The number of people chronically abusing and/or falling victim to fatal overdose due to excessive ingestion of opioids has skyrocketed in the past 15 years.1 The start of this opioid crisis can be traced back to the late 1990’s, and there has been an increasing trend in overdoses as the crisis had taken flight.2 Today, both federal and state governments are taking extreme measures to try and reduce the number of people being prescribed, and subsequently overdosing on prescription opioids.1 Unfortunately, the stricter the regulations on prescription opioids become, the more clever individuals with substance use disorder seem to become as well.
In recent years, a few unlikely drugs have surfaced, and are now being labeled, as part of the opioid crisis. One of these drugs is gabapentin. A drug commonly prescribed for the off-label management of diabetic neuropathy, but holds label and off-label indications for a variety of other diseases too, such as partial onset seizures, post-herpetic neuralgia, social anxiety disorder, alcohol withdrawal, and even hiccups.3 Other medications being abused are loperamide (Imodium) and diphenoxylate + atropine (Lomotil); 2 drugs holding labeled indications for the treatment of diarrhea.
Loperamide made its debut on the market in 1976, after being approved for the prescription use of chronic and acute diarrhea. After subsequent studies, in 1988 it was approved for over-the-counter (OTC) use for diarrhea as well. When compared to morphine, loperamide has been shown to be 40-50 times more potent in producing antidiarrheal and central nervous system (CNS) depressive effects. The difference with loperamide, in contrast to morphine, is it really only produces its depressive effects in the gut due to poor gastrointestinal absorption.1 Additionally, any loperamide that does happen to make it across the blood brain barrier (BBB) is rapidly pumped back out via P-gp efflux pumps.4 Conversely, diphenoxylate is metabolized into difenoxin which is upwards of 250 times more potent than its parent-drug.5 This active metabolite readily crosses the BBB to produce depressive effects on the CNS, which in turn, produces depressive effects on the gut as well. By itself, diphenoxylate is classified as a Schedule II narcotic with high abuse potential. Adding Atropine, an anticholinergic medication that produces its beneficial effects towards diarrhea by basically drying up bodily fluids, to the diphenoxylate formulation is supposed to make the drug much less appealing for abuse. 6
It may not be easily understood how these medications for GI disturbances are being abused for opioid-like highs when 1 is not absorbed well from the GI tract and the other is already a controlled substance. The answer can largely be attributed to two main factors: 1) the way the drug is metabolized, and 2) gaps in care between healthcare professionals.
Both loperamide and diphenoxylate are metabolized in the liver. While diphenoxylate’s route of metabolism does not play a large role in how it is abused, loperamide’s does. Loperamide’s hepatic metabolism, most notably, via CYP enzymes 3A4 and 2C8 helps explain why a drug that should not be well absorbed is being abused recreationally. Many individuals with substance use disorder appear to have a foundational understanding of drug interactions, and utilize this knowledge to increase the amount and duration of time the drug spends in their body. The usual maximum recommended dose of loperamide ranges from 8mg/day (OTC) to 16mg/day (prescription strength).4 An article in the Journal of the American Pharmacists Association looked at trends, and cases of loperamide toxicity/overdose between the years of 1985 to 2016. The authors found that the most common substances used in combination with loperamide were cimetidine, and grapefruit juice, both strong CYP3A4 inhibitors which will delay loperamide’s metabolism and thereby increase serum concentrations. In the cases reviewed, patients who fell victim to loperamide overdose had serum concentrations ranging from 63-140 nanograms/mL. To compare, the normal therapeutic dose of loperamide is no more than 2 nanograms/mL, which can normally be achieved by taking one 2mg capsule.7 The article noted that about 19 patients that were not included in their findings because they were unresponsive upon presentation, but were later reported by the North Carolina Office of the Chief Medical Examiner to have an average loperamide serum level of 240 nanograms/mL.
Perhaps the most concerning statistic found by the authors was the reasoning behind the patients’ loperamide misuse. It was shown that between 1985 and 2013, the most reported reason people overdosed on loperamide was for diarrhea relief. However, from 2014-2016, 'opioid alternative' became the number 1 reported reason for overdose.4
The most common adverse events reported to be seen with loperamide overdose are CNS depression, respiratory depression, and extreme pupil constriction. Severe cardiac arrhythmias including QTc prolongation were also commonly seen.4 Today, loperamide holds a Black Box Warning for reports of Torsades de Pointes and sudden death when used in higher than recommended doses.7 Unlike loperamide, CYP enzyme drug/food interactions are not the biggest concern when looking at why diphenoxylate + atropine is also a commonly abused antidiarrheal medication. While diphenoxylate + atropine is hepatically metabolized, it is broken down by mechanisms that do not involve CYP-enzymes, making the potential for food and drug interactions related to metabolism relatively non-concerning.6 Diphenoxylate is structurally similar to meperidine; because of this, its labeling contains a warning about its potential for abuse and dependence. Additionally in the same section, the labeling explains that at the recommended therapeutic doses diphenoxylate is actually devoid of any opiate-like effects but at high doses, which are separated widely from normal therapeutic doses, opiate like effects can be seen.8
Adverse effects that accompany ingesting high doses of the combination drug include, dehydration and electrolyte imbalances, GI inhibition leading to toxic megacolon or bacterial overgrowth, dizziness/drowsiness, sedation, and atroponism which is characterized by hyperthermia, tachycardia, urinary retention, flushing and dryness of the skin and mucous membranes.8 To overcome or avoid some of the adverse effects that can be caused by the atropine component of the drug combination, patients are advised to take the drug with plenty of water, and electrolyte replenishing beverages ,and avoid becoming overheated by weather and exercise. Additionally, those with substance use disorder may also take the medication with other CNS depressants like alcohol to potentiate the opiate like effects of the diphenoxylate.8 While the subtherapeutic dose (0.025mg) of atropine added to the formulation is supposed to deter the potential for abuse, normal doses of atropine prescribed for indications that include symptomatic sinus bradycardia, and atrioventricular block start around 0.5mg and increase from there. 9 Meaning, individuals can take at least 20 tablets of Lomotil before taking what is considered a therapeutic dose of atropine that may produce unwanted side effects.9 Taking high doses of diphenoxylate + atropine for extended periods of time has also been shown to precipitate opioid-like withdrawal symptoms once stopped. One study administered doses of 100-300mg/day, equating to 40-120 tablets, to humans for 40-70 days. The results when the drug was discontinued was opiate withdrawal symptoms that commonly included anxiety, aching muscles, insomnia, nausea and sweating.8
With the death toll continuing to rise across the globe due to overdosing on antidiarrheal medications, there must be measures taken to try and halt this epidemic. Federal and state governments are continuing to brainstorm ideas about how to keep the abuse of antidiarrheal medications like loperamide and diphenoxylate + atropine to a minimum. The most recent proposal by the FDA has been to work with manufacturers of loperamide to change its packaging, in that each box only contains enough tablets for a few doses. At the moment, loperamide can be bought in packaging sizes as large as 200 tablets.10 While limiting package quantities is probably the most appropriate first step, there is still the problem of abusers simply shopping around at multiple stores for the drug. By doing this, abusers will still be able to obtain large quantities without raising any red flags. If the trend continues, the next potential step will be the need to regulate the over-the-counter sales like that of pseudophedrine. In this way, it can be monitored per Driver’s License, how much of the drug a person is buying.
Until that heavy of regulation becomes a reality, there are many steps we as pharmacists can take to help prevent abuse and overdose on antidiarrheal medications. The first and easiest is to use our common sense. Now that it is apparent the abuse of antidiarrheal medications is on the rise, watching for customers buying absurdly large amounts of loperamide at a time should be incorporated into everyday practice. Some retailers that sell the drug in bulk are already taking matters into their own hands, and restricting the purchase quantity to 1 bottle per customer, and keeping the over flow behind the pharmacy counter.10 For other retailers who have not adopted these practices, simply telling a customer that attempts to buy large quantities of loperamide that they should consult their doctor if they have diarrhea that serious or simply stating that they should need no more than 4 tablets per day to fix the problem are subtle ways to try and prevent its abuse.
Another way to prevent abuse is good communication with physicians. From duplicate medications to inappropriate dosing, it is important for pharmacists and physicians to work collaboratively to prevent these types of medication errors from occurring. As we often see with substance use disorder, patients will go 'doctor shopping' to see who will provide them with their drug of choice with the most ease. Pharmacists and physicians must make sure both dosing and length of therapy are appropriate for the indication, and that the prescription is both valid and within the physician’s scope of practice. By adding these little habits into our everyday practice, we can help to prevent patients within our own community from falling victim to the misuse of anti-diarrheal medications that is becoming so common in today’s society.
This article was co-written by Allison Bachtle, a 2019 PharmD Candidate at Harrison School of Pharmacy, Auburn University.
- QuarterWatch. Discovering a Dangerous New Use for OTC Loperamide. ISMP Medication Safety Alert! Acute Care. 2018 May 17; Vol. 23(10): 3-4. Horsham, PA. https://www.ismp.org/sites/default/files/attachments/2018-05/20180517.pdf. Accessed July 10, 2018.
- Caitlin Esch. How One Sentence Helped Set Off the Opioid Crisis [Internet]. Los Angeles, California: Marketplace Productions; 2017 Dec 13 [cited 2018 May 22]. https://www.marketplace.org/2017/12/13/health-care/uncertain-hour/opioid. Accessed July 10, 2018.
- Gabapentin. In: Lexi‐Drugs, Lexi‐Comp Online [AUHSOP Intranet]. Hudson, OH: Lexi‐Comp/Wolters Kluwer Health. [updated 2018 June 8; cited 2018 June 8]. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/6961#f_uses. Accessed July 10, 2018.
- Miller, H., Panahi, L., Tapia, D., Tran, A., Bowman, J. Loperamide Misuse and Abuse. JAPHA [Internet]. 2016 Dec 26 [cited 2018 May 22]; Vol 57(2017): S45-S50. https://www.japha.org/article/S1544-3191(16)31028-7/pdf. Accessed July 10, 2018.
- Journey Healing Centers [Internet]. Cottonwood Heights, Utah: Journey Centers; 2018 [2018 June 2]; [about 1 page]. https://www.journeycenters.com/news/the-scary-truth-about-lomotil-abuse/. Accessed July 10, 2018.
- Escobar A. Lomotil Addiction [Internet]. Drug Addiction Treatment; 2013 June 13 [cited 2018 May 28]. https://www.drugaddictiontreatment.com/types-of-addiction/prescription-drug-addiction/lomotil-addiction/. Accessed July 10, 2018.
- U.S. Food and Drug Administration [Internet]. Silver Spring, Maryland: FDA; last updated 2018 May 22 [cited 2018 May 22]; [Imodium Capsules Monograph]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/017690s005lbl.pdf. Accessed July 10, 2018.
- DailyMed Label: Lomotil [Internet]. Bethesda, Maryland: U.S. National Library of Medicine; 1993 Jan 3 [last updated 2018 Apr 5; cited 2018 May 30]. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f170584a-1072-4fd7-b1dc-6756703483b9. Accessed July 10, 2018.
- Atropine. In: Lexi‐Drugs, Lexi‐Comp Online [AUHSOP Intranet]. Hudson, OH: Lexi‐Comp/Wolters Kluwer Health. [updated 2018 June 1; cited 2018 June 8]. http://online.lexi.com/lco/action/doc/retrieve/docid/patch_f/5699355#f_preparations. Accessed July 10, 2018.
- Gottlieb S. Emerging issues of misuse and abuse of OTC loperamide challenge FDA to address a new turn in the opioid addiction crisis, while maintaining access for patients [Internet]. Silver Spring, Maryland: U.S. Food and Drug Administration; 2018 May 9 [cited on 2018 June 11]. https://blogs.fda.gov/fdavoice/index.php/2018/05/emerging-issues-of-misuse-and-abuse-of-otc-loperamide-challenge-fda-to-address-a-new-turn-in-the-opioid-addiction-crisis-while-maintaining-access-for-patients/. Accessed July 10, 2018.
Marilyn Bulloch, PharmD, BCPS, FCCM
Marilyn Novell Bulloch, PharmD BCPS, is an Associate Clinical Professor of Pharmacy Practice at the Auburn University School of Pharmacy and an Adjunct Associate Professor at the University of Alabama-Birmingham School of Medicine and the University of Alabama College of Community Health Sciences . She completed a post-graduate pharmacy practice residency at the University of Alabama-Birmingham Hospital and a post-graduate specialty residency in critical care pharmacy at Charleston Area Medical Center in Charleston, West Virginia. Dr. Bulloch also completed a Faculty Scholars Program in geriatrics through the University of Alabama-Birmingham Geriatric Education Center in 2011. She serves on multiple committees and in leadership positions for many local, state, and national pharmacy and interdisciplinary medical organizations.