Helge Waal

Prevalence and clinical relevance of corrected QT interval prolongation during methadone and buprenorphine treatment: a mortality assessment study

AIMS To determine the prevalence of corrected QT interval (QTc) prolongation among patients in opioid maintenance treatment (OMT) and to investigate mortality potentially attributable to QTc prolongation in the Norwegian OMT programme. PARTICIPANTS AND SETTING Two hundred OMT patients in Oslo were recruited to the QTc assessment study between October 2006 and August 2007. The Norwegian register of all patients receiving OMT in Norway (January 1997-December 2003) and the national death certificate register were used to assess mortality. Mortality records were examined for the 90 deaths that had occurred among 2382 patients with 6450 total years in OMT. DESIGN AND MEASURES The QTc interval was assessed by electrocardiography (ECG). All ECGs were examined by the same cardiologist, who was blind to patient history and medication. Mortality was calculated by cross-matching the OMT register and the national death certificate register: deaths that were possibly attributable to QTc prolongation were divided by the number of patient-years in OMT. FINDINGS In the QTc assessment sample (n = 200), 173 patients (86.5%) received methadone and 27 (13.5%) received buprenorphine. In the methadone group, 4.6% (n = 8) had a QTc above 500 milliseconds; 15% (n = 26) had a QTc interval above 470 milliseconds; and 28.9% (n = 50) had a QTc above 450 milliseconds. All patients receiving buprenorphine (n = 27) had QTc results <450 milliseconds. A positive dose-dependent association was identified between QTc length and dose of methadone, and all patients with a QTc above 500 milliseconds were taking methadone doses of 120 mg or more. OMT patient mortality, where QTc prolongation could not be excluded as the cause of death, was 0.06/100 patient-years. Only one death among 3850 OMT initiations occurred within the first month of treatment. CONCLUSION Of the methadone patients, 4.6% had QTc intervals above 500 milliseconds. The maximum mortality attributable to QTc prolongation was low: 0.06 per 100 patient-years.

Mortality among opiate users: opioid maintenance therapy, age and causes of death

AIMS This study investigates how age of opioid users is related to causes of death prior to, during and after opioid maintenance treatment (OMT), and estimates risks of death from various causes in relation to age. DESIGN, SETTING AND PARTICIPANTS Data on all opiate dependents in Norway (1997-2003) who applied for and were accepted for OMT (n = 3789) were cross-linked with the Norwegian death register. The total observation time was 10 934 person-years. FINDINGS A total of 213 deaths was recorded. Of these, 73% were subject to autopsy, and causes of death were known for 208 cases: the overall death rate was 1.9%. Deaths were due to drug overdose (54%), somatic (32%) and traumatic causes (14%). Overdose deaths among all age groups were reduced during OMT but age had a differential effect upon risk when out of treatment. Younger opioid users were at greater risk of overdose before entering treatment; older users were at greater risk after leaving treatment. Older OMT patients were at higher risk of both somatic and traumatic deaths, and deaths during OMT were most likely to be due to somatic causes. CONCLUSIONS The high rates of overdose prior to and after treatment emphasize the need to provide rapid access to OMT, to retain patients in treatment and to re-enrol patients. The high prevalence among older patients of deaths due to somatic causes has implications for screening, treatment and referral, and may also lead to increased treatment costs.

The pharmacological treatment of opioid addiction—a clinical perspective

This article reviews the main pharmacotherapies that are currently being used to treat opioid addiction. Treatments include detoxification using tapered methadone, buprenorphine, adrenergic agonists such as clonidine and lofexidine, and forms of rapid detoxification. In opioid maintenance treatment (OMT), methadone is most widely used. OMT with buprenorphine, buprenorphine-naloxone combination, or other opioid agonists is also discussed. The use of the opioid antagonists naloxone (for the treatment of intoxication and overdose) and oral and sustained-release formulations of naltrexone (for relapse prevention) is also considered. Although recent advances in the neurobiology of addictions may lead to the development of new pharmacotherapies for the treatment of addictive disorders, a major challenge lies in delivering existing treatments more effectively. Pharmacotherapy of opioid addiction alone is usually insufficient, and a complete treatment should also include effective psychosocial support or other interventions. Combining pharmacotherapies with psychosocial support strategies that are tailored to meet the patients’ needs represents the best way to treat opioid addiction effectively.

Neonatal outcomes following in utero exposure to methadone or buprenorphine: A National Cohort Study of opioid-agonist treatment of Pregnant Women in Norway from 1996 to 2009

BACKGROUND In Norway, most opioid-dependent women are in opioid maintenance treatment (OMT) with either methadone or buprenorphine throughout pregnancy. The inclusion criteria for both medications are the same and both medications are provided by the same health professionals in any part of the country. International studies comparing methadone and buprenorphine in pregnancy have shown differing neonatal outcomes for the two medications. METHOD This study compared the neonatal outcomes following prenatal exposure to either methadone or buprenorphine in a national clinical cohort of 139 women/neonates from 1996 to 2009. RESULTS After adjusting for relevant covariates, buprenorphine-exposed newborns had larger head circumferences and tended to be heavier and longer than methadone-exposed newborns. The incidence of neonatal abstinence syndrome (NAS) and length of treatment of NAS did not differ between methadone- and buprenorphine-exposed newborns. There was little use of illegal drugs and benzodiazepines during the pregnancies. However, the use of any drugs or benzodiazepines during pregnancy was associated with longer lasting NAS-treatment of the neonates. CONCLUSIONS The clinical relevance of these findings is that both methadone and buprenorphine are acceptable medications for the use in pregnancy, in line with previous studies. If starting OMT in pregnancy, buprenorphine should be considered as the drug of choice, due to more favorable neonatal growth parameters. Early confirmation of the pregnancy and systematic follow-up throughout the pregnancy are of importance to encourage the women in OMT to abstain from the use of tobacco, alcohol, illegal drugs or misuse of prescribed drugs.

Naltrexone implants after in-patient treatment for opioid dependence: randomised controlled trial

BACKGROUND Naltrexone has considerable potential in helping to prevent relapse in heroin dependency. A longer-lasting formulation for naltrexone treatment is desirable to further reduce non-adherence and relapse during treatment of opiate dependence. AIMS To evaluate the safety and effectiveness of a 6-month naltrexone implant in reducing opioid use after in-patient treatment. METHOD A group of 56 abstinence-oriented patients who completed in-patient treatment for opioid dependence were randomly and openly assigned to receive either a 6-month naltrexone implant or their usual aftercare. Drug use and other outcomes were assessed at 6-month follow-up. RESULTS Patients receiving naltrexone had on average 45 days less heroin use and 60 days less opioid use than controls in the 180-day period (both P<0.05). Blood tests showed naltrexone levels above 1 ng/ml for the duration of 6 months. Two patients died, neither of whom had received an implant. CONCLUSIONS Naltrexone implant treatment safely and significantly reduces opioid use in a motivated population of patients.

Engagement with opioid maintenance treatment and reductions in crime: a longitudinal national cohort study

AIMS This study investigates changes in criminal involvement among patients in opioid maintenance treatment (OMT) over a 7-year period prior to, during and after treatment, particularly in relation to differences in treatment engagement. DESIGN, SETTING AND PARTICIPANTS Treatment data on all patients who started OMT in Norway between 1997 and 2003 (n = 3221) were cross-linked with national criminal records. The period of observation was divided into four phases; pre-treatment, in-treatment, between treatments and post-treatment. FINDINGS During OMT, rates of criminal convictions for the cohort were reduced to fewer than half of waiting-list levels [incidence rate (IR) 0.63 versus 1.57]. Patients in continuous treatment had the fewest convictions (IR 0.47) during treatment. The highest rates were found among patients out of treatment after several treatment episodes (IR 1.52). All groups had significantly fewer criminal convictions during treatment compared to before treatment. Staying in OMT for 2 years or more was associated with significantly reduced rates of convictions during treatment. Younger age and pre-treatment criminal convictions were associated with significantly (P < 0.001) more convictions during treatment. Those who left treatment, permanently or temporarily, relapsed into high levels of convictions outside treatment. CONCLUSIONS Criminal activity appears to be reduced in Norway during opiate maintenance treatment. Younger age and prior history of criminal activity are important risk factors for continued criminal activity during treatment.

Naltrexone Implants Compared to Methadone: Outcomes Six Months after Prison Release

Background:After prison release, offenders with heroin use problems are at high risk of relapse and overdose death. There is a particular need for treatments that can be initiated in prison and continued after release into the community. Methadone maintenance treatment has been shown to reduce heroin use, criminality and mortality. Naltrexone implant treatment has not previously been evaluated in prison settings. Methods:This study compares the effects of naltrexone implants and methadone treatment on heroin and other illicit drug use, and criminality among heroin-dependent inmates after release from prison. Results:Forty-six volunteers were randomly allocated to naltrexone implants or methadone before release. Intention-to-treat analyses showed reductions in both groups in frequency of use of heroin and benzodiazepines, as well as criminality, 6 months after prison release. Conclusions:Naltrexone implants may be a valuable treatment option in prison settings.

Methadone-related deaths in Norway.

INTRODUCTION The use of methadone in opioid maintenance treatment (OMT) is potentially associated with a number of adverse effects and the risk of fatal toxicity. Increased methadone availability may lead to an increase in methadone-related deaths. We have investigated methadone-related deaths in Norway over the period 2000-2006. MATERIALS AND METHODS Methadone-positive samples over the period 2000-2006 were identified from forensic toxicological investigations, and demographic and toxicological data were retrieved. The cases were cross-linked with the Norwegian Cause of Death Registry and regional OMT registers. RESULTS A total of 312 individuals had died after taking methadone over the period 2000-2006, predominantly men with a mean age of 36. In 85% of cases (n=264), the deceased had died of a methadone-related intoxication, most often in combination with other drugs, including benzodiazepines, cannabis and other opioids. Only 22% of the deceased had been in OMT at the time of death. A larger proportion of OMT patients had died of causes other than intoxications compared to those not in OMT (30% vs. 8%, respectively), most commonly related to disease. CONCLUSIONS One methadone-related death occurred, on average, every week over the time period investigated. Only 22% of the deceased were registered in opioid maintenance treatment (OMT) programs. The findings underline the need to control diversion of medication from OMT programs.

Naltrexone Depot Formulations for Opioid and Alcohol Dependence: A Systematic Review

Naltrexone is an opioid receptor antagonist that blocks the reinforcing effects of opioids and reduces alcohol consumption and craving. It has no abuse potential, mild and transient side effects, and thus appears an ideal pharmacotherapy for opioid dependence. Its effectiveness in alcohol dependence is less evident, but compliance with naltrexone combined with psychosocial support has been repeatedly shown to improve drinking outcomes. Limited compliance with oral naltrexone treatment is a known drawback. Several naltrexone implant and injectable depot formulations are being investigated and provide naltrexone release for at least 1 month. Studies among opioid‐dependent patients indicate significant reductions in heroin use, but sample sizes are usually small. In alcohol dependence, two large multicenter trials report alcohol and craving reductions for naltrexone and placebo groups, indicating a significant but moderate effect. The pharmacokinetic profile of the injectable formulation indicates reliable naltrexone release over 1 month at therapeutic levels. Implant formulations releasing naltrexone up to 7 months are reported. Findings on safety and tolerability confirm the generally mild adverse effects described for naltrexone tablets. However, further research on therapeutic levels (i.e., opioid blocking) is warranted. The majority of naltrexone implants lacks approval for regular clinical use and larger longitudinal studies are needed. The available naltrexone depot formulations have the potential to significantly improve medication compliance in opioid and alcohol dependence. In certain circumstances, they may constitute a promising new treatment option.

Substance use disorders among psychotic patients admitted to inpatient psychiatric care.

Previous epidemiological and clinical studies have shown high rates of substance use disorders in patients with psychotic disorders. There are few studies from the Scandinavian countries. The aim of this study was to investigate the rate of substance use disorders in a group of Norwegian psychotic inpatients from a specific catchment area. Sixty patients, aged 18–40 years, were interviewed through standardized methods: the Addiction Severity Index (EuropASI) and the Structured Clinical Interview for DSM-IV axis I disorders (SCID-I). Urine toxicology screens confirmed patients’ self-report of recent substance use. The lifetime rate of substance use disorders was 70% when all psychotic disorders were included and 62.5% when substance-induced psychotic disorders were excluded. Fifty percent of all the patients studied had current substance use disorders. The majority of substance use disorders were dependence disorders. Alcohol, amphetamine and cannabis were the dominant substances. The level of comorbidity found in this study is comparable with that found in American studies, despite lower prevalence of substance use in the Norwegian population. The high rate of substance use disorders in psychotic inpatients has implications for the treatment and the organization of psychiatric care for these patients.