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.

The aim of our study was to evaluate possible effect of ABCB1, and OPRM1 polymorphisms on the efficacy and safety of remifentanil in women undergoing elective cesarean section under general anesthesia. Women received remifentanil (1 µg/kg i.v.) 30 s prior to the induction to standardized general anesthesia. The ABCB1 (rs2032582, rs1045642) and OPRM1 (rs1799971) polymorphisms were analyzed from maternal peripheral blood. The basal hemodynamic and demographic parameters in the study population (n=54) were similar in all the subgroups. The median ± SD increase of systolic blood pressure at 5 min from the baseline was practically completely abolished in homozygous carriers of ABCB1 variants in comparison with wild-type subjects -2.67±25.0 vs. 16.57±15.7 mm Hg, p<0.05 for rs2032582, and 2.00±23.9 vs. 22.13±16.8 mm Hg, p<0.05, for rs1045642, respectively. While no neonate belonging to ABCB1 wild-type homozygous or OPRM1 variant carrying mothers needed any resuscitative measure, 10.5 % of the neonates belonging to OPRM1 wild-type homozygous mothers received resuscitative support similarly as 11.1 %, and 12.5 % of neonates of mothers carrying variants of rs2032582, and rs1045642, respectively. Decreased stabilizing effects of remifentanil on maternal hemodynamics has been observed in ABCB1 wild type mothers, while the adaptation of the neonates was clinically worse in OPRM1 wild type, and ABCB1 variant allele carriers.

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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.

SummaryBent-shaped mesogens possessing a biphenyl as a central core have been synthesized and the role of the terminal chain and the orientation of the ester as a linkage group have been investigated. For the studied molecular core we have established that both parameters play an important role for the mesomorphic properties. The polyfluoroalkyl terminal chain supports the formation of mesophases, and the introduction of a chiral lactate terminal chain destabilizes mesophases for the first type of mutual orientation of ester groups, attached to the central core. On the contrary, for the opposite orientation of esters, the terminal chain has no effect on the mesomorphic properties, and columnar phases have been found for all compounds. A unique phase sequence has been found for the mesogen with the fluorinated chain. A generalized tilted smectics, SmCG, have been observed in a temperature interval between two different lamellar SmCP phases and characterized by X-ray and dielectric measurements. The dielectric spectroscopy data are unique and presented for the first time in the SmCG phase providing new information about the molecular dynamics.

The aim of prospective study was to evaluate the pain relief in the postoperative period and consumption of opioid and non-opioid analgesics as a risk factor of the anastomotic insufficiency after rectal and rectosigmoideal resection for carcinoma. Anastomotic insufficiency is one of the most feared and life threatening early complications. No articles about the effect of the response to opioid therapy in the postoperative period on the risk of this major clinical problem have been published. We compared the effect of opioid and non-opioid analgesics in 109 patients who underwent rectal and rectosigmoideal resection in a prospective study. We evaluated the appearance of anastomotic insufficiency and clinical conditions in the relationship with the pain relief in the postoperative period and consumption of opioid and non-opioid analgesics. The pain intensity and the consumption of analgesics were significantly increased in the group of nonresponders. The rate of PONV (postoperative nausea and vomiting) in the responders and nonresponders groups was 69% and 78%, respectively. However, the differences did not reach significant level. Other clinical conditions were not significantly different between the both groups, too. The difference in the incidence of anastomotic insufficiency between both groups was highly significant, 6% cases of anastomotic insufficiency in the responders group and 19% in nonresponders group (χ2 = 7.73; p=0.0054). Nonrespoders to opioid therapy and their high consumption of second-line analgesics is a high risk factor for anastomotic insufficiency.

In this open-label, laboratory-blinded, 2-way single dose study in 24 volunteers of both sexes we found that (1) nabumetone reaches mean Cmax ± SD of 0.56 ± 0.20 mg·L at mean tmax of 8.63 ± 7.05 hours, and mean area under the curve (AUC)last of 18.07 ± 7.19 h·mg·L; (2) there are no statistically significant differences between both sexes in pharmacokinetics of nabumetone; (3) 6-methoxy-2-naphthylacetic acid (6-MNA) reaches higher AUClast in men compared with women (mean ± SD, 721.23 ± 185.53 h·mg·L and 545.27 ± 97.69 h·mg·L, respectively; P = 0.013); (4) there is lower 6-MNA clearance in men (0.65 ± 0.22 L·h) in comparison with women (0.88 ± 0.18 L·h, P = 0.019), (5) intersubject variability of nabumetone and 6-MNA is between 35%-45% and 10%-30% for all assessed pharmacokinetics parameters (AUClast, Cmax, partial AUC values); (6) intrasubject variability (ISCV) for AUClast is low, 15.59% and 6.40% for nabumetone and 6-MNA, respectively, (7) ISCV for Cmax is 13.66% and 5.42% for nabumetone and 6-MNA, respectively. Nabumetone thus belongs to compounds with low to moderate ISCV and therefore this product is expected to produce consistent effects in clinical practice.

BackgroundRemifentanil is a rapid onset, ultra-short acting opioid that displays a stabilising effect on the maternal circulation during caesarean section under general anaesthesia while its effects on postnatal adaptation of the neonate are usually only modest.PurposeThe aim of our study was to evaluate the possible effect of ABCB1 and OPRM1 polymorphisms on the therapeutic efficacy and neonatal safety of remifentanil in women undergoing elective caesarean section under general anaesthesia.Material and methodsWomen undergoing general anaesthesia for caesarian section were administered remifentanil bolus (1 µg/kg iv) 30 s prior to the induction of standardised general anaesthesia. The ABCB1 (rs2032582, rs1045642) and OPRM1 (rs1799971) polymorphisms were analysed from maternal peripheral blood.ResultsBasal haemodynamic and demographic parameters in the study population (n = 54) were similar in the subgroups. The median±SD increase in systolic blood pressure at 5 min from baseline was practically completely abolished in homozygous carriers of ABCB1 variants in comparison with wild-type subjects: -2.67 ± 25.0 vs. 16.57 ± 15.7 mm Hg, p < 0.05, for rs2032582, and 2.00 ± 23.9 vs. 22.13 ± 16.8 mm Hg, p < 0.05, for rs1045642. There was a trend towards better stabilisation of the haemodynamic parameters in OPRM1 wild-type homozygous subjects in comparison with carriers of the variant allele carriers. Neonatal safety was not statistically different among genotype subgroups, however, clinical differences were clearly pronounced. While no neonate belonging to ABCB1 wild-type homozygous or OPRM1 variant allele carrying mothers needed any resuscitative measure, 10.5% of neonates belonging to OPRM1 wild-type homozygous mothers received early resuscitative support similarly as neonates belonging to mothers carrying variants of rs2032582 and rs1045642 (11.1% and 12.5%, respectively).ConclusionSignificantly decreased stabilising effects of remifentanil were observed in ABCB1 wild-type mothers, while adaptation of their neonates was clinically worse in ABCB1 variant allele carriers. A similar trend was noted for OPRM1 wild-type homozygote mothers for both haemodynamic effects and neonatal safety.References and/or AcknowledgementsHwang IC, Park JY, Myunk SK, et al. OPRM1 A118G gene variant and postoperative opioid requirement: a systematic review and meta-analysis. Anesthesiology 2014;121:825–34No conflict of interest.