Pruritus secondary to opioids without evidence of allergic reaction after a graded drug challenge with oxycodone

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at NSU

A 24-year-old Caucasian female with a history of recurrent back pain and several back surgeries is referred for symptoms of urticaria and pruritus secondary to multiple pain medications during the last 3 to 4 years. She reports reactions to morphine, codeine, oxycodone, Topamax, Ultram, Celebrex and sulfa. In all cases hives occur soon after taking the medication and they never last more than 24 hours. The hives disappear after taking an antihistamine. She also has a history of panic attacks. During those episodes on a few occasions she had hives and had trouble breathing, but no real episodes of throat closing, low blood pressure, abdominal or respiratory symptoms during the episodes of urticaria with taking opioids.

Past medical history (PMH)

Recurrent back pain and several back surgeries, urticaria and pruritus secondary to multiple medications.


Elavil, Lexapro, ibuprofen p.r.n.

Social history and family history


Physical Examination


What is the most likely diagnosis?

This is a patient with evidence of intolerance to opioids manifested by histamine release and acute urticarial episodes which typically resolve with or without antihistamines within 24 hours. There is no evidence of allergic or pseudoallergic reaction. There is no evidence of anaphylaxis or life-threatening reactions to opioids.

What tests would you suggest?

Graded drug challenge with oxycodone (short-acting opioid).

Table 1. Graded drug challenge with oxycodone

Q 15 minutes

0.078125 mg
0.15625 mg
0.3125 mg
0.625 mg
1.25 mg
2.5 mg
5 mg = full capsule

What happened next?

There was a suspicion that she may be allergic to opioids and several other medications as listed above. However, this is unlikely with her history - pruritus induced by opioid medications is quite common, and it occurs in about 12% to 15% of patients taking opioids. It is mediated both by peripheral release of histamine by the mast cells in the skin and also by central effect via the mu receptors. Antihistamines are not particularly effective, but they are worth a therapeutic trial, and that was done in this patient.

The patient returned for graded drug challenge 10 days after the initial visit. The current medications included Zyrtec 10 mg p.o. daily and she came with a prescription of oxycodone 5 mg capsules to be taken 4 to 6 times a day p.r.n. pain.

She had been on Zyrtec 10 mg p.o. daily for the last 4 days. We performed a graded drug challenge, starting with a dose of 0.078 mg of oxycodone dissolved in water. The patient was able to tolerate that. After the first and second dose of the medication, she developed pruritus affecting her extremities, face, the back of the head and the abdomen, but no hives, and no other changes in her physical condition.

She was able to tolerate up to 5 mg of oxycodone (total dose) in increments according to the drug challenge protocol. She had pruritus which worsened and improved spontaneously. With the dose of 1.25 mg of oxycodone, we gave her cetirizine 10 mg p.o. x1 in addition to the dose she had taken in the morning, and she reported no improvement in the pruritus with that.

Approximately 2 hours after the first dose of oxycodone, we provided a second dose of 5 mg of oxycodone, and the patient continued to have pruritus, but her blood pressure was stable, and there were no other symptoms. However, she reported feeling somnolent and dizzy, and she was advised to have lunch, which she did, with some improvement. There was no significant change in the blood pressure or other vital signs.

In summary, this is a patient with intolerance to oxycodone manifested by pruritus and feelings of dizziness and somnolence which again are quite common, with somnolence occurring between 23% to 24% of patients in general, dizziness 13% to 16%, and pruritus in 12% to 13%. She did not have hypotension, nausea, or vomiting. She stayed at the clinic for 2 hours after the challenge to recover from the somnolence, but there were no allergic symptoms.


The pruritus secondary to opioids experienced by this patient is most likely centrally mediated and antihistamines may be of limited effect. From an allergy and immunology perspective, there is no evidence of allergy to opioid medications, and there is no contraindication to starting methadone at this point as recommended by the pain management specialist. However, considering that she has reactions in terms of somnolence, dizziness and headache, it is probably best to give her the first dose at the physician's office and also start with a low dose of the opioid pain medication.

Final diagnosis

Pruritus secondary to opioids without evidence of allergic reaction after a graded drug challenge with oxycodone.

Classification of adverse reactions to drugs: "SOAP III" mnemonic (click to enlarge the image):

Adverse drug reactions (ADRs) affect 10–20% of hospitalized patients and 25% of outpatients.

Rule of 10s in ADR

10% of patients develop ADR
10% of these are due to allergy
10% of these lead to anaphylaxis
10% of these lead to death

There is a difference between graded dose challenge and rapid desensitization. Minimum requirements for rapid desensitization: 1-on-1 RN, CPR/ACLS, crash cart, Epi at bedside, anesthesia/code team, allergist 3 minutes from bedside.


To be updated.

Published: 07/03/2010
Updated: 04/03/2012

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