Opioid side effects can be divided into three categories:

Side effects with no immune mechanism These include nausea/vomiting, constipation, sedation, delirium, respiratory depression, and urinary retention.

Side effects that mimic immune reactions Common signs/symptoms include mild itching, urticaria, brochospasm, or hypotension. For most patients, these symptoms are mild and self-limited.
The etiology most commonly involves direct mast cell degranulation with histamine release, unrelated to a true immune-mediated reaction. Such reactions to opioids are usually idiosyncratic and may or may not recur with re-challenge of the same opioid; they are not a contraindication to continued opioid use, since an alternative opioid may be well tolerated.

Immune mediated reactions:
- Allergic dermatitis is characterized as erythroderma, scarlatina, eczema, or exudative vesicular eruptions; these may represent a Type IV (delayed) hypersensitivity reaction.

- Anaphylaxis/anaphylactoid reactions. Anaphylaxis is a systemic IgE mediated reaction resulting in the immediate release of potent mediators; anaphylactoid reactions are clinically the same, but are not IgE mediated. Early symptoms include nasal congestion, flushing, pruritus, angioedema; if the process worsens, patients can develop nausea, diarrhea, urinary urgency, brochospasm, hypotension, and death.

Management. Anaphylactoid reactions (extremely rare) require emergent management with epinephrine and histamine blockers. For milder histamine-related symptoms, common practice is to rotate to an opioid in a different pharmacologic along with use of antihistamines or steroids. Anecdotal reports suggest that methadone and fentanyl cause fewer instances of itching.

Adapted from Woodall HE, Chiu A and Weissman DE. Palliative Care Network of Wisconsin. Fast facts and concepts #175. Opioid Allergic Reactions. Accessed on January 27, 2016.