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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.

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.

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.

Objectives: To examine the incidence of suicides due to co-proxamol compared with tricyclic antidepressants and paracetamol, and to compare fatality rates for self poisonings with these drugs., Design: Analysis of routinely collected national and local data on suicides and self poisonings., Setting: Records of suicides in England and Wales 1997-9; non-fatal self poisonings in Oxford District 1997-9., Data Sources: Office for National Statistics and Oxford monitoring system for attempted suicide., Main Outcome Measures: Incidence of suicides with co-proxamol or tricyclic antidepressants or paracetamol. Ratios of fatal to non-fatal self poisonings., Results: Co-proxamol alone accounted for 5% of all suicides. Of 4162 drug related suicides, 18% (766) involved co-proxamol alone, 22% (927) tricyclic antidepressants alone, and 9% (368) paracetamol alone. A higher proportion of suicides in the 10-24 year age group were due to co-proxamol than in the other age groups. The odds of dying after overdose with co-proxamol was 2.3 times (95% confidence interval 2.1 to 2.5) that for tricyclic antidepressants and 28.1 times (24.9 to 32.9) that for paracetamol., Conclusions: Self poisoning with co-proxamol is particularly dangerous and contributes substantially to drug related suicides. Restricting availability of co-proxamol could have an important role in suicide prevention.

Paracetamol and dextropropoxyphene were implicated on clinical and analytical grounds in 237 poison deaths in England and Wales in 1979. In addition to paracetamol, dextropropoxyphene and ethanol, other agents were detected in 61 of these cases (26%). Analytical evidence suggests that very substantial overdoses of paracetamol and dextropropoxyphene were ingested in the majority of cases; their mean plasma concentrations in those ingesting no other agents were 252 and 8.64 mg/l respectively. Significant quantities of ethanol were ingested in 133 of 237 cases (56%). The mean ethanol concentration in those in whom quantitative estimations of paracetamol, dextropropoxyphene and ethanol were undertaken and who had not ingested other drugs, was 1588 mg/l. There was no analytical support for the diagnosis of paracetamol and dextropropoxyphene poisoning in 74 of 305 cases (24%) of H.M. Coroners' returns to the Office of Population, Censuses and Surveys for the period 1 January-31 December 1979. In addition, dextropropoxyphene was detected analytically in six cases classified as being due to paracetamol alone.

Many of the agents held responsible for fatal poisoning in England and Wales--particularly dextropropoxyphene, tricyclic antidepressants, beta-adrenergic antagonists, and chlorpromazine--possess membrane stabilising activity (MSA). This pharmacological property, although regarded as being of little importance in therapeutic use, may be responsible for death in more than 30% of fatal poisonings. Awareness of this possibility may lead to greater care in the prescribing of drugs with this property, to the development of safer alternatives, and to more rational therapy of the poisoned patient.