Benzocaine

Benzocaine
Names
Trade namesAnbesol, Lanacane, Orajel, others
IUPAC name
  • Ethyl 4-aminobenzoate
Clinical data
Drug classLocal anesthetic (ester)[1]
Main usesMinor skin injury, mouth pain, hemorrhoids, premature ejaculation[2][3]
Side effectsContact dermatitis, methemoglobinemia[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • US: C (Risk not ruled out)
    Routes of
    use    		Topical, by mouth
    External links
    AHFS/Drugs.comTopical: Monograph
    ENT: Monograph
    Legal
    Legal status
    • UK: GSL, P
    • US: OTC
    Chemical and physical data
    FormulaC9H11NO2
    Molar mass165.192 g·mol−1
    3D model (JSmol)
    SMILES
    • O=C(OCC)c1ccc(N)cc1
    InChI
    • InChI=1S/C9H11NO2/c1-2-12-9(11)7-3-5-8(10)6-4-7/h3-6H,2,10H2,1H3 checkY
    • Key:BLFLLBZGZJTVJG-UHFFFAOYSA-N checkY

    Benzocaine, sold under the brand name Orajel amongst others, is a local anesthetic.[2][3] Applied to the skin it may be used to help with minor skin injury, hemorrhoids, and premature ejaculation.[2] It may also be used mouth or ear pain.[3] Use in not recommended in those under 2 years old.[3]

    While generally well tolerated, contact dermatitis may occur.[2] Other side effects may include methemoglobinemia, seizures, and respiratory depression.[2] Safety in pregnancy is unclear.[4] Use by the mom when breastfeeding is unlikely to be harmful.[5] It is an ester.[1]

    Benzocaine was first made in 1890 in Germany and approved for medical use in 1902.[6] It is available as a generic medication and over the counter.[2][3] It is commonly used used many brand names.[1][3] In the United States a tube of 28 grams of 20% costs about 7 USD as of 2022.[7]

    Medical uses

    Benzocaine is indicated to treat a variety of pain-related conditions. It may be used for:

    • Local anesthesia of sore throat, cold sores, mouth ulcers, toothache, sore gums, denture irritation[8]
    • Earache[8]
    • Surgical or procedural local anesthesia[9]

    Other uses

    Jiffy Toothache Drops bottle (7.75% Benzocaine)

    Benzocaine is used as a key ingredient in numerous pharmaceuticals:

    • Some glycerol-based ear medications for use in removing excess wax as well as relieving ear conditions such as otitis media and swimmers ear.
    • Some previous diet products such as Ayds.
    • Some condoms designed to prevent premature ejaculation. Benzocaine largely inhibits sensitivity on the penis, and can allow for an erection to be maintained longer (in a continuous act) by delaying ejaculation. Conversely, an erection will also fade faster if stimulus is interrupted.[10][11]
    • Benzocaine mucoadhesive patches have been used in reducing orthodontic pain.[12]
    • In Poland it is included, together with menthol and zinc oxide, in the liquid powder (not to be confused with the liquid face powder) used mainly after mosquito bites. Today's ready made Pudroderm[13] was once used there as pharmaceutical compound.

    Available forms

    Benzocaine can come in a variety of preparations including:

    Oral preparations:

    • Lozenges (ex. Cepacol, Mycinettes)[14]
    • Throat Spray (ex. Ultra Chloraseptic)[15]

    Topical preparations:

    • Aerosol (ex. Topex)[16]
    • Gel (ex. Orajel)[17]
    • Paste (ex. Orabase)[18]
    • Cream (ex. Lanacane - active ingredient 3% Benzocaine)

    Otic preparations:

    • Solution (ex. Allergen)

    It is also combined with antipyrine to form antipyrine and benzocaine ear drops to relieve ear pain.

    Side effects

    Benzocaine is generally well tolerated and non-toxic when applied topically as recommended.[19]

    However, there have been reports of serious, life-threatening adverse effects (e.g., seizures, coma, irregular heart beat, respiratory depression) with over-application of topical products or when applying topical products that contain high concentrations of benzocaine to the skin.[20]

    Overapplication of oral anesthetics such as benzocaine can increase the risk of pulmonary aspiration by relaxing the gag-reflex and allowing regurgitated stomach contents or oral secretions to enter the airway. Applying an oral anesthetic and consuming beverages before going to bed can be particularly hazardous.

    The topical use of higher concentration (10–20%) benzocaine products applied to the mouth or mucous membranes has been found to be a cause of methemoglobinemia, a disorder in which the amount of oxygen carried by the blood is greatly reduced.[21] This side effect is most common in children under two years of age.[22] As a result, the FDA has stated that benzocaine products should not be used in children under two years of age, unless directed by and supervised by a healthcare professional.[23] In European countries, the contraindication applies to children under 12 years of age. Symptoms of methemoglobinemia usually occur within minutes to hours of applying benzocaine, and can occur upon the first-time use or after additional use.[23]

    Benzocaine may cause allergic reactions.[24][25][26][27] These include:

    Pharmacology

    Pharmacodynamics

    Pain is caused by the stimulation of free nerve endings. When the nerve endings are stimulated, sodium enters the neuron, causing depolarization of the nerve and subsequent initiation of an action potential. The action potential is propagated down the nerve toward the central nervous system, which interprets this as pain. Benzocaine acts to inhibit the voltage-dependent sodium channels (VDSCs) on the neuron membrane, stopping the propagation of the action potential.

    Chemistry

    Benzocaine is the ethyl ester of p-aminobenzoic acid (PABA). It can be prepared from PABA and ethanol[29] by Fischer esterification or via the reduction of ethyl p-nitrobenzoate. Benzocaine is sparingly soluble in water; it is more soluble in dilute acids and very soluble in ethanol, chloroform, and ethyl ether. The melting point of benzocaine is 88–90 °C,[30] and the boiling point is about 310 °C.[31] The density of benzocaine is 1.17 g/cm3.

    Benzocaine is commonly found, particularly in Britain, as an additive in street cocaine and also as a bulking agent in "legal highs".[32] Whilst giving a numbing effect similar to cocaine, users prefer Benzocaine as it is a better bulking and binding agent that can't be detected once mixed. Benzocaine is the most popular cutting agent worldwide,[33] Benzocaine was used in synthesis of leteprinim. Treatment of benzocaine with hydrazine leads to aminostimil - a compound related to isoniazid.

    Synthesis

    Benzocaine can be prepared by esterification using 4-aminobenzoic acid and ethanol.[34][35] It can also be prepared by reduction of ethyl 4-nitrobenzoate to the amine.[36][37] In industrial practice, the reducing agent is usually iron and water in the presence of a little acid.[38]

    History

    Benzocaine was first synthesized in 1890 by the German chemist Eduard Ritsert (1859–1946),[39] in the town of Eberbach[40] and introduced to the market in 1902 under the name "Anästhesin".[41][42]

    Other animals

    A bath solution of benzocaine has been used to anesthetize amphibians for surgery.[43][44]

    References

    1. 1 2 3 McFadden, John; Puangpet, Pailin; Pongpairoj, Korbkarn; Thaiwat, Supitchaya; Lee, Shan Xian (January 21, 2020). Common Contact Allergens: A Practical Guide to Detecting Contact Dermatitis. John Wiley & Sons. p. 297. ISBN 978-1-119-40566-5. Archived from the original on January 11, 2022. Retrieved January 9, 2022.
    2. 1 2 3 4 5 6 7 "Benzocaine (Topical) Monograph for Professionals". Drugs.com. Archived from the original on March 4, 2021. Retrieved January 9, 2022.
    3. 1 2 3 4 5 6 "Benzocaine (EENT) Monograph for Professionals". Drugs.com. Archived from the original on April 17, 2021. Retrieved January 9, 2022.
    4. ↑ "Benzocaine topical Use During Pregnancy". Drugs.com. Archived from the original on April 22, 2021. Retrieved January 9, 2022.
    5. ↑ "Benzocaine". Drugs and Lactation Database (LactMed). National Library of Medicine (US). 2006. Archived from the original on February 26, 2021. Retrieved January 9, 2022.
    6. ↑ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 475. ISBN 9783527607495. Archived from the original on December 29, 2016. Retrieved May 26, 2021.
    7. ↑ "Compare Benzocaine Prices - GoodRx". GoodRx. Retrieved January 9, 2022.
    8. 1 2 AHFS Drug Information 2007. McEvoy GK, ed. Benzocaine. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 2844-5.
    9. ↑ Sultan Healthcare. Topex metered spray (benzocaine 20%) prescribing information. Englewood, NJ; 2006.
    10. ↑ "'Longer-lasting' condom launched". BBC News. June 17, 2002. Archived from the original on February 14, 2009. Retrieved May 26, 2021.
    11. ↑ Garner, Dwight (December 15, 2002). "Endurance Condoms". The New York Times. Archived from the original on March 6, 2016. Retrieved May 26, 2021.
    12. ↑ Eslamian L, Borzabadi-Farahani A, Edini HZ, Badiee MR, Lynch E, Mortazavi A (2013). "The analgesic effect of benzocaine mucoadhesive patches on orthodontic pain caused by elastomeric separators, a preliminary study". Acta Odontol Scand. 71 (5): 1168–73. doi:10.3109/00016357.2012.757358. PMID 23301559. S2CID 22561192.
    13. ↑ "Produkty | PUDRODERM" (in polski). Archived from the original on October 18, 2016. Retrieved May 9, 2014.
    14. ↑ "Cepacol". Cepacol.com. Archived from the original on October 31, 2014. Retrieved June 2, 2015.
    15. ↑ "Ultra Chloraseptic Anaesthetic Throat Spray 0.71% - Summary of Product Characteristics (SmPC) - (eMC)". www.medicines.org.uk. Archived from the original on May 5, 2018. Retrieved May 5, 2018.
    16. ↑ "Topex Metered Spray-Sultan Healthcare". Sultanhc.com. Archived from the original on October 31, 2014. Retrieved June 2, 2015.
    17. ↑ "Orajel - Oral Care for the Whole Family". Orajel.com. May 11, 2015. Archived from the original on May 10, 2015. Retrieved June 2, 2015.
    18. ↑ "Colgate Orabase Paste with Benzocaine | Indications | Dental Products". Colgateprofessional.com. Archived from the original on May 23, 2015. Retrieved June 2, 2015.
    19. ↑ Lexicomp Online, Adult and Pediatric Lexi-Drugs Online, Hudson, Ohio: Lexi-Comp, Inc.; 2013; April 15, 2013.
    20. ↑ Food and Drug Administration. FDA Public Health Advisory: Life-threatening side effects with use of skin products containing numbing ingredients for cosmetic procedures. 2007 Feb 6, updated 2007 Feb 9. From FDA website
    21. ↑ Shua-Haim, J. R.; Gross, J. S. (1995). "Methemoglobinemia toxicity from topical benzocaine spray". Journal of the American Geriatrics Society. 43 (5): 590. doi:10.1111/j.1532-5415.1995.tb06117.x. PMID 7730550.
    22. ↑ "Benzocaine Topical Products: Sprays, Gels and Liquids – Risk of Methemoglobinemia". Drugs.com. Archived from the original on September 9, 2017. Retrieved March 20, 2014.
    23. 1 2 "FDA Drug Safety Communication: Reports of a rare, but serious and potentially fatal adverse effect with the use of over-the-counter (OTC) benzocaine gels and liquids applied to the gums or mouth". Fda.gov. Archived from the original on April 19, 2012. Retrieved June 2, 2015.
    24. ↑ "Allergy to Benzocaine" (PDF). Archived from the original (PDF) on March 20, 2014. Retrieved March 20, 2014.
    25. ↑ Sidhu, S. K.; Shaw, S; Wilkinson, J. D. (1999). "A 10-year retrospective study on benzocaine allergy in the United Kingdom". American Journal of Contact Dermatitis. 10 (2): 57–61. doi:10.1016/s1046-199x(99)90000-3. PMID 10357712.
    26. ↑ González-Rodríguez, A. J.; Gutiérrez-Paredes, E. M.; Revert Fernández, Á.; Jordá-Cuevas, E (2013). "Allergic contact dermatitis to benzocaine: The importance of concomitant positive patch test results" (PDF). Actas Dermo-Sifiliográficas. 104 (2): 156–8. doi:10.1016/j.ad.2011.07.023. PMID 22551703. Archived from the original (PDF) on March 3, 2016. Retrieved March 20, 2014.
    27. ↑ Leslie Goldman (February 5, 2008). "Go easy on medicated lotions, creams, gels". CNN. Archived from the original on March 4, 2016. Retrieved March 20, 2014.
    28. 1 2 Cetylite Industries. Cetacaine (benzocaine 14%, tetracaine 2% and butamben 2%) spray, gel and liquid prescribing information. Pennsauken, NJ; 2006 Sept.
    29. ↑ Demare, Patricia; Regla, Ignacio (2012). "Synthesis of Two Local Anesthetics from Toluene: An Organic Multistep Synthesis in a Project-Oriented Laboratory Course". Journal of Chemical Education. 89 (1): 147. Bibcode:2012JChEd..89..147D. doi:10.1021/ed100838a.
    30. ↑ "Monographs: Pharmaceutical substances: Benzocainum – Benzocaine". The International Pharmacopoeia. Archived from the original on December 13, 2019. Retrieved September 29, 2009.
    31. ↑ D'Ans-Lax, Taschenbuch für Chemiker und Physiker, 4. Auflage, Band 2, Springer Verlag 1982, ISBN 3-540-12263-X
    32. ↑ "Drug war targets cutting agents". August 9, 2010. Archived from the original on September 22, 2018. Retrieved May 26, 2021 – via www.bbc.co.uk.
    33. ↑ "Drug prices: All cut up : Cocaine is cheaper, but weaker". The Economist. August 11, 2012. Archived from the original on September 9, 2017. Retrieved March 15, 2022.
    34. ↑ Salkowski, H. (1895). "Ueber Esterbildung bei aromatischen Amidosäuren". Berichte der Deutschen Chemischen Gesellschaft. 28 (2): 1917–1923. doi:10.1002/cber.189502802150. Archived from the original on April 20, 2021. Retrieved May 26, 2021.
    35. ↑ Erlenmeyer, E.; Wanklyn, J. A. (1865). "Ueber das durch Einwirkung von Jodwasserstoff auf Mannit beziehungsweise auf Melampyrin (Dulcit) entstehende β Hexyljodür und einige seiner Derivate". Annalen der Chemie und Pharmacie. 135 (2): 129. doi:10.1002/jlac.18651350202. Archived from the original on April 26, 2021. Retrieved May 26, 2021.
    36. ↑ Limpricht, H. (1898). "Ueber die Verbindungen aus Benzoylchlorid oder Phtalylchlorid und den Estern der drei Oxybenzoësäuren". Justus Liebig's Annalen der Chemie. 303 (3): 274–289. doi:10.1002/jlac.18983030303. Archived from the original on April 26, 2021. Retrieved May 26, 2021.
    37. ↑ Adams, Roger & Cohen, F.L. (1928). "Ethyl p-aminobenzoate". Organic Syntheses. 8: 66.; Collective Volume, vol. 1, p. 240
    38. ↑ Ali, S. L. (1983). Benzocaine. Analytical Profiles of Drug Substances. Vol. 12. pp. 73–104. doi:10.1016/S0099-5428(08)60164-1. ISBN 978-0-12-260812-4.
    39. ↑ Biography of Eduard Ritsert (in German): Deutsche Biographie: Ritsert, Eduard. Archived June 8, 2019, at the Wayback Machine
    40. ↑ "100 years of Dr. Ritsert". Dr. Ritsert Pharma. Archived from the original on September 9, 2017. Retrieved March 14, 2010.
    41. ↑ Harry Auterhoff, Lehrbuch der pharmazeutischen Chemie (Stuttgart, Germany: Wissenschaftliche Verlagsgesellschaft, 1968).
    42. ↑ Ritsert, E. (1925) "Über den Werdegang des Anästhesins" (On the development of Anästhesin), Pharmazeutische Zeitung, vol. 60, pages 1006–1008. See also: Christoph Friedrich and Magdalena Klimonow, "150. Geburtstag: Eduard Ritsert und das Anaesthesin" Archived March 20, 2014, at the Wayback Machine (150th birthday: Eduard Ritsert and Anästhetsin [Benzocaine]"), Pharmazeutische Zeitung online. First published clinical study demonstrating the efficacy of benzocaine: Noorden, C. v. (1902) "Ueber para-Aminobenzoesäure-Ester als locales Anästhetikum" (On [an] ester of para-aminobenzoic acid as a local anaesthetic), Klinische Wochenschrift, vol. 39, pages 373–375.
    43. ↑ Guénette, SA; Giroux, MC; Vachon, P (2013). "Pain perception and anaesthesia in research frogs". Experimental Animals. 62 (2): 87–92. doi:10.1538/expanim.62.87. PMID 23615302. Archived from the original on August 25, 2017. Retrieved May 26, 2021.
    44. ↑ "Amphibian Anesthesia — Research at Penn State". PennState Animal Resource Program. State College, U.S.: The Pennsylvania State University. November 8, 2010. Archived from the original on November 3, 2018. Retrieved August 24, 2017.
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