Paragastric Autonomic Neural Blockade to Prevent Early Visceral Pain and Associated Symptoms After Laparoscopic Sleeve Gastrectomy: a Randomized Clinical Trial.

BACKGROUND: Visceral pain (VP) following laparoscopic sleeve gastrectomy remains a substantial problem. VP is associated with autonomic symptoms, especially nausea and vomiting, and is unresponsive to traditional pain management algorithms aimed at alleviating somatic (incisional) pain. The present study was performed to evaluate the safety and effectiveness of laparoscopic paragastric autonomic neural blockade (PG-ANB) in managing the symptoms associated with VP following sleeve gastrectomy. STUDY DESIGN: This prospective, double-blinded, randomized clinical trial involved patients undergoing laparoscopic sleeve gastrectomy at two high-volume institutions. The patients were randomized to laparoscopic transversus abdominis plane block with or without PG-ANB. The primary outcome was patient-reported pain scores assessed at 1, 8, and 24 h postoperatively. The secondary outcome measures were analgesic requirements, nausea, vomiting, hiccups, and hemodynamic changes immediately after PG-ANB and postoperatively. RESULTS: In total, 145 patients (block group, n = 72; control group, n = 73) were included in the study. The heart rate and mean arterial pressure significantly decreased 10 min after PG-ANB. The visual analog scale score for pain was significantly lower in the PG-ANB than in the control group at 1 h postoperatively (p < 0.001) and 8 h postoperatively (p < 0.001). Vomiting, nausea, sialorrhea, and hiccups were significantly less prevalent in the PG-ANB group. Patients in the PG-ANB group received fewer cumulative doses of analgesics at 1 h postoperatively (p = 0.003) and 8 h postoperatively (p < 0.001). No differences between the groups were detected at 24 h (p = 0.298). No complications related to PG-ANB occurred. CONCLUSION: PG-ANB safely and effectively reduces early VP, associated autonomic symptoms, and analgesic requirements after laparoscopic sleeve gastrectomy.

[Eosinophilic duodenitis associated to food allergy debuting as acute visceral pain in an adult with vitiligo: a case report]. / Duodenitis eosinofílica asociada a alergia alimentaria debutando como dolor visceral agudo en un adulto con vitíligo: reporte de un caso.

BACKGROUND: Eosinophilic duodenitis has a prevalence of 5.1 to 8.2 per 100000 persons. The underlying molecular mechanisms are unknown, but hypersensitivity (seasonal and food allergies, asthma, eczema) response plays a major role in its pathogenesis, allergic predisposition can be found up-to 25-35% of cases. The diagnosis includes clinical manifestation, imaging findings and histological evidence of eosinophilic infiltration >20 eosinophils per high-power field. This is a clinical case report. a 25-years old man with vitiligo consult to emergency department referring dyspepsia symptoms, vomiting and abdominal pain of maximal intensity, in the medical exam upper abdominal pain was found, blood laboratories were unremarkable except a high net eosinophil-count >2000 cells/ul, abdominal ultrasound were normal, upper endoscopy revealed duodenitis with rigid and thickened folds, colonoscopy show hemorrhoids grade I. Coproscopy exam was negative for parasites, total IgE, IgA and IgG were in normal range, a positive IgG to Toxoplasma gondii was reported, autoimmunity panel was negative. In the following 4 days the abdominal pain and eosinophils count increase, a new abdomin-pelvic tomography was done showing thickened duodenum with a new endoscopy showing marked edema in duodenum with severe biliary reflux with biopsies describing an atrophic chronic duodenitis. Allergy tests -skin prick and patch tests- were done resulting positive to cereals (rye, soy, barley), Manihot esculenta, green banana, tomato, cow milk, orange and pineapple. A restrictive diet and protons pump inhibitor was indicated, ambulatory control at 45 days after show symptoms resolution with a normal blood eosinophils count. Here is reported a case of eosinophilic duodenitis related to food allergy in a young man with vitiligo debuting with an unusual clinical presentation of acute visceral pain and biliary reflux which resolved with elimination diet and pantoprazole without use of corticoids, with both, IgE and non-IgE mechanisms playing important roles explaining food sensitization.

Peripheral mechanisms contribute to comorbid visceral hypersensitivity induced by preexisting orofacial pain and stress in female rats.

BACKGROUND: Stress exacerbates many chronic pain syndromes including irritable bowel syndrome (IBS). Among these patient populations, many suffer from comorbid or chronic overlapping pain conditions and are predominantly female. Nevertheless, basic studies investigating chronic psychological stress-induced changes in pain sensitivity have been mostly carried out in male rodents. Our laboratory developed a model of comorbid pain hypersensitivity (CPH) (stress in the presence of preexisting orofacial pain inducing chronic visceral pain hypersensitivity that significantly outlasts transient stress-induced pain hypersensitivity (SIH)) facilitating the study of pain associated with IBS. Since CPH and SIH are phenotypically similar until SIH resolves and CPH persists, it is unclear if underlying mechanisms are similar. METHODS: In the present study, the visceromotor response (VMR) to colorectal distention was recorded in the SIH and CPH models in intact females and ovariectomized rats plus estradiol replacement (OVx + E2). Over several months, rats were determined to be susceptible or resilient to stress and the role of peripheral corticotrophin-releasing factor (CRF) underlying in the pain hypersensitivity was examined. KEY RESULTS: Stress alone induced transient (3-4 weeks) visceral hypersensitivity, though some rats were resilient. Comorbid conditions increased susceptibility to stress prolonging hypersensitivity beyond 13 weeks. Both models had robust peripheral components; hypersensitivity was attenuated by the CRF receptor antagonist astressin and the mast cell stabilizer disodium cromoglycate (DSCG). However, DSCG was less effective in the CPH model compared to the SIH model. CONCLUSIONS AND INFERENCES: The data indicate many similarities but some differences in mechanisms contributing to comorbid pain conditions compared to transient stress-induced pain.

Co-occurrence of pain syndromes.

Many pain conditions in patients tend to co-occur, influencing the clinical expressions of each other in various ways. This paper summarizes the main concurrent pain conditions by analyzing the major interactions observed. In particular, co-occurrence will be examined in: visceral pain (especially ischemic heart disease, irritable bowel syndrome, dysmenorrhea/endometriosis and urinary pain), fibromyalgia, musculoskeletal pain and headache. Two concurrent visceral pains from internal organs sharing at least part of their central sensory projection can give rise to viscero-visceral hyperalgesia, i.e., enhancement of typical pain symptoms from both districts. Visceral pain, headache and musculoskeletal pains (myofascial pain from trigger points, joint pain) can enhance pain and hyperalgesia from fibromyalgia. Myofascial pain from trigger points can perpetuate pain symptoms from visceral pain conditions and trigger migraine attacks when located in the referred pain area from an internal organ or in cervico-facial areas, respectively. The pathophysiology of these pain associations is complex and probably multifactorial; among the possible processes underlying the mutual influence of symptoms recorded in the associations is modulation of central sensitization phenomena by nociceptive inputs from one or the other condition. A strong message in these pain syndrome co-occurrence is that effective treatment of one of the conditions can also improve symptoms from the other, thus suggesting a systematic and thorough evaluation of the pain patient for a global effective management of his/her suffering.

Extracellular signal-regulated kinase activation in the spinal cord contributes to visceral hypersensitivity induced by craniofacial injury followed by stress.

BACKGROUND: We previously developed an animal model to examine mechanisms that underlie the emergence of visceral hypersensitivity modeling pain characteristics of temporomandibular disorder (TMD) patients with comorbid irritable bowel syndrome (IBS). In ovariectomized (OVx) rats with estradiol (E2) replacement, visceral hypersensitivity developed subsequent to masseter muscle inflammation followed by repeated forced swim (FS) stress. The purpose of this study was to investigate whether activation of extracellular signal-regulated kinase (ERK) in the spinal cord contributes to visceral hypersensitivity in this overlapping pain model. METHODS: In OVx with E2 replacement rats masseter muscle inflammation was followed by 3 day FS (comorbid condition). Depression-like behaviors were assessed by sucrose preference and in the elevated plus maze, and visceral sensitivity was measured by the visceromotor response (VMR) to colorectal distention. The protein level of ERK1/2 and phosphorylated ERK1/2 (p-ERK1/2) in the L6-S2 dorsal spinal cord was analyzed by western blot. KEY RESULTS: FS stress decreased sucrose consumption in E2 replaced rats in sucrose preference test. The expression of p-ERK1/2 in the L6-S2 dorsal spinal cord increased significantly in E2 with comorbid rats. Intrathecal injection of mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor PD98059 blocked the visceral hypersensitivity induced by masseter muscle inflammation combined with FS stress. CONCLUSIONS & INFERENCES: These data indicate that ERK1/2 activation contributes to the visceral hypersensitivity evoked by craniofacial inflammation pain combined with stress. The results may provide a new therapeutic avenue for alleviating overlapping pain conditions.

Visceral pain as a triggering factor for fibromyalgia symptoms in comorbid patients.

Fibromyalgia syndrome (FMS) is a central sensitization syndrome; however, peripheral pain sources potentially exacerbate its symptoms of chronic diffuse musculoskeletal pain and hyperalgesia. This prospective study evaluated visceral pain as a possible triggering factor for FMS pain and hyperalgesia in comorbid patients. Women with (1) FMS + irritable bowel syndrome (IBS); (2) FMS + primary dysmenorrhea (Dys); (3) FMS + Dys secondary to endometriosis (Endo); (4) FMS + colon diverticulosis (Div) were compared with FMS-only women, for fibromyalgia pain (number and intensity of episodes and analgesic consumption) over comparable periods and for somatic hyperalgesia (electrical and pressure pain thresholds) in painful (tender points) and control areas (trapezius, deltoid, quadriceps muscles, and overlying subcutis and skin). In comorbid subgroups, FMS symptoms were also reassessed after treatment of the visceral condition or no treatment. All comorbid groups vs FMS-only had significantly higher FMS pain (number/intensity of episodes and analgesic consumption) and hyperalgesia in deep somatic tissues (subcutis and muscle) at all sites (0.05 < P < 0.0001). Visceral pain (number of IBS days, painful menstrual cycles, and abdominal pain episodes from diverticulitis) correlated directly with all parameters of FMS pain and inversely with muscle pain thresholds at all sites (0.03 < P < 0.0001). Fibromyalgia syndrome pain and hyperalgesia in all tissues and all sites significantly decreased in patients after visceral comorbidity treatment (dietary for 6 months [IBS], hormonal for 6 months [dysmenorrhea], laser [endometriosis], and surgery [diverticulosis]) (0.05 < P < 0.0001) vs no change in untreated patients. Visceral pain enhances FMS symptoms, probably augmenting the level of central sensitization typical of the syndrome. Systematic assessment and treatment of visceral pain comorbidities should be a part of FMS management strategy.

Neonatal bladder inflammation induces long-term visceral pain and altered responses of spinal neurons in adult rats.

Painful events early in life have been shown to increase the incidence of interstitial cystitis/painful bladder syndrome in adulthood. However, the intrinsic mechanism is not well studied. We previously reported that neonatal bladder inflammation causes chronic visceral hypersensitivity along with molecular disruption of spinal GABAergic system in rats. The present study investigates whether these molecular changes affect the integrative function and responses of bladder-sensitive primary afferent and spinal neurons. Neonatal bladder inflammation was induced by intravesicular injection of zymosan during postnatal (P) days 14-16. In adulthood (P60), the viscero-motor response (VMR) to visceral stimuli was significantly inhibited by intrathecal (i.t) HZ166 (GABAAα-2 agonist) only in neonatally saline-treated, but not in neonatally zymosan-treated rats. HZ166 significantly inhibited the responses of bladder-responsive lumbosacral (LS) spinal neurons to urinary bladder distension (UBD) and slow infusion (SI) in neonatally saline-treated rats. Similar results were also observed in naïve adult rats where HZ166 produced significant inhibition of bladder-responsive spinal neurons. However, HZ166 did not inhibit responses of UBD-responsive spinal neurons from neonatally zymosan-treated rats. The drug did not attenuate the responses of UBD-sensitive pelvic nerve afferent (PNA) fibers to UBD and SI in either group of rats tested. Immunohistochemical studies showed a significantly lower level of GABAAα-2 receptor expression in the LS spinal cord of neonatally zymosan-treated rats compared to saline-treated rats. These findings indicate that neonatal bladder inflammation leads to functional and molecular alteration of spinal GABAAα-2 receptor subtypes, which may result in chronic visceral hyperalgesia in adulthood.

Changes in mast cell infiltration: a possible mechanism in detrusor overactivity induced by visceral hypersensitivity.

OBJECTIVE: To establish the detrusor overactivity (DO) model induced by visceral hypersensitivity (VH) and investigate the relationship between mast cell (MC) infiltration and DO. MATERIALS AND METHODS: Sixty rats are divided into 4 groups randomly: Group 1:Baseline group; Group 2: DO group; Group 3: CON group; Group 4: VH group. The colorectal distension (CRD) and abdominal withdral reflex (AWR) scores are performed to evaluate VH. The cystometric investigation and histological test of MC infiltration are assessed. RESULTS: The threshold pressure of CRD in the VH group is significantly lower than that in the CON group (P<0.001). At the distension pressure ≥20 mmHg, the AWR scores of the VH group are significantly higher than those of the CON group (10 mmHg: P=0.33; 20 mmHg: P=0.028; 40 mmHg: P<0.001; 60 mmHg: P<0.001; 80 mmHg: P<0.001). DO model is successfully established in the VH group (DO rate=100%). Compared with the CON group, the numbers of MC infiltration are significantly increased in the VH group, including submucosa of bladder (P<0.001), mucosa lamina propria/mesentery of small intestine (P<0.001), and mucosa lamina propria/mesentery of large intestine (P<0.001). Furthermore, more MC activation as well as degranulation are observed in the VH group. CONCLUSIONS: It is indicated that DO model can be established in the VH rats. The MC infiltration may play an important role in DO induced by VH, and may be helpful to understand the mechanisms of DO in VH patients.

Changes in mast cell infiltration: a possible mechanism in detrusor overactivity induced by visceral hypersensitivity

ABSTRACT Objective: To establish the detrusor overactivity (DO) model induced by visceral hypersensitivity (VH) and investigate the relationship between mast cell (MC) infiltration and DO. Materials and Methods: Sixty rats are divided into 4 groups randomly: Group 1:Baseline group; Group 2: DO group; Group 3: CON group; Group 4: VH group. The colorectal distension (CRD) and abdominal withdral reflex (AWR) scores are performed to evaluate VH. The cystometric investigation and histological test of MC infiltration are assessed. Results: The threshold pressure of CRD in the VH group is significantly lower than that in the CON group (P<0.001). At the distension pressure ≥20 mmHg, the AWR scores of the VH group are significantly higher than those of the CON group (10 mmHg: P=0.33; 20 mmHg: P=0.028; 40 mmHg: P<0.001; 60 mmHg: P<0.001; 80 mmHg: P<0.001). DO model is successfully established in the VH group (DO rate=100%). Compared with the CON group, the numbers of MC infiltration are significantly increased in the VH group, including submucosa of bladder (P<0.001), mucosa lamina propria/mesentery of small intestine (P<0.001), and mucosa lamina propria/mesentery of large intestine (P<0.001). Furthermore, more MC activation as well as degranulation are observed in the VH group. Conclusions: It is indicated that DO model can be established in the VH rats. The MC infiltration may play an important role in DO induced by VH, and may be helpful to understand the mechanisms of DO in VH patients.

Arthralgias, fatigue, paresthesias and visceral pain: can joint hypermobility solve the puzzle? A case report.

BACKGROUND: Joint hypermobility syndrome describes a disorder in which musculoskeletal pain occurs in a generalized joint hypermobility substrate. The clinical picture comprises variable manifestations which involve mainly but not exclusively the musculoskeletal system, and evolve over the person's lifetime. CASE PRESENTATION: Describing the case of a 20-year-old female with generalized arthro-myalgias, persistent fatigue and troublesome visceral pain, we illustrate how a frequently ignored clinical sign such as joint hypermobility can be the keystone to clarify different simultaneous symptoms. All of the patient's physical complaints had been investigated separately during her previous medical examinations, and several tests repeatedly gave negative results. The patient received different diagnoses that describe only part of her problems, such as irritable bowel syndrome for visceral pain, fibromyalgia for arthralgias or depression for fatigue. These approaches gave rise to pharmacological or physical treatments which did not improve her quality of life in any way and in some instances worsened the situation. Pronounced joint hypermobility which led the patient to flex her joints excessively, causing subluxations in several districts, was the only sign overlooked. CONCLUSION: Exploring the patient's articular features in her clinical context led us to diagnose joint hypermobility syndrome, a complex and often ignored condition. The case highlights the utility of a multidisciplinary approach and coordinated interventions to define and manage this clinical entity.

Effects of NB001 and gabapentin on irritable bowel syndrome-induced behavioral anxiety and spontaneous pain.

Irritable bowel syndrome (IBS) is characterized by recurrent abdominal discomfort, spontaneous pain, colorectal hypersensitivity and bowel dysfunction. Patients with IBS also suffer from emotional anxiety and depression. However, few animal studies have investigated IBS-induced spontaneous pain and behavioral anxiety. In this study, we assessed spontaneous pain and anxiety behaviors in an adult mouse model of IBS induced by zymosan administration. By using Fos protein as a marker, we found that sensory and emotion related brain regions were activated at day 7 after the treatment with zymosan; these regions include the prefrontal cortex, anterior cingulate cortex, insular cortex and amygdala. Behaviorally, zymosan administration triggered spontaneous pain (decreased spontaneous activities in the open field test) and increased anxiety-like behaviors in three different tests (the open field, elevated plus maze and light/dark box tests). Intraperitoneal injection of NB001, an adenylyl cyclase 1 (AC1) inhibitor, reduced spontaneous pain but had no significant effect on behavioral anxiety. In contrast, gabapentin reduced both spontaneous pain and behavioral anxiety. These results indicate that NB001 and gabapentin may inhibit spontaneous pain and anxiety-like behaviors through different mechanisms.

Bloating and distention in irritable bowel syndrome: the role of gas production and visceral sensation after lactose ingestion in a population with lactase deficiency.

OBJECTIVES: Bloating and distention are often attributed to dietary factors by patients with irritable bowel syndrome (IBS). This study examined the effects of gas production and visceral hypersensitivity on digestive symptoms after lactose ingestion in a population with lactase deficiency. METHODS: IBS patients (n=277) and healthy controls (HCs, n=64) underwent a 20-g lactose hydrogen breath test (LHBT) with evaluation of hydrogen gas production and lactose intolerance (LI) symptoms. Abdominal distention (199 IBS, 40 HCs) was measured during LHBT. Rectal sensitivity (74 IBS, 64 HCs) was assessed by barostat studies. RESULTS: Hydrogen production and distention were similar in IBS patients and HCs during LHBT; however, LI was more frequent in IBS (53.8 vs. 28.1%, P<0.001), especially bloating (39.0% vs. 14.1%, P<0.001) and borborygmi (39.0 vs. 21.9%, P=0.010). Only 59.0% of patients with bloating had distention. No correlation was observed between girth increment and bloating (P=0.585). IBS patients had lower rectal sensory thresholds (P=0.001). Multivariate analysis indicated that hydrogen production increased bloating (odds ratio (OR) 2.19, 95% confidence interval (CI) 1.09-4.39, P=0.028) and borborygmi (OR 12.37, 95% CI 3.34-45.83, P<0.001) but not distention (P=0.673). Visceral hypersensitivity was associated with bloating (OR 6.61, 95% CI 1.75-25.00, P=0.005) and total symptom score (OR 3.78, 95% CI 1.30-10.99, P=0.014). CONCLUSIONS: Gas production and visceral hypersensitivity both contribute to digestive symptoms, especially bloating and borborygmi, in IBS patients after lactose ingestion. Objective abdominal distention is not correlated with subjective bloating.

Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.

Postural tachycardia syndrome (POTS) is defined by a heart rate increment of 30 beats/min or more within 10 minutes of standing or head-up tilt in the absence of orthostatic hypotension; the standing heart rate is often 120 beats/min or higher. POTS manifests with symptoms of cerebral hypoperfusion and excessive sympathoexcitation. The pathophysiology of POTS is heterogeneous and includes impaired sympathetically mediated vasoconstriction, excessive sympathetic drive, volume dysregulation, and deconditioning. POTS is frequently included in the differential diagnosis of chronic unexplained symptoms, such as inappropriate sinus tachycardia, chronic fatigue, chronic dizziness, or unexplained spells in otherwise healthy young individuals. Many patients with POTS also report symptoms not attributable to orthostatic intolerance, including those of functional gastrointestinal or bladder disorders, chronic headache, fibromyalgia, and sleep disturbances. In many of these cases, cognitive and behavioral factors, somatic hypervigilance associated with anxiety, depression, and behavioral amplification contribute to symptom chronicity. The aims of evaluation in patients with POTS are to exclude cardiac causes of inappropriate tachycardia; elucidate, if possible, the most likely pathophysiologic basis of postural intolerance; assess for the presence of treatable autonomic neuropathies; exclude endocrine causes of a hyperadrenergic state; evaluate for cardiovascular deconditioning; and determine the contribution of emotional and behavioral factors to the patient's symptoms. Management of POTS includes avoidance of precipitating factors, volume expansion, physical countermaneuvers, exercise training, pharmacotherapy (fludrocortisone, midodrine, ß-blockers, and/or pyridostigmine), and behavioral-cognitive therapy. A literature search of PubMed for articles published from January 1, 1990, to June 15, 2012, was performed using the following terms (or combination of terms): POTS; postural tachycardia syndrome, orthostatic; orthostatic; syncope; sympathetic; baroreceptors; vestibulosympathetic; hypovolemia; visceral pain; chronic fatigue; deconditioning; headache; Chiari malformation; Ehlers-Danlos; emotion; amygdala; insula; anterior cingulate; periaqueductal gray; fludrocortisone; midodrine; propranolol; ß-adrenergic; and pyridostigmine. Studies were limited to those published in English. Other articles were identified from bibliographies of the retrieved articles.