A new study questions whether acetaminophen is a risk-free pain reliever for patients aged 65 and older, including those with osteoarthritis (OA).
Although acetaminophen is often touted as an alternative to non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, a population-based cohort study found it carried an increased risk of peptic ulcers, bleeding and other side effects.
Background
The researchers acknowledge that many clinical guidelines advocate acetaminophen as a first-line oral treatment for OA pain because of its perceived safety compared with other oral analgesics.
However, “acetaminophen can cause COX-dependent side effects analogous to those of [NSAIDs],” according to the authors.2-4 The U.K.’s National Institute for Health and Care Excellence (NICE) addressed this safety concern in its 2014 updated guidance on OA management and chose not to recommend acetaminophen as a regular treatment in its 2022 update.5
Although randomized controlled trials (RCTs) can provide evidence of drug efficacy and safety, they come with ethical concerns and cost implications when it comes to the use of acetaminophen, the researchers noted. For this reason, most safety evidence regarding acetaminophen comes from post-marketing observational studies. These are accompanied by channeling bias and other such challenges.
“This bias occurs when individuals, particularly older adults at higher risk of gastrointestinal and cardiovascular adverse events, are less likely to be given NSAIDs but are more likely to receive acetaminophen,” the study’s authors wrote.
To minimize this bias, the study researchers compared like-to-like, such as selecting people aged 65 or older, comparing acetaminophen users vs. non-users in the general population and in a subgroup of people with OA using the U.K. Clinical Practice Research Datalink (CPRD). They simulated an RCT in the CPRD by matching two groups for all potential confounding factors, such as age, sex, comorbidity and other risk factors, identified in the database. The CRPD is a large healthcare database in the U.K. that compiles routinely collected anonymized patient data from 736 general practices, covering 17 million U.K. residents. It’s one of the largest electronic health records used to evaluate the effectiveness of prescribed medications.
Researchers aimed to measure the incidence of GI bleeding, heart failure, myocardial infarction, hypertension and chronic renal failure, and analyze the dose-response relationship between acetaminophen prescriptions and specific adverse events.
Study Details
The study included participants aged 65 and older because they are eligible in the U.K. to receive free prescriptions from their general practitioner. Participants who received at least two acetaminophen prescriptions within two months, but not in combination with other analgesics, such as codeine, were defined by the researchers as exposed to acetaminophen. This helped exclude occasional use of acetaminophen for other acute conditions, such as headache or the flu.
The control group was made up of participants also aged 65 and older with fewer than two acetaminophen prescriptions within six months during the study period. They were individually matched to acetaminophen users by year of birth, sex, general practice, comorbidity and other confounding factors.
The study ultimately included 180,483 acetaminophen users and 402,478 non-users. The mean participant age was 74.8 years old; more women were participants than men.
Researchers found an increased incidence of peptic ulcer bleeding, uncomplicated ulcers, lower GI bleeding, heart failure, hypertension and chronic renal failure in participants exposed to acetaminophen vs. those who were not. The development of peptic ulcer bleeding, uncomplicated ulcers and chronic renal failure rose with the number of acetaminophen prescriptions.
Among the sub-group of patients with OA (i.e., 24,406 acetaminophen exposed and 24,406 unexposed), acetaminophen exposure was associated with a higher incidence of lower GI bleeding, hypertension and chronic renal failure.
Implications & Context
The study fundings match what other observational studies have reported regarding a link between acetaminophen use and GI complications, as well as hypertension, according to the researchers, citing studies from Rahme et al., Chan et al., Zeng et al. and others.6-8
One study they cited found acetaminophen “exerts an inhibitory effect on peripheral cyclooxygenase [COX] enzymes,” which meant it could be a potential mechanism for GI bleeding when it occurs.9
The researchers noted that most RCTs with acetaminophen have not found any major adverse effects. “This is because the RCTs were primarily designed for efficacy rather than adverse events, solely reported short-term effects, were less powered and recruited healthier and younger participants,” they wrote.
It’s possible that long-term use of acetaminophen could inhibit prostacyclin synthesis, which would lead to GI lesions and bleeding. Medical professionals may want to proceed with caution when considering long-term acetaminophen use for patients.
Prof. Zhang
“Although the incidence of acetaminophen side effects may be lower than that of NSAIDs and COX 2 inhibitors,” the authors said, “their side effect profiles are similar, which reflects the now recognized COX inhibitory effect of acetaminophen. These data further challenge whether acetaminophen should be retained as the first-line oral analgesic, especially in older people for common chronic painful conditions, given its non-clinically meaningful benefits and potential harms, and support the recent recommendation by NICE to not use acetaminophen for OA.”
Future research should focus on confirming these findings and developing a safer pain reliever for older adults, says study author Professor Weiya Zhang, BMed, MMed, PhD, who is with the NIHR Biomedical Research Centre in the School of Medicine at the University of Nottingham.
Vanessa Caceres is a medical writer in Bradenton, Fla.
References
- Kaur J, Nakafero G, Abhishek A, et al. Incidence of side effects associated with acetaminophen in people aged 65 years or more: A prospective cohort study using data from the clinical practice research datalink. Arthritis Care Res (Hoboken). Published online Nov. 24, 2024.
- de Vries F, Setakis E, van Staa TP. Concomitant use of ibuprofen and paracetamol and the risk of major clinical safety outcomes. Br J Clin Pharmacol. 2010;70(3):429–438.
- Rahme E, Marentette MA, Kong SX, et al. Use of NSAIDs, COX-2 inhibitors, and acetaminophen and associated coprescriptions of gastroprotective agents in an elderly population. Arthritis Rheum. 2002;47(6):595–602.
- Rodríguez LA, Hernández-Díaz S. Relative risk of upper gastrointestinal complications among users of acetaminophen and nonsteroidal anti-inflammatory drugs. Epidemiology. 2001;12(5):570–576.
- National Clinical Guideline Centre (UK). Osteoarthritis: Care and Management in Adults. London: National Institute for Health and Care Excellence (UK);2014.
- Rahme E, Barkun A, Nedjar H, et al. Hospitalizations for upper and lower GI events associated with traditional NSAIDs and acetaminophen among the elderly in Quebec, Canada. Am J Gastroenterol. 2008;103(4):872–882.
- Chan AT, Manson JE, Albert CM, et al. Nonsteroidal anti-inflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation. 2006;113(12):1578–1587.
- Zeng C, Doherty M, Persson MS, et al. Comparative efficacy and safety of acetaminophen, topical and oral non-steroidal anti-inflammatory drugs for knee osteoarthritis: Evidence from a network meta-analysis of randomized controlled trials and real-world data. Osteoarthritis Cartilage. 2021;29(9):1242–1251.
- Hinz B, Brune K. Paracetamol and cyclooxygenase inhibition: Is there a cause for concern? Ann Rheum Dis. 2012;71(1):20–25.
