title: Human Genetic Variability Contributes to Postoperative Morphine Consumption.
abstract: High interindividual variability in postoperative opioid consumption is related to genetic and environmental factors. We tested the association between morphine consumption, postoperative pain, and single nucleotide polymorphisms (SNPs) within opioid receptor μ 1 (OPRM1), catechol-O-methyltransferase (COMT), uridine diphosphate glucose-glucuronosyltransferase-2B7, and estrogen receptor (ESR1) gene loci to elucidate genetic prediction of opioid consumption. We analyzed 20 SNPs in 201 unrelated Caucasian patients who underwent abdominal surgery and who were receiving postoperative patient-controlled analgesia-administered morphine. Morphine consumption and pain intensity were dependent variables; age and sex were covariates. A haplotype of 7 SNPs in OPRM1 showed significant additive effects on opioid consumption (P = .007); a linear regression model including age and 9 SNPs in ESR1, OPRM1, and COMT explained the highest proportion of variance of morphine consumption (10.7%; P = .001). The minimal model including 3 SNPs in ESR1, OPRM1, and COMT explained 5% of variance (P = .007). We found a significant interaction between rs4680 in COMT and rs4986936 in ESR1 (P = .007) on opioid consumption. SNPs rs677830 and rs540825 of OPRM1 and rs9340799 of ESR1 were nominally associated with pain Numeric Rating Scale scores. Combinations of genetic variants within OPRM1, COMT, and ESR1 better explain variability in morphine consumption than single genetic variants. Our results contribute to the development of genetic markers and statistical models for future diagnostic tools for opioid consumption/efficacy.
  
  
  
  This article presents the efforts dedicated to detect correlations between the genetic polymorphisms and the clinical morphine effect self-administered by patients using a patient-controlled analgesia pump after major surgery. The clinical effect is expressed in terms of morphine consumption and pain scores. REGISTERED ON CLINICALTRIALS.GOV: NCT01233752.
authors.affiliation: Pain Therapy Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; YAP (Young Against Pain) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: De Gregori
authors.affiliation: SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Alan Edwards Pain Centre For Research on Pain, McGill University, Montrèal, Quebec, Canada.
authors.forename: Luda
authors.initials: L
authors.lastname: Diatchenko
authors.affiliation: SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Anesthesia, Montreal Children's Hospital, Montrèal, Quebec, Canada.
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Ingelmo
authors.affiliation: SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Palo Alto, California.
authors.forename: Valerio
authors.initials: V
authors.lastname: Napolioni
authors.affiliation: SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway; Department of Anesthesiology and Intensive Care Medicine, St. Olav's University Hospital, Trondheim, Norway, Norway.
authors.forename: Pal
authors.initials: P
authors.lastname: Klepstad
authors.affiliation: SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Anesthesiology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Inna
authors.initials: I
authors.lastname: Belfer
authors.affiliation: Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Molinaro
authors.affiliation: Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Garbin
authors.affiliation: Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
authors.forename: Guglielmina N
authors.initials: GN
authors.lastname: Ranzani
authors.affiliation: First Service of Anesthesia, Azienda Ospedaliera San Gerardo, Monza, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Alberio
authors.affiliation: First Service of Anesthesia, Azienda Ospedaliera San Gerardo, Monza, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Normanno
authors.affiliation: First Service of Anesthesia, Azienda Ospedaliera San Gerardo, Monza, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Lovisari
authors.affiliation: First Service of Anesthesia, Azienda Ospedaliera San Gerardo, Monza, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Somaini
authors.affiliation: SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Experimental and Applied Pharmacology, University of Pavia, Pavia, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Govoni
authors.affiliation: Department of Experimental and Applied Pharmacology, University of Pavia, Pavia, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Mura
authors.affiliation: SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Clinical, Surgical, Pediatric and Diagnostic Science, University of Pavia, Pavia, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Bugada
authors.affiliation: SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Department of Clinical, Surgical, Pediatric and Diagnostic Science, University of Pavia, Pavia, Italy.
authors.forename: Thekla
authors.initials: T
authors.lastname: Niebel
authors.affiliation: Laboratory of Biochemistry and Genetics, Division of Pneumology, Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Zorzetto
authors.affiliation: Clinical and Experimental Pharmacokinetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: De Gregori
authors.affiliation: Clinical and Experimental Pharmacokinetics Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
authors.forename: Mariadelfina
authors.initials: M
authors.lastname: Molinaro
authors.affiliation: SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Anesthesia, Critical Care and Pain Medicine, Department of Surgical Sciences, University of Parma, Parma, Italy; UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Fanelli
authors.affiliation: SIMPAR (Study In Multidisciplinary Pain Research) Group, UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; Anesthesia, Critical Care and Pain Medicine, Department of Surgical Sciences, University of Parma, Parma, Italy; UO 2(a) Anestesia, Rianimazione e Terapia Antalgica, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy. Electronic address: massimo.allegri@unipr.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Allegri
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid / Q000627:therapeutic use*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000627:therapeutic use*; D017063:Outcome Assessment, Health Care; D010149:Postoperative Pain / Q000188:drug therapy* / Q000235:genetics*; D000071185:Pharmacogenomic Testing; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017450:Receptors, Opioid, mu / Q000235:genetics; D013997:Time Factors; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D009020:Morphine; D002394:Catechol O-Methyltransferase
keywords: Acute postoperative pain; OPRM1 haplotype; genetic variability; genetic variants combination; postoperative opioid consumption