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

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 + 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 + 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 + morphine combination.

Neuropathic pain in the community: prevalence, impact, and risk factors

“…They replicated this association in thirty-seven patients who were taking amitriptyline or nortriptyline along with morphine or fentanyl from the UK Biobank cohort (p=0.02). [5] Pharmacogenomics research in neuropathic pain are still at an early stage and this finding, like others, warrants replication in a large-scale cohort of patients with neuropathic pain. GWAS using large cohorts are also needed to uncover genetic variants associated with treatment response.…”

Pharmacogenetics and Pain Treatment with a Focus on Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Antidepressants: A Systematic Review

“…Efficacy. Benavides et al [98] examined the association between genetic markers and the analgesic effect of the combination therapy with morphine and nortriptyline or the respective monotherapies in patients with neuropathic pain. Thirty-four SNPs in genes such as OPRM1, COMT, HT2RA, CYP2C19, and CYP2D6 were tested among the 25 neuropathic pain patients.…”

Combination Therapy for Neuropathic Pain: A Review of Recent Evidence

“…Even among individuals with seemingly singular neuropathic conditions (e.g., PHN), substantial diversity exists with respect to various clinical manifestations, sensory examination features, and presumably underlying pain mechanisms [21,22]. For instance, recently, Benavides et al found a functional polymorphism that could predict pharmacologic response to a combination of nortriptyline and morphine in NP patients [88].…”