Abstract
In 1998, legislation was introduced restricting pack sizes of paracetamol sold over the counter in an attempt to reduce self-poisonings and paracetamol-induced hepatotoxicity. We conducted four studies related to this legislation. Analysis of mortality data for England and Wales and UK liver unit data showed that the legislation was followed by significant reductions in deaths over an 11-year period (43% or 765 fewer deaths; 990 when accidental deaths were included) and in liver transplantation for paracetamol-induced hepatotoxicity (61% fewer transplantations). Interviews with 60 general hospital patients who had been admitted after taking overdoses of ≥ 16 paracetamol tablets showed that most used paracetamol because it was readily available, although few breaches of sales guidance were reported. Evidence of media (including internet) influence on the choice of paracetamol for self-poisoning was found. Examination of data from the Multicentre Study of Self-harm in England and the National Registry of Deliberate Self Harm in Ireland indicated that, despite smaller pack sizes in Ireland, there was no major difference in overdose size between the two settings. More ‘pack equivalents’ were generally consumed in Ireland, raising questions about whether sales guidance is followed as strictly as in the UK. Finally, GP prescribing data for the UK (from IMS Health) showed that prescribing of NSAIDs following the 1998 legislation increased in line with prescribing of other analgesics, with no evidence of an increase in admissions for GI bleeds in Hospital Episode Statistics (HES) data. However, a gradual increase in use of antiulcerants may have offset any increase in incidence of GI symptoms.
Although the 1998 legislation appears to have been beneficial, the continuing toll of deaths from paracetamol overdose suggests that further initiatives may be necessary. Media (including internet) influences should be addressed.
Background
Paracetamol, an analgesic available over the counter, is the most common drug used for self-poisoning in the UK.22,46 It is also a frequent cause of poisoning in many other countries.47–53 If untreated, an overdose of 10–15 g (20–30 tablets) of paracetamol can result in fatal hepatotoxicity.54,55
In September 1998, legislation was introduced by the UK government following a recommendation by the UK Medicines Control Agency (now the MHRA) restricting pack sizes of paracetamol (and other analgesics) sold through pharmacies to a maximum of 32 tablets and restricting non-pharmacy sales to 16 tablets56,57 (although MHRA guidance in 2009 suggests that up to two packs of 16 tablets can be bought from the latter58). This policy was introduced because of the large number of people taking paracetamol overdoses59–61 and the increasing numbers of deaths62 and liver transplants63 resulting from paracetamol-induced hepatotoxicity. Another motivation for the legislation was the knowledge gained from interviewing people who had presented to hospital following paracetamol overdoses, many of whom reported that the act was often impulsive and involved the use of medication already stored in the home.64,65
Our research group showed that the UK legislation had beneficial effects in England and Wales during the first few years following its introduction in terms of paracetamol-related deaths, liver transplants and numbers of tablets consumed in overdoses.12,66 Although other studies supported these findings,67,68 some commentators have questioned the impact of the legislation.69,70 Furthermore, in Scotland, no evidence of an impact on deaths has been found.71,72 More long-term studies are therefore required to assess whether or not the legislation has been a success.68
There is also evidence that some retail outlets have not fully complied with the intention of the legislation, and that it is possible to purchase large quantities of paracetamol over the counter.73–76 Furthermore, the increase in internet sites from which drugs can be bought is also a potential cause for concern.
In Ireland, similar legislation was introduced in October 2001,77 but pack sizes were restricted to lower maximum amounts than in the UK, namely a maximum pack size of 24 tablets in pharmacies and 12 tablets in non-pharmacy outlets, with just a single pack to be supplied in any one transaction.
One area of concern relating to the introduction of this legislation is whether the reduced paracetamol pack size may have resulted in increased use of NSAIDs, with adverse consequences in terms of GI bleeds,78 which might also be reflected in increased prescribing of drugs for GI disorders.
To investigate some of these issues, we conducted four research studies to address the following questions:
What has been the long-term impact of the 1998 legislation to reduce pack sizes of paracetamol in terms of deaths and liver disease?
What are the circumstances associated with larger overdoses of paracetamol, and are the intentions of the legislation being complied with?
Do differences in pack sizes of paracetamol in the UK and Ireland have an impact on overdoses of the drug?
Did the UK legislation on pack sizes of paracetamol result in an increased rate of GI disorders because of greater use of NSAIDs?
STUDY 1: LONG-TERM EVALUATION OF THE IMPACT OF REDUCED PACK SIZES OF PARACETAMOL ON POISONING DEATHS AND LIVER TRANSPLANT ACTIVITY IN ENGLAND AND WALES
Objective
The objective of the study was to investigate the long-term impact in England and Wales of the 1998 introduction of smaller paracetamol pack sizes on poisoning deaths, especially suicides, and liver unit activity for paracetamol-induced hepatotoxicity, in terms of registration for liver transplantation and actual transplants.
Methods
Data sources
Deaths
To evaluate the impact of the legislation on suicides, we used data on deaths receiving a suicide verdict and deaths recorded as being of undetermined intent (open verdicts) (see Chapter 2). The ONS provided quarterly information on drug-poisoning deaths (suicides, open verdicts and accidental poisonings) involving paracetamol, the more common paracetamol compounds used for self-poisoning (paracetamol with codeine, dihydrocodeine, ibuprofen or aspirin) and all drugs, based on death registrations from 1993 to 2009 in England and Wales. We did not include deaths involving the paracetamol/dextropropoxyphene compound (co-proxamol) as dextropropoxyphene is usually the lethal agent in co-proxamol poisonings and the drug was withdrawn in 200779 (see Chapter 4). We have restricted our analyses to deaths involving single drugs (paracetamol or paracetamol compounds) with or without alcohol, for individuals aged ≥ 10 years. Similar data were supplied for all deaths receiving suicide and open verdicts.
Registrations for liver transplantation and actual transplants
We used data supplied by UK Transplant (now NHS Blood and Transplant) on registrations for liver transplantation and actual liver transplants as a result of paracetamol poisoning between 1995 and 2009 in residents of England and Wales aged ≥ 10 years.
Non-fatal self-poisoning with paracetamol
We used data collected through the Oxford Monitoring System for Attempted Suicide25 (which includes all hospital presentations for self-harm) to examine trends in non-fatal overdoses involving paracetamol (in pure or compound form) throughout the period 1993–2009.
Statistical analyses
Analyses were conducted using Stata version 10.0. We used interrupted time-series analysis80 to estimate changes in levels and trends following the 1998 legislation. We compared the mean quarterly numbers of deaths and liver unit registrations and transplantations that might have occurred in the post-intervention period without the legislation with the number that occurred with the legislation.81 The end of the third quarter of 1998 was chosen as the point of intervention. For more details of this method see Appendix 3.
In addition to the basic regression model for the analysis of paracetamol-related deaths, we included adjustment for potentially confounding trends in ‘all drug-poisoning suicide deaths’ by inclusion of ‘all drug suicide deaths excluding paracetamol' as a covariate. We also calculated a conservative estimate of the absolute effect, which assumed no increase in the number of deaths in the absence of the legislation. The absolute effect of the legislation was determined as the difference between the outcome expected at the last point of the pre-intervention period and the outcome expected at the mid-point of the post-intervention period. For analysis of liver unit registrations and transplantations we also used the basic regression model and the conservative estimate analysis.
We also conducted a sensitivity analysis to determine whether our results changed when January 1998 was used as the intervention point – this corresponds to the date when the packaging changes began to occur (9 months before the legislation).
Results
Deaths
The numbers of deaths in England and Wales between 1993 and 2009 from poisoning with all drugs and from paracetamol specifically that received suicide, open and accidental verdicts are shown in . Paracetamol poisoning deaths constituted between approximately 9% and 10% of drug-poisoning suicide deaths before the legislation and between approximately 7% and 9% after the legislation.
Suicide and open verdict deaths by all causes, and suicide, open verdict and accidental deaths from poisoning with all drugs, paracetamol alone and paracetamol compounds (with or without alcohol) in England and Wales for individuals aged ≥ 10 (more...)
Regression analysis of quarterly data indicated a significant decrease corresponding to the September 1998 legislation in both level (i.e. step change) and trend in deaths involving paracetamol in England and Wales that received a suicide or open verdict ( and ).
Number of suicide and open verdict deaths involving paracetamol alone in England and Wales, 1993–2009, by quarter years, and best fit regression lines related to the 1998 legislation.
Interrupted time-series segmented regression analysis of deaths in England and Wales from paracetamol poisoning, other drug poisoning and all causes for individuals aged ≥ 10 years, 1993–2009, with September 1998 as the point of (more...)
The estimated average decrease in number of deaths was 17 per quarter (95% CI − 25 to − 9 deaths per quarter) in the post-intervention period compared with the expected number based on trends in the pre-intervention period (). This change equated to an overall decrease in number of deaths of about 43% in the 11.25 years post legislation, or 765 fewer deaths than would have been predicted based on trends during 1993–September 1998. An overall decrease of 36% was found when a conservative method of analysis was used (see ).
Changes in numbers of poisoning deaths involving paracetamol in England and Wales for individuals aged ≥ 10 years associated with the 1998 legislation to reduce pack size, 1993–2009
There was also a downwards trend in all drug-poisoning (excluding paracetamol) deaths receiving a suicide or open verdict during the post-legislation period, although this was smaller in magnitude (25%) and was not associated with the step change seen for paracetamol following the introduction of the 1998 legislation. When the change in paracetamol deaths was adjusted to take account of the fall in poisoning deaths involving other drugs, the decline in paracetamol deaths changed very little (see ). Similar results were found when accidental poisoning deaths involving paracetamol were included with suicides and open verdicts (see ). The reduction in deaths in the post-legislation period when accidents were included equated to 990 fewer deaths than expected. Although suicides (including open verdicts) involving any method showed a significant downwards trend during the post-legislation period, there was no step change associated with the legislation (see ).
When the intervention point was moved back 9 months to the beginning of 1998 to take account of earlier introduction of packaging changes, there remained a significant downwards trend in suicide and open verdict deaths involving paracetamol during 1998–2009 but no step change (see Appendix 3, Table 45).
There was no major change in number of deaths involving paracetamol compounds following the 1998 legislation (see and ). These deaths represented a relatively small proportion of overall paracetamol-related deaths (see ).
Liver unit activity
Registration for liver transplantation
There was a decrease in level and trend of the number of registrations for liver transplantation related to paracetamol-induced hepatotoxicity in England and Wales following the 1998 legislation (). The mean quarterly change compared with the expected number of registrations based on trends in the pre-intervention period was − 10.7 (95% CI − 20 to − 1), equating to a 61% reduction (mean 6.9 individuals per quarter vs. mean 17.6 in the pre-legislation period) (). This was equivalent to 482 fewer registrations over the 11.25-year period following the legislation. We obtained a similar result when we used the beginning of 1998 as the legislation point. A conservative estimate of the absolute change in number of registrations for liver transplants was smaller, and was not significant.
Paracetamol-related registrations for liver transplantation waiting list in England and Wales, 1995–2009, by quarter years, and best fit regression lines related to the 1998 legislation.
Changes in number of paracetamol-related registrations for liver transplantation and liver transplants in England and Wales, 1995–2009, associated with 1998 legislation to reduce pack size
Liver transplantation
There was a non-significant reduction in number of liver transplantations for paracetamol-induced hepatotoxicity in England and Wales in the period October 1998–2009 following the legislation compared with the estimated level based on the 1995–September 1998 trend (). The estimated mean quarterly change was − 3.4 (95% CI − 12 to 6) transplantations (see ). The number of liver transplantations for all causes in the UK showed a small but non-significant increase during the post-legislation period (from a mean estimated quarterly number of 132.3 before the legislation to 148.8 after).
Paracetamol-related liver transplantations in England and Wales, 1995–2009, by quarter years, and best fit regression lines related to the 1998 legislation.
Non-fatal self-poisoning with paracetamol
There was no decline in the number of hospital presentations in Oxford between 1993 and 2009 for non-fatal overdoses involving paracetamol (pure or compound form) (1993–8 mean = 567.0 per year vs. 1999–2009 mean = 601.6 per year).
Discussion
We have shown that the 1998 legislation to restrict pack sizes of paracetamol was associated with a significant reduction in the number of deaths from paracetamol poisoning in England and Wales over an 11-year period, in terms of both deaths receiving a suicide or an open verdict from the coroner and deaths receiving a suicide, an open or an accidental verdict from the coroner. This effect was found in analyses with estimates based on a continuation of the pre-legislation trend, as well as with more conservative estimates assuming no increasing trend in the absence of the legislation. The downwards step change was not apparent when the intervention point was moved back to the beginning of 1998.
There was no significant change in number of deaths from fatal poisoning with paracetamol compounds, but these constituted a relatively small proportion of paracetamol-related deaths. There was also a significant reduction in number of deaths from poisoning with drugs excluding paracetamol between 1998 and 2009, but to a lesser extent than was found for paracetamol and without the step change associated with the 1998 paracetamol legislation. When we repeated the analyses for paracetamol with an adjustment for underlying trends in poisoning deaths (excluding those that were paracetamol related) the findings for paracetamol deaths were largely unaltered.
Following the legislation a significant reduction was also found in the number of registrations for liver transplantation in England and Wales for paracetamol-induced hepatotoxicity, although a downwards step change was also apparent when the beginning of 1998 was used as the intervention point, and the change was not significant using a conservative estimate of the effect. Although there was also a reduction in the number of liver transplants of a similar order to that for registrations, this was not statistically significant because of the smaller numbers involved. It is interesting that the decline in liver unit activity (see and ) shows a somewhat different pattern from that for paracetamol poisoning deaths (see Figure 2), with the former flatlining after an initial abrupt reduction and the latter a more continuous reduction. The reasons for this are unclear.
The reduction in number of registrations for liver transplantation is particularly striking because in 2005 the criteria for registration were broadened, with a lowering of the thresholds for consideration for surgery.83 It is possible that some of the reduction in liver transplant registrations may have resulted from improvements in the early management of patients presenting to hospital with paracetamol poisoning, including administration of the antidote N-acetylcysteine and the increasing sophistication and success of intensive care support provided to patients with paracetamol-induced acute liver failure.84 These factors could also have accounted for some of the downwards trend in numbers of paracetamol deaths observed over the study period; however, the process of change has been one of continuous evolution and would be unlikely to account for the step change seen in outcomes coincident with the introduction of pack size restrictions. It is important to note, however, that, based on data from Oxford, presentations of non-fatal overdoses to hospital involving paracetamol did not decrease during the study period.
The impact of the 1998 legislation restricting pack sizes of paracetamol is likely to reflect the fact that many people who self-poison with paracetamol take what is available in the household,65,85 especially if the overdose is impulsive. Also, when individuals buy paracetamol specifically for the purpose of an overdose, the quantity per purchase is limited. Perhaps the most convincing evidence that reduced pack sizes of paracetamol have contributed to a reduced occurrence of hepatotoxicity and mortality is our earlier finding that the legislation was followed by a reduction in the number of tablets taken in paracetamol overdoses and in the number of large overdoses.12,65
Strengths and limitations
One limitation of this study is that we used only data on deaths from poisoning with paracetamol (with or without alcohol) in pure or compound form, not deaths in which paracetamol was consumed with other drugs. This approach, however, ensured that the findings of the study were restricted primarily to paracetamol and not substantially affected by the toxicity of other drugs or compounds. One strength of the study is that it was based on national data for both deaths and liver unit activity.
We have not been able to estimate the number of possible substitutions of paracetamol overdoses with other methods of poisoning or self-harm, but the trend in total suicides (all methods) during the post-1998 legislation period was downwards, as was the trend in suicides by ingestion. This downwards trend in all suicides probably reflects other factors that have favourably influenced suicide rates and, hence, may have contributed to the findings for paracetamol poisoning deaths. A further limitation was that data on non-fatal overdoses of paracetamol were restricted to one hospital, but this included all presentations, not just admissions.
Conclusions
The legislation introduced in 1998 to restrict pack sizes of paracetamol was associated with long-term benefits in terms of reduced numbers of deaths from paracetamol poisoning and registrations for liver transplantation. The number of deaths annually from paracetamol poisoning suggests, however, that further methods of prevention should be sought.
STUDY 2: AN INTERVIEW STUDY OF PATIENTS WHO HAVE TAKEN LARGER PARACETAMOL OVERDOSES
Objectives
The objectives were to conduct an interview study to investigate the characteristics of larger paracetamol overdoses and the people who use this method of self-poisoning, and to assess whether the intention of the legislation to restrict sales of large numbers of tablets is being complied with by shops and pharmacies.
Methods
Patients were eligible for inclusion if they had taken an overdose of > 16 pure paracetamol tablets, were aged ≥ 16 years and had received a psychosocial assessment by a member of the clinical self-harm team in the Department of Psychological Medicine at the John Radcliffe Hospital in Oxford.
The research interview consisted of standardised and open-ended questions regarding the circumstances of the act, the number of tablets consumed, the number available, the source of the tablets, whether the patient had tried to buy more than the recommended amount and his or her expectations of the physical effects of overdose (see Appendix 4).
Patients were shown cards with common motives for overdoses written on them (modified from Bancroft et al. 197986) and were asked to choose those that best explained their own motivation. They were also asked about previous paracetamol overdoses and potential influences on their decision to take the current overdose. Scores on the Suicidal Intent Scale (SIS)87 were recorded, using data collected by the clinician during the psychosocial assessment. At the end of the research interview, patients completed the Hospital Anxiety and Depression Scale (HADS).88
The patients' verbatim responses to open-ended questions were recorded manually by the interviewer. The interviews were carried out between November 2008 and July 2010 by a research interviewer, members of the clinical self-harm team and a research support facilitator.
The study received ethical approval from Oxfordshire Research Ethics Committee C (REC reference 08/H0606/45) and from the Research and Development Departments of the Oxford Radcliffe Hospitals NHS Trust and Oxford Health NHS Foundation Trust.
Quantitative data were analysed with SPSS for Windows version 14 (SPSS Inc., Chicago, IL, USA) using descriptive statistics, including chi-squared and Mann–Whitney tests. A simplified thematic approach was used to examine qualitative data arising from the patients' responses to open-ended questions. Themes were identified by SS from the written comments and reviewed and approved by KH.
Results
Sixty patients were included in the study. shows the flow diagram for inclusion and exclusion of potential participants.
Flow chart of recruitment to the study. Source: Simkin S, Hawton K, Kapur N, Gunnell D. What can be done to reduce mortality from paracetamol overdoses? A patient interview study. Q J Med 2012;105:41–51. By permission of Oxford University Press. (more...)
Patient characteristics
The study sample included 35 females [mean age 29.9 years, standard deviation (SD) 13.2 years, range 16–65 years] and 25 males (mean age 33.3 years, SD 14.9 years, range 19–65 years) (). For 24 patients (40.0%) this was their first overdose, but 10 patients (16.7%) were multiple repeaters, having taken at least five previous overdoses (see ). Over half (n = 32, 53.3%) had taken a previous overdose of paracetamol. The SIS was completed for 59 patients. High (13–20) or very high (21+) scores were recorded for over half (n = 33, 56.0%) of these patients. At the time of the research interview, 43 patients (72.9%) reached case status for anxiety (score > 9) on the HADS and 37 (62.7%) reached case status for depression (score > 9).
Characteristics of patients included in the study (n = 60)
Nature of the overdose
Over one-third of the patients had consumed alcohol at the time of the overdose (). Presentation to hospital was delayed by > 6 hours after taking the tablets in 22 cases (36.7%). The majority (n = 50, 83.3%) were treated with the antidote N-acetylcysteine. Seventeen patients took one or more other drugs in their overdose.
Characteristics of the overdose (n = 60)
The number of paracetamol tablets taken ranged from 18 to 224. Over three-quarters of the patients took fewer than 50 tablets, but over half (n = 35, 58.3%) took all of the tablets available. Half of the patients had taken the overdose impulsively, within an hour of first thinking about it (see ). One-quarter said that they had thought about the act for < 15 minutes before taking the tablets. However, seven people had considered the overdose for more than a week.
Source of the paracetamol
In many cases (n = 32, 53.3%) the tablets were already in the home, mostly for general pain relief. Three people had boxes of 100 tablets, which had been prescribed after operations or for back pain. Over half (n = 32, 58.3%) bought tablets specifically for the overdose (nine of these also had supplies at home). Most purchases were made from a supermarket or pharmacy (see ). Other outlets included four garages and an online pharmacy site.
Ten people tried to buy > 32 tablets in one transaction; four succeeded. Of these, one was able to buy in bulk from a cash and carry outlet, one purchased 14 packs of 16 tablets from an online pharmacy, and one obtained multiple packs by telling pharmacy staff that he was going away on holiday and needed supplies to take with him. The fourth bought three packs of 16 tablets from a supermarket. Nine patients commented that they were aware of the limit on sales and had therefore bought supplies in more than one transaction.
Anticipated effects of the overdose
When asked what they had thought the physical effects of the overdose would be if untreated, the majority (n = 53, 88.3%) said that they knew that a paracetamol overdose could cause death or permanent damage (see ). Over three-quarters (n = 48, 80.0%) knew that excess paracetamol could harm the liver. However, 42 (70.0%) thought that they would lose consciousness after the overdose. Over half of these (n = 23, 54.8%) said that they would not have taken paracetamol if they had known that they would not lose consciousness and that the effects would not be immediate.
The patients were asked how many tablets they thought would cause death. Twelve (20.0%) did not know. Of the rest, the number chosen ranged from 7 to 200. Five people (8.3%) thought that ≤ 16 tablets could kill, and 17 (28.3%) thought that 17–32 tablets would be lethal. Nine (15.0%) thought that ≥ 100 tablets would be necessary to cause death. Some people's opinion was influenced by the pack sizes: ‘I thought that over 32 tablets would be toxic, as that is the limit you can buy over the counter'; ‘Ten tablets could kill, because it says on the pack not to take over eight’.
Paracetamol packs include a warning about the dangers of overdose. Just under half of the patients (n = 29, 48.3%) said that they had noticed this, but in most of these cases (23/29, 79.3%) this had not affected their decision to take the tablets. Six people reported that the warning had strengthened their decision, for example, ‘The wording [i.e. go straight to doctor if you take more than eight] implies that it would be good to overdose on . . . The warning made it seem that an overdose would be effective.'
Most of those who had not noticed the warning said that they would still have taken the overdose if they had seen it (24/30, 80.0%). Only five people thought that seeing the warning would have deterred them from taking the tablets. Almost all (52/58, 89.7%) said that they would still have taken a paracetamol overdose even if the packs had contained fewer tablets.
Motivation
When asked to indicate which of the motives shown on cards best explained why they had taken their overdose (they could choose as many as they liked), over three-quarters said that they had wanted to die (). Other common reasons were ‘to get relief from a terrible state of mind’ and ‘to escape from an unbearable situation’.
Reasons for taking the overdose
Influences and reasons for taking paracetamol
Over one-third of the patients (n = 23, 38.3%) knew someone else who had taken an overdose of paracetamol. Twenty-one patients (35.0%) had seen or read about paracetamol overdoses in the media; nine (42.9%) of these thought that this had influenced their decision to take an overdose. For example, two people had read newspaper articles that specified the number of tablets taken in fatal overdoses and then took the same number of tablets in their own overdose. Another person saw a local news item about someone who had taken paracetamol together with alcohol and other medication; she went out the next day to buy paracetamol to take with her own prescribed medication and alcohol. Eight people had used the internet to obtain information on suicide methods. Five of them said that this had influenced their decision to take paracetamol and had provided them with information on toxic amounts.
When asked why they had chosen to take paracetamol in their overdose, over one-third (n = 23, 38.3%) said that the tablets were already in the household. Twelve (20.0%) bought paracetamol because it was cheap and readily available. Sixteen people (26.7%) had chosen paracetamol because they knew that it was effective: ‘. . . catastrophic effect on the liver’.
Although patients were aware of the unpleasant effects of paracetamol, this did not deter them: ‘I heard it was a slow and painful death’; ‘I don't deserve any better than a horrible death’. Five people (8.3%) said that they had taken paracetamol because they had done so in the past: ‘I've always done paracetamol – I know it's a nasty killer, it takes a long time to do it’; ‘I've always done so in the past and always managed to get through it’.
Discussion
The overall aim of this study was to obtain information that might assist in the identification of further initiatives to reduce paracetamol overdoses, especially those involving large and hence potentially life-threatening numbers of tablets.
As found in other studies,26,64 the main reasons that patients gave for using paracetamol for overdose were that it was cheap and easily available (either already in the household or easy to buy from multiple outlets). Over half of the patients took all of the tablets that were available to them, compared with one-third of patients in an earlier interview study in Oxford65 (in which patients who took smaller overdoses were included). In both studies, similar proportions of patients had bought tablets specifically for the overdose: 58.3% in the current study compared with 52.5% in the earlier study. In a study of patients who took paracetamol overdoses and presented to an emergency department in south London after the legislation, 48% of patients who had ingested > 16 tablets had purchased paracetamol specifically for the act, whereas those who had taken < 16 tablets were more likely to have taken tablets already in the household.74
Nearly one-third of those who bought tablets specifically for the act had spent < 1 hour planning it. If their distress was apparent, this might suggest the potential for intervention at the point of sale, but it is probably unrealistic to expect sales staff to identify such individuals and to intervene in any positive way, apart from refusing to supply more than the recommended number of tablets.
Four of the 10 people in our study who tried to buy more than the recommended amount of paracetamol in one transaction were able to do so, including a person who bought 224 tablets from an online pharmacy. We alerted the MHRA about the internet sale, and the online outlet subsequently restricted purchases of paracetamol to 32 tablets.
One of the intentions behind the pack size legislation was to reduce the dangers of impulsive overdoses by limiting the number of tablets available in the household at any one time. Half of the patients in our study had taken the overdose within an hour of first seriously contemplating it, including one-quarter who had thought about the act for < 15 minutes.
Public knowledge of the dangers of paracetamol overdose has increased considerably since the late 1970s.31 In our study, 88% of patients knew that an overdose could cause death or permanent damage, a similar figure to the 78% of patients in the earlier (1992–3) Oxford study.64 However, 80% in the present study knew of the potential for hepatotoxicity compared with 43% in the earlier study. Despite being aware of the harmful effects of paracetamol overdose, a high proportion of the patients thought that they would quickly become unconscious. This finding is consistent with that from other studies.26,31,64 If people who take a paracetamol overdose expect to lose consciousness but do not, they may think that they have not taken a dangerous amount and may not seek medical attention until symptoms of liver damage appear, by which time it may be too late to treat successfully. Half of the patients in our study who were unaware that they would not lose consciousness immediately said that they would not have taken the paracetamol overdose if they had known this. There may be potential for educational initiatives highlighting this aspect of paracetamol toxicity, although it is possible that this may have a reverse effect (e.g. an episode of a popular television drama featuring a fatal paracetamol overdose was followed by an increase in similar overdoses among viewers89).
Nearly half of the patients had noticed the warnings about the dangers of overdose printed on the pack, but in most cases this did not affect their decision to take the tablets; indeed, for some people the warning had reinforced their decision by confirming that an overdose could be lethal. This apparent lack of a positive impact of warning signs on packs in this sample was also found in the earlier Oxford study.65
The role of the media and the internet in providing information about paracetamol overdose was clear in some cases. It is important that media guidelines that emphasise the importance of not providing precise details of suicide methods be followed.90,91
Limitations
The study was based in a single large general hospital and so it is uncertain if the findings are generalisable to patients presenting to other hospitals. However, the characteristics of people presenting to the hospital in Oxford with paracetamol overdoses are similar to those seen elsewhere.46 We relied on patient report of the number of tablets that they had taken in overdose, and this may be unreliable.42,46,92
Conclusions
The characteristics of the patients in our study who took paracetamol overdoses were remarkably similar to those in the previous Oxford study64 over 15 years earlier. The impulsive nature of many of the overdoses and the fact that a substantial proportion of patients used household supplies of paracetamol for self-poisoning mean that special attention needs to continue to be paid to the availability of paracetamol, especially in quantities that can cause hepatotoxicity. There appears to be reasonable adherence to the sales guidance. Media influences on use of paracetamol for self-poisoning, including through the internet, are important in some cases.
STUDY 3: A COMPARATIVE STUDY OF THE IMPACT OF DIFFERENT PACK SIZES OF PARACETAMOL ON INTENTIONAL OVERDOSES IN ENGLAND AND IRELAND
Objective
The objective of this study was to compare sizes of overdoses of paracetamol taken in England and in Ireland to answer the question of whether or not it might be beneficial to further reduce pack sizes of paracetamol in the UK.
Methods
We investigated the number of tablets of paracetamol consumed in overdoses that resulted in presentation to six general hospitals in three centres in England and all general hospitals in Ireland between 2002 and 2007 for those aged ≥ 10 years. Data were restricted to non-fatal, intentional self-poisoning episodes in which paracetamol was the sole medicinal agent consumed (with or without co-ingestion of alcohol) and at least four tablets were taken at one time (i.e. double the maximum recommended single therapeutic dose of two tablets). The data collected in the study hospitals included patient sex and age, drugs used for self-poisoning, numbers of tablets, and alcohol involvement at the time of the overdose.
Data sources
Multicentre Study of Self-harm in England
The Multicentre Study of Self-harm in England project is based on data collected on general hospital presentations for self-harm in six major general hospitals in England:1,93 one in Oxford, three in Manchester and two in Derby.
National Registry of Deliberate Self Harm in Ireland
Information is collected in the National Registry of Deliberate Self Harm for all presentations for intentional self-poisoning and self-injury to general hospitals in Ireland.53
Ethical approval
The monitoring systems in Oxford, Manchester and Derby all have approval from local ethics committees to collect data on self-harm for local and multicentre projects. The National Registry of Deliberate Self Harm in Ireland has ethical approval from the National Research Ethics Committee of the Faculty of Public Health Medicine, and from the relevant hospitals and Health Service Executive ethics committees.
Data analysis
We used SPSS for Windows version 14 to compare overdoses of paracetamol in England and Ireland. Analyses comparing the numbers of tablets consumed, and numbers of packs used, in overdoses of paracetamol in England and Ireland were conducted using the chi-squared test, Mann–Whitney U-test and Kruskal–Wallis test. Analyses were conducted on combined data and separately by sex, age group and alcohol involvement with the overdose (data from the English study on alcohol consumed during the 6 hours before self-poisoning and/or as part of the overdose were combined for this analysis). The number of packs used was calculated as a multiple of the non-pharmacy maximum pack size in each country, from one pack to nine or more packs (e.g. in England an overdose involving up to one pack was 4–16 tablets, two packs was 17–32 tablets, three packs was 33–48 tablets, and so on; in Ireland, up to one pack was 4–12 tablets, two packs was 13–24 tablets, three packs was 25–36 tablets, and so on).
Results
Study samples
During the 6-year study period (2002–7) there were 31,107 hospital presentations for self-poisoning (alone) in the three English centres (six hospitals) and 42,877 in Ireland (up to 40 hospitals: 34 in 2002, 37 in 2003, 38 in 2004–5 and 40 in 2006–7). Of these, paracetamol was involved in 10,208 (32.8%) episodes in the English centres and in 9057 (21.1%) episodes in Ireland. Paracetamol alone (with or without alcohol) was involved in 5444 episodes in the English centres and in 3886 episodes in Ireland.
Of the episodes involving paracetamol alone, data on number of tablets taken in overdose were missing for 559 (10.3%) episodes in the English centres and 358 (9.2%) in Ireland. We also excluded episodes in which fewer than four tablets were taken, data on sex or age were missing or patients were < 10 years old [totalling 27 (0.5%) in the English centres and 19 (0.5%) in Ireland]. Thus, the samples for inclusion in the study consisted of 4858 episodes in the English centres and 3509 in Ireland.
The female to male ratio for episodes was somewhat larger among the Irish sample (2.1 : 1) than among the English sample (1.8 : 1) (). The age distributions of the two samples showed a greater proportion of younger individuals among the Irish sample and a greater proportion of older people among the English sample. Alcohol use at the time of overdose occurred with similar frequency in the English and the Irish samples.
Episodes of self-poisoning with a known number of paracetamol tablets for those aged ≥ 10 years in three centres (six general hospitals) in England and in Ireland, 2002–7
Number of tablets taken in overdoses
The distribution of the number of tablets taken in paracetamol overdose in the English centres and in Ireland is shown in . There were clear peaks in each of the countries corresponding to the pack size limits for non-pharmacy and pharmacy sales. Thus, in the English sample there were peaks at 16 and 32 tablets and in the Irish sample there were peaks at 12 and 24 tablets. There were also peaks at multiples of these pack sizes. There were, in addition, peaks in both samples at 10 and multiples of 10 tablets.
Distribution of the number of tablets taken in paracetamol overdose by those aged ≥ 10 years in England (n = 4858) and Ireland (n = 3509), 2002–7, shown as percentages of the total number of overdoses (more...)
The median number of tablets consumed in paracetamol overdoses did not differ significantly between the English (median 22 tablets) and the Irish (median 24 tablets) samples (). When the samples were divided into three age groups and the two countries compared, a small but statistically significant difference in the median number of paracetamol tablets consumed between the English (median = 24) and the Irish (median = 23) samples was found among women in the ≥ 35 years age group (see ).
Numbers of tablets of pure paracetamol taken alone in overdose in England and Ireland, 2002–7, by sex and age group
In both England and Ireland, more paracetamol tablets tended to be taken by men but not women when alcohol was involved in overdoses (England: Z = − 3.141, p = 0.002; Ireland: Z = − 2.105, p = 0.035) (). There was a non-significant trend for smaller overdoses in males in Ireland who had not consumed alcohol than in those in England who had not consumed alcohol.
Number of tablets of pure paracetamol taken alone in overdose in England and Ireland, 2002–7, by alcohol use at the time of, or before, the overdose
Number of packs used in overdoses
When the numbers of tablets consumed in overdoses by individuals in each country were categorised into numbers of pack equivalents used, the mean number of packs used was greater in Ireland (2.63, 95% CI 2.57 to 2.69 packs) than in England (2.07, 95% CI 2.03 to 2.10 packs). For both sexes combined, the largest proportion of overdoses in England (39.0%) involved one pack only, but the largest proportion of overdoses in Ireland (37.9%) involved three or more packs (). Females and the younger age group (15–24 years) in England were more likely to use one pack, but two packs were more likely in Ireland in these groups. Males and older age groups (25–34 years and 35+ years) were far more likely to use three or more packs in Ireland than in England.
Number of non-pharmacy pack equivalents of pure paracetamol used in overdoses in England (maximum pack size = 16 tablets) and in Ireland (maximum pack size = 12 tablets), 2002–7
Discussion
We found little evidence that different restrictions on paracetamol pack sizes in England and Ireland had an impact on sizes of overdoses taken in the two countries. There were peaks in the numbers of tablets taken in paracetamol overdoses in both England and Ireland that reflected the maximum pack sizes in the respective countries. Peaks were also found for multiples of these pack sizes, which could reflect overdoses in which multiple packs were purchased for the acts. The additional peaks in both samples at 10 and multiples of 10 tablets presumably reflect effects of rounding or approximation by patients and possibly clinicians.
There was a marked difference between England and Ireland in terms of the number of pack equivalents of paracetamol taken in overdoses. More pack equivalents were in general consumed in overdoses in Ireland. This difference was found for both sexes and across all three age groups examined. This raises the following questions:
Is advice on sales of packs being followed to the same extent in the two countries?
Do purchasing patterns differ, with paracetamol packs being bought with greater frequency in Ireland, so that more are available in households?
Are there differences in patient characteristics between the two countries influencing patterns of self-poisoning?
Are individuals in Ireland who have taken paracetamol overdoses less likely to present to hospital when the amount taken is relatively small?
Unfortunately, we do not have access to over-the-counter (OTC) sales data for the two countries. We have no reason to believe that there are major differences between the sociodemographic characteristics of patients who take paracetamol overdoses in England and the characteristics of patients who take paracetamol overdoses in Ireland, except that it appears that paracetamol is taken more frequently in overdose in England, that the female to male ratio is greater in Ireland, and a somewhat greater proportion of patients in Ireland are in the youngest age group. These differences do not, however, appear large enough to explain the extent of the difference in patterns of pack consumption in overdoses. However, there might be differences in other characteristics that contributed to the findings but which we were unable to compare, such as degree of suicidal intent and other psychological factors. We do not have information in this study on the frequency of hospital presentations in relation to the size of overdoses in the two countries. One important difference between the two countries is that many individuals who present to emergency departments in Ireland are subject to a fee, whereas this is not the case in England. Also, obtaining general practitioner care in Ireland often involves a fee, which could influence willingness to seek help for emotional problems and therefore increase the risk of self-poisoning. The more rural nature of Ireland, and hence larger distances to hospitals for many residents, could also influence presentation to emergency departments.
An important possible explanation for the difference in number of packs used for overdoses in England and Ireland may be less rigorous enforcement of sales advice contained in regulatory notices in Ireland than in England. A study conducted before the Irish legislation was introduced indicated that sales advice for non-pharmacy outlets from the Irish Medicines Board was often not being followed.94 Following the introduction of the legislation, researchers visiting pharmacy and non-pharmacy outlets in Dublin were able to purchase in excess of statutory limits of paracetamol in a single transaction in half of all pharmacies and the majority of non-pharmacy outlets – a situation that largely persisted when the researchers revisited outlets a year later.95 Although there is also evidence of breaches of the legislation in non-pharmacy outlets in England,74 this appears to happen to a far lesser degree than in the post-legislation study in Ireland95 (see earlier in this chapter).
Strengths and limitations
The study involved large numbers of patients in both countries: the Irish sample included all overdose presentations to general hospitals in Ireland, and the English sample included presentations to six general hospitals in three centres (although these may not be fully representative of all general hospitals in England). The recording of the number of tablets taken in overdoses relied largely on patient self-report, which is known to be subject to inaccuracy.42,54,92
It is not known whether or not there was any change in the sizes of overdoses in Ireland following the introduction of the 2001 legislation on pack sizes there.77 However, the size of overdose for which calls were made to the National Poisons Centre decreased in the first 2 years after the legislation was introduced.96
We have not been able to examine the impact on actual suicides of the differing legislation in the two countries because data for suicide deaths according to specific drugs ingested are not currently available in Ireland.
Conclusions
No major difference was found between England and Ireland in the size of paracetamol overdose, in spite of differences in maximum pack sizes between the two countries. Although this may suggest that further reductions in pack sizes in the UK would not be effective in further reducing self-poisoning with paracetamol, the finding may reflect differences in adherence to sales guidance in Ireland compared with England, and other factors such as patient characteristics and ease of access to clinical care.
STUDY 4: THE IMPACT OF LIMITATIONS ON PACK SIZES OF ANALGESICS ON USE OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS AND CONSEQUENT GASTROINTESTINAL BLEEDING AND USE OF MEDICATION FOR GASTROINTESTINAL DISORDERS
Objectives
To investigate whether 1998 legislation to reduce pack sizes of paracetamol (and other analgesics) was followed by increased prescribing of NSAIDs with possible adverse effects on GI bleeding.
Methods
We examined prescriptions for NSAIDs and other analgesics, plus those for medication for GI symptoms, and hospital admissions for GI haemorrhage for the period 1994–2004. We limited the study period to 1994–2004 because in 2004 prescribing of NSAIDs changed markedly because of the withdrawal of some COX-2 inhibitor drugs.97
Sources of data
Prescriptions
IMS Health provided quarterly data from Disease Analyzer UK on the numbers of patients prescribed drugs in the therapy classes listed below, by age groups 15–34, 35–54, 55–64 and 65+ years, for the years 1994–2004. IMS Disease Analyzer UK is a primary care database containing de-identified general practice patient records continuously collected from around 210 computerised practices throughout the UK. The sample is designed to be representative of the UK population. The drugs for which we analysed data were non-narcotic analgesics (including NSAIDs), antirheumatic non-steroidal drugs, and drugs that might be prescribed to alleviate GI symptoms, including antiulcerants as one category and all other GI drugs as a second category (antacids, antiflatulents, antispasmodics, anticholinergics and gastroprokinetics). The Disease Analyzer data set also contains the number of patients available for diagnosis/treatment.
Hospital admissions
We used the Department of Health's Hospital Episode Statistics Database for England98 to extract quarterly data on the number of hospital admissions for GI haemorrhage between 1994 and 2004, for age groups 15–34, 35–54, 55–64 and 65+ years. Admission rates were calculated using quarterly population figures interpolated from the corresponding annual mid-year population estimates for England from the ONS.99
Statistical analysis
Gastrointestinal admission and prescription rates (number of admissions and prescriptions per 100,000 population) for each age group were calculated on a quarterly basis using the population data. The impact of the legislation on numbers of GI admissions and prescriptions and trends in GI admission and prescription rates was analysed using interrupted time-series analysis. This method controls for baseline rate and trend when estimating expected changes in the number of GI admissions (or prescriptions) due to the intervention. The third quarter of 1998 was chosen as the point of intervention. All analysis was carried out using Stata version 11.2.
Results
Prescriptions for non-steroidal anti-inflammatory drugs and other analgesics
There was a significant increase in the rate of prescribing of NSAIDs following the 1998 legislation regarding pack sizes of paracetamol of 31.5 per 100,000 per quarter (p = 0.009). There was also an increase in prescribing of other non-narcotic analgesics (p = 0.05) ( and ).
Changes in prescriptions involving NSAIDs and other drugs associated with and without the 1998 legislation
Rates of prescribing of NSAIDs, other non-narcotic analgesics, antiulcerants and other GI drugs, 1994–2004 (second quarter), from a UK primary care database. Source: IMS Health.
Hospital admissions for gastrointestinal bleeds
There was an immediate increase in the hospital admission rate for GI bleeds of 3.66 per 100,000 per quarter after the 1998 legislation (p = 0.012). However, the rate of change of GI admissions during the whole post-legislation period declined by 0.4 per 100,000 per quarter (p = 0.012) compared with beforehand ( and ).
Changes in GI admission rates associated with and without the 1998 legislation
Rates of hospital admissions in England for GI haemorrhage, 1994–2004 (second quarter).
During the study period, the rate of admission for GI bleeds was highest in the 65+ years age group and lowest in the 15–34 years age group. Trends in admission rates showed a decline after the legislation in some age groups (), including in those aged 55–64 years (estimated mean change in the trend from before to after the legislation = − 0.63, 95% CI − 1.12 to − 0.14, p = 0.014) and 65+ years (mean change in trend = − 1.34, 95% CI − 2.06 to − 0.62, p = 0.001).
Rates of hospital admissions in England for GI haemorrhage, 1994–2004 (second quarter), by age group.
Prescriptions for gastrointestinal drugs
There was a steady overall increase in prescriptions for antiulcerants following the legislation (p < 0.001) (see and ). The increase was significant in the younger age groups [mean change in trend (95% CI) for those aged 15–34 years, 35–54 years and 55–64 years = 9.41 (7.03 to 11.79), 38.25 (17.09 to 59.42) and 90.37 (69.80 to 110.94), respectively (all p ≤ 0.001)], but not in those aged 65+ years [mean change in trend (95% CI) = 22.21 (− 130.76 to 175.17), p = 0.77].
There was no evidence of an increase in prescribing of other GI drugs following the legislation (p = 0.85) (see ). This applied to all age groups except those aged 15–34 years, in whom there was a gradual rise in prescribing over time [mean change in trend (95% CI) = 9.55 (3.32 to 15.77), p = 0.004].
Discussion
The 1998 legislation that limited pack sizes of paracetamol and aspirin was followed by increased prescribing of NSAIDs. There was also an increase in prescribing of other non-narcotic analgesics (which included paracetamol and aspirin). However, these changes were gradual, with no indication of a specific effect of the legislation.
There was no convincing evidence that the legislation had a major secondary impact on hospital admissions for GI bleeds. Although there was an immediate increase in admissions for GI bleeds following the legislation, it was relatively small and was followed by a decreasing trend in hospital admissions (possibly related to increased prescribing of antiulcerants). This decline in admissions was found only in age groups 55–64 years and 65+ years.
Although prescribing of antiulcerants increased following the 1998 legislation, there was no evidence of a stepwise increase, just a rising trend. There was no major change in prescribing of other GI drugs except for an increased trend in the 15–34 years age group. This is in keeping with an earlier finding in relation to the withdrawal of COX-2 inhibitors that no consistent evidence was seen of an adverse influence on trends in the incidence of GI haemorrhages.97
Limitations
We were unable to examine the impact of the legislation on OTC sales of analgesics, as this information was not available. This is important as any impact might be expected to occur primarily in relation to OTC sales. However, use of the data on admissions for GI bleeds and drugs used to treat GI disturbances allowed us to examine any negative effects of possible changes in use of NSAIDs on gastric health.
Conclusions
Prescribing of NSAIDs increased following the 1998 legislation on pack sizes of paracetamol and other analgesics. However, there was no clear evidence that the legislation had a specific impact on prescribing of NSAIDs as the gradual increase in prescribing of these drugs over time was also seen for other analgesics. There was also no evidence that GI bleeds increased as a result of any altered prescribing (or changes in OTC sales) associated with the legislation. However, a gradual increase in prescribing of antiulcerants could have offset changes in the incidence of GI symptoms.
