High-dose Methadone Research Articles

Factors associated with methadone maintenance therapy discontinuation among people who inject drugs

BackgroundMethadone maintenance therapy (MMT) continues to be a key treatment for opioid use disorder, although premature discontinuation of MMT can increase risk for overdose and other severe harms. We examined sociodemographic characteristics, substance use patterns and social-structural exposures associated with MMT discontinuation among a cohort of people who use drugs (PWUD) in Vancouver, Canada. MethodsData were derived from VIDUS and ACCESS, prospective cohorts of PWUD in Vancouver, Canada. The outcome of interest was self-reported discontinuation of MMT within the last six months. Multivariable Generalized Estimating Equations (GEE) were conducted to identify factors independently associated with MMT discontinuation. ResultsBetween 2005 and 2015, 1301 PWUD who had accessed MMT were recruited, among whom 288 (22.1%) discontinued MMT at least once during the study period. In multivariable GEE analyses, homelessness (Adjusted Odds Ratio [AOR] = 1.46, 95% Confidence Interval [95% CI]: 1.09–1.95), daily heroin injection (AOR = 5.17, 95% CI: 3.82–6.99), daily prescription opioid use (injection or non-injection) (AOR = 2.18, 95% CI: 1.30–3.67), recent incarceration (AOR = 1.46, 95% CI: 1.01–2.12), and not being on any form of income assistance (AOR = 2.14, 95% CI: 1.33–3.46) were each independently positively associated with MMT discontinuation. Participants with more study visits on methadone (>50% vs. ≤50% of visits) (AOR = 0.63, 95% CI: 0.47–0.85) and those with higher methadone dose (>100 mg vs. <60 mg per day) (AOR = 0.44, 95% CI: 0.31–0.62) were less likely to discontinue MMT. Discussion and conclusionsDiscontinuation of MMT in this urban setting was associated with recent homelessness and incarceration, not accessing social income assistance, as well as daily prescription opioid use and daily heroin injection drug use. These findings underscore a need to reduce potential barriers to MMT retention by providing access to stable housing and preventing treatment interruptions during transitions between community and custodial settings.

Torsades de Pointes on Chronic Methadone Use

Methadone is a drug associated with the development of prolonged Correcred QT (QTc) interval, as QT interval prolongation can occur in up to 15% of methadone-maintenance patients. In recent years, methadone found to be associated with an increased risk of sudden death in a community-based study (1, 2). ‘‘Torsades de Pointes’’ is a quick and dangerous rhythm that quickly becomes ventricular fibrillation. If this rhythm is rapid or prolonged, it can lead to ventricular fibrillation or sudden cardiac death. The usual clinical manifestations of TdP are palpitations, dizziness, and syncope. It is certain that no cardiac drugs are recognized to increase the propensity for TdP. The most common risk factors of methadone-associated QT prolongation and TdP include a high dose of methadone or chronic use, old age, accompaniment with enhancing drugs methadone levels, infections such as AIDS, old age, low potassium, kidney failure, heart disease, female gender, and cirrhosis of the liver (3). Despite the availability of methadone for over 60 years, only in the past 10 years has this medication received attention for its potential to cause QTc prolongation leading to Torsades de Pointes (4-6). We report 4 cases of methadone-induced Torsades de pointes. Through rapid taper of methadone, the patient’s ECG normalized.

Corrected QT Interval and Methadone Dose and Concentrations in Pregnant and Postpartum Women

Methadone is a standard treatment for opioid dependence in pregnancy; however, its impact on maternal corrected QT interval (QTc) has not been evaluated. We studied the association between methadone dose and enantiomer-specific plasma concentrations and QTc among pregnant and postpartum women and newborns. We assessed the relevance of QTc screening guidelines for pregnant women and infants. From 2006 to 2008, plasma methadone concentrations were measured during pregnancy, postpartum, and in cord blood in women treated for opioid dependence at a single treatment program. Electrocardiograms (ECGs) were obtained at peak methadone concentrations in mothers and within 48 hours of birth for infants. Pearson correlations were performed at each time point for QTc and R-methadone, S-methadone, and total methadone concentrations and ratio of R-methadone/S-methadone concentrations. Mean (SD) daily methadone dose for the 25 women was 94.2 (39.1) mg during pregnancy and 112.5 (46.6) mg postpartum. During the third trimester, higher methadone dose and R-methadone concentration correlated with longer QTc (Pearson r = 0.67, P < .001 and Pearson r = 0.49, P = .02, respectively), while S-methadone concentration, R-methadone/S-methadone concentration ratio, and total methadone concentration did not. Postpartum, QTc did not significantly correlate with dose or enantiomer concentrations. Infant QTc did not correlate with maternal dose at delivery or enantiomer-specific cord methadone concentrations. In pregnant and postpartum women, 13% and 17%, respectively, had QTc ≥ 450 ms, as did 19% of infants. QTc correlated with dose and R-methadone concentration during the third trimester. However, longer QTc was common among women during and after pregnancy. Given the relatively high rate of QTc > 450 ms, an ECG before and after methadone initiation is advisable for pregnant and postpartum women.

Prevalence of pain and its socio-demographic and clinical correlates among heroin-dependent patients receiving methadone maintenance treatment

To date there have been no studies investigating the characteristics of pain in Chinese heroin-dependent patients (HDPs) receiving methadone maintenance treatment (MMT). This study examined the frequency and socio-demographic and clinical correlates of pain in HDPs under MMT. A consecutive sample of 603 HDPs was recruited from three MMT clinics in Wuhan, China. These patients completed a standardized questionnaire concerning socio-demographic and clinical data. Pain intensity was assessed with the 5-point Verbal Rating Scale (“Overall, how intense is your pain now?”) with responses of: 1 = none, 2 = mild, 3 = moderate, 4 = severe, 5 = very severe. A pain score of three or higher was used to denote clinical significant pain (CSP). The prevalence of CSP in HDPs receiving MMT was 53.6%. Factors significantly associated CSP in multiple logistics regression analysis were old age, marital status of “non-married”, unemployment, having religious beliefs, a history of injecting heroin, a high dose of methadone, and more depressive symptoms. Over a half of Chinese HDPs receiving MMT have CSP. Services for HDPs in MMT settings should include periodic screening for pain, psychosocial supports, and professional treatment for pain.

Recurrent Foreign Body Ingestions Following Rapid Methadone Taper: Neurological Aspects of Self-Injury and Opioid Therapy

Recurrent Foreign Body Ingestions Following Rapid Methadone Taper: Neurological Aspects of Self-Injury and Opioid Therapy

Commentary on Nikoo et al. (2017): The role of research.

Opium tincture (OT) is used in Iran because it has two critical advantages—it is cheap, and it is less stigmatized than methadone. Stigma, and the problem of funding stigmatized treatments, is an issue in every country. Might OT be a solution? The evidence is limited, but reviewing it is useful. Nikoo and colleagues 1 report that in Iran there are 64 000 people in treatment with opium tincture (OT), the majority in slow withdrawal programmes. They have weighed the evidence concerning this preparation and found it wanting. They found observational trials of OT in substitution treatment, but no controlled trials. There were two controlled trials of OT in opioid withdrawal, with inconclusive results. Is OT a suitable medication for managing opioid dependence? Cost is one reason why the government of Iran used OT, and in low-income countries lower-cost treatment options are critical. Parsimony might seem a poor basis for choosing a medication without evidence to support it. However, absence of evidence of effectiveness is not evidence of absence of effectiveness. There are grounds for believing that almost any opioid can be used satisfactorily in substitution treatment 2. Well-controlled trials might reveal marginal differences in efficacy, but morphine, codeine and dihydrocodeine, to name a few opioids, have been used in observational studies 3, 4. OST medications do not even need to be long-acting or administered orally, as demonstrated by the effectiveness of injectable diamorphine and hydromorphone 5. Substitute medications work more effectively if they attenuate the effect of injected heroin—which is why high-dose methadone, inducing high opioid tolerance, is more effective than lower doses 6. As expected, a dose effect with OT was noted by Nikoo, with higher doses being more effective. In choosing between opioid drugs for substitution treatment, it might be a case of ‘anything goes’ (as long as given in sufficient dose); but in delivering medication to individuals, it is not the case that any approach is good enough. There are wide variations in how treatment is delivered 7—and better structured and supported treatment is more expensive to deliver and produces more effective outcomes 8. A more relevant question is whether slow opioid withdrawal a suitable treatment. Nikoo and colleagues comment that ‘we still do not have a satisfactory safe and effective treatment for detoxification and maintenance treatment of opioid dependence’; but spontaneous opioid withdrawal is not life-threatening. Most people dependent upon street opioids go through multiple episodes of withdrawal without formal treatment. On safety grounds, there is little need to offer detoxification—on the contrary, there is consistent evidence that post-detoxification heroin users are at increased risk of death 9. We can make withdrawal faster (rapid detoxification), or we can make it slower and less aversive, but however it is conducted relapse rates are high and risks of death post-withdrawal are increased 2, 10. The other major for using OT in Iran was the stigma against methadone. Stigma corrodes all aspects of substitution treatment. Stigma deters people from participating, and families pressure patients to avoid OST 11. People hate being on methadone, and drop out. Stigma against substitution treatment is one reason that professionals offer, and patients choose, detoxification rather than maintenance. The research reviewed by Nikoo and colleagues may permit few conclusions about OT relative to other medications, but it is important, none the less. Research helps to destigmatize treatment. It frames addiction as an empirical problem to be investigated, rather than an ethical problem to be corrected. It focuses not on the daily frustrations of dosing large numbers of people with minimal friction, but on the question of whether there are things we could do more effectively. It identifies end-points against which to evaluate treatment, guiding staff and patients towards realistic objectives and away from magical thinking. These ‘side effects’ of research into addiction are its greatest benefits—more valuable even than the occasional reporting of a vaguely relevant finding. Most of us have given up waiting for the big breakthrough that will cure addiction, but we still value the research enterprise. Research, even negative findings, helps us to think—and to cope with the stigma that bears down upon everyone involved in addiction. J.B. has received speaker's fees from Indivior and consultancy fees from Martindale Pharma.

Genome-wide association study of therapeutic opioid dosing identifies a novel locus upstream of OPRM1.

Opioids are very effective analgesics, but they are also highly addictive. Methadone is used to treat opioid dependence (OD), acting as a selective agonist at the μ-opioid receptor encoded by the gene OPRM1. Determining the optimal methadone maintenance dose is time consuming; currently, no biomarkers are available to guide treatment. In methadone-treated OD subjects drawn from a case and control sample, we conducted a genome-wide association study of usual daily methadone dose. In African-American (AA) OD subjects (n=383), we identified a genome-wide significant association between therapeutic methadone dose (mean=68.0 mg, s.d.=30.1 mg) and rs73568641 (P=2.8 × 10-8), the nearest gene (306 kilobases) being OPRM1. Each minor (C) allele corresponded to an additional ~20 mg day-1 of oral methadone, an effect specific to AAs. In European-Americans (EAs) (n=1027), no genome-wide significant associations with methadone dose (mean=77.8 mg, s.d.=33.9 mg) were observed. In an independent set of opioid-naive AA children being treated for surgical pain, rs73568641-C was associated with a higher required dose of morphine (n=241, P=3.9 × 10-2). Similarly, independent genomic loci previously shown to associate with higher opioid analgesic dose were associated with higher methadone dose in the OD sample (AA and EA: n=1410, genetic score P=1.3 × 10-3). The present results in AAs indicate that genetic variants influencing opioid sensitivity across different clinical settings could contribute to precision pharmacotherapy for pain and addiction.

Evaluation of QTc Interval Prolongation Among Cancer Patients Using Oral Methadone (FR420D)

•Describe the incidence of QTc prolongation in cancer patients taking oral methadone.•Discuss the effect of increasing methadone doses on QTc prolongation in cancer patients. Methadone’s effect on QTc in cancer pain patients is not well known. The lone published study may not represent all palliative prescribing patterns. The objective of this study is to describe and characterize the effect of low-, moderate-, and high-dose methadone on QTc in cancer patients. This retrospective cohort study was exempt from IRB. Cancer patients with an order for enteral methadone over a 27-month period were included. Participants were divided into three methadone daily dose groups: <30mg (low-dose), 30 to 59mg (moderate-dose), >60mg (high-dose). Primary outcome was the incidence of QTc prolongation in each group. Secondary outcomes included change in QTc from baseline to study electrocardiogram (ECG), incidence of clinically significant QTc prolongation (> 500ms), and prevalence of adverse cardiac outcomes including Torsades de Pointes. A total of 203 of 430 met the inclusion criteria for the study; low-dose: 91 patients (45%), moderate-dose: 52 (26%), and high-dose: 60 (29%). Incidence of QTc prolongation for low-, moderate-, and high-dose groups was 50 (55%), 37 (71%), and 43 (72%), respectively (p=0.039). Incidence of clinically significant QTc prolongation was 10 (11%), 4 (8%), and 7 (12%) for low-, moderate-, and high-dose groups. Median change in QTc interval from baseline to study ECG for low-, moderate-, and high-dose groups was 6ms, 18ms, 14.5ms, respectively (p=0.068). Sixty-two percent of patients in the moderate-dose group and 67% of patients in the high-dose group without QTc prolongation at baseline had QTc prolongation at study ECG. Our data suggest there may be a higher incidence of QTc prolongation in patients using oral methadone in the cancer population than previously defined in the literature.

Effects of three methadone doses combined with acepromazine on sedation and some cardiopulmonary variables in dogs

ObjectiveTo evaluate the sedative and cardiopulmonary effects of three methadone doses, combined with acepromazine, in dogs. Study designProspective, randomized, complete block study. AnimalsSix healthy, adult, cross-bred dogs weighing 17.2±4.4 kg (mean±standard deviation). MethodsEach dog was administered four treatments: acepromazine (0.05 mg kg−1) alone or acepromazine (same dose) in combination with methadone (0.25, 0.50 or 0.75 mg kg−1). All drugs were administered intramuscularly. Sedation was scored by a numeric descriptive scale (NDS, range 0–3) and a simple numerical scale (SNS, range 0–10). Heart rate, invasive blood pressure, arterial blood gases and rectal temperature were measured at 15 to 30 minute intervals for 120 minutes. ResultsAccording to NDS scores, mild to moderate sedation (NDS=1–2) was observed in most dogs in the acepromazine treatment, with only one out of six dogs scored as exhibiting intense sedation (NDS=3). All treatments with methadone resulted in significantly higher SNS scores compared with acepromazine alone. In these treatments, most dogs exhibited intense sedation (NDS=3). Increasing the dose of methadone from 0.25 to 0.50 or 0.75 mg kg−1 prolonged sedation in a dose-related manner, but did not influence the degree of sedation. The main adverse effects following administration of acepromazine–methadone treatments were decreased blood pressure, mild respiratory acidosis and decreased rectal temperature. These effects were well tolerated and resolved without treatment. Conclusions and clinical relevanceIn this study in six dogs, acepromazine–methadone administration resulted in intense sedation in most dogs. The results are interpreted to indicate that a low dose of methadone (0.25 mg kg−1) administered in combination with acepromazine (0.05 mg kg−1) will induce short-term sedation in dogs, whereas higher doses of methadone should be administered when prolonged sedation is desired.

Poly Pharmacy-Induced Long-QT Syndrome and Torsades de Pointes: A Case Report

Polypharmacy-induced QT prolongation is a possible hazardous adverse effect of several medication combinations. When QT prolongation leads to torsade de pointes, life-threatening or mortal outcomes can result. A 45-year-old man presented to the emergency department due to the use of methadone in the field with ventricular tachycardia and after successful resuscitation after cardiac arrest, under ICU care, has been exacerbated torsade de point due to polypharmacy with high-dose methadone, the patient had multiple risk factors for prolonged QT syndrome including methadone therapy, multiple drug therapy leading to potential drug interactions, electrolyte disturbances such as hypomagnesaemia. Clinical pharmacy must be aware of multidrug interactions potentiating QT prolongation and leading to torsade de pointes. In this article has emphasized the importance of considering the cumulative effects of several drugs used in the ICU and their timely treatment and possible avoidance of poly pharmacy.

Pharmacokinetics and analgesic effects of methadone in children and adults with sickle cell disease.

Vaso-occlusive episodes (VOEs) are a significant source of morbidity among children and adults with sickle cell disease (SCD). There is little information on methadone use for SCD pain. This investigation evaluated methadone pharmacokinetics in children and adults with SCD, with a secondary aim to assess pain relief and opioid consumption. Participants included children (<18 years) and adults with a VOE requiring hospitalization. Patients were randomly assigned to receive standard care (opioid patient-controlled analgesia; control group) or one dose of intravenous methadone (0.1-0.125mg/kg) in addition to standard care (methadone group). Venous methadone and metabolite concentrations were measured. Pain scores, pain relief scores, and opioid consumption were recorded. Twenty-four children (12 methadone, 12 controls) and 23 adults (11 methadone, 12 controls) were studied. In children, the half-life of R- and S-methadone enantiomers was 34 ± 16 and 24 ± 9hr, respectively. In adults, R- and S-methadone half-lives were 52 ± 17 and 38 ± 12hr, respectively. Pain scores were lower (P = 0.002) and pain relief scores were higher (P = 0.0396) in children receiving methadone versus controls. There was no difference in pain scores and pain relief in adults receiving methadone versus controls. There was no difference in opioid consumption between methadone and control groups, in both adults and children. Intravenous methadone disposition in children and adults with SCD was comparable to that in subjects without SCD from prior studies. Methadone produced more pain relief than standard care in children with SCD. Higher methadone doses may be more effective and should be evaluated in both children and adults with SCD.

Multifaceted impairments in impulsivity and brain structural abnormalities in opioid dependence and abstinence

Chronic opioid exposure, as a treatment for a variety of disorders or as drug of misuse, is common worldwide, but behavioural and brain abnormalities remain under-investigated. Only a small percentage of patients who receive methadone maintenance treatment (MMT) for previous heroin misuse eventually achieve abstinence and studies on such patients are rare. The Cambridge Neuropsychological Test Automated Battery and T1 weighted magnetic resonance imaging (MRI) were used to study a cohort of 122 male individuals: a clinically stable opioid-dependent patient group receiving MMT (n = 48), an abstinent previously MMT maintained group (ABS) (n = 24) and healthy controls (n = 50). Stable MMT participants deliberated longer and placed higher bets earlier in the Cambridge Gambling Task (CGT) and showed impaired strategic planning compared with healthy controls. In contrast, ABS participants showed impairment in choosing the least likely outcome, delay aversion and risk adjustment on the CGT, and exhibited non-planning impulsivity compared with controls. MMT patients had widespread grey matter reductions in the orbitomedial prefrontal cortex, caudate, putamen and globus pallidus. In contrast, ABS participants showed midbrain-thalamic grey matter reductions. A higher methadone dose at the time of scanning was associated with a smaller globus pallidus in the MMT group. Our findings support an interpretation of heightened impulsivity in patients receiving MMT. Widespread structural brain abnormalities in the MMT group and reduced brain structural abnormality with abstinence suggest benefit of cessation of methadone intake. We suggest that a longitudinal study is required to determine whether abstinence improves abnormalities, or patients who achieve abstinence have reduced abnormalities before methadone cessation.

Use of microdoses for induction of buprenorphine treatment with overlapping full opioid agonist use: the Bernese method.

BackgroundBuprenorphine is a partial µ-opioid receptor agonist used for maintenance treatment of opioid dependence. Because of the partial agonism and high receptor affinity, it may precipitate withdrawal symptoms during induction in persons on full µ-opioid receptor agonists. Therefore, current guidelines and drug labels recommend leaving a sufficient time period since the last full agonist use, waiting for clear and objective withdrawal symptoms, and reducing pre-existing full agonist therapies before administering buprenorphine. However, even with these precautions, for many patients the induction of buprenorphine is a difficult experience, due to withdrawal symptoms. Furthermore, tapering of the full agonist bears the risk of relapse to illicit opioid use.CasesWe present two cases of successful initiation of buprenorphine treatment with the Bernese method, ie, gradual induction overlapping with full agonist use. The first patient began buprenorphine with overlapping street heroin use after repeatedly experiencing relapse, withdrawal, and trauma reactivation symptoms during conventional induction. The second patient was maintained on high doses of diacetylmorphine (ie, pharmaceutical heroin) and methadone during induction. Both patients tolerated the induction procedure well and reported only mild withdrawal symptoms.DiscussionOverlapping induction of buprenorphine maintenance treatment with full µ-opioid receptor agonist use is feasible and may be associated with better tolerability and acceptability in some patients compared to the conventional method of induction.

Effective drug therapy for cocaine dependence: a milestone.

In The Lancet, Mascha Nuijten and colleagues 1 Nuijten M Blanken P van de Wetering B Nuijen B van den Brink W Hendriks VM Sustained-release dexamfetamine in the treatment of chronic cocaine-dependent patients on heroin-assisted treatment: a randomised, double-blind, placebo-controlled trial. Lancet. 2016; (published online March 22.)http://dx.doi.org/10.1016/S0140-6736(16)00205-1 Google Scholar present the results of a multicentre, randomised, double-blind, placebo-controlled trial assessing the acceptance, safety, and efficacy of sustained-release dexamfetamine in cocaine-dependent patients on heroin-assisted treatment. The study findings showed that 60 mg/day oral sustained-release dexamfetamine over 12 weeks was well accepted, safe, and superior to placebo in terms of days of cocaine use (mean 44·9 days [SD 29·4] in the sustained-release dexamfetamine group vs 60·6 days [24·3] in the placebo group [95% CI of difference 3·1–28·4]; p=0·031; Cohen's standardised effect size d=0·58) and all self-reported and urine-based cocaine use-related outcomes. Cocaine dependence is prevalent throughout the world and causes major morbidity and mortality. 2 Degenhardt L Hall W Extent of illicit drug use and dependence, and their contribution to the global burden of disease. Lancet. 2012; 379: 55-70 Summary Full Text Full Text PDF PubMed Scopus (868) Google Scholar At present, no effective pharmacotherapy exists. Agonist replacement therapy has been successfully applied to opioid and tobacco dependence, 3 Strain EC Bigelow GE Liebson IA Stitzer ML Moderate- vs high-dose methadone in the treatment of opioid dependence: a randomized trial. JAMA. 1999; 281: 1000-1005 Crossref PubMed Scopus (359) Google Scholar , 4 Aubin HJ Luquiens A Berlin I Pharmacotherapy for smoking cessation: pharmacological principles and clinical practice. Br J Clin Pharmacol. 2014; 77: 324-336 Crossref PubMed Scopus (73) Google Scholar but previous studies examining this approach in cocaine dependence failed to find statistically significant benefits in terms of reduced cocaine use, or showed indecisive results. This could be due to limitations in the methods, such as small sample sizes, 5 Shearer J Wodak A van Beek I Mattick RP Lewis J Pilot randomized double blind placebo-controlled study of dexamphetamine for cocaine dependence. Addiction. 2003; 98: 1137-1141 Crossref PubMed Scopus (120) Google Scholar inadequate dosing schemes, 6 Dursteler KM Berger EM Strasser J et al. Clinical potential of methylphenidate in the treatment of cocaine addiction: a review of the current evidence. Subst Abuse Rehabil. 2015; 6: 61-74 Crossref PubMed Google Scholar or large attrition rates. 7 Grabowski J Rhoades H Stotts A et al. Agonist-like or antagonist-like treatment for cocaine dependence with methadone for heroin dependence: two double-blind randomized clinical trials. Neuropsychopharmacology. 2004; 29: 969-981 Crossref PubMed Scopus (168) Google Scholar The study by Nuijten and colleagues 1 Nuijten M Blanken P van de Wetering B Nuijen B van den Brink W Hendriks VM Sustained-release dexamfetamine in the treatment of chronic cocaine-dependent patients on heroin-assisted treatment: a randomised, double-blind, placebo-controlled trial. Lancet. 2016; (published online March 22.)http://dx.doi.org/10.1016/S0140-6736(16)00205-1 Google Scholar overcomes most of these shortcomings. Sustained-release dexamfetamine in the treatment of chronic cocaine-dependent patients on heroin-assisted treatment: a randomised, double-blind, placebo-controlled trialSustained-release dexamfetamine is a well accepted, effective, and safe agonist pharmacotherapy for comorbid treatment-refractory cocaine dependence in heroin-dependent patients in heroin-assisted treatment. Future research should aim to replicate these findings in chronic cocaine-dependent and other stimulant-dependent patients in more routine treatment settings, including strategies to optimise treatment adherence like medication management interventions and contingency management. Full-Text PDF

Torsades-de-Pointes Predisposing Risk Factors (TdPPRFs) in a cohort of patients maintained on high dose methadone – a clinical safety caseload analysis

IntroductionMethadone, a long-acting opioid agonist commonly used in the treatment of opiate dependence, has been reported to cause QTc interval prolongation, increasing the risk of a fatal cardiac arrhythmia – Torsades-de-Pointes (TdP). This effect seems to be attributable to methadone's inhibitory effect on the cardiac “hERG”-K+ ion channel and is dose-dependent. There is a lack of consensus regarding when to perform an ECG for patients on methadone.ObjectivesIdentifying other TdPPRFs in a cohort of patients receiving ≥ 85 mg (high dose) methadone daily to inform local clinical safety guidelines.MethodsOur outpatient caseload was filtered to select opiate-dependent patients receiving more than 85 mg methadone daily. Primary care summaries and laboratory results databases were analysed for the presence of other TdPPRFs: female sex a documented history of ECG abnormalities, electrolyte imbalance, liver or renal failure, and concomitant use of other QT prolonging medication or stimulants.ResultsFourteen opiate-dependent patients (10.29% of patients on methadone) were maintained on ≥ 85 mg methadone daily. Gender distribution was F:M = 1:1.8; 64% misused illicit stimulants; 57% were prescribed other QTc prolonging medication and 29% had a documented history of liver/renal failure or electrolyte imbalance. Only 14% had previous ECGs documented in primary care summaries. Of patients on high dose methadone, 85.7% had at least one TdPPRFs present and 64.3% had at least two.ConclusionsThese results demonstrate an increased rate of TdPPRFs in this patient group and highlight the importance of ECG monitoring which ideally should be offered to patients receiving even lower doses of methadone.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Impact of blended treatment literacy and psychoeducation on methadone maintenance treatment outcomes in Yunnan, China.

BackgroundOutcomes of methadone maintenance treatment (MMT) in the management of opioid dependency can be impaired by poor adherence and retention, concomitant drug use, poor adjustment of methadone dosage, and low levels of awareness regarding methadone among drug users, among other factors. This study investigated the effects of intensive blended treatment literacy and psychoeducation on treatment compliance, methadone dose, and heroin use among MMT clients in China.MethodsA total of 492 MMT clients who tested positive for urine morphine at least once during a 12-week intervention period preceding the study were recruited from 16 MMT clinics. Employing a client-centred approach, a blended treatment literacy and psychoeducation intervention was then implemented between March and June 2014, comprising (1) intensified methadone treatment literacy sessions; (2) participatory goal setting; (3) continuous adherence monitoring and support; and (4) engagement of both peers and doctors in delivering psychoeducation. Wilcoxon signed-rank test was used to compare urine morphine positive rates, daily methadone dosage, and the number of days that clients successfully accessed methadone before and during the intervention.ResultsDuring the intervention, urine morphine positive rates reduced to 27 % from 49.3 % previously; p < 0.001. In response to client needs, methadone dosages increased among 74 % of participants, remained unchanged among 12.0 %, and reduced among 13.4 % during the intervention. In addition, the average daily methadone dose increased from 63.0 to 72.6 mg; p < 0.001, while the average number of days that clients successfully accessed methadone increased from 69.4 to 73.9 over a period of 12 weeks; p < 0.001.ConclusionsBlended treatment literacy and psychoeducation delivered by a combination of peers and doctors was associated with reduced heroin use, improved treatment adherence, and higher methadone doses among our sample of MMT clients.

Gender Differences in Heroin Addiction and Treatment: Results from the VEdeTTE Cohort

ABSTRACTBackground: Gender differences strongly affect heroin addiction, from risk factors to patterns of consumption, access to treatments, and outcomes. Objectives: To investigate gender differences in the VEdeTTE cohort of heroin addicts. Methods: VEdeTTE is a cohort of 10,454 heroin users enrolled between 1998 and 2001 in 115 public drug treatment centres in Italy. Clinical and personal information were collected at intake through a structured interview. Treatments were recorded using a standardized form. Gender differences were explored with regard to characteristics at intake, treatments, and retention in methadone maintenance and therapeutic community. Cox Proportional models were carried out to identify risk factors for treatment abandon. Results: Compared with men, at their first access to treatment women with drug addiction were younger, more frequently married, legally separated, divorced or widow, unemployed though better educated, HIV+; more frequently they lived with their partner and sons. They reported a higher use of sedatives, but a lower use of alcohol; more frequently they had psychiatric comorbidity, including depression, self-injuries, and suicide attempts. Psychotherapy was more frequently prescribed to women, pharmacological treatments to men. Methadone maintenance was less frequently abandoned by women. Drug abuse severity factors predicted abandon of methadone among women. High methadone doses and the combination with psychotherapy improved treatment retention in both genders. Low education level and severity factors among women and young age among men predicted abandon of therapeutic community. Conclusions: Gender differences in the VEdeTTE cohort suggest the need of a gender sensitive approach to improve treatment outcomes among heroin addicts.

Variability of response to methadone: genome-wide DNA methylation analysis in two independent cohorts.

Methadone maintenance treatment is characterized by large interindividual dose variability. The aim of this study was to evaluate whether DNA methylations are associated with daily dose of methadone. Subjects stabilized at high (n = 12) or low (n = 12) methadone doses were selected from two independent cohorts (French and Swiss). DNA methylation patterns were analyzed using HumanMethylation450 BeadChips. In total, 584 differentially methylated sites were identified in the French cohort corresponding to 352 genes. Of these, 26 were replicated in the Swiss cohort. The methylation status of 13 genes varied similarly in both cohorts and calcium signaling pathway was significantly enriched. Our results indicate that differentially methylated sites are associated with methadone daily dose and give insights into the molecular pathways underlying this interindividual dose variability.

Demographic and clinical factors predicting retention in methadone maintenance: results from an Irish cohort.

Retention in Methadone Maintenance Treatment (MMT) is superior to that of other therapies for opioid addiction, but with international retention rates around 50% after 1year of treatment, there remains a need for improved retention rates. This study aimed to explore the demographic and clinical factors predicting retention in MMT. Face-to-face surveys with MMT patients in a Dublin methadone clinic were conducted. Retention was assessed by the presence and duration of breaks in treatment at any stage. 189 patients participated in the study. 46% (n=87) reported having at least one break in treatment, and the median duration of a break was 3months. Age, current methadone dose and prescription of antipsychotic medication were significant predictors of retention. Patients who were older, single, living in their own home, on a higher dose of methadone, or taking antipsychotic medications had fewer breaks in treatment. Males tended to have significantly longer breaks. Patients reported that the main reasons for breaks were relapse into drug use (21.8%, n=19), incarceration (11.4%, n=10), weary of MMT (13.7%, n=12) or problems at the clinic (10.3%, n=9). Factors enabling regular attendance included wanting to get or stay clean (37.5%, n=51), avoidance of withdrawal symptoms (16.1%, n=22), methadone dependence (13.9%, n=19) and services provided (10.2%, n=14). Patients who were older, single, living in their own home, on a higher dose of methadone, or taking antipsychotic medications had fewer breaks in treatment.

Implementation and Operational Research: Linkage to Care Among Methadone Clients Living With HIV in Dar es Salaam, Tanzania.

Background:The first methadone maintenance treatment clinic in Tanzania was launched in February 2011 to address an emerging HIV epidemic among people who inject drugs. We conducted a retrospective cohort study to understand factors associated with linkage to HIV care and explore how a methadone maintenance treatment clinic can serve as a platform for integrated HIV care and treatment.Methods:This study used routine programmatic and clinical data on clients enrolled in methadone at Muhimbili National Hospital from February 2011 to January 2013. Multivariable proportional hazards regression model was used to examine time to initial CD4 count.Results:Final analyses included 148 HIV-positive clients, contributing 31.7 person-years. At 30, 60, and 90 days, the probability of CD4 screening was 40% [95% confidence interval (CI): 32% to 48%], 55% (95% CI: 47% to 63%), and 63% (95% CI: 55% to 71%), respectively. Clients receiving high methadone doses (≥85 mg/d) [adjusted hazard ratio (aHR): 1.68, 95% CI: 1.03 to 2.74] had higher likelihood of CD4 screening than those receiving low doses (<85 mg/d). Clients with primary education or lower (aHR: 1.62, 95% CI: 1.05 to 2.51) and self-reported poor health (aHR: 1.96, 95% CI: 1.09 to 3.51) were also more likely to obtain CD4 counts. Clients with criminal arrest history (aHR: 0.56, 95% CI: 0.37 to 0.85]) were less likely to be linked to care. Among 17 antiretroviral therapy eligible clients (CD4 ≤ 200), 12 (71%) initiated treatment, of which 7 (41%) initiated within 90 days.Conclusions:Levels of CD4 screening and antiretroviral therapy initiation were similar to Sub-Saharan programs caring primarily for people who do not inject drugs. Adequate methadone dosing is important in retaining clients to maximize HIV treatment benefits and allow for successful linkage to services.