Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Safety was also assessed. RESULTS: In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. The incidence of infection (of any severity) with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Elevated liver aminotransferase levels were more common with ozanimod. CONCLUSIONS: Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. (Funded by Bristol Myers Squibb; True North ClinicalTrials.gov number, NCT02435992.).

P037 Effect of Ozanimod Treatment and Discontinuation on Absolute Lymphocyte Count in Moderate-to-Severe Ulcerative Colitis: Results from a Phase 3 Trial.

BACKGROUND: Ozanimod is an oral sphingosine 1-phosphate (S1P) receptor modulator selectively targeting S1P1 and S1P5, which reduces migration of lymphocytes involved in adaptive immunity from lymphoid tissues to blood and inflamed tissues while preserving components of the innate immune response. Ozanimod is approved in multiple countries for the treatment of relapsing forms of multiple sclerosis and in the US for the treatment of moderately-to-severely active ulcerative colitis (UC). The reduction of circulating lymphocytes is expected based on the mechanism of action of ozanimod and thought to be an important driver of efficacy. METHODS: We assessed absolute lymphocyte count (ALC) during ozanimod induction and maintenance, and after ozanimod discontinuation, per protocol, in adults with moderately-to-severely active UC to characterize the time course of ALC reduction and recovery. The analysis included patients who received ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg) or placebo once daily in True North, a phase 3 randomized trial (NCT02435992). During a 10-week induction period, patients were randomized 2:1 to double-blind treatment with ozanimod or placebo (Cohort 1) or received open-label ozanimod (Cohort 2). Patients from either cohort with a clinical response to ozanimod at week 10 were re-randomized 1:1 to double-blind treatment with ozanimod or placebo during maintenance through week 52. Placebo-treated patients with a clinical response at week 10 continued placebo during maintenance. ALC was assessed at baseline and at visits throughout induction and maintenance. RESULTS: A total of 69 patients received continuous placebo treatment, 230 received continuous ozanimod treatment, and 227 received ozanimod during induction and placebo during maintenance. In patients who received continuous placebo, mean ALC remained stable between 1.8‒2.1 x 109/L over time (normal range: 1.02‒3.36 x 109/L). In ozanimod-treated patients, mean ALC was reduced to 43%‒45% of baseline and 70%‒73% of patients had ALC shifts from normal at baseline to low (9/L) at week 10. In patients who continued ozanimod, mean ALC reductions were sustained at approximately the same level and ALC shifts from normal at baseline to low were maintained in 73%‒89% of patients during maintenance. In patients who received ozanimod induction therapy and then were re-randomized to placebo for maintenance, mean ALC recovered within 8 weeks to levels similar to baseline at induction and the proportion of patients with ALC shifts from normal at baseline to low decreased from 73% at week 10 to 6% at week 52. Fewer than 2% of ozanimod-treated patients had ALC 9/L during either induction or maintenance and ALC generally returned to ≥ 0.2 x 109/L while patients remained on ozanimod. Among those who switched from ozanimod induction to placebo maintenance, there were no occurrences of ALC 9/L at the end of maintenance. No patients with a serious/opportunistic infection had concurrent ALC 9/L. CONCLUSION: Consistent with the mechanism of action of ozanimod, ALC reductions occurred during ozanimod induction and were sustained during maintenance. Incidence of ALC 9/L was low. ALC recovered after switching to placebo and most patients did not require treatment discontinuation because of changes in ALC.

Effects of Apremilast, an Oral Inhibitor of Phosphodiesterase 4, in a Randomized Trial of Patients With Active Ulcerative Colitis.

BACKGROUND & AIMS: New oral therapeutic agents are needed for patients with ulcerative colitis (UC) who are unresponsive or intolerant to conventional therapy. METHODS: We performed a double-blind, phase 2 trial of adults with active UC for 3 months or more who were naïve to biologic therapy or had been failed by, could not tolerate, or had contraindications to conventional therapies. The study was performed at 61 sites in 14 countries (screening from January 2015 through May 2017). Patients were randomly assigned to groups given apremilast 30 mg (n = 57), apremilast 40 mg (n = 55), or placebo (n = 58) twice daily for 12 weeks; patients were then randomly assigned to groups that received apremilast, 30 or 40 mg twice daily, for an additional 40 weeks. Endoscopies were performed and biopsies were collected during the screening phase, at week 12, and at week 52. Blood and fecal samples were also collected and analyzed throughout the study. The primary endpoint was clinical remission at week 12, defined as a total Mayo score of 2 or less, with no individual subscore above 1. RESULTS: Clinical remission was achieved at week 12 by 31.6% of patients in the 30 mg apremilast group and 12.1% of patients in the placebo group (P = .01). However, only 21.8% of patients in the 40 mg apremilast group achieved clinical remission at week 12 (P = .27 compared with placebo). Differences in clinical remission between the 30 mg and 40 mg apremilast groups were associated with differences in endoscopic improvement. Both apremilast groups had similar improvements from baseline in Mayo score components (stool frequency score, rectal bleeding score, physician's global assessment). The 30 mg and 40 mg apremilast groups had greater median percent reductions in C-reactive protein (measured by a high-sensitivity blood test) and fecal calprotectin through week 12 than the placebo group. At week 52, clinical remission was achieved by 40.4% of patients initially assigned to the apremilast 30 mg group and 32.7% of patients initially assigned to the apremilast 40 mg group. The most frequent apremilast-associated adverse events were headache and nausea. CONCLUSIONS: Although the primary endpoint of clinical remission was not met in this phase 2 trial, a greater proportion of patients with active UC who received apremilast (30 mg or 40 mg) had improvements in clinical and endoscopic features, and markers of inflammation, at 12 weeks. Clinical remission was maintained to week 52 in up to 40% of patients who continued apremilast until that time point. ClinicalTrials.gov no: NCT02289417.

Safety and efficacy of intramuscular human placenta-derived mesenchymal stromal-like cells (cenplacel [PDA-002]) in patients who have a diabetic foot ulcer with peripheral arterial disease.

The objective of this study was to examine the safety of cenplacel (PDA-002) in patients with peripheral arterial disease (PAD) and a diabetic foot ulcer (DFU). Cenplacel is a mesenchymal-like cell population derived from full-term human placenta. This phase 1, dose-escalation study investigated cenplacel in diabetic patients with chronic DFUs (Wagner grade 1 or grade 2) and PAD [ankle-brachial index (ABI) >0·5 and ≤0·9], enrolled sequentially into each of four dose cohorts (3 × 106 , 10 × 106 , 30 × 106 and 100 × 106 cells; administered intramuscularly on study days 1 and 8 in combination with standard of care). Overall, cenplacel was well tolerated in all 15 patients in the study. Before enrollment, nine patients had an ulcer for ≥6 months and 11 had an ABI of 0·7-0·85. No patient met dose-limiting toxicity criteria and no treatment-related serious adverse events were reported. There was preliminary evidence of ulcer healing in seven patients (five complete; two partial) within 3 months of cenplacel treatment, and circulating endothelial cell levels (a biomarker of vascular injury in PAD) were decreased within 1 month. Cenplacel was generally safe and well tolerated in patients with chronic DFUs and PAD. Outcomes from this study informed the doses, endpoints, biomarkers and patient population for an ongoing phase 2 trial.

Partial remission in ankylosing spondylitis and non-radiographic axial spondyloarthritis in treatment with infliximab plus naproxen or naproxen alone: associations between partial remission and baseline disease characteristics.

OBJECTIVES: To evaluate partial remission during treatment with infliximab (IFX) + naproxen (NPX) vs NPX alone in patients from the two subgroups of SpA and explore baseline predictors of partial remission. METHODS: Infliximab as First Line Therapy in Patients with Early Active Axial Spondyloarthritis Trial was a double-blind, randomised controlled trial of IFX in biologic-naïve patients with early, active axial SpA. Patients were randomised (2:1) to receive 28 weeks of treatment with i.v. IFX 5 mg/kg (weeks 0, 2, 6, 12, 18 and 24) + NPX 1000 mg/day or i.v. placebo (PBO) + NPX 1000 mg/day. The current post hoc analysis evaluated outcomes in patients who did or did not meet modified New York radiographic criteria for AS. RESULTS: The analysis included 94 patients who met AS criteria and 56 with non-radiographic axial SpA (nr-axSpA). At week 28, Assessment of SpondyloArthritis international Society (ASAS) partial remission was greater with IFX + NPX than PBO + NPX for both the AS group (70.5 vs 33.3%, respectively) and the nr-axSpA group (50.0 vs 37.5%, respectively). A similar pattern occurred with several efficacy measures. Larger treatment effects occurred in the AS group than the nr-axSpA group, possibly due to baseline differences in disease characteristics. Multivariable analyses identified the type of treatment, age and HLA-B27 status as predictors of ASAS partial remission in the total study population. MRI sacroiliac joint scores were associated with partial remission during IFX + NPX treatment. CONCLUSION: Patients with AS had greater partial remission with IFX + NSAID than NSAID therapy alone; patients with nr-axSpA had a smaller treatment effect. Baseline disease characteristics and age were associated with partial remission with IFX therapy.

Aprepitant triple therapy for the prevention of chemotherapy-induced nausea and vomiting following high-dose cisplatin in Chinese patients: a randomized, double-blind, placebo-controlled phase III trial.

PURPOSE: Aprepitant, an oral neurokinin-1 receptor antagonist, has demonstrated improved control of chemotherapy-induced nausea and vomiting (CINV) in previous studies. This is the first phase III study to evaluate the efficacy and tolerability of aprepitant in patients receiving highly emetogenic chemotherapy (HEC) in Asian countries. METHODS: This multicenter, double-blind, placebo-controlled trial assessed the prevention of CINV during the acute phase (AP), delayed phase (DP), and overall phase (OP). Patients receiving HEC were randomized to either an aprepitant group (day 1, aprepitant 125 mg; days 2-3, aprepitant 80 mg) or a standard therapy group (days 1-3, placebo). Both groups received intravenous granisetron and oral dexamethasone. The primary end point was complete response (CR; no emesis and no use of rescue therapy) during the OP. RESULTS: Of the 421 randomized patients, 411 (98%) were assessable for efficacy; 69.6% (142/204) and 57.0% (118/207) of patients reported CR during the OP in the aprepitant and standard therapy groups, respectively (P = 0.007). CR rates in the aprepitant group were higher during the DP (74.0% vs. 59.4%, P = 0.001) but were similar during the AP (79.4% vs. 79.3%, P = 0.942). Toxicity and adverse events were comparable in both groups. CONCLUSIONS: The addition of aprepitant to standard antiemetic treatment regimens for Chinese patients undergoing HEC provided superior CINV prevention and was well tolerated.

Evaluation of etoricoxib in patients undergoing total knee replacement surgery in a double-blind, randomized controlled trial.

BACKGROUND: Optimal postoperative pain management is important to ensure patient comfort and early mobilization. METHODS: In this double-blind, placebo- and active-controlled, randomized clinical trial, we evaluated postoperative pain following knee replacement in patients receiving placebo, etoricoxib (90 or 120 mg), or ibuprofen 1800 mg daily for 7 days. Patients ≥18 years of age who had pain at rest ≥5 (0-10 Numerical Rating Scale [NRS]) after unilateral total knee replacement were randomly assigned to placebo (N = 98), etoricoxib 90 mg (N = 224), etoricoxib 120 mg (N = 230), or ibuprofen 1800 mg (N = 224) postoperatively. Co-primary endpoints included Average Pain Intensity Difference at Rest over Days 1-3 (0- to 10-point NRS) and Average Total Daily Dose of Morphine over Days 1-3. Pain upon movement was evaluated using Average Pain Intensity Difference upon Knee Flexion (0- to 10-point NRS). The primary objective was to demonstrate analgesic superiority for the etoricoxib doses vs. placebo; the secondary objective was to demonstrate that the analgesic effect of the etoricoxib doses was non-inferior to ibuprofen. Adverse experiences (AEs) including opioid-related AEs were evaluated. RESULTS: The least squares (LS) mean (95% CI) differences from placebo for Pain Intensity Difference at Rest over Days 1-3 were -0.54 (-0.95, -0.14); -0.49 (-0.89, -0.08); and -0.45 (-0.85, -0.04) for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively (p < 0.05 for etoricoxib vs. placebo). Differences in LS Geometric Mean Ratio morphine use over Days 1-3 from placebo were 0.66 (0.54, 0.82); 0.69 (0.56, 0.85); and 0.66 (0.53, 0.81) for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively (p < 0.001 for etoricoxib vs. placebo). Differences in LS Mean Pain Intensity upon Knee Flexion were -0.37 (-0.85, 0.11); -0.46 (-0.94, 0.01); and -0.42 (-0.90, 0.06) for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively. Opioid-related AEs occurred in 41.8%, 34.7%, 36.5%, and 36.3% of patients on placebo, etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively. CONCLUSIONS: Postoperative use of etoricoxib 90 and 120 mg in patients undergoing total knee replacement is both superior to placebo and non-inferior to ibuprofen in reducing pain at rest and also reduces opioid (morphine) consumption. CLINICAL TRIAL REGISTRATION: NCT00820027.

Direct medical costs of constipation from childhood to early adulthood: a population-based birth cohort study.

BACKGROUND: Although direct medical costs for constipation-related medical visits are thought to be high, to date there have been no studies examining whether longitudinal resource use is persistently elevated in children with constipation. Our aim was to estimate the incremental direct medical costs and types of health care use associated with constipation from childhood to early adulthood. METHODS: A nested case-control study was conducted to evaluate the incremental costs associated with constipation. The original sample consisted of 5718 children in a population-based birth cohort who were born during 1976 to 1982 in Rochester, MN. The cases included individuals who presented to medical facilities with constipation. The controls were matched and randomly selected among all noncases in the sample. Direct medical costs for cases and controls were collected from the time subjects were between 5 and 18 years of age or until the subject emigrated from the community. RESULTS: We identified 250 cases with a diagnosis of constipation in the birth cohort. Although the mean inpatient costs for cases were $9994 (95% Confidence interval [CI] 2538-37,201) compared with $2391 (95% CI 923-7452) for controls (P = 0.22) during the time period, the mean outpatient costs for cases were $13,927 (95% CI 11,325-16,525) compared with $3448 (95% CI 3771-4621) for controls (P < 0.001) during the same time period. The mean annual number of emergency department visits for cases was 0.66 (95% CI 0.62-0.70) compared with 0.34 (95% CI 0.32-0.35) for controls (P < 0.0001). CONCLUSIONS: Individuals with constipation have higher medical care use. Outpatient costs and emergency department use were significantly greater for individuals with constipation from childhood to early adulthood.

Unexplained gastrointestinal symptoms after abuse in a prospective study of children at risk for abuse and neglect.

PURPOSE: Unexplained gastrointestinal symptoms are more common in adults who recall abuse as a child; however, data available on children are limited. The aim of this study was to investigate the association of childhood maltreatment and early development of gastrointestinal symptoms and whether this relation was mediated by psychological distress. METHODS: Data were obtained from the Longitudinal Studies of Child Abuse and Neglect, a consortium of 5 prospective studies of child maltreatment. The 845 children who were observed from the age of 4 through 12 years were the subjects of this study. Every 2 years information on gastrointestinal symptoms was obtained from parents, and maltreatment allegations were obtained from Child Protective Services (CPS). At the age of 12 years children reported gastrointestinal symptoms, life-time maltreatment, and psychological distress. Data were analyzed by logistic regression. RESULTS: Lifetime CPS allegations of sexual abuse were associated with abdominal pain at age 12 years (odds ratio [OR] = 1.75; 95% confidence interval [CI] = 1.1-2.47). Sexual abuse preceded or coincided with abdominal pain in 91% of cases. Youth recall of ever having been psychologically, physically, or sexually abused was significantly associated with both abdominal pain and nausea/vomiting (range, OR = 1.5 [95% CI, 1.1-2.0] to 2.1 [95% CI, 1.5-2.9]). When adjusting for psychological distress, most effects became insignificant except for the relation between physical abuse and nausea/vomiting (OR = 1.5; 95% CI, 1.1-2.2). CONCLUSION: Youth who have been maltreated are at increased risk for unexplained gastrointestinal symptoms, and this relation is partially mediated by psychological distress. These findings are relevant to the clinical care for children who complain of unexplained gastrointestinal symptoms.

Lack of utility of abdominal x-rays in the evaluation of children with constipation: comparison of different scoring methods.

BACKGROUND AND AIM: Abdominal x-rays are used diagnostically in the evaluation of children with constipation. However, their clinical utility has not been established. The aim of the study was to assess the accuracy of different methods in identifying children with functional constipation (FC) or nonretentive fecal incontinence (NRFI). PATIENTS AND METHODS: Retrospective review of abdominal x-rays in which colonic transit (CT), Barr, Leech, and fecal loading (FL) scores were blindly measured by blinded pediatric gastroenterologists and a radiologist. Children were classified a priori as FC or NRFI. RESULTS: One hundred sixty patients (125 FC, 35 NRFI) were studied. There were significant differences (P < 0.05) when comparing those with FC and those with NRFI: CT: 51 +/- 18 vs 40 +/- 21 hours; Barr: 14 +/- 5 vs 11 +/- 4; Leech: 10 +/- 2 vs 8 +/- 2; FL: 2 +/- 0.5 vs 1.7 +/- 0.4. More than 20% of FC had normal Barr and Leech scores, whereas >50% of NRFI had abnormal scores. CT discriminated better between FC and NRFI. There was a significant correlation (P < 0.05) between CT and Barr (0.45), Leech (0.41) and FL scores (0.36), and between Barr and Leech scores (r = 0.94). There was good intraobserver correlation between Barr, Leech, and FL scores but poor interobserver reproducibility. CONCLUSIONS: Although significant differences in overall FC and NRFI scores exist, the discriminative value is low for all scores. There is poor interobserver reproducibility of the Barr, Leech, and FL scores. These findings confirm the limited value of the plain abdominal x-ray in the evaluation of children with constipation.

Recollection of childhood abdominal pain in adults with functional gastrointestinal disorders.

OBJECTIVE: It is hypothesized that adults who can recall abdominal pain as children are at risk of experiencing a functional gastrointestinal disorder (FGID), but this is not specific to any particular FGID. The aim of this study was to evaluate the association between recollecting abdominal pain as a child and experiencing a FGID. MATERIAL AND METHODS: A valid self-reported questionnaire of GI symptoms was mailed to a random population-based sample in Olmsted County, Minnesota. Logistic regression models adjusting for age, gender, body mass index (BMI), somatization, and other factors were used to estimate the odds ratios (ORs) for having a FGID in individuals recalling bouts of stomach or abdominal pain in childhood (before age 15). RESULTS: Overall, 2298 (55%) of a total of 4194 eligible adult subjects returned a completed questionnaire. Of the respondents, 213 (9%) recalled experiencing abdominal pain as children. Adults who recalled experiencing abdominal pain in childhood had greater odds for reporting symptoms of a FGID (OR 1.9; 95% CI 1.4-2.7). Recalling abdominal pain in childhood was significantly associated with irritable bowel syndrome (IBS) (OR 2.5; 95% CI 1.7-3.6) but not gastroesophageal reflux, dyspepsia, constipation, or diarrhea, adjusting for age, gender, BMI, somatic symptoms, marital status, and education. CONCLUSIONS: Recollection of childhood abdominal pain is specifically associated with IBS in adults. This suggests that a proportion of adults with IBS may have onset of symptoms of abdominal pain during childhood.

Parental worries and beliefs about abdominal pain.

BACKGROUND: Solicitous parental responses to stomachaches may perpetuate chronic abdominal pain in children. Discussing these issues in clinical practice is difficult because parents feel misunderstood and blamed for their child's pain. Focusing on parental worries and beliefs that motivate solicitous responses may be better accepted. OBJECTIVES: Our aim was to determine parental fears, worries, and beliefs about their child's chronic abdominal pain that influence parental responses to child's pain. MATERIALS AND METHODS: In 2 studies, a large online sample and a smaller community sample consisting of parents with children who have abdominal pain, we developed and evaluated a self-report questionnaire to assess parental Worries and Beliefs about Abdominal Pain (WAP). RESULTS: Principal component analysis identified 4 subscales: "pain is real," "desire for care," "worry about coping," and "exacerbating factors." The WAP is easily understood and possesses adequate initial reliability (Cronbach alpha=0.7-0.9). It shows good initial validity (ie, families who consulted a physician for their child's pain scored higher on the WAP than families who did not consult a physician and the WAP correlates with parental reactions to the child's pain). CONCLUSIONS: Discussing parents' fears and worries about their children's chronic abdominal pain may facilitate discussions of social learning of gastrointestinal illness behavior.

The role of psychological factors in pediatric functional abdominal pain disorders.

BACKGROUND: Pediatric functional abdominal pain disorders (FAPDs) are disorders of brain-gut dysregulation. Psychological factors are known to be related to etiology, maintenance, and exacerbation of pediatric FAPDs. With the evolving literature in the past two decades, a better understanding has emerged of precisely which psychological factors are associated with childhood FAPDs. PURPOSE: This narrative literature review summarizes the literature of both child and parent psychological factors in pediatric FAPD. Where anxiety and depression were major targets in the older literature, present-day focus is increasingly on pain-specific cognitions and coping strategies including disease threat and catastrophizing. In addition, parental reaction to a child's pain is increasingly recognized as an important moderator of a child's outcomes and has become an area for clinical intervention. Screening for these factors and integrative treatment approaches are recommended in childhood FAPD.

Ambulatory care for constipation in the United States, 1993-2004.

OBJECTIVES: Chronic constipation is one of the most common disorders seen in primary care. In order to examine longitudinal changes in the ambulatory care that occur in constipation evaluation and management, we examined national trends in physician office visits associated with constipation between 1993 and 2004. METHODS: Data were derived from the National Ambulatory Medical Care Survey (NAMCS) and the National Hospital Ambulatory Care Survey (NHAMCS) for 1993-2004. Patient visits were classified as encounters for constipation-related care. Analyses were performed by combining 4 yr of data (1993-1996, 1997-2000, and 2001-2004). RESULTS: Ambulatory visits for constipation increased from 4 million (95% CI 3.3-4.7 million) ambulatory visits for constipation annually during 1993-1996 period to 7.95 million (95% CI 6.6-9.4 million) visits during the 2001-2004 period. The proportion of medical visits for constipation increased for pediatricians, but decreased for adult primary care providers from 1993 to 2004. During the observed time period, the proportion of medical visits for constipation did not change for gastroenterologists. The primary treatment for constipation shifted from bulking agents (fiber) to osmotic laxatives. CONCLUSION: There has been a significant increase in physician office visits for constipation between 1993 and 2004, with the highest rate of increase in the pediatric population. Longitudinal trends indicate an increase in constipation-related visits for pediatricians. The primary treatment for constipation among medical providers shifted from using bulking agents to osmotic laxatives for unknown reasons.

Contributions of pain sensitivity and colonic motility to IBS symptom severity and predominant bowel habits.

OBJECTIVES: Irritable bowel syndrome (IBS) patients show pain hypersensitivity and hypercontractility in response to colonic or rectal distention. Aims were to determine whether predominant bowel habits and IBS symptom severity are related to pain sensitivity, colon motility, or smooth muscle tone. METHODS: One hundred twenty-nine patients classified as IBS with diarrhea (IBS-D, N = 44), IBS with constipation (IBS-C, N = 29), mixed IBS (IBS-M, N = 45), and unspecified IBS (IBS-U, N = 11) based on stool consistency, and 30 healthy controls (HC) were studied. A manometric catheter containing a 600-mL capacity plastic bag was positioned in the descending colon. Pain threshold was assessed using a barostat. Motility was assessed for 10 min with the bag minimally inflated (individual operating pressure [IOP]), 10 min at 20 mmHg above the IOP, and for 15-min recovery following bag inflation. Motility was also recorded for 30 min following an 810-kcal meal. RESULTS: Compared with HC, IBS patients had lower pain thresholds (medians 30 vs 40 mmHg, P < 0.01), but IBS subtypes were not different. IBS symptom severity was correlated with pain thresholds (rho =-0.36, P < 0.001). During distention, the motility index (MI) was significantly higher in IBS compared with HC (909 +/- 73 vs 563 +/- 78, P < 0.01). Average barostat bag volume at baseline was higher (muscle tone lower) in HC compared with IBS-D and IBS-M but not compared with IBS-C. The baseline MI and bag volume differed between IBS-D and IBS-C and correlated with symptoms of abdominal distention and dissatisfaction with bowel movements. Pain thresholds and MI during distention were uncorrelated. CONCLUSIONS: Pain sensitivity and colon motility are independent factors contributing to IBS symptoms. Treatment may need to address both, and to be specific to predominant bowel habit.

Incidence of presentation of common functional gastrointestinal disorders in children from birth to 5 years: a cohort study.

BACKGROUND & AIMS: Gastroesophageal reflux disease (GERD), abdominal pain of unknown origin, and constipation are thought to be causes for frequent medical visits during childhood. The aim of this study was to estimate the incidences, repeat presentation, clinical symptoms, and sociodemographic risk factors in children who medically presented for GERD, abdominal pain of unknown origin, and constipation from birth to 5 years. METHODS: This was a population-based, retrospective birth cohort study of all children born to mothers residing in Rochester, Minnesota who remained in the area until at least age 5 (n = 5718). The medical records of all individuals were searched for relevant diagnostic billing codes for GERD, abdominal pain of unknown origin, and constipation, without another underlying diagnosis, and manually reviewed. Parental sociodemographic factors collected from birth certificate records on patients and matched controls were compared. RESULTS: The incidence for childhood (age, <5 y) presentation of GERD, abdominal pain of unknown origin, and constipation was .9/1000 person-years, 4.5/1000 person-years, and 6.8/1000 person-years, respectively; there were no significant differences between boys and girls. Three or more medical visits by age 5 occurred in 11%, 19%, and 24% of children who were seen for abdominal pain of unknown origin, constipation, and GERD, respectively. Single parentage, maternal age (<18 y), and maternal education (

Medical presentation of constipation from childhood to early adulthood: a population-based cohort study.

BACKGROUND & AIMS: Constipation is a common disorder in children and adults, but the role of gender and early life risk factors remains undefined. The aims of the study were as follows: (1) to estimate the incidence of medical presentation for constipation in a population-based birth cohort, and (2) to examine factors associated with constipation presentation from childhood to adulthood. METHODS: A birth cohort of all children born between 1976 and 1982 to mothers who were residents of Rochester, Minnesota, and who remained in the community until age 5 was used for this study. Medical visits for constipation were identified by diagnoses codes and chart review. Subjects were followed up based on their diagnoses accumulated while younger than 21 years old, and 80% of subjects remained in the area until 18 years of age. RESULTS: Of 5299 birth cohort members without constipation presentation before age 5, the overall age- and sex-adjusted incidence was 3.9 per 1000 person-years. A higher incidence for constipation in females occurred beginning at 13 years to early adulthood (rate ratio, 2.6 for 13-16 y and 4.2 for 17 to <21 y). Children with a diagnosis for constipation at younger than 5 years of age had a significantly higher incidence for subsequent medical visits for constipation through adolescence and early adulthood compared with the incidence rate of children without an early medical presentation (rate ratio, 4.5 for 5-8 y, 2.5 for 9-12 y, and 3.9 for 17-20 y). CONCLUSIONS: Early medical presentation and female sex influence incident and repeat medical visits for constipation from childhood to early adulthood.

Pharmacotherapy for functional gastrointestinal disorders in children.

Functional gastrointestinal disorders are among the most common medical problems in pediatrics. However, only a few well-designed trials have evaluated the efficacy and safety of treatments in these conditions. Data obtained from studies conducted in adults are often utilized to tailor treatment to children with functional gastrointestinal disorders. This practice might lead to substantial medication under- or over-dosing, or use of drugs for an incorrect indication.

Audio-recorded guided imagery treatment reduces functional abdominal pain in children: a pilot study.

OBJECTIVE: This study was designed to develop and to test a home-based, guided imagery treatment protocol, using audio and video recordings, that is easy for health care professionals and patients to use, is inexpensive, and is applicable to a wide range of health care settings. METHODS: Thirty-four children, 6 to 15 years of age, with a physician diagnosis of functional abdominal pain were assigned randomly to receive 2 months of standard medical care with or without home-based, guided imagery treatment. Children who received only standard medical care initially received guided imagery treatment after 2 months. Children were monitored for 6 months after completion of guided imagery treatment. RESULTS: All treatment materials were reported to be self-explanatory, enjoyable, and easy to understand and to use. The compliance rate was 98.5%. In an intention-to-treat analysis, 63.1% of children in the guided imagery treatment group were treatment responders, compared with 26.7% in the standard medical care-only group (P = .03; number needed to treat: 3). Per-protocol analysis showed similar results (73.3% vs 28.6% responders). When the children in the standard medical care group also received guided imagery treatment, 61.5% became treatment responders. Treatment effects were maintained for 6 months (62.5% responders). CONCLUSION: Guided imagery treatment plus medical care was superior to standard medical care only for the treatment of abdominal pain, and treatment effects were sustained over a long period.