A narrative review on local anesthetics in dentistry: mechanism of action, characteristics, and clinical considerations

Introduction

Background

Local anesthesia can be defined as the absence of sensitivity in a localized area of the body without causing loss of consciousness (1). Ideal local anesthetics should be reversible, non-toxic, fast-acting, long-lasting, potent at low doses, sterile, and free of allergic reactions (1,2).

An interesting article published by dos Reis [2009] (3) provides an overview of how the discovery of local anesthetics for clinical use occurred. The first clinically used local anesthetic, cocaine, was initially studied by Sigmund Freud [1856–1939] for medical applications but was later abandoned due to its addictive properties and health risks (3). In 1884, Karl Koller [1857-1944] demonstrated its anesthetic potential in ophthalmic surgery, paving the way for its use in infiltration and nerve block anesthesia (4).

Since the introduction of cocaine as the first local anesthetic in 1884, a number of agents have been developed and refined, many of which remain central to dental practice, such as benzocaine [1890], lidocaine [1943], prilocaine [1953], mepivacaine [1957], bupivacaine [1957], and articaine [1969].

Rationale and knowledge gap

Clinically, dentists often face challenges in selecting the most appropriate local anesthetic, particularly when considering pharmacological properties and use in patients with systemic conditions. Despite the extensive pharmacological knowledge available, few publications effectively bridge this information with practical guidance on the selection of anesthetics and vasoconstrictors for clinical application.

Objective

Given that local anesthesia involves the injection of drugs, a route associated with higher risk, clarity and confidence in its application are essential. Hence, the objective of this review is to provide robust scientific evidence, combined with clinical evidence, to ensure that dentists have clarity and discernment when performing local anesthesia. We present this article in accordance with the Narrative Review reporting checklist (available at https://joma.amegroups.com/article/view/10.21037/joma-25-8/rc).

Methods

The methods are described in Table 1. Briefly, a bibliographic search was conducted in the PubMed, Scopus, Web of Science, and Google Scholar databases from their start dates to March 5, 2025. The descriptors used included [(“local anesthetic” OR “dental anesthesia”) AND (“vasoconstrictor agents” OR “vasoconstrictor dentistry”)]. Studies published in English and Portuguese that addressed the characteristics and indications of anesthetic salts and associated vasoconstrictors, their mechanism of action, allergenic potential, clinical indications, toxicity, and maximum doses of each local anesthetic solution used in dentistry were included. The selection of articles was carried out in three stages: (I) screening of titles and abstracts; (II) full-text reading of potentially relevant studies; and (III) extraction of key information from the selected studies. Data analysis was conducted qualitatively, considering the most relevant findings of each study.

Mechanism of action of local anesthetics

How does pain occur?

Pain occurs when nerve impulses from dental tissues reach the brain (1,5) (Figure 1). Neurons are nerve cells capable of transmitting electrical impulses. Sensory neurons transmit pain signals through three steps: transduction (nerve sensitization), transmission (impulse propagation), and translation (pain recognition in the brain).

Figure 1 Transduction, transmission, and translation processes. Sensory neurons can be divided into three parts: the peripheral process (dendritic zone), axon, and cell body. The peripheral process, located in the most distal portion of the neuron, is sensitized when tissue stimulation occurs (e.g., trauma). This process is called transduction, which is simply the sensitization of the nerve cell. Once sensitized, the peripheral process generates a nerve (electrical) impulse that is transmitted through the axon to the central nervous system (brain). This process is known as transmission. In the central nervous system, this electrical impulse is recognized by the brain as a painful nerve impulse, leading the individual to perceive pain. This phenomenon is termed translation.

The axon consists of a layer of neural cytoplasm (axoplasm) surrounded by a nerve membrane. This nerve membrane plays a fundamental role in the initiation and conduction of nerve impulses. At rest, it acts as an insulator between the internal environment of the nerve fiber and the extracellular medium and regulates the entry and exit of ions. When excited, it allows the exchange of ions within the nerve fiber, generating immediate energy for nerve impulse conduction. The axons of afferent sensory nerve fibers, responsible for the pain phenomenon, are covered by a lipid layer called myelin. This characteristic enables these nerves to transmit nerve impulses much faster than unmyelinated fibers (1,6). Thus, once a stimulus (physical, chemical, electrical, or thermal) occurs, the nerve fiber membrane is sensitized, and the nerve impulse is transmitted from the periphery toward the central nervous system without energy loss.

Nerve impulse conduction occurs through nerve depolarization and repolarization processes. At rest, the nerve has a negative polarity inside and a positive polarity outside. This depolarization and repolarization process depends on the exchange of ions between the external and internal environment of the neuron. The regulation of these exchanges, as previously mentioned, is carried out by the nerve membrane, which at rest is fully permeable to potassium ions (K⁺) and chloride ions (Cl⁻) but has low permeability to sodium ions (Na⁺). Under these conditions, K⁺ remain inside the axon, while Na⁺ and Cl⁻ remain outside (Figure 2).

Figure 2 Depolarization and repolarization processes.

Depolarization: when a segment of the nerve is stimulated, sodium channels in the nerve membrane open, allowing a rapid influx of Na⁺ into the axon. This process is extremely fast (0.3 ms), causing a temporary reversal of polarity, making the internal environment positive and the external environment negative (Figure 2).

Repolarization: after depolarization of a segment of the axon, sodium channels close. With the polarity reversed (internal positive, external negative), Na⁺ struggle to exit the axon due to the closed sodium channels. However, the nerve membrane remains highly permeable to K⁺, which passively exit the axon, leading to repolarization, restoring the negative internal and positive external environment (pre-depolarization state). This repolarization process takes approximately 0.7 ms, during which the nerve segment cannot receive new stimuli—known as the refractory period (1) (Figure 2). At the end of repolarization, when the nerve returns to its normal excitability level, the same segment can be stimulated again, generating a new depolarization-repolarization cycle.

A depolarized segment of the nerve cell generates energy to stimulate the adjacent segment, which is still at rest, to also undergo the process of depolarization, followed by repolarization. In the same manner as the previous segment, sodium channels in the membrane open, allowing Na⁺ to enter the cell, reversing its polarity. Subsequently, K⁺ exit the cell, repolarizing this segment, during which it temporarily becomes unable to receive a new stimulus (refractory period). It is precisely the existence of this refractory period that ensures the nerve impulse remains unidirectional (always traveling from the periphery toward the central nervous system), as illustrated in Figure 3.

Figure 3 Propagation of the nerve impulse.

Once this nerve impulse reaches the central nervous system, the brain interprets it as a painful stimulus, leading to the perception of pain.

Mechanism of action of local anesthetics

Over the years, various theories have attempted to explain how local anesthetics block pain sensation. The most widely accepted theory today is the specific receptor theory, which suggests that local anesthetics act by directly binding to sodium channels in the nerve membrane, thereby blocking the influx of Na⁺ into the cell. In 1976, Strichartz (7) published a review in which he presented strong arguments refuting other theories (such as the interaction between calcium ions and local anesthetics, as well as changes in electrical potentials at the membrane-water interface). He emphasized that amine-type local anesthetics (lidocaine, mepivacaine, bupivacaine, prilocaine, and articaine) penetrate the nerve and bind to sodium channels on the inner portion of the nerve membrane, which open during depolarization. This prevents the influx of Na⁺ into the neuron, thereby eliminating the propagation of the nerve impulse. Once the nerve impulse ceases to propagate, the message does not reach the central nervous system, and pain is not perceived.

Another theory, known as the membrane expansion theory, could explain the mechanism of action of topical anesthetics such as benzocaine. According to this theory, the local anesthetic induces an expansion of the lipoprotein matrix of the nerve membrane, reducing the diameter of sodium channels and making it more difficult for Na⁺ to enter the nerve cell (1).

An important consideration is that sensory nerves are myelinated, and this myelin acts as an insulator for ionic exchanges. As a result, sodium channels are abundantly located in the gaps between the myelin sheaths, known as Nodes of Ranvier (6). Since the electrical impulse can bypass or “jump” some nodes, it is crucial that the local anesthetic blocks at least three adjacent nodes to maximally reduce nerve impulse propagation. This corresponds to a length of approximately 10 mm (1).

Chemical structure of local anesthetics

From a chemical structure perspective, injectable local anesthetics are divided into three main components (5,8): a hydrophilic group (aids tissue diffusion; if they lack this part they are recommended for topical use, e.g., benzocaine), a lipophilic group (facilitates nerve penetration), and an intermediate chain (amide or ester) (Figure 4). All injectable anesthetics in dentistry are amide-based, as ester-based anesthetics are less stable and more allergenic (1,5). The chemical structure of injectable local anesthetics is illustrated in Figure 4B.

Figure 4 Chemical structures of the anesthetics. (A) Chemical structure of articaine; (B) chemical structure of injectable local anesthetics; (C) ionized and non-ionized bases of local anesthetics. CH₃ or H₃C, methyl group; CO, carbonyl group (C=O); H⁺, proton; Me, methyl group; N, nitrogen atom (typically part of an amine group); NH, secondary amine (nitrogen bonded to one hydrogen and two other atoms); O, oxygen atom; R, generic organic residue; RN, non-ionized amine base (neutral form); RNH⁺, ionized (protonated) amine; S, sulfur atom (in the thiophene ring).

Importance of the dissociation constant (pKa)

In its pure form, the anesthetic salt is extremely unstable and has very low solubility in aqueous media, making its clinical use impractical (1). However, since local anesthetics are extremely weak bases, they readily bind with acids, forming an anesthetic salt, which has excellent stability and solubility (1). The most commonly used acid salt is hydrochloride. Thus, commercially available anesthetic salts include lidocaine hydrochloride, mepivacaine hydrochloride, and articaine hydrochloride, among others.

Local anesthetics, being weak bases, can exist in two forms: ionized and non-ionized (9,10), as represented in Figure 4C. As previously mentioned, for a local anesthetic to exert its mechanism of action, it must penetrate the nerve cell. Only the non-ionized form can cross the lipid membrane of the nerve cell and reach its site of action.

The pKa is defined as the pH at which the anesthetic has equal amounts of ionized and non-ionized forms (1,9,10). The tissue pH at the injection site is approximately 7.4 (1). Since, in most cases, the tissue pH differs from the pKa of the anesthetic, there will be a predominance of either the ionized or non-ionized form. When the tissue pH is more acidic than the pKa of the anesthetic, the ionized form predominates, making it more difficult for the anesthetic to penetrate the nerve membrane, which results in a delayed onset of anesthesia (1,5,10).

The pKa is directly related to the latency period (the time interval between anesthetic administration and the onset of its effect). The more acidic the tissue pH in relation to the anesthetic’s pKa, the longer the time required for anesthesia to take effect (9,10). The pharmacokinetic profiles of commonly used local anesthetics vary notably in terms of pKa, the percentage of unionized base at physiological pH (7.4), and onset time (1). Benzocaine, with a pKa of 3.5, is almost entirely in its unionized form (100%) at pH 7.4; however, due to its topical use, the onset time is not applicable in the same way as injectable agents. Lidocaine, mepivacaine, and prilocaine all have a pKa of 7.7, with unionized base fractions of approximately 29%, 33%, and 25%, respectively. Their onset times range from 2 to 5 minutes, with lidocaine typically acting within 2 to 3 minutes, and mepivacaine and prilocaine taking slightly longer (3 to 5 minutes). Articaine, with a slightly higher pKa of 7.8 and 29% unionized base at pH 7.4, has the fastest onset among the injectables, typically between 1 and 2 minutes. In contrast, bupivacaine, which has a higher pKa of 8.1 and only 17% in the unionized form at physiological pH, shows a slower onset, typically between 6 and 10 minutes (1).

Onset, duration, recovery, and readministration of local anesthetics

After the injection of the anesthetic into the tissue, it diffuses in multiple directions, including toward the nerve endings. This free movement of ions and molecules occurs through the tissue fluid medium, always influenced by the concentration gradient. Thus, the higher the initial concentration of the anesthetic, the faster its diffusion, the quicker its onset of action, and the greater its efficacy. In a recent systematic review with meta-analysis, Nagendrababu et al. (11) evaluated anesthetic efficacy in permanent mandibular molars with symptomatic irreversible pulpitis, comparing the use of 1.8 mL (one cartridge) with 3.6 mL (two cartridges). The meta-analysis revealed that using 3.6 mL of anesthetic significantly increases the success rate of inferior alveolar nerve blocks compared to using only 1.8 mL. The quality of evidence was classified as high. This can be explained by the fact that higher concentrations of anesthetic can induce anesthesia in the more central portion of the nerve, as the periphery is more easily reached by the local anesthetic solution. Another important factor to consider is the degree of liposolubility of the anesthetic. The greater its liposolubility, the easier it penetrates the nerve membrane, since the membrane is composed of 90% lipids (1).

The duration of the anesthetic effect is directly related to the retention of the anesthetic within the nerve. The degree of protein binding plays a decisive role in the duration of anesthetic action. Once inside the nerve, local anesthetics bind to membrane proteins (with the nerve membrane being composed of approximately 10% protein) (1), increasing the duration of nerve impulse blockade. Thus, anesthetics with a high degree of protein binding tend to have a prolonged working time. The vascularization of the injection site and the possible presence of vasoconstrictors also influence anesthesia duration, as high local blood flow facilitates the reduction of anesthetic concentration.

During more extensive dental procedures, it may be necessary to reapply the anesthetic to prolong its effect or, occasionally, to restore nerve impulse blockade if the patient reports intraoperative pain. However, especially in cases where the patient experiences intraoperative pain, the re-administration of anesthesia may face challenges in achieving effective anesthetic action due to a phenomenon known as tachyphylaxis. The literature on tachyphylaxis is extremely scarce, making it difficult to precisely determine its mechanism. Edema formation following the initial anesthetic injection, as well as possible hemorrhages and clots, could hinder the diffusion of the anesthetic to the nerve membrane (12). Another possible explanation is a change in tissue pH to an acidic pH due to the primary injection of the local anesthetic (13).

Anesthetic salts

Lidocaine hydrochloride

Lidocaine was synthesized in 1943, introduced to the market in 1948, and, due to its safety profile (compared to other local anesthetics used at the time), was quickly adopted. As an amide-based anesthetic, allergic reactions, while possible, are extremely rare (14). The potential toxic and systemic effects are typically associated with continuous use or extremely high doses (15). Even today, it remains the most widely used local anesthetic worldwide and has the most extensive literature available among local anesthetics.

Lidocaine has good potency and low toxicity. It is metabolized in the liver and excreted via the kidneys, requiring special attention in patients with hepatic and renal impairment. Its pKa is 7.9, and its pH is approximately 3.5 in solutions containing vasoconstrictors. It has a rapid onset time, ranging from 2 to 3 minutes in supraperiosteal infiltration techniques. Its optimal concentration is 2%, with no superior effect at concentrations of 3% (which, in fact, increases toxicity). According to the Food and Drug Administration (FDA), it is classified as a category B drug in terms of fetal safety and is considered safe for use in lactating individuals. At a 2% concentration combined with epinephrine 1:100,000, it provides approximately 60 minutes of pulpal anesthesia, which may extend to 3 to 5 hours in soft tissues. Its elimination half-life is approximately 90 minutes (1,2).

The maximum recommended dose, as with all local anesthetics, depends on the area to be anesthetized, tissue vascularization, the number of nerve segments to be blocked, individual tolerance, and the anesthetic technique used. The maximum dose suggested by the Council on Dental Therapeutics of the American Dental Association and the United States Pharmacopeia (USP) convention is 4.4 mg/kg (16,17). It is important to note that in Brazil, the maximum doses used are extremely safe, as the FDA suggests a maximum dose of 7.0 mg/kg (equivalent to 500 mg—11 1.8 mL cartridges for an 80 kg adult).

Prilocaine hydrochloride

Prilocaine was synthesized in 1953 and approved for commercial use in 1965. Since it is not commercially produced in combination with adrenergic vasoconstrictors (in Brazil, it is marketed with felypressin, while internationally, it is available without a vasoconstrictor), it serves as an alternative for patients with absolute contraindications to adrenaline or noradrenaline.

As an amide-based anesthetic, it presents a low risk of allergy. Its metabolism occurs primarily in the liver (similar to lidocaine), but also in the kidneys and lungs to a lesser extent, being metabolized more rapidly than lidocaine. For this reason, it is considered to have lower systemic toxicity (1). As a secondary amine, its metabolism results in high levels of carbon dioxide, which may lead to methemoglobinemia (an increase in methemoglobin production in the blood, significantly impairing oxygen transport). In cases of overdose or accidental intravascular injection, methemoglobinemia can result in severe cyanosis. Although extremely rare, some case reports are available in the literature (18,19). It is eliminated via the renal system and is rapidly cleared from circulation. Its elimination half-life is approximately 1.6 hours.

Its pKa is 7.9, and its pH is approximately 4.0 in vasoconstrictor-containing solutions. In Brazil, it is marketed at a 3% concentration, while internationally, it can be found at 4%. It has a latency period of 3 to 5 minutes, similar to lidocaine. Although it is classified as category B for fetal safety, it should not be used in pregnant women due to the increased risk of methemoglobinemia and the potential for uterine contraction induced by felypressin, the vasoconstrictor combined with prilocaine in commercially available formulations in Brazil. Caution is also advised for lactating individuals, as it is uncertain whether it is excreted in breast milk. In solutions containing a vasoconstrictor, it provides pulpal anesthesia for approximately 60 to 90 minutes and soft tissue anesthesia for 3 to 5 hours (20).

The maximum recommended dose is 4.5 mg/kg of body weight, with an upper limit of 378 mg, according to the medication package insert approved by Anvisa (Brazilian National Health Surveillance Agency) (20). Since each cartridge at a 3% concentration contains 54 mg of prilocaine, the maximum recommended dose for an 80 kg adult is 6.5 cartridges, with up to 7 cartridges permissible for individuals weighing 90 kg or more.

Prilocaine has been used as an alternative for patients with contraindications to adrenaline due to its association with a non-adrenergic vasoconstrictor (felypressin), particularly in patients with uncontrolled hypertension (5). However, its use in these conditions should be carefully evaluated. In a 2020 study, Yamashita et al. assessed the effects on the autonomic nervous system in third molar extractions, comparing the use of 2% lidocaine (epinephrine 1:80,000) with 3% prilocaine [felypressin 0.03 international units (IU)]. The results showed a significant increase in heart rate in the prilocaine group, and in both groups (lidocaine and prilocaine), there was a significant increase in systolic blood pressure during anesthetic administration and surgical procedures (21).

Mepivacaine hydrochloride

Mepivacaine was synthesized in 1957 and introduced into the dental market in 1960. In Brazil, it is available at a concentration of 3%, with or without a vasoconstrictor. As an amide-based anesthetic, it presents a low risk of allergy. Its metabolism occurs in the liver, similar to lidocaine; however, its slow half-life (1.9 hours) places a greater demand on hepatic and renal function. Therefore, special attention should be given when using it in patients with hepatic or renal impairment. It has potency and toxicity levels comparable to lidocaine. Its pKa is 7.6, and its pH ranges from 5.5 to 6.0 in solutions without a vasoconstrictor and is approximately 4.0 in solutions containing a vasoconstrictor. Its latency period is around 3 to 5 minutes, also similar to lidocaine. Its ideal concentration is 3%, and it is classified as category C regarding fetal safety. It can be safely used in lactating individuals (1,5,22).

One characteristic that differentiates mepivacaine from lidocaine is its low vasodilatory effect. Although all anesthetics induce vasodilation, the vasodilatory effect of mepivacaine is quite mild, allowing it to be marketed without a vasoconstrictor. This makes it a possible choice for patients with contraindications to adrenergic vasoconstrictors. In solutions without a vasoconstrictor, its working time is approximately 20 to 40 minutes for pulpal anesthesia and 2 to 3 hours for soft tissues. In solutions with a vasoconstrictor, this duration increases to 1 hour for pulpal anesthesia and 3 to 5 hours for soft tissue anesthesia (1,5,22).

The maximum recommended dose is 4.4 mg/kg, with an upper limit of 300 mg, according to the medication package insert approved by Anvisa (22). Since each cartridge at a 3% concentration contains 54 mg of mepivacaine, the maximum recommended dose for an 80 kg adult is 5.5 cartridges.

It is common for clinicians, based on purely empirical observations, to claim that they prefer using mepivacaine for inferior alveolar nerve blocks in cases of symptomatic irreversible pulpitis, believing it to be more effective than lidocaine. However, in a systematic review with meta-analysis published by Vieira et al. in 2018, the authors concluded that there were no significant differences in pulpal anesthesia of mandibular molars with symptomatic pulpitis or in pain control during endodontic procedures when comparing the use of lidocaine and mepivacaine (23). A previous study by Porto et al. [2007], comparing the use of lidocaine and mepivacaine (both with vasoconstrictors) in third molar extraction surgeries, also indicated no differences between the two anesthetics in terms of working time and the occurrence of postoperative pain (24).

Bupivacaine hydrochloride

Bupivacaine was synthesized in 1957 and became commercially available in 1972. Its optimal concentration for dental use is 0.5%. As an amide-based anesthetic, it presents a low risk of allergy. Its metabolism occurs in the liver, similar to lidocaine, but with an elimination half-life of approximately 2.7 hours (almost twice that of lidocaine). It is also excreted by the kidneys. Its use should be carefully evaluated in patients with hepatic and/or renal impairment. It is four times more potent than lidocaine but also has four times the cardiotoxicity of lidocaine (5).

Due to its pKa of 8.1 (the highest among all anesthetics used in dentistry), it also has the longest latency period, ranging from 6 to 10 minutes, which may be even longer in nerve block techniques (10 to 16 minutes). Its pH ranges from 3.0 to 4.5 in vasoconstrictor-containing solutions. Because it has a strong vasodilatory effect, its use without a vasoconstrictor is not recommended for medium- or long-duration procedures. It is classified as category C regarding fetal safety, and its excretion in breast milk remains unclear, so its use should be avoided in lactating individuals (1,5).

The recommended dose is 2 mg/kg, with a maximum of 150 mg (according to the manufacturer’s package insert) (25) or 90 mg (according to the FDA). However, due to its high cardiotoxic potential, this dosage is strongly discouraged. Additionally, because of its significant cardiotoxicity and prolonged anesthetic duration, its use in individuals under 12 years of age is also not recommended.

An important characteristic that differentiates bupivacaine from other local anesthetics used in dentistry is its prolonged anesthetic effect. In solutions containing epinephrine, pulpal anesthesia can last between 1.5 and 3 hours, while soft tissue anesthesia may extend up to 12 hours. Due to this characteristic, bupivacaine is commonly chosen for surgical procedures to aid in postoperative pain control (26,27). However, 24 hours after bupivacaine administration, there may be stimulation of pro-inflammatory chemical mediators at the anesthetized site, leading to increased postoperative pain (28).

Articaine hydrochloride

Articaine was synthesized in 1969 and was first marketed in Europe in 1976, with FDA approval for use in the United States only in 2000. Its molecular structure is one of its main distinguishing features compared to other local anesthetics. It is an amide-based anesthetic (therefore, presenting a low risk of allergy), but it is the only one that contains a thiophene aromatic ring instead of a benzene ring, along with an ester side chain (29) (Figure 4A). The thiophene ring grants articaine a high degree of liposolubility, a characteristic responsible for its increased potency. Compared to lidocaine, articaine is 2.6 times more potent but does not exhibit increased toxicity (30). The ester side chain allows almost the entire amount of articaine to be metabolized in the bloodstream, placing minimal demand on the liver during this process (only 5% to 16% of articaine metabolites undergo additional hepatic metabolism) (31). Since it is predominantly metabolized in the bloodstream, its plasma half-life is also shorter than that of other anesthetics, averaging 27 minutes (1).

Its optimal clinical concentration is 4%, and it has a pKa of 7.8, which provides a rapid onset of action (approximately 1 to 2 minutes). Its pH in vasoconstrictor-containing solutions ranges from 4.0 to 5.5, and its anesthetic effect lasts approximately 1 to 2 hours for pulpal anesthesia and 2 to 6 hours for soft tissue anesthesia (1). It has a high vasodilatory capacity, which makes its clinical use in dentistry unfeasible without the addition of a vasoconstrictor. In terms of fetal safety, it is classified as category C, and it is unclear whether it is excreted in high concentrations in breast milk, requiring special caution when used in lactating individuals.

The maximum recommended dose is 7.0 mg/kg, according to the medication package insert approved by Anvisa (32). Since each 4% concentration cartridge contains 72 mg of articaine, the maximum recommended dose for an 80 kg adult is 8 cartridges, increasing to 10 cartridges for a 100 kg individual.

Another important distinguishing feature of articaine is its significantly superior ability to diffuse through bone tissue compared to other local anesthetics. This property allows for successful infiltration anesthesia in mandibular posterior teeth. The presence of the thiophene ring has been identified as the factor responsible for this high level of bone penetration (5). Some authors agree that an infiltrative buccal injection of 4% articaine for mandibular molars provides pain control comparable to an inferior alveolar nerve block with 2% lidocaine, both in endodontic and surgical procedures, in adults and children (33-37).

Vasoconstrictors

Vasoconstrictor: friend or enemy?

When anesthetizing a patient, a common concern is the effect of vasoconstrictors (present in some anesthetic solutions) on the individual’s cardiovascular system. Some professionals express uncertainty in certain situations and, when in doubt, often choose anesthetics without vasoconstrictors, sometimes mistakenly, assuming this to be the safest approach. To understand why manufacturers add vasoconstrictors to anesthetic cartridges, it is essential to review some characteristics of local anesthetics and their clinical effects.

The fundamental reason for using vasoconstrictors in most anesthetic solutions is that all local anesthetics cause vasodilation (1,5,9). This means that once the local anesthetic is injected into the target area, the blood vessels in that region dilate, increasing blood flow at the anesthetized site. For anesthesia to be maintained, the anesthetic must remain in contact with local nerve fibers. As blood flow increases, the anesthetic is absorbed more rapidly into the bloodstream, reducing its local concentration and, consequently, shortening the duration of anesthesia. One advantage of including a vasoconstrictor in the anesthetic solution is its ability to constrict blood vessels, thereby reducing blood flow in the anesthetized area and slowing the absorption of the anesthetic into the bloodstream. As a result, the clinical duration of anesthesia is significantly prolonged for both pulpal and soft tissue anesthesia.

Another benefit of using vasoconstrictors is the reduced risk of systemic toxicity and cardiovascular effects (16,17,20,22,25,32). Since toxicity and cardiovascular reactions are associated with high intravascular concentrations of anesthetics, using an anesthetic combined with a vasoconstrictor slows its absorption into the bloodstream, lowering intravascular anesthetic concentrations and enhancing systemic and cardiovascular safety. Special care must be taken during anesthetic injection to avoid accidental intravascular administration, which could lead to the undesirable occurrence of these adverse effects (16,17,20,22,25,32).

A third important aspect to consider is the hemostatic effect that adrenergic vasoconstrictors can provide in surgical procedures, contributing to effective bleeding control. The vasoconstrictive action of adrenergic agents not only counteracts the vasodilatory effect of anesthetic agents but also induces a more intense vasoconstriction than the anesthetic’s vasodilatory effect, ultimately reducing local blood flow (16,17,20,22,25,32). The vasoconstrictors currently used in commercial anesthetics include epinephrine (adrenaline), norepinephrine (noradrenaline), phenylephrine, and felypressin. Each of these vasoconstrictors and their main characteristics will be discussed in the following sections.

1:25,000, 1:100,000, 1:200,000, etc., what do these numbers mean?

On commercial packaging, it is common to observe some numerical information, which may be described in percentages (e.g., 2%, 3%, or 4%) or in fractional form (e.g., 1:100,000, 1:200,000, etc.). The number expressed as a percentage (%) refers to the concentration of the anesthetic salt within the cartridge. The higher the number, the greater the amount of anesthetic salt contained within the anesthetic cartridge. The number expressed in fractional format (1:100,000, 1:200,000, etc.) refers to the dilution of the vasoconstrictor in the anesthetic solution. This information often causes confusion among many readers; therefore, we will provide an example to facilitate understanding.

Imagine that the total volume of anesthetic solution inside a cartridge (1.8 mL) was divided into 100,000 equally sized drops. When the manufacturer states that the amount of vasoconstrictor in this anesthetic solution is 1:100,000, it means that among these 100,000 drops, only one drop would be the vasoconstrictor (Figure 5A). Thus, when the manufacturer states that the vasoconstrictor dilution within the cartridge is 1:200,000, and that only one drop corresponds to the vasoconstrictor, the amount of vasoconstrictor within the cartridge would be lower than in the 1:100,000 dilution (Figure 5B).

Figure 5 Dilution of vasoconstrictors. (A) Vasoconstrictor in a 1:100,000 dilution; (B) vasoconstrictor in a 1:200,000 dilution.

Epinephrine (adrenaline)

Epinephrine is the most widely used vasoconstrictor in the world and should be the first choice for dentists whenever possible. It is considered the gold standard among vasoconstrictor agents. Known as the fight-or-flight hormone, epinephrine’s action in an emergency situation causes the heart muscle to pump more blood while simultaneously promoting vasodilation in skeletal muscles, preparing the individual to react to danger, either by fleeing or fighting.

Its mechanism of action consists of stimulating α1, α2, β1, and β2 adrenergic receptors, with the degree of stimulation depending on the concentration of epinephrine acting on these receptors (1,5). The action of epinephrine on α receptors, which are abundantly present in the blood vessels of the skin and mucosa, is responsible for vasoconstriction, which aims to reduce blood flow at the anesthetized site and consequently slow the absorption rate of the anesthetic into the bloodstream, thereby prolonging the duration of local anesthesia. Its action on α receptors also helps hemostasis during surgical procedures by contracting local blood vessels. The effect of epinephrine on β1 receptors, located in the heart muscle, can significantly increase both contraction strength and heart rate, in addition to potentially inducing cardiac arrhythmias. Thus, the stimulation of β1 receptors in the myocardium may elevate patients’ blood pressure, particularly in cases of accidental intravascular injection (38).

Regarding β2 receptors, which are abundantly found in skeletal muscle vasculature, the clinical effects of epinephrine can be observed in the postoperative period, when epinephrine concentrations around the blood vessels decrease as the anesthetic solution is absorbed into the circulatory system. At low doses, epinephrine’s effect on β2 receptors is more pronounced than on α receptors, and β2 receptor stimulation promotes vasodilation. Consequently, there is a potential risk of bleeding in the first few hours following surgical intervention.

According to Malamed [2021] (1), epinephrine in 1:100,000 and 1:200,000 dilutions presents equivalent efficacy regarding anesthesia duration in vital pulps and soft tissues. Therefore, clinically, there are no significant differences between these two dilutions. The maximum recommended dose for an American Society of Anesthesiologists (ASA) I patient is 198 µg, which corresponds to 11 cartridges at a 1:100,000 dilution and 22 cartridges at a 1:200,000 dilution (1).

The main contraindications for adrenergic vasoconstrictors are related to patients with uncontrolled hypertension (blood pressure exceeding 160/100 mmHg) (5), as well as other cardiovascular conditions such as arrhythmias, unstable angina, a history of myocardial infarction with sequelae, a recent history of stroke (within the past 6 months), and recent cardiac surgery. In cases of hyperthyroidism, a clinical condition that enhances the side effects of vasoconstrictors, the use of epinephrine should also be avoided. Another important consideration regarding adrenergic vasoconstrictors is their extreme susceptibility to oxidation. To prevent oxidation, manufacturers add an antioxidant, usually from the sulfite class, inside the cartridge. Consequently, patients with sulfite allergies should avoid adrenergic vasoconstrictors (39-41).

Norepinephrine (levarterenol)

When compared to epinephrine, norepinephrine exhibits only 25% of its vasoconstrictive action, offering absolutely no advantage over epinephrine (5). As a result, manufacturers use it in extremely high concentrations in cartridges, around 1:50,000, to achieve a vasoconstrictive effect similar to that of epinephrine. Its mechanism of action is primarily based on its effect on α receptors, with a lesser effect on β1 receptors. Stimulation of β1 receptors can lead to arrhythmias, while its action on α receptors can cause sudden spikes in blood pressure due to vasoconstriction and increased peripheral vascular resistance. This intense α-receptor stimulation has also been associated with severe vasoconstriction, which can result in tissue necrosis, particularly in the palatal region (1). Because it is not a suitable alternative when epinephrine is contraindicated and due to the risks involved, this author strongly recommends that norepinephrine should not be used as a vasoconstrictor in clinical dental practice.

Phenylephrine hydrochloride

Compared to epinephrine, phenylephrine has only 5% of its vasoconstrictive potency and, for this reason, is commercially available at a concentration of 1:2,500 (5).

Its mechanism of action is almost exclusively based on its effect on α receptors, with nearly negligible action on β1 receptors in the myocardium. Due to its excessively high concentration in anesthetic cartridges and its primary action on α receptors, it may cause side effects such as increased blood pressure and headaches in cases of accidental intravascular injection. Prolonged use of this vasoconstrictor may lead to a loss of its pharmacological effect, a phenomenon known as tachyphylaxis. Because it is not a suitable alternative when epinephrine is contraindicated and offers no advantages, this author strongly recommends that phenylephrine should not be used as a vasoconstrictor in clinical dental practice.

Felypressin

Felypressin is a synthetic analog of vasopressin, which is an antidiuretic hormone. Its action is primarily observed in the venous microcirculation rather than the arteriolar network. As a result, its hemostatic effect is practically negligible. The major advantage of felypressin is that it does not affect the patient’s blood pressure or heart rate. It is an interesting alternative when adrenergic vasoconstrictors are contraindicated due to cardiovascular conditions. However, special caution should be taken when using felypressin in pregnant patients, as it has an effect similar to oxytocin, a hormone produced by the pituitary gland responsible for uterine contractions during labor. In Brazil, its dosage is 0.03 IU, and it is combined with prilocaine. One IU corresponds to 0.01 mL, meaning the amount contained within an anesthetic cartridge is minimal.

Allergies and toxicity

Allergic reactions are extremely rare and, when they do occur, the likelihood of being related to anesthetic salts is very low. This is because all local anesthetics currently used in dentistry have an amide base rather than an ester base, which is a potent inducer of allergic reactions. However, it is important to remember that in addition to the anesthetic salt, other substances may be present in the anesthetic cartridge, such as antimicrobials and antioxidants, which do have allergenic potential.

Methylparaben, an antimicrobial agent, can be found in some (few) formulations to prevent microbial growth inside the anesthetic cartridge. Parabens, in general, have a high capacity to induce allergic reactions. Since modern anesthetic packaging processes and technologies can keep the solution sterile for long periods, manufacturers are increasingly removing parabens from formulations. This substance should be avoided whenever possible, especially in patients with a history of allergic reactions to anesthesia in the past.

As previously mentioned in the section discussing epinephrine, sulfites also require special attention regarding allergic reactions. As described earlier, adrenergic vasoconstrictors tend to oxidize over time, and this oxidation can cause a burning sensation during anesthetic application. Consequently, anesthetics nearing their expiration date may cause greater discomfort upon injection. To slow down this oxidation process, manufacturers add an antioxidant from the sulfite class (such as bisulfite) to the anesthetic cartridge. However, sulfites are also known to trigger allergic reactions in a portion of the population. It is important to note that sulfites are present in processed foods such as cured meats, dried fruits, sausages, and wine. If a patient reports a food allergy to this class of foods, it is advisable to avoid anesthetics with adrenergic vasoconstrictors, as the patient is likely allergic to sulfites. Another relevant point is that patients with asthma have an eightfold increased likelihood of being allergic to sulfites. Therefore, when a patient reports asthma, it is crucial to carefully investigate any history of food allergies before deciding to use anesthetics containing adrenergic vasoconstrictors (42).

Regarding toxicity, local anesthetics used in dentistry are extremely safe, provided that maximum dosage limits are adhered to based on the type of anesthetic solution used, while also considering the patient’s body weight (in kg). The greatest concern is accidental intravascular anesthesia, where even a single cartridge may cause toxic effects and severe reactions due to the rapid and concentrated introduction of adrenergic vasoconstrictors into the patient’s bloodstream. To minimize the risk of medical emergencies related to anesthesia, the following precautions are essential: prior aspiration, slow injection of the anesthetic, observation of the cartridge during administration to detect possible blood presence, and monitoring the patient’s reactions and behavior both during and immediately after the anesthetic procedure. Regional nerve block techniques have a higher likelihood of accidental intravascular injection than supraperiosteal infiltration techniques (1).

This narrative review provides a comprehensive and clinically oriented synthesis of the main local anesthetics used in dentistry, along with their pharmacological properties, indications, and considerations for the use of vasoconstrictors. By integrating scientific and practical evidence, the review aims to support dentists in making safer and more informed choices in daily practice. However, certain limitations should be acknowledged. Although the review addresses the use of anesthetics in patients with systemic conditions, some complex scenarios, such as those involving severe cardiovascular disease, endocrine disorders, or polypharmacy, were not explored in depth. These cases require individualized planning and may benefit from future targeted reviews that provide more detailed clinical algorithms or guidelines.

Conclusions

The role of local anesthetics in dentistry extends beyond technical execution; it demands clinical judgment shaped by pharmacological understanding and patient-specific considerations. This review reinforces that the effectiveness and safety of dental anesthesia depend not only on drug selection but also on context-driven decision-making, especially when systemic health conditions or contraindications are present. Rather than offering rigid protocols, this synthesis encourages thoughtful adaptation of anesthetic strategies to the individual clinical scenario.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://joma.amegroups.com/article/view/10.21037/joma-25-8/rc

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Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://joma.amegroups.com/article/view/10.21037/joma-25-8/coif). The authors have no conflicts of interest to declare.

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