Frontiers in pain research (Lausanne, Switzerland)最新文献

Background: Toothache of cardiac origin is a rare but significant form of referred pain originating from cardiac pathology such as angina pectoris. Although jaw and throat discomfort are known referred pain sites, toothache alone is an uncommon presentation. Misdiagnosis often leads to unnecessary dental interventions and delays in appropriate cardiac treatment, highlighting the need for greater awareness among both dentists and internists.

Case presentation: A 76-year-old woman presented with persistent pain in the gingiva around teeth #33 and #34, accompanied by sharp chest discomfort which would subside in about 5-6 min. Extensive dental examinations, including extractions, failed to resolve her symptoms. Initial cardiac evaluations-electrocardiogram, Holter monitoring, echocardiography, and chest computed tomography-were unremarkable. Consequently, she was diagnosed with atypical odontalgia and prescribed antidepressants, but these proved ineffective. However, over several months, the toothache worsened upon exertion, accompanied by chest pain unresponsive to standard analgesics. A specialized cardiac imaging center finally detected severe stenosis (90%-99%) of the left anterior descending artery and Right Coronary Artery, as well as a left ventricular thrombus. Coronary angiography confirmed unstable angina, and the patient underwent a Dor procedure to remove the thrombus alongside coronary artery bypass grafting. Following surgery, her toothache and chest pain completely resolved.

Conclusion: This case features a protracted course from symptom onset to definitive treatment. In older patients reporting persistent tooth or gingival pain with intermittent chest discomfort-especially when symptoms are exertional and dental findings are negative-clinicians should consider a cardiac origin and expedite cardiologic imaging to avert hazardous delays. Systematic accumulation of cases and cross-disciplinary research are essential to establish actionable diagnostic guidance and move beyond anecdotal evidence.

Introduction: Biological aging and sex interact to shape systemic metabolism, yet their role in chronic pain resolution remains unexplored. We hypothesized that metabolic resilience-the ability to flexibly switch fuel sources and maintain energy homeostasis-rules successful recovery from nerve injury in a sex-dependent manner during aging.

Methods: In 12-month-old male and female mice, corresponding to the perimenopausal phase in females and the onset of hormonal decline in both sexes, we induced sciatic nerve chronic constriction injury and performed multi-omics profiling during Wallerian degeneration, a phase known to trigger long-term neurobiological remodeling.

Results: Aging females exhibited early activation of fatty acid oxidation, increased resting energy expenditure, upregulation of mitochondrial redox enzymes and circulating progesterone and corticosterone. Proteomic and metabolomic analysis revealed pentose phosphate pathway enrichment and gluconeogenesis, supporting redox balance and metabolic flexibility. Conversely, males displayed persistent glycolytic reliance, long-chain acylcarnitine accumulation, suppression of adiponectin and PPARγ, indicating metabolic inflexibility. Longitudinal behavioral analysis revealed that aging females recovered earlier and more fully than aging males, reversing the pattern previously shown in our adult mouse study, where females developed persistent pain and males recovered rapidly.

Discussion: These patterns highlight a non-linear, sex-specific interaction between biological aging and injury response, where hormonal decline reprograms the metabolic trajectory and reshapes pain outcomes. Metabolic resilience governs sex-specific recovery following nerve injury by directing early systemic adaptations that precede and predict long-term pain trajectories. These results define mechanistically anchored, sex- and age-specific biomarkers, and propose preclinical targets for timely, personalized interventions in age-associated neuropathic pain.

Objective: To investigate the trajectories of acute postsurgical pain (APSP) following total knee arthroplasty (TKA), its influencing factors, and its impact on knee function recovery at 3 months postoperatively.

Methods: A convenience sample of patients undergoing TKA at a tertiary hospital in Panzhihua City between June 2024 and February 2025 was recruited. Preoperatively (T0), baseline data including demographics, anxiety, depression, family care index, pain level, and pain catastrophizing were collected. Postoperative pain levels were assessed on days 1 (T1), 2 (T2), 3 (T3), and 5 (T4), while joint functional outcomes were evaluated at 3 months postoperatively (T5). Growth mixture modeling (GMM) was used to identify distinct APSP trajectory subgroups, logistic regression was used to analyze influencing factors, and multiple linear regression was used to examine the association between APSP trajectories and joint functional outcomes.

Results: Among 227 enrolled patients, two APSP trajectory subgroups were identified: a moderate-high persistent pain group (45.16%) and a moderate-low rapid relief group (54.84%). Logistic regression revealed that age, preoperative pain level, pain catastrophizing, and family care index significantly influenced APSP trajectories. APSP trajectory membership positively predicted 3-month knee joint functional outcomes.

Conclusion: TKA patients exhibit two distinct APSP trajectory patterns, which serve as significant predictors of joint functional outcomes. Clinicians should identify the persistent pain subgroup and implement enhanced multimodal analgesia to prevent chronic postsurgical pain and optimize rehabilitation outcomes.

The prevalence of acute pain has grown substantially over the past two decades, due primarily to more surgeries, an aging population, and the rapid growth in the prevalence of metabolic disease. Although opioids are often the only effective treatment for many types of acute pain, especially severe acute pain, their use, even over a short period of time, comes with substantial risks of dependence, misuse, and diversion. Moreover, a large fraction of the patients currently suffering from opioid use disorder and those dying from opioid overdoses had their first exposure as pain patients. Conversely, refraining from using opioids in cases where other treatment options are ineffective creates a different set of risks. This potential undertreatment of acute pain, especially severe acute pain, increases the risk of acute pain transitioning to chronic pain. The use of opioids to treat acute pain and the ineffective treatment of acute pain have important implications for population health and health care costs.

Background: Bone cancer pain is a common complication of advanced malignant tumors.Chemotherapeutic drugs, regardless of their origin or type, are often associated with various adverse effects such as gastrointestinal toxicity, immune suppression, and acquired drug resistance, which can compromise patients' quality of life and treatment compliance. Electroacupuncture, known for its safety and analgesic effects, has been increasingly studied in bone cancer pain but the underlying mechanism is not fully understood.

Objective: To explore the mechanism of electroacupuncture in rats with bone cancer pain.

Methods: Forty-eight SD rats were divided into four groups: blank control, sham electroacupuncture, electroacupuncture-1, and electroacupuncture-2, with 12 rats in each group. Except the control group, rats were inoculated with cancer cells in the left tibia to induce bone cancer pain. The electroacupuncture groups received interventions starting on the 6th day after modeling. Mechanical pain sensitivity (PWT) and thermal pain sensitivity (PWL) were assessed, and the expression of phosphorylated glycogen synthase kinase-3 (p-GSK-3) and glial fibrillary acidic protein (GFAP) in the spinal cord were analyzed. HE staining was used to observe tibial pathological changes.

Results: From the 6th day, PWT and PWL were significantly reduced in the control group compared to the sham group (P < 0.05). Electroacupuncture-1 significantly increased PWT and PWL compared to the sham group (P < 0.05), while no significant changes were observed in electroacupuncture-2 compared to the control. On day 12, spinal p-GSK-3 levels were significantly lower and GFAP levels significantly higher in the model and control groups compared to the electroacupuncture-1 group (P < 0.05). The electroacupuncture-2 group showed no significant changes. Inflammatory cytokines IL-1, IL-6, and TNF-α were significantly elevated in the model group compared to the control (P < 0.05), but significantly reduced in the electroacupuncture-1 group (P < 0.05). HE staining showed cancer cell infiltration and bone tissue damage in the sham and electroacupuncture groups.

Conclusion: Electroacupuncture significantly reduced the pain threshold in rats with bone cancer pain. This effect is likely due to the down-regulation of GSK-3 activity, inhibition of astrocyte activation, and reduction in inflammatory responses.

Background: While prior studies suggest an increased risk of stroke among individuals with migraine, particularly those with migraine with aura, data on how specific migraine characteristics and comorbidities influence this risk across diverse populations remain limited. The All of Us database provides a unique opportunity to address this gap given its large sample size and inclusion of historically underrepresented groups.

Methods: A cross-sectional case-control analysis using multivariable regression models accounting for vascular risk factors and comorbidities was performed to compare the risk of stroke between individuals with and without migraine, odds ratios (OR) using a 95% confidence interval (CI) were calculated.

Results: Within the All of Us database, 31,444 individuals received a migraine diagnosis [female = 25,374/81%, male = 5,391/17%, other = 679/2%; mean (std) age = 54.9 (15.6)] and 379,283 did not have a migraine diagnosis [female = 222,104/59%, male = 149,182/39%, other = 7,997/2%; mean (SD) age = 55.9 (17.2)]. The migraine group had a greater proportion of women (81% vs. 59%), a higher proportion of white individuals (61% vs. 55%) and fewer African American individuals (15% vs. 19%). Compared to the non-migraine group, individuals with migraine had higher rates of comorbidities, including depression (46% vs. 12%), diabetes (16% vs. 7%), tobacco use (36% vs. 15%), hyperlipidemia (52% vs. 24%), hypertension (54% vs. 26%), and atrial fibrillation (3% vs. 2%).A multivariable regression model adjusted for differences between group demographics and comorbidities found that compared to those without migraine, individuals with migraine had a higher risk of overall stroke [OR 1.97, 95% CI (1.88, 2.07)], ischemic stroke [OR 1.38, 95% CI (1.24, 1.53)] and hemorrhagic stroke [OR 1.75, 95% CI (1.60, 1.92)]. Individuals with chronic migraine had a higher risk of overall stroke compared to the non-migraine group [OR 2.56, 95% CI ( 2.32, 2.84)] and compared to episodic migraine [OR 1.90, 95% CI (1.81, 2.00)]. Those with migraine with aura had a higher risk of stroke compared to individuals with migraine without aura [OR 1.33, 95% CI (1.20, 1.48)].

Conclusions: Individuals with migraine, particularly those with chronic migraine had a higher risk of stroke compared to those without migraine and compared to individuals with episodic migraine. The risk of stroke was higher in those with migraine with aura compared to those with migraine without aura even after adjusting for vascular comorbidities. Our analysis, using data from the All of Us database, confirms previous findings and suggests that while vascular comorbidities are more prevalent in those with migraine, they do not fully account for the increased risk of stroke.

Background: Pulse dosing of high frequency spinal cord stimulation at 10 kHz (10 kHz SCS) may offer comparable clinical benefits as continuous 10 kHz SCS, but extreme pulse dosing (EPD) has not been studied.

Methods: Patients using an implantable pulse generator (IPG) with 10 kHz SCS to treat chronic back or leg pain were enrolled. After baseline assessments, patients underwent "EPD titration" starting at an EPD setting of 3%. Patients who preferred the EPD tried progressively lower EPD settings (0.6%, 0.3%, 0.14%, 0.06%), each for 7-10 days, until reaching an EPD they did not prefer over that previously tried. Patients were then followed up for 3 months at their lowest preferred EPD. All study visits included assessment of adverse events and patient-reported outcomes, including the numeric rating score (NRS) for pain intensity, Patient Global Impression of Change (PGIC), Oswestry Disability Index (ODI), and the PROMIS-SF for sleep disturbance. Device charging information was uploaded from the IPG at each visit.

Results: Eighteen patients completed testing (13 M/5 F; mean age, 61 years); 14 patients (78%) reporting a preferred EPD (at any setting) to standard 10 kHz SCS. Among 18 patients, the most common lowest preferred EPD was 0.14% (28%), followed by 0.06% (22%) and 3% (17%). All post-SCS pain scores were lower than pre-SCS pain scores (median NRS, 8.5 vs. 3.0; p = .004). For overall pain, NRS values did not vary significantly across timepoints after the pre-SCS period (median range, 3.0-4.0; p > .05). Similarly, patient satisfaction, PGIC, ODI, PCS, and PROMIS-SF scores for EPD did not vary significantly from those at baseline. Daily IPG recharge times were significantly shorter using the patient's lowest preferred EPD than at baseline (median minutes, 3.0 vs. 31.8; p = .0001).

Conclusions: EPD 10 kHz SCS may offer the same pain relief and quality-of-life benefits as standard 10 kHz SCS, while reducing recharge requirements and potentially lowering the risk of therapy habituation.

Introduction: This study evaluated the effects of low-intensity muscle contraction exercise on pain sensitivity, peripheral pathology, and central sensitization in the spinal dorsal horn in a rat model of end-stage knee osteoarthritis (OA) induced by monosodium iodoacetate (MIA).

Methods: Sixty-two male Wistar rats were assigned to three groups: OA, Exercise, and Sham. The Exercise group underwent quadriceps muscle contractions induced by electrical stimulation (50 Hz, 250 µs, 2-3 mA) with a duty cycle of 1:2 (2 s On, 4 s Off) for 20 min daily, five days per week, from day 29 to day 56 post-MIA administration. Pain sensitivity was assessed by measuring knee joint pressure pain thresholds (PPT) and paw withdrawal thresholds using von Frey filaments. Histological and immunohistochemical analyses of the knee joint and spinal cord included toluidine blue staining, tartrate-resistant acid phosphatase staining, and markers for CD68, CD11c, CD206, osteoclasts, nerve growth factor (NGF), calcitonin gene-related peptide (CGRP), and phosphorylated NR1 (pNR1).

Results: Knee joint PPTs were significantly higher in the Exercise group after day 35, accompanied by reductions in CD68-, CD11c-positive cells, NGF-positive cells, CGRP-positive fibers, osteoclasts, and pNR1-positive cells, as well as an increase in CD206-positive cells, compared to the OA group.

Discussion: Despite no significant changes in cartilage or subchondral bone degeneration, these findings suggest that low-intensity muscle contraction exercise alleviates pain sensitivity by modulating peripheral pathology and central sensitization. This study highlights the potential of therapeutic exercise as a strategy for OA pain management.

Classical trigeminal neuralgia (TN) is a severe chronic pain disorder characterized by sudden, intense facial pain attacks and represents a major burden for affected individuals. Microvascular decompression (MVD) can provide pain relief, yet not all patients benefit equally. A key challenge in selecting candidates for MVD lies in the limited predictive accuracy of current diagnostics, which mainly rely on subjective pain history and structural MRI findings. Since many asymptomatic individuals show neurovascular contact on imaging, its prognostic value remains limited. Electrophysiological measures, particularly cortical oscillations, may offer more objective insights into nociceptive system function. In this case series, we investigated 15 TN patients scheduled for MVD using magnetoencephalography prior to surgery to assess laser-evoked fields. Noxious stimuli were applied to the symptomatic and contralateral trigeminal dermatome. Ten patients achieved complete postoperative pain relief (responders), while five patients reported persistent symptoms (non-responders). Source reconstruction showed activation in the contralateral primary somatosensory cortex in all participants. Responders exhibited reduced low-frequency oscillatory activity at the pain site, whereas non-responders displayed increased activity in the same frequency band. Group-level analysis revealed distinct differences in oscillatory dynamics between responders and non-responders. These findings indicate altered cortical processing in TN and suggest that oscillatory activity patterns might serve as functional biomarkers. Incorporating these measures could improve preoperative stratification and guide treatment decisions for patients undergoing MVD.

In this perspective article we contend that acousmatic music, which departs from the traditional "instrumental music paradigm" by obscuring or removing the origin of sounds, may deepen a person's understanding and expression of pain and suffering, offering therapeutic potential. We propose that intentional engagement with acousmatic music can reshape listening habits, articulate and reframe the meaning of bodily and emotional experiences, and alleviate distressing sensations, feelings and thoughts. We propose that acousmatic music evokes memories of previous psychological traumas, such as painful events, and by doing so can prompt listeners to curiously explore the meaning and purpose of distressing symptoms. We argue that creative engagement with acousmatic music may allow individuals to express their somatic, emotional, and cognitive experiences, potentially leading to a deeper understanding of their living experiences. We discuss future directions for research and practice. We offer readers a stereo reduction excerpt of acousmatic music to facilitate an appreciation of the unusual nature of acousmatic music composition (https://soundcloud.com/nikos-stavropoulos/topophilia).