Benzocaine/Lidocaine/Tetracaine

Benzocaine (ethyl 4-aminobenzoate) is an ester-type local anesthetic with low water solubility, used only topically. It is an OTC monograph topical anesthetic ingredient and appears in prescription combination products such as Cetacaine (benzocaine 14% / butamben 2% / tetracaine 2% topical spray). Lake Hills Pharmacy uses benzocaine in compounded topical anesthetic combinations.

• OTC skin use: temporary relief of pain and itching from minor burns, sunburn, minor cuts, scrapes, insect bites and minor skin irritation.
• OTC oral use: temporary relief of pain from canker sores, minor mouth irritation and sore throat. FDA has stated that OTC oral benzocaine should not be used for teething in infants and children under 2 years.
• Cetacaine (Rx): topical anesthesia of accessible mucous membranes, except the eyes, to control pain or gagging.
• Prescribers use benzocaine in compounded combinations with lidocaine and tetracaine for anesthesia of intact skin before procedures.

Benzocaine reversibly binds voltage-gated sodium channels in neuronal membranes, preventing the sodium influx needed for depolarization and blocking conduction of pain impulses from free nerve endings. Because it is uncharged at physiologic pH, it acts mainly on superficial nerve endings at the site of application.

Benzocaine is poorly absorbed through intact skin and better absorbed through mucous membranes and damaged or inflamed skin; absorption rises with larger areas, longer contact and occlusion. Onset on mucosa is rapid. It is hydrolyzed by plasma pseudocholinesterase and hepatic esterases to para-aminobenzoic acid (PABA), and metabolites are excreted in the urine. Oxidized metabolites can convert hemoglobin to methemoglobin.

• Hypersensitivity to benzocaine, other ester-type local anesthetics, PABA or its derivatives, or any component.
• Congenital or idiopathic methemoglobinemia.
• OTC oral benzocaine: infants and children under 2 years.

• Methemoglobinemia: can follow a single application and appear within minutes to hours. Risk is higher in infants, the elderly, and patients with G6PD deficiency, heart or lung disease, or concurrent oxidizing drugs. Signs include gray or blue skin, headache, fatigue, tachycardia, shortness of breath and low oxygen saturation that does not improve with oxygen; treatment is with methylene blue.
• Hypersensitivity: benzocaine is a common contact sensitizer; cross-reactivity with other para-amino compounds can occur.
• Avoid the eyes. Do not apply to large areas, broken skin or under occlusion unless directed, since absorption and toxicity increase.

• Other methemoglobin-inducing drugs (dapsone, nitrates and nitrites including nitroglycerin, nitric oxide, sulfonamides, primaquine, chloroquine, nitrofurantoin, rasburicase): increased methemoglobinemia risk.
• Other local anesthetics: additive toxicity.
• Sulfonamide antibacterials: the PABA metabolite may antagonize their effect.
• Cholinesterase inhibitors can slow ester hydrolysis and prolong exposure.

Burning, stinging, erythema, edema, contact dermatitis and urticaria at the application site; methemoglobinemia; rarely, anaphylaxis.

Systemic absorption from intact skin is limited, but human data in pregnancy and lactation are lacking. Large-area or mucosal use should be avoided unless clearly needed.

Signs of methemoglobinemia (cyanosis, chocolate-brown blood, low pulse oximetry readings), confirmed by co-oximetry if suspected; local skin reactions; and adherence to the prescribed amount, area and contact time.

• FDA Drug Safety Communication: risk of methemoglobinemia with benzocaine and other local anesthetics (2018).
• Cetacaine (benzocaine, butamben, tetracaine) Topical Anesthetic Prescribing Information, Cetylite Industries.
• FDA OTC monograph for external analgesic drug products for over-the-counter human use.
• Martindale: The Complete Drug Reference, benzocaine monograph.

Lidocaine is an amide local anesthetic and a class IB antiarrhythmic. US products include Xylocaine and generic injections (infiltration, nerve block, epidural and intravenous antiarrhythmic use) and many topical forms: 5% ointment, 4% solution, 2% jelly, 2% viscous oral solution, Lidoderm 5% patch, ZTlido 1.8% patch, and combinations such as EMLA (lidocaine/prilocaine) and Pliaglis (lidocaine/tetracaine). Lake Hills Pharmacy uses lidocaine in compounded topical anesthetic preparations.

• Injection: local or regional anesthesia by infiltration, peripheral nerve block and epidural techniques; intravenous treatment of ventricular arrhythmias.
• Lidoderm and ZTlido patches: relief of pain associated with postherpetic neuralgia.
• Topical ointment, solution and jelly: anesthesia of accessible mucous membranes and of the urethra, and relief of pain from minor burns and skin irritation.
• EMLA and Pliaglis: dermal anesthesia or analgesia on intact skin before superficial procedures.
• Prescribers use lidocaine in compounded topical anesthetic creams for procedural skin anesthesia and for localized pain.

Lidocaine blocks voltage-gated sodium channels, binding preferentially to the inactivated state, which stabilizes neuronal membranes and blocks initiation and conduction of nerve impulses. In the heart it shortens the action potential duration in Purkinje fibers and suppresses ventricular automaticity.

Systemic absorption depends on dose, site, area treated, contact time, skin integrity, vascularity, heat and occlusion; it is low through intact skin and high through mucous membranes. Lidocaine is 60 to 80% protein bound, mainly to alpha-1-acid glycoprotein. It is metabolized in the liver by CYP1A2 and CYP3A4 to the active metabolites monoethylglycinexylidide and glycinexylidide; less than 10% is excreted unchanged. The half-life is about 1.5 to 2 hours and is prolonged in hepatic impairment and heart failure.

• Hypersensitivity to lidocaine, other amide-type local anesthetics or any component.
• Intravenous antiarrhythmic use: Stokes-Adams syndrome, Wolff-Parkinson-White syndrome, and severe sinoatrial, atrioventricular or intraventricular block without a pacemaker.

• Methemoglobinemia: reported with local anesthetics; risk is higher with G6PD deficiency, congenital methemoglobinemia, cardiac or pulmonary compromise, infants under 6 months, and concurrent oxidizing drugs.
• Systemic toxicity: CNS effects (lightheadedness, perioral numbness, tinnitus, confusion, tremor, seizures, respiratory depression) and cardiovascular effects (bradycardia, hypotension, arrhythmia, cardiac arrest).
• Topical use over large areas, for long periods, on broken skin, with heat or under occlusion increases absorption; FDA has warned of seizures and deaths with compounded topical anesthetics used this way.
• Use caution in hepatic impairment, heart failure, debilitated or elderly patients, and in patients with conduction disorders. Avoid the eyes.

• Class I antiarrhythmics (such as mexiletine) and other local anesthetics: additive toxicity.
• CYP1A2 inhibitors (fluvoxamine, ciprofloxacin), CYP3A4 inhibitors (erythromycin, itraconazole), amiodarone, cimetidine and beta-blockers such as propranolol: raise lidocaine levels.
• Methemoglobin-inducing drugs (dapsone, nitrates and nitrites, sulfonamides, primaquine, nitrofurantoin): increased methemoglobinemia risk.
• Class III antiarrhythmics such as amiodarone: additive cardiac effects.

Topical: erythema, edema, blanching, burning, itching and contact dermatitis. Systemic: dizziness, drowsiness, paresthesia, tinnitus, blurred vision, tremor, seizures, bradycardia, hypotension, arrhythmia and, rarely, methemoglobinemia or anaphylaxis.

Lidocaine crosses the placenta and has been used widely in obstetric anesthesia without evidence of teratogenicity at clinical exposures. Small amounts pass into breast milk and are poorly absorbed orally by the infant, so topical use during breastfeeding is generally considered compatible.

With high-strength or large-area topical use: early signs of systemic toxicity (perioral numbness, tinnitus, dizziness, confusion, arrhythmia), pulse oximetry and co-oximetry if methemoglobinemia is suspected, and adherence to the prescribed amount, area and time. With intravenous use: ECG, blood pressure and CNS status.

• Xylocaine (lidocaine HCl) Injection Prescribing Information, Fresenius Kabi.
• Lidoderm (lidocaine patch 5%) Prescribing Information.
• Lidocaine Hydrochloride Oral Topical Solution USP 2% (viscous) prescribing information.
• FDA Drug Safety Communication: risk of methemoglobinemia with benzocaine and other local anesthetics (2018).
• FDA Public Health Advisory: life-threatening side effects with skin numbing products used for cosmetic procedures (2009).

Tetracaine is a potent, long-acting ester-type local anesthetic. US products include tetracaine hydrochloride ophthalmic solution 0.5%, Pliaglis (lidocaine 7% / tetracaine 7% cream), Synera (lidocaine 70 mg / tetracaine 70 mg topical patch), Kovanaze (tetracaine 3% / oxymetazoline 0.05% nasal spray) and Cetacaine (benzocaine / butamben / tetracaine spray). Lake Hills Pharmacy uses tetracaine in compounded topical anesthetic combinations.

• Ophthalmic solution: procedures requiring a rapid, short-acting topical ocular anesthetic.
• Pliaglis: local dermal analgesia on intact skin for superficial dermatologic procedures such as dermal filler injection, pulsed-dye laser therapy, facial laser resurfacing and laser-assisted tattoo removal.
• Synera: local dermal analgesia for superficial venous access and superficial dermatologic procedures such as excision, ablation or biopsy.
• Kovanaze: regional anesthesia for restorative dental procedures on specified maxillary teeth in adults and children weighing at least 40 kg.
• Prescribers use tetracaine in compounded topical anesthetic combinations for procedural skin anesthesia.

Tetracaine reversibly blocks voltage-gated sodium channels in neuronal membranes, preventing depolarization and conduction of nerve impulses. Its high lipid solubility and protein binding account for its potency and long duration compared with other ester anesthetics.

Absorption through intact skin is limited and is greater through mucous membranes and damaged skin, and with larger areas, longer contact, heat or occlusion. Tetracaine is hydrolyzed by plasma pseudocholinesterase to p-butylaminobenzoic acid, a PABA derivative, and dimethylaminoethanol, which are excreted in the urine. Hydrolysis is slower than for procaine, and patients with pseudocholinesterase deficiency have prolonged exposure.

• Hypersensitivity to tetracaine, other ester-type local anesthetics, PABA or its derivatives, or any component.
• For combination products, the contraindications of each component also apply (for example, amide anesthetic hypersensitivity for lidocaine/tetracaine products).

• Methemoglobinemia: reported with local anesthetics; higher risk with G6PD deficiency, congenital methemoglobinemia, cardiac or pulmonary compromise, infants and concurrent oxidizing drugs.
• Systemic toxicity: CNS excitation then depression, seizures, bradycardia, hypotension, arrhythmia and cardiac arrest, especially with large-area, prolonged or occluded application.
• Pseudocholinesterase deficiency increases the risk of toxicity.
• Ophthalmic: prolonged or repeated use can cause corneal epithelial toxicity, keratitis and permanent corneal damage; the eye should be protected while anesthetized.
• Topical products: apply only to intact skin and avoid the eyes and mucous membranes unless labeled. Synera contains a heating element and must be removed before MRI.

• Other local anesthetics and, with lidocaine-containing combinations, Class I antiarrhythmics: additive toxicity.
• Methemoglobin-inducing drugs (dapsone, nitrates and nitrites, sulfonamides, primaquine, nitrofurantoin): increased methemoglobinemia risk.
• Sulfonamide antibacterials: the PABA-derived metabolite may antagonize their effect.
• Cholinesterase inhibitors, such as echothiophate, slow tetracaine hydrolysis and increase exposure.

Topical: erythema, blanching, edema, burning, itching and contact dermatitis. Ophthalmic: stinging, burning, conjunctival redness and keratitis. Systemic: dizziness, tinnitus, perioral numbness, seizures, bradycardia, hypotension and arrhythmia. Allergic reactions are more common with ester than amide anesthetics.

Human data are limited. Systemic exposure from labeled topical use is low. Whether tetracaine is excreted in human milk is unknown; with limited absorption, infant exposure from topical use is expected to be small.

With high-strength or large-area topical use: early signs of systemic toxicity, pulse oximetry and co-oximetry if methemoglobinemia is suspected, local skin reactions, and adherence to the prescribed amount, area and contact time.

• Pliaglis (lidocaine and tetracaine) Cream 7%/7% Prescribing Information.
• Synera (lidocaine and tetracaine) Topical Patch Prescribing Information.
• Tetracaine Hydrochloride Ophthalmic Solution 0.5% Prescribing Information.
• Kovanaze (tetracaine HCl and oxymetazoline HCl) Nasal Spray Prescribing Information, Septodont.
• FDA Drug Safety Communication: risk of methemoglobinemia with benzocaine and other local anesthetics (2018).