G. Nicholas Verne

The contributions of suggestion, desire, and expectation to placebo effects in irritable bowel syndrome patients. An empirical investigation

In order to investigate external factors that may influence the magnitude of placebo analgesia as well as psychological factors that mediate placebo analgesia, 13 irritable bowl syndrome (IBS) patients rated evoked rectal distension and cutaneous heat pain under the conditions of natural history (NH), rectal placebo (RP), rectal nocebo (RN), rectal lidocaine (RL) and oral lidocaine (OL). Patients were given verbal suggestions for pain relief and rated expected pain levels and desire for pain relief for both evoked visceral and cutaneous pain, respectively. Large reductions in pain intensity and pain unpleasantness ratings were found in the RP, RL and OL condition as compared to the natural history condition, whereas no significant difference in pain reduction between the three treatment conditions was found. Ratings during RN and NH were not statistically different. Compared to a previous study, which shows that rectal lidocaine reverses visceral and cutaneous hyperalgesia, these results suggest that adding a verbal suggestion for pain relief can increase the magnitude of placebo analgesia to that of an active agent. Since IBS patients rate these stimuli as much higher than do normal control subjects and since placebo effects were very large, they probably reflect anti‐hyperalgesic mechanisms to a major extent. Expected pain levels and desire for pain relief accounted for large amounts of the variance in visceral pain intensity in the RP, RL, and OL condition (up to 81%), and for lower amounts of the variance in cutaneous pain intensity. Hence, the combination of expected pain levels and desire for pain relief may offer an alternative means of assessing the contribution of placebo factors during analgesia.

Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome

&NA; Irritable bowel syndrome (IBS) is one of the most common gastrointestinal illnesses and is characterized by altered visceral perception. Previous studies in IBS have failed to demonstrate altered somatic or cutaneous perception. The aims of the study were to determine whether IBS patients have visceral hypersensitivity and cutaneous heat‐induced hyperalgesia restricted to lumbosacral dermatomes, consistent with a localized segmental mechanism. Twelve patients (ten women, two men) with IBS and 17 control subjects (13 women, four men) rated pain intensity and unpleasantness to distension of the rectum (35, 55 mmHg) and thermal stimulation (45, 47°C) of the hand and foot. Patients with IBS demonstrated cutaneous allodynia/hyperalgesia to thermal pain applied to the hand and foot. The cutaneous hyperalgesia was pronounced in the lower extremity yet present in the upper extremity to a lesser extent. Psychological testing revealed the IBS patients report more state anxiety and a greater number of somatic symptoms that significantly correlated with most of the pain measures. However, they did not differ from controls on several personality trait measures. These results suggest that patients with IBS have visceral hyperalgesia and cutaneous hyperalgesia that is distributed over a considerable rostral‐caudal distance yet optimally expressed in lumbosacral dermatomes. This distribution is consistent with patterns of spinal hyperexcitability observed in experimentally induced persistent pain conditions.

Central representation of visceral and cutaneous hypersensitivity in the irritable bowel syndrome

&NA; We have previously shown that irritable bowel syndrome (IBS) patients have both visceral and cutaneous hyperalgesia. The neural mechanisms of these forms of hyperalgesia were further characterized by comparing cortical processing of both rectal distension (35, 55 mmHg) and cutaneous heat nociceptive stimuli (foot immersion in 45 and 47°C water bath) in IBS patients and in a group of healthy age/sex‐matched controls. Our approach relied on functional magnetic resonance imaging neuroimaging analyses in which brain activation in age/sex‐matched control subjects was subtracted from that found in IBS patients. These analyses revealed that both rectal distension and cutaneous heat stimuli evoked greater neural activity in several brain regions of IBS patients in comparison to age/sex‐matched control subjects. These include those related to early stages of somatosensory processing (e.g. thalamus, somatosensory cortex) as well as those more related to cognitive and affective processing (insular, anterior cingulate, posterior cingulate, prefrontal cortex). Thus, our results support the hypothesis that hyperalgesia of IBS is manifested by increased somatosensory processing at all cortical levels. This was found to be the case not only for visceral hyperalgesia but also for cutaneous heat hyperalgesia, a likely form of secondary hyperalgesia. Furthermore, visceral and heat hyperalgesia were accompanied by increased neural activity within the same brain structures. These results support the hypothesis that visceral and cutaneous hyperalgesia in IBS patients is related to increased afferent processing in pathways ascending to the brain rather than to selectively increased activity at higher cortical levels (e.g. limbic and frontal cortical areas).

Placebo analgesia is accompanied by large reductions in pain-related brain activity in irritable bowel syndrome patients

Abstract Previous experiments found that placebos produced small decreases in neural activity of pain‐related areas of the brain, yet decreases were only statistically significant after termination of stimuli and in proximity to when subjects rated them. These changes could reflect report bias rather than analgesia. This functional magnetic resonance imaging (fMRI) study examined whether placebo analgesia is accompanied by reductions in neural activity in pain‐related areas of the brain during the time of stimulation. Brain activity of irritable bowel syndrome patients was measured in response to rectal distension by a balloon barostat. Large reductions in pain and in brain activation within pain‐related regions (thalamus, somatosensory cortices, insula, and anterior cingulate cortex) occurred during the placebo condition. Results indicate that decreases in activity were related to placebo suggestion and a second factor (habituation/attention/conditioning). Although many factors influence placebo analgesia, it is accompanied by reduction in pain processing within the brain in clinically relevant conditions.

Intestinal membrane permeability and hypersensitivity in the irritable bowel syndrome

ABSTRACT Irritable bowel syndrome (IBS) is a common gastrointestinal disorder in which the underlying pathophysiology is poorly understood; however, increased intestinal permeability in diarrhea‐predominant IBS patients has been reported. Here we demonstrate that diarrhea‐predominant IBS (D‐IBS) patients display increased intestinal permeability. We have also found that increased intestinal membrane permeability is associated with visceral and thermal hypersensitivity in this subset of D‐IBS patients. We evaluated 54 D‐IBS patients and 22 controls for intestinal membrane permeability using the lactulose/mannitol method. All subjects ingested 5 g of lactulose and 2 g of mannitol in 100 ml of water after which their urine was collected. We also evaluated the mean mechanical visual analogue scale (M‐VAS) pain rating to nociceptive thermal and visceral stimulation in all subjects. All study participants also completed the FBDSI scale. Approximately 39% of diarrhea‐predominant IBS patients had increased intestinal membrane permeability as measured by the lactulose/mannitol ratio. These IBS patients also demonstrated higher M‐VAS pain intensity reading scale. Interestingly, the IBS patients with hypersensitivity and increased intestinal permeability had a higher FBDSI score (100.8 ± 5.4) than IBS patients with normal membrane permeability and sensitivity (51.6 ± 12.7) and controls (6.1 ± 5.6) (p < 0.001). A subset of D‐IBS patients had increased intestinal membrane permeability that was associated with an increased FBDSI score and increased hypersensitivity to visceral and thermal nociceptive pain stimuli. Thus, increased intestinal membrane permeability in D‐IBS patients may lead to more severe IBS symptoms and hypersensitivity to somatic and visceral stimuli.

Reversal of visceral and cutaneous hyperalgesia by local rectal anesthesia in irritable bowel syndrome (IBS) patients

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal illnesses and is characterized by altered visceral perception. The aim of the study was to determine if local anesthetic blockade of peripheral visceral nociceptive input reduces both visceral and cutaneous secondary hyperalgesia in IBS patients. Ten women with IBS (mean age 30±10 years) and ten control subjects (all women) (mean age 29±7 years) rated pain intensity and unpleasantness to distension of the rectum (35 mmHg) and thermal stimulation (47 °C) of the foot before and after rectal administration of either lidocaine jelly or saline jelly in a double blind crossover design. Intrarectal lidocaine (300 mg) reduced reported rectal and cutaneous pain in all of the IBS patients. The effects were statistically much greater than those of placebo and most of the effects were present within 5–15 min after the onset of the treatment. In the control subjects, rectal lidocaine did not decrease pain report from visceral and cutaneous stimuli. The results of this study support the hypothesis that local anesthetic blockade of peripheral impulse input from the rectum/colon reduces both visceral and cutaneous secondary hyperalgesia in IBS patients. The results provide further evidence that visceral hyperalgesia and secondary cutaneous hyperalgesia in IBS reflects central sensitization mechanisms that are dynamically maintained by tonic impulse input from the rectum/colon. Rectal administration of lidocaine jelly may also be a safe and effective means of reducing pain symptoms in IBS patients.

MicroRNA-29a Regulates Intestinal Membrane Permeability in Patients with Irritable Bowel Syndrome

Background The molecular mechanisms underlying the pathophysiology of irritable bowel syndrome (IBS) are poorly understood. One mechanism may involve increased intestinal permeability that is reversed with glutamine supplementation. Our goal was to evaluate the expression of glutamine synthetase and its complementary miRNA in blood microvesicles and gut tissues of IBS patients with increased intestinal membrane permeability. Methods We evaluated 19 diarrhoea-predominant IBS patients and 10 controls for intestinal membrane permeability using the lactulose/mannitol method. miRNA expression was evaluated in blood microvesicles and gut tissue. To further confirm the relationship between miRNA and glutamine synthetase expression, cell culture experiments were conducted. Glutamine synthetase was also evaluated in the gut tissues of patients. Results A subset of patients with IBS (8/19, 42%) had increased intestinal membrane permeability and decreased glutamine synthetase expression compared to patients with IBS normal membrane permeability, and to controls. Expression of miR-29a was increased in blood microvesicles, small bowel and colon tissues of IBS patients with increased intestinal membrane permeability. Increased intestinal permeability was modulated by miR-29a which has a complementary site in the 3′-UTR of the GLUL gene. Conclusions The results support the conclusion that GLUL regulates intestinal membrane permeability and miR-29a regulates both GLUL and intestinal membrane permeability. The data suggests that miR-29a effects on intestinal membrane permeability may be due to its regulation of GLUL. Targeting this signalling pathway could lead to a new therapeutic approach to the treatment of patients with IBS, especially because small molecules that mimic or inhibit miRNA-based mechanisms are readily available.

Effect of octreotide and erythromycin on idiopathic and scleroderma-associated intestinal pseudoobstruction

Treatment of chronic intestinal pseudoobstruction with prokinetic agents has been disappointing. Our study was designed to determine if octreotide and erythromycin would provide sustained relief from nausea, abdominal pain, and bloating in pseudoobstruction. Using gastrointestinal manometry, quantitative parameters of the activity front of the migrating motor complex at baseline and after prokinetic therapy with erythromycin and octreotide were determined in 14 patients with intestinal pseudoobstruction who had nausea, abdominal pain, and bloating. Patients were treated with erythromycin and octreotide for 20–33 weeks. Octreotide increased the frequency, duration, and motility index of activity fronts (AFs) from 1.2±0.3 AFs/4hr, 2.7±0.7 min, and 85±23 min mm Hg to 4.1±0.8 AFs/4 hr, 5.5±0.7 min, and 152±24 min mm Hg, respectively (P<0.05). Antral activity was decreased from 63±14 to 23±8% by octreotide (P<0.05). Erythromycin induced antral activity; however, small intestinal motor activity was suppressed. While on erythromycin and octreotide, five patients had long-term improvement of nausea and abdominal pain. All responders had at least 5 AFs/4 hr induced by octreotide. We conclude that octreotide and erythromycin relieve abdominal pain and nausea in pseudoobstruction. Patients who have at least 5 AFs/4 hr after octreotide administration are most likely to clinically respond.

DIABETES AND THE GASTROINTESTINAL TRACT

Gastrointestinal motility disorders are common in patients with diabetes. The entire gastrointestinal tract may be involved from the esophagus to the anal sphincter. Before instituting therapy, people with diabetes first require a careful diagnostic evaluation. Treatment includes tight glucose control and the use of antiemetics and prokinetic agents.

Functional brain interactions that serve cognitive-affective processing during pain and placebo analgesia

Pain requires the integration of sensory, cognitive, and affective information. The use of placebo is a common methodological ploy in many fields, including pain. Neuroimaging studies of pain and placebo analgesia (PA) have yet to identify a mechanism of action. Because PA must result from higher order processes, it is likely influenced by cognitive and affective dimensions of the pain experience. A network of brain regions involved in these processes includes the anterior and posterior insula (A-Ins, P-Ins), dorsal anterior cingulate cortex (DACC), dorsolateral prefrontal cortex (DLPFC), and the supplementary motor area (SMA). We used connectivity analyses to investigate the underlying mechanisms associated with Placebo analgesia in a group of chronic pain patients. Structural equation models (SEM) of fMRI data evaluated the inter-regional connectivity of these regions across three conditions: (1) initial Baseline (B1), (2) placebo (PA), and (3) Placebo Match (PM). SEM results of B1 data in the left hemisphere confirmed hypothesized regional relationships. However, inter-regional relationships were dynamic and the network models varied across hemispheres and conditions. Deviations from the B1 model in the PA and PM conditions correspond to our manipulation of expectation for pain. The dynamic changes in inter-regional influence across conditions are interpreted in the context of a self-reinforcing feedback loop involved in the induction and maintenance of PA. Although it is likely that placebo analgesia results partly from afferent inhibition of a nociceptive signal, the mechanisms likely involve the interaction of a cognitive-affective network with input from both hemispheres.