Common side effects include abdominal pain,
constipation, sleepiness, vomiting, and a dry mouth.[4] It may increase the risk of
toxic megacolon.[4] Loperamide's safety in
pregnancy is unclear, but no evidence of harm has been found.[5] It appears to be safe in
breastfeeding.[6] It is an
opioid with no significant absorption from the gut and does not cross the
blood–brain barrier when used at normal doses.[7] It works by slowing the contractions of the
intestines.[4]
Loperamide is effective for the treatment of a number of types of diarrhea.[13] This includes control of acute nonspecific diarrhea, mild
traveler's diarrhea, irritable bowel syndrome, chronic diarrhea due to bowel resection, and chronic diarrhea secondary to inflammatory bowel disease. It is also useful for reducing
ileostomy output.
Off-label uses for loperamide also include chemotherapy-induced diarrhea, especially related to
irinotecan use.
Treatment should be avoided in the presence of high
fever or if the
stool is bloody. Treatment is not recommended for people who could have negative effects from rebound
constipation. If a suspicion exists of diarrhea associated with organisms that can penetrate the intestinal walls, such as
E. coli O157:H7 or Salmonella, loperamide is
contraindicated as a primary treatment.[14] Loperamide treatment is not used in symptomatic C. difficile infections, as it increases the risk of toxin retention and precipitation of toxic megacolon.
Loperamide should be administered with caution to people with
liver failure due to reduced
first-pass metabolism.[22] Additionally, caution should be used when treating people with advanced
HIV/AIDS, as cases of both viral and bacterial toxic megacolon have been reported. If abdominal distension is noted, therapy with loperamide should be discontinued.[23]
Children
The use of loperamide in children under two years is not recommended. Rare reports of fatal
paralytic ileus associated with
abdominal distention have been made. Most of these reports occurred in the setting of acute
dysentery, overdose, and with very young children less than two years of age.[24] A review of loperamide in children under 12 years old found that serious adverse events occurred only in children under three years old. The study reported that the use of loperamide should be contraindicated in children who are under 3, systemically ill, malnourished, moderately dehydrated, or have bloody diarrhea.[25]
In 1990, all formulations for children of the antidiarrheal loperamide were banned in Pakistan.[26]
The
National Health Service in the United Kingdom recommends that loperamide should only be given to children under the age of twelve if prescribed by a doctor. Formulations for children are only available on prescription in the UK.[27]
Pregnancy and breast feeding
Loperamide is not recommended in the United Kingdom for use during
pregnancy or by
nursing mothers.[28] Studies in rat models have shown no
teratogenicity, but sufficient studies in humans have not been conducted.[29] One controlled, prospective study of 89 women exposed to loperamide during their first trimester of pregnancy showed no increased risk of malformations. This, however, was only one study with a small sample size.[30] Loperamide can be present in breast milk, and is not recommended for breast-feeding mothers.[23]
Drug interactions
Loperamide is a substrate of
P-glycoprotein; therefore, the concentration of loperamide increases when given with a P-glycoprotein inhibitor.[18] Common P-glycoprotein inhibitors include
quinidine,
ritonavir, and
ketoconazole.[31] Loperamide is capable of decreasing the absorption of some other drugs. As an example,
saquinavir concentrations can decrease by half when given with loperamide.[18]
Loperamide is an antidiarrheal agent, which decreases intestinal movement. As such, when combined with other antimotility drugs, the risk of constipation is increased. These drugs include other
opioids,
antihistamines,
antipsychotics, and
anticholinergics.[32]
Mechanism of action
Loperamide is an opioid-receptor
agonist and acts on the
μ-opioid receptors in the
myenteric plexus of the large intestine. It works like
morphine, decreasing the activity of the myenteric plexus, which decreases the tone of the longitudinal and circular
smooth muscles of the intestinal wall.[33][34] This increases the time material stays in the intestine, allowing more water to be absorbed from the fecal matter. It also decreases colonic mass movements and suppresses the
gastrocolic reflex.[35]
Loperamide's circulation in the bloodstream is limited in two ways. Efflux by P-glycoprotein in the intestinal wall reduces passage of loperamide, and the fraction of drug crossing is then further reduced through
first-pass metabolism by the liver.[36][37] Loperamide metabolizes into an
MPTP-like compound, but is unlikely to exert
neurotoxicity.[38]
Blood–brain barrier
Efflux by P-glycoprotein also prevents circulating loperamide from effectively crossing the blood–brain barrier,[39] so it can generally only antagonize muscarinic receptors in the
peripheral nervous system, and currently has a score of one on the anticholinergic cognitive burden scale.[40] Concurrent administration of P-glycoprotein inhibitors such as
quinidine potentially allows loperamide to cross the blood–brain barrier and produce central morphine-like effects. At high doses (>70mg), loperamide is able to saturate P-glycoprotein (thus overcoming the efflux) and produce euphoric effects.[41] Loperamide taken with quinidine was found to produce respiratory depression, indicative of central opioid action.[42]
High doses of loperamide have been shown to cause a mild
physical dependence during preclinical studies, specifically in mice, rats, and rhesus monkeys. Symptoms of mild opiate withdrawal were observed following abrupt discontinuation of long-term treatment of animals with loperamide.[43][44]
Chemistry
Synthesis
Loperamide is synthesized starting from the
lactone 3,3-diphenyldihydrofuran-2(3H)-one and ethyl 4-oxopiperidine-1-carboxylate, on a lab scale.[45] On a large scale a similar synthesis is followed, except that the lactone and piperidinone are produced from cheaper materials rather than purchased.[46][47]
Physical properties
Loperamide is typically manufactured as the hydrochloride salt. Its main
polymorph has a
melting point of 224 °C and a second polymorph exists with a melting point of 218 °C. A
tetrahydrate form has been identified which melts at 190 °C.[48]
The first clinical reports on loperamide were published in 1973 in theJournal of Medicinal Chemistry[45] with the inventor being one of the authors. The trial name for it was "R-18553".[50]Loperamide oxide has a different research code: R-58425.[51]
The trial against
placebo was conducted from December 1972 to February 1974, its results being published in 1977 in the journal
Gut.[52]
In 1973, Janssen started to promote loperamide under the brand name Imodium. In December 1976, Imodium got
US FDA approval.[53]
During the 1980s, Imodium became the best-selling prescription antidiarrheal in the United States.[54]
In the 1980s, loperamide also existed in the form of drops (Imodium Drops) and syrup. Initially, it was intended for children's usage, but
Johnson & Johnson voluntarily withdrew it from the market in 1990 after 18 cases of
paralytic ileus (resulting in six deaths) were registered in Pakistan and reported by the
World Health Organization (WHO).[56] In the following years (1990-1991), products containing loperamide have been restricted for children's use in a number of countries (ranging from two to five years of age).[57]
In the late 1980s, before the US patent expired on 30 January 1990,[54] McNeil started to develop
Imodium Advanced containing
loperamide and simethicone for treating both
diarrhea and
gas. In March 1997, the company patented this combination.[58] The drug was approved in June 1997, by the FDA as Imodium Multi-Symptom Relief in the form of a chewable tablet.[59] A caplet formulation was approved in November 2000.[60]
Loperamide is sold as a
generic medication.[4][10] In 2016, Imodium was one of the biggest-selling branded over-the-counter medications sold in Great Britain, with sales of £32.7 million.[66]
Brand names
Loperamide was originally marketed as Imodium, and many generic brands are sold.[1]
Off-label/unapproved use
Loperamide has typically been deemed to have a relatively low risk of misuse.[67] In 2012, no reports of loperamide abuse were made.[68] In 2015, however, case reports of extremely high-dose loperamide use were published.[69][70] The primary intent of users has been to manage symptoms of opioid withdrawal such as diarrhea, although a small portion derive psychoactive effects at these higher doses.[71] At these higher doses central nervous system penetration occurs and long term use may lead to tolerance, dependence, and withdrawal on abrupt cessation.[71] Dubbing it "the poor man's
methadone", clinicians warned that increased restrictions on the availability of prescription opioids passed in response to the
opioid epidemic were prompting recreational users to turn to loperamide as an over-the-counter treatment for withdrawal symptoms.[72] The FDA responded to these warnings by calling on drug manufacturers to voluntarily limit the package size of loperamide for public-safety reasons.[73][74] However, there is no quantity restriction on number of packages that can be purchased, and most pharmacies do not feel capable of restricting its sale, so it is unclear that this intervention will have any impact without further regulation to place loperamide behind the counter.[75] Since 2015, several reports of sometimes-fatal
cardiotoxicity due to high-dose loperamide abuse have been published.[76][77]
^World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization.
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^Sadeque AJ, Wandel C, He H, Shah S, Wood AJ (September 2000). "Increased drug delivery to the brain by P-glycoprotein inhibition". Clinical Pharmacology and Therapeutics. 68 (3): 231–7.
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^Yanagita T, Miyasato K, Sato J (1979). "Dependence potential of loperamide studied in rhesus monkeys". NIDA Research Monograph. 27: 106–13.
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abStokbroekx RA, Vandenberk J, Van Heertum AH, Van Laar GM, Van der Aa MJ, Van Bever WF, et al. (July 1973). "Synthetic antidiarrheal agents. 2,2-Diphenyl-4-(4'-aryl-4'-hydroxypiperidino)butyramides". Journal of Medicinal Chemistry. 16 (7): 782–786.
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^Van Rompay J, Carter JE (January 1990). Florey K (ed.). "Loperamide hydrochloride". Analytical Profiles of Drug Substances. 19. Academic Press: 341–365.
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^Schuermans V, Van Lommel R, Dom J, Brugmans J (1974). "Loperamide (R 18 553), a novel type of antidiarrheal agent. Part 6: Clinical pharmacology. Placebo-controlled comparison of the constipating activity and safety of loperamide, diphenoxylate and codeine in normal volunteers". Arzneimittelforschung. 24 (10): 1653–7.
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^US patent 5612054, Jeffrey L. Garwin, "Pharmaceutical compositions for treating gastrointestinal distress", issued 1997-03-18, assigned to McNeil-PPC, Inc.
^World Health Organization (2014). The selection and use of essential medicines: report of the WHO Expert Committee, 2013 (including the 18th WHO model list of essential medicines and the 4th WHO model list of essential medicines for children). Geneva: World Health Organization.
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^Dierksen J, Gonsoulin M, Walterscheid JP (December 2015). "Poor Man's Methadone: A Case Report of Loperamide Toxicity". The American Journal of Forensic Medicine and Pathology. 36 (4): 268–70.
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