Treatment should be avoided in the presence of highfever or if thestool is bloody. Treatment is not recommended for people who could have negative effects from reboundconstipation. If suspicion exists of diarrhea associated with organisms that can penetrate the intestinal walls, such asE. coliO157:H7 orSalmonella, loperamide iscontraindicated as a primary treatment.[3] Loperamide treatment is not used in symptomaticC. difficile infections, as it increases the risk of toxin retention and precipitation of toxic megacolon.
Loperamide should be administered with caution to people withliver failure due to reducedfirst-pass metabolism.[22] Additionally, caution should be used when treating people with advancedHIV/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]
A review of loperamide in children under twelve years of age found that serious adverse events occurred only in children under three years of age.[24] The study reported that the use of loperamide should be contraindicated in children who are under three years of age, systemically ill, malnourished, moderately dehydrated, or have bloody diarrhea.[24]
In 1990, all formulations of loperamide for children were banned in Pakistan.[25]
Formulations for children aged less than twelve years of age are only available via prescription in the UK.[26]
Loperamide is not recommended in the United Kingdom for use duringpregnancy or bynursing mothers.[27] Studies in rat models have shown noteratogenicity, but sufficient studies in humans have not been conducted.[28] 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.[29] Loperamide can be present in breast milk and is not recommended for breastfeeding mothers.[23]
Loperamide is a substrate ofP-glycoprotein; therefore, the concentration of loperamide increases when given with a P-glycoprotein inhibitor.[3] Common P-glycoprotein inhibitors includequinidine,ritonavir, andketoconazole.[30] Loperamide can decrease the absorption of some other drugs. As an example,saquinavir concentrations can decrease by half when given with loperamide.[3]
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 otheropioids,antihistamines,antipsychotics, andanticholinergics.[31]
Loperamide is an opioid-receptoragonist and acts on theμ-opioid receptors in themyenteric plexus of the large intestine. It works likemorphine, decreasing the activity of the myenteric plexus, which decreases the tone of the longitudinal and circularsmooth muscles of the intestinal wall.[32][33] 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 thegastrocolic reflex.[34]
Loperamide's circulation in the bloodstream is limited in two ways. Efflux by P-glycoprotein in the intestinal wall reduces the passage of loperamide, and the fraction of drug crossing is then further reduced throughfirst-pass metabolism by the liver.[35][36] Loperamide metabolizes into anMPTP-like compound, but is unlikely to exertneurotoxicity.[37]
Efflux by P-glycoprotein also prevents circulating loperamide from effectively crossing the blood-brain barrier,[38] so it can generally only agonize mu-opioid receptors in theperipheral nervous system, and currently has a score of one on the anticholinergic cognitive burden scale.[39] Concurrent administration of P-glycoprotein inhibitors such asquinidine potentially allows loperamide to cross the blood-brain barrier and produce central morphine-like effects. At high doses (>70mg), loperamide can saturate P-glycoprotein (thus overcoming the efflux) and produce euphoric effects.[40] Loperamide taken with quinidine was found to produce respiratory depression, indicative of central opioid action.[41]
High doses of loperamide have been shown to cause a mildphysical 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.[42][43]
Loperamide is synthesized starting from thelactone 3,3-diphenyldihydrofuran-2(3H)-one and ethyl 4-oxopiperidine-1-carboxylate, on a lab scale.[44] On a large scale a similar synthesis is followed, except that the lactone and piperidinone are produced from cheaper materials rather than purchased.[45][46]
Loperamide is typically manufactured as the hydrochloride salt. Its mainpolymorph has amelting point of 224 °C and a second polymorph exists with a melting point of 218 °C. Atetrahydrate form has been identified which melts at 190 °C.[47]
The first clinical reports on loperamide were published in 1973[44] with the inventor being one of the authors. The trial name for it was "R-18553".[49]Loperamide oxide has a different research code: R-58425.[50]
The trial againstplacebo was conducted from December 1972 to February 1974, its results being published in 1977.[51]
In 1973, Janssen started to promote loperamide under the brand name Imodium. In December 1976, Imodium gotUS FDA approval.[52]
During the 1980s, Imodium became the best-selling prescription antidiarrheal in the United States.[53]
In the 1980s, loperamide also existed in the form of drops (Imodium Drops) and syrup. Initially, it was intended for children's usage, butJohnson & Johnson voluntarily withdrew it from the market in 1990 after 18 cases ofparalytic ileus (resulting in six deaths) were registered in Pakistan and reported by theWorld Health Organization (WHO).[55] In the following years (1990-1991), products containing loperamide have been restricted for children's use in several countries (ranging from two to five years of age).[56]
In the 1980s, before the US patent expired on 30 January 1990,[53] McNeil started to developImodium Advanced containingloperamide and simethicone for treating bothdiarrhea andgas. In March 1997, the company patented this combination.[57] The drug was approved in June 1997, by the FDA as Imodium Multi-Symptom Relief in the form of a chewable tablet.[58] A caplet formulation was approved in November 2000.[59]
Loperamide can be sold freely to the public and is available in most supermarkets, convenience stores and chemists for the treatment of diarrhea and acute diarrhea associated with medically diagnosed irritable bowel syndrome to adults aged 18 years of age and older.[64]
Loperamide is available as ageneric medication.[5][12] In 2016, Imodium was one of the biggest-selling branded over-the-counter medications sold in Great Britain, with sales of £32.7 million.[65]
Loperamide has typically been deemed to have a relatively low risk of misuse.[66] In 2012, no reports of loperamide abuse were made.[67] In 2015, however, case reports of extremely high-dose loperamide use were published.[68][69] 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.[70] At these higher doses central nervous system penetration occurs and long-term use may lead to tolerance, dependence, and withdrawal on abrupt cessation.[70] Dubbing it "the poor man'smethadone", clinicians warned that increased restrictions on the availability of prescription opioids enacted in response to theopioid epidemic were prompting recreational users to turn to loperamide as an over-the-counter treatment for withdrawal symptoms.[71] The FDA responded to these warnings by calling on drug manufacturers to voluntarily limit the package size of loperamide for public-safety reasons.[72][73] 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.[74] Since 2015, several reports of sometimes-fatalcardiotoxicity due to high-dose loperamide abuse have been published.[75][76]
^abWorld Health Organization (2025).The selection and use of essential medicines, 2025: WHO Model List of Essential Medicines, 24th list. Geneva: World Health Organization.doi:10.2471/B09474.hdl:10665/382243. License: CC BY-NC-SA 3.0 IGO.
^Litovitz T, Clancy C, Korberly B, Temple AR, Mann KV (1997). "Surveillance of loperamide ingestions: an analysis of 216 poison center reports".Journal of Toxicology. Clinical Toxicology.35 (1):11–9.doi:10.3109/15563659709001159.PMID9022646.
^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.doi:10.1067/mcp.2000.109156.PMID11014404.S2CID38467170.
^Yanagita T, Miyasato K, Sato J (1979). "Dependence potential of loperamide studied in rhesus monkeys".NIDA Research Monograph.27:106–13.PMID121326.
^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.doi:10.1021/jm00265a009.PMID4725924.
^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.PMID4611432.
^"Loperamide: voluntary withdrawal of infant fomulations"(PDF).WHO Drug Information.4 (2):73–74. 1990. Archived fromthe original(PDF) on 7 September 2014. Retrieved6 September 2014.The leading international supplier of this preparation, Johnson and Johnson, has since informed WHO that having regard to the dangers inherent in improper use and overdosing, this formulation (Imodium Drops), was voluntarily withdrawn from Pakistan in March 1990. The company has since decided not only to withdraw this preparation worldwide but also to remove all syrup formulations from countries where WHO has a programme for the control of diarrhoeal diseases.
^US patent 5612054, Jeffrey L. Garwin, "Pharmaceutical compositions for treating gastrointestinal distress", issued 18 March 1997, 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.hdl:10665/112729.ISBN978-92-4-120985-4.ISSN0512-3054. WHO technical report series;985.
^Connelly D (April 2017). "A breakdown of the over-the-counter medicines market in Britain in 2016".The Pharmaceutical Journal.298 (7900). Royal Pharmaceutical Society.doi:10.1211/pj.2017.20202662.ISSN2053-6186.
^Baker DE (2007). "Loperamide: a pharmacological review".Reviews in Gastroenterological Disorders.7 (Suppl 3): S11-8.PMID18192961.
^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.doi:10.1097/PAF.0000000000000201.PMID26355852.S2CID19635919.
^Feldman R, Everton E (November 2020). "National assessment of pharmacist awareness of loperamide abuse and ability to restrict sale if abuse is suspected".Journal of the American Pharmacists Association.60 (6):868–873.doi:10.1016/j.japh.2020.05.021.PMID32641253.S2CID220436708.
^Eggleston W, Clark KH, Marraffa JM (January 2017). "Loperamide Abuse Associated With Cardiac Dysrhythmia and Death".Annals of Emergency Medicine.69 (1):83–86.doi:10.1016/j.annemergmed.2016.03.047.PMID27140747.
