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Background About 500 drug poisoning deaths involving paracetamol (acetaminophen) occur every year in England and Wales. To reduce the number of deaths, regulations were introduced in 1998 to restrict the sale of paracetamol. In this paper, we evaluate the impact of these regulations. [ABSTRACT FROM PUBLISHER]

Background Rituximab is an anti-CD20 chimeric monoclonal antibody that depletes pre-plasma B cells. It is used in paediatric rheumatology for conditions including juvenile systemic lupus erythematosus (jSLE), juvenile dermatomyositis (JDM), vasculitides and refractory juvenile idiopathic arthritis (JIA). We aim to describe the cohort of patients treated with rituximab in the Scottish Paediatric and Adolescent Rheumatology Network (SPARN) in a 5-year period, and assess the need for a network guideline. Methods A review of paper and electronic case records. Patients seen within the SPARN network who received Rituximab between 2014 and 2018 were included. Results Vasculitis Rituximab was given to 16 patients in 5 different SPARN centres between 2014 and 2018. Male: Female ratio was 1:4.3. Mean age at first dose of rituximab was 12.75 years. Mean disease duration pre rituximab was 1 year. 8 (50%) patients had jSLE, 7 multisystem and 1 isolated lupus nephritis. 3 had ANCA-positive vasculitis and 5 had other conditions. (1 had RF+ve JIA; 1 severe panuveitis; 1 had an unspecified autoinflammatory condition; 1 had COPA syndrome with severe interstitial lung disease and 1 had autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Documentation of pre-rituximab checks was poor. Baseline bloods were done in all 16 patients. 11 patients had lymphocyte subsets and 13 immunoglobulins documented. Disease-specific antibodies were measured in all patients in whom applicable (11). 11 had a chest x-ray prior to rituximab. In 9 cases a pre-rituximab pregnancy test was indicated: none were documented. In only 3 patients was a pre-rituximab history of recent infections documented. In 8 patients a discussion regarding treatment risks and benefits was documented. Post-infusion lymphocyte subset monitoring was variable but documented in 15. 1 patient was never B cell deplete. 9 never fully reconstituted. RTX dose information was available for 14. All received doses of 750mg/m2 with 6 having the dose capped at 1g. Dose frequency information was available for all. The majority (9) received 2 doses. Of the rest, 1 patient received a single dose. 3 received 3 doses, 2 had 4 and 1 had 5. All patients in whom information was available, received pre-medication with paracetamol, chlorphenamine and methylprednisolone (n = 14). 4 patients had side effects noted (rash/itch in 1, anaphylaxis in 1, facial flushing in 1 and post-infusion infection in 1). Clinical response was clearly documented in 8 patients, 7 of whom showed clinical improvement (2 had systemic jSLE, 2 had ANCA +ve vasculitis, 1 had isolated lupus nephritis, 1 had COPA syndrome and 1 had RF+ JIA). Conclusion Rituximab is used for a range of conditions and in a number of centres within SPARN. This review highlights variation in and poor documentation of pre-rituximab discussions and investigations, prescribing, monitoring and response. A SPARN rituximab protocol is being developed to address this. Conflicts of Interest The authors declare no conflicts of interest. [ABSTRACT FROM AUTHOR]

Why you should read this article: • To enhance your knowledge of the prevalence and pathophysiology of snake bites • To enable you to recognise the signs and symptoms of snake bites and how to determine their severity • To understand the steps that need to be taken when assessing and managing patients with a suspected or confirmed snake bite Snake bites are a relatively rare presentation to emergency departments in the Western world. In the UK, there were 510 cases of snake bites between 2004 and 2010. However, it is important that nurses are aware of how to assess and manage these presentations and understand the importance of ascertaining information on factors such as the type of snake involved and how long the snake was biting the patient for. This article uses a case study to discuss the assessment and management of snake bites, and provides information on the steps nurses should take to manage patients presenting with a snake bite. [ABSTRACT FROM AUTHOR]

Aims: Toxicity in paracetamol overdose with opioid co‐ingestion is poorly understood. We compared outcomes in both paracetamol‐only and paracetamol–opioid overdoses to determine whether toxicity differed significantly between the groups, and to assess the utility of the ratio of measured plasma paracetamol concentration relative to the 4‐hour nomogram‐adjusted level (APAPpl/APAPt). Methods: We conducted a retrospective observational study of all patients (n = 1159) presenting to 2 large UK hospitals between 2005 and 2013 with acute single‐dose ingestion paracetamol overdose, with (n = 221) or without (n = 938) opioid co‐ingestion. Adverse outcomes included biomarkers of hepatotoxicity and the need for extended treatment. Several outcomes were assessed in relation to the APAPpl/APAPt ratio. Results: Median ingested dose of paracetamol was low in both groups (10 g). Statistical comparison of the median APAPpl/APAPt ratios showed a significant difference (0.65 vs. 0.56 for the paracetamol‐only and paracetamol–opioid groups respectively, P =.0329). Although there was a trend towards a lower risk of predefined toxic outcomes with opioid co‐ingestion, statistical analysis did not show a significant difference, with outcomes for the paracetamol‐only and paracetamol–opioid groups including the following: alanine transaminase >2× upper limit of normal, 7.7 vs. 5.7% (P =.6480); alanine transaminase >1000 IU/L, 2.4 vs. 0% (P =.2145); international normalised ratio > 1.3, 8.6 vs. 4.4% (P =.2774); and transfer to tertiary liver unit, 0.2 vs. 0% (P nonsignificant). Conclusion: Our study does not support a change in current clinical practise beyond standard testing at 4 hours or longer post ingestion for mixed low dose paracetamol–opioid overdose. [ABSTRACT FROM AUTHOR]

In 1998 the United Kingdom limited the availability of paracetamol sold over-the-counter in an effort to reduce serious paracetamol overdose. Since that time debate has continued on the effectiveness of this policy in reducing what is acknowledged as a major public health problem. This commentary reviews recent publications on this topic which suggest that the effects were small. Reasons for this are discussed using data from recent work. [ABSTRACT FROM AUTHOR]

Paracetamol is used widely in pediatrics because it has a high drug safety when used in therapeutic dosages. In case of overdose the majority of paracetamol is metabolized to N-acetyl-p-benzoquinone imine (NAPQI), which is responsible for the severe toxic effects. The covalent connection between NAPQI and hepatic proteins leads to hepatocellular damage and possibly to severe liver failure. The antidote for paracetamol is N-acetylcysteine (NAC). It is a precursor of glutathione and aids to fill glutathione stores. The Rumack-Matthew nomogram should be used to decide on antidote treatment. Pediatric drug metabolism differs from adult metabolism. Children have a larger liver size compared to their body weight than adults, resulting in a higher metabolism rate. Young children seem to be less sensitive to acute intoxication than adults. One hypothesis to explain the lower rate refers to the larger liver size. The acute toxic dosage for children is more than 200 mg/kg body weight. There seems to be a global increase in accidental pediatric paracetamol overdose. Governmental websites of various European Union (EU) countries were searched for legal information on paracetamol availability in pharmacies and non-pharmacy stores. Various EU countries permit prescription-free sales of paracetamol in pharmacies and non-pharmacy stores. In Sweden paracetamol 500 mg may be sold in both pharmacies and non-pharmacies in a maximum pack size of 20 units. In the United Kingdom (UK) paracetamol 500 mg is listed in the general sales list with a maximum pack size of 30 effervescent tablets or 16 tablets. In Ireland paracetamol 500 mg may be sold in a maximum pack size of 12 units in a non-pharmacy. In the Netherlands paracetamol 500 mg is legal to be sold in a maximum pack size of 50 units in a drug store and with a maximum of 20 units in any other non-pharmacy. Several countries in the European Union are permitted to offer paracetamol prescription-free in pharmacies and non-pharmacy stores without legal guidance on the storage position within the store. Further research is needed to investigate whether paracetamol is located directly accessible to young children within the stores in EU countries which permit prescription-free sales of paracetamol. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate reported ingested dose of paracetamol as a risk assessment tool in acute paracetamol overdose. Methods: Data was retrospectively obtained from a clinical toxicology database linked to one Australian and two United Kingdom hospitals. Plasma paracetamol concentrations (PPCs) of adult patients presenting with acute single ingestion, non-staggered paracetamol deliberate self-poisoning between 2006 and 2012 were recorded and plotted on a treatment nomogram to determine accuracy of reported dose ingested as an indicator for antidotal treatment. PPC plotted on a treatment nomogram with a line intersecting a 4-h concentration of 100 mg/L [667 μmol/L] was considered an indication for antidotal treatment in the UK; the corresponding Australasian population utilised a line intersecting 150 mg/L [1000 μmol/L]. Results: Of 1246 patients, 65.7 % were female and 88 % were from the UK. Fifty-two percent of patients reporting ingestion of ≥8 g paracetamol had a PPC above the 100 mg/L treatment line; PPV 52 % [95 % confidence interval (CI) 49 %, 55 %], sensitivity 81 % [95 %CI 78 %, 85 %]. Forty-four of patients reporting percent ingestion of ≥10 g had a PPC above the 150 mg/L treatment line; PPV 44 % [95 % CI 41 %, 49 %], sensitivity 85 % [95 % CI 78 %, 89 %], 72 % of patients reporting ingestion of ≥16 g had a PPC above the 100 mg/L treatment line; PPV 72 % [95% CI 67 %, 77 %], sensitivity 50 % [95 % CI 45 %, 54 %]. Overall, there was moderate correlation ( R = 0.58) between reported paracetamol dose ingested and extrapolated 4-h PPC. Conclusions: There is a positive correlation between reported ingested dose of paracetamol and subsequent chance of a PPC being above a defined treatment line; however, ingested dose of paracetamol alone is a poor risk assessment tool in accurately determining need for treatment with an antidote. [ABSTRACT FROM AUTHOR]

Background. On 3 September 2012, the licensed indication for acetylcysteine was changed in the United Kingdom (UK) so that all patients with a plasma paracetamol concentration above a '100 mg/L' (4 h post ingestion) nomogram treatment line after an acute paracetamol (acetaminophen) overdose should be treated. This is a lower threshold than that used in the United States, Canada, Australia, and New Zealand. Here we report the impact of this change in the UK on the management of patients with acute overdose in different paracetamol concentration ranges. Methods. This is a cohort study, consisting of a retrospective analysis conducted on prospectively collected audit data in three UK hospitals. Following appropriate ethical and data protection authority approval, data for patients presenting within 24 h of an acute timed single paracetamol overdose were extracted. Numbers of admissions and use of antidote in relation to different paracetamol concentration bands (< 100 mg/L; 100-149 mg/L; 150-199 mg/L; and ≥ 200 mg/L at 4 h) were analyzed for one-year periods before and after the change. Results. Comparing the year before with the year after the change, there was no change in the numbers of patients presenting to hospital within 24 h of acute timed paracetamol overdose (1246 before and 1251 after), but more patients were admitted (759 before and 849 after) and treated with acetylcysteine (389 before and 539 after). Of the 150 additional patients treated with acetylcysteine in the year following the change, 114 (76%, 95% CI: 68.4-82.6) were in the 100-149 group and 9 (6.0%, 95% CI: 2.8-11.1) in the 150-199 group. Conclusions. Changes to national guidelines for managing paracetamol poisoning in the UK have increased the numbers of patients with acute overdose treated with acetylcysteine, with most additional treatments occurring in patients in the 100-149 mg/L dose range, a group at low risk of hepatotoxicity and higher risk of adverse reactions. [ABSTRACT FROM AUTHOR]

Purpose: Paracetamol (acetaminophen, APAP) overdose is often fatal due to progressive and irreversible hepatic necrosis. The aim of this work was to design Andrographolide (AG) loaded nanoparticles to prevent similar hepatic necrosis. Methods: Functionalized AG-loaded PLGA nanoparticles carrying different densities of heparin were prepared following a facile emulsion solvent evaporation technique. Nanoparticle morphology, loading and release kinetics were studied. Hepatic localization of the nanoparticles was investigated in both normal and APAP damaged conditions using FITC fluorescent probe. Different serum parameters and liver histopathology were further examined as indicators of hepatic condition before and after treatment. Result: A collection of heparin functionalized AG-loaded PLGA nanoparticles were designed. Low amount of heparin on the particle surface could rapidly localize the nanoparticles up to the liver. The new functionalized AG nanoparticles affect efficient hepatoprotection in experimental mouse APAP overdose conditions. AG nanoparticle hepatoprotection was due to the rapid regeneration of antioxidant capacity and hepatic GSH store. Conclusions: Engineered nanoparticles loaded with AG provided a fast protection in APAP induced acute liver failure. [ABSTRACT FROM AUTHOR]

smith c.j., sammons h.m., fakis a. & conroy s. (2013) A prospective study to assess the palatability of analgesic medicines in children. Journal of Advanced Nursing 69(3), 655-663. doi: 10.1111/j.1365-2648.2012.06050.x Abstract Aim. This study examined children's opinions on the taste of three analgesic medicines: paracetamol, ibuprofen and codeine. Background. Many medicines for children are unpleasant and unacceptable. Research has shown that children's taste preferences differ to adults, in whom palatability is often tested. Little British research exists on children's opinions on the palatability of medicines. This study aimed to address this gap in knowledge. Design. Prospective observational study. Methods. Between May-September 2008, hospital inpatients aged 5-16 years rated the taste of required analgesics on a 100-mm visual analogue scale. This incorporated a 5-point facial hedonic scale. They were also asked their favourite flavour and colour for a medicine. Results. A total of 159 children took part. Eighty-five males (53·5%) and 74 females (46·5%). The median age was 8 years (Inter-quartile range 6-11). The taste of ibuprofen was significantly preferred to paracetamol or codeine. Significant differences were observed depending if the medicine rated was taken first or second (for example pre-medication with paracetamol and ibuprofen). Younger children (5-8 years) were more likely to choose the extremes of the scale when grading than older children were. Preferred flavours on questioning were strawberry 44% and banana 17%. Favourite colours were pink 25·8% and red 20·8%, with girls more likely to choose pink and boys blue. Conclusion. Ibuprofen was the most palatable analgesic medicine tested. Children reported they preferred fruit flavours and colour was sex dependent. Nurses when administering two medicines together should consider giving the least palatable first, for example paracetamol before ibuprofen for pre-medication. [ABSTRACT FROM AUTHOR]

The United Kingdom's Medicines and Healthcare Products Regulatory Agency (MHRA) modified the indications for N-acetylcysteine therapy of acetaminophen (paracetamol) overdose in September 2012. The new treatment threshold line was lowered to 100 mg/L (662 μmol/L) for a 4 hours acetaminophen concentration from the previous 200 mg/L (1325 μmol/L). This decision has the potential to substantially increase overall costs associated with acetaminophen overdose with unclear benefits from a marginal increase in patients protected from hepatotoxicity, fulminant hepatic failure, death, or transplant. Changing the treatment threshold for acetaminophen overdose also implies that ingestion amounts previously thought not to require acetaminophen concentration measurements would need to be revised. As a result, more individuals will be sent to hospitals in order that everyone with a predicted 4 hours concentration above the 100 mg/L line will have concentrations measured and potentially be treated with N-acetylcysteine. Before others consider adopting this new treatment guideline, formal cost-effectiveness analyses need to be performed to define the appropriate thresholds for referral and treatment. [ABSTRACT FROM AUTHOR]

Information on dietary supplements, medications, and other xenobiotics in epidemiologic surveys is usually obtained from questionnaires and is subject to recall and reporting biases. The authors used metabolite data obtained from hydrogen-1 (or proton) nuclear magnetic resonance (1H NMR) analysis of human urine specimens from the International Study of Macro-/Micro-Nutrients and Blood Pressure (INTERMAP Study) to validate self-reported analgesic use. Metabolic profiling of two 24-hour urine specimens per individual was carried out for 4,630 participants aged 40–59 years from 17 population samples in Japan, China, the United Kingdom, and the United States (data collection, 1996–1999). 1H NMR-detected acetaminophen and ibuprofen use was low (∼4%) among East Asian population samples and higher (>16%) in Western population samples. In a comparison of self-reported acetaminophen and ibuprofen use with 1H NMR-detected acetaminophen and ibuprofen metabolites among 496 participants from Chicago, Illinois, and Belfast, Northern Ireland, the overall rate of concordance was 81%–84%; the rate of underreporting was 15%–17%; and the rate of underdetection was approximately 1%. Comparison of self-reported unspecified analgesic use with 1H NMR-detected acetaminophen and ibuprofen metabolites among 2,660 Western INTERMAP participants revealed similar levels of concordance and underreporting. Screening for urinary metabolites of acetaminophen and ibuprofen improved the accuracy of exposure information. This approach has the potential to reduce recall bias and other biases in epidemiologic studies for a range of substances, including pharmaceuticals, dietary supplements, and foods. [ABSTRACT FROM PUBLISHER]

Background: Paracetamol (acetaminophen) is the most common self-poisoning agent in the UK and a leading cause of fatal hepatotoxicity. Following legislation in 1998 to limit pack sizes, beneficial effects on paracetamol-related mortality and morbidity were reported in England. However, there are still over 100 deaths a year and evidence of breaches of sales guidelines.Aim: To investigate characteristics of people taking larger paracetamol overdoses and compliance with sales guidelines, to inform possible further initiatives to reduce paracetamol fatalities.Design and methods: Interview study of 60 general hospital patients who took overdoses of over 16 paracetamol tablets (8 g).Results: Half of all paracetamol overdoses involved over 16 tablets. Patients were predominantly young (three-quarters aged 16–40 years) and female (58.3%); over half (53.3%) had taken a previous paracetamol overdose. Three-quarters said they wanted to die. Half took the overdose within an hour of first thinking of it, half (53.3%) took tablets already in the home and 58.3% bought tablets specifically for the overdose. Ten people tried to buy more than 32 tablets in one transaction; four succeeded. Most knew that a paracetamol overdose could cause death or permanent damage (88.3%) and harm the liver (80.0%) but 70.0% thought they would lose consciousness. Warnings on packs had little deterrent effect. Media and internet influences were identified. Patients chose paracetamol because it was cheap and easily available.Conclusions: Further measures to reduce breaches of sales guidelines and the dangers of paracetamol overdose are required. Media and internet site producers should follow guidelines on reporting suicide. [ABSTRACT FROM PUBLISHER]

Objective To evaluate the evidence surrounding the use of combinations of paracetamol and ibuprofen in the treatment of fever. Design Systematic narrative review of randomised controlled trials using the UK Economic and Social Research Council guidance on the conduct of narrative synthesis. Setting Inpatient, outpatient and home care. Patients Children with fever. Main outcome measures The effect of combination treatments of paracetamol and ibuprofen on fever and comfort, and identification of side effects. Results Seven studies were identified, six of which provided useful data for the evaluation of the effect of treatment on temperature. Overall these studies showed limited benefit from the combined treatment until around 4 h, after which there was a statistically but only marginally clinically significant benefit. Two studies contained data directly relating to comfort; these suggest a marginal benefit from the combined treatment, but the clinical significance of this was limited. There was no evidence of greater side effects or toxicities associated with the combined treatment. However, it is important to note that these studies were small, short term, and not conducted in the normal setting in which these treatments are given. Conclusions There is little evidence of any benefit or harm from the combined treatment compared with the use of each drug alone. In the absence of such benefit, there is little to recommend the unnecessary use of polypharmaceutical methods to treat a symptom that does not require treatment, when effective monotherapies exist. [ABSTRACT FROM AUTHOR]

Background: In order to reduce fatal self-poisoning legislation was introduced in the UK in 1998 to restrict pack sizes of paracetamol sold in pharmacies (maximum 32 tablets) and non-pharmacy outlets (maximum 16 tablets), and in Ireland in 2001, but with smaller maximum pack sizes (24 and 12 tablets). Our aim was to determine whether this resulted in smaller overdoses of paracetamol in Ireland compared with the UK. Methods: We used data on general hospital presentations for non-fatal self-harm for 2002 - 2007 from the Multicentre Study of Self-harm in England (six hospitals), and from the National Registry of Deliberate Self-harm in Ireland. We compared sizes of overdoses of paracetamol in the two settings. Results: There were clear peaks in numbers of non-fatal overdoses, associated with maximum pack sizes of paracetamol in pharmacy and non-pharmacy outlets in both England and Ireland. Significantly more pack equivalents (based on maximum non-pharmacy pack sizes) were used in overdoses in Ireland (mean 2.63, 95% CI 2.57-2.69) compared with England (2.07, 95% CI 2.03-2.10). The overall size of overdoses did not differ significantly between England (median 22, interquartile range (IQR) 15-32) and Ireland (median 24, IQR 12-36). Conclusions: The difference in paracetamol pack size legislation between England and Ireland does not appear to have resulted in a major difference in sizes of overdoses. This is because more pack equivalents are taken in overdoses in Ireland, possibly reflecting differing enforcement of sales advice. Differences in access to clinical services may also be relevant. [ABSTRACT FROM AUTHOR]

Paracetamol (acetaminophen) is one of the most commonly taken drugs in overdose in many areas of the world, and the most common cause of acute liver failure in both the UK and USA. Paracetamol poisoning can result in lactic acidosis in two different scenarios. First, early in the course of poisoning and before the onset of hepatotoxicity in patients with massive ingestion; a lactic acidosis is usually associated with coma. Experimental evidence from studies in whole animals, perfused liver slices and cell cultures has shown that the toxic metabolite of paracetamol, N-acetyl-p-benzo-quinone imine, inhibits electron transfer in the mitochondrial respiratory chain and thus inhibits aerobic respiration. This occurs only at very high concentrations of paracetamol, and precedes cellular injury by several hours. The second scenario in which lactic acidosis can occur is later in the course of paracetamol poisoning as a consequence of established liver failure. In these patients lactate is elevated primarily because of reduced hepatic clearance, but in shocked patients there may also be a contribution of peripheral anaerobic respiration because of tissue hypoperfusion. In patients admitted to a liver unit with paracetamol hepatotoxicity, the post-resuscitation arterial lactate concentration has been shown to be a strong predictor of mortality, and is included in the modified King's College criteria for consideration of liver transplantation. We would therefore recommend that post-resuscitation lactate is measured in all patients with a severe paracetamol overdose resulting in either reduced conscious level or hepatic failure. [ABSTRACT FROM AUTHOR]

Paracetamol overdose (POD) is a major cause of acute liver failure (ALF) requiring liver transplantation in the United Kingdom. To characterize the early and late outcome after orthotopic liver transplantation (OLT) for POD in the Scottish Liver Transplant Unit over a 14-year period (1992–2006). Data were obtained from a prospective database combined with case-note review. Of 127 liver transplants performed for ALF, 44 were for POD. The median age was 30 (range 18–51). In 18 patients (63.7%), POD was associated with alcohol/other drugs, nine (20.5%) had a staggered overdose and four patients (9.1%) accidentally overdosed. Nineteen patients (43.2%) had a history of previous overdose/psychiatric illness. Post-transplant mortality during the index admission was 30% (13 patients), whilst five patients died during follow-up. The actuarial 5-year patient survival was 54.5%, whilst graft survival was 49.5%. Some 23% of the patients were re-transplanted: primary nonfunction (1), hepatic artery thrombosis (3) and chronic rejection (2). Three patients had a subsequent transplant; three patients had two further transplants. Nine patients (35%) continue to have social/psychiatric issues. OLT for POD is associated with significant early and late morbidity and mortality. A multidisciplinary approach is required to identify the suitable candidates, in whom transplantation should be pursued promptly. [ABSTRACT FROM AUTHOR]

Paracetamol (acetaminophen) is the most common drug taken in overdose in the UK, accounting for 48% of poisoning admissions to hospital and being involved in an estimated 100-200 deaths per year. In 1998, the UK government introduced legislation that reduced the maximum pack size of all non-effervescent tablets and capsules containing aspirin (acetylsalicylic acid) or paracetamol that can be sold or supplied from outlets other than registered pharmacies from 25 to 16 tablets or capsules. This article reviews the literature to determine the effectiveness of the legislation, focusing specifically on paracetamol poisoning. Seventeen studies on this subject were identified. Three studies found reductions in mortality rates; one study found an increase in mortality rates, while one found an initial reduction followed by an eventual increase; three found no significant difference in mortality rates before and after introduction of the legislation. Five studies found reductions in admissions to liver units, three of these finding a reduction in liver transplantation rates; two further studies found no change in liver function tests and rates of paracetamol-induced acute liver injury or failure. Four studies found a sustained decrease in hospital admissions, while two found an initial decrease followed by an eventual increase. One study found a decline in admissions for paracetamol poisoning and an increase in admissions for non-paracetamol poisoning. Sales data are conflicting, with two studies finding no significant difference in paracetamol sales before and after the introduction of the legislation and one reporting a decline. The severity of overdose appears to have decreased since the maximum permitted packet size was reduced, with five studies reporting a reduction in the number of severe overdoses (measured by numbers of tablets ingested, serum paracetamol concentrations and usage of antidotes). Only two studies reported an increase in the number of severe overdoses.Paracetamol-associated mortality rates, admissions to liver units/liver transplants, hospital admissions and the severity of paracetamol overdose appear to have been decreasing since 1998. However, one study showed that the reductions in mortality and hospital admissions began in 1997; therefore, the contribution of the 1998 legislation to the observed changes is unclear. Most of the studies are based on short-term follow-up so it is difficult to draw any conclusions regarding long-term trends. Many of the studies were also restricted to relatively small areas of the UK; this, combined with a variety of outcome measures, makes it difficult to distinguish any conclusive trends. The studies also suffer from a lack of comparison and control groups. Some studies do not clearly differentiate between the paracetamol preparations covered by the legislation and those not. The limited number of studies to date, combined with a variety of outcome measures, make it difficult to determine with accuracy whether or not the legislation has been a success. More long-term studies are needed to fully assess the impact of the legislation. [ABSTRACT FROM AUTHOR]

Case-crossover and case-series analyses are 2 epidemiologic approaches that can be used to evaluate the association of exposures with acute events. Using a primary care database from the United Kingdom and these 2 statistical approaches, the authors investigated the impact of using benzodiazepines, nonbenzodiazepine hypnotics, beta-blockers, selective serotonin reuptake inhibitors, tricyclic antidepressants, opioids, and antihistamines on the risk of motor vehicle crashes in 1986–2004. For 49,821 individuals aged 18–74 years, involvement in a motor vehicle crash was documented. The outcome of the case-crossover analyses varied according to the choice of control period, so the case-series approach was preferred. The first 4 weeks of treatment with a combined acetaminophen and opioid preparation was associated with an increased risk of motor vehicle crash (incidence rate ratio = 2.06, 99% confidence interval: 1.84, 2.32), as was use of an opioid alone (incidence rate ratio = 1.70, 99% confidence interval: 1.39, 2.08) and benzodiazepines (incidence rate ratio = 1.94, 99% confidence interval: 1.62, 2.32). Use of selective serotonin reuptake inhibitors, nonbenzodiazepine hypnotics, and antihistamines for more than 4 weeks was associated with motor vehicle crash, but shorter term use was not. The results obtained are broadly consistent with those from well-designed case-control studies and demonstrate how case-only techniques optimize the use of routinely collected data for epidemiologic studies. [ABSTRACT FROM AUTHOR]