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Associations of catechol-O-methyltransferase (rs4680) single nucleotide polymorphism with heat pain perception and opioid use in adults with chronic pain
Session: MP-03b
Thurs, Nov. 16, 1:30-3:30 pm
Saybrook Room

Please note, medically challenging cases are removed three months after the meeting and scientific abstracts after three years.

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•Catechol-O-methyltransferase (COMT) regulates extracellular catecholamines.

•A widely studied single nucleotide polymorphism (SNP) results in a G to A substitution in codon 158 (rs4680). This substitution changes the translated amino acid from valine (Val) to methionine (Met) and reduces the activity of the enzyme to 25% of the wild-type.

•This SNP is important because it influences pain perception and opioid analgesia.1

•The primary aim of this study was to investigate the influence of the Val158Met polymorphism on heat pain (HP) perception and opioid use in a cohort of adults with chronic pain.

•All adults consecutively admitted to the Mayo Comprehensive Pain Rehabilitation Center from March 2009 to March 2010 were eligible for this study.

•During this period, 524 patients were admitted; 300 met inclusion criteria and 276 were successfully recruited.

•Upon admission, raw sensory scores (just noticeable difference; JND) and standardized scores (normal deviates; ND) of HP perception (HP 5-0.5) were derived using the automated Computer Aided Sensory Evaluator IV (CASE IV; WR Electronics, Stillwater, MN) system.

•The HP 5-0.5 is a measure of the slope of the line connecting HP threshold (HP 0.5) and an intermediate value of HP tolerance (HP 5).2 This parameter has been used to measure opioid-induced hyperalgesia in adults with chronic pain.3, 4

•Individuals were genotyped for COMT Val158Met (rs4680).

The primary aim of this study was to investigate the influence of opioid use grouped by COMT Val158Met polymorphisms on HP tolerance, by utilizing quantitative sensory testing (QST) by the method of levels, in a heterogeneous cohort of community-dwelling adults with chronic pain


•The COMT polymorphism was analyzed using three genotype models: additive (V/V vs. V/M vs. M/M), dominant (V/V vs. V/M and M/M), and recessive (M/M vs. V/V and V/M).


•Mean and standard deviation (SD) were reported for continuous variables, and count and proportion were reported for categorical variables. For MED, the median and interquartile range (IQR) were reported.


•Nonparametric tests (Kruskal-Wallis Test) were used to assess the main effect of the genotype models on demographic and clinical characteristics. Focused contrast analyses were performed to identify specific group differences (Mann-Whitney Test). Univariate and multivariate multinomial logistic regression analyses were performed using genotype as the dependent variable.

•The distribution of genotypes (N=276) was 24% (N=65) for Val/Val, 49% (N=136) for Val/Met and 27% (N=75) for Met/Met (Hardy–Weinberg equilibrium, P>.90)

•The majority of patients were white females (94.9%) with a mean age of 45.6 years and mean pain duration of 9.3 years. Upon admission, 51% (N=142) were using opioids (morphine equivalent dose; MED=46.2 mg/d) (Table 1).

•In the total cohort, no main effect of HP perception based on genotype (Val/Val vs. Val/Met vs. Met/Met) was observed (Kruskal-Wallis Test; P>0.05).

•Among opioid users, a significant effect based on genotype was observed where the Val/Met group had significantly worse hyperalgesia compared to the Val/Val and Met/Met groups (Figure 1).

•In multivariate multinomial logistic regression analysis adjusted for age, sex, race, pain diagnosis, MED, pain severity, and depression, the Val/Met group had significantly worse hyperalgesia compared to the Val/Val (JND units, OR=1.38, P=0.005; ND units, OR=1.50, P=0.03 ) and Met/Met groups (JND units, OR=1.28, P=0.018; ND units, OR=1.54, P=0.009) in the opioid subgroup (Table 2)

•In a diverse group of patients with chronic pain who were using opioids, the Val/Met genotype was associated with worse hyperalgesia in ND and JND units compared to the Val/Val and Met/Met groups.

•Peripherally, catecholamines enhance nociception through activation of beta adrenergic and mu-opioid receptors. Centrally, dopamine activates the mesolimbic pathway and depletes enkephalin. This complex mechanism may result in a non-linear relationship between enzyme activity and pain perception which may be amplified by the hyperalgesic effects of opioids.

•Following exposure to exogenous opioids, modest decreases in COMT activity (Val/Met genotype) could potentiate mechanisms that enhance nociception without a compensatory activation of antinociceptive pathways.

•Compared to chronic pain patients with Val/Val and Met/Met genotypes and to those who are not using opioids, chronic pain patients with the Val/Met genotype of rs4680 who are using opioids experience hyperalgesia.

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