DESCRIPTION

Diphenoxylate is an oral antidiarrheal agent possessing opioid-like effects.

FORMS AND USES

• Substances include diphenoxylate, diphenoxylate hydrochloride, diphenoxylate with atropine (Lomotil), difenoxin (a metabolite of diphenoxylate) with atropine (Motofen), Diphenatrol, Lofene, Logen, Lomanate, Lonox, Lo-trol, Low-Ouel, and Nor-Mil.
• Diphenoxylate is used for treatment of diarrhea.
• A Lomotil tablet contains 2.5 mg diphenoxylate and 0.025 mg atropine.
• The adult dose is 5 mg diphenoxylate four times daily.
• Phenoxylate is not indicated for children less than 2 years of age.
• The dosage for older children is 0.3 to 0.4 mg/kg/day in four divided doses, not to exceed 6 mg daily in 2- to 5-year-olds, 8 mg in 5- to 8-year-olds, and 10 mg in 8- to 12-year-olds.

TOXIC DOSE

• As little as 15 mg has produced coma and respiratory depression in a child.
• The minimum lethal dose is unknown.

PATHOPHYSIOLOGY

• Diphenoxylate is structurally related to meperidine and produces opioid effects at high doses.
• Atropine produces anticholinergic effects that may delay absorption.
• Onset of symptoms following overdose may be delayed 6 to 8 hours or longer.
• Prolonged or cyclic effects may occur for 12 to 24 hours.

EPIDEMIOLOGY

• Poisoning is uncommon.
• Toxic effects are usually mild to moderate.
• Death is a rare event occurring in patients without adequate airway management.

CAUSES

• Poisoning usually results from accidental childhood exposure.
• Poisoning may result from substance abuse.
• The possibility of child neglect or abuse should be considered in patients under 1 year of age; suicide attempt should be considered in patients over 6 years of age.

RISK FACTORS

• In pediatric patients, there is greater susceptibility to CNS and respiratory depressant effects.
• In geriatric patients, underlying cardiac and respiratory disease may complicate management.

DRUG AND DISEASE INTERACTIONS

Diphenoxylate may have additive effects with other CNS and respiratory depressants.

PREGNANCY AND LACTATION

US FDA Pregnancy Category C. The drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• RISK FACTORS
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

• Other toxic causes of CNS depression or anticholinergic syndrome include opioids, clonidine, ethanol, sedative-hypnotics, scopolamine, diphenhydramine, cyclic antidepressants, benztropine, anticholinergic plants, and many others.
• Nontoxic causes include CNS infection or bleed, sepsis, and electrolyte abnormalities, among many others.

SIGNS AND SYMPTOMS

• Primary effects in overdose are CNS and respiratory depression.
• With large doses, anticholinergic effects may be the initial manifestation, followed by CNS depression.

Vital Signs

• Respiratory depression with bradypnea and apnea may occur.
• Transient tachycardia and mild hypertension and hyperthermia may be seen initially due to anticholinergic effect.

HEENT

Miosis is common.

Dermatologic

Flushing of the skin from anticholinergic effects may occur.

Cardiovascular

Tachycardia is a common effect.

Pulmonary

Respiratory depression with apnea may occur.

Gastrointestinal

Depressed or absent bowel sounds and constipation may develop.

Renal

Urinary retention may occur.

Neurologic/Psychiatric

• Ataxia (especially in children), drowsiness, lethargy, stupor, and coma occur; these may be delayed 6 to 8 hours or longer.
• Seizures may occur secondary to hypoxia or anticholinergic toxicity.
• Hallucinations and agitation may develop.

PROCEDURES AND LABORATORY TESTS

Essential Tests

No tests may be needed for asymptomatic patients.

Recommended Tests

• Oxygenation should be monitored by pulse oximetry in symptomatic patients to detect hypoxia.
• ECG should be performed and serum electrolytes, acetaminophen, and aspirin levels should be measured in an overdose setting to detect occult ingestion.
• Head CT, lumbar puncture, and cultures should be performed as needed to evaluate altered mental status.

Not Recommended Tests

Serum levels are not clinically useful.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • HEENT
  • Dermatologic
  • Cardiovascular
  • Pulmonary
  • Gastrointestinal
  • Renal
  • Neurologic/Psychiatric
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests
  • Not Recommended Tests

• Treatment should focus on naloxone administration to reverse opioid effects and respiratory and cardiovascular supportive care as needed.
• Dose and time of exposure should be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care provider should call the poison control center when:

• Ingestion occurs in a child.
• Respiratory depression, seizure, or other severe effects occur.
• Toxic effects are not consistent with di-phenoxylate toxicity.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

The patient should be referred to a health-care facility when:

• Ingestion occurs in a child.
• Attempted suicide or homicide is possible.
• Patient or caregiver seems unreliable.
• Any toxic effects are present.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

Admission Considerations

Inpatient treatment in an intensive care setting is warranted when:

• The patient develops hypotension, respiratory depression, seizures, or altered mental status.
• The patient is 6 years of age or younger.

DECONTAMINATION

Out of Hospital

Ipecac-induced emesis is not recommended.

In Hospital

• Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult patients (tube size 36-42 French) presenting within 1 hour of a large ingestion or if serious effects are present.
• One dose of activated charcoal (1-2 g/kg) should be administered without a cathartic if a substantial ingestion has occurred within the previous few hours.

ANTIDOTES

Naloxone

• Indication. Respiratory depression from known opioid overdose.
• Contraindication. Documented naloxone allergy.
• Method of administration
  • The patient should be given 2.0 mg by intravenous push and the response observed.
  • If there is no response, the dose should be repeated in 2.0-mg increments up to a total dose of 10.0 mg.
  • If a reversal of response occurs, the patient should be observed for 24 hours after the final dose.
  • Patients with persistent or recurrent effects may be treated with a constant infusion of naloxone.
• Physostigmine
  • Physostigmine is a cholinergic agonist that can be used in the treatment of a life-threatening anticholinergic syndrome.
  • It is rarely required and should be considered only in patients unresponsive to supportive therapy.
  • See SECTION III, Physostigmine chapter, for details of administration.

ADJUNCTIVE TREATMENT

Seizures

• Patent airway should be ensured.
• A benzodiazepine should be administered for initial control.
• If seizures persist or recur, another anticonvulsant such as phenobarbital should be added.

Hypotension

• The patient should be given 10 to 20 ml/kg 0.9% saline intravenously and placed in the Trendelenburg position.
• Further fluid therapy should be guided by central pressure monitoring to avoid volume overload.
• A vasopressor should be added if needed.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
  • Naloxone
• ADJUNCTIVE TREATMENT
  • Seizures
  • Hypotension

PATIENT MONITORING

• Continuous respiratory and cardiovascular monitoring should be performed.
• Children 6 years of age or younger should be observed for 24 hours because toxicity may be delayed.

EXPECTED COURSE AND PROGNOSIS

• Following small doses, the onset of opioid effects is delayed, and anticholinergic effects may not develop.
• Following larger doses, anticholinergic effects predominate initially, followed by opioid effects.
• Patients generally recover completely over 24 hours unless sequelae of hypoxia intercede.

DISCHARGE CRITERIA AND INSTRUCTIONS

• From the emergency department. Asymptomatic adults may be discharged following 6 hours of observation, gastrointestinal decontamination, and psychiatric evaluation, as indicated. Patients who have a transient recovery in the emergency department may be discharged too soon.
• From the hospital. Patients may be discharged when CNS and respiratory effects have resolved for 8 to 12 hours or following 24 hours for pediatric patients undergoing observation.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA AND INSTRUCTIONS

• Early asymptomatic period does not preclude the possibility of toxic ingestion, especially in children.
• The effects of phenoxylate may be confused with those of other opioid or anticholinergic medications.
• The clinician may fail to appreciate that small doses in children are sufficient to produce significant toxicity and that the onset of symptoms may be delayed.

Poisoning by agents primarily affecting the gastrointestinal system: antidiarrheal drugs.

See Also: SECTION II, Hypotension and Seizure (Unexplained) chapters; SECTION III, Naloxone and Nalmephene, and Physostigmine chapters; SECTION IV, Anticholinergic Compounds and Narcotics chapters.

RECOMMENDED READING

Cutler EA, Barrett GA, Craven PW, et al. Delayed cardiopulmonary arrest after Lomotil ingestion. Pediatr 1980;65:157-158.

McCarron MA, Challoner KR, Thompson GA. Diphenoxylate-atropine (Lomotil) overdose in children: an update (report of eight cases and review of the literature). Pediatr 1991;87:694-700.

Moore RA, Rumack BH, Conner CS, et al. Naloxone underdosage after narcotic poisoning. Am J Dis Child 1980;134:156-158.

Author: Steven A. Seifert

Reviewer: Katherine M. Hurlbut