Benzonatate (/bɛnˈzoʊnəteɪt/), sold under the brand name Tessalon among others, is a medication that is used for the symptomatic relief of cough.[7][8] Benzonatate is taken by mouth.[7][5] Effects generally begin within 20minutes and last 3 to 8hours.[7][3]
Benzonatate was discovered in 1956 and was approved for medical use in the United States in 1958.[5][7] It is available as a generic medication.[9] Availability worldwide is limited, with the drug remaining marketed only in the United States and Mexico.[13][12][14] In 2022, it was the 130th most commonly prescribed medication in the United States, with more than 4million prescriptions.[15][16] A 2023 systematic review found that there is inadequate evidence to support the effectiveness and safety of benzonatate for cough and highlighted rising safety concerns.[17]
Compared to codeine, benzonatate has been reported to be more effective in reducing the frequency of induced cough in experiments.[7]
Benzonatate does not treat the underlying cause of the cough.[19]
According to a 2001 literature review, more than 29 clinical studies have assessed benzonatate for the treatment of cough in more than 2,100 patients.[5]
A systematic review of the literature of benzonatate for cough was published in 2023.[17] The review identified 37 relevant articles including 21 cohort studies, 5 experimental studies, and 11 case studies and series.[17] The data were of very low quality.[17] Most of the studies on benzonatate are decades old and were conducted shortly after its introduction.[12] The systematic review concluded that there is inadequate evidence to support the effectiveness and safety of benzonatate and emphasized rising safety concerns surrounding the drug.[17] It further concluded that there is a need for large observational studies or randomized trials to assess the place of benzonatate in modern medicine.[17]
Hiccups
Benzonatate has been reported to be useful in the suppression of hiccups.[8]
Intubation
Benzonatate acts as a local anesthetic and the liquid inside the capsule can be applied in the mouth to numb the oropharynx for awake intubation.[7] However, there can be life-threatening adverse effects when the medication is absorbed by the oral mucosa, including choking, hypersensitivity reactions, and circulatory collapse.[7]
Hypersensitivity to benzonatate or any related compounds is a contraindication to its administration.[3]
Side effects
Benzonatate is generally well-tolerated[vague] if the liquid-capsule is swallowed intact.[7] Potential adverse effects of benzonatate include:
Constipation, dizziness, fatigue, stuffy nose, nausea, and headache are frequently reported.[21]
Sedation, a feeling of numbness in the chest, sensation of burning in the eyes, a vague "chilly" sensation, itchiness, and rashes are also possible.[7][3]
Ingestion of a small handful of capsules has caused seizures, cardiac arrhythmia, and death in adults.[22]
Hypersensitivity reactions
Benzonatate is structurally related to anesthetic medications of the para-aminobenzoic acid (PABA) class which includes procaine and tetracaine.[3][22][12] Procaine and tetracaine, previously used heavily in the fields of dentistry and anesthesiology, have fallen out of favor due to allergies associated with their metabolites.[22] Similarly, severe hypersensitivity reactions to benzonatate have been reported and include symptoms of laryngospasm, bronchospasm, and cardiovascular collapse.[3][23] These reactions are possibly associated with chewing, sucking, or crushing the capsule in the mouth.[3][22]
Improper use
Benzonatate should be swallowed whole.[3] Crushing or sucking on the liquid-filled capsule, or "softgel," will cause release of benzonatate from the capsule and can produce a temporary local anesthesia of the oral mucosa.[3] Rapid development of numbness of the tongue and choking can occur.[3][22] In severe cases, excessive absorption can lead to laryngospasm, bronchospasm, seizures, and circulatory collapse.[3][22] This may be due to a hypersensitivity reaction to benzonatate or a systemic local anesthetic toxicity, both of which have similar symptoms.[22] There is a potential for these adverse effects to occur at a therapeutic dose, that is, a single capsule if chewed or sucked on in the mouth.[22]
Psychiatric effects
Isolated cases of bizarre behavior, mental confusion, and visual hallucinations have been reported during concurrent use with other prescribed medications.[3]Central nervous system effects associated with other para-aminobenzoic acid (PABA) derivative local anesthetics, for example procaine or tetracaine, could occur with benzonatate and should be considered.[7]
Children
Safety and efficacy in children below the age of ten have not been established.[3] Accidental ingestion resulting in death has been reported in children below the age of ten.[3] Benzonatate may be attractive to children due to its appearance, a round-shaped liquid-filled gelatin capsule, which looks like candy.[23][24] Chewing or sucking of a single capsule can cause death of a small child.[3][24] Signs and symptoms can occur rapidly after ingestion (within 15–20 minutes) and include restlessness, tremors, convulsions, coma, and cardiac arrest.[24] Death has been reported within one hour of ingestion.[21][24]
Pregnancy and breastfeeding
It is not known if benzonatate can cause fetal harm to a pregnant woman or if it can affect reproduction capacity.[3][11] Animal reproductive studies have not been conducted with benzonatate to evaluate its teratogenicity.[3]
It is not known whether benzonatate is excreted in human milk.[3][11]
Despite a long history of safe and appropriate usage, the safety margin of benzonatate is reportedly narrow.[22] Toxicity above the therapeutic dose is relatively low and ingestion of a small handful of pills can cause symptoms of overdose.[22][19] Children are at an increased risk for toxicity, which has occurred with administration of only one or two capsules.[24][25][19] Following cardiopulmonary collapse with benzonatate overdose, most people have significant neurological deficits or other end-organ damage.[10]
Due to increasing usage of benzonatate and the rapid onset of symptoms, there are accumulating cases of benzonatate overdose deaths, especially in children.[19][10]
Benzonatate is hydrolyzed by plasma butyrylcholinesterase (BChE) to the metabolite 4-(butylamino)benzoic acid (BABA) as well as polyethylene glycol monomethyl ethers.[22] Like many other local anesthetic esters, the hydrolysis of the parent compound is rapid.[22] There are concerns that those with pseudocholinesterase deficiencies may have an increased sensitivity to benzonatate as this hydrolysis is impaired, leading to increased levels of circulating medication.[22]
Benzonatate was first synthesized in 1956 and was introduced as an antitussive in the United States in 1958.[5]
Society and culture
Benzonatate was first made available in the United States in 1958 as a prescription medication for the treatment of cough in individuals over the age of 10.[24][25] There is a variety of prescription opioid-based cough relievers, such as hydrocodone and codeine, but have unwanted side effects and potential of abuse and diversion.[22] However, benzonatate is currently the only prescription non-opioid antitussive and its usage has been rapidly increasing.[22][19] The exact reasons of this increase are unclear.[19]
Economics
In the United States between 2004 and 2009, prescriptions increased 50% from 3.1 million to 4.7 million, the market share of benzonatate among antitussives increased from 6.3% to 13%, and the estimated number of children under the age of 10 years receiving benzonatate increased from 10,000 to 19,000.[22][19] Throughout this same period, greater than 90% of prescriptions were given to those 18 or older.[19] The majority of prescriptions were given by general, family, internal, and physicians with pediatricians accounting for about 3% of prescribed benzonatate.[19]
In 2022, it was the 130th most commonly prescribed medication in the United States, with more than 4million prescriptions.[15][16]
Brand names
Tessalon is a brand name version of benzonatate manufactured by Pfizer.[22][19] It is available as perles (capsules).[3] Zonatuss was a brand name manufactured by Atley Pharmaceuticals, Inc. and Vertical Pharmaceuticals, Inc.[26][27] Other brand names of benzonatate include Exangit, Tessalin, Tesalon, Tusical, Tusitato, and Ventussin.[1]
Availability
Benzonatate is available in the United States and Mexico.[12][14]
^Estfan B, LeGrand S (November 2004). "Management of cough in advanced cancer". The Journal of Supportive Oncology. 2 (6): 523–527. PMID16302303.
^ abcdefghijklMcLawhorn MW, Goulding MR, Gill RK, Michele TM (January 2013). "Analysis of benzonatate overdoses among adults and children from 1969-2010 by the United States Food and Drug Administration". Pharmacotherapy. 33 (1): 38–43. doi:10.1002/phar.1153. PMID23307543. S2CID35165660.
