What literature is available assessing the maximum dose of acetaminophen (3g vs 4g)?

Comment by InpharmD Researcher

Safety data have reported daily doses of acetaminophen 4 grams may possibly observe an increase in hepatic clinical markers. These events are typically reported as asymptomatic without leading to hepatotoxicity unless overdose is involved. However, the FDA recommends a lower daily dose for acetaminophen and the manufacturer for Tylenol® has adopted a daily limit of 3250 mg for regular strength or 3000 mg for maximum strength. The lower max dose is debated due to lack of data supporting the recommendation.

Background

Chronic doses of acetaminophen at 4 grams daily in adults have been observed to acutely increase serum aminotransferase levels. This is typically asymptomatic which resolves upon therapy discontinuation. Reports of hepatotoxicity come from overdose episodes using more than 7.5 g/day to 10 g/day (generally more than 15 g). [1]

Some recommendations were made to further reduce the daily dosing of acetaminophen from 4 g. This is a debated topic among researchers. The Food and Drug Administration (FDA) recommended lowering the max daily dose of acetaminophen from 4 g daily to 3.25 g and 3 g daily depending on the formulation, yet some authors claim the recommendations lack evidence. Even so, the manufacturers of Tylenol® have voluntarily reduced max dose recommendations of regular strength tablets to 3.25 g daily and extra strength tablets to 3 g daily (though under the direction of a health care provider, patients may take up to 4 g daily). [2], [3], [4], [5]

A systematic review observed the occurrence of hepatic-related outcomes in prospective trials and retrospective reports. To be included, the studies must have observed adults who received repeated dosing of acetaminophen = 4 g/day for at least 24 hours. Among the 791 prospective trials identified (N=30,865), there were no incidence of fulminant hepatic injury or death due to acetaminophen. Serum aminotransferase levels that exceeded ULN were identified in 129 (0.4%) of patients. The studies with placebo groups had elevated levels similar to the acetaminophen group. However, only 13.8% of patients were noted to be receiving maximum therapeutic dose of acetaminophen (3.9 to 4 g). Retrospective studies included 9337 patients and observed 32 patients (0.3%) developing acute liver failure, 7 patients (0.07%) undergoing liver transplantation, and 6 deaths. There were noticeably more patients receiving maximum therapeutic doses (n=6071; 65.0%) but some reports indicated patients may have overdosed or did not report accurate dosing. [6]

An observational study where 7579 U.S. adults recorded their intake of acetaminophen found those using a higher dose formulation (650 mg) versus lower formulations (325 mg to 500 mg) were more likely to exceed the recommended 4 grams dose limit, less likely to recall the 8-hour dosing interval, and more likely to redose sooner. This may indicate greater strengths of acetaminophen may increase patient noncompliance to recommendations. [7]

References:

[1] LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Acetaminophen. [Updated 2016 Jan 28]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548162/
[2] Krenzelok EP. The fda acetaminophen advisory committee meeting – what is the future of acetaminophen in the united states? The perspective of a committee member. Clinical Toxicology. 2009;47(8):784-789.
[3] Krenzelok EP, Royal MA. Confusion: acetaminophen dosing changes based on NO evidence in adults. Drugs R D. 2012;12(2):45-48. doi:10.2165/11633010-000000000-00000
[4] Johnson & Johnson Consumer Inc. Tylenol For Healthcare Professionals. https://www.tylenolprofessional.com/adult-dosage. Accessed January 22, 2020.
[5] Aminoshariae A, Khan A. Acetaminophen: old drug, new issues. J Endod. 2015;41(5):588-593. doi:10.1016/j.joen.2015.01.024
[6] Dart RC, Bailey E. Does therapeutic use of acetaminophen cause acute liver failure?. Pharmacotherapy. 2007;27(9):1219-1230. doi:10.1592/phco.27.9.1219
[7] Shiffman S, Battista DR, Kelly JP, Malone MK, Weinstein RB, Kaufman DW. Exceeding the maximum daily dose of acetaminophen with use of different single-ingredient OTC formulations. J Am Pharm Assoc (2003). 2018;58(5):499-504. doi:10.1016/j.japh.2018.05.012
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What literature is available assessing the maximum dose of acetaminophen (3g vs 4g)?

Please see Tables 1-2 for your response.

 

Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial

Design

Randomized, single-blind, placebo-controlled, 5-treatment, parallel-group, diet-controlled, impatient, longitudinal study

N=145

Objective

To assess whether there are differences in the likelihood of exceeding the daily limit of 4 grams of acetaminophen when using different formulations (325 mg, 500 mg, 650 mg) of OTC single-ingredient (SI) acetaminophen medications.

Study Groups

Placebo (n=39)

Oxycodone+acetaminophen (n=27)

hydromorphone+acetaminophen (n=27)

Morphine+acetaminophen (n=26)

Acetaminophen alone (n=26)

Inclusion Criteria

 Healthy men and women age 18 to 45 years without concomitant medications.

Exclusion Criteria

 N/A

Methods

Patients were randomized (1:1:1:1:1.5) into 1 of 5 treatment regimens all administered orally Q6H up to 14 days (56 doses) for a total acetamine daily dose of 4 grams.

Treatment 1: Percocet 2 tablets (7.5 mg oxycodone/500 mg acetaminophen) plus 2 placebo tablets

Treatment 2: Dilaudid 2 tablets (2 mg hydromorphone) pus Extra Strength Tylenol 2 caplets (500 mg each)

Treatment 3: Morphine 2 tablets (15 mg) plus Extra Strength Tylenol 2 caplets (500 mg each)

Treatment 4: Placebo 2 tablets plus Extra Strength Tylenol 2 caplets (500 mg each)

Treatment 5: Placebo 2 tablets plus 2 additional placebo tablets (placebo group)

Patient's diet was controlled and consisted of whole-food meals for breakfast, lunch, dinner, and nighttime snack. Routine serum liver chemistries were measured daily until day 8, which were then measured on alternating days. Plasma acetaminophen concentrations were measured daily and a 6-hour dosing interval on day 3. Per protocol, treatment will discontinue if ALT/AST exceed 120 U/L (3xULN).

Duration

 14 days

Outcome Measures

Alanine aminotransferase level elevations multiplied by the upper limit of normal.

Ratio of medians when comparing placebo versus treatment in terms of maximum ALT.

Baseline Characteristics

  

Placebo (n=39)

Acetaminophen alone (n=26)

Oxycodone+acetaminophen (n=27)

hydromorphone+acetaminophen (n=27)

 Morphine+acetaminophen (n=26)

Age, years

 32.8 34.0 36.7 32.6 33.5

Female

7 (18%) 8 (31%) 3 (11%) 5 (19%) 9 (35%)

White

Black

11 (28%)

5 (13%)

8 (31%)

3 (12%)

7 (26%)

4 (15%)

10 (37%)

3 (11%)

8 (31%)

4 (15%)

Mean body mass index

 25.8 25.8 26.0 25.4 25.2

Results

Endpoint

Placebo (n=39)

Acetaminophen alone (n=26)

 

Oxycodone+acetaminophen (n=27)

 

hydromorphone+acetaminophen (n=27)

 

 Morphine+acetaminophen (n=26)

>1x ULN

>2x ULN

>3x ULN

>5x ULN

>8x ULN

15 (38%)

1 (3%)

0

0

0

21 (81%)

13 (50%)

10 (38%)

6 (23%)

1 (4%)

 

20 (74%)

14 (52%)

11 (41%)

5 (19%)

1 (4%)

21 (78%)

15 (56%)

12 (44%)

10 (37%)

4 (15%)

19 (73%)

14 (54%)

8 (31%)

6 (23%)

2 (8%)

Ratio of 2 medians versus placebo

-

2.78 (1.47 to 4.09; p<0.001)

3.08 (1.64 to 4.52; p<0.001)

2.67 (1.40 to 3.94; p<0.001)

2.57 (1.37 to 3.77; p<0.001)

Elevations in either bilirubin or international normalized ratios were observed.

Adverse Events

No patients developed symptomatic conditions. 

Study Author Conclusions

Initiation of recurrent daily intake of 4 g of acetaminophen in healthy adults is associated with ALT elevations and concomitant treatment with opioids does not seem to increase this effect. History of acetaminophen ingestion should be considered in the differential diagnosis of serum aminotransferase elevations, even in the absence of measurable serum acetaminophen concentrations.

InpharmD Researcher Critique

 A strength of the study was accounting for other influencers of liver functions such as diet and living condition by placing participants in a shared space with a strict meal regimen. Yet 14 days does not denote the potential risks with long-term administration of acetaminophen 4 mg daily.



References:

Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006;296(1):87-93. doi:10.1001/jama.296.1.87

 

Multicenter, randomized, double-blind, active-controlled, parallel-group trial of the long-term (6-12 months) safety of acetaminophen in adult patients with osteoarthritis

Design

Multicenter, multidose, single-dummy, randomized, double-blind, active-controlled, parallel-group study

N=571

Objective

This study evaluated the safety of acetaminophen 4 g/d administered for up to 12 months to adult patients with osteoarthritis pain, using naproxen 750 mg/d as an active comparator.

Study Groups

Acetaminophen 4 g/day (n=290)

Naproxen 750 mg/day (n=291)

Inclusion Criteria

 Age 40 to 75 years, symptomatic osteoarthritis of the hip or knee for > 6 months, history of mild/moderate pain on a 5-point scale.

Exclusion Criteria

History of recent surgery, major trauma to study joint, active inflammation, more severe radiographic criteria, other evidence of serious joint disease, secondary osteoarthritis, pseudogout. Patients requiring long-term treatment with drugs that may interfere with assessment (e.g. aspirin > 325 mg/day, anticoagulation, corticosteroids, hyaluronan, unstable anticonvulsant/antidepressant doses, etc.). Others include pregnancy/lactation; previous gastric surgery; allergy to aspirin NSAIDs, or study medication; active illness; inflammatory bowel disease; or clinically important renal/hepatic disease.

Methods

Patients were randomized to receive either acetaminophen 4 g/day (1 g Q4-6H) for 12 months or naproxen 750 mg/day (375 mg BID) for 6 months. Patients self-recorded doses and missed doses using a diary. Follow-up occurred at 1, 3, and 6, months of treatment or at withdrawal. Acetaminophen group additionally underwent follow-up on months 9 and 12.

Duration

12 months in acetaminophen group

6 months in naproxen group

Outcome Measures

Primary endpoint: Mean change in WOMAC pain subscale score at 6 months

Secondary: Renal and hepatic parameters

Baseline Characteristics

  

Acetaminophen 4 g/day (n= 287)

Naproxen 750 mg/day (n= 291)

Age, years

 59.1 59.5

Female

66.6% 71.8%

White

 84.0% 84.2%

Weight, lb

 204.8 200.0

Results

Endpoint

Acetaminophen 4g/day (n= 287)

Naproxen 750 mg/day (n= 291)

Overall mean adherence rate (SD)

83.0% (21.5)

-

Overall median adherence rate (SD)

93.1%

-

WOMAC score difference from baseline to 6 month

Pain

Stiffness

Physical function

 

-21.6

-20.6

-18.9

 Unreported. Stated to not be statistically different

Hepatic failure

Hepatic dysfunction

Aminotransferase levels > 2xULN

Renal failure

SCr levels > 1.5 x ULN

0

0

0

0

0

0

0

0

0

0

Reported AST/ALT levels within range

97.6%

-

Reported SCr levels below reference range

98.1%

-

There was a high rate of dropouts during the study. At 12 months, only 23.2% of the acetaminophen group remained for analysis.

Adverse Events

Common Adverse Events:

Acetaminophen > 2%: Abdominal pain (10.1%), dyspepsia (9.4%), diarrhea (7.0%), nausea (5.2%), constipation (3.1%), flatulence (3.1%), pruritus (2.8%), headache (2.4%)

Serious Adverse Events: None reported in the acetaminophen group

Percentage that Discontinued due to Adverse Events:

Acetaminophen: n= 71 (24.7%): Abdominal pain, nausea, diarrhea, pain, dyspepsia.

Naproxen: n= 63 (22.2%)

Study Author Conclusions

 With physician supervision, acetaminophen was found to be generally well-tolerated in these patients for the treatment of osteoarthritis pain of the hip or knee for periods of up to 12 months.

InpharmD Researcher Critique

This study recruited an older and specific population (age 40 to 75 with symptomatic osteoarthritis) with a robust exclusion criterion. Over 3/4 of patients in the acetaminophen group did not complete all 12 months of evaluation. As dosing was self-reported by the patients, there may have been inaccurate reporting. It is possible transient levels of AST/ALT have occurred between the follow-up intervals or those lost during the study. 



References:

Temple AR, Benson GD, Zinsenheim JR, Schweinle JE. Multicenter, randomized, double-blind, active-controlled, parallel-group trial of the long-term (6-12 months) safety of acetaminophen in adult patients with osteoarthritis. Clin Ther. 2006;28(2):222-235. doi:10.1016/j.clinthera.2006.02.004