Adjunctive Loperamide Therapy Reduces Acute Diarrhea in Children
Adjunctive Loperamide Therapy Reduces Acute Diarrhea in Children
News Author: Laurie Barclay, MD
CME Author: Désirée Lie, MD, MSEd
April 2, 2007 — Loperamide used as an adjunctive therapy may reduce frequency and duration of acute diarrhea in children, according to the results of a meta-analysis reported in the March issue of PloS Medicine.
"Loperamide is widely used in adults for acute diarrhea," write Su-Ting T. Li, from the University of California Davis, and colleagues. "However, its use in children has been discouraged by the World Health Organization and the American Academy of Pediatrics owing to concerns over safety and efficacy in young children."
The investigators reviewed MEDLINE, EMBase, the the Cochrane Central Register of Controlled Trials, and bibliographies of known clinical trials and of review articles, and they also interviewed leading experts in the field. This systematic review and meta-analysis included randomized controlled trials of children younger than 12 years with acute diarrhea, comparing loperamide with placebo. Trials meeting inclusion criteria reported data on diarrhea duration or severity, or on adverse effects.
Compared with patients who received placebo, patients treated with loperamide were less likely to continue to have diarrhea at 24 hours (prevalence ratio, 0.66; 95% confidence interval [CI], 0.57 - 0.78). They also had a shorter duration of diarrhea by 0.8 days (95% CI, 0.7 - 0.9 days) and had a lower stool count at 24 hours (count ratio, 0.84; 95% CI, 0.77 - 0.92). Estimation of random-effects summaries gave similar results.
Serious adverse events, defined as ileus, lethargy, or death, occurred in 8 (0.9%) of 927 children receiving loperamide (95% CI, 0.4% - 1.7%) but in none (0%) of the 764 children receiving placebo (95% CI. 0% - 0.5%). Among the children receiving loperamide, serious adverse events were reported only in children younger than 3 years of age.
"In children who are younger than 3 y, malnourished, moderately or severely dehydrated, systemically ill, or have bloody diarrhea, adverse events outweigh benefits even at doses ≤ 0.25 mg/kg/d," the authors write. "In children who are older than 3 y with no/minimal dehydration, loperamide may be a useful adjunct to oral rehydration and early refeeding."
Limitations of this review include failure to search conference proceedings, lack of consistency in outcome measures, inability to account for the observed heterogeneity in several subgroup analyses, and lack of generalizability from the children recruited in the studies to all children worldwide with diarrhea.
"Oral rehydration therapy and early refeeding should remain the focus of management of diarrhea," the authors conclude. "Loperamide may be considered as an adjunct to oral rehydration therapy and early refeeding. Since diarrhea is usually a self-limited disease in industrialized societies, physicians and families should weigh the possibility of adverse events against a modest improvement in diarrhea."
The authors have disclosed no relevant financial relationships.
PloS Med. 2007;4:e98.
Clinical Context
Worldwide children younger than 5 years have about 3 cases of diarrhea annually and 1.6 to 2.5 million children younger than 5 years die each year from diarrhea, with 34% of adults and children reporting taking an antidiarrheal medication in the United States and loperamide as a first-line agent. However, both the World Health Organization and the American Academy of Pediatrics are concerned about the use of loperamide in children because of efficacy and safety issues, but loperamide is approved for use in the United States for children older than 2 years.
This is a systematic review and meta-analysis of studies examining the efficacy of loperamide compared with placebo in children younger than 12 years on duration and frequency of acute diarrhea.
Study Highlights
* The MEDLINE, EMBase, and Cochrane Central Register of Controlled Trials were searched, and major health organizations that focus on diarrhea prevention and treatment were contacted.
* Major pharmaceutical companies that manufacture loperamide and authors for other clinical trials were contacted.
* Conference proceedings were not searched, and all languages were included.
* Studies were selected based on meeting 4 criteria: study design (randomized controlled trial), population (age younger than 12 years with acute diarrhea), intervention (loperamide vs placebo), and outcome data on diarrhea duration or severity.
* Primary outcomes were clinical course of diarrhea and adverse events.
* Measures of diarrhea intensity included duration in days, number of stools daily, and stool volume.
* Data were extracted independently by 2 authors, and heterogeneity was assessed by loperamide dosage and definition of diarrhea resolution across trials.
* 13 studies, which met all 4 criteria, were included.
* 975 children were assigned to loperamide and 813 to placebo.
* Of the 13 studies, 6 used loperamide doses of 0.25 mg/kg/day or more and 4 used doses of more than 0.25 mg/kg/day with the remaining giving unclear doses.
* The definition of diarrhea resolution varied from "time to last unformed stool" to "change in stool consistency" to "two or fewer liquid/soft stools/d" to "return to normal bowel habits."
* Most patients were mildly dehydrated, had a nonbacterial cause for diarrhea, and received oral rehydration therapy.
* 4 studies mentioned intravenous rehydration therapy in addition to oral therapy.
* Those assigned to loperamide had an average of 0.8 days' (95% CI, 0.7 - 0.9 days) shorter duration of diarrhea; for doses less than 0.25/kg/day, the difference was 0.7 days.
* Stool count in the first 24 hours was lower in the loperamide group compared with placebo (count ratio, 0.84; 95% CI, 0.77 - 0.92).
* In 4 studies reporting diarrhea at 48 hours, the prevalence of diarrhea was less among those allocated to loperamide with a prevalence ratio of 0.59 (95% CI, 0.45 - 0.78).
* 10.1% of those in the loperamide vs 2.1% in the placebo group had any adverse events, with a difference of 8.6% (95% CI, 6.4% - 10.9%).
* Serious adverse events, defined as ileus, lethargy, or death, occurred only in children younger than 3 years (0.9% of loperamide vs 0% of placebo patients).
* When the definition of serious adverse events was expanded to include abdominal distension and sleepiness, adverse events occurred in 2.3% of the loperamide vs 0.5% of the placebo group (difference, 1.8%).
* The associations did not change when analysis was adjusted for dose, methodologic quality, definition of diarrhea resolution, or cause of diarrhea.
* The authors concluded that modest improvement in diarrhea can be expected when loperamide was used as an adjunct to oral or intravenous rehydration in children older than 3 years.
* Oral rehydration should remain the focus of therapy for acute diarrhea.
* The authors recommended that loperamide should not be used in children younger than 3 years, or those who are malnourished or moderately or severely dehydrated, as the risks outweigh the benefits.
Pearls for Practice
* In children younger than 12 years but older than 3 years with mild diarrhea and minimal dehydration, loperamide improves diarrhea duration and frequency when used with oral rehydration.
* In children younger than 3 years, use of loperamide for acute diarrhea is associated with a higher risk for serious adverse events and is not recommended.
