The dug called acetaminophen (used in the United States, Canada, Japan, South Korea, Hong Kong, and Iran^[12]) called elsewhere paracetamol is the most widely sold over-the-counter drug for the relief of pain[1], fever, and  headaches .  It is frequently added to prescription medications especially opioids for the supposed enhancement of relief[2].   Acetaminophen based on its chemical name is simply abbreviated as APAP, for acetyl-para-aminophenol.  APAP.  It is found in over a 100 over the counter and 25 prescription medications (for prescription list go to http://www.rxlist.com/script/main/srchcont_rxlist.asp?src=acetaminophen).   U.S. sales totals over $1 billion annually, which makes it the best-selling over-the-counter drug. 

Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of Antifebrin by A. Cahn and P. Hepp in 1886.   But its unacceptable toxic effects, the most alarming being cyanosis[3] prompted the search for less toxic aniline derivatives.  Harmon Northrop Morse had already synthesized paracetamol at John Hopkins University in 1877, but it was not until 1887 that clinical pharmacologist Joseph von Mering tried APAP on patients.  However its precursor phenacetin became popular.  APAP, the metabolite of phenacetin, was first marketed in the US in 1953, and promoted as being safer than aspirin. 

APAP’s peak absorption 30-60 minutes after oral administration and its half-life is 2 hours.  Dosing is 10-15 mg/kg every 4 hours, 5 doses per day maximum.  Recommend maximum dose is 1,000 mgs, and 4,000 mg per day. Though its efficacy is questioned, it is approved for reduction of fever (FDA approval requires only that it be slightly better than the placebo).   It purportedly has an analgesic property comparable to those of aspirin, however, APAP lacks a major anti-inflammatory of block efficiently prostaglandins.   It is supposedly an opioid agonist and thus is frequently added to them.  

Uninformed users presume it is safe like aspirin, and will up the dosage as pain persists.  APAP is added to a number of popular medication.  This results in unintentionally doubling the dosage.  My uncle spent a week in the hospital in the summer of 2010 for this reason.  (Some of the opioids that contain APAP (Vicodin, Darvocet-N, Endocet, Tylenol-Codeine, Percodan etc. at Rxlist).  Common over the counter drugs include Tylenol, Excedrin, Coricidin-D and Nyquil for which 30 mls. has 700 mgs of APAP.)   In prescription drugs it is listed on the bottles label as APAP.

There are major health issues.  Acetaminophen is by far the leading cause of drug induced liver failure.  In one study of acute liver failure, n = 133 (49%) were due to APAP, the next leading cause was isoniazid, n = 24 (17.5%) at http://onlinelibrary.wiley.com/doi/10.1002/lt.20204/full.  The authors of the study concluded:  “..., acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States.”  In another study published in the December 2005 issue of the medical journal Hepatology found that the annual percentage of potentially fatal acute liver failure (ALF) cases caused by acetaminophen (TYLENOL) rose from 28 percent in 1998 to 51 percent in 2003.”   This increase correlates with increasing usage of APAP.  The reason is genetic, a significant portion of the population are sensitive to APAP.   Numerous studies have investigated this phenomena.  One well designed study examined the biomarker for liver toxicity, alanine transaminase and found that 39% of volunteers experienced an elevation of ALT[4] more than 3 times the upper limit , and a quarter of that number had 8 times the clinically significant level of ALT, at (http://jama.ama-assn.org/content/296/1/87.short).  These volunteers were given the recommended upper limit of 4 grams a day.  The number would have been much higher if elderly population was used, since their liver doesn’t clear medications as quickly.  The cause for this sensitivity in the 39% of volunteers is the CD44 gene.  A sizeable population is at risk from liver toxicity.

Acetaminophen has been found to cause asthma.  The rapid rise in asthma over the last 3 decades has been a puzzle that has been recently solved.  A study of 205,487 children age 6 to 7 years published in Lancet found a 323% increase in risk of asthma for those with high use group versus no use.  “Use of paracetamol in the first year of life and in later childhood, is associated with risk of asthma, rhino-conjunctivitis, and eczema at age 6 to 7 years.”  (http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2808%2961445-2/fulltext).   A similar large study of teens came to the same conclusion at http://171.66.122.149/content/183/2/171.abstract.  Another study found that childhood asthma risk increased if APAP was taken during pregnancy, at http://www.sciencedirect.com/science/article/pii/S0890623810003023 Such findings are robust.

Until 2010 APAP was believed safe in pregnancy however, in a study published in October 2010 it has been linked to infertility in the adult life of the unborn.  Clearly acetaminophen’s benefits are not worth its risks, risk that in general ignored for the sake of profits[5].  The FDA is an extension of big PhARMA, and APAP sales are over $1 billion annually.   A number of nations have acted to significantly limit its inclusion, but not the U.S.

NEW EVIDENCE OF LIVER TOXICITY
                  IN HEALTHY ADULTS TAKING THE MAXIMUM RECOMMENDED DOSE OF ACETAMINOPHEN (TYLENOL) IS THE MAXIMUM RECOMMENDED DOSE SAFE?

Research published in the July 1 Journal of the American
                  Medical Association found that healthy research subjects given the maximum daily dose of the popular pain and fever reducer
                  acetaminophen (TYLENOL) of 4.0 grams (4,000 milligrams) per day developed a sign of early liver toxicity. This is equivalent
                  to two extra-strength acetaminophen tablets per day. The people in the study were not using any alcoholic beverages, which
                  would have further increased their liver toxicity.

BRAND NAME - AMOUNT OF ACETAMINOPHEN PER 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 two or more products.  Many prescription painkillers contain a combination of a narcotic
                  drug and acetaminophen.  Examples of these drugs from the list above are Lortab, percocet, and Tylox.  If you are
                  prescribed a painkiller, ask your pharmacist if it also contains acetaminophen.  Mixing various OTC drugs and 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 alcoholic
                  drinks every day, ask your doctor whether you should take acetaminophen or other pain relievers/fever reducers. Acetaminophen
                  may cause liver damage.
 
There are two 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 symptoms.  See your physician
                  if symptoms persist. 
 
What You Can Do
 
You should carefully read the labels on OTC drug products. 
                  If you are rescribed a painkiller, ask your pharmacist if it contains acetaminophen. There is new reason for concern in using
                  4 grams a day of acetaminophen for more than 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 symptoms
                  of potential liver toxicity, stop taking all acetaminophen-containing products and call your physician immediately. These
                  symptoms are:  
-Pruritus (itchy skin) 
-Jaundice (yellowing of the skin or whites of the eyes) 
-Dark urine 
-Upper right-sided abdominal tenderness (location of the liver) 
                  
                  
-Unexplained "flu-like" symptoms.
                  
                  
 
                  
                  
 
                  
                  

The research used the scientific "gold standard" method
                  for determining a cause and effect relationship between a drug and 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 and size of blood level increases of an enzyme known as alanine aminotransferase,
                  or ALT, in the groups receiving acetaminophen versus the group receiving a placebo.  ALT elevation is an early sign of
                  potential liver damage.

An ALT elevation of more than three 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, and frequently misused timed-release narcotic oxycodone (OXYCONTIN) that was promoted as a less
                  addictive painkiller.  The researchers were employees of two contract research organizations, or CROs.

The study involved 145 healthy male and female volunteers
                  who ranged in age from 18 to 45 years. The volunteers were randomized to receive one of five treatments.  Four of these
                  treatments included 4.0 grams of acetaminophen daily and the fifth was a placebo.  The intended duration of the study
                  was 14 days.

Overall, 41 of the volunteers (39 percent) 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 percent) patients with ALT elevations of >5 X ULN and 8 (8 percent) 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 patients in clinical trials developed ALT
                  elevations when repeatedly treated 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 and 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 percent in 1998 to 51 percent
                  in 2003. The authors of this study concluded:  ... acetaminophen hepatotoxicity far exceeds other causes of acute liver
                  failure in the  United States.

This study found that unintentional overdoses were responsible
                  for 48 percent of the acute liver failure cases. Intentional overdoses, or suicide attempts, accounted for 44 percent of episodes.
                  In eight percent of the cases, the intent was unknown. Of the patients who overdosed unintentionally, 38 percent took two
                  or more acetaminophen containing products simultaneously, and 63 percent used narcotic combination painkillers that contained
                  acetaminophen.

The list of acetaminophen containing prescription and
                  over-the-counter (OTC) drug products is long.  The list below gives the brand names and amount of acetaminophen contained
                  in one dose of various painkillers and products widely promoted for colds and flu.  

BRAND NAME - AMOUNT OF ACETAMINOPHEN PER 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 two or more products.  Many prescription painkillers contain a combination of a narcotic
                  drug and acetaminophen.  Examples of these drugs from the list above are Lortab, percocet, and Tylox.  If you are
                  prescribed a painkiller, ask your pharmacist if it also contains acetaminophen.  Mixing various OTC drugs and 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 alcoholic
                  drinks every day, ask your doctor whether you should take acetaminophen or other pain relievers/fever reducers. Acetaminophen
                  may cause liver damage.
 
There are two 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 symptoms.  See your physician
                  if symptoms persist. 
 
What You Can Do
 
You should carefully read the labels on OTC drug products. 
                  If you are rescribed a painkiller, ask your pharmacist if it contains acetaminophen. There is new reason for concern in using
                  4 grams a day of acetaminophen for more than 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 symptoms
                  of potential liver toxicity, stop taking all acetaminophen-containing products and call your physician immediately. These
                  symptoms are:  
-Pruritus (itchy skin) 
-Jaundice (yellowing of the skin or whites of the eyes) 
-Dark urine 
-Upper right-sided abdominal tenderness (location of the liver) 
                  
                  
-Unexplained "flu-like" symptoms.