Adrian Miranda

Multicenter, Randomized, Placebo-Controlled Trial of Amitriptyline in Children With Functional Gastrointestinal Disorders

BACKGROUND & AIMS There are no prospective, multicenter, double-blind, placebo-controlled, randomized pharmacologic trials for the treatment of pain-predominant functional gastrointestinal disorders in children. The aim of this study was to evaluate the efficacy of amitriptyline in children with pain-predominant functional gastrointestinal disorders. METHODS In this multicenter placebo-controlled trial, children with irritable bowel syndrome, functional abdominal pain, or functional dyspepsia were randomized to 4 weeks of placebo or amitriptyline (10 mg/d, weight <35 kg; 20 mg/d, weight >35 kg). Assessment of gastrointestinal symptoms, psychological traits, and daily activities occurred before and after intervention. Pain was assessed daily with self-report diaries. The primary outcome was overall response to treatment (childs assessment of pain relief and sense of improvement). Secondary outcomes were effect on psychosocial traits and daily functioning. RESULTS Ninety children were enrolled, and 83 completed the study (placebo, 40 children [30 girls]; drug, 43 children [35 girls]). A total of 63% of patients reported feeling better and 5% feeling worse in the amitriptyline arm compared with 57.5% feeling better and 2.5% feeling worse in the placebo arm (P = .63). Pain relief was excellent in 7% and good in 38% of children receiving placebo compared with excellent in 15% and good in 35% of children treated with amitriptyline (P = .85). Logistic regression analysis of those reporting excellent or good response versus fair, poor, or failed response showed no difference between amitriptyline and placebo (P = .83). Children who had more severe pain at baseline in both groups (P = .0065) had worse outcome. Amitriptyline reduced anxiety scores (P < .0001). CONCLUSIONS Both amitriptyline and placebo were associated with excellent therapeutic response. There was no significant difference between amitriptyline and placebo after 4 weeks of treatment. Patients with mild to moderate intensity of pain responded better to treatment.

The role of transient receptor potential vanilloid 1 in mechanical and chemical visceral hyperalgesia following experimental colitis.

The transient receptor potential vanilloid 1 receptor (TRPV1) is an important nociceptor involved in neurogenic inflammation. We aimed to examine the role of TRPV1 in experimental colitis and in the development of visceral hypersensitivity to mechanical and chemical stimulation. Male Sprague-Dawley rats received a single dose of trinitrobenzenesulfonic acid (TNBS) in the distal colon. In the preemptive group, rats received the TRPV1 receptor antagonist JYL1421 (10 mumol/kg, i.v.) or vehicle 15 min prior to TNBS followed by daily doses for 7 days. In the post-inflammation group, rats received JYL1421 daily for 7 days starting on day 7 following TNBS. The visceromotor response (VMR) to colorectal distension (CRD), intraluminal capsaicin, capsaicin vehicle (pH 6.7) or acidic saline (pH 5.0) was assessed in all groups and compared with controls and naïve rats. Colon inflammation was evaluated with H&E staining and myeloperoxidase (MPO) activity. TRPV1 immunoreactivity was assessed in the thoraco-lumbar (TL) and lumbo-sacral (LS) dorsal root ganglia (DRG) neurons. In the preemptive vehicle group, TNBS resulted in a significant increase in the VMR to CRD, intraluminal capsaicin and acidic saline compared the JYL1421-treated group (P<0.05). Absence of microscopic colitis and significantly reduced MPO activity was also evident compared with vehicle-treated rats (P<0.05). TRPV1 immunoreactivity in the TL (69.1+/-4.6%) and LS (66.4+/-4.2%) DRG in vehicle-treated rats was increased following TNBS but significantly lower in the preemptive JYL1421-treated group (28.6+/-3.9 and 32.3+/-2.3 respectively, P<0.05). JYL1421 in the post-inflammation group improved microscopic colitis and significantly decreased the VMR to CRD compared with vehicle (P<0.05, >/=30 mm Hg) but had no effect on the VMR to chemical stimulation. TRPV1 immunoreactivity in the TL and LS DRG was no different from vehicle or naïve controls. These results suggest an important role for TRPV1 channel in the development of inflammation and subsequent mechanical and chemical visceral hyperalgesia.

Dermatologic manifestations of Crohn disease in children: response to infliximab.

Dermatologic extraintestinal manifestations of Crohn disease may be refractory to treatment with corticosteroids and immunomodulators. The authors describe four children with Crohn disease with dermatologic manifestations: pyoderma gangrenosum, orofacial involvement, erythema nodosum, and idiopathic lymphedema. These dermatologic conditions were unresponsive to conventional therapy but had rapid and sustained response to the anti–TNF-&agr; antibody infliximab. No adverse reactions occurred. Infliximab should be considered for treating the extraintestinal dermatologic manifestations of Crohn disease in children.

MicroRNA-mediated GABAAα-1 receptor subunit down-regulation in adult spinal cord following neonatal cystitis-induced chronic visceral pain in rats

Summary In an experimental model of neonatal cystitis, microRNA‐mediated post‐transcriptional deregulation of spinal GABAergic system is involved in long‐lasting visceral hyperalgesia. Abstract The nociceptive transmission under pathological chronic pain conditions involves transcriptional and/or translational alteration in spinal neurotransmitters, receptor expressions, and modification of neuronal functions. Studies indicate the involvement of microRNA (miRNA) – mediated transcriptional deregulation in the pathophysiology of acute and chronic pain. In the present study, we tested the hypothesis that long‐term cross‐organ colonic hypersensitivity in neonatal zymosan‐induced cystitis is due to miRNA‐mediated posttranscriptional suppression of the developing spinal GABAergic system. Cystitis was produced by intravesicular injection of zymosan (1% in saline) into the bladder during postnatal (P) days P14 through P16 and spinal dorsal horns (L6–S1) were collected either on P60 (unchallenged groups) or on P30 after a zymosan re‐challenge on P29 (re‐challenged groups). miRNA arrays and real‐time reverse transcription–polymerase chain reaction (RT‐PCR) revealed significant, but differential, up‐regulation of mature miR‐181a in the L6–S1 spinal dorsal horns from zymosan‐treated rats compared with saline‐treated controls in both the unchallenged and re‐challenged groups. The target gene analysis demonstrated multiple complementary binding sites in miR‐181a for GABAA receptor subunit GABAAα‐1 gene with a miRSVR score of −1.83. An increase in miR‐181a concomitantly resulted in significant down‐regulation of GABAAα‐1 receptor subunit gene and protein expression in adult spinal cords from rats with neonatal cystitis. Intrathecal administration of the GABAA receptor agonist muscimol failed to attenuate the viscero‐motor response (VMR) to colon distension in rats with neonatal cystitis, whereas in adult zymosan‐treated rats the drug produced significant decrease in VMR. These results support an integral role for miRNA‐mediated transcriptional deregulation of the GABAergic system in neonatal cystitis‐induced chronic pelvic pain.

Acute nociceptive somatic stimulus sensitizes neurones in the spinal cord to colonic distension in the rat

The common co‐existence of fibromyalgia and chronic abdominal pain could be due to sensitization of spinal neurones (SNs), as a result of viscero‐somatic convergence. The objective of this study is to explore the influence of acute nociceptive somatic stimulation in the form of acid injections, into the ipsilateral somatic receptive field of neurones responsive to colorectal distension (CRD), and the potential role of ionotropic glutamate receptors on sensitization. Action potentials of CRD‐sensitive SNs were recorded extracellularly from the lumbar (L2–L5) spinal cord. Stimulus–response functions (SRFs) to graded CRD (10–80 mmHg, 30 s) were constructed before and 30 min after ipsilateral injection of low pH (4.0, 100 μl) saline into the somatic receptive fields. In some experiments, cervical (C1–C2) spinalization was performed to eliminate supraspinal influence. The selective NMDA receptor antagonist CGS 19755 and AMPA receptor antagonist NBQX were injected (25 μmol kg−1, i.v.) to examine their influence on sensitization. Three types of neurones were characterized as short‐latency abrupt (SLA, n= 24), short latency sustained (SLS, n= 12), and long‐latency (LL, n= 6) to CRD. Ipsilateral injection of low pH (4.0) in the somatic receptive field, but not the contralateral gastrocnemius (GN) or front leg muscles, sensitized responses of these neurones to CRD. Spinalization had no influence on the development of low pH‐induced sensitization. Both CGS 19755 and NBQX significantly attenuated the sensitized response to CRD in intact and spinalized animals. Acute nociceptive somatic stimulus sensitizes CRD‐sensitive SNs receiving viscero‐somatic convergence. The sensitization occurs at the spinal level and is independent of supraspinal influence. Ionotropic glutamate receptors in the spinal cord are involved in sensitization.

Antinociceptive effects of melatonin in a rat model of post-inflammatory visceral hyperalgesia: a centrally mediated process.

&NA; Previous reports suggest that melatonin may play an important role in visceral nociception and neurogenic inflammation. We aimed to examine the role of melatonin on visceral hypersensitivity and to explore the site of action using a rat model of post‐inflammatory visceral hyperalgesia. In all rats, a baseline viscero‐motor response (VMR) to graded colorectal distension (CRD; 10–60 mmHg) was recorded prior and 1 week following tri‐nitrobenzenesulfonic acid (TNBS) induced colonic inflammation. Melatonin (30, 45 or 60 mg/kg, ip) was given 20 min before testing the VMR in naïve and TNBS‐treated rats. Extracellular single‐unit recordings were made from CRD‐sensitive pelvic nerve afferent (PNA) fibers and lumbosacral (LS) spinal neurons in TNBS‐treated animals. The effect of melatonin (60 mg/kg) was examined on responses of PNAs and spinal neurons to graded CRD. In separate experiments, luzindole (non‐specific MT1/MT2 receptor antagonist) or naltrexone (non‐specific opiod receptor antagonist) was injected prior to melatonin. Following TNBS, there was a significant increase in the VMR to CRD compared to baseline. This increase was attenuated by melatonin (60 mg/kg) at pressures >20 mmHg. The same dose of melatonin had no effect on the VMR in naïve animals. In TNBS‐treated rats, melatonin significantly attenuated the responses of CRD‐sensitive spinal neurons to CRD, but had no effect in spinal transected rats or PNA fibers. Both luzindole and naltrexone blocked melatonins effect on the VMR and LS spinal neurons. Results indicate melatonins antinociceptive effects are not via a peripheral site of action but rather a supra‐spinal process linked to the central opioidergic system.

Neonatal gastric suctioning results in chronic visceral and somatic hyperalgesia: role of corticotropin releasing factor

Abstract Gastric suctioning is common in neonatal intensive care units. Studies suggest that gastric suctioning in premature infants may play a role in the development of visceral hyperalgesia. We hypothesized that repeated orogastric suctioning during the neonatal period results in chronic alterations in visceral and somatic sensation through a corticotropin‐releasing factor mediated mechanism. Neonatal male Long Evans rats (n = 13) received daily orogastric suctioning for 10 days starting at postnatal day two (P2). Control rats (n = 15) were handled similarly without orogastric suction. A second study group was subjected to a similar protocol, only with pre‐emptive administration of a CRF1 receptor antagonist (antalarmin, 20 mg/kg, IP) (n = 8). The control group received vehicle only (n = 8). An additional group was given antalarmin without suctioning (n = 5). After these rats grew to adulthood (PN 60), a visceromotor response to graded colorectal distension was recorded (10–80 mmHg, 30s, 180s inter‐stimulus intervals) to assess changes in visceral sensitivity. Paw withdrawal latency to noxious heat applied to the hind paws was measured to assess changes in cutaneous sensitivity. Orogastric suctioning during the neonatal period results in global chronic somatic and visceral hyperalgesia in adult rats. Visceral hyperalgesia is prevented by pre‐emptive administration of the CRF1 receptor antagonist, antalarmin.

Effects of the 5-HT3 receptor antagonist, alosetron, in a rat model of somatic and visceral hyperalgesia.

&NA; Conflicting results exist regarding the role of 5‐HT3 receptors in somatic and visceral nociceptive processing. We aimed to investigate the effects of the 5‐HT3 receptor antagonist, alosetron, in a rat model of somatic and visceral hyperalgesia. Two injections (100 &mgr;l) of either pH 4.0 or 7.2 saline were given unilaterally in the gastrocnemius (GN) muscle. In all groups, the paw withdrawal thresholds (PWT) to von Frey filaments and the visceromotor responses (VMR) to colorectal distension (CRD) were recorded before the saline injections and 72 h, and 1 week after the second injection. Intrathecal (i.t.) (25 nmol) or intravenous (i.v.) (100 &mgr;g/kg/day) alosetron was given daily following the second injection and compared to either i.v. or i.t. saline (vehicle). There was a significant decrease in the mean PWT bilaterally in all groups following pH 4.0 injections (p < 0.05). Intravenous alosetron resulted in a significant increase in the PWT bilaterally on days 2 and 3. Intrathecal alosetron resulted in significant increase in the PWT starting at day 3 and was significantly higher than baseline on days 4–7 (p < 0.05). At CRD pressures ≥30 mmHg, the VMR of pH 4.0 injected rats was significantly increased at 72 h and 1 week (p < 0.05). Both i.v. and i.t. alosetron treated rats failed to demonstrate any alteration in the VMR. Control rats (pH 7.2) failed to show any alteration in the VMR and were unaffected by alosetron. Both, systemically and centrally administered alosetron, reversed the mechanical somatic hypersensitivity and prevented the development of visceral hyperalgesia, suggesting a centrally mediated effect.

Identifying youth nonadherence in clinical settings: Data-based recommendations for children and adolescents with inflammatory bowel disease†

Background: To examine the validity of patient self‐report of thiopurine adherence in pediatric inflammatory bowel disease (IBD) against an objective electronic monitoring adherence measure, and to investigate the role of youth and maternal involvement in remembering to take daily medications as predictors of medication adherence. Methods: Fifty‐one youths with IBD, ages 11–18 years, participated. Youths completed questionnaire assessments of their own and their maternal caregivers involvement in remembering to take daily medications at baseline, completed monthly interviews assessing thiopurine adherence over the past week for a period of 6 months, and utilized a Medication Events Monitoring System (MEMS) electronic monitor for their thiopurine medication for 6 months. Participants were grouped into adherent (at least 80% of doses taken based on objective MEMS caps) or nonadherent for analyses. Results: Youths who were nonadherent based on electronic monitoring overestimated their adherence by 23%, whereas adherent youths overestimated their adherence by only 2%, and as such patient self‐report offered little utility in identifying youths who were nonadherent. Youths who reported high levels of involvement in remembering to take their medications were nearly eight times less likely to be nonadherent. Conclusions: The current findings provide evidence that clinicians who work with children and adolescents with IBD may benefit from modifying their approach to nonadherence screening. Asking about youth involvement in remembering daily medications may be more informative than asking them to recall their medication‐taking behavior over the last week in identifying those at highest risk for nonadherence. (Inflamm Bowel Dis 2011;)

One-day bowel preparation with polyethylene glycol 3350: an effective regimen for colonoscopy in children.

BACKGROUND Polyethylene glycol (PEG) 3350 is commonly used and has been proven safe and effective for the treatment of chronic constipation and as a 4-day bowel preparation in children. A 1-day PEG 3350 bowel preparation regimen has been recently developed for adults; however, data regarding its use in children are lacking. OBJECTIVE To evaluate the safety and effectiveness of a 1-day PEG 3350 regimen for bowel preparation in children before colonoscopy. DESIGN Retrospective review. SETTING Tertiary-care center. PATIENTS This study involved all children prescribed a 1-day PEG 3350 bowel preparation regimen before colonoscopy at our center in 2008. INTERVENTION We reviewed medical records of patients (< or = 18 years of age) who underwent colonoscopy during 2008 and received the 1-day bowel preparation regimen. MAIN OUTCOME MEASUREMENTS Adequate preparation for colonoscopy, success of colonoscopy, and factors associated with inadequate bowel preparation. RESULTS Inclusion criteria were met by 272 patients. The median age of the children receiving the 1-day PEG 3350 preparation regimen was 13.7 years (range 1.08-17.92 years). Fifty-two percent were male; 48% were female. The most common indications for colonoscopy included abdominal pain (65%), bloody stools (29%), diarrhea (21%), and weight loss (18%). The 1-day bowel preparation regimen was effective in 253 patients (93%). The indication for colonoscopy, the age of the child, or a history of constipation did not significantly alter the success rate of colonoscopy. LIMITATIONS A retrospective study at one tertiary-care center. CONCLUSION The 1-day PEG 3350 bowel preparation regimen is safe and effective and should be considered for use as preparation for colonoscopy in children.