The FDA has acted recently to make consumers more aware of the risks associated with the use and overuse of acetaminophen-containing products, including boxed warnings about potential safety risks, and recommendations from advisory committees to include weight-based dosing on the labels of pediatric products and restricting solid oral dosages to a single concentration. Advisory committees have previously recommended similar changes for adult products.

	In May, 2011, the FDA’s Nonprescription Drugs Advisory Committee and Pediatric Advisory Committee met to consider whether weight-based dosing directions should be added to the existing age-based labeled dosing directions for children ages 2-12; whether the existing data supported the addition of new labeled dosing directions (10-15 mg/kg) for children age 6 months-2 years; and whether pediatric single-ingredient, acetaminophen-containing solid oral dosage forms should be restricted to a single dosage/concentration. Based on the testimony and data presented at the meeting, the panel voted unanimously in favor of adding weight-based dosing to the labels of these products, with a “a fairly strong consensus” that “the weight should be listed first and that the label should reflect in some way the priority towards weight-based dosing” (

). On the question of whether the pharmacokinetic, safety, and efficacy data support the addition of new labeled dosing directions corresponding to a 10-15 mg/kg dose for children age 6 months-2 years, the panel again voted “yes” unanimously. The panel also recommended that “infant acetaminophen should be labeled only for fever reduction in children age 2 and under, but labels may recommend acetaminophen for both fever and pain in children age 2 and older” (

). On the final question, of whether the FDA should consider restricting all oral dosage forms of pediatric acetaminophen-containing products to a single concentration, the panel voted 17 in favor and three against, with one abstention. Although the FDA usually follows the advice and recommendations of the advisory committees, it is not required to do so.

	Do you recommend OTC acetaminophen products to your patients for mild to moderate pain?	

		In your experience, are patients generally well-informed about the risks associated with these medications?

		Are they aware of the recommended daily maximum dose for acetaminophen, and of the fact that many products may also contain acetaminophen in addition to other active ingredients?

		Do you agree with the recommendations of FDA advisory committee to include weight-based dosing on the labels of pediatric acetaminophen-containing products? Do also agree with the move to limit these products to a single concentration?

		Did you support the FDA advisory committee recommendations in 2009 to lower the maximum total daily dose of nonprescription acetaminophen from 4,000 mg/day?

		Should the maximum nonprescription single adult dose be limited to 650 mg (or do you favor a different maximum single dose strength)?

		E-mail answers and comments to tkunkler@mdmag.com.

	In a related move, two weeks prior to the FDA advisory committee meeting, the Consumer Healthcare Products Association (a trade association for OTC medication manufacturers) announced that the makers of OTC single-ingredient liquid pediatric acetaminophen medicines were voluntarily taking steps “to convert these pediatric products to just one concentration” (

). After the changeover (which began in mid-2011), “the current children’s strength of liquid acetaminophen (160 mg / 5 mL) will become the only liquid concentration available for all children under 12-years-old, and the current concentrated infant drops will no longer be sold.”

The FDA and prescription acetaminophen dosing: Part of the bigger picture

	Earlier this year, in response to reports of severe liver injury associated with the use of acetaminophen-containing products, the FDA asked manufacturers of oral prescription acetaminophen combination products to “limit the maximum amount of acetaminophen in these products to 325 mg per tablet, capsule, or other dosage unit, with the exception of intravenous injection” (

). The FDA took this action in part because patients often do not know that the product they are using contains acetaminophen (there are over 600 products available), and they do not know what the recommended daily dosage is, or the risks and dangers associated with exceeding the dosage recommendations. The FDA said it believes this action “will reduce the risk of severe liver injury from acetaminophen overdosing, an adverse event that can lead to liver failure, liver transplant, and death. The FDA also directed manufacturers of these products to add a boxed warning to the label of all prescription drug products that contain acetaminophen describing the risks of severe liver injury. Companies will have until January, 2014 to comply with the new requirements. However, these new dose limits will apply only to prescription products that contain acetaminophen; for now, OTC products are not affected by the new 325 mg limits. But, if the FDA’s recent statements and past actions are any indication, this may not be the case for long.

		Additional Questions and Comments from the 2009 Joint Meeting of the FDA Drug Safety and Risk Management Advisory Committee, Nonprescription Drugs Advisory Committee, and the Anesthetic and Life Support Drugs Advisory Committee

Committee member comments from the discussion around lowering the recommended daily maximum dose from 4,000 mg/day and limiting the maximum nonprescription single adult dose to 650 mg:

		“Although the toxicity data for the 4 gram/day dose was not compelling it is clear that there is a small window between the dose that is therapeutic and the dose that may be toxic.”

		“The potential for unintentional overdosing is most likely to occur when the patient is standing in front of a shelf making a decision on their own.”

Comments from the discussion around whether the committee recommends switching “the current maximum dosage of acetaminophen (i.e., 2 x 500 mg)” to prescription status:

		“I feel comfortable with patients being able to obtain 500mg tablets without an office visit.”

		“Making 500mg tablets prescription only would be a barrier to care, particularly for the elderly.”

		“Making the 500mg tablets prescription is a compromise, making the formulation available and giving the practitioner an opportunity to discuss the toxicity with the patient.”

The advisory committee in 2009 was also asked to consider recommending whether pack size limits should be implemented for nonprescription acetaminophen products (the UK had recently put into place mandated pack size restrictions with no mandated sales restriction).

		“If pack size of acetaminophen is restricted, consideration should be given to limiting pack size of nonsteroidals (ibuprofen and naproxen) and salicylates (aspirin) to avoid an inadvertent, unintentional, impact on safety.”

		“Consider the negative impact that limiting the pack size may have on: the elderly who are not mobile, people who have to take acetaminophen for chronic pain, people who live in rural areas and large families.”

		“Skepticism that decreasing the pack size will have any impact on preventing liver toxicity, given that there is conflicting data from the UK experience, even with their large educational campaign.”

	The FDA recently announced that it is “currently working to address the recommendations of the Advisory Committee with regard to OTC acetaminophen products. Additional safety measures relating to OTC monograph products will be taken through separate action, such as a rulemaking as part of the ongoing OTC monograph proceeding for internal analgesic drug products” (

). This would appear to be a continuation of previous attempts to address safety issues related to OTC acetaminophen products. In 2009, an FDA advisory panel voted by a fairly narrow margin to recommend the agency to reduce the maximum daily dose of nonprescription single ingredient and combination acetaminophen-containing products from 4 grams per day, but did not recommend a new maximum dose (see sidebar). The panel also voted to limit the maximum nonprescription single adult dose of acetaminophen to 650 milligrams, and voted to make the 1,000 mg dose of acetaminophen available only by prescription (

). Some manufacturers are not waiting for the FDA to mandate additional labeling and dosage changes; in July the maker of Extra Strength Tylenol announced that it was voluntarily lowering the maximum daily dose from 4,000 mg/day to 3,000 mg/day, “to help encourage appropriate acetaminophen use and reduce the risk of accidental overdose” (

	With some makers of OTC acetaminophen-containing products taking voluntary steps in some cases to reduce the maximum dose of their products, more public attention being drawn to the potential renal effects associated with prolonged high levels of acetaminophen use, and calls for greater attention to be paid to consumers’ lack of information and education regarding key features of OTC acetaminophen products (dosage strength, whether the product contains acetaminophen, maximum daily dose, appropriateness for use in infants and children, etc), it is hardly surprising that the FDA and industry may take additional steps in the future to clarify the labeling on these products and streamline the choices available to consumers.

Articles

Feature Article

Recent labeling and dosage revisions to pediatric OTC products may be a sign of future changes for adult products.

The Changing Landscape of OTC Acetaminophen Pain Products

Patients selecting an over-the-counter (OTC) remedy for pain have a bewildering array of options from which to choose.

	Acetaminophen is effective for mild to moderate pain in children and adults and is considered to be safe if taken as directed. The current recommended daily dose of acetaminophen is 4,000 mg per day (4 g). However, recent concerns over the potential for liver damage in patients who take more than the recommended dose has prompted the FDA to recommend labeling changes to prescription acetaminophen products to limit the maximum dose, and to also consider additional action with regards to OTC products that contain acetaminophen. The chief concern is that because a number of OTC and prescription products combine acetaminophen with other medications, patients can be unaware that they have exceeded the recommended daily dose, thus increasing their risk for liver damage and other complications. In 2009, the FDA Patient Safety News (

) issued an “Advice for Patients” bulletin that reminded physicians that “acetaminophen toxicity is a leading cause of acute liver failure,” because “people may not be aware that they are in danger of liver damage if they exceed the maximum recommended dose, or that alcohol exacerbates the risk. Also, they may not realize how much acetaminophen they are consuming if they take more than one product containing this drug.” The FDA noted that accidental overdose can happen “because acetaminophen is widely found in both OTC and prescription drug products, in as many as 600 of them, including analgesics, antipyretics, cough/cold remedies and sleep aids. In this situation, people may not even recognize that some of the drugs they are taking contain acetaminophen.”

		For Managing Pain in Children, Is Ibuprofen a Better Choice?

	The authors of a study in the March 2010 issue of Annals of Pharmacotherapy (

) evaluated “the analgesic and antipyretic efficacy and safety of ibuprofen compared to acetaminophen in children and adults” by analyzing the result of 85 studies that directly compared ibuprofen to acetaminophen. They reported that, “Qualitative review of the literature revealed that, for the most part, ibuprofen was more efficacious than acetaminophen for the treatment of pain and fever in both pediatric and adult populations,” and that the two medications were equally safe. Results of a meta-analysis of “of all studies in which single-dose acetaminophen or ibuprofen were measured in a randomly blinded way in children younger than 18 years old” published in 2005 in the Journal of Pediatrics reached similar conclusions (

). The authors wrote that “In children, lower doses of ibuprofen (4 to 10 mg/kg) were as effective as acetaminophen (7 to 15 mg/kg) for the management of pain. Ibuprofen (5 to 10 mg/kg) was a more effective antipyretic than acetaminophen (10 to 15 mg/kg) at 2, 4, and 6 hours after treatment. There was no difference in safety between the two drugs or between each one and placebo.”

Ibuprofen: Effective, but Patients with GI and Cardiovascular Complications should be Monitored

	Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID) that is also effective for mild to moderate pain in children and adults and is considered to be safe if taken as directed. It may be more effective than acetaminophen for inflammatory pain, such as that associated with arthritis. The current recommended daily dose of ibuprofen is 1,200 mg (1.2 g). As with most NSAIDs, ibuprofen can increase the risk of stomach ulcers and gastrointestinal bleeding in patients. The authors of a recent study in Current Medical Research and Opinion (

) conducted a literature review to “evaluate the risk of GI bleeding events related to OTC ibuprofen use.” They found 20 studies that reported “incidence rates and proportions of a GI bleeding-related event associated with OTC or OTC-specific doses of ibuprofen. Although they reported finding that the “incidence of a GI bleeding-related event increased with age and the use of concomitant medications,” as well as a “general, though not always statistically significant, ibuprofen dose—response relationship,” overall they reported that the studies found a “low incidence of GI bleeding events with use of OTC ibuprofen.” Ibuprofen may also increase the risk of heart attack and stroke in some patients, especially those with a history of heart attack or heart disease, smoking, high cholesterol, high blood pressure, or diabetes. Physicians are advised to exercise caution if recommending this medication in these patients.

	As always, physicians and patients should discuss all OTC medications the patient is taking in order to make the safest, most effective medication choices, and ensure the patient is fully aware of the risks and benefits associated with those medications. There are several valuable online educational resources for patients, including MedLinePlus (

) that can provide additional accurate and reliable information on OTC pain remedies.

Acetaminophen vs. Ibuprofen for Pain: Helping Patients Choose the Best Option

Brief overviews of commonly asked questions regarding OTC acetaminophen and ibuprofen:

	Acetaminophen is “the most widely used pharmaceutical analgesic and antipyretic agent” in the US. Overdosing on acetaminophen can cause liver damage and, in more severe cases, even liver failure and death. In fact, in the US “acetaminophen toxicity has not only replaced viral hepatitis as the most common cause of acute hepatic failure, but it is also the second most common cause of liver failure requiring transplantation” (

). The recommended maximum daily adult dose of acetaminophen is 4,000 mg/day. Taking more than this recommended dose “can cause liver damage, ranging from abnormalities in blood tests used to assess liver function to acute liver failure, and even death. Many cases of acetaminophen overdose are caused by consumers inadvertently taking more than the recommended dose” (

	• Although liver injury from acetaminophen overdose remains a serious concern, these medications are safe when taken as directed. In fact, one of the benefits of acetaminophen compared to NSAIDs is their reduced risk of gastrointestinal complications.

	• The National Pain Foundation reminds patients that it is up to them to calculate how much acetaminophen they are taking, “especially if both OTC and prescription drugs are being used at the same time” (

). Keeping track of daily doses in a journal may be helpful.

	• Because many patients may be exceeding the recommended daily dose of acetaminophen without realizing it, they may not recognize the onset of symptoms of liver toxicity. Symptoms “may be non-specific and mimic flu symptoms, resulting in the individual continuing to use acetaminophen” (

	• Alcohol and acetaminophen are a particularly potent combination. Patients who drink three or more alcoholic drinks per day should consult with their physician before taking acetaminophen.

What are the risks of ulcers and GI bleeding associated with ibuprofen?

	NSAIDs are “implicated in nearly 25% of all adverse drug reactions, with the most commonly reported effects being GI irritation. NSAIDs increase the relative risk of gastrointestinal hemorrhage by approximately three-fold, although estimations as high as 10-fold have been reported in the literature” (

). A literature review of 20 studies “reporting incidence rates and proportions of a GI bleeding-related event associated with OTC or OTC-specific doses of ibuprofen” found “a relative risk of any GI bleeding-related event ranged from 1.1 to 2.4 for users of OTC-specific doses of ibuprofen compared to non-users” (

). In clinical trials of patients taking high doses of ibuprofen, “the percentage of patients reporting one or more gastrointestinal complaints ranged from 4% to 16%” (

	• Taking ibuprofen (or other NSAID) with alcohol can increase the risk of GI bleeding and other GI complications.

	• Patients age 65 and older, patients taking higher doses of ibuprofen or other NSAIDs, and patients who are also taking anticoagulants or corticosteroids are at higher risk for GI bleeding.

	• There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events (

	• Proton pump inhibitors (PPIs) “significantly reduce gastric and duodenal ulcers and their complications in patients taking NSAIDs.” Misoprostol is “very effective in preventing ulcers, and ulcer complications in patients taking NSAIDs;” in small doses, its side-effect profile “is the same as that of PPIs, and it is equally effective.” High-dose histamine-2 receptor antagonists (such as famotidine) can reduce the risk of NSAID-induced endoscopic peptic ulcers, though they are less effective than PPIs (

Does this contain acetaminophen? (Or ibuprofen? Or something else entirely?)

	Consumers’ lack of knowledge about the active ingredients of the OTC pain remedies they use is a major cause of overdose and other improper use of these products. In a recent study, researchers conducting focus groups on consumers’ knowledge of the active ingredients and dosing information for OTC analgesics found that only 44% of the adults surveyed read at or below the 6th-grade level, less than 50% of the study participants reported that they routinely read the product labels for OTC analgesics, and only 31% of participants knew that Tylenol contained acetaminophen (

). The sheer number of products that contain acetaminophen (more than 600 OTC and prescription) and ibuprofen (more than 200) contributes to this confusion.

	Always read the labels of any OTC and prescription medications they take. There are several good online resources (such as OTCSafety.org) that provide additional information about labeling and product ingredients.

Brief overviews of commonly asked questions regarding OTC acetaminophen and ibuprofen, and key messages for patients.

Talking with Patients about Risks associated with OTC Pain Relievers

With so much health care information online, it can be hard sometimes for patients to tell which websites and resources provide reliable and accurate information, especially when it comes to complex topics such as the risks and benefits of different OTC options for pain. This page features a useful collection of links to online resources for patients who want to learn more about the safe use of OTC pain medications.

The Acetaminophen Awareness Coalition: Know Your Dose

	The Know Your Dose campaign educates patients and consumers about the appropriate use of acetaminophen. The campaign is organized by the Acetaminophen Awareness Coalition—“a group of health, healthcare professional, and consumer organizations working to educate patients and consumers about acetaminophen so that it is only used as directed or labeled.” 

Rx and OTC Medications Containing Acetaminophen

	A glance at this handy chart, which is designed to serve as a guide and is not meant to be a comprehensive directory of all available acetaminophen-containing products, should give patients an idea of just how many acetaminophen-containing products there are on the market. 

Understanding Ulcers, NSAIDs, and GI Bleeding: A Consumer Health Guide from the American College of Gastroenterology

	This excellent resource from the ACG explains the symptoms and different types of GI bleeding, the symptoms and complications of ulcers, and issues associated with the use of NSAIDs. 

Ulcers and GI Bleeding: What You Need to Know about the Safe and Appropriate Use of Common Pain Medications

	This resource explains that a major cause for ulcers is irritation of the stomach arising from regular use of NSAIDs, including common OTC products that contain aspirin, ibuprofen, and naproxen. 

Connecting with Your Physician to Reduce NSAID Risks: A Patient Discussion Guide

	Patients can use this guide to facilitate discussions during their next office visit about the gastrointestinal risks associated with the use of ibuprofen and other NSAIDs. 

The Appropriate Use of Common OTC Analgesics and Cough and Cold Medications

	Although this monograph, created by the American Academy of Family Physicians and the American Pharmacists Association, was intended for clinicians, it offers a wealth of detailed information about the safety, effectiveness, and side effects of OTC products, along with advice and guidance on their appropriate use. 

American Chronic Pain Association Consumer Guide to Pain Medication and Treatments 2011

	The section of this guide that covers the use of OTC pain medications reminds patients that “the key to the effective use of OTC medications is understanding what you are taking and how much of it. You need to read the medication’s ingredients to know what you are taking. Be sure that the medication you select contains an appropriate amount of the drug you need for your symptoms and does not include medications or ingredients you do not need.” 

	Designed to provide education on the appropriate and safe use of OTC medicines and nutritional supplements, this site offers useful tips for the safe use of OTC medicines containing acetaminophen, aspirin, ibuprofen, naproxen, and topical pain relievers. 

	Part of the American Pain Foundation’s PainSAFE program, this excellent resource explains what information can be found on a drug facts label and why it is important for patients to take the time to read it. 

	This print-friendly handout offers an overview of OTC pain medication types, tips on the safe use of pain medications, and information about misuse and abuse. 

With so much health care information online, it can be hard sometimes for patients to tell which websites and resources provide reliable and accurate information, especially when it comes to complex topics such as the risks and benefits of different OTC options for pain.

Reliable Online Resources on OTC Analgesics for Patients

There are many herbs and supplements on the market that are thought to be effective by some patients and practitioners for managing pain. However, for many of these herbs and supplements, there is little in the way of reliable evidence supporting these claims. Nonetheless, millions of patients may be using these agents to supplement the pain care provided by their physicians and other clinicians, often without informing them of this fact. Because many of these products can interact with other medications the patient is taking, or exacerbate pre-existing conditions, it is important for pain practitioners to be aware of the popularity of these products, learn more about their basic properties, and ask their patients if they are taking any herbs and/or supplements.

	Here is a print-friendly version of this article you can download, print, and use as a handout in your office or clinic. 

 There is little evidence to support the use of turmeric for the relief of pain

Potential side effects/drug interactions:

 May slow blood clotting, so may possibly enhance the effects of anticoagulant and antiplatelet medications

The Glucosamine/chondroitin Arthritis Intervention Trial (GAIT) found that “the dietary supplements glucosamine and chondroitin, taken alone or in combination, are generally ineffective for knee osteoarthritis (OA) pain” (

Potential side effects/drug interactions: May increase the effect of warfarin, may worsen asthma symptoms

rheumatoid arthritis, osteoarthritis, other painful conditions

 There is little convincing evidence to support the use of boswellia for the relief of pain

Potential side effects/drug interactions: 

May interfere with anticoagulant drugs and leukotreine inhibitors (

 There is insufficient evidence demonstrating the effectiveness of kava kava for the treatment of any painful conditions

 There are serious concerns regarding severe liver damage with this supplement (

). It may also increase drowsiness in patients who are taking alprazolam and/or CNS depressants

 headache, migraine, muscle pain, neuralgia, sciatica, fibromyalgia

 Little to no reliable evidence supporting the use of St. John’s wort for the treatment of painful disorders

 May interfere with a wide range of medications, including antidepressants, anticoagulants, digoxin, seizure medications, and others (

Echinacea purpurea, Echinacea angustifolia, Echinacea pallida

 There is little evidence supporting the use of Echinacea for the treatment of these conditions

May exacerbate symptoms of autoimmune disorders, may interact with CYP3A4 and CYP1A2 substrates

 Indian valerian, Mexican valerian, Valeriana

 There is insufficient reliable evidence supporting the use of valerian for these conditions

 May add to the sedative effect of barbiturates and benzodiazepines, may change the rate at which CYP3A4 substrates are metabolized

“There are not enough reliable data to determine whether black cohosh is effective for rheumatism or other uses” (

 May be associated with severe liver side effects, especially in women.

 muscle soreness/pain, arthritis, knee pain

 The NIH reports that bromelain may be effective for arthritis when used in combination with trypsin and rutin. There is insufficient evidence to determine its effectiveness in other conditions.

 May interact with amoxicillin and other antibiotics, may interact with anticoagulants and antiplatelet drugs.

(Tanacetum parthenium, Chrysanthemum parthenium)

 The NIH reports that “there is some evidence that taking feverfew by mouth can reduce the frequency of migraine headaches” and reduce the pain associated with them (

). There is no strong evidence that it reduces the symptoms of rheumatoid arthritis.

 Possible interactions with a wide range of medications that are changed and broken down by the liver. May also enhance the effects of anticoagulants.

		For more information on herbs and natural supplements for pain:

	Office of Dietary Supplements of the National Institutes of Health

	The National Center for Complementary and Alternative Medicine

	Natural Medicines Comprehensive Database

	The Natural Standard Research Collaboration

There are many herbs and supplements on the market that are thought to be effective by some patients and practitioners for managing pain. However, for many of these herbs and supplements, there is little in the way of reliable evidence supporting these claims. Nonetheless, millions of patients may be using these agents to supplement the pain care provided by their physicians and other clinicians, often without informing them of this fact.

November 2011

The Changing Landscape of OTC Acetaminophen Pain Products

Acetaminophen vs. Ibuprofen for Pain: Helping Patients Choose the Best Option

Talking with Patients about Risks associated with OTC Pain Relievers

Reliable Online Resources on OTC Analgesics for Patients

Know Your Herbs and Supplements!