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JAMA Mar 2023In January 2011, the US Food and Drug Administration (FDA) announced a mandate to limit acetaminophen (paracetamol) to 325 mg/tablet in combination acetaminophen and...
IMPORTANCE
In January 2011, the US Food and Drug Administration (FDA) announced a mandate to limit acetaminophen (paracetamol) to 325 mg/tablet in combination acetaminophen and opioid medications, with manufacturer compliance required by March 2014.
OBJECTIVE
To assess the odds of hospitalization and the proportion of acute liver failure (ALF) cases with acetaminophen and opioid toxicity prior to and after the mandate.
DESIGN, SETTING, AND PARTICIPANTS
This interrupted time-series analysis used hospitalization data from 2007-2019 involving ICD-9/ICD-10 codes consistent with both acetaminophen and opioid toxicity from the National Inpatient Sample (NIS), a large US hospitalization database, and ALF cases from 1998-2019 involving acetaminophen and opioid products from the Acute Liver Failure Study Group (ALFSG), a cohort of 32 US medical centers. For comparison, hospitalizations and ALF cases consistent with acetaminophen toxicity alone were extracted from the NIS and ALFSG.
EXPOSURES
Time prior to and after the FDA mandate limiting acetaminophen to 325 mg in combination acetaminophen and opioid products.
MAIN OUTCOMES AND MEASURES
Odds of hospitalization involving acetaminophen and opioid toxicity and percentage of ALF cases from acetaminophen and opioid products prior to and after the mandate.
RESULTS
In the NIS, among 474 047 585 hospitalizations from Q1 2007 through Q4 2019, there were 39 606 hospitalizations involving acetaminophen and opioid toxicity; 66.8% of cases were among women; median age, 42.2 (IQR, 28.4-54.1). In the ALFSG, from Q1 1998 through Q3 2019, there were a total of 2631 ALF cases, of which 465 involved acetaminophen and opioid toxicity; 85.4% women; median age, 39.0 (IQR, 32.0-47.0). The predicted incidence of hospitalizations 1 day prior to the FDA announcement was 12.2 cases/100 000 hospitalizations (95% CI, 11.0-13.4); by Q4 2019, it was 4.4/100 000 hospitalizations (95% CI, 4.1-4.7) (absolute difference, 7.8/100 000 [95% CI, 6.6-9.0]; P < .001). The odds of hospitalizations with acetaminophen and opioid toxicity increased 11%/y prior to the announcement (odds ratio [OR], 1.11 [95% CI, 1.06-1.15]) and decreased 11%/y after the announcement (OR, 0.89 [95% CI, 0.88-0.90]). The predicted percentage of ALF cases involving acetaminophen and opioid toxicity 1 day prior to the FDA announcement was 27.4% (95% CI, 23.3%-31.9%); by Q3 2019, it was 5.3% (95% CI, 3.1%-8.8%) (absolute difference, 21.8% [95% CI, 15.5%-32.4%]; P < .001). The percentage of ALF cases involving acetaminophen and opioid toxicity increased 7% per year prior to the announcement (OR, 1.07 [95% CI, 1.03-1.1]; P < .001) and decreased 16% per year after the announcement (OR, 0.84 [95% CI, 0.77-0.92]; P < .001). Sensitivity analyses confirmed these findings.
CONCLUSIONS AND RELEVANCE
The FDA mandate limiting acetaminophen dosage to 325 mg/tablet in prescription acetaminophen and opioid products was associated with a statistically significant decrease in the yearly rate of hospitalizations and proportion per year of ALF cases involving acetaminophen and opioid toxicity.
Topics: Adult; Female; Humans; Male; Acetaminophen; Analgesics, Opioid; Hospitalization; Liver Failure, Acute; Prescriptions; United States; United States Food and Drug Administration; Drug Combinations; Analgesics; Middle Aged
PubMed: 36881033
DOI: 10.1001/jama.2023.1080 -
European Review For Medical and... Mar 2017To summarize the different clinical features of drug-induced acute liver failure, the diagnostic work-up, conservative management and the prognostic scores currently... (Review)
Review
OBJECTIVES
To summarize the different clinical features of drug-induced acute liver failure, the diagnostic work-up, conservative management and the prognostic scores currently used to list patients for liver transplantation.
EVIDENCE AND INFORMATION SOURCES
The current review is based on an analysis of the current literature and the caseload experience of the Authors on this topic.
STATE OF THE ART
Drug-induced liver injury is the leading cause of acute liver failure in the adult population in Western countries, with a transplant-free survival rate of less than 50%. Main subtypes include paracetamol and idiosyncratic drug-induced injury, which differ in epidemiology, clinical course, prognosis and conservative management. In cases of a high likelihood of death, urgent hepatic transplantation is indicated, but the decision whether and when to put a patient with drug-induced acute liver failure on the list for urgent liver transplant is extremely difficult and requires constant interdisciplinary exchange and continuous updating of the clinical picture.
CONCLUSIONS
Intensive management should be done in a clinical tertiary referral center which has a specialized team of hepatologists and a liver transplant center.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Chemical and Drug Induced Liver Injury; Humans; Liver Failure, Acute; Liver Transplantation; Prognosis
PubMed: 28379596
DOI: No ID Found -
The Journal of Clinical Psychiatry Feb 2016Acetaminophen (paracetamol) is available over the counter in most countries and is widely considered to be safe for use during pregnancy; studies report gestational... (Review)
Review
Acetaminophen (paracetamol) is available over the counter in most countries and is widely considered to be safe for use during pregnancy; studies report gestational exposures to acetaminophen that lie in the 46%-65% range. Acetaminophen influences inflammatory and immunologic mechanisms and may predispose to oxidative stress; these and other effects are hypothesized to have the potential to compromise neurodevelopment in the fetal and infant brain. Two ecological studies suggested that population-level trends in the use of acetaminophen were associated with trends in the incidence/prevalence of autism; one of these studies specifically examined acetaminophen use during pregnancy. One large prospective observational cohort study found that gestational exposure to acetaminophen (especially when the duration of exposure was 28 days or more) was associated with motor milestone delay, gross and fine motor impairments, communication impairment, impairments in internalizing and externalizing behaviors, and hyperactivity, all at age 3 years; however, social and emotional developmental behaviors were mostly unaffected. A very recent large cohort study with a 12.7-year follow-up found that gestational exposure to acetaminophen was associated with an increased risk of autism spectrum disorder, but only when a hyperkinetic disorder was also present. In the light of existing data associating acetaminophen use during pregnancy and subsequent risk of attention-deficit/hyperactivity disorder, this new finding suggests that the predisposition, if any, is toward the hyperkinetic syndrome rather than to autism. In summary, the empirical data are very limited, but whatever empirical data exist do not support the suggestion that the use of acetaminophen during pregnancy increases the risk of autism in the offspring.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Autism Spectrum Disorder; Female; Humans; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 26930528
DOI: 10.4088/JCP.16f10637 -
Ecotoxicology and Environmental Safety Mar 2023Nanoplastics (NPs) and acetaminophen (APAP) are thought to be common contaminants and are invariably detected in the environment. Despite the increasing awareness of...
Nanoplastics (NPs) and acetaminophen (APAP) are thought to be common contaminants and are invariably detected in the environment. Despite the increasing awareness of their toxicity to humans and animals, the embryonic toxicity, skeletal development toxicity, and mechanism of action of their combined exposure have not been clarified. This study was performed to investigate whether combined exposure to NPs and APAP induces abnormal embryonic and skeletal development in zebrafish and to explore the potential toxicological mechanisms. All zebrafish juveniles in the high-concentration compound exposure group showed some abnormal phenomena such as pericardial edema, spinal curvature, cartilage developmental abnormality and melanin inhibition together with a significant downward trend in body length. Behavioral data also implicated that the exposure of APAP alone, as well as the co-exposure of NPs and APAP, caused a depression in the total distance, swimming speed and the maximum acceleration. Furthermore, real-time polymerase chain reaction analysis showed that compared with exposure alone, the expression level of genes related to osteogenesis, runx2a, runx2b, Sp7, bmp2b and shh was significantly reduced with compound exposure. These results suggest that the compound exposure of NPs and APAP has adverse impacts on zebrafish embryonic development and skeletal growth.
Topics: Animals; Humans; Acetaminophen; Zebrafish; Microplastics; Embryonic Development; Embryo, Nonmammalian
PubMed: 36796208
DOI: 10.1016/j.ecoenv.2023.114640 -
Journal of Food and Drug Analysis Apr 2018Acetaminophen (paracetamol or APAP) is an analgesic and antipyretic drug that can induce oxidative stress-mediated hepatotoxicity at high doses. Several studies reported... (Review)
Review
Acetaminophen (paracetamol or APAP) is an analgesic and antipyretic drug that can induce oxidative stress-mediated hepatotoxicity at high doses. Several studies reported that antioxidant nutraceuticals, in particular phenolic phytochemicals from dietary food, spices, herbs and algae have hepatoprotective effects. Others, however, suggested that they may negatively impact the metabolism, efficacy and toxicity of APAP. The aim of this review is to discuss the pros and cons of the association of antioxidant nutraceuticals and APAP by reviewing the in vivo evidence, with particular reference to APAP pharmacokinetics and hepatotoxicity. Results from the murine models of APAP-induced hepatotoxicity showed amelioration of liver damage with nutraceuticals coadministration, as well as reductions in tissue markers of oxidative stress, and serum levels of hepatic enzymes, bilirubin, cholesterol, triglycerides and inflammatory cytokines. On the other hand, both increased and decreased APAP plasma levels have been reported, depending on the nutraceutical type and route of administration. For example, studies showed that repeated administration of flavonoids causes down-regulation of cytochrome P450 enzymes and up-regulation of uridine diphosphate glucuronosyltransferases (UGT). Moreover, nutraceuticals can alter the levels of APAP metabolites, such as mercapturate glucuronide, sulfate and cysteine conjugates. Overall, the reviewed in vivo studies indicate that interactions between APAP and nutraceuticals or plant foods exist. However, the majority of data come from animal models with doses of phytochemicals far from dietary ones. Human studies should investigate gene-diet interactions, as well as ethnic variability in order to clarify the pros and cons of co-administering antioxidant nutraceuticals and APAP.
Topics: Acetaminophen; Animals; Antioxidants; Dietary Supplements; Herb-Drug Interactions; Humans; Oxidative Stress
PubMed: 29703389
DOI: 10.1016/j.jfda.2017.11.004 -
Basic & Clinical Pharmacology &... Mar 2016Acetaminophen (paracetamol) is the most commonly used analgesic worldwide and recommended as first-line treatment in all pain conditions by WHO. We performed a... (Review)
Review
Acetaminophen (paracetamol) is the most commonly used analgesic worldwide and recommended as first-line treatment in all pain conditions by WHO. We performed a systematic literature review to evaluate the efficacy of acetaminophen when used for chronic pain conditions. Applying three broad search strategies for acetaminophen use in chronic pain in both Embase and PubMed, 1551 hits were obtained. After cross-reference searches of both trials and 38 reviews, seven studies comparing acetaminophen in continuous dosing regimens of more than 2 weeks with placebo were included. The review was conducted according to the PRISMA guidelines. All studies were conducted in patients with hip- or knee osteoarthritis and six of seven studies had observation periods of less than 3 months. All included studies showed no or little efficacy with dubious clinical relevance. In conclusion, there is little evidence to support the efficacy of acetaminophen treatment in patients with chronic pain conditions. Assessment of continuous efficacy in the many patients using acetaminophen worldwide is recommended.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Chronic Disease; Chronic Pain; Databases, Factual; Humans; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 26572078
DOI: 10.1111/bcpt.12527 -
Anaesthesia Oct 2016
Topics: Acetaminophen; Administration, Intravenous; Administration, Oral; Analgesics, Non-Narcotic; Critical Care; Humans
PubMed: 27611037
DOI: 10.1111/anae.13517 -
International Journal of Environmental... Feb 2022Paracetamol is the most commonly used antipyretic and analgesic in pregnancy. It is also increasingly used off-label in the neonatal intensive care unit. Despite the... (Review)
Review
INTRODUCTION
Paracetamol is the most commonly used antipyretic and analgesic in pregnancy. It is also increasingly used off-label in the neonatal intensive care unit. Despite the frequent use of paracetamol, concerns have been raised regarding the high variability in neonatal dosing regimens and the long-term safety of early life exposure.
OBJECTIVE
To investigate the available evidence on the long-term safety of prenatal and neonatal paracetamol exposure.
METHODS
We conducted a systematic search of the electronic databases Ovid Medline, Ovid Embase and Web of Science from inception to August 2021 for original research studies of any design that described the use of paracetamol in the prenatal or neonatal (within the first four weeks of life) periods and examined the occurrence of neurodevelopmental, atopic or reproductive adverse outcomes at or beyond birth.
RESULTS
We identified 1313 unique articles and included 30 studies in the final review. Of all studies, 27 (90%), two (7%) and one (3%) were on the long-term safety of prenatal, neonatal and both prenatal and neonatal exposure, respectively. Thirteen (46%), 11 (39%) and four (15%) studies examined neurodevelopmental, atopic and reproductive outcomes. Eleven (100%), 11 (100%), and three (27%) studies on prenatal exposure reported adverse neurodevelopmental, atopic and reproductive outcomes. Only one study found a possible correlation between neonatal paracetamol exposure and long-term adverse outcomes.
CONCLUSIONS
The available evidence, although limited, suggests a possible association between prenatal paracetamol exposure and an increased risk of neurodevelopmental, atopic and reproductive adverse outcomes. There is an immediate need for robust data on the long-term safety of paracetamol exposure in the prenatal and neonatal periods.
Topics: Acetaminophen; Female; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Pregnancy; Vitamins
PubMed: 35206317
DOI: 10.3390/ijerph19042128 -
British Journal of Clinical Pharmacology Jul 2015Paracetamol poisoning is the commonest overdose seen in the UK. The management of patients with paracetamol poisoning has been little changed for the past 40 years,... (Review)
Review
Paracetamol poisoning is the commonest overdose seen in the UK. The management of patients with paracetamol poisoning has been little changed for the past 40 years, with a weight related dose of antidote (acetylcysteine) and treatment based on nomograms relating paracetamol concentration to time from ingestion. In 2012 the UK Commission on Human Medicines recommended a revision of the nomogram, following the death of a young woman, lowering the treatment threshold for all patients. As a result many more patients were treated. This has resulted in a large increase in admissions and in the proportion suffering adverse reactions to the antidote acetylcysteine since, interestingly, higher paracetamol concentrations inhibit anaphylactoid reactions to the antidote. New approaches to assessing the toxicity of paracetamol are now emerging using new biomarkers in blood. This article discusses new approaches to risk assessment and treatment for paracetamol overdose based on recent research in this area.
Topics: Acetaminophen; Acetylcysteine; Analgesics, Non-Narcotic; Biomarkers; Drug Overdose; Humans; Nomograms; Risk Assessment
PubMed: 26099917
DOI: 10.1111/bcp.12604 -
Pediatric Pulmonology Oct 2021To conduct an umbrella review collating the existing evidence to determine whether there is an association between exposure of Paracetamol in-utero or in infancy and the... (Review)
Review
OBJECTIVE
To conduct an umbrella review collating the existing evidence to determine whether there is an association between exposure of Paracetamol in-utero or in infancy and the development of childhood Asthma.
METHODS
In this review, systematic reviews with or without meta-analysis that reported the association between paracetamol and asthma in children were included. To identify relevant reviews, a search was performed in the electronic databases PubMed, the Cochrane Library, and Ovid MEDLINE. The protocol was registered in PROSPERO CRD42020156023. A separate search was conducted for primary studies from the last 5 years not yet included in systematic reviews reporting the association from January 2016 to March 2021.
RESULTS
The electronic searches identified 1966 review titles. After the removal of 493 duplicates, 1475 titles and abstracts were screened against the eligibility criteria. Full-text screening yielded six systematic reviews to be included in this review. The search for primary studies in the last 5 years yielded 1214 hits, out of which 5 studies were found suitable for inclusion. Three of them, that were not included in the systematic reviews, and have been summarised in this paper. The odds ratios (ORs) for the outcome of asthma in offspring of mothers with prenatal paracetamol consumption in any trimester were 1.28 (1.13-1.39) and 1.21 (1.02-1.44). For first trimester exposures, they were 1.12 (0.99-1.27), 1.39 (1.01-1.91), and 1.21 (1.14-1.28), for the second or third trimester, they were 1.49 (1.37-1.63) and 1.13 (1.04-1.23). For the third trimester only, the figure was 1.17 (1.04-1.31). Of the six reviews included, 1 had a low risk of bias, 2 had an unclear risk while 3 had a high risk of bias assessed using the ROBIS tool. There was no significant increased risk of asthma with early infancy exposure. The inter-study heterogeneity varied from I = 41% to I = 76% across reviews. In the primary studies, the OR for prenatal exposure ranged from 1.12 (0.25-4.98) to 4.66 (1.92-11.3) and for infancy exposure was 1.56 (1.06-2.30). All three included primary studies were adjudged to be of high quality using the Newcastle Ottawa scale.
CONCLUSIONS
There is a modest association between paracetamol exposure in-utero and the future development of asthma. Exposure in infancy has a less consistant association. All the studies done thus far are observational in nature, with their inherent biases. Further research, preferably randomized controlled trials are recommended to answer this pertinent question.
Topics: Acetaminophen; Asthma; Female; Humans; Pregnancy; Risk; Systematic Reviews as Topic
PubMed: 34425045
DOI: 10.1002/ppul.25595