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Background: Analgesics are used most frequently in fatal and non-fatal medicinal self-poisonings. Knowledge about their relative toxicity in overdose is important for clinicians and regulatory agencies., Methods: Using data for 2005-2012 we investigated case fatality (number of suicides relative to number of non-fatal self-poisonings) of paracetamol, aspirin, codeine, dihydrocodeine, tramadol, paracetamol with codeine (co-codamol), paracetamol with dihydrocodeine (co-dydramol), ibuprofen and co-proxamol (paracetamol plus dextropropoxyphene; withdrawn in the UK in 2008 due to high toxicity). Data on suicides obtained from the Office for National Statistics and on non-fatal self-poisonings from the Multicentre Study of Self-harm in England. Case fatality was estimated for each drug, using paracetamol as the reference category., Results: Compared to paracetamol and based on single drug deaths the case fatality index of dihydrocodeine was considerably elevated (odds ratio (OR) 12.81, 95% Confidence Interval (CI) 10.19-16.12). Case fatality indices for tramadol (OR 4.05, 95% CI 3.38-4.85) and codeine (OR 2.21, 95% CI 1.81-2.70) were also significantly higher than for paracetamol. The results when multiple drug deaths were included produced similar results. The relative toxicity of co-proxamol far exceeded that of the other analgesics., Limitations: Data on fatal self-poisonings were based on national data, whereas those for non-fatal poisonings were based on local data., Conclusions: Dihydrocodeine and tramadol are particularly toxic in overdose and codeine is also relatively toxic. They should be prescribed with caution, particularly to individuals at risk of self-harm., (Copyright © 2019. Published by Elsevier B.V.)

The synthetic opioid propoxyphene was a schedule IV controlled substance with multiple reported health risks before the US Food and Drug Administration issued a request for voluntary market withdrawal in November 2010. The purpose of this study is to investigate the characteristics and occurrences of propoxyphene-related deaths in Florida before and after voluntary market removal. Decedent-level toxicology data from Florida's Medical Examiners Commission was used to compare the temporal, polysubstance use, sociodemographic, and geographic profiles associated with propoxyphene-involved deaths for a pre-withdrawal (November 2008-November 2010) and post-withdrawal (December 2010-December 2012) period. Sensitivity analyses using multiple data sources, including Florida's Prescription Drug Monitoring Program and other states' data, were conducted to examine potential reporting bias. Results showed that the number of propoxyphene-involved deaths declined by 84% from 580 deaths to 92 deaths after market withdrawal. The co-occurrence of other prevalent drugs, such as oxycodone (17.2% to 26.1%, p=0.0422) increased significantly in the post-withdrawal study period. A larger proportion of the propoxyphene-related deaths were reported from South Florida after the withdrawal (28.4% to 56.5%, p<0.0001). No significant changes in age and race/ethnicity were observed. Sensitivity analyses revealed that several deaths occurred in other states after market withdrawal, as recently as 2016. Our findings are consistent with previous studies that propoxyphene was still available after removal from the US market. Continued surveillance is recommended after highly abused opioids are withdrawn from the market due to on-going safety risks., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The Scottish Poisons Information Bureau was established in Edinburgh in September 1963 and shortly afterwards one of the wards of the city's Royal Infirmary was designated a Regional Poisoning Treatment Centre. Both units were soon to be brought under one roof. To mark this 50th anniversary, we review how they built upon a history dating from the early 19th century and highlight their influence on current clinical toxicological practice and the delivery of poisons information. While many centres worldwide seek to improve the care of poisoned patients, the contribution of Edinburgh over the past 50 years has been notable.

Many times at autopsy, on the basis of colour change of the stomach and intestinal mucosa, the forensic pathologist is able to suspect a particular nature of poisoning which leads to conclusive investigation of the case. An intense bluish discolouration of the gastric mucosa owing to capsule shell instead of the content is rarely encountered at autopsy. We report a case of fatal dextropropoxyphene poisoning, where gastric and small intestinal mucosa showed bluish discolouration owing to the gelatine capsule of the drug. Other causes of bluish discolouration of gastrointestinal tract mucosa at autopsy are also discussed.

Background: The analgesic co-proxamol (paracetamol/dextropropoxyphene combination) has been widely involved in fatal poisoning. Concerns about its safety/effectiveness profile and widespread use for suicidal poisoning prompted its withdrawal in the UK in 2005, with partial withdrawal between 2005 and 2007, and full withdrawal in 2008. Our objective in this study was to assess the association between co-proxamol withdrawal and prescribing and deaths in England and Wales in 2005-2010 compared with 1998-2004, including estimation of possible substitution effects by other analgesics., Methods and Findings: We obtained prescribing data from the NHS Health and Social Care Information Centre (England) and Prescribing Services Partneriaeth Cydwasanaethau GIG Cymru (Wales), and mortality data from the Office for National Statistics. We carried out an interrupted time-series analysis of prescribing and deaths (suicide, open verdicts, accidental poisonings) involving single analgesics. The reduction in prescribing of co-proxamol following its withdrawal in 2005 was accompanied by increases in prescribing of several other analgesics (co-codamol, paracetamol, codeine, co-dydramol, tramadol, oxycodone, and morphine) during 2005-2010 compared with 1998-2004. These changes were associated with major reductions in deaths due to poisoning with co-proxamol receiving verdicts of suicide and undetermined cause of -21 deaths (95% CI -34 to -8) per quarter, equating to approximately 500 fewer suicide deaths (-61%) over the 6 years 2005-2010, and -25 deaths (95% CI -38 to -12) per quarter, equating to 600 fewer deaths (-62%) when accidental poisoning deaths were included. There was little observed change in deaths involving other analgesics, apart from an increase in oxycodone poisonings, but numbers were small. Limitations were that the study was based on deaths involving single drugs alone and changes in deaths involving prescribed morphine could not be assessed., Conclusions: During the 6 years following the withdrawal of co-proxamol in the UK, there was a major reduction in poisoning deaths involving this drug, without apparent significant increase in deaths involving other analgesics.

The Medicines and Healthcare products Regulatory Authority (MHRA) is the government body with responsibility for regulating new and existing medicines and medical devices in the United Kingdom. The Yellow Card scheme is a well-established pharmacovigilance system that collects voluntary reports of adverse effects associated with therapeutic drug use. In contrast, data concerning clinical toxicological effects are more poorly characterised. No comparable surveillance processes exist in the United Kingdom or elsewhere in Europe that might allow systematic collection of clinical data and outcomes after drug overdose. Toxicological effects are normally ascertained from individual patient reports or small case series from a few specialised poisons units, so that these data are generally under-represented in post-marketing consideration of risks and benefits. Safety concerns may lead to withdrawal of the Marketing Authorisation or restricted prescribing conditions, which are conveyed to health care professionals by means of safety warnings. These may have a variable impact, and three selected examples are presented to illustrate the complex interaction between drug regulation and clinical toxicology. First, the effects of the withdrawal of rofecoxib in 2004 shows that regulatory responses may reduce the prescribing of drugs across a particular class, and this has resulted in fewer enquiries to Poisons Control Centres regarding all cyclooxygenase-2 selective inhibitors. Secondly, data concerning the impact of safety warnings about antipsychotic medications illustrate that regulatory decisions may have a variable impact due to other factors that influence prescribing, including clinical guidelines, marketing pressures, and lack of alternative safe medications. Finally, the recent withdrawal of co-proxamol serves as an example of how clinical toxicology data can inform the drug regulation process and improve safety by minimising the risk of death associated with overdose. Greater reliance on clinical toxicology data could better inform the drug regulation process, perhaps through coordinated data collection systems that already exist in certain national poisons centres. Routine collection of high quality data concerning the effects of drug overdose could allow a more comprehensive review of risk and benefit by the regulatory authorities.

Background: In early 2005 the UK Committee on Safety of Medicines (CSM) announced gradual withdrawal of the analgesic co-proxamol because of its adverse benefit/safety ratio, especially its use for intentional and accidental fatal poisoning. Prescriptions of co-proxamol were reduced in the 3-year withdrawal phase (2005 to 2007) following the CSM announcement., Aims: To assess the impact of the CSM announcement in January 2005 to withdraw co-proxamol on nonfatal self-poisoning with co-proxamol and other analgesics., Methods: Interrupted time series analysis of general hospital presentations for nonfatal self-poisoning (five hospitals in three centers in England), comparing the 3-year withdrawal period 2005-2007 with 2000-2004., Results: A marked reduction in the number of episodes of nonfatal self-poisoning episodes involving co-proxamol was found following the CSM announcement (an estimated 62% over the period 2005 to 2007 compared to 2000 to 2004). There was no evidence of an increase in nonfatal self-poisoning episodes involving other analgesics (co-codamol, codeine, co-dydramol, dihydrocodeine, and tramadol) in relation to the CSM announcement over the same period, nor a change in the number of all episodes of self-poisoning., Limitations: Data were from three centers only., Conclusions: The impact of the policy appears to have reduced nonfatal self-poisoning with co-proxamol without significant substitution with other analgesics. This finding is in keeping with that for suicide.

Background: Distalgesic, the prescription-only analgesic compound of paracetamol (325 mg) and dextropropoxyphene (32.5 mg) known as co-proxamol in the UK, was withdrawn from the Irish market as of January 2006. This study aimed to evaluate the impact of the withdrawal of distalgesic in terms of intentional drug overdose (IDO) presentations to hospital emergency departments (EDs) nationally., Methods: A total of 42,849 IDO presentations to 37 of the 40 hospitals EDs operating in Ireland in 2003-2008 were recorded according to standardised procedures. Data on sales of paracetamol-containing drugs to retail pharmacies for the period 1998-2008 were obtained from IMS Health., Results: The withdrawal of distalgesic from the Irish market resulted in an immediate reduction in sales to retail pharmacies from 40 million tablets in 2005 to 500,000 tablets in 2006 while there was a 48% increase in sales of other prescription compound analgesics. The rate of IDO presentations to hospital involving distalgesic in 2006-2008 was 84% lower than in the three years before it was withdrawn (10.0 per 100,000). There was a 44% increase in the rate of IDO presentations involving other prescription compound analgesics but the magnitude of this rate increase was five times smaller than the magnitude of the decrease in distalgesic-related IDO presentations. There was a decreasing trend in the rate of presentations involving any paracetamol-containing drug that began in the years before the distalgesic withdrawal., Conclusions: The withdrawal of distalgesic has had positive benefits in terms of IDO presentations to hospital in Ireland and provides evidence supporting the restriction of availability of means as a prevention strategy for suicidal behaviour.

Objective: To assess the effect of the UK Committee on Safety of Medicines' announcement in January 2005 of withdrawal of co-proxamol on analgesic prescribing and poisoning mortality., Design: Interrupted time series analysis for 1998-2007., Setting: England and Wales., Data Sources: Prescribing data from the prescription statistics department of the Information Centre for Health and Social Care (England) and the Prescribing Services Unit, Health Solutions Wales (Wales). Mortality data from the Office for National Statistics., Main Outcome Measures: Prescriptions. Deaths from drug poisoning (suicides, open verdicts, accidental poisonings) involving single analgesics., Results: A steep reduction in prescribing of co-proxamol occurred in the post-intervention period 2005-7, such that number of prescriptions fell by an average of 859 (95% confidence interval 653 to 1065) thousand per quarter, equating to an overall decrease of about 59%. Prescribing of some other analgesics (co-codamol, paracetamol, co-dydramol, and codeine) increased significantly during this time. These changes were associated with a major reduction in deaths involving co-proxamol compared with the expected number of deaths (an estimated 295 fewer suicides and 349 fewer deaths including accidental poisonings), but no statistical evidence for an increase in deaths involving either other analgesics or other drugs., Conclusions: Major changes in prescribing after the announcement of the withdrawal of co-proxamol have had a marked beneficial effect on poisoning mortality involving this drug, with little evidence of substitution of suicide method related to increased prescribing of other analgesics.

Aim: To determine what effect the withdrawal of co-proxamol from the UK market has had on mortality from poisoning in Scotland., Methods: This was a retrospective, observational study of mortality relating to poisoning by single agents in Scotland for the period 2000-2006. Mortality data were obtained from the General Register Office Scotland, and primary care prescribing data from the Information and Statistics Division of the Scottish Executive Health Department., Results: A significant reduction in the proportion of poisoning deaths due to co-proxamol was observed following legislation [mean 2000-2004, 37 deaths (21.8% of total poisoning deaths); 2006, 10 (7.8%); P < 0.0001]. The most significant reduction was seen in male out-of-hospital deaths [mean 2000-2004, 17 (21.8%); 2006, two (2.9%); P < 0.0001]. This was associated with a decline in prescriptions by 60% within 6 months of legislation. The total number of poisoning deaths also fell, slightly earlier than the full impact on co-proxamol deaths (mean 2000-2004, 171.2; mean 2005-2006, 129.5; P = 0.005)., Conclusions: Legislation has resulted in a major reduction in the number of deaths associated with co-proxamol poisoning in Scotland, with no compensatory rise in mortality from poisonings from other common analgesics. We estimate from this study that a minimum of 300 lives across the UK will have been saved by the withdrawal of co-proxamol.

Restriction of means for suicide is an important part of suicide preventive strategies in different countries. The effect on method-specific suicide rate and overall suicide rate of restrictions on availability of carbon monoxide, barbiturates, and dextropropoxyphene was examined. From 1970 to 2000, overall suicide mortality and method-specific suicide mortality in Denmark were compared with official information about availability of barbiturates and analgesics and carbon monoxide in vehicle exhaust and household gas. Restrictions on availability of household gas with carbon monoxide content and barbiturates was associated with a decline in the number of suicides and suicides by self-poisoning with these compounds after controlling for the effect of calender year. Restricted access occurred concomittantly with a 55 percent decrease in suicide rate.

Introduction: Fulminant hepatic encephalopathy has a high mortality., Methods: This case report describes the role of cerebral microdialysis as an adjunct to the management of a 49 - year-old woman with hepatic encephalopathy secondary to a paracetamol overdose., Results: The application of the microdialysis technique, by detecting a very low cerebral glucose concentration in the presence of a normal plasma glucose, assisted in clinical decision making., Conclusions: Cerebral microdialysis, by enabling continuous on-line monitoring of substrate delivery and metabolism, may have a role in the management of patients with fulminant hepatic failure.

1. The aims of the present paper are to: (i) review progress in clinical toxicology over the past 40 years and to place it in the context of modern health care by describing its development; and (ii) illustrate the use of clinical toxicology data from Scotland, in particular, as a tool for informing clinical care and public health policy with respect to drugs. 2. A historical literature review was conducted with amalgamation and comparison of a series of published and unpublished clinical toxicology datasets from NPIS Edinburgh and other sources. 3. Clinical databases within poisons treatment centres offer an important method of collecting data on the clinical effects of drugs in overdose. These data can be used to increase knowledge on drug toxicity mechanisms that inform licensing decisions, contribute to evidence-based care and clinical management. Combination of this material with national morbidity datasets provides another valuable approach that can inform public health prevention strategies. 4. In conclusion, clinical toxicology datasets offer clinical pharmacologists a new study area. Clinical toxicology treatment units and poisons information services offer an important health resource.

Drugs and alcohol often occur together in fatal poisonings, complicating the process of determining the cause of death. Especially when found in concentrations generally regarded as toxic but not lethal, the question arises whether the combination of sublethal amounts was the likely cause of death. In this study, we examined poisoning deaths involving amitriptyline, propoxyphene and promazine, which are, after benzodiazepines, the most frequently occurring drugs in Finnish alcohol-related poisonings. From the forensic toxicology database, covering the years 1995-2002, we extracted 332 fatal poisonings, calculated median blood alcohol and drug concentrations, constructed concentration-concentration and concentration-response curves and evaluated the significance of the presence of therapeutic amounts of benzodiazepines. Median amitriptyline and propoxyphene concentrations were lower in alcohol-related cases than in clean drug poisonings. Correspondingly, the median blood alcohol concentrations in all drug-related poisonings were 1.5-2.2 mg/g lower than that found in clean alcohol poisonings. Alcohol concentration proved to be a more sensitive indicator of alcohol-drug interaction than drug concentration. This result suggests that when alcohol is present, relatively small overdoses of the studied drugs may result in fatal poisoning. In this context, fatal drug and alcohol concentrations and the issue of determining the most important agent in fatal drug-alcohol intoxications are discussed.

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., Methods: Mortality data for England and Wales were provided by the Office for National Statistics. Deaths were defined as due to compound paracetamol (paracetamol in combination with another analgesic, a low dose opioid or other ingredients) or paracetamol only, with or without alcohol or other drugs. The Department of Health provided data on all hospital admissions with a primary diagnosis of paracetamol poisoning., Results: Mortality rates for paracetamol only were similar for males and females, and decreased from about 4.5 to 2.8 per million between 1997 and 1999 and again from about 3.1 to 2.2 per million between 2001 and 2002. These falls may be attributable to random variation in the rates. Deaths involving compound paracetamol, which were not subject to the 1998 regulations, remained relatively constant over the study period. There was evidence of a decreasing trend in paracetamol only mortality rates and this followed overall trends for other drug poisoning excluding opioids and drugs of misuse. Hospital admissions due to paracetamol poisoning increased from about 27 000 to 33 000 between 1995/1996 and 1997/1998 and then decreased to 25 000 in 2001/2002. There were almost 50 per cent more admissions for females than males, with the highest admission rates amongst females aged 15-24 years old., Conclusions: Between 1993 and 2002, mortality rates and hospital admissions due to paracetamol poisoning declined. However, the contribution of the 1998 regulations to this decline is not clear. Paracetamol poisoning continues to be an important public health issue in England and Wales and represents significant workload for the NHS in England.

Restricting means for suicide is a key element in suicide prevention strategies of all countries where these have been introduced. Preventing deaths from analgesic overdoses is highlighted in the National Suicide Prevention Strategy for England. The problem of self-poisoning with the prescription-only drug co-proxamol (dextropropoxyphene plus paracetamol) has received attention in several countries. We have conducted a review of the international literature related to possible strategies to tackle this problem. In England and Wales in 1997-1999, 18% of drug-related suicides involved co-proxamol; these constituted 5% of all suicides. Death usually results from the toxic effects of dextropropoxyphene on respiration or cardiac function. Death from co-proxamol overdose may occur rapidly, the lethal dose can be relatively low, and the effects are potentiated by alcohol and other CNS depressants. The majority of co-proxamol overdose deaths occur before hospital treatment can be received. The risk can extend to others in the household of the person for whom the drug is prescribed. While there is limited evidence that educational strategies have been effective in reducing deaths from co-proxamol poisoning, initiatives in Scandinavia, Australia and the UK to restrict availability of co-proxamol have produced promising results. Given the paucity of evidence for superior therapeutic efficacy of co-proxamol over other less toxic analgesics, there are good reasons to question whether it should continue to be prescribed.

Aims: To examine in detail a series of coproxamol overdose deaths in order to provide information that will assist in the development of strategies to prevent such fatalities., Method: Inquest records in 24 coroners' jurisdictions in England on deaths between January 2000 and December 2001 which received a verdict of either suicide or undetermined cause (with a high or moderate probability of suicide) were examined., Results: One hundred and twenty-three coproxamol poisoning suicides were identified. Alcohol was involved in 58.5% of the overdoses and these individuals generally had lower blood drug levels and consumed fewer tablets. Younger people were more likely to have consumed alcohol and to have lower levels of suicide intent. Nearly half the individuals had a history of self harm, and a third were under psychiatric care. The coproxamol had been prescribed for the individual in 81.5% of cases, although only in 55.0% of those aged 10-34 years. In other cases the source of the coproxamol was nearly always a family member or partner. Some deaths resulted from relatively small overdoses., Conclusions: Strategies to reduce self poisoning deaths due to coproxamol should take account of the high toxicity of coproxamol in overdose, especially when combined with alcohol, and the fact that risk of death extends beyond the person for whom the drug is prescribed.

Objectives: 1) To investigate ECG changes following co-proxamol (paracetamol 325 mg and dextropropoxyphene 32.5 mg) overdose in comparison to co-codamol (paracetamol and codeine) or co-dydramol (paracetamol and dihydrocodeine) in a prospective study. 2) To examine the relationship between estimated dextropropoxyphene dose and ECG changes in a larger patient population., Background: Co-proxamol is a common cause of drug-induced death and hospital admission in the United Kingdom. ECG changes following dextropropoxyphene have been reported in animals and man, including QRS prolongation., Methods: The prospective study was conducted on 15 patients and controls with overdose. A retrospective study of a cohort of 159 co-proxamol overdoses from a combined data set from Edinburgh and Newcastle, Australia was also conducted. The measured or estimated "four hour" plasma paracetamol level was used as a surrogate of the amount of dextropropoxyphene ingested., Results: In the prospective study co-proxamol overdose caused statistically significant QRS prolongation (mean [95% CI] 99.36 [96.19, 102.53] msec), compared to the other combination opioid-paracetamol products (82.84 [80.81, 84.88] msec) but no effect on PR or QTc. QRS duration increase was evident soon after exposure and remained prolonged and stable over the following 24 h. In the retrospective cohort study a dose dependency of effect on QRS was documented, although the correlation coefficient relating paracetamol level to effect was relatively weak (r = 0.338, Sig. [2-tailed] 0.003, n = 74)., Conclusions: QRS is significantly prolonged in co-proxamol overdose, and this prolongation is dose dependent. These findings have clinical relevance to the management of patients with co-proxamol poisoning.