Opioid response in paediatric cancer patients and the Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene: an Italian study on 87 cancer children and a systematic review

Ersilia Lucenteforte,Sabrina Giglio,Lisa Giovannelli,Alessandra Pugi,Andrea Messeri,Alfredo Vannacci,Alessandro Mugelli,Laura Giunti,Laura Vagnoli,Niccolò Lombardi,Maurizio Aricò,Valentina Cetica,Giada Crescioli,Roberto Bonaiuti,Valentina Maggini,Maria Luisa Coniglio,Roberto Barale

doi:10.1186/s12885-019-5310-4

Abstract

BackgroundGenetic polymorphisms in genes involved in pain modulation have been reported to be associated to opioid efficacy and safety in different clinical settings.MethodsThe association between COMT Val158Met polymorphism (rs4680) and the inter-individual differences in the response to opioid analgesic therapy was investigated in a cohort of 87 Italian paediatric patients receiving opioids for cancer pain (STOP Pain study). Furthermore, a systematic review of the association between opioid response in cancer patients and the COMT polymorphism was performed in accordance with the Cochrane Handbook and the Prisma Statement.ResultsIn the 87 paediatric patients, pain intensity (total time needed to reach the lowest possible level) was significantly higher for G/G than A/G and A/A carriers (p-value = 0.042). In the 60 patients treated only with morphine, the mean of total dose to reach the same pain intensity was significantly higher for G/G than A/G and A/A carriers (p-value = 0.010). Systematic review identified five studies on adults, reporting that opioid dose (mg after 24 h of treatment from the first pain measurement) was higher for G/G compared to A/G and A/A carriers.ConclusionsPresent research suggests that the A allele in COMT polymorphism could be a marker of opioid sensitivity in paediatric cancer patients (STOP Pain), as well as in adults (Systematic Review), indicating that the polymorphism impact could be not age-dependent in the cancer pain context.Trial registrationRegistration number: CRD42017057831.

Highlights

Genetic polymorphisms in genes involved in pain modulation have been reported to be associated to opioid efficacy and safety in different clinical settings
We evaluated association between efficacy and safety parameters and COMT rs4680 polymorphism by calculating odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression models adjusted for gender, age, body mass index (BMI), diagnosis, metastasis, pain location, and pain intensity at baseline
STOP Pain study Patient population One hundred thirty-three patients were evaluated from June 2011 to December 2014

Summary

Introduction

Genetic polymorphisms in genes involved in pain modulation have been reported to be associated to opioid efficacy and safety in different clinical settings. Sequence variations in genes involved in opioid pharmacokinetics and pharmacodynamics, as well as in the modulation of pain pathways, have been reported to be associated with parameters of efficacy, such as the dose or the time to obtain analgesia, and of safety, such as the occurrence and severity of opioid side effects, in different clinical settings [3, 4]. Among genes associated with variability in the response to opioid analgesics, the gene encoding for catechol-o-methyltransferase (COMT) is known to be involved in pain modulation, presumably through dopamine-mediated change of enkephalins neuronal content [5], followed in turn by a compensatory regulation of μ-opioid receptors in various brain regions [5, 6]. The common (50% frequency in Caucasian population) 472G > A single nucleotide polymorphism (SNP) in exon 4 of the COMT gene, Val158Met (rs4680), leading to a three- to four-fold reduced activity of the enzyme [7, 8], has been shown to be associated to higher sensory and regional density of μ-opioid receptors and affect experimental pain ratings [9]

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