Why do individuals with opioid use disorder use antidiarrheal medications, such as loperamide (Lopid), for non-diarrheal purposes?

From the Guidelines

Antidiarrheals, particularly loperamide, are used by opioid addicts to produce opioid-like effects at high doses, which can lead to serious health complications, including cardiac issues and respiratory depression. The primary reason for this misuse is that loperamide is an opioid receptor agonist that can enter the brain at extremely high doses, producing euphoria or preventing withdrawal symptoms 1. Some key points to consider are:

• Loperamide normally doesn't cross the blood-brain barrier at therapeutic doses (2-4 mg), but high doses (50-200 mg) can cause it to enter the brain and produce opioid-like effects.
• Combining loperamide with other substances like quinine or grapefruit juice can enhance central nervous system penetration, increasing the risk of serious health complications.
• The FDA has issued warnings about this misuse and has limited package sizes of over-the-counter loperamide products to reduce the risk of abuse.
• Healthcare providers should be aware of this form of misuse when treating patients with opioid use disorder, and consider evidence-based treatments such as medication-assisted treatment with buprenorphine or methadone in combination with behavioral therapies 1. It's essential to prioritize the patient's safety and well-being, and to address the underlying opioid use disorder with appropriate treatment, rather than just managing the symptoms with antidiarrheals.

From the FDA Drug Label

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. 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.

Antidiarrheals like loperamide are used by opioid addicts because they can produce mild-moderate euphoria at high doses, and are also used for relief from opioid withdrawal symptoms 2, 2.

• Key reasons for misuse include:
  • Euphoric effects: Loperamide can cause CNS opioid effects at higher doses.
  • Relief from withdrawal: Loperamide can prevent signs of morphine withdrawal in some cases.

From the Research

Antidiarrheal Use in Opioid Addicts

• Opioid use disorder (OUD) is a chronic condition characterized by loss of control of opioid use, compulsive use, and continued use despite harms 3.
• Individuals with OUD may seek alternative substances to manage their opioid withdrawal symptoms or to achieve a euphoric effect.
• Antidiarrheal drugs, such as loperamide, are sometimes misused by individuals with OUD due to their opioid-like effects 4.
• Loperamide is a peripheral opioid mu-receptor agonist that can cause dependence and overdose when taken in high doses 4.
• The misuse of loperamide has been reported to be increasing, with cases of dependence, overdose, and mortality 4.

Mechanism of Antidiarrheal Drugs

• Antidiarrheal drugs, including opiate antidiarrheal drugs, work by slowing motility and allowing more time for absorption in the gut 5.
• Opiate antidiarrheal drugs are effective for a wide variety of diarrheal conditions and can be used safely if monitored closely 5.
• However, these drugs can be addictive and may be misused by individuals with OUD 5, 4.

Treatment Considerations

• Treatment for OUD typically involves medication-assisted therapy, such as methadone, buprenorphine, or naltrexone 3, 6, 7.
• Antidiarrheal drugs, including loperamide, are not a recommended treatment for OUD and can be harmful if misused 4.
• Healthcare providers should be aware of the potential for antidiarrheal drug misuse and monitor patients with OUD closely for signs of misuse or dependence 4.