase (ALT)

elevations was observed.

Objective

To characterize the incidence & magnitude of ALT elevations in

healthy participants receiving 4 g of acetaminophen daily, either

alone or in combination with selected opioids, as compared with

participants tx’d with placebo.

Design, Setting, & Participants

A randomized, single-blind, placebo-controlled, 5-tx, parallel-group,

inpatient, diet-controlled (meals provided), longitudinal study of

145 healthy adults in 2 U.S. inpt clinical pharmacology units.

Intervention

Each participant received either placebo (n = 39), 1 of 3 acetaminophen/

opioid combinations (n = 80), or acetaminophen alone (n = 26). Each

active tx included 4 g of acetaminophen daily,the max recommended

daily dosage. The intended tx duration was 14 days.

Main Outcomes

Serum liver chemistries & trough acetaminophen concentrations measured

daily through 8 days, & at 1- or 2-day intervals thereafter.

Results

None of the 39 participants assigned to placebo had a max ALT of >

3 times the upper limit of normal. In contrast, the incidence

of maximum ALT of > 3 times the upper limits of normal was 31% to

44% in the 4 tx groups receiving acetaminophen, including those

participants tx’d with acetaminophen alone. Compared with placebo,

tx with acetaminophen was associated with a markedly higher median

max ALT (ratio of medians, 2.78; 95% confidence interval, 1.47-4.09;

P<.001). Trough acetaminophen concentrations did not exceed

therapeutic limits in any participant & , after active tx was

discontinued, often decreased to undetectable levels before ALT

elevations resolved.

Conclusions

Initiation of recurrent daily intake of 4 g of acetaminophen in

healthy adults is associated with ALT elevations & concomitant tx

with opioids does not seem to increase this effect. Hx of

acetaminophen ingestion should be considered in the differential

dx of serum aminotransferase elevations, even in the absence of

measurable serum acetaminophen concentrations.

====================================================================

NEW EVIDENCE OF LIVER TOXICITY IN HEALTHY ADULTS TAKING THE MAXIMUM

RECOMMENDED DOSE OF ACETAMINOPHEN (TYLENOL)

IS THE MAXIMUM RECOMMENDED DOSE SAFE?

This is an automated email sent by Public Citizen's Worst Pills,

Best Pills News Online Drug E-Alert.

http://www.citizen.org

Research published in the July 1 Journal of the American Medical

Association found that healthy research subjects given the max

daily dose of the popular pain & fever reducer acetaminophen

(TYLENOL) of 4.0 grams/day (4,000 milligrams) developed a sign

of early liver toxicity. This is equivalent to 2 extra-strength

acetaminophen tablets/day. The people in the study were not

using any ETOHic beverages, which would have further increased

their liver toxicity.

The research used the scientific " gold standard " method for

determining a cause & effect relationship between a drug & an

outcome, either good or bad. The purpose of the study was to test

a new combination product containing the old narcotic painkiller

hydrocodone in combination with acetaminophen. The study was

stopped early because of the frequency & size of blood level

increases of an enzyme known as alanine aminotransferase, or ALT,

in the groups receiving acetaminophen vs the group receiving a

placebo. ALT elevation is an early sign of potential liver damage.

An ALT elevation of > 3 times the upper limit of what is

considered normal (abbreviated >3 X ULN) is generally considered

to be clinically significant. This requires further investigation

for the possibility of liver disease.

The study was entirely funded by the producer of the new

drug combination, Purdue Pharma LP, headquartered in Stamford,

CT. Purdue Pharma is notorious as the manufacturer of the

potent, over-promoted, & frequently misused timed-release

narcotic oxycodone (OXYCONTIN) that was promoted as a less

addictive painkiller. The researchers were employees of 2

contract research organizations, or CROs.

The study involved 145 healthy male & female volunteers who

ranged in age from 18- 45 yrs. The volunteers were randomized

to receive 1 of 5 txs. 4 of these txs included 4.0 grams of of

the study was 14 days.

Overall, 41 of the volunteers (39%) experienced ALT elevations

of >3 X ULN, while none of the volunteers receiving the placebo

had ALT elevations of this level. There were 27 (25%) pts with

ALT elevations of >5 X ULN & 8 (8%) with ALT values >8 X ULN.

The authors of the study commented that their review of

published medical studies supports their observations that some

healthy adult pts in clinical trials developed ALT elevations

when repeatedly tx’d with 4.0 grams of acetaminophen daily.

The researchers noted that the incidence of ALT elevations they

observed was higher than those reported in similar published

studies. They speculate that, in part, their results may be

related to relatively high proportion of Hispanics in their study.

Previous research suggests that people of Hispanic origin have

increased susceptibility to ALT elevations.

Whatever the reason for the frequency & size of blood level increases

seen with acetaminophen use in this study, the results are troubling.

It may well be the case that the upper daily recommended limit, 4

grams, is not safe.

In the February 2006 issue of Worst Pills, Best Pills News, we

reported on a study published in the December 2005 issue of the

medical journal Hepatology that found that the annual percentage

of potentially fatal acute liver failure cases caused by

acetaminophen rose from 28% in 1998 to 51% in 2003. The authors

of this study concluded:

.. acetaminophen hepatotoxicity far exceeds other causes of acute

liver failure in the U.S.

This study found that unintentional overdoses were responsible

for 48% of the acute liver failure cases. Intentional overdoses,

or suicide attempts, accounted for 44% of episodes. In 8% of the

cases, the intent was unknown. Of the pts who overdosed

unintentionally, 38% took 2 or more acetaminophen containing

products simultaneously, & 63% used narcotic combination

painkillers that contained acetaminophen.

The list of acetaminophen containing prescription & over-the-counter

(OTC) drug products is long. The list below gives the brand names

& amount of acetaminophen contained in 1 dose of various

painkillers & products widely promoted for colds & flu.

BRAND NAME - AMOUNT OF ACETAMINOPHEN/DOSE

Drixoral Plus - 500 milligrams

Excedrin Migraine - 250 milligrams

Extra Strength Tylenol - 500 milligrams

Fioricet - 325 milligrams

Lortab - 500 milligrams

Percocet - 325 milligrams

Regular Strength Tylenol - 325 milligrams

Tavist Allergy/Sinus/Headache - 500 milligrams

Tylenol Caplets - 650 milligrams

Tylenol Geltabs - 650 milligrams

Tylox - 500 milligrams

Vicks DayQuil Multisymptom Cold/Flu Relief - 325 milligrams

Vicks NyQuil - 500 milligrams

Vicodin - 500 milligrams

The amount of acetaminophen contained in OTC drugs is clearly

listed on the label. Always read these labels before taking any

OTC drug to make sure you are not taking the same drug such as

acetaminophen in 2 or more products. Many prescription painkillers

contain a combination of a narcotic drug & acetaminophen. Examples

of these drugs from the list above are Lortab, Percocet, & Tylox.

If you are prescribed a painkiller, ask your pharmacist if it also

contains acetaminophen. Mixing various OTC drugs & prescription

painkillers may result in taking too much acetaminophen.

Alcohol in combination with acetaminophen can increase the risk

of liver toxicity. OTC acetaminophen products now have the following

warning on their labels:

Warnings

Alcohol warning: If you consume 3 or more ETOHic drinks every

day, ask your doctor whether you should take acetaminophen or

other pain relievers/fever reducers. Acetaminophen may cause

liver damage.

There are 2 important points that you should always consider. One,

just because a drug is sold OTC does not mean that it is totally

safe. Acetaminophen is a prime example. Two, when using any OTC

product, always use the lowest dose that helps your sxs. See your

physician if sxs persist.

What You Can Do

You should carefully read the labels on OTC drug products. If

you are prescribed a painkiller, ask your pharmacist if it

contains acetaminophen. There is new reason for concern in using

4 grams/day of acetaminophen for > 4 days that should preclude

such usage. If you consume alcoholic beverages (see above),

even this amount may be dangerous.

If you or a family member develop any of the sxs of potential

liver toxicity, stop taking all acetaminophen-containing products

& call your physician immediately. These sxs are:

-Pruritus

-Jaundice

-Dark urine

-Upper right-sided abdominal tenderness

-Unexplained " flu-like " sxs

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