A time-series study conducted by Keith Hawton and colleagues reports on the links between withdrawal of the analgesic co-proxamol and subsequent prescribing and deaths associated with analgesic poisoning.
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.
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.
Please see later in the article for the Editors' Summary
Every year, about a million people worldwide die by suicide. Most people who take their own life are mentally ill. For some, stressful events have made life seem worthless or too painful to bear. Suicide rates can be reduced by improving the treatment of mental illness and of stress and by limiting access to common suicide methods. These methods differ from place to place. For example, in England and Wales, where 4,528 suicides were recorded in 2010, drug-related poisoning is responsible for about a fifth of all suicides. Notably, between 1997 and 1999, the prescription analgesic (pain killer) co-proxamol, which contains paracetamol and the opioid dextropropoxyphene, was implicated in a fifth of drug-poisoning suicides in England and Wales. In response to concerns about co-proxamol's widespread use for suicidal poisoning and its safety/effectiveness profile, the UK Committee on Safety of Medicines announced on January 31, 2005 that the drug would be withdrawn completely from use in the UK by December 31, 2007, and that between 2005 and 2007, doctors should not prescribe co-proxamol to any new patients and should try to move patients already taking the drug onto other medications.
Why Was This Study Done?
Public health experts need to quantify the impact of co-proxamol withdrawal on analgesic prescribing in England and Wales and on suicide rates. In particular, they need to know whether its withdrawal has increased the use of other analgesics in suicide (substitution). Reassuringly, between 2005 and 2007, there was a reduction in both co-proxamol prescribing and in co-proxamol–related suicides in England and Wales but no evidence of increased poisoning deaths involving other prescription analgesics. But what about the longer-term effects of co-proxamol withdrawal? In this interrupted time-series study, the researchers assess the impact of co-proxamol withdrawal in England and Wales by comparing data on analgesic prescribing and suicide rates collected between 1998 and 2004 and between 2005 and 2010. An interrupted time-series study uses serial measurements of events in a population before and after an intervention to look for changes in response to the intervention.
What Did the Researchers Do and Find?
The researchers obtained prescribing data from 1998 to 2010 for co-proxamol and several other analgesics from government sources in England and Wales, and data on suicides, open verdicts (poisoning of undetermined intent), and accidental poisonings involving single analgesics from the UK Office for National Statistics. They then estimated changes in levels and trends in prescribing and deaths following the 2005 announcement of co-proxamol withdrawal using interrupted time-series analysis. There was a marked reduction in co-proxamol prescribing that was accompanied by increased prescribing of several other analgesics after co-proxamol withdrawal. These changes were associated with a major reduction in suicide deaths due to poisoning that equated to 500 fewer deaths occurring between 2005 and 2010 than would have occurred had co-proxamol not been withdrawn. On average, there were 20 co-proxamol-related deaths (suicides and accidental poisonings) per year during 2008–2010 compared to more than 250 per year in the 1990s. Finally, there was little evidence of a change in the number of deaths involving other analgesics after co-proxamol withdrawal except for a small increase in the number of deaths involving the opioid oxycodone.
What Do These Findings Mean?
These findings show that, during the six years that followed the beginning of the phased withdrawal of co-proxamol in the UK, there has been a major reduction in poisoning deaths involving this drug in England and Wales. The findings provide little evidence for an increase in deaths involving other analgesics. However, because the Office of National Statistics does not distinguish between deaths due to oral and intravenous morphine or between deaths due to morphine and heroin, the researchers did not assess whether there have been any changes in deaths involving morphine since 2005. Moreover, this study did not assess suicides related to the use of multiple drugs or investigate whether suicides involving methods other than drug-related poisoning have increased since co-proxamol withdrawal. Despite these limitations, these findings suggest that the withdrawal of co-proxamol in the UK and possibly elsewhere should have major beneficial effects on suicide rates, at least in the relatively short term.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001213.
The World Health Organization provides information on the global burden of suicide and on suicide prevention (in several languages)
The US National Institute of Mental Health provides information on suicide and suicide prevention web page
The UK National Health Service Choices website has detailed information about suicide and its prevention
The University of Oxford Centre for Suicide Research provides information about co-proxamol and suicide and links to other research on suicide
The 2005 announcement of the withdrawal of co-proxamol in the UK is available through the UK Medicines and Healthcare products Regulatory Agency, which also provides a question and answer document about the risks and benefits of co-proxamol
MedlinePlus provides links to further resources about suicide (in English and Spanish)
The charity Healthtalkonline has personal stories about dealing with suicide
Help is at Hand is a resource for people bereaved by suicide