ABCB1 and OPRM1 single-nucleotide polymorphisms collectively modulate chronic shoulder pain and dysfunction in South African breast cancer survivors.

Background: Chronic shoulder pain/disability is a well-recognized side effect of treatment for breast cancer, with ∼40% of patients experiencing this, despite receiving pain management. To manage acute and chronic pain, several opioids are commonly prescribed. Pharmacogenomics have implicated genes within the opioid signaling pathway, including ABCB1 and OPRM1, to contribute to an individual's variable response to opioids. Aim: To evaluate ABCB1 (rs1045642 G>A, rs1128503 G>A) and OPRM1 (rs1799971 A>G, rs540825 T>A) single-nucleotide polymorphisms (SNPs) in chronic shoulder pain/disability in BCS. Materials & methods: TaqManTM assays were used to genotype ABCB1 and OPRM1 SNPs within the BCS (N = 252) cohort. The Shoulder Pain and Disability Index was used to evaluate pain and disability features associated with shoulder pathologies. Participants end scores for each feature (pain, disability and combined [pain and disability]) were categorized into no-low (>30%) and moderate-high (≥30%) scores. Statistical analysis was applied, and significance was accepted at p < 0.05. Results: Of participants, 27.0, 19.0 and 22.0% reported moderate-high pain, disability and combined (pain and disability) scores, respectively. ABCB1:rs1045642-(A/A) genotype was significantly associated with disability (p = 0.028: no-low [14.9%] vs mod-high [4.3%]) and combined (pain and disability) (p = 0.011: no-low [15.9%] vs mod-high [5.7%]). The ABCB1:rs1045642-(A) allele was significantly associated with disability (p = 0.015: no-low [37.9%] vs mod-high [23.9%]) and combined (pain and disability) (p = 0.003: no-low [38.5%] vs mod-high [23.6%]). The inferred ABCB1 (rs1045642 G>A - rs1128503 G>A): A-G (p = 0.029; odds ratio [OR]: 0.0; 95% CI: 0.0-0.0) and the OPRM1 (rs1799971 A>G - rs540825 T>A): G-T (p = 0.019; OR: 0.33; 95% CI: 0.14-0.75) haplotypes were associated with disability and pain, respectively. Gene-gene interactions showed the ABCB1 (rs1045642 G>A) - OPRM1 (rs540825 T>A) combinations, (A-T) (p = 0.019; OR: 0.62; 95% CI: 0.33-1.16) and (G-A) (p = 0.021; OR: 1.57; 95% CI: 0.30-3.10) were associated with disability. Conclusion: The study implicated ABCB1 with shoulder pain and disability; and haplotype analyses identified specific genetic intervals within ABCB1 and OPRM1 to associate with chronic shoulder pain and disability. Evidence suggests that potentially gene-gene interactions between ABCB1 and OPRM1 contribute to chronic shoulder pain and disability experienced in this SA cohort.

Polymorphisms in COMT and OPRM1 Collectively Contribute to Chronic Shoulder Pain and Disability in South African Breast Cancer Survivors'.

Chronic shoulder pain and disability is a common adverse effect experienced by >40% of breast cancer survivors (BCS). Pain management protocols for acute and chronic pain include the use of opioids and opioid derivatives. Furthermore, pain-modulating genes, such as COMT and OPRM1, have been linked to the aetiology of chronic pain. This study aimed to investigate the association between genetic variants of major pain modulator genes and chronic pain/disability in BCS. Assessment of pain, disability and combined (pain and disability) symptoms were determined using the Shoulder Pain and Disability Index (SPADI). Participants were grouped according to their scores such as no-low (<30%) and moderate-high (≥30%) groups of pain, disability and combined (pain and disability). Genotyping of the COMT rs6269 (A > G), rs4633 (C > T), rs4818 (C > G) and the functional rs4680(G > A) SNPs within the BCS (N = 252) cohort were conducted using TaqMan® SNP assays. Genotype, allele, haplotype, and allele-allele combination frequencies were evaluated. Statistical analysis was applied, with significance accepted at p < 0.05. The COMT rs4680:A/A genotype was significantly associated with moderate-high pain (p = 0.024, OR: 3.23, 95% CI: 1.33-7.81) and combined (pain and disability) (p = 0.015, OR: 3.81, 95% CI: 1.47-9.85). The rs4680:A allele was also significantly associated with moderate-high pain (p = 0.035, OR: 1.58, 95% CI: 1.03-2.43) and combined (pain and disability) (p = 0.017, OR: 1.71, 95% CI: 1.07-2.71). For the inferred COMT (rs6269 A > G-rs4680 G > A) haplotype analyses, the G-G (p = 0.026, OR: 0.67, 95% CI: 0.38-1.18) and A-A (p = 0.007, OR: 2.09, 95% CI: 0.89-4.88) haplotypes were significantly associated with reduced and increased likelihoods of reporting moderate-high pain, respectively. The inferred A-A (p = 0.003, OR: 2.18, 95% CI: 0.92-5.17) haplotype was also significantly associated with combined (pain and disability). Gene-gene interaction analyses further showed allele-allele combinations for COMT (rs4680 G > A)-OPRM1 (rs1799971 A > G) and COMT (rs4680 G > A)-OPRM1(rs540825 T > A) were associated with reporting pain and combined (pain and disability) symptoms, p < 0.05. The findings of this study suggest that COMT and OPRM1 SNPs play a role in the development of chronic shoulder pain/disability in BCS in a unique South African cohort from the Western Cape.

Regulatory VCAN polymorphism is associated with shoulder pain and disability in breast cancer survivors.

BACKGROUND AND PURPOSE: Shoulder morbidity following breast cancer treatment is multifactorial. Despite several treatment- and patient-related factors being implicated, unexplained inter-individual variability exists in the development of such morbidity. Given the paucity of relavant genetic studies, we investigate the role of polymorphisms in candidate proteoglycan genes. PATIENTS AND METHODS: We conducted a cross-sectional study on 254 South African breast cancer survivors, to evaluate associations between shoulder pain/disability and ten single nucleotide polymorphisms (SNPs) within four proteoglycan genes: ACAN (rs1126823 G>A, rs1516797 G>T, rs2882676 A>C); BGN (rs1042103 G>A, rs743641 A>T, rs743642 G>T); DCN rs516115 C>T; and VCAN (rs11726 A>G, rs2287926 G>A, rs309559). Participants were grouped into no-low and moderate-high shoulder pain/disability based on total pain/disability scores: < 30 and ≥ 30, respectively using the Shoulder Pain and Disability Index (SPADI). RESULTS: The GG genotype of VCAN rs11726 was independently associated with an increased risk of being in the moderate-to-high shoulder pain (P = 0.005, OR = 2.326, 95% CI = 1.259-4.348) or disability (P = 0.011, OR = 2.439, 95% CI = 1.235-4.762) categories, after adjusting for participants' age. In addition, the T-T-G inferred allele combination of BGN (rs74364-rs743642)-VCAN rs11726 was associated with an increased risk of being in the moderate-to-high shoulder disability category (0 = 0.002, OR = 2.347, 95% CI = 1.215-4.534). CONCLUSION: Our study is first to report that VCAN rs11726, independently or interacting with BGN polymorphisms, is associated with shoulder pain or disability in breast cancer survivors. Whereas our findings suggest an involvement of proteoglycans in the etiology of shoulder pain/disability, further studies are recommended.

Sensory and Psychological Factors Predict Exercise-Induced Shoulder Injury Responses in a High-Risk Phenotype Cohort.

Our prior studies identified a high-risk phenotype (ie, high pain sensitivity variant of the catechol-O-methyltransferase gene (Single Nucleotide Polymorphism [SNP] rs6269) and pain catastrophizing scores) for shoulder pain. The current study identified sensory and psychological predictors of heightened pain responses following exercise-induced shoulder injury. Healthy participants (N = 131) with the SNP rs6269 catechol-O-methyltransferase gene and Pain Catastrophizing Scale scores ≥5 underwent baseline sensory and psychological testing followed by an established shoulder fatigue protocol, to induce muscle injury. Movement-evoked pain, pain intensity, disability, and strength were assessed 24 hours postinjury. Demographic, sensory, and psychological variables were included as predictors in full and parsimonious models for each outcome. The highest variance explained was for the shoulder disability outcome (full model R2 = .20, parsimonious R2 = .13). In parsimonious models, the individual predictors identified were: 1) 1st pulse heat pain sensitivity for isometric shoulder movement-evoked pain and pain intensity; 2) pressure pain threshold for shoulder disability; 3) fear of pain for active shoulder movement-evoked pain and shoulder disability; and 4) depressive symptoms for shoulder strength. Findings indicate specific pain sensitivity and psychological measures may have additional prognostic value for self-reported disability within a high-risk phenotype. These findings should be tested in a clinical cohort for validation. PERSPECTIVE: The current study extends previous work by providing insight regarding how poor shoulder outcomes may develop within a high-risk phenotype. Specifically, 1st pulse heat pain sensitivity and pressure pain threshold were sensory measures, and fear of pain and depressive symptoms were psychological measures, that improved prediction of different shoulder outcomes.

Analysis of genetically independent phenotypes identifies shared genetic factors associated with chronic musculoskeletal pain conditions.

Chronic musculoskeletal pain affects all aspects of human life. However, mechanisms of its genetic control remain poorly understood. Genetic studies of pain are complicated by the high complexity and heterogeneity of pain phenotypes. Here, we apply principal component analysis to reduce phenotype heterogeneity of chronic musculoskeletal pain at four locations: the back, neck/shoulder, hip, and knee. Using matrices of genetic covariances, we constructed four genetically independent phenotypes (GIPs) with the leading GIP (GIP1) explaining 78.4% of the genetic variance of the analyzed conditions, and GIP2-4 explain progressively less. We identified and replicated five GIP1-associated loci and one GIP2-associated locus and prioritized the most likely causal genes. For GIP1, we showed enrichment with multiple nervous system-related terms and genetic correlations with anthropometric, sociodemographic, psychiatric/personality traits and osteoarthritis. We suggest that GIP1 represents a biopsychological component of chronic musculoskeletal pain, related to physiological and psychological aspects and reflecting pain perception and processing.

A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank.

BACKGROUND: Common types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203 309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK. METHODS: A genome-wide association study was performed adjusting for age, sex, BMI and nine population principal components. Significant and independent genetic variants were then sent to GS:SFHS and TwinsUK for replication. RESULTS: We identified three genetic loci that were associated with neck or shoulder pain in the UK Biobank samples. The most significant locus was in an intergenic region in chromosome 17, rs12453010, having P = 1.66 × 10-11. The second most significant locus was located in the FOXP2 gene in chromosome 7 with P = 2.38 × 10-10 for rs34291892. The third locus was located in the LINC01572 gene in chromosome 16 with P = 4.50 × 10-8 for rs62053992. In the replication stage, among four significant and independent genetic variants, rs2049604 in the FOXP2 gene and rs62053992 in the LINC01572 gene were weakly replicated in GS:SFHS (P = 0.0240 and P = 0.0202, respectively). CONCLUSIONS: We have identified three loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.

Two-stage adaptive enrichment design for testing an active factor.

We propose an adaptive enrichment approach to test an active factor, which is a factor whose effect is non-zero in at least one subpopulation. We implement a two-stage play-the-winner design where all subjects in the second stage are enrolled from the subpopulation that has the highest observed effect in the first stage. We recommend a weighted Fisher's combination of the most powerful test for each stage, respectively: the first stage Hotelling's test and the second stage noncentral chi-square test. The test is further extended to cover binary outcomes and time-to-event outcomes.

Biopsychosocial Influence on Shoulder Pain: Influence of Genetic and Psychological Combinations on Twelve-Month Postoperative Pain and Disability Outcomes.

OBJECTIVE: To identify novel combinations of genetic and psychological factors that predicted 12-month postoperative pain and disability outcomes following arthroscopic shoulder surgery. METHODS: A prospective presurgical cohort (n = 150) was recruited to complete validated psychological questionnaires and have their DNA collected from saliva. DNA was genotyped for a priori selected genes involved with pain modulation (ADRB2, OPRM1, AVPR1A, GCH1, and KCNS1) and inflammation (IL1B, TNF/LTA, and IL6). The outcome measures of interest were the Brief Pain Inventory and Disabilities of the Arm, Shoulder, and Hand questionnaire. Followup for the cohort was at 3, 6, and 12 months postoperatively. After controlling for age, sex, race, and preoperative status, genetic and psychological factors were entered as main effects and interaction terms in separate general linear models for predicting postoperative pain and disability outcomes. RESULTS: Seven interactions involving pain-modulatory genes were identified. Three provided strong statistical evidence for different outcomes, including KCNS1 and kinesiophobia for preoperative pain intensity, ADRB2 and depressive symptoms for postoperative course, and GCH1 and anxiety symptoms for 12-month pain-intensity outcome. Ten interactions involving inflammatory genes were identified. Three provided strong statistical evidence for the 12-month postoperative course outcome, including 2 different IL6 single-nucleotide polymorphism and pain catastrophizing, and IL6 and depressive symptoms. CONCLUSION: The current study identified novel genetic and psychological interactions that can be used in future studies to further understand the development of persistent postoperative pain and investigate the effectiveness of tailored treatment.

Muscle gene expression patterns in human rotator cuff pathology.

BACKGROUND: Rotator cuff pathology is a common source of shoulder pain with variable etiology and pathoanatomical characteristics. Pathological processes of fatty infiltration, muscle atrophy, and fibrosis have all been invoked as causes for poor outcomes after rotator cuff tear repair. The aims of this study were to measure the expression of key genes associated with adipogenesis, myogenesis, and fibrosis in human rotator cuff muscle after injury and to compare the expression among groups of patients with varied severities of rotator cuff pathology. METHODS: Biopsies of the supraspinatus muscle were obtained arthroscopically from twenty-seven patients in the following operative groups: bursitis (n = 10), tendinopathy (n = 7), full-thickness rotator cuff tear (n = 8), and massive rotator cuff tear (n = 2). Quantitative polymerase chain reaction (qPCR) was performed to characterize gene expression pathways involved in myogenesis, adipogenesis, and fibrosis. RESULTS: Patients with a massive tear demonstrated downregulation of the fibrogenic, adipogenic, and myogenic genes, indicating that the muscle was not in a state of active change and may have difficulty responding to stimuli. Patients with a full-thickness tear showed upregulation of fibrotic and adipogenic genes; at the tissue level, these correspond to the pathologies most detrimental to outcomes of surgical repair. Patients with bursitis or tendinopathy still expressed myogenic genes, indicating that the muscle may be attempting to accommodate the mechanical deficiencies induced by the tendon tear. CONCLUSIONS: Gene expression in human rotator cuff muscles varied according to tendon injury severity. Patients with bursitis and tendinopathy appeared to be expressing pro-myogenic genes, whereas patients with a full-thickness tear were expressing genes associated with fatty atrophy and fibrosis. In contrast, patients with a massive tear appeared to have downregulation of all gene programs except inhibition of myogenesis. CLINICAL RELEVANCE: These data highlight the difficulty in treating massive tears and suggest that the timing of treatment may be important for muscle recovery. Specifically, earlier interventions to address tendon injury may allow muscles to respond more appropriately to mechanical stimuli.

Inflammatory genes and psychological factors predict induced shoulder pain phenotype.

PURPOSE: The pain experience has multiple influences, but little is known about how specific biological and psychological factors interact to influence pain responses. The current study investigated the combined influences of genetic (pro-inflammatory) and psychological factors on several preclinical shoulder pain phenotypes. METHODS: An exercise-induced shoulder injury model was used, and a priori selected genetic (IL1B, TNF/LTA region, and IL6 single nucleotide polymorphisms (SNP)) and psychological (anxiety, depression symptoms, pain catastrophizing, fear of pain, and kinesiophobia) factors were included as the predictors of interest. The phenotypes were pain intensity (5-d average and peak reported on numerical rating scale), upper extremity disability (5-d average and peak reported on the Quick Disabilities of the Arm, Shoulder and Hand instrument), and duration of shoulder pain (d). RESULTS: After controlling for age, sex, and race, the genetic and psychological predictors were entered separately as main effects and interaction terms in regression models for each pain phenotype. Results from the recruited cohort (n = 190) indicated strong statistical evidence for the interactions between 1) TNF/LTA SNP rs2229094 and depression symptoms for average pain intensity and duration and 2) IL1B two SNP diplotype and kinesiophobia for average shoulder pain intensity. Moderate statistical evidence for prediction of additional shoulder pain phenotypes included interactions of kinesiophobia, fear of pain, or depressive symptoms with TNF/LTA rs2229094 and IL1B. CONCLUSIONS: These findings support the combined predictive ability of specific genetic and psychological factors for shoulder pain phenotypes by revealing novel combinations that may merit further investigation in clinical cohorts to determine their involvement in the transition from acute to chronic pain conditions.

Biopsychosocial influence on exercise-induced injury: genetic and psychological combinations are predictive of shoulder pain phenotypes.

UNLABELLED: Chronic pain is influenced by biological, psychological, social, and cultural factors. The current study investigated potential roles for combinations of genetic and psychological factors in the development and/or maintenance of chronic musculoskeletal pain. An exercise-induced shoulder injury model was used, and a priori selected genetic (ADRB2, COMT, OPRM1, AVPR1 A, GCH1, and KCNS1) and psychological (anxiety, depressive symptoms, pain catastrophizing, fear of pain, and kinesiophobia) factors were included as predictors. Pain phenotypes were shoulder pain intensity (5-day average and peak reported on numerical rating scale), upper extremity disability (5-day average and peak reported on the QuickDASH), and shoulder pain duration (in days). After controlling for age, sex, and race, the genetic and psychological predictors were entered as main effects and interaction terms in separate regression models for the different pain phenotypes. Results from the recruited cohort (N = 190) indicated strong statistical evidence for interactions between the COMT diplotype and 1) pain catastrophizing for 5-day average upper extremity disability and 2) depressive symptoms for pain duration. There was moderate statistical evidence for interactions for other shoulder pain phenotypes between additional genes (ADRB2, AVPR1 A, and KCNS1) and depressive symptoms, pain catastrophizing, or kinesiophobia. These findings confirm the importance of the combined predictive ability of COMT with psychological distress and reveal other novel combinations of genetic and psychological factors that may merit additional investigation in other pain cohorts. PERSPECTIVE: Interactions between genetic and psychological factors were investigated as predictors of different exercise-induced shoulder pain phenotypes. The strongest statistical evidence was for interactions between the COMT diplotype and pain catastrophizing (for upper extremity disability) or depressive symptoms (for pain duration). Other novel genetic and psychological combinations were identified that may merit further investigation.

High heritability for concurrent low back and neck-shoulder pain: a study of twins.

STUDY DESIGN: A cross-sectional study on 21,225 twins based on a Web-based questionnaire was performed in 2005-2006 and administered by the Swedish Twin Registry. OBJECTIVE: To investigate the importance of genetic factors for the occurrence of "Concurrent low back (LBP) and neck-shoulder pain (NSP)" as well as of "Solely LBP," and "Solely NSP" in an adult population of women and men. SUMMARY OF BACKGROUND DATA: Many individuals suffering from LBP also have concurrent NSP, and little is known about the factors influencing the occurrence of this spinal comorbidity. METHODS: Heritability of Concurrent LBP and NSP, solely LBP, and solely NSP was analyzed in 2934 monozygotic twin pairs, 2009 same-sex dizygotic (DZ) twin pairs, and 1960 opposite-sex DZ twin pairs without any known rheumatic disorders using structural equation modeling (SEM). RESULTS: The SEM showed that 60% of the total variance for concurrent LBP and NSP can be explained by additive genetic effects, which was twice as large as for solely LBP (30%) and more than twice as large as for solely NSP (24%). CONCLUSION: Genetic factors had a considerably greater importance for the occurrence of concurrent LBP and NSP compared with solely LBP or solely NSP. The influence of genetic factors was similar for solely LBP and solely NSP.

Genetic influences in the progression of tears of the rotator cuff.

The aim of this study was to investigate genetic influences on the development and progression of tears of the rotator cuff. From a group of siblings of patients with a tear of the rotator cuff and of controls studied five years earlier, we determined the prevalence of tears of the rotator cuff with and without associated symptoms using ultrasound and the Oxford Shoulder Score. In the five years since the previous assessment, three of 62 (4.8%) of the sibling group and one of the 68 (1.5%) controls had undergone shoulder surgery. These subjects were excluded from the follow-up. Full-thickness tears were found in 39 of 62 (62.9%) siblings and in 15 of 68 (22.1%) controls (p = 0.0001). The relative risk of full-thickness tears in siblings as opposed to controls was 2.85 (95% confidence interval (CI) 1.75 to 4.64), compared to 2.42 (95% CI 1.77 to 3.31) five years earlier. Full-thickness tears associated with pain were found in 30 of 39 (76.9%) tears in the siblings and in eight of 15 (53.3%) tears in the controls (p = 0.045). The relative risk of pain associated with a full-thickness tear in the siblings as opposed to the controls was 1.44 (95% CI 2.04 to 8.28) (p = 0.045). In the siblings group ten of 62 (16.1%) had progressed in terms of tear size or development compared to one of 68 (1.5%) in the control group which had increased in size. Full-thickness rotator cuff tears in siblings are significantly more likely to progress over a period of five years than in a control population. This implies that genetic factors have a role, not only in the development but also in the progression of full-thickness tears of the rotator cuff.

Physical workload, low back pain and neck-shoulder pain: a Swedish twin study.

OBJECTIVES: To investigate if high physical workload is associated with low back pain (LBP) and/or neck-shoulder pain (NSP) when taking into account the influence of genetic and shared environmental factors. Further, the study aims to explore the potential influence of genetic and shared environmental factors in the associations between high physical workload and the three disorder subgroups: solely LBP, solely NSP, and concurrent LBP and NSP. METHODS: Data on 16,107 monozygotic and dizygotic twins, born during 1959-1985, were obtained from a cross-sectional study, performed in 2005-2006 by the Swedish Twin Registry. Odds ratios (ORs) calculated in cohort analyses and co-twin control analyses were used to assess the associations between high physical workload and LBP and NSP when controlling for genetic and shared environmental factors. RESULTS: In the cohort analysis, the association between high physical workload and the group with any one symptom (LBP and/or NSP) was OR 1.47 (95% CI 1.37 to 1.57). The co-twin control analyses indicated that the association was not confounded by genetic and shared environmental factors with OR 1.34 (95% CI 1.02 to 1.75) for dizygotic twins and OR 1.44 (95% CI 1.06 to 1.95) for monozygotic twins. In the cohort analyses the association with high physical workload was higher for concurrent LBP and NSP (OR 1.80 (95% CI 1.62 to 1.99)) than for solely LBP (OR 1.41 (95% CI 1.27 to 1.57)) and solely NSP (OR 1.31 (95% CI 1.20 to 1.43)). Concurrent LBP and NSP was the only group that showed a stepwise decrease of the point estimates between the cohort analysis and the co-twin control analyses, OR 1.71 (95% CI 1.00 to 2.94) for dizygotic twins, and OR 1.29 (95% CI 0.64 to 2.59) for monozygotic twins indicating confounding by genetic and shared environmental factors. CONCLUSIONS: High physical workload was associated with LBP and/or NSP even after adjusting for genetic or shared environmental factors. Only for concurrent LBP and NSP, genetic and shared environmental factors seemed to have an influence on the association with high physical workload.

Biopsychosocial influence on exercise-induced delayed onset muscle soreness at the shoulder: pain catastrophizing and catechol-o-methyltransferase (COMT) diplotype predict pain ratings.

OBJECTIVE: The experience of pain is believed to be influenced by psychologic and genetic factors. A previous study suggested pain catastrophizing and catechol-O-methyltransferase (COMT) genotype influenced clinical pain ratings for patients seeking operative treatment of shoulder pain. This study investigated whether these same psychologic and genetic factors predicted responses to induced shoulder pain. METHODS: Participants (n=63) completed self-report questionnaires and had COMT genotype determined before performing a standardized fatigue protocol to induce delayed onset muscle soreness. Then, shoulder pain ratings, self-report of upper-extremity disability ratings, and muscle torque production were reassessed 24, 48, and 72 hours later. RESULTS: This cohort consisted of 35 women and 28 men, with a mean age of 20.9 years (SD=1.7). The frequency of COMT diplotypes was 42 with "high COMT enzyme activity" (low pain sensitivity group) and 21 with "low COMT enzyme activity" (average pain sensitivity/high pain sensitivity group). A hierarchical regression model indicated that an interaction between pain catastrophizing and COMT diplotype was the strongest unique predictor of 72-hour pain ratings. The same interaction was not predictive of self-report of disability or muscle torque production at 72 hours. The pain catastrophizingxCOMT diplotype interaction indicated that participants with high pain catastrophizing and low COMT enzyme activity (average pain sensitivity/high pain sensitivity group) were more likely (relative risk=3.5, P=0.025) to have elevated pain intensity ratings (40/100 or higher). DISCUSSION: These findings from an experimental model converge with those from a surgical cohort and provide additional evidence that the presence of elevated pain catastrophizing and COMT diplotype indicative of low COMT enzyme activity have the potential to increase the risk of developing chronic pain syndromes.

Evidence for a biopsychosocial influence on shoulder pain: pain catastrophizing and catechol-O-methyltransferase (COMT) diplotype predict clinical pain ratings.

The experience of pain is believed to be influenced by social, cultural, environmental, psychological, and genetic factors. Despite this assertion, few studies have included clinically relevant pain phenotypes when investigating interactions among these variables. This study investigated whether psychological variables specific to fear-avoidance models and catechol-O-methyltransferase (COMT) genotype influenced pain ratings for a cohort of patients receiving operative treatment of shoulder pain. Patients (n=58) completed questionnaires and had COMT genotype determined pre-operatively. Then, shoulder pain ratings were collected 3-5 months post-operatively. This cohort consisted of 24 females and 34 males, with mean age of 50.3 (SD=15.0) and pre-operative pain rating of 4.5/10 (SD=1.8). The frequency of COMT diplotypes was 34 with "high COMT activity" (LPS group) and 24 with "low COMT activity" (APS/HPS group). Preliminary analysis indicated that of all the fear-avoidance variables considered (fear of pain, kinesiophobia, pain catastrophizing, and anxiety), only pain catastrophizing was a unique contributor to clinical pain ratings. A hierarchical regression model indicated that an interaction between pain catastrophizing and COMT diplotype contributed additional variance in pre-operative pain ratings. The pain catastrophizingxCOMT diplotype interaction demonstrated predictive validity as patients with high pain catastrophizing and low COMT activity (APS/HPS group) were more likely (RR=6.8, 95% CI=2.8-16.7) to have post-operative pain ratings of 4.0/10 or higher. Our findings suggest that an interaction between pain catastrophizing and COMT diplotype has the potential to influence pain ratings in patients seeking operative treatment of their shoulder pain.