Osteosarcoma (OS) is a prevalent primary malignant bone tumor, and many patients with OS experience severe pain. Bisphosphonates, such as zoledronic acid (ZA), reduce bone resorption and pain. However, further clinical pharmacological usefulness for ZA in the pathology of OS has not yet been elucidated. In this study, we generated a mouse model of bone cancer pain by transplanting mouse OS cells into the femoral bone marrow cavity of mice and examined the effects of ZA treatment on persistent pain and survival under OS conditions. We found that in vivo treatment with ZA significantly relieved pain and extended the survival of mice bearing OS cells. Using human iPS cell–derived sensory neurons and human OS cells, in vitro treatment of the supernatant obtained from activated sensory neurons with human OS cells significantly suppressed the anti–cancer effect of cisplatin. Moreover, the supernatant obtained from activated sensory neurons dramatically increased NF–κB–related tumor–promoting signals in OS cells and the enhanced cell migration ability of OS cells. Under these conditions, the suppression of cisplatin–induced anti–cancer effects, the increased expression of NF–κB–related tumor–promoting factors and the increased migration activity of OS cells were inhibited by the co–treatment with ZA. These findings suggest that ZA may suppress severe pain associated with OS progression and induce significant recovery from OS–induced cancer aggravation. Furthermore, the combination of ZA with anti–cancer drugs may pave the way for new therapies against osteosarcoma.

Platelet–derived growth factor receptors (PDGFRs; PDGFRα and PDGFRβ) play an important role in wound–healing after tissue injury. They are expressed in the peripheral tissues and nervous system. However, their role within the peripheral nervous system is not fully understood. In this study, we investigated the expression of PDGFRs in primary afferents and its role in pain perception in rats. In situ hybridization histochemistry (ISHH) revealed that PDGFRα mRNA was expressed in approximately 15% of small–, medium–, and large–sized dorsal root ganglion (DRG) neurons. PDGFRβ mRNAs were expressed in approximately 30% of small–sized DRG neurons, suggesting that PDGFRβ was localized in a subpopulation of nociceptors. Double labeling analysis of ISHH with immunohistochemistry showed that PDGFRβ mRNAs were relatively colocalized with P2X3–positive neurons. In behavioral tests, intraplantar injection of both PDGF–AA and PDGF–BB, ligands for PDGFRα and PDGFRβ, respectively, did not alter withdrawal threshold or latencies to mechanical and thermal stimulation compared to that in vehicle–treated rats and did not evoke spontaneous nocifensive behaviors. Interestingly, PDGF–BB, but not PDGF–AA, increased nocifensive behaviors and c–Fos expression in the superficial dorsal horn induced by αβ–Me–ATP, a P2X3 agonist. Further, pretreatment with PDGF–BB enhanced Ca²⁺ influx and the number of responsive DRG neurons in response to αβ–Me–ATP. These results suggests that PDGF–BB sensitizes P2X3 receptors via PDGFRβ in primary afferents, leading to nocifensive behaviors.

The TSK–11, a short version of the Tampa Scale for Kinesiophobia, is commonly used to assess fear of movement and (re)injury in patients with musculoskeletal pain. The two–factor model of the TSK–11, consisting of activity avoidance (TSK–AA) and somatic focus (TSK–SF), is known for its high consistency and reliability. However, the subscales of the Japanese version of the TSK–11 have not been validated, and the differences between them are unclear. The aim of our study is to validate the TSK–J11 subscales in Japanese, investigate their associations with pain and pain–related measures, and identify differences between the subscales using data from our prior studies.

Data were collected from 349 participants in 2018 and 216 in 2020. The measures included the TSK–AA and TSK–SF, pain intensity, sleep disorders, the multidimensional assessment of interoceptive awareness, EuroQol 5 Dimensions, and presenteeism. Reliability was assessed using Cronbach’s alpha, and validity was determined through the confirmatory factor analysis. Correlation analyses were performed to explore the relationships between the subscales and the pain–related variables.

Cronbach’s alpha for the TSK–AA and TSK–SF was 0.72 and 0.71. The TSK–SF was significantly associated with pain intensity, and both TSK–AA and TSK–SF were significantly associated with sleep disorders, lower interoceptive awareness, reduced quality of life, and increased presenteeism.

TSK–AA and TSK–SF were reliable and valid in the Japanese population, exhibiting consistent associations with several pain–related measures. TSK–SF scores were increased in people with pain, while TSK–AA scores were not.

The effects of exercise–induced hypoalgesia (EIH) and the barriers to its effectiveness in elderly individuals aged over 70 years remain unexplored. This study aimed to investigate whether reduced EIH effects are associated with a decline in endogenous pain inhibitory system function and skeletal muscle mass, a key indicator of sarcopenia, in the elderly. Thirty–four individuals aged over 70 years participated in the study. Demographic data, pain intensity (numerical rating scale: NRS), pressure pain threshold (PPT) at the affected hip joint and forearm, conditioned pain modulation (CPM), skeletal muscle mass index (SMI), and sarcopenia status, as defined by the Asian Working Group for Sarcopenia, were assessed. Participants performed 15 minutes of aerobic exercise using a stationary cycle ergometer. EIH effects were defined as the change in NRS and PPT before and immediately after exercise. PPT significantly increased at all measured sites following exercise, but the changes, ranging from 5.7% to 9.8%, were not clinically meaningful. Additionally, NRS showed no significant change. EIH effects, reflected by changes in PPT, were positively correlated with CPM and SMI. These findings suggest that EIH effects are impaired in individuals over 70 years, with a dysfunctional endogenous pain inhibitory system and reduced skeletal muscle mass identified as barrier factors. Exercise interventions targeting sarcopenia and pain modulation may improve pain management strategies for this population.

Introduction: Women often experience cyclical pain outside their menstrual phase, suggesting that hormonal fluctuations influence pain perception. Additionally, the pain modulation system, assessed using pressure pain thresholds (PPT) and conditioned pain modulation (CPM), may contribute to cyclical pain. This study investigated the characteristics of cyclical pain in young women during hormonal fluctuations, excluding menstrual pain, and explored whether pain was more closely associated with menstrual–related symptoms (e.g., autonomic dysregulation, water retention, emotional distress) or dysfunction in pain modulation.

Methods: This cross–sectional study included 40 healthy women with regular menstrual cycles (mean age: 21.3 ± 4.8; range: 18–30). Participants completed three sessions during the early follicular (EF [E/P–]), the late follicular (LF [E+]), and the mid–luteal (ML [E/P+]) phases, when estrogen and progesterone levels significantly fluctuated. Pain– and menstruation–related symptoms were assessed using the menstrual distress questionnaire (MDQ). Pain modulation was evaluated using the PPT and CPM measurements.

Results: The MDQ total pain scores were significantly higher during the E/P+ phase compared to the E/P– and the E+ phases. The subcategory analysis revealed significant positive correlations between pain symptoms and autonomic reactions, water retention, impaired concentration, and negative affect during the E/P+ phase. No significant correlations were found between pain symptoms and the PPT or CPM across all phases.

Discussion: Cyclical pain intensified during the E/P+ phase, when estrogen and progesterone levels fluctuated. The relationship between pain symptoms and menstruation–related factors suggests that hormonal fluctuations, rather than dysfunction in pain modulation, predominantly drive cyclical pain.

This study aimed to investigate the relationship between women’s health issues (WHI) and pain symptoms among Japanese female workers, influencing health–related quality of life (HRQOL) and work productivity. A population–based cross–sectional online survey targeting Japanese female workers aged 20–69 years was conducted in July 2023. A total of 3,564 participants with 2,999 valid responses were recorded. The prevalence of pain was 49.8%, with comorbidity rate of 29.9% for pain and WHI. The key risk factors included menstrual–related symptoms, menopausal symptoms, and pelvic floor disorders. The number of pain sites was greater in women experiencing both pain and WHI than in those experiencing pain alone. Women with menstrual, menopausal, and pelvic floor disorders reported more severe pain in multiple areas of the body, along with elevated levels of occupational stress, reduced HRQOL, increased psychological distress, and markedly higher levels of presenteeism than those with pain alone. Overall, this study highlights the coexistence of WHI, such as menstrual, menopausal, and pelvic floor disorders, with pain in female workers, which potentially exacerbates pain severity, lowers HRQOL, and negatively impacts work productivity. Therefore, addressing the WHI in female workers experiencing pain is crucial for alleviating the symptoms, enhancing HRQOL, and improving workplace productivity.

Background: The adverse events (AEs) of tramadol hydrochloride biphasic immediate–release ⁄ extended–release tablet (tramadol IR/ER tablet) in patients with chronic pain related to commonly examined spine diseases have not been extensively studied. Purpose: To clarify the safety and continuity of tramadol IR/ER tablet for chronic pain associated with spine diseases. Methods: This was a retrospective observational study conducted at 9 institutions. We surveyed the records of patients with chronic pain related to spine diseases who were prescribed twice–daily oral tramadol IR/ER tablets. We evaluated AEs associated with tramadol IR/ER tablets and the continuation rate of tramadol IR/ER tablets at 4 weeks. Results: In total, 139 patients met the study criteria. One hundred thirty patients (93.5%) continued to take tramadol IR/ER tablets for 4 weeks. AEs were observed in 39 patients (28.1%) and included constipation in 18 patients (12.9%), nausea in 10 patients (7.2%), somnolence in 8 patients (5.8%), and dizziness in 4 patients (2.9%). Among 41 patients who switched from other tramadol formulations to tramadol IR/ER tablets, the daily dose of tramadol was increased, yet the incidence of AEs was equivalent (9 patients, 22.0%), with no reported occurrences of nausea. Conclusions: The overall incidence of AEs after administration of tramadol IR/ER tablets was 28.1%, and the continuation rate after 4 weeks was 93.5%. For patients with chronic pain related to spine diseases, switching to tramadol IR/ER tablets may allow for safe continuation of pain treatment.

Objective: Post–stroke shoulder pain (PSSP) is a common complication of stroke, with complex mechanisms involving structural and neurological factors. This study aimed to investigate the role of pain sensitization—specifically peripheral sensitization and dysfunction of the endogenous pain inhibitory system— in patients with PSSP. Methods: Post–stroke patients with and without PSSP were recruited. Pain sensitization was assessed using quantitative sensory testing, including pressure pain threshold (PPT) at the shoulder joint and conditioned pain modulation (CPM). Logistic regression analysis was used to analyze factors associated with PSSP, adjusting for age and sex. Receiver operating characteristic analysis was performed to determine cut–off values for PPT and CPM. The prevalence rate of PSSP was then calculated among patients with lower PPT, diminished CPM, or both. Results: Lower PPT and diminished CPM were independently associated with PSSP. Subgroup analysis revealed that the prevalence of PSSP was 60% among patients with either lower PPT or diminished CPM alone, and 100% among those with both. Conclusion: This study demonstrates that both peripheral and central sensitization are associated with PSSP. These findings suggest that altered pain processing, alongside structural impairments, contributes to its pathophysiology. Incorporating pain sensitization assessment into clinical practice may offer novel insights for the prevention and management of PSSP.

Background: Noxious stimulation caused by abdominal para–aortic lymph node (PAN) swelling sometimes causes intractable back pain. It is speculated that splanchnic nerve neurolysis (SNN) blocks the transmission of this noxious stimulus at the splanchnic nerve level and exerts an analgesic effect. Case presentation: The patient was female in her 50s who underwent a radical surgery for rectal cancer, but lumbar spinal metastasis appeared two years later, and pain relief was achieved with opioids and radiotherapy. However, four more years later, her back pain gradually worsened, and then CT imaging revealed PAN metastases which were thought to be the cause of this backache. When SNN was performed and the opioid was switched to methadone, the required amount of opioid and drug cost were reduced by more than one tenth. Conclusion: SNN combined with switching opioid to methadone may be a treatment of choice for intractable back pain due to PAN swelling.

Photobiomodulation (PBM) has gained significant attention as a non–invasive and effective treatment for pain. However, the precise mechanisms and quantitative assessment of PBM’s effects remain unclear. This study aimed to develop an in vivo electrophysiological evaluation system to quantitatively measure the effects of PBM, using the firing frequency of neurons in the spinal dorsal horn as an indicator. An 808 nm semiconductor laser was used to irradiate the sciatic nerve in rats, and the neuronal responses evoked by the von Frey filaments were measured. Our findings revealed that PBM significantly suppressed the firing frequency evoked by a 15.0 g von Frey filament, with effects persisting up to 180 min post–irradiation, whereas no changes were observed in the sham group. Additionally, PBM reduced neuronal responses to varying von Frey filament intensities, suggesting a selective effect on noxious stimuli. This evaluation system offers a robust and quantitative method for assessing the effects of PBM, and provides valuable insights into its mechanisms. This tool has the potential to enhance clinical outcomes and improve the chronic pain by providing a precise and reliable means of assessing the efficacy of PBM.

Balneotherapy has been used as complementary therapy for many diseases. In Japan, bath salts from the Myoban Spa, which contains a high concentration of aluminum potassium sulfate, have been approved for its analgesic effects. However, the molecular mechanisms underlying the analgesic effects of these ions have not been reported. We focused on TRPV1 and TRPA1, which are known pain sensors. In this study, we evaluated the inhibitory effects of Myoban bath salts and their components, aluminum potassium sulfate and iron sulfate, on TRPV1 and TRPA1 activity using electrophysiological experiments. We found not only bath salts, but also aluminum potassium sulfate inhibited both TRPV1 and TRPA1 activation in the acidic condition. Our study suggested that aluminum potassium sulfate is the main component responsible for the pain–reducing effect of bath salts from the Myoban Spa.

Severe zoster–associated pain and impaired quality of life (QOL) during the acute phase of onset are known risk factors for postherpetic neuralgia (PHN). Injury to the ventral ramus of the thoracic spinal nerve causes a skin rash and pain anterior to the posterior axillary line, while injury to the dorsal ramus of the thoracic spinal nerve results in symptoms posterior to the posterior axillary line. Patients with pain in both rami of the spinal nerves experience more widespread pain than those with pain only in the ventral ramus. We examined whether more widespread pain was associated with chronicity. Fifty–one patients with pain in both rami of the spinal nerves were compared retrospectively with 31 patients who had pain in the ventral ramus only. There was no significant difference between the two groups regarding chronicity.

Physical activity and exercise not only improve physical fitness, mental health, and quality of life but also play an important role in preventing and improving several chronic diseases, including chronic pain. Exercise–induced hypoalgesia (EIH) is a notable phenomenon underlying pain relief, which has been demonstrated in healthy adults, chronic pain patients, and animals. In this mini–review, we describe the possible roles of anti–inflammatory cytokines, serotonin, endogenous opioids, and myokines in developing the EIH effect. We consider three brain systems involved in producing EIH: the reward, the medial part of the basal amygdala–nucleus accumbens, and the ventral hippocampus–basolateral amygdala systems constituting the mesocorticolimbic system. Furthermore, we discuss how orexin neurons located in the lateral hypothalamus may assist in triggering this system. Notably, the EIH effect was not observed in mice that were subjected to ultrahigh–intensity treadmill running and exhibited anxiety, fear, and aversion behaviors, suggesting that negative emotions hinder EIH development. Thus, the effects of exercise are not only dependent on the intensity, duration, and frequency of exercise but also strongly influenced by emotions, which may be produced by or during the exercise. In conclusion, the present review supports the development of more effective pain relief strategies for both chronic pain patients and healthy people.