Local Anesthetic

This is the main drug and the one that induces the anesthetic effect. The five modern anesthetics used in dentistry today are all amides: lidocaine, articaine, mepivacaine, prilocaine, and bupivacaine.

With the exception of lidocaine, which is achiral, i.e. has no optical isomers (Tucker 1986; Calvey 1995; Mather and Chang 2001), the others are administered as a racemic mixture, i.e. equal parts of the two (levo or S‐ and dextro or R+) stereoisomers or asymmetric carbons (Tucker 1986; Strichartz et al. 1990; Calvey 1995; Mather and Chang 2001). In most, the two isomers have approximately the same anesthetic activity (Calvey 1995).

Vasoconstrictor

This second most important component enhances the effect of the local anesthetic by promoting vasoconstriction of the blood vessels near the target tissue and inducing a mass‐volume‐time effect that heightens potency, lengthens the duration of the anesthetic effect, reduces hemorrhage where the solution is injected, and lowers the toxicity of the anesthetic by slowing its absorption into the bloodstream. There are two types of vasoconstrictors: one derived from vasopressin, namely felypressin (Octapressin^®), which is less powerful and much less frequently used, and sympathomimetic vasoconstrictors such as epinephrine, norepinephrine, and levonordefrin, the three most powerful. Epinephrine is the one most commonly used worldwide.

These sympathomimetic vasoconstrictors are characterized by features with implications for dentistry.

• As they are highly sensitive to primarily oxidation‐induced degradation, they determine the shelf life of local anesthetic solutions.
• They are combined with an antioxidant (sulfite) to increase shelf life (Milano et al. 1982; Klein 1983).
• They have an acidic pH, normally around 4 (Annex 14), but ranging from 2.7 to 5.5 (USP 38 2015), which also improves their stability and enhances their solubility in aqueous solutions.
• Their levo isomeric form is used, as it is 10–200 times more powerful than the dextro form (Table 6.5, Chapter 6).
• The bitartrate form of epinephrine is used because it is more stable than the base or hydrochloride forms and like those forms is water soluble (Smith 1920; Bonica 1959).

Antioxidants (Sulfites)

These compounds lengthen the half‐life of sympathomimetic vasoconstrictors such as epinephrine because they capture the oxygen penetrating the cartridge before it engages with and inactivates the vasoconstrictor (Milano et al. 1982; Klein 1983; Huang and Fraser 1984; Schwartz and Sher 1985; Seng and Gay 1986).

The sulfites most widely used are 0.5 mg/ml sodium bisulfite (Seng and Gay 1986), sodium or potassium metabisulfite (Klein 1983; Seng and Gay 1986), and acetone sodium bisulfite 1 mg/ml (Seng and Gay 1986). Other characteristics associated with these compounds include their bitter taste, to which local anesthetics owe that same feature (Klein 1983), their contribution to maintaining an acid pH to preserve vasoconstrictors (Moorthy et al. 1984), and their efficacy in protecting vasoconstrictors for the first 18 months (American Dental Association 1983; Bennett 1984; Jastak et al. 1995). That capacity gradually declines with the amount of active antioxidant, lowering sympathomimetic vasoconstrictor activity and pH (Hondrum and Ezell 1996).

Although deemed to be safe (Bush et al. 1986; Seng and Gay 1986), low allergenic additives (Bush et al. 1986), the sulfites in local anesthetics used in dentistry have been known to trigger allergic reactions (Huang and Fraser 1984; Schwartz and Sher 1985; Schwartz et al. 1989; Dooms‐Goossens et al. 1989; Campbell et al. 2001). For poorly understood reasons this intolerance is associated with severe, corticoid‐treated asthma (Bush et al. 1986; Schwartz et al. 1989).

Seng and Gay (1986) proposed replacing sulfites with antioxidants suggested by Klein (1983), such as ascorbic acid and thioglycerol (only with Marcaine^®), but they are less effective, more costly, and also pose health risks (Bush et al. 1986).

Preservatives (Methylparaben)

Preservatives are used to keep dental cartridges containing local anesthesia sterile (i.e., bacterium‐free) (Latronica et al. 1969; Larson 1977; Luebke and Walker 1978). These compounds are parabens (propyl‐, butyl‐, and methylparaben), the most widely used being methylparaben or methyl 4‐hydroxy‐benzoate (Larson 1977; Klein 1983) at concentrations of 1 mg/ml = 0.1% (Larson 1977).

Parabens are used for their bacteriostatic and fungistatic power (Schorr 1968; Latronica et al. 1969; Nagel et al. 1977; Larson 1977; Luebke and Walker 1978), low‐dose efficacy (Larson 1977; Luebke and Walker 1978), and scant toxicity (Luebke and Walker 1978). Their primary drawback is that, like the alkyl‐esters of aminobenzoic acid (Latronica et al. 1969; Nagel et al. 1977; Larson 1977; Luebke and Walker 1978; Giovannitti and Bennett 1979), they share a chemical structure with ester‐type anesthetics. Allergic reactions to anesthetic solutions induced by these compounds and the cross‐sensitivity to ester‐type local anesthetics (Aldrete and Jonhson 1969; Latronica et al. 1969; Larson 1977; Luebke and Walker 1978) are consequently common (Aldrete and Jonhson 1969; Luebke and Walker 1978; Giovannitti and Bennett 1979). The US Food and Drug Administration (FDA) has therefore banned these compounds in dental cartridges and single (although not multi‐dose) vials (Malamed 2004) because cartridge preparation and single‐dose packaging with modern industrial techniques guarantee sterility and prevent infectious disease transmission. As a result, the use of parabens, the primary cause of allergic reactions, is no longer necessary. Since their prohibition this type of adverse reaction to local dental anesthesia has declined drastically (Malamed 2004).

Non‐parabenic preservatives exist, but are seldom used. One, 0.25% (0.25 mg/ml) chlorobutanol (Klein 1983), is less effective (Luebke and Walker 1978) and edetate disodium calcium is only used in Marcaine, a brand name for bupivacaine (Klein 1983).

pH Adjustment

Solutions with sympathomimetic vasoconstrictors such as epinephrine are the most acidic, around pH = 4, ranging from 3.5 to 4.5 (Annex 14), because a low (acid) pH is needed to preserve the vasoconstrictor, which breaks down in basic media (Tainter et al. 1939; Fyhr and Brodin 1987; Bowles et al. 1995). Epinephrine is most stable at pH = 3.4 (Hondrum et al. 1993) and breaks down in a matter of hours at pH > 6 (De Jong and Cullen 1963). Acidity poses problems, however.

1. Clinical trials have shown that injections are more painful, creating a burning or stinging sensation (Oikarinen et al. 1975; Moorthy et al. 1984; Kramp et al. 1999; Wahl et al. 2001).
2. The anesthetic effect may be delayed because at acidic pHs, most of the anesthetic molecules are cationic and unable to penetrate the cell membrane. Very few are free bases, the lipid‐soluble form that crosses the membrane, establishing a new equilibrium with the cations in the axoplasm. That in turn activates the receptor that blocks the sodium channels, generating the anesthetic effect. The tissue is alkaline in pH (= 7.4) and buffers in the tissue mitigate the initial acidity of the solution (Tainter et al. 1939; Björn 1947b), however, although some studies (Björn 1947b) have shown that to take longer than initially believed. Today, it is known that cations can penetrate the membrane in other ways, crossing TRPV1 channels, for example (Butterworth and Oxford 2009) (see Chapter 4).
3. If the acidic solution comes into contact with a metal, such as in former hypodermic metal syringes, within a few hours the release of nickel, zinc, and especially copper ions begins to irritate the tissues, an effect that may last for several days (Lundqvist et al. 1948). Dental solutions fortunately come in glass cartridges that elude such problems.

For anesthetic solutions with sympathomimetic vasoconstrictors (epinephrine and levonordefrin) the USP has established pH ranges of 3.3–5.5 for solutions with lidocaine, mepivacaine, prilocaine, and bupivacaine, and of 2.7–5.2 for articaine with epinephrine (USP 38 2015). As these solutions age, their pH tends to decline further, with both the active antioxidant and vasoconstrictor content decreasing (Hondrum and Ezell 1996).

Solutions with non‐sympathomimetic vasoconstrictors such as felypressin (Octapressin^®), which is available in many European countries although not in the United States, have a pH of around 5 (Annex 14), more or less midway between solutions without vasoconstrictors and those with the sympathomimetic type.

The chemical compounds added to solutions to attempt to regulate their pH include hydrochloric acid (ClH) to lower it, and sodium hydroxide (NaOH) and sodium lactate (C₃H₅NaO₃) (only in Marcaine^®, a brand name for bupivacaine) to raise it (Klein 1983).

Other Compounds

Sterile water is used as a vehicle and salts, normally 3–6 mg/ml sodium chloride (NaCl), to render the solutions isotonic (Klein 1983). Clinical studies have shown that non‐isotonic solutions do not raise anesthetic efficacy (Nordenram 1966) and irritate subcutaneous tissue, with concomitant pain (Lewis 1919; Nordenram 1966).

Metabolism

When injected alone, procaine is retained in the injection site for 1.5 hours and in the presence of epinephrine for up to 3 h (Sung and Truant 1954). It has a short half‐life, under 8 minutes (Seifen et al. 1979), because once in the bloodstream it is hydrolyzed by pseudocholinesterase (or plasma cholinesterase or butyrylcholinesterase). It scarcely penetrates the placenta. Its metabolites are eliminated in the urine, with only 2% eliminated in the free non‐metabolized form (Brodie et al. 1948). Nonetheless, the pseudocholinesterase deficits or alterations found in one per 3000 people (Kalow and Gunn 1959) lengthen the half‐life of procaine. Its possible biotransformation pathways are listed in Annex 12.

Procaine with Epinephrine

Procaine is no longer marketed in dental cartridges, although 2% procaine ampoules and 1:1000 (1000 μg/ml) epinephrine ampoules are available. Therefore 50 ml of 2% procaine can be mixed with 1 ml of 1:1000 epinephrine to obtain 51 ml of 2% procaine with 1:50 000 (20 μ/ml) epinephrine.

The maximum absolute dose of this local anesthetic solution for adults weighing 70 kg or more is five and a half 1.8‐ml cartridges. The limiting factor is the high epinephrine concentration, at 1:50 000. The maximum absolute dose established for procaine alone in dentistry is 400 mg (5.7 mg/kg) (American Dental Association 1984).

Remarks

While procaine is less efficacious than other anesthetics (see anesthetic parameters and physical‐chemical properties in Table 7.1), in the first half of the twentieth century it proved to be sufficiently effective and much safer than its predecessor cocaine, the first of the local anesthetics. Its primary drawback is the potential for hypersensitivity reactions (allergy reactions) and in particular its cross‐sensitivity with all ester‐type anesthetics (Aldrete and Johnson 1970).

Today procaine can be used in the event of multiple and severe allergies to several amide group anesthetics, although it has fallen into disuse and been replaced by modern amide‐type anesthetic solutions that are less allergenic and exhibit an anesthetic parameter that attests to higher potency and efficacy.

Metabolism

At a 2% concentration with 1:100 000 (10 μg/ml) epinephrine, lidocaine is removed from the injection site in around 4 hours and without epinephrine in less than 2 hours (Sung and Truant 1954). Once in the bloodstream it accumulates, in descending order, in the kidneys, lungs, brain, and heart (Sung and Truant 1954; Akerman et al. 1966). The hepatic microsomal system (Sung and Truant 1954; Akerman et al. 1966; Boyes et al. 1971; Stenson et al. 1971; Thomson et al. 1973), primarily isoform 3A of cytochrome P450 (Bargetzi et al. 1989), catabolizes 70% of the anesthetic (Boyes et al. 1971; Stenson et al. 1971). Around 80% is eliminated in the urine, although only 4% of it is excreted unchanged (Annex 12). Elimination is enhanced in acidic urine (Eriksson et al. 1966; Mihaly et al. 1978).

Lidocaine has a half‐life of around 110 minutes (Annex 11). Severe liver and kidney disorders affect its catabolism, albeit in different manners (Thomson et al. 1973). Severe liver disease may raise its half‐life by up to three times, whereas severe kidney conditions affect not half‐life but the metabolites in the blood (Thomson et al. 1973), particularly monoethylglycinexylidide (MEGX) and glycinexylidide (GX), active agents involved in lidocaine toxicity (Blumer et al. 1973; Strong et al. 1973).

This drug diffuses passively across the placenta, reaching a concentration in the umbilical vein of 60% of that found in the maternal blood vessels (Covino 1971). Its possible biotransformation pathways are listed in Annex 12.

Remarks

L‐100 or 2% lidocaine with 1:100 000 (10 μg/ml) epinephrine and L‐80, the same solution with 1:80 000 (12.5 μg/ml) epinephrine, are deemed to be the standard solutions in dentistry for several reasons (Cowan 1964):

1. Their efficacy in attaining pulpal anesthesia via buccal infiltration is only exceeded by potent solutions such as 4% articaine (double the anesthetic content) with 1:100 000 (10 μg/ml) epinephrine (A‐100), or 2% lidocaine with 1:50 000 (20 μg/ml) epinephrine (L‐50) (double the vasoconstrictor content) (Annex 21).
2. It is very safe, with a maximum absolute dose in dentistry of eight and a half cartridges in adults weighing 70 kg or over, more than most other solutions (Annex 10).
3. As an FDA pregnancy risk category B drug, it is very safe for pregnant or nursing women.

Lidocaine concentrations of 5% have shown to be highly toxic in animal experiments and are consequently not recommended (Lambert et al. 1994; Strichartz et al. 1994; Strichartz and Lambert 1995). Conversely, 2% lidocaine solutions with 1:200 000 (5 μg/ml) epinephrine (half the vasoconstrictor as in the standard solution) have proven to be scantly effective in clinical trials (Annex 21).

Indications

Two local anesthetic solutions with epinephrine are presently available. Their characteristics and uses are discussed below.

Metabolism

Much less articaine (5–15%) than other amide anesthetics is metabolized in the liver by the P450 microsomal enzyme system (Isen 2000; Rahn and Ball 2001). Therein lies the advantage of this solution, as the ester side chain on its thiophene ring is rapidly hydrolyzed by plasma pseudocholinesterases (Becker and Reed 2006), which catabolize 85–95% of the drug. As articainic acid, the compound formed has no anesthetic activity or effect on the central nervous system (Müller et al. 1991; Oertel et al. 1997), the half‐life of articaine is just 25 minutes. Nonetheless, in the 1 in 3000 individuals with deficient or altered plasma cholinesterases (Kalow and Gunn 1959) the drug is metabolized in the liver. Catabolism is a two‐stage process (Vree et al. 1988; Van Oss et al. 1989) accelerated by alkaline pH (Oertel et al. 1996).

Articaine is classified as an amide‐type local anesthetic, not an ester, and exhibits no cross‐allergenic activity with para‐aminobenzoic acid anesthetics, nor is allergic sensitization common (Becker and Reed 2006). The reason for the lack of allergic potential is that when articaine is metabolized to articanic acid, a metabolite with the structure similar to para‐aminobenzoic acid (PABA) is not formed. The formation of a PABA metabolite is the reason for cross‐allergenicity amongst ester anesthetics, not amides including articaine.

Articaine is eliminated primarily (85%) in the urine, 75% as articainic acid and only 3% as free and unaltered articaine (Annex 12). Two percent is also found in the feces (Hornke et al. 1984). This drug diffuses across the placenta passively, lodging in the umbilical vein at 32% of the concentration found in the maternal blood vessels (Strasser et al. 1977). Its possible biotransformation pathways are listed in Annex 12.

Remarks

Several features of articaine merit comment.