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Abstract: Preclinical research supports a critical role for nervous system glia in pain pathophysiology. This systematic review of human trials of potential glia-modulating drugs for the prevention or treatment of pain followed a predefined search strategy and protocol registration. We searched for English language, randomized, double-blind trials comparing putative glia-modulating drugs to placebo or other comparators. The primary outcomes included validated participant-reported measures of pain intensity or relief and, in studies of opioid administration, measures of opioid consumption and/or opioid-related adverse effects. Twenty-six trials (2132 participants) of glial modulators (12 minocycline, 11 pentoxifylline, and 3 ibudilast) were included. Because of clinical heterogeneity related to study drug, participant population, outcome measures, and trial design, no meta-analysis was possible. Only 6 trials reported a positive effect of the treatment (pentoxifylline-4 trials; minocycline-2 trials), whereas 11 trials reported mixed results and 9 trials reported no effect. This review does not provide convincing evidence of efficacy of current pharmacological targets of nervous system glial function for pain treatment or prevention. However, in light of ample preclinical evidence of the importance of neuroimmune signalling and glial functions in pain pathophysiology, continued strategic human research is anticipated to identify (1) drugs with maximal activity as selectively targeted glial modulators, (2) the necessary timing and duration of pharmacological glial modulation needed for pain prevention or treatment for specific injuries or pain conditions, and (3) the best design of future clinical trials of glial-targeted drugs for pain treatment and/or prevention., (Copyright © 2024 International Association for the Study of Pain.)

Although several genetic factors have been associated with postsurgical morphine requirements, those involving the innate immune system and cytokines have not been well investigated. The aim of this study was to investigate the contribution of genetic variability in innate immune signalling pathways to variability in morphine dosage after elective caesarean section under spinal anaesthesia in 133 Indian, 230 Malay, and 598 Han Chinese women previously studied. Twenty single nucleotide polymorphisms in 14 genes involved in glial activation (TLR2, TLR4, MYD88, MD2), inflammatory signalling (IL2, IL6, IL10, IL1B, IL6R, TNFA, TGFB1, CRP, CASP1), and neuronal regulation (BDNF) were newly investigated, in addition to OPRM1, COMT, and ABCB1 genetic variability identified previously. Postsurgical patient-controlled analgesia morphine use (mg/24 hours) was binned into 6 normally distributed groups and scored 0 to 5 to facilitate step-down multiple linear regression analysis of genetic predictors, controlling for ethnicity and nongenetic variables. Ethnicity, OPRM1 rs1799971 (increased), TLR2 rs3804100 (decreased), and an interaction between ethnicity and IL1B rs1143634 (increased), predicted 9.8% of variability in morphine use scores in the entire cohort. In the Indian cohort, 14.5% of the variance in morphine use score was explained by IL1B rs1143634 (increased) and TGFB1 rs1800469 (decreased). In Chinese patients, the incidence of postsurgical pain was significantly higher in variant COMT rs4680 genotypes (P = 0.0007) but not in the Malay or Indian cohorts. Innate immune genetics may contribute to variability in postsurgical opioid requirements in an ethnicity-dependent manner.

Objective: To synthesize and critically evaluate all available evidence investigating whether localized, provoked vestibulodynia is associated with a specific inflammatory profile at both a local and a systemic level., Data Sources: Comprehensive electronic searches were performed in MEDLINE, EMBASE, Scopus, PubMed, Web of Science, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Collaboration databases, and ClinicalTrials.gov. The search strategy was developed using MeSH terms related to localized, provoked vestibulodynia, and inflammatory markers., Methods of Study Selection: Two independent investigators screened titles and abstracts and performed data extraction and risk of bias assessments. Studies were included if they reported at least one baseline inflammatory marker in women with localized, provoked vestibulodynia and compared them with healthy women. Reference lists from published reviews on localized, provoked vestibulodynia were screened for additional studies., Tabulation, Integration, and Results: There were 1,619 studies identified. Eighteen studies met the inclusion criteria, including 400 women with localized, provoked vestibulodynia and 212 healthy women in a control group. Risk of bias assessment revealed that the methodologic quality was generally low. Fifteen studies investigated local inflammation and three studies investigated systemic inflammation. On a local level, the number of mast cells expressed in vestibular tissues was greater in women with localized, provoked vestibulodynia expressed than in women in the control group. Several studies reported undefined inflammatory infiltrate in vestibular tissues to a greater level in women with localized, provoked vestibulodynia than in women in the control group. Systemically, levels of natural killer cells were lower in women with localized, provoked vestibulodynia than in women in the control group. There were no systemic differences in systemic interferon-α and interferon-υ levels between groups., Conclusion: There is limited and contradictory evidence regarding the characteristics of local and systemic inflammation in women with localized, provoked vestibulodynia.

Objective: To examine the association between genetic variability of IL-1B, which encodes for the proinflammatory cytokine IL-1beta and the risk of developing opioid dependence. To confirm a previous study, we also examined the association between the IL-1B genetic polymorphism and alcohol dependence., Methods: Genomic DNA was isolated from 60 opioid-dependent, 99 alcohol-dependent patients and 60 healthy nondependent controls. Polymerase chain reaction and restriction fragment length polymorphism were used to determine the presence of single nucleotide polymorphisms at positions -511, -31 and 3954 of IL-1B., Results: IL-1B -511C and -31T alleles were more frequent in both the opioid-dependent and alcohol-dependent patients compared with the control group: odds ratio (OR, 95% confidence interval) P values corrected for false discovery rate=1.91 (1.14-3.20), P=0.043 and 1.89 (1.19-2.99), P=0.014, respectively, for IL-1B -511C>T; and OR=1.74 (1.02-2.97), P=0.066 and 1.80 (1.13-2.88), P=0.017, respectively, for IL-1B -31T>C. In contrast, no association was observed between opioid dependence and the IL-1B 3954C>T single nucleotide polymorphism [OR=1.60 (0.84-3.02), P=0.15]., Conclusion: This study confirms the previous finding that IL-1B polymorphism is associated with altered risk of alcohol dependence. IL-1B single nucleotide polymorphisms at position -511 and -31, which increase IL-1beta production, occur at a higher frequency in opioid-dependent populations and may be associated, albeit weakly, with an increased risk of opioid dependence.

There is substantial evidence for bidirectional communication between the immune system and the central nervous system, as the cells and signalling molecules of the immune system influence many central nervous system functions, for instance nociception. Opioids, such as morphine, produce analgesia and numerous other central and peripheral effects including sedation and euphoria, while their effects on the immune system are wide-ranging. There is considerable interindividual variability in basal nociception and response to opioids, however, the physiological and biological mechanisms underlying this are unclear. Therefore, we investigated the relationship between the immune system and basal nociceptive thresholds, using the proliferative response of isolated peripheral blood mononuclear cells and cold pressor pain tolerance. Here we show that the percent increase in proliferation of peripheral immune cells from 13 healthy subjects incubated with morphine ex vivo is highly correlated with the subjects' tolerance to noxious cold stimuli (Pearson r = 0.92, P < 0.0001). These pilot data provide evidence of a novel objective biological marker of pain tolerance in humans, which also links the immune and opioid systems with basal pain tolerance.

The midline fascial splitting approach is a modified midline approach to the iliac crest for bone graft that takes advantage of the anatomic planes between layers of the dorsal lumbar fascia. Two hundred consecutive grafts were taken by this technique with one superficial infection, two cases of serous hematoma, and three patients with significant postoperative pain at the harvest site, for an overall complication rate of 3%. In comparison, bone grafts were harvested from 200 consecutive patients by the midline subcutaneous approach to the iliac crest with 2 deep infections, 1 cluneal nerve injury, 15 patients with severe and disabling pain at the harvest site, and 12 patients with a serous hematoma, for an overall complication rate of 15%. The midline fascial splitting approach significantly reduced the incidence of postoperative serous hematoma (P < 0.007) as well as the incidence of significant and disabling pain (P < 0.001). In addition, the approach is simple, straightforward, anatomic, and decreases trauma to soft tissues.

Thoracic and lumbar fracture-dislocations with 100% spinal column displacement are uncommon injuries that usually have associated neurologic injury. Severe spinal malalignment and instability can result in blood loss, tenting of skin and, severe pain. Four patients with thoracic or lumbar fracture-dislocations were initially treated and reduced with halo-bifemoral traction. Fracture reduction with halo-bifemoral traction decreased pain, controlled instability, relieved skin pressure, and prevented the need for acute surgical intervention. In addition, use of halo-bifemoral traction allowed for the resolution of spinal shock, allowed time for complete presurgical planning, and simplified the reduction portion of the operative procedure, thereby reducing operative time and blood loss.