US Pharm. 2008;33(5):18-21.

Community pharmacists field hundreds of self-care questions yearly on the topic of pain management. Many concern minor pains, such as headaches, toothaches, and muscle pains. For this reason, it is vital to understand the labeling of the various nonprescription internal analgesic products and the decision points in recommending them. This allows the pharmacist to identify appropriate products for each patient, as well as to offer justifiable referrals to the physician or other prescriber when the patient's situation requires it.

Age Limitations
There are several age restrictions that must be considered when recommending internal analgesics. 1 The lowest age that is safe for self-care (without a physician recommendation) varies according to the specific ingredient. For instance, aspirin is contraindicated for those younger than 3 years of age. On the other hand, acetaminophen (e.g., Tylenol), commonly abbreviated as APAP, can be given down to the age of 2 years. Ibuprofen (e.g., Advil, Motrin) is safe for patients as young as 6 months, unless the infant has a sore throat, when it should not be given under the age of 3 years. However, naproxen (e.g., Aleve) must not be recommended for self-care in patients under the age of 12 years. Interestingly, ibuprofen products carry a warning against use for patients over the age of 65 years, unless a physician advises them to do so.1

Several points are important to consider in making age-specific recommendations. The specific dosage form is also critical. For instance, although ibuprofen may be recommended down to the age of 6 months, the only product to carry this labeling is infants' concentrated drops (e.g., Infants' Motrin Concentrated Drops).1 Children's Motrin Suspension carries an age cut-off of 2 years (3 years for sore throat).1 Thus, the pharmacist must scan each product label to make sure it carries labeling appropriate for the age of the patient.

Another issue concerns that of manufacturer-supplied pediatric dosing charts. For many years, various manufacturers have created dosage charts purporting to allow pharmacists to make dosing recommendations below the FDA-approved age cut-offs. In the case of Tylenol, dosage charts suggested giving the products to patients as young as 0 months of age, essentially to newborns.1 The FDA has never approved labeling on acetaminophen packages for patients under the age of 2 years.2 Pharmacists should not rely on these unapproved doses and should refer questions about dosing at these ages to the patient's physician.

Duration of the Pain
Another factor that determines whether pain is self-treatable is how long it has lasted. Generally, if pain has persisted for longer than 10 days in adults, the patient should be referred to a physician.1 Pain may be self-treated for five days in children, when using aspirin or acetaminophen, but self-treatment in children is only safe for three days when ibuprofen is used. However, if the pain is due to sore throat, the patient may only self-treat for two days with any internal analgesic before a physician's advice is required.1

Alcohol Use
All internal analgesics warn against concurrent use with alcohol unless a physician is consulted first. The exact wording is important: "Alcohol Warning: If you consume 3 or more alcoholic drinks every day, ask your doctor whether you should take [insert name of ingredient] or other pain relievers/fever reducers."1 If the product contains aspirin, magnesium salicylate, ibuprofen, or naproxen, the label states that stomach bleeding may occur. If the product contains acetaminophen, the label states that acetaminophen may cause liver damage. Thus, the pharmacist should strive to discover whether the patient is a habitual, daily user of any type of alcoholic beverage, stressing to these patients the risks associated with unsupervised use of internal analgesics.

New FDA Labeling Proposals
As of this writing, the most recent FDA action in regard to internal analgesics is a set of proposed rules published in the Federal Register in December 2006, as a result of a meeting held in September 2002.2 If these guidelines are finalized, they will affect internal analgesic labeling in several important ways. The FDA justified the proposed changes by describing the accumulating mass of serious adverse event reports, such as unintentional acetaminophen hepatotoxicity and nonsteroidal anti-inflammatory drug (NSAID)–related gastrointestinal bleeding and renal toxicity. The agency stressed that these events are rare in relation to their extensive use, but also asserted that labeling changes could reduce morbidity.

Acetaminophen labeling was scrutinized carefully. In the 2002 meeting, William M. Lee, MD, of Southwestern Medical Center at Dallas explained that acetaminophen causes 1,000 to 2,000 cases of acute liver failure (ALF) yearly in the United States. 2 In a prospective study, he found that over 40% of cases of ALF were caused by acetaminophen toxicity.2 Concurrent alcohol use was a factor in over half of the cases.

FDA staff examined its adverse event reporting system (AERS) for spontaneous reports of hepatotoxicity in which one or more acetaminophen products had been ingested (without suicidal intent), finding a total of 282 adult cases and 25 pediatric cases (patients aged 1 day to 8 years) from January 1998 to July 2001.2

For pediatric cases where gender was reported to the FDA's AERS system, 70% of the patients were males. 2 Fifteen of the 25 pediatric cases involved liver injury that was severe and life-threatening. Ten of the 25 patients died and 21 required hospitalization. The FDA mentioned a possible safe dose of APAP as 75 mg/kg/day. For 10 of the pediatric cases, the estimated doses administered were 106 to 375 mg/kg/day. In 20 cases, one or more medication errors contributed to the hepatotoxicity. In three, infants' concentrated drops were given instead of the less concentrated children's liquid formulation. In four cases, the dose was measured using household teaspoons rather than the recommended measuring device.2

The lessons for pharmacists are clear when selling these products for use in pediatric patients. It is vital to stress to parents that dosing instructions must be followed exactly and that the dropper or other dosage device that came with the product is the only measuring device that can be safely used to deliver a dose. Furthermore, parents must be taught to follow the age-related instructions without deviation, using only the label on the specific product. Finally, they must be taught that different products have different concentrations and that a given volume of infants' concentrated drops contains a greater amount of APAP than standard liquid children's formulations.

In adult cases reported to the FDA's AERS system, 25% involved use of more than one APAP-containing product. 2 The typical scenario involved use of a narcotic/APAP combination along with a nonprescription APAP product. Patients often exceeded maximum recommended doses; the 65 patients with severe liver injury took an average of 7.1 g daily (as opposed to the FDA-approved maximum safe adult dose of 4 g daily). One hundred and sixteen of the 282 cases involved alcohol use. It reached the extent of abuse or overt alcoholism in 64 cases. Seventy-four percent of the 116 patients developed severe liver injury.2

The lessons for pharmacists are also quite clear for adult patients contemplating use of acetaminophen. At the point of sale, pharmacists must stress not to combine the product with any other analgesic containing APAP, to follow the dosing instructions exactly, and to heed the alcohol warning on the label.

A manufacturer present at the FDA meeting questioned the nature of APAP advertising. "Advertising portrays acetaminophen as a totally safe ingredient. This portrayal may exacerbate use and contribute to the silent danger resulting from overdose."2 Indeed, one company's Web site contains the following statement: "When taken as directed, according to the package label and dosing instructions, Tylenol (acetaminophen) does not cause liver damage."3 This statement must be examined closely as it shifts the blame for liver damage to the patient, clearly stating that following the label and dosing correctly will invariably prevent liver damage.

Is the patient always at fault when liver damage occurs, as the above statement implies? Part of this hinges on the question, "Do patients risk liver damage with normal doses of APAP?" The FDA stated: "Twenty-three of the 65 cases with severe liver injury reported doses of less than 4 g/day."2 (The FDA-approved, safe adult dose of APAP is 4 g daily.) The FDA also conducted an analysis of APAP-associated hepatotoxicity cases, discovering that patients ingested more than 4 g of APAP daily in 70% of cases; 32% ingested more than 10 g daily. Apparently, 30% of patients experienced hepatotoxicity with the recommended daily doses.2

The manufacturer must address these cases in which patients apparently taking labeled doses of acetaminophen nevertheless experienced liver damage. It should demonstrate in each case in the FDA files how the patient was at fault; i.e., did not take the product according to the package label. If each case of liver failure cannot be explained in this manner, the manufacturer should modify its categorical assertion of safety in regard to liver damage. If the manufacturer chooses to responsibly undertake this examination of the serious liver injury cases, it may help the FDA determine how to mandate more complete warning labels on APAP packages in order to prevent liver damage to other patients.

As a result of the 2002 meeting, the FDA proposed to change APAP labeling to reduce the risk of adverse events. The FDA would require a new liver warning for all APAP-containing products. The agency would also remove the current alcohol warning and incorporate a new alcohol warning in the proposed liver warning. The following label modifications were proposed for adult acetaminophen products:

"Liver warning: This product contains acetaminophen. Severe liver damage may occur if you take:
•      More than [insert maximum number of daily dosage units] in 24 hours
•      With other drugs containing acetaminophen
•      Three or more alcoholic drinks every day while using this product

Do not use with any other drug containing acetaminophen (prescription or nonprescription). Ask a doctor or pharmacist before using with other drugs if you are not sure. Ask a doctor before use if you have liver disease."2

The FDA's proposed changes would also require that the ingredient acetaminophen be prominently identified on the product's principal display panel of the immediate container as well as the outer carton when applicable. These proposed updates should help both the pharmacist and the patient to better understand the necessary precautions to take when using OTC pain relievers.

1. Pray WS. Nonprescription Product Therapeutics. 2nd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006.
2. Internal analgesic, antipyretic, and antirheumatic drug products for over-the-counter human use; proposed amendment of the tentative final monograph; required warnings and other labeling. Fed Regist. 2006;71:77314-77352.
3. Tylenol. Frequently asked questions. Accessed March 27, 2008.
4. Raymond J. Parents say acet­ aminophen killed student. The Oklahoman. February 29, 2008:1-2.

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