Trends in hepatic injury associated with unintentional overdose of paracetamol (Acetaminophen) in products with and without opioid: An analysis using the national Poison Data System of the American Association of Poison Control Centers, 2000-7
ABSTRACT Unintended hepatic injury associated with the use of paracetamol (acetaminophen)-containing products has been growing. Objective: The aim of the study was to seek a better understanding of the causes of this observation in order to evaluate the potential impact of proposed preventive measures.
Retrospective analysis of a large database containing prospectively collected patient exposure data, clinical symptomatology and outcome.
The National Poison Data System database for 2000-7 involving exposures to paracetamol and an opioid was obtained and analysed. This dataset was limited to non-suicidal cases in patients 13 years of age and older. For comparison, the parallel, mutually exclusive dataset involving exposures to one or more non-opioid containing paracetamol products was analysed. Outcome Measure: Trends in the numbers of patients exposed, treated, and mildly and severely injured were obtained and compared with each other and with trends calculated from publicly available data on sales and population. The association of injury with the number of paracetamol-containing products and the reason for taking them were also assessed.
Comparators: During the study period, the US population of those 15 years of age and over rose 8.5%; all pharmaceutical-related calls to all US poison centres rose 25%. For the 8-year period from 2001 to 2008, sales of over-the-counter paracetamol products rose 5% (single-ingredient products fell 3%; paracetamol-containing combination cough and cold products rose 11%) and prescription paracetamol combination products rose 67%. Opioids with paracetamol: A total of 119 731 cases were identified, increasing 70% over the period. The exposure merited acetylcysteine treatment in 8995 cases (252% increase). In total, 2729 patients (2.3%) experienced some hepatic injury (500% increase). Minor injuries rose faster than severe injuries (833% vs 280%) and most injuries (73.0%) were from overuse of a single combination product only, but the injury rate increased with use of more than one paracetamol-containing product. Abuse and misuse accounted for 34% of cases but 58% of the severe injuries. Paracetamol without opioid: A total of 126 830 cases were identified, increasing 44%, and 15 706 cases merited acetylcysteine (70% increase). A total of 4674 patients (3.7%) experienced some hepatic injury (134% increase). [corrected] Use of more than one non-opioid paracetamol product occurred in 7.3% of patients and was associated with a lower injury rate.
Hepatic injury associated with paracetamol use is increasing significantly faster than population, paracetamol product sales and poison centre use. This suggests a growing portion of consumers is self-dosing paracetamol beyond the toxic threshold. This is true for paracetamol with and without opioids, but the increase in hepatic injury is greater when paracetamol is taken with an opioid. This disproportionate rise is greatest with misuse and abuse of paracetamol products in combination with opioids. Increasing self-dosage of the opioid combination products for the opioid effect is likely to result in more cases of toxic exposure to paracetamol. In contrast, cases of exposure to paracetamol-containing cough and cold products are underrepresented among those injured. In the absence of opioid-containing products, consumption of more than one paracetamol-containing product did not contribute to injury. Efforts to modulate unintentional paracetamol-related hepatic injury should consider these associations.
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ABSTRACT: Paracetamol (acetaminophen) overdose remains the leading cause of death or transplantation due to acute liver failure in many parts of the world. Acetylcysteine has long been recognized as an effective antidote, via oral or intravenous administration, minimizing the risk and severity of acute liver injury if administered sufficiently early after a paracetamol overdose. Despite this, its mechanisms of action remain obscure, and there is uncertainty regarding the optimal dose and duration of treatment. The intravenous infusion protocol was originally developed as a three-step loading regimen; it causes very high early peak plasma concentrations of acetylcysteine whereas the later maintenance infusion is associated with much lower concentrations. This pharmacokinetic profile is associated with two particular concerns: a high rate of occurrence of adverse effects that occur after the initial loading infusion, and the possibility that the maintenance phase of treatment might deliver too low a dose of acetylcysteine for optimum protection against liver injury. Recently described novel administration regimens offer different rates of intravenous acetylcysteine administration in both the loading and maintenance phases. These alternative regimens appear to be well tolerated in small patient groups, but too few clinical data are available to evaluate their comparative efficacy in preventing paracetamol-induced liver injury.12/2012; 3(6):305-15. DOI:10.1177/2042098612464265
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ABSTRACT: There is no general consensus among clinicians on the superior route or duration of treatment with N-acetylcysteine (NAC) for acute acetaminophen (APAP) poisoning, and head-to-head studies comparing intravenous (IV) and oral NAC have not been done. Recent 20-hour IV NAC protocol failures in the United States prompted some to question its safety. Our objective was to determine if treatment with the 20-hour IV NAC protocol results in clinical outcomes different from the longer 36-hour oral or 72-hour oral NAC protocols in cases of acute APAP poisoning. We performed a retrospective analysis of all consecutive cases of acute APAP overdose where NAC treatment was initiated within 8 hours of ingestion between January 1, 2002, and December 31, 2007. Outcomes were survival, transplant, and death; secondary outcomes were based on King's College Criteria; interrater reliability was calculated with a kappa score. Out of 4642 cases of APAP overdose, 795 met study inclusion criteria: 213 were treated with 20-hour IV protocol, 213 with the 36-hour oral protocol, and 369 with the 72-hour oral protocol. The mean age in these groups was 25 years [95% confidence interval (CI): 22-26], 26 years (95%CI: 23-29), and 27 years (95%CI: 25-28), respectively. The mean 4-hour APAP concentration was 199 μg/mL (95%CI: 188-211), 174 μg/mL (95%CI: 164-184), and 205 μg/mL (95%CI: 195-216), respectively. No cases of transplant or death occurred, and secondary outcomes were rare. When administered within 8 hours of acute APAP poisoning, the 20-hour IV treatment protocol was as effective as the longer 36-hour oral and 72-hour oral treatment protocols. Further study is needed to determine outcome differences between IV and oral NAC when treatment is initiated >8 hours after overdose or in cases of coingestion with other drugs.American journal of therapeutics 01/2013; 20(1):37-40. DOI:10.1097/MJT.0b013e318250f829 · 1.13 Impact Factor
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ABSTRACT: Acetaminophen poisoning is the most frequent cause of acute hepatic failure in the US. Toxicity requires reductive metabolism of acetaminophen, primarily via CYP2E1. Liquid acetaminophen preparations contain propylene glycol, a common excipient that has been shown to reduce hepatocellular injury in vitro and in rodents. Children are less susceptible to acetaminophen toxicity for unclear reasons. We conducted a pharmacokinetic single-blinded crossover study of 15 healthy adult volunteers comparing the CYP2E1 and conjugative metabolism of a 15 mg/kg dose of liquid versus solid preparations of acetaminophen. Measured AUC's for the CYP2E1 metabolites were 16-17% lower and extrapolated AUC's were 25-28% lower in the liquid formulation arm while there was no difference in conjugative metabolite production. The formation rate constants for reductive metabolites were equivalent between solid and liquid formulations indicating that enzyme inhibition was competitive. Propylene glycol, an established CYP2E1 competitive antagonist, was detected in the liquid formulation but not solid formulation arm. Since children tend to ingest liquid preparations, the protective effect of this excipient could explain their decreased susceptibility to acetaminophen toxicity. A less hepatotoxic formulation of acetaminophen could potentially be developed if co-formulated with a CYP2E1 inhibitor.The Journal of Clinical Pharmacology 04/2013; 53(4). DOI:10.1002/jcph.24 · 2.47 Impact Factor