DRUG ABUSE AND DEPENDENCE SECTION

DRUG ABUSE AND DEPENDENCE

Controlled Substance

Loperamide is not a controlled substance.

Abuse

Loperamide is a mu-opioid agonist. A human abuse potential study of loperamide hydrochloride at single doses up to 60 mg (3.75 times the recommended maximum adult dosage of 16 mg per day) was compared, in a double-blind cross-over design using nine subjects who had been active opiate users, to a threshold dose of codeine sulfate at 120 mg (96 mg base) or placebo. This resulted in one subject (11%) feeling a drug on placebo and identifying it as "dope" (heroin) and liking it slightly. Codeine was felt by 56% of subjects and identified as "dope" by 44%. Loperamide was felt by 44% of subjects and identified as "dope" by 11% and possibly dope mixed with some other kind of drug by another 22%. Loperamide abuse and misuse have been reported, especially at doses of 60 mg or greater. Loperamide can have greater CNS opioid effects at higher doses or with co-administration of drugs that increase systemic exposure and/or increase CNS penetration of loperamide (through inhibition of the CYP450 enzyme system or inhibition of P-glycoprotein). Loperamide is primarily being misused for relief from opioid withdrawal, and abused by a few users who obtain some (reportedly mild- moderate) level of euphoria.

Dependence

In animals, parenteral administration of loperamide hydrochloride can cause physical dependence, cross-tolerance to opioids, and all the other pharmacologic effects typical of mu-opioid agonists.

Studies in morphine-dependent monkeys demonstrated that loperamide hydrochloride at doses above those recommended for humans prevented signs of morphine withdrawal.

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OVERDOSAGE SECTION

OVERDOSAGE

The use of higher than recommended loperamide hydrochloride doses may result in life-threatening cardiac, CNS and respiratory adverse reactions.

If over-exposure occurs, call your Poison Control Center at 1-800-222-1222 for current information on the management of poisoning or overdosage.

Cardiac Effects

Symptoms

Cases of overdosage with loperamide hydrochloride (chronic ingestion of doses ranging from 70 mg to 1,600 mg daily; 4 times to 100 times the recommended dose) have resulted in life-threatening cardiac adverse reactions, including QT/QTc and QRS interval prolongation, Torsades de Pointes, Brugada syndrome and other ventricular arrhythmias, syncope, cardiac arrest, and death. Cases include patients who were abusing (using supratherapeutic doses in place of opioids to induce euphoria) or misusing (taking higher than recommended doses to control diarrhea or to prevent opioid withdrawal) loperamide. The following are representative cases that included cardiac adverse reactions:

• 25-year old abused loperamide and presented to the hospital on multiple occasions with symptoms of syncope, nausea, vomiting, bradycardia, hypotensive shock. The patient also experienced ventricular tachycardia, a prolonged QTc of 527 ms and QRS interval of 170 ms, frequent premature ventricular contractions, and subsequent cardiac arrest and death (elevated loperamide blood concentration of 32 ng/ml).
• 54-year old misused loperamide hydrochloride (up to 144 mg per day) as a self-treatment for chronic diarrhea for over 2 years. Signs of cardiac toxicity included syncope, prolonged QT of 500 ms sinus arrest with junctional escape rhythm, and polymorphic ventricular tachycardia, which required cardioversion and implantable cardioverter-defibrillator (ICD) management.
• 26-year old, with prior opioid abuse, presented to the hospital with recurrent syncope and developed Torsades de Pointes requiring electrical cardioversion. An ECG revealed a sinus rhythm with a heart rate of 85 bpm and a markedly prolonged QTc interval of greater than 700 ms. The patient reported ingesting 100 mg to 250 mg of loperamide hydrochloride with 400 mg of cimetidine daily for several months to simulate the euphoric sensation associated with opioids.

Management

Consider loperamide as a possible cause of cardiac arrhythmias in patients who may have a history of opioid abuse or recent ingestion of unknown drugs and in the differential diagnosis of unstable arrhythmias, prolonged QTc or QRS intervals, and Torsades de Pointes.

If loperamide-induced cardiac toxicity is suspected, promptly discontinue the drug and initiate therapy to manage and prevent cardiac arrhythmias and serious outcomes.

In many cases of loperamide overdosage, anti-arrhythmic medications (e.g., magnesium sulfate) were ineffective in resolving the arrhythmias and preventing further episodes of Torsades de Pointes. Electrical cardioversion and overdrive pacing, and isoproterenol continuous infusion were reported to manage QTc prolongation in the setting of overdose.

Laboratory Testing

Loperamide serum concentrations are not widely available or clinically useful to guide patient management.

CNS and Respiratory Depression

Symptoms

Cases of loperamide overdose (including relative overdose due to hepatic dysfunction), may cause opioid toxic effects including CNS depression (e.g. altered mental status, stupor, coordination disorders, somnolence, miosis, muscular hypertonia, respiratory depression), hypotension, urinary retention, and paralytic ileus. Pediatric patients may be more sensitive to CNS effects, including respiratory depression, than adults.

Management

Loperamide non-cardiac arrhythmia overdosages should be treated as opioid overdosages. Naloxone may reverse the opioid-related toxicity, including CNS and respiratory depression, and hypotension, associated with loperamide overdosage.

In adults and pediatric patients, naloxone may be administered intravenously. Appropriate doses of naloxone, via intranasal, intramuscular, intraosseus, or subcutaneous administration may be necessary if the intravenous route is not available. If the desired degree of opioid-related toxicity counteraction and improvement are not obtained, naloxone may be repeated at two- to three-minute intervals. If no response in opioid-related effects is observed after naloxone has been administered, then diagnosis of opioid-induced toxicity should be questioned.

Refer to the naloxone prescribing information for complete information on initial and subsequent dosages.

For patients whose adverse reactions are responsive to naloxone, monitor vital signs, neurologic and cardiopulmonary status for recurrence of opioid overdose symptoms for at least 24 hours after the last dose of naloxone, due to the prolonged intestinal retention of loperamide and the short duration (one to three hours) of naloxone. Patients with severe CNS or respiratory depression, and those who require multiple doses of naloxone to reverse symptoms, should be admitted to the hospital and may require intensive care.

Laboratory Testing

Standard drug screens for opioids do not include an assay for loperamide; such testing for opioids will yield negative results even in the presence of loperamide.

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