Opioid Allergy

Full update August 2018

Opioid allergy is a common patient complaint. But less than 2% of opioid reactions are true allergies.21 Upon questioning, it often becomes clear the “allergy” is only a side effect, such as stomach upset. But when the symptoms are those associated with allergic-type reactions (e.g., hives), there’s a need to determine which, if any, opioid is safe. To choose a safer alternative, 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). Options for this patient include:
    1. A non-opioid analgesic (e.g., acetaminophen, an NSAID).3
    2. Avoidance of codeine, morphine, and meperidine, the opioids most commonly associated with pseudoallergy.1
    3. Use of a more potent opioid less likely to release histamine.28 Potency, from lower to higher:29-31
      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 antihistamines plus low-dose naloxone or nalbuphine3).
    4. Consider tramadol, which does not appear to cause histamine release.28
    5. If needed, concurrent administration of an antihistamine (H1-blocker and an H2-blocker [e.g., cimetidine]).3,21,28
    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, an NSAID).3
    2. An opioid in a chemical class different (see chart below) from the one to which the patient reacted, with close monitoring.4


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.2 Common culprits are codeine, morphine, and meperidine.1 Itching due to spinally administered fentanyl and sufentanil is also a pseudoallergy, but it is thought not to be histamine-related.3 Symptoms of pseudoallergy include itching, flushing, and sweating.3 Hives, increased heart rate, and low blood pressure can be due to pseudoallergy,1 but are also seen with true allergy.4,5 In vitro and clinical data suggest risk of pseudoallergy depends on the concentration of the opioid at the mast cell.2,4 This is dependent on opioid potency, dose, and route of administration (e.g., rapid intravenous administration).3,28

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].3,4,18

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].18 If possible, avoid parenteral administration, or slow the administration rate (e.g., administer intravenous morphine over four or five minutes25)[Evidence level C].2 Tramadol is another option; it does not appear to cause histamine release.28

Some patients have a reaction under the fentanyl patch. For these patients, spraying triamcinolone nasal spray (Nasacort) to the area before patch application may be helpful [Evidence level C].19

Treat life-threatening reactions as you would for any anaphylactoid reaction (e.g., epinephrine, corticosteroids, antihistamines).3

What symptoms suggest true opioid allergy?

True allergy to opioids seems to be IgE-mediated or T-cell mediated.5-7 Allergic skin reactions to opioids include hives, maculopapular rash, erythema multiforme,8 and pustular rash.9 Bronchospasm is thought to represent true allergy only.10 Reports suggest angioedema is usually a manifestation of true allergy, but pseudoallergy is also possible.7,11,13

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].1,4

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

It is important to take steps to avoid labeling nonallergic patients as allergic.1 If the nature and cause of the reaction are not clarified, opioids may be withheld unnecessarily.

Patient history is the most important diagnostic tool.15 Information from the history can be used to choose a safer opioid.4 Ask about 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.15 Also inquire about preceding activities, and the possibility of bites or stings.15 Medical records pertaining to the reaction, if available, should be reviewed.15 Alternate diagnoses (e.g., hereditary angioedema, scombroid fish poisoning, carcinoid syndrome) should be considered.15

Elevated total IgE levels during the acute reaction suggest true allergy.4 But IgE could be elevated for reasons unrelated to drug allergy.16 Tests for IgE to specific opioids have been developed,10 but are not readily available.28

Skin testing has been suggested before using a structurally unrelated opioid in a patient with a serious opioid reaction.4 But false-positive results due to pharmacologic histamine release have been documented with codeine, morphine, and meperidine.17,28 Patch testing may produce false-negative results.7

Patients requiring a detailed workup for diagnosis of opioid allergy should be referred to an allergist or immunologist.15

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).4 But because true allergy is rare, there’s not enough information to assess the chance of cross-reactivity.10,13

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.14 Morphine antibodies have also shown some reactivity with methadone and meperidine.14

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.20 In fact, product labeling for all non-injectable fentanyl products specifies their use for opioid-tolerant patients only (i.e., taking 60 mg or more oral morphine [or its equivalent] daily for at least a week). Both methadone and levorphanol (U.S.) must be dosed cautiously.22,23 Their long half-lives can cause drug accumulation and CNS and respiratory depression with repeated dosing.22,23 And meperidine is not routinely recommended because of its neurotoxic metabolite.20 Codeine is also a poor choice due to unpredictable efficacy and toxicity due to interindividual differences in metabolism.24 The analgesic efficacy of pentazocine, nalbuphine, butorphanol, and buprenorphine is limited by a dose ceiling.26 They can also cause dysphoria, psychomimetic effects, and feedback inhibition of the endorphin system, leading to dysesthesia.26,27 These drugs may cause withdrawal in opioid-tolerant patients.28 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.

Which opioids are in which classes?

Morphine group: morphine, codeine, hydrocodone, oxycodone (e.g., OxyContin), oxymorphone (U.S.), hydromorphone (e.g., Dilaudid), nalbuphine (Nubain [Canada]), butorphanol, levorphanol (U.S.), pentazocine (Talwin),12 buprenorphine21

Phenylpiperidines: meperidine (Demerol), fentanyl, sufentanil, remifentanil4,21

Phenylpropyl amines: tramadol, tapentadol21

Diphenylheptanes: methadone4

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 RCT
  2. 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).

RCT = randomized controlled trial; SR = systematic review [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. http://www.aafp.org/afp/2004/0201/p548.pdf.]

Project Leader in preparation of this clinical resource (340805): Melanie Cupp, Pharm.D., BCPS


  1. Gilbar PJ, Ridge AM. Inappropriate labeling of patients as opioid allergic. J Oncol Pharm Practice 2004;10:177-82.
  2. VanArsdel PP. Pseudoallergic drug reactions. Introduction and general review. Immunol Allergy Clin North Am 1991;11:635-44.
  3. Shepherd G, Guyton J. Drug hypersensitivity reactions. . In: Zeind CS, Carvalho MG, editors. Applied Therapeutics: the Clinical Use of Drugs. 11th ed. Philadelphia, PA: Wolters Kluwer Health, 2018: pp. 679-99.
  4. Crabe Erush S. Narcotic allergy. P&T 1996;21:250-2, 292.
  5. Harle DG, Baldo BA, Coroneos NJ, Fisher MM. Anaphylaxis following administration of papaveretum. Case report: Implication of IgE antibodies that react with morphine and codeine, and identification of an allergenic determinant. Anesthesiology 1989;71:489-94.
  6. Estrada JL, Puebla MJ, de Urbina JJ, et al. Generalized eczema due to codeine. Contact Dermatitis 2001;44:185.
  7. Mohrenschlager M, Glockner A, Jessberger B, et al. Codeine caused pruritic scarlatiniform exanthemata: patch test negative but positive to oral provocation test. Br J Dermatol 2000;143:663-4.
  8. Cooper SM, Shaw S. Dihydrocodeine: a drug allergy diagnosed by patch testing. Contact Dermatitis 2000;42:307-8.
  9. Machet L, Martin L, Machet MC, et al. Acute generalized exanthematous pustulosis induced by dextropropoxyphene and confirmed by patch testing. Acta Dermatol Venereol 2000;80:224-5.
  10. Fisher MM, Harle DG, Baldo BA. Anaphylactoid reactions to narcotic analgesics. Clin Rev Allergy 1991;9:309-18.
  11. Vidal C, Perez-Leiros P, Bugarin R, Armisen M. Fever and urticaria to codeine. Allergy 2000;55:416-7.
  12. Baumann TJ. Analgesic selection when the patient is allergic to codeine. Clin Pharm 1991;10:658.
  13. Anibarro B, Vila C, Seoane FJ. Urticaria induced by meperidine allergy. Allergy 2000;55:305.1989;71:489-94.
  14. Baldo BA, Pham NH, Zhao Z. Chemistry of drug allergenicity. Curr Opin Allergy Clin Immunol 2001;1:327-35.
  15. Lieberman P, Nicklas RA, Randolph C, et al. Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015;115:341-84.
  16. Emanuel IA. In vitro testing for allergy diagnosis. Otolaryngol Clin North Am 2003;36:879-93.
  17. Nasser SM, Ewan PW. Opiate-sensitivity: clinical characteristics and the role of skin prick testing. Clin Exp Allergy 2001;31:1014-20.
  18. Nutescu E, Hunt C, Teeters J. Multidisciplinary approach to improving allergy documentation. Am J Health Syst Pharm 1998;55:364-8.
  19. Otis JA, Fudin J. Use of long-acting opioids for the management of chronic pain. U.S. Pharmacist 2005;30(3 Suppl):1-14.
  20. Kral LA, Ghafoor VL. Pain and its management. In: Zeind CS, Carvalho MG, editors. Applied Therapeutics: the Clinical Use of Drugs. 11th ed. Philadelphia, PA: Wolters Kluwer Health, 2018: pp. 1170-1204.
  21. Wang K, Raouf M. Opioid allergy, pseudo-allergy, or adverse effect? March 6, 2018. https://www.pharmacytimes.com/contributor/jeffrey-fudin/2018/03/opioid-allergy-pseudo-allergy-or-adverse-effect (Accessed July 8, 2018).
  22. Product information for levorphanol. Sentynl Therapeutics. Solana Beach, CA 92075. December 2016.
  23. Chou R, Cruciani RA, Fiellin DA, et al. Methadone safety: a clinical practice guideline for the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain 2014;15:321-7.
  24. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther 2014;95:376-82.
  25. Clinical Pharmacology powered by ClinicalKey. Tampa (FL): Elsevier. 2018. http://www.clinicalkey.com. (Accessed July 12, 2018).
  26. Helm S, Trescot AM, Colson J, et al. Opioid antagonists, partial agonists, and agonists/antagonists: the role of office-based detoxification. Pain Physician 2008;11:225-35.
  27. Terrie YC. An overview of opioids. Pharmacy Times. June 13, 2011. http://www.pharmacytimes.com/publications/issue/2011/june2011/an-overview-of-opioids. (Accessed July 8, 2018).
  28. Baldo BA, Pham NH. Histamine-releasing and allergenic properties of opioid analgesic drugs: resolving the two. Anaesth Intensive Care 2012;40:216-235.
  29. Prommer E. Levorphanol: the forgotten opioid. Support Care Cancer 2007;15:259-64.
  30. Sundwall DN, Rolfs RT, Johnson E. Utah Department of Health. Utah clinical guidelines on prescribing opioids for treatment of pain. 2009. http://www.dopl.utah.gov/licensing/forms/OpioidGuidlines.pdf. (Accessed July 9, 2018).
  31. Agency for Healthcare Research and Quality. Morbidity & mortality rounds on the web. Cases & commentaries. Strassels SA. Miscalculated risk. Hospital medicine. August 2006. https://psnet.ahrq.gov/cases/case/132. (Accessed July 9, 2018).

Cite this document as follows: Clinical Resource, Opioid Allergy. Pharmacist’s Letter/Prescriber’s Letter. August 2018.

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