Periodic shortages and eventual discontinuation of the production of IC in 2014 have prompted the use of several compounds to serve this purpose. One of the most common is the use of methylene blue (MB). However, as the previously mentioned short comment points out, MB is a strong inhibitor of monoamine oxidase (MOA) and, by this action, is capable of causing life-threatening drug-drug interactions. MB was approved as an intravenous treatment for patients with acquired methemoglobinemia in 2016. A “black Box” warning was issued in 2016 after reports of serious central nervous system reactions in patients taking serotonergic psychiatric medications that interact with peripheral and central postsynaptic serotonin receptors, 5-HT1A and 5-HT2A. MB, as a MOA inhibitor, prevents breakdown of monoamine neurotransmitters, thereby increasing their concentration and duration of action at synaptic terminals in the brain and periphery. The dosage quoted in the literature as able to elicit a clinically relevant MOA inhibition is less than 1mg/kg, a dose range that may be administered during cystoscopy to evaluate the ureters. This property of MB, when combined with other medications with serotonin reuptake inhibiting properties, creates a risk for serotonin syndrome (SS), the symptoms of which range from mild to life threatening. The classical triad of SS is altered mental status, autonomic hyperactivity, and neuromuscular abnormalities. Other signs can include febrile tachycardia, tremor, diarrhea in mild cases, to delirium, neuromuscular rigidity, and hyperthermia in life threatening cases. The Urogynecology article contains a table of common drugs associated with SS when used in combination with MOA inhibitor. These include:
- Selective serotonin reuptake inhibitors, such as sertraline, fluoxetine, paroxetine, citalopram, and escitalopram
- Serotonin- norepinephrine reuptake inhibitors, such as duloxetine, venlafaxine, desvenlafaxine, and milnacipran
- Other antidepressants, such as buspirone and imipramine
- Analgesics, including fentanyl, tramadol and meperidine
- Antiemetics, including ondansetron and metoclopramide
- Analgesics including fentanyl, tramadol and meperidine
- The migraine treatment Sumatriptan.
- Sodium fluorescein intravenously, a widely available and low-cost substance that shows bright yellow within 3- 13 minutes after injection. This may cause temporary yellow discoloration of the urine and is associated with occasional hypotension or allergic reactions but is considered one of the most reliable substitutes for IC.
- Oral phenazopyridine, 200mg, familiar to surgeons for post bladder procedure pain relief, given one hour preoperatively, produces orange colored urine. However, it can cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase deficiency, so caution is advised in this regard. Visualization may be delayed depending on renal function and absorption.
- Modifying the distension media during cystoscopy by using high viscosity substances that make ureteral efflux easier to detect. Options include 10 to 50% dextrose, mannitol, and normal saline or sterile water. Mannitol seems to provide the best visualization.
Written by: Alan Wein, MD, PhD, FACS, Professor of Clinical Urology, Department of Urology, Desai Sethi Urology Institute (DSUI), University of Miami Miller School of Medicine, University of Miami Health Systems, Miami, FL
References:
- Brown, O et al, Methylene Blue and Serotonin Syndrome: A Caution Against Intravenous Use. Urogynecology, 2026; 32: 90-93
- Boytim, M et al, Comparison of Methods for Ureteral Patency Visualization. Reviews in Urology, 2024; 23: e67-74