This primary care based study has characterised the population of people engaged with a methadone programme as being predominantly young men from a lower socioeconomic background.21
Psychiatric admission in the 12 years of follow-up occurred in almost half the cohort, co-prescribing of benzodiazepines occurred in three quarters of the cohort, and co-prescribing of antidepressants occurred in half. The population could thus be classified as a vulnerable and deprived group.
The overall mortality of 8% in the cohort during the 12 year study period is slightly above the annual mortality rate of four to five per 100
000 described in a previous Scottish study.12
Clear signals emerge in relation to safe prescribing and monitoring of methadone maintenance treatment in primary care, but caution is needed in that these associations may not be causal because of the nature of this observational study.23
Overuse of methadone may be a marker of less rigorous follow-up and communication between prescribing general practitioners and dispensing community pharmacists. Alternatively, overuse may be a marker for people who have dispersed the drug to others. UK guidance emphasises that methadone maintenance treatment needs a coordinated multidisciplinary approach.19
Although only a relatively small proportion of the people used a higher than recommended dose of methadone, their relative risk of death was more than one and a half times that of people who took the correct dosage. Not unexpectedly, comorbidity remains an independent risk factor in relation to all cause mortality in the cohort, and the strongest association was for patients with a history of psychiatric admission (table 3). In terms of protective factors, longer duration of treatment, increasing time since last methadone prescription, and a history of involvement in urine testing programmes (irrespective of the result) were associated with a reduced risk of all cause mortality. These are likely to be markers of people who are stabilised on maintenance treatment and engaged in monitoring procedures or who have successfully completed a methadone treatment reduction programme.
We found substantial under-dosing with methadone; 84% of the cohort were receiving a mean dose that was less than the recommended 60-120 mg advised by UK Advisory Council on the Misuse of Drugs and National Institute for Health and Clinical Excellence (NICE).19
This finding is consistent with comparative data in other countries.25
Commentators suggest that some proponents of methadone are strong advocates of higher doses of methadone in terms of retention and reduction of heroin usage.26
Evidence from randomised controlled trials comparing different methadone dosages supports this view, but the findings in relation to mortality from overdose, although favouring higher doses of methadone (>75 mg daily versus 5-55 mg daily), are based on a very small number of deaths (one death in high dose versus four deaths in low dose groups).27
More research is needed in relation to the risks and benefits of a low dose versus high dose approach to methadone maintenance in terms of retention and risk of overdose.
More than a third of the cohort who died had a principal cause of death attributed to a drug related cause. A different picture emerges in relation to individual and organisational risk factors in terms of drug dependent cause specific mortality (table 4). Co-prescription of benzodiazepines had the strongest association with drug dependent death, history of psychiatric admission remained an independent risk factor, and co-prescribing of antipsychotics and antidepressants was independently protective. Markers of stability with methadone or cessation of methadone remain protective—history of urine testing and time since last methadone prescription was filled (table 44
). These findings are important to community based methadone programmes. As NICE guidelines acknowledge,24
most randomised controlled trials of methadone in the treatment of drug dependence were done in outpatient or inpatient settings or specialist treatment centres. This community based study gives a clear indication of the prescribing, monitoring, and management of these patients and the subsequent impact on all cause and drug dependent mortality.
The unique nature of this dataset in terms of record linkage provides evidence that recommendations on best practice improve patients’ outcomes and that the improvements that have taken place in terms of the delivery of methadone maintenance programmes in the UK are likely to reduce the risk of death in this vulnerable group of people.8
This study also provides evidence about subgroups of people, particularly those with a history of psychiatric admission, who have a higher risk of death. Similarly, for general practitioners who are prescribing methadone, monitoring of urine and avoidance of co-prescribing of benziodiazepines should be implemented. The findings from this study emphasise the need for a psychosocial perspective in relation to ongoing management of people enrolled in methadone maintenance programmes. In some situations, people at higher risk (history of psychiatric illness, poor engagement with services including urine testing) might be more appropriately managed in a specialist, rather than a generalist, environment.
To avoid methadone related deaths and improve the quality of methadone prescribing, the UK Advisory Council on the Misuse of Drugs has produced guidelines that recommend a structured delivery of service with clear roles and responsibilities, particularly for the prescribing doctor, alongside psychosocial care.11
By providing clear and explicit recommendations about the prescribing and dispensing of methadone, in conjunction with an organised system of delivery, drug related mortality and morbidity are expected to be reduced.14
However, commentators acknowledge that many of the recommendations in the guidelines are “very loosely evidence-based,”14
and quality markers associated with the prescribing and delivery of methadone need to be validated and related to individual outcomes. The results of this cohort study provide evidence of the value of stabilised prescribing, regular monitoring of urine, and avoidance of co-prescribing of benzodiazepines when possible.
Context of other studies
In the context of other studies, our findings are consistent with the demographic pattern of drug related deaths occurring in young, socially deprived men.21
The findings in relation to all cause mortality are consistent with the high mortality described in the drug outcomes research in Scotland (DORIS) study.31
Although a relatively small proportion of the Tayside population were prescribed methadone, the proportion who died during the follow-up period was substantial. The applicability of our findings in terms of methadone maintenance programmes in primary care is therefore likely to be robust. Co-prescribing of benzodiazepines was associated with drug related death, which supports findings that these substances, along with alcohol, are commonly found in subsequent toxicological reports of drug related deaths.21
Previous UK research showed that people prescribed methadone as well as benzodiazepines were at greater risk of overdose than patients taking methadone alone.32
More detailed toxicology reports were not available, and we are unable to report on this. Nevertheless, the high proportion of co-prescribing of benzodiazepines throughout the study period, combined with its association with drug related death, is a troublesome finding.
Limitations of study
This study has some shortcomings. The significant association of a mean dose of methadone higher than that recommended with all cause mortality could be attributed to factors other than use of a higher dose of methadone in itself—for instance, it could be a marker for more chaotic drug using behaviour or dispersion of methadone. Furthermore, in observational studies of this sort, the possibility of residual confounding may remain a problem; caution is needed when interpreting the association of organisational and prescribing factors with all cause and drug dependent cause specific mortality, and these associations should be viewed principally as hypothesis generating. We could not collect data on cause of death for 15 (8%) of the total cohort who died and acknowledge that documented cause of death may have been difficult to ascertain or attribute for some people. Other shortcomings of the study relate to the limited details of practice arrangements regarding initial assessment, supervised consumption, and counselling arrangements. As a previous national study of drug related deaths found, the completeness of primary care records in relation to antecedent management is often poor.24
Lastly, our cut-off point of three months or more since the filling of the last prescription is likely to be conservative—many people will have stopped taking methadone by this time.
Implications for methadone programmes
This cohort did not have a record of psychological, quality of life, or other patient centred indices of wellbeing. Other community based studies have interviewed participants and obtained these types of data, albeit in a more selected sample.33
The interaction of psychological wellbeing, history of psychiatric admission, and the impact of psychosocial support alongside methadone prescribing and monitoring needs further study. In terms of improving the delivery of methadone maintenance programmes in primary care, paper based guidance may no longer be sufficient. Health information technology systems have been shown to improve quality of care by increasing adherence to guideline based recommendations, enhancing surveillance and monitoring, and decreasing the incidence of drug errors.35
Similarly, computerised clinical decision support systems that are focused more on clinical decision making and provide support on drug prescribing (dose, duration, and appropriateness), drug monitoring, and drug interactions may have a role. The requirement of an evidence based approach to methadone maintenance is well suited to implementation by means of such support systems, particularly in relation to coordination of care and multidisciplinary working.6
Computerised clinical decision support systems would also support alternative forms of opioid replacement treatment such as buprenorphine.37
This community based study shows that important elements in the process of care when providing methadone maintenance are likely to influence each patient’s risk of death. Prescribing of methadone could be improved, particularly as regards dosage, co-prescribing of benzodiazepines, and monitoring. Further research is needed into health information technology systems that provide structure to the planning, coordination, and monitoring needed for an effective methadone maintenance programme in primary care.35
What is already known on this topic
- Randomised controlled trials have shown that methadone maintenance is an effective intervention, decreasing illicit drug use, reducing injecting behaviour, and reducing opioid related deaths
- Concern exists about the safety of prescribing methadone in community settings, as methadone itself is associated with drug related deaths
What this study adds
- Overuse of methadone, history of psychiatric admission, and increased comorbidity were associated with all cause mortality; drug dependent deaths were associated with co-prescription of benzodiazepines and history of psychiatric admission
- History of urine testing, longer duration of use of methadone, and increasing time since last filled prescription were all associated with a reduced risk of death
- Important elements in the process of care when providing methadone maintenance in the community may influence each person’s risk of death.