A functional polymorphism in the ATP-Binding Cassette B1 transporter predicts pharmacologic response to combination of nortriptyline and morphine in neuropathic pain patients

Rodrigo Benavides, Olga Vsevolozhskaya, Stefano Cattaneo, Dmitri Zaykin, Ashley Brenton, Marc Parisien, Vivek Verma, Samar Khoury, Ian Gilron, Luda Diatchenko

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Many genetic markers have been associated with variations in treatment response to analgesics, but none have been assessed in the context of combination therapies. In this study, the treatment effects of nortriptyline and morphine were tested for an association with genetic markers relevant to pain pathways. Treatment effects were determined for single and combination therapies. A total of 24 functional single nucleotide polymorphisms were tested within the gene loci of mu-opioid receptor (OPRM1) gene locus, ATP-Binding Cassette B1 Transporter (ABCB1), Cytochrome P450 gene family (CYP2C19 and CYP2D6), catecholamine inactivator Catechol-O-Methyl Transferase (COMT), and serotonin receptor 2A (HTR2A). Genotyping was performed in a population of neuropathic pain patients who previously participated in a clinical trial. For monotherapy, neither nortriptyline nor morphine responses were associated with single nucleotide polymorphisms. However, for nortriptyline 1 morphine combination therapy, the single nucleotide polymorphism rs1045642 within the drug efflux pump ABCB1 transporter significantly predicted analgesic response. The presence of the C allele accounted for 51% of pain variance in this subgroup in response to combination treatment. The T-allele homozygotes demonstrated only 20% improvement in pain scores, whereas the C-allele homozygotes 88%. There was no significant contribution of rs1045642 to the medication side effects under all treatment conditions. The UK Biobank data set was then used to validate this genetic association. Here, patients receiving similar combination therapy (opioid 1 tricyclic antidepressant) carrying the C allele of rs1045642 displayed 33% fewer body pain sites than patients without that allele, suggesting better pain control. In all, our results show a robust effect of the rs1045642 polymorphism in response to chronic pain treatment with a nortriptyline 1 morphine combination.

Original languageEnglish
Pages (from-to)619-629
Number of pages11
JournalPain
Volume161
Issue number3
DOIs
StatePublished - Mar 1 2020

Bibliographical note

Publisher Copyright:
© 2019 International Association for the Study of Pain.

Keywords

  • Clinical trials
  • Drug therapy
  • Genetics
  • Neuropathic pain
  • Pharmacogenetics

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology
  • Anesthesiology and Pain Medicine

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