Welcome to the eighth edition
of the Alchemist Lab newsletter.
This article from Life Extension caught my
eye and I wanted to pass it on to all my hepatitis patients.
This article also underscores the importance of glutathione.
The next newsletter will be on acetyl glutathione, which
will be a breakthrough product in the treatment of Hepatitis
C.
- Steven Finkbine
Dec 07 Hidden Dangers Of Acetaminophen
Even when used as directed, acetaminophen can
lead to liver toxicity or death. Here's how to use acetaminophen
safely.
By Jay S. Cohen, MD, (Introduction by William Faloon)
What if a dietary supplement was proven to
cause liver damage, liver failure and death? What if each
year, this same supplement caused 100,000 calls to poison
control centers, 56,000 emergency room visits, 26,000 hospitalizations,
and more than 450 deaths from liver failure alone?
You know the answer. The FDA would immediately
shut down the supplement company and seek to incarcerate
the principals for life.
What if, on the other hand, a highly profitable
drug caused this much disease and death? To no one's surprise,
the FDA's response is to do the equivalent of nothing.
As we learned long ago, the FDA too often functions
to protect the financial interests of pharmaceutical companies.
The FDA's intentional inaction in this instance proves that
this agency could care less about how many Americans suffer
and die each year.
In his eye-opening article, Dr. Jay Cohen exposes
a lethal hoax that has been perpetrated on infants, children,
and adults by immoral drug companies and their conspirators
within the FDA.
Many people assume that over-the-counter medications
are safe when taken as directed. Yet even at recommended
doses, aspirin can cause ulcers, antihistamines can cause
sedation, and acetaminophen can cause serious liver damage.
You can read about some of these risks in the
product information that accompanies over-the-counter medicines.
For example, the acetaminophen package insert warns about
taking the drug if you consume three or more alcoholic drinks
a day. The link between acetaminophen, alcohol, and an increased
risk of liver damage was identified in the 1980s. This research
identified another factor that can increase the risks associated
with acetaminophen: fasting. This can refer to fasting due
to abdominal upset or pain, nausea, vomiting, loss of appetite,
anorexia, or malnutrition. Consider this case published in
1992:
A 25-year-old, healthy Swedish man developed
gastroenteritis while on holiday in Turkey. For a day and
a half before flying home, the man experienced nausea and
vomiting, and he was unable to keep food or liquid down.
Noticeably ill during the flight, upon landing he
was taken directly to a hospital. As his condition worsened,
he was diagnosed with liver failure and transferred to await
a liver transplant. Information from his brother, who had been
with him in Turkey, indicated that the patient had taken 500
mg to 1,000 mg of acetaminophen two to three times each day,
with a maximum total intake of 5,000-6,000 mg over two days.
Unexpectedly, the patient's condition began to improve, liver
transplantation was canceled, and he was discharged ten days
later.1
What had the Swedish man done wrong to develop
liver failure? Nothing. His use of acetaminophen was within
the recommended dosage range. The maximum recommended dosage
of acetaminophen is 4,000 mg/day. The man took only 2,000
or 3,000 mg/day. He took acetaminophen merely to ease the
pain of acute gastroenteritis, as do thousands of people
each day. He followed the rules but nearly died.
The doctors presenting this case concluded
that liver toxicity "can occur after low, repeated
doses of acetaminophen." They
added, "the drug should not be used under conditions
of starvation, including acute gastroenteritis with nausea
and vomiting."1 Yet
today, despite this report and many others, acetaminophen
products do not list a warning against using the drug when
unable to eat.
A Powerful Liver Toxin
Many drugs can cause liver damage, liver failure,
and death. Yet, acetaminophen prompts the most calls to poison
control centersâ•"more than 100,000 per year.
Each year, acetaminophen accounts for about 56,000 emergency
room visits, 26,000 hospitalizations, and more than 450 deaths
from liver failure. 2 Acetaminophen causes more cases of
acute liver failure than all other medications combined.3
In comparison to the millions of people who
take acetaminophen each day without harm, the occurrence
of liver failure and death is relatively rare. Still, many
experts believe the numbers are too high and must be reduced.
Dr. William Lee, a highly respected expert on acetaminophen,
wrote, "It still must be asked:
Is this amount of injury and death really acceptable for
an over-the-counter pain reliever?"4
Why does acetaminophen affect the liver? Acetaminophen
is a dose-dependent liver toxin. Even at standard doses,
the metabolism of acetaminophen in humans releases small
amounts of a toxic substance, N-acetyl-benzoquinoneimine
(or NAPQI).5 With excessive doses, a much larger amount of
this toxin is formed. There is a fine line between a safe
dose of acetaminophen and one that is dangerous, which means
that doses even slightly above the maximum recommended dose
of 4 g/day can cause liver damage. "Just
doubling the maximum adult dosage for a few days can be toxic,
even deadly," warns Consumer Reports.6 Dr. T.M. MacDonald
adds, "Used
incorrectly and taken in excessive dose either accidentally
or intentionally, acetaminophen is a very toxic drug."7
Fasting reduces the body's store of glutathione,
which is needed to metabolize acetaminophen safely. Decreased
levels of glutathione lead to an increased risk of acetaminophen
toxicity. Liver damage may occur at recommended doses, as
seen with the Swedish man, or in people who unintentionally
overmedicate with acetaminophen.
Unintentional Overdoses Take a Heavy Toll
Another daunting statistic about acetaminophen
is that nearly half of all overdoses are unintentional.8
These people do not intentionally take excessive amounts
of acetaminophen; instead, they lose track of the amount
they are taking and inadvertently take more than recommended.
Other individuals intentionally take 5,000-8,000
mg/day of acetaminophen because their pain is not relieved
by the recommended doses. These people are not trying to
harm themselves, but merely seeking relief from pain and
are not aware that doses even slightly above the maximum
therapeutic dose of 4,000 mg/day can be toxic.
Another type of accidental overdose occurs
when people take multiple remedies, for example, for the
flu, cough and cold, headache, and fever, without realizing
that each contains acetaminophen. Accidental overdoses can
also occur in those who take prescription medications containing
acetaminophen, such as Vicodin® or Percocet®, since
they may not be aware of the medications' acetaminophen content.
Unknowingly, they can overmedicate with acetaminophen when
they reach for an over-the-counter product containing this
drug at the onset of flu, a cold, or fever. It is all too
easy to make this mistake. A 2003 study found that when doctors
prescribed narcotic-acetaminophen combination pain medications
to 108 patients, not one was warned that the medications
contained acetaminophen and that they should reduce or discontinue
the use of other acetaminophen-containing products, including
over-the-counter remedies.9
Unintentional overdoses of acetaminophen are
often more toxic and difficult to treat than intentional
overdoses.10 Doctors often see people who take intentional
overdoses within a few hours of ingestion. In these cases
(usually attempted suicide), the amount taken is usually
known and liver damage is not yet extensive. The acutely
high blood levels of acetaminophen seen in these cases help
doctors make a quick diagnosis and start treatment.
In contrast, unintentional overdose cases usually
occur after people have been taking acetaminophen over several
days and the exact amount ingested may not be known. Blood
levels of acetaminophen are often deceptively low, yet liver
damage may already be extensive and critical time may be
lost while doctors struggle to make a diagnosis.
Requests for Better Warnings Ignored
In addition to its alcohol warning, over-the-counter
acetaminophen packaging also warns against use "with
any other product containing acetaminophen."11 Unfortunately,
this weak warning does not convey the serious risks of acetaminophen
overmedication, even at slightly elevated doses. Overuse
can cause liver injury, liver failure, and death, but you
would never know it by reading the information provided with
acetaminophen products.
You would also never know about the risks of
taking acetaminophen while fasting. Current product information
does not mention it at all. Meanwhile, cases continue to
be reported as highlighted below:
A 45-year-old man developed severe liver toxicity
while taking 4,000 mg/day of acetaminophen for four days.
He had several risk factors, including malnutrition and illness-induced
starvation.12
A 54-year-old woman developed liver failure
after unintentionally overmedicating with 5,000-6,000 mg/day
of acetaminophen for six to eight weeks. She had taken 3,000
to 4,000 mg/day of over-the-counter acetaminophen and was
unaware that her prescription pain medication (Lortab®)
also contained acetaminophen.13 Her history provided no risk
factors except for a gastric bypass, which can lead to malabsorption
of micronutrients needed to synthesize glutathione.14
A 16yearold boy underwent surgery for severe
scoliosis. Fever developed postoperatively, and a low dose
of 1,200 mg/day of acetaminophen was given for three days.
The boy was malnourished, and he was fasting during the postoperative
period with only limited intravenous support. A few days
later, the boy developed acute liver failure, and he died
soon after. Autopsy revealed liver injury consistent with
acetaminophen toxicity. The doctors commented, "This
case may illustrate that acetaminophen may cause liver injury
even in therapeutic doses, if certain risk factors are present.
Such factors are malnutrition and starvation."15
A 58-day-old infant girl was seen in an emergency
room after two days of fever, decreased appetite, lethargy,
and irritability. As instructed, the parents had given acetaminophen
every four hours to the infant. Tests revealed highly elevated
liver enzymes and an elevated acetaminophen level. Tests
for other liver disorders were negative. The girl improved
quickly with treatment. The authors
noted that children who have fever, vomiting, or diarrhea
often have inadequate oral intake, and that a fasting state
could increase the toxicity of acetaminophen.16
Two children developed severe liver and kidney
damage after receiving repeated doses of acetaminophen for
illness and fever. The authors commented that when low doses
of acetaminophen are used at frequent intervals for a number
of days, the drug puts children who are vomiting or have
sharply reduced caloric intakes at increased risk for liver
and/or kidney toxicity.17
In this last case, the authors added that there
was a need for increased caution and awareness among health
care professionals about the toxic effects of acetaminophen.
This increased awareness required "appropriate packagelabel
warnings,"17
and is one of many calls for more informative warnings on
acetaminophen products.
Dangers of Acetaminophen: What You Need to Know
The FDA Fails to Act
Despite calls for better warnings, nothing
has changed. Over the years, the FDA has intermittently voiced
a desire to reduce the number of cases of acetaminophen toxicity.
In 2004, the agency launched an educational campaign on the
safe use of over-the-counter medications.18 This initiative
appears to have had no impact on acetaminophen statistics.
Since then, a large study has been published demonstrating
that therapeutic doses of acetaminophen cause liver injuries
in a substantial number of users,19 and has raised serious
questions about the safety of therapeutic doses of acetaminophen.
In 2007, an FDA medical officer revealed that
the staff of the FDA's Office of Surveillance and Epidemiology
(formerly Office of Drug Safety) had recommended initiating
measures similar to those adopted in Great Britain to reduce
acetaminophen toxicity. These measures include limiting the
number of acetaminophen pills in a package and packing the
pills individually in foil packs. This recommendation never
reached the FDA's Nonprescription Drugs Advisory Committee,
where it could have been considered and approved.20
Recently, in response to a scathing report
by the Institute of Medicine, the FDA has made a lot of noise
about enhancing its efforts to promote drug safety. Until
proven otherwise, the FDA's promises are hollow. The tilt
of the FDA will continue to be in favor of the drug industry.
For years, the FDA has understaffed and underfunded its safety
divisions. It has not been unusual for high-ranking FDA officials
to approve new drugs despite serious concerns of FDA medical
officers about the drugs' safety. Indeed, just recently another
article critical of the FDA was published in the New England
Journal of Medicine (September 6, 2007), in which Dr. Sheila
Weiss Smith concluded that the FDA's actions once again underscored "the
low priority it assigns to its responsibility for arbitrating
drug safety."21
FDA Ignores Its Own Guidelines
With acetaminophen, FDA officials have long
ignored their own regulations. FDA guidelines require drug
companies to list adverse drug events if: 1) they are serious;
2) they occur in close proximity to using the drug; and 3)
they are consistent with a drug's known effects.22 Acetaminophen
fits all of these requirements. In addition, animal studies
provide ample evidence of a link between fasting, acetaminophen
use, and liver failure.23
Moreover, a recent report demonstrated the
link between acetaminophen, fasting, and liver toxicity.
Doctors were at first puzzled why a nine-month-old child
had developed liver toxicity after only two days of therapeutic
doses of acetaminophen. Laboratory analysis revealed that
the child had a genetically determined glutathione deficiency,
causing her glutathione activity to be only 5% of normal.
Without adequate glutathione, standard doses of acetaminophen
were toxic in this child.24 The case provides human evidence
that markedly decreased glutathione activity, which can also
be caused by fasting, increases the risk of acetaminophen
liver toxicity in humans.
FDA guidelines also state that rare, serious
adverse events should be listed in product information "even
if there are only one or two reported events."22 The
first cases linking acetaminophen, fasting, and liver toxicity
were reported in the 1980s. More than 20 years have passed,
during which time many more cases have been published. Where
is the warning? Where are the meaningful measures to improve
acetaminophen safety?
Perhaps the FDA's inaction is related to resistance
by the largest producer of acetaminophen products (McNeil
Consumer Health, Tylenol® products) to implement a fasting
warning and other safety measures. Acetaminophen is a widely
used drug that generates more than two billion dollars per
year in sales in the US. Additional warnings might undo acetaminophen's
reputation as the safest over-the-counter pain and fever
remedy, and safety packaging might depress sales.
Some argue that it has not been fully proven
that fasting increases the risk of liver toxicity from acetaminophen.
This is a specious argument. Experts know that absolute proof
will be difficult to obtain. Liver toxicity from acetaminophen
and fasting is a rare event. If it occurs in one in 100,000
users, a study demonstrating this would require at least
300,000 patients, and it would take years to accomplish.
This is why FDA guidelines do not require absolute proof
of causality. The FDA simply requires a close, plausible
association between a drug and an adverse event. This is
certainly the case with acetaminophen and fasting.
Over the years, more and more physicians have
accepted fasting as a legitimate risk factor for acetaminophen
toxicity. In 2001, the Harvard Health Letter stated flatly: "It
is dangerous to take acetaminophen after you've been fasting."25
Three years later, in response to articles debating fasting
and other risk factors with acetaminophen, Dr. Timothy Davern
noted that in the gastroenterology division at the University
of California, San Francisco, "fasting due to intercurrent
illness [e.g. flu] appears to be a common predisposing factor" for
acetaminophen toxicity.26
Things You Can Do
Given the potential risks of overusing acetaminophen,
it is wise to use it sparingly, if at all. Those who have
to take acetaminophen need to be aware of the factors that
can increase the risks. These include taking acetaminophen
while having three or more alcohol drinks a day, using multiple
acetaminophen-containing products, or taking acetaminophen
when you are unable to eat because of nausea, vomiting, loss
of appetite, anorexia, malnutrition, or other causes of reduced
nutrition. If your doctor prescribes a medication for pain,
headache, or muscle tension, be sure to ask whether the drug
contains acetaminophen. If you forget to ask your doctor,
ask your pharmacist.
Be sure to read the label of any over-the-counter
medication. If you are taking more than one medication, make
sure that only one contains acetaminophen. Read the warnings.
Stay within the recommended doses of acetaminophen. Overmedicating
by even small amounts raises acetaminophen's risks.
It should also be remembered that alternative
medications such as ibuprofen, naproxen, or other anti-inflammatory
drugs have their own risks (e.g. stomach ulceration and cardiovascular
complications).27,28
For those who need to take these over-the-counter
medications, consider taking antioxidants and other supplements
at the same time to mitigate any adverse effects on the liver,
kidney, and stomach.29 These nutrients provide antioxidant
support to counteract the harmful build-up of oxidant by-products
caused by taking acetaminophen. They also preserve the liver's
supply of glutathione, an antioxidant that is essential for
the body's detoxification of a number of drugs and toxins,
and which is depleted by the metabolism of acetaminophen.
Furthermore, glutathione levels fall with aging, thus increasing
the risk of acetaminophen-induced liver damage, so it is
even more important to maintain healthy liver function in
the elderly.30
Nutritional supplements that may be used in
conjunction with acetaminophen include N-acetylcysteine (NAC),31
vitamins C and E,32,33 S-adenosylmethionine (SAMe),34 whey
protein,35-7 milk thistle extracts (silymarin and silibinin),38,39
and polyenylphosphatidylcholine.40
N-acetylcysteine is part of the body's natural
antioxidant system and helps maintain stores of glutathione
in the liver.31 This nutrient is also used intravenously
in conventional therapy as a primary treatment for liver
toxicity triggered by acetaminophen overdose. Life Extension
recommends taking 600 mg of N-acetylcysteine with at least
1 g of vitamin C per dose of acetaminophen, which will provide
significant protection for the liver. Alternatively, whey
protein, 20 g/day, mixed with cereal or a liquid, contains
a high concentration of cysteine, which acts a key precursor
to restoring glutathione levels in the liver.36,37
A lack of vitamin C or glutathione also causes
vitamin E levels to fall. Supplementing with vitamin E, 400
IU per day (along with at least 200 mg of gamma tocopherol)
can protect the liver while taking acetaminophen.33
For those who must take acetaminophen chronically,
the herb milk thistle, which contains the active ingredients,
silymarin and silibinin, restores the body's supplies of
glutathione, while reducing free radical production and lipid
peroxidation in the liver.38,39 The recommended dose is 250
mg of milk thistle extract two or three times a day in patients
taking long-term acetaminophen therapy.
In cases where liver function has already become
compromised by analgesics or other toxins, S-adenosylmethionine
(SAMe) may help repair the liver and prevent further damage.34
Polyenylphosphatidylcholine (PPC) is a soy
extract that also protects the liver against injury from
fibrosis, oxidative stress, and toxicity due to acetaminophen
use.40 Life Extension recommends taking 1800 mg/day of PPC
to protect the liver from noxious substances. Polyenylphosphatidyl-choline
also offers powerful protection for the gastric mucosa, which
is vulnerable to irritation and ulceration from high-dose
analgesics such as aspirin, ibuprofen, or prescription anti-inflammatory
drugs.41
It should be noted that any dietary supplementation
regime should not be launched without the supervision of
a physician or a qualified health care practitioner, who
will be able to create a program that is appropriate for
you.
Jay S. Cohen, MD, is an associate professor
of family and preventive medicine and psychiatry at the University
of California, San Diego. Dr. Cohen is a nationally recognized
expert on medications and their side effects. He has published
books and medical journal articles and has spoken at major
conferences and at the US Food and Drug Administration regarding
the need for improved drug safety. Dr. Cohen also provides
expert analyses and opinions in cases involving medication-induced
injuries. His most recent book, What You Must Know About
Statin Drugs and Their Natural Alternatives (Square One Publishers,
2006), explains who needs to reduce cholesterol or other
risk factors for heart disease, and how they can do so safely.
For more information, visit Dr. Cohen's website at www.MedicationSense.com.
PRESCRIPTION DRUGS CONTAINING ACETAMINOPHEN
Here are some frequently prescribed medications
that contain acetaminophen. This list is not exhaustive;
there are many other prescription drugs and scores of over-the-counter
remedies that contain acetaminophen. If your doctor prescribes
a drug for pain, headache, or muscle tension, ask your doctor
or pharmacist whether it contains acetaminophen.
