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.

  • Review Article
  • Published:

A review of the existing literature on buprenorphine pharmacogenomics

Abstract

Buprenorphine is an effective treatment for opioid dependence; however, it demonstrates individual variability in efficacy. Pharmacogenomics may explain this drug response variability and could allow for tailored therapy on an individual basis. The Food and Drug Administration and the Clinical Pharmacogenomics Implementation Consortium have guidelines on pharmacogenomic testing for some opioids (e.g., codeine); however, no guidelines exist for the partial opioid agonist buprenorphine. Pharmacogenomic testing targets for buprenorphine include pharmacodynamic genes like the mu-opioid receptor (MOP receptor) and catechol-O-methyltransferase (COMT), as well as the pharmacokinetic genes like the CYP enzymes. In this review we identified genotypes in patients with opioid addiction receiving buprenorphine that may result in altered therapeutic dosing and increased rate of relapse. The OPRM1 A118G single nucleotide polymorphism (SNP rs1799971) gene variant encoding the N40D MOP receptor has been associated with variable efficacy and response to treatment in both adult and neonatal patients receiving buprenorphine for treatment of opioid withdrawal. An SNP associated with rs678849 of OPRD1, coding for the delta opioid receptor, was associated with opioid relapse as indicated by opioid positive urine drug screens; there was also sex specific SNP identified at rs581111 and rs529520 in the European American population. COMT variability, particularly in rs4680, has been associated with length of stay and need for opioid treatment in patients with neonatal abstinence syndrome. Variations of the pharmacokinetic gene for CYP3A4 showed that the ultrarapid metabolizer phenotype required higher doses of buprenorphine. Genotyping of patients may allow us to appropriately tailor buprenorphine therapy to individual patients and lead to improved patient outcomes; however, further research on the pharmacogenomics of buprenorphine is needed.

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

Access options

Buy this article

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

Similar content being viewed by others

References

  1. US Food Drug Administration. Pharmacogenomics: Overview of the Genomics and Targeted Therapy Group. 2018; https://www.fda.gov/drugs/science-and-research-drugs/pharmacogenomics-overview-genomics-and-targeted-therapy-group. Accessed 21 January, 2020.

  2. Caudle KE, Klein TE, Hoffman JM, Muller DJ, Whirl-Carrillo M, Gong L, et al. Incorporation of pharmacogenomics into routine clinical practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline development process. Curr Drug Metab. 2014;15:209–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. US Food Drug Administration. Table of pharmacogenomic biomarkers in drug labeling. 2019; https://www.fda.gov/drugs/science-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling. Accessed 21 January, 2020.

  4. Jones HE. Practical considerations for the clinical use of buprenorphine. Sci Pract Perspect. 2004;2:4–20.

    PubMed  PubMed Central  Google Scholar 

  5. Crist RC, Clarke TK, Berrettini WH. Pharmacogenetics of opioid use disorder treatment. CNS Drugs. 2018;32:305–20.

    PubMed  PubMed Central  Google Scholar 

  6. Crist RC, Li J, Doyle GA, Gilbert A, Dechairo BM, Berrettini WH. Pharmacogenetic analysis of opioid dependence treatment dose and dropout rate. Am J Drug Alcohol Abus. 2018;44:431–40.

    Google Scholar 

  7. Janecka A, Fichna J, Janecki T. Opioid receptors and their ligands. Curr Top Medicinal Chem. 2004;4:1–17.

    CAS  Google Scholar 

  8. Nicholls L, Bragaw L, Ruetsch C. Opioid dependence treatment and guidelines. J Managed Care Pharm 2010;16:S14–21.

    Google Scholar 

  9. Huang P, Kehner GB, Cowan A, Liu-Chen LY. Comparison of pharmacological activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent opioid agonist. J Pharmacol Exp Ther. 2001;297:688–95.

    CAS  PubMed  Google Scholar 

  10. Kajiwara M, Aoki K, Ishii K, Numata H, Matsumiya T, Oka T. Agonist and antagonist actions of buprenorphine on three types of opioid receptor in isolated preparations. Jpn J Pharmacol. 1986;40:95–101.

    CAS  PubMed  Google Scholar 

  11. Negus SS, Bidlack JM, Mello NK, Furness MS, Rice KC, Brandt MR. Delta opioid antagonist effects of buprenorphine in rhesus monkeys. Behavioural Pharmacol. 2002;13:557–70.

    CAS  Google Scholar 

  12. Belcheva MM, Barg J, McHale RJ, Dawn S, Ho MT, Ignatova E, et al. Differential down-and up-regulation of rat brain opioid receptor types and subtypes by buprenorphine. Mol Pharmacol. 1993;44:173.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Iribarne C, Picart D, Dreano Y, Bail JP, Berthou F. Involvement of cytochrome P450 3A4 in N-dealkylation of buprenorphine in human liver microsomes. Life Sci. 1997;60:1953–64.

    CAS  PubMed  Google Scholar 

  14. Kobayashi K, Yamamoto T, Chiba K, Tani M, Shimada N, Ishizaki T, et al. Human buprenorphine N-dealkylation is catalyzed by cytochrome P450 3A4. Drug Metab Dispos. 1998;26:818–21.

    CAS  PubMed  Google Scholar 

  15. Picard N, Cresteil T, Djebli N, Marquet P. In vitro metabolism study of buprenorphine: evidence for new metabolic pathways. Drug Metab Dispos. 2005;33:689–95.

    CAS  PubMed  Google Scholar 

  16. Bruce RD, McCance-Katz E, Kharasch ED, Moody DE, Morse GD. Pharmacokinetic interactions between buprenorphine and antiretroviral medications. Clin Infect Dis. 2006;43:S216–23.

    CAS  PubMed  Google Scholar 

  17. McCance-Katz EF, Moody DE, Morse GD, Ma Q, DiFrancesco R, Friedland G, et al. Interaction between buprenorphine and atazanavir or atazanavir/ritonavir. Drug Alcohol Depend. 2007;91:269–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Meyer MR, Maurer HH. Absorption, distribution, metabolism and excretion pharmacogenomics of drugs of abuse. Pharmacogenomics. 2011;12:215–33.

    CAS  PubMed  Google Scholar 

  19. Herz A. Opioid reward mechanisms: a key role in drug abuse? Can J Physiol Pharmacol. 1998;76:252–8.

    CAS  PubMed  Google Scholar 

  20. Mayer P, Rochlitz H, Rauch E, Rommelspacher H, Hasse HE, Schmidt S, et al. Association between a delta opioid receptor gene polymorphism and heroin dependence in man. Neuroreport. 1997;8:2547–50.

    CAS  PubMed  Google Scholar 

  21. Zhang H, Kranzler HR, Yang BZ, Luo X, Gelernter J. The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk. Mol Psychiatry. 2008;13:531–43.

    CAS  PubMed  Google Scholar 

  22. Zhang H, Gelernter J, Gruen JR, Kranzler HR, Herman AI, Simen AA. Functional impact of a single-nucleotide polymorphism in the OPRD1 promoter region. J Hum Genet. 2010;55:278–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Levran O, Londono D, O’hara K, Nielsen DA, Peles E, Rotrosen J, et al. Genetic susceptibility to heroin addiction: a candidate gene association study. Genes Brain Behav. 2008;7:720–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Crist RC, Clarke TK, Ang A, Ambrose-Lanci LM, Lohoff FW, Saxon AJ, et al. An intronic variant in OPRD1 predicts treatment outcome for opioid dependence in African-Americans. Neuropsychopharmacol. 2013;38:2003–10.

    CAS  Google Scholar 

  25. Crist RC, Phillips KA, Furnari MA, Moran LM, Doyle GA, McNicholas LF, et al. Replication of the pharmacogenetic effect of rs678849 on buprenorphine efficacy in African-Americans with opioid use disorder. Pharmacogenomics J. 2019;19:260–8.

    CAS  PubMed  Google Scholar 

  26. Clarke TK, Crist RC, Ang A, Ambrose-Lanci LM, Lohoff FW, Saxon AJ, et al. Genetic variation in OPRD1 and the response to treatment for opioid dependence with buprenorphine in European-American females. Pharmacogenomics J. 2014;14:303–8.

    CAS  PubMed  Google Scholar 

  27. Robinson SE. Buprenorphine: an analgesic with an expanding role in the treatment of opioid addiction. CNS Drug Rev. 2002;8:377–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Yuferov V, Fussell D, LaForge KS, Nielsen DA, Gordon D, Ho A, et al. Redefinition of the human kappa opioid receptor gene (OPRK1) structure and association of haplotypes with opiate addiction. Pharmacogenetics. 2004;14:793–804.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Gerra G, Leonardi C, Cortese E, D’Amore A, Lucchini A, Strepparola G, et al. Human kappa opioid receptor gene (OPRK1) polymorphism is associated with opiate addiction. Am J Med Genet Part B Neuropsychiatr Genet 2007;144b:771–5.

    CAS  Google Scholar 

  30. Gerra G, Somaini L, Leonardi C, Cortese E, Maremmani I, Manfredini M, et al. Association between gene variants and response to buprenorphine maintenance treatment. Psychiatry Res. 2014;215:202–7.

    CAS  PubMed  Google Scholar 

  31. Lotsch J, Skarke C, Liefhold J, Geisslinger G. Genetic predictors of the clinical response to opioid analgesics: clinical utility and future perspectives. Clin Pharmacokinet. 2004;43:983–1013.

    PubMed  Google Scholar 

  32. Goldman D, Oroszi G, Ducci F. The genetics of addictions: uncovering the genes. Nat Rev Genet. 2005;6:521–32.

    CAS  PubMed  Google Scholar 

  33. Kakko J, von Wachenfeldt J, Svanborg KD, Lidstrom J, Barr CS, Heilig M. Mood and neuroendocrine response to a chemical stressor, metyrapone, in buprenorphine- maintained heroin dependence. Biol Psychiatry. 2008;63:172–7.

    CAS  PubMed  Google Scholar 

  34. Wachman EM, Hayes MJ, Brown MS, Paul J, Harvey-Wilkes K, Terrin N, et al. Association of OPRM1 and COMT single- nucleotide polymorphisms with hospital length of stay and treatment of neonatal abstinence syndrome. JAMA. 2013;309:1821–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Browne CA, Erickson RL, Blendy JA, Lucki I. Genetic variation in the behavioral effects of buprenorphine in female mice derived from a murine model of the OPRM1 A118G polymorphism. Neuropharmacology. 2017;117:401–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Muriel J, Margarit C, Planelles B, Serralta MJ, Puga C, Inda M, et al. OPRM1 influence on and effectiveness of an individualized treatment plan for prescription opioid use disorder patients. Ann NY Acad Sci. 2018;1425:82–93.

    CAS  PubMed  Google Scholar 

  37. Knapman A, Santiago M, Connor M. Buprenorphine signalling is compromised at the N 40 D polymorphism of the human μ opioid receptor in vitro. Br J Pharmacol. 2014;171:4273–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. U.S. National Library of Medicine. https://ghr.nlm.nih.gov/.

  39. Barratt DT, Coller JK, Somogyi AA. Association between the DRD2 A1 allele and response to methadone and buprenorphine maintenance treatments. Am J Med Genet Part B. 2006;141B:323–31.

    CAS  PubMed  Google Scholar 

  40. Blanco F, Muriel C, Labrador J, Gonzalez-Porras JR, Gonzalez-Sarmiento R, Lozano FS. Influence of UGT2B7, CYP3A4, and OPRM1 gene polymorphisms on transdermal buprenorphine pain control in patients with critical lower limb ischemia awaiting revascularization. Pain Pract. 2016;16:842–9.

    PubMed  Google Scholar 

  41. Ettienne EB, Chapman E, Maneno M, Ofoegbu A, Wilson B, Settles-Reaves B, et al. Pharmacogenomics-guided policy in opioid use disorder (OUD) management: an ethnically-diverse case-based approach. Addictive Behav Rep. 2017;6:8–14.

    Google Scholar 

  42. Ettienne EB, Ofoegbu A, Maneno MK, Briggs J, Ezeude G, Williams S, et al. Pharmacogenomics and opioid use disorder: clinical decision support in an African American cohort. J Natl Med Assoc. 2019;111:674–81.

    PubMed  Google Scholar 

  43. Rouguieg K, Picard N, Sauvage F-L, Gaulier J-M, Marquet P. Contribution of the different UDP-glucuronosyltransferase (UGT) isoforms to buprenorphine and norbuprenorphine metabolism and relationship with the main UGT polymorphisms in a bank of human liver microsomes. Drug Metab Dispos. 2010;38:40–5.

    CAS  PubMed  Google Scholar 

  44. Chang Y, Moody DE. Glucuronidation of buprenorphine and norbuprenorphine by human liver microsomes and UDP-glucuronosyltransferases. Drug Metab Lett. 2009;3:101–7.

    CAS  PubMed  Google Scholar 

  45. Coffman BL, King CD, Rios GR, Tephly TR. The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268). Drug Metab Dispos. 1998;26:73–7.

    CAS  PubMed  Google Scholar 

  46. Sastre JA, Varela G, Lopez M, Muriel C, Gonzalez-Sarmiento R. Influence of uridine diphosphate-glucuronyltransferase 2B7 (UGT2B7) variants on postoperative buprenorphine analgesia. Pain Pract. 2015;15:22–30.

    PubMed  Google Scholar 

  47. Liao MZ, Gao C, Shireman LM, Phillips B, Risler L, Neradugomma NK, et al. P-gp/ABCB1 exerts differential impacts on brain and fetal exposure to norbuprenorphine. Pharmacol Res. 2017;119:61–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Neradugomma NK, Liao MZ, Mao Q. Buprenorphine, norbuprenorphine, R-methadone, and S-methadone upregulate BCRP/ABCG2 expression by activating aryl hydrocarbon receptor in human placental trophoblasts. Mol Pharmacol. 2017;91:237–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Berrettini W. A brief review of the genetics and pharmacogenetics of opioid use disorders. Dialogues Clin Neurosci. 2017;19:229.

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

The corresponding and last author, CDS, is responsible for the concept, content, design, and final editing of the article. The primary author, CWM, contributed much to the background research, content, and tables. The secondary and third author, AM and RA also contributed to much of the draft of the manuscript and assisted in the editorial process. All authors discussed the findings and implications and commented on the manuscript at all stages. All authors contributed extensively to the work presented in this paper.

Corresponding author

Correspondence to Cynthia D. Santos.

Ethics declarations

Conflict of interest

None of the authors have any affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Meaden, C.W., Mozeika, A., Asri, R. et al. A review of the existing literature on buprenorphine pharmacogenomics. Pharmacogenomics J 21, 128–139 (2021). https://doi.org/10.1038/s41397-020-00198-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41397-020-00198-1

Search

Quick links