This paper reviews the impact of genetic variability of drug metabolizing enzymes, transporters, receptors, and pathways involved in chronic pain perception on the efficacy and safety of analgesics and other drugs used for chronic pain treatment. Several candidate genes have been identified in the literature, while there is usually only limited clinical evidence substantiating for the penetration of the testing for these candidate biomarkers into the clinical practice. Further, the pain-perception regulation and modulation are still not fully understood, and thus more complex knowledge of genetic and epigenetic background for analgesia will be needed prior to the clinical use of the candidate genetic biomarkers.

Several candidate genes have been proposed as potential biomarkers for altered pharmacodynamics or pharmacokinetics of immunosuppressive drugs. However, there is usually only limited clinical evidence substantiating the implementation of biomarkers into clinical practice. Testing for thiopurine-S-methyltransferase polymorphisms has been put into routine clinical use quite widely, while the other pharmacogenetic tests are much less frequently used. Relatively good evidence appeared for tacrolimus-related biomarkers; thus, their utilization may be envisaged in the near future. Although the biomarkers related to mycophenolate, sirolimus or other drugs in the therapeutic class may be promising, further research is necessary to provide more robust evidence. The present review focuses on immunosuppressive drugs, excluding biological treatment.

Our aim was to describe the effect of dosing and genetic factors on sufentanil- and midazolam-induced analgosedation and withdrawal syndrome (WS) in pediatric population. Analgosedation and withdrawal syndrome development were monitored using COMFORT-neo/-B scores and SOS score. Length of therapy, dosing of sufentanil and midazolam were recorded. Genotypes of selected candidate polymorphisms in CYP3A5, COMT, ABCB1, OPRM1 and PXR were analysed. In the group of 30 neonates and 18 children, longer treatment duration with midazolam of 141 h (2 – 625) vs. 88 h (7 – 232) and sufentanil of 326.5 h (136 – 885) vs. 92 h (22 – 211) (median; range) was found in the patients suffering from WS vs. non-WS group, respectively. Median midazolam cumulative doses were in the respective values of 18.22 mg/kg (6.93 – 51.25) vs. 9.94 mg/kg (2.12 – 49.83); P=0.03, and the respective values for sufentanil were 88.60 µg/kg (20.21 – 918.52) vs. 21.71 µg/kg (4.5 – 162.29); P<0.01. Cut off value of 177 hours for sufentanil treatment duration represented predictive factor for WS development with 81 % sensitivity and 94 % specificity. SNPs in the candidate genes COMT, PXR and ABCB1 affected the dosing of analgosedative drugs, but were not associated with depth of analgosedation or WS. Cumulative dose and length of analgosedative therapy with sufentanil significantly increases the risk of WS in critically ill neonates and children.