Drug and Alcohol Findings home page in a new window EFFECTIVENESS BANK BULLETIN 18 July 2012

The entries below are our accounts of documents collected by Drug and Alcohol Findings as relevant to improving outcomes from drug or alcohol interventions in the UK. The original documents were not published by Findings; click on the Titles to obtain copies. Free reprints may also be available from the authors. If displayed, click prepared e-mail to adapt the pre-prepared e-mail message or compose your own message. The Summary is intended to convey the findings and views expressed in the document. Below may be a commentary from Drug and Alcohol Findings.


Contents

Will heart attack risk undermine recovery potential of methadone?

All the entries in this bulletin focus on medications which substitute for heroin and in particular methadone, in Britain and internationally the most widely prescribed, a long-acting drug taken by mouth which promises to stabilise the roller-coaster of heroin injection and enable addicts to get on with their lives. In Britain an expert group has addressed head on the criticism that methadone substitution means giving up on recovery for too many patients. In its favour above all is the compelling mantra that dead people cannot recover; methadone saves lives, giving patients a chance to overcome their problems. That is why the assertion that methadone itself risks death through heart attack is potentially so damaging and so controversial. Is the risk real enough to enforce cautionary measures which curtail methadone treatment and might themselves cost lives? A US expert panel changed its mind and British and US studies suggest the risk is very small.

Crucial report aims to rehabilitate methadone as a recovery tool ...

No need for heart tests on all methadone patients ...

Heart tests reveal no heightened risk at London methadone clinic ...

Cocaine aggravates any methadone-related heart risk ...


Medications in recovery: re-orientating drug dependence treatment.

Strang J. et al.
[UK] National Treatment Agency for Substance Misuse, 2012.
Unable to obtain a copy by clicking title? Try this alternative source.

On behalf of the UK government an expert group has developed and documented a clinical consensus on how prescribing-based treatment for heroin addiction can be made more recovery-oriented in line with national strategy. Their report will be the main reference point in tussles over what recovery means for methadone services and patients.

Summary Acting on behalf of the UK Department of Health, in August 2010 the National Treatment Agency for Substance Misuse – a special health authority which aims to improve treatment for drug problems in England – asked Professor John Strang to chair a group of experts (the Recovery Orientated Drug Treatment Expert Group) to guide the drug treatment field on the use of medications to aid recovery from drug addiction and on how patient care can be more fully orientated to optimise recovery, objectives consistent with the 2010 English national drug strategy.

That strategy expressed concern that "for too many people currently on a substitute prescription, what should be the first step on the journey to recovery risks ending there", and wanted to "ensure that all those on a substitute prescription engage in recovery activities". The group's task was to reach a clinical consensus which would guide clinicians and agencies in helping opioid substitution Editor's note: The use of legally prescribed medications like methadone and buprenorphine with effects similar to those of heroin (sometimes heroin itself is also prescribed) to substitute for the illegal heroin or other opiates patients have become dependent on, ideally releasing them from the experienced need to obtain and use illegal supplies and providing the stability and therapeutic contact which can promote lasting recovery from addiction. patients achieve their fullest personal recovery, improve support for long-term recovery, and avoid unplanned drift into open-ended maintenance prescribing. The group sought to reflect the evidence and contextualise it within the current UK environment and the ambitions of the 2010 English drug strategy.

In framing its recommendations the expert group had available to it a review of the evidence which combined research findings on evidence-based practice with humanitarian, recovery-based considerations based on values such as responsibility, choice, and empowerment.

The authors' conclusions

This account is based on the summary in the main report.

Heroin users are the largest single group in treatment and use an especially tenacious, habit-forming drug in the most dangerous ways. The main task of the Recovery Orientated Drug Treatment Expert Group was to describe how to meet the national strategy's ambition to help more heroin users recover and break free of dependence.

Entering and staying in treatment, coming off opioid substitution treatment, and leaving structured treatment, are all important indicators of an individual's recovery progress, but do not in themselves constitute recovery. Leaving substitution treatment or any treatment prematurely can harm individuals, especially if it leads to relapse, which is also harmful to society. Recovery is a broader and more complex journey that incorporates overcoming dependence, reducing risktaking behaviour and offending, improving health, functioning as a productive member of society, and becoming personally fulfilled. These recovery outcomes are often mutually reinforcing.

The ambition for more people to recover is legitimate, deliverable and overdue. Previous strategies focused on reducing crime and drug-related harm to public health, in respect of which society benefited from people being retained in treatment as much from completing it. This allowed a culture of commissioning and practice to develop that gave insufficient priority to an individual's desire to overcome his or her drug or alcohol dependence, particularly for heroin users receiving substitution treatment, where the protective benefits have too often become an end in themselves rather than a safe platform from which users might progress towards further recovery.

Overcoming drug or alcohol dependence is often difficult, and especially so for dependence on heroin. US studies suggest that over 30 years, half of all dependent users will die, a fifth will recover, and the remainder will continue to use opiates, some at a lower level. An accessible, evidence-based, drug treatment system in every part of England affords an excellent opportunity to improve on the past, seeing international, historical evidence as the floor for current ambition, not its ceiling.

England has lower rates of drug-related deaths and blood-borne virus infections than most of Europe and North America. Most people who enter treatment want to recover and break free of their drug dependence. More can be helped to realise this ambition if safe, evidence-based, recovery-orientated practice can be allied with the public health and wider social benefits already accrued from treatment.

Research, the international track record, and clinical experience, show that not everyone who comes into treatment will overcome their dependence, but that it is not possible or ethical to predict who will eventually do so – why we are obliged to create a treatment system which makes every effort to provide the right package of support to maximise each individual's chances of recovery.

Fewer young people are now coming into treatment for dependence on the most damaging drugs such as heroin, but there is an ageing cohort of drug dependent and ex-dependent individuals who will experience an increase in morbidity and mortality as they develop multisystem diseases that need complex treatment. Primary and secondary care services will be needed to treat them.

Well-delivered opioid substitution treatment provides a platform of stability and safety that protects people and creates the time and space for them to move forward in their personal recovery journeys; it has an important and legitimate place in recovery-orientated systems of care. The drug strategy is clear that medication-assisted recovery can and does happen. We need to ensure this treatment is the best platform it can be, but focus equally on the quality, range and purposeful management of the broader care and support it sits within.

Sticking closely to the compelling evidence for effective opioid substitution treatment and existing guidance based on that evidence will deliver many of the improvements needed, but more can and should be done. A determined assessment of the shortfalls in provision, followed by remedial action, is a priority if treatment is to fulfil its potential in supporting recovery. It is not acceptable to leave people in opioid substitution treatment without actively supporting their recovery and regularly reviewing the benefits of their treatment, as well as checking, responding to, and stimulating their readiness for change. Nor is it acceptable to impose time limits on their treatment that take no account of individual history, needs and circumstances, or the benefits of continued treatment. Treatment must be supportive and aspirational, realistic and protective.

Some people have the personal and other resources ('recovery capital') which enable them to stabilise and leave treatment more quickly than others. Many others have long-term problems and complex needs, meaning their recovery may take much longer and they require help to build their recovery capital. Treatment given over this time scale must maintain its recovery orientation.

Arbitrarily or prematurely curtailing opioid substitution treatment will not help the patient sustain their recovery and is not in the interests of the wider community. It risks losing any advances because it is externally imposed and so has no meaning; the individual does not own the decision. This would likely lead to an increase in blood-borne virus rates, drug-related deaths, and crime. However, clear and ambitious goals, with time scales for action, are key components of effective individualised treatment, especially when the individual collaborates in planning them. The expert group strongly supports continued reference and adherence to NICE drug misuse guidance and to the more practitioner-orientated 2007 clinical guidelines.

The more ambitious approach outlined will sometimes lead to people following a potentially more hazardous path, with the risk of relapse (or at least occasional lapse) as they seek to disengage from the opioid substitution treatment that has supported them. Individuals (and their families), clinicians, and services need to understand this potential risk. They need to approach the change with careful planning and increased support, and provide a 'safety net' in case of relapse.

Opioid substitution treatment will improve as a result of changes at a system, service and individual level. These include:
• treatment systems and services having a clear and coherent vision and framework for recovery visible to people in treatment, owned by all staff and maintained by strong leadership;
• purposeful treatment interventions that are properly assessed, planned, measured, reviewed and adapted;
• 'phased and layered' interventions that reflect the different needs of people at different times;
• treatment that creates the therapeutic conditions and optimism through which people, and especially those with few internal and external resources, can meet the challenge of initiating and maintaining change;
• programmes that optimise the medication according to the evidence and guidance;
• measuring recovery by assessing and tracking improvements in severity, complexity and recovery capital, then using this information to tailor interventions and support that boost an individual's chances of recovering and promote progress towards that goal;
• treatment services that are not expected to deliver recovery on their own but are integrated with, and benefit from, other services such as mutual aid, employment support and housing; and
• treatment that works alongside peers and families to give people direct access to, or signposts and facilitated support to, opportunities to reduce and stop their drug use, improve their physical and mental health, engage with others in recovery, improve relationships (including with their children), find meaningful work, build key life skills, and secure housing.

Supplement on reviewing treatment

Following the publication of the report the Chief Medical Officer asked the same expert group for further advice on:
• the frequency at which an individual receiving treatment for addiction should be reviewed (to determine the benefit of the treatment and thus whether alternative treatments should be tried);
• the structure of the review meetings (what should be considered, how to assess the benefit a patient is receiving, tools for decision making, etc).

The group’s response was published in 2013. It recommended:
• care planning, with its ongoing and planned reviews of specific goals and actions, should be part of a phased and layered treatment programme;
• a strategic review of the client’s recovery pathway will normally be necessary within three months (and no later than six months) of treatment entry, and will then usually be repeated at six-monthly intervals;
• a strategic review should always revisit recovery goals and pathways (to support clients to move towards a drug-free lifestyle);
• drug treatment should be reviewed based on an assessment of improvement (or preservation of benefit) across the core domains of successful recovery.

To enable this to happen, the group said commissioners will want to ensure that the services they support: have the resources (sufficient staff, with appropriate competences and the time) to conduct ongoing, specific and strategic reviews; monitor a range of recovery outcomes to understand and demonstrate the benefits being derived from treatment; have access to a diverse range of interventions, intensities and settings (including residential) to optimise treatment and care.


Findings logo commentary The featured report can be understood as facing two ways. Firstly it faces forward to show that methadone maintenance and allied treatments can be part of the new recovery agenda, despite that agenda's associations in some quarters with abstinence from all drugs including legal substitutes (no methadone) and with leaving treatment (no or curtailed maintenance). At the same time it faces backward to protect previously accepted views critiqued and threatened by this agenda: acceptance of the need for long-term and even indefinite prescribing in the face of the tenacity of heroin addiction and the vulnerabilities of its sufferers; the legitimacy in recovery terms of staying in as well as leaving treatment; and the value of harm reduction objectives and achievements short of what it accepts is the abstinence ideal.

In particular, it draws a 'line in the sand', rejecting the imposition of time limits or treatment exits other than those decided between clinician and patient "When they are ready", with specifically engineered safety nets to respond to actual or impending relapse through treatment re-entry. It accepts the government's vision of more people successfully leaving treatment, but rejects as life-threatening and counterproductive any attempt to enforce this from outside the therapeutic relationship. In this respect it continues the tradition most notably established by the 1926 Rolleston report, which protected the privileged doctor-patient relationship in the treatment of addiction from encroachment by penal drug control regulations.

The report's commitment to the new vision of recovery and how much this means services will need to change is most visible in the passages which stress links with local mutual aid networks and other peer-based recovery support groups such as Narcotics Anonymous, and the need to help support and create such networks. For many prescribing services, this kind of community inreach and outreach will not even have been peripheral, let alone central, to their work. To foster recovery as understood by the national drug strategy, they are now expected to: identify and appoint local strategic, therapeutic and community 'recovery champions'; integrate with peer support structures; link with key contacts in the various local mutual aid and peer support groups and services; undertake related staff training; ensure all patients have access to a recovery coach or can speak to people who are in recovery through local peer support services; invite mutual aid representatives in to their services to address patients and staff; offer their premises for meetings; and maximise attendance at mutual aid meetings by their patients, including making the initial contact for them, organising travel, and accompanying them to their first meeting.

Pre-recovery origins

The report traces its impetus to the 2010 English drug strategy formulated by the new Conservative-led UK government, but its origins date back to the preceding Labour years. Before the discovery of recovery as an overarching rationale, the emphasis had already shifted to getting patients to the point where they could leave treatment as a counter to the previous emphasis on retention. Since long-term retention in continuous treatment is characteristic of opioid substitute 'maintenance' programmes, the sometimes unspoken challenge was to the dominance of this approach in the treatment of heroin addiction.

In 2005 an "efficiency" strategy developed by the National Treatment Agency for Substance Misuse complained of the "lack of emphasis on progression through the treatment system" leading to "insufficient attention ... to planning for exit". Foreseeing a time when funding would be less available, the agency's board was told that "Moving people through and out of treatment" will create the space for new entrants "without having continually to expand capacity". This trend was given what at the time was an unwelcome boost when in 2007 the crime-reduction justification for investing in treatment was challenged by the BBC on the grounds that treatment should be about getting people off drugs, leading to the admission that in England in 2006/07 just 3% of patients had completed treatment for drug problems and left drug-free.

The shock of that challenge fed through to Labour's 2008 English national drug policy, in which the word 'recovery' in the sense of recovering from addiction was used just once and incidentally. Instead the emphasis was on components (in particular those which would relieve the burden on the state at a time of when policy sought to rein in public spending) later to be subsumed under recovery – leaving treatment, getting off benefits, and going back to work: "In return for benefit payments, claimants will have a responsibility to move successfully through treatment and into employment". Announcement of a three-year standstill in central treatment funding until 2011 while numbers were expected to rise, further focused attention on squaring the circle by more patients leaving as well as coming in to treatment.

The featured report extracts what the experts on the group saw as the positives (in therapeutic terms) from these challenges, in the form of a renewed emphasis on patients progressing in treatment towards what for them and for society are more satisfactory and fulfilling lives – which mean more can stop drug use and leave treatment sooner – while rejecting extensions to this ambition which pose moving out of treatment as a must do step in the process of moving forwards to what has been dubbed 'full' recovery marked by abstinence from drugs and from legal substitutes. Neither leaving treatment in general, nor withdrawing from prescribing-based treatments in particular, are seen in the report as essential to recovery.

That supplementary advice was called for may be indicative that government concern over patients ‘getting stuck’ in maintenance programmes was not assuaged by the initial report. Those concerned over this issue may gain reassurance from the group’s advice that six-monthly reviews should “revisit recovery goals and pathways” with a view to supporting clients “to move towards a drug-free lifestyle”. However, the group maintained the initial report’s opposition to “arbitrarily or prematurely curtailing opioid substitution treatment”, its insistence that such decisions are for the individual patient and clinical team, and that both will need to balance risk and maintenance of gains with the ambition to move on: “Balancing support for optimistic, abstinence-based recovery steps – and fully-informed risk-taking to achieve this – and supporting reduction of risk of premature drop-out and avoidable harm and death, is an important contextual issue within which strategic reviews of care always take place, and need to be addressed with the patient”.

Challenges to the challenges

The report's challenging agenda itself faces challenges from outside the world of humane and patient-centred medical practice within which its recommendations were framed. The economic forces and moral (or in some eyes, moralistic) values which predated recovery and helped elevate it to an overarching principle remain. Falling per-patient spending in addiction treatment allied with austerity threatening general support for the poor and vulnerable will make it harder to build the 'recovery capital' the report saw as often the prerequisite to safe treatment exit. At the same time, health service funding restrictions and the possible diversion of addiction treatment funding to other public health objectives will make it harder to fund continued treatment.

The temptation will be for commissioners and services to make non-patient centred limitations on the length and intensity of treatment journeys, and to focus on simple and clear 'recovery' outcomes like end-of-treatment abstinence and treatment exit, in lieu of more nebulous and harder to evidence outcomes like a more satisfying and productive life and the prevention of disease, or those much more difficult to engineer like a job and a house and the resumption of family life.

Another option is to find the resources to implement the spirit of the report's recommendations and ambitions by cutting patient numbers. The report might be seen as justifying increased investment in building the 'recovery capital' of the subset of actual or potential methadone patients committed to recovery in the form of abstinence and social reintegration and for whom these are feasible aims – transitioning methadone from a mass but relatively low intensity public health intervention for the many, to more of a Rolls Royce option for the few. The result may be more complete recovery for those who qualify, but also to jeopardise the crime reduction benefits which in economic terms justify services, and to weaken the lifesaving impact of mass treatment entry resulting in heroin use reductions seemingly unavailable on this scale from other treatment modalities. In April 2010 the chair of the group which produced the featured report was among 41 experts who came together to defend "this life-saving treatment", an unprecedented alliance which shows how seriously they took moves to curtail methadone. It should, they said, "be readily available to every person using heroin that seeks help, accepts this option and meets national criteria." Those who agree with this sentiment might not want a 'recovery-oriented' service if this means making methadone less available and cutting patient numbers. For the time being treatment funding allocations largely based on numbers in treatment will it is thought restrain this tendency. The saving grace which might rescue services from this dilemma is the retreat from heroin use across the population, automatically reducing patient numbers.

Any form of patient-centred treatment, whether or not under the umbrella of recovery, is threatened by 'payment by results' schemes which pre-set the treatment destination in detail without reference to what the individual patient wants, and in a way services cannot afford to ignore because their financial survival depends on meeting the criteria for payment. Some local schemes have created a space for the patient's ambitions in their payment criteria, but this is not a required element, or one which sits easily within a system predicated on observable outcomes the public and their representatives recognise and are willing to pay for.

At the same time the upheaval caused by these developments and the loosening of central control both force and permit innovative ways of working by new players, which some treatment systems and some patients may be able to take advantage of to breach the boundaries of custom and risk aversion which have limited productive change.

The editor of Drug and Alcohol Findings who drafted this analysis was a member of the expert group responsible for the featured report.

Thanks for their comments on this entry in draft to John Strang of the National Addiction Centre in London who chaired the expert group, and to Jon Derricot. Commentators bear no responsibility for the text including the interpretations and any remaining errors.

Last revised 15 January 2014. First uploaded 30 July 2012

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QT interval screening in methadone maintenance treatment: report of a SAMHSA expert panel.

Martin J.A., Campbell A., Killip T. et al.
Journal of Addictive Diseases: 2011, 30, p. 283–306.
Unable to obtain a copy by clicking title? Try asking the author for a reprint by adapting this prepared e-mail or by writing to Dr Wilford at BBWilford@aol.com. You could also try this alternative source.

Concerned that this might on balance cause more deaths by limiting an effective treatment for opiate addiction, an expert panel convened by the US government has changed its mind on whether the risk of a fatal heart attack potentially posed by methadone justifies routine electrocardiogram screening of patients.

Summary The QT interval (or QTc as corrected for the heart rate) is an indicator of heart function derived from electrocardiogram measures. It refers to the delay between two phases of the electrical activity of the heart which drives it in pumping blood round the body. The health risks associated with a prolonged interval are not clear. It can lead to torsades de pointes, a potentially life threatening heart attack, but some medications prolong the interval yet rarely cause this condition, and it can occur even when the interval is normal. The risk threshold has been set variously at for example 450ms (0.45 seconds) for men and 460ms to 470ms for women or 450ms for both, though it is generally accepted that intervals greater than 500ms pose a significant risk of torsades de pointes.

Some studies have reported that methadone may contribute to the elongation of the QT interval, heightening the risk of torsades de pointes. In response the US government convened an expert panel to assess the risk to patients and make recommendations to enhance their cardiac safety. The featured article is the latest report of that panel, superseding an earlier version.

The panel framed its recommendations on the understanding that methadone must remain widely available because it has been associated with an overall reduction in deaths, there are few therapeutic alternatives, and it is cost-effective. Treatment providers are encouraged to consider the report and take action to the extent that they are clinically, administratively, and financially able to do so, but nothing in the report is intended to create a legal standard of care or accreditation requirement, or to interfere with the judgment of the clinicians treating the patients.

Main findings

Based on evidence published in the peer-reviewed literature, the panel concluded that both oral and intravenous methadone are not just associated with QT prolongation but actually cause it. Prolongation to over 500ms is thought to confer a significant risk of heart arrhythmias. In all but one study of methadone maintenance treatment, a QT of this level was seen in 2% of patients. Taken in the aggregate, the evidence also supports the view that as methadone doses increase, so too does the likelihood of significant QT prolongation.

The panel's recommendations

Panel members agreed that their recommendations must preserve patients' access to addiction treatment. Among patients with QT prolongation related to relatively high doses of methadone, it is unclear to what degree reducing doses would risk them relapsing [to illicit opiate use], but higher doses are associated with better treatment retention and better outcomes.

The Panel affirmed that methadone can be used with reasonable assurance that it is effective and that its benefits exceed its risks, providing that the potential for QT prolongation is recognised, that patients receive electrocardiogram screening at indicated intervals, and that appropriate clinical action is taken in the presence of significant QT prolongation.

Panel members agreed that, to the extent possible, every opioid treatment programme should have a cardiac risk management plan with the following elements:
Clinical assessment: Intake assessments should include: a complete medication history; personal and family history of structural heart disease; Including long QT syndrome, sudden cardiac death, myocardial infarction, and heart failure. any personal history of arrhythmia or syncope (fainting); and use of QT-prolonging medications or illicit drugs such as cocaine which also have this effect.
Electrocardiogram assessment: Largely due to concerns over the resource implications and its effectiveness in achieving meaningful reductions in methadone-associated cardiac events, panel members and ex officio members could not agree whether to recommend routine electrocardiogram screening within the first 30 days of treatment. However, they did agree that a baseline electrocardiogram at the time of admission and within 30 days should be performed on patients with significant risk factors Including a history of cardiac arrhythmia or prolonged QT interval; symptoms suggestive of arrhythmia, such as episodes of syncope, dizzy spells, palpitations, or seizures; medication history; family history of premature death; or any other historical information suggestive of a possible cardiac arrhythmia. for QT prolongation. Among these patients, additional tests should be performed annually or whenever the methadone dose exceeds 120mg a day. In addition to scheduled electrocardiograms, any patient who experiences unexplained syncope or generalised seizures should be tested. If marked QT prolongation is documented, torsades de pointes should be suspected and the patient hospitalised for monitoring through telemetry.
Risk stratification: If the QT interval is over 450ms but less than 500ms, methadone may be initiated or continued, accompanied by a risk-benefit discussion with the patient and more frequent monitoring. For methadone-maintained patients with marked QT prolongation of 500ms or more, strong consideration should be given to adopting a risk minimisation strategy, such as reducing the methadone dose, eliminating other contributing factors, transitioning the patient to an alternative treatment such as buprenorphine, or discontinuing methadone treatment.

Methadone-related cardiac risk should be mentioned in the informed consent document presented to patients at intake, and patients should receive plain-language educational materials explaining this risk. Medical staff too should be educated about the risks posed by a prolonged QT interval and trained in assessing patients for risk of torsades de pointes and other cardiac problems.

The panel acknowledged that acting on these conclusions will challenge many opioid addiction treatment programmes. Identifying clinically relevant QT prolongation remains difficult, given the variability of electrocardiogram machine measurements and the difficulty of defining the precise risk a prolonged QT portends for any given individual. Programmes will find it a challenge to integrate cardiac arrhythmia risk assessment into the care of opioid-addicted patients without reducing access to vital addiction treatment services. The panel was also aware that not all methadone maintenance treatment providers can administer an electrocardiogram to every patient in all the circumstances they recommended. Opioid addiction treatment programmes and other providers are encouraged to consider implementing these conclusions to the extent that they are practically or financially capable of doing so.


Findings logo commentary These recommendations differ in content and in their directiveness from those released by the panel in 2009, described by a panel member as "preliminary". That earlier version recommended electrocardiogram screening of all methadone patients when they start treatment and then a month and a year later, with extra tests as indicated, and in particular for anyone on doses exceeding 100mg daily.

There was immediate controversy over whether the so far largely theoretical and circumstantial risk of death from torsades de pointes due to methadone's effects justified routine and repeated electrocardiogram screening of all patients. The preliminary report was followed by critical letters concerned that such a requirement might restrict the availability of methadone treatment, with a net increase in deaths. An editorial in the same issue of the journal which published the report complained that its recommendations had "venture[d] well beyond the evidence presented". Additional to possibly counterproductively limiting treatment and/or doses, the editorial said there was no evidence that screening was an effective preventive measure.

As well as now limiting its call for routine screening to high risk patients, this new version of the panel's recommendations does not replicate earlier advice to screen every patient over a certain dose of methadone. A risk of setting such a threshold is that it may justify and reinforce the tendency in the USA (also in the UK) to prescribe sub-optimal doses of methadone which put patients at risk from continued illicit drug use. Instead the corresponding recommendation is now limited to the same high risk patients, among whom screening should be intensified if doses exceed 120mg a day.

The panel's recommendations are now also much more clearly framed as suggestions to be considered subject to resources and clinical judgement, and with the overriding concern that access to methadone treatment should not be curtailed in order to minimise the risk of cardiac complications, when the risk of not being in effective treatment is, from the available evidence, much greater.

Division in the panel over blanket electrocardiogram screening prompted the issue of the journal which published its latest conclusions to also publish two commentaries arguing for and against. For a cardiologist who favoured blanket screening, the issue was simple: "the best way to predict who will develop significant QTc prolongation on drug is to see who has a long QTc off drug. To a cardiologist, [electrocardiogram] screening of patients receiving a QT-prolonging drug is the proverbial 'no-brainer'." The alternative of identifying high risk patients by questioning them about their medical and family history was useful but, it was suggested, inadequate, because few patients know they have a prolonged QT interval or a family history of arrhythmias. But even this authority limited his recommendation to an "ideal" if resources allow: "if one has access to the resources, universal screening remains the ideal risk evaluation and management approach".

On the other side was (it seems) an addiction specialist who commended the recommendations regarding obtaining a history from the patient and making a physical examination, but (as others have done) saw the reliance on QTc measurement to assess risk as misguided because "there is no evidence that identification of QTc prolongation saves lives in a general population ... QTc prolongation is absent in the majority of [sudden cardiac deaths] and is not a necessary antecedent to ventricular arrhythmia. In other words, it lacks predictive value". Focusing on this unreliable indicator could, he suggested, threaten patient safety by diverting attention from other important risk factors.

The featured report's recommendations are close to those made by a team based in Italy after reviewing essentially the same literature. For new patients, electrocardiograms should only be resorted to they said if assessment revealed patient or family histories of recurrent syncope of unknown origin or sudden death and/or the patient might be at risk of QT prolongation due to other drugs such as cocaine. If methadone is nevertheless prescribed, such patients should continue to be tested. The authors cautioned that case reports seemingly cumulating to a worrying mass of indications of risk might merely reflect selective attention to a single risk factor prompted by an initial report.

National monitoring records

If there is a risk of sudden cardiac death due to methadone-provoked QT prolongation, it is likely to be small and best revealed through large-scale monitoring. Such records have the weakness that the doctors concerned voluntarily report adverse events, so many may have gone unreported, and some may have been reported but the cause of death not identified as torsade de pointes. However, they do afford a national-scale feel for the minimum incidence of deaths thought due to methadone-related QT prolongation and/or torsade de pointes.

At least two major such reports are available for Europe. Between 1996 and the end of 2007 the French monitoring system collating reports from doctors of adverse effects of medications recorded one heart attack death of a patient on methadone with prolonged QT, but torsade de pointes was not recorded as the cause. If it was, this may have been the only such death yet recorded. Importantly, the final year of the reporting period included at least 11 months during which relevant doctors in France had been personally alerted to methadone-related QT prolongation and asked to closely monitor at-risk patients. Other deaths were unaccounted for, but most occurred during induction on to methadone, a high risk period for overdose. The study notes that from 1996 to 2005 about 15,000 patients were treated with methadone in France.

Among 2382 patients who started methadone treatment in Norway between 1997 and the end of 2003 (who during this time spent in total 6450 years in treatment) there was not a single case among the 90 fatalities where the cause of death was officially recorded as ventricular arrhythmia, and in particular, no mention of torsade de pointes. In just two cases was the cause of death unknown. Importantly this study did not rely on doctors' reports but matched treatment records with death certificates.

In the 33 years from 1969 to 2002, 59 cases of QT prolongation or torsade de pointes suffered by US methadone patients were reported to a federal monitoring system, among whom there were five deaths. Just one of these patients was recorded as having suffered torsade de pointes, but in this case myocardial infarction was a complicating factor, a cause of heart failure distinct from the causes of which methadone is suspected.

UK guidance and its implications

UK addiction treatment guidance dating from 2007 incorporates the panel's earlier threshold for increased risk of 100mg of methadone a day, but says only that electrocardiograms "might be considered before induction onto methadone or before increases in methadone dose and subsequently after stabilisation – at least with doses over 100mg per day and in those with substantial risk factors". According to UK medicines regulators, these factors include "heart or liver disease, electrolyte abnormalities, concomitant treatment with CYP 3A4 inhibitors, or other drugs with the potential to cause QT interval prolongation". Reflecting the controversy sparked by the US panel, the UK guidance was unclear whether QT prolongation would "prove to be a minor or a major issue measured against the many benefits afforded by methadone treatment".

An addiction clinic in London assessed 155 stabilised methadone patients to determine what proportion would qualify for electrocardiogram monitoring according to these UK criteria, and conducted electrocardiograms on 83 of the patients, mainly at the addictions clinic; attendance for off-site testing was very poor. The study found that three quarters would qualify, largely due to liver disease including hepatitis infection, being prescribed over 100mg methadone or other QT-prolonging medications, and/or taking cocaine. Just over 18% had prolonged QTc intervals, of which just one would not have been identified without the electrocardiogram. However, none exceeded the 500ms high-risk threshold and there were no known instances of torsade de pointes during the 25 months of the study. When all assessed risk factors were taken in to account, higher doses of methadone (and also stimulant use) were weakly related to longer QTc intervals, but not to the likelihood that the interval would exceed prolongation thresholds. The authors observed that following UK recommendations in this caseload would have meant electrocardiogram monitoring for up to three quarters with "huge resource implications" yet uncertain benefits.

It must be considered reassuring that in this high risk, high methadone dose caseload, no patient was significantly at risk of torsade de pointes as indicated by the generally accepted 500ms criterion, and only one with less extreme prolongation would have been missed without electrocardiogram screening. Less reassuring was the apparent need to arrange for electrocardiograms to be conducted at the addictions clinic with associated extra costs. The results sharpen the dilemma over whether diverting resources to this screening, and possibly delaying the initiation of methadone so it can be conducted, would on balance do more harm than good, even when screening is limited to patients with identified risk factors.

Last revised 17 July 2012. First uploaded 12 July 2012

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STUDY 2011 Methadone maintenance, QTc and torsade de pointes: who needs an electrocardiogram and what is the prevalence of QTc prolongation?

STUDY 2010 Onsite QTc interval screening for patients in methadone maintenance treatment

REVIEW 2012 BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP

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STUDY 2005 Addressing medical and welfare needs improves treatment retention and outcomes

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Methadone maintenance, QTc and torsade de pointes: who needs an electrocardiogram and what is the prevalence of QTc prolongation?

Mayet S., Gossop M., Lintzeris N. et al.
Drug and Alcohol Review: 2011, 30(4), p. 388–396.
Unable to obtain a copy by clicking title? Try asking the author for a reprint by adapting this prepared e-mail or by writing to Dr Mayet at soraya.mayet@tewv.nhs.uk.

British guidelines suggest electrocardiogram screening of methadone patients at heightened risk of a form of possibly methadone-aggravated cardiac disorder which can result in sudden death. But a London clinic found this would still mean testing most patients, with huge resource implications yet uncertain benefits.

Summary The QTc interval is an indicator of heart function derived from electrocardiogram measures. It refers to the delay between two phases of the electrical activity of the heart which drives it in pumping blood round the body. Extended intervals may lead to torsades de pointes, a potentially life threatening irregular heartbeat. Several studies have reported that methadone may contribute to the elongation of this interval, heightening the risk. The risk threshold has been variously set at 450ms (0.45 seconds) for men and 470ms for women or 450ms for both, though it is generally accepted that intervals greater than 500ms constitute a significant risk of abnormal heart function.

UK addiction treatment guidance dating from 2007 says that electrocardiograms "might be considered before induction onto methadone or before increases in methadone dose and subsequently after stabilisation – at least with doses over 100mg per day and in those with substantial risk factors". According to UK medicines regulators, these factors include "heart or liver disease, electrolyte abnormalities, concomitant treatment with CYP 3A4 inhibitors, or other drugs with the potential to cause QT interval prolongation".

An addiction clinic in London assessed 155 methadone patients stabilised on their doses for at least four weeks to determine what proportion would qualify for electrocardiogram monitoring according to these criteria, and conducted electrocardiograms on 83 of the patients who attended for testing to determine whether they were at risk according to the readings of their QT intervals.

Main findings

Three quarters of the patients would have met the criteria for electrocardiogram testing, largely due to liver disease including hepatitis infection, being prescribed over 100mg methadone or other QT-prolonging medications, and/or taking cocaine. Of the roughly half of the patients who attended for electrocardiograms, 8 in 10 did so at the addictions clinic; attendance for off-site testing was very poor.

Among those with electrocardiogram results, the total daily dose of prescribed and illicit methadone was about 99mg and other substance use was common. Just over 18% had prolonged QTc intervals defined as at least 450ms in men and 470ms in women, of which just one would not have been identified without the electrocardiogram. However, none exceeded the 500ms high-risk threshold and there were no known instances of torsade de pointes during the 25 months of the study. When all assessed risk factors were taken in to account, higher doses of methadone (and also stimulant use) were weakly related to longer QTc intervals, but not to the likelihood that the interval would exceed prolongation thresholds.

The authors' conclusions

The authors observed that following UK recommendations in this caseload would have meant electrocardiogram monitoring for up to three quarters with "huge resource implications" yet uncertain benefits. They suggested the decision to conduct an electrocardiogram should be based on a risk–benefit analysis by clinician and patient, and that if QT prolongation is found, attempts to redress this should focus on other factors before considering changes in the methadone regimen.


Findings logo commentary Whether the so far largely theoretical and circumstantial risk of death from torsades de pointes due to methadone's effects justifies routine and repeated electrocardiogram screening of all patients is a matter of some contention. Based on their results, the authors of the featured study effectively come down against this, suggesting that the decision to test be made on a case-by-case basis.

It must be considered reassuring that in this high risk, high methadone dose caseload, no patient was significantly at risk of torsade de pointes as indicated by the generally accepted 500ms criterion, and only one with less extreme prolongation would have been missed without electrocardiogram screening. Less reassuring was the apparent need to arrange for electrocardiograms to be conducted at the addictions clinic with associated extra costs. The results sharpen the dilemma over whether diverting resources to this screening would on balance do more harm than good, even when screening is limited to patients with identified risk factors.

After initially recommending universal screening, an expert panel convened by the US government changed its mind, due largely to concern that this might on balance cause more deaths by limiting an effective treatment for opiate addiction. It could mean delays as patients await electrocardiogram testing and results, divert resources from methadone treatment, lead some patients to reject or drop out of the treatment, or to sub-optimal doses, all of which could lead to preventable deaths. Faced with these risks the panel opted for screening high risk patients only. However, as the featured study shows, this could mean still having to screen most patients.

See this Findings analysis of the US panel's report for more on the risk of death due to methadone-provoked QT prolongation and on whether universal electrocardiogram screening is advisable given the size of this risk and the possible unintended consequences of requiring such screening.

Thanks for their comments on this entry in draft to Soraya Mayet of the Tees, Esk and Wear Valleys NHS Foundation Trust in England. Commentators bear no responsibility for the text including the interpretations and any remaining errors.

Last revised 17 July 2012

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STUDY 2010 Onsite QTc interval screening for patients in methadone maintenance treatment

REVIEW 2011 QT interval screening in methadone maintenance treatment: report of a SAMHSA expert panel

REVIEW 2012 BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP

STUDY 2012 Randomized trial of standard methadone treatment compared to initiating methadone without counseling: 12-month findings

STUDY 2005 Addressing medical and welfare needs improves treatment retention and outcomes

REVIEW 2008 Treating pregnant women dependent on opioids is not the same as treating pregnancy and opioid dependence: a knowledge synthesis for better treatment for women and neonates

REVIEW 2010 Gender issues in the pharmacotherapy of opioid-addicted women: Buprenorphine

DOCUMENT 2014 Consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations

STUDY 2010 Effect of motivational interviewing on reduction of alcohol use

DOCUMENT 2009 Buprenorphine: a guide for nurses





Onsite QTc interval screening for patients in methadone maintenance treatment.

Fareed A., Vayalapalli S., Byrd-Sellers J. et al.
Journal of Addictive Diseases: 2010, 29(1), p. 15–22.
Unable to obtain a copy by clicking title? Try asking the author for a reprint by adapting this prepared e-mail or by writing to Dr Fareed at ayman.fareed@va.gov. You could also try this alternative source.

Does the small risk of fatal heart attack potentially posed by methadone justify routine electrocardiogram screening of patients, or will this cause more deaths by limiting an effective treatment for opiate addiction? A US clinic tried it and found three at-risk patients in three years.

Summary The QTc interval is an indicator of heart function derived from electrocardiogram measures. It refers to the delay between two phases of the electrical activity of the heart which drives it in pumping blood round the body. Extended intervals may lead to torsades de pointes, a potentially life threatening heart attack. Several studies have reported that methadone may contribute to the elongation of this interval, heightening the risk. The risk threshold has been variously set at 450ms (0.45 seconds) for men and 470ms for women or 450ms for both, though it is generally accepted that intervals greater than 500ms constitute a significant risk of abnormal heart function.

Given the risk, an expert US panel recommended electrocardiogram screening of all methadone patients when they start treatment and then a month and a year later, with extra tests as indicated.

A medical clinic for former US military personnel instigated such screening at the clinic itself to identify high risk patients. Alongside it offered brief on-site counselling for patients about the risks of cardiac arrhythmias associated with methadone and how to spot the symptoms of any impending problems. Electrocardiogram results were reviewed by the clinic's psychiatrist, who provided feedback for each patient and arranged for appropriate referrals as needed. Patients with automated readings between 450ms and 500ms received more education and further electrocardiogram monitoring. If the interval reading exceeded 500ms, methadone dose was reduced and the patient was referred to a cardiology clinic.

The featured article reports on the feasibility and effectiveness of these procedures instigated in 2007 based on the records of 55 patients treated between 2002 and 2009 who were among the clinic's established caseload and had been retained in methadone treatment for at least six months and not dropped out. These patients averaged 90mg methadone daily.

Main findings

Urine drug screens revealed that illicit opiate and cocaine use fell during treatment, until just 4–5% of the latest tests were positive for each drug. All but 5% of patients underwent electrocardiogram screening as intended at admission and annually. At baseline the QTc interval averaged 417ms but increased to 442ms at the latest test, a statistically significant prolongation. Two thirds of the patients registered a significant prolongation but remained below 450ms. Another 27% ended up between 450ms and 500ms while just 6% experienced a statistically significant QTc prolongation which ended by exceeding 500ms. No patient was required as a result to discontinue methadone.

Statistical tests were used to determine whether QTc prolongation was significantly related to methadone dose, duration in treatment, whether the patient smoked, concomitant use of antidepressants and antipsychotics, or cocaine use either at baseline or recently. Of these, only recent cocaine use was significantly related to QTc prolongation, both when each variable was tested one by one and when all were taken in to account at the same time.

The authors' conclusions

This study confirms that methadone is a safe and effective treatment for opiate dependence. Although other factors such as continued illicit drug use, hepatitis C, HIV and smoking are much more likely to lead to premature death in methadone patients than cardiac arrhythmias, QTc prolongation in addition to other chronic medical conditions may increase the risk. An electrocardiogram is an objective tool to identify patients at risk for cardiac arrhythmias. Although such screening itself is not expensive, referral to specialty care could be, but in practice providing on-site electrocardiogram screening with a focus on patient education and limiting referral to cardiology specialty care led over a three-year period to just three of 55 patients being referred.

Two thirds of retained patients in the clinic had QTc intervals within the normal range and only three of 55 exhibited significantly increased risk for torsades de pointes with a QTc of over 500ms. Interventions initiated by the addictions clinic included methadone dose reduction, elimination or reduction of other QTc-prolonging medications, education about the possible contributions of caffeine and nicotine to QTc prolongation, and detailed information about the signs and symptoms of arrhythmias.

The key finding in this study was that recent but not baseline use of cocaine among methadone patients – meaning that even when established in treatment these patients had continued with its use – was associated with QTc prolongation.


Findings logo commentary Whether the so far largely theoretical and circumstantial risk of death from torsades de pointes due to methadone's effects justifies routine and repeated electrocardiogram screening of all patients is a matter of some contention. The expert panel convened by the US government whose initial recommendations prompted the featured study later changed its mind, due largely to concern that this might on balance cause more deaths by limiting an effective treatment for opiate addiction. It could mean delays as patients await electrocardiogram testing and results, divert resources from methadone treatment, lead some patients to reject or drop out of methadone treatment, or to sub-optimal doses, all of which could lead to preventable deaths. Faced with these risks the panel opted for screening high risk patients only. However, this could mean still having to screen most patients, as a UK study demonstrated.

In line with the featured study's findings, the latest report of the US expert panel noted that cocaine use seems to aggravate any impact of methadone on the QT interval. Laboratory studies have shown that in its own right cocaine has a marked impact on the QT interval. Such findings justify including use of the drug among the variables indicating high risk among methadone patients, one of the reasons why in parts of Britain so many would qualify for this designation.

High methadone doses are thought to heighten the cardiac risk but also protect against potentially fatal illicit opiate use. In this respect it would have been useful if the featured report had been able to record the consequences of the cautionary dose reductions it implemented among the sampled patients, especially whether urine screens indicated increased illicit drug use after methadone was reduced. Also of interest is whether these or other initiatives implemented as part of the described programme led any patients to refuse or drop out of treatment (in which case they would not have been among the sample reported on), or to be offered or insist on a lower than optimal dose.

See this Findings analysis of the US panel's latest report for more on the risk of death due to methadone-provoked QT prolongation, on whether universal electrocardiogram screening is advisable given the size of this risk and the possible unintended consequences of requiring such screening, and on UK guidance.

Thanks for their comments on this entry in draft to Ayman Fareed of the Atlanta Veterans' Affairs medical service and Emory University School of Medicine in the USA. Commentators bear no responsibility for the text including the interpretations and any remaining errors.

Last revised 17 July 2012. First uploaded 12 July 2012

Comment/query to editor
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Top 10 most closely related documents on this site. For more try a subject or free text search

STUDY 2011 Methadone maintenance, QTc and torsade de pointes: who needs an electrocardiogram and what is the prevalence of QTc prolongation?

REVIEW 2011 QT interval screening in methadone maintenance treatment: report of a SAMHSA expert panel

REVIEW 2012 BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP

STUDY 2012 Randomized trial of standard methadone treatment compared to initiating methadone without counseling: 12-month findings

STUDY 2005 Addressing medical and welfare needs improves treatment retention and outcomes

REVIEW 2010 Gender issues in the pharmacotherapy of opioid-addicted women: Buprenorphine

DOCUMENT 2014 Consolidated guidelines on HIV prevention, diagnosis, treatment and care for key populations

REVIEW 2008 Treating pregnant women dependent on opioids is not the same as treating pregnancy and opioid dependence: a knowledge synthesis for better treatment for women and neonates

STUDY 2010 Effect of motivational interviewing on reduction of alcohol use

STUDY 2015 Risk of mortality on and off methadone substitution treatment in primary care: a national cohort study





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