How Effective are the Treatments for Functional Abdominal Pain?

Posted on February 19, 2015 by gutsandgrowth

According to a recent systematic review (Korterink JJ et al. J Pediatr 2015; 166: 424-31), “there is no evidence to support routine use of any pharmacologic therapy” for pediatric functional abdominal pain (FAP). How many pediatric gastroenterologists want to discuss this conclusion with their patients?

How did the authors reach their conclusion?

Design: The authors screened 557 articles and ultimately identified only four articles with a total of 6 studies met inclusion criteria which included the following:

systemic review or randomized control trial
children 4-18 years
diagnosis of FAP established with well-defined criteria
intervention was compared to placebo or alternative treatment

Results: All of the studies were reviewed –each received an overall quality rating by the authors as “very low.” The particular treatments included amitriptyline, peppermint oil, famotidine, miralax, tegaserod, and cyprohepatadine. The study with the most patients had only 90 patients and the longest treatment period was 4 weeks.

In the discussion, the authors make several key points:

there is a lack of adequately powered, high-quality, placebo-controlled drug trials in children with FAP
weak evidence was found in support of peppermint oil, cyproheptadine, and laxatives at reducing pain; amitriptyline and famotidine had weak evidence supporting some improvement in global symptoms or quality of life.
problems with the studies: small sample sizes, poorly reported side effects, lack of follow-up, risk of bias
“several nonpharmacologic therapies (e.g.. hypnotherapy and cognitive behavioral therapy) have shown their efficacy in treating children with” FAP…with success rates up to 85%. Moreover, these therapies are not hampered by severe side effects.”

Bottomline: Our office-based psychologist may be more helpful for our patients than all the medications combined.

Related posts:

Prucalopride -Not Better Than Placebo for Children with Constipation

Posted on January 27, 2015 by gutsandgrowth

Background: There were high expectations for prucalopride for the treatment of constipation based on previous small studies as well as a placebo-controlled trial in adults. In adults, after 12 weeks of treatment, between 19.5-29% were responders compared to 9.6-12.1% in placebo patients. Prucalopride is a 5-hydroxytryptamine receptor-4 (5HT4) agonist which has been shown to accelerate colonic motility and is similar structurally to agents like cisapride and tegaserod; these latter medications have shown effectiveness as prokinetics but were limited by life-threatening cardiovascular side effects.

Design: Large (n=213), multicenter, placebo-controlled trial (Mugie SM, et al. Gastroenterol 2014; 147: 1285-95, editorial 1214-16). Response to medication indicated by >3 spontaneous bowel movements per week and <1 episode of fecal incontinence every 2 weeks.

Findings:

17% of prucalopride subjects and 17.8% of placebo subjects were considered responders.
If based solely on bowel movement frequency, 29.2% of prucalopride achieved >3 BMs/week, whereas 35.5% of placebo-treated patients achieved this frequency.
Adverse effects were similar

Why did Prucalopride not work?

The authors and editorial make several speculations. In children, withholding behavior is much more important in the pathophysiology of functional constipation (FC) than in adults. In addition, slow transit constipation is much more common in adults than in children. In the adolescents (≥12 to <18) there was a mild response noted: 18.5% compared with 14.8% of placebo-treated patients (P=.38). The editorial notes that the short length of the trial (8 weeks) could explain the negative results, though this is unlikely.

The editorial, by Samuel Nurko and Miguel Saps, notes a much higher response to polyethylene glycol which “is the mainstay of treatment.” “PEG-based solutions achieved a successful outcome in 56% of participants compared with 29% in the lactulose group.”

Take-home message: “This study does not provide new data to justify a change in the indication of PEG as first line of treatment for FC in children.”

In followup to questions regarding Miralax safety, here is a link from NASPGHAN’s Neurogastroenterology and Motility Committee: Miralax FAQ

Related blog posts:

A Sign in Our Office –Needs Clarification

AGA Guidelines on Medicines for Irritable Bowel

Posted on November 25, 2014 by gutsandgrowth

New guidelines on the use of medicines for irritable bowel syndrome from Atlanta Gastroenterology Association (AGA) have been published (Gastroenterol 2014; 1146-48, technical review: 1149-72).

Here’s the link: AGA IBS Guidelines.

In brief:

For IBS-C

Linaclotide: AGA recommends as better than no drug treatment in adult. This is the only “strong” recommendation with high-quality evidence.
Lubiprostone: AGA suggests over no drug treatment.
PEG Laxatives: AGA suggests over no drug treatment.

For IBS-D:

Rifaximin: AGA suggests over no drug treatment.
Alosetron: AGA suggests over no drug treatment.
Loperamide: AGA suggests over no drug treatment.

For IBS:

Tricyclic antidepressants: AGA suggests over no drug treatment.
Selective Serotonin Reuptake Inhibitors: AGA suggests against using for IBS.
Antispasmotics: AGA suggests over no drug treatment.

Also noted:

Am J Gastroenterol 2014; 109: 1547-61. (Thanks to Ben Gold for this reference.) Meta-analysis of prebiotics/probiotics for IBS. 43 RCTs were eligible for inclusion. Key finding: IBS symptoms, including pain, bloating and flatulence were improved with RR of 0.79 compared with placebo. “Probiotics are effective treatments for IBS, although which individual species and strains are the most beneficial remains unclear.”

Related blog posts:

NASPGHAN “Best Practices Cleanout Regimens”

Posted on October 3, 2014 by gutsandgrowth

The authors of a recent report (JPGN 2014; 59: 409-16) acknowledge that “bowel regimens vary significantly” and “few clinical studies in pediatrics have evaluated the use of various bowel preparation regimens.” Furthermore, “pediatric studies did not have a common efficacy measure.”

Nevertheless, they provide a “NASPGHAN best practices cleanout regimens.” According to Table 7:

Option 1: PEG-3350 (eg. Miralax) -1-day cleanout: If less than 50 kg, then 4 g/kg/day + bisacodyl 5 mg. If >50 kg, then 238 g in 1.5 L sports drink + bisacodyl 10 mg. PEG-3350 administered over 4-6 hours.
Option 2: PEG-3350 -2-day cleanout: If <50 kg, then 2 g/kg/day + bisacodyl 5 mg; if >50 kg, then 2 g/kg/day + bisacodyl 10 mg.
Option 3: NG cleanout: PEG-ELS (eg. Nulytely) 25 mL/kg/h (max 450 mL/h). NG cleanouts mainly in those with history of failed preps or other adherence problems (eg. vomiting).
Option 4: non-PEG cleanout: Magnesium citrate 4-6 mL/kg/day + bisacodyl 5-10 mg.

My personal opinion is that Table 7 could drop the words “best practices” since the report states “alternative dosing regimens may be entirely reasonable” and the data are quite limited.

With regard to split dosing preparations which are now recommended in adults, their role in pediatrics is a “potential area for future research.” For adults, the U.S. Multi-Society Task Force Consensus Statement on Adequate Bowel Cleansing for Colonoscopy (Johnson DA et al. Optimizing Adequacy of Bowel Cleansing for Colonoscopy: Recommendations from the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2014; 147(4):903-924) recommends:

Use of a split-dose bowel cleansing regimen is strongly recommended for elective colonoscopy, meaning roughly half of the bowel cleansing dose is given the day of the colonoscopy.
The second dose of split preparation ideally should begin four to six hours before the time of colonoscopy with completion of the last dose at least two hours before the procedure time.
During a split-dose bowel cleansing regimen, diet recommendations can include either low-residue or full liquids until the evening on the day before colonoscopy.

Take-home message: This NASPGHAN report summarizes the literature and provides recommendations for effective bowel preparations.

Related blog posts:

Will Lubiprostone Help Children with Functional Constipation?

Posted on April 21, 2014 by gutsandgrowth

A recent open-label study of lubiprostone examined its use in children younger than 18 years (2007-2008) at 22 U.S. centers (JPGN 2014; 58: 283-91).

Lubiprostone (Amitiza) activates chloride-channel protein-2 in the gastrointestinal epithelium and promotes secretion of chloride ions and fluid. This results in more frequent bowel movements (BMs) and improved motility. To determine its safety and effectiveness in the pediatric population, the investigators enrolled 127 patients (124 were treated and analyzed and 109 completed the 4-week study). After a 2-week observation period, several doses of lubiprostone were compared: 12 μg QD, 12 μg BID, 24 μg BID. There was no placebo group. The mean age of the participants was 10.2 years.

Results:

Mean spontaneous BM frequency increased from baseline: 3.1/week versus 1.5/week. Overall, at each week in treatment ≥ 43% achieved ≥ 3 spontaneous BMs/week.
62% experienced a spontaneous BM within 48 hours of starting treatment.
Common adverse reactions: Nausea (18.5%), vomiting (12.1%), diarrhea (8.1%), abdominal pain (7.3%) and headache (5.6%). Overall, 65% of patients experienced ≥ 1 adverse effect and this was highest (78%) in the subset of patients receiving the highest dosage

Bottomline: Current guidelines recommend osmotic agents like polyethylene glycol (PEG) (Miralax) as first-line treatment. This short-term study shows lubiprostone may be an alternative in nonresponders, though more data on long-term outcomes are needed.

Related blog posts:

Three PEG Pediatric Cleanouts

Posted on February 13, 2013 by gutsandgrowth

Several articles highlight the use of polyethylene glycol (Miralax) as a bowel prep for children:

JPGN 2013; 56: 215-19
JPGN 2013; 56: 220-24
JPGN 2013; 56: 225-28

These studies and the accompanying editorial (pg 115) show fairly good results with PEG cleanout regimens.

The first study compared PEG versus senna in a blinded, prospective randomized trial. After enrolling 30 children (6-21 years of age) at a planned interim analysis, the study showed superiority of PEG (1.5 g/kg/day) when used for 2 days prior to colonoscopy. In addition to laxatives, patients were instructed to consume full liquid diet for 2 days prior to procedure & clear liquid on day prior (up to 3 hours before procedure). In the PEG group, good or excellent cleanout scores were noted in 88% compared with only 29% in the senna group. There were no significant adverse effects or electrolyte changes which are well-detailed in this study (Table 2).

The second study evaluated a 1-day regimen with 46 children in a prospective open-label study. 238 g of PEG was mixed with 1.9 L of gatorade and administered over several hours. Patients (8-18 years) were instructed to take only clears after noon the day prior to procedure Only 37 (82%) were able to take the full preparation. 43 (93%) took at least 75% of the preparation. Despite issues with tolerance and nausea/vomiting (noted in 60%), 77% were rated as having an effective cleanout.

The third study enrolled 45 children (5-21 years) in a prospective study of a 1-day bowel preparation. Patients <45 kg received 136 g of PEG solution with 32 ounces of Gatorade; patients >45 kg received 255 g in 64 ounces. 44 children completed study. Patients were told to take PEG over 3 hours the evening prior to procedure and allowed clears until 3 hours prior to procedure. In this group, nausea was noted in 34% and vomiting in 16%. However, patients reported that preparation was easy in 61% and tolerable in 39%. The quality of the preparation was considered excellent in 23%, good in 52%, fair in 23% and poor in 2%. There were no significant electrolyte changes.

Take Home Message:

Numerous small studies show that PEG solutions can be used as a safe, effective bowel preparation in children. Shorter duration preparations are more convenient and may result in nausea or vomiting.

In our institution, we frequently use PEG cleanouts. However, typically our doses of PEG are lower (eg. 136-168 g) and often combined with an enema to complete cleanout process. Unlike adult preparations, we have not instructed families in split-dose regimens mainly due to concerns about the ability of pediatric patients to adhere to these regimens.

Related blog entry:

Colonoscopy, Split–dosing bowel preps, and Ottawa scores …

Miralax Safety

Posted on February 12, 2013 by gutsandgrowth

Periodically questions about the safety of Miralax arise. Recently, several colleagues have received some questions about the use of Miralax due to information on the internet. You may want to familiarize yourself with this link due to the misinformation which is provided:

http://www.gutsense.org/gutsense/the-role-of-miralax-laxative-in-autism-dementia-alzheimer.html

Some of the misleading statements:

Miralax has never been tested for safety in children
Miralax makes one cancer-prone by leaving the colon unprotected
Miralax may result in severe malnutrition ..leading to Autism
Miralax can cause memory loss and neurologic side effects

It is true that there is not enough adequate long-term data on the use of Miralax, though there are studies showing its effectiveness/safety (see below). However, according to the FDA, there are no neuropsychiatric warnings needed for Miralax:

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm295585.htm

As with all medications, one has to weigh the risks and the benefits. Clearly, the risk and consequences of untreated defecation problems can be severe in some children and may have terrible adverse effects on daily living. The known safety profile of Miralax is very good and its usage has been recommended by the American Gastroenterological Association (AGA) and by the North American Society for Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN) in position statements on the treatment of constipation:

An article from NY Times on this subject:

Miralax, a Drug for Adults, Is Popular as a Children’s Remedy …

Stimulants for constipation

Posted on March 15, 2012 by gutsandgrowth

Overall, 12-19% of Americans are affected by chronic constipation (Am J Gastroenterol 2004; 9: 750-59). Despite the fact that constipation problems are widespread, the amount of useful research available to guide treatment is quite limited. Two recent articles do offer some information:

Clin Gastroenterol Hepatol 2011; 9: 577-83.
Gut 2011; 60: 209-18.

The first reference examined the use of bisacodyl in a randomized, double-blind placebo-controlled study in the UK. During the 4-week treatment period, patients receiving 10mg/day bisacodyl (n=247) had increased stools, from 1.1 per week to 5.2 per week. Stool frequency also increased to 1.9 per week in the placebo group (n=121). All secondary endpoints including constipation-associated symptoms (eg. quality of life indices, physical discomfort) improved significantly compared to placebo. Average age of patients in this study was 55 years. The main adverse effect was diarrhea –mainly during the 1st week of therapy.

A selected summary in Gastroenterology (Gastroenterology 2012; 142: 402-404) reviews the first study and makes several useful points:

Stimulant laxative use has been hindered by myths & misconceptions along with lack of supporting data. Most recent studies do not support a role of stimulant use in causing enteric neuropathies, a cathartic colon or increasing the risk of colon cancer
Osmotic laxatives have been favored in guidelines but this has not been bolstered by supporting data
Only recently have two large randomized controlled studies proven the efficacy and safety of stimulant laxatives over the short-term
Long-term prospective studies are not available on the use of stimulant laxatives.

The second reference is a systematic review and meta-analysis of randomized controlled trials (RCTs) of pharmacologic therapy for chronic idiopathic constipation. Twenty one eligible RCTs were identified: eight laxative studies (n=1411), seven prucalopride studies (n=2639), three lubiprostone (n=610), and three linactolide trials (n=1582). All of these studies showed treatment was superior to placebo. These studies involved subjects who were mainly adults (>90% older than 16 years).

The results showed benefit from both stimulant and osmotic laxatives. Overall, the osmotic and stimulant laxative studies showed higher response than the pharmacologic agents like prucalopride, lubiprostone, and linaclotide. Nevertheless, between 50% and 85% of patients did not fulfill criteria for response to therapy.

Additional references:

-J Clin Gastro 2003; 36: 386-389. Safety of stimulants for long-term use.
-Am J Gastro 2005; 100: 232-242. Myths about constipation. Stimulants have not been proven to cause a “cathartic colon”
-J Pediatr 2009; 154: 258. Constipation associated w 3-fold increase in health utilization/cost.
-Clin Gastro Hep 2009; 7: 20. Review of complications assoc c constipation in adults.
-Pediatrics 2008; 121: e1334. Behavioral therapy ineffective in treating childhood constipation.
-NEJM 2008; 358: 2332, 2344. Use of methylnatrexone for opioid-induced constipation & trial of n=620 of prucalopride for severe constipation. Both drugs were helpful.
-Gastroenterology 2004; 126: S33. Review of pediatric incontinence.
-J Pediatr 2004; 145: 253-4. Prevalence of encopresis 15% /constipation 23% in obese children (n=80). Questionnaire administered to 80 consecutive obese children.
-Gastroenterology 2003; 125: 357. Longterm constipation followup. one-third with persistent constipation; 60% better at 1 year. (tertiary referral group)
-Pediatrics 2004; 113: 1753 & e520. When constipation & toileting difficulties both occur, constipation usually precedes toileting problems

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Pediatric Gastroenterology

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