Acetaminophen: Examining the Dosage Conundrum

For many years, I have been a fan of using acetaminophen for persons requiring analgesia who did not need an anti-inflammatory agent or a stronger medication. Whenever possible, I use acetaminophen as a baseline analgesic for persons with prolonged pain, reserving stronger medications for breakthrough pain. Although the 650-mg dose was commonly prescribed in the past, a randomized, double-blind, parallel-group, placebo-controlled study of 540 patients showed that 1000 mg provides incremental benefit over doses limited to 650 mg.¹ The study, which was presented during a poster session at the 31st Annual Scientific Meeting of the American Pain Society in May 2012, was not the first to illustrate a dose-related effect, and based on such findings, my current practice is to use the higher dose. I typically prescribe 1000 mg every 6 hours for pain, for a maximum of 4 g daily in the absence of hepatic illness. Although studies have shown that this dosing regimen is generally safe and has little chance of inducing hepatotoxicity, in rare cases, individuals have had changes noted in their liver function tests, even at this level of use. For this reason, I monitor aspartate aminotransferase (AST) levels in anyone receiving long-term acetaminophen treatment.

Recently, there has been a movement to lower the dosage of single-agent acetaminophen in an attempt to avoid liver toxicity; however, this approach may prove fruitless, as acetaminophen is a component of many other medications, including Percocet and numerous cold remedies. Therefore, it is easy for patients to exceed the recommended maximum daily dose if they are not cognizant of what is contained in the medicines they are using, even if they are taking no more than 4 g of acetaminophen daily as a single prescribed entity.

In 2011, McNeil Consumer Healthcare, manufacturer of Tylenol brand acetaminophen, announced that the recommended maximum daily dose of single-ingredient, over-the-counter (OTC) products was lowered from 4 g daily (equal to 8 pills) to 3 g daily (equal to 6 pills).² The new dosing instructions appeared on product packaging beginning in the fall. Additionally, the recommended dosing frequency was changed from 1 g every 4 to 6 hours (potentially yielding an excessive dose of 6 g per day if consistently taken at 4-hour intervals) to 1 g every 6 hours, also yielding more than the recommended 3 g per day dose if taken consistently. Given these recommendations on OTC packaging, one would be at odds with the manufacturer’s recommendations if basal levels were to be used throughout the day, as only three doses of 1 g each could be taken every 6 hours, which is the maximum duration of action of this medication, resulting in suboptimal levels of pain control for many hours during the day. Alternatively, one would need to give 750 mg every 6 hours to reach the maximum recommended 3-g level per day, a dose lower than what is needed to obtain maximum analgesia. In addition, there are practical issues with such an acetaminophen regimen, as only 325-mg and 500-mg pills are available to choose from. Since a physician can still elect to prescribe medication dosages beyond that recommended by drug manufacturers, we are free to continue administering 1 g every 6 hours, although this leaves us open to criticism should an unwanted side effect occur.

While acute liver failure from acetaminophen use is most common in persons taking more than 4 g daily, particularly those with underlying liver disease and those who consume more than three alcoholic beverages daily, increases in transaminases may result from lower dosing. In addition, excess intake may occur unknowingly from the use of combination medications that contain acetaminophen. Patients should be advised to carefully read package labels and to refrain from using more than one product containing acetaminophen. Physicians choosing to prescribe a combination medication, such as Percocet, should take extra precaution by explaining to their patients exactly what agents are included in the prescribed medication and warning them of the possible risks of exceeding acetaminophen’s maximum recommended daily dose.

The exhaustive number of OTC and prescription products containing acetaminophen prohibits the inclusion of a complete listing in this brief column, but common examples include Actifed Plus; Alka-Seltzer Plus Cold & Sinus; Vicks NyQuil Cold & Flu Relief; Coricidin HBP NightTime; Robitussin Cold Cough and Flu NightTime; Excedrin; Roxicet; and Ultracet, among many others. A listing of prescribed products containing acetaminophen can be found on the FDA’s Website at www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm239874.htm. In addition, a list of brand name combination products containing acetaminophen can be found at www.nlm.nih.gov/medlineplus/druginfo/meds/a681004.html#brand-name-1. Still, lists are no replacement for reading drug labels, as they do not account for store brands, new formulations that are being brought to market, and variations in formulations that fall under a particular brand. For example, although Vicks NyQuil Cold and Flu Relief contains acetaminophen, Vicks NyQuil Cold does not.

For now, when warranted, I will continue favoring 1 g of acetaminophen every 6 hours for pain control, as I still believe that this dose provides maximal analgesia and has less potential for toxicity than use of narcotic agents or aspirin. While it may not provide sufficient analgesia for some forms of pain, it may be all that is required in certain circumstances, or may serve as a nice adjunct to stronger medications when necessary. I like to periodically monitor AST levels when acetaminophen is being used at this level for longer periods of time. I also advise patients against using alcohol and strongly urge them to read the labels of any other medications they are taking, whether OTC or prescription drugs, to prevent them from unwittingly adding additional doses of acetaminophen, increasing their risk of liver toxicity. Once targeted pain relief has been achieved, I try to reduce the dose and the dosing interval using a pain scale to better quantify the patient’s pain. I also recognize that pain has both objective and subjective components; thus, whenever possible, I always recommend concomitant nonpharmacological interventions for persons with chronic pain. Such interventions may include biofeedback, meditation, reassurance, and local comfort.

The art of medicine requires being an advocate for one’s patients, which involves making difficult decisions that require carefully balancing risks and benefits. We often look to guidelines, medical associations, and regulatory agencies for guidance, and try to base our practices on evidence-based medicine. At times, however, we just need to do what we feel is right for our patiets, while monitoring outcomes and hoping for the best.

References

1. Qi D, May L, Zimmerman B, et al. A randomized, double-blind, placebo-controlled, efficacy and safety study of acetaminophen 1000 mg and acetaminophen 650 mg in postoperative dental pain. Poster presented at: 31st Annual Scientific Meeting of the American Pain Society; May 16-19, 2012; Honolulu, HI. www.ampainsoc.org/abstract/2012/view/5165.

2. McNeil Consumer Healthcare announces plans for new dosing instructions for Tylenol products [news release]. Fort Washington, PA: Johnson & Johnson; July 28, 2011. www.jnj.com/connect/news/all/mcneil-consumer-healthcare-announces-plans-for-new-dosing-instructions-for-tylenol-products. Accessed July 23, 2012.