Loperamide

Loperamide is effective for the treatment of a number of types of diarrhea.{{cite journal | vauthors = Hanauer SB | title = The role of loperamide in gastrointestinal disorders | journal = Reviews in Gastroenterological Disorders | volume = 8 | issue = 1 | pages = 15–20 | date =Winter 2008 | pmid = 18477966 }} 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.

Loperamide should not be used as the primary treatment in cases of bloody diarrhea, acute exacerbation of ulcerative colitis, or bacterial enterocolitis.{{cite web|url=https://www.drugs.com/pro/loperamide.html|title=Loperamide|access-date=14 May 2016|url-status=live|archive-url=https://web.archive.org/web/20160520143952/http://www.drugs.com/pro/loperamide.html|archive-date=20 May 2016}}

Loperamide is often compared to diphenoxylate. Studies suggest that loperamide is more effective and has lower neural side effects.{{cite book| vauthors = Miftahof R |date=2009 |title=Mathematical Modeling and Simulation in Enteric Neurobiology |url= https://books.google.com/books?id=3Qyd9TmOY5EC&pg=PA18 |publisher=World Scientific |isbn=9789812834812 |pages = 18|url-status=live |archive-url=https://web.archive.org/web/20170728102724/https://books.google.com/books?id=3Qyd9TmOY5EC&pg=PA18&dq=|archive-date=28 July 2017}}{{cite book| veditors = Benson A, Chakravarthy A, Hamilton SR, Elin S |date=2013|title=Cancers of the Colon and Rectum: A Multidisciplinary Approach to Diagnosis and Management |url= https://books.google.com/books?id=afb1AAAAQBAJ&q=D&pg=PA225 |publisher=Demos Medical Publishing|isbn=9781936287581 |pages = 225|url-status=live |archive-url= https://web.archive.org/web/20170908145128/https://books.google.com/books?id=afb1AAAAQBAJ&pg=PA225&dq=D#v=onepage&q=D&f=false|archive-date=8 September 2017}}{{cite book| vauthors = Zuckerman JN |date=2012|title=Principles and Practice of Travel Medicine|url=https://books.google.com/books?id=FXxksru7IQYC&pg=PA203|publisher=John Wiley & Sons|isbn=9781118392089|pages = 203|url-status=live|archive-url=https://web.archive.org/web/20170908145128/https://books.google.com/books?id=FXxksru7IQYC&pg=PA203&dq=|archive-date=8 September 2017}}

Adverse drug reactions most commonly associated with loperamide are constipation (which occurs in 1.7–5.3% of users), dizziness (up to 1.4%), nausea (0.7–3.2%), and abdominal cramps (0.5–3.0%).{{cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/017694s050lbl.pdf |title=Imodium label |publisher=U.S. Food and Drug Administration (FDA) |access-date=21 April 2014 |url-status=live |archive-url=https://web.archive.org/web/20140423055633/http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/017694s050lbl.pdf |archive-date=23 April 2014 }} Rare, but more serious, side effects include toxic megacolon, paralytic ileus, angioedema, anaphylaxis/allergic reactions, toxic epidermal necrolysis, Stevens–Johnson syndrome, erythema multiforme, urinary retention, and heat stroke.{{cite web|url=https://online.epocrates.com/noFrame/showPage.do;jsessionid=FB4C4C42205138677A3F9E475E6C6299?method=drugs&MonographId=44&ActiveSectionId=5|title=loperamide adverse reactions|access-date=14 May 2016|archive-url=https://web.archive.org/web/20181101071123/https://online.epocrates.com/noFrame/showPage.do;jsessionid=FB4C4C42205138677A3F9E475E6C6299?method=drugs&MonographId=44&ActiveSectionId=5|archive-date=1 November 2018|url-status=dead}} The most frequent symptoms of loperamide overdose are drowsiness, vomiting, and abdominal pain, or burning.{{cite journal | vauthors = Litovitz T, Clancy C, Korberly B, Temple AR, Mann KV | title = Surveillance of loperamide ingestions: an analysis of 216 poison center reports | journal = Journal of Toxicology. Clinical Toxicology | volume = 35 | issue = 1 | pages = 11–9 | date = 1997 | pmid = 9022646 | doi = 10.3109/15563659709001159 }} High doses may result in heart problems such as abnormal heart rhythms.{{cite web|title=Safety Alerts for Human Medical Products - Loperamide (Imodium): Drug Safety Communication - Serious Heart Problems With High Doses From Abuse and Misuse|url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm505303.htm|website=U.S. Food and Drug Administration (FDA)|access-date=12 June 2016|url-status=dead|archive-url=https://web.archive.org/web/20160611093318/https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm505303.htm|archive-date=11 June 2016}}

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 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. 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.{{ cite web | title = rxlist.com | year = 2005 | url = http://www.rxlist.com/imodium-drug/indications-dosage.htm | url-status = live | archive-url = https://web.archive.org/web/20121127021744/http://www.rxlist.com/imodium-drug/indications-dosage.htm | archive-date = 27 November 2012 | df = dmy-all }} 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.{{cite web|url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory|title=Drugs@FDA: FDA Approved Drug Products|publisher=U.S. Food and Drug Administration (FDA)|access-date=14 May 2016|url-status=dead|archive-url=https://web.archive.org/web/20160506041852/http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory|archive-date=6 May 2016}}

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.{{ cite web | url = http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=6651 | title = Imodium (Loperamide Hydrochloride) Capsule | work = DailyMed | publisher = NIH | url-status = live | archive-url = https://web.archive.org/web/20100413032222/http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=6651 | archive-date = 13 April 2010 | df = dmy-all }} 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.{{cite journal | vauthors=Li ST, Grossman DC, Cummings P | title = Loperamide therapy for acute diarrhea in children: systematic and meta-analysis | journal = PLOS Medicine | volume = 4 | issue = 3 | date = 2007 | pages = e98 | pmid=17388664 | doi=10.1371/journal.pmed.0040098 | pmc=1831735 | doi-access = free }}

In 1990, all formulations for children of the antidiarrheal loperamide were banned in Pakistan.{{ cite web|url=http://www.essentialdrugs.org/edrug/archive/199708/msg00056.php |title=E-DRUG: Chlormezanone |publisher=Essentialdrugs.org |url-status=dead |archive-url=https://web.archive.org/web/20110726035911/http://www.essentialdrugs.org/edrug/archive/199708/msg00056.php |archive-date=26 July 2011 }}

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.{{cite web |date=20 December 2018 |title=Loperamide: a medicine used to treat diarrhoea |url=https://www.nhs.uk/medicines/loperamide/ |access-date=7 October 2023 |website=National Health Service }}

Loperamide is not recommended in the United Kingdom for use during pregnancy or by nursing mothers.{{cite web|url=http://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?condition=Diarrhoea&medicine=imodium|title=Medicines information links - NHS Choices|access-date=14 May 2016|url-status=dead|archive-url=https://web.archive.org/web/20140110171045/http://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?condition=Diarrhoea&medicine=imodium|archive-date=10 January 2014}} Studies in rat models have shown no teratogenicity, but sufficient studies in humans have not been conducted.{{cite web|url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#labelinfo|title=Drugs@FDA: FDA Approved Drug Products|publisher=U.S. Food and Drug Administration (FDA) |access-date=14 May 2016|url-status=dead|archive-url=https://web.archive.org/web/20160506041852/http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Label_ApprovalHistory#labelinfo|archive-date=6 May 2016}} 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.{{cite journal | vauthors = Einarson A, Mastroiacovo P, Arnon J, Ornoy A, Addis A, Malm H, Koren G | title = Prospective, controlled, multicentre study of loperamide in pregnancy | journal = Canadian Journal of Gastroenterology | volume = 14 | issue = 3 | pages = 185–7 | date = March 2000 | pmid = 10758415 | doi = 10.1155/2000/957649 | doi-access = free }} Loperamide can be present in breast milk and is not recommended for breastfeeding mothers.

Loperamide is a substrate of P-glycoprotein; therefore, the concentration of loperamide increases when given with a P-glycoprotein inhibitor. Common P-glycoprotein inhibitors include quinidine, ritonavir, and ketoconazole.{{cite web|url=https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm#PgpTransport|title=Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers|publisher=U.S. Food and Drug Administration (FDA) |access-date=14 May 2016|url-status=dead|archive-url= https://web.archive.org/web/20160510152158/https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm#PgpTransport|archive-date=10 May 2016}} Loperamide can decrease the absorption of some other drugs. As an example, saquinavir concentrations can decrease by half when given with loperamide.

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.{{cite web |title=Loperamide Drug Interactions - Epocrates Online |url=https://online.epocrates.com/noFrame/showPage.do?method=drugs&MonographId=44&ActiveSectionId=4 |website=online.epocrates.com |access-date=5 November 2020 |archive-date=1 November 2018 |archive-url=https://web.archive.org/web/20181101070900/https://online.epocrates.com/noFrame/showPage.do?method=drugs&MonographId=44&ActiveSectionId=4 |url-status=live }}

File:Loperamide 3D ball.png

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.{{cite web|url=http://www.drugbank.ca/drugs/DB00836|title=DrugBank: Loperamide|access-date=14 May 2016|url-status=live|archive-url=https://web.archive.org/web/20160510135146/http://www.drugbank.ca/drugs/DB00836|archive-date=10 May 2016}}{{cite web|url=https://www.drugs.com/mmx/loperamide-hydrochloride.html|title=Loperamide Hydrochloride Drug Information, Professional|access-date=14 May 2016|url-status=live|archive-url=https://web.archive.org/web/20160503123442/http://www.drugs.com/mmx/loperamide-hydrochloride.html|archive-date=3 May 2016}} 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.{{ cite book | vauthors = Katzung BG | title = Basic and Clinical Pharmacology | edition = 9th | year = 2004 | publisher = Lange Medical Books/McGraw Hill | isbn = 978-0-07-141092-2 }}{{Page needed|date=September 2010}}

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 through first-pass metabolism by the liver.{{cite book|url=https://books.google.com/books?id=R0W1ErpsQpkC|title=Foye's Principles of Medicinal Chemistry| vauthors = Lemke TL, Williams DA |date=2008|publisher=Lippincott Williams & Wilkins |isbn=9780781768795 |pages = 675 |url-status=live |archive-url= https://web.archive.org/web/20170908145128/https://books.google.com/books?id=R0W1ErpsQpkC |archive-date=8 September 2017 }}{{cite journal | vauthors = Dufek MB, Knight BM, Bridges AS, Thakker DR | title = P-glycoprotein increases portal bioavailability of loperamide in mouse by reducing first-pass intestinal metabolism | journal = Drug Metabolism and Disposition | volume = 41 | issue = 3 | pages = 642–50 | date = March 2013 | pmid = 23288866 | doi = 10.1124/dmd.112.049965 | df = dmy-all | s2cid = 11014783 }} Loperamide metabolizes into an MPTP-like compound, but is unlikely to exert neurotoxicity.{{cite journal | vauthors = Kalgutkar AS, Nguyen HT | title = Identification of an N-methyl-4-phenylpyridinium-like metabolite of the antidiarrheal agent loperamide in human liver microsomes: underlying reason(s) for the lack of neurotoxicity despite the bioactivation event | journal = Drug Metabolism and Disposition | volume = 32 | issue = 9 | pages = 943–52 | date = September 2004 | doi = 10.1016/S0090-9556(24)02977-5 | pmid = 15319335 | url = http://dmd.aspetjournals.org/content/32/9/943 | url-status = live | archive-url = https://web.archive.org/web/20170908145128/http://dmd.aspetjournals.org/content/32/9/943 | df = dmy-all | archive-date = 8 September 2017 | url-access = subscription }}

Efflux by P-glycoprotein also prevents circulating loperamide from effectively crossing the blood-brain barrier,{{cite journal | vauthors = Upton RN | title = Cerebral uptake of drugs in humans | journal = Clinical and Experimental Pharmacology & Physiology | volume = 34 | issue = 8 | pages = 695–701 | date = August 2007 | pmid = 17600543 | doi = 10.1111/j.1440-1681.2007.04649.x | s2cid = 41591261 }} so it can generally only agonize mu-opioid receptors in the peripheral nervous system, and currently has a score of one on the anticholinergic cognitive burden scale.{{cite web |url=http://www.agingbraincare.org/uploads/products/ACB_scale_-_legal_size.pdf |title=Anticholinergic Cognitive Burden Scale |access-date=23 September 2017 |archive-url=https://web.archive.org/web/20180307142553/http://www.agingbraincare.org/uploads/products/ACB_scale_-_legal_size.pdf |archive-date=7 March 2018 |url-status=dead }} 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 can saturate P-glycoprotein (thus overcoming the efflux) and produce euphoric effects.{{cite journal | vauthors = Antoniou T, Juurlink DN | title = Loperamide abuse | journal = CMAJ | volume = 189 | issue = 23 | pages = E803 | date = June 2017 | pmid = 28606977 | pmc = 5468105 | doi = 10.1503/cmaj.161421 }} Loperamide taken with quinidine was found to produce respiratory depression, indicative of central opioid action.{{cite journal | vauthors = Sadeque AJ, Wandel C, He H, Shah S, Wood AJ | title = Increased drug delivery to the brain by P-glycoprotein inhibition | journal = Clinical Pharmacology and Therapeutics | volume = 68 | issue = 3 | pages = 231–7 | date = September 2000 | pmid = 11014404 | doi = 10.1067/mcp.2000.109156 | s2cid = 38467170 }}

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.{{cite journal | vauthors = Yanagita T, Miyasato K, Sato J | title = Dependence potential of loperamide studied in rhesus monkeys | journal = NIDA Research Monograph | volume = 27 | pages = 106–13 | year = 1979 | pmid = 121326 }}{{cite journal | vauthors = Nakamura H, Ishii K, Yokoyama Y, Motoyoshi S, Suzuki K, Sekine Y, Hashimoto M, Shimizu M | title = [Physical dependence on loperamide hydrochloride in mice and rats] | language = ja | journal = Yakugaku Zasshi | volume = 102 | issue = 11 | pages = 1074–85 | date = November 1982 | pmid = 6892112 | doi = 10.1248/yakushi1947.102.11_1074 | doi-access = free }}

Loperamide is synthesized starting from the lactone 3,3-diphenyldihydrofuran-2(3H)-one and ethyl 4-oxopiperidine-1-carboxylate, on a lab scale.{{cite journal | vauthors = Stokbroekx RA, Vandenberk J, Van Heertum AH, Van Laar GM, Van der Aa MJ, Van Bever WF, Janssen PA | title = Synthetic antidiarrheal agents. 2,2-Diphenyl-4-(4'-aryl-4'-hydroxypiperidino)butyramides | journal = Journal of Medicinal Chemistry | volume = 16 | issue = 7 | pages = 782–786 | date = July 1973 | pmid = 4725924 | doi = 10.1021/jm00265a009 }} On a large scale a similar synthesis is followed, except that the lactone and piperidinone are produced from cheaper materials rather than purchased.{{cite patent | inventor = Janssen PA, Niemegeers CJ | country = US | number = 3714159 | gdate = 1973 }}{{cite patent | inventor = Janssen PA, Niemegeers CJ | country = US | number = 3884916 | gdate = 1975 }}

File:Loperamide synthesis.png

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.{{cite journal | vauthors = Van Rompay J, Carter JE | title = Loperamide hydrochloride. | journal = Analytical Profiles of Drug Substances | date = January 1990 | volume = 19 | pages = 341–365 | publisher = Academic Press | veditors = Florey K |doi=10.1016/s0099-5428(08)60372-x| isbn = 9780122608193 }}

Loperamide hydrochloride was first synthesized in 1969 by Paul Janssen from Janssen Pharmaceuticals in Beerse, Belgium, following previous discoveries of diphenoxylate hydrochloride (1956) and fentanyl citrate (1960).{{cite book|vauthors=Florey K|date=1991|title=Profiles of Drug Substances, Excipients and Related Methodology, Volume 19|url=https://books.google.com/books?id=5ndDXC2L5Q8C&pg=PA342|publisher=Academic Press|isbn=9780080861142|pages=342|access-date=18 May 2016|archive-date=14 January 2023|archive-url=https://web.archive.org/web/20230114195404/https://books.google.com/books?id=5ndDXC2L5Q8C&pg=PA342|url-status=live}}

The first clinical reports on loperamide were published in 1973 in the Journal of Medicinal Chemistry with the inventor being one of the authors. The trial name for it was "R-18553".{{cite journal | pmid = 4611432 | volume=24 | issue=10 | title=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 | year=1974 | journal=Arzneimittelforschung | pages=1653–7 |vauthors=Schuermans V, Van Lommel R, Dom J, Brugmans J }} Loperamide oxide has a different research code: R-58425.{{cite web |url=https://www.ebi.ac.uk/chembl/compound/inspect/CHEMBL2105114 |title=Compound Report Card |access-date=23 June 2016 |url-status=live |archive-url=https://web.archive.org/web/20160811174542/https://www.ebi.ac.uk/chembl/compound/inspect/CHEMBL2105114 |archive-date=11 August 2016 }}

The trial against placebo was conducted from December 1972 to February 1974, its results being published in 1977 in the journal Gut.{{cite journal | vauthors = Mainguet P, Fiasse R | title = Double-blind placebo-controlled study of loperamide (Imodium) in chronic diarrhoea caused by ileocolic disease or resection | journal = Gut | volume = 18 | issue = 7 | pages = 575–9 | date = July 1977 | pmid = 326642 | pmc = 1411573 | doi = 10.1136/gut.18.7.575 | df = dmy }}

In 1973, Janssen started to promote loperamide under the brand name Imodium. In December 1976, Imodium got US FDA approval.{{cite web|url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=017694&DrugName=IMODIUM&ActiveIngred=LOPERAMIDE%20HYDROCHLORIDE&SponsorApplicant=MCNEIL%20CONS&ProductMktStatus=1&goto=Search.DrugDetails|title=IMODIUM FDA Application No.(NDA) 017694|year=1976|publisher=U.S. Food and Drug Administration (FDA)|archive-url=https://web.archive.org/web/20140813131107/http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails|archive-date=13 August 2014|url-status=dead|access-date=5 September 2014}}

During the 1980s, Imodium became the best-selling prescription antidiarrheal in the United States.

{{cite court| litigants=McNeil-PPC, Inc., Plaintiff, v. L. Perrigo Company, and Perrigo Company, Defendants| vol=207| reporter=F. Supp. 2d| opinion=356| court=E.D. Pa.| date=25 June 2002| url=http://law.justia.com/cases/federal/district-courts/FSupp2/207/356/2346092/ }}

In March 1988, McNeil Pharmaceutical began selling loperamide as an over-the-counter drug under the brand name Imodium A-D.{{cite web|url=https://www.accessdata.fda.gov/scripts/cder/daf/|title=IMODIUM A-D FDA Application No.(NDA) 019487|year=1988|publisher=U.S. Food and Drug Administration (FDA)|archive-url=https://web.archive.org/web/20140813131107/http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails|archive-date=13 August 2014|url-status=live|access-date=5 September 2014}}

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).{{cite journal|url=http://apps.who.int/medicinedocs/index/assoc/h5785e/h5785e.pdf|title=Loperamide: voluntary withdrawal of infant fomulations|year=1990|journal=WHO Drug Information|volume=4|issue=2|pages=73–74|archive-url=https://web.archive.org/web/20140907004301/http://apps.who.int/medicinedocs/index/assoc/h5785e/h5785e.pdf|archive-date=7 September 2014|url-status=dead|access-date=6 September 2014|quote=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.}} 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).{{cite book|date=2003|title=Consolidated List of Products Whose Consumption And/or Sale Have Been Banned, Withdrawn, Severely Restricted Or Not Approved by Governments, 8th Issue|url=https://books.google.com/books?id=leVCukUgNlsC&pg=PA131|publisher=United Nations|isbn=978-92-1-130230-1|pages=130–131|url-status=live|archive-url=https://web.archive.org/web/20170908145128/https://books.google.com/books?id=leVCukUgNlsC&pg=PA131&lpg=PA131&dq=#v=onepage&q&f=true|archive-date=8 September 2017}}

In the late 1980s, before the US patent expired on 30 January 1990, McNeil started to develop Imodium Advanced containing loperamide and simethicone for treating both diarrhea and gas. In March 1997, the company patented this combination.{{cite patent|country=US|number=5612054|title=Pharmaceutical compositions for treating gastrointestinal distress|gdate=1997-03-18|fdate=1995-04-19|pridate=1989-11-01|invent1=Jeffrey L. Garwin|assign1=McNeil-PPC, Inc.|status=patent}} The drug was approved in June 1997, by the FDA as Imodium Multi-Symptom Relief in the form of a chewable tablet.{{cite web|url=http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Set_Current_Drug&ApplNo=020606&DrugName=IMODIUM%20MULTI%2DSYMPTOM%20RELIEF&ActiveIngred=LOPERAMIDE%20HYDROCHLORIDE%3B%20SIMETHICONE&SponsorApplicant=MCNEIL&ProductMktStatus=2&goto=Search.DrugDetails|title=IMODIUM MULTI-SYMPTOM RELIEF FDA Application No.(NDA) 020606|year=1997|publisher=U.S. Food and Drug Administration (FDA)|archive-url=https://web.archive.org/web/20140813131107/http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails|archive-date=13 August 2014|url-status=dead|access-date=5 September 2014}} A caplet formulation was approved in November 2000.{{cite web | title=Drug Approval Package: Imodium Advanced (Loperamide HCI and Simethicone NDA #21-140 | website=U.S. Food and Drug Administration (FDA) | date=24 December 1999 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-140_Imodium.cfm | access-date=16 December 2020 | archive-date=2 September 2023 | archive-url=https://web.archive.org/web/20230902195525/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21-140_Imodium.cfm | url-status=dead }}

In November 1993, loperamide was launched as an orally disintegrating tablet based on Zydis technology.{{cite web|url=http://www.thefreelibrary.com/SCHERER+ANNOUNCES+LAUNCH+OF+ANOTHER+PRODUCT+UTILIZING+ITS+ZYDIS...-a014279075|archive-url=https://web.archive.org/web/20140830174558/http://www.thefreelibrary.com/SCHERER+ANNOUNCES+LAUNCH+OF+ANOTHER+PRODUCT+UTILIZING+ITS+ZYDIS...-a014279075|url-status=dead|archive-date=30 August 2014|title=Scherer announces launch of another product utilizing its Zydis technology|date=9 November 1993|publisher=PR Newswire Association LLC|access-date=30 August 2014}}{{cite book| vauthors = Rathbone MJ, Hadgraft J, Roberts MS |date=2002|title=Modified-Release Drug Delivery Technology|chapter=The Zydis Oral Fast-Dissolving Dosage Form|chapter-url=https://books.google.com/books?id=mw9W82MLYZ8C&q=%20janssen&pg=PA200 |publisher=CRC Press|pages = [https://archive.org/details/modifiedreleased00mich/page/200 200]|isbn=9780824708696|access-date=26 August 2014|url-access=registration|url=https://archive.org/details/modifiedreleased00mich/page/200}}

In 2013, loperamide in the form of 2-mg tablets was added to the WHO Model List of Essential Medicines.{{cite book | vauthors = ((World Health Organization)) | title = 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) | year = 2014 | publisher = World Health Organization | location = Geneva | author-link = World Health Organization | hdl = 10665/112729 | id = WHO technical report series;985 | hdl-access=free | isbn = 9789241209854 | issn = 0512-3054 }}

In 2020, it was discovered by researchers at Goethe University that Loperamide was effective at killing glioblastoma cells.{{cite web |url=https://aktuelles.uni-frankfurt.de/englisch/anti-diarrhoea-drug-drives-cancer-cells-to-cell-death/ |title=Anti-diarrhoea drug drives cancer cells to cell death – Aktuelles aus der Goethe-Universität Frankfurt |website=aktuelles.uni-frankfurt.de |url-status=dead |archive-url=https://web.archive.org/web/20201223113316/https://aktuelles.uni-frankfurt.de/englisch/anti-diarrhoea-drug-drives-cancer-cells-to-cell-death/ |archive-date=23 December 2020}}

Loperamide was formerly a controlled substance in the United States. First, it was a Schedule II controlled substance. However, this was lowered to Schedule V. Loperamide was finally removed from control by the Drug Enforcement Administration in 1982, courtesy of then-Administrator Francis M. Mullen Jr.{{cite web | vauthors = Mullen F |date=3 November 1982 |title=FR Doc. 82-30264 |url=https://archives.federalregister.gov/issue_slice/1982/11/3/49841-49843.pdf |archive-url=https://archive.today/20230627043028/https://archives.federalregister.gov/issue_slice/1982/11/3/49841-49843.pdf |archive-date=27 June 2023 |access-date=26 June 2023 |website=Federal Register |publisher=DEA}}

Loperamide can be sold freely to the public by chemists (pharmacies) as the treatment of diarrhoea and acute diarrhoea associated with medically diagnosed irritable bowel syndrome in adults over 18 years of age{{cite web | url=https://bnf.nice.org.uk/drugs/loperamide-hydrochloride/#:~:text=Loperamide%20can%20be%20sold%20to%20the%20public%2C%20provided,doctor%29%20in%20adults%20over%2018%20years%20of%20age | title=BNF is only available in the UK }}

Loperamide is sold as a generic medication. In 2016, Imodium was one of the biggest-selling branded over-the-counter medications sold in Great Britain, with sales of £32.7 million.{{cite journal | title=A breakdown of the over-the-counter medicines market in Britain in 2016 | journal=The Pharmaceutical Journal | publisher=Royal Pharmaceutical Society | vauthors=Connelly D | date=April 2017 | issn=2053-6186 | doi=10.1211/pj.2017.20202662 | volume=298 | issue=7900 }}

Loperamide was originally marketed as Imodium, and many generic brands are sold.

Loperamide has typically been deemed to have a relatively low risk of misuse.{{cite journal | vauthors = Baker DE | title = Loperamide: a pharmacological review | journal = Reviews in Gastroenterological Disorders | volume = 7 | issue = Suppl 3 | pages = S11-8 | date = 2007 | pmid = 18192961 }} In 2012, no reports of loperamide abuse were made.{{cite book|title=Mediators and Drugs in Gastrointestinal Motility II: Endogenous and Exogenous Agents|url=https://books.google.com/books?id=d-TrCAAAQBAJ&pg=PA290|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-68474-6|pages=290–|access-date=18 May 2016|archive-date=12 January 2023|archive-url=https://web.archive.org/web/20230112234947/https://books.google.com/books?id=d-TrCAAAQBAJ&pg=PA290|url-status=live}} In 2015, however, case reports of extremely high-dose loperamide use were published.{{cite journal | vauthors = MacDonald R, Heiner J, Villarreal J, Strote J | title = Loperamide dependence and abuse | journal = BMJ Case Reports | volume = 2015 | pages = bcr2015209705 | date = May 2015 | pmid = 25935922 | pmc = 4434293 | doi = 10.1136/bcr-2015-209705 }}{{cite journal | vauthors = Dierksen J, Gonsoulin M, Walterscheid JP | title = Poor Man's Methadone: A Case Report of Loperamide Toxicity | journal = The American Journal of Forensic Medicine and Pathology | volume = 36 | issue = 4 | pages = 268–70 | date = December 2015 | pmid = 26355852 | doi = 10.1097/PAF.0000000000000201 | s2cid = 19635919 }} 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. At these higher doses central nervous system penetration occurs and long-term use may lead to tolerance, dependence, and withdrawal on abrupt cessation.{{cite journal | vauthors = Stanciu CN, Gnanasegaram SA | title = Loperamide, the "Poor Man's Methadone": Brief Review | journal = Journal of Psychoactive Drugs | volume = 49 | issue = 1 | pages = 18–21 | date = 2017 | pmid = 27918873 | doi = 10.1080/02791072.2016.1260188 | s2cid = 31713818 }} 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.{{cite news|url=https://www.washingtonpost.com/news/morning-mix/wp/2016/05/04/physicians-alarmed-by-abuse-of-over-the-counter-diarrhea-medicine-you-know-well/|title=Abuse of diarrhea medicine you know well is alarming physicians|vauthors=Guarino B|date=4 May 2016|newspaper=Washington Post|access-date=6 May 2016|archive-date=6 May 2016|archive-url=https://web.archive.org/web/20160506050851/https://www.washingtonpost.com/news/morning-mix/wp/2016/05/04/physicians-alarmed-by-abuse-of-over-the-counter-diarrhea-medicine-you-know-well/|url-status=live}} The FDA responded to these warnings by calling on drug manufacturers to voluntarily limit the package size of loperamide for public-safety reasons.{{cite news|url=https://www.washingtonpost.com/news/to-your-health/wp/2018/01/30/fda-wants-to-curb-abuse-of-imodium-the-poor-mans-methadone/|title=FDA wants to curb abuse of Imodium, 'the poor man's methadone'|vauthors=McGinley L|date=30 January 2018|newspaper=Washington Post|access-date=30 January 2018|issn=0190-8286|archive-date=30 January 2018|archive-url=https://web.archive.org/web/20180130194140/https://www.washingtonpost.com/news/to-your-health/wp/2018/01/30/fda-wants-to-curb-abuse-of-imodium-the-poor-mans-methadone/|url-status=live}}{{cite web|author=Office of the Commissioner|title=Safety Alerts for Human Medical Products - Imodium (loperamide) for Over-the-Counter Use: Drug Safety Communication - FDA Limits Packaging To Encourage Safe Use|url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm594403.htm|website=U.S. Food and Drug Administration (FDA)|access-date=2 February 2018|archive-date=8 April 2018|archive-url=https://web.archive.org/web/20180408052631/https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm594403.htm|url-status=dead}} 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.{{cite journal | vauthors = Feldman R, Everton E | title = National assessment of pharmacist awareness of loperamide abuse and ability to restrict sale if abuse is suspected | journal = Journal of the American Pharmacists Association | volume = 60 | issue = 6 | pages = 868–873 | date = November 2020 | pmid = 32641253 | doi = 10.1016/j.japh.2020.05.021 | s2cid = 220436708 }} Since 2015, several reports of sometimes-fatal cardiotoxicity due to high-dose loperamide abuse have been published.{{cite journal | vauthors = Eggleston W, Clark KH, Marraffa JM | title = Loperamide Abuse Associated With Cardiac Dysrhythmia and Death | journal = Annals of Emergency Medicine | volume = 69 | issue = 1 | pages = 83–86 | date = January 2017 | pmid = 27140747 | doi = 10.1016/j.annemergmed.2016.03.047 }}{{cite journal | vauthors = Mukarram O, Hindi Y, Catalasan G, Ward J | title = Loperamide Induced Torsades de Pointes: A Case Report and Review of the Literature | journal = Case Reports in Medicine | volume = 2016 | pages = 4061980 | year = 2016 | pmid = 26989420 | pmc = 4775784 | doi = 10.1155/2016/4061980 | doi-access = free }}

• Fluperamide

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