Opioid Analgesics Do Not Improve Abdominal Pain or Quality of Life in Crohn's Disease.

BACKGROUND: Abdominal pain and opioid analgesic use are common in Crohn's disease (CD). AIMS: We sought to identify factors associated with abdominal pain in CD and evaluate the impact of opioid analgesics on pain and quality-of-life scores in this setting. METHODS: We performed a longitudinal cohort study using a prospective, consented IBD natural history registry from a single academic center between 2009 and 2013. Consecutive CD patients were followed for at least 1 year after an index visit. Data were abstracted regarding pain experience (from validated surveys), inflammatory activity (using endoscopic/histologic findings), laboratory studies, coexistent psychiatric disorders, medical therapy, opioid analgesic, and tobacco use. RESULTS: Of 542 CD patients (56.6% women), 232 (42.8%) described abdominal pain. Individuals with pain were more likely to undergo surgery and were more frequently prescribed analgesics and/or antidepressants/anxiolytics. Elevated ESR (OR 1.79; 95%CI 1.11-2.87), coexistent anxiety/depression (OR 1.87; 95%CI 1.13-3.09), smoking (OR 2.08; 95%CI 1.27-3.40), and opioid use (OR 2.46; 95%CI 1.33-4.57) were independently associated with abdominal pain. Eighty patients (14.8%) were prescribed opioids, while 31 began taking them at or after the index visit. Patients started on opioids demonstrated no improvement in abdominal pain or quality-of-life scores on follow-up compared to patients not taking opioids. CONCLUSIONS: Abdominal pain is common in CD and is associated with significant opioid analgesic utilization and increased incidence of anxiety/depression, smoking, and elevated inflammatory markers. Importantly, opioid use in CD was not associated with improvement in pain or quality-of-life scores. These findings reinforce the limitations of currently available analgesics in IBD and support exploration of alternative therapies.

Adult cyclical vomiting syndrome: a disorder of allostatic regulation?

Cyclic vomiting syndrome (CVS) is an idiopathic illness characterized by stereotypic and sudden-onset episodes of intense retching and repetitive vomiting that are often accompanied by severe abdominal pain. Many associated factors that predict CVS attacks, such as prolonged periods of fasting, sleep deprivation, physical and emotional stress, or acute anxiety, implicate sympathetic nervous system activation as a mechanism that may contribute to CVS pathogenesis. Furthermore, adult patients with CVS tend to have a history of early adverse life events, mood disorders, chronic stress, and drug abuse-all associations that may potentiate sympathetic neural activity. In this review, we set forth a conceptual model in which CVS is viewed as a brain disorder involving maladaptive plasticity within central neural circuits important for allostatic regulation of the sympathetic nervous system. This model not only can account for the varied clinical observations that are linked with CVS, but also has implications for potential therapeutic interventions. Thus, it is likely that cognitive behavioral therapy, stress management ("mind-body") interventions, regular exercise, improved sleep, and avoidance of cannabis and opiate use could have positive influences on the clinical course for patients with CVS.

Wireless ambulatory pH studies: manometric or endoscopic guidance?

Wireless pH studies are widely used to assess the presence and severity of gastroesophageal reflux disease. We hypothesized that sedation or air insufflation during a preceding endoscopy may systematically alter results. A retrospective review of ambulatory pH studies completed between January 2008 and April 2010 was performed. The pH capsule was placed 6 cm above the endoscopically determined location of the squamocolumnar junction or 5 cm above the manometrically localized upper border of the lower esophageal sphincter (LES). A total of 356 patients (65% women) underwent pH studies using the BRAVO system (GIVEN Imaging, Yoqneam, Israel). In 186 patients (E-P), the capsule was placed during endoscopy. In 170 patients (M-P), capsule placement was based on manometric determination of LES boundaries using pharyngeal anesthesia only. Endoscopic placement was successful in all cases, whereas two patients could not tolerate capsule insertion with topical anesthesia only. The mean recording time did not differ between the two groups (E-P: 2468 ± 38 min; M-P: 2415 ± 40 min). The number of patients with abnormal findings on day 1 but normal results for day 2 was similar with 15% for E-P compared with 11% for M-P. However, there was a significant difference in total acid exposure times between days 1 and 2 for endoscopically (day 1: 7.3 ± 1.2; day 2: 4.8 ± 0.5; P < 0.01), but not manometrically based placement (day 1: 7.7 ± 0.7; day 2: 7.2 ± 0.6). There was no difference in the number of symptoms between days or groups (E-P day 1:13.4 ± 1.3; E-P day 2: 16.0 ± 1.6; M-P day 1: 14.1 ± 2.1; M-P day 2: 15.7 ± 2.0). Similarly, the symptom sensitivity index did not differ significantly between days and groups (E-P: day 1: 4.1 ± 0.5; day 2: 5.9 ± 0.8; M-P: day 5.3 ± 0.8; day 2: 5.7 ± 0.8). The majority of patients tolerate insertion of a wireless pH monitoring capsule without sedation. Unsedated placement did not negatively affect total recording times. Although endoscopy resulted in higher acid exposure on day one it did not significantly increase the overall fraction of abnormal tests. If confirmed in prospective studies, the more consistent findings and a potential to lower cost favor manometrically guided capsule placement.

An innovative sphincter preserving pull-through technique with en bloc colon and small bowel transplantation.

This report describes a new innovative pull-through technique of hindgut reconstruction with en bloc small bowel and colon transplantation in a Crohn's disease patient with irreversible intestinal failure. The approach was intersphincteric and the anastomosis was established between the allograft colon and the recipient anal verge with achievement of full nutritional autonomy and anal continence.

Nitric oxide as an autocrine regulator of sodium currents in baroreceptor neurons.

Arterial baroreceptors are mechanosensitive nerve endings in the aortic arch and carotid sinus that play a critical role in acute regulation of arterial blood pressure. A previous study has shown that nitric oxide (NO) or NO-related species suppress action potential discharge of baroreceptors. In the present study, we investigated the effects of NO on Na+ currents of isolated baroreceptor neurons in culture. Exogenous NO donors inhibited both tetrodotoxin (TTX) -sensitive and -insensitive Na+ currents. The inhibition was not mediated by cGMP but by NO interaction with channel thiols. Acute inhibition of NO synthase increased the Na+ currents. NO scavengers (hemoglobin and ferrous diethyldithiocarbamate) increased Na+ currents before but not after inhibition of NO synthase. Furthermore, NO production in the neuronal cultures was detected by chemiluminescence and immunoreactivity to the neuronal isoform of NO synthase was identified in fluorescently identified baroreceptor neurons. These results indicate that NO/NO-related species function as autocrine regulators of Na+ currents in baroreceptor neurons. Modulation of Na+ channels may represent a novel response to NO.

Systematic review and meta-analysis: Gastric electrical stimulation for gastroparesis.

BACKGROUND: Controlled trials of gastric electrical stimulation (GES) for gastroparesis reported no significant improvement in symptoms, while open label studies suggested substantial clinical benefits. AIM: To determine if GES is effective in reducing symptoms in patients with gastroparesis. METHODS: We searched PubMed and Embase for articles published in English (1990-2014) using "gastroparesis" as a search term restricted to "clinical trial". We included studies describing repeated patient-based symptom ratings before and during standardized treatments of at least one week duration. RESULTS: Five studies randomly allocated patients to periods with or without GES. Total symptom severity (TSS) scores did not differ between these periods (0.17 [95% confidence interval: -0.06 to 0.4]; P=0.15). However, sixteen open label studies of GES showed a significant TSS decrease (2.68 [2.04-3.32]; Q=39.0; P<0.001). Other treatment modalities similarly improved TSS by 1.97 [1.5-2.44] for medical therapy (MED), by 1.52 [0.9-2.15] for placebo arms (PLA), and by 2.32 [1.56-3.06] for botulinum toxin (BTx). There were significant differences in baseline TSS ratings among these studies (GES: 6.28 [6.28-7.42]; MED: 4.76 [4.09-5.42]; PLA: 4.59 [3.77-5.42]; BTx: 6.02 [5.3-6.74]; Q=35.1; P<0.001). Meta-regression analysis showed these baseline differences to significantly impact TSS ratings during treatment (Q=71.8; P<0.001). CONCLUSION: Independent of the treatment modality, baseline symptom severity impacts treatment results in gastroparesis. Considering the skewed population with refractory symptoms, regression to the mean likely contributes to the substantial discrepancies between the reported results of controlled and open label GES studies, raising questions about the use of GES outside of defined clinical trials.

Angiotensin selectively activates a subpopulation of postganglionic sympathetic neurons in mice.

Angiotensin II (Ang II) increases renal sympathetic nerve activity in anesthetized mice before and after ganglionic blockade, suggesting that Ang II may directly activate postganglionic sympathetic neurons. The present study directly tested this hypothesis in vitro. Neurons were dissociated from aortic-renal and celiac ganglia of C57BL/6J mice. Cytosolic Ca(2+) concentration ([Ca(2+)](i)) was measured with ratio imaging using fura 2. Ang II increased [Ca(2+)](i) in a subpopulation of sympathetic neurons. At a concentration of 200 nmol/L, 14 (67%) of 21 neurons responded with a rise in [Ca(2+)](i). The Ang II type 1 (AT(1)) receptor blocker (losartan, 2 micromol/L) but not the Ang II type 2 (AT(2)) receptor blocker (PD123,319, 4 micromol/L) blocked this effect. The Ang II-induced [Ca(2+)](i) increase was abolished by removal of extracellular Ca(2+) but not altered by depletion of intracellular Ca(2+) stores with thapsigargin. Ang II no longer elicited a [Ca(2+)](i) increase in the presence of lanthanum (25 micromol/L). The specific N-type and L-type Ca(2+) channel blockers, omega-conotoxin GVIA and nifedipine, respectively, significantly inhibited the Ang II-induced [Ca(2+)](i) increase. The protein kinase C inhibitor H7 but not the protein kinase A inhibitor H89 blocked the response to Ang II. These results demonstrate that Ang II selectively activates a subpopulation of postganglionic sympathetic neurons in aortic-renal and celiac ganglia, triggering Ca(2+) influx through voltage-gated Ca(2+) channels. This effect is mediated through AT(1) receptors and requires the activation of protein kinase C. The activation of a subgroup of sympathetic neurons by Ang II may exert unique effects on kidney function in pathological states associated with elevated Ang II.

Basic and clinical aspects of visceral sensation: transmission in the CNS.

Pain and discomfort are the leading cause for consultative visits to gastroenterologists. Acute pain should be considered a symptom of an underlying disease, thereby serving a physiologically important function. However, many patients experience chronic pain in the absence of potentially harmful stimuli or disorders, turning pain into the primary problem rather than a symptom. Vagal and spinal afferents both contribute to the sensory component of the gut-brain axis. Current evidence suggests that they convey different elements of the complex sensory experience. Spinal afferents play a key role in the discriminatory dimension, while vagal input primarily affects the strong emotional and autonomic reactions to noxious visceral stimuli. Drugs, surgical and non-pharmacological treatments can target these pathways and provide therapeutic options for patients with chronic visceral pain syndromes.

Colectomy for constipation: time trends and impact based on the US Nationwide Inpatient Sample, 1998-2011.

BACKGROUND: Current guidelines include subtotal colectomy as treatment for refractory slow transit constipation. AIM: To use the US Nationwide Inpatient Sample (NIS) (1998-2011) and longitudinal data from the State Inpatient Database (2005-2011), comparable to NIS, to examine colectomy rates, in-hospital morbidity and emergency department (ED) visits or readmissions among patients treated for constipation. METHODS: Colectomies for any reason were identified based on the primary procedural code (ICD-9-CM 45.8x). Index hospitalisations were defined by the primary diagnosis of constipation (ICD-9-CM 564.x) associated with the primary procedural code for colectomy (ICD-9-CM45.8x) after exclusion of other diseases associated with colectomy. Demographic variables, comorbidities, complications and adverse events during the hospitalisation were captured, and ED visits and admissions were recorded for periods before and after colectomy. RESULTS: Nationally, colectomies for constipation rose from 104 procedures in 1998 (1.2% of annual colectomies) to 311 in 2011 (2.4% of annual colectomies). While there were no perioperative deaths, perioperative complications occurred in 42.7% of patients during the index hospitalisation. Longitudinal data were analysed for 181 patients, with similar perioperative complications and a readmission rate of 28.9% within the first 30 days after the index hospitalisation. Resource utilisation was tracked for a median time of 630 (0-2386) before and 463 (0-2204) days after colectomy with unchanged ED visits (median: 2 vs. 2, P = 0.21), but increased hospitalisations (median: 1 vs. 2, P = 0.003). CONCLUSIONS: Colectomy rates for constipation are rising, are associated with significant morbidity and do not decrease resource utilisation, raising questions about the true benefit of surgery for slow transit constipation.

Tacrolimus (FK506) modulates calcium release and contractility of intestinal smooth muscle.

Several proteins have been identified that associate with calcium release channels and potentially regulate their function. Using tacrolimus as a pharmacological tool, we investigated whether the immunophilin FKBP12 modulates ryanodine receptor channels in intestinal smooth muscle. Results with PCR demonstrated the presence of type-3 ryanodine receptor and FKBP12 in this tissue. Tacrolimus caused an irreversible increase of the intracellular calcium concentration, which was abolished by pretreatment with caffeine. The calcium channel blocker verapamil did not affect the response to tacrolimus. Tacrolimus decreased the calcium concentration in the sarcoplasmic reticulum. Caffeine, but not inositol 1,4,5-trisphosphate or heparin, abolished this effect. Finally, tacrolimus significantly and irreversibly decreased the tension generated by intestinal muscle strips. These data support our hypothesis that the immunophilin FKBP12 modulates ryanodine receptor function in smooth muscle. Interactions between such regulatory proteins and calcium release channels may play an important role in excitation-contraction coupling and other intracellular signaling processes.

Differential effects of capsaicin on rat visceral sensory neurons.

Nodose neurons play an important role in the regulation of visceral function. Recent studies demonstrated that about 80% of these neurons contain messenger RNA for the capsaicin receptor, a heat-sensitive ion channel. Nodose neurons express voltage-sensitive sodium currents that can be differentiated based on their sensitivity to tetrodotoxin. Considering the potential role of tetrodotoxin-resistant sodium currents in somatosensory neurons, sodium channel expression and sodium currents were studied in nodose neurons. The results were correlated with the response to capsaicin. Nodose neurons contain messenger RNA for the tetrodotoxin-resistant sodium channel PN3. Consistent with these findings, about half of the neurons predominantly expressed tetrodotoxin-resistant sodium currents. In 54% (47/87) of the cells, capsaicin triggered an increase in intracellular calcium. Similarly, in 42% (18/43) of the cells, capsaicin elicited an inward current. There was no relationship between cell size (r=0.07) or sodium current properties (r=0.14) and the response to capsaicin. Micromolar concentrations of capsaicin inhibited voltage-dependent sodium, calcium and potassium currents. This effect was use dependent and did not involve the capsaicin receptor. In conclusion, capsaicin changed the excitability of visceral sensory neurons by blocking voltage-dependent ion channels, an effect that may contribute to the analgesic properties of capsaicin.

Regulation of sodium currents through oxidation and reduction of thiol residues.

Changes in redox state are involved in several physiological and pathophysiological processes. Previous experiments have demonstrated that nitric oxide can function as a reactive oxygen species, inhibiting neuronal sodium currents by nitrosylation of thiol residues. We hypothesized that nitric oxide and thiol oxidizers similarly modulate voltage-dependent sodium currents. Voltage-dependent sodium currents were studied with the whole-cell patch-clamp technique in NB41A3 neuroblastoma cells. The nitric oxide donor 3-(2-hydroxy-2-nitroso-1-propylhydrazino)-1-propanamine did not affect sodium currents. In contrast, the thiol oxidizers thimerosal and 4,4'-dithiopyridine significantly inhibited sodium currents. The effect of thimerosal persisted after washout, but could be fully reversed by the reducing agent dithiothreitol. Reduced glutathione did not restore the sodium current amplitude when given extracellularly, while intracellular glutathione prevented the inhibitory effect of thimerosal. Pretreatment with the alkylating agent N-ethylmaleimide blocked the inhibitory action of thimerosal. Thiol oxidation caused a shift in the voltage dependence of fast and slow inactivation to more hyperpolarized potentials without concomitant effects on the voltage dependence of activation. Mercaptoethanol and reduced glutathione enhanced sodium currents by shifting the voltage dependence of inactivation to depolarized potentials. These results demonstrate that the oxidation and reduction of thiol residues alters the properties of voltage-sensitive sodium channels and may play an important role in the regulation of membrane excitability.

Effects of cisapride on ano-rectal sphincter function.

To investigate the effects of cisapride, a motility-inducing agent, on ano-rectal sphincter functions, standard manometry was performed in 10 healthy male volunteers after 5 days on a 20-mg dose of cisapride in a placebo-controlled double-blind randomized crossover fashion. All subjects kept stool diaries during the experiment. Cisapride significantly increased stool frequency by adding soft and liquid stools; in addition, anal resting pressure was reduced with cisapride in seven of the 10 subjects; mean resting pressure decreased by 16%, while all other measurements were not altered. This suggests that cisapride may act directly on the smooth muscle of the internal anal sphincter. It also supports the view that enhanced defaecation in chronic constipation induced by cisapride may not be achieved by propulsive motor activity in the colon but also by a decreased anal sphincter tone.

Nerve growth factor and gastric hyperalgesia in the rat.

We recently demonstrated an association between the development of hyperalgesia and an increase in nerve growth factor (NGF) during gastric inflammation. We hypothesized that block of NGF signalling will blunt injury-induced hyperalgesia. Male Sprague-Dawley rats (300-400 g) were anaesthetized, the stomach was exposed and placed in a circular clamp. Acetic acid (60%) or saline (control) was injected into this area and aspirated 45 s later, resulting in kissing ulcers. A balloon was surgically placed into the stomach and electromyographic responses to gastric distension (GD) were recorded from the acromiotrapezius muscle. Animals received a daily injection of neutralizing NGF antibody or control serum for 5 days. NGF in the stomach wall was measured with an ELISA. The severity of gastric injury was assessed macroscopically and by determination of myeloperoxidase (MPO) activity. Gastric injury enhanced the visceromotor response to GD and increased NGF content. Anti-NGF significantly blunted the development of hyperalgesia and led to a decrease in gastric wall thickness and MPO activity. Increases in NGF contribute to the development of hyperalgesia after gastric injury. This may be partly mediated by direct effects on afferent nerves and indirectly by modulatory effects on the inflammatory response.

Increased nerve growth factor expression triggers bladder overactivity.

UNLABELLED: Prior studies have demonstrated an association between visceral inflammation, an increase in nerve growth factor (NGF) expression, and development of hyperalgesia. Because multiple mediators are released during inflammatory processes, we examined the effect of NGF alone using viral gene transfer in vivo. Replication-deficient adenoviral vectors encoding for NGF or beta-galactosidase were injected into the bladder wall. NGF levels were determined with an enzyme-linked immunoabsorbance assay. Cystometrograms were obtained 3 and 5 days after gene transfer by using a surgically implanted bladder catheter in awake male rats. Although the treatment with a control virus did not change NGF levels compared with those of naive animals, the vector encoding for NGF increased NGF protein levels in the bladder 4-fold. Histologically, no evidence of inflammation was noted. Expression of NGF led to bladder overactivity, whereas beta-galactosidase expression was without effect. These data demonstrate that a transient increase in NGF expression without associated inflammation sensitizes visceral reflex pathways, leading to bladder overactivity. Treatment strategies targeting NGF signaling might be useful in disorders involving sensitization of peripheral nerves. PERSPECTIVE: Growth factors have been implicated in the pathogenesis of inflammatory pain. This study uses gene transfer to demonstrate that NGF sensitizes afferent pathways in the absence of inflammation, making it a potentially relevant treatment target.

Nitric oxide enhances slow inactivation of voltage-dependent sodium currents in rat nodose neurons.

Nitric oxide (NO) can alter neuronal excitability by decreasing the current through voltage-sensitive sodium channels. We hypothesized that NO inhibits sodium currents in part by promoting slow inactivation. We performed whole-cell voltage clamp experiments on sensory neurons from the nodose ganglion. The voltage-dependence of inactivation was determined after stepping the neurons to various potentials between -100 and 30 mV for 200 ms (fast inactivation) and 3 min (slow inactivation) prior to depolarization to 10 mV. NO shifted the voltage of half-inactivation for fast and slow inactivation to more hyperpolarized potentials by 7 and 12 mV, respectively. Sodium currents exhibited a more profound closed state and slow inactivation after exposure to NO. These results demonstrate for the fist time that the slow inactivation of sodium currents is subject to modulation. Due to its effects on fast and slow inactivation, NO may cause a prolonged decrease in neuronal excitability.

Slow inactivation of sodium currents in the rat nodose neurons.

Nodose neurons express sodium currents that can be differentiated based on their sensitivity to tetrodotoxin. Several studies have demonstrated significant differences in voltage-dependence and kinetics of activation and inactivation between tetrodotoxin-sensitive and tetrodotoxin-resistant currents. However, little is known about the slow inactivation. Using whole cell patch-clamp technique fast and slow inactivation of sodium currents were studied in cultured rat nodose neurons. Tetrodotoxin-resistant currents recovered much more rapidly after a 15-ms depolarization than tetrodotoxin-sensitive currents. However, repeated 5-ms depolarizations at 10 Hz induced a cumulative inhibition that was more prolonged in tetrodotoxin-resistant compared to tetrodotoxin-sensitive currents. Consistent with these findings, slow inactivation proceeded more rapidly and was more complete for the tetrodotoxin-resistant than for tetrodotoxin-sensitive currents. While the voltage-dependence of fast inactivation differed significantly between the pharmacologically distinct currents, the voltage-dependence of slow inactivation was similar for both sodium currents. We conclude that slow inactivation of sodium currents can be triggered by trains of brief depolarizations. The resulting prolonged decrease in membrane excitability may contribute to the different patterns of action potential generation observed in primary afferent neurons.

Asthma and gastroesophageal reflux.

Gastroesophageal reflux and asthma are common diseases in the developed world, and they often coexist in patients. Animal experiments, epidemiologic data, and clinical studies suggest that gastroesophageal reflux may contribute to the pathogenesis of asthma. In addition to classic reflux symptoms, such patients may notice nightly exacerbations of asthma or postprandial worsening of their pulmonary symptoms. Empiric treatment with an acid-suppressive regimen is the most cost-effective approach for asthmatic patients with classic gastroesophageal reflux symptoms, especially if the asthma remains poorly controlled despite conventional treatment. If patients have persistent problems after an adequate duration of acid-suppressive therapy or if they report symptoms indicating complicated reflux disease, such as dysphagia, additional diagnostic studies should be initiated. In most cases, medical therapy should be chosen for the long-term treatment of patients with asthma and gastroesophageal reflux. With the availability of less-invasive laparoscopic surgery, fundoplication may be an alternative in selected, mostly young individuals who have documented reflux and symptoms responsive to appropriate acid-suppressive regimens.

[Autonomic neuropathy in diabetes mellitus, chronic renal failure and liver cirrhosis]. / Untersuchungen zur autonomen Neuropathie bei Diabetes mellitus, chronischer Niereninsuffizienz und Leberzirrhose.

Chronic diseases (diabetes mellitus, end stage renal failure on hemodialysis, post-hepatitic liver cirrhosis) caused autonomic neuropathy in 34 of 65 cases. The frequency of autonomic neuropathy was 14 of 30 diabetics (typ I and typ II), twelve of 19 patients on dialysis, and eight of 16 non-alcoholic liver cirrhotics. We did not find a correlation between the tests of the cardiovascular and of the gastrointestinal system. The distribution of the neuropathic changes was undependent of the underlying disorder. Using appropriate tests, alterations of the autonomic functions can be discovered frequently even in asymptomatic patients. At least two pathological test results are necessary to reach a significant difference between patients and healthy controls. This indicates that the diagnosis of autonomic neuropathy should rely on two or more pathological test results. The evidence of autonomic neuropathy identifies a population of high risk patients.

[Hypoglycemia in type II diabetic patients]. / Hypoglykämie bei Typ-II-Diabetikern.

The incidence of hypoglycemia was determined in 138 type-2 diabetics treated with insulin (40%) or sulfonylureas (60%). Within one year, ten patients (7%) experienced one severe hypoglycemic episode characterized by a loss of consciousness and the necessity of parenteral glucose administration. Insulin treatment and advanced age increased the risk of hypoglycemia. The knowledge about hypoglycemia was poor. Only 45% of the patients could give a correct definition, 18% knew more than two symptoms, and 15% knew at least one cause of hypoglycemia. 66% would treat hypoglycemia with oral carbohydrates. The risk of hypoglycemia should be considered in the planning of adopted teaching and treatment programs for patients with type-2 diabetes.