• David C Currow, Stephen Quinn, Magnus Ekstrom, Stein Kaasa, Miriam J Johnson, Andrew A Somogyi, and Päl Klepstad.
• 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.
• BMJ Open. 2015 May 6; 5 (5): e006818.

ObjectivesOpioids 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.Setting17 hospice/palliative care services (tertiary services) in 11 European countries.Participants2294 people over 18 years of age on regular opioids for pain related to cancer or its treatment.Primary Outcome MeasuresThe 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).Secondary Outcome MeasuresThe same measures for people on oxycodone (n=402) or fentanyl (n=429).ResultsSNPs 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.ConclusionsThis large, exploratory study identified 1 biologically plausible SNP that warrants further study in the response of breathlessness to morphine therapy.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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