Relation of pain sensitization to self-reported and performance-based measures of physical functioning: the Multicenter Osteoarthritis (MOST) study.

OBJECTIVE: It is unclear if alterations in nociceptive signaling contribute to poor physical functioning in persons with knee osteoarthritis (OA). We aimed to characterize the relation of pain sensitization to physical functioning in persons with or at risk for knee OA, and determine if knee pain severity mediates these relationships. MATERIALS AND METHODS: We used cross-sectional data from the Multicenter Osteoarthritis Study, a cohort study of persons with or at risk for knee OA. Pressure pain thresholds (PPTs) and temporal summation (TS) were assessed with quantitative sensory testing. Self-reported function was quantified with the Western Ontario and McMaster Universities Arthritis Index function subscale (WOMAC-F). Walking speed was determined during a 20-m walk. Knee extension strength was assessed with dynamometry. Relations of PPTs and TS to functional outcomes were examined with linear regression. The mediating role of knee pain severity was assessed with mediation analyses. RESULTS: Among 1560 participants (60.5% female, mean age (SD) 67 (8), body mass index (BMI) 30.2 (5.5) kg/m2), lower PPTs and the presence of TS were associated with worse WOMAC-F scores, slower walking speeds, and weaker knee extension. The extent of mediation by knee pain severity was mixed, with the greatest mediation observed for self-report function and only minimally for performance-based function. CONCLUSIONS: Heightened pain sensitivity appears to be meaningfully associated with weaker knee extension in individuals with or at risk for knee OA. Relations to self-reported physical function and walking speed do not seem clinically meaningful. Knee pain severity differentially mediated these relationships.

Depressive symptoms and multi-joint pain partially mediate the relationship between obesity and opioid use in people with knee osteoarthritis.

OBJECTIVES: To assess the relation of obesity to opioid use in people with or at risk of knee osteoarthritis (OA), and the extent to which this association is mediated by number of painful joints or depressive symptoms. METHODS: We used data from the Multicenter Osteoarthritis Study, a longitudinal cohort of older adults with or at risk of knee OA. Opioid use was identified by prescription medications and self-report. Obesity was defined as BMI ≥ 30 kg/m2. Multi-joint pain was assessed using a standardized body homunculus, and depressive symptoms using the Center for Epidemiological Studies Depression scale. We quantified the direct and indirect effect of obesity on opioid use through the number of painful joints or depressive symptoms using causal mediation analysis by natural-effects models. RESULTS: We studied 2,335 participants (mean age: 68; mean BMI 31 kg/m2; 60% women). Persons with obesity had ∼50% higher odds of opioid use than those without. Estimates of indirect (mediated) effect by the number of painful joints and depressive symptoms suggested an increased odds of opioid use by 34% (odds ratio [OR] = 1.34, 95% CI: 1.04, 1.70) and 35% (OR 1.35, 95% CI: 1.05, 1.71), respectively, in obese vs non-obese individuals. The total effect of obesity on opioid use was higher in women than in men. CONCLUSIONS: Multi-joint pain and depressive symptoms partially explained greater opioid use among obese persons with knee OA, demonstrating that the negative impact of obesity on knee OA extends beyond its influence on knee pain and structural progression.

Association between hamstring coactivation during isokinetic quadriceps strength testing and knee cartilage worsening over 24 months.

OBJECTIVE: This study aimed to determine longitudinal associations, including sex-specific differences, between greater knee flexor antagonist coactivation and worsening cartilage morphology in knees with or at risk for osteoarthritis (OA). DESIGN: Baseline measurements were collected at the 60-month visit of a longitudinal osteoarthritis study following community-dwelling participants (MOST). Knee flexor and extensor muscle activity were measured with surface electromyography during a maximal isokinetic knee extension task. MRI analyzed knee cartilage morphology at baseline and 24-month follow-up. Multivariable adjusted logistic regression models were used to assess associations between coactivation level and cartilage morphology worsening. RESULTS: Analysis of 373 women (mean ± SD age 67.4 ± 7.3 years and BMI 29.7 ± 5.0 kg/m2) and 240 men (66.5 ± 7.8 years and 29.9 ± 4.5 kg/m2) revealed that women had greater medial (P < 0.001), lateral (P < 0.001), and combined (P < 0.001) hamstring coactivation than men. In both sexes, combined hamstring coactivation was associated with patellofemoral cartilage morphology worsening [1.23 (1.02, 1.49)] and to a less significant degree with whole knee cartilage morphology worsening [1.21 (0.98, 1.49)]. In men, greater combined hamstring coactivation was associated with increased risk for whole knee [1.59 (1.06, 2.39)] and patellofemoral [1.38 (1.01, 1.88)] cartilage morphology worsening and point estimates suggested association between medial hamstring coactivation and medial tibiofemoral cartilage morphology worsening. No significant associations were detected between greater hamstring coactivation and cartilage morphology worsening in women. CONCLUSIONS: These findings suggest a longitudinal relationship between antagonist hamstring coactivation during isokinetic knee extensor testing and worsening of cartilage morphology over 24 months in men with or at risk for knee OA.

Does weight-bearing versus non-weight-bearing pain reflect different pain mechanisms in knee osteoarthritis?: the Multicenter Osteoarthritis Study (MOST).

OBJECTIVE: Knee osteoarthritis (OA) is predominantly characterized by pain with weight-bearing activities. Pain at rest also occurs but the mechanisms for this are not clear. We evaluated the relations of nociceptive signal alterations to weight-bearing and non-weight-bearing pain in knee OA. DESIGN: We used data from a NIH-funded longitudinal cohort of older adults with or at risk of knee OA. We evaluated quantitative sensory testing (QST) measures (pressure pain threshold (PPT) at patellae and the wrist; mechanical temporal summation (TS); conditioned pain modulation (CPM)). Each WOMAC pain question was dichotomized as having at least moderate pain, and we further categorized them as weight-bearing pain and non-weight-bearing pain. We evaluated the relation of QST measures to each pain outcome using logistic regression, adjusting for potential confounders. RESULTS: 2,749 participants (5,479 knees) were included (mean age 64 ± 11, 57% female). Each SD unit decrease in patellar PPT was associated with greater odds of both weight-bearing pain (OR 1.51 (95% CI 1.27, 1.79)) and non-weight-bearing pain (OR 1.46 (1.20-1.77)), while wrist PPT was associated with greater odds of weight-bearing pain (OR 1.27 (1.15, 1.39)) but only with pain during sitting/lying (OR 1.20 (1.01, 1.43)). TS was significantly associated with greater odds of pain with walking and stairs (OR 1.11 (1.01, 1.23), 1.11 (1.03, 1.20), respectively). CPM was not associated with any pain outcomes. CONCLUSIONS: Our findings challenge the hypothesis that non-weight-bearing pain may reflect greater pain sensitization and/or inefficient CPM than weight-bearing pain in knee OA, suggesting other mechanisms are likely responsible.

Is the association between physical activity and fatigue mediated by physical function or depressive symptoms in symptomatic knee osteoarthritis? The Multicenter Osteoarthritis Study.

Objectives: To examine whether physical activity (PA) was associated with fatigue, and quantify the extent of potential mediation through depressive symptoms or physical function (PF) on the relationship between PA and fatigue in symptomatic knee osteoarthritis (KOA).Method: This longitudinal study used data from the Multicenter Osteoarthritis Study (n = 484), comprising subjects aged ≥ 50 years. Baseline PA was quantified via an ankle-worn accelerometer. The outcome was fatigue, measured using a 0-10 rating scale at 2 year follow-up. Mediators included gait speed as a measure of PF and depressive symptoms at 2 year follow-up. Mediation analysis was carried out after adjustment for baseline confounders. Stratified analysis by baseline fatigue status [no/low (< 4) and high (≥ 4) fatigue] was performed.Results: A significant direct association was found between PA and fatigue at 2 years [unstandardized coefficient (B) = -0.054; 95% confidence interval (CI) -0.107, -0.002, p = 0.041]. The PA-fatigue relationship was not mediated by gait speed (B = -0.006; 95% CI -0.018, 0.001) or depressive symptoms (B = 0.009; 95% CI 0.009, 0.028). In the subgroup with high baseline fatigue, direct associations were found between PA and fatigue (gait speed model:, B = -0.107; 95% CI -0.212, -0.002, p = 0.046; depressive symptoms model: B = -0.110; 95% CI -0.120, -0.020, p = 0.017); but in the no/low baseline fatigue group, no significant association was found between PA and fatigue.Conclusion: In the symptomatic KOA population, higher baseline PA was directly associated with reduced fatigue 2 years later, especially in those with high baseline fatigue. However, this relationship was not mediated by depressive symptoms or PF.

The relation of peripheral and central sensitization to muscle co-contraction: the MOST study.

OBJECTIVE: To examine the relation of pain sensitization to altered motor activity in knee OA as assessed by hamstrings muscle co-contraction during maximal effort knee extension. DESIGN: Medial, lateral, and overall hamstring co-contraction was assessed in the Multicenter Osteoarthritis (MOST) Study cohort using electromyography during isokinetic knee extension at 60°/second. Mechanical temporal summation of pain (TS) was assessed at the right wrist and pressure pain thresholds (PPT) were assessed at the patellae; PPTs were categorized into sex-specific tertiles. Muscle co-contraction was categorized into age- and sex-specific tertiles. We evaluated the relation of measures of sensitization to muscle co-contraction using a generalized logistic regression model. RESULTS: 1633 participants were included: mean age and BMI was 67.3 ± 7.7 years and 30.3 ± 5.6 kg/m2, respectively; 58% were female. Presence of TS was associated with higher overall (OR 1.3, 95% confidence interval (CI) (1.0-1.8)), medial (1.4 (1.0-1.9), and lateral (1.3 (1.0, 1.9)) hamstring co-contraction. The lowest PPT tertile (greater sensitivity) was associated with higher overall (1.5 (1.0, 2.3)) and medial (1.5 (1.0, 2.3)) hamstring co-contraction compared with those in the highest PPT tertile. CONCLUSION: Greater pain sensitization, as assessed by presence of TS at the wrist and low patellar PPT, was associated with greater overall and medial hamstring co-contraction during knee extension. This provides support to the possibility that peripheral and/or central nervous system alterations may not only affect pain sensitivity, but also motor function.

The association between walking speed from short- and standard-distance tests with the risk of all-cause mortality among adults with radiographic knee osteoarthritis: data from three large United States cohort studies.

OBJECTIVE: Adults with radiographic knee OA (rKOA) are at increased risk of mortality and walking difficulty may modify this relation. Little is known about specific aspects of walking difficulty that increase mortality risk. We investigated the association of walking speed (objective measure of walking difficulty) with mortality and examined the threshold that best discriminated this risk in adults with rKOA. METHODS: Participants with rKOA from the Johnston County Osteoarthritis Project (JoCoOA, longitudinal population-based cohort), Osteoarthritis Initiative and Multicenter Osteoarthritis Study (OAI and MOST, cohorts of individuals with or at high risk of knee OA) were included. Baseline speed was measured via 2.4-meter (m) walk test (short-distance) in JoCoOA and 20-m walk test (standard-distance) in OAI and MOST. To examine the association of walking speed with mortality risk over 9 years, hazard ratios (HR) and 95% confidence intervals (CI) were calculated from Cox regression models adjusted for potential confounders. A Maximal Likelihood Ratio Chi-square Approach was utilized to identify an optimal threshold of walking speed predictive of mortality. RESULTS: Deaths after 9 years of follow-up occurred in 23.3% (290/1244) of JoCoOA and 5.9% (249/4215) of OAI + MOST. Walking 0.2 m/s slower during short- and standard-distance walk tests was associated with 23% (aHR [95%CI]; 1.23 [1.10, 1.39]) and 25% (1.25 [1.09, 1.43]) higher mortality risk, respectively. Walking <0.5 m/s on short-distance and <1.2 m/s standard-distance walk tests, best discriminated those with and without mortality risk. CONCLUSION: Slower walking speed measured via short- and standard-distance walk tests was associated with increased mortality risk in adults with rKOA.

The association between antagonist hamstring coactivation and episodes of knee joint shifting and buckling.

OBJECTIVE: Hamstring coactivation during quadriceps activation is necessary to counteract the quadriceps pull on the tibia, but coactivation can be elevated with symptomatic knee osteoarthritis (OA). To guide rehabilitation to attenuate risk for mobility limitations and falls, this study evaluated whether higher antagonistic open kinetic chain hamstring coactivation is associated with knee joint buckling (sudden loss of support) and shifting (a sensation that the knee might give way). DESIGN: At baseline, median hamstring coactivation was assessed during maximal isokinetic knee extensor strength testing and at baseline and 24-month follow-up, knee buckling and shifting was self-reported. Associations between tertiles of co-activation and knee (1) buckling, (2) shifting and (3) either buckling or shifting were assessed using logistic regression, adjusted for age, sex, knee OA and pain. RESULTS: 1826 participants (1089 women) were included. Mean ± SD age was 61.7 ± 7.7 years, BMI was 30.3 ± 5.5 kg/m(2) and 38.2% of knees had OA. There were no consistent statistically significant associations between hamstring coactivation and ipsilateral prevalent or incident buckling or the combination of buckling and shifting. The odds ratios for incident shifting in the highest in comparison with the lowest tertile of coactivation had similar magnitudes in the combined and medial hamstrings, but only reached statistical significance for lateral hamstring coactivation, OR(95%CI) 1.53 (0.99, 2.36). CONCLUSIONS: Hamstring coactivation during an open kinetic chain quadriceps exercise was not consistently associated with prevalent or incident self-reported knee buckling or shifting in older adults with or at risk for knee OA.

Examining sex differences in knee pain: the multicenter osteoarthritis study.

OBJECTIVE: To determine whether women experience greater knee pain severity than men at equivalent levels of radiographic knee osteoarthritis (OA). DESIGN AND METHODS: A cross-sectional analysis of 2712 individuals (60% women) without knee replacement or a recent steroid injection. Sex differences in pain severity at each Kellgren-Lawrence (KL) grade were assessed by knee using visual analog scale (VAS) scale and Western Ontario and McMaster Universities Arthritis Index (WOMAC) with and without adjustment for age, analgesic use, Body mass index (BMI), clinic site, comorbid conditions, depression score, education, race, and widespread pain (WSP) using generalized estimating equations. Effect sizes (Cohen's d) were also calculated. Analyses were repeated in those with and without patellofemoral OA (PFOA). RESULTS: Women reported higher VAS pain at all KL grades in unadjusted analyses (d = 0.21-0.31, P < 0.0001-0.0038) and in analyses adjusted for all covariates except WSP (d = 0.16-0.22, P < 0.0001-0.0472). Pain severity differences further decreased with adjustment for WSP (d = 0.10-0.18) and were significant for KL grade ≤2 (P = 0.0015) and 2 (P = 0.0200). Presence compared with absence of WSP was associated with significantly greater knee pain at all KL grades (d = 0.32-0.52, P < 0.0001-0.0008). In knees with PFOA, VAS pain severity sex differences were greater at each KL grade (d = 0.45-0.62, P = 0.0006-0.0030) and remained significant for all KL grades in adjusted analyses (d = 0.31-0.57, P = 0.0013-0.0361). Results using WOMAC were similar. CONCLUSIONS: Women reported greater knee pain than men regardless of KL grade, though effect sizes were generally small. These differences increased in the presence of PFOA. The strong contribution of WSP to sex differences in knee pain suggests that central sensitivity plays a role in these differences.

The relationship between quadriceps muscle weakness and worsening of knee pain in the MOST cohort: a 5-year longitudinal study.

OBJECTIVE: To determine whether quadriceps weakness is associated with elevated risk of worsening knee pain over 5 years. METHODS: The Multicenter Osteoarthritis Study (MOST) is a longitudinal study of 50-79-year-old adults with knee osteoarthritis (OA) or known risk factors for knee OA. The predictor variable was baseline isokinetic quadriceps strength. Covariates included baseline body mass index (BMI), physical activity level, and history of knee surgery. The outcome was worsening pain reported on the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain subscale or knee replacement surgery between baseline and 5-year follow-up. Analyses were knee-based and used generalized estimating equations, stratified by sex to assess whether the lowest compared with the highest tertile of baseline quadriceps strength was associated with an increased risk of worsening knee pain at 5-year follow-up, controlling for age, BMI, history of knee surgery, and physical activity level as well as correlation between knees within participants. RESULTS: Analyses of worsening knee pain included 4,648 knees from 2,404 participants (61% female). Men with lower quadriceps strength did not have a higher risk of worsening knee pain (RR {95% CI} = 1.01 {0.78-1.32}, P = 0.9183). However, women in the lowest compared with the highest strength tertile had a 28% increased risk of worsening knee pain (RR {95% CI} = 1.28 {1.08-1.52}, P = 0.0052). CONCLUSION: Quadriceps weakness was associated with an increased risk of worsening of knee pain over 5 years in women, but not in men.

Psychological factors predict local and referred experimental muscle pain: a cluster analysis in healthy adults.

BACKGROUND: Recent studies suggest an underlying three- or four-factor structure explains the conceptual overlap and distinctiveness of several negative emotionality and pain-related constructs. However, the validity of these latent factors for predicting pain has not been examined. METHODS: A cohort of 189 (99 female, 90 male) healthy volunteers completed eight self-report negative emotionality and pain-related measures (Eysenck Personality Questionnaire - Revised, Positive and Negative Affect Schedule, State-Trait Anxiety Inventory, Pain Catastrophizing Scale, Fear of Pain Questionnaire; Somatosensory Amplification Scale, Anxiety Sensitivity Index and Whiteley Index). Using principal axis factoring, three primary latent factors were extracted: general distress, catastrophic thinking and pain-related fear. Using these factors, individuals clustered into three subgroups of high, moderate and low negative emotionality responses. Experimental pain was induced via intramuscular acidic infusion into the anterior tibialis muscle, producing local (infusion site) and/or referred (anterior ankle) pain and hyperalgesia. RESULTS: Pain outcomes differed between clusters (multivariate analysis of variance and multinomial regression), with individuals in the highest negative emotionality cluster reporting the greatest local pain (p = 0.05), mechanical hyperalgesia (pressure pain thresholds; p = 0.009) and greater odds (2.21 odds ratio) of experiencing referred pain when compared to the lowest negative emotionality cluster. CONCLUSION: Our results provide support for three latent psychological factors explaining the majority of the variance between several pain-related psychological measures, and that individuals in the high negative emotionality subgroup are at increased risk for (1) acute local muscle pain; (2) local hyperalgesia; and (3) referred pain using a standardized nociceptive input.

Association between patella alta and the prevalence and worsening of structural features of patellofemoral joint osteoarthritis: the multicenter osteoarthritis study.

OBJECTIVE: To examine the relationship between patella alta and the prevalence and worsening at followup of structural features of patellofemoral joint (PFJ) osteoarthritis (OA) on magnetic resonance imaging (MRI). METHODS: The Multicenter Osteoarthritis Study is a cohort study of persons ages 50-79 years with or at risk for knee OA. Patella alta was measured using the Insall-Salvati ratio (ISR) on the baseline lateral radiograph, and cartilage damage, bone marrow lesions (BMLs), and subchondral bone attrition (SBA) were graded on MRI at baseline and at 30 months of followup in the PFJ. We examined the association of the ISR with the prevalence and worsening of cartilage damage, BMLs, and SBA in the PFJ using logistic regression. RESULTS: A total of 907 knees were studied (mean age 62 years, body mass index 30 kg/m(2), ISR 1.10), 63% from female subjects. Compared with knees in the lowest ISR quartile at baseline, those in the highest quartile had 2.4 (95% confidence interval [95% CI] 1.7-3.3), 2.9 (95% CI 2.0-4.3), and 3.5 (95% CI 2.3-5.5) times the odds of having lateral PFJ cartilage damage, BMLs, and SBA, respectively, and 1.5 (95% CI 1.1-2.0), 1.3 (95% CI 0.9-1.8), and 2.2 (95% CI 1.4-3.4) times the odds of having medial PFJ cartilage damage, BMLs, and SBA, respectively. Similarly, those with high ISRs were also at risk for worsening of cartilage damage and BMLs over time than those with low ISRs. CONCLUSION: A high ISR, indicative of patella alta, is associated with structural features of OA in the PFJ. Additionally, the same knees have an increased risk of worsening of these same features over time.