1. This recent meta-analysis found a slightly increased cardiovascular, renal, and gastrointestinal adverse outcomes with prolonged, chronic acetaminophen (tylenol/paracematol) use.
2. While dose-response relationships were seemingly found in the included studies, dosage definitions varied, study populations were not generalizable, and prospective studies were limited.
Evidence Rating Level: 2 (Good)
Study Rundown: Acetaminophen (tylenol/paracetamol) is one of the most widely used analgesic medications around the world, and while it is often considered an over-the-counter medication, there are many risks associated with its use. As recent studies have cast some doubt on the efficacy of long-term acetaminophen use for chronic pain, a reassessment of the benefits and risks of the prolonged acetaminophen use. This meta-analysis compiled data from eight cohort studies, but was unable to analyze outcomes due to the non-comparable nature of the studies (different dosage definitions). However, the included studies showed increased gastrointestinal, renal, and cardiovascular adverse events when acetaminophen was taken chronically and for long periods of time.
The need to assess the relative safety of drugs as ubiquitous as acetaminophen is extremely important, but this study fell short of contributing much evidence to the existing literature. The inclusion of only eight cohort studies out of 1888 made it impossible to pool data, and the pre-meditated exclusion of RCTs, reportedly due to short follow-up times and homogeneous populations, is worrisome. Further, the studies that were included were often unable to compare acetaminophen to alternative analgesics, did not take into account adverse events due to the diseases the analgesics were prescribed for. They also lacked generalizability as most of the studies followed nurses or male physicians. This study also reports that all research included had low to very low quality of data. In addition, systematic reviews of short-term RCTs showed similar dose-related toxicity to those reported by this study, again raising doubts as to why RCTs were not included in this meta-analysis. It is clear that there are risks of prolonged acetaminophen use, but this study should not raise or lower clinician’s concern in prescribing or suggesting use of this medication any more than at present.
Relevant Reading: OARSI recommendations for the management of hip and knee osteoarthritis. Part III: changes in evidence following systematic cumulative update of research published through January 2009
In-Depth [meta-analysis]: 8 out of 1888 studies were included in this meta-analysis, with inclusion/exclusion criteria influenced by recommendations made by the Meta-analysis Observational Studies in Epidemiology and the Preferred Reporting Items for Systematic Reviews and Meta-analyses. Inclusion criteria were for studies to be observational, non-RCT studies of patients >18 years of age who used acetaminophen at a standard therapeutic dose of 0.5-1g/4-6hrs and were compared against non-users. All 8 studies were assessed for evidence quality using Grading and Recommendations Assessment, Development and Evaluation (GRADE), and all studies had low to very low evidence quality and ultimately had varying definitions of paracetamol dosage. Two of the studies reported increased mortality with those taking the highest levels of acetaminophen compared to non-users. Four studies reported dose-response increases in adverse cardiovascular events, but significantly increased risk of these events were only found at the highest level of acetaminophen usage, which was defined differently for each study. One study reported a dose-response relationship between acetaminophen and adverse gastrointestinal events. Four studies showed an impact of acetaminophen on renal function, with some studies showing a protective event of acetaminophen at low doses and some showing a detrimental effect of acetaminophen at high doses, estimated by measuring glomerular filtration rates.
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