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11 Articles in Volume 21, Issue #1
Advanced Practice Matters with Theresa & Jeremy: Mentorship
Ask the PharmD: What is a true opioid allergy?
Behavioral Medicine: How Clinicians Can Reduce the Stigma Attached to Chronic Pain
Chronic Headache: How to Conduct a Virtual Neurological Examination
COVID-19 Long Haulers: A Look at Cardiovascular Risk
How COVID Has Changed Pain Practice and Policies
How to Conduct a Pain Evaluation Using Telemedicine
Inside the Potential of Biologics for the Treatment of Rheumatoid Arthritis
Managing Pain in Parkinson’s Disease
Spinal Cord Stimulation Shown to Improve Pain and Movement in Parkinson’s Disease
TeleRheumatology Before and During the COVID-19 Pandemic

Ask the PharmD: What is a true opioid allergy?

True opioid allergies are rare but differentiating patient reactions from adverse events provides prescribers with more treatment options.

Although prescribing of opioids has declined because of safety concerns in recent years, it is important to differentiate true allergies from other intolerances that exist with opioids, namely, adverse events and pseudo-allergies.

Two types of opioid-related allergic reactions are: immunoglobulin E-mediated or due to mast cell degranulation (Image: iStock).

Allergic Reactions: Prevalence and Types

Overall, immune-mediated allergic reactions to opioids are extremely rare.1,2 Opioids with the highest incidence of allergic-type reactions include:3

  • morphine
  • codeine
  • heroin
  • meperidine

True Allergies

A true allergy is defined as an abnormal response of the immune system to a normally harmless substance.Two types of opioid-related allergic reactions are:

  • immunoglobulin E-mediated
  • due to mast cell degranulation

IgE-mediated allergic reactions occur when an allergen binds with IgE antibodies on mast cells, triggering an immune response. Upon activation of the immune system, inflammatory mediators are released from granules and leukotrienes and cytokines are synthesized, leading to the symptoms of an allergic reaction.5 Most reactions to opioids are non-IgE-mediated, though true allergies rarely occur.1

More commonly, opioids may cause an allergic reaction independent of IgE through mast cell degranulation. Mast cells are activated by stimuli independently of IgEvia various pathogen-associated molecular patterns such as toll-like receptors (TLRs). The TLRs then induce large quantities of histamine to be released from the mast cells within minutes after activation, known as degranulation.6

Furthermore, mast cells from different sites of the human body do not display homogeneity. For example, a morphine challenge causes degranulation of skin mast cells, but the same stimulus does not induce the release of histamine from human lung, heart, or intestinal mast cells.7 Some opioids – specifically fentanyl, the fentanyl derivatives (sufentanil, remifentanil, and alfentanil), tramadol, and taopentadol – are not likely to provoke direct mast cell degranulation.

Note that true opioid allergies are frequently associated with angioedema (OR 5.66, CI 95% 1.49 to 21.47) and hypotension (OR 5.00, CI 95% 1.15 to 21.70).5

Pseudo Allergies

Non-IgE mediated reactions can be split into either pseudo-allergies that are mild and self-limiting or anaphylactoid reactions that present similarly to anaphylactic reactions. The reason for this differentiation is because pseudo-allergies are not true allergies while anaphylactoid reactions are true allergies.2 It is unfortunately unknown how common pseudo-allergies occur as  laboratory testing that is performed to determine if an allergy is a true allergy versus a pseudo-allergy is often unreliable.

Allergies as Adverse Events

Frequently, opioid allergies are reported when patients experience opioid-related adverse effects such as dry mouth, nausea, vomiting, and confusion, with more than 10% of patients taking morphine, for example, experiencing nausea and vomiting, and up to 10% of these patients experiencing dry mouth. The occurrence of these adverse effects leads to unnecessary drug avoidance.1 In one study, 50% of individuals with self-reported or chart-documented opioid allergies were determined to be intolerances and 92.5% tolerated an opioid retrial.8,9

Another study using opioid drug provocation testing – a gold standard for diagnosing true opioid allergies – found that only 15% of individuals with suspected opioid allergies had a true allergy.1


Mistaken Allergies & Trialing Alternatives

Mistakenly identifying opioid adverse effects as opioid allergies is not surprising given that up to 80% of individuals who receive opioids experience at least one adverse effect.10 Opioid-related adverse effects can be severe and overlap with signs and symptoms of a true allergy (see Table I to differentiate).


Clinicians can trial an opioid of a different chemical class (eg, morphine to fentanyl) in individuals with true opioid allergies as there is no cross-reactivity between subclasses. Even within the same subclass the risk of cross reactivity is ≤ 6.7%. However, there may be a higher risk of cross-reactivity between morphine and codeine due to their similar IgE antibody-binding. Additional information on structure activity relationships is limited for both cross reactivity and the likelihood of causing a true allergic reaction.1,8,9,11,12

Practical Takeaway

To conclude, true opioid allergies are rare, and many documented opioid allergies are in fact due to adverse effects of an opioid. It is important to differentiate a true allergy from an adverse reaction as this knowledge can impact both current and future treatment options for patients.

See also, PPM’s previous case report of tapentadol therapy and a true opioid allergy.

Last updated on: January 5, 2021
Continue Reading:
Tapentadol: A Real-World Look at Misuse, Abuse, and Diversion
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