What is the risk of cross-reactivity with Zanaflex (tizanidine), Ultracet (tramadol/acetaminophen), and Relafen (nabumetone) in patients with a known allergy to chlorzoxazone?

Cross-Reactivity Risk Between Chlorzoxazone and Zanaflex, Ultracet, and Relafen

There is minimal risk of cross-reactivity between chlorzoxazone and Zanaflex (tizanidine), Ultracet (tramadol/acetaminophen), or Relafen (nabumetone) as these medications belong to different structural and pharmacological classes with no shared allergenic determinants.

Understanding Chlorzoxazone Allergy

Chlorzoxazone is a centrally-acting muscle relaxant with a unique chemical structure. According to the FDA drug label:

• Allergic reactions to chlorzoxazone can include urticaria, redness, itching, and rarely angioneurotic edema or anaphylactic reactions 1
• The drug should be discontinued immediately if any sensitivity reaction occurs 1

Cross-Reactivity Analysis by Medication

Tizanidine (Zanaflex)

• Tizanidine is an alpha-2 adrenergic agonist with a completely different chemical structure from chlorzoxazone
• There is no documented cross-reactivity between these two muscle relaxants
• Both medications are effective for musculoskeletal conditions but work through different mechanisms 2
• The risk of cross-reactivity is negligible due to structural dissimilarity

Tramadol/Acetaminophen (Ultracet)

• Tramadol is an opioid analgesic and acetaminophen is a non-opioid analgesic
• Neither component shares structural similarities with chlorzoxazone
• The allergenic determinants are completely different
• No documented cases of cross-reactivity exist between chlorzoxazone and either tramadol or acetaminophen

Nabumetone (Relafen)

• Nabumetone is a non-steroidal anti-inflammatory drug (NSAID)
• It has no structural similarity to chlorzoxazone
• The allergenic determinants and metabolic pathways are distinct
• No evidence suggests cross-reactivity between these medications

Management Algorithm for Patients with Chlorzoxazone Allergy

1. Assess the severity of the previous reaction to chlorzoxazone:

   • Severe reactions (anaphylaxis, angioedema): Avoid chlorzoxazone permanently
   • Non-severe reactions (mild rash, itching): Consider alternative muscle relaxants

2. For patients requiring muscle relaxants:

   • Tizanidine (Zanaflex) can be safely administered as a first-line alternative
   • Monitor for the first dose but no special precautions are needed beyond standard care

3. For patients requiring pain management:

   • Ultracet (tramadol/acetaminophen) and Relafen (nabumetone) can be safely administered
   • No special precautions are needed beyond standard monitoring for first-time use

4. Documentation:

   • Document the specific reaction to chlorzoxazone in the patient's medical record
   • Clarify that there is no cross-reactivity concern with Zanaflex, Ultracet, or Relafen

Special Considerations

• While the Dutch Working Party on Antibiotic Policy guideline discusses cross-reactivity patterns between antibiotics 3, these principles do not apply to the medications in question as they belong to entirely different drug classes
• The absence of shared allergenic determinants between these medications makes cross-reactivity extremely unlikely
• Chlorzoxazone has been associated with rare hepatotoxicity 2, 4, but this is an idiosyncratic reaction rather than an allergic one and does not predict cross-reactivity with other medications

Conclusion

Patients with a history of chlorzoxazone allergy can safely receive Zanaflex (tizanidine), Ultracet (tramadol/acetaminophen), and Relafen (nabumetone) without special precautions beyond standard monitoring for first-time medication use. The structural and pharmacological differences between these medications make allergic cross-reactivity extremely unlikely.