Scientists seek odontological injection-free anesthesia

Brazilian study aims to dispense with dental injections by creating an anesthetic gel or cream.

By Luiz Paulo Juttel

Agência FAPESP – Painless and needle-free buccal anesthesia has long been a desire of odontological professionals and is considered by many to be the “Holy Grail” of the profession. After all, anesthetics have been applied to the buccal mucosa through the same painful injections for almost 100 years. Isn’t there a less invasive alternative?

Researchers from Universidade Estadual de Campinas (Unicamp) believe there is. The team coordinated by biochemist Eneida de Paula of the Biology Institute developed the FAPESP-funded Thematic Project “New formulations for the controlled release of local anesthetics in dentistry: from development to clinical tests,” whose main objective was to create an anesthetic gel or cream for use by dentists.

De Paula explains that the proposal was not to produce new anesthetic molecules because that would require at least 10 years of development and clinical trials. The purpose was to broaden the efficacy of the anesthetic salts available on the market and encapsulate them within carriers or nanoparticles capable of taking the active ingredients to the desired area and releasing them in a controlled manner.

The association between carriers and anesthetics could, theoretically, extend the duration of anesthesia, require a lower concentration of the main active ingredient and lower the risk of the compound entering the blood stream and spreading through the body in harmful ways.

The study began in 2007 with the choice of an ideal carrier for each anesthetic. “It cannot cause adverse reactions in the organism, it would have to be chemically stable and would need to maintain the anesthesia on the application site for the longest possible time,” commented De Paula in an interview with Agência FAPESP.

Liposomes, particles made of lipids and similar biological membranes, were the first carriers tested by the group. According to De Paula, liposomes are capable of carrying anesthetics without generating adverse reactions and are already used by the pharmaceutical industry in antivirals and antifungals as well as for the development of vaccine and cancer medicines.

The researcher explains that liposomes offer a molecular environment similar to the site of action site of local anesthetics. “Furthermore, its [the liposome’s] chemical properties attract these medicines, which are retained in its membranes, preventing rapid absorption outside the site of action.”

Tests in animals and humans show that the use of liposomes as carriers prolonged the action time of the anesthetics mepivacaine and prilocaine three- to fourfold compared to the duration of the commercially available anesthetic formulations, which act for two to four hours. This efficacy, however, still depends on the use of syringes for application.

To eliminate pain, the anesthetic salt must cross the mucosa and the compact bone of the mouth to block the conduction of the nerve impulses that transmit sensory information from the dental region to the brain.

“We imagined that liposomes would pass through the bone with more ease and therefore reach the nerve to be anesthetized. But this did not happen,” explained Francisco Carlos Groppo and Maria Cristina Volpato, researchers at the Unicamp’s School of Odontology in Piracicaba.

The scientists involved in the Thematic Project are seeking to extend the duration of anesthetic action by many hours, with or without the use of syringes. To this end, they have decided to study alternative carriers.

De Paula has initiated tests with cyclodextrins, molecules produced by breaking down starch. “One of the main advantages of cyclodextrins is that they increase the water solubility of the anesthetics, allowing a greater quantity of the compound to reach the nerve that needs to be anesthetized. In standard formulations, large quantities of anesthetics are necessary to bathe the region of the nerve and impede propagation of the painful impulse,” explained the researcher responsible for the Thematic Project.

Animal trials have shown that when anesthetics such as bupivacaine and ropivacaine are formulated in complex with hydroxypropyl-beta-cyclodextrin, the duration and intensity of anesthesia increases to over six hours after a single application.

Studies also indicate that when anesthetics are encapsulated by carriers, lower quantities of the main active ingredient are needed for anesthetization. In animals, mepivacaine (2%) encapsulated in liposomes exhibited an anesthetic activity similar to that of mepivacaine (3%) without a carrier.

The study led by De Paula has also generated a patent that has sparked interest among pharmaceutical industries. The researchers have perfected the composition of a gel that, in some cases, can be applied to the buccal mucosa to reduce the pain of an anesthetic injection.

Liposomes were used to encapsulate local anesthetics such as benzocaine and mepivacaine. In the case of benzocaine, the efficacy of the gel was maintained even when the concentration of the main active ingredient was reduced by half, from 20% to 10%.

“The gel also presented several interesting rheological properties that allow drugs to remain on the application site, without dissolving or losing activity, for more time than products available on the market,” said De Paula. Companies interested in selling this technology can contact Inova Unicamp.

The researcher highlights that the Thematic Project also plays a relevant role in training qualified practitioners in this research area. Throughout the project, the participants published 46 scientific articles in indexed international journals, resulting in 19 doctoral theses and 22 master’s dissertations.

Furthermore, three professionals trained under the auspices of the project have become leaders of new research groups, helping to develop medication transport systems based on polymers for topical use or determine the pharmacokinetics of sustained release, at the Universidade Estadual Paulista (Unesp), Universidade Federal do ABC and Universidade São Francisco.

The advances made through the project led Unicamp researchers to believe that it is possible to develop a buccal anesthetic that can be administered without an injection. “Nevertheless, it is necessary to advance research with new carriers such as polymers, improve the technology for developing liposomes and reduce the production costs of these compounds,” said De Paula.