The metabolism of methadone and its significance in the treatment of patients in LAR.

Project 3 will be conducted in collaboration with the Centre for Addiction Research (SERAF) at the University of Oslo and the Norwegian Institute of Public Health (FHI). The main collaborators here are Professor Jørgen Bramnes (head of SERAF) and Gudrun Høiseth at FHI. The purpose of Project 3 is to increase knowledge about the metabolism of methadone, what factors influence this, and what consequences it will have for opioid substitution treatment (OST). Funding will be sought for a three-year PhD project.

Methadone is one of the medications used in OST. Currently, there are around 3,000 methadone users in OST in Norway. Despite methadone being on the market for more than 50 years, there are many aspects of methadone treatment that we still do not fully understand. One of these is how methadone is metabolised in the body, how this varies among patients, and how it can affect the efficacy of treatment and the risk of side effects, and in the worst case, the risk of overdose.

Methadone has several beneficial properties as an OST medication. It is taken once a day, provides a stable concentration in the blood, and is generally well tolerated by patients. The medication is effective in keeping patients in treatment programmes. It reduces their level of illness, decreases mortality rates, reduces crime, and increases the chances of psychosocial rehabilitation among patients. Methadone also has some side effects, such as weight gain and reduced sexual function, as well as some serious side effects like cardiac arrhythmia and overdose. Most patients are stabilised with daily doses between 60-120 mg. Furthermore, there are reports of significant individual variations in the size of the daily dose, achieved serum concentration, and experienced effects/side effects. Therefore, it is important to increase knowledge about the metabolism of methadone and to investigate whether there is a correlation between dose, serum concentration, and effect. This is crucial for optimising efficacy and avoiding serious consequences of treatment.

Methadone is primarily metabolised by cytochrome P450 isoenzymes (CYP) in the liver. Individual differences in enzyme activity and genetic polymorphisms may influence the achieved serum concentration of methadone and possibly its efficacy and side effects. Knowledge in this area is sparse and somewhat contradictory. Methadone is also subject to interactions with the concurrent use of other medications, which can lead to reduced efficacy or increased risk of side effects and overdose. Additionally, there is generally a higher prevalence of HCV liver involvement among OST patients. There is no data on whether this condition can affect methadone treatment and thus its efficacy/side effects.

Project 3 will address the following questions through the use of biological data (two naturalistic observational studies) and OST patients in Bergen (two prospective studies):

1. What is the relationship between methadone dose and serum concentration in a general OST population, and how do factors such as age, gender, and particularly the use of other medications affect this ratio?
2. How much does genetic variation in the enzymes that metabolise methadone influence the relationship between dose and serum concentration of methadone in OST patients?
3. Does the dose/concentration ratio of methadone have any significance for how OST patients experience the effects of methadone treatment? Does it have implications for experienced side effects?
4. How do HCV and reduced liver function affect the metabolism of methadone?

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