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Moderation of buprenorphine therapy for cocaine dependence efficacy by variation of the Prodynorphin gene

  • Pharmacogenetics
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP).

Methods

Cocaine-dependent participants (N = 302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4 mg BUP (BUP4), 16 mg BUP (BUP16), or placebo (PLB) for 8 weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines.

Results

In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P = 0.0021). The interactions of genetic variant × treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N = 35) had fewer cocaine-positive urines (P = 0.0006) than did the PLB group (N = 26) and in the rs1997794 A-allele carrier group where the BUP16 group (N = 49) had fewer cocaine-positive urines (P = 0.0003) than did the PLB group (N = 58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response.

Conclusion

These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.

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Availability of data and material

Data and materials will be made available upon reasonable request.

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Funding

Support came from the National Drug Abuse Treatment Clinical Trials Network, NIH/NIDA (DA020024 (RW), 5 P50 DA018197-05 (TK), DA013045 (WL); DA013035 (JR); DA013046 (JR), DA015815 (JR), HHSN271200900034C/N01DA-9–2217, HHSN271201200017C/N01DA-12–2229, HHSN271201500065C/N01DA-15–2243), Reckitt Benckiser Pharmaceuticals, Alkermes Pharmaceuticals, MD Anderson’s Cancer Center Support Grant NIH/NIDA DA026120 (DN), and the Toomim Family Fund. Alkermes donated the naltrexone and Reckitt Benckiser donated the buprenorphine/naloxone and placebo for the parent CURB study. This material is the result of work supported with resources and the use of facilities at the Michael E. DeBakey VA Medical Center, Houston, TX.

Author information

Authors and Affiliations

  1. The Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, 2002 Holcombe Blvd., Research 151, Building 110, Suite 227, Houston, TX, 77030, USA

    David A. Nielsen, David P. Graham, Ellen M. Nielsen & Thomas R. Kosten

  2. Department of Pharmacology and Chemical Biology, Baylor College of Medicine, Houston, TX, USA

    David A. Nielsen

  3. Michael E. DeBakey V.A. Medical Center, Houston, TX, USA

    David A. Nielsen & David P. Graham

  4. University of Texas Southwestern Medical Center, Dallas, TX, USA

    Robrina Walker, Kathy Shores-Wilson & Madhukar H. Trivedi

  5. Statistical and Genetic Consulting LLC, Daren, CT, USA

    Sara C. Hamon

  6. Integrated Substance Abuse Programs, UCLA, Los Angeles, CA, USA

    Maureen Hillhouse & Walter Ling

  7. The Emmes Company, Rockville, MD, USA

    Dikla Shmueli-Blumberg

  8. Department of Psychiatry and Behavioral Sciences, Howard University, Washington, D.C, USA

    William B. Lawson & Beverlyn D. Settles-Reaves

  9. New York University School of Medicine, New York University, New York, NY, USA

    John Rotrosen

  10. Center of Excellence in Substance Addiction Treatment and Education, VA Puget Sound Health Care System and Center of Excellence in Substance Addiction Treatment and Education, VA Puget Sound Health Care System and Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA, USA

    Andrew J. Saxon

Authors
  1. David A. Nielsen
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  2. Robrina Walker
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  3. David P. Graham
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  4. Ellen M. Nielsen
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  5. Sara C. Hamon
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  7. Dikla Shmueli-Blumberg
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  8. William B. Lawson
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  9. Kathy Shores-Wilson
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  10. Beverlyn D. Settles-Reaves
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  11. John Rotrosen
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  12. Madhukar H. Trivedi
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  13. Andrew J. Saxon
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  14. Walter Ling
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  15. Thomas R. Kosten
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Contributions

Conceptualization and methodology: D.A. Nielsen, T.R. Kosten; performed research: D.A. Nielsen, R. Walker, E.M. Nielsen, S.C. Hamon, M. Hillhouse, D. Shmueli-Blumberg, W.B. Lawson, K. Shores-Wilson, B.D. Settles-Reaves, J. Rotrosen, M.H. Trivedi, A.J. Saxon, W. Ling, T.R. Kosten; analyzed data: D.A. Nielsen, R. Walker, D.P. Graham, E.M. Nielsen, S.C. Hamon, T.R. Kosten; writing — original draft: D.A. Nielsen, R. Walker, T.R. Kosten; review and editing: all authors.

Corresponding author

Correspondence to David A. Nielsen.

Ethics declarations

Ethics approval

The parent study and genetic sub-study were approved by the Institutional Review Boards of the participating sites as well as by the Institutional Review Board of the Baylor College of Medicine and the Research and Development Committee of the Michael E. DeBakey Veterans Affairs Medical Center.

Conflict of interest

Drs. Nielsen, Graham, Hamon, Hillhouse, Shmueli-Blumberg, Lawson, Shores-Wilson, Settles-Reaves, Rotrosen, Ling and Kosten, and Nielsen declare no potential conflict of interest. Drs. Rotrosen, Walker, and Trivedi have served as PI or co-I on studies for which Reckitt Benckiser Pharmaceuticals/Indivior and/or Alkermes have contributed funds, medication, or both. Dr. Trivedi has received compensation as a member of the scientific advisory board of Alkermes Pharmaceuticals and owns stock in the company. Dr. Saxon received compensation as an advisory board member to Alkermes Pharmaceuticals and also received travel support from Alkermes as well as royalties from UpToDate, Inc. and research support from Medicasafe, Inc.

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Nielsen, D.A., Walker, R., Graham, D.P. et al. Moderation of buprenorphine therapy for cocaine dependence efficacy by variation of the Prodynorphin gene. Eur J Clin Pharmacol 78, 965–973 (2022). https://doi.org/10.1007/s00228-022-03302-5

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  • DOI: https://doi.org/10.1007/s00228-022-03302-5

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