UNASSIGNED: Acute pain episodes, also known as vaso-occlusive crises (VOC), are a major symptom of sickle cell disease (SCD) and lead to frequent hospitalizations. The diagnosis of VOC can be challenging, particularly in adults with SCD, 50% of whom have chronic pain. Several potential biomarkers have been proposed for identifying individuals with VOC, including elevation above the baseline of various vascular growth factors, cytokines, and other markers of inflammation. However, none have been validated to date.
UNASSIGNED: We summarize prospective biomarkers for the diagnosis of acute pain in SCD, and how they may be involved in the pathophysiology of a VOC. Previous and current strategies for biomarker discovery, including the use of omics techniques, are discussed.
UNASSIGNED: Implementing a multi-omics-based approach will facilitate the discovery of objective and validated biomarkers for acute pain.

MRS was shown to reliably quantify relative levels of degenerative pain biomarkers, differentiating painful versus non-painful discs in patients with chronic discogenic low back pain (DLBP), and this correlates with surgical success rates. We now report results based on more patients and longer follow-up.
Disc MRS was performed in DLBP patients who subsequently received lumbar surgery. Custom post-processing (NOCISCAN-LS®; Aclarion Inc.) calculated disc-specific NOCISCORES® that reflect relative differences in degenerative pain biomarkers for diagnosing chemically painful discs. Outcomes in 78 patients were evaluated using Oswestry Disability Index (ODI) scores. Surgical success (≥ 15-point ODI improvement) was compared between surgeries that were \"Concordant\" (Group C) versus \"Discordant\" (Group D) with NOCISCORE-based diagnosis for painful discs.
Success rates were higher for Group C versus Group D: 6 months (88% vs. 62%; p = 0.01), 12 months (91% vs. 56%; p < 0.001), and 24 months (85% vs. 63%; p = 0.07). Success rates for Group C surgeries were also higher than Group D surgeries in a variety of sub-group comparisons. Group C had a greater reduction in ODI from pre-operative to follow-up than Group D [absolute change (% change), (p)]: 6 months: - 35 (- 61%) versus - 23 (- 39%), (p < 0.05); 12 months: - 39 (- 69%) versus - 22 (- 39%), (p < 0.01); and 24 months:  - 38 (- 66%) versus - 26 (- 48%), (p < 0.05).
More successful, sustained outcomes were obtained when surgically treating chemically painful discs identified by NOCISCAN-LS post-processed disc MRS exams. Results suggest that NOCISCAN-LS provides a valuable new diagnostic tool to help clinicians better select treatment levels.

The evaluation of chronic pain is challenging because of the lack of specific biomarkers. We identified the Mu opioid receptor-positive (Mu+) B cell percentage of expression, named Mu-Lympho-Marker (MLM), as a candidate marker for chronic pain in fibromyalgia (FM) and osteoarthritis (OA) patients. Here, we investigate the role of MLM on natural killer (NK) cells in the same patients. Twenty-nine FM and twelve OA patients were analyzed, and twenty-three pain-free subjects were considered as the control group. Blood samples were collected to perform immunophenotyping and Western blot analysis. Biological and clinical data were statistically analyzed. The final results showed that the percentage of NK cells expressing Mu was statistically lower in FM and OA patients than in pain-free subjects, as already demonstrated for B cells. A Western blot analysis was performed in order to detect NK cells\' functional status. Moreover, the correlation analysis of MLM expression with pharmacological therapy did not show any significant results. In conclusion, here, we confirm the role of MLM as a suitable marker for chronic pain and underline NK cells as a new possible immune cell type involved in the \"Mu opioid receptor reserve theory\".

The potential of Se to alleviate pain associated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity was investigated. Swiss mice were intraperitoneally injected with MPTP (20 mg/kg) 4 times with an interval of 2 h in 1 day. Seven days after MPTP injection, the mice (n = 5 mice per group) were randomly assigned to groups: MPTP-, DOPA (50 mg/kg)-, Se4 (0.4 mg/kg)-, Se6 (0.6 mg/kg)-, DOPA+Se4-, and DOPA+Se6-treated groups were compared with controls. MPTP mice were treated for seven days; thereafter, motor-coordination and nociceptive-motor reactions were assessed. Pro-inflammatory cytokines (IL-1β, IL-6 and TNFα), and selected pain biomarkers (substance P (SP), glutamate and β-endorphin) were assessed in the serum and the substantial nigra pars compacta (SNpc). Motor activity was increased slightly by Se (0.6 or 0.4 mg/kg) vs. MPTP (10.48 ± 2.71 or 11.81 ± 1.28 s vs. 3.53 ± 0.06 s respectively) but considerably increased by DOPA (50 mg/kg) vs. MPTP (50.47 ± 3.06 s vs. 3.53 ± 0.06 s respectively). Se and DOPA increased nociceptive threshold but Se alone reduced both serum and SN pro-inflammatory cytokines. Se modulates SP while DOPA modulates SP and glutamate in the SNpc of mice treated with MPTP. Se suppressed pro-inflammatory cytokines and restored the basal pain biomarkers in the SNpc of mice treated with MPTP. Se requires further study as analgesic adjuvant.

OBJECTIVE: Chronic pancreatitis (CP) is associated with debilitating refractory pain. Distinct subtypes of CP pain have been previously characterized based on severity (none, mild-moderate, severe) and temporal (none, intermittent, constant) nature of pain, but no mechanism-based tools are available to guide pain management. This exploratory study was designed to determine if potential pain biomarkers could be detected in patient serum and whether they associate with specific pain patterns.
METHODS: Cytokines, chemokines, and peptides associated with nociception and pain were measured in legacy serum samples from CP patients (N = 99) enrolled in the North American Pancreatitis Studies. The unsupervised hierarchical cluster analysis was applied to cluster CP patients based on their biomarker profile. Classification and regression tree was used to assess whether these biomarkers can predict pain outcomes.
RESULTS: The hierarchical cluster analysis revealed a subset of patients with predominantly constant, mild-moderate pain exhibited elevated interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), and monocyte chemoattractant protein-1 (MCP1) whereas patients with higher interleukin-4 (IL-4), interleukin-8 (IL-8) and calcitonin gene related peptide (CGRP) were more likely to have severe pain. Interestingly, analyses of each individual biomarker revealed that patients with constant pain had reduced circulating TNFα and fractalkine. Patients with severe pain exhibited a significant reduction in TNFα as well as trends towards lower levels of IL-6 and substance P.
CONCLUSIONS: The observations from this study indicate that unique pain experiences within the chronic pancreatitis population can be associated with distinct biochemical signatures. These data indicate that further hypothesis-driven analyses combining biochemical measurements and detailed pain phenotyping could be used to develop precision approaches for pain management in patients with chronic pancreatitis.

The worlds of chronic pain and addiction continue to intersect too often in many ways. Chronic pain significantly impairs and disrupts the quality of life of millions of people worldwide. Opioids remain the most prescribed pharmacotherapy offered to patients to alleviate chronic pain. The extensive and often unnecessary prescription of opioids has created a surge in the prevalence of opioid use disorders and opioid overdose-related deaths. In this brief review, we aim to provide a bench-to-bedside overview of promising biomarkers, therapeutic targets, and challenges related to treating patients with chronic pain. We hope this review will inspire new opportunities and insights into the development of novel, nonaddictive treatments for chronic pain that will be available to patients in the near future.

Photobiomodulation (PBM) is a simple, efficient and cost-effective treatment for both acute and chronic pain. We previously showed that PBM applied to the mouse head inhibited nociception in the foot. Nevertheless, the optimum parameters, location for irradiation, duration of the effect and the mechanisms of action remain unclear. In the present study, the pain threshold in the right hind paw of mice was studied, after PBM (810 nm CW laser, spot size 1 or 6 cm2 , 1.2-36 J/cm2 ) applied to various anatomical locations. The pain threshold, measured with von Frey filaments, was increased more than 3-fold by PBM to the lower back (dorsal root ganglion, DRG), as well as to other neural structures along the pathway such as the head, neck and ipsilateral (right) paw. On the other hand, application of PBM to the contralateral (left) paw, abdomen and tail had no effect. The optimal effect occurred 2 to 3 hours post-PBM and disappeared by 24 hours. Seven daily irradiations showed no development of tolerance. Type 1 metabotropic glutamate receptors decreased, and prostatic acid phosphatase and tubulin-positive varicosities were increased as shown by immunofluorescence of DRG samples. These findings elucidate the mechanisms of PBM for pain and provide insights for clinical practice.

This review was focused on understanding which substances inside the human body increase and decrease with increasing neuropathic pain. We reviewed various studies, and saw correlations between neuropathic pain and components of the immune system (this system defends the body against diseases and infections). Our findings will especially be useful for understanding ways to reduce or eliminate the discomfort, chronic neuropathic pain brings with it. Spinal cord stimulation (SCS) procedure is one of the few fairly efficient remedial treatments for pain. A follow-up study will apply our findings from this review to SCS, in order to understand the mechanism, and further optimize efficaciousness.

Pharmacological approaches to our understanding and treatment of pain have had a long history and have traditionally relied on very few drugs that either have significant side effects and abuse liability, such as the nonsteroidal anti-inflammatory drugs or the opioids, respectively, or those that have been developed for other conditions such as the tricyclic antidepressants. The pathophysiology of pain is undoubtedly complex, complicated in part by the fact that it is not a singular condition, and has a variety of etiologies and a number of associated comorbidities that make treatment interventions challenging. Moreover, there are changes in the central nervous system during the course of the development of chronic pain that, in a manner parallel to neurodegenerative disorders, likely require different pharmacological approaches in the early stages of acute pain compared to those that would be effective when pain has become chronic. This chapter reviews the current status of the field of pain research focusing on some relatively underdeveloped areas, such as pain and its associated comorbidities, and the use of transgenic animals and drug self-administration procedures in the context of analgesic assessment. This chapter also incorporates more recent developments and emerging trends in the area of epigenetics, biomarkers, and the use of induced pluripotent stem cells for pharmacological evaluation, target identification, and validation. Recent progress in the study of \"organs-on-a-chip\" will also be included in this overview, setting expectations for future progress that integrates these advances for deeper insights into mechanisms, novel treatments, and facilitated efforts in drug discovery.

Recent studies have posited that machine learning (ML) techniques accurately classify individuals with and without pain solely based on neuroimaging data. These studies claim that self-report is unreliable, making \"objective\" neuroimaging classification methods imperative. However, the relative performance of ML on neuroimaging and self-report data have not been compared. This study used commonly reported ML algorithms to measure differences between \"objective\" neuroimaging data and \"subjective\" self-report (ie, mood and pain intensity) in their ability to discriminate between individuals with and without chronic pain. Structural magnetic resonance imaging data from 26 individuals (14 individuals with fibromyalgia and 12 healthy controls) were processed to derive volumes from 56 brain regions per person. Self-report data included visual analog scale ratings for pain intensity and mood (ie, anger, anxiety, depression, frustration, and fear). Separate models representing brain volumes, mood ratings, and pain intensity ratings were estimated across several ML algorithms. Classification accuracy of brain volumes ranged from 53 to 76%, whereas mood and pain intensity ratings ranged from 79 to 96% and 83 to 96%, respectively. Overall, models derived from self-report data outperformed neuroimaging models by an average of 22%. Although neuroimaging clearly provides useful insights for understanding neural mechanisms underlying pain processing, self-report is reliable and accurate and continues to be clinically vital.
CONCLUSIONS: The present study compares neuroimaging, self-reported mood, and self-reported pain intensity data in their ability to classify individuals with and without fibromyalgia using ML algorithms. Overall, models derived from self-reported mood and pain intensity data outperformed structural neuroimaging models.