QTc interval screening for cardiac risk in methadone treatment of opioid dependence (Review)

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1 QTc interval screening for cardiac risk in methadone treatment of opioid dependence (Review) Pani PP, Trogu E, Maremmani I, Pacini M This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2013, Issue 6

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS Figure DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES ADDITIONAL TABLES APPENDICES CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST i

3 [Intervention Review] QTc interval screening for cardiac risk in methadone treatment of opioid dependence Pier Paolo Pani 1, Emanuela Trogu 1, Icro Maremmani 2, Matteo Pacini 3 1 Social-Health Division, Health District 8 (ASL 8) Cagliari, Cagliari, Italy. 2 Vincent P. Dole Dual Diagnosis Unit, Department of Neurosciences, Santa Chiara University Hospital, University of Pisa, Italy, Pisa, Italy. 3 Policlinico Umberto I, University La Sapienza, Rome, European Addiction Treatment Association (Europad), Rome, Italy Contact address: Pier Paolo Pani, Social-Health Division, Health District 8 (ASL 8) Cagliari, Via Logudoro 17, Cagliari, Sardinia, 09127, Italy. Editorial group: Cochrane Drugs and Alcohol Group. Publication status and date: New, published in Issue 6, Review content assessed as up-to-date: 23 July Citation: Pani PP, Trogu E, Maremmani I, Pacini M. QTc interval screening for cardiac risk in methadone treatment of opioid dependence. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD DOI: / CD pub2. Background A B S T R A C T Methadone represents today the gold standard of efficacy for the pharmacological treatment of opioid dependence. Methadone, like many other medications, has been implicated in the prolongation of the rate-corrected QT (QTc) interval of the electrocardiogram (ECG), which is considered a marker for arrhythmias such as torsade de pointes (TdP). Indications on the association between methadone, even at therapeutic dosages, and TdP or sudden cardiac death have been reported. On these bases, consensus and recommendations involving QTc screening of patients receiving methadone treatment have been developed to identify patients with QTc above the thresholds considered at risk for cardiac arrhythmias, and they provide these individuals with alternative treatment (reduction of methadone dosage; provision of alternative opioid agonist treatment; treatment of associated risk factors). Objectives To evaluate the efficacy and acceptability of QTc screening for preventing cardiac-related morbidity and mortality in methadone-treated opioid dependents. Search methods We searched MEDLINE, EMBASE, CINAHL (to April 2013), the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library Cochrane Drug and Alcohol Review Group Specialised Register (Issue 3, 2013), main electronic sources of ongoing trials, specific trial databases and reference lists of all relevant papers. Selection criteria Randomised controlled trials (RCTs), controlled clinical trials (CCTs) and non-randomised studies (cohort studies, controlled before and after studies, interrupted time series studies, case control studies) examining the efficacy of QTc screening for the prevention of methadone-related mortality and morbidity in opioid addicts. Data collection and analysis Two review authors independently screened and extracted data from studies. 1

4 Main results The search strategy led to the identification of 872 records. Upon full-text assessment, no study was found to meet the quality criteria used for this review. Authors conclusions It is not possible to draw any conclusions about the effectiveness of QTc screening strategies for preventing cardiac morbidity/mortality in methadone-treated opioid addicts. Research efforts should focus on strengthening the evidence about the effectiveness of widespread implementation of such strategies and clarifying the associated benefits and harms. P L A I N L A N G U A G E S U M M A R Y Use of ECG to prevent cardiac risk in opioid dependents treated with methadone No evidence has been found to support the use of the electrocardiogram (ECG) for preventing cardiac arrhythmias in methadone-treated opioid dependents. A maintenance program with methadone is an effective treatment for people who are dependent on opioids, in terms of increased retention in treatment, reduced use of opioids, reduced human immunodeficiency virus (HIV) transmission and reduced mortality. Nowadays methadone represents the most frequently used medication for this disorder. However, the use of methadone has been associated with a potentially fatal cardiac arrhythmia called torsade de pointes (TdP). Evidence supporting the relationship between methadone and TdP is limited. However, given the risk involved for the life of patients, consensus and recommendations for patients receiving methadone treatment have been developed. Recommended procedures aim to identify patients who present a specific alteration of the ECG, represented by prolongation of the QT interval, which is considered a marker for arrhythmias such as TdP. Patients identified as at risk may then be provided with alternative treatment (reduction of methadone dosage; provision of alternative opioid agonist treatment; treatment of associated risk factors). However, the acceptability of ECG screening has been questioned because the procedures involved may be too demanding and stressful, may interfere with the availability of patients to undergo methadone maintenance and may expose patients to health consequences of untreated opioid addiction, including increased mortality risk. This review looked at the evidence on the efficacy and acceptability of such ECG-based screening procedures. Even though the search was extended to different experimental and non- experimental study designs, the authors did not find any study that fulfilled methodological criteria for the review. Therefore, it is not possible to draw any conclusions about the effectiveness of ECG-based screening strategies for preventing cardiac morbidity/mortality in methadone-treated opioid addicts. Research efforts should focus on strengthening the evidence about the effectiveness of widespread implementation of such strategies and clarifying associated benefits and harms. B A C K G R O U N D Description of the condition Methadone represents today the gold standard of efficacy for the pharmacological treatment of opioid dependence (Faggiano 2003; Gowing 2008; Mattick 2008) and is the most frequently used medication for this condition, with 650,000 patients in treatment around the world (WHO 2008). According to Cochrane reviews, methadone has been shown to be more efficacious than placebo in terms of retention in treatment and use of opioids (Mattick 2008). Moreover, for these outcomes, higher dosages of methadone have been shown to be superior than lower dosages (Faggiano 2003). Evidence of infective complications, although limited by lack of data from randomised controlled studies, is consistent with a reduction in drug-related behaviours at risk for human immunodeficiency virus (HIV) transmission (Gowing 2008). Other single studies have consistently shown the efficacy of long-term methadone treatment in the reduction of mortality (Brugal 2005; Davoli 2007; Clausen 2008; Degenhardt 2009). The principal methadone-related safety issue is the risk of respiratory depression by overdose (Corkery 2004; Wolff 2002). In fact, although methadone maintenance treatment has been shown to reduce heroin-related mortality essentially reducing overdose, trauma and suicide-related deaths (Caplehorn 1996, Brugal 2005; Davoli 2007; Degenhardt 2009) its contribution to opioid overdose mortality has to be considered. For patients enrolled in meth- 2

5 adone maintenance programs, this risk has been shown to be maximum at the beginning of treatment, when a sufficient degree of tolerance has not yet been established (Pilgrim 2013; Buster 2002; Degenhardt 2009). However, methadone-related overdose also is seen in the population not enrolled in treatment programs; diversion from treatment settings may be implicated (Bell 2010; Madden 2011; Pilgrim 2013). Actually, diversion has been shown to occur less from methadone programs for opioid dependence than from methadone prescriptions for pain (Madden 2011). During the past 10 to 15 years, a dramatic rise in poisoning deaths associated with increased use of this medication for the treatment of pain has been reported (Cerdà 2013; Dasgupta 2011; Sims 2007). Besides respiratory depression, methadone, like many other medications, has been involved in another cardiac-related safety issue, represented by torsade de pointes (TdP). TdP is a cardiac rhythm disorder that usually presents as a transient tachyarrhythmia with palpitations or, if sustained, with symptoms of impaired brain circulation such as dizziness, syncope and seizures. However, sometimes it degenerates into ventricular fibrillation and sudden cardiac death. The overall estimated mortality for TdP is on the order of 10% to 17% (Fung 2000). The possible contribution of methadone to the determination of this condition has been attributed to its interference with ventricular repolarization caused by its inhibitory action on the human ether-à-go-go related gene -coded voltage-gated potassium channel (herg channel) and/or to the blockade of calcium channels in the cardiac myocyte membrane (Kornick 2003; Seyler 1983). Consistent with this action, association of the use of methadone with prolongation of the rate-corrected QT (QTc) interval of the electrocardiogram (ECG), which represents a measure of delayed ventricular repolarization, has been pointed out (Ehret 2006; Fanoe 2007; Justo 2006 a; Krantz 2002; Pearson 2005). QTc prolongation is not a safety concern per se; however, it is applied as a surrogate marker, although sharply imperfect, for the risk of developing TdP. A QTc of 500 milliseconds is generally accepted as a threshold of increased danger for TdP (Bednar 2002; Priori 2003). A QTc longer than this has been found in around 2% to 16% of methadone-maintained patients (Anchersen 2009; Ehret 2006; Fonseca 2009; Wedam 2007). Other studies have shown an increase in QTc in association with the start of methadone treatment (Fredheim 2006; Martell 2005; Krantz 2005a; Wedam 2007), a dose-dependent effect of methadone on QTc length (Kornick 2003; Peles 2007; Ehret 2006; Fanoe 2007; Martell 2005; Krantz 2003; Florian 2012) and QTc interval normalization after methadone discontinuation or dose reduction (Gil 2003; Krantz 2005b; Thavanaro 2011). Additional factors predicting QTc interval prolongation in methadone-treated patients according to multivariate regression analysis have included hypokalaemia, liver disease and concomitant use of hepatic cytochrome P450 inhibitors (Ehret 2006). Indications of a relationship between methadone and TdP or sudden cardiac mortality (for which only 25% of cases may be attributed to ventricular tachyarrhythmia (Nichol 2008)), have been reported, even at therapeutic dosages (Chugh 2008; De Bels 2003; Ehret 2006; Krantz 2002; Pearson 2005), and cases of TdP that lead to a change in therapy and normalization of the QTc have been described (Krantz 2005b; de Jong 2013). A maximum mortality rate for cardiac arrhythmia attributable to methadone has been estimated in a Norvegian opioid maintenance treatment programme (0.06 deaths per 100 patient-years) (Anchersen 2009). However, evidence supporting the relationship between methadone and TdP is limited, and most studies are carried out in small, cross-sectional settings or as case series, where the contributions of a host of other known risk factors (including other medications, drugs, electrolyte abnormalities, structural heart disease, etc.) have not been appropriately ruled out (Justo 2006 b). Description of the intervention Given the long and growing list of drugs that may be implicated in TdP, QTc interval screening has became part of the current approach to assessment of the safety of medications in clinical practice, drug development, post-marketing surveillance and regulatory interventions (De Ponti 2002; Elming 2002; Redfern 2003). On this background, recommendations, consensus and guidelines on the application of such screening procedures to patients receiving methadone treatment have been developed (Krantz 2009; Methadone Maintenance Guidelines 2011; UK guidelines 2007; Martin 2011). Recommended approaches differ among proponents in terms of the target population (all patients who are candidates for methadone maintenance treatment; those bearing other risk factors for QTc prolongation; those treated with high dosages of methadone) and the timing of the ECG evaluation (pretreatment, after one month and annually; at the time of an increase in dosage; at the presentation of syncope or seizures). In cases of QTc prolongation, suggested interventions include reduction of methadone dosage, provision of an alternative opioid agonist treatment and treatment of patients with associated risk factors. See Table 1. How the intervention might work QTc screening may allow the identification of patients with QTc above thresholds considered at risk for cardiac arrhythmias and may provide these patients with alternative treatment (reduction of methadone dosage; provision of alternative opioid agonist treatment; treatment of associated risk factors) (Fonseca 2009; Krantz 2009; Methadone Maintenance Guidelines 2011; UK guidelines 2007). Why it is important to do this review Quidelines and recommendations on QTc screening of patients receiving methadone treatment are based on assumed risk of TdP 3

6 associated with use of this medication (Krantz 2009; Martin 2011; Methadone Maintenance Guidelines 2011; UK guidelines 2007). However, although these recommendations are based on etiological studies investigating the role of methadone in QTc prolongation, TdP and sudden death, no studies have been reported as documenting the efficacy of QTc screening in preventing such consequences. Moreover, interference of the screening procedure with the availability of patients to comply with treatment (because of unnecessary evaluation, additional investigations and treatment associated with false-positive findings), thus exposing patients to competing causes of mortality associated with untreated opioid addiction, does not seem to have been appropriately ruled out (Gourevitch 2009). Lack of evaluation of whether expected benefits of the widespread implementation of such screening outweigh potential harms undermines the validity of screening interventions. Therefore, although methadone treatment may be implicated as a potential condition of risk for a major health consequence, the evaluation of benefit/risk associated with QTc screening for prevention of cardiac morbidity/mortality in methadone-treated opioid addicts represents a priority, providing evidence-based support for the decision to introduce routine ECG examination before and during methadone treatment. O B J E C T I V E S The primary aim of the review is to evaluate the efficacy and acceptability of QTc screening for prevention of cardiac-related morbidity and mortality in methadone-treated opioid dependents. M E T H O D S Criteria for considering studies for this review it) or with no screening intervention for the prevention of methadone-related mortality, cardiac-related morbidity and other specified primary and secondary outcomes (defined in the outcome measures section) in opioid addicts. (2) Cohort studies Longitudinal observational studies in which mortality, cardiac-related morbidity and other specified primary and secondary outcomes (defined in the outcome measures section) are longitudinally assessed in opioid dependents receiving methadone treatment. Within the cohort, a study group (for whom the intervention is QTc screening) and a comparison group (receiving no screening) are identified. (3) Controlled before and after studies (CBAs) Studies in which data on mortality, cardiac-related morbidity and other specified primary and secondary outcomes (defined in the outcome measures section) are gathered for samples of methadonetreated opioid addicts before and after the introduction of a QTc screening procedure along with samples from comparison sites where the QTc screening procedure is not available. Two minimum criteria were considered for inclusion of CBAs in the review. Contemporaneous data collection among intervention and control populations: Where pre- and post-intervention periods for study and control sites were the same, the study had to be included. Where this information is not clear in the article, for example, dates of collection were not mentioned in the text, and if the information could not be obtained from the authors, the study had to be excluded. Appropriate choice of control site: Studies using a second site as a control had to be included if study and control sites were comparable with respect to level of care, setting of care and academic status. If it was not clear from the article whether study and control sites were comparable, and if the information could not be obtained from the authors, the study had to be excluded. Types of studies Randomised controlled trials (RCTs), controlled clinical trials (CCTs) and non-randomised studies. The inclusion of non-randomised studies as a complement to randomised evidence is based on the unlikely availability of randomised studies on rare outcomes included in the review, such as sudden death. More specifically, the following study designs were included: (1) Controlled clinical trials Randomised and quasi-randomised studies comparing QTc screening with placebo (such as doing an ECG without reading (4) Interrupted time series studies (ITSs) Studies in which data on mortality, cardiac-related morbidity and other specified primary and secondary outcomes (defined in the outcome measures section) are collected for a single sample of methadone-treated opioid addicts before and after commencement of a QTc screening procedure. Two minimum criteria were considered for inclusion of ITS studies in this review. Clearly defined point in time when the intervention occurred: The study had to be included if it was reported that the intervention occurred at a clearly defined point in time. If this information was not reported in the article, and if the 4

7 information could not be obtained from the authors, the study had to be excluded. At least three data points before and three after the intervention: The study had to be included if three or more data points before and three or more data points after the intervention were recorded. If this was not specified in the article, for example, if the number of discrete data points was not mentioned in text or tables, and if this information could not be obtained from the authors, the study had to be excluded. measures of QT lengthening, had to be considered according to measures used in included studies. Where possible, different categories of screening strategies involving timing and conditions of ECG registration (pre-treatment, annual, linked to an established dose of methadone) and of the consequent interventions (QTc cut-offs chosen for applying the intervention, typology of interventions applied) had to be considered. (5) Case control studies Studies that entail identification of patients who died or that show conditions such as cardiac-related morbidity and other specified primary and secondary outcomes (defined in the outcome measures section) during methadone treatment and selection of a similar comparison group of methadone subjects alive or not showing the conditions reported above. These two groups are then compared in terms of previous exposure to QTc screening procedures. Types of participants Opioid dependents to be enrolled or already enrolled in methadone treatment. Studies involving participants using other drugs, included other QTc-prolonging medications, in addition to opioids were included. Patients with additional diagnoses of substance abuse or dependence were also eligible. People younger than 18 years of age and pregnant women were excluded because of the substantially different approach to clinical management required for these people. Types of interventions Study intervention Interventions considered consist of ECG registration before or periodically after entry into methadone treatment, followed in cases of long QTc by each of the following interventions: Withdrawal from methadone treatment; Assignment to an alternative opioid agonist treatment; Reduction of methadone dosage; Interventions intended to correct associated risk factors for QTc prolongation. Comparison intervention ECG without measurement of QTc; ECG with measurement of QTc not followed by any intervention; No intervention. Long QTc had to be considered according to two cut-offs with different risks for arrhthymia: > 450 milliseconds; > 500 milliseconds. However, other cut-offs or QT prolongation definitions, such as QTc increase > 60 milliseconds from baseline or other advanced Types of outcome measures Primary outcomes Sudden death (defined as sudden unexpected death either within 1 hour of witnessed onset of symptoms or within 24 hours of observation of the participant alive and symptom free); whenever possible, the following had to be distinguished: unexpected death in the absence of structural cardiac abnormalities and noncardiac causes of sudden death (such as trauma, pulmonary embolism, etc.) that can point toward fatal cardiac arrhythmia as the cause; drug overdose-related death. Mortality by any other cause. Cardiac-related morbidity (distinguishing, whenever possible, torsades de pointes and ventricular arrhythmias from other cardiac-related morbidities). Dropouts from methadone treatment defined as number of participants who did not start or leave treatment before the end of the study. Use of primary substance of abuse defined as number of participants who reported the use of opioids and/or number of participants who produced urine samples positive for opioids. Secondary outcomes QTc length: The following outcome measures had to be used: group mean scores for QTc length; number of participants who showed a QTc length considered at risk for torsades de pointes (two cut-offs had to be considered: length equal to or greater than 500 milliseconds; length equal to or greater than 450 milliseconds), or who showed a QTc increase > 60 milliseconds from baseline or values of other measures of QT lengthening, such as QT dispersion, considered at risk for arrhythmias. Use of other drugs defined as number of participants who reported such use and/or number of participants who produced urine samples positive for cocaine. Physical health (including loss of consciousness and syncope). Psychological health. 5

8 Search methods for identification of studies Electronic searches Relevant randomised trials were identified by a search of the following databases: The Cochrane Drug and Alcohol Review Group Specialised Register (April 2013); The Cochrane Central Register of Controlled Trials (CENTRAL; Issue 3, 2013); MEDLINE (PubMed) (1966 to April 2013); EMBASE (embase.com) (1980 to April 2013); CINAHL (EBSCO) (1982 to April 2013). For details on searches, see Appendix 1, Appendix 2, Appendix 3, Appendix 4 and Appendix 5. Trial databases of the following drug-approving agencies were searched for published, unpublished and ongoing controlled trials: Food and Drug Administration (FDA) in the USA; Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK; European Medicines Agency (EMEA) in the EU; Pharmaceuticals and Medical Devices Agency (PMDA) in Japan; Therapeutic Goods Administration (TGA) in Australia; Ongoing trial registers (clinicaltrials.gov in the USA, ISRCTN and National Research Register in the UK, Nederlands Trial Register in the Netherlands, EUDRACT in the EU, UMIN-CTR in Japan and the Australian Clinical Trials Registry in Australia). All searches included non-english language literature and studies with English abstracts. When considered likely to meet inclusion criteria, studies had be translated. Searching other resources We searched the reference lists of all relevant articles to identify further studies and conference proceedings likely to contain trials relevant to the review. Data collection and analysis Selection of studies Two review authors (PPP, ET) inspected the search hits by reading titles and abstracts. Each potentially relevant study located in the search was obtained in full text and was assessed for inclusion independently by the two review authors (PPP, ET). Doubts were resolved by discussion between all review authors. Data extraction and management Data were extracted independently by two review authors (ET, PPP). A standardised checklist had to be used to collect information on methodology, participants (socio-demographic and clinical information relevant to the review aims), interventions (ECG registration, QTc length, subsequent clinical decisions, medications and their dosage and non-pharmacological interventions) and primary and secondary outcomes. Any disagreement had to be discussed, and persisting disagreement had to be dealt with by a third review author, who acted as a mediator. Assessment of risk of bias in included studies RCT, CCT Two review authors (PPP, ET) had to assess study quality according to the criteria provided in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011).The risk of bias assessment for RCTs and CCTs in this review had to be performed using the five criteria recommended by the Cochrane Handbook (Higgins 2011). The recommended approach for assessing risk of bias in studies included in Cochrane reviews involves use of a two-part tool to address seven specific domains, namely, sequence generation and allocation concealment (selection bias), blinding of participants and providers (performance bias), blinding of outcome assessors (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias) and other sources of bias. The first part of the tool involves describing what was reported to have happened in the study. The second part of the tool involves assigning a judgement related to the risk of bias for that entry, in terms of low, high or unclear risk. To make these judgments, we had to use the criteria provided in the Cochrane Handbook as adapted to the field of addiction. The domains of sequence generation and allocation concealment (avoidance of selection bias) had to be addressed by using the instrument described above to provide a single entry for each study. Blinding of participants, personnel and outcome assessors (avoidance of performance bias and detection bias) had to be considered separately for objective outcomes (e.g. mortality, retention in treatment, use of substance of abuse as measured by urine analysis) and subjective outcomes (e.g. loss of consciousness, self-reported use of substance of abuse, psychological distress, severity of dependence). Incomplete outcome data (avoidance of attrition bias) had to be considered for all outcomes except for dropout from treatment, which very often is the primary outcome measure in trials on addiction. Retention had to be assessed separately at the end of the study period and at follow-up. See Appendix 6 for a detailed description of assessment of risk of bias in included studies. Observational cohort studies, Controlled CBAs The criteria drawn from the Newcastle-Ottawa Scale (NOS scale; NOS) for prospective cohort studies and the criteria developed by the EPOC Group (EPOC 2009) had to be used to assess observational studies. The Risk of bias table was operationalized to be 6

9 used for assessment of RCTs, CCTs, observational cohort studies and CBA studies according to the criteria recommended by the Cochrane Drug and Alcohol Review Group. See Appendix 6 for details. ITS studies For ITS studies, we had to assess risk of bias associated with the following six domains: intervention independent of other changes; shape of intervention effect pre-specified; intervention unlikely to affect data collection; blinding of outcome assessors to intervention allocation; incomplete outcome data and selective outcome reporting (EPOC 2009). For a detailed description of the criteria used, see Appendix 7. Case control studies The criteria drawn from the Newcastle-Ottawa Scale (NOS scale; NOS) for case control studies had to be used. For a detailed description of the criteria used, see Appendix 8. We had to consider the risk of confounding and bias for all included studies, with particular attention to: Baseline characteristics of study and comparison groups; Methods for recruiting and assessing eligibility of study participants; Identification of confounders and use of statistical methods to adjust for confounding; Extent of loss to follow-up, assessment of differences between those contacted and those lost to follow-up and approaches used to adjust for losses to follow-up; Differences in exposure to interventions other than ECG screening; Timing and methods of data collection used. Measures of treatment effect Dichotomous outcomes (mortality, retention in treatment, use of primary substance, results at follow-up) had to be analysed by calculating the relative risk (RR) for each trial, with the uncertainty in each result expressed by 95% confidence intervals (CIs) for all study designs except case control studies. For case control studies, the odds ratio (OR) had to be used. Continuous outcomes (QTc length) had to be analysed by calculating the mean difference (MD) with 95% CI. Weighted mean differences and 95% CIs had to be calculated by comparing and pooling mean score differences from the post-screening intervention to baseline for each group. In cases of missing data on the standard deviation (SD) of changes, this measure had to be imputed using the SD provided at the post-screening phase for each group. For interrupted time series design studies, we had to abstract the difference in slope and the difference in level from pre- to post-intervention. The post- versus pre-intervention difference (adjusted for trends) at specific time points had to be reported. If the differences were not provided in the primary reports, we had to attempt re-analysis using data from graphs or tables. We did not have to use data presented as the number of positive urine tests over the total number of tests in the experimental and control groups as measures of substance use. This decision was made because using the number of tests instead of the number of subjects as a unit of the analysis violates the hypothesis of independence among observations. In fact, the results of tests done for each participant are not independent. Unit of analysis issues If all arms of a multi-arm trial had to be included in the meta-analysis and one arm had to be included in more than one of the treatment comparisons, we had to divide the number of events and the number of participants in that arm by the number of comparisons made. This method avoids the multiple use of participants in the pooled estimate of treatment effect while retaining information from each arm of the trial. The precision of the pooled estimate results slightly compromised. Dealing with missing data Data missing from the studies had to be collected by requests made to the original investigators. Whenever the assumption that data are missing at random was supported by available information, only available data had to be analysed; if this was not the case, other approaches such as the last observation carried forward option or the assumption that missing data correspond to poor outcomes had to be applied. To assess how results are sensitive to changes made in the assumptions, sensitivity analysis had to be performed. Moreover, the potential impact of missing data on the findings of the review had to be addressed in the Discussion section. Assessment of heterogeneity The presence of heterogeneity between trials had to be tested using the I-squared (I 2 ) statistic. A P value of the test lower than 0.05 indicates significant heterogeneity. Assessment of reporting biases A funnel plot (plot of the effect estimate from each study against the sample size or the effect standard error) had to be used to assess the potential for bias related to the size of the trials. Data synthesis Outcomes from the individual trials, when possible, had to be combined through meta-analysis (comparability of interventions and outcomes between trials) by using a random-effects model. Results from ITS studies had to be presented in tables for each 7

10 comparison with summary statistics for each of the included studies, change in the level of outcome at the first point after introduction of the intervention, post-intervention slope minus pre-intervention slope and information on effect modifiers. This information had also to be presented graphically by using, for example, scatter plots of change in level versus change in slope, with combinations of statistical significance denoted by different symbols. Quantitative meta-analysis had to be undertaken only for groups of studies of similar design. at different risk of bias, we had then to perform sensitivity analysis while excluding the analysis with high risk of bias. Other issues suitable for sensitivity analysis had to be identified during the review process by looking at individual peculiarities of the studies under investigation. R E S U L T S Subgroup analysis and investigation of heterogeneity Analysis of subgroups had to be performed according to type of study (randomised and non-randomised). Moreover, subgroup analysis had to be performed to examine different categories of screening strategies and to take into account other confounders/ effect modifiers. Sensitivity analysis To incorporate assessment in the review process, we had first to plot intervention effect estimates stratified for risk of bias for each relevant domain. If differences in results were noted among studies Description of studies See Characteristics of excluded studies Results of the search The search strategy used led to the identification of 872 records. After independent examination by the review authors, we retrieved just 2 articles that were potentially eligible for the review. Upon full text assessment, no study was found to meet the quality criteria used in considering studies for this review (see Figure 1). Descriptions of retrieved studies and reasons for their exclusion are presented in the Characteristics of excluded studies section. 8

11 Figure 1. Study flow diagram. 9

12 Included studies No eligible studies were found for inclusion in this review. Excluded studies Two potentially eligible studies did not meet the criteria for inclusion in this review. Grounds for exclusion included study design not in the inclusion criteria and objectives not in the inclusion criteria. See Characteristics of excluded studies section. Risk of bias in included studies No eligible studies were found for inclusion in this review. Effects of interventions No eligible studies were found for inclusion in this review. D I S C U S S I O N Summary of main results Unfortunately, our review does not shed any light on the efficacy and safety of QTc screening procedures. Even though our search was extended to RCTs, CCTs, cohort studies, etc., we did not find any study that fulfilled the methodological criteria used for this review. The only examples of research in which investigators attempted to evaluate the impact of the introduction of routine ECG screening procedures into methadone maintenance programs were substantially focused on the feasibility of the procedure. Mayet 2011, in applying the Medicines and Healthcare Products Regulatory Agency (MHRA) recommendations (UK guidelines 2007), found that 57.4% (n = 89 out of 155 screened) fulfilled MHRA criteria for ECG monitoring (75.5%; n = 117); this has economic implications. Moreover, almost half of the patients referred did not attend for an ECG. Fareed 2010 conducted a retrospective chart review in a service providing on-site baseline and yearly QTc screening with a focus on patient education while limiting the referral to specialty care provided to patients at high risk for cardiac arrhythmias. In this service, out of 55 patients included in the chart review, 95% underwent on-site QTc screening. Among those evaluated by ECG, about 6% had a statistically significant QTc prolongation from baseline longer than 500 ms, which, according to the screening procedure, required the intervention of cardiology specialty care. These two studies did not measure the association with outcomes under study and have not been included. Potential biases in the review process Reporting bias can jeopardize the validity of any meta-analysis. We have tried to limit the influence of reporting bias by screening all applicable data sets and by searching the reference lists of all relevant articles to identify further studies and conference proceedings likely to contain studies relevant to the review. We did not find information on unpublished or incomplete studies that could be clarified with investigators. Agreements and disagreements with other studies or reviews The possible implications of methadone in cardiac arrhythmia have been advanced by different kinds of research: Experimental preclinical studies have supported a biological plausibility involving the negative chronotropic effect of methadone (due to calcium channel antagonism) and the interference of this medication with cardiac repolarization (via blockade of herg channels) (Kornick 2003; Seyler 1983); clinical case series have documented TdP in patients treated with methadone (Krantz 2002; Krantz 2003; Pearson 2005; Patel 2008; Hanon 2010; Thavanaro 2011), often associated with relatively high doses of the medication; toxicological investigations of patients who had sudden cardiac death have indicated an excess of mortality that is not overdose related and is not associated with cardiac abnormalities in patients treated with therapeutic levels of methadone (Chugh 2008); cross-sectional studies carried out in patients receiving methadone maintenance therapy have shown baseline QTc intervals exceeding the population-expected value and exceeding the values observed in drug users not receiving methadone or the values observed in patients receiving buprenorphine (Maremmani 2005; Peles 2007; Ehret 2006: Fanoe 2007); prospective and randomised studies have consistently shown an increase in QTc in association with the start of methadone but not with the start of buprenorphine treatment (Fredheim 2006; Martell 2005; Krantz 2005a; Wedam 2007). A dose-dependent effect of methadone on cardiac repolarization has also been observed in case reports and cross-sectional and prospective studies (Kornick 2003; Peles 2007; Ehret 2006; Fanoe 2007; Martell 2005; Krantz 2003), and some case reports highlight QTc interval normalization after methadone discontinuation or dose reduction (Gil 2003; Krantz 2005b; Thavanaro 2011). Other factors predicting QTc interval prolongation according to multivariate regression analysis have included hypokalaemia, liver disease and concomitant use of hepatic cytochrome P450 inhibitors (Ehret 2006). On these bases, and consistent with the approach to other medications that block the same potassium channels that are blocked by methadone, as is the case with sotalol and dofetilide, where base- 10

13 line QTc has been shown to predict TdP (Soyka 1990; Pedersen 2007), regulatory agencies have intervened on the subject: The U.S. Food and Drug Administration issued a physician safety alert regarding fatalities and cardiac arrhythmias associated with methadone (FDA 2006); other national agencies and expert consensus committees in different countries (UK, US, Canada, Denmark, Italy, Norway) have issued guidelines and recommendations implying the need for forms of routine ECG screening of the QTc interval at some point (Krantz 2009; Methadone Maintenance Guidelines 2011; UK guidelines 2007; Martin 2011). However, in the absence of consistent evidence of their efficacy, concern has been raised about the disadvantages of these screening practices (Gourevitch 2009; Byrne 2009; Cohen 2009). Worries are principally based on these considerations: Methadone efficacy has been established in different settings and across multiple outcomes (Faggiano 2003; Gowing 2008; Mattick 2008), including mortality. Mortality of untreated heroin dependence is consistently estimated at 1 to 3 per 100 person-years, with a standardised mortality ratio more than10 times (6 to 54 times) that of the general population, half of which is the result of heroin overdose (Bargagli 2006; Bartu 2004; Darke 2003; Hickman 2003; Sporer 1999). Despite the supposed involvement of methadone in TdP-related mortality, estimated at 0.06 deaths per 100 patient-years (Anchersen 2009), its protective effect against heroin-related deaths cannot be understated: methadone maintenance, with an annual mortality rate of 0.1% (Davoli 2007) and a standardised mortality ratio of 3.9 to 4.5 (Davoli 2007; Degenhardt 2009), has been shown to reduce by 2 to 11 times the mortality risk of the opioid-dependent population (Brugal 2005; Davoli 2007; Degenhardt 2009); QTc screening can interfere with the availability of patients to undergo methadone maintenance because of how demanding and stressful the procedures can be (unnecessary evaluations, additional investigations and treatment associated with falsepositive findings, inappropriate treatment of opioid addiction), thus exposing patients to competing causes of mortality associated with untreated opioid addiction (Gourevitch 2009). To be noted with regard to this, established evidence indicates that leaving treatment and relapsing in addictive behaviour is a very common event in a drug addict s life (Daley 1993; Fiellin 2006; McLellan 2000); Although treatments for opioid dependence with substantially lower risk of cardiac complications, such as buprenorphine, are available (Wedam 2007), their pharmacological profile, efficacy and acceptability by patients do not allow them to be thought of as an easy alternative to methadone (Mattick 2008); Qtc screening may not be an appropriate method of identifying individuals at risk for TdP. Ventricular tachyarrhythmia has many causes, including underlying cardiac disease, electrolyte abnormalities, inherited disorders of cardiac conduction, metabolic disorders, and drug/medication toxicity not necessarily preceded by prolongation of QTc; no prospective data are available to support the use of QTc in risk stratification of sudden cardiac death (Bart 2011; Montanez 2004); undue focus on QTc prolongation may divert attention away from other important risk factors, thereby decreasing patient safety (Bart 2011); Executing ECG screenings is not a simple decision or task. Most physicians, including many cardiologists, cannot accurately calculate a QTc and cannot correctly identify a long QTc (Viskin 2005). Tecnical difficulties and experience, including the need to take more than one ECG to get a reliable QTc and refer the patient to a cardiologist, can interfere with the organization of health services providing assistance to those with substance use disorders; The scientific rigour applied to other areas of medicine is not always applied to screening. Actually, many examples of screening tests that were believed to be efficacious and recommended until rigourous evaluation showed their disadvantages are reported in the literature (Grimes 2002; Law 2004). Actually, variations in recommended procedures (i.e. universal vs selective screening for those showing specific risk factors), even though supported by some advancements in the science linking methadone to QTc prolongation and TdP (Eap 2007; Anchersen 2010; Ansermot 2010), still reflect the substantial uncertainty in critical points involved in the balance of risks versus benefits of procedures. Our results confirm the lack of scientific evidence supporting this ECG-based screening procedure and testify for the relevance of conducting appropriate clinical research to clarify this issue. A U T H O R S C O N C L U S I O N S Implications for practice No conclusions can be made about the risk-benefit balance of ECG-based strategies in preventing long QTcrelated cardiac morbidity and mortality in methadone-treated opioid addicts. Healthcare organisations considering the implementation of interventions aimed at reducing heart-related risks associated with methadone treatment should seriously look upon the need for clinically relevant research to clarify this subject. Absence of evidence on the efficacy and safety of QTc screening may leave to clinicians the alternative of balancing for each patient the risk for development of cardiac-related side effects against the potential adverse effects of the procedure, especially those constituting possible barriers to treatment access. 11

14 Implications for research Evidence on the effectiveness of QTc screening strategies in preventing long QTcrelated cardiac morbidity and mortality in methadone-treated opioid addicts is lacking. Research efforts should focus on evaluation of the effectiveness of the widespread implementation of such strategies and on clarification of associated benefits and harms, the variation of risk-benefit balance according to the level of exposure to risk factors (universal vs selective screening) and the level at which expected benefits outweigh expected harms. Interventions considered should be those recommended in guidelines and by consensus regarding the timing of the ECG evaluation, the QTc threshold chosen for the implementation of consequent interventions and the characteristics of the interventions. Regarding the design of future studies, RCTs and CCTs may not be appropriate because of ethical considerations and because of the low frequency of some of the expected primary outcomes, such as mortality and cardiac-related morbidity. Other non-randomised designs, such as observational and case control studies, although burdened with a higher risk of bias, may offer better ways of handling ethical problems and rare events. A C K N O W L E D G E M E N T S We want to thank Zuzana Mitrova for her help in developing search strategies and retrieving articles. R E F E R E N C E S References to studies excluded from this review Fareed 2010 {published data only} Fareed A, Vayalapalli S, Byrd-Sellers J, Casarella J, Drexler K, Amar R, et al.onsite QTc interval screening for patients in methadone maintenance treatment. Journal of Addictive Diseases 2010;29: Mayet 2011 {published data only} Mayet S, Gossop M, Lintzeris N, Markides V, Strang J. Methadone maintenance, QTc and torsade de pointes: who needs an electrocardiogram and what is the prevalence of QTc prolongation?. Drug and Alcohol Review 2011;30: Additional references Anchersen 2009 Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Prevalence and clinical relevance of corrected QT interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Addiction 2009; 104: Anchersen 2010 Anchersen K, Hansteen V, Gossop M, Clausen T, Waal H. Opioid maintenance patients with QTc prolongation: congenital long QT syndrome mutation may be a contributing risk factor. Drug and Alcohol Dependence 2010; 112: Ansermot 2010 Ansermot N, Albayrak Ö, Schläpfer J, Crettol S, Croquette- Krokar M, Bourquin M, et al.substitution of (R,S)- methadone by (R)-methadone impact on QTc interval. Archives of Internal Medicine 2010;170: Bargagli 2006 Bargagli AM, Hickman M, Davoli M, Perucci CA, Schifano P, Buster M, et al.cosmo European Group. Drugrelated mortality and its impact on adult mortality in eight European countries. European Journal of Public Health 2006;16: Bart 2011 Bart G. CSAT s QT interval screening in methadone report: outrageous fortune or sea of troubles?. Journal of Addictive Diseases 2011;30: Bartu 2004 Bartu A, Freeman NC, Gawthorne GS, Codde JP, Holman CD. Mortality in a cohort of opiate and amphetamine users in Perth, Western Australia. Addiction 2004;99: Bednar 2002 Bednar MM, Harrigan EP, Ruskin JN. Torsades de pointes associated with non antiarrhythmic drugs and observations on gender and QTc. American Journal of Cardiology 2002; 89: Bell 2010 Bell J. The global diversion of pharmaceutical drugs: opiate treatment and the diversion of pharmaceutical opiates: a clinician s perspective. Addiction 2010;105: Brugal 2005 Brugal MT, Domingo-Salvany A, Puig R, Barrio G, García de Olalla P, de la Fuente L. Evaluating the impact of methadone maintenance programmes on mortality due to overdose and aids in a cohort of heroin users in Spain. Addiction 2005;100: Buster 2002 Buster MC, van Brussel GH, van den Brink W. An increase in overdose mortality during the first 2 weeks after entering or re-entering methadone treatment in Amsterdam. Addiction 2002;97: Byrne 2009 Byrne A. Concerns about consensus guidelines for QTc interval screening in methadone treatment. Annals of Internal Medicine 2009;151:

15 Caplehorn 1996 Caplehorn JR, Dalton MS, Haldar F, Petrenas AM, Nisbet JG. Methadone maintenance and addicts risk of fatal heroin overdose. Substance Use and Misuse 1996;31: CDC 2012 Centers for Disease Control and Prevention (CDC). Vital signs: risk for overdose from methadone used for pain relief United States, MMWR CDC Morbidity and Mortality Weekly Report 2012;61: Cerdà 2013 Cerdá M, Ransome Y, Keyes KM, Koenen KC, Tracy M, Tardiff KJ, et al.prescription opioid mortality trends in New York City, : examining the emergence of an epidemic. Drug and Alcohol Dependence 2013 [Epub ahead of print]. [DOI: /j.drugalcdep ] Chugh 2008 Chugh SS, Socoteanu C, Reinier K, Waltz J, Jui J, Gunson K. A community-based evaluation of sudden death associated with therapeutic levels of methadone. American Journal of Medicine 2008;121: Clausen 2008 Clausen T, Anchersen K, Waal H. Mortality prior to, during and after opioid maintenance treatment (OMT): a national prospective cross-registry study. Drug and Alcohol Dependence 2008;94: Cohen 2009 Cohen SP, Mao J. Concerns about consensus guidelines for QTc interval screening in methadone treatment. Annals of Internal Medicine 2009;151: Corkery 2004 Corkery JM, Schifano F, Ghodse AH, Oyefeso A. The effects of methadone and its role in fatalities. Human Psychopharmacology 2004;19: Daley 1993 Daley DC, Marlatt GA. Relapse prevention: cognitive and behavioral interventions. In: Lowinson JH, Ruiz P, Millman BR, Langrod JC editor(s). Substance Abuse, A Comprehensive Textbook. Baltimore: Williams & Wilkins, 1993: Darke 2003 Darke S, Hall W. Heroin overdose: research and evidence based intervention. Journal of Urban Health 2003;80: Dasgupta 2011 Dasgupta N, Bailey EJ, Cicero T, Inciardi J, Parrino M, Rosenblum A, et al.postmarketing surveillance of methadone and buprenorphine in the United States. Pain Medicine 2010;11: Davoli 2007 Davoli M, Bargagli AM, Perucci CA, Schifano P, Belleudi V, Hickman M, et al.vedette Study Group. Risk of fatal overdose during and after specialist drug treatment: the VEdeTTE study, a national multi-site prospective cohort study. Addiction 2007;102: De Bels 2003 De Bels D, Staroukine M, Devriendt J. Torsades de pointes due to methadone. Annals of Internal Medicine 2003;139: E156. de Jong 2013 de Jong IM, de Ruiter GS. Buprenorphine as a safe alternative to methadone in a patient with acquired long QT syndrome: a case report. Netherlands Heart Journal 2013;21: De Ponti 2002 De Ponti F, Poluzzi E, Cavalli A, Recanatini M, Montanaro N. Safety of non-antiarrhythmic drugs that prolong the QT interval or induce torsade de pointes: an overview. Drug Safety 2002;25: Degenhardt 2009 Degenhardt L, Randall D, Hall W, Law M, Butler T, Burns L. Mortality among clients of a state-wide opioid pharmacotherapy program over 20 years: risk factors and lives saved. Drug and Alcohol Dependence 2009;105:9 15. Eap 2007 Eap CB, Crettol S, Rougier JS, Schlapfer J, SintraGrilo L, Deglon JJ. Stereoselective block of herg channel by (S)- methadone and QT interval prolongation in CYP2B6 slow metabolizers. Clinical Pharmacology and Therapeutics 2007; 81: Ehret 2006 Ehret GB, Voide C, Gex-Fabry M, Chabert J, Shah D, Broers B, et al.drug induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalised patients and risk factors. Archives of Internal Medicine 2006;166: Elming 2002 Elming H, Brendorp B, Køber L, Sahebzadah N, Torp- Petersen C. QTc interval in the assessment of cardiac risk. Cardiac Electrophysiology Review 2002;6: EPOC 2009 Cochrane Effective Practice and Organisation of Care (EPOC) Group. Draft EPOC Risk of Bias guideline. http: //www.epoc.cochrane.org/en/handsearchers.html. John Wiley and Sons, Faggiano 2003 Faggiano F, Vigna-Taglianti F, Versino E, Lemma P. Methadone maintenance at different dosages for opioid dependence. Cochrane Database of Systematic Reviews 2003, Issue 3. [DOI: / CD002208] Fanoe 2007 Fanoe S, Hvidt C, Ege P, Jensen GB. Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen. Hearth 2007;93: FDA 2006 Food, Drug Administration. FDA ALERT: death, narcotic overdose, and serious cardiac arrhythmias, PostmarketDrugSafetyInformationforPatientsandProviders/ ucm htm accessed May

16 Fiellin 2006 Fiellin DA, Friedland GH, Gourevitch MN. Opioid dependence: rationale for and efficacy of existing and new treatments. Clinical Infectious Diseases 2006;43:S Florian 2012 Florian J, Garnett CE, Nallani SC, Rappaport BA, Throckmorton DC. A modeling and simulation approach to characterize methadone QT prolongation using pooled data from five clinical trials in MMT patients. Clinical Pharmacology & Therapeutics 2012;91: Fonseca 2009 Fonseca F, Marti-Almor J, Pastor A, Cladellas M, Farré M, de la Torre R, et al.prevalence of long QTc interval in methadone maintenance patients. Drug and Alcohol Dependence 2009;99: Fredheim 2006 Fredheim OM, Borchgrevink PC, Hegrenaes L, Kaasa S, Dale O, Klepstad P. Opioid switching from morphine to methadone causes a minor but not clinically significant increase in QTc time: a prospective 9-month follow-up study. Journal of Pain Symptom Management 2006;32: Fung 2000 Fung MC, Hsiao-hui Wu H, Kwong K, Hornbuckle K, Muniz E. Evaluation of the profile of patients with QTc prolongation in spontaneous adverse event reporting over the past three decades Pharmacoepidemiology and Drug Safety 2000;9 Suppl 1:S24. Gil 2003 Gil M, Sala M, Anguera I, Chapinal O, Cervantes M, Guma JR, et al.qt prolongation and torsades de pointes in patients infected with human immunodeficiency virus and treated with methadone. American Journal of Cardiology 2003;92: Gourevitch 2009 Gourevitch MN. First do no harm... reduction?. Annals of Internal Medicine 2009;150: Gowing 2008 Gowing L, Farrell M, Bornemann R, Sullivan L, Ali R. Substitution treatment of injecting opioid users for prevention of HIV infection. Cochrane Database of Systematic Reviews 2008, Issue 2. [DOI: / CD004145] Grimes 2002 Grimes DA, Schulz KF. Uses and abuses of screening tests. Lancet 2002;359: Hanon 2010 Hanon S, Seewald RM, Yang F, Schweitzer P, Rosman J. Ventricular arrhythmias in patients treated with methadone for opioid dependence. Journal of Interventional Cardiac Electrophysiology 2010;28: Hickman 2003 Hickman M, Carnwath Z, Madden P, Farrell M, Rooney C, Ashcroft R, et al.drug-related mortality and fatal overdose risk: pilot cohort study of heroin users recruited from specialist drug treatment sites in London. Journal of Urban Health 2003;80: Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version [updated March 2011]. The Cochrane Collaboration, Justo 2006 a Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated torsades de pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction 2006;101: Justo 2006 b Justo D. Methadone-induced long QT syndrome vs methadone-induced torsades de pointes. Archives of Internal Medicine 2006;166:2288. Kornick 2003 Kornick CA, Kilborn MJ, Santiago-Palma J, Schulman G, Thaler HT, Keefe DL, et al.qtc interval prolongation associated with intravenous methadone. Pain 2003;105: Krantz 2002 Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, Robertson AD, Mehler PS. Torsade de pointes associated with very-high-dose methadone. Annales of Internal Medicine 2002;137: Krantz 2003 Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Doserelated effects of methadone on QT prolongation in a series of patients with torsades de pointes. Pharmacotherapy 2003; 23: Krantz 2005a Krantz MJ, Lowery CM, Martell BA, Gourevitch MN, Arnsten JH. Effects of methadone on QT-interval dispersion. Pharmacotherapy 2005;25: Krantz 2005b Krantz MJ, Garcia JA, Mehler PS. Effects of buprenorphine on cardiac repolarization in a patient with methadonerelated torsade de pointes. Pharmacotherapy 2005;25: Krantz 2009 Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MC. QTc interval screening in methadone treatment. Annales of Internal Medicine 2009;150: Law 2004 Law M. Screening without evidence of efficacy. BMJ 2004; 328: Madden 2011 Madden ME, Shapiro SL. The methadone epidemic: methadone-related deaths on the rise in Vermont. The American Journal of Forensic Medicine and Pathology 2011; 32: Maremmani 2005 Maremmani I, Pacini M, Cesaroni C, Lovrecic M, Perugi G, Tagliamonte A. QTc interval prolongation in patients 14

17 on long-term methadone maintenance therapy. European Addiction Research 2005;11:44 9. Martell 2005 Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of methadone treatment on cardiac repolarization and conduction in opioid users. American Journal of Cardiology 2005;95: Martin 2011 Martin JA, Campbell A, Killip T, Kotz M, Krantz MJ, Kreek MJ, et al.qt interval screening in methadone maintenance treatment: report of a SAMHSA expert panel. Journal of Addictive Diseases 2011;30: Mattick 2008 Mattick RP, Kimber J, Breen C, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database of Systematic Reviews 2008, Issue 2. [DOI: / CD002207] McLellan 2000 McLellan AT, Lewis DC, O Brien CP, Kleber HD. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. Journal of the American Medical Association 2000;284: Methadone Maintenance Guidelines 2011 Methadone Maintenance Treatment Program Standards and Clinical Guidelines. College of Physicians & Surgeons of Ontario, Totonto, Ontario,. 4th Montanez 2004 Montanez A, Ruskin JN, Hebert PR, Lamas GA, Hennekens CH. Prolonged QTc interval and risks of total and cardiovascular mortality and sudden death in the general population: a review and qualitative overview of the prospective cohort studies. Archives of Internal Medicine 2004;164: Nichol 2008 Nichol G, Thomas E, Callaway CW, Hedges J, Powell JL, Aufderheide TP, et al.resuscitation Outcomes Consortium Investigators. Regional variation in out-of-hospital cardiac arrest incidence and outcome. Journal of the American Medical Association 2008;300: NOS Wells GA, Shea B, O Connell D, Peterson J, Welch V, Losos M, et al.the Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomised studies in meta-analyses, clinical epidemiology/oxford.htm. programs/clinical epidemiology/oxford.htm, accessed May Patel 2008 Patel AM, Singh JP, Ruskin JN. Role of implantable cardioverter-defibrillators in patients with methadoneinduced long QT syndrome. American Journal of Cardiology 2008;101: Pearson 2005 Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmacoepidemiology and Drug Safety 2005;14: Pedersen 2007 Pedersen HS, Elming H, Seibaek M, Burchardt H, Brendorp B, Torp-Pedersen C, et al.diamond Study Group. Risk factors and predictors of torsade de pointes ventricular tachycardia in patients with left ventricular systolic dysfunction receiving dofetilide. American Journal of Cardiology 2007;100: Peles 2007 Peles E, Bodner G, Kreek MJ, Rados V, Adelson M. Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients: a cross-sectional study. Addiction 2007;102: Pilgrim 2013 Pilgrim JL, McDonough M, Drummer OH. A review of methadone deaths between 2001 and 2005 in Victoria, Australia. Forensic Science International 2013;226: Priori 2003 Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, et al.risk stratification in the long-qt syndrome. New England Journal of Medicine 2003;348: Redfern 2003 Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, et al.relationships between preclinical cardiac electrophysiology, clinical QTinterval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovascular Research 2003;58: Seyler 1983 Seyler DE, Borowitz JL, Maickel RP. Calcium channel blockade by certain opioids. Fundamental and Applied Toxicology 1983;3: Sims 2007 Sims SA, Snow LA, Porucznik CA. Surveillance of methadone-related adverse drug events using multiple public health data sources. Journal of Biomedical Informatics 2007;40: Soyka 1990 Soyka LF, Wirtz C, Spangenberg RB. Clinical safety profile of sotalol in patients with arrhythmias. American Journal of Cardiology 1990;65 Suppl:74A 81A. Sporer 1999 Sporer KA. Acute heroin overdose. Annals of Internal Medicine 1999;130: Thavanaro 2011 Thanavaro KL, Thanavaro JL. Methadone-induced torsades de pointes: a twist of fate. Heart Lung 2011;40: UK guidelines 2007 Drug Misuse and Dependence: UK Guidelines on Clinical Management. Department of Health (England), the Scottish Government, Welsh Assembly Government, and Northern Ireland Executive,

18 Viskin 2005 Viskin S, Rosovski U, Sands AJ, Chen E, Kistler PM, Kalman JM, et ak. Inaccurate electrocardiographic interpretation of long QT: the majority of physicians cannot recognize a long QT when they see one. Heart Rhythm 2005;2: Wedam 2007 Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MC. QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomised trial. Archives of Internal Medicine 2007;167: WHO 2008 WHO. The methadone fix. Bulletin of the World Health Organization 2008;86: Wolff 2002 Wolff K. Characterization of methadone overdose: clinical considerations and the scientific evidence. Therapeutic Drug Monitoring 2002;24: Indicates the major publication for the study 16

19 C H A R A C T E R I S T I C S O F S T U D I E S Characteristics of excluded studies [ordered by study ID] Study Fareed 2010 Mayet 2011 Reason for exclusion Study design not in the inclusion criteria; objectives not in the inclusion criteria; no control group. Trial retrospectively studies some outcomes of ECG screeningexposed participants and the contribution of risk factors in prolonging QTc Study design not in the inclusion criteria. Outcome measures not in the inclusion criteria: This is a cross-sectional study. Objectives not in the inclusion criteria: This study describes characteristics of opioid dependents maintained on methadone and fulfilling pre-specified criteria for ECG screening 17

20 D A T A A N D A N A L Y S E S This review has no analyses. A D D I T I O N A L T A B L E S Table 1. Recommendations on QTc screening of patients receiving methadone treatment Study Target population Timing of the screening Consequent interventions Krantz 2009 All patients Patients taking doses above 100 mg/day Patients having unexpected syncope or seizures Pretreatment, within 30 days and annually Additional ECG for dosages exceeding 100 mg/day, syncope or seizures If the QTc interval is greater than 450 ms but less than 500 ms, discuss potential risks and benefits with patients and monitor them more frequently If the QTc interval exceeds 500 ms, consider discontinuing or reducing the methadone dose; eliminating contributing factors such as drugs that promote hypokalaemia; or using an alternative therapy Methadone Guidelines 2011 Maintenance Patients taking doses above 120 mg/day if known risk factors are present Patients taking doses above 150 mg/day Patients taking more than mg/day At the time of dose variation If the QTc interval exceeds 500 ms, provide cardiology referral and/or methadone dose reduction Physician should take steps to modify risk factors when possible Buprenorphine may be an alternative UK guidelines 2007 Patients presenting risk factors (heart or liver disease, electrolyte abnormalities, concomitant treatment with CYP 3A4 inhibitors or medicines with the potential to cause QT interval prolongation) Patients requiring more than 100 mg/day of methadone Careful monitoring Screening before commencing methadone treatment is not currently advocated but may be considered QT prolongation needs full investigation, consideration of specialist referral, identification of options for QT risk factor modification and ECG monitoring Alternatives to methadone should be considered Other QTc risk factors (such as cocaine use) should be reassessed 18

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