A functional polymorphism in the ATP-Binding Cassette B1 transporter predicts pharmacologic response to combination of nortriptyline and morphine in neuropathic pain patients
Bibliographic record
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.014 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".