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Objective: Transcutaneous auricular vagus nerve stimulation (tVNS) may be an innovative treatment for symptoms of knee osteoarthritis (OA) due to possible shared pathological mechanisms between diminished parasympathetic function, central pain mechanisms, and knee pain. Thus, we sought to test the safety and preliminary efficacy of tVNS in people with knee OA. Design: A pilot trial in which participants received a 60-min tVNS was conducted. At baseline, immediately after, and 15 ​min after tVNS, we assessed knee pain, pressure pain threshold (PPT), temporal summation (TS), conditioned pain modulation (CPM), and high-frequency power of heart rate variability (HF). We examined the extent to which these outcome measures changed after tVNS using linear mixed models. Results: 30 participants with knee OA were included, and all completed the intervention without any major side effects. Compared to baseline, knee pain was reduced by 1.27 (95 ​% CI, −1.74, −0.80) immediately after and by 1.87 (−2.33, −1.40) 15 ​min after tVNS; CPM improved by 0.11 (0.04, 0.19) and 0.07 (−0.01, 0.15); and HF improved by 213.29 (−0.38, 426.96) and 234.17 (20.49, 447.84). PPT and TS were not changed after tVNS. Conclusions: Our preliminary data demonstrated that tVNS may be a safe pain-relieving treatment for people with knee OA. Our findings suggest that improvement of knee pain might be derived from improvement of parasympathetic function and central pain mechanisms as no local therapy was applied. A large study is needed to confirm that tVNS is a novel intervention to ameliorate knee pain in people with knee OA. Clinical Trial: ClinicalTrials.gov (NCT05625178).

Objective: Conservative pain management strategies for knee osteoarthritis (KOA) have limited effectiveness and do not employ a pain-mechanism informed approach. Pain Informed Movement is a novel intervention combining mind-body techniques with neuromuscular exercise and pain neuroscience education (PNE), aimed at improving endogenous pain modulation. While the feasibility and acceptability of this program has been previously established, it now requires further evaluation in comparison to standard KOA care. Design: This protocol describes the design of a pilot two-arm randomized controlled trial (RCT) with an embedded qualitative component. The primary outcome is complete follow-up rate. With an allocation ratio of 1:1, 66 participants (33/arm) (age ≥40 years, KOA diagnosis or meeting KOA NICE criteria, and pain intensity ≥3/10), will be randomly allocated to two groups that will both receive 8 weeks of twice weekly in-person exercise sessions. Those randomized to Pain Informed Movement will receive PNE and mind-body technique instruction provided initially as videos and integrated into exercise sessions. The control arm will receive neuromuscular exercise and standard OA education. Assessment will include clinical questionnaires, physical and psychophysical tests, and blood draws at baseline and program completion. Secondary outcomes are program acceptability, burden, rate of recruitment, compliance and adherence, and adverse events. Participants will be invited to an online focus group at program completion. Conclusion: The results of this pilot RCT will serve as the basis for a larger multi-site RCT aimed at determining the program's effectiveness with the primary outcome of assessing the mediating effects of descending modulation on changes in pain.

Objective: To determine whether the comorbidity burden and co-existing comorbidities are cross-sectionally and/or longitudinally associated with pain and pain sensitization in a cohort study of people with hand OA. Design: We examined whether comorbidity burden and individual comorbidities based on the self-administered Comorbidity Index (range: 0–42) at baseline were associated with pain outcomes at baseline and 3 years follow-up. Pain outcomes included hand and overall bodily pain (range: 0–10) as well as pressure pain thresholds at the tibialis anterior muscle (kg/cm2) and temporal summation (distal radioulnar joint) as measures of central pain sensitization. We performed linear regression analyses adjusted for age, sex, body mass index, physical exercise and education. Results: We included 300 and 196 participants in cross-sectional and longitudinal analyses, respectively. Using baseline data, the burden of comorbidities was associated with greater pain in hands (beta ​= ​0.61, 95% CI 0.37, 0.85) and overall body (beta ​= ​0.60, 95% CI 0.37, 0.87). Similar strength of associations was found between comorbidity burden (baseline) and follow-up pain. Among the individual comorbidities, back pain and depression were associated with nearly one unit higher pain score in hands and overall body at both baseline and follow-up. Only back pain was related to lower pressure pain thresholds at follow up (beta ​= ​−0.24, 95% CI −0.50, −0.001). Conclusion: People with hand OA and greater comorbidity burden, co-existing back pain or depression reported greater pain severity than their counterparts, also 3 years later. These results acknowledge the relevance of accounting for comorbidities in the pain experience in people with hand OA.

Objective: Pain persistence following knee replacement (KR) occurs in ∼20–30% of patients. Although several studies have identified preoperative risk factors for persistent post-KR pain, few have focused on post-KR contributing factors. We sought to determine whether altered nociceptive signaling and other peripheral nociceptive drivers present post-operatively contribute to post-KR pain. Design: We included participants from the Multicenter Osteoarthritis Study who were evaluated ∼12 months after KR. We evaluated the relation of measures of pain sensitivity [pressure pain threshold (PPT), temporal summation (TS), and conditioned pain modulation (CPM)] and the number of painful body sites to post-KR WOMAC knee pain, and of the number of painful sites to altered nociceptive signaling using linear or logistic regression models, as appropriate. Results: 171 participants (mean age 69 years, 62% female) were included. TS was associated with worse WOMAC pain post-KR (β ​= ​0.77 95% CI:0.19–1.35) and reduced odds of achieving patient acceptable symptom state (aOR ​= ​0.54 95%CI:0.34–0.88). Inefficient CPM was also associated with worse WOMAC pain post-KR (β ​= ​1.43 95% CI:0.15–2.71). In contrast, PPT was not associated with these outcomes. The number of painful body sites present post-KR was associated with TS (β ​= ​0.05, 95% CI:0.01, 0.05). Conclusions: Post-KR presence of central sensitization and inefficient descending pain modulation was associated with post-KR pain. We also noted that presence of other painful body sites contributes to altered nociceptive signaling, and this may thus also contribute to the experience of knee pain post-KR. Our findings provide novel insights into central pain mechanisms and other peripheral pain sources contributing to post-KR persistent knee pain.

Objective: To examine whether psychological symptoms and cognitive patterns are associated with self-reported pain and pain sensitization in people with hand osteoarthritis (OA). Design: In the Nor-Hand study (n ​= ​300), people with hand OA self-reported psychological symptoms (Hospital Anxiety and Depression Scale), cognitive patterns (Pain catastrophizing Scale and Arthritis Self-Efficacy Scale) as well as their pain severity in hands, overall pain and multi-joint pain. Central pain sensitization was measured clinically by temporal summation and pressure pain threshold tests. We examined whether psychological symptoms and cognitive patterns were cross-sectionally associated with pain using linear regression. Beta coefficients (β) per one standard deviation of the independent variable were presented. Stratified analyses were performed in cases of significant interactions (p ​

Objective: This study aims to increase the understanding of pain mechanisms in hand OA and explore potential risk factors for pain development or worsening in a biopsychosocial framework. Another important aim is to validate potential soluble and imaging OA biomarkers. Design: The follow-up examination of the Nor-Hand hospital-based observational cohort study started in October 2019 and was completed in May 2021. In total, 212 of the 300 participants with hand OA who were examined at baseline attended the follow-up study. The participants underwent clinical joint examinations, medical and functional assessments, quantitative sensory testing, fluorescence optical imaging, ultrasound of the hands, acromioclavicular joints, feet, knees and hips, conventional radiographs of the hands and feet and magnetic resonance imaging of the dominant hand. Blood and urine samples were collected, and all participants answered questions about demographic factors and OA-related questionnaires. Associations between disease variables and symptoms will be examined in cross-sectional and longitudinal analyses. Longitudinal analyses will be performed to assess the predictive value of baseline variables on hand OA outcomes. Conclusion: Current knowledge about predictors for disease progression in hand OA is limited, but with longitudinal data we will be able to explore the predictive value of baseline variables on hand OA outcomes, such as changes in patient-reported outcomes or changes in soluble and imaging biomarkers. This provides a unique opportunity to gain more knowledge about the natural disease course of hand OA.

Background: Anti-nerve growth factor (NGF) has shown promise for osteoarthritis (OA) pain efficacy, but an unanticipated joint safety signal occurred in trials. To what extent this was related to OA natural history, or was a consequence of anti-NGF agents is unclear. Of the adverse joint safety events identified, osteonecrosis has specific diagnostic codes available in the medical record to enable assessment of its frequency in the general community. We therefore investigated the rates of knee osteonecrosis in three real-world cohorts using two data sources to place these trial data in context. Methods: We used data from UK-based IQVIA Medical Research Data (IMRD) of adults diagnosed with incident knee OA between 2000 and 2018 to examine the incidence of knee osteonecrosis using different definitions. Additionally, we evaluated the incidence of knee osteonecrosis in the year prior to knee replacement in IMRD and among US Medicare beneficiaries who received a knee replacement in 2011–2014. Results: In IMRD, among 122,343 subjects with incident knee OA (mean age 68 years, 58% female), incidence estimates for knee osteonecrosis were 0.006–0.10%, with incidence rates of 0.01–0.17 per 1000 person-years. Among the 81,807 who had a knee replacement, the incidence of knee osteonecrosis in the year prior to knee replacement was 0.004–0.06%. In Medicare, among 316,593 with knee replacement (mean age 74, 68% female), the incidence of knee osteonecrosis was 0.24–0.7%. Conclusion: Knee osteonecrosis is rare among people with knee OA, including in the year prior to knee replacement. These data provide context for interpreting osteonecrosis events in NGF trials.

Summary: Objective: To summarize proceedings of a workshop convened to discuss advances in disease modifying osteoarthritis (OA) drugs and regulatory challenges in bringing these drugs to market. Design: Summary of a one day workshop held in Washington, DC in May 2019. Results: Attendees presented data documenting the prevalence, cost and disability burden of OA; recent documentation of disease modification without concomitant clinical benefit in trials of disease modifying drugs; regulatory considerations pertinent to disease modifying therapy; and methodologic approaches to addressing these regulatory considerations. Conclusions: The research, pharmaceutical and regulatory communities must continue to collaborate on defining pathways for approval of disease modifying osteoarthritis drugs that document effects on clinical endpoints (such as pain, function or joint replacement) as well as on bone, cartilage and other structures.