Toxicity profile of supratherapeutic loperamide: a systematic review and dose-response analysis.

Introduction Life-threatening cardiotoxicity resulting from supratherapeutic loperamide exposure (i.e., >16 mg per day) has been increasingly reported in recent years. However, systematic data on the toxicity profile and dose-response relationship are lacking.Methods We conducted a systematic review of publications on supratherapeutic loperamide exposure in humans, defined by dose or concentration, and identified through database (Medline/Pubmed, Embase, and Scopus), citation, and conference abstract searches. Cases with missing data on clinical course or outcome, as well as remote or unclear exposures (e.g., inconsistent history or undetectable loperamide concentration) were excluded. The database search strategy employed a combination of search terms encompassing the substance, the context of use and signs of toxicity. The primary outcome was a binary severity endpoint. Secondary outcomes included the five-level Poisoning Severity Score, as well as the maximum QTc and QRS durations. Regression models were used to examine exposure-toxicity relationships, adjusting for demographics, comorbidities, co-ingestions, electrolyte imbalances and bradycardia.Results We included 129 cases (median age 31 years (IQR 26-39), 66% (n = 85) male, 57% (n = 73) with known or suspected substance use disorder) from case reports and case series. The median daily ingested dose was 200 mg (IQR 113-343, n = 112) and the median blood concentration was 87 µg/L (IQR 33-210, n = 39). Most cases (91%, n = 117) were chronic or subacute exposures. Purposeful co-ingestion of substances in order to increase loperamide exposure was reported in 5% cases (n = 6, all cimetidine). Syncope was frequently reported (45%, n = 58). Severe cases (64%, n = 83) were mainly characterized by polymorphic (55%, n = 46) or sustained monomorphic (40%, n = 33) ventricular tachycardias. Typical signs of opioid toxicity were reported in 12% (n = 16) of the cases. Severity was dose-dependent (adjusted OR 1.04, 95% confidence interval (CI) 1.01-1.07, per 10 mg), with severe toxicity occurring at doses as low as 20-40 mg/day and a median severe toxicity dose (TD50) estimated at 85 mg (95% CI 12-230 mg). Fatalities were reported in 13% of the cases (n = 17) and mortality was positively associated with concentration (adjusted OR 1.07, 95% CI 1.01-1.16, per 10 µg/L), with a median lethal concentration (LC50) estimated at 210 µg/L (95% CI 70-436 μg/L). Bradycardia was independently associated with severity (adjusted OR 4.96, 95% CI 1.83-15.45), and QRS prolongation was positively associated with plasma concentration but not dose. Pharmacologic treatments included most commonly magnesium (26%, n = 34), sodium bicarbonate (23%, n = 30) and isoproterenol (20%, n = 26), while non-pharmacologic interventions included cardioversion/defibrillation (20%, n = 26), pacing (15%, n = 19), and mechanical life support (4%, n = 5).Discussion In case reports and case series, supratherapeutic loperamide was associated with dose-dependent cardiotoxicity; classical signs of opioid toxicity, however, were uncommon. There was considerable risk for severe toxicity at lower doses than previously appreciated, suggesting cardiac monitoring might be indicated even at modestly supratherapeutic doses. Bradycardia and loperamide dose were independent risk factors for severe outcomes and mortality was positively associated with concentration. Management included various pharmacologic and non-pharmacologic rhythm control interventions and invasive mechanical life support in a few cases.Conclusion Patients presenting with supratherapeutic loperamide exposure appear to be at high risk for life-threatening dysrhythmias, and close cardiac monitoring should be broadly considered in this population. Management options include appropriate antiarrhythmic and cardiocirculatory support measures.