Introduction
Diphenoxylate is a synthetic opioid medication primarily used in combination with atropine for the management of acute and chronic diarrhea. Marketed under brand names such as Lomotil®, it is classified as a Schedule V controlled substance in the United States due to its potential for abuse at high doses. Despite its opioid structure, diphenoxylate exerts minimal analgesic effects at therapeutic doses when combined with atropine, which serves as an abuse deterrent.
Mechanism of Action
Diphenoxylate is a phenylpiperidine derivative that acts primarily on the μ-opioid receptors in the intestinal wall. It inhibits gastrointestinal motility and propulsion by decreasing circular smooth muscle contractions and increasing segmentation contractions. This action results in delayed intestinal transit time, allowing for increased fluid absorption and reduced fecal volume. The addition of atropine sulfate (0.025 mg per 2.5 mg diphenoxylate) serves as an abuse deterrent by producing unpleasant anticholinergic effects at supratherapeutic doses.
Indications
- Management of acute and chronic diarrhea
- Adjunctive therapy in diarrhea-predominant irritable bowel syndrome (off-label)
- Reduction of ileostomy output (off-label)
Dosage and Administration
Adults: Initial dose of 5 mg (2 tablets) four times daily, with maintenance dosage adjusted based on response Children:- 2-5 years: 2 mg twice daily (not recommended as first-line therapy)
- 5-8 years: 2 mg three times daily
- 8-12 years: 2 mg four times daily
- Hepatic impairment: Use with caution; consider reduced dosing
- Renal impairment: Contraindicated in advanced renal disease
- Elderly: Initiate at lower doses due to increased sensitivity
Available as oral tablets containing 2.5 mg diphenoxylate hydrochloride and 0.025 mg atropine sulfate.
Pharmacokinetics
Absorption: Well absorbed from the gastrointestinal tract Distribution: Extensive tissue distribution; crosses blood-brain barrier minimally Metabolism: Extensive first-pass metabolism in liver to active metabolite difenoxin Elimination: Primarily hepatic metabolism with renal excretion of metabolites Half-life: 12-14 hours (difenoxin active metabolite) Onset of action: 45-60 minutes Duration of action: 3-4 hoursContraindications
- Hypersensitivity to diphenoxylate, atropine, or any component
- Obstructive jaundice
- Diarrhea associated with enterotoxin-producing bacteria
- Advanced hepatic or renal disease
- Children under 2 years of age
- Acute diarrhea associated with pseudomembranous colitis
Warnings and Precautions
- Risk of dependence: Potential for abuse and psychological dependence
- Toxic megacolon: Avoid use in patients with ulcerative colitis
- Hepatic impairment: Use with extreme caution due to reduced metabolism
- Dehydration: May mask dehydration and electrolyte imbalance
- Respiratory depression: Risk increases with concomitant CNS depressants
- Paralytic ileus: Discontinue immediately if suspected
Drug Interactions
- CNS depressants: Enhanced sedation with alcohol, benzodiazepines, barbiturates
- MAO inhibitors: Risk of hypertensive crisis
- Anticholinergic agents: Additive effects with atropine component
- Opioid agonists: Enhanced opioid effects
- Protease inhibitors: May increase diphenoxylate levels
Adverse Effects
Common (≥1%):- Dizziness
- Drowsiness
- Sedation
- Headache
- Nausea
- Dry mouth
- Abdominal discomfort
- Respiratory depression
- Toxic megacolon
- Paralytic ileus
- Angioedema
- Anaphylaxis
- Severe constipation
- Hyperthermia (from atropine component)
Monitoring Parameters
- Bowel sounds and abdominal examination
- Hydration status and electrolyte balance
- Signs of excessive sedation or CNS depression
- Respiratory rate, especially in elderly or debilitated patients
- Liver function tests in patients with hepatic impairment
- Signs of anticholinergic toxicity (dry skin, flushing, hyperthermia)
- Assessment for dependence or misuse behaviors
Patient Education
- Take exactly as prescribed; do not exceed recommended dosage
- Avoid alcohol and other CNS depressants during therapy
- Maintain adequate fluid intake to prevent dehydration
- Report severe constipation, abdominal distension, or persistent diarrhea
- Be aware of potential drowsiness; avoid driving or operating machinery
- Store securely away from children and others
- Do not use for more than 2 days unless directed by healthcare provider
- Seek immediate medical attention for difficulty breathing or severe dizziness
References
1. American Society of Health-System Pharmacists. AHFS Drug Information. Diphenoxylate hydrochloride and atropine sulfate. 2023. 2. Thwaites R, Chamberlain K, Tran D. Management of infectious diarrhea. Gut. 2021;70(3):595-604. 3. FDA prescribing information: Lomotil® (diphenoxylate hydrochloride and atropine sulfate). 2022. 4. Sweetser S. Evaluating the patient with diarrhea: a case-based approach. Mayo Clin Proc. 2012;87(6):596-602. 5. Schiller LR, Pardi DS, Sellin JH. Chronic diarrhea: diagnosis and management. Clin Gastroenterol Hepatol. 2017;15(2):182-193. 6. Lexicomp Online. Diphenoxylate/atropine. Wolters Kluwer Clinical Drug Information. 2023. 7. World Health Organization. Guidelines for the control of diarrhoeal diseases. WHO. 2021.