title: Genetic Predisposition to Poor Opioid Response in Preterm Infants: Impact of KCNJ6 and COMT Polymorphisms on Pain Relief After Endotracheal Intubation.
abstract: Single-nucleotide polymorphisms in genes involved in pain control might predispose to exaggerated sensitivity or difference in opioid analgesic effect. The relevance of the KCNJ6 -1250G>A (rs6517442, c.-1787G>A) and the catecholamine-O-methyltransferase (COMT) c.472G>A (rs4680, ValMet) single-nucleotide polymorphisms were studied in preterm infants needing intubation and randomized to a premedication strategy including remifentanil (n = 17) or morphine (n = 17).
  
  
  
  Pain was scored with Astrid Lindgren and Lund Children's Hospital Pain Assessment Scale every 30 minutes for 6 hours. The pain relief provided by the opioids was compared between the different KCNJ6 and COMT genotypes.
  
  
  
  Infants homozygous for the KCNJ6 -1250A allele had an increased duration after intubation to achieve a score indicating no pain compared with infants with the A/G or G/G genotypes (182 ± 30, 109 ± 29, and 60 ± 21 minutes, respectively; Logrank = 7.5, P = 0.006). Similarly, the duration was increased in individuals with the COMT Val/Val alleles compared with Val/Met and Met/Met (285 ± 37, 137 ± 25, and 63 ± 15 minutes, respectively; Logrank = 14.4, P = 0.0021). Cox proportional hazards analysis confirmed that the variation in both genes was independently associated with susceptibility to respond to therapy.
  
  
  
  We conclude that the KCNJ6 -1250A and COMT Val alleles are predisposing preterm newborns to diminished opioid-induced pain relief.
authors.affiliation: *Department Clinical Chemistry, Erasmus University Medical Center, Rotterdam, the Netherlands; †Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium; ‡Unit of Pediatrics, Department of Clinical Sciences, Lund, Lund University and Skåne University Hospital, Lund, Sweden; §Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden; and ¶Children's Hospital, University of Helsinki and Helsinki University Hospital, Finland.
authors.forename: Laure
authors.initials: L
authors.lastname: Elens
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Norman
authors.forename: Maja
authors.initials: M
authors.lastname: Matic
authors.forename: Anders
authors.initials: A
authors.lastname: Rane
authors.forename: Vineta
authors.initials: V
authors.lastname: Fellman
authors.forename: Ron H N
authors.initials: RH
authors.lastname: van Schaik
mesh_terms: D000483:Alleles; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007442:Intubation, Intratracheal / Q000379:methods; D009020:Morphine / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy* / Q000235:genetics*; D059408:Pain Management / Q000379:methods; D010147:Pain Measurement / Q000379:methods; D010880:Piperidines / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D000077208:Remifentanil
chemical_list: D000701:Analgesics, Opioid; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C094401:KCNJ6 protein, human; D010880:Piperidines; D009020:Morphine; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; D000077208:Remifentanil