Drops, Ointments, Gels, and Patches: The Dangers of Topical Medications

Benzocaine is metabolized into oxidizing compounds that lead to methemoglobin formation. Humans normally reduce methemoglobin to hemoglobin through the cytochrome b₅ reductase pathway²⁰; however, when an oxidizing agent overwhelms the reducing system, concentrations of methemoglobin begin to rise. Methemoglobin has a decreased oxygen-carrying capacity, and also has a higher subunit binding affinity that leads to a leftward shift of the oxygen dissociation curve.

Findings of benzocaine toxicity range greatly and depend on the amount of methemoglobin formed. Patients can develop asymptomatic cyanosis with low-methemoglobin concentrations (around 15%). At levels of 30% to 40%, neurological complaints may manifest, including weakness, disturbances in coordination, and headaches. High concentrations of methemoglobin (55% to 70%) can cause altered mental status, unresponsiveness, and seizures. When levels are extremely high (>70%), patients are at risk for life-threatening hemodynamic instability and death.²¹Treatment. For patients with methemoglobinemia, treatment depends upon the serum concentration of methemoglobin. Supportive care, including airway and circulatory management, is critical. If methemoglobin concentrations are low (<15%), close observation can be considered, as healthy individuals can reduce methemoglobin quickly.²⁰ In patients with severe methemoglobinemia (a level above 25%, or clinical findings such as shortness of breath or altered mental status), treatment with methylene blue should be initiated. Methylene blue, an oxidizing agent, initiates a series of events that culminates with the reduction of methemoglobin into hemoglobin.²² Methylene blue is typically dosed 1 to 2 mg/kg^17,21,22; dosing can be repeated to a maximum of 4 mg/kg in infants and 7 mg/kg in children.^20-22 One should use caution when dosing methylene blue: As an oxidizing agent, when given in excess, methylene blue can worsen methemoglobinemia. Furthermore, methylene blue should not be given to patients with glucose-6-phosphate dehydrogenase deficiency, as this combination can cause massive hemolysis.^17,20-22

Though rare, if patients are hemodynamically unstable or have life-threatening methemoglobinemia, hyperbaric oxygen therapy, exchange transfusion, or hemodialysis can be attempted—if these are readily available.^17,20-22

Recognizing methemoglobinemia early is essential, and when a patient receives prompt treatment, mortality from methemoglobinemia secondary to benzocaine overdose is extremely low.

Transdermal Patches

Transdermal drug delivery is a relatively new route of administration—one that has gained increasingly in popularity. Patches are being used more frequently because they are easy to administer, have improved compliance due to decreased dosing frequency, allow concealment, and avoid first-pass metabolism, which increases the concentration of the parent compound.²³

Although patches have several clinical advantages, they can pose a significant threat, particularly to pediatric patients, for several reasons. Patches, which work by delivering medication transdermally through a concentration gradient, are often impregnated with high concentrations of medication. If the patch is heated or damaged, this can significantly increase the amount of medication released onto the skin, leading to an overdose. Patches also normally contain high concentrations of medication even after they are worn for the prescribed time, though retained quantities vary depending on the drug and device.^23,24 One study using fentanyl patches found 28% to 84.4% of the original drug remained in the patch after its clinical use.²⁵ Toxicity from patches normally occurs from transdermal exposure as well as oral exposure/ingestion.

Fentanyl Patch

Fentanyl, a powerful synthetic opioid, has been available via transdermal delivery route since the early 1990s. Use of fentanyl patches has proven to be popular and efficacious in pain management. Unintentional exposure in pediatric patients is especially dangerous because children are often opioid-naive, and even small doses of fentanyl can be toxic.

Several cases of pediatric fentanyl toxicity secondary to transdermal exposure have been described in the literature. Though fewer in number, cases involving toxicity from patch ingestion have also been reported in adult patients²⁶; to the best of our knowledge, no cases have been published on pediatric fentanyl-patch ingestions, though this should be considered when evaluating a patient with an opioid toxidrome.

Fentanyl, a mu-opioid agonist, can lead to significant morbidity and mortality. Findings from fentanyl toxicity are dose-dependent but include miosis, altered mental status, bradypnea, respiratory arrest, coma, and death, if left untreated.

Treatment. Airway protection is essential, and once opioid toxicity is suspected, patients who lack spontaneous respiration should receive immediate noninvasive respiratory support followed by naloxone administration; mechanical ventilation is sometimes required in patients with severe overdose. A thorough physical examination is crucial, and transdermal patches must be immediately identified and removed to prevent further drug absorption.

If a patch is found, the area should be thoroughly cleansed to remove any residual drug from the affected area. Removal of the patch does not result in an immediate reversal of toxicity. Due to the reservoir in the skin, spontaneous reversal may take up to 1 day. Oral ingestion can lead to a fatal outcome, so if ingestion is suspected, providers must examine the oral cavity to ensure that no piece of the patch is present.²⁷Naloxone, a competitive opioid receptor antagonist, is used to reverse opioid overdose. It is typically dosed at 0.001 mg/kg²⁸ and can be increased incrementally up to 0.01 mg/kg, or even higher if findings do not improve. Many patients require sequential doses of naloxone due to its relatively short half-life compared to the prolonged elimination of transdermal or ingested fentanyl.^28,29

Naloxone infusions are commonly needed for these patients, and are typically dosed at about two-thirds of the dose required for initial opioid reversal.²⁸ Given the prolonged duration of possible toxicity, any patient who presents to the ED with signs of opioid overdose from transdermal exposure or oral ingestion of a patch should be admitted to the hospital³⁰ and monitored for 24 hours^28,31 to ensure that symptoms do not rebound, especially once the naloxone drip is weaned. Patients should be monitored for 4 to 6 hours after cessation of a naloxone infusion. Fortunately, timely and adequate management can result in positive clinical outcomes in most of these situations.