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Kaplan MA, Prior MJ, Ash RR, et al. Loperamide-simethicone vs lopera-mide alone, simethicone alone, and placebo in the treatment of acute diarrhea with gas-related abdominal discomfort. A randomized controlled trial. Arch Fam Med. 1999 May/Jun; 8:243-8.
In patients with diarrhea and gas-related abdominal discomfort, is loperamide plus simethicone as effective as each drug alone for decreasing the duration of diarrhea and relieving abdominal discomfort?
Randomized (concealed), double-blind, placebo-controlled trial with follow-up at 48 to 72 hours after start of treatment.
A primary care, ambulatory clinic in Acapulco, Mexico.
493 patients (mean age 30 y, 51% women, 100% white) with acute diarrhea symptoms for < 48 hours. Inclusion criteria were age 18 years, 3 unformed stools within 24 hours before study entry, most recent bowel movement unformed, and moderate-to-severe gas-related abdominal discomfort. Exclusion crite ria were need for hospital admission, parenteral hydration, or antibiotics; fever > 38.6 °C; gross blood or pus in the stool; orthostatic hypotension; in- ability to take medication or fluids orally; comorbid conditions aggravated by untreated acute diarrhea; hypersen-sitivity to study drugs; recent use of antibiotics, promotility drugs, antidiarrheals, antiflatulents, or analgesics; pregnancy; lactation; or perimenstrual discomfort. Follow-up was 92%.
Patients were allocated to both drugs combined in 1 tablet (n = 124), lopera-mide (n = 123), simethicone (n = 123), or placebo (n = 123). Doses were 2 mg for loperamide and 125 mg for si-methicone. Patients took 2 chewable tablets immediately and were given 6 more: 1 tablet to be used after each unformed stool up to 4 tablets/d for 48 hours. Taking other drugs or consuming carbonated liquids, alcohol, and milk or milk products was discouraged.
Main outcome measures
Time to last unformed stool and complete relief of gas-related symptoms. Secondary outcomes were time to cessation of diarrhea, number of unformed stools, and patient-reported symptom relief.
The time to all end points was shorter in the combined group than for any other group. The time to the last unformed stool in the combined drug group was 10 hours compared with 23 hours for loperamide, 33 hours for simethicone, and 39 hours for placebo (P < 0.001). A similar pattern was shown for time to cessation of diarrhea (P < 0.001), time to complete relief of gas-related discomfort (12 h in the combined drug group vs 42 h for loperamide, 21 h for simethicone, and 48 h for placebo, P < 0.001), and self-reported overall relief of illness at the end of the study (P < 0.001). The groups did not differ for number of adverse effects (P = 0.3), and no serious adverse effects were reported.
A combination of loperamide and simethicone was more effective than either drug alone for reducing the duration of acute diarrhea and relieving gas-related abdominal discomfort.
Source of funding: McNeil Consumer Healthcare.
For correspondence: Dr. M.A. Kaplan, Medical Department, McNeil Consumer Healthcare, 7050 Camp Hill Road, Fort Washington, PA 19034, USA.
Abstract and Commentary also published in ACP Journal Club. 1999;131:66.
Although acute diarrhea is usually self-limited, it can be highly disabling and associated with symptoms that can last for several days. Some authorities recommend that adults, including travelers, with severe community-acquired diarrhea receive an antimicrobial drug, preferably a fluoro-quinolone (1). Yet, because of the concern about emergence of resistant bacteria caused by widespread antibiotic use, safe and effective antidiarrheal agents are preferred.
Loperamide hydrochloride, a peripherally acting opiate-receptor agonist that has gut antimotility and antisecretory actions, is marketed in several countries as an over-the-counter antidiarrheal agent. Several randomized controlled trials (RCTs) in adults and children have shown that loperamide relieves diarrhea faster than placebo, diphenoxylate, or bismuth subsalicylate and causes few serious adverse effects (2).
In their methodologically sound clinical trial, Kaplan and colleagues provide useful data in the search for optimal antidiarrheal agents without antibacterial activity. Although they show that the combination of loperamide and simethicone is clinically more effective than either drug alone, 2 caveats exist. First, prescribing an antimotility agent without an anti-biotic is discouraged in the management of dysentery (acute diarrhea with blood, mu- cus, or fever) because cases of loperamide- related toxic megacolon and necrotizing enterocolitis, although rare, have been reported (3). Second, loperamide is not recommended for use in infants and small children.
We need well-designed RCTs that compare the efficacy of loperamide plus simeth- icone and of other promising novel anti-diarrheal agents, such as new calmodulin antagonists and enkephalinase inhibitors, with antimicrobial agents. We must offer the maximum benefit to our patients and preserve our ecology by avoiding un- necessary antibiotic use.
Juan J. Calva, MD, MSc
Instituto Nacional de la Nutrición "Salvador Zubirán"
Mexico City, Mexico
1. Gorbach SL. Treating diarrhoea. BMJ. 1997;314:1776-7.
2. Ericsson CD, Johnson PC. Safety and efficacy of loperamide. Am J Med. 1990; 88:10S-4S.
3. Brown JW. Toxic megacolon associated with loperamide therapy. JAMA. 1979;241:501-2.
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