Neurotropin® ameliorates chronic pain associated with scar formation in a mouse model: A gene expression analysis of the inflammatory response.

Background: Scar formation after trauma and surgery involves an inflammatory response and can lead to the development of chronic pain. Neurotropin® (NTP) is a nonprotein extract of inflamed skin of rabbits inoculated with vaccinia virus. It has been widely used for the treatment of chronic pain. However, the in vivo effects of NTP on painful scar formation have not been determined. To investigate the molecular mechanisms underlying the effects of NTP on the inflammatory response, we evaluated gene expression in the scar tissues and dorsal root ganglions (DRGs) of mice administered NTP and control mice. Methods and results: Mice injected with saline or NTP were used as controls; other mice were subjected to surgery on the left hind paw to induce painful scar formation, and then injected with saline or NTP. Hind paw pain was evaluated by measuring the threshold for mechanical stimulation using the von Frey test. The paw withdrawal threshold gradually returned to pre-operative levels over 4 weeks post-operation; NTP-treated mice showed a significantly shortened recovery time of approximately 3 weeks, suggesting that NTP exerted an analgesic effect in this mouse model. Total RNA was extracted from the scarred hind paw tissues and DRGs were collected 1 week post-operation for a microarray analysis. Gene set enrichment analysis revealed that the expression of some gene sets related to inflammatory responses was activated or inhibited following surgery and NTP administration. Quantitative real-time reverse transcription-polymerase chain reaction analysis results for several genes were consistent with the microarray results. Conclusion: The administration of NTP to the hind paws of mice with painful scar formation following surgery diminished nociceptive pain and reduced the inflammatory response. NTP inhibited the expression of some genes involved in the response to surgery-induced inflammation. Therefore, NTP is a potential therapeutic option for painful scar associated with chronic pain.

Predictors of high-cost patients with acute whiplash-associated disorder in Japan.

INTRODUCTION: The proportion of neck injuries due to traffic accidents is increasing. Little is known about high-cost patients with acute whiplash-associated disorder (WAD). The present study aimed to investigate whether time to first visit for conventional medicine, multiple doctor visits, or alternative medicine could predict high-cost patients with acute WAD in Japan. METHODS: Data from a compulsory, no-fault, government automobile liability insurance agency in Japan between 2014 and 2019 were used. The primary economic outcome was the total cost of healthcare per person. Treatment-related variables were assessed based on the time to first visit for conventional and alternative medicine, multiple doctor visits, and visits for alternative medicine. Patients were categorized according to total healthcare cost (low, medium, and high cost). The variables were subjected to univariate and multivariate analysis to compare high-cost and low-cost patients. RESULTS: A total of 104,911 participants with a median age of 42 years were analyzed. The median total healthcare cost per person was 67,366 yen. The cost for consecutive medicine, for consecutive and alternative medicine, and total healthcare costs were significantly associated with all clinical outcomes. Female sex, being a homemaker, a history of WAD claim, residential area, patient responsibility in a traffic accident, multiple doctor visits, and visits for alternative medicine were identified as independent predictive factors for a high cost in multivariate analysis. Multiple doctor visits and visits for alternative medicine showed large differences between groups (odds ratios 2673 and 694, respectively). Patients with multiple doctor visits and visits for alternative medicine showed a significantly high total healthcare cost per person (292,346 yen) compared to those without (53,587 yen). CONCLUSIONS: A high total healthcare cost is strongly associated with multiple doctor visits and visits for alternative medicine in patients with acute WAD in Japan.

[Neuropathic Pain].

Many diseases are associated with "neuropathic pain", which is not usually manageable with common analgesics, such as NSAIDs and acetaminophen. Calcium ion channel α2δ ligands, serotonin-noradrenaline reuptake inhibitors, and tricyclic antidepressants have been used as first-line drugs. If there are no improvements after using these drugs for a while, vaccinia virus inoculation of rabbit inflammatory skin extract, tramadol, and eventually opioid analgesics, may be considered.

Long-Term Safety and Efficacy of Mirogabalin for Central Neuropathic Pain: A Multinational, Phase 3, 52-Week, Open-Label Study in Asia.

INTRODUCTION: Central neuropathic pain (CNeP) is difficult to treat and has diverse etiology, including spinal cord injury (CNePSCI), Parkinson's disease (CNePPD), and central post-stroke pain (CPSP). The safety and efficacy of mirogabalin have been demonstrated in short-term trials, including patients with CNePSCI. The objective of our study was to confirm the safety/efficacy of mirogabalin in patients with CNePPD and CPSP, and obtain long-term data for CNePSCI. METHODS: This 52-week, open-label extension of a previous randomized controlled study was conducted across Japan, Korea, and Taiwan. Patients with CNePSCI, CNePPD, or CPSP received twice daily (BID) 5-10 mg mirogabalin for a 4-week titration period, after which the dosage was maintained for 47 weeks at a maximum of 15 mg BID, followed by a 1-week taper period receiving the same dose but only administered once daily. The primary endpoint was safety, assessed primarily by incidence and severity of treatment-emergent adverse events (TEAEs). Efficacy was assessed in a post hoc analysis of data obtained by the short-form McGill Pain Questionnaire (SF-MPQ). RESULTS: Of the 210 patients enrolled, 106, 94, and 10 had CNePSCI, CPSP, and CNePPD, respectively. The mean overall age of patients was 62.9 years, and most patients were male and of Japanese ethnicity. TEAEs occurred in 84.8% of patients, the most common being somnolence (16.7%), peripheral edema (12.4%), edema (11.4%), nasopharyngitis (11.0%), and dizziness (7.6%). Most TEAEs were mild. Severe and serious TEAEs occurred in 6.2% and 13.3% of patients, respectively. All patient groups experienced reductions in SF-MPQ visual analog scores for pain: mean ± standard deviation changes from baseline at week 52 were -2.3 ± 21.13 mm (CNePSCI), -17.0 ± 24.99 mm (CPSP), and -17.1 ± 35.32 mm (CNePPD). CONCLUSION: Mirogabalin was generally safe, well tolerated, and effective for treatment of CNeP in this long-term study. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03901352.

[Chronic Pain: Definition/Conception/Classification of Pain].

Understanding what pain is necessary to understand the pathomechanisms of chronic pain. The International Association for the Study of Pain (IASP) defines pain as "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage" and its further states that pain is a personal experience, influenced to varying degrees by biological, psychological, and social factors. It also mentions that person learn the concept of the pain through life experiences, and that it does not always play an adaptive role and has a negative impact on our physical, social, and psychological health. In order to classify chronic pain, IASP created a coding system in ICD11 that focuses on chronic secondary pain, which has clear organic factors, and chronic primary pain, which is difficult to explain from the organic aspect alone. When considering pain treatment, it is necessary to consider three pain mechanisms, including nociceptive pain, neuropathic pain, and nociplastic pain, which is a condition in which the patient feels strong pain due to sensitization of the nervous system.

Perioperative Analgesics and Anesthesia as Risk Factors for Postoperative Chronic Opioid Use in Patients Undergoing Total Knee Arthroplasty: A Retrospective Cohort Study Using Japanese Hospital Claims Data.

BACKGROUND: Patients with chronic postsurgical pain are commonly prescribed opioids chronically because of refractory pain although chronic opioid use can cause various severe problems. OBJECTIVE: We aimed to investigate postoperative chronic opioid use and its association with perioperative pain management in patients who underwent a total knee arthroplasty in a Japanese real-world clinical setting. METHODS: We conducted a retrospective cohort study using an administrative claims database. We used a multivariate logistic regression analysis to examine the association between perioperative analgesic and anesthesia prescriptions and postoperative chronic opioid use. We calculated all-cause medication and medical costs for each patient. RESULTS: Of the 23,537,431 patient records, 14,325 patients met the criteria and were included in the analyses. There were 5.4% of patients with postoperative chronic opioid use. Perioperative prescriptions of weak opioids, strong and weak opioids, and the α2δ ligand were significantly associated with postoperative chronic opioid use (adjusted odds ratio [95% confidence interval], 7.22 [3.89, 13.41], 7.97 [5.07, 12.50], and 1.45 [1.13, 1.88], respectively). Perioperative combined prescriptions of general and local anesthesia were also significantly associated with postoperative chronic opioid use (3.37 [2.23, 5.08]). These medications and local anesthesia were more commonly prescribed on the day following surgery, after routinely used medications and general anesthesia were prescribed. The median total direct costs were approximately 1.3-fold higher among patients with postoperative chronic opioid use than those without postoperative chronic opioid use. CONCLUSIONS: Patients who require supplementary prescription of analgesics for acute postsurgical pain are at high risk of postoperative chronic opioid use and these prescriptions should be given careful consideration to mitigate the patient burden.

The Relationship between Numbness and Quality of Life.

BACKGROUND: Numbness is a term commonly used in clinical practice to describe an abnormal sensory experience that is produced by a stimulus or is present even without a stimulus. However, there is still much that remains obscure in this field, and also, few reports have focused on its symptoms. In addition, while pain itself is known to have a significant impact on quality of life (QOL), the relationship between numbness and QOL is often unclear. Therefore, we conducted an epidemiological survey and analyzed the relationship between painless numbness and QOL, using type, location, and age as influencing factors, respectively. METHODS: A nationwide epidemiological survey was conducted by mail using a survey panel designed by the Nippon Research Center. Questionnaires were sent to 10,000 randomly selected people aged 18 and over from all over Japan. Out of the 5682 people who responded, the relationship between numbness and QOL was analyzed using the EuroQol 5 Dimension-3L (EQ5D-3L) for patients who are currently experiencing painless numbness. FINDINGS: The results suggest that painless numbness affects QOL and that QOL decreases as its intensity increases. Furthermore, the two factors of numbness of feet and numbness among the young may be less likely to affect QOL. This study may be of great significance in the field of numbness research.

Mirogabalin for Central Neuropathic Pain After Spinal Cord Injury: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study in Asia.

BACKGROUND AND OBJECTIVES: Patients with spinal cord injury (SCI) commonly experience central neuropathic pain (CNeP), which is challenging to treat. Mirogabalin is effective for peripheral neuropathic pain, but evidence for CNeP is lacking. METHODS: This randomized, double-blind, placebo-controlled, phase 3 study investigated mirogabalin efficacy and safety for the treatment of CNeP in patients with traumatic SCI. Adult patients from 120 sites throughout Japan, Korea, and Taiwan were randomized (1:1) to receive placebo or mirogabalin (5 mg twice daily [BID] for 1 week, 10 mg BID for 1 week, and 10 or 15 mg BID for 12 weeks). Patients with moderate renal impairment received half the dosage. The primary efficacy endpoint was change from baseline in the weekly average daily pain score (ADPS) at week 14. The secondary endpoints included ADPS responder rates, the Short-Form McGill Pain Questionnaire (SF-MPQ), average daily sleep interference score (ADSIS), and Neuropathic Pain Symptom Inventory (NPSI). Adverse events were monitored for safety. RESULTS: Each treatment group comprised 150 patients. Mirogabalin elicited a statistical and clinically relevant improvement in change from baseline in the weekly ADPS at week 14 (least-squares mean difference [95% CI] vs placebo -0.71 [-1.08 to -0.34], p = 0.0001). Responder rates at week 14 were higher for mirogabalin than those for placebo (odds ratio [95% CI] 1.91 [1.11-3.27] for the ≥30% responder rate; 2.52 [1.11-5.71] for the ≥50% responder rate). Statistical improvements (i.e., least-squares mean difference [95% CI] vs placebo) were also observed in the SF-MPQ (-2.4 [-3.8 to -1.1]), ADSIS -0.71 (-1.04 to -0.38), and NPSI -7.7 (-11.1 to -4.4) scores. Most treatment-emergent adverse events were mild; no serious adverse drug reactions were reported. DISCUSSION: Mirogabalin elicited clinically relevant decreases in pain and was well tolerated, suggesting that mirogabalin is a promising treatment for patients with CNeP due to SCI. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov (NCT03901352); first submitted April 3, 2019; first patient enrolled March 14, 2019; available at clinicaltrials.gov/ct2/show/NCT03901352. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in adult patients with CNeP due to traumatic SCI, mirogabalin, 10 or 15 mg BID, effectively improves weekly ADPS at week 14.

Efficacy of Combination Therapy with Pregabalin in Neuropathic Pain: A Preclinical Study in the Rat L5 Spinal Nerve Ligation Model.

Purpose: Neuropathic pain is sometimes difficult to manage because of limited efficacy of analgesic monotherapy even at high doses. Combination therapy may help address this issue, but there is little evidence for its effectiveness. Therefore, we evaluated the efficacy of combination therapy with pregabalin, an anchor drug for treating neuropathic pain, using the rat L5 spinal nerve ligation model. Methods: Experiments were performed on four-week-old L5 spinal nerve ligated male Sprague-Dawley rats. Mechanical allodynia was assessed using the von Frey test, where the 50% withdrawal threshold was evaluated for five drugs: pregabalin, duloxetine, venlafaxine, tramadol, and celecoxib. The single-drug experiment included 112 rats, where each drug was tested independently. Median effective doses (ED50s) were determined. Combinations of pregabalin with each of the other four drugs were tested (n=84). The 50% withdrawal threshold in the von Frey test was evaluated. The ED50 of each combination was determined experimentally. Isobolographic analyses were conducted to assess the synergistic potential of the drug combinations, excluding pregabalin-celecoxib, since the ED50 of celecoxib could not be determined. Results: In the single-drug experiment, all drugs except celecoxib resulted in a dose-dependent increase in the 50% withdrawal threshold 2 h after administration, with a maximum possible effect ranging from 4.4% to 79.6%. Similarly, all pregabalin combinations demonstrated a dose-dependent increase in the 50% withdrawal threshold, with pregabalin-tramadol showing the greatest increment. Isobolographic analysis of this combination revealed synergistic effects. Specifically, the combination index was γ=0.4 (<1). Combinations of pregabalin with duloxetine and venlafaxine demonstrated additive (γ=0.9) and antagonistic effects (γ=2.0), respectively. Conclusion: This study demonstrated that combination of pregabalin with tramadol has synergistic antiallodynic effects, while that with duloxetine has additive effects. Moreover, pregabalin combined with venlafaxine was potentially antagonistic. Pregabalin combined with tramadol may serve as a promising drug combination for the effective management of neuropathic pain.

Evaluating the Relationship Between Acute Pain Perception and Gut Microbiota Among Female University Students in Japan: A Prospective Cohort Study.

The gut microbiota (GM) plays an important role in gut-brain communication, and the 'gut-brain axis' has attracted much attention as a factor influencing human host health. We previously reported that pain perception may be associated with GM composition in males. The aim of this study was to investigate the relationship between GM composition and pain perception among 42 healthy female university students in Japan. Pain perception was evaluated by pressure pain threshold (PPT), current perception threshold (CPT), temporal summation of pain (TSP), conditioned pain modulation (CPM), and a questionnaire on psychological state. CPT was stimulated at 5, 250, and 2,000 Hz, which reflected the thresholds of the C, Aδ, and Aß fibers, respectively. Also, GM composition was estimated using 16S rRNA analysis. The lower alpha diversity was associated with, the lower PPT (rs = 0.330, P < 0.05) and CPT of 2000 Hz (re = 0.339, P < 0.05). Furthermore, alpha diversity was identified as an explanatory variable for PPT (ß = 0.424, P < 0.01) and TSP (ß = -0.317, P < 0.05), alpha diversity and state anxiety for CPT of 2000 Hz (ß = 0.321, P < 0.05), and state anxiety for CPT of 250 Hz (ß = 0.320, P < 0.05). However, there was no relationship between the rate of major phylum and pain perception.

Possible Repositioning of an Oral Anti-Osteoporotic Drug, Ipriflavone, for Treatment of Inflammatory Arthritis via Inhibitory Activity of KIAA1199, a Novel Potent Hyaluronidase.

KIAA1199 has a strong hyaluronidase activity in inflammatory arthritis. This study aimed to identify a drug that could reduce KIAA1199 activity and clarify its effects on inflammatory arthritis. Rat chondrosarcoma (RCS) cells were strongly stained with Alcian blue (AB). Its stainability was reduced in RCS cells, which were over-expressed with the KIAA1199 gene (RCS-KIAA). We screened the drugs that restore the AB stainability in RCS-KIAA. The effects of the drug were evaluated by particle exclusion assay, HA ELISA, RT-PCR, and Western blotting. We further evaluated the HA accumulation and the MMP1 and three expressions in fibroblast-like synoviocytes (FLS). In vivo, the effects of the drug on symptoms and serum concentration of HA in a collagen-induced arthritis mouse were evaluated. Ipriflavone was identified to restore AB stainability at 23%. Extracellular matrix formation was significantly increased in a dose-dependent manner (p = 0.006). Ipriflavone increased the HA accumulation and suppressed the MMP1 and MMP3 expression on TNF-α stimulated FLS. In vivo, Ipriflavone significantly improved the symptoms and reduced the serum concentrations of HA. Conclusions: We identified Ipriflavone, which has inhibitory effects on KIAA1199 activity. Ipriflavone may be a therapeutic candidate based on its reduction of KIAA1199 activity in inflammatory arthritis.

Features and methods to discriminate between mechanism-based categories of pain experienced in the musculoskeletal system: a Delphi expert consensus study.

ABSTRACT: Classification of musculoskeletal pain based on underlying pain mechanisms (nociceptive, neuropathic, and nociplastic pain) is challenging. In the absence of a gold standard, verification of features that could aid in discrimination between these mechanisms in clinical practice and research depends on expert consensus. This Delphi expert consensus study aimed to: (1) identify features and assessment findings that are unique to a pain mechanism category or shared between no more than 2 categories and (2) develop a ranked list of candidate features that could potentially discriminate between pain mechanisms. A group of international experts were recruited based on their expertise in the field of pain. The Delphi process involved 2 rounds: round 1 assessed expert opinion on features that are unique to a pain mechanism category or shared between 2 (based on a 40% agreement threshold); and round 2 reviewed features that failed to reach consensus, evaluated additional features, and considered wording changes. Forty-nine international experts representing a wide range of disciplines participated. Consensus was reached for 196 of 292 features presented to the panel (clinical examination-134 features, quantitative sensory testing-34, imaging and diagnostic testing-14, and pain-type questionnaires-14). From the 196 features, consensus was reached for 76 features as unique to nociceptive (17), neuropathic (37), or nociplastic (22) pain mechanisms and 120 features as shared between pairs of pain mechanism categories (78 for neuropathic and nociplastic pain). This consensus study generated a list of potential candidate features that are likely to aid in discrimination between types of musculoskeletal pain.

A large-scale database study for the prescription status of a new voltage-gated Ca2+ channel α2δ ligand, mirogabalin, in Japan.

BACKGROUND: A new voltage-gated Ca2+ channel α2δ ligand, mirogabalin, was first approved for treating peripheral neuropathic pain in Japan in 2019. This is the first report on the prescription status of mirogabalin using a large-scale prescription database. RESEARCH DESIGN AND METHODS: The authors analyzed the prescription data of 12,924 patients prescribed mirogabalin between 1 June and 31 August 2020. The endpoints were the number of patients prescribed, prescription days, prescription doses, dose changes, co-prescription patterns, medication possession ratio (MPR), and treatment discontinuation rates (TDRs). RESULTS: Mirogabalin was newly prescribed to 7,914 patients in the 3-month study period. Most patients were prescribed mirogabalin at about 10 mg/day during the study period, and 30.9% of patients were prescribed ≥ 20 mg/day on Day 90 after the first prescription. The most frequently prescribed concomitant drug was celecoxib. The MPR (80 to 110%) was 86.2%, indicating good treatment adherence. The cumulative TDRs during ≤ 7 Days, Days 31-60, and 61-90 were 14.0%, 70.0%, and 77.9%, respectively. CONCLUSIONS: Mirogabalin was prescribed to a considerable number of patients. These results may be useful for optimizing mirogabalin use for patients with peripheral neuropathic pain in daily clinical practice. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000042592.

"But it feels swollen!": the frequency and clinical characteristics of people with knee osteoarthritis who report subjective knee swelling in the absence of objective swelling.

INTRODUCTION: There are complex interactions between pain and perceptions of the painful body part in musculoskeletal disorders, and disruption of various body representations in people with chronic pain. OBJECTIVES: The purpose of this study was to investigate how frequently people with knee osteoarthritis (OA) complain of swelling without objective evidence of swelling, and describe the clinical characteristics of this population. METHODS: Forty-six people with knee OA (68.1 ± 8.8 years) participated in this cross-sectional study. Subjective and objective swelling was evaluated by knee-specific body perception questionnaire and ultrasonography, respectively. Pain intensity, disability, pain-related beliefs, 2-point discrimination threshold, and quadriceps muscle strength were also evaluated. RESULTS: Approximately 1/3 of participants (n = 15) had subjective feelings of knee swelling in the absence of objective swelling (S only). Fifteen participants had both subjective and objective knee swelling (S + O group) and 16 had neither subjective nor objective knee swelling (No S/O group). Participants in the S only group had similar pain or disability as those in the S + O group but had more severe pain or disability than those with in the No S/O group. Those in the S only group also had larger 2-point discrimination distance threshold at the medial knee (impaired tactile acuity) than those in the S + O group and had more dysfunctional pain catastrophizing and pain-related self-efficacy than both other groups. CONCLUSION: Our results suggest that about 30% of people with knee OA perceive swelling of the knee in the absence of any objective swelling and that this is accompanied by severe pain and functional disability. Considering altered body image of the knee may reveal relevant treatment-based subgroups in people with knee OA.

A novel mice model of acute flares in osteoarthritis elicited by intra-articular injection of cultured mast cells.

PURPOSE: Mast cells are multifunctional in osteoarthritis (OA), and infiltration of activated mast cells likely contributes to disease severity and progression. However, the detailed mechanisms of action are unclear. The purpose of this study was to elucidate the role of mast cell infiltration in OA at histological level using a new mice model and to investigate pharmacological inhibitory effects of existing mast cell stabilizers in this model. METHODS: Mice were injected intra-articularly with monosodium iodoacetate (MIA 0.5 mg) or PBS on day 0, and PBS, with or without mast cells (MC: 1 × 106 cells) on day 14. They were divided into four groups: OA flare (MIA + MC), OA (MIA + PBS), MC non-OA (PBS + MC), and PBS non-OA (PBS + PBS). In OA flare, the MC stabilizer drug (tranilast: 400 mg/kg/day) or PBS was administered intraperitoneally from days 15 to 21. RESULTS: Histologically, modified Mankin score of the OA flare was significantly higher than that of OA (7.0 [1.8] vs. 3.3 [1.3], P < 0.05), and a larger number of mast cells was observed in OA flare than in OA (34.5 [6.3]/mm2 vs. 27.2 [2.3]/mm2, P < 0.05) on day 22. OA flare also showed acute exacerbation of pain and increased gene expression of pro-inflammatory cytokines and aggrecanase compared with OA. Administration of tranilast to OA flare-up provoked significant improvements in term of histological changes, pain, and gene expression at day 22. CONCLUSION: Our novel model possibly mimics OA flare conditions, which may open a new strategy of disease-modifying treatment for OA, focused on controlling the multiple functions of mast cells.

Efficacy and safety of magnetic resonance-guided focused ultrasound treatment for refractory chronic pain of medial knee osteoarthritis.

OBJECTIVE: To elucidate the efficacy and safety of MRgFUS in the treatment for refractory pain derived from medial knee OA. METHODS: Twenty patients with medial knee OA eligible for total knee arthroplasty were included in this prospective, non-controlled study (UMIN000010193). MRgFUS treatment was provided at the site of most severe tenderness around the medial femorotibial joint of each patient under real-time monitoring of temperature. The goal temperature of the targeted bone surface was 55 °C. Numerical rating scale (NRS) worst pain scores, Western Ontario and McMaster Universities osteoarthritis index (WOMAC) scores, EuroQol 5 dimensions index (EQ-5D) scores and pressure pain threshold (PPT) were evaluated before treatment (baseline) and at 1 week and 1, 3, 6, and 12 months post-treatment, respectively. Complications and adverse events were also assessed clinically and radiographically. RESULTS: Treatment response (a 50% or greater decrease in NRS score) was seen in 14 patients (14/19, 73.7%) at 12 months post-treatment. Mean NRS score rapidly decreased at 1 month after treatment and continued to decline through the following 12 months. At final follow-up, mean NRS score was 3.2 ± 1.9, significantly lower than at baseline (p = 0.0013). Mean WOMAC and EQ-5D scores also improved significantly from 1 month after treatment. Fifteen patients showed significant sustained increases in PPTs at the sites of most severe tenderness. No serious adverse events were observed during and after treatment. CONCLUSIONS: MRgFUS treatments were effective not only for managing refractory pain, but also for improving physical functions without adverse events in elderly patients with medial knee OA.

The Cut-off Value of Physical Activity for Undergoing Total Knee Arthroplasty in Patients with Knee Osteoarthritis.

BACKGROUND: We aimed to determine a cut-off value for physical activity (PA), measured using an accelerometer, between patients with knee osteoarthritis (OA) who decided to undergo total knee arthroplasty (TKA) and those who continued conservative treatment. METHODS: Forty-two participants were assigned to either a TKA group or a non-TKA group (21 per group). They were instructed to wear an accelerometer throughout the day. Average daily steps (steps/day), average daily time of light PA (LPA) (min/day), and average daily time of moderate-to-vigorous PA (MVPA) (min/day) were measured for seven days. Variables between the two groups were compared using univariate analyses, and then a stepwise logistic regression was conducted to determine which variables best correlated with undergoing TKA. The PA cut-offs were analysed using the receiver operating characteristic curve. RESULTS: Pain severity (p = 0.002), KL grade (p = 0.001), and MVPA (p = 0.012) differed significantly between the groups. The most useful cut-off value was 5.84 (min/day) for MVPA (AUC = 0.773), although only pain severity and KL grade were found to be significant contributors to undergoing TKA. CONCLUSIONS: Our results revealed there was a significant decrease in PA levels (MVPA cut-off, 5-6 min/day) in the TKA group compared with the non-TKA group.

Bone marrow derived mast cells injected into the osteoarthritic knee joints of mice induced by sodium monoiodoacetate enhanced spontaneous pain through activation of PAR2 and action of extracellular ATP.

Conditions that resemble osteoarthritis (OA) were produced by injection of sodium monoiodoacetate (MIA) into the knee joints of mice. Bone marrow derived mast cells (BMMCs) injected into the OA knee joints enhanced spontaneous pain. Since no spontaneous pain was observed when BMMCs were injected into the knee joints of control mice that had not been treated with MIA, BMMCs should be activated within the OA knee joints and release some pain-inducible factors. Protease activated receptor-2 (PAR2) antagonist (FSLLRY-NH2) almost abolished the pain-enhancing effects of BMMCs injected into the OA knee joints, suggesting that tryptase, a mast cell protease that is capable of activating PAR2, should be released from the injected BMMCs and enhance pain through activation of PAR2. When PAR2 agonist (SLIGKV-NH2) instead of BMMCs was injected into the OA knee joints, it was also enhanced pain. Apyrase, an ATP degrading enzyme, injected into the OA knee joints before BMMCs suppressed the pain enhanced by BMMCs. We showed that purinoceptors (P2X4 and P2X7) were expressed in BMMCs and that extracellular ATP stimulated the release of tryptase from BMMCs. These observations suggest that ATP may stimulate degranulation of BMMCs and thereby enhanced pain. BMMCs injected into the OA knee joints stimulated expression of IL-1ß, IL-6, TNF-α, CCL2, and MMP9 genes in the infrapatellar fat pads, and PAR2 antagonist suppressed the stimulatory effects of BMMCs. Our study suggests that intermittent pain frequently observed in OA knee joints may be due, at least partly, to mast cells through activation of PAR2 and action of ATP, and that intraarticular injection of BMMCs into the OA knee joints may provide a useful experimental system for investigating molecular mechanisms by which pain is induced in OA knee joints.

Effects of a 12-week workplace counseling program on physical activity and low back pain: A pilot randomized controlled study.

BACKGROUND: Physical activity (PA) is essential in the management and rehabilitation of low back pain (LBP). However, it is not clear that PA interventions in the workplace can improve LBP. OBJECTIVE: This study aimed to investigate the effects of workplace counseling on PA and LBP among workers. METHODS: We recruited 37 people with 12 weeks of LBP who worked in a manufacturing company in Aichi, Japan. Participants were randomly assigned to the intervention (n= 20) or control group (n= 17). All participants of both groups were affixed with waist-worn accelerometers to monitor PA. The intervention group also received a program of face-to-face counseling with a physical therapist or nurse once a week for 12 weeks to reassure and encourage participants to maintain a high level of PA. PA and LBP severity were assessed at baseline, 3 and 6 months. RESULTS: PA was significantly higher in the intervention group than in the control group at 3 and 6 months. In the intervention group, PA significantly increased at 3 and 6 months from baseline, and LBP severity at 6 months improved significantly from baseline. CONCLUSIONS: Our data suggest that workplace PA intervention can increase PA and improve LBP among workers.

Changes in visual attentional behavior in complex regional pain syndrome: A preliminary study.

PURPOSE: The purpose of the present study was to investigate the visual attentional behavior towards a pain-affected area and face/body images using eye tracking in complex regional pain syndrome (CRPS) patients. Moreover, we investigated the relationship between visual attentional behavior and clinical symptoms. PATIENTS AND METHODS: Eight female patients with CRPS type 1 in their upper limbs and 8 healthy adult women participated in this study. First, the participants were asked to watch videoclips in a relaxed manner (Videoclip 1 featured young adults who introduced themselves; Videoclip 2 featured young adults touching the hand of the other person sitting across from them with their hand.) Eye movement data were tracked with eye-tracking glasses. RESULTS: In video clip 1, the fixation duration (FD) and fixation count (FC) on faces tended to be lower in CRPS patients than in healthy controls. This tendency was found in patients with low body cognitive distortions. In video clip 2, CRPS patients displayed significantly lower FD and FC on the unaffected hand while watching a video of the unaffected hand being touched compared with healthy controls. Moreover, patients with low body cognitive distortion displayed significantly longer FD on the affected hand. CONCLUSION: Some CRPS patients differed in visual attentional behavior toward the face and body compared with healthy controls. In addition, our findings suggest that patients with lower body cognitive distortion may have a high visual attention for the affected hand, while patients with higher distortion may be neglecting the affected hand.