Benzydamine

History

It was synthesized in Italy in 1964 and marketed in 1966.

Uses

Medical

• Odontostomatology: gingivitis, stomatitis, glossitis, aphthous ulcers, dental surgery and oral ulceration due to radiation therapy.
• Otorhinolaryngology: glandular fever, pharyngitis, tonsillitis, post-tonsillectomy, radiation or intubation mucositis. It may be used alone or as an adjunct to other therapy giving the possibility of increased therapeutic effect with little risk of interaction.

In some markets, the drug is supplied as an over-the-counter cream (Lonol in Mexico from Boehringer Ingelheim) used for topical treatment of musculoskeletal system disorders: sprains, strains, bursitis, tendinitis, synovitis, myalgia, periarthritis.

Recreational

Benzydamine has been used recreationally. If taken in excess amounts, it acts as a deliriant and CNS stimulant. Poland, Romania, and Turkey.

Contraindications

There are no contraindications to the use of benzydamine except for known hypersensitivity.

Side effects

Benzydamine is well tolerated. Occasionally oral tissue numbness or stinging sensations may occur, as well as itching, a skin rash, skin swelling or redness, difficulty breathing and wheezing.

Pharmacology

It selectively binds to inflamed tissues (Prostaglandin synthetase inhibitor) and is normally free of adverse systemic effects. Unlike other NSAIDs, it does not inhibit cyclooxygenase or lipooxygenase, and is not ulcerogenic.

It is described as having powerful reinforcing effects in animals and showing cross-sensitization with drugs of misuse such as heroin and cocaine. It is hypothesized that it has cannabinoid agonistic activity and this may account for its recreational and hallucinogenic effects. However, it has also been theorized that, based on structural similarity to lysergic acid diethylamide (LSD) and descriptions of its visual hallucinatory effects, benzydamine might be acting as a serotonin 5-HT2A receptor agonist and hence as a serotonergic psychedelic. More research is needed to determine the mechanism of action of the effects of benzydamine as a drug of misuse.

Pharmacokinetic

Benzydamine is poorly absorbed through skin and vagina.

Synthesis

Synthesis starts with the reaction of the N-benzyl derivative from methyl anthranilate with nitrous acid to give the N-nitroso derivative. Reduction by means of sodium thiosulfate leads to the transient hydrazine (3), which undergoes spontaneous internal hydrazide formation. Treatment of the enolate of this amide with 3-chloro-1-dimethylamino propane gives benzydamine (5). Please note there is an error in this section: US3318905 states that the nitroso derivative is reduced with sodium hydrosulfite (sodium dithionite) and not with sodium hyposulfite (sodium thiosulfate), as shown in the above scheme and stated in text.

An interesting alternative synthesis of this substance starts by sequential reaction of N-benzylaniline with phosgene, and then with sodium azide to produce the corresponding carbonyl azide. On heating, nitrogen is evolved and a separatable mixture of nitrene insertion product and the desired ketoindazole # results. The latter reaction appears to be a Curtius rearrangement type product to produce an N-isocyanate #, which then cyclizes. Alkylation of the enol with sodium methoxide and 3-dimethylaminopropyl chloride gives benzydamine.

Alternatively, use of chloroacetamide in the alkylation step followed by acid hydrolysis produces bendazac instead.

Research

Studies indicate that benzydamine has notable in vitro antibacterial activity and also shows synergism in combination with other antibiotics, especially tetracyclines, against antibiotic-resistant strains of Staphylococcus aureus and Pseudomonas aeruginosa.

It also has some cannabinoid activity in rats but has not been tested in humans. It is also hypothesized to act on 5-HT2A receptors due to its structural similarity with serotonin.

References

References

1. (May 2025). "Therapeutic Goods (Poisons Standard— June 2025) Instrument 2025".
2. Anvisa. (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial". [[Diário Oficial da União]].
3. "Benzydamine hydrochloride Medicinal forms".
4. (February 1995). "Benzydamine Hydrochloride (Tantum) in the management of oral inflammatory conditions". Journal.
5. "DEXTROMETHORPHAN AND BENZYDAMINE'S USE AND MISUSE".
6. (September 2009). "Recreational use of benzydamine as a hallucinogen among street youth in Brazil". Revista Brasileira de Psiquiatria.
7. (May 2010). "Use abusive of benzydamine in Brazil: an overview in pharmacovigilance". Ciencia & Saude Coletiva.
8. (2007). "Recreational abuse with benzydamine hydrochloride (tantum rosa)". Clinical Toxicology.
9. (May 1987). "New pharmacologic and biochemical findings on the mechanism of action of the non-steroidal antiphlogistic, benzydamine. A synopsis". [[Arzneimittel-Forschung]].
10. (April 2023). "Benzydamine-An Affordable Over-the-Counter Drug with Psychoactive Properties-From Chemical Structure to Possible Pharmacological Properties". Pharmaceuticals (Basel).
11. (October 2021). "The Benzydamine Experience: A Systematic Review of Benzydamine Abuse". Curr Neuropharmacol.
12. (October 1991). "Pharmacokinetics of benzydamine after intravenous, oral, and topical doses to human subjects". [[Biopharmaceutics & Drug Disposition]].
13. (1987). "Concentration of benzydamine in vaginal mucosa following local application: an experimental and clinical study". [[International Journal of Tissue Reactions]].
14. (January 1966). "Synthesis and pharmacological properties of 1-substituted 3-dimethylaminoalkoxy-1H-indazoles". Journal of Medicinal Chemistry.
15. {{cite patent. 3318905 (1964, 1967 both to Angelini Francesco).
16. (1965). "Ricerche nel campo degli indazoli.—Nota 1. Sulla ciclizzazione termica di azidi di acidi N-aril-N-benzil-carbamici.". Annali di Chimica.
17. (December 1992). "Antimicrobial activity of benzydamine, a non-steroid anti-inflammatory agent". Journal of Chemotherapy.
18. (March 1996). "Antibacterial activity of benzydamine and antibiotic-benzydamine combinations against multifold resistant clinical isolates". Arzneimittel-Forschung.
19. (March 2018). "Intravenous self-administration of benzydamine, a non-steroidal anti-inflammatory drug with a central cannabinoidergic mechanism of action". [[Addiction Biology]].