Pharmacological interventions on early functional gastrointestinal disorders

Regurgitation is the passage of refluxed contents into the pharynx or mouth. In young infants, daily regurgitation is within the range of expected behaviors, and the great majority of infants are thriving and do not develop any disease [3]. Regurgitation reaches the peak at 4 to 6 months of age and decreases in frequency during the second semester of life [18]. Although regurgitation is a physiologic, frequent and spontaneously recovering phenomenon in healthy infants, almost 25 % of the parents are concerned and seek medical care [19].

Despite a wide use of drugs in infants with gastroesophageal reflux (GER) symptoms there are limited data on clinical outcome in the first year of life and there is no evidence that acid inhibitors or prokinetic agents improve regurgitation [20‐22].

For H2-receptor antagonists only one small trial (35 participants) comparing famotidine to placebo reported results for infants and showed only a slightly reduced frequency and volume of regurgitation [23]. Eleven patients had no-serious, possibly drug-related adverse experiences including fussing or irritability, somnolence, anorexia, headache, vomiting, hiccups, and candidiasis. Guillet [24] first reported necrotizing enterocolitis in newborns treated with H2 blockers. Another cohort study [6] confirmed the increased risk in the newborns treated with ranitidine compared to controls (OR = 5.5).

Two double-blind, placebo-controlled trials in irritable infants with GER showed that both omeprazole and lansoprazole exert little effect on regurgitation and may be associated with adverse events [25, 26]. Another randomized single-blind study using esomeprazole for 8 days in 50 infants with GER symptoms did not report a significant clinical improvement [27]. The FDA reviewer experience published in 2012 [28] pointed out that in the 3 double-blinded and placebo-controlled clinical trials testing esomeprazole, lansoprazole, and pantoprazole, there were no statistically significant between-group differences.

The ESPGHAN-NASPGHAN guidelines do not recommend any pharmacological treatment in regurgitation [3]. Acid inhibitors are restricted to GER-disease demonstrated by investigations reserved to infants with alarm symptoms [3, 5].

The NICE guidelines in 2015 do not indicate a routine treatment in infants with regurgitation without marked distress or “red flags” symptoms or signs. However, a short trial with alginate (for 1–2 weeks) is considered when regurgitation is associated with marked distress and other non-pharmacological approach failed (stepped-care approach) [4].

A good quality systematic review [5] showed that the studies published so far on the efficacy of alginate in infants, present an underpowered population, and controversial results. A recent randomized controlled trial in 64 full-term infants with GER symptoms, showed a statistically significant improvement in overall symptoms evaluated through a validated questionnaire (I-GERQ) in the group treated with Mg alginate plus simethicone compared to the thickened formula or reassurance groups [29].

In conclusion there is no evidence that proton pump inhibitors (PPI), Histamine2 Receptor Antagonist or domperidone improves regurgitation whilst evidence of efficacy of alginate is still limited. Safety concerns are represented by neurological and cardiological effects for prokinetic, and by diarrhea/constipation, headache, hypergastrinemia and increased risk of infections for acid inhibitors.

Cyclic vomiting syndrome (CVS) is a functional disorder characterized by recurrent (3 attacks in 6 months or 5 attacks in any time), individually stereotyped, transient (from a few hours up to 10 days) episodes of intense nausea and vomiting (at least 4 times/per hour for at least one hour) [30]. Attacks are separated by periods (one week or more) of complete well-being and no underlying pathology is recognised [30]. Despite the on-off pattern with inter-critical wellness, the severity and frequency of the acute emetic phases determine a negative impact of CVS on quality of life, frequent hospital referral, extensive investigations and, in some cases, a significant impairment of daily social activities and on school performance [31].

The incomplete knowledge of CVS pathophysiology currently limits the specificity and efficacy of its treatment. As reported in the NASPGHAN Guidelines [7] and in 3 more recent reviews [8‐10] antimigraine, antiemetic, and anticonvulsant molecules have been studied in retrospective open-label trials for both prevention and acute phase with different and individual benefits. No prospective RCTs were identified.

As several precipitating (including psychological, physical, infective and dietary) factors are identified in about 2/3 of patients, a psychotherapeutic and nutritional support and avoidance of individual triggers should be considered before and in addition to pharmacological therapy.

Pharmacological prophylaxis is suggested if the crises are frequent (more than 6 episodes/year) and/or severe (requiring hospitalization) or disabling (lasting 3 days or longer). In children aged less than 5 years antihistamines such as cyproheptadine (0.25–0.5 mg/kg/day, twice per day) and pizotifen (0.5–1.5 mg/day, once or twice per day) are considered as “first-line therapy”. Propranolol (0.25–1 mg/kg/day in 2–3 administrations) is suggested as “second-line drug”, but is contraindicated in children with asthma, diabetes, depression and heart disease. Heart rate monitoring during the first days of therapy is recommended in all patients as well as discontinuation: tapering for 1–2 weeks. When the diagnosis for CVS is confirmed and individualized therapy is initiated, low dose first line drug should be progressively increased every 1 to 4 weeks up to therapeutic range, for at least 2 cycles of vomiting episodes. If the medication is not effective in preventing the attack of episodes or if there are significant adverse effects, the second-line drug or combination therapy should be started.

Anti-emetic agents (ondansetron and granisetron), anti-anxiety agents (lorazepam), and anti-migraine agents (sumatriptan and zolmitriptan) have also been attempted in prodromal phase. 5HT1B/1D receptor agonists (sumatriptan) showed more efficacies in patients with family history of migraine. However, this drug is not approved for use in children. Tricyclic anti-depressive agent amitriptyline was considered in the NASPGHAN guidelines in 2008 more effective as prophylactic drug in children older than 5 years [7]. To minimize side effects, the treatment is commonly initiated at a single nighttime dose of 0.25–0.5 mg/kg/day and increased weekly by 5 to 10 mg until 1.0–1.5 mg/kg. The risk of ventricular arrhythmias is reduced by monitoring the QTc interval (to maintain it <460 msec) before and after reaching the targeted dose. Other side effects reported were constipation, sedation and behavioral changes [8‐10].

The benefit of oral erythromycin (20 mg/kg/day) as a prokinetic agent, or anti-epileptic drugs such as valproic acid and phenobarbital reported in initial trials was not confirmed by other authors [8‐10].

The incapacity of increasing the energy production required during stress conditions, as a consequence of mutations of mtDNA, predisposes patients to the beginning of a vomit cycle and perpetuates the dysfunction of autonomic nervous system neurons [32]. Retrospective studies suggest the use of mitochondrial supplements such as L-carnitine (50-100 mg per day divided into 2 or 3 doses to a maximum of 1 g three times a day) and coenzyme Q-10 (10 mg per kg per day in two or three divided doses up to a maximum of 100 mg three times a day). However, there is still insufficient data to recommend their use in all children to prevent or reduce the length and gravity of the cyclic vomit episodes [7‐10].

During the acute phase of vomiting, intravenous infusion of glucoelctrolytic solutions (with 10 % dextrose to terminate ketosis) to prevent dehydration and electrolyte imbalance,antiemetic drugs (5-HT3 receptor antagonist Ondasetron at 0.3–0.4 mg/kg/dose every 6 h if necessary, with an upper limit of 20 mg/dose), sedatives, such as lorazepam (0.05–1 mg/kg per dose every 6 h) and acid inhibitors to manage epigastric pain and prevent esophageal damage are suggested [7, 33].

A quiet, dark room is a non-stimulating environment that will help patients sleep.

Infantile colic was originally defined by Wessel as crying lasting three or more hours a day, at least 3 days a week and for at least 3 weeks [34]. According to Rome III Criteria infantile colics are defined as irritability paroxysms with fussiness or crying that starts and ends without clear reasons, lasting at least 3 h a day, 3 days a week, for at least one week, in healthy, well fed and thriving babies [2].

Numerous hypotheses have been generated and multiple etiologies have been proposed to explain infant colic, leading to a variety of possible treatments. There are no uniform criteria for a specific therapeutic approach and no medication has definitively proved to be beneficial.

There are neither evidence-based recommendations from GL nor dedicated SR.

The 2013 Consensus [11] and the review article by Vandenplas et al. in 2015 [12] included 6 studies evaluating: simethicone (anti-foaming agent), simethicone-lactase, cimetropium bromide (anticholinergic antimuscarinic antispasmodic molecule), dicycloverine (anti-cholinergic agent), trimebutine (weak opioid and antimuscarinic effects), and PPIs. None of the above treatment showed a significant effect and some of them, such as dicyclomine [35] and cimetropium, can cause potentially serious adverse reactions.

A recent SR including 5 randomized controlled trials (and 430 infants enrolled) did not support the use of PPIs to decrease infant crying and irritability and highlighted related side effects specifically increased risk of gastrointestinal and/or respiratory tract infections [36].

Two studies found a comparable decrease in crying duration in infants given simethicone or placebo [37, 38].

Drugs with antispasmodic activity are commonly used, based on the assumption that contractions of the intestinal smooth muscles cause colic. Dicyclomine was more effective than placebo in three trials [39‐41], but dangerous side effects were described, such as respiratory symptoms, seizures, syncope, pulse rate fluctuations, muscular hypotonia, and even coma that contraindicate its use in infants [42].

Cimetropium bromide was reported to be more effective than placebo in reducing the duration of crying but lethargy, motion sickness and somnolence may occur [43].

The first step in managing functional constipation in infants is to educate and reassure the parents [13]. In infants younger than 6 months of age glycerine suppositories can be helpful if rectal emptying is necessary to provide acute relief whilst lactulose is recommended as maintenance therapy [12].

In infants older than 6 months, several studies evaluated the efficacy and safety of polyethylene glycol (PEG), both for fecal disimpaction and for maintenance therapy [44, 45]. PEG is an unabsorbable compound and is not digested by colonic bacteria. Its mechanism of action is increasing osmotic load in the large intestine, which results in expansion of stool volume [46].

Successful disimpaction occurred in 75–92 % of children after 3–6 consecutive days, with the most effective dose being 1.0–1.5 g/kg per day [46]. A RCT showed that the use of oral PEG solution (1–1.5 gr/kg/die) for 6 consecutive days has the same efficacy of retrograde enemas. Bekkali et al demonstrated that successful disimpaction was achieved in 80 % of the children using retrograde enemas once daily and in 68 % of children using oral PEG solution for 6 consecutive days [47].

PEG with or without electrolytes is safe and its collateral effects, as diarrhea and abdominal pain, are determined by its mechanism of action. In a prospective observational study, Pashankar et al failed to find any side effects following PEG therapy [48].

Once the impaction has been removed, the treatment focuses on the prevention of recurrence. The main pharmacological agents are osmotic and stimulant laxatives. Good quality clinical trials are lacking on effectiveness of stimulant laxatives as maintenance therapy of childhood constipation.

Lactulose is an unabsorbable, osmotically active carbohydrate, which drags water into the gut, keeps the stools soft and facilitates their passage avoiding pain. Two randomized controlled trials comparing lactitol and lactulose found that both are equally effective in increasing stool frequency and normalizing stool consistency [49‐51].

Candy et al., in a randomized, double-blind study, noted that PEG with electrolytes was more effective compared to lactulose in increasing defecation frequency in children with intractable constipation [45].

Loening-Baucke, comparing PEG without electrolytes with milk of magnesia, showed that no difference was found [52]. In another randomized study, PEG and milk of magnesia were equally effective in the long-term treatment of children with constipation and fecal incontinence [53].

Evidence does not support the use of mineral oil, which could lead to a risk of lipoid pneumonia, due to lung aspiration.

The 2014 ESPGHAN-NASPGHAN combined guidelines state that PEG and enemas are equally effective for fecal disimpaction. PEG administered orally is associated with a higher frequency of fecal incontinence during treatment of the fecal impaction compared with enema; however, based on the argument that PEG can be administered orally, the working group decided that PEG is to be preferred (1.1.5 g/kg/die) [13]. The use of PEG with or without electrolytes is recommended as first-line maintenance treatment and the starting dose is 0.4 g/kg/day. PEG resulted better than lactulose, milk of magnesia and mineral oil [13]. The use of enemas for maintenance therapy is not recommended in children with constipation. Glycerin suppositories can be considered for occasional use in disimpaction [13].