Association of OPRM1, MIR23B, and MIR107 genetic variability with acute pain, chronic pain and adverse effects after postoperative tramadol and paracetamol treatment in breast cancer.

BACKGROUND: Tramadol is an opioid analgesic often used for pain management after breast cancer surgery. Its analgesic activity is due to the activation of the µ-opioid receptor, encoded by the OPRM1 gene. This study investigated the association of genetic variability in OPRM1 and its regulatory miRNA genes with outcomes of tramadol/paracetamol treatment after breast cancer surgery with axillary lymphadenectomy. PATIENTS AND METHODS: The study included 113 breast cancer patients after breast cancer surgery with axillary lymphadenectomy treated with either 75/650 mg or 37.5/325 mg of tramadol with paracetamol for pain relief within the randomized clinical trial KCT 04/2015-DORETAonko/si at the Institute of Oncology Ljubljana. All patients were genotyped for OPRM1 rs1799971 and rs677830, MIR23B rs1011784, and MIR107 rs2296616 using competitive allele-specific PCR. The association of genetic factors with acute and chronic pain as well as adverse effects of tramadol treatment was evaluated using logistic regression, Fisher's exact test, and Mann-Whitney test. RESULTS: The investigated OPRM1 related polymorphisms were not associated with acute pain assessed with the VAS scale within four weeks after surgery (all P > 0.05). Carriers of at least one polymorphic OPRM1 rs1799971 allele had a higher risk of constipation in the first four weeks after surgery compared to non-carriers (OR = 4.5, 95% CI = 1.6-12.64, P = 0.004). Carriers of at least one polymorphic OPRM1 rs677830 allele had a higher risk of constipation after third week of tramadol treatment (OR = 3.11, 95% CI = 1.08-8.89, P = 0.035). Furthermore, carriers of two polymorphic MIR23B rs1011784 alleles had a higher risk of nausea after 28 days of tramadol treatment (OR = 7.35, 95% CI = 1.27-42.6, P = 0.026), while heterozygotes for MIR107 rs2296616 allele had a lower risk of nausea after 21 days of tramadol treatment (OR = 0.21, 95% CI = 0.05-0.87, P = 0.031). In carriers of two polymorphic MIR107 rs2296616 alleles, chronic pain was significantly more common than in carriers of two wild-type alleles (P = 0.004). Carriers of at least one polymorphic MIR23B rs1011784 allele experienced more neuropathic pain after adjustment for tramadol dose (OR = 2.85, 95% CI = 1.07-7.59, P = 0.036), while carriers of at least one polymorphic OPRM1 rs677830 allele experienced less neuropathic pain compared to carriers of two wild-type alleles (OR = 0.38, 95% CI = 0.15-0.99, P = 0.047). CONCLUSIONS: Genetic variability of OPRM1 and genes coding for miRNAs that could affect OPRM1 expression may be associated with adverse effects of tramadol/paracetamol treatment as well as with chronic and neuropathic pain after breast cancer surgery with axillary lymphadenectomy.

Timing of elective cesarean section and neonatal morbidity: a population-based study.

PURPOSE: To assess the incidence of neonatal complications related to gestational age at elective cesarean section near term. METHODS: We used a population-based dataset to compare neonatal outcomes by gestational age in uncomplicated singleton pregnancies delivered by elective cesarean section ≥37 weeks. RESULTS: A total of 7364 mothers had an elective cesarean during 2002-2012; 343 (4.7%) at 37, 21 753 (3.8%) at 38, 3140 (2.6%) at 39, 1718 (23.3%) at 40 and 410 (5.6%) at ≥41 weeks. Infants born at a lower gestational age had a higher rate of Apgar scores <7 (2%, 0.4%, 0.6%, 0,3%, 0.2% at 37, 38, 39, 40 and ≥41 week, p = 0.013), hypoglycemia (1.5%, 1.0%, 0.8%, 0.4%, 0.5% at 37, 38, 39, 40 and ≥ 41 week, p = 0.012), hyperbilirubinemia (12.2%, 9.5%, 6.4%, 4.8%, 4.1% at 37, 38, 39, 40 and ≥ 41 week, p < 0.001), respiratory distress syndrome (5.5%, 2.2%, 1.6%, 0.5%, 0.7% at 37, 38, 39, 40 and ≥ 41 week, p < 0.001), and neonatal intensive care admissions (8.7%, 2.3%, 1.9%, 1.0%, 1.7% at 37, 38, 39, 40 and ≥ 41 week, p < 0.001). CONCLUSIONS: Elective cesarean section at ≥ 39 weeks gestation would significantly reduce neonatal complications.