What is diphenoxylate?

What is Diphenoxylate?

Diphenoxylate is a peripherally acting opioid derivative that slows intestinal motility by directly affecting circular smooth muscle of the bowel, resulting in prolonged gastrointestinal transit time—it is always combined with atropine (as Lomotil) and is classified as a Schedule V controlled substance. 1, 2

Chemical Structure and Pharmacology

• Diphenoxylate is chemically related to the narcotic analgesic meperidine and works through opioid mechanisms 2
• The drug is rapidly and extensively metabolized by ester hydrolysis to diphenoxylic acid (difenoxine), which is the biologically active major metabolite in the blood 2
• The elimination half-life of diphenoxylic acid is approximately 12 to 14 hours, with peak plasma concentrations occurring around 2 hours after ingestion 2
• Less than 1% of the drug is excreted unchanged in urine, while about 6% is excreted as diphenoxylic acid plus its glucuronide conjugate 2

Mechanism of Action

• Diphenoxylate has a direct effect on circular smooth muscle of the bowel, conceivably resulting in segmentation and prolongation of gastrointestinal transit time 2
• The clinical antidiarrheal action is a consequence of enhanced segmentation that allows increased contact of intraluminal contents with the intestinal mucosa 2
• Diphenoxylate-atropine produces more prolonged effects on intestinal transit than loperamide, which increases the risk of complications in infectious diarrhea 1, 3

Formulation and Controlled Substance Status

• Diphenoxylate is always combined with atropine sulfate in the commercial preparation known as Lomotil 1
• The atropine component is added to discourage abuse, as it causes unpleasant anticholinergic effects at high doses 4
• It is classified as a Schedule V controlled substance because at high doses (100-300 mg/day, equivalent to 40-120 tablets) it can produce opiate withdrawal symptoms and addiction is possible 2
• The insolubility of diphenoxylate in commonly available aqueous media precludes intravenous self-administration 2
• Lomotil requires a prescription, while loperamide is available over-the-counter 1

Clinical Position Relative to Other Antidiarrheals

• The American Gastroenterological Association recommends loperamide as the first-line antimotility agent due to its effectiveness and fewer central nervous system side effects compared to diphenoxylate-atropine 1, 3
• Diphenoxylate is generally less effective than loperamide for acute diarrhea and has more problematic side effects 1, 5
• In comparative studies, diphenoxylate was significantly less effective in producing solid stool and relieving urgency compared to both loperamide and codeine 6
• Side effects, particularly central nervous system effects, were greatest with diphenoxylate and least with loperamide 6

Limited Clinical Scenarios for Use

• Diphenoxylate-atropine may be considered for mild diarrhea (grade 1: <4 additional bowel movements/day) without colitis symptoms, after excluding infection and with negative fecal lactoferrin 3
• The American Gastroenterological Association suggests that diphenoxylate-atropine may be used in loperamide-refractory diarrhea in cancer patients, but only after infectious causes have been excluded 3
• In critically ill patients with acute noninfectious diarrhea, diphenoxylate/atropine is conditionally recommended and was as effective as loperamide and more effective than placebo 7

Critical Safety Warnings and Contraindications

Pediatric Contraindications

• The American Academy of Pediatrics advises against using diphenoxylate-atropine in children under 2 years of age due to the risk of severe respiratory depression, coma, and potential permanent brain damage or death 3, 5
• This is likely due to immature hepatic function and blood-brain barrier in young children 5
• Pediatric overdoses are primarily opioid intoxications, with respiratory depression being the major problem—hypoxia can be associated with cardiac arrest, cerebral edema, and death 8
• Respiratory depression can recur 13 to 24 hours after ingestion, probably due to accumulation of difenoxine, the active metabolite 8

Infectious Diarrhea Contraindications

• The Centers for Disease Control and Prevention recommend avoiding diphenoxylate-atropine in severe dysentery with high fever or bloody stools, as it may worsen outcomes and prolong illness 3, 5
• The Infectious Diseases Society of America suggests that diphenoxylate-atropine should not be used in suspected invasive bacterial infections, as antimotility agents can prolong and worsen diarrhea 3

Special Populations

• Neutropenic patients require careful risk-benefit assessment when considering Lomotil, as overdosage may lead to iatrogenic ileus with increased risk of bacteremia 5

Adverse Effects Profile

• At therapeutic doses for diarrhea, diphenoxylate has not produced addiction and is devoid of morphine-like subjective effects 2
• At high doses it exhibits codeine-like subjective effects, though the dose producing antidiarrheal action is widely separated from the dose causing central nervous system effects 2
• The atropine component can cause significant adverse effects including central nervous system excitement, hypertension, fever, and flushed dry skin 4, 8
• In overdose cases, only 6 of 36 children showed signs of atropine toxicity, while opioid overdose (CNS and respiratory depression with miosis) predominated in 92% of cases 8