Morphine Slow-release Capsules in Substitution Therapy

To compare the effectiveness of slow release oral morphine treatment in patients that previously have been treated with methadone

The objective of this study is to compare the effectiveness of slow-release oral morphine (SROM) treatment in patients that previously have been treated with methadone. Efficacy is assessed by the frequency of by-consumption of illicit substances. The primary efficacy endpoint in this study is the proportion of positive urine tests for by-consumption of target substances per subject. Target substances are defined as all opioids except the study drug.

The proportions are compared between substitution with methadone and SROM treatment in a crossover design.

The secondary endpoints are:

1. The effects of SROM on retention rate.
2. By-consumption of other drugs (cocaine, alcohol, cannabis, benzodiazepines).
3. Occurring psychopathological and somatic symptoms.
4. Effect of treatment on the ECG (QTc prolongation).
5. Group characterisation of patients that is keen to change the medication.
6. The change in dosage of treatment over time.
7. Self-assessed craving for Opioids.
8. Self-assessed satisfaction with treatment.
9. Nature, frequency and severity of occurring adverse events in the two treatment groups.
10. Assessment of safety parameters.

Study Design (Methodology):

This is a multicentre, multinational phase III study. It is conducted using a randomised, open label cross-over design. The subjects will be randomised to either 10 weeks of treatment with methadone or SROM. After an adjustment phase of one week they first will be medicated for 10 weeks with the treatment to which SUB9001 - Integrated Study Protocol 9/58 June 13, 2009 they have been randomised. The cross-over, in which all subjects change to their opposite treatment, will serve for an additional adjustment phase of one week. After the second and new adjustment phase they are treated for 10 weeks with the newly adjusted medication. After the end of week 22 all participants continue with or switch back to SROM for another 6 month (week 23 to 47).

Eligibility Criteria:
Inclusion criteria:

* Minimum age: 18 years
* Fixed abode
* At least 26 weeks of treatment (up to date) receiving a minimum dose of 50 mg methadone or

  ≥ 25 mg/day levomethadone at inclusion. Patients on levomethadone must be informed and agree to be switched to methadone
* Mature and capable of acting responsibly, in possession of all mental faculties
* Female subjects must have a negative urine pregnancy test recorded prior to the first dose of study medication and regular negative urine pregnancy tests every 4 weeks. SUB9001 - Integrated Study Protocol 10/58 June 13, 2009
* Hormonal contraception (oral, transdermal, vaginal, intrauterine or subcutaneous) by women of child-bearing age
* No intention of reducing the substitute medication during the trial
* Acceptance of the trials rules and regulations
* Acceptance to participate in the study.

Exclusion criteria:

* (Desired) pregnancy during the trial
* Breastfeeding women
* Grave or acute somatic illnesses (e.g. cardio-vascular, serious kidney or liver affection (ALAT or ASAT \> 5x augmented)) or other somatic disorder
* If suffering from severe unstable mental health problems
* If MAO-Inhibitors or are being taken
* Intracranial injury
* Intracranial hypertension
* History of epilepsy
* Severe chronic obstructive lung disease
* Chronic respiratory failure
* Known hypersensitivity to morphine or methadone
* Pancreatitis
* Paralytic ileus
* Baseline QTc interval greater than 450 msec
* Long QT Syndrome
* Patients who have participated in another clinical research study involving a new chemical entity within 3 months of study entry
* Patients with pending imprisonment at the time of inclusion.