Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Opioid-induced respiratory depression: ABCB1 transporter pharmacogenetics

The Pharmacogenomics Journal volume 15, pages 119–126 (2015)Cite this article

Subjects

Abstract

Opioid-related respiratory depression (RD) is a serious clinical problem as it causes multiple deaths and anoxic brain injuries. Morphine is subject to efflux via P-glycoprotein transporter encoded by ABCB1, also known as MDR1. ABCB1 polymorphisms may affect blood–brain barrier transport of morphine and therefore individual response to its central analgesic and adverse effects. This study aimed to determine specific associations between common ABCB1 genetic variants and clinically important outcomes including RD and RD resulting in prolonged stay in hospital with intravenous morphine in a homogenous pediatric surgical pain population of 263 children undergoing tonsillectomy. Children with GG and GA genotypes of ABCB1 polymorphism rs9282564 had higher risks of RD resulting in prolonged hospital stays; adding one copy of the minor allele (G) increased the odds of prolonged hospital stay due to postoperative RD by 4.7-fold (95% confidence interval: 2.1–10.8, P=0.0002).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Erickson BK, Larson DR St, Sauver JL, Meverden RA, Orvidas LJ . Changes in incidence and indications of tonsillectomy and adenotonsillectomy 1970-2005. Otolaryngol Head Neck Surg 2009; 140: 894–901.

    Article  Google Scholar 

  2. Marcus CL, Moore RH, Rosen CL, Giordani B, Garetz SL, Taylor HG et al. A randomized trial of adenotonsillectomy for childhood sleep apnea. N Engl J Med 2013; 368: 2366–2376.

    Article  CAS  Google Scholar 

  3. Brouillette RT . Let's CHAT about adenotonsillectomy. N Engl J Med 2013; 368: 2428–2429.

    Article  CAS  Google Scholar 

  4. Goldman JL, Baugh RF, Davies L, Skinner ML, Stachler RJ, Brereton J et al. Mortality and major morbidity after tonsillectomy: etiologic factors and strategies for prevention. Laryngoscope 2013; 123: 2544–2553.

    PubMed  Google Scholar 

  5. Food and Drug Administration. Safety review update of codeine use in children; new boxed warning and contraindication on use after tonsillectomy and/or adenoidectomy. FDA Drug Safety Communication, 2013; http://www.fda.gov/Drugs/DrugSafety/ucm339112.htm.

  6. Biavati MJ, Manning SC, Phillips DL . Predictive factors for respiratory complications after tonsillectomy and adenoidectomy in children. Arch Otolaryngol Head Neck Surg 1997; 123: 517–521.

    Article  CAS  Google Scholar 

  7. Rosen GM, Muckle RP, Mahowald MW, Goding GS, Ullevig C . Postoperative respiratory compromise in children with obstructive sleep apnea syndrome: can it be anticipated?. Pediatrics 1994; 93: 784–788.

    CAS  PubMed  Google Scholar 

  8. Lasky T, Greenspan J, Ernst FR, Gonzalez L . Morphine use in hospitalized children in the United States: a descriptive analysis of data from pediatric hospitalizations in 2008. Clin Ther 2012; 34: 720–727.

    Article  Google Scholar 

  9. Brown KA, Laferriere A, Lakheeram I, Moss IR . Recurrent hypoxemia in children is associated with increased analgesic sensitivity to opiates. Anesthesiology 2006; 105: 665–669.

    Article  Google Scholar 

  10. Zhang Z, Xu F, Zhang C, Liang X . Activation of opioid mu receptors in caudal medullary raphe region inhibits the ventilatory response to hypercapnia in anesthetized rats. Anesthesiology 2007; 107: 288–297.

    Article  CAS  Google Scholar 

  11. Pattinson KT . Opioids and the control of respiration. Br J Anaesth 2008; 100: 747–758.

    Article  CAS  Google Scholar 

  12. Pattinson KT, Governo RJ, MacIntosh BJ, Russell EC, Corfield DR, Tracey I et al. Opioids depress cortical centers responsible for the volitional control of respiration. J Neurosci 2009; 29: 8177–8186.

    Article  CAS  Google Scholar 

  13. Meineke I, Freudenthaler S, Hofmann U, Schaeffeler E, Mikus G, Schwab M et al. Pharmacokinetic modelling of morphine, morphine-3-glucuronide and morphine-6-glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short-term infusion of morphine. Br J Cin Pharmacol 2002; 54: 592–603.

    CAS  Google Scholar 

  14. Park HJ, Shinn HK, Ryu SH, Lee HS, Park CS, Kang JH . Genetic polymorphisms in the ABCB1 gene and the effects of fentanyl in Koreans. Clin Pharmacol Ther 2007; 81: 539–546.

    Article  CAS  Google Scholar 

  15. Boehmer U, Kressin NR, Berlowitz DR, Christiansen CL, Kazis LE, Jones JA . Self-reported vs administrative race/ethnicity data and study results. Am J Public Health 2002; 92: 1471–1472.

    Article  Google Scholar 

  16. Lalovic B, Phillips B, Risler LL, Howald W, Shen DD . Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos 2004; 32: 447–454.

    Article  CAS  Google Scholar 

  17. Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S . The FLACC: a behavioral scale for scoring postoperative pain in young children. Pediatr Nurs 1997; 23: 293–297.

    CAS  PubMed  Google Scholar 

  18. Jensen MP, Smith DG, Ehde DM, Robinsin LR . Pain site and the effects of amputation pain: further clarification of the meaning of mild, moderate, and severe pain. Pain 2001; 91: 317–322.

    Article  CAS  Google Scholar 

  19. Nafiu OO, Shanks A, Abdo S, Taylor E, Tremper TT . Association of high body mass index in children with early post-tonsillectomy pain. Int J Pediatr Otorhinolaryngol 2013; 77: 256–261.

    Article  Google Scholar 

  20. Sadhasivam S, Chidambaran V, Ngamprasertwong P, Esslinger HR, Prows C, Zhang X et al. Race and unequal burden of perioperative pain and opioid related adverse effects in children. Pediatrics 2012; 129: 832–838.

    Article  Google Scholar 

  21. Stern C . The Hardy-Weinberg Law. Science 1943; 97: 137–138.

    Article  CAS  Google Scholar 

  22. Oderda GM, Said Q, Evans RS, Stoddard GJ, Lloyd J, Jackson K et al. Opioid-related adverse drug events in surgical hospitalizations: impact on costs and length of stay. Ann Pharmacother 2007; 41: 400–406.

    Article  Google Scholar 

  23. Ishikawa T, Tsuji A, Inui K, Sai Y, Anzai N, Wada M et al. The genetic polymorphism of drug transporters: functional analysis approaches. Pharmacogenomics 2004; 5: 67–99.

    Article  CAS  Google Scholar 

  24. Crettol S, Deglon JJ, Besson J, Croquette-Krokar M, Hammig R, Gothuey I et al. ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther 2006; 80: 668–681.

    Article  CAS  Google Scholar 

  25. Paice JA, Gordon DB, Contreras J . The Joint Commission Sentinel Event Alert. Joint Comm 2012; 49: 1–5.

    Google Scholar 

  26. Kelly LE, Rieder M, van den Anker J, Malkin B, Ross C, Neely MN et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics 2012; 129: e1343–e1347.

    Article  Google Scholar 

  27. Sadhasivam S, Myer CM 3rd . Preventing opioid-related deaths in children undergoing surgery. Pain Med 2012; 13: 982–983.

    Article  Google Scholar 

  28. Barratt DT, Coller JK, Hallinan R, Byrne A, White JM, Foster DJ et al. ABCB1 haplotype and OPRM1 118A > G genotype interaction in methadone maintenance treatment pharmacogenetics. Pharmacogenomics Pers Med 2012; 5: 53–62.

    Article  CAS  Google Scholar 

  29. Cook-Sather SD, Li J, Goebel TK, Sussman EM, Rehman MA, Hakonarson H . TAOK3, a novel genome-wide association study locus associated with morphine requirement and postoperative pain in a retrospective pediatric day surgery population. Pain 2014; 155: 1773–1783.

    Article  CAS  Google Scholar 

  30. Jimenez N, Anderson GD, Shen DD, Nielsen SS, Farin FM, Seidel K et al. Is ethnicity associated with morphine's side effects in children? Morphine pharmacokinetics, analgesic response, and side effects in children having tonsillectomy. Paediatr Anaesth 2012; 22: 669–675.

    Article  Google Scholar 

  31. Sadhasivam S, Krekels EH, Chidambaran V, Esslinger HR, Ngamprasertwong P, Zhang K et al. Morphine clearance in children: does race or genetics matter? J Opioid Manag 2012; 8: 217–226.

    Article  Google Scholar 

  32. Hodges LM, Markova SM, Chinn LW, Gow JM, Kroetz DL, Klein TE et al. Very important pharmacogene summary: ABCB1 (MDR1, P-glycoprotein). Pharmacogenet Genomics 2010; 21: 152–161.

    Article  Google Scholar 

  33. Kesimci E, Engin AB, Kanbak O, Karahalil B . Association between ABCB1 gene polymorphisms and fentanyl's adverse effects in Turkish patients undergoing spinal anesthesia. Gene 2012; 493: 273–277.

    Article  CAS  Google Scholar 

  34. Coulbault L, Beaussier M, Verstuyft C, Weickmans H, Dubert L, Tregouet D et al. Environmental and genetic factors associated with morphine response in the postoperative period. Clin Pharmacol Ther 2006; 79: 316–324.

    Article  CAS  Google Scholar 

  35. Campa D, Gioia A, Tomei A, Poli P, Barale R . Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther 2008; 83: 559–566.

    Article  CAS  Google Scholar 

  36. Leschziner GD, Andrew T, Pirmohamed M, Johnson MR . ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research. Pharmacogenomics J 2007; 7: 154–179.

    Article  CAS  Google Scholar 

  37. Meyer UA . Pharmacogenetics and adverse drug reactions. Lancet 2000; 356: 1667–1671.

    Article  CAS  Google Scholar 

  38. Caraco Y . Genes and the response to drugs. N Engl J Med 2004; 351: 2867–2869.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by USPHS Grant #UL1 RR026314 from the National Center for Research Resources, NIH and with the Place Outcomes Research Award (PI: SS) and Translational Research Award (PIs: JMA and SS), Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA. Additional research funding support was provided by the Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA. This work received no financial support, except departmental salary support for the authors. This pharmacogenetic study was designed and undertaken by the authors. The sponsor of this study, the Cincinnati Children’s Hospital Medical Center (CCHMC) provided funding support for the genetic analyses and supported salary of the research team.

Author information

Authors and Affiliations

  1. Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    S Sadhasivam, V Chidambaran, H Esslinger & J McAuliffe

  2. Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    S Sadhasivam, V Chidambaran, X Zhang, J Meller, K Zhang, L J Martin & J McAuliffe

  3. Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    X Zhang, K Zhang & L J Martin

  4. Division of Bioinformatics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    J Meller

Authors
  1. S Sadhasivam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V Chidambaran
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. X Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Meller
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Esslinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. L J Martin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J McAuliffe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Sadhasivam.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sadhasivam, S., Chidambaran, V., Zhang, X. et al. Opioid-induced respiratory depression: ABCB1 transporter pharmacogenetics. Pharmacogenomics J 15, 119–126 (2015). https://doi.org/10.1038/tpj.2014.56

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/tpj.2014.56

This article is cited by

Search

Advanced search

Quick links