Systemic administration of a ß2-adrenergic receptor agonist reduces mechanical allodynia and suppresses the immune response to surgery in a rat model of persistent post-incisional hypersensitivity.

Beta 2 adrenergic receptor (ß2 AR) activation in the central and peripheral nervous system has been implicated in nociceptive processing in acute and chronic pain settings with anti-inflammatory and anti-allodynic effects of ß2-AR mimetics reported in several pain states. In the current study, we examined the therapeutic efficacy of the ß2-AR agonist clenbuterol in a rat model of persistent postsurgical hypersensitivity induced by disruption of descending noradrenergic signaling in rats with plantar incision. We used growth curve modeling of ipsilateral mechanical paw withdrawal thresholds following incision to examine effects of treatment on postoperative trajectories. Depletion of spinal noradrenergic neurons delayed recovery of hypersensitivity following incision evident as a flattened slope compared to non-depleted rats (-1.8 g/day with 95% CI -2.4 to -1.085, p < 0.0001). Chronic administration of clenbuterol reduced mechanical hypersensitivity evident as a greater initial intercept in noradrenergic depleted (6.2 g with 95% CI 1.6 to 10.8, p = 0.013) and non-depleted rats (5.4 g with 95% CI 1.2 to 9.6, p = 0.018) with plantar incision compared to vehicle treated rats. Despite a persistent reduction in mechanical hypersensitivity, clenbuterol did not alter the slope of recovery when modeled over several days (p = 0.053) or five weeks in depleted rats (p = 0.64). Systemic clenbuterol suppressed the enhanced microglial activation in depleted rats and reduced the density of macrophage at the site of incision. Direct spinal infusion of clenbuterol failed to reduce mechanical hypersensitivity in depleted rats with incision suggesting that beneficial effects of ß2-AR stimulation in this model are largely peripherally mediated. Lastly, we examined ß2-AR distribution in the spinal cord and skin using in-situ hybridization and IHC. These data add to our understanding of the role of ß2-ARs in the nervous system on hypersensitivity after surgical incision and extend previously observed anti-inflammatory actions of ß2-AR agonists to models of surgical injury.

Sufentanil postoperative analgesia reduce the increase of T helper 17 (Th17) cells and FoxP3+ regulatory T (Treg) cells in rat hepatocellular carcinoma surgical model: A randomised animal study.

BACKGROUND: Surgery-related pain and opioids might exacerbate immune defenses in immunocompromised cancer patients which might affect postoperativd overall survival. Sufentanil is a good postoperative pain control drug,the present study aimed to figure out whether it effect T cell immunity in rat hepatocellular carcinoma surgical model. METHODS: A rat hepatocellular carcinoma (HCC) models was established by N-nitrosodiethylamine. Forty-eight of them were randomly divided into 3 equal groups: surgery without postoperative analgesia (Group C), surgery with morphine postoperative analgesia (Group M), surgery with sufentanil postoperative analgesia (Group S). Each animal underwent a standard left hepatolobectomy, and intraperitoneally implanted with osmotic minipumps filled with sufentanil, morphine or normal saline according to the different group. The food and water consumptions, body weight changes, locomotor activity and mechanical pain threshold (MPT) were observed. The ratio of CD4+/CD8+, proportions of Th1, Th2, Th17 and Treg cells in blood were detected using flow cytometry. The liver function and the rats' survival situation of each group were observed. RESULTS: The food and water consumption, locomotor activity and MPT of group C declined than those of group S and M on d1, d2, d3 (P < 0.05). The CD4+/CD8+ ratio and the proportion of Th1 cells were significantly higher while the proportion of Th2, Th17 and Treg cells were significantly lower in group S and group M compared with group C. The rats of group S have higher CD4+/CD8+ ratio on d3, while lower proportion of Treg cells on d7 compared with group M. The plasma ALT and AST values in group C were significantly higher than that of group S and group M on both d3 and d7. There were not significant differences in mortality rate between 3 groups. CONCLUSIONS: Sufentanil and morphine postoperative analgesia in HCC rats accepted hepatectomy could relieve postoperative pain, promote the recovery of liver function after surgery, alleviate the immunosuppressive effect of pain. Furthermore, Compared to morphine, sufentanil might have a slighter effect on CD4+/CD8+ ratio and Treg frequencies. Therefore, sufentanil postoperative analgesia is better than morphine in HCC hepatectomy rats.

Microarray analyses of the dorsal root ganglia support a role for innate neuro-immune pathways in persistent pain in experimental osteoarthritis.

OBJECTIVE: Following destabilization of the medial meniscus (DMM), mice develop experimental osteoarthritis (OA) and associated pain behaviors that are dependent on the stage of disease. We aimed to describe changes in gene expression in knee-innervating dorsal root ganglia (DRG) after surgery, in order to identify molecular pathways associated with three pre-defined pain phenotypes: "post-surgical pain", "early-stage OA pain", and "persistent OA pain". DESIGN: We performed DMM or sham surgery in 10-week old male C57BL/6 mice and harvested L3-L5 DRG 4, 8, and 16 weeks after surgery or from age-matched naïve mice (n = 3/group). RNA was extracted and an Affymetrix Mouse Transcriptome Array 1.0 was performed. Three pain phenotypes were defined: "post-surgical pain" (sham and DMM 4-week vs 14-week old naïve), "early OA pain" (DMM 4-week vs sham 4-week), and "persistent OA pain" (DMM 8- and 16-week vs naïve and sham 8- and 16-week). 'Top hit' genes were defined as P < 0.001. Pathway analysis (Ingenuity Pathway Analysis) was conducted using differentially expressed genes defined as P < 0.05. In addition, we performed qPCR for Ngf and immunohistochemistry for F4/80+ macrophages in the DRG. RESULTS: For each phenotype, top hit genes identified a small number of differentially expressed genes, some of which have been previously associated with pain (7/67 for "post-surgical pain"; 2/14 for "early OA pain"; 8/37 for "persistent OA pain"). Overlap between groups was limited, with 8 genes differentially regulated (P < 0.05) in all three phenotypes. Pathway analysis showed that in the persistent OA pain phase many of the functions of differentially regulated genes are related to immune cell recruitment and activation. Genes previously linked to OA pain (CX3CL1, CCL2, TLR1, and NGF) were upregulated in this phenotype and contributed to activation of the neuroinflammation canonical pathway. In separate sets of mice, we confirmed that Ngf was elevated in the DRG 8 weeks after DMM (P = 0.03), and numbers of F4/80+ macrophages were increased 16 weeks after DMM (P = 0.002 vs Sham). CONCLUSION: These transcriptomics findings support the idea that distinct molecular pathways discriminate early from persistent OA pain. Pathway analysis suggests neuroimmune interactions in the DRG contribute to initiation and maintenance of pain in OA.

Morphine immunomodulation prolongs inflammatory and postoperative pain while the novel analgesic ZH853 accelerates recovery and protects against latent sensitization.

BACKGROUND: Numerous studies have identified the proinflammatory, pronociceptive effects of morphine which ultimately exacerbate pain. Our novel endomorphin analog ZH853 does not produce proinflammatory effects on its own and gives potent, long-lasting analgesia. This study investigates whether ZH853's lack of interaction with the neuroimmune system reduces the risk of prolonged pain. METHODS: Adult male Sprague-Dawley rats were subjected to one of two treatment paradigms. Either (1) chronic pain followed by chronic treatment with morphine, ZH853 or vehicle, or (2) chronic drug administered prior to pain induction. Complete Freund's adjuvant (CFA) was injected or paw incision surgery was performed on the left hind plantar foot pad. Drugs were administered through Alzet osmotic minipumps at a rate of 1 µl/h for 5 days at appropriate doses based on prior experiments. Animals were tested for mechanical allodynia and thermal hyperalgesia using von Frey filaments and the Hargreaves apparatus, respectively. Additionally, several gait parameters were measured using the CatWalk XT. When all animals had recovered from pain, 1 mg/kg of naltrexone was administered to test for development of latent sensitization (LS). A second set of animals was used to investigate dorsal horn inflammation following CFA and drug treatment. ANOVAs were used to assess differences between drug treatment groups. RESULTS: As expected, morphine increased and prolonged pain in all experiments compared to vehicle treatment. However, ZH853 treatment reduced the overall time spent in pain and the severity of pain scores compared to morphine. ZH853 not only reduced inflammation versus morphine treatment but also, in some instances, acted as an anti-inflammatory drug compared to vehicle treatment. Finally, ZH853 prevented the development of LS while vehicle- and morphine-treated animals showed robust relapse to pain. CONCLUSIONS: ZH853 has a favorable side effect profile versus morphine and provides superior analgesia in a number of pain states. We now know that chronic use of this compound reduces time spent in a chronic pain state, the opposite of common opioids like morphine, and reduces the risk of LS, making ZH853 an excellent candidate for clinical development in humans for inflammatory and postoperative pain.

Effect of Preoperative Uric Acid Level and Neutrophil / Lymphocyte Ratio on Preoperative and Postoperative Visual Analogue Pain Scores in Patients with Lumbar Disc Herniation: A Cross-Sectional Study.

AIM: To determine the relationship between the serum urate (SU) level, neutrophil / lymphocyte ratio (NLR), and pain severity using preoperative and postoperative visual analogue scale (VAS) scores in patients with lumbar disc herniation (LDH). MATERIAL AND METHODS: This single-center, cross-sectional study included 20 consecutive patients who were operated for LDH by the same surgeon. The patients'pre- and postoperative UA levels, NLRs, and intensity severity VAS scores were investigated. Preoperative magnetic resonance imaging (MRI) findings, serum UA levels, and neutrophil and lymphocyte counts were recorded. Pain severity was recorded preoperatively and at 6 months postoperatively. Effects of the preoperative SU levels and NLRs on the pre- and postoperative VAS scores were statistically assessed. RESULTS: Statistically significant positive correlation coefficients were determined between NLR and the preoperative and postoperative VAS scores. Negative correlation coefficients were found between the SU levels and preoperative VAS scores; in contrast, positive correlation coefficients were found between the SU levels and the postoperative VAS scores. CONCLUSION: Our results demonstrate the importance of not ignoring the serum UA level and NLR in pre- and postoperative pain in patients with LDH. Nevertheless, further extensive studies are warranted.

Lymphocyte Transformation Testing (LTT) in Cases of Pain Following Total Knee Arthroplasty: Little Relationship to Histopathologic Findings and Revision Outcomes.

BACKGROUND: The utilization of lymphocyte transformation testing (LTT) has increased for diagnosing metal sensitivity associated with total knee arthroplasty (TKA), but its validity for the diagnosis of TKA failure due to an immune reaction has not been established. In this study, we sought to characterize the relationship of a positive LTT result to histopathologic findings and clinical and functional outcomes. METHODS: This was a retrospective study of 27 well-fixed, aseptic, primary TKA cases in which the patient had persistent pain and/or stiffness and underwent revision due to a suspected metal allergy to nickel, as determined on the basis of positive LTT. Revision procedures were performed by a single experienced arthroplasty surgeon. Periprosthetic tissue samples obtained at the time of revision surgery were scored using the aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL) scoring system. RESULTS: Eight patients were categorized as mildly reactive; 8 patients, moderately reactive; and 11 patients, highly reactive to nickel by LTT. The predominant findings on routine histopathologic analysis were fibrosis and varying degrees of lymphocytic infiltration in 17 (63%) of the 27 cases. The average ALVAL score of the cohort was 3.1 ± 1.9, of a maximum score of 10. Average Knee Society Score (KSS) values improved post-revision, as did range of motion (all p < 0.01). Neither LTT stimulation index as a continuous variable nor as a categorical variable (mildly reactive, moderately reactive, highly reactive) was correlated with ALVAL score, pre-revision function (as assessed by KSS-clinical, KSS-functional, and range of motion), or change in function at the most recent follow-up (0.015 < r < 0.30, 0.13 < p < 0.95). In addition, the ALVAL score did not correlate significantly with either pre-revision or post-revision KSS or range of motion (0.061 < r < 0.365, 0.09 < p < 0.88). CONCLUSIONS: On the basis of this analysis, including histopathologic assessment, LTT results alone were insufficient for the diagnosis of TKA failure due to an immune reaction. A positive LTT may not indicate that an immune reaction is the cause of pain and stiffness post-TKA. The role of LTT in assessing TKA failure from an immune reaction needs further investigation. Diagnostic criteria for such TKA failure need to be established. LEVEL OF EVIDENCE: Diagnostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Immunomodulatory Effects of Fentanyl or Dexmedetomidine Hydrochloride Infusion After Allogeneic Heart Transplantation in Mice.

BACKGROUND AND OBJECTIVES: Postoperatively, transplant recipients receive immunosuppressants, as well as sedatives and analgesics. The immunomodulatory effects of these other agents during the induction period following transplantation remain unclear. We aimed to determine whether the agents dexmedetomidine hydrochloride (Dex) and fentanyl (Fen) have immunomodulatory effects during the induction period following heart transplantation (HTx). METHODS: Fifty mice were used for antinociception tests after administration of Dex and Fen, and T cells from 3 naive animals were used for in vitro lymphocyte transformation test (study 1). Fifty-four B6 mice received HTx from BALB/c mice and were treated with Dex, Fen, or neither (study 2). Thirty-six recipients were used for graft survival data and were humanely killed at the time of cessation of heart graft contraction. The remaining 18 were humanely killed at either postoperative day (POD) 4 or 6 for histologic examination of graft survival, as well as in vitro analysis. RESULTS: Based on the results of study 1, daily intraperitoneal administration of Dex at 30 µg/kg or Fen at 0.25 mg/kg was determined to be the optimal dose to induce analgesia without oversedation following HTx. Graft survivals in both Dex- or Fen-treated animals were statistically prolonged compared with control (P < 0.01). Graft survival of Fen-treated recipients was increased up to 15 days, and graft survival of Dex-treated animals was also increased up to 10 days, whereas control mice rejected heart grafts by POD 7. Mixed lymphocyte reaction responses on POD 4 showed statistically lower responses in Dex-treated recipients and Fen-treated recipients when compared with controls (P < 0.01). Cytokine profiles of splenocytes showed markedly fewer interferon γ-positive splenocytes in Fen-treated recipients on POD 4. CONCLUSIONS: These data suggest that both Dex and Fen have immunomodulatory properties in the induction period following transplantation.

Induction of suppressor of cytokine signaling 3 via HSF-1-HSP70-TLR4 axis attenuates neuroinflammation and ameliorates postoperative pain.

Postoperative pain is a common form of acute pain that, if not managed effectively, can become chronic pain. Evidence has shown that glia, especially microglia, mediate neuroinflammation, which plays a vital role in pain sensitization. Moreover, toll-like receptor 4 (TLR4), the tumor necrosis factor receptor (TNF-R), the interleukin-1 receptor (IL-1R), and the interleukin-6 receptor (IL-6R) have been considered key components in central pain sensitization and neuroinflammation. Therefore, we hypothesized that activation of the body's endogenous "immune brakes" will inhibit these receptors and achieve inflammation tolerance as well as relieve postoperative pain. After searching for potential candidates to serve as this immune brake, we identified and focused on the suppressor of cytokine signaling 3 (SOCS3) gene. To regulate SOCS3 expression, we used paeoniflorin to induce heat shock protein 70 (HSP70)/TLR4 signaling. We found that paeoniflorin significantly induced SOCS3 expression both in vitro and in vivo and promoted the efflux of HSP70 from the cytoplasm to the extracellular environment. Furthermore, paeoniflorin markedly attenuated incision-induced mechanical allodynia, and this effect was abolished by small interfering RNAs targeting SOCS3. These findings demonstrated an effective and safe strategy to alleviate postoperative pain.

Influence of opioids on immune function in patients with cancer pain: from bench to bedside.

In patients with cancer, opioids are principally used for the management of acute surgical and chronic cancer-related pain. However, opioids have many non-analgesic effects, including direct and indirect effects on cancer cells and on anti-tumour immunity (NK cells, macrophages and T-cells). Direct effects on immune cells are manifested via opioid and non-opioid toll-like receptors, whereas indirect effects are manifested via the sympathetic nervous system and hypothalamic-pituitary-adrenal axis. Opioids can also decrease/alter immune cell infiltration into the tumour micro-environment. Animal models have shown that this is not a class effect, in that morphine and fentanyl suppress NK cell cytotoxicity; buprenorphine does not affect NK cell cytotoxicity, whereas tramadol increases NK cell cytotoxicity, reducing metastasis. In healthy individuals, morphine suppresses and fentanyl enhances NK cell cytotoxicity. In patients undergoing surgery, fentanyl decreased and tramadol increased NK cell cytotoxicity; clinical outcomes were not determined. Meta-analyses of opioid-sparing surgical studies report an association between improved recurrence-free and/or overall survival with regional/neuraxial anaesthesia compared with systemic opioids. In patients receiving opioids for non-surgical cancer-related pain, morphine has variable effects on immunity; clinical outcomes were not assessed. Although there is a potential association between systemic opioid administration and shorter survival in cancer patients with a prognosis of months to years, studies have not been designed to primarily assess survival, as a consequence of which causality cannot be apportioned. Pain is immunosuppressive, so analgesia is important. Opioids for cancer-related pain will continue to be recommended until definitive data on the effects of opioids on clinical outcomes in specific patient groups becomes available. LINKED ARTICLES: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.

Suppression of Wnt5a, but not Wnts, relieves chronic post-thoracotomy pain via anti-inflammatory modulation in rats.

With regard to post-surgical pain, the incidence of chronic post-thoracotomy pain (CPTP) is second only to that caused by amputation and the underlying mechanism remains elusive. The emerging role of Wnts has been confirmed in the pathogenesis of neuropathic and inflammatory pain, both of which are known components of CPTP. We investigated whether Wnt3a and Wnt5a were involved in the development of CPTP, concerning their regulation of inflammatory responses in a previously established rat model. We observed up regulated protein levels of Wnt3a, Wnt5a, ß-catenin, and TLR4, along with activated astrocytes and pro-inflammatory cytokines, in both dorsal root ganglia and the spinal cord dorsal horn. Furthermore, intrathecal inhibition of Wnt5a but not Wnts relieved mechanical hyperalgesia, down regulated expression of TLR4, and inactivated astrocytes and pro-inflammatory cytokines. These results suggest Wnt5a, but not Wnts, contributes to the development of CPTP, possibly by regulating the inflammatory response.

Systemic Inflammatory and Th17 Immune Activation among Patients Treated for Lumbar Radiculopathy Exceeds that of Patients Treated for Persistent Postoperative Neuropathic Pain.

BACKGROUND: The pathophysiology of lumbar radiculopathy includes both mechanical compression and biochemical irritation of apposed neural elements. Inflammatory and immune cytokines have been implicated, induced by systemic exposure of immune-privileged intervertebral disc tissue. Surgical intervention provides improved symptoms and quality of life, but persistent postoperative neuropathic pain (PPNP) afflicts a significant fraction of patients. OBJECTIVE: To compare the inflammatory and immune phenotypes among patients undergoing structural surgery for lumbar radiculopathy and spinal cord stimulation for neuropathic pain. METHODS: Consecutive patients undergoing surgical intervention for lumbar radiculopathy or neuropathic pain were studied. Demographic data included age, gender, and VAS and neuropathic pain scores. Serum was evaluated for cytokine levels (IL-6, Il-17, TNF-α) and cellular content [white blood cell (WBC)/differential, lymphocyte subtypes]. The primary analysis differentiated molecular and cellular profiles between radiculopathy and neuropathic pain patients. Subgroup analysis within the surgical radiculopathy population compared those patients achieving relief of symptoms and those with PPNP. RESULTS: Heightened IL-6, Il-17, and TNF-α levels were observed for the lumbar radiculopathy group compared with the neuropathic pain group. This was complemented by higher WBC count and a greater fraction of Th17 lymphocytes among radiculopathy patients. In the lumbar discectomy subgroup, pain relief was seen among patients with preoperatively elevated IL-17 levels. Those patients with PPNP refractory to surgical discectomy exhibited normal cytokine levels. CONCLUSION: Differences in Th17 immune activation are seen among radiculopathy and neuropathic pain patients. These cellular and molecular profiles may be translated into biomarkers to improve patient selection for structural spine surgery.

[Effect of Subcutaneous Injection of Lidocaine in Zusanli (ST 36) and Jiaji (EX-B 2) Regions on Immune Function in Patients Undergoing Laparoscopic Cholecystectomy].

OBJECTIVE: To observe the effect of acupoint injection of Lidocaine on serum IL-1ß, TNF-α and T-lymphocyte subset activities in patients undergoing laparoscopic cholecystectomy (LC), so as to reveal its mechanisms underlying relieving postoperative pain and potentiating rehabilitation. METHODS: Eighty patients scheduled for elective LC surgery (grade I or II, according to American Standards of Association, ASA) were randomly divided into four groups, namely intravenous analgesia (IVA) , right forearm-injection (forearm-), Jiaji (EX-B 2, Thorax 8)-injection (EX-B 2-1), and Zusanli-injection (ST 36-1), with 20 patients in each group. The conventional anesthetic induction and maintenance with Penehyclidine Hydrochloride, Midazolam, Sulfentanil, Propofol, Atracurium Besilate, and Remifentanil were same in all the 4 groups. For patients of the forearm-I, EX-B 2-I and ST 36-1 groups, 5% Lidocaine was injected into the subcutaneous layer of the anterior side of right forearm near the elbow, EX-B 2 and ST 36 regions, respectively. Analgesia pump (filled with Sulfentanil, Ramosetron + normal saline) was connected af- ter the tracheal extubation. The visual analog scale (VAS) was used to assess the patient's pain reaction after tracheal extubation (T 1), and 6 h (T 2), 24 h (T 3) and 48.h (T 4) after surgery. The times of RCA pressing and the total dose of Sufentanil in the process of postoperative analgesia were recorded as well. The contents of serum IL-1ß and TNF-α were analyzed by ELISA, and the counts of CD4+ and CD+ T cells were detected by flow cytometry. RESULTS: Compared with T 1 in the same one group, the VAS scores at time-points of T 2, T 3 and T 4 after surgery of all the IVA, forearm-1, ST 36- and EX-B 2- groups were reduced significaantly (P < 0.05). The times of PCA-pump pressing and the doses of the administrated Sufentanil were considerably lower in the ST 36-1 and EX-B 2-I groups than in the IVA and forearm-I groups (P < 0.05). In comparison with pre-anesthesia in the same one group, serum TNF-α and IL-1ß contents at T 1 were remarkably increased, while the ratios of CD4⁺/CD8⁺ at T 4 in the 4 groups were evidently down-regulated (P < 0.05). The contents of serum TNF-α and IL-1ß at T 3 and T 4 were obviously lower in both ST 36-1 and EX-B 2-1 groups than in the IVA and forearm-I groups (P < 0.05). No significant differences were found among the 4 groups in the VAS scores at the 4 time-points, in the serum TNF-α and IL-1ß contents at T 0 and T 1, in the counts of CD4⁺ and CD8⁺ T cells and ratios of CD4⁺/CD8⁺ at T 0, T 3 and T 4, and between the ST 36-1 and EX-B 2-groups in all the 8 indexes (P > 0.05). CONCLUSION: Acupoint injection of Lidocaine is effective in relieving pain in LC patients, which is demonstrated by reducing VAS score, PCA pump pressing times, and administrated Sufentanil dose, and may be associated with its effects in down-regulating serum TNF-α and IL-1ß contents.

Neuroimmune mechanisms in cancer pain.

PURPOSE OF REVIEW: The current review provides a summary of recent advances in our understanding of the neuroimmune interactions which influence the development of pain associated with cancer. RECENT FINDINGS: Common signalling pathways, mediators and immune cell types are involved in the generation of pain as a result of both cancer and its treatment. Distinct alterations in central and peripheral neuronal function occur in multiple forms of cancer pain. Other more unusual neuroimmune processes such as graft-versus-host disease may cause cancer pain. SUMMARY: Identification of the cellular processes which underlie the generation of cancer pain provide potential novel targets for drug development and may eventually lead to improved pain management for cancer patients.

Gabapentin-induced changes of plasma cortisol level and immune status in hysterectomized women.

AIM: We have examined the effects of gabapentin (GBP) on stress-related changes of cortisol and catecholamines in patients who underwent hysterectomy because of uterine fibrinoids. Additionally, we have observed the effect of GBP on the immune status in the acute stress response to surgery. METHODS: Sixty patients scheduled for an abdominal hysterectomy were randomly assigned to the GBP administration 1h before surgery (n=30 pts), or to the placebo group (n=30 pts). Blood samples were collected before and 24h after the surgery. The intensity of pain was assessed by a visual analogue scale (VAS) every 8h at rest. Immunomodulatory effects of GBP were determined by flow cytometry. We followed the total proportion of CD3(+) lymphocytes, CD3(+)CD4(+), CD3(+)CD8(+), CD19(+) B lymphocytes, CD16(+)CD56(+)CD3(-)NK cells and CD16(+)CD56(+)CD3(+) NKT cells before and 24h after hysterectomy. The plasma cortisol and catecholamines concentration was used to estimate the level of the stress response. RESULTS: VAS pain score at rest was significantly lower in the GBP group than in the placebo group (P=0.003). Application of GBP significantly decreased the plasma cortisol level 24h after the operation in comparison to the placebo group (P<0,001). We found significant positive correlation between the VAS pain score and concentration of cortisol in all patients (P=0.025). GBP reduced the concentration of catecholamines (p<0.05). The proportion of CD3(+) (P=0.027) and CD3(+)CD4(+)cells (P=0.006) was significantly lower in the GBP group 24h after operation, while the contribution of CD19(+) (P=0.033) was significantly higher. CONCLUSION: Preoperative administration of GBP reduced the pain scores at rest in patients at 0, 16 and 24h after abdominal hysterectomy. Additionally, GBP reduced the stress response and changed immune parameters in the reaction to surgery.

Effect of thoracic epidural analgesia on pro-inflammatory cytokines in patients subjected to protective lung ventilation during Ivor Lewis esophagectomy.

BACKGROUND: Thoracic epidural analgesia (TEA) has a well-known effect on neurohormonal response. Attenuation of stress response by post-operative epidural analgesia has shown beneficial effects such as lower pain scores and less immunological alterations. OBJECTIVES: Investigation of the combined effects of TEA and protective lung ventilation on pro-inflammatory cytokines and patients' outcome after Ivor Lewis esophagectomy. STUDY DESIGN: A randomized controlled study. SETTING: Academic medical center. METHODS: Thirty patients of the American Society of Anesthesiologists (ASA) I and II were randomly allocated into 2 groups: G1 (n = 15) patients received general anesthesia and were mechanically ventilated with 9 mL/kg during 2 lung ventilations, reduced to 5 mL/kg and 5cm H2O positive end expiratory pressure (PEEP) during one lung ventilation (OLV) or GII) (n = 15) patients received TEA and the same general anesthesia and mechanical ventilation used in G1. Assessment parameters included hemodynamics, pain severity, total analgesic consumption, and measurement of interleukins (IL) (IL-6 and IL-8) at baseline time after anesthetic induction (TBaseline,); at the end of the abdominal stage of the operation (TAbdo,); 15 minutes after initiation and at the end of OLV (TOLV 15) and (TOLV End) respectively; one and 20 hours after the end of the surgical procedure (TPostop1 and TPostop20), respectively, and patient's outcome also recorded. RESULTS: There was a significant reduction in mean arterial blood pressure (MAP) and pulse rate in GII during the intraoperative period, at Tabdo, TOLV15, and TOLV End (P < 0.05). The mean of systolic blood pressure (SBP) values were significantly lower in GII over all 3 post-operative days (P = 0.001), and the mean diastolic blood pressure (DBP) showed a significant reduction in GII for 16 hours post-operatively (P = 0.001). The mean of heart rate values showed a significant reduction in GII over all 3 post-operative days in comparison to GI (P = 0.001). The mean resting and dynamic VAS scores were significantly reduced in GII at all time periods studied in comparison to G1 (P = 0.001). The daily PCA morphine consumption was markedly decreased in GII compared to GI in the first 3 days post-operatively (P = 0.001). There were significant reductions in blood level of IL-6 and IL-8 in GII compared to G1 over the entire study period (P < 0.05). There were no significant differences in post-operative adverse effects between the 2 groups (P > 0.05). The duration of stay in PACU was significantly decreased in GII (10 ± 2 days) compared to GI (15 ± 3 days) (P = 0.001). LIMITATIONS: This study is limited by its sample size. CONCLUSION: Our study concluded that TEA reduced the systemic pro-inflammatory response and provided optimal post-operative pain relief. Although there were no significant differences in adverse events, there was a trend towards improved outcome. Further clinical studies with larger numbers of patients are required.

Th17 cell frequency and IL-17 concentration correlate with pre- and postoperative pain sensation in patients with intervertebral disk degeneration.

Numerous studies have revealed the presence of T helper 17 (Th17) cells in pathologic intervertebral disk (IVD) tissues and the contribution of Th17-associated cytokines to the development of this disease. However, the pre- and postoperative changes in the proportion of Th17 cells and the concentration of IL-17 in the peripheral blood of patients with IVD degeneration are not clear. The levels of Th17 frequency and the interleukin-17 (IL-17) concentration in peripheral blood from patients and volunteers were examined by flow cytometry and by enzyme-linked immunosorbent assay (ELISA), respectively. The clinical results were evaluated using the visual analogue scale (VAS). These results were subjected to a correlation analysis. Compared with the normal controls, the proportion of Th17 cells and the concentration of IL-17 were significantly increased preoperatively in patients with IVD degeneration. Postoperatively, the levels of Th17 cells and the expression of IL-17 were dramatically decreased. The correlation analysis of the VAS pain scores, Th17 cell frequency, and IL-17 concentration, including the pre- and postoperative levels and the changes induced by the surgery, revealed a positive correlation. The authors' results explain the contribution of Th17 cells and IL-17 to the pain sensation experienced by patients with IVD degeneration. These 2 factors may be good indicators for the evaluation of the surgical outcome of patients with lumbar disk herniation.

A prospective study concerning the relationship between metal allergy and post-operative pain following total hip and knee arthroplasty.

PURPOSE: A prospective study was conducted to detect whether a relationship exists between metal allergy and post-operative pain in total hip and knee arthroplasty patients. We postulated that to some extent a relationship does exist between them. MATERIALS AND METHODS: Patients who had undergone total hip and knee arthroplasty surgery because of hip and knee disease were included. The exclusion criteria were patients who were treated with immunosuppressor two weeks pre-operatively, skin conditions around the patch testing site, and other uncontrollable factors. Each patient agreed to patch testing for three days before surgery. Photographic images before patch testing, two and three days after patch testing were obtained to evaluate the final incidence of metal allergy. The patch tests contained 12 metal elements; chromium, cobalt, nickel, molybdenum, titanium, aluminium, vanadium, iron, manganese, tin, zirconium, and copper. Two independent observers evaluated the images. The results were divided into a non-metal allergy group and a metal allergy group. Pre-operative and postoperative VAS score, lymphocyte transforming test, and X-rays were collected to detect the relationship between metal allergy and post-operative pain following total hip and knee arthroplasty. RESULTS: There were 96 patients who underwent pre-operative patch testing. The overall metal allergy rate was 51.1% (49/96) in our study. Nickel, cobalt, manganese, and tin were the most common allergic metal elements in our study. Nine inappropriate cases were excluded, and 87 patients were finally included in our study. There were 36 metal allergy and 26 non-metal allergy patients in the THA group, while 11 metal allergy and 14 non-metal allergy patients were found in the TKA group. We found no relationship existed between metal allergy and post-surgery pain in total hip and knee arthroplasty. CONCLUSION: Pain caused by metal allergy usually presents as persistent and recurrent pain. The white cell count, C-reactive protein, erythrocyte sedimentation rate and postoperative radiographs were not affected. Currently, patch testing and lymphocyte transforming tests are used for metal allergy diagnosis. We deemed that a relationship between post-surgery pain and metal allergy in total hip and knee patients may exist to some extent. Larger samples and longer follow-up time are essential for further study.

[ASSESSMENT OF POSTOPERATIVE PAIN SYNDROME AT SINGLE-PORT TRANSUMBILICAL LAPAROSCOPIC CHOLECYSTECTOMY COMPARED TO TRADITIONAL LAPAROSCOPIC CHOLECYSTECTOMY].

The article analyzes the dynamics of postoperative pain at single-port transumbilical laparoscopic cholecystectomy compared to traditional laparoscopic cholecystectomy. It is shown that the intensity of pain in patients who have undergone laparoscopic procedures through a single transumbilical access was significantly less than in patients with traditional laparoscopic intervention. Furthermore, the use of a single-port transumbilical laparoscopic cholecystectomy accompanied by a smaller increase in the concentration of proinflammatory cytokines compared with patients who had laparoscopic procedures through four trocar accesses.

[Effects of epidural anesthesia on stress-induced immune supression during major corrective spine surgery].

STUDY DESIGN: A prospective, randomized study wias performed to compare two anesthetic methods. OBJECTIVE: To evaluate the effect of epidural analgesia on postoperative pain, endocrine- metabolic and inflammatory stress response and cellular inmmune responses during major corrective spine surgetry. METHODS: The study included 350 patients aged 15 to 65 who were randomly allocated to two equal groups. Group I (n=205) had continuous epidural analgesia (E4) and sevoflurane anesthesia during surgety and continuous epidural analgesia with ropivacaine and fentanil after surgery; Group 2 (n= 145) had general anesthesia with sevoflurane and fentanil and systemic administration of opioids after surgery. Patient pain, PONV syndrome, mobility, and satisfaction were measured after surgery along with plasma levels ofcortisol, ghmcose, interleukins IL-1ß, IL-6, and IL-10 during and after surgemy C-reactive protein (CRP), and cell-surface receptor expression of immune cells (cluster of differentiation) HLA-DR+/CD3-, HLA-DR+/CD3+, HILA-DR, CD3, CD4, CD8, CD16, CD19 CD16/56+, and CD16/56+/CD3+) were measured perioperatively. RESULTS: In group 1, there were significantly less pain, less nausea, earlier mobility, and higher satisfaction than those in group 2. Group I has also demonstrated significantly less plasma levels of glucose, cortisol, CRP, IL-lß, IL-6, IL-10 at various stages. The ratio of CD4/CD8 (p=0.001) and B cells (p=0.01) have increased by postoperative day 3 in group 1. NK-cells (CD16/56+) have decreased significantly by day 3 after surgery (p=0.001) compared to the group 2. T-lymphocytes, (CD3) have decreased in all patients, but they were significantly lower in patients receiving opioids, compared wiith EA. CONCLUSIONS: Polerfulr afferent stimulation in major corrective spine surgery accompanied by immunosuppression for at least a wieek after surgery. EA reduces the surgical stress response, prevents postoperative lymphocyte apoptosis and thus, increases stress and infectious resistance.