Paracetamol-induced hepatotoxicity after normal therapeutic doses in the Hong Kong Chinese population.

INTRODUCTION: Paracetamol is generally safe at normal therapeutic doses of ≤4 g/day in adults. However, paracetamol-induced hepatotoxicity after normal therapeutic doses use has been reported. We investigated the epidemiology of this adverse drug reaction in the Hong Kong Chinese population. METHODS: This territory-wide retrospective observational study included adult patients with suspected paracetamol-induced hepatotoxicity after normal therapeutic doses use from January 2011 to June 2022. We evaluated the demographic characteristics; paracetamol dose, duration, and reason for use; preexisting hepatotoxicity risk factors; laboratory findings; and their relationship with clinical outcomes. RESULTS: We identified 76 patients (median age: 74 years, 23 males) with suspected paracetamolinduced hepatotoxicity after normal therapeutic doses use. There were 14 cases with significant clinical outcomes (five deaths and nine cases of acute hepatic failure), with an incidence of 1.2 cases per year. For patients with significant clinical outcomes, they were significantly older (age >80 years), had a lower body weight (<50 kg), exposed to longer durations (>2 days) and higher daily doses (>3 g), and with higher proportion of malnutrition. CONCLUSION: Paracetamol-induced hepatotoxicity can occur at normal therapeutic doses in the Hong Kong Chinese population. The identified risk factors are consistent with international guidelines regarding susceptible patients. Considering the widespread local use of paracetamol and low incidence of severe hepatotoxicity, the current dosage recommendations are considered safe for the general population. For susceptible patients, a reduced maximum dose of ≤3 g/day is recommended, with liver function and serum paracetamol monitoring in place.

Neurodevelopmental outcomes following paracetamol use for treatment of patent ductus arteriosus: A review.

AIM: Concerns exist regarding potential adverse neurodevelopmental outcomes associated with paracetamol exposure during pregnancy and early infancy. This review evaluates the evidence for the impact of paracetamol use for patent ductus arteriosus (PDA) treatment on neurodevelopmental outcomes in preterm infants. METHODS: A literature search was performed via Medline, Ovid Embase and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases. The search details are below: ('Infant, Newborn' [MeSH] OR 'neonate*' [Title/Abstract]) AND ('Paracetamol' [MeSH] OR 'Acetaminophen' [Title/Abstract]) AND ('Ductus Arteriosus, Patent/drug therapy' [MeSH] OR 'patent ductus arteriosus' [Title/Abstract]) AND ('Neurodevelopmental Disorders' [MeSH] OR 'neurodevelopment*' [Title/Abstract] OR 'Child Development' [MeSH] OR 'Developmental Disabilities' [MeSH]). All studies were critically appraised and synthesised. RESULTS: Seven studies reported neurodevelopmental outcomes after paracetamol use for PDA treatment in preterm infants <32 weeks gestation. The studies varied in dosage, route, and duration of paracetamol administration and in the methods used to assess neurodevelopmental outcomes. None of the studies revealed different outcomes between paracetamol-exposed preterm infants and controls. CONCLUSION: Current low-to-moderate quality evidence suggests no association between paracetamol used for PDA treatment and adverse neurodevelopmental outcomes in preterm infants. Future well-powered studies with standardised neurodevelopmental assessments are warranted to strengthen the current evidence base.

Perioperative N-acetylcysteine: evidence and indications.

Nonopioid analgesics serve to improve analgesia and limit side effects and risks of perioperative opioids. N-acetylcysteine (NAC), the primary treatment of acetaminophen toxicity, may have perioperative indications, including analgesia. NAC impacts glutathione synthesis, oxidant scavenging, glutamate receptor modulation and neuroinflammation. Potential perioperative benefits include arrhythmia prevention after cardiac surgery, decreased contrast-induced nephropathy, improved post-transplant liver function and superior pulmonary outcomes with general anesthesia. NAC may improve perioperative analgesia, with some studies displaying a reduction in postoperative opioid use. NAC is generally well tolerated with an established safety profile. NAC administration may predispose to gastrointestinal effects, while parenteral administration may carry a risk of anaphylactoid reactions, including bronchospasm. Larger randomized trials may clarify the impact of NAC on perioperative analgesic outcomes.

Nonopioid mediations are important to help pain control after surgery and may decrease risks of opioids. N-acetylcysteine (NAC), the treatment of acetaminophen overdose, decreased inflammation and has other positive effects on the body that may help pain after surgery. Thus, NAC has been studied to prevent abnormal heart rhythms with heart surgery, help kidneys after surgery, improve the liver after liver transplant or other live surgeries and improve breathing after anesthesia. NAC may also decrease pain and the amount of pain medications needed after surgery. While NAC is generally well tolerated and considered safe, stomach upset can occur as can itching or asthma like reactions in certain patients. This review describes how NAC may improve pain, summarizes the other ways NAC may help a patient undergoing surgery, and describes potential side effects when NAC is given.

Acetaminophen use during pregnancy was not linked to autism, ADHD, or intellectual disability in offspring.

SOURCE CITATION: Ahlqvist VH, Sjöqvist H, Dalman C, et al. Acetaminophen use during pregnancy and children's risk of autism, ADHD, and intellectual disability. JAMA. 2024;331:1205-1214. 38592388.

A case report of Paracetamol related pyroglutamic acidosis: mind the gap in a malnourished patient.

BACKGROUND: Pyroglutamic acidosis is a rare cause of high anion gap metabolic acidosis. Most cases of paracetamol related pyroglutamic acidosis are described in malnourished women and patients with kidney/liver failure, alcohol use or severe sepsis. In this report, we describe how pyroglutamic acidosis could be related to the use of chronic therapeutic paracetamol with only malnutrition as an associated risk factor. CASE PRESENTATION: We report a case of a 67-year-old male patient developing a pyroglutamic acidosis. The patient was initially admitted to hospital for infectious osteoarthritis and developed a metabolic acidosis during his hospital stay. Analgesics included daily therapeutic doses of paracetamol. What makes our case unusual is that our malnourished male patient did not have renal or hepatic failure. The diagnosis of paracetamol related pyroglutamic acidosis was made after ruling out the main causes of metabolic acidosis. It was further confirmed by urine organic acids measurement showing a markedly elevated level of pyroglutamic aciduria. Paracetamol was discontinued allowing a prompt correction of the anion gap. CONCLUSION: This case is a representative of pyroglutamic acidosis related to chronic therapeutic paracetamol with only malnutrition as an associated risk factor. Physicians should be aware of such unusual cause of metabolic acidosis, which may be more common than expected in hospitalized patients. A high clinical suspicion is needed when urine organic acids analysis is not available.

[Prehospital analgesia with nalbuphine and paracetamol compared to piritramide by paramedics-A multicenter observational study]. / Prähospitale Analgesie mit Nalbuphin und Paracetamol im Vergleich zu Piritramid durch Notfallsanitäter*innen ­ eine multizentrische Observationsstudie.

OBJECTIVE: Following recent changes to the German Narcotics Act, this article examines prehospital analgesia by paramedics using piritramide vs. nalbuphine + paracetamol. MATERIAL AND METHODS: Prehospital analgesia administered by paramedics from the Fulda (piritramide) and Gütersloh (nalbuphine + paracetamol) emergency services was compared regarding pain intensity at the beginning and end of the mission, measured using the numeric rating scale (NRS). Additionally, an analysis of the resulting complications was carried out. RESULTS: In this study 2429 administrations of analgesia were evaluated (nalbuphine + paracetamol: 1635, 67.3%, initial NRS: 8.0 ± 1.4, end of NRS: 3.7 ± 2.0; piritramide: 794, 32.7%, initial NRS: 8.5 ± 1.1, end of NRS: 4.5 ± 1.6). Factors influencing NRS change were initial NRS (regression coefficient, RC: 0.7075, 95% confidence interval, CI: 0.6503-0.7647, p < 0.001), treatment with nalbuphine + paracetamol (RC: 0.6048, 95% CI: 0.4396-0.7700, p < 0.001). Treatment with nalbuphine + paracetamol (n = 796 (48.7%)) compared to piritramide (n = 190 (23.9%)) increased the odds of achieving NRS < 4 (odds ratio, OR: 2.712, 95% CI: 2.227-3.303, p < 0.001). Complications occurred in n = 44 (5.5%) with piritramide and in n = 35 (2.1%) with nalbuphine + paracetamol. Risk factors for complications were analgesia with piritramide (OR: 2.699, 95% CI: 1.693-4.301, p < 0.001), female sex (OR: 2.372, 95% CI: 1.396-4.029, p = 0.0014), and age (OR: 1.013, 95% CI: 1.002-1.025, p = 0.0232). CONCLUSION: Compared with piritramide, prehospital analgesia with nalbuphine + paracetamol has favorable effects in terms of analgesic efficacy and complication rates and should therefore be considered in future recommendations for paramedics.

Analgesic medication considerations for chronic pain management post-bariatric surgery.

INTRODUCTION: Bariatric surgery, an option for obesity management, can significantly alter gastrointestinal structure and processes. These changes can impact the pharmacokinetics (PK) of medications, which can translate to clinical differences in efficacy and safety. Chronic pain is prevalent in obesity and often persists post-bariatric surgery. AREAS COVERED: This narrative review examines the PubMed literature from 1990 to January 2024 for the impact of bariatric surgery on the management of chronic pain medications including non-opioid (acetaminophen, non-steroidal anti-inflammatory drugs, antidepressants, and cannabinoids) and opioid medications. EXPERT OPINION: An individualized medication management approach is ideal for post-bariatric surgery patients, as PK parameters, type of surgery, time since surgery, and patient-specific factors make it difficult to support blanket recommendations. Close monitoring of efficacy and safety outcomes is essential in chronic pain management. While the PK of acetaminophen and opioids are impacted, the value of these medications in the setting of chronic pain is dwindling as more efficacy and safety data emerges. A life-long ban of NSAIDs due to marginal ulcer risk is not endorsed; rather, we advocate for shifting the focus to marginal ulcer prevention strategies, individualized benefit-risk analysis, and safety monitoring using surrogate markers.

Patterns of acetaminophen toxicity among patients with low-risk serum concentrations.

OBJECTIVE: In 2012, the Commission on Human Medicines mandated lowering the acetaminophen toxicity nomogram treatment threshold in the UK to 100 µg/ml at 4 h post-ingestion. The present study aim was to evaluate biochemical and liver toxicity patterns in patients who presented with acetaminophen overdose and had low serum acetaminophen concentrations (<150 µg/ml). METHODS: Patients admitted to the emergency department with a clear history of acute acetaminophen overdose with or without other medication or ethanol were consecutively enrolled into this retrospective cohort study. Patients with serum acetaminophen concentration >150 µg/ml or an unknown ingestion time were excluded. Data were extracted from electronic medical records and are presented as mean ± SD or median (interquartile range). RESULTS: A total of 103 patients were included (median age, 17 [4-21] years) and 80 (78%) were female. The median ingested acetaminophen dose was 5000 (2850-7650) mg. At baseline, the median serum acetaminophen concentration was 42 (4.5-64.8) µg/ml, and median alanine aminotransferase and aspartate aminotransferase levels were 22 (17-28) and 27 (16-45) IU/L, respectively. Twenty patients were treated with acetylcysteine, with none developing adverse reactions. No patient developed hepatotoxicity, including patients with initial multiple product ingestion or other risk factors. CONCLUSIONS: Patients presenting with an acute acetaminophen overdose with acetaminophen level <150 µg/ml, including patients with other risk factors, are at low risk of hepatotoxicity.

Acetaminophen for Patent Ductus Arteriosus and Risk of Mortality and Pulmonary Morbidity.

OBJECTIVE: Emerging data indicate that acetaminophen may adversely affect lung health. We examined whether acetaminophen compared with cyclooxygenase (COX) inhibitor alone for patent ductus arteriosus (PDA) is associated with mortality or respiratory morbidity in extremely preterm infants. METHODS: This is a retrospective cohort study using data from the National Institute of Child Health and Human Development Neonatal Research Network. Infants were born at 22 to 28 weeks' gestation or weighing 401 to 1000 g between 2016 and 2020 and received acetaminophen, ibuprofen, and/or indomethacin for PDA closure. The primary outcome was death or grade 2 to 3 bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age. Secondary outcomes included predischarge mortality and respiratory morbidities. Risk ratios were adjusted for baseline and early postnatal factors. Additional exploratory analyses were adjusted for later postnatal covariates. RESULTS: Of 1921 infants, 627 (32.6%) received acetaminophen and 1294 (67.3%) received COX inhibitor only. Multidrug therapy (42.9% vs 4.7%) and surgical or catheter PDA closure (26.5% vs 19.9%) were more common among acetaminophen-exposed infants. Death or grade 2 to 3 BPD at 36 weeks' postmenstrual age was similar between infants treated with acetaminophen versus COX inhibitor only (57.1% vs 58.3%; adjusted relative risk [aRR] 0.96, 95% confidence interval [CI] 0.87-1.06). Acetaminophen was associated with increased risk of predischarge mortality (13.3% vs 10.0%) when adjusting for perinatal and early postnatal factors (aRR 1.42, 95% CI 1.02-1.93), but not in exploratory analyses that included later postnatal factors (aRR 1.28, 95% CI 0.91-1.82). CONCLUSIONS: Treatment with acetaminophen versus COX inhibitor alone for PDA was not associated with the composite outcome of death or BPD in extremely preterm infants. Our results support further evaluation of whether acetaminophen for PDA increases mortality.

Paracetamol Combination Therapy for Back Pain and Osteoarthritis: A Systematic Review and Meta-Analyses.

BACKGROUND AND OBJECTIVE: Although paracetamol (acetaminophen) combined with other analgesics can reduce pain intensity in some pain conditions, its effectiveness in managing low back pain and osteoarthritis is unclear. This systematic review investigated whether paracetamol combination therapy is more effective and safer than monotherapy or placebo in low back pain and osteoarthritis. METHODS: Online database searches were conducted for randomised trials that evaluated paracetamol combined with another analgesic compared to a placebo or the non-paracetamol ingredient in the combination (monotherapy) in low back pain and osteoarthritis. The primary outcome was a change in pain. Secondary outcomes were (serious) adverse events, changes in disability and quality of life. Follow-up was immediate (≤ 2 weeks), short (> 2 weeks but ≤ 3 months), intermediate (> 3 months but < 12 months) or long term (≥ 12 months). A random-effects meta-analysis was conducted. Risk of bias was assessed using the original Cochrane tool, and quality of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: Twenty-two studies were included. Pain was reduced with oral paracetamol plus a non-steroidal anti-inflammatory drug (NSAID) at immediate term in low back pain (paracetamol plus ibuprofen vs ibuprofen [mean difference (MD) - 6.2, 95% confidence interval (CI) -10.4 to -2.0, moderate evidence]) and in osteoarthritis (paracetamol plus aceclofenac vs aceclofenac [MD - 4.7, 95% CI - 8.3 to - 1.2, moderate certainty evidence] and paracetamol plus etodolac vs etodolac [MD - 15.1, 95% CI - 18.5 to - 11.8; moderate certainty evidence]). Paracetamol plus oral tramadol reduced pain compared with placebo at intermediate term for low back pain (MD - 11.7, 95% CI - 19.2 to - 4.3; very low certainty evidence) and osteoarthritis (MD - 6.8, 95% CI - 12.7 to -0.9; moderate certainty evidence). Disability scores improved in half the comparisons. Quality of life was infrequently measured. All paracetamol plus NSAID combinations did not increase the risk of adverse events compared to NSAID monotherapy. CONCLUSIONS: Low-to-moderate quality evidence supports the oral use of some paracetamol plus NSAID combinations for short-term pain relief with no increased risk of harm for low back pain and osteoarthritis compared to its non-paracetamol monotherapy comparator.

Deciphering Acetaminophen-Induced Hepatotoxicity: The Crucial Role of Transcription Factors like Nuclear Factor Erythroid 2-Related Factor 2 as Genetic Determinants of Susceptibility to Drug-Induced Liver Injury.

Acetaminophen (APAP) is the most commonly used over-the-counter medication throughout the world. At therapeutic doses, APAP has potent analgesic and antipyretic effects. The efficacy and safety of APAP are influenced by multifactorial processes dependent upon dosing, namely frequency and total dose. APAP poisoning by repeated ingestion of supratherapeutic doses, depletes glutathione stores in the liver and other organs capable of metabolic bioactivation, leading to hepatocellular death due to exhausted antioxidant defenses. Numerous genes, encompassing transcription factors and signaling pathways, have been identified as playing pivotal roles in APAP toxicity, with the liver being the primary organ studied due to its central role in APAP metabolism and injury. Nuclear factor erythroid 2-related factor 2 (NRF2) and its array of downstream responsive genes are crucial in counteracting APAP toxicity. NRF2, along with its negative regulator Kelch-like ECH-associated protein 1, plays a vital role in regulating intracellular redox homeostasis. This regulation is significant in modulating the oxidative stress, inflammation, and hepatocellular death induced by APAP. In this review, we provide an updated overview of the mechanisms through which NRF2 activation and signaling critically influence the threshold for developing APAP toxicity. We also describe how genetically modified rodent models for NRF2 and related genes have been pivotal in underscoring the significance of this antioxidant response pathway. While NRF2 is a primary focus, the article comprehensively explores other genetic factors involved in phase I and phase II metabolism of APAP, inflammation, oxidative stress, and related pathways that contribute to APAP toxicity, thereby providing a holistic understanding of the genetic landscape influencing susceptibility to this condition. SIGNIFICANCE STATEMENT: This review summarizes the genetic elements and signaling pathways underlying APAP-induced liver toxicity, focusing on the crucial protective role of the transcription factor NRF2. This review also delves into the genetic intricacies influencing APAP safety and potential liver harm. It also emphasizes the need for deeper insight into the molecular mechanisms of hepatotoxicity, especially the interplay of NRF2 with other pathways.

Safety and efficacy of carbamazepine in the treatment of trigeminal neuralgia: A metanalysis in biomedicine.

Trigeminal neuralgia is a debilitating condition characterized by severe facial pain. Carbamazepine has been widely used as a first-line treatment option for trigeminal neuralgia, but there is a need to evaluate its safety and efficacy based on existing evidence. This meta-analysis aims to systematically assess the available literature and provide a comprehensive evaluation of the safety and efficacy of carbamazepine in the treatment of trigeminal neuralgia. A thorough search of electronic databases yielded a total of 15 relevant studies that met the inclusion criteria. The pooled analysis of these studies revealed that carbamazepine demonstrated significant efficacy in reducing pain intensity and frequency in patients with trigeminal neuralgia. Moreover, the drug was generally well-tolerated, with the most common adverse events being mild and transient. Subgroup analyses based on different dosages and treatment durations further supported the overall findings. However, caution should be exercised in patients with certain comorbidities or specific populations, as some rare but severe adverse events were reported. In conclusion, this meta-analysis provides strong evidence supporting the safety and efficacy of carbamazepine as a valuable therapeutic option for the management of trigeminal neuralgia. These results can guide clinicians in making informed decisions regarding the use of carbamazepine and contribute to optimizing treatment strategies for patients with trigeminal neuralgia. Further research is warranted to explore long-term safety and efficacy outcomes, as well as to compare carbamazepine with alternative treatment modalities.

Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial.

Importance: Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates. Objective: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo. Design, Setting, and Participants: Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up. Adults with sepsis and respiratory or circulatory organ dysfunction were enrolled in the emergency department or intensive care unit of 40 US academic hospitals within 36 hours of presentation. Intervention: Patients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days. Main Outcome and Measures: The primary end point was days alive and free of organ support (mechanical ventilation, vasopressors, and kidney replacement therapy) to day 28. Treatment effect modification was evaluated for acetaminophen by prerandomization plasma cell-free hemoglobin level higher than 10 mg/dL. Results: Of 447 patients enrolled (mean age, 64 [SD, 15] years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4 [SD, 2.5]), 227 were randomized to acetaminophen and 220 to placebo. Acetaminophen was safe with no difference in liver enzymes, hypotension, or fluid balance between treatment arms. Days alive and free of organ support to day 28 were not meaningfully different for acetaminophen (20.2 days; 95% CI, 18.8 to 21.6) vs placebo (19.6 days; 95% CI, 18.2 to 21.0; P = .56; difference, 0.6; 95% CI, -1.4 to 2.6). Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm as was the rate of development of acute respiratory distress syndrome within 7 days (2.2% vs 8.5% acetaminophen vs placebo; P = .01; difference, -6.3; 95% CI, -10.8 to -1.8). There was no significant interaction between cell-free hemoglobin levels and acetaminophen. Conclusions and Relevance: Intravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04291508.

Acute liver failure.

ABSTRACT: Acute liver failure, commonly caused by acetaminophen overdose, is associated with numerous systemic complications including cerebral edema, hypotension, acute kidney injury, and infection. Management is primarily supportive, with an emphasis on excellent neurocritical care. Although some antidotes and targeted treatments exist, the only definitive treatment remains orthotopic liver transplant.