The Associations Between OPRM 1 and COMT Genotypes and Postoperative Pain,Opioid Use,and Opioid-Induced Sedation

Abstract

Previous studies have associated mu-opioid receptor (OPRM1) genotype with pain and analgesia responses in postoperative and patient populations. This study investigates the role of catechol-O-methyltransferase (COMT) and OPRM1 genotypes in acute postoperative pain scores, opioid use, and opioid-induced sedation after surgical procedures for orthopedic trauma in an otherwise healthy patient population. Verbal pain/sedation scores, opioid use, and physiologic responses in the immediate postoperative period were examined for association with genetic variants in Caucasians genotyped for OPRM1 single nucleotide polymorphisms (SNPs) A118G and C17T and COMT SNPs. The OPRM1 A118G genotype was associated with patients’ postoperative Numerical Pain scale (NPS) ratings at 15 min in the postanesthesia care unit (PACU) (p = .01) and patients' sedation scores at 15 min in the PACU (p = .02). COMT genotype (rs4818) was associated with opioid consumption in the first 45 min in the PACU (p = .04). NPS ratings at 45 min were also higher in the group of patients with A/A genotype of rs4680 than in patients with the other two genotypes at this SNP (p = .03). Our haplotype trend analysis identified a COMT haplotype “GCGG” significantly associated with NPS at 15 min (p = .0013), amount of opioids consumed in the first 45 min (p = .0024), and heart rate at 45 min in the PACU (p = .017). The results indicate that genetic variations in COMT contribute to the acute postoperative pain and analgesia responses and physiologic responses in this group of otherwise healthy postoperative orthopedic trauma patients.

Keywords

pain opioid use sedation

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References

Attia

Thakkinstian

McElduff

Milne

Dawson

Scott

R. J.

Thompson

(2010). Detecting genotyping error using measures of degree of Hardy-Weinberg disequilibrium. Statistical Applications in Genetics and Molecular Biology, 9, Article 5.

Barrett

J. C.

Fry

Maller

Daly

M. J.

(2005). Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics, 21, 263–265.

Berry

P. H.

Covington

E. C.

Dahl

J. L.

Katz

J. A.

Miskowski

(2006). Pain: Current understanding of assessment, management, and treatments. Glenview, IL: American Pain Society.

Bond

LaForge

K. S.

Tian

Melia

Zhang

Borg

(1998). Single-nucleotide polymorphism in the human mu opioid receptor gene alters beta-endorphin binding and activity: Possible implications for opiate addiction. Proceedings of the National Academy of Sciences of the United States of America, 95, 9608–9613.

Bovard

R. S.

(2008). Risk behaviors in high school and college sport. Current Sports Medicine Reports, 7, 359–366. doi:10.1249/JSR.0b013e31818f0bed

Cepeda

M. S.

Carr

D. B.

(2003). Women experience more pain and require more morphine than men to achieve a similar degree of analgesia. Anesthesia & Analgesia, 97, 1464–1468.

Chou

W. Y.

Wang

C. H.

Liu

P. H.

Liu

C. C.

Tseng

C. C.

Jawan

(2006). Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy. Anesthesiology, 105, 334–337.

Chou

W. Y.

Yang

L. C.

H. F.

J. Y.

Wang

C. H.

Lin

S. H.

Hsu

C. J.

(2006). Association of mu-opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty. Acta Anaesthesiologica Scandinavica, 50, 787–792.

Deng

H. W.

Chen

W. M.

Recker

R. R.

(2001). Population admixture: Detection by Hardy-Weinberg test and its quantitative effects on linkage-disequilibrium methods for localizing genes underlying complex traits. Genetics, 157, 885–897.

10.

Diatchenko

Nackley

A. G.

Slade

G. D.

Bhalang

Belfer

Max

M. B.

Maixner

(2006). Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain, 125, 216–224.

11.

Diatchenko

Slade

G. D.

Nackley

A. G.

Bhalang

Sigurdsson

Belfer

Maixner

(2005). Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Human Molecular Genetics, 14, 135–143.

12.

Feder

J. N.

Gnirke

Thomas

Tsuchihashi

Ruddy

D. A.

Basava

Wolff

R. K.

(1996). A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature Genetics, 13, 399–408.

13.

Fillingim

R. B.

Kaplan

Staud

Ness

T. J.

Glover

T. L.

Campbell

C. M.

Wallace

M. R.

(2005). The A118G single nucleotide polymorphism of the mu-opioid receptor gene (OPRM1) is associated with pressure pain sensitivity in humans. Journal of Pain, 6, 159–167.

14.

Furst

(1990). Brain monoamines are involved in the sedative effects of opiates and neuroleptics. Progress in Clinical Biological Research, 328, 311–314.

15.

Jiang

Dong

Wang

Sun

F. Z.

(2001). Fine-scale mapping using Hardy–Weinberg disequilibrium. Annals of Human Genetics, 65, 207–219.

16.

Kim

Lee

Rowan

Brahim

Dionne

(2006). Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post-surgical pain in humans. Molecular Pain, 2, 24.

17.

Lee

W. C.

(2003). Searching for disease-susceptibility loci by testing for Hardy-Weinberg disequilibrium in a gene bank of affected individuals. American Journal of Epidemiology, 158, 397–400.

18.

Lentschener

Tostivint

White

P. F.

Gentili

M. E.

Ozier

(2007). Opioid-induced sedation in the postanesthesia care unit does not insure adequate pain relief: A case-control study. Anesthesia and Analgesia, 105, 1143–1147.

19.

Likar

Vadlau

E.-M.

Breschan

Kager

Korak-Leiter

Ziervogel

(2008). Comparable analgesic efficacy of transdermal buprenorphine in patients over and under 65 years of age. Clinical Journal of Pain, 24, 536–543. doi:10.1097/AJP.0b013e3181673b65

20.

Lotsch

Skarke

Liefhold

Geisslinger

(2004). Genetic predictors of the clinical response to opioid analgesics: Clinical utility and future perspectives. Clinical Pharmacokinetics, 43, 983–1013.

21.

Lotta

Vidgren

Tilgmann

Ulmanen

Melen

Julkunen

Taskinen

(1995). Kinetics of human soluble and membrane-bound catechol-O-methyltransferase: A revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry, 34, 4202–4210.

22.

Patanwala

A. E.

Jarzyna

D. L.

Miller

M. D.

Erstad

B. L.

(2008). Comparison of opioid requirements and analgesic response in opioid-tolerant versus opioid-naive patients after total knee arthroplasty. Pharmacotherapy, 28, 1453–1460.

23.

Pattinson

K. T. S.

(2008). Opioids and the control of respiration. British Journal of Anaesthesia, 100, 747–758.

24.

Paulson

P. E.

Minoshima

Morrow

T. J.

Casey

K. L.

(1998). Gender differences in pain perception and patterns of cerebral activation during noxious heat stimulation in humans. Pain, 76, 223–229.

25.

Purcell

Neale

Todd-Brown

Thomas

Ferreira

M. A.

Bender

Sham

P. C.

(2007). PLINK: A tool set for whole-genome association and population-based linkage analyses. American Journal of Human Genetics, 81, 559–575.

26.

Rakvag

T. T.

Ross

J. R.

Sato

Skorpen

Kaasa

Klepstad

(2008). Genetic variation in the catechol-O-methyltransferase (COMT) gene and morphine requirements in cancer patients with pain. Molecular Pain, 4, 12.

27.

Reyes-Gibb

C. C.

Shete

Rakvag

Bhat

S. V.

Skorpen

Bruera

Klepstad

(2007). Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1 and COMT gene. Pain, 130, 25–30.

28.

Schermer

C. R.

Omi

E. C.

Ton-That

Grimley

Van Auken

Santaniello

Esposito

T. J.

(2008). A clustering of injury behaviors. Journal of Trauma, 65, 1000–1004. doi:10.1097/TA.0b013e318182f76b

29.

Sia

A. T.

Lim

E. C. P.

Goh

R. W. C.

Law

H. Y.

Landau

Tan

E. C.

(2008). A118G single nucleotide polymorphism of human [mu]-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia. Anesthesiology, 109, 520–526. doi:10.1097/ALN.0b013e318182af21

30.

Tan

E. C.

Tan

C. H.

Karupathivan

Yap

E. P.

(2003). Mu opioid receptor gene polymorphisms and heroin dependence in Asian populations. Neuroreport, 14, 569–572.

31.

Tsao

Shabalina

S. A.

Gauthier

J. E.

Dokholyan

N. V.

Diatchenko

(2011). Disruptive mRNA folding increases translational efficiency of catechol-O-methyltransferase variant. Nucleic Acids Research, 39, 6201–6212.

32.

Wigginton

J. E.

Cutler

D. J.

Abecasis

G. R.

(2005). A note on exact tests of Hardy-Weinberg equilibrium. American Journal of Human Genetics, 76, 887–893.

33.

Zaykin

D. V.

Westfall

P. H.

Young

S. S.

Karnoub

M. A.

Wagner

M. J.

Ehm

M. G.

(2002). Testing association of statistically inferred haplotypes with discrete and continuous traits in samples of unrelated individuals. Human Heredity, 53, 79–91.

34.

Zubieta

J. K.

Gorelick

D. A.

Stauffer

Ravert

H. T.

Dannals

R. F.

Frost

J. J.

(1996). Increased mu opioid receptor binding detected by PET in cocaine-dependent men is associated with cocaine craving. Nature Medicine, 2, 1225–1229.