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Loperamide

  • Claud Regnard
    Affiliations
    St. Oswald's Hospice (C.R.), Newcastle, United Kingdom; Oxford University (R.T.), Oxford, United Kingdom; Mylan School of Pharmacy (M.M.), Duquesne University, Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom
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  • Robert Twycross
    Affiliations
    St. Oswald's Hospice (C.R.), Newcastle, United Kingdom; Oxford University (R.T.), Oxford, United Kingdom; Mylan School of Pharmacy (M.M.), Duquesne University, Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom
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  • Mary Mihalyo
    Affiliations
    St. Oswald's Hospice (C.R.), Newcastle, United Kingdom; Oxford University (R.T.), Oxford, United Kingdom; Mylan School of Pharmacy (M.M.), Duquesne University, Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom
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  • Andrew Wilcock
    Correspondence
    Address correspondence to: Andrew Wilcock, DM, FRCP, Hayward House Macmillan Specialist Palliative Care Unit, Nottingham University Hospitals NHS Trust, Nottingham NG5 1PB, United Kingdom.
    Affiliations
    St. Oswald's Hospice (C.R.), Newcastle, United Kingdom; Oxford University (R.T.), Oxford, United Kingdom; Mylan School of Pharmacy (M.M.), Duquesne University, Pittsburgh, Pennsylvania, USA; and University of Nottingham (A.W.), Nottingham, United Kingdom
    Search for articles by this author
Open AccessPublished:June 23, 2011DOI:https://doi.org/10.1016/j.jpainsymman.2011.06.001
      Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativebooks.com. The series editors welcome feedback on the articles ([email protected]).

      Abbreviations/Key

      b.i.d.
      Twice daily
      CNS
      Central nervous system
      CYP
      Cytochrome P450
      GI
      Gastrointestinal
      OTC
      Over the counter (i.e., can be obtained without prescription)
      PO
      Per os, by mouth
      p.r.n.
      Pro re nata, as needed/required
      q2 h
      Every 2 hours, etc.
      q.i.d.
      Four times daily
      Class: Antimotility drug.
      Indications: Acute and chronic diarrhea, †ileostomy (to improve fecal consistency).
      Contraindications: Colitis (ulcerative, infective, or antibiotic-associated).

      Pharmacology

      Loperamide is a potent μ-opioid receptor agonist.
      • Shannon H.
      • Lutz E.
      Comparison of the peripheral and central effects of the opioid agonists loperamide and morphine in the formalin test in rats.
      Although well absorbed from the GI tract, loperamide is almost completely extracted and metabolized by cytochrome P450 in the liver (particularly CYP3A4) where it is conjugated, and the conjugates excreted in the bile. Because of this, little loperamide reaches the systemic circulation.
      The antidiarrheal action of loperamide results from direct absorption into the gut wall. Like morphine and other μ-receptor agonists, loperamide increases intestinal transit time by decreasing propulsive activity and increasing non-propulsive activity via its effect on the myenteric plexus in the longitudinal muscle layer.
      • Van Nueten J.M.
      • Helsen L.
      • Michiels M.
      • Heykants J.J.
      Distribution of loperamide in the intestinal wall.
      • Ooms L.A.
      • Degryse A.D.
      • Janssen P.A.
      Mechanisms of action of loperamide.
      Loperamide also increases anal sphincter tone and improves night-time continence in patients with ileo-anal pouches.
      • Hallgren T.
      • Fasth S.
      • Delbro D.S.
      • et al.
      Loperamide improves anal sphincter function and continence after restorative proctocolectomy.
      Loperamide also modifies the intestinal transport of water and electrolytes by stimulating absorption,
      • Dashwood M.R.
      • Sykes R.M.
      • Thomson C.S.
      Autoradiographic demonstration of [3H] loperamide binding to opioid receptors in rat and human small intestine.
      and by an antisecretory action mediated by calmodulin antagonism, a property not shared by other opioids.
      • Merritt J.E.
      • Brown B.L.
      • Tomlinson S.
      Loperamide and calmodulin.
      • Zavecz J.H.
      • Jackson T.E.
      • Limp G.L.
      • Yellin T.O.
      Relationship between anti-diarrheal activity and binding to calmodulin.
      • Daly J.
      • Harper J.
      Loperamide: novel effects on capacitative calcium influx.
      Paradoxically, loperamide reduces the sodium-dependent uptake of glucose and other nutrients from the small bowel.
      • Klaren P.H.
      • Giesberts A.N.
      • Chapman J.
      • et al.
      Effect of loperamide on Na+/D-glucose cotransporter activity in mouse small intestine.
      The development of tolerance to the GI effects of loperamide has been demonstrated in animal studies.
      • Tan-No K.
      • Niijima F.
      • Nakagawasai O.
      • et al.
      Development of tolerance to the inhibitory effect of loperamide on gastrointestinal transit in mice.
      However, loperamide has been successfully used in patients with chronic diarrhea for several years without evidence of tolerance.
      • Heel R.C.
      • Brogden R.N.
      • Speight T.M.
      • Avery G.S.
      Loperamide: a review of its pharmacological properties and therapeutic efficacy in diarrhoea.
      Loperamide is a substrate for P-glycoprotein, the efflux membrane transporter in the blood-brain barrier, and, although highly lipophilic,
      • Ooms L.A.
      • Degryse A.D.
      • Janssen P.A.
      Mechanisms of action of loperamide.
      loperamide is actively excluded from the CNS.
      • Heykants J.
      • Michiels M.
      • Knaeps A.
      • Brugmans J.
      Loperamide (R 18553), a novel type of antidiarrheal agent. Part 5: The pharmacokinetics of loperamide in rats and man.
      • Sadeque A.J.
      • Wandel C.
      • He H.
      • Shah S.
      • Wood A.J.
      Increased drug delivery to the brain by P-glycoprotein inhibition.
      Consequently, unlike morphine, which has both central and peripheral constipating effects, loperamide generally acts only peripherally
      • Shannon H.
      • Lutz E.
      Comparison of the peripheral and central effects of the opioid agonists loperamide and morphine in the formalin test in rats.
      (but see Drug interactions and Undesirable Effects).
      Loperamide has an effect on peripheral μ-opioid receptors activated by inflammation, and has been investigated as a possible topical analgesic for painful ulcers of the skin or mouth.
      • Nozaki-Taguchi N.
      • Yaksh T.L.
      Characterization of the antihyperalgesic action of a novel peripheral mu-opioid receptor agonist – loperamide.
      • Nozaki-Taguchi N.
      • Shutoh M.
      • Shimoyama N.
      Potential utility of peripherally applied loperamide in oral chronic graft-versus-host disease related pain.
      There are preliminary reports of the successful use of orodispersible tablets, e.g., Imodium® Instants (not USA), 2 mg q2–3 hp.r.n., as an adjuvant analgesic for oral pain arising from mucositis or cancer.
      • Regnard C.
      Personal communication.
      However, the orodispersible tablets are relatively expensive. Theoretically, the oral solution is a possible alternative, but formulations which contain alcohol should not be used as this may exacerbate pain. Oral morphine solution (without alcohol) may be a better option, particularly long term.
      Unlike other drugs used for diarrhea, e.g., diphenoxylate and codeine, loperamide has no analgesic effect in therapeutic and supratherapeutic doses. The lack of CNS effects is one reason why loperamide is a popular first-line choice for the control of diarrhea, including when secondary to surgery, radiotherapy or chemotherapy.
      • Benson 3rd, A.B.
      • Ajani J.A.
      • Catalano R.B.
      • et al.
      Recommended guidelines for the treatment of cancer treatment-induced diarrhea.
      • Maroun J.A.
      • Anthony L.B.
      • Blais N.
      • et al.
      Prevention and management of chemotherapy-induced diarrhea in patients with colorectal cancer: a consensus statement by the Canadian Working Group on Chemotherapy-Induced Diarrhea.
      However, octreotide (see a previous Therapeutic Review)
      • Murphy E.
      • Prommer E.E.
      • Mihalyo M.
      • Wilcock A.
      is recommended first-line for chemotherapy or radiotherapy-induced diarrhea when severe (i.e., an increase of ≥7 stools/24 h over baseline, hospital admission and IV fluids required for >24 h), and second-line for less severe diarrhea which does not respond to loperamide 16–24 mg/24 h.
      • Benson 3rd, A.B.
      • Ajani J.A.
      • Catalano R.B.
      • et al.
      Recommended guidelines for the treatment of cancer treatment-induced diarrhea.
      • Maroun J.A.
      • Anthony L.B.
      • Blais N.
      • et al.
      Prevention and management of chemotherapy-induced diarrhea in patients with colorectal cancer: a consensus statement by the Canadian Working Group on Chemotherapy-Induced Diarrhea.
      • Bhattacharya S.
      • Vijayasekar C.
      • Worlding J.
      • Mathew G.
      Octreotide in chemotherapy induced diarrhoea in colorectal cancer: a review article.
      As an antidiarrheal, loperamide is about 3 times more potent mg for mg than diphenoxylate and 50 times more potent than codeine.
      • Schuermans V.
      • Van Lommel R.
      • Dom J.
      • Brugmans J.
      Loperamide (R18553), a novel type of antidiarrhoeal agent. Part 6: clinical pharmacology. Placebo-controlled comparison of the constipating activity and safety of loperamide, diphenoxylate and codeine in normal volunteers.
      It is longer acting and, if used regularly, generally needs to be given only b.i.d. However, its maximum therapeutic impact may not manifest for 16–24 h; this has implications for initial dosing.
      • Sadeque A.J.
      • Wandel C.
      • He H.
      • Shah S.
      • Wood A.J.
      Increased drug delivery to the brain by P-glycoprotein inhibition.
      The following regimens are approximately equivalent:
      • loperamide 2 mg b.i.d.
      • diphenoxylate 2.5 mg q.i.d. (in combined diphenoxylate and atropine tablets)
      • codeine phosphate 60 mg q.i.d.
      Loperamide is available in a range of formulations. Orodispersible tablets (not USA), which melt on the tongue, are bioequivalent to the capsules and are preferred by some patients. A combination product with simethicone provides more rapid relief of diarrhea and abdominal discomfort from bloating in acute non-specific diarrhea than either loperamide or simethicone alone.
      • Kaplan M.A.
      • Prior M.J.
      • Ash R.R.
      • et al.
      Loperamide-simethicone vs loperamide alone, simethicone alone, and placebo in the treatment of acute diarrhea with gas-related abdominal discomfort. A randomized controlled trial.
      • Hanauer S.B.
      • DuPont H.L.
      • Cooper K.M.
      • Laudadio C.
      Randomized, double-blind, placebo-controlled clinical trial of loperamide plus simethicone versus loperamide alone and simethicone alone in the treatment of acute diarrhea with gas-related abdominal discomfort.
      One suggested explanation is that the surfactant effect of simethicone enhances the contact of loperamide with the gut mucosa. However, both these formulations are only available OTC and are relatively expensive (see Supply).
      Bioavailability: <2%.
      Onset of action: about 1 h; maximum effect 16–24 h.
      • Dreverman J.W.M.
      • van der Poel A.J.
      Loperamide oxide in acute diarrhoea: a double-blind placebo-controlled trial.
      Time to peak plasma concentration: 2.5 h (oral solution); 5 h (capsules).
      • Killinger J.M.
      • Weintraub H.S.
      • Fuller B.L.
      Human pharmacokinetics and comparative bioavailability of loperamide hydrochloride.
      Plasma half-life: 11 h.
      • Killinger J.M.
      • Weintraub H.S.
      • Fuller B.L.
      Human pharmacokinetics and comparative bioavailability of loperamide hydrochloride.
      Duration of action: up to 3 days.
      • Heel R.C.
      • Brogden R.N.
      • Speight T.M.
      • Avery G.S.
      Loperamide: a review of its pharmacological properties and therapeutic efficacy in diarrhoea.

      Cautions

      Severe hepatic impairment could increase plasma concentrations of loperamide and the risk of undesirable effects.
      • Baker D.E.
      Loperamide: a pharmacological review.

      Drug Interactions

      CYP3A4 inhibitors (e.g., erythromycin, fluconazole, ketoconazole, quinidine, ritonavir) can increase plasma concentrations of loperamide.
      • Baker D.E.
      Loperamide: a pharmacological review.
      Inhibitors of P-glycoprotein (e.g., cyclosporin, clarithromycin, erythromycin, intraconazole, ketoconazole, quinidine, ritonavir, verapamil) could potentially allow more loperamide to cross the blood-brain barrier and cause central opioid effects. Although one study in healthy volunteers of quinidine with loperamide found a blunted respiratory response to CO2 (indicating respiratory depression),
      • Sadeque A.J.
      • Wandel C.
      • He H.
      • Shah S.
      • Wood A.J.
      Increased drug delivery to the brain by P-glycoprotein inhibition.
      others have failed to demonstrate significant CNS effects.
      • Vandenbossche J.
      • Huisman M.
      • Xu Y.
      • Sanderson-Bongiovanni D.
      • Soons P.
      Loperamide and P-glycoprotein inhibition: assessment of the clinical relevance.
      However, with typical doses of loperamide, it is unlikely that these interactions are clinically relevant.
      • Vandenbossche J.
      • Huisman M.
      • Xu Y.
      • Sanderson-Bongiovanni D.
      • Soons P.
      Loperamide and P-glycoprotein inhibition: assessment of the clinical relevance.

      Undesirable Effects

      Ileus, fecal impaction, urinary retention. CNS effects can occur in children <2 years who receive excessive doses,
      • Friedli G.
      • Haenggeli C.A.
      Loperamide overdose managed by naloxone.
      • Minton N.
      • Smith P.
      Loperamide toxicity in a child after a single dose.
      or in children after unintentional overdose (e.g., drowsiness).
      • Litovitz T.
      • Clancy C.
      • Korberly B.
      • Temple A.R.
      • Mann K.V.
      Surveillance of loperamide ingestions: an analysis of 216 poison center reports.
      If necessary, use naloxone to reverse these effects.
      A patient on clozapine (an atypical antipsychotic) died of toxic megacolon after taking loperamide during an episode of food poisoning. Additive inhibition of intestinal motility was considered the precipitating cause.
      • Eronen M.
      • Putkonen H.
      • Hallikainen T.
      • Vartiainen H.
      Lethal gastroenteritis associated with clozapine and loperamide.

      Dose and Use

      Ensure that the diarrhea is not secondary to fecal impaction.

      Acute diarrhea

      • start with 4 mg PO stat
      • continue with 2 mg after each loose bowel action for up to 5 days
      • maximum recommended dose 16 mg/24 h.

      Chemotherapy- or radiotherapy-induced diarrhea

      • if mild–moderate, give 4 mg stat and 2 mg after each loose bowel action
      • if not responding to doses of 24 mg/24 h, switch to octreotide
      • if severe, use octreotide first-line.

      Chronic diarrhea

      If symptomatic treatment is appropriate, the same initial approach is used for 2–3 days, after which a prophylactic b.i.d. regimen is instituted based on the needs of the patient during the previous 24 h, plus 2 mg after each loose bowel action. The effective dose varies widely. In palliative care, it is occasionally necessary to increase the dose to as much as 32 mg/24 h; this is twice the recommended maximum daily dose.

      Supply

      Loperamide (generic)
      Tablets 2 mg, 28 days @ 2 mg q.i.d.=$8 OTC.
      Capsules 2 mg, 28 days @ 2 mg q.i.d=$11.
      Oral solution 1 mg/5 mL, 28 days @ 2 mg q.i.d.=$51 OTC.
      Imodium® A-D (Janssen); all OTC
      Caplets (capsule-shaped tablets) 2 mg, 28 days @ 2 mg q.i.d.=$27.
      Tablets chewable 2 mg, 28 days @ 2 mg q.i.d.=$145.
      Oral solution 1 mg/5 mL, 28 days @ 2 mg q.i.d.=$70.
      Combination products with simethicone
      Imodium® Multi-Symptom Relief (McNeil); all OTC
      Caplets (capsule-shaped tablets) loperamide 2 mg, simethicone 125 mg, 28 days @ 1 q.i.d.=$56.
      Tablets chewable loperamide 2 mg, simethicone 125 mg, 28 days @ 1 q.i.d.=$162.

      References

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        • Lutz E.
        Comparison of the peripheral and central effects of the opioid agonists loperamide and morphine in the formalin test in rats.
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        • Helsen L.
        • Michiels M.
        • Heykants J.J.
        Distribution of loperamide in the intestinal wall.
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        • Janssen P.A.
        Mechanisms of action of loperamide.
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        • et al.
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        • Sykes R.M.
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        Loperamide and calmodulin.
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        • Harper J.
        Loperamide: novel effects on capacitative calcium influx.
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        Arzneimittelforschung. 1974; 24: 1649-1653
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        Increased drug delivery to the brain by P-glycoprotein inhibition.
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        Characterization of the antihyperalgesic action of a novel peripheral mu-opioid receptor agonist – loperamide.
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        • Shimoyama N.
        Potential utility of peripherally applied loperamide in oral chronic graft-versus-host disease related pain.
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        Personal communication.
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        Octreotide in chemotherapy induced diarrhoea in colorectal cancer: a review article.
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        Arzneimittelforschung. 1974; 24: 1653-1657
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        • Prior M.J.
        • Ash R.R.
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        Loperamide-simethicone vs loperamide alone, simethicone alone, and placebo in the treatment of acute diarrhea with gas-related abdominal discomfort. A randomized controlled trial.
        Arch Fam Med. 1999; 8: 243-248
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        Randomized, double-blind, placebo-controlled clinical trial of loperamide plus simethicone versus loperamide alone and simethicone alone in the treatment of acute diarrhea with gas-related abdominal discomfort.
        Curr Med Res Opin. 2007; 23: 1033-1043
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        Loperamide oxide in acute diarrhoea: a double-blind placebo-controlled trial.
        Aliment Pharmacol Ther. 1995; 9: 441-446
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        • Weintraub H.S.
        • Fuller B.L.
        Human pharmacokinetics and comparative bioavailability of loperamide hydrochloride.
        J Clin Pharmacol. 1979; 19: 211-218
        • Baker D.E.
        Loperamide: a pharmacological review.
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        • Huisman M.
        • Xu Y.
        • Sanderson-Bongiovanni D.
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        Loperamide and P-glycoprotein inhibition: assessment of the clinical relevance.
        J Pharm Pharmacol. 2010; 62: 401-412
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        • Haenggeli C.A.
        Loperamide overdose managed by naloxone.
        Lancet. 1980; 1: 1413
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        • Smith P.
        Loperamide toxicity in a child after a single dose.
        Br Med J (Clin Res Ed). 1987; 294: 1383
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