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Naloxone hypersensitivity

Question:

3/20/2019
Are there any comments or data that can be shared about possible naloxone allergy, including skin testing strengths or desensitization? With the rise of patients being treated with buprenorphine-naloxone combinations for opioid dependency or rapid reversal of possible opioid overdose, I am getting questioned more frequently about possible hypersensitivity (flushing, hives, wheezing, GI) upset to naloxone.
 

Answer:

Most naloxone-associated adverse events, as you have described, are secondary to the opiate withdrawal.

Most opiates are direct mast cell activators. Codeine has been historically used as a positive control for skin testing when histamine was unavailable. Naloxone is not a direct mast cell activator.

Clinically significant IgE-mediated hypersensitivity to naloxone has never been convincingly demonstrated. It is theoretically possible, because naloxone has about 50% binding to serum proteins. One could safely perform puncture and intradermal skin testing using naloxone at 0.16 mg/ml (0.0005 Molar) and then follow this up with a 4 mg nasal challenge to confirm current tolerance. If there is a reaction, check an acute serum tryptase. If you do identify a naloxone skin test positive or acute naloxone nasal challenge positive individual with a positive tryptase, I would encourage you to publish the case. A naloxone 4 mg nasal challenge will induce opiate withdrawal in an addicted individual.

Desensitization would be a problem because the naloxone is needed acutely and there is insufficient time during an opiate over-dose event to perform any multi-step re-administration.

I would personally treat the opiate over-dosed patient, even if confirmed IgE-mediated allergy to naloxone was present, and then treat anaphylaxis, if needed, also.

Reference:
Levy JH, Brister NW, Shearin A, Ziegler J, Hug CC Jr, Adelson DM, Walker BF. Wheal and flare responses to opioids in humans. Anesthesiology. 1989 May;70(5):756-60.

I hope this information is of help to you and your patient.

Regards,
Eric Macy, MD, MS, FAAAAI