Many, many drugs can be abused. Some of those drugs are available over the counter. The purpose of this post is to review the abuse of loperamide (Imodium), an over-the-counter, μ-opioid receptor agonist used as an antidiarrheal agent. Loperamide taken in supratherapeutic doses can lead to feelings of euphoria and/or to avoid symptoms of opioid withdrawal. Aside from depression of mental status and respiration, loperamide can lead to and things like torsades de pointes, cardiac arrest, and death.

How is loperamide normally used?

Technically it is not recommended for acute diarrheal illnesses. The typical oral dosing is as follows:

2 to 5 years / 13 to <21 kg: Initial: 1 mg with first loose stool followed by 1 mg/dose after each subsequent loose stool; maximum daily dose: 3 mg/day
6 to 8 years / 21 to 27 kg: Initial: 2 mg with first loose stool followed by 1 mg/dose after each subsequent loose stool; maximum daily dose: 4 mg/day
9 to 11 years – 27 to 43 kg: Initial: 2 mg with first loose stool followed by 1 mg/dose after each subsequent loose stool; maximum daily dose: 6 mg/day
≥12 years : Initial: 4 mg with first loose stool followed by 2 mg/dose after each subsequent loose stool; maximum daily dose: 8 mg/day

Loperamide is a phenylpiperidine opioid derivative – like haloperidol. It works predominantly by binding to opioid receptors in the mesenteric nerves of the gut, inhibiting acetylcholine and prostaglandin release and slowing peristalsis. It may also antagonize calcium channels, which may also reduces gastrointestinal motility.

How is loperamide being abused?

This is where the biochemistry comes in – so bear with me… Patients have figured out that if they take A LOT of loperamide they can get high. We are talking up to 400mg a day – recall that the usual starting dose is 2mg. Case reports of loperamide induced fatalities show blood levels hundreds of times above normal. Following a normal dose the majority of the drug is protein bound – approximately 95% – with a half-life of about 11 hours. The cytochrome p450 system metabolizes it first and it is excreted in the stool. Because the oral bioavailability is low very little of its metabolites ever cross the blood-brain barrier. There is an additional efflux system that pumps metabolites out of the brain called the P-glycoprotein (P-gp) efflux transporter. Per Miller et al in 2017 “although loperamide predominantly acts peripherally, taking sufficiently high doses or taking concomitant medications [more on that in a minute] that inhibit P-gp, CYP3A4, or CYP2C8 can result in toxic serum levels and central nervous system effects.” These massive doses overwhelm the first-pass metabolism of cytochrome p450 leading to increased serum concentrations and metabolites getting across the blood Brian barrier. And again, because loperamide acts on the μ-opioid receptor you get high.

Wait, they have figured out you can take it with other drugs?

Yep, of course they have. Drugs or foods that inhibit cytochrome p450 (cimetidine, grapefruit) lead to fewer opioid withdrawal symptoms. Drugs that inhibit the P-gp efflux transporter (the thing that keeps it out of the brain) increase CNS concentrations. Examples include corticosteroids, quinidine, methadone, ketoconazole, protease inhibitors, antineoplastic drugs, and verapamil. I have learned that some local drug stores/grocery stores have been “sold out” of loperamide and fluticasone (Flonase). Folks are taking the loperamide in massive doses, and drinking the Flonase. You can’t make this stuff up.

What are the adverse effects of loperamide abuse?

Common adverse effects of therapeutic doses are nausea, constipation, drowsiness, and headache. In overdoses (with or without another substance) you can see miosis, central nervous system depression, and respiratory depression. Via blocking calcium and potassium channels loperamide can also cause cardiac arrhythmias, including QTc prolongation and even tornadoes de pointes.

Why are you telling us this? Don’t we have enough going on?

It is unlikely that you will see a patient abusing loperamide. However, it is also not a recommended medicine for diarrhea. So, if someone is being pushy and asking for it – or wants a prescription for their child then you should be suspicious. If you do have an overdose naloxone will work, as will the usual principles for supportive care in opioid toxicity.