Abstract
Before 2005, the analgesic co-proxamol (a paracetamol and dextropropoxyphene combination) was involved in about 20% of all drug-poisoning suicides and a substantial number of accidental poisonings in the UK. In January 2005, following a review of the efficacy/safety profile of co-proxamol by the MHRA, the Committee on Safety of Medicines (CSM) advised that co-proxamol should be withdrawn from use in the UK; the final date for withdrawal was 31 December 2007. Using interrupted time-series analyses of 1998–2010 data for England and Wales on deaths and prescribing of analgesics, we have shown that withdrawal of co-proxamol has had major beneficial effects on the number of poisoning deaths involving this drug, including deaths by suicide and by accidental poisoning. Furthermore, there is no evidence of significant substitution by poisoning with other analgesics, in spite of their increased prescribing. There were an estimated 500 fewer deaths from suicide between 2005 and 2010 than would be expected without the withdrawal, and 600 fewer deaths when accidental poisonings were included. During the full withdrawal phase (2008–10) there was an average of just 19 suicide and open verdict deaths involving co-proxamol per year (23 per year including accidents), compared with 228 deaths per year during 1998–2004 (271 per year including accidents). In 2009, following the UK lead, the European Medicines Agency recommended that dextropropoxyphene-containing medication be withdrawn throughout the European Union, and a similar initiative has been introduced in the USA and Canada.
Background
For many years concerns have been expressed about the extent of fatal poisoning with the analgesic co-proxamol (a combination of paracetamol and dextropropoxyphene) and, in particular, its use for suicide.100,101 Death from poisoning with co-proxamol occurs largely because of the toxic effects of high levels of dextropropoxyphene on respiration and cardiac conduction.102,103 There is also a relatively narrow margin between therapeutic and potentially lethal levels.104 Between 1997 and 1999, co-proxamol was the single drug used most frequently for suicide in England and Wales (766 deaths over the 3-year period), being implicated in nearly one-fifth of all drug-related poisoning suicides.101,105
In January 2005, after the MHRA conducted a review of the efficacy/safety profile of co-proxamol,106 the CSM advised that co-proxamol should be withdrawn from use in the UK; the final date of withdrawal was 31 December 2007.107 During the intervening period (2005–7), doctors were advised not to prescribe co-proxamol to any new patients and to make efforts to move patients currently taking the drug to suitable alternative medication (although patients for whom this was difficult could continue to receive the drug through normal prescribing).
We have conducted two evaluations assessing the impact of co-proxamol withdrawal on prescribing of co-proxamol and other analgesics, and on deaths involving these drugs, in England and Wales. The first evaluation was of the impact of the initial withdrawal phase (2005–7). The second evaluation was of the overall impact of this phase and the 3 subsequent years of full withdrawal. We have investigated drug-poisoning deaths that received a suicide or an open verdict, and also those with a verdict of accidental death, some of which may have been suicidal acts (see Chapter 2 for a full discussion of these terms). Substitution of method is a potential concern when a common means used for suicide becomes less available, particularly when the substituted method has a higher case fatality than the restricted method.108 For this reason we have also investigated the impact of the withdrawal of co-proxamol on the prescribing of, and deaths involving, other analgesics.
Objective
To investigate the impact of the withdrawal of co-proxamol on the prescribing of analgesics and their use in poisoning deaths, both suicidal and accidental.
Methods
Data types
Prescriptions
Quarterly data for 1998–2010 on prescriptions of co-proxamol, co-codamol, codeine, co-dydramol, dihydrocodeine, NSAIDs, paracetamol and tramadol in England and Wales were obtained from the NHS Health and Social Care Information Centre (England) and Prescribing Services Partneriaeth Cydwasanaethau GIG Cymru (Wales). Prescription data for Wales were not available for the first quarter of 1998 and so figures for this quarter were estimated using least-squares methods to extrapolate from trend data for subsequent quarters.
We also obtained prescription data for oral morphine and oxycodone for England only between 1998 and 2010 (data for Wales were unavailable for some of this period).
Deaths
To evaluate the impact of the withdrawal of co-proxamol on suicide, we have used data on deaths receiving a suicide verdict and those coded as injury or poisoning of undetermined intent (open verdicts) by the ONS (see Chapter 2). In England and Wales it has been customary to assume that most of the latter are cases in which the harm was self-inflicted but there was insufficient evidence to prove intent to die.32,109
The ONS provided quarterly data on drug-poisoning deaths (suicides, open verdicts and accidental poisonings) involving co-proxamol, co-codamol, codeine, co-dydramol, dihydrocodeine, NSAIDs, paracetamol and tramadol based on death registrations during 1998–2010 in England and Wales. We also received annual death data for oxycodone. Data were obtained from the ONS database of deaths related to drug poisoning, which is extracted from the national mortality database for England and Wales.110 Analyses were restricted to deaths involving single drugs or single drugs and alcohol. Similar data were supplied for overall drug-poisoning deaths.
Statistical analyses
Analyses of trends in prescribing and deaths were conducted using Stata version 10.0. We used interrupted time-series analysis to estimate changes in levels and trends in prescribing and deaths following the CSM announcement of the withdrawal of co-proxamol. This method controls for baseline level and trend when estimating expected changes in the number of prescriptions (or deaths) due to the intervention.81
Specifically, segmented regression analysis80 was used to estimate the mean quarterly numbers of prescriptions and deaths that might have occurred in the post-intervention period without the CSM announcement, and the numbers of prescriptions and deaths that actually occurred following the CSM announcement. The latter were obtained from best-fitted data lines from the regressions and are better estimates than taking the average of the actual values. The beginning of 2005 was chosen as the point of intervention. Thus, our data comprised 28 quarters in the pre-intervention segment and 12 in the post-intervention segment for the evaluation of the initial impact of the withdrawal (2005–7) and 24 for the evaluation of the longer-term impact (2005–10). Slope and level regression coefficients were used to estimate the mean quarterly absolute differences in prescriptions and deaths (first, at the mid-point of the withdrawal phase, midway between quarter two and quarter three of 2006; and, second, at the mid-point of the post-intervention period, midway between quarter four of 2007 and quarter one of 2008).
Preliminary analyses indicated some autocorrelation in the data; therefore, the Cochrane–Orcutt autoregression procedure was used (rather than ordinary linear regression) to correct for first-order serially correlated errors. The Durbin–Watson statistic of all final models was close to the preferred value of 2, indicating that no serious autocorrelation remained.
Results
Impact of initial withdrawal phase (2005–7)
Because the impact of the initial withdrawal phase is included in our longer-term evaluation to the end of 2010 (see below), we will only summarise the results of our investigation of this phase.
Prescriptions
There was a 59% reduction in prescribing of co-proxamol in the initial withdrawal period ( and ), with increased prescribing of some other analgesics but also decreased prescribing of NSAIDs and dihydrocodeine.
Changes in the numbers of prescriptions and poisoning deaths involving co-proxamol, other analgesics and all drugs in England and Wales, 1998–2007, associated with the CSM announcement
Trends in prescriptions dispensed for co-proxamol and seven other analgesics in England and Wales, 1998–2010.
Deaths
There was a marked reduction in the numbers of suicides and open verdicts involving co-proxamol between 2005 and 2007 ( and ). Before 2005, deaths from poisoning with co-proxamol alone made up 17.5% of all drug-poisoning suicides (95% CI 15.5% to 19.5%), whereas between 2005 and 2007 they constituted just 8.3% (95% CI 4.3 to 12.3%) (see ).
Deaths in England and Wales from poisoning with co-proxamol and other analgesics, 1998–2010 (suicide and open verdicts, substances taken alone, with or without alcohol).
Suicide and open verdict deaths by all causes, and suicide, open verdict and accidental deaths from poisoning with all drugs, co-proxamol alone and seven other analgesics alone (or with alcohol) in England and Wales, 1998–2010
Regression analyses indicated a significant decrease in both level and slope for deaths involving co-proxamol that received a suicide or an open verdict (). The number of deaths decreased by an average of 19 per quarter in the post-intervention period (95% CI 8 to 29 deaths per quarter) (see ). This equated to an estimated overall decrease of 226 deaths (95% CI 190 to 262 deaths), approximately 48%, in the 3-year post-intervention period (2005–7) compared with 1998–2004.
Interrupted time-series segmented regression analysis of prescriptions and deaths from co-proxamol, other analgesics, all drugs and all causes in England and Wales that received a suicide or an open verdict, 1998–2010
When accidental poisoning deaths involving co-proxamol were included, there was a mean quarterly decrease of 22 deaths (95% CI 13 to 32 deaths), which equated to an overall decrease of 268 deaths (95% CI 235 to 300 deaths), approximately 47%, in the 3-year post-intervention period (2005–7) (see ).
There were no statistically significant changes in level or slope in the post-intervention period for deaths involving the other analgesics, both for those deaths that received a suicide or open verdict (mean quarterly change = 6, 95% CI − 4 to 16 deaths) and when accidental poisoning deaths were also included (mean quarterly change = 5, 95% CI − 9 to 19 deaths).
Impact of longer-term withdrawal (2005–10)
Prescriptions
At the beginning of 2008, following the initial step-change reduction in prescribing of co-proxamol in England and Wales during 2005–7 compared with the trend in prescribing during 1998–2004, there was a further downwards step in prescribing such that there were very few prescriptions dispensed during 2008–10 (see ). Overall, between 2005 and 2010 there was a 53% reduction in prescribing of co-proxamol compared with previous trends ().
Changes in the number of prescriptions involving co-proxamol and seven other analgesics in England and Wales, 1998–2010, associated with the CSM announcement in January 2005
There were significant increases in prescribing of co-codamol (+ 23%), paracetamol (+ 16%), codeine (+ 10%), co-dydramol (+ 6%) and tramadol (+ 19%) during 2005–10 (see and and ), and a sharp decrease in prescribing of NSAIDs (which was due to safety concerns about COX-2 inhibitors114), which began shortly before the withdrawal of co-proxamol. There was also a decrease in prescribing of dihydrocodeine (− 10%) in 2005–10. Overall, when all seven analgesics (excluding co-proxamol) were combined, there was no significant change in prescriptions, in either level or trend, associated with the withdrawal of co-proxamol. With NSAIDs excluded, however, there was a significant 15% increase in prescribing of the other six analgesics combined.
Prescription data for morphine were available only for England for the study period. Our analysis showed a significant mean quarterly increase in the number of prescriptions of morphine associated with the CSM announcement, up to 71,000 prescriptions (95% CI 62,000 to 79,000 prescriptions), equating to a 35% increase in the period 2005 to 2010.
Prescription data for oxycodone were also available only for England for the study period. The number of prescriptions increased steadily from very low levels (mean of 69,000 per year in 1998–2004) to a mean of 527,000 per year in 2005–10. Because of small numbers, an interrupted time-series analysis (as conducted on other prescription data) did not generate meaningful estimates.
Deaths involving co-proxamol and other analgesics
shows the numbers of deaths reported as suicide (including open verdicts) or accidental poisoning between 1998 and 2010 involving co-proxamol alone and those involving the seven other analgesics alone (both with and without alcohol), together with all drug-poisoning deaths and all suicides. Between 2005 and 2010 there was a marked reduction in the number and proportion of all poisoning deaths recorded as suicide that involved co-proxamol. Although the number of deaths involving other analgesics receiving a suicide or an open verdict was lower in 2007–10 than in earlier years, their proportionate contribution to total drug-poisoning deaths increased somewhat (presumably because the overall number of deaths declined in line with the reduction in co-proxamol deaths). There was a similar marked decrease in number of deaths involving co-proxamol when accidental deaths were included, but without an increase in percentage of poisoning deaths involving other analgesics (although the number of accidental poisonings with other analgesics increased slightly in 2008–10). Exclusion of NSAIDs made little difference to the results of these analyses.
shows graphically the impact of the initial withdrawal phase (2005–7) and the full withdrawal (2008–10) on both deaths involving co-proxamol and deaths involving other analgesics. There was some reduction in number of deaths involving co-proxamol in the years preceding the beginning of the initial withdrawal phase (1998–2005), then a steady, marked reduction during the initial withdrawal phase (2005–7), with a further, smaller reduction during the first 3 years of the full withdrawal (2008–10). The number of deaths involving other analgesics did not appear to change markedly during these periods.
The overall apparent beneficial changes following the withdrawal of co-proxamol were confirmed when the data were subjected to interrupted time-series regression analyses (). During the 2005–10 period, there was a highly significant mean quarterly reduction in number of deaths involving co-proxamol alone that received a suicide (including open) verdict (− 21, 95% CI − 34 to − 8 deaths), and a similar reduction when accidental deaths were included (− 25, 95% CI − 38 to − 12 deaths). There was no significant change in number of deaths involving the seven other analgesics combined. When we examined these drugs separately (see ), none showed a significant step or trend change associated with the withdrawal of co-proxamol. There were increases in numbers of deaths involving co-codamol and codeine during the overall study period, but these began well before the withdrawal of co-proxamol. All drug-poisoning deaths (excluding those involving co-proxamol and other analgesics) receiving a suicide or open verdict were reduced following the withdrawal of co-proxamol, although when accidental deaths were included there was a significant increase of 84 deaths per quarter (95% CI 28 to 141 deaths per quarter) (see ).
Changes in numbers of poisoning deaths involving co-proxamol, other analgesics and all drugs in England and Wales, 1998–2010, associated with the CSM announcement in January 2005
The estimated reduction in number of deaths involving co-proxamol alone between 1998–2004 and 2005–10 was 61% for suicide and open verdict deaths and 62% when accidental deaths were included. This reduction equated to approximately 500 fewer deaths from suicide between 2005 and 2010 than would be expected without the withdrawal, and 600 fewer deaths when accidental poisonings were included. As can be seen in , during the full withdrawal phase (2008–10) there was an average of just 19 deaths per year (23 per year including accidents). This figure is in contrast to the 228 deaths per year during 1998–2004 (271 per year including accidents).
We have not presented data on deaths involving morphine because the ONS cannot distinguish between deaths resulting from oral administration and deaths resulting from intravenous administration (and between those due to morphine and those due to heroin). Deaths involving oxycodone alone and receiving suicide, open or accidental verdicts increased during the study period from a mean of 2.3 per year between 2001 and 2004 to a mean of 8.2 per year between 2005 and 2010 (including 15 in 2010).
Discussion
We have demonstrated an apparent beneficial effect of withdrawal of co-proxamol in England and Wales during the initial 3-year withdrawal phase (2005–7) in terms of numbers of deaths (suicides, open verdicts and accidents). We have also shown that there were further significant changes following full withdrawal of co-proxamol in January 2008, in terms of not only the expected reduced prescribing of co-proxamol, but also the increased prescribing of some other analgesics suggested by the CSM as substitutes for co-proxamol (paracetamol, co-codamol, codeine and co-dydramol; and, for progressive chronic pain, oxycodone and morphine), and also tramadol. During 2005–10 there was a 61% reduction in deaths from co-proxamol poisoning, equating to approximately 500 fewer deaths receiving suicide or open verdicts, and 600 when accidental poisonings were included. Some of the accidental poisonings are also likely to have been probable suicides, especially because of the recent increase in narrative verdicts by coroners, as highlighted in Chapter 2, and the fact that those responsible for coding cause of death at the ONS have difficulty in deciding the cause from the narrative and are therefore obliged by international convention to record the death as accidental.29 Most importantly, the major reduction in number of deaths involving co-proxamol was not associated with a compensatory overall increase in number of deaths from poisoning with other analgesics (although the number of accidental poisonings with other analgesics increased in the period 2008–10).
During the full withdrawal phase, prescribing of co-proxamol did not cease completely, presumably because of off-licence prescribing. Also, deaths from poisoning with co-proxamol did not reach zero (although there were just eight suicide deaths involving co-proxamol in 2010, and 10 including accidental poisonings); again, this may be partly because of off-licence prescribing, but also because of residual supplies remaining in homes, and possibly supplies obtained through the internet. The acute reduction in prescribing of NSAIDs that began just before the withdrawal of co-proxamol because of concerns about COX-2 inhibitors111 would have been unlikely to have affected the findings as NSAIDs alone are rarely implicated in poisoning deaths, especially by suicide.12
There was an overall reduction in number of poisoning deaths receiving suicide or open verdicts in England and Wales in 2005–10, although this did not reach statistical significance and was not paralleled by a decline in number of overall drug-poisoning deaths (possibly because of an increase in narrative verdicts; see Chapter 2). However, the number of suicides overall was not reduced, possibly because of the effects of the recession that began in 2008.112,113 The increase in number of overall poisoning deaths during 2005–10 appears to be related to increased numbers of deaths involving methadone and also benzodiazepines, usually combined with other drugs.110
Strengths and limitations
One strength of this study is that it is based on national data and includes reasonably long pre-intervention (7 years) and post-intervention (6 years) periods. Also, the method of statistical analysis (interrupted time-series regression) controls for baseline trends when estimating effects of the intervention on prescribing and deaths, which is preferable to methods such as comparison of changes in proportions before and after the intervention. However, estimates of overall effects do involve extrapolation and hence are subject to some degree of uncertainty. Also, percentage changes during the post-intervention period compared with the pre-intervention period are based on mean quarterly change estimates, which have associated uncertainty, and therefore should be interpreted with caution.
To ensure that we were examining deaths due to specific drugs, we based our mortality calculations solely on deaths involving single analgesics alone (with or without alcohol). There are also considerable numbers of poisoning deaths involving multiple drugs.110 When co-proxamol is one of the drugs, it is very likely to have been the lethal agent, given its high toxicity. It is possible, therefore, that our findings underestimate the full effects of the withdrawal of co-proxamol. The increasing number of narrative verdicts recorded by coroners in England and Wales29 could have influenced the findings through a small reduction in suicide verdicts, although this would probably have equally affected poisonings with co-proxamol and the other analgesics, and any impact would have been included in our analysis of suicide, open and accidental deaths combined.
We have presented prescription data for the analgesics that we have investigated. For some analgesics, notably paracetamol and co-codamol, sales will mainly be OTC rather than through prescription. Comprehensive OTC sales data are unfortunately not available; this would not, of course, affect the validity of the mortality data.
As noted above, we were unable to investigate the impact of the withdrawal of co-proxamol on deaths involving morphine; however, most of such deaths result from illicit drug use.110
Finally, we have not been able to assess possible compensatory increases in numbers of deaths involving methods other than poisoning that may have occurred following the withdrawal of co-proxamol. This is because of the range of other potential methods of suicide and also the likely temporal effects of other influences, such as the economic recession. However, as individuals tend to show a preference for particular methods of suicide,108 it is unlikely that any such effect would have been substantial.
Conclusions
Withdrawal of co-proxamol in the UK appears to have had major beneficial effects on the number of poisoning deaths involving this drug, including suicides and accidental poisonings, with no evidence of significant substitution by poisoning with other analgesics, in spite of their increased prescribing. In June 2009, following the UK lead, the European Medicines Agency recommended that dextropropoxyphene-containing medication be withdrawn throughout the European Union.114 This became European policy in June 2010, with full withdrawal by September 2011. In 2009, a US Food and Drug Administration (FDA) panel recommended that the FDA should withdraw dextropropoxyphene from the US market,115 and in 2010 the FDA instructed manufacturers to cease production.116 Also, in 2010 all dextropropoxyphene products were withdrawn in Canada.117 The impact of this initiative should now be evaluated on a larger scale.
