Doktoravhandlinger ved NTNU

Härtill 4 uppsatser PhD i molekylærmedisin The number of cancer patients in the world is increasing mainly because of ageing populations. In developed countries it is estimated that about one in three will get cancer during their lifetime. In addition to anticancer treatment, pain treatment at all stages of the cancer disease is of high priority and an ongoing challenge in clinical practice. Whilst oral morphine has been the first line drug of choice for moderate to severe cancer pain, 10-30 % of patients treated with morphine do not have successful outcomes, either because of intolerable adverse effects or inadequate analgesia - or a combination of both. Another issue of morphine treatment is that in cases where it does prove efficient, the dose needed to relieve pain varies widely between patients. One explanation of the interindividual variation in response to morphine may lie within the genes. How many genes are involved, and which variation within well studied genes and yet unknown genes, however, is still an unraveled puzzle. Pharmacogenetics is the studies of how genetic variability influences the responses to drugs. In this thesis, using a pharmacogenetic approach, we have investigated the geneopioid interaction in patients receiving oral morphine for cancer pain. The genetic focus in this thesis has been on two systems, the μ-opioid receptor system and the catechol- O- methyltransferase system. The μ-opioid receptor is the major site for activation of most clinically important opioids, including morphine. Therefore, the gene encoding the μ-opioid receptor (the -OPRM1 gene) was selected for investigation . Catecholamines are involved in the modulation of pain and are partly metabolized by the catechol-O-methyltransferase (COMT) enzyme. Variation within the COMT gene is believed to influence pain sensitivity and therefore we hypothesized that the COMT gene is a contributor that influences the response of morphine in cancer pain treatment. Our findings indicate that genetic variation in the OPRM1 and the COMT genes are influencing the analgesic effect of morphine for patients experiencing cancer pain. Our data also indicate that two genetic variants of the OPRM1 and COMT genes display joint effects, but larger cohorts are needed to investigate whether these effects are enhancing the efficacy of morphine. The phenotype “morphine response in cancer pain treatment” is a multiplex phenotype that has a complex genetic basis. Most likely more than two