Recherche de facteurs génétiques intervenant dans la variabilité de la réponse aux opioïdes dans le traitement de la douleur et les traitements de substitution

Abstract : The main objective of this thesis was to explore the association between genetic variants potentially involved in inter-individual variability of opioids’ response and side effects in the treatment of pain and opiate substitution treatment. Initially, we investigated whether genetic factors influence the response to morphine in the treatment of acute pain. The T allele of the polymorphism ABCB1 c.3435C>T was significantly associated with doses of morphine and the outcome of nausea in a pilot study in Lebanese postoperative patients. Next, we examined the response to morphine in patients with morbid obesity (BMI>40); in these patients, the frequency of the 118G OPRM1 allele and the pain threshold appeared to be higher than in patients with normal BMI. The search for factors influencing the variability in response to methadone in patients treated for drug substitution showed that two polymorphisms (DRD2/ANKK1 TaqIA and OPRM1 c.118A>G) were significantly associated with the maximum doses of methadone. In addition, three factors were associated with the CYP3A phenotype, involved in the metabolism of methadone: the use of benzodiazepines, HIV infection and a polymorphism in POR gene, which encodes an oxidoreductase. Finally, the exploration of the cardiac side effects of methadone has highlighted three factors significantly correlated with QT prolongation: methadone doses, HIV infection and the polymorphism p.Lys897Thr in KCNH2 encoding a cardiac potassium ion channel. This work demonstrates the importance of integrating both clinical and genetic data in the personalized prescription of opioids.
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Theses
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Aline Hajj. Recherche de facteurs génétiques intervenant dans la variabilité de la réponse aux opioïdes dans le traitement de la douleur et les traitements de substitution. Médecine humaine et pathologie. Université René Descartes - Paris V, 2012. Français. ⟨NNT : 2012PA05P617⟩. ⟨tel-00750878⟩

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