Human Studies

Patients with Gaucher disease (GD) have progressive bone involvement that clinically presents with debilitating bone pain, structural bone changes, bone marrow infiltration (BMI), Erlenmeyer (EM) flask deformity, and osteoporosis. Pain is referred by the majority of GD patients and continues to persist despite the type of therapy. The pain in GD is described as chronic deep penetrating pain; however, sometimes, patients experience severe acute pain. The source of bone pain is mainly debated as nociceptive pain secondary to bone pathology or neuropathic or inflammatory origins. Osteocytes constitute a significant source of secreted molecules that coordinate bone remodeling. Osteocyte markers, sclerostin (SOST) and Dickkopf-1 (DKK-1), inactivate the canonical Wnt signaling pathway and lead to the inhibition of bone formation. Thus, circulated sclerostin and DKK-1 are potential biomarkers of skeletal abnormalities. This study aimed to assess the circulating levels of sclerostin and DKK-1 in patients with GD and their correlation with clinical bone pathology parameters: pain, bone mineral density (BMD), and EM deformity. Thirty-nine patients with GD were classified into cohorts based on the presence and severity of bone manifestations. The serum levels of sclerostin and DKK-1 were quantified by enzyme-linked immunosorbent assays. The highest level of sclerostin was measured in GD patients with pain, BMI, and EM deformity. The multiparameter analysis demonstrated that 95% of GD patients with pain, BMI, and EM deformity had increased levels of sclerostin. The majority of patients with elevated sclerostin also have osteopenia or osteoporosis. Moreover, circulating sclerostin level increase with age, and GD patients have elevated sclerostin levels when compared with healthy control from the same age group. Pearson's linear correlation analysis showed a positive correlation between serum DKK-1 and sclerostin in healthy controls and GD patients with normal bone mineral density. However, the balance between sclerostin and DKK-1 waned in GD patients with osteopenia or osteoporosis. In conclusion, the osteocyte marker, sclerostin, when elevated, is associated with bone pain, BMI, and EM flask deformity in GD patients. The altered sclerostin/DKK-1 ratio correlates with the reduction of bone mineral density. These data confirm that the Wnt signaling pathway plays a role in GD-associated bone disease. Sclerostin and bone pain could be used as biomarkers to assess patients with a high risk of BMI and EM flask deformities.

Diabetic peripheral neuropathic pain (DPNP) is a prevalent chronic complication in patients with diabetes. Using a questionnaire is helpful for DPNP screening in outpatients. In this retrospective cohort, we aimed to examine whether DPNP diagnosed based on scoring questionnaires could predict long-term mortality in outpatients with type 2 diabetes.

Recent clinical guidelines have emphasized non-opioid treatments in lieu of prescription opioids for chronic non-cancer pain, exempting cancer patients from these recommendations. In this study, we determine trends in opioid and non-opioid treatment among privately insured adults with chronic non-cancer pain (CNCP) or cancer. Using administrative claims data from IBM MarketScan Research Databases, we identified privately-insured adults who were continuously enrolled in insurance for at least one calendar year from 2012 to 2019. We identified individuals with CNCP diagnosis, defined as a diagnosis of arthritis, headache, low back pain, and/or neuropathic pain, and a individuals with cancer diagnosis in a calendar year. Outcomes included receipt of any opioid, non-opioid medication, or non-pharmacologic CNCP therapy and opioid prescribing volume, MME-per-day, and days' supply. Estimates were regression-adjusted for age, sex, and region. Between 2012 and 2019, the proportion of patients who received any opioid decreased across both groups (CNCP: 49.7 to 30.5%, p<0.01; cancer: 86.0 to 78.7%, p<0.01). Non-opioid pain medication receipt remained steady for individuals with CNCP (66.7 to 66.4%, p<0.01) and increased for individuals with cancer (74.4 to 78.8%, p<0.01), while non-pharmacologic therapy use rose among individuals with CNCP (62.4 to 66.1%, p<0.01). Among those prescribed opioids, there was a decrease in the receipt of at least one prescription with >90 MME/day (CNCP: 13.9% in 2012 to 4.9% in 2019, p<0.01; Cancer: 26.2% to 7.6%, p<0.01); >7 days of supply (CNCP: 56.3% to 30.7%, p <0.01; Cancer: 47.5% to 22.7%, p<0.01), the mean number of opioid prescriptions (CNCP: 5.2 to 3.9, p<0.01; Cancer: 4.0 to 2.7, p<0.01) and mean MME/day (CNCP: 49.9 to 38.0, p<0.01; Cancer: 62.4 to 44.7, p<0.01). Overall, from 2012-2019, opioid prescribing declined for CNCP and cancer, with larger reductions for patients with CNCP. For both groups, reductions in prescribed opioids outpaced increases in non-opioid alternatives.

Safe and non-invasive on-demand relief is a crucial and effective treatment for postoperative pain because it considers variable timing and intensity of anesthetics. Ultrasound modulation is a promising technique for this treatment because it allows convenient timed and non-invasive controlled drug release. Here, we created an ultrasound-triggered lidocaine (Lido) release platform using an amino acid hydrogel functioning as three-dimensional (3D) scaffold material (Lido-PPIX@ER hydrogel). It allows control of the timing, intensity and duration of lidocaine (Lido) to relieve postoperative pain. The hydrogel releases Lido due to the elevated reactive oxygen species (ROS) levels generated by PPIX under ultrasound triggering. The Lido-PPIX@ER hydrogel under individualized ultrasound triggering released lidocaine and provided effective analgesia for more than 72 h. The withdrawal threshold was higher than that in the control group at all time points measured. The hydrogel showed repeatable and adjustable ultrasound-triggered nerve blocks , the duration of which depended on the extent and intensity of insonation. On histopathology, no systemic effect or tissue reaction was observed in the ultrasound-triggered Lido-PPIX@ER hydrogel-treated group. The Lido-PPIX@ER hydrogel with individualized (highly variable) ultrasound triggering is a convenient and effective method that offers timed and spatiotemporally controlled Lido release to manage postoperative pain. This article presents the delivery system for a new effective strategy to reduce pain, remotely control pain, and offer timed and spatiotemporally controlled release of Lido to manage postoperative pain.

: Chronic neck pain (CNP) is highly prevalent and complicated, associated with limited movement, and accompanied by shoulder pain and other clinical manifestations such as dizziness, anxiety, and insomnia. Brain structural and functional abnormalities often occur in patients with CNP. However, knowledge of the brain's functional organization and temporal dynamics in CNP patients is limited. Dynamic functional connectivity density (dFCD) can reflect the ability of brain areas or voxels to integrate information, and could become neuroimaging markers for objectively reflecting pain to a certain extent. Therefore, this study compared the dFCD between CNP patients and healthy controls (HCs) and investigated potential associations of the abnormal density variability in dynamic functional connectivity with pain characteristics in CNP patients. : Resting functional magnetic resonance imaging was performed for 89 CNP patients and 57 HCs. After preprocessing resting-state fMRI images by the Data Processing and Analysis of Brain Imaging toolbox, the sliding window method was applied to investigate dFCD changes in CNP patients and HCs using the DynamicBC toolbox. Then we quantified dFCD variability using their standard deviation. Based on the pain-associated factors collected from the case report form of CNP patients, the mean dFCD variability values of each dFCD from region of interest were extracted to calculate Pearson's correlation coefficient to study the potential correlation between dFCD abnormal variability and pain. : Compared with HCs, the dFCD values of the anterior cingulate cortex, occipital lobe, temporal lobe, and cerebellum were statistically different in patients with CNP. Subsequent correlation analysis showed that the variable dFCD in the related brain region was correlative with the course of the disease and clinical symptoms, such as pain and depression, in patients with CNP. : Dynamic functional alterations were observed in the brain regions of CNP patients, and the dFCD of these brain regions could become neuroimaging markers for objectively reflecting pain to a certain extent. This suggests that chronic pain may cause changes in pain processing and emotional feedback and highlights the link between dynamic neural communication in brain regions and disease conditions, deepening our understanding of chronic pain diseases, and guiding clinical practice.

Neuropathic pain is intractable and current treatment modalities are ineffective to cure this intractable pain, which has become a global problem. In recent years, there have been an increasing number of studies on stem cell therapy for neuropathic pain that have shown enormous potential. Using a visual analysis approach of the existing literature on stem cell therapy for neuropathic pain, we hope to understand the current research status and hot issues in this field and to provide valuable predictions for future research in this field.

Chronic pain and reward processing are understood to be reciprocally related to one another. Previous studies of reward processing in chronic pain patients have reported incongruent findings. While several factors likely contribute to these disparate findings, these previous studies did not stratify their analyses by sex-a factor previously shown to robustly impact reward-related responses. Thus, we examined sex as a factor of interest in level of striatal activation during anticipation of monetary incentives among patients with chronic non-specific back pain and healthy controls (HC). This study utilized functional magnetic resonance imaging during a monetary incentive delay task to evaluate reward and loss responsivity in the striatum among males and females with and without chronic pain ( = 90). Group, sex, and group-by-sex interactions were analyzed repeated measures analysis of variance. Among HC, males exhibited significantly greater blood oxygen level dependent (BOLD) signal in the striatum during reward anticipation, particularly during large reward trials. By contrast, no significant sex differences were observed among patients. A significant group-by-sex interaction was also observed, revealing diminished BOLD responses among males with chronic pain relative to control males. These results provide novel evidence of sex-specific reductions in anticipatory responses to reward in patients with chronic pain. Altered striatal reward responsivity among males, but not females, suggests that the reward systems of males and females are uniquely disrupted by chronic pain, and highlights the value of including sex as a factor of interest in future studies of reward responsivity in the context of persistent pain.

Central and peripheral nervous systems are all involved in type 2 diabetic polyneuropathy mechanisms, but such subclinical changes and associations remain unknown. This study aims to explore subclinical changes of the central and peripheral and unveil their association.