Circulating Inflammatory Biomarkers Predict Pain Change Following Exercise-Induced Shoulder Injury: Findings From the Biopsychosocial Influence on Shoulder Pain Preclinical Trial.

Shoulder pain is a highly prevalent musculoskeletal condition that frequently leads to suboptimal clinical outcomes. This study tested the extent to which circulating inflammatory biomarkers are associated with reports of shoulder pain and upper-extremity disability for a high-risk genetic by psychological subgroup (catechol-O-methyltransferase [COMT] variation by pain catastrophizing [PCS]). Pain-free adults meeting high-risk COMT × PCS subgroup criteria completed an exercise-induced muscle injury protocol. Thirteen biomarkers were collected and analyzed from plasma 48 hours after muscle injury. Shoulder pain intensity and disability (Quick-DASH) were reported at 48 and 96 hours to calculate change scores. Using an extreme sampling technique, 88 participants were included in this analysis. After controlling for age, sex, and BMI, there were moderate positive associations between higher c-reactive protein (CRP; ߈ = .62; 95% confidence interval [CI] = -.03, 1.26), interleukin-6 (IL-6; ߈ = 3.13; CI = -.11, 6.38), and interleukin-10 (IL-10; ߈ = 2.51; CI = -.30, 5.32); and greater pain reduction from 48 to 96 hours post exercise muscle injury. Using an exploratory multivariable model to predict pain changes from 48 to 96 hours, we found participants with higher IL-10 were less likely to experience a high increase in pain (߈ = -10.77; CI = -21.25, -2.69). Study findings suggest CRP, IL-6, and IL-10 are related to shoulder pain change for a preclinical high-risk COMT × PCS subgroup. Future studies will translate to clinical shoulder pain and decipher the complex and seemingly pleiotropic interplay between inflammatory biomarkers and shoulder pain change. PERSPECTIVE: In a preclinical high-risk COMT × PCS subgroup, 3 circulating inflammatory biomarkers (CRP, IL-6, and IL-10) were moderately associated with pain improvement following exercise-induced muscle injury.

Biopsychosocial influence on shoulder pain: results from a randomized preclinical trial of exercise-induced muscle injury.

ABSTRACT: Prior cohort studies validated that a subgroup defined by a specific COMT genotype and pain catastrophizing is at increased risk for heightened responses to exercise-induced or surgically induced shoulder pain. In this clinical trial, we used our preclinical model of exercise-induced muscle injury and pain to test the efficacy of interventions matched to characteristics of this high-risk subgroup (ie, personalized medicine approach). Potential participants provided informed consent to be screened for eligibility based on subgroup membership and then, as appropriate, were enrolled into the trial. Participants (n = 261) were randomized to 1 of 4 intervention groups comprised of pharmaceutical (propranolol or placebo) and informational (general education or psychologic intervention) combinations. After muscle injury was induced, participants received randomly assigned treatment and were followed for the primary outcome of shoulder pain intensity recovery over 4 consecutive days. Recovery rates were 56.4% (placebo and psychologic intervention), 55.4% (placebo and general education), 62.9% (propranolol and psychologic intervention), and 56.1% (propranolol and general education). No statistical differences were found between intervention groups in the primary analyses. Additional analyses found no differences between these intervention groups when shoulder pain duration was an outcome, and no differential treatment responses were detected based on sex, race, or level of pain catastrophizing. This trial indicates that these treatments were not efficacious for this high-risk subgroup when shoulder pain was induced by exercise-induced muscle injury. Accordingly, this phenotype should only be used for prognostic purposes until additional trials are completed in clinical populations.

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.

Biopsychosocial influence on shoulder pain: Rationale and protocol for a pre-clinical trial.

BACKGROUND: Chronic musculoskeletal pain conditions are a prevalent and disabling problem. Preventing chronic musculoskeletal pain requires multifactorial treatment approaches that address its complex etiology. Prior cohort studies identified a high risk subgroup comprised of variation in COMT genotype and pain catastrophizing. This subgroup had increased chance of heightened pain responses (in a pre-clinical model) and higher 12month post-operatives pain intensity ratings (in a clinical model). This pre-clinical trial will test mechanisms and efficacy of personalized pain interventions matched to the genetic and psychological characteristics of the high-risk subgroup. METHODS: Potential participants will be screened for high risk subgroup membership, appropriateness for exercise-induced muscle injury protocol, and appropriateness for propranolol administration. Eligible participants that consent to the study will then be randomized into one of four treatment groups; 1) personalized pharmaceutical and psychological education; 2) personalized pharmaceutical and general education; 3) placebo pharmaceutical and psychological education; 4) placebo pharmaceutical and psychological education. Over the 5-day study period participants will complete an exercise-induced muscle injury protocol and receive study interventions. Pain and disability assessments will be completed daily, with primary outcomes being duration of shoulder pain (number of days until recovery), peak shoulder pain intensity, and peak shoulder disability. Secondary outcomes include inflammatory markers, psychological mediators, and measures of pain sensitivity regulation. CONCLUSION: This pre-clinical trial builds on prior cohort studies and its completion will provide foundational data supporting efficacy and mechanisms of personalized interventions for individuals that may be at increased risk for developing chronic shoulder pain. TRIAL REGISTRATION: ClinicalTrials.gov registry, NCT02620579 (Registered on November 13, 2015).

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.

Predicting Pain and Disability After Shoulder Arthroscopy: Rotator Cuff Tear Severity and Concomitant Arthroscopic Procedures.

OBJECTIVES: Study the influence of concomitant arthroscopic procedures and rotator cuff tear (RCT) severity on daily pain intensity and disability after shoulder arthroscopy. MATERIALS AND METHODS: A sample of 145 patients (mean age, 42.66±17.6; number of males=96) completed daily pain intensity and disability measures before shoulder arthroscopy. RCT severity was assessed on a 7-point scale based on operative report. Operative procedures were categorized based on anatomic location and invasiveness to calculate a weighted concomitant procedure estimate. Postoperative daily pain and disability were assessed 3 months, 6 months, and 1 year status after surgery. RESULTS: Only concomitant procedures were associated with 3-month daily pain intensity after adjusting for age, sex, pain duration, and baseline daily pain intensity (R=0.03; standardized ß=0.203; P=0.036). Moreover, post hoc analysis revealed concomitant procedures remained predictive of 3-month daily pain intensity when the estimate was calculated independent of RCT procedures (R=0.05; standardized ß=0.233; P=0.007), and when accounting for postoperative factors of physical therapy and analgesic medication (R=0.05; standardized ß=0.237; P=0.007). Neither RCT severity nor concomitant procedures were predictive of daily pain intensity at 6 months and 1 year, or disability at any time-point, in the adjusted models (P>0.05). DISCUSSION: This study introduces a novel means for estimating concurrent procedures for use as a prognostic factor. Our findings are similar to previous research of RCT severity that was found to have limited influence on postoperative outcomes. In contrast, this study highlights the potential importance of accounting for concomitant arthroscopic procedures as a predictor of early postoperative pain intensity outcomes.

Biopsychosocial influence on shoulder pain: risk subgroups translated across preclinical and clinical prospective cohorts.

Tailored treatment based on individual risk factors is an area with promise to improve options for pain relief. Musculoskeletal pain has a biopsychosocial nature, and multiple factors should be considered when determining risk for chronic pain. This study investigated whether subgroups comprised genetic and psychological factors predicted outcomes in preclinical and clinical models of shoulder pain. Classification and regression tree analysis was performed for an exercise-induced shoulder injury cohort (n = 190) to identify high-risk subgroups, and a surgical pain cohort (n = 150) was used for risk validation. Questionnaires for fear of pain and pain catastrophizing were administered before injury and preoperatively. DNA collected from saliva was genotyped for a priori selected genes involved with pain modulation (COMT and AVPR1A) and inflammation (IL1B and TNF/LTA). Recovery was operationalized as a brief pain inventory rating of 0/10 for current pain intensity and <2/10 for worst pain intensity. Follow-up for the preclinical cohort was in daily increments, whereas follow-up for the clinical cohort was at 3, 6, and 12 months postoperatively. Risk subgroups comprised the COMT high pain sensitivity variant and either pain catastrophizing or fear of pain were predictive of heightened shoulder pain responses in the preclinical model. Further analysis in the clinical model identified the COMT high pain sensitivity variant and pain catastrophizing subgroup as the better predictor. Future studies will determine whether these findings can be replicated in other anatomical regions and whether personalized medicine strategies can be developed for this risk subgroup.

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.