A Comprehensive Pharmacological and Clinical Monograph on Benzocaine (Ethyl 4-aminobenzoate)

Executive Summary

Benzocaine, identified chemically as ethyl 4-aminobenzoate, is a widely accessible ester-type local anesthetic predominantly available in over-the-counter (OTC) formulations.[1] Its primary clinical function is to provide temporary, topical relief from pain and pruritus associated with a broad spectrum of minor medical conditions, ranging from sunburn and insect bites to sore throats and dental irritation.[2] The ubiquity of benzocaine in consumer health products stems from its efficacy in producing rapid, localized anesthesia.

The core mechanism of action for benzocaine involves the reversible blockade of voltage-gated sodium channels (VGSCs) within the neuronal membrane. By inhibiting the influx of sodium ions that is necessary for nerve cell depolarization, benzocaine effectively prevents the generation and propagation of action potentials, thereby interrupting the transmission of pain signals from the periphery to the central nervous system.[1] This targeted action allows it to numb nerve endings in the skin and mucous membranes upon topical application.

This monograph provides a comprehensive examination of benzocaine, framed by the critical dichotomy between its broad therapeutic utility for minor ailments and its significant, albeit rare, potential to induce life-threatening methemoglobinemia.[4] This adverse event, characterized by the oxidation of hemoglobin and a subsequent reduction in the blood's oxygen-carrying capacity, has become the central focus of regulatory scrutiny and clinical risk management strategies associated with the drug.

A pivotal aspect of this report is the analysis of the U.S. Food and Drug Administration's (FDA) evolving regulatory stance. Responding to accumulating post-market safety data, the FDA has issued critical warnings, most notably a contraindication against the use of oral benzocaine products for teething pain in infants and children under two years of age.[5] This regulatory action underscores the report's emphasis on evidence-based, safety-conscious clinical practice and highlights the need for a nuanced understanding of the drug's risk-benefit profile.

This document is structured to guide the reader from the fundamental chemical and physicochemical properties of benzocaine through its detailed molecular pharmacology, clinical pharmacokinetics, therapeutic applications, and available formulations. It culminates in an in-depth analysis of its safety profile, toxicology, and regulatory history, providing an expert synthesis intended to inform clinical decision-making, guide patient counseling, and contextualize the ongoing role of benzocaine in modern pharmacotherapy.

Chemical Identity and Physicochemical Characteristics

The precise and unambiguous identification of a pharmaceutical agent is foundational to its study and safe application. Benzocaine is well-characterized across numerous chemical, pharmacological, and regulatory databases, ensuring its consistent identification worldwide.

Systematic Identification and Nomenclature

Benzocaine is systematically known by its International Union of Pure and Applied Chemistry (IUPAC) name, Ethyl 4-aminobenzoate.[1] Its identity is further secured by a unique Chemical Abstracts Service (CAS) Registry Number, 94-09-7.[1] It is cataloged in major drug and chemical databases under specific identifiers, including DrugBank ID DB01086, PubChem CID 2337, and UNII U3RSY48JW5, among many others.[1] This extensive cross-referencing is critical for accurate data retrieval and regulatory tracking.

Synonyms and Trade Names

Reflecting its long history of use and widespread commercialization, benzocaine is known by numerous synonyms and trade names. Common chemical synonyms include Ethyl p-aminobenzoate, p-Aminobenzoic acid ethyl ester, and 4-(Ethoxycarbonyl)aniline.[9] Historically, it was also referred to by names such as Anaesthesin and Parathesin.[10]

Its commercial presence is extensive, with benzocaine serving as the active ingredient in a vast array of OTC products. Prominent trade names include Orajel, Anbesol, Cepacol, Solarcaine, Lanacane, HurriCaine, and Dermoplast.[1] The sheer number of branded products underscores its status as a staple in first-aid and self-medication markets.

Molecular Structure and Formula

The definitive molecular formula for benzocaine is C9​H11​NO2​.[7] This corresponds to a molecular weight of approximately 165.19 g/mol.[7] Its structure consists of a para-aminobenzoic acid (PABA) core esterified with ethanol. This structure is represented by the Canonical SMILES string

CCOC(=O)C1=CC=C(C=C1)N and the InChI string InChI=1S/C9H11NO2/c1-2-12-9(11)7-3-5-8(10)6-4-7/h3-6H,2,10H2,1H3.[8] These structural representations are essential for computational modeling and understanding its chemical reactivity and pharmacological interactions.

Physical and Chemical Properties

The physicochemical properties of benzocaine are paramount as they directly dictate its formulation, route of administration, and mechanism of action.

• Appearance and State: At room temperature, benzocaine is a solid, described as colorless or white trapezial crystals.[2]
• Solubility Profile: A defining characteristic of benzocaine is its poor aqueous solubility. It is sparingly soluble in water, with approximately 1 g dissolving in 2500 ml of water.[1] Conversely, it is very soluble in organic solvents such as ethanol (1 g in 5 ml), chloroform (1 g in 2 ml), and ether (1 g in 4 ml), as well as in dilute acids and oils like almond and olive oil.[1] This pronounced lipophilicity (fat-solubility) is a direct consequence of its molecular structure, particularly the aromatic ring and the ethyl ester group.
• Thermal Properties: Benzocaine has a melting point in the range of 88–92 °C and a boiling point of approximately 310 °C.[1]
• Stability: The compound is generally stable in air.[2] However, some sources note that it is sensitive to air and light, which has implications for its storage in tight, light-resistant containers to prevent degradation.[15]

The physicochemical properties of benzocaine are not merely descriptive data points; they are the fundamental determinants of its clinical role and limitations. The molecule's high lipophilicity and poor water solubility are precisely the characteristics that make it an effective topical anesthetic. Its mechanism of action requires the drug molecule to traverse the lipid-rich neuronal cell membrane to access its binding site within the voltage-gated sodium channel.[4] Its lipophilic nature allows it to readily partition into and be retained by the fatty layers of the skin and mucous membranes. This ensures a high local concentration at the site of action while simultaneously limiting its systemic absorption.[2] This property directly explains its clinical niche; benzocaine is almost exclusively formulated for topical application and is unsuitable for parenteral administration (injection), a route reserved for water-soluble local anesthetics like lidocaine hydrochloride. Thus, its fundamental chemistry is inextricably linked to its entire clinical application profile, defining both its utility and its boundaries.

Synthesis and Manufacturing Pathways

Benzocaine can be prepared through well-established organic chemistry reactions. The most common laboratory and industrial methods include:

1. Fischer Esterification: This classic method involves the acid-catalyzed reaction of p-aminobenzoic acid (PABA) with ethanol.[1]
2. Reduction of Ethyl p-nitrobenzoate: An alternative pathway involves the reduction of the nitro group on ethyl p-nitrobenzoate to an amine group. In industrial settings, this reduction is typically achieved using iron powder and water in the presence of a small amount of acid.[1]

These synthetic routes are efficient and utilize readily available starting materials, contributing to the low cost and widespread availability of benzocaine.

Identifier/Property	Value	Description/Reference Source(s)
IUPAC Name	Ethyl 4-aminobenzoate	The systematic chemical name 1
CAS Number	94-09-7	Unique identifier from the Chemical Abstracts Service 1
DrugBank ID	DB01086	Identifier in the DrugBank database 1
PubChem CID	2337	Identifier in the PubChem Compound database 1
UNII	U3RSY48JW5	Unique Ingredient Identifier by the FDA 1
Molecular Formula	C9​H11​NO2​	The elemental composition of the molecule 7
Molecular Weight	165.19 g/mol	The mass of one mole of the substance 7
Appearance	Colorless or white trapezial crystals	Physical state at room temperature 2
Melting Point	88–92 °C	The temperature at which it transitions from solid to liquid 1
Boiling Point	~310 °C	The temperature at which it transitions from liquid to gas 1
Water Solubility	Sparingly soluble (~0.4 g/L or 1 g in 2500 ml)	Its limited ability to dissolve in water 1
Organic Solubility	Very soluble in ethanol, chloroform, ether, dilute acids	Its high ability to dissolve in non-polar solvents 1

Molecular Pharmacology: Mechanism of Action

The anesthetic effect of benzocaine is achieved through a precise and well-characterized interaction with specific molecular targets in the nervous system. Its action is not systemic but localized to the site of application, where it interrupts the fundamental process of nerve signal transmission.

Primary Target: Voltage-Gated Sodium Channels (Navs)

The primary pharmacological target of benzocaine, and indeed all local anesthetics, is the family of voltage-gated sodium channels (Navs).[1] These are complex transmembrane proteins embedded in the cell membranes of excitable cells, most notably neurons. In their normal function, Nav channels are responsible for the rapid influx of sodium ions (

Na+) that constitutes the rising phase of an action potential—the basic unit of nerve signaling.[21] The sensation of pain is initiated when free nerve endings are stimulated, triggering a series of action potentials that propagate along the nerve fiber to the central nervous system.[1]

Benzocaine exerts its anesthetic effect by reversibly binding to and inhibiting these sodium channels.[2] This binding physically obstructs the channel pore or stabilizes it in a non-conducting conformation, thereby preventing the influx of sodium ions.[19] Without this influx, the neuronal membrane cannot depolarize to the threshold required to generate an action potential. The result is a blockade of nerve impulse conduction, which the central nervous system interprets as a loss of sensation, or numbness, in the affected area.[1] The specific binding site for local anesthetics is located within the inner pore of the channel's large α-subunit, which forms the central ion-conducting pathway.[4]

Molecular Interactions and Binding Sites

Advanced computational studies and molecular dynamics simulations, often using bacterial sodium channels (e.g., NavAb) as structural models for their mammalian counterparts, have provided remarkable insight into the precise nature of the drug-channel interaction.[19] These studies confirm that benzocaine binds within the central, water-filled cavity of the channel, a region walled by the four S6 transmembrane helices of the protein.[19]

A critical interaction has been identified between local anesthetics and a highly conserved phenylalanine residue located on the S6 helix of Domain IV (often referred to as the FS6 residue).[20] Simulations of benzocaine binding to the NavAb channel show a high-affinity site at the homologous F203 residue.[20] The binding is not mediated by strong covalent or ionic bonds but rather by weaker, non-specific hydrophobic interactions between the aromatic ring of benzocaine and the hydrophobic residues lining the channel pore.[19] This hydrophobic nature of the interaction is consistent with benzocaine's high lipid solubility.

State-Dependent Inhibition and Use-Dependence

The inhibitory action of local anesthetics is often state-dependent, meaning they bind with different affinities to the various conformational states of the sodium channel (resting, open, and inactivated).[20] Most local anesthetics exhibit a higher affinity for the open and inactivated states than for the resting (closed) state.[4] This property gives rise to "use-dependent" or "frequency-dependent" block, where the anesthetic effect becomes more pronounced with repetitive stimulation (i.e., a higher frequency of nerve firing), as more channels are driven into the high-affinity open and inactivated states.[20]

However, benzocaine represents a notable exception to this general rule. While it can bind more easily to open channels, it does not demonstrate a strong frequency-dependent block.[4] This is attributed to its very rapid binding and unbinding kinetics. Because it can dissociate from the channel so quickly between nerve impulses, a cumulative blocking effect does not build up, distinguishing its pharmacological profile from that of other local anesthetics like lidocaine.[23]

Drug Access Pathways: The Hydrophobic vs. Intracellular Routes

A key question in local anesthetic pharmacology has been how the drug molecule reaches its binding site, which is located deep within the channel pore and seemingly inaccessible from the outside. Two primary pathways have been proposed and are now supported by substantial evidence from molecular simulations.[19]

1. The Hydrophobic Pathway: This route involves the drug molecule accessing the channel's central cavity directly from the lipid bilayer of the cell membrane. Molecular models have revealed the existence of lateral "fenestrations," or openings in the sides of the channel pore that connect directly to the surrounding membrane.[19] A neutral, lipophilic drug like benzocaine can partition from the membrane through these fenestrations to reach its binding site.[22]
2. The Hydrophilic (Aqueous) Pathway: This route requires the drug to first cross the cell membrane into the cytoplasm. From there, it can enter the channel pore through the intracellular activation gate, but only when the gate is in its open conformation during an action potential.[20]

The chemical properties of benzocaine make it uniquely suited to one of these pathways. Most common local anesthetics, such as lidocaine, are weak bases with a pKa value near physiological pH (around 7.4). This means that in the body, they exist in an equilibrium between a neutral, lipid-soluble form (which can cross the cell membrane) and a charged, protonated form (which is the more active form at the binding site).[22] This dual nature allows them to utilize both pathways.

Benzocaine, however, is chemically distinct. It has a very low pKa of approximately 2.6.[4] At the physiological pH of 7.4, it exists almost exclusively (>99.99%) in its neutral, uncharged form. The charged, protonated form required for effective use of the hydrophilic pathway is virtually absent. Consequently, benzocaine must rely predominantly on the hydrophobic pathway. Its high lipophilicity allows it to rapidly partition into the cell membrane and access the channel pore via the lateral fenestrations.[19] This primary reliance on the hydrophobic route explains two key pharmacological observations: first, why benzocaine is an effective anesthetic even when applied extracellularly (topically), and second, why its speed of onset is relatively independent of the surrounding tissue pH, a factor that significantly influences anesthetics with higher pKa values.[4] This provides a cohesive model that links benzocaine's unique chemical structure directly to its molecular mechanism of action and its distinct pharmacological behavior.

Clinical Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of a drug describes its journey through the body—how it is absorbed, distributed to tissues, metabolized, and ultimately excreted. For benzocaine, a drug intended for local action, its pharmacokinetic properties are crucial for understanding both its efficacy and its potential for systemic toxicity.

Absorption

Benzocaine is designed for topical application, and its absorption characteristics reflect this purpose. As a highly lipophilic (fat-soluble) weak base, it is well absorbed across mucous membranes (such as in the mouth, throat, or rectum) and from skin that is traumatized or abraded.[4] In contrast, its absorption through intact, healthy skin is poor.[25] This differential absorption helps to concentrate the drug where it is needed for local effect while minimizing entry into the systemic circulation.

The onset of anesthetic action is rapid, a key feature for its use in acute pain relief. With a 20% concentration formulation, the numbing effect typically begins within 30 seconds, although achieving the full depth and intensity of anesthesia may take 2 to 3 minutes.[4] The duration of action is relatively short, lasting approximately 10 minutes, which is suitable for temporary relief of minor pain but requires frequent reapplication for sustained effect.[26]

Distribution

In cases where benzocaine is absorbed into the systemic circulation (e.g., through application to large areas of damaged skin or mucous membranes), it undergoes distribution throughout the body. The drug is known to cross the placental barrier, a consideration for its use during pregnancy.[2] In the bloodstream, benzocaine binds to plasma proteins, specifically to serum albumin and alpha-1-acid glycoprotein.[26] As an ester-type local anesthetic, its degree of protein binding is generally less than that of the amide-type local anesthetics (e.g., lidocaine).[27] The extent of distribution to various tissues is proportional to the tissue's mass and blood perfusion.[4]

Metabolism

The metabolism of benzocaine is a critical determinant of its short duration of action and its safety profile. As a member of the amino ester class of local anesthetics, its metabolic pathway is distinct from that of the amide class.[4] The primary metabolic process is rapid hydrolysis, which occurs predominantly in the plasma, catalyzed by the enzyme pseudocholinesterase (also known as plasma cholinesterase or butyrylcholinesterase).[4] Some metabolism also takes place in the liver.[2]

This enzymatic hydrolysis cleaves the ester bond in the benzocaine molecule, yielding two main products:

1. Para-aminobenzoic acid (PABA): This is the principal metabolite.[4]
2. Ethanol.

In addition to hydrolysis, minor metabolic pathways exist, including acetylation to form acetylbenzocaine and N-hydroxylation to produce benzocaine hydroxide.[26] The PABA metabolite can be further acetylated to form 4-acetaminobenzoic acid.[26] The rapid breakdown of benzocaine in the plasma is the main reason for its short systemic half-life and generally low risk of systemic toxicity when used as directed.

The metabolic pathway of benzocaine is not just a process of elimination; it is the direct origin of the drug's most significant clinical concerns. The hydrolysis to para-aminobenzoic acid (PABA) is central to this. First, PABA is a known allergen for a subset of the population, which directly explains why ester-type anesthetics as a class, including benzocaine, are associated with hypersensitivity reactions such as allergic contact dermatitis.[1] Second, the structure of PABA is very similar to a substrate that bacteria require to synthesize folic acid. This molecular mimicry is the basis for the antibacterial action of sulfonamide drugs. Consequently, the PABA produced from benzocaine metabolism can competitively inhibit the efficacy of sulfonamide antibiotics, representing a clinically relevant drug-drug interaction.[2] Finally, and most critically, the minor metabolic pathway of N-hydroxylation can produce metabolites, such as nitrobenzene, which are potent oxidizing agents.[4] These metabolites are responsible for oxidizing the ferrous iron (

Fe2+) in hemoglobin to its ferric state (Fe3+), forming methemoglobin. This altered form of hemoglobin is incapable of binding and transporting oxygen, leading to the life-threatening condition of methemoglobinemia.[4] Therefore, a comprehensive understanding of benzocaine's metabolism provides a unified biochemical explanation for three distinct and important clinical phenomena: its allergic potential, a specific drug interaction class, and its most severe toxicity.

Excretion

Following metabolism, the water-soluble metabolites of benzocaine are eliminated from the body. The primary route of excretion is via the kidneys, with the metabolites being cleared into the urine.[2] A very small amount of unchanged drug is excreted, and a minor portion of metabolites may be eliminated through the feces.[2] The efficiency of renal clearance means that accumulation of metabolites could potentially occur in patients with severe renal failure.[27]

Parameter	Description	Reference Source(s)
Onset of Action	~30 seconds (for 20% concentration)	4
Duration of Action	~10 minutes	26
Absorption Sites	Well absorbed from mucous membranes and traumatized skin; poorly from intact skin	4
Plasma Protein Binding	Binds to serum albumin and alpha-1-acid glycoprotein	26
Primary Metabolic Enzyme	Plasma pseudocholinesterase (butyrylcholinesterase)	4
Primary Metabolite	Para-aminobenzoic acid (PABA)	4
Route of Elimination	Primarily renal (excretion of metabolites in urine)	2

Therapeutic Applications and Clinical Efficacy

Benzocaine is utilized in a wide range of clinical and self-medication settings for its ability to provide rapid, temporary local anesthesia. Its applications span dermatology, dentistry, otology, and other specialized areas. The efficacy for several of these indications has been supported by formal clinical trials.

Dermatological and Topical Indications

One of the most common uses of benzocaine is for the self-medicated, temporary relief of pain and pruritus (itching) arising from various minor skin conditions. It is a key active ingredient in numerous over-the-counter preparations intended for:

• Sunburn and other minor burns [1]
• Minor cuts, scrapes, and skin irritations [3]
• Insect bites or stings [2]
• Irritation from conditions like poison ivy, poison oak, or poison sumac [2]

Oromucosal and Dental Anesthesia

Benzocaine is extensively used for topical anesthesia of the oral and pharyngeal mucous membranes. It provides temporary relief from pain associated with a variety of conditions, including:

• Sore throat and pharyngitis [1]
• Mouth ulcers, including canker sores and cold sores (fever blisters) [1]
• Toothache and sore gums [1]
• Irritation caused by dentures or orthodontic appliances [1]
• Pain following minor dental procedures [4]

Specialized Applications

Beyond general skin and mouth pain, benzocaine is formulated for several more specific applications:

• Otic Pain: It is an ingredient in some glycerol-based ear drop preparations designed to relieve earache (otic pain), such as that associated with otitis media, and to help soften and remove excess or impacted earwax.[1]
• Hemorrhoids: Topical creams and ointments containing 5-20% benzocaine are used for the temporary relief of local pain, itching, and discomfort associated with hemorrhoids.[1]
• Premature Ejaculation: Benzocaine is used as a male genital desensitizer. By temporarily reducing sensitivity on the penis, it can help delay ejaculation and prolong intercourse. It is incorporated into some condoms and is available as a topical gel for this purpose.[1]
• Procedural Anesthesia: Historically, benzocaine sprays were used in clinical settings for local anesthesia of mucous membranes prior to surgical, endoscopic (e.g., laryngoscopy, proctoscopy), or other medical procedures, and to suppress the gag reflex.[1] However, due to the significant risk of methemoglobinemia associated with this use, the FDA has stated that benzocaine sprays are not approved for these purposes and their use is now strongly discouraged.[5]

Review of Evidence from Clinical Trials

The efficacy of benzocaine for several key indications is supported by data from randomized controlled clinical trials, which provide a higher level of evidence for its therapeutic benefit.

• A completed Phase 3 clinical trial (NCT03116737) specifically evaluated the use of topical benzocaine for the treatment of pain associated with acute otitis media in children, providing evidence for its otic applications.[30]
• Another completed Phase 3 trial (NCT03432923) investigated the efficacy and safety of a benzocaine-containing lozenge for the treatment of sore throat, supporting its common use in throat preparations.[31]
• A Phase 4 post-marketing study (NCT01925469) compared benzocaine spray against a placebo for pain relief during hysterosalpingography, a gynecological procedure, demonstrating its utility in providing analgesia for procedural pain.[32]
• Additionally, a clinical trial (NCT01860235) has been completed evaluating a combination product containing benzocaine and lidocaine (EMLA) for providing topical anesthesia during dental scaling and root planing procedures.[33]

Veterinary and Non-Therapeutic Uses

Benzocaine also has notable applications outside of human medicine, as well as a significant presence in illicit contexts.

• Veterinary Anesthesia: In veterinary medicine, particularly with amphibians and fish, benzocaine is widely used. Bath solutions containing benzocaine are a potent and highly effective method for anesthetizing these animals for surgical procedures or for humane euthanasia.[1] It is also used in topical ointments for wounds on livestock such as cattle, sheep, and horses.[2]
• Illicit Drug Adulterant: Benzocaine has gained notoriety as the most popular cutting agent for street cocaine worldwide.[1] Its local anesthetic properties produce a numbing effect on mucous membranes that is similar to that of cocaine, making it difficult for users to discern the purity of the product by taste. As a cheap, white, crystalline powder, it also serves as an effective bulking agent that is not easily detected once mixed.[1] This widespread use as an adulterant poses additional risks to individuals using illicit drugs.

Formulations, Dosage, and Administration

Benzocaine's versatility as a topical anesthetic is reflected in the vast array of commercially available formulations, each designed for a specific application site and therapeutic need. Proper administration and adherence to dosage guidelines are paramount to ensure efficacy while minimizing the risk of local and systemic adverse effects.

Compendium of Commercial Formulations

Benzocaine is available over-the-counter in a multitude of dosage forms and strengths, often in combination with other active ingredients like menthol or antibacterials.[2]

• Dosage Forms: The most common formulations include:
• Gels, Creams, Ointments, and Pastes: These are widely used for both skin and oral applications, providing a vehicle that adheres to the application site.[34]
• Liquids and Solutions: Applied directly or with a swab for oral or dental pain.[28]
• Aerosol and Pump Sprays: Used for broader application on the skin (e.g., for sunburn) or for targeting the throat.[4]
• Lozenges: Designed to dissolve slowly in the mouth to provide prolonged relief for sore throat pain.[1]
• Swabs and Pads: Pre-medicated single-use applicators for convenient and hygienic application.[3]
• Mucoadhesive Patches: Used in specialized applications, such as reducing orthodontic pain.[1]
• Strengths: The concentration of benzocaine varies significantly depending on the product and its intended use:
• Topical Skin Products: Typically range from 5% to 20% concentration.[18]
• Oral/Dental Products: Generally available in concentrations of 6.3%, 7.5%, 10%, and 20%.[28]
• Lozenges: Contain a fixed dose of benzocaine, commonly ranging from 3 mg to 15 mg per lozenge.[36]

Formulation Type	Common Strengths	Common Brand Names	Primary Indications
Gel / Cream / Ointment	5%, 6.3%, 7.5%, 10%, 20%	Orajel, Anbesol, Lanacane, Americaine	Oral/dental pain, skin irritation, hemorrhoids, minor burns
Aerosol / Pump Spray	5%, 20%	Solarcaine, Dermoplast, HurriCaine, Ultra Chloraseptic	Sunburn, skin pain/itching, sore throat
Lozenge	3 mg, 4 mg, 6 mg, 10 mg, 15 mg	Cepacol, Chloraseptic	Sore throat pain
Liquid / Solution	5%, 6.3%, 7.5%, 10%, 20%	Anbesol, Kank-A, Outgro	Oral/dental pain, canker sores, ingrown toenails
Swab / Pad	20%	Sting Kill	Insect bites, minor skin pain

Administration Guidelines by Indication

Adherence to proper dosing and administration is critical, especially given the FDA's safety warnings. The following are general guidelines; specific product labeling should always be consulted.

• Dermatologic Conditions (Adults and Children ≥2 years): Apply a thin layer of a 5-20% preparation to the affected skin area three or four times daily as needed.[3] For aerosol sprays, hold the canister 6-12 inches from the skin and spray until the area is wet.[38]
• Oral/Dental Pain (Adults and Children ≥2 years): Apply a small amount of a 10-20% gel, liquid, or ointment directly to the affected area. Use should not exceed four times per day.[28] Use in children under 2 years is contraindicated.[5]
• Sore Throat (Adults and Children ≥5 years): Dissolve one lozenge slowly in the mouth every 2 hours as needed. Use is generally not recommended for more than 2 days.[28] For sprays, apply one spray to the affected area and spit out after one minute; may be repeated up to 4 times daily.[28]
• Hemorrhoids (Adults and Children ≥12 years): Apply a 5-20% ointment to the cleansed external anal area up to six times daily.[18]
• Premature Ejaculation (Adults): Apply a small amount of a 3-7.5% gel preparation to the head and shaft of the penis 15-20 minutes before intercourse. The product should be washed off after intercourse.[18]

Patient Counseling and Proper Application Techniques

Effective patient counseling is essential to ensure safe use and prevent adverse events, particularly methemoglobinemia and aspiration. Key counseling points include:

• Use the Minimum Effective Amount: Always use the smallest amount of product necessary to relieve pain and apply it sparingly.[34]
• Avoid Inappropriate Application Sites: Do not apply to large areas of the body, deep or puncture wounds, infected skin, or serious burns, as this can increase systemic absorption and the risk of toxicity.[3]
• Prevent Eye Contact: Benzocaine can cause severe eye irritation. Avoid contact with the eyes, and if accidental contact occurs, flush with water immediately.[3]
• Gag Reflex and Aspiration Risk: The numbing effect of oral benzocaine products can relax the gag reflex. Patients should be advised not to eat or drink for at least one hour after oral application to prevent choking or aspiration of food, drink, or oral secretions. Applying an oral anesthetic before going to bed is particularly hazardous.[1]
• Hygiene: Hands should be washed thoroughly before and after applying the product to prevent contamination and unintended spread of the anesthetic.[12]
• Storage: All benzocaine products should be stored securely and out of the reach of children to prevent accidental ingestion, which can be toxic.[3]

Safety Profile, Toxicology, and Risk Management

While generally well-tolerated when used as directed for topical application, benzocaine is associated with a range of adverse effects, from common local reactions to a rare but life-threatening systemic toxicity. A thorough understanding of this safety profile is essential for clinicians and consumers to make informed decisions about its use.

Common and Minor Adverse Reactions

The most frequently reported adverse effects are localized to the site of application and are typically mild.

• Contact Dermatitis: Benzocaine can act as a contact allergen, causing a localized hypersensitivity reaction. This typically manifests as redness (erythema), itching (pruritus), burning, stinging, tenderness, and sometimes rash, urticaria (hives), or edema at the application site.[1]
• Hypersensitivity: As an ester of para-aminobenzoic acid (PABA), benzocaine can trigger allergic reactions in individuals sensitized to PABA or other ester-type local anesthetics.[2] While rare, systemic hypersensitivity reactions, including anaphylaxis, have been reported.[1]

Critical Safety Warning: Benzocaine-Induced Methemoglobinemia

The most serious and life-threatening adverse event associated with benzocaine is methemoglobinemia. This risk has prompted significant regulatory action from the FDA and is the primary safety concern guiding clinical use.

• Pathophysiology: Methemoglobinemia is a hematological disorder in which the iron atom within the heme portion of hemoglobin is oxidized from its normal ferrous state (Fe2+) to the ferric state (Fe3+).[4] This transformation is caused by oxidizing metabolites of benzocaine, such as nitrobenzene.[4] The resulting molecule, methemoglobin (MetHb), is incapable of binding and transporting oxygen. Furthermore, the presence of MetHb in red blood cells increases the oxygen affinity of the remaining normal hemoglobin, shifting the oxygen-hemoglobin dissociation curve to the left and impairing the release of oxygen to peripheral tissues. The result is a state of functional anemia and profound tissue hypoxia that does not improve with the administration of supplemental oxygen.[4]
• Clinical Presentation: The signs and symptoms of methemoglobinemia are directly correlated with the percentage of total hemoglobin that has been converted to MetHb.
• Mild (<20% MetHb): Patients may be asymptomatic or exhibit a slate-gray cyanosis, particularly of the skin, lips, and nail beds.[42]
• Moderate (20-45% MetHb): As tissue hypoxia worsens, symptoms include fatigue, headache, dizziness, shortness of breath (dyspnea), and tachycardia.[42]
• Severe (>45% MetHb): Life-threatening symptoms can develop, including severe dyspnea, metabolic acidosis, cardiac arrhythmias, bradycardia, seizures, coma, and ultimately, death.[42]

Symptoms typically appear rapidly, often within minutes to two hours after benzocaine application, and can occur after the first use or subsequent exposures.44

• Diagnosis: A key diagnostic clue is the presence of central cyanosis that is unresponsive to 100% oxygen therapy. Standard two-wavelength pulse oximetry is notoriously unreliable in the presence of MetHb and will often give a falsely reassuring or stable reading around 85%, regardless of the patient's true oxygenation status.[41] Definitive diagnosis requires arterial blood gas analysis with co-oximetry, which can directly measure the MetHb level.[41] A simple bedside test involves placing a drop of the patient's blood on white filter paper; blood with a high MetHb level will appear "chocolate-brown" and will not turn red upon exposure to air.[41]
• Management: The standard and definitive treatment for significant methemoglobinemia (typically MetHb >20-30% or in symptomatic patients) is the intravenous administration of a 1% solution of methylene blue (1-2 mg/kg).[4] Methylene blue acts as a cofactor for the NADPH-methemoglobin reductase enzyme system, accelerating the reduction of MetHb back to normal hemoglobin. Supplemental oxygen should also be administered.[4]
• High-Risk Populations: The risk of developing methemoglobinemia is not uniform across the population. Certain groups are at a significantly higher risk and require special consideration:
• Infants and Children <2 Years: This group is particularly vulnerable due to immature metabolic enzyme systems, making them unable to efficiently reduce MetHb back to hemoglobin. This heightened risk is the basis for the FDA's contraindication.[3]
• The Elderly: Similar to infants, elderly patients may have reduced enzymatic capacity.[41]
• Patients with Pre-existing Conditions: Individuals with heart disease or lung diseases such as asthma, bronchitis, or emphysema, as well as smokers, have a reduced physiological reserve to tolerate hypoxia and are at greater risk for complications.[3]
• Patients with Congenital Metabolic Disorders: Individuals with hereditary deficiencies of enzymes involved in hemoglobin reduction, such as glucose-6-phosphate dehydrogenase (G6PD) deficiency or NADH-methemoglobin reductase deficiency, are highly susceptible.[3]

Contraindications and Precautions

Based on the known risks, there are several key contraindications and precautions for the use of benzocaine.

• Absolute Contraindications:
• Known history of hypersensitivity or allergic reaction to benzocaine, other ester-type local anesthetics, or para-aminobenzoic acid (PABA).[25]
• Use for teething pain or any other oral application in infants and children under 2 years of age, as mandated by the FDA.[5]
• Precautions:
• Extreme caution should be exercised when considering use in any of the high-risk populations identified above.[3]
• Application to broken, inflamed, or infected skin or mucous membranes should be avoided, as this can substantially increase systemic absorption and the risk of toxicity.[3]

Clinically Significant Drug and Disease Interactions

The potential for adverse interactions with other drugs or underlying diseases must be considered.

• Pharmacodynamic Interactions (Increased Methemoglobinemia Risk): The most significant drug-drug interactions are those that potentiate the risk of methemoglobinemia. Concurrent use of benzocaine with other oxidizing agents can have an additive effect. These include:
• Nitrates and nitrites (e.g., nitroglycerin, isosorbide dinitrate, amyl nitrite).[4]
• Dapsone.[4]
• Other local anesthetics (e.g., prilocaine, lidocaine).[26]
• Antineoplastic agents (e.g., cyclophosphamide, flutamide).[26]
• Acetaminophen, phenobarbital, and phenytoin have also been implicated.[26]
• Pharmacokinetic Interactions:
• Sulfonamides: As previously discussed, the PABA metabolite of benzocaine can antagonize the antibacterial effect of sulfonamide antibiotics.[2]
• Disease Interactions: The primary disease interaction is with any condition that predisposes a patient to methemoglobinemia, such as G6PD deficiency or pre-existing cardiopulmonary disease.[47]

Interacting Drug/Class	Mechanism of Interaction	Clinical Consequence	Recommended Management
Nitrates/Nitrites (e.g., Nitroglycerin)	Additive oxidizing effect on hemoglobin	Markedly increased risk of severe methemoglobinemia	Concurrent use should be avoided if possible. If necessary, monitor patient closely for signs of cyanosis and hypoxia.
Dapsone	Additive oxidizing effect on hemoglobin	Increased risk of methemoglobinemia	Avoid concurrent use. Monitor methemoglobin levels if combination is unavoidable.
Other Local Anesthetics (e.g., Prilocaine)	Additive oxidizing effect on hemoglobin	Increased risk of methemoglobinemia	Avoid using multiple oxidizing local anesthetics simultaneously.
Sulfonamide Antibiotics	Competitive inhibition by PABA metabolite	Reduced antibacterial efficacy of the sulfonamide	Avoid concurrent use. Select an alternative antibiotic if benzocaine use is necessary.

Regulatory History and Status

The regulatory journey of benzocaine in the United States provides a compelling case study in post-market pharmacovigilance and the evolving risk-benefit assessment of widely used over-the-counter drugs. The U.S. Food and Drug Administration (FDA) has progressively tightened its regulations on benzocaine in response to accumulating evidence of serious harm, particularly in vulnerable populations.

Early Regulatory Status

For many years, benzocaine was widely marketed and considered by FDA advisory panels to be generally recognized as safe and effective (GRASE) for OTC use as a topical anesthetic and analgesic for oral and dermal applications.[50] Even in these early reviews, however, the potential risk of inducing methemoglobinemia was acknowledged, though it was considered a rare event.[50] Based on this initial assessment, benzocaine became a ubiquitous active ingredient in a vast number of consumer health products.

Chronology of FDA Actions

The shift in the FDA's regulatory stance was driven by the steady accumulation of adverse event reports submitted to its MedWatch program, which revealed a persistent and serious safety signal related to methemoglobinemia.

• February 2006: The FDA issued its first major Public Health Advisory concerning benzocaine. This advisory specifically warned about the risk of methemoglobinemia associated with the use of benzocaine sprays to numb the mucous membranes of the mouth and throat during medical procedures.[44] This action was prompted by numerous case reports from clinical settings.
• April 2011: Five years later, the FDA issued updated Drug Safety Communications after continued reports of methemoglobinemia. These communications expanded the warning to include not only the procedural sprays but also the OTC gels and liquids commonly used for oral pain.[5] By this time, the agency had documented a total of 319 cases of benzocaine-associated methemoglobinemia. The 2011 communication specifically highlighted the risk in children under two years of age, signaling a growing concern for this pediatric population.[51]
• May 2018: The FDA took its most decisive regulatory action. In a new Drug Safety Communication, the agency declared that oral benzocaine products should not be used for teething pain in infants and children under two years of age.[5] The agency concluded that the serious risks of methemoglobinemia in this vulnerable group far outweighed what it described as "little to no benefit" for treating teething pain.[5] This marked a fundamental reassessment of the drug's risk-benefit profile for this specific indication and population.

Current Labeling Requirements and Market Status

The 2018 FDA action fundamentally changed the regulatory landscape for OTC benzocaine products.

• The FDA formally requested that manufacturers voluntarily stop marketing oral benzocaine products specifically for the indication of teething in infants and children under two years of age. The agency stated it would take enforcement action to remove these products from the market if companies did not comply.[45]
• For all other OTC oral benzocaine products intended for adults and children two years and older, the FDA urged manufacturers to add new, stronger warnings to the Drug Facts label. These changes included:

1. A specific warning about the risk of methemoglobinemia.
2. A contraindication, the FDA's strongest warning, explicitly stating "do not use" for teething and "do not use" in children under two years of age.[39]

• Concurrently, the FDA announced it was taking action to require standardized methemoglobinemia warnings to be included in the prescribing information for all prescription local anesthetics (e.g., lidocaine, bupivacaine), recognizing the risk, though often lower, across the entire class of drugs.[45]

Other regulatory considerations for benzocaine have included a 1992 final rule establishing its use as an OTC male genital desensitizer [53] and a 2011 proposed rule to reclassify it as nonmonograph (i.e., not GRASE) for use in weight control products, an indication for which its efficacy was not established.[54]

The regulatory history of benzocaine serves as a critical example of the function and importance of post-market surveillance. A drug that was available for decades and widely perceived as safe for common minor ailments was subjected to a fundamental re-evaluation based on the slow but steady accumulation of spontaneous adverse event reports. This process demonstrates that a drug's risk-benefit profile is not static but can be reassessed as new evidence emerges, particularly concerning its effects in vulnerable populations like infants. The FDA's response, which evolved from advisories to market-altering actions, highlights a central challenge in drug regulation: balancing the convenience and accessibility of OTC medications with the imperative to protect the public from serious, even if infrequent, harm. Benzocaine's story is a textbook illustration of this dynamic regulatory process in action.

Expert Synthesis and Concluding Recommendations

Benzocaine remains a widely used and effective topical local anesthetic for the temporary relief of pain and itching from a variety of minor conditions in adults and older children. Its rapid onset of action and availability in numerous over-the-counter formulations make it a convenient option for self-medication. However, this broad utility must be carefully and consistently weighed against the well-documented, albeit rare, risk of inducing life-threatening methemoglobinemia. The extensive body of evidence reviewed in this monograph culminates in a nuanced risk-benefit profile that demands stringent adherence to safety guidelines and informed clinical practice.

The central conclusion of this analysis is that the risk of methemoglobinemia, while low in the general adult population, is unacceptably high in infants and young children, for whom the therapeutic benefit, particularly for teething pain, is considered minimal by regulatory authorities. The pathophysiology is clear: oxidizing metabolites of benzocaine disrupt the oxygen-carrying capacity of hemoglobin, leading to tissue hypoxia that can be fatal if not promptly recognized and treated. This risk is magnified in populations with immature or compromised metabolic pathways.

Based on this integrated analysis, the following clinical recommendations are provided to guide the safe and appropriate use of benzocaine:

Clinical Recommendations

• Strict Adherence to Contraindications: The FDA's contraindication against the use of any oral benzocaine product in children under two years of age must be considered absolute. Clinicians, pharmacists, and caregivers must understand that these products should never be used for teething pain. Healthcare professionals have a critical role in educating parents and caregivers about this specific danger and providing guidance on safer, non-pharmacologic alternatives, such as the use of firm rubber teething rings or gently massaging the child's gums.[5]
• Prudent Patient Selection and Counseling: For appropriate patients (adults and children aged two years and older), the principle of using the lowest effective concentration for the shortest possible duration should be strictly followed. The most critical component of its use is patient counseling. All patients or their caregivers must be educated on the early signs and symptoms of methemoglobinemia (e.g., pale, gray, or blue-colored skin, lips, or nail beds; shortness of breath; fatigue; rapid heart rate). They should be explicitly instructed to discontinue the product and seek immediate medical attention if any of these symptoms develop.[39]
• High-Risk Patient Management: Extreme caution is warranted when considering benzocaine use in patients with known risk factors. This includes the elderly and individuals with pre-existing cardiopulmonary conditions (e.g., asthma, COPD, heart disease), anemia, or known congenital metabolic disorders (e.g., G6PD deficiency). In many of these cases, alternative local anesthetics or non-pharmacologic approaches may be preferable.
• Awareness of Drug Interactions: Clinicians should maintain a high index of suspicion for increased methemoglobinemia risk when patients are concurrently taking other oxidizing drugs, such as nitrates or dapsone. The potential for benzocaine metabolites to interfere with the efficacy of sulfonamide antibiotics should also be considered when making therapeutic choices.

Future Research Directions

While much is known about benzocaine, several areas warrant further investigation. The significant disconnect between the widespread marketing of benzocaine for various types of oral pain and the FDA's assessment of its "little to no benefit" for teething suggests a need for more robust, placebo-controlled efficacy studies for other common oral pain indications. Furthermore, research into the development of benzocaine derivatives or novel formulations with altered metabolic pathways could be a promising avenue. The goal of such research would be to design molecules that are less prone to forming the oxidizing metabolites responsible for methemoglobinemia, thereby preserving the anesthetic benefit while enhancing the safety profile.[55] Finally, continued public health education and research into effective non-pharmacologic pain relief strategies are essential to reduce reliance on topical anesthetics, especially for common and self-limiting conditions in pediatric populations.

Works cited

1. Benzocaine - Wikipedia, accessed September 7, 2025, https://en.wikipedia.org/wiki/Benzocaine
2. Benzocaine | 94-09-7 - ChemicalBook, accessed September 7, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB1217951.htm
3. Benzocaine (topical application route) - Side effects & dosage ..., accessed September 7, 2025, https://www.mayoclinic.org/drugs-supplements/benzocaine-topical-application-route/description/drg-20072913
4. Benzocaine - StatPearls - NCBI Bookshelf, accessed September 7, 2025, https://www.ncbi.nlm.nih.gov/books/NBK541053/
5. Safety Information on Benzocaine-Containing Products - FDA, accessed September 7, 2025, https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/safety-information-benzocaine-containing-products
6. Benzocaine (EENT) Monograph for Professionals - Drugs.com, accessed September 7, 2025, https://www.drugs.com/monograph/benzocaine-eent.html
7. Benzocaine | CAS 94-09-7 | SCBT - Santa Cruz Biotechnology, accessed September 7, 2025, https://www.scbt.com/p/benzocaine-94-09-7
8. Benzocaine | C9H11NO2 | CID 2337 - PubChem, accessed September 7, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Benzocaine
9. Benzocaine (CAS 94-09-7) - Cayman Chemical, accessed September 7, 2025, https://www.caymanchem.com/product/20132/benzocaine
10. Benzocaine - the NIST WebBook - National Institute of Standards and Technology, accessed September 7, 2025, https://webbook.nist.gov/cgi/cbook.cgi?ID=94-09-7&Units=SI
11. Benzocaine | C9H11NO2 - ChemSpider, accessed September 7, 2025, https://www.chemspider.com/Chemical-Structure.13854242.html
12. Benzocaine - Memorial Sloan Kettering Cancer Center, accessed September 7, 2025, https://www.mskcc.org/cancer-care/patient-education/medications/adult/benzocaine
13. Benzocaine Over-the-Counter Products Can Increase the Risk of Serious or Life-threatening Methemoglobinemia | Pharmacy Services | University of Utah Health, accessed September 7, 2025, https://pharmacyservices.utah.edu/alerts/2018/06/benzocaine-over-counter-products-can-increase-risk-of-serious-or-life-threatening
14. Compound: BENZOCAINE (CHEMBL278172) - ChEMBL - EMBL-EBI, accessed September 7, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL278172
15. CAS Number 94-09-7 | Benzocaine - Spectrum Pharmacy Products, accessed September 7, 2025, https://www.spectrumrx.com/cas/94-09-7
16. Benzocaine - 4-Aminobenzoic acid ethyl ester, Ethyl 4-aminobenzoate - Sigma-Aldrich, accessed September 7, 2025, https://www.sigmaaldrich.com/US/en/substance/benzocaine1651994097
17. Showing metabocard for Benzocaine (HMDB0004992) - Human Metabolome Database, accessed September 7, 2025, https://hmdb.ca/metabolites/HMDB0004992
18. Benzocaine (Topical) Monograph for Professionals - Drugs.com, accessed September 7, 2025, https://www.drugs.com/monograph/benzocaine-topical.html
19. Locating the Route of Entry and Binding Sites of Benzocaine and Phenytoin in a Bacterial Voltage Gated Sodium Channel | PLOS Computational Biology - Research journals, accessed September 7, 2025, https://journals.plos.org/ploscompbiol/article%3Fid%3D10.1371/journal.pcbi.1003688
20. Local anesthetic and antiepileptic drug access and binding to a bacterial voltage-gated sodium channel | PNAS, accessed September 7, 2025, https://www.pnas.org/doi/10.1073/pnas.1408710111
21. The Sodium Channel as a Target for Local Anesthetic Drugs - Frontiers, accessed September 7, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2011.00068/full
22. Protonation state of inhibitors determines interaction sites within voltage-gated sodium channels | PNAS, accessed September 7, 2025, https://www.pnas.org/doi/10.1073/pnas.1714131115
23. Mechanism of sodium channel block by local anesthetics, antiarrhythmics, and anticonvulsants | Journal of General Physiology | Rockefeller University Press, accessed September 7, 2025, https://rupress.org/jgp/article/149/4/465/43632/Mechanism-of-sodium-channel-block-by-local
24. Protomers of Benzocaine: Solvent and Permittivity Dependence - ACS Publications, accessed September 7, 2025, https://pubs.acs.org/doi/10.1021/jacs.5b01338
25. Benzocaine | Drug Lookup | Pediatric Care Online - AAP Publications, accessed September 7, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/5607/Benzocaine
26. Benzocaine: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 7, 2025, https://go.drugbank.com/drugs/DB01086
27. Basic pharmacology of local anaesthetics - PMC - PubMed Central, accessed September 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7808030/
28. EjectDelay (benzocaine) dosing, indications, interactions, adverse effects, and more., accessed September 7, 2025, https://reference.medscape.com/drug/benzocaine-343361
29. Benzocaine (oral route, oromucosal route) - Side effects & dosage - Mayo Clinic, accessed September 7, 2025, https://www.mayoclinic.org/drugs-supplements/benzocaine-oral-route-oromucosal-route/description/drg-20072824
30. Pain Completed Phase 3 Trials for Benzocaine (DB01086) | DrugBank Online, accessed September 7, 2025, https://go.drugbank.com/indications/DBCOND0012160/clinical_trials/DB01086?phase=3&status=completed
31. Benzocaine Completed Phase 3 Trials for Sore Throat Treatment | DrugBank Online, accessed September 7, 2025, https://go.drugbank.com/drugs/DB01086/clinical_trials?conditions=DBCOND0033906&phase=3&purpose=treatment&status=completed
32. Benzocaine Completed Phase 4 Trials for Pain Relief / Analgesia Treatment - DrugBank, accessed September 7, 2025, https://go.drugbank.com/drugs/DB01086/clinical_trials?conditions=DBCOND0020862%2CDBCOND0039455&phase=4&purpose=treatment&status=completed
33. Benzocaine Completed Phase N/A Trials for Postoperative pain / Self Perception / Local Anaesthesia therapy Treatment - DrugBank, accessed September 7, 2025, https://go.drugbank.com/drugs/DB01086/clinical_trials?conditions=DBCOND0120558%2CDBCOND0022333%2CDBCOND0146612&purpose=treatment&status=completed
34. Benzocaine Topical Products What are oral numbing agents? How do I use an oral numbing agent? How much oral numbing - American College of Medical Toxicology, accessed September 7, 2025, https://www.acmt.net/wp-content/uploads/2022/06/FAQ_Oral-Numbing-Gels.pdf
35. Benzocaine Products: Fast Relief for Pain and Discomfort - Mountainside Medical, accessed September 7, 2025, https://www.mountainside-medical.com/collections/benzocaine
36. Anbesol, Orajel (benzocaine oropharyngeal) dosing, indications, interactions, adverse effects, and more. - Medscape Reference, accessed September 7, 2025, https://reference.medscape.com/drug/anbesol-orajel-adult-benzocaine-oropharyngeal-999415
37. Benzocaine: Uses, Alternatives, Side Effects, & More - GoodRx, accessed September 7, 2025, https://www.goodrx.com/benzocaine/what-is
38. Benzocaine Topical Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed September 7, 2025, https://www.drugs.com/dosage/benzocaine-topical.html
39. Risk of serious and potentially fatal blood disorder prompts FDA action on oral over-the-counter benzocaine products used for teething and mouth pain and prescription local anesthetics, accessed September 7, 2025, https://www.fda.gov/drugs/drug-safety-and-availability/risk-serious-and-potentially-fatal-blood-disorder-prompts-fda-action-oral-over-counter-benzocaine
40. Benzocaine Gel (Oral): Uses & Side Effects - Cleveland Clinic, accessed September 7, 2025, https://my.clevelandclinic.org/health/drugs/20991-benzocaine-dental-or-oral-gel-paste-or-solution
41. Benzocaine-Induced Methemoglobinemia: A Case Report - Touro Scholar, accessed September 7, 2025, https://touroscholar.touro.edu/cgi/viewcontent.cgi?article=1004&context=tcopny_pubs
42. pmc.ncbi.nlm.nih.gov, accessed September 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC1586795/#:~:text=Most%20patients%20are%20asymptomatic%20until,and%20cardiac%20arrhythmias%20may%20occur.
43. Benzocaine-induced Methemoglobinemia - PMC, accessed September 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC1586795/
44. FDA Drug Safety Communication: FDA continues to receive reports ..., accessed September 7, 2025, https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-continues-receive-reports-rare-serious-and-potentially-fatal
45. Oral Over-the-Counter Benzocaine Products: Drug Safety Communication - Risk of Serious and Potentially Fatal Blood Disorder | American Society of Anesthesiologists (ASA), accessed September 7, 2025, https://www.asahq.org/advocacy-and-asapac/fda-and-washington-alerts/fda-alerts/2018/05/oral-otc-benzocaine-products-drug-safety-comms-risk-of-serious-potentially-fatal-blood-disorder
46. Benzocaine: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed September 7, 2025, https://www.rxlist.com/benzocaine/generic-drug.htm
47. Benzocaine/resorcinol topical Interactions - Drugs.com, accessed September 7, 2025, https://www.drugs.com/drug-interactions/benzocaine-resorcinol-topical.html
48. Benzocaine topical Interactions - Drugs.com, accessed September 7, 2025, https://www.drugs.com/drug-interactions/benzocaine-topical.html
49. Benzocaine/menthol topical Interactions - Drugs.com, accessed September 7, 2025, https://www.drugs.com/drug-interactions/benzocaine-menthol-topical.html
50. FEB 14 2012 - Regulations.gov, accessed September 7, 2025, https://downloads.regulations.gov/FDA-1981-N-0013-0029/attachment_1.pdf
51. FDA Issues Reminder on Risk for Methemoglobinemia with Topical Benzocaine, accessed September 7, 2025, https://www.jwatch.org/fw201104080000003/2011/04/08/fda-issues-reminder-risk-methemoglobinemia-with
52. FDA Letter Regarding Benzocaine, accessed September 7, 2025, https://www.fda.gov/files/drugs/published/FDA-Letter-Regarding-Benzocaine.pdf
53. Rulemaking History for OTC External Analgesic Drug Products - FDA, accessed September 7, 2025, https://www.fda.gov/drugs/historical-status-otc-rulemakings/rulemaking-history-otc-external-analgesic-drug-products
54. Rulemaking History for OTC Weight Control Drug Products - FDA, accessed September 7, 2025, https://www.fda.gov/drugs/historical-status-otc-rulemakings/rulemaking-history-otc-weight-control-drug-products
55. Synthesis and microbiological evaluation of several benzocaine derivatives - ResearchGate, accessed September 7, 2025, https://www.researchgate.net/publication/256205720_Synthesis_and_microbiological_evaluation_of_several_benzocaine_derivatives
56. Antibacterial and anticancer profiling of new benzocaine derivatives: Design, synthesis, and molecular mechanism of action - PubMed, accessed September 7, 2025, https://pubmed.ncbi.nlm.nih.gov/35102593/