Do local anesthetics exhibit cross‑allergy between different agents (e.g., between ester‑type and amide‑type drugs)?

Cross-Allergy Between Local Anesthetics

Cross-reactivity between ester-type and amide-type local anesthetics is rare, making it safe to switch between these two chemical classes when a patient has a documented allergy to one group. 1, 2

Chemical Classification and Cross-Reactivity Patterns

Local anesthetics are divided into two distinct chemical classes with different cross-reactivity profiles:

Between Ester and Amide Classes

• Cross-reactivity between ester-type (e.g., tetracaine, procaine, chloroprocaine) and amide-type (e.g., lidocaine, bupivacaine, mepivacaine, ropivacaine) local anesthetics is rare. 1, 2
• The American Academy of Dermatology guidelines specifically recommend switching to an amide-type local anesthetic for patients with documented ester-type allergies. 1, 2
• When cross-reactions do occur between these classes, they are usually attributed to paraben preservatives in amide preparations or co-sensitization rather than true cross-reactivity. 1, 3

Within the Amide Class

• Cross-reactivity within the amide group is not scarce and occurs in a clinically significant proportion of cases. 4, 5
• Lidocaine-mepivacaine cross-reactivity has been documented in all six cases where cross-reactivity was identified in one major case series. 4
• Cross-reactivity between levobupivacaine and ropivacaine has been reported with negative reactions to articaine and lidocaine in the same patient. 6
• Prilocaine can cross-react with articaine but not necessarily with other amide anesthetics. 7
• Mepivacaine has shown cross-reactivity with lidocaine and ropivacaine, but not with bupivacaine or levobupivacaine in documented cases. 8

Within the Ester Class

• Patients allergic to one ester-type anesthetic (e.g., tetracaine) often cross-react with other esters (e.g., procaine, chloroprocaine). 2

Clinical Management Algorithm

For Patients with Documented Ester-Type Allergy:

1. Switch to any amide-type local anesthetic (lidocaine, bupivacaine, mepivacaine, ropivacaine, articaine) as cross-reactivity is rare. 1, 2
2. No skin testing is typically required before using an amide agent. 1

For Patients with Documented Amide-Type Allergy:

1. Do not assume other amides are safe—cross-reactivity within the amide class occurs frequently enough to warrant caution. 4, 5
2. Perform skin testing (prick test, intradermal testing at 1:100 dilution, and challenge tests) with multiple alternative amide local anesthetics before use. 4, 5
3. The negative predictive value of intradermal testing at 1:100 dilution is high (97.56%) for immediate-type reactions. 5
4. Consider switching to an ester-type local anesthetic if all amides test positive. 1

Alternative Options When Both Classes Are Contraindicated:

• 1% diphenhydramine (onset 5 minutes vs. 1 minute for lidocaine, with limited efficacy). 1, 3
• Bacteriostatic normal saline (0.9% benzyl alcohol in normal saline), which may be less painful than diphenhydramine when combined with epinephrine. 1, 3

Critical Clinical Considerations

Identifying True Allergy vs. Other Reactions:

• True immunologic reactions to local anesthetics represent only 1% of all adverse reactions. 1, 9, 3
• Most "allergic reactions" are actually due to inadvertent intravascular injection, systemic epinephrine absorption, vasovagal reactions, or preservative reactions (methylparaben, metabisulfites). 9, 2, 3
• Independent risk factors for true LA allergy include: personal history of ADR with local anesthetics (RR=4.007), generalized cutaneous symptoms during past reaction (RR=9.043), and hypotension during past reaction (RR=10.445). 5

Testing Recommendations:

• Because cross-reactivity within the amide class is unpredictable, skin tests should involve several local anesthetics, not just one alternative. 4, 7
• Testing should include prick tests, intradermal reactions, and challenge tests to confirm both the diagnosis and identify safe alternatives. 4, 5
• In emergency situations without allergy testing available, avoid all drugs in the same chemical class as the known allergen. 2

Common Pitfall:

• Do not assume that all amide local anesthetics are interchangeable in allergic patients—the evidence clearly demonstrates that cross-reactivity within this class occurs with sufficient frequency to require individual testing of alternative agents. 4, 7, 5, 8