Allergy to Local Anesthetics

Allergy is an adverse drug reaction triggered by immune mechanisms. Its duration is unlimited because of immunological memory (Seskin 1978), therefore allergy is an absolute contraindication for this type of drug and an alternative local anesthetic must be used.

Ester anesthetics undergo hydrolysis in the circulatory system and form metabolites such as para‐aminobenzoic acid, which has considerable sensitizing power (Giovannitti and Bennett 1979). Consequently, allergic sensitization in this group is common, as is cross‐sensitization (Adler and Simon 1949; Aldrete and Johnson 1970; Giovannitti and Bennett 1979; Schatz 1984; Adriani et al. 1986). The only drugs from this group used at present are tetracaine and benzocaine (very rarely procaine and cocaine), and these are used mainly as topical anesthetics.

Allergy to modern amide local anesthetics is very rare. At least 1% of adverse reactions attributed to local anesthetics are allergic (Verril 1975; Giovannitti and Bennett 1979) and rarely cross‐reactions. However, cases of allergy to each of these drugs have been reported (Chapter 23).

There are no cases of cross‐sensitization between amide and ester anesthetics since these have very different chemical structures, therefore in the case of multiple allergy to one group, we can use anesthetics from the other group (Incaudo et al. 1978; Schatz 1984).

Long‐acting Anesthetics

Long‐acting anesthetics such as bupivacaine, which is available in 1.8‐ml cartridges for dental use, are contraindicated in the following cases:

1. Routine short‐ or medium‐duration procedures (Laskin et al. 1977; Jensen et al. 1981).
2. Children aged under 12 years, owing to the high risk of self‐injury of soft tissues (Laskin et al. 1977; Jensen et al. 1981; Moore 1984).
3. Patients with developmental disabilities and special needs (Pricco 1977; Jensen et al. 1981) or patients with psychiatric diseases (Jensen et al. 1981), for the same reason as children aged under 12 years.

The main reason for these contraindications is to prevent discomfort on drinking, eating, and speaking, as well as the risk of self‐injury of the soft tissues (tongue, lips, and buccal mucosa) owing to the long duration of anesthesia in these tissues. Furthermore, the absence of pulpal anesthesia in infiltrations is a major disadvantage in routine procedures (Chapter 7).

Prilocaine, Benzocaine, and Methemoglobinemia

Hemoglobin is an iron transport protein in the red cells that transports oxygen to tissues. Through their metabolites, prilocaine and benzocaine can alter this protein to form methemoglobin (MHb), which does not fulfill its function of transporting oxygen. A review of 242 cases of local anesthetic‐induced toxic MHb collected between 1947 and 2007 revealed that 65% were caused by benzocaine and 30% by prilocaine; both anesthetics were clearly the most frequently involved (Guay 2009).

Patients with diseases or disorders that hamper transport of oxygen to tissues are more vulnerable to the toxic methemoglobinemia caused by these local anesthetics. These diseases include the following:

1. Cardiovascular diseases:
   • Heart diseases (heart failure, coronary artery insufficiency, arrhythmia, etc.) because they reduce oxygen transport (Olson and McEvoy 1981; Duncan and Kobrinsky 1983; Rodriguez et al. 1994) and reduce the flow of blood to the liver, where the anesthetics are metabolized (Spoerel et al. 1967; Wilburn‐Goo and Lloyd 1999).
   • Anemia and red cell disorders (Spoerel et al. 1967; Olson and McEvoy 1981; Duncan and Kobrinsky 1983; Rodriguez et al. 1994; Wilburn‐Goo and Lloyd 1999).
   • Insufficient cerebral or peripheral irrigation (Spoerel et al. 1967).
2. Severe respiratory diseases, since oxygen exchange is reduced (Anonymous 1994; Wilburn‐Goo and Lloyd 1999).
3. Extreme age groups:
   • Newborns and nursing infants have an immature enzyme system, therefore they have a larger proportion than normal of methemoglobinemia (Künzer von and Schneider 1953; Ross and Desforges 1959; Lo and Agar 1986). This situation continues, with some degree of risk, until the infant is 1 year old (Severinghaus et al. 1991; Kellet and Copeland 1983; Rodriguez et al. 1994).
   • Elderly people, given that they have diseases that reduce the oxygen supply to tissues (see points 1 and 2) and take drugs that can produce toxic methemoglobinemia (Wilburn‐Goo and Lloyd 1999).
4. Congenital methemoglobinemia. A few hundred patients throughout the world have these diseases, which are diagnosed during the first year of life (Curry 1982):
   • Hemoglobin M.
   • Nicotinamide‐adenine‐dinucleotide‐methemoglobinreductase (NADH‐MHb‐reductase) system deficiency.
   • Nicotinamide‐adenine‐dinucleotide‐phosphate‐methemoglobin‐reductase (NADPH‐MHb‐reductase) system deficiency.
   • Glucose‐6‐phosphatedehydrogenase deficiency.

Cases of congenital methemoglobinemia are considered absolute contraindications (Jastak et al. 1995; Coleman and Coleman 1996; Wilburn‐Goo and Lloyd 1999). The first three causes are considered relative contraindications, therefore they can be administered with local anesthetics, albeit at reduced maximum doses, but the first three causes are considered absolute contraindications in ASA III patients. Other anesthetics, such as lidocaine and tetracaine, have been involved, although the association is much weaker. Chapter 23 contains a review of methemoglobinemia caused by dental local anesthetic.

Cholinesterase Deficiency and Esther Anesthetics

Procaine and tetracaine are ester local anesthetics that are metabolized by the enzyme cholinesterase or pseudocholinesterase in blood (Kalow 1952). It is known that one in every 3000 people have a deficiency or abnormality of this enzyme (Kalow and Gunn 1959) and that the deficiency is hereditary (Kalow and Staron 1957; Foldes et al. 1963). Consequently, affected patients are at risk of intolerance and toxicity (Foldes et al. 1963).

At present, this problem is of little relevance, since procaine is rarely used as an injectable anesthetic (it has been replaced by more modern amide agents). In any case, the contraindication is absolute.

Myasthenia Gravis and Esters

Myasthenia gravis is a rare autoimmune disease characterized by skeletal muscle weakness resulting from antibodies attacking acetylcholine receptors in the postsynaptic (motor) membrane. In patients with myasthenia gravis, injected ester anesthetics (procaine and tetracaine) must be avoided because they are hydrolyzed by plasma cholinesterases and the patients are treated with anticholinesterases (pyridostigmine, neostigmine), which inhibit the enzymes that metabolize these anesthetics, therefore there is a risk of poisoning by ester anesthetics (Patton and Howard 1997; Yarom et al. 2005; Patil et al. 2012). This is not the case, however, with benzocaine (also an ester anesthetic, although topical) (Yarom et al. 2005).

Procaine and Sulfonamides

Procaine, or novocaine, is an ester anesthetic, like tetracaine. It inhibits the bacteriostatic effect of sulfonamides, which compete with para‐aminobenzoic acid. This acid results from the metabolization of ester anesthetics (Woods 1940), which are a substrate of the acid for folic acid synthesis (De Jong 1977).

In conclusion, procaine and sulfonamides are not widely used today; in addition, this interaction between the doses and regimens used in dental local anesthetics is considered of minor relevance (Moore 1999).

Lidocaine and Propranolol

Propranolol is a nonselective betablocker (it blocks adrenergic β₁and β₂ receptors) that is used to treat patients with arterial hypertension, arrhythmia, angina pectoris, hyperthyroidism, etc. (Weiner 1988).

Clinical studies have shown how propranolol can reduce the metabolism of lidocaine by 20–40% (Svendsen et al. 1982; Bax et al. 1985) and thus increase its plasma levels by 20–30% (Ochs et al. 1980; Svendsen et al. 1982). This is because propranolol reduces blood flow in the liver by 20–30% (Price et al. 1967; Trap‐Jensen et al. 1976; Westaby et al. 1984) – with the result that lower quantities of lidocaine are metabolized – and because of the direct action when enzyme activity against lidocaine is reduced in the liver (Bax et al. 1983, 1985).

Of note, other nonselective betablockers such as pindolol (Svendsen et al. 1982) do not present this interaction.

In conclusion, this interaction is considered to be of minor relevance in the doses and regimens used with lidocaine in dentistry (Tucker 1986; Moore 1999). However, it may prove important in medical practice during infusions for the treatment of arrhythmia (Moore 1999).

Lidocaine and Succinylcholine

Succinylcholine is a potent muscle relaxant with rapid and short action (minutes). It is used for induction of general anesthesia to relax the muscles and thus facilitate intubation.

Clinical studies have shown that intravenous high‐dose lidocaine prolongs the muscle block induced by succinylcholine (Usubiaga et al. 1967; Winkinski et al. 1970; Telivuo and Katz 1970