-
The New England Journal of Medicine Aug 2023The Na1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The Na1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral, highly selective inhibitor of Na1.8, on control of acute pain is being studied.
METHODS
After establishing the selectivity of VX-548 for Na1.8 inhibition in vitro, we conducted two phase 2 trials involving participants with acute pain after abdominoplasty or bunionectomy. In the abdominoplasty trial, participants were randomly assigned in a 1:1:1:1 ratio to receive one of the following over a 48-hour period: a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours (the high-dose group); a 60-mg loading dose of VX-548, followed by a 30-mg maintenance dose every 12 hours (the middle-dose group); hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. In the bunionectomy trial, participants were randomly assigned in a 2:2:1:2:2 ratio to receive one of the following over a 48-hour treatment period: oral high-dose VX-548; middle-dose VX-548; low-dose VX-548 (a 20-mg loading dose, followed by a 10-mg maintenance dose every 12 hours); oral hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour period (SPID48), a measure derived from the score on the Numeric Pain Rating Scale (range, 0 to 10; higher scores indicate greater pain) at 19 time points after the first dose of VX-548 or placebo. The main analysis compared each dose of VX-548 with placebo.
RESULTS
A total of 303 participants were enrolled in the abdominoplasty trial and 274 in the bunionectomy trial. The least-squares mean difference between the high-dose VX-548 and placebo groups in the time-weighted SPID48 was 37.8 (95% confidence interval [CI], 9.2 to 66.4) after abdominoplasty and 36.8 (95% CI, 4.6 to 69.0) after bunionectomy. In both trials, participants who received lower doses of VX-548 had results similar to those with placebo. Headache and constipation were common adverse events with VX-548.
CONCLUSIONS
As compared with placebo, VX-548 at the highest dose, but not at lower doses, reduced acute pain over a period of 48 hours after abdominoplasty or bunionectomy. VX-548 was associated with adverse events that were mild to moderate in severity. (Funded by Vertex Pharmaceuticals; VX21-548-101 and VX21-548-102 ClinicalTrials.gov numbers, NCT04977336 and NCT05034952.).
Topics: Humans; Acetaminophen; Hydrocodone; Acute Pain; Analgesics, Opioid; Pain, Postoperative; Analgesics; Double-Blind Method
PubMed: 37530822
DOI: 10.1056/NEJMoa2209870 -
Acetaminophen Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability.JAMA Apr 2024Several studies suggest that acetaminophen (paracetamol) use during pregnancy may increase risk of neurodevelopmental disorders in children. If true, this would have...
IMPORTANCE
Several studies suggest that acetaminophen (paracetamol) use during pregnancy may increase risk of neurodevelopmental disorders in children. If true, this would have substantial implications for management of pain and fever during pregnancy.
OBJECTIVE
To examine the associations of acetaminophen use during pregnancy with children's risk of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability.
DESIGN, SETTING, AND PARTICIPANTS
This nationwide cohort study with sibling control analysis included a population-based sample of 2 480 797 children born in 1995 to 2019 in Sweden, with follow-up through December 31, 2021.
EXPOSURE
Use of acetaminophen during pregnancy prospectively recorded from antenatal and prescription records.
MAIN OUTCOMES AND MEASURES
Autism, ADHD, and intellectual disability based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes in health registers.
RESULTS
In total, 185 909 children (7.49%) were exposed to acetaminophen during pregnancy. Crude absolute risks at 10 years of age for those not exposed vs those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability. In models without sibling control, ever-use vs no use of acetaminophen during pregnancy was associated with marginally increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD] at 10 years of age, 0.09% [95% CI, -0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04% [95% CI, -0.04% to 0.12%]). To address unobserved confounding, matched full sibling pairs were also analyzed. Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, -0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, -0.02% [95% CI, -0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, -0.10% to 0.13%]). Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively.
CONCLUSIONS AND RELEVANCE
Acetaminophen use during pregnancy was not associated with children's risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.
Topics: Child; Female; Humans; Pregnancy; Acetaminophen; Attention Deficit Disorder with Hyperactivity; Autistic Disorder; Cohort Studies; Confounding Factors, Epidemiologic; Follow-Up Studies; Intellectual Disability; Neurodevelopmental Disorders; Prenatal Exposure Delayed Effects; Sweden
PubMed: 38592388
DOI: 10.1001/jama.2024.3172 -
Oral magnesium prevents acetaminophen-induced acute liver injury by modulating microbial metabolism.Cell Host & Microbe Jan 2024Acetaminophen overuse is a common cause of acute liver failure (ALF). During ALF, toxins are metabolized by enzymes such as CYP2E1 and transformed into reactive species,...
Acetaminophen overuse is a common cause of acute liver failure (ALF). During ALF, toxins are metabolized by enzymes such as CYP2E1 and transformed into reactive species, leading to oxidative damage and liver failure. Here, we found that oral magnesium (Mg) alleviated acetaminophen-induced ALF through metabolic changes in gut microbiota that inhibit CYP2E1. The gut microbiota from Mg-supplemented humans prevented acetaminophen-induced ALF in mice. Mg exposure modulated Bifidobacterium metabolism and enriched indole-3-carboxylic acid (I3C) levels. Formate C-acetyltransferase (pflB) was identified as a key Bifidobacterium enzyme involved in I3C generation. Accordingly, a Bifidobacterium pflB knockout showed diminished I3C generation and reduced the beneficial effects of Mg. Conversely, treatment with I3C or an engineered bacteria overexpressing Bifidobacterium pflB protected against ALF. Mechanistically, I3C bound and inactivated CYP2E1, thus suppressing formation of harmful reactive intermediates and diminishing hepatocyte oxidative damage. These findings highlight how interactions between Mg and gut microbiota may help combat ALF.
Topics: Humans; Mice; Animals; Acetaminophen; Magnesium; Cytochrome P-450 CYP2E1; Liver; Liver Failure, Acute
PubMed: 38056458
DOI: 10.1016/j.chom.2023.11.006 -
British Journal of Sports Medicine Aug 2023Clinical guidelines recommend exercise as a core treatment for knee or hip osteoarthritis (OA). However, how its analgesic effect compares to analgesics, for example,... (Meta-Analysis)
Meta-Analysis
Comparative efficacy of exercise therapy and oral non-steroidal anti-inflammatory drugs and paracetamol for knee or hip osteoarthritis: a network meta-analysis of randomised controlled trials.
OBJECTIVE
Clinical guidelines recommend exercise as a core treatment for knee or hip osteoarthritis (OA). However, how its analgesic effect compares to analgesics, for example, oral non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol-the most commonly used analgesics for OA, remains unknown.
DESIGN
Network meta-analysis.
DATA SOURCES
PubMed, Embase, Scopus, Cochrane Library and Web of Science from database inception to January 2022.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Randomised controlled trials (RCTs) comparing exercise therapy with oral NSAIDs and paracetamol directly or indirectly in knee or hip OA.
RESULTS
A total of n=152 RCTs (17 431 participants) were included. For pain relief, there was no difference between exercise and oral NSAIDs and paracetamol at or nearest to 4 (standardised mean difference (SMD)=-0.12, 95% credibility interval (CrI) -1.74 to 1.50; n=47 RCTs), 8 (SMD=0.22, 95% CrI -0.05 to 0.49; n=2 RCTs) and 24 weeks (SMD=0.17, 95% CrI -0.77 to 1.12; n=9 RCTs). Similarly, there was no difference between exercise and oral NSAIDs and paracetamol in functional improvement at or nearest to 4 (SMD=0.09, 95% CrI -1.69 to 1.85; n=40 RCTs), 8 (SMD=0.06, 95% CrI -0.20 to 0.33; n=2 RCTs) and 24 weeks (SMD=0.05, 95% CrI -1.15 to 1.24; n=9 RCTs).
CONCLUSIONS
Exercise has similar effects on pain and function to that of oral NSAIDs and paracetamol. Given its excellent safety profile, exercise should be given more prominence in clinical care, especially in older people with comorbidity or at higher risk of adverse events related to NSAIDs and paracetamol.CRD42019135166.
Topics: Aged; Humans; Acetaminophen; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Exercise Therapy; Network Meta-Analysis; Osteoarthritis, Hip; Osteoarthritis, Knee; Pain; Randomized Controlled Trials as Topic
PubMed: 36593092
DOI: 10.1136/bjsports-2022-105898 -
Neurotoxicology and Teratology 2024Acetaminophen is currently the only analgesic considered safe for use throughout pregnancy, but recent studies indicate that prenatal exposure to acetaminophen may be...
Acetaminophen is currently the only analgesic considered safe for use throughout pregnancy, but recent studies indicate that prenatal exposure to acetaminophen may be related to poorer neurodevelopmental outcomes. Multiple studies have suggested that it may be associated with attention problems, but few have examined this association by trimester of exposure. The Illinois Kids Development Study is a prospective birth cohort located in east-central Illinois. Exposure data were collected between December 2013 and March 2020, and 535 newborns were enrolled during that period. Mothers reported the number of times they took acetaminophen at six time points across pregnancy. When children were 2, 3, and 4 years of age, caregivers completed the Child Behavior Checklist for ages 1.5-5 years (CBCL). Associations of acetaminophen use during pregnancy with scores on the Attention Problems and ADHD Problems syndrome scales, the Internalizing and Externalizing Behavior composite scales, and the Total Problems score were evaluated. Higher acetaminophen exposure during the second trimester of fetal development was associated with higher Attention Problems, ADHD Problems, Externalizing Behavior, and Total Problems scores at ages 2 and 3. Higher second trimester exposure was only associated with higher Externalizing Behavior and Total Problems scores at 4 years. Higher cumulative exposure across pregnancy was associated with higher Attention Problems and ADHD Problems scores at ages 2 and 3. Findings suggest that prenatal acetaminophen exposure, especially during the second trimester, may be related to problems with attention in early childhood.
Topics: Child; Female; Pregnancy; Humans; Child, Preschool; Infant, Newborn; Infant; Acetaminophen; Prospective Studies; Child Behavior Disorders; Prenatal Exposure Delayed Effects; Mothers; Child Behavior
PubMed: 38199313
DOI: 10.1016/j.ntt.2024.107319 -
Cell Metabolism Jan 2024Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide...
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects one-third of the global population. Understanding the metabolic pathways involved can provide insights into disease progression and treatment. Untargeted metabolomics of livers from mice with early-stage steatosis uncovered decreased methylated metabolites, suggesting altered one-carbon metabolism. The levels of glycine, a central component of one-carbon metabolism, were lower in mice with hepatic steatosis, consistent with clinical evidence. Stable-isotope tracing demonstrated that increased serine synthesis from glycine via reverse serine hydroxymethyltransferase (SHMT) is the underlying cause for decreased glycine in steatotic livers. Consequently, limited glycine availability in steatotic livers impaired glutathione synthesis under acetaminophen-induced oxidative stress, enhancing acute hepatotoxicity. Glycine supplementation or hepatocyte-specific ablation of the mitochondrial SHMT2 isoform in mice with hepatic steatosis mitigated acetaminophen-induced hepatotoxicity by supporting de novo glutathione synthesis. Thus, early metabolic changes in MASLD that limit glycine availability sensitize mice to xenobiotics even at the reversible stage of this disease.
Topics: Animals; Mice; Acetaminophen; Carbon; Chemical and Drug Induced Liver Injury; Fatty Liver; Glutathione; Glycine; Glycine Hydroxymethyltransferase; Serine
PubMed: 38171331
DOI: 10.1016/j.cmet.2023.12.013 -
Annual Review of Pathology Jan 2024Acetaminophen (APAP) overdose is the clinically most relevant drug hepatotoxicity in western countries, and, because of translational relevance of animal models, APAP is... (Review)
Review
Acetaminophen (APAP) overdose is the clinically most relevant drug hepatotoxicity in western countries, and, because of translational relevance of animal models, APAP is mechanistically the most studied drug. This review covers intracellular signaling events starting with drug metabolism and the central role of mitochondrial dysfunction involving oxidant stress and peroxynitrite. Mitochondria-derived endonucleases trigger nuclear DNA fragmentation, the point of no return for cell death. In addition, adaptive mechanisms that limit cell death are discussed including autophagy, mitochondrial morphology changes, and biogenesis. Extensive evidence supports oncotic necrosis as the mode of cell death; however, a partial overlap with signaling events of apoptosis, ferroptosis, and pyroptosis is the basis for controversial discussions. Furthermore, an update on sterile inflammation in injury and repair with activation of Kupffer cells, monocyte-derived macrophages, and neutrophils is provided. Understanding these mechanisms of cell death led to discovery of -acetylcysteine and recently fomepizole as effective antidotes against APAP toxicity.
Topics: Humans; Animals; Acetaminophen; Chemical and Drug Induced Liver Injury; Apoptosis; Acetylcysteine; Autophagy
PubMed: 38265880
DOI: 10.1146/annurev-pathmechdis-051122-094016 -
Dental Clinics of North America Jan 2024During the development of multimodal pain management protocols, practitioners need to consider the potential risks each treatment modality inherently carries in order to... (Review)
Review
During the development of multimodal pain management protocols, practitioners need to consider the potential risks each treatment modality inherently carries in order to prevent or diminish harmful outcomes. As an example, the part dentists played in the early stages of the opioid epidemic in the United States of America should serve as a cautionary account. By understanding the roots of this crisis, as practitioners we are better equipped to implement the novel analgesic agents available today to optimize post-operative pain control while minimizing any risk of addiction and harm to our communities. It is therefore critical that our colleagues understand the variety of accessible options for pain management to assure that our profession is able to seek adequate and sustainable relief for our post-operative patients. This article will go in depth to explain the analgesic tools practitioners can implement for an effective low-risk protocol, including a combination of NSAIDS and acetaminophen approach, using long-acting local anesthetics such as Exparel, pregabalin, gabapentin, ketamine, dexmedetomidine, and corticosteroids, and enhanced recovery after surgery protocols.
Topics: Humans; Pain, Postoperative; Analgesics; Anti-Inflammatory Agents, Non-Steroidal; Pain Management; Acetaminophen; Analgesics, Opioid
PubMed: 37951635
DOI: 10.1016/j.cden.2023.07.003 -
Journal of Pain and Symptom Management Sep 2023Pain is common among cancer patients. The evidence recommends using strong opioids in moderate to severe cancer pain. No conclusive evidence supports the effectiveness... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Pain is common among cancer patients. The evidence recommends using strong opioids in moderate to severe cancer pain. No conclusive evidence supports the effectiveness of adding acetaminophen to patients with cancer pain who are already using this regime.
OBJECTIVES
To assess the analgesic efficacy of acetaminophen in hospitalized cancer patients with moderate to severe pain receiving strong opioids.
METHODS
In this randomized blinded clinical trial, hospitalized cancer patients with moderate or severe acute pain managed with strong opioids were randomized to acetaminophen or placebo. The primary outcome was pain intensity difference between baseline and 48 hours using the Visual Numeric Rating Scales (VNRS). Secondary outcomes included change in morphine equivalent daily dose (MEDD), and patients' perception of improved pain control.
RESULTS
Among 112 randomized patients, 56 patients received placebo, 56 acetaminophen. Mean (standard deviation [SD]) decrease in pain intensity (VNRS) at 48 hours were 2.7 (2.5) and 2.3 (2.3), respectively (95% Confidence Interval (CI) [-0.49; 1.32]; P = 0.37). Mean (SD) change in MEDD was 13.9 (33.0) mg/day and 22.4 (57.7), respectively (95% CI [-9.24; 26.1]; P = 0.35). The proportion of patients perceiving pain control improvement after 48 hours was 82% in the placebo and 80% in the acetaminophen arms (P = 0.81).
CONCLUSION
Among patients with cancer pain on strong opioid regime, acetaminophen may not improve pain control, or decrease total opioid use. These results add to the current evidence available suggesting not to use acetaminophen as an adjuvant for advanced cancer patients with moderate to severe cancer pain who are on strong opioids.
Topics: Humans; Acetaminophen; Analgesics, Opioid; Analgesics, Non-Narcotic; Cancer Pain; Morphine; Acute Pain; Neoplasms; Double-Blind Method; Pain, Postoperative
PubMed: 37207788
DOI: 10.1016/j.jpainsymman.2023.05.002 -
Nature Communications Mar 2024Liver injury is a core pathological process in the majority of liver diseases, yet the genetic factors predisposing individuals to its initiation and progression remain...
Liver injury is a core pathological process in the majority of liver diseases, yet the genetic factors predisposing individuals to its initiation and progression remain poorly understood. Here we show that asialoglycoprotein receptor 1 (ASGR1), a lectin specifically expressed in the liver, is downregulated in patients with liver fibrosis or cirrhosis and male mice with liver injury. ASGR1 deficiency exacerbates while its overexpression mitigates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice. Mechanistically, ASGR1 binds to an endoplasmic reticulum stress mediator GP73 and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels and promotes the interaction between GP73 and BIP to activate endoplasmic reticulum stress, leading to liver injury. Neutralization of GP73 not only attenuates ASGR1 deficiency-induced liver injuries but also improves survival in mice received a lethal dose of acetaminophen. Collectively, these findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target for the treatment of liver injury.
Topics: Animals; Humans; Male; Mice; Acetaminophen; Asialoglycoprotein Receptor; Endoplasmic Reticulum Stress; Fibrosis; Liver; Liver Cirrhosis
PubMed: 38459023
DOI: 10.1038/s41467-024-46135-9