Severity of intervertebral disc herniation regulates cytokine and chemokine levels in patients with chronic radicular back pain.

OBJECTIVE: The contributions of intervertebral disc disease and subject-specific covariates to systemic inflammation in low back pain are unknown. We examined the effects of symptomatic disc herniation (DH) and MRI herniation severity on serum cytokine levels in clinical subjects. DESIGN: Cytokine levels from lumbar DH subjects (N = 78) were compared to control subjects (N = 57) accounting for effects of DH, age, body mass index (BMI) and gender. Effect of DH severity on cytokine levels was analyzed on subsets of subjects with acute or chronic pain. Serum cytokines were also analyzed in a subset of patients between pre- and 3 months post-surgery. RESULTS: Cytokine levels were elevated in the serum of patients with symptomatic DH, and the covariates age, BMI and gender significantly contributed to levels of some cytokines. Severity of herniation was a significant contributor to pain intensity (VAS), serum levels of HMGB1, PDGFbb, and IL-9. The relationship between DH severity and cytokine levels was confirmed in subjects with chronic, but not acute symptoms. Serum levels of macrophage migration inhibitory factor (MIF) decreased, whereas levels of CCL3, CCL11, CXCL1, and CXCL10 were significantly elevated post surgery. CONCLUSIONS: This study is the first to show that DH severity is coordinately associated with changes in serum levels of inflammatory cytokines in chronic pain subjects. HMGB1, PDGFbb and IL-9 are novel mediators of increasing DH severity, indicative of cellular damage, neuro-inflammation and angiogenesis. Resolution of inflammation was observed with decrease in MIF post surgery. However, elevated chemokine levels indicate ongoing remodeling and wound healing at 3-month time point.

A systematic review of the role of inflammatory biomarkers in acute, subacute and chronic non-specific low back pain.

BACKGROUND: Low back pain (LBP) is one of the greatest contributors to disability in the world and there is growing interest on the role of biomarkers in LBP. To purpose of this review was to analyze available evidence on the relationship between inflammatory biomarkers, clinical presentation, and outcomes in patients with acute, subacute and chronic non-specific low back pain (NSLBP). METHODS: A search was performed in Medline, Embase, Cinahl and Amed databases. Studies which measured levels of inflammatory biomarkers in participants with NSLBP were included. Two reviewers independently screened titles and abstracts, full-texts, and extracted data from included studies. Methodological quality was assessed using the Newcastle Ottawa Quality Assessment Scale. Level of evidence was assessed using the modified GRADE approach for prognostic studies. RESULTS: Seven primary studies were included in this review. All results assessed using the modified GRADE demonstrated low to very low quality evidence given the small number of studies and small sample. Three studies examined C-reactive protein (CRP), one of which found significantly higher CRP levels in an acute NSLBP group than in controls and an association between high pain intensity and elevated CRP. Three studies examined tumor necrosis factor alpha (TNF-α), two of which found elevated TNF-α in chronic NSLBP participants compared to controls. Two studies examined interleukin 6 (IL-6), none of which found a significant difference in IL-6 levels between NSLBP groups and controls. Two studies examined interleukin 1 beta (IL-ß), none of which found a significant difference in IL-ß levels between NSLBP groups and controls. CONCLUSIONS: This review found evidence of elevated CRP in individuals with acute NSLBP and elevated TNF-Α in individuals with chronic NSLBP. There are a limited number of high-quality studies evaluating similar patient groups and similar biomarkers, which limits the conclusion of this review.

Diagnostic Value of D-dimer in Distinguishing between Spontaneous Subarachnoid Hemorrhage and Nontraumatic Acute Headache.

BACKGROUND: Spontaneous subarachnoid hemorrhage (SSAH) and nontraumatic acute headache patients presented with symptoms similar to headache. This study was to investigate the diagnostic value of D-dimer (DD) in distinguishing patients with SSAH from those with nontraumatic acute headache. METHODS: This retrospective study was performed and data were gathered from medical records of patients with acute headache symptoms from the Emergency Department and Neurology Clinics who were admitted to the Fourth Affiliated Hospital Zhejiang University School of Medicine between January 2015 and January 2019. Of the total 114 patients with headache symptoms enrolled in this study, 46 patients were diagnosed with SSAH (SAH group) and 68 cases with nontraumatic acute headache due to other causes (non-SAH group). The plasmatic levels of PT, INR, APTT, TT, FIB, and DD were compared between the two groups. Student's t-test of independent samples was adopted for comparing the mean between the two groups. Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC). Comparison of AUC was performed using the Z-test. RESULTS: There were no significant statistical differences of the PT, INR, TT and FIB (all p > 0.05). The APTT was significantly decreased in the SSAH group compared with non-SAH group, while DD was significantly increased (all p < 0.001); moreover, AUC in distinguishing patients with SSAH from those with nontraumatic acute headache was 0.721 (95% confidence interval (CI), 0.629 to 0.801) for APTT and 0.886 (95% CI, 0.813 to 0.938) for DD. There was a significant statistical difference (p < 0.01). Finally, the cutoff values were 25.2s in distinguishing patients with SSAH from those with nontraumatic acute headache (specificity 73.53% and sensitivity 60.87%) for APTT and 0.31 mg/L (specificity 83.82% and sensitivity 84.78%) for DD. CONCLUSIONS: As an easy-to-obtain and potential biomarker, DD could demonstrate more accurate and reliable diagnostic value than APTT in distinguishing between SSAH and nontraumatic acute headache.

Serum zinc level during and after acute painful episodes in children with sickle cell anemia at the aminu kano teaching hospital, Kano, Northern Nigeria.

BACKGROUND: Acute painful crisis due to vaso-occlusive event is the leading cause of hospitalization in patients with sickle cell anemia (SCA). Zinc deficiency in children with SCA is associated with increased frequency and severity of acute painful events. We determined serum zinc level in children with SCA during acute painful crisis and compared the same with children with SCA who are in steady state and healthy non-sickle cell disease children. SUBJECTS AND METHODS: This was a descriptive longitudinal study, involving children with SCA age 6 months to 15 years at Aminu Kano Teaching Hospital, Kano, Northern Nigeria. Subjects were recruited into three groups, which consisted of SCA in acute painful crisis, SCA in steady state, and normal subjects with hemoglobin AA (HbAA). A total of 210 subjects were recruited, 70 subjects each for SCA in acute painful crisis, SCA in steady state, and HbAA groups, respectively. Serum zinc was analyzed with atomic absorption spectrophotometery. Serum zinc levels were repeated in children with SCA and acute painful crisis 4 weeks after resolution of painful events. RESULTS: The mean serum zinc level of SCA with acute painful crisis was higher than SCA in steady state, but the difference was not statistically significant (24.4 [11.0] and 23.4 [7.4]) µg/dL, respectively (t = 16.04, P = 0.54). While the HbAA control had significantly higher mean serum zinc level than SCA groups, both in acute painful and in steady state (F = 59.3, P = 0.001). Among children with SCA and acute painful crisis, repeat serum zinc level 4 weeks after resolution of acute painful events was significantly higher than during pain crisis (t = 64, P = 0.001). CONCLUSION: Zinc deficiency occurs in children with SCA and the deficiency is worsened by acute painful events Therefore, it is recommended that zinc level should be assessed and any deficiency treated. Supplementation of zinc should also be enhanced as this may reduce painful crisis in SCA.

ISSLS PRIZE IN CLINICAL SCIENCE 2018: longitudinal analysis of inflammatory, psychological, and sleep-related factors following an acute low back pain episode-the good, the bad, and the ugly.

STUDY DESIGN: Prospective longitudinal study. OBJECTIVE: To determine whether systemic cytokines and C-reactive protein (CRP) during an acute episode of low back pain (LBP) differ between individuals who did and did not recover by 6 months and to identify sub-groups based on patterns of inflammatory, psychological, and sleep features associated with recovery/non-recovery. Systemic inflammation is observed in chronic LBP and may contribute to the transition from acute to persistent LBP. Longitudinal studies are required to determine whether changes present early or develop over time. Psychological and/or sleep-related factors may be related. METHODS: Individuals within 2 weeks of onset of acute LBP (N = 109) and pain-free controls (N = 55) provided blood for assessment of CRP, tumor necrosis factor (TNF), interleukin-6 (IL-6) and interleukin-1ß, and completed questionnaires related to pain, disability, sleep, and psychological status. LBP participants repeated measurements at 6 months. Biomarkers were compared between LBP and control participants at baseline, and in longitudinal (baseline/6 months) analysis, between unrecovered (≥pain and disability), partially recovered (reduced pain and/or disability) and recovered (no pain and disability) participants at 6 months. We assessed baseline patterns of inflammatory, psychological, sleep, and pain data using hierarchical clustering and related the clusters to recovery (% change in pain) at 6 months. RESULTS: CRP was higher in acute LBP than controls at baseline. In LBP, baseline CRP was higher in the recovered than non-recovered groups. Conversely, TNF was higher at both time-points in the non-recovered than recovered groups. Two sub-groups were identified that associated with more ("inflammatory/poor sleep") or less ("high TNF/depression") recovery. CONCLUSIONS: This is the first evidence of a relationship between an "acute-phase" systemic inflammatory response and recovery at 6 months. High inflammation (CRP/IL-6) was associated with good recovery, but specific elevation of TNF, along with depressive symptoms, was associated with bad recovery. Depression and TNF may have a two-way relationship. These slides can be retrieved under Electronic Supplementary Material.

[PROTECTIVE PROPERTIES OF DRUGS OF PLANT ORIGION IN ACUTE EMOTIONAL AND PAINFUL STRESS IN RATS].

The aim of the investigation was to study the protective properties of the herbal preparation - biotrite and tranquilizer diazepam under the modeling of emotional and painful stress in rats. Materials and methods. The experiment was conducted on 24 white male rats of 5 months of age. Animals (6 rats in the group) were kept on the standard diet of the vivarium: 1st group was intact; rats of the 2nd, 3rd and 4th groups were reproduced acute painful emotional stress for 3 hours. 60 minutes before the stress, rats received per os: the 2nd group - water, the 3rd group - diazepam in a dose of 1.25 mg / kg body weight of rats; 4th group - a preparation of biotrite in a dose of 50 mg / kg. Results and conclusion. The conducted studies demonstrated significant adaptive properties of the biotrite preparation, and the degree of their manifestations was higher than the stress-protective effects of diazepam.

Dipyrone (metamizole) markedly interferes with platelet inhibition by aspirin in patients with acute and chronic pain: A case-control study.

BACKGROUND: Nonopioid analgesic drugs may interfere with platelet inhibition by aspirin. Recent in vitro and clinical studies in patients with cardiovascular disease have suggested that this pharmacodynamic interaction may also occur with dipyrone, a nonopioid analgesic popular in Europe, Asia and South America. OBJECTIVE: Dipyrone is used extensively in acute and chronic pain. This study was undertaken to provide clinical data, so far missing, on its interactions in this group of patients. DESIGN: A case-control study. SETTING: Primary care in one European university hospital centre. PATIENTS: In total, 27 patients with stable cardiovascular, cerebrovascular or peripheral arterial disease and acute or chronic pain were identified and given dipyrone for at least 5 days in combination with low-dose aspirin. In total, 10 comparable patients on low-dose aspirin alone served as controls. MAIN OUTCOME MEASURES: Platelet-rich plasma was prepared to determine arachidonic acid-induced aggregation (aggregometry) and thromboxane formation (immunoassay). Platelet sensitivity to aspirin was examined in vitro. The presence of dipyrone (metabolites) in plasma was confirmed by HPLC. Additional in vitro measurements examined the aspirin/dipyrone interaction in healthy donors. RESULTS: Inhibition of aggregation was observed in only six of 27 patients receiving aspirin with dipyrone, with absence of complete inhibition by antiplatelet therapy showing in 78% of patients. In contrast, aggregation was completely inhibited in nine of 10 control patients (P < 0.001). Platelet thromboxane synthesis was higher in patients receiving dipyrone + aspirin compared with controls (387 ±â€Š89 vs. 7 ±â€Š1 ng ml, P < 0.001). Aspirin added in vitro failed to inhibit aggregation and thromboxane synthesis in platelet-rich plasma from dipyrone-treated patients. In vitro measurements with blood from healthy individuals confirmed that dipyrone dramatically reduces inhibition of platelet thromboxane synthesis by aspirin. CONCLUSIONS: Dipyrone given for 5 days or longer blunts platelet inhibition by low-dose aspirin in the majority of recipients. TRIAL REGISTRATION: German Clinical Trials Register: DRKS ID DRKS00000204. Universal Trial Number (UTN): U1111-1113-3946.

Clinical application of neutrophil CD64 quantification for differential diagnosis of acute scrotum.

The management of acute scrotum can be challenging, especially in infants or patients with a neurological or neurodevelopmental disorder in whom presentation, diagnosis and definitive management tends to be delayed. This leads to poor outcomes, such as loss of the affected testis. Here we present two cases of testicular torsion in patients with neurodevelopmental disorders, and a further two cases of epidydimo-orchitis in whom measurement of CD64 expression on neutrophils was helpful for differential diagnosis. These data suggest that the levels of expression of CD64 by neutrophils, known as a marker of infection, could also be useful for differentiating between testicular torsion and infection in acute scrotum.

Effect of high-dose paracetamol on needle procedures in children with cancer--an RCT.

AIM: The aim was to investigate whether children experience less pain, fear and/or distress when they receive high-dose paracetamol compared with placebo, using a needle insertion in a subcutaneously implanted intravenous port as a model. METHODS: Fifty-one children ranging from 1 to 18 years of age being treated in a paediatric oncology setting were included consecutively when undergoing routine needle insertion into a subcutaneously implanted intravenous port. All children were subjected to one needle insertion following topical anaesthetic (EMLA) application in this double-blind, placebo-controlled RCT, comparing orally administered paracetamol (n = 24) 40 mg/kg body weight (max 2000 mg) with placebo (n = 27). The patients' pain, fear and distress were reported by parents, nurses and children (≥7 years of age) using 0- to 100-mm visual analogue scales (VAS). In addition, pain observation, procedure time and cortisol reduction were assessed. RESULTS: No differences between the paracetamol and the placebo group were found with respect to demographic characteristics. According to VAS reports, paracetamol did not reduce pain, fear and distress compared with placebo. Pain observation, cortisol reduction and procedure time did not differ between the study groups. CONCLUSION: Paracetamol provides no additive effect in reducing pain, fear and distress when combined with topical anaesthesia in children undergoing port needle insertion.

Bis(phenylimidazoselenazolyl) diselenide: a compound with antinociceptive properties in mice.

The present study examined the effect of peroral administration of bis(phenylimidazoselenazolyl) diselenide (BPIS) in thermal and chemical models of pain in mice. The involvement of the opioid system in the BPIS antinociceptive effect was also examined, as well as potential nonspecific disturbances in locomotor activity or signs of acute toxicity. BPIS (25-100 mg/kg) induced an increase in tail-immersion response latency and this effect was significant at pretreatment times of 15 min to 4 h, but not at 8 h. The hot-plate response latency was also increased by the administration of BPIS (25-100 mg/kg). BPIS, at doses of 25 and 50 mg/kg, inhibited writhing behaviour caused by an intraperitoneal acetic acid injection. Both early and late phases of nociception caused by the intraperitoneal formalin injection were inhibited by BPIS (10-50 mg/kg). BPIS, administered at doses equal to or greater than 10 and 25 mg/kg, reduced nociception produced by an intraperitoneal injection of capsaicin and glutamate, respectively. The antinociceptive effect of BPIS, when assessed in the tail-immersion test, was not abolished by naloxone. BPIS (10-50 mg/kg) did not alter alanine transaminase and aspartate transaminase activities (parameters of hepatic function) or urea and creatinine levels (parameters of renal function), and did not affect motor activity in the open-field test. The results indicate that BPIS produced an antinociceptive action without causing motor disturbances or toxicity. Moreover, opioidergic mechanisms seem not to be involved in the antinociceptive action of BPIS. Here, BPIS has been found to be a novel organoselenium compound with antinociceptive properties; however, more studies are required to examine its therapeutic potential for pain treatment.

Within-limb somatotopic representation of acute muscle pain in the human contralateral dorsal posterior insula.

It is well established that the insular cortex processes noxious information. We have previously shown that noxious inputs from the arm and leg are coarsely organized somatotopically within the dorsal posterior insula. The same has been shown for inputs from C tactile afferents, which mediate affective touch, and it has been suggested that the insula may be responsible for the localization of some somatosensory stimuli. Knowing the degree of spatial detail may have significant implications for the potential role of the dorsal posterior insula in the processing of noxious stimuli. Using high-resolution functional magnetic resonance imaging (fMRI), we compared insula activation patterns in 13 subjects during muscle pain induced by injection of hypertonic saline (5%) into three muscles within the same limb: shoulder (deltoid), forearm (flexor carpi radialis), and hand (first dorsal interosseous). Mapping the maximally activated voxels within the contralateral dorsal posterior insula in each individual subject during each pain stimulus revealed a clear somatotopy of activation within the contralateral dorsal posterior insula. Shoulder pain was represented anterior to forearm pain and medial to hand pain. This fine somatotopic organization may be crucial for pain localization or other aspects of the pain experience that differ depending on stimulation site.

Sex Differences in Interleukin-6 Responses Over Time Following Laboratory Pain Testing Among Patients With Knee Osteoarthritis.

Epidemiological studies suggest that women are not only at a higher risk for developing knee osteoarthritis (KOA), but also report greater symptom severity compared to men. One potential underlying mechanism of these sex differences may be exaggerated inflammatory responses to pain among women compared to men. The present study examined sex differences in interleukin-6 (IL-6) response over time following experimental pain testing. We hypothesized that women, when compared to men, would show greater IL-6 reactivity when exposed to acute pain in a human laboratory setting. Eighty-four participants (36 men and 48 women) with KOA scheduled for total knee arthroplasty underwent a quantitative sensory testing (QST) battery. A total of seven IL-6 measurements were taken, twice at baseline, once immediately after QST, and every 30 minutes up to 2 hours after QST. Consistent with our hypothesis, women, when compared to men, showed accelerated increases in IL-6 levels following laboratory-evoked pain, even after controlling for body mass index, marital status, clinical pain, evoked pain sensitivity, and situational pain catastrophizing. Given that KOA is a chronic condition, and individuals with KOA frequently experience pain, these sex differences in IL-6 reactivity may contribute to the maintenance and/or exacerbation of KOA symptoms. PERSPECTIVES: The present study demonstrates that women, when compared to men, exhibit greater IL-6 reactivity after exposure to laboratory-evoked pain. Such sex differences may explain the mechanisms underlying women's higher chronic pain risk and pain perception, as well as provide further insight in developing personalized pain interventions.

An up-to-date overview of sublingual sufentanil for the treatment of moderate to severe pain.

INTRODUCTION: Sufentanil is a selective µ-opioid agonist, used intravenously and intrathecally for moderate to severe acute pain. Sublingual sufentanil nanotablets have been developed; 15 mcg tablet for a patient-controlled analgesia device and 30-mcg tablet for a single-dose device administered by a healthcare professional. Dosing interval is a minimum of 20 min for a 15 mcg tablet and a treatment duration of up to 72 hours. The single 30-mcg nanotablet dosing interval is 1 hour. Mean plasma elimination half-life is 13 hours and bioavailability 47-57% after the first sublingual sufentanil tablet. AREAS COVERED: This review focuses on the effectiveness, safety, and feasibility of sublingual sufentanil 30-mcg single dose suspended by a healthcare professional for the management of moderate to severe acute pain. A few Phase 4 studies concerning the sublingual sufentanil tablet system containing 15-mcg nanotablets are also reviewed. EXPERT OPINION: Sufentanil sublingual 30-mcg nanotablets provide effective pain relief in various acute moderate to severe pain states. The safety profile of sublingual sufentanil 30 mcg is typical to opioids nausea, vomiting, and sedation being the most common ones. Sublingual sufentanil 30-mcg nanotablet has the potential for efficient moderate to severe pain management in supervised healthcare facilities.

Nonspecific Low Back Pain: Inflammatory Profiles of Patients With Acute and Chronic Pain.

BACKGROUND: The pathogenesis of low back pain (LBP) remains unclear. However, recent studies suggest that the inflammatory response may be inherent in spinal pain. The purpose of this study was to discern inflammatory profiles in patients with nonspecific acute and chronic LBP in relation to those in asymptomatic individuals. MATERIALS AND METHODS: Peripheral blood samples were obtained from asymptomatic controls and patients with nonspecific acute and chronic LBP reporting a minimum pain score of 3 on a 10-point Visual Analogue Scale (VAS). The levels of in vitro production of proinflammatory (tumor necrosis factor α [TNFα], interleukin [IL] 1ß, IL-6, IL-2, interferon γ) and anti-inflammatory (IL-1 receptor antagonist, soluble receptors of TNF2, and IL-10) mediators were determined by specific immunoassays. RESULTS: The mean VAS scores were comparable between the acute and chronic LBP patient groups. Compared with asymptomatic group, the production of TNFα, IL-1ß, IL-6 and their ratios to IL-10 levels were significantly elevated in both patient groups (P=0.0001 to 0.003). In acute LBP group, the ratio of IL-2:IL-10 was also significantly increased (P=0.02). In contrast, the production of interferon γ was significantly reduced compared with the other study groups (P=0.005 to 0.01), nevertheless, it was positively correlated (P=0.006) with pain scores. In chronic LBP patients, the production of TNFα, IL-1 receptor antagonist, and soluble receptors of TNF2 was significantly increased (P=0.001 to 0.03) in comparison with the control and acute LBP groups, and TNFα and IL-1ß levels were positively correlated (P<0.001) with VAS scores. CONCLUSIONS: The inflammatory profiles of patients with acute and chronic LBP are distinct. Nonetheless, in both patient groups, an imbalance between proinflammatory and anti-inflammatory mediator levels favors the production of proinflammatory components.

Progesterone relates to enhanced incisional acute pain and pinprick hyperalgesia in the luteal phase of female volunteers.

The role of sex hormones on postsurgical pain perception is basically unclear. Here, we studied the role of endogenous gonadal hormones for pain and hyperalgesia in human volunteers after experimental incision. A 4-mm incision was made in the volar forearm of 15 female volunteers both in the follicular and the luteal phase (random block design). Somatosensory profiles were assessed at baseline and 1 to 72 hours after incision by quantitative sensory testing, compared between both cycle phases, and related to individual plasma levels of gonadal hormones. Sensory testing at baseline revealed significantly lower pain thresholds (25 vs 46 mN, P < 0.005) and increased pain ratings to pinprick (0.96 vs 0.47, P < 0.0001) in the luteal phase; similarly, 1 hour after incision, pain intensity to incision (38 vs 21/100, P < 0.005), pinprick hyperalgesia by rating (P < 0.05), and area of secondary hyperalgesia (P < 0.001) were enhanced in the luteal phase. Multiple regression analysis revealed that pinprick pain sensitivity at baseline was significantly predicted by progesterone (partial r = 0.67, P < 0.001), follicle-stimulating hormone (FSH) (partial r = 0.61, P < 0.005), and negatively by testosterone (partial r = -0.44, P < 0.05). Likewise, incision-induced pain and pinprick hyperalgesia (rating and area) were significantly predicted by progesterone (partial r = 0.70, r = 0.46, and r = 0.47, respectively; P < 0.05-0.0001) and in part by FSH; the contribution of estrogen, however, was fully occluded by progesterone for all measures. In conclusion, pinprick pain and incision-induced pain and mechanical hyperalgesia were greater in the luteal phase and predicted by progesterone, suggesting a major role for progesterone. Other hormones involved are testosterone (protective) and in part FSH.

The glycation products before and after therapy for acute and chronic pain.

Pain increased the number of free radicals in the body. Previously, we studied changes mainly in oxygen and nitroxide free radicals and described these changes relative to the lipids and saccharides. In this article we focus on changes relative to proteins. Assessment of AGE products (advanced glycation end-products) was carried out by measuring fluorescence. Patients were divided into two groups: 15 patients with acute pain and 17 patients with chronic pain. Acute pain was associated with a variety of surgical procedures and patients were examined before and after surgical procedures. The group of patients with chronic pain suffered from various types of chronic pain, but mainly back pain. In patients with acute pain, total protein (TP) decreased after surgery, as did the level of AGE and the AGE/TP ratio. Nonetheless, post-operative pain increased. In patients with chronic pain, neither total protein, AGE, or AGE/TP changed, despite significant pain relief being reported after treatment. Changes in proteins, as biochemical markers, before and after pain treatment did not show any significant changes. In patients with acute pain, the recorded changes only lasted for 3-5 days after the operation. While in chronic pain, there were no significant changes at all. The assumption that changes in proteins, as biomarkers, would have the same importance as changes in lipids and saccharides was not proven.

Acute pain and peripheral sensitization following cautery disbudding in 1- and 4-week-old calves.

Acute pain and peripheral sensitization development after cautery disbudding was investigated in 33 calves administered preventive multimodal analgesia. The animals were assigned randomly to three groups: 1) Group SH (Control), undergoing sham disbudding at 1 and 4weeks of age; 2) Group ED (Early Disbudding), undergoing disbudding at 1week of age and sham disbudding at 4weeks of age; 3) Group LD (Late Disbudding), undergoing sham disbudding at 1week of age and disbudding at 4weeks of age. Physiological parameters (heart rate, respiratory rate, rectal temperature, invasive blood pressure, cortisol, ß-endorphin, interleukin-1ß, interleukin-6, tumor necrosis factor-α and haptoglobin plasmatic concentration), local variables (tactile sensitivity score, pressure pain thresholds and horn temperature), behavior and pain scores [multidimensional pain scale and visual analogue scale (VAS)] were assessed at baseline and at several pre-determined time points until 24h after disbudding. Tactile sensitivity score significantly and equally increased in both groups ED and LD and pressure pain thresholds significantly decreased in group LD until 24h after disbudding compared to group SH. Pain and VAS scores significantly and equally increased in both groups ED and LD until 24h after disbudding compared to group SH. No significant differences in physiological parameters, behavior and horn temperature were detected among groups. The present study suggests that acute pain and peripheral sensitization develop and do not differ in calves disbudded at 1week and 4weeks of age. Moreover, the use of physiological and behavioral parameters as sole indicators of acute pain might lead to improper conclusions and should be reassessed.