D Ladewig’s research while affiliated with Universitäre Psychiatrische Kliniken Basel and other places

Seit Jahren ist der Kokainkonsum unter Opiatabhängigen verbreitet und stellt auch in opioidgestützten Behandlungen ein Problem dar. Bislang gibt es keine effektive Pharmakotherapie. Eine vielversprechende Behandlungsform ist die kognitiv-behaviorale Therapie. Die vorliegende randomisierte kontrollierte Pilotstudie mit vier Armen hat bei 62 kokainabhängigen Personen aus einer heroingestützten Behandlung placebokontrolliert und doppelblind die Einsatzmöglichkeit von Methylphenidat (MP) mit und ohne kognitiv-behaviorale Gruppentherapie (CBT) untersucht. Primäre Zielvariablen waren das Verbleiben in der medikamentösen Behandlung, der Kokainkonsum und unerwünschte Ereignisse. Die Studie wurde in zwei Zentren durchgeführt. Nach einer umfassenden Basiserhebung wurden die Versuchspersonen über zwölf Wochen entsprechend der Zufallszuteilung behandelt (MP oder Placebo, jeweils mit oder ohne CBT). Die Studienmedikation (30 mg MP oder Placebo) wurde zweimal täglich unter Aufsicht eingenommen. Die manualisierten Gruppentherapien wurden einmal pro Woche durchgeführt, die Teilnahme war freiwillig. Die Zielvariablen wurden regelmässig mit Befragungen und Urinproben erfasst. Die Datenanalyse erfolgte nach dem „Intent-to-treat-Prinzip“, wobei neben herkömmlichen statistischen Verfahren auch Multilevel-Modelle (GEE) gerechnet wurden. Von der Stichprobe verblieben 71% über zwölf Wochen in der Studie. Die Medikation wurde insgesamt gut toleriert. Die Studie lieferte keine Hinweise dafür, dass MP und/oder CBT in diesem Kollektiv den Kokainkonsum reduzieren. Die CBT besitzt für die Zukunft aber dennoch Potenzial.

In the morphine group of the Swiss government’s PROVE project, a high occurrence of side-effects has been reported. Therefore, 16 patients with a diagnosis of opioid dependence were recruited from a methadone maintenance programme and treated with morphine for a period of 3 weeks. During the first 10 days, 7 patients dropped out, mostly due to dissatisfaction. In 5 cases severe side-effects occurred: swollen arms and severe headache. Other, less severe side-effects were erythemas and localised or generalised nettle-rash. Well-being improved above doses of 70 mg per injection. Thus, morphine is a possible substitute for opioid-dependent patients and a viable alternative to methadone substitution.

The purpose of the study was to assess prevalence of benzodiazepine use in the Swiss adult population and to assess on benzodiazepine prescription patterns of physicians in domiciliary practice. A retrospective, population-based cross-sectional study with 520 000 patients covering a 6-month period. We estimated the prevalence, amount and duration of benzodiazepine use using a pharmacy dispensing database. Of all patients, 9.1% (n=45 309) received at least one benzodiazepine prescription in the 6-month period. Most persons receiving benzodiazepine prescriptions were women (67%), and half of all patients were aged 65 or older. Of 45 309 patients with benzodiazepine prescriptions, 44% (n=19 954) had one single prescription, mostly for a short period (<90 days) and in lower than the recommended dose range. Fifty-six percent (n=25 354) had repeated benzodiazepine prescriptions, mostly for a long time period (>90 days), and in lower than the recommended or within the recommended dose range. In patients with long-term use (n=25 354), however, 1.6% had benzodiazepine prescriptions in extremely high doses. The sample of patients with repeated prescriptions allowed an estimation of a benzodiazepine use of 43.3 daily defined doses per 1000 inhabitants in Switzerland. Benzodiazepine prescriptions were appropriate for most patients and thus were prescribed in therapeutic doses, as indicated in the treatment guidelines. On the other hand, our survey showed that 1.6% of the patients had prescriptions for long time periods at very high doses, indicating an abuse or dependence on benzodiazepines in this subgroup.

There is a growing debate about injectable opioid treatment programs in many Western countries. This is the first placebo-controlled study of the safety of injectable opioids in a controlled treatment setting. Twenty-five opioid-dependent patients on intravenous (IV) heroin or IV methadone maintenance treatment were randomly assigned to either their individual prescribed IV maintenance dose or placebo. Acute drug effects were recorded, focusing on electrocardiography, respiratory movements, arterial blood oxygen saturation, and electroencephalography (EEG). After heroin injection, marked respiratory depression progressing to a Cheyne-Stokes pattern occurred. Peripheral arterial blood oxygenation decreased to 78.9 +/- 8.7% (mean +/- SD) ranging from 52%-90%. During hypoxia, 7 of the 16 subjects experienced intermittent and somewhat severe bradycardia. Five subjects exhibited paroxysmal EEG patterns. After methadone injection, respiratory depression was less pronounced than after heroin injection. No relevant bradycardia was noted. Opioid doses commonly prescribed in IV opioid treatment induce marked respiratory and circulatory depression, as well as occasionally irregular paroxysmal EEG activity. Further studies are needed to optimize the clinical practice of IV opioid treatment to prevent serious complications. Moreover, the extent of the observed effects raises questions about the appropriateness of IV opioid treatment in the present form.

Ethyl glucuronide (EtG) is a promising new biological state marker of recent alcohol consumption that detects alcohol use reliably over a definite time period. Other currently available markers lack acceptable sensitivity and specificity. Our aim is to elucidate under naturalistic conditions the time course of EtG excretion in urine following alcohol consumption and to show how this can be utilized for monitoring and prognosis in patients. There are no other existing data on this issue to date. One hundred and thirty-eight urine samples from 28 male alcohol withdrawal patients were drawn every 3-24 hours for up to 94 hours after hospitalization. Breath ethanol concentration (mean) at hospitalization was 900 mg/L. Patient age in years was 40.3 (mean). Determination of urine EtG was performed by gas chromatography/mass spectrometry (GC/MS) with deuterium-labelled EtG as an internal standard. The strongest correlations (p<0.01) were found between EtG determinations in the different patient when breath ethanol concentrations (BEC) were 0 and 48 hours after BEC=0 (r=0.747), EtG 24 and 48 hours after BEC=0 (r=0.872), and in the time frame of detection (hours) of EtG and EtG 48 hours after BEC=0 (r=0.762). No significant correlation was found (Mann-Whitney test) between EtG concentrations in urine at different time points between the groups of patients with (a) 1 or less-2, (b) 3-4 or more previous hospitalizations, (c) a history of seizures (yes/no) or (d) an age above or below the median (40.5). EtG excretion in urine is not random, but seems rather to follow a kinetic profile. Furthermore our preliminary data indicate, that there is no significant difference for EtG concentration in urine when correlated to group variables such as age, seizures and hospitalizations.

Resumen Los ensayos suizos sobre la prescripción médica de diacetilmorfina inyectable (heroína farmacéutica) para la dependencia “grave” de la heroína provocaron comentarios muy polémicos. A pesar de las limitaciones metodológicas, la evaluación de los ensayos de heroína suizos produjo algunos hallazgos interesantes. Los participantes en el estudio mostraron mejorías sustanciales en la salud y el bienestar y disminuciones sensibles en el uso de drogas ilegales y actividades delictivas. Así, la prescripción de heroína puede ser útil para algunos de los que continúan utilizando regularmente heroína ilegal mientras están en mantenimiento con metadona o rechazan otras opciones de tratamiento disponibles. Sin embargo, los datos basados en la investigación indican que la aplicación intravenosa (IV) de heroína bajo supervisión médica puede tener efectos secundarios adversos. Estudios recientes han mostrado que las inyecciones de heroína producen disminuciones pasajeras pero significativas en la oxigenación sistémica y cortical, muy probablemente secundarias a la depresión respiratoria. Estos efectos, entre otros, son objeto de estudios en curso.

The Swiss trials on medical prescription of injectable diacetylmorphine (pharmaceutical heroin) for "severe" heroin dependence provoked very controversial commentaries. Despite methodological shortcomings, the evaluation of the Swiss heroin trials yielded some interesting findings. Study participants showed substantial improvements in health and well-being and noticeable declines in illicit drug use and criminal activities. Heroin prescription may thus be helpful for some of those who continue to regularly use illicit heroin while maintained on methadone or who refuse other available treatment options. However, research-based evidence suggests that the intravenous (IV) application of heroin under medical supervision may have untoward side effects. Recent studies have shown that heroin injections produce transient, but significant decreases in systemic and cortical oxygenation most likely secondary to respiratory depression. Among others, these effects are the subject of ongoing studies.

The Swiss trials on medical prescription of injectable diacetylmorphine (pharmaceutical heroin) for “severe” heroin dependence provoked very controversial commentaries. Despite methodological shortcomings, the evaluation of the Swiss heroin trials yielded some interesting findings. Study participants showed substantial improvements in health and well-being and noticeable declines in illicit drug use and criminal activities. Heroin prescription may thus be helpful for some of those who continue to regularly use illicit heroin while maintained on methadone or who refuse other available treatment options. However, research-based evidence suggests that the intravenous (IV) application of heroin under medical supervision may have untoward side effects. Recent studies have shown that heroin injections produce transient, but significant decreases in systemic and cortical oxygenation most likely secondary to respiratory depression. Among others, these effects are the subject of ongoing studies.