Is Dyssynergic Defecation an Unrecognized Cause of Chronic Constipation in Patients Using Opioids?

OBJECTIVES: The impact of opioids on anorectal function is poorly understood but potentially relevant to the pathogenesis of opioid-induced constipation (OIC). To evaluate anorectal function testing (AFT) characteristics, symptom burden, and quality of life in chronically constipated patients prescribed an opioid (OIC) in comparison with constipated patients who are not on an opioid (NOIC). METHODS: Retrospective analysis of prospectively collected data on 3,452 (OIC = 588 and NOIC = 2,864) chronically constipated patients (Rome 3) who completed AFT. AFT variables included anal sphincter pressure and response during simulated defecation, balloon expulsion test (BET), and rectal sensation. Dyssynergic defecation (DD) was defined as an inability to relax the anal sphincter during simulated defecation and an abnormal BET. Patients completed Patient Assessment of Constipation Symptoms (PAC-SYM) and Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaires. RESULTS: The mean age of the study cohort was 49 years. Most patients were women (82%) and whites (83%). Patients with OIC were older than NOIC patients (50.7 vs 48.3, P = 0.001). OIC patients were significantly more likely to have DD (28.6% vs 21.4%, P < 0.001), an abnormal simulated defecation response on anorectal manometry (59% vs 43.8%, P < 0.001), and an abnormal BET (48% vs 42.5%, P = 0.02) than NOIC patients. OIC patients reported more severe constipation symptoms (P < 0.02) and worse quality of life (P < 0.05) than NOIC patients. DISCUSSION: Chronically constipated patients who use opioids are more likely to have DD and more severe constipation symptoms than NOIC.

Long-term sensitization of mechanosensitive and -insensitive afferents in mice with persistent colorectal hypersensitivity.

Afferent input contributes significantly to the pain and colorectal hypersensitivity that characterize irritable bowel syndrome. In the present study, we investigated the contributions of mechanically sensitive and mechanically insensitive afferents (MIAs; or silent afferents) to colorectal hypersensitivity. The visceromotor response to colorectal distension (CRD; 15-60 mmHg) was recorded in mice before and for weeks after intracolonic treatment with zymosan or saline. After CRD tests, the distal colorectum with the pelvic nerve attached was removed for single-fiber electrophysiological recordings. Colorectal afferent endings were located by electrical stimulation and characterized as mechanosensitive or not by blunt probing, mucosal stroking, and circumferential stretch. Intracolonic zymosan produced persistent colorectal hypersensitivity (>24 days) associated with brief colorectal inflammation. Pelvic nerve muscular-mucosal but not muscular mechanosensitive afferents recorded from mice with colorectal hypersensitivity exhibited persistent sensitization. In addition, the proportion of MIAs (relative to control) was significantly reduced from 27% to 13%, whereas the proportion of serosal afferents was significantly increased from 34% to 53%, suggesting that MIAs acquired mechanosensitivity. PGP9.5 immunostaining revealed no significant loss of colorectal nerve fiber density, suggesting that the reduction in MIAs is not due to peripheral fiber loss after intracolonic zymosan. These results indicate that colorectal MIAs and sensitized muscular-mucosal afferents that respond to stretch contribute significantly to the afferent input that sustains hypersensitivity to CRD, suggesting that targeted management of colorectal afferent input could significantly reduce patients' complaints of pain and hypersensitivity.

Effects of mu and kappa opioid receptor agonists and antagonists on contraction of isolated colon strips of rats with cathartic colon.

AIM: To study the effects of mu and kappa opioid receptor agonists and antagonists on the isolated colon strips of rats with cathartic colon. METHODS: Cathartic colon model was established by feeding rats with contact laxatives, and effects of mu and kappa opioid receptor agonists and antagonists on electricity-stimulated contraction of isolated colon strips of rats with cathartic colon were observed. RESULTS: Compared with control group, exogenous mu and kappa agonists inhibited significantly electricity-stimulated contraction of strips of cathartic colon (8.50+/-0.89 mm, 6.24+/-0.91 mm, 3.35+/-0.6 mm vs 11.40+/-0.21 mm P<0.01; 8.98+/-0.69 mm, 6.89+/-0.71 mm, 4.43+/-0.99 mm vs 11.40+/-0.21 mm, P<0.01). In contrast, the exogenous mu antagonist significantly enhanced electricity-stimulated contraction of isolated colon strips (13.18+/-0.93 mm, 15.87+/-0.98 mm, 19.46+/-1.79 mm vs 11.40+/-0.21 mm, P<0.01), but kappa antagonist had no effect on the isolated colon strips of rats with cathartic colon. CONCLUSION: Mu and kappa opioid receptors are involved in the regulation of colon motility of rats with cathartic colon.

Short-chain fatty acid enemas fail to decrease colonic hypersensitivity and inflammation in TNBS-induced colonic inflammation in rats.

BACKGROUND AND AIMS: Short-chain fatty acid (SCFA) (especially butyrate) enemas are widely used to reduce symptoms associated with human inflammatory bowel disease. The purpose of this study was to evaluate their real effect on colonic sensitivity in rats. METHODS: The effects of saline and SCFA enemas (acetate, propionate and particularly butyrate) were studied on visceral pain thresholds following colonic distension in control rats and in rats with colitis (instilled with trinitrobenzene sulfonic acid (TNBS)). RESULTS: Butyrate enemas (40 mM twice daily for 14 days) decreased colonic pain thresholds in control rats; they did not reduce the TNBS-induced hypersensitivity, but on the contrary increased its duration (without modifying the inflammation score). This pronociceptive effect was confirmed in control rats receiving twice daily enemas of 80 mM for 3 days and two enemas of 240 mM of a butyrate solution. The other SCFA enemas did not modify the hypersensitivity of rats with colitis and induced proinflammatory effects. CONCLUSIONS: The beneficial effect of SCFA (especially butyrate) enemas on hypersensitivity and inflammation in inflammatory bowel disease is questionable and needs to be thoroughly investigated in humans.

A new model of chronic visceral hypersensitivity in adult rats induced by colon irritation during postnatal development.

BACKGROUND & AIMS: The irritable bowel syndrome (IBS) is a common disorder characterized by abdominal pain in the setting of altered perception of viscerosensory stimuli. This so-called visceral hyperalgesia occurs in the absence of detectable organic disease in the peripheral organs and may cause normal or physiologic contractions to be perceived as painful. Although the pathogenesis of IBS remains speculative and is probably multifactorial, a prevailing paradigm is that transient noxious events lead to long-lasting sensitization of the neural pain circuit, despite complete resolution of the initiating event. METHODS: Neonatal male Sprague-Dawley rats received either mechanical or chemical colonic irritation between postnatal days 8 and 21 and were tested when they became adults. The abdominal withdrawal reflex and the responses of viscerosensitive neurons were recorded during colon distention. RESULTS: Colon irritation in neonates, but not in adults, results in chronic visceral hypersensitivity, with characteristics of allodynia and hyperalgesia, associated with central neuronal sensitization in the absence of identifiable peripheral pathology. CONCLUSIONS: These results concur largely with observations in patients with IBS, providing a new animal model to study IBS and validating a neurogenic component of functional abdominal pain that encourages novel approaches to health care and research.

Risk factors for irritable bowel syndrome: role of analgesics and food sensitivities.

OBJECTIVE: Symptoms of irritable bowel syndrome (IBS) are reported by 10% of the general population; however, evaluation of traditional risk factors has not provided any insight into the pathogenesis of this condition. The objective of this study was to identify additional risk factors for irritable bowel syndrome. METHODS: A valid self-report questionnaire that records the gastrointestinal (GI) symptoms required for a diagnosis of IBS, self-reported measures of potential risk factors, and a psychosomatic symptom checklist was mailed to an age-and gender-stratified random sample of Olmsted County, Minnesota residents aged 30-64 yr. A logistic regression model that adjusted for age, gender, and psychosomatic symptom score was used to identify factors significantly associated with IBS. RESULTS: A total of 643 (72%) of 892 eligible subjects returned the survey. IBS symptoms were reported by 12% of the respondents. IBS was significantly associated with use of analgesics (acetaminophen, aspirin, or nonaspirin nonsteroidal antiinflammatory drugs) for reasons other than IBS, reporting a food allergy or sensitivity, and ratings of somatic symptoms. No association was detected for age, gender, body mass index, smoking history, alcohol use, educational level, exposure to pets in the household, or water supply. Among subjects reporting the use of just one type of analgesic, IBS was associated with acetaminophen but not aspirin or nonaspirin nonsteroidal antiinflammatory drugs used alone. The odds of having IBS were higher among subjects reporting more reasons for taking analgesics and intolerance to a higher number of foods. CONCLUSIONS: IBS is significantly associated with analgesic use. However, this is confounded by other somatic pain complaints. IBS symptoms are associated with the reporting of many food allergies or sensitivities. The role of food-induced symptoms in IBS requires further investigation.

Reactive Intestinal Dysfunction Syndrome (RIDS) caused by chemical exposures.

In this study, the authors describe a new "reactive syndrome," Reactive Intestinal Dysfunction Syndrome (RIDS), which has similarities to the previously described clinical syndromes Reactive Airway Dysfunction Syndrome (RADS) and Reactive Upper Airway Dysfunction Syndrome (RUDS). Given that at least 5 neuropeptides are common to both the respiratory tract and digestive tract, the authors propose that the abnormal secretion of these neuropeptides or the abnormal numbers of their receptors play a role in what is perceived clinically as RADS, RUDS, and RIDS. The relatively large surface areas of both the lungs and gut render them especially vulnerable to the environment to which they are exposed constantly.

Misoprostol accelerates colonic mucosal repair in acetic acid-induced colitis.

The objectives of this study were 1) to determine whether misoprostol (MISO) (prostaglandin E1 analog) pretreatment protects the colonic mucosa from the injurious effects of acetic acid by attenuating the initial injury or by enhancing the rate of repair and 2) to assess the relationship between the protective effect of MISO pretreatment and mucosal ornithine decarboxylase activity in the inflamed colon. We found that the intrarectal administration of acetic acid caused rapid and extensive injury to the colonic mucosa, such that mucosal permeability increased 88-, 75-, 26-, 7.5- and 9.3-fold at 1, 2, 6, 24 and 48 hr after the enema, respectively. Intrarectal pretreatment with 50 micrograms of MISO for 30 min did not attenuate the increase in mucosal permeability at 1 hr after enema; however, it did significantly reduce mucosal permeability by 50 to 60% at 2, 6 and 48 hr after enema. We also demonstrated that acetic acid produced an 8.4-fold increase in colonic myeloperoxidase activity and a 1.8-fold increase in colonic weight at 48 hr after enema. MISO significantly reduced the increases in both myeloperoxidase activity and colon weight. Ornithine decarboxylase activity in the descending colon of vehicle-pretreated animals increased significantly only at 24 hr after the acetic acid enema. In addition, MISO pretreatment followed by acetic acid enema resulted in significantly higher ornithine decarboxylase activities in the descending colon at 2 and 6 hr, compared with the vehicle plus acetic acid and MISO plus saline groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Fish oil-enriched diet is mucosal protective against acetic acid-induced colitis in rats.

Products of arachidonic acid metabolism are elevated in patients with inflammatory bowel disease and this elevation is correlated with disease activity. Eicosapentaenoic acid competes with arachidonic acid and alters eicosanoid biosynthesis. In this experiment, the possibility that eicosapentaenoic acid could be used in the treatment of inflammatory bowel disease was investigated by determining the effect of 6 weeks of a fish oil-supplemented diet, enriched in eicosapentaenoic acid, on colonic and ileal morphology, histology, and in vivo fluid absorption in rats with 4% acetic acid-induced colitis. The results of an eicosapentaenoic acid-enriched diet were compared with results of saturated and polyunsaturated fatty acid-enriched diets. In rats with misoprostol pretreated acetic acid-induced colitis, an eicosapentaenoic acid-enriched diet reversed net colonic fluid secretion to absorption and prevented macroscopic and histologic injury, compared with saturated and poly-unsaturated fatty acid-enriched diets, which did not. The fish oil mucosal protective effect occurred in the presence of a 30-fold enhancement of PGE2 synthesis. In rats with non-misoprostol pretreated acetic acid-induced colitis, an eicosapentaenoic acid-enriched diet returned ileal fluid absorption to control levels, as compared with saturated and polyunsaturated fatty acid-enriched diets, which did not. In conclusion, a fish oil (eicosapentaenoic acid)-enriched diet, but not a saturated- or a polyunsaturated-enriched diet, protected colonic and ileal net fluid absorption in an experimental model of inflammatory bowel disease.

[Irritable colon syndrome in intolerance to food additives]. / La sindrome del colon irritabile nelle intolleranze agli additivi alimentari.

The rate of the irritable bowel syndrome (IBS) and the follow-up of its symptoms on diet and in therapy with disodium cromoglycate have been studied in a group of patients suffering from mainly extra-digestive symptoms related to food intolerance. Following our observation, we can draw the conclusion that food additives intolerance may be a major factor in the pathogenesis of IBS.