, Volume 15, Issue 1, pp 33–52 | Cite as

Loperamide: A Review of its Pharmacological Properties and Therapeutic Efficacy in Diarrhoea

  • R. C. Heel
  • R. N. Brogden
  • T. M. Speight
  • G. S. Avery
Evaluations on New Drugs


Synopsis: Loperamide, a butyramide derivative is a new agent for use in symptomatic control of acute non-specific diarrhoea and chronic diarrhoea. Unlike diphenoxylate or codeine, loperamide does not appear to exert opiate activity in man at normal therapeutic doses.

In acute diarrhoea, loperamide provides more rapid control of symptoms than diphenoxylate when given in a flexible dosage according to unformed bowel movements, and in single dose studies 4mg loperamide has a much longer duration of effect than 5mg diphenoxylate. Loperamide is probably superior to diphenoxylate in providing symptomatic control of chronic diarrhoea such as that associated with chronic inflammatory bowel disease or following gastrointestinal surgery, It has been used for up to 3 years in such conditions without evidence of tolerance. The possibility of once daily dosage of loperamide in chronic diarrhoea is an advantage. Side-effects have not proved a problem.

Pharmacodynamic studies: Loperamide is an orally-active drug which reduces gastrointestinal motility in animals and man. In isolated-organ studies loperamide caused a dose-related reduction of pressure-induced activity of longitudinal and circular muscles in the ileum and inhibited the spasmogenic effects of electrical stimulation, nicotine and prostaglandins. Loperamide is more potent than diphenoxylate, morphine or codeine in slowing gastrointestinal progression of a charcoal bolus in mice and in reducing castor oil-induced diarrhoea in rats and mice. Oral doses (2.5 to 40mg/kg) several times the antidiarrhoeal dose, unlike diphenoxylate, do not produce narcotic-like actions. Intravenous (0.1mg/kg) or high subcutaneous doses (40 to 240mg/kg) of loperamide may however, result in opiate agonist activity. Loperamide, unlike diphenoxylate, does not possess analgesic activity after non-toxic oral doses.

In man, loperamide has a significant constipating effect in healthy volunteers, with a similar onset but longer duration of activity than diphenoxylate. Central opiate activity, as demonstrated by pupillary diameter measurements with or without challenge by the narcotic antagonist naloxone, does not occur at normal therapeutic oral doses.

Pharmacokinetic studies: Peak plasma levels occur within 4 hours after administration and the plasma half-life in man is 7 to 15 hours. 25 % of an oral dose is excreted in the faeces unchanged in 3 days, and 1 to 2 % in the urine as free drug or glucuronic acid conjugate. Biliary elimination is an important route of excretion in rats but this has not been studied in man.

Therapeutic trials: Loperamide has been effective and safe in the symptomatic treatment of both acute and chronic diarrhoea and in reducing ileostomy output in patients with ileostomies. Most controlled studies in acute diarrhoea have shown loperamide to provide more rapid control of symptoms than a placebo, kaolin-morphine mixture or diphenoxylate plus atropine. In 2 studies involving large numbers of patients, about one-half of patients receiving loperamide required further treatment after the first 12 to 24 hours compared with about two-thirds of those on diphenoxylate. In patients with severe chronic diarrhoea associated with chronic inflammatory bowel disease or following gastrointestinal surgery, loperamide is superior to a placebo and probably superior to diphenoxylate. Patient preferences and reduction in stool frequency have favoured loperamide over diphenoxylate, and in 1 study it had a more rapid onset of action. Further studies involving larger numbers of patients are needed to clarify the relative efficacy of the 2 agents in chronic diarrhoea, but the possibility of once daily dosage with loperamide is an advantage. Loperamide has not been compared with codeine in therapeutic trials but has the advantage of a longer duration of effect and apparent freedom from opiate side-effects.

In a single dose study in acute diarrhoea, 4mg loperamide had a much longer duration of effect than 5mg diphenoxylate or 400mg clioquinol plus 40mg phanquone.

In studies in acute and chronic diarrhoea involving a flexible dosage according to unformed bowel movements, loperamide 2mg per dose has controlled diarrhoea at a lower dose level (i.e. total number of doses or average daily doses) than diphenoxylate 2.5mg per dose. It seems that a larger initial and subsequent dosage of diphenoxylate is needed to provide equivalent control of diarrhoea. Thus, in 1 study which compared loperamide 2mg per dose with diphenoxylate 5mg per dose in chronic diarrhoea, the number of doses required for control did not differ, although diarrhoea was better controlled by loperamide in terms of reduced stool frequency and improved stool consistency. In acute diarrhoea, a larger initial dose ( 10mg instead of 5mg) and subsequent larger fixed dosage (5mg every 6 hours instead of 2.5mg as needed) of diphenoxylate achieved similar control as the standard flexible dose schedule of loperamide (4mg initially then 2mg after each loose bowel movement).

Side-effects: Loperamide appears to be well tolerated. Side-effects are usually gastrointestinal in nature and may be related to the diarrhoeal condition rather than to the drug itself. Nausea, abdominal cramping, dizziness, rash, and dry mouth have occasionally been reported.

Dosage: In adults the initial dose for acute diarrhoea is 4mg followed by 2mg after each loose bowel movement. For chronic diarrhoea, an initial dose of 4mg should be subsequently adjusted to obtain 1 or 2 normal stools daily. When the optimum individual dosage has been established, it may be given on a once daily basis or in divided doses. Adult dosage in acute diarrhoea should not exceed 16mg per day. Children* over 8 years of age should receive 2mg initially with subsequent adjustments not to exceed 8 to 12mg daily. In children younger than 8 years, the therapeutic dosage is of the order of 0.08mg/kg body weight per day.


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  1. Abuassi, W.L.; Filho, P.J. de C. and Jacob, N.: The use of a drug controlling intestinal motility in a sequential scheme for the treatment of diarrhoea. A Folha Medica 65: 113 (1972).Google Scholar
  2. Amery, W.; Duyck, F.; Polak, J. and Van Den Bouwhuysen, G.: A multicentre double-blind study in acute diarrhoea comparing loperamide (R 18553) with two common antidiarrhoeal agents and a placebo. Current Therapeutic Research 17: 263 (1975).PubMedGoogle Scholar
  3. Awouters, F.; Niemegeers, C.J.E.; Kuyps, J. and Janssen, P.A.J.: Loperamide antagonism of castor oil-induced diarrhoea in rats: A quantitative study. Archives internationale de Pharmacodynamie et de Therapie: in press (1977).Google Scholar
  4. Bank, S.; Saunders, S.J.; Marks, I.N.; Novis, B.H. and Barbezat, C.O.: Gastrointestinal and hepatic disease; in Avery (Ed) Drug Treatment: Principles and Practice of Clinical Pharmacology and Therapeutics, p.520, 539 (ADIS Press, Sydney; Churchill Livingstone, Edinburgh 1976).Google Scholar
  5. Bianchi, C. and Goi, A.: On the antidiarrhoeal and analgesic properties of diphenoxylate, difenoxine and loperamide in mice and rats. Arzneimittel-Forschung 27: 1040 (1977).PubMedGoogle Scholar
  6. Brasil, R.M.C.; de Azevedo, C.E.S.; Aires, V.L.T. and Galvas, I.S.: Use of loperamide in children with acute and chronic diarrhoea. A Folha Medica 68: 259 (1974).Google Scholar
  7. Buts, J.P.; Petit, B.F. and de Meyer, R.: Loperamide in treatment of persistent diarrhoea in children. British Medical Journal 3: 766 (1975).PubMedCrossRefGoogle Scholar
  8. Clay, G.A.; Mackerer, C.R. and Lin, T.K.: Interaction of loperamide with 3H naloxone binding sites in guinea pig brain and myenteric plexus. Molecular Pharmacology 13: 533 (1977).PubMedGoogle Scholar
  9. Colpaert, F.C.; Niemegeers, C.J.E.; Lal, H. and Janssen, P.A.J.: Investigations on drug produced and subjectively experienced discriminative stimuli. 2. Loperamide, an antidiarrhoeal devoid of narcotic cue producing actions. Life Sciences 16: 717 (1975).PubMedCrossRefGoogle Scholar
  10. Cornett, J.W.D.; Aspeling, R.L. and Mallegol, D.: A double-blind comparative evaluation of loperamide versus diphenoxylate with atropine in acute diarrhoea. Current Therapeutic Research 21: 629 (1977).Google Scholar
  11. De Coster, M.; Kerremans, R. and Beckers, J.: A comparative double-blind study of two antidiarrhoeals, difenoxine and loperamide. Tijdschrift voor Gastro-enterologie 15: 337 (1972).PubMedGoogle Scholar
  12. Demeulenaere, L.; Verbeke, S.; Muls, M. and Reyntjens, A.: Loperamide: An open multicentre trial and a double-blind cross-over comparison with placebo in patients with chronic diarrhoea. Current Therapeutic Research 16: 32 (1974).PubMedGoogle Scholar
  13. Dom, J.; Leyman, R.; Schuermans, V. and Brugmans, J.: Loperamide (R 18553), a novel type of antidiarrhoeal agent. Part 8: Clinical investigation. Use of a flexible dosage schedule in a double-blind comparison of loperamide with diphenoxylate in 614 patients suffering from acute diarrhoea. Arzneimittel-Forschung 24: 10 (1974).Google Scholar
  14. Dubru, J.M. and Lambrechts, A.: Le R18553 dans le traitment des diarrhees aigues du jeune enfant. Revue Medicale de Liege 24: 579 (1974).Google Scholar
  15. Du Pont, H.L. and Hornick, R.B.: Adverse effect of Lomotil therapy in shigellosis. Journal of the American Medical Association 226: 1525 (1973).CrossRefGoogle Scholar
  16. Galambos, J.T.; Hersh, T.; Spalding, S. and Wenger, J.: Loperamide: A new antidiarrhoeal agent in the treatment of chronic diarrhoea. Gastroenterology 70: 1026 (1976).PubMedGoogle Scholar
  17. Geraldo, S.J. and de Sa Tercio, T.: Clinical evaluation of loperamide in the control of diarrhoea. A Folha Medica 67: 269 (1973).Google Scholar
  18. Gianutsos, G. and Lal, H. Effect of loperamide, haloperidol and methadone in rats trained to discriminate morphine from saline. Psychopharmacologia 41: 267 (1975).PubMedCrossRefGoogle Scholar
  19. Gordon, S.J.; Kinsey, M.D. and Kowlessar, O.D.: Efficacy of loperamide in control of diarrhoea after ileal resection (IR). Gastroenterology 72: 1064 (1977).Google Scholar
  20. Heilman, R.D.; Salvatore, A.T. and McGuire, J.L.: Ethanol-induced sleep; lack of potentiation by loperamide. Federation Proceedings 36: 1019 (1977).Google Scholar
  21. Heykants, J.; Meuldermans, W.; Knaeps, A. and Michiels, L.: The excretion and metabolism of the antidiarrhoeal loperamide in the wistar rat. Eur. J. Drug Metab. (In press, 1977).Google Scholar
  22. Heykants, J.; Michiels, M.; Knaeps, A. and Brugmans, J.: Loperamide (R18553) a novel type of antidiarrhoeal agent. Part 5: The pharmacokinetics of loperamide in rats and man. Arzneimittel-Forschung 24: 1649 (1974).Google Scholar
  23. Jaffe, G.: A comparison of Lomotil and Imodium in acute nonspecific diarrhoea. Journal of International Medical Research 5: 195 (1977).PubMedGoogle Scholar
  24. John, G.I.: Symptomatic treatment of acute self-limiting diarrhoea in adults. Practitioner 219: 396 (1977).PubMedGoogle Scholar
  25. Karim, S.M.M. and Adaikan, P.G.: The effect of loperamide on prostaglandin-induced diarrhoea in rat and man. Prostaglandins 13: 321 (1977).PubMedCrossRefGoogle Scholar
  26. Karim, A. and Heykants, J.: Metabolism of synthetic antidiarrheal drugs, diphenoxylate, difenoxine and loperamide. In van Bever, W. and Lal, H. (Eds.), Modern Pharmacology-Toxicology Vol. 7. Synthetic Antidiarrheal Drugs p.141–155 (Marcel Dekker, New York 1976).Google Scholar
  27. Mackerer, C.R.; Clay, G.A. and Dajani, E.Z.: Loperamide binding to opiate receptor sites of brain and myenteric plexus. The Journal of Pharmacology and Experimental Therapeutics 199: 131 (1976).PubMedGoogle Scholar
  28. Mainguet, P. and Fiasse, R.: Double-blind placebo-controlled study of loperamide (Imodium) in chronic diarrhoea caused by ileocolic disease or resection. Gut: 18: 575 (1977).PubMedCrossRefGoogle Scholar
  29. Mainguet, P.; Fiasse, R. and Turine, J.B.: Long-term survey of treatment of diarrhoea with loperamide. Digestion: in press (1977).Google Scholar
  30. Marsboom, R.; Herin, V.; Verstraeten, A.; Vandesteene, R. and Fransen, J.: Loperamide (R18553), a novel type of antidiarrhoeal agent. Part 4: Studies on subacute and chronic toxicity and the effect on reproductive processes in rats, dogs and rabbits. Arzneimittel-Forschung 24: 1645 (1974).Google Scholar
  31. Michiels, M.; Hendriks, R. and Heykants, J.: Radioimmunoassay of the antidiarrhoeal loperamide. Life Sciences 21: 451 (1977).PubMedCrossRefGoogle Scholar
  32. Niemegeers, C.J.E.; Lenaerts, F.M. and Janssen, P.AJ.: Loperamide (R 18553), a novel type of antidiarrhoeal agent. Part 2: In vivo parenteral pharmacology and acute toxicity in mice. Comparison with morphine, codeine and diphenoxylate. Arzneimittel-Forschung 24: 1636 (1974a).PubMedGoogle Scholar
  33. Niemegeers, C.J.E.; Lenaerts, F.M. and Janssen, P.A.J.: Loperamide (R 18553), a novel type of antidiarrhoeal agent. Part I: in vivo oral pharmacology and acute toxicity. Comparison with morphine, codeine, diphenoxylate and difenoxine. Arzneimittel-Forschung 24: 1633 (1974b).PubMedGoogle Scholar
  34. Niemegeers, C.J.E. and McGuire, J.L.: The antidiarrhoeal specificity of loperamide HCl. Federation Proceedings 36: 1019 (1977).Google Scholar
  35. Pelemans, W. and Vantrappen, G.: A double-blind crossover comparison of loperamide with diphenoxylate in the symptomatic treatment of chronic diarrhoea. Gastroenterology 70: 1030 (1976).PubMedGoogle Scholar
  36. Pert, C.B.; Pasternak, G. and Snyder, S.H.: Opiate agonists and antagonists discriminated by receptor binding in brain. Science 182: 1359 (1973).PubMedCrossRefGoogle Scholar
  37. Pittman, A.F.: Antibiotic-associated colitis — lincomycin and clindamycin. Adverse Drug Reaction Bulletin 63: 220 (1977).CrossRefGoogle Scholar
  38. Rao, U.P.; Ravi, N. and Madanagopalan, N.: Clinical evaluation of loperamide (R 18553) in chronic diarrhoea. Current Medical Practice 20: 161 (1976).Google Scholar
  39. Rodriguez, L.: The use of loperamide in acute non-specific diarrhoea. Gastroenterology 68: 974 (1975).Google Scholar
  40. Roge, J.: Un nouveau traitement symptomatique de la diarrhee. Semain Hopitaux Paris Therapeutique 52: 482 (1976).Google Scholar
  41. Schuermans, V.; Van Lommel, R.; Dom, J. and Brugmans, J.: Loperamide (R 18553), a novel type of antidarrhoeal agent. Part 6: Clinical Pharmacology. Placebo-controlled comparison of the constipating activity and safety of loperamide, diphen oxylate and codeine in normal volunteers. Arzneimittel-Forschung 24: 1653 (1974).PubMedGoogle Scholar
  42. Tytgat, G.N. and Hibregtse, K.: Loperamide in ileostomy output — placebo-controlled double-blind crossover study. British Medical Journal 2: 667 (1975).PubMedCrossRefGoogle Scholar
  43. Tytgat, G.N.; Huibregste, K.; Dagevos, J. and Van Den Ende, A.. Effect of loperamide on faecal output and composition in wellestablished ileostomy and ileorectal anastomosis. Digestive Diseases 22: 669 (1977).CrossRefGoogle Scholar
  44. Tytgat, G.N.; Huibregtse, K. and Meuwissen, S.G.M.: Loperamid in chronic diarrhoea and after ileostomy. A placebo-controlled double-blind cross-over study. Archivum Chirurgicum Neerlandicum 28: 13 (1976).Google Scholar
  45. Van Nueten, J.M.; Janssen, P.A.J. and Fontaine, J.: Loperamide (R 18553), a novel type of antidiarrhoeal agent. Part 3: In vitro studies on the peristaltic reflex and other experiments on isolated tissues. Arzneimittel-Forschung 24: 1641 (1974).Google Scholar
  46. Verhaegen, H.; De Cree, J. and Schuermans, V.: Loperamide (R 18553), a novel type of antidiarrhoeal agent. Part 7: Clinical investigation. Efficacy and safety of loperamide in patients with severe chronic diarrhoea. Arzneimittel-Forschung 24: 1657 (1974).PubMedGoogle Scholar
  47. Weintraub, H.S.; Killinger, J.M.; Heykants, J.; Kanzler, M. and Jaffe, J.H.: Studies on the elimination rate of loperamide in man after administration of increasing oral doses of Imodium. Current Therapeutic Research 21: 867 (1977).Google Scholar
  48. Zelvelder, W.G. and Nelemans, F.A.: A double-blind placebocontrolled trial of loperamide in acute diarrhoea. Journal of Drug Research 2: 54 (1976).Google Scholar

Copyright information

© ADIS Press 1978

Authors and Affiliations

  • R. C. Heel
    • 1
  • R. N. Brogden
    • 1
  • T. M. Speight
    • 1
  • G. S. Avery
    • 1
  1. 1.Australasian Drug Information ServicesBirkenhead, Auckland 10New Zealand

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