Opioid Allergy

Full update December 2022

Opioid allergy is a common patient complaint. But less than 2% of opioid reactions are true allergies.1,2 Upon questioning, it often becomes clear the “allergy” is only a side effect, such as stomach upset. But when patients have symptoms that are associated with allergic-type reactions (e.g., hives), it may be more difficult to distinguish between a true allergy and a side effect, which is necessary to determine which, if any, opioid is safe for the patient to take.3 A thorough description of the reaction and an understanding of opioid reactions are needed. Answer the questions below and follow the instructions to find the best options for your patient. For more details about opioid intolerance, see the FAQ chart below. For information on switching opioids, see our chart, Equianalgesic Dosing of Opioids for Pain Management.

Check the symptoms the patient describes and follow the instructions in the far-right column.

Flushing, itching, hives, sweating, and/or mild hypotension only

Go to A

Itching, flushing, or hives at injection or application site only

Go to A

Severe hypotension

Go to B

Skin reaction other than itching, flushing, or hives (e.g., rash)

Go to B

Breathing, speaking, or swallowing difficulties

Go to B

Swelling of face, lips, mouth, tongue, pharynx, or larynx

Go to B

  1. These symptoms may be due to a pseudoallergy (a result of direct histamine release caused by some opioids; not immune mediated; see chart, below for more information).4 Options for this patient include:
    1. A non-opioid analgesic (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]).5
    2. Avoidance of codeine, morphine, and meperidine (the opioids most commonly associated with pseudoallergy).6
    3. Use of a more potent opioid less likely to release histamine.7 Potency, from lower to higher:meperidine <codeine<morphine<hydrocodone <oxycodone <oxymorphone <hydromorphone <levorphanol <fentanyl. (Note that fentanyl and related opioids commonly cause itching with spinal administration, which can be managed with antihistamines plus low-dose naloxone or nalbuphine.)5
    4. Consider tramadol, which does not appear to cause histamine release.7
    5. If needed, concurrent administration of an antihistamine (H1-blocker [e.g., cetirizine] and/or an H2-blocker [e.g., famotidine]).1,5,7,9
    6. Dose reduction, if tolerated. Reduce infusion rate, if applicable.
  1. This patient may have experienced a true allergy. Options for this patient include:
    1. A non-opioid analgesic (e.g., acetaminophen, NSAIDs).5
    2. An opioid in a chemical class different (see chart below) from the one to which the patient reacted, with close monitoring.10,11

--Continue to the next section for an FAQ about Opioid Allergies--

Clinical Question

Pertinent Information

What is a pseudoallergy?

Pseudoallergy is a side effect of opioids that can resemble a true allergy, but it is usually caused by histamine release from cutaneous mast cells, a nonimmunologic effect.6

  • Common culprits are codeine, morphine, and meperidine.6 Itching due to spinally administered fentanyl and sufentanil is also a pseudoallergy, but it is thought not to be histamine related.5
  • Symptoms of pseudoallergy include itching, flushing, and sweating.5 Hives, increased heart rate, and low blood pressure can be due to pseudoallergy,2 but are also seen with true allergy.13
  • In vitro and clinical data suggest risk of pseudoallergy depends on the concentration of the opioid at the mast cell.6 This is dependent on opioid potency,dose, and route of administration (e.g., higher risk with a rapid intravenous administration).5,7
  • Prior exposure to the specific opioid or a related opioid is not necessary for a patient to experience a pseudoallergic response.

How do you handle pseudoallergy?

If the reaction is only flushing, itching, sweating, hives, and/or mild hypotension, the opioid can usually be continued with an antihistamine or dose reduction [Evidence level C].5,13,14

Because pseudoallergic reactions appear to be a function of opioid dose and potency, consider use of a higher potency opioid [Evidence level C]. Start with a low dose [Evidence level C].14 If possible, avoid parenteral administration, or slow the administration rate (e.g., administer intravenous morphine over four or five minutes15) [Evidence level C].16 Tramadol is another option; it does not appear to cause histamine release.7

Some patients have a reaction on the skin under the fentanyl patch. For these patients, spraying triamcinolone nasal spray (Nasacort) to the area before patch application may be helpful [Evidence level C].17

Treat life-threatening reactions as you would any anaphylactoid reaction (e.g., epinephrine, corticosteroids).4

What symptoms suggest true opioid allergy?

True allergy to opioids seems to be IgE-mediated or T-cell mediated.18,19 Allergic skin reactions to opioids include hives, maculopapular rash, erythema multiforme, and pustular rash.20,21 Bronchospasm is thought to represent true allergy only.22 Angioedema and/or hypotension are significantly more likely to suggest a true allergy, but pseudoallergy is also possible.2,19,23,24

It’s prudent to assume reactions such as rash, severe hypotension, bronchospasm, or angioedema have an allergic mechanism. If an opioid is necessary, choose one in a different structural class if possible, and monitor the patient closely [Evidence level C].12,13

What are some points to consider when evaluating potential opioid allergy?

It is important to take steps to avoid labeling nonallergic patients as allergic.12 If the nature and cause of the reaction are not clarified, opioids may be withheld unnecessarily.

Patient history is the most important diagnostic tool.25 Information from the history can be used to choose a safer opioid.13 Ask about (and record) tolerability of other opioids, specific symptoms, and symptom severity. This information can provide clues to the mechanism of the reaction and guide analgesic choice.

Patients should be asked about symptoms, and foods and other medications ingested several hours before the reaction.25 Also inquire about preceding activities, and the possibility of bites or stings.25 Medical records pertaining to the reaction, if available, should be reviewed.25 Alternate diagnoses (e.g., hereditary angioedema, scombroid fish poisoning, carcinoid syndrome) should be considered.25

Elevated total IgE levels during the acute reaction suggest true allergy.13 But IgE could be elevated for reasons unrelated to drug allergy.26 Some opioid-specific IgE tests (e.g., morphine) have been developed; however, they are not always readily available.2,7

Skin testing has been suggested before using a structurally unrelated opioid in a patient with a serious opioid reaction.13 However, results are questionable (i.e., false positives) because most opioids release histamine.2,7 Specific IgE testing and skin prick testing may add information for diagnosis of an allergy but are not conclusive on their own.2

Patients requiring a detailed workup for diagnosis of opioid allergy should be referred to an allergist or immunologist.25 Workup may include a drug provocation test with the index opioid, which should be performed and interpreted by an experienced clinician.2

How do you choose an opioid in a patient suspected of true opioid allergy?

Patients allergic to one opioid are thought to be less likely to react to an opioid in a different structural class (see below).13 But because true allergy is rare, there’s not enough information to assess the chance of cross-reactivity.22,24

It’s important to note there is evidence patients can be allergic to more than one narcotic class. For example, IgE antibodies isolated from a patient allergic to morphine were able to bind to fentanyl.27 Morphine antibodies have also shown some reactivity with methadone and meperidine.27

When choosing an alternative opioid, consider the risks, benefits, and practicality of the drug. For example:

  • The fentanyl patch is only for chronic, stable pain in opioid-tolerant patients.28
  • All non-injectable fentanyl products should be used only in opioid-tolerant patients (i.e., taking ≥60 MME/day for at least a week).28,29
  • Both methadone and levorphanol(US) must be dosed cautiously.30,31 Their long half-lives can cause drug accumulation and CNS and respiratory depression with repeated dosing.30,31
  • Meperidine is NOT routinely recommended for pain management because of its neurotoxic metabolite.28 
  • Codeine is usually avoided due to its unpredictable efficacy and toxicity due to interindividual differences in metabolism.32 
  • The analgesic efficacy of pentazocine, nalbuphine, butorphanol, and buprenorphine is limited by a dose ceiling.33 They can also cause dysphoria, psychomimetic effects, and feedback inhibition of the endorphin system, leading to dysesthesia.33,34 These drugs may cause withdrawal in opioid-tolerant patients.
  • Buprenorphine also has a limited role in pain management.
  • Note that for several opioids, product labeling contraindicates their use in patients hypersensitive to any opioid.15

Which opioids are in which classes?

Morphine group (phenanthrenes):35 buprenorphine,butorphanol, codeine, hydrocodone, hydromorphone, levorphanol (US), morphine, oxycodone, oxymorphone (US), nalbuphine, pentazocine.

Phenylpiperidines:35 alfentanil, fentanyl, meperidine, remifentanil, sufentanil.

Phenylpropyl amines:35 tapentadol, tramadol.

Diphenylheptanes:35 methadone.

Abbreviations: CNS = central nervous system, MME = morphine milligram equivalent.

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.



Study Quality


Good-quality patient-oriented evidence.*

  1. High-quality randomized controlled trial (RCT)
  2. Systematic review (SR)/Meta-analysis of RCTs with consistent findings
  3. All-or-none study


Inconsistent or limited-quality patient-oriented evidence.*

  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study


Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56.  https://www.aafp.org/pubs/afp/issues/2004/0201/p548.html.]


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Cite this document as follows: Clinical Resource, Opioid Allergy. Pharmacist’s Letter/Prescriber’s Letter. December 2022. [381227]

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