title: Can variability in the effect of opioids on refractory breathlessness be explained by genetic factors?
abstract: OBJECTIVE
  Opioids modulate the perception of breathlessness with a considerable variation in response, with poor correlation between the required opioid dose and symptom severity. The objective of this hypothesis-generating, secondary analysis was to identify candidate single nucleotide polymorphisms (SNP) from those associated with opioid receptors, signalling or pain modulation to identify any related to intensity of breathlessness while on opioids. This can help to inform prospective studies and potentially lead to better tailoring of opioid therapy for refractory breathlessness.
  
  
  METHODS
  17 hospice/palliative care services (tertiary services) in 11 European countries.
  
  
  METHODS
  2294 people over 18 years of age on regular opioids for pain related to cancer or its treatment.
  
  
  METHODS
  The relationship between morphine dose, breathlessness intensity (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire; EORTCQLQC30 question 8) and 112 candidate SNPs from 25 genes (n=588).
  
  
  METHODS
  The same measures for people on oxycodone (n=402) or fentanyl (n=429).
  
  
  RESULTS
  SNPs not in Hardy-Weinberg equilibrium or with allele frequencies (<5%) were removed. Univariate associations between each SNP and breathlessness intensity were determined with Benjamini-Hochberg false discovery rate set at 20%. Multivariable ordinal logistic regression, clustering over country and adjusting for available confounders, was conducted with remaining SNPs. For univariate morphine associations, 1 variant on the 5-hydroxytryptamine type 3B (HTR3B) gene, and 4 on the β-2-arrestin gene (ARRB2) were associated with more intense breathlessness. 1 SNP remained significant in the multivariable model: people with rs7103572 SNP (HTR3B gene; present in 8.4% of the population) were three times more likely to have more intense breathlessness (OR 2.86; 95% CIs 1.46 to 5.62; p=0.002). No associations were seen with fentanyl nor with oxycodone.
  
  
  CONCLUSIONS
  This large, exploratory study identified 1 biologically plausible SNP that warrants further study in the response of breathlessness to morphine therapy.
authors.affiliation: Discipline, Palliative and Supportive Services, School of Health Sciences, Flinders University, Bedford Park, South, Australia Southern Adelaide Palliative Services, Repatriation General Hospital, Adelaide, South Australia, Australia.
authors.forename: David C
authors.initials: DC
authors.lastname: Currow
authors.affiliation: School of Medicine, Flinders University, Adelaide, South Australia, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Quinn
authors.affiliation: Discipline, Palliative and Supportive Services, School of Health Sciences, Flinders University, Bedford Park, South, Australia University of Lund, Lund, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Ekstrom
authors.affiliation: Department of Cancer Research and Molecular Medicine, Medical Faculty, Norwegian University of Science and Technology, Trondheim, Norway Department of Oncology, St Olav's University Hospital, Trondheim, Norway.
authors.forename: Stein
authors.initials: S
authors.lastname: Kaasa
authors.affiliation: Hull York Medical School, The University of Hull, Hull, UK.
authors.forename: Miriam J
authors.initials: MJ
authors.lastname: Johnson
authors.affiliation: Discipline of Pharmacology, University of Adelaide, School of Medical Sciences, Adelaide, South Australia, Australia.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Somogyi
authors.affiliation: Department of Circulation and Medical Imaging, Medical Faculty, Norwegian University of Science and Technology, Trondheim, Norway Department of Anaesthesia and Intensive Care Medicine, St Olav's University Hospital, Trondheim, Norway.
authors.forename: Päl
authors.initials: P
authors.lastname: Klepstad
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D004417:Dyspnea / Q000188:drug therapy* / Q000235:genetics; D005060:Europe / Q000453:epidemiology; D005260:Female; D006801:Humans; D008297:Male; D009020:Morphine / Q000008:administration & dosage*; D010148:Intractable Pain / Q000188:drug therapy* / Q000235:genetics; D010166:Palliative Care / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011788:Quality of Life; D011957:Receptors, Opioid / Q000187:drug effects* / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000701:Analgesics, Opioid; D011957:Receptors, Opioid; D009020:Morphine
keywords: THERAPEUTICS