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Daru : Journal of Faculty of Pharmacy,... Dec 2019Acetaminophen (Paracetamol, APAP) poisoning is frequently implicated in self-harm. Cases of acetaminophen-associated cardiotoxicity are rare in relation to the number of... (Review)
Review
PURPOSE
Acetaminophen (Paracetamol, APAP) poisoning is frequently implicated in self-harm. Cases of acetaminophen-associated cardiotoxicity are rare in relation to the number of patients with acetaminophen poisoning. A review of acetaminophen cardiotoxicity in 1996 concluded that there was no decisive evidence demonstrating that acetaminophen overdose has a cardiotoxic effect. This review study aimed to determine whether acetaminophen could induce heart injury.
METHODS
We searched for keywords of acetaminophen, paracetamol, cardiotoxicity, heart injury, heart damage, myocarditis, pericarditis, myocardial infarction, and myocardial ischemia in Web of Science, PubMed, Scopus, Embase, Google Scholar, and Persian databases. The search included articles published from January 1950 to October 2018 with no language restrictions.
RESULTS
The search yielded 64 citations in English; 36 of the articles were excluded as they were not relevant; 5 articles were excluded since they were duplicates, leaving 23 articles. Full-text articles of the 23 citations were obtained and reviewed. Myocardial infarction, heart dysfunction and failure, cardiac arrhythmias, pericarditis, heart cell necrosis, and sudden cardiac death were reported in acetaminophen overdose.
CONCLUSIONS
Ddysrhythmias, heart failure, and various other cardiac effects could occur following acetaminophen induced hepatic failure. However, the evidence for direct injury on cardiac tissue is weak. Graphical abstract Potential mechanisms for cardiotoxicity of acetaminophen.
Topics: Acetaminophen; Drug Overdose; Female; Heart Injuries; Humans; Male
PubMed: 31713183
DOI: 10.1007/s40199-019-00307-x -
Social Cognitive and Affective... Sep 2020Acetaminophen, an analgesic and antipyretic available over-the-counter and used in over 600 medicines, is one of the most consumed drugs in the USA. Recent research has... (Randomized Controlled Trial)
Randomized Controlled Trial
Acetaminophen, an analgesic and antipyretic available over-the-counter and used in over 600 medicines, is one of the most consumed drugs in the USA. Recent research has suggested that acetaminophen's effects extend to the blunting of negative as well as positive affect. Because affect is a determinant of risk perception and risk taking, we tested the hypothesis that acute acetaminophen consumption (1000 mg) could influence these important judgments and decisions. In three double-blind, placebo-controlled studies, healthy young adults completed a laboratory measure of risk taking (Balloon Analog Risk Task) and in Studies 1 and 2 completed self-report measures of risk perception. Across all studies (total n = 545), acetaminophen increased risk-taking behavior. On the more affectively stimulating risk perception measure used in Study 2, acetaminophen reduced self-reported perceived risk and this reduction statistically mediated increased risk-taking behavior. These results indicate that acetaminophen can increase risk taking, which may be due to reductions in risk perceptions, particularly those that are highly affect laden.
Topics: Acetaminophen; Adolescent; Affect; Analgesics, Non-Narcotic; Decision Making; Double-Blind Method; Female; Humans; Judgment; Male; Risk-Taking; Treatment Outcome; Young Adult
PubMed: 32888031
DOI: 10.1093/scan/nsaa108 -
The Cochrane Database of Systematic... Jun 2016Analgesic medication is the most frequently prescribed treatment for low back pain (LBP), of which paracetamol (acetaminophen) is recommended as the first choice... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Analgesic medication is the most frequently prescribed treatment for low back pain (LBP), of which paracetamol (acetaminophen) is recommended as the first choice medication. However, there is uncertainty about the efficacy of paracetamol for LBP.
OBJECTIVES
To investigate the efficacy and safety of paracetamol for non-specific LBP.
SEARCH METHODS
We conducted searches on the Cochrane Central Register of Controlled Trials (CENTRAL, which includes the Back and Neck Review Group trials register), MEDLINE, EMBASE, CINAHL, AMED, Web of Science, LILACS, and IPA from their inception to 7 August 2015. We also searched the reference lists of eligible papers and trial registry websites (WHO ICTRP and ClinicalTrials.gov).
SELECTION CRITERIA
We only considered randomised trials comparing the efficacy of paracetamol with placebo for non-specific LBP. The primary outcomes were pain and disability. We also investigated quality of life, function, adverse effects, global impression of recovery, sleep quality, patient adherence, and use of rescue medication as secondary outcomes.
DATA COLLECTION AND ANALYSIS
Two review authors independently performed the data extraction and assessed risk of bias in the included studies. We also evaluated the quality of evidence using the GRADE approach. We converted scales for pain intensity to a common 0 to 100 scale. We quantified treatment effects using mean difference for continuous outcomes and risk ratios for dichotomous outcomes. We used effect sizes and 95% confidence intervals as a measure of treatment effect for the primary outcomes. When the treatment effects were smaller than 9 points on a 0 to 100 scale, we considered the effect as small and not clinically important.
MAIN RESULTS
Our searches retrieved 4449 records, of which three trials were included in the review (n = 1825 participants), and two trials were included in the meta-analysis. For acute LBP, there is high-quality evidence for no difference between paracetamol (4 g per day) and placebo at 1 week (immediate term), 2 weeks, 4 weeks, and 12 weeks (short term) for the primary outcomes. There is high-quality evidence that paracetamol has no effect on quality of life, function, global impression of recovery, and sleep quality for all included time periods. There were also no significant differences between paracetamol and placebo for adverse events, patient adherence, or use of rescue medication. For chronic LBP, there is very low-quality evidence (based on a trial that has been retracted) for no effect of paracetamol (1 g single intravenous dose) on immediate pain reduction. Finally, no trials were identified evaluating patients with subacute LBP.
AUTHORS' CONCLUSIONS
We found that paracetamol does not produce better outcomes than placebo for people with acute LBP, and it is uncertain if it has any effect on chronic LBP.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Humans; Low Back Pain; Middle Aged; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 27271789
DOI: 10.1002/14651858.CD012230 -
Drugs & Aging Jul 2018Paracetamol is the most commonly used analgesic in older people, and is mainly dosed according to empirical dosing guidelines. However, the pharmacokinetics and thereby... (Review)
Review
Paracetamol is the most commonly used analgesic in older people, and is mainly dosed according to empirical dosing guidelines. However, the pharmacokinetics and thereby the effects of paracetamol can be influenced by physiological changes occurring with ageing. To investigate the steps needed to reach more evidence-based paracetamol dosing regimens in older people, we applied the concepts used in the paediatric study decision tree. A search was performed to retrieve studies on paracetamol pharmacokinetics and safety in older people (> 60 years) or studies that performed a (sub) analysis of pharmacokinetics and/or safety in older people. Of 6088 articles identified, 259 articles were retained after title and abstract screening. Further abstract and full-text screening identified 27 studies, of which 20 described pharmacokinetics and seven safety. These studies revealed no changes in absorption with ageing. A decreased (3.9-22.9%) volume of distribution (V) in robust older subjects and a further decreased V (20.3%) in frail older compared with younger subjects was apparent. Like V, age and frailty decreased paracetamol clearance (29-45.7 and 37.5%) compared with younger subjects. Due to limited and heterogeneous evidence, it was difficult to draw firm and meaningful conclusions on changed risk for paracetamol safety in older people. This review is a first step towards bridging knowledge gaps to move to evidence-based paracetamol dosing in older subjects. Remaining knowledge gaps are safety when using therapeutic dosages, pharmacokinetics changes in frail older people, and to what extent changes in paracetamol pharmacokinetics should lead to a change in dosage in frail and robust older people.
Topics: Acetaminophen; Aged; Analgesics, Non-Narcotic; Dose-Response Relationship, Drug; Humans; Middle Aged
PubMed: 29916138
DOI: 10.1007/s40266-018-0559-x -
Drugs & Aging Apr 2019Osteoarthritis (OA) is a major cause of pain and physical disability in adults, and an increasingly common disease given its associations with aging and a growing... (Review)
Review
Osteoarthritis (OA) is a major cause of pain and physical disability in adults, and an increasingly common disease given its associations with aging and a growing obese/overweight population. Paracetamol is widely recommended for analgesia at an early stage in the management of OA, and, although frequently prescribed, evidence suggests the efficacy of paracetamol for OA pain is low. Furthermore, there have been recent concerns over the safety profile of paracetamol, with reports of gastrointestinal, cardiovascular, hepatic and renal adverse events. This narrative review summarizes recent literature on the benefits and harms of paracetamol for OA pain. Data on long-term paracetamol safety are derived largely from observational evidence, and are difficult to interpret given the potential biases of such data. Nonetheless, a considerable degree of toxicity is associated with paracetamol use among the general population, especially at the upper end of standard analgesic doses. Paracetamol is linked to liver function abnormalities and there is evidence for liver failure associated with non-intentional paracetamol overdose. Safety data for paracetamol use in the older population (aged >65 years) are sparse; however, there is some evidence that frail elderly people may have impaired paracetamol clearance. Given that the analgesic benefit of paracetamol in OA joint pain is uncertain and potential safety issues have been raised, more careful consideration of its use is required.
Topics: Acetaminophen; Aged; Analgesics, Non-Narcotic; Arthralgia; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Humans; Osteoarthritis; Pain Management
PubMed: 31073920
DOI: 10.1007/s40266-019-00658-9 -
The Cochrane Database of Systematic... Aug 2017Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for... (Review)
Review
BACKGROUND
Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as important.We designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol as priority areas) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents.As the leading cause of morbidity in children and adolescents in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (lasting three months or longer) can arise in the paediatric population in a variety of pathophysiological classifications: nociceptive, neuropathic, idiopathic, visceral, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and other unknown reasons.Paracetamol (acetaminophen) is one of the most widely used analgesics in both adults and children. The recommended dosage in the UK, Europe, Australia, and the USA for children and adolescents is generally 10 to 15 mg/kg every four to six hours, with specific age ranges from 60 mg (6 to 12 months old) up to 500 to 1000 mg (over 12 years old). Paracetamol is the only recommended analgesic for children under 3 months of age. Paracetamol has been proven to be safe in appropriate and controlled dosages, however potential adverse effects of paracetamol if overdosed or overused in children include liver and kidney failure.
OBJECTIVES
To assess the analgesic efficacy and adverse events of paracetamol (acetaminophen) used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews, and searched online clinical trial registries.
SELECTION CRITERIA
Randomised controlled trials, with or without blinding, of any dose and any route, treating chronic non-cancer pain in children and adolescents, comparing paracetamol with placebo or an active comparator.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and numbers needed to treat, using standard methods where data were available. We assessed GRADE (Grading of Recommendations Assessment, Development and Evaluation) and planned to create a 'Summary of findings' table.
MAIN RESULTS
No studies were eligible for inclusion in this review. We rated the quality of the evidence as very low. We downgraded the quality of evidence by three levels due to the lack of data reported for any outcome.
AUTHORS' CONCLUSIONS
There was no evidence from randomised controlled trials to support or refute the use of paracetamol (acetaminophen) to treat chronic non-cancer pain in children and adolescents. We are unable to comment about efficacy or harm from the use of paracetamol to treat chronic non-cancer pain in children and adolescents.We know from adult randomised controlled trials that paracetamol, can be effective, in certain doses, and in certain pain conditions (not always chronic).This means that no conclusions could be made about efficacy or harm in the use of paracetamol (acetaminophen) to treat chronic non-cancer pain in children and adolescents.
Topics: Acetaminophen; Adolescent; Analgesics, Non-Narcotic; Child; Chronic Pain; Humans
PubMed: 28770975
DOI: 10.1002/14651858.CD012539.pub2 -
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 -
Neurobiology of Disease Feb 2023Acetaminophen (N-acetyl-p-aminophenol (APAP), also known as paracetamol) is one of the most common medications used by the general population, including pregnant people....
Acetaminophen (N-acetyl-p-aminophenol (APAP), also known as paracetamol) is one of the most common medications used by the general population, including pregnant people. Although many human observational and animal model studies have shown associations between prenatal and early postnatal APAP exposure and attention deficit hyperactivity disorder, autism spectrum disorders, and altered neurodevelopment, the existing literature is limited. In particular, no mouse studies of prenatal APAP exposure have investigated offspring attention deficits in behavioral tasks specifically designed to measure attention, and no prior rodent studies have utilized 'omics' technologies, such as transcriptomics, for an untargeted exploration of potential mechanisms. We randomly assigned pregnant mice (starting embryonic day 4-10) to receive APAP (150 mg/kg/day) or vehicle control through postnatal day 14. We evaluated 111 mouse offspring in a battery of behavioral tests, including pup ultrasonic vocalizations, elevated plus-maze, open field test, CatWalk (gait), pre-pulse inhibition, and the automated 5-choice serial reaction time task. Prefrontal cortex was collected at birth from 24 pups for RNA sequencing. Developmental APAP treatment resulted in increased and hastened separation-induced pup vocalizations between postnatal days 2 and 11, as well as decreased ambulation and vertical rearings in the open field in male but not female adult offspring. APAP treatment was also associated with altered sex-specific prefrontal cortex gene expression relating to glutathione and cytochrome p450 metabolism, DNA damage, and the endocrine and immune systems. This study provides additional evidence for the neurodevelopmental harm of prenatal APAP exposure and generates hypotheses for underlying molecular pathways via RNA sequencing.
Topics: Humans; Pregnancy; Animals; Female; Adult; Mice; Male; Acetaminophen; Gene Expression Regulation; Autism Spectrum Disorder; Prefrontal Cortex; Gene Expression
PubMed: 36549432
DOI: 10.1016/j.nbd.2022.105970 -
IARC Monographs on the Evaluation of... 1990
Review
Topics: Acetaminophen; Animals; Carcinogens; Dogs; Female; Humans; Mice; Molecular Structure; Mutagens; Pregnancy; Rats; Reproduction
PubMed: 2152767
DOI: No ID Found -
Drug Metabolism Reviews Feb 2015Acetaminophen (APAP, paracetamol, N-acetyl-p-aminophenol) is a widely used analgesic that is safe at therapeutic doses but is a major cause of acute liver failure (ALF)... (Review)
Review
Acetaminophen (APAP, paracetamol, N-acetyl-p-aminophenol) is a widely used analgesic that is safe at therapeutic doses but is a major cause of acute liver failure (ALF) following overdose. APAP-induced hepatotoxicity is related to the formation of an electrophilic reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified through conjugation with reduced glutathione (GSH). One method that has been applied to study APAP metabolism and hepatotoxicity is that of metabolic phenotyping, which involves the study of the small molecule complement of complex biological samples. This approach involves the use of high-resolution analytical platforms such as NMR spectroscopy and mass spectrometry to generate information-rich metabolic profiles that reflect both genetic and environmental influences and capture both endogenous and xenobiotic metabolites. Data modeling and mining and the subsequent identification of panels of candidate biomarkers are typically approached with multivariate statistical tools. We review the application of multi-platform metabolic profiling for the study of APAP metabolism in both in vivo models and humans. We also review the application of metabolic profiling for the study of endogenous metabolic pathway perturbations in response to APAP hepatotoxicity, with a particular focus on metabolites involved in the biosynthesis of GSH and those that reflect mitochondrial function such as long-chain acylcarnitines. Taken together, this body of work sheds much light on the mechanism of APAP-induced hepatotoxicity and provides candidate biomarkers that may prove of translational relevance for improved stratification of APAP-induced ALF.
Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Liver; Phenotype
PubMed: 25533740
DOI: 10.3109/03602532.2014.982865