A Single SNP in ADRB2 Halves the Opioid Requirement for Mucositis Pain in Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation

Pain from mucositis after hematopoietic cell transplantation (HCT) is a major burden for pediatric patients. Adequate pain management is often delayed by trial and error of various agents and doses. Despite advances in other peri-transplant supportive cares, little progress has been made in optimizing treatment of oral mucositis. The beta-2 adrenergic receptor (ADRB2) gene encodes receptors targeted by epinephrine. Polymorphisms in the ADRB2 gene have been linked to both acute and chronic pain in different adult cohorts, but not evaluated in a pediatric population. We hypothesized that host ADRB2 polymorphisms will predict mucositis pain perception and resulting opioid requirement in HCT patients. We tested our hypothesis by genotyping 100 consecutive HCT patients using a panel of 46 single nucleotide polymorphisms (SNPs) in a set of candidate genes, including ADRB2, known to influence opioid effects. We collected demographic and HCT data, together with detailed daily pain medication use from patient records. Our cohort included 65% male and 87% Caucasian patients at a median age of 9.9 years (range .5-32.8). Seventy-six patients (78%) experienced mucositis a median of 3 days (range −2 to +17) post-HCT; 63 (83%) required either scheduled intravenous (IV) opioid or patient-controlled analgesia (PCA). Amongst the 63 patients requiring opioids, 55 had GA/GG and had 8 AA genotypes for ADRB2. We defined optimal pain control as time after which no further opioid increases were required. Patients required a PCA for a median of 16 days (range 1-32), and optimal pain control was achieved at a median of 8 days (range 1-23) after initiation of opioids. We previously reported our findings of the impact of race and the catechol-O-methyltransferase gene on mucositis pain perception and opioid requirement. Presence of at least one wild type allele (GA/GG) for the ADRB2 SNP, rs1042713, was associated with increased total number of days on IV opioids (Figure 1). These patients spent a median of 17 days on IV opioids/PCA, compared to patients with two minor alleles (AA), who spent a median of 8.5 days on IV opioids/PCA (P = .0012). Similarly, patients with GA/GG genotype required more time to reach optimal pain control than did patients with AA genotype (median 8 and 1.5 days, respectively; P = .007) (Figure 2). ADRB2 genotype was not associated with race.Figure 2Days to optimal pain control by rs1042713 Genotype.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Our data suggest that wild type alleles in rs1042713 are associated with prolonged time to optimal pain control and longer time on scheduled opioids in patients with mucositis following HCT. Pre-transplant genotyping at a single locus (ADRB2) is inexpensive, easy to perform, and can optimize pain control by influencing how quickly opioids should be titrated up and later weaned.