Does oxycodone (opioid analgesic) cause histamine release?

From the Guidelines

Oxycodone does not typically cause significant histamine release. Oxycodone is an opioid pain medication that primarily works by binding to mu-opioid receptors in the brain and spinal cord. Unlike some other opioids like morphine or codeine, oxycodone has a low propensity for triggering histamine release from mast cells, as suggested by the lack of direct evidence in the provided studies 1. This means that when taking oxycodone as prescribed, patients are less likely to experience histamine-related side effects such as itching, flushing, or hives compared to opioids that do cause more histamine release. However, some individuals may still be sensitive and experience mild histamine effects. Key points to consider:

• Isolated skin symptoms can result from non-specific histamine release in response to some drugs, most commonly opioids 1
• The diagnosis of non-specific histamine release is mostly concluded after further investigations when all substances test negative, and this is corroborated by the history and a normal tryptase result 1
• Patients with systemic mastocytosis or other clonal mast cell disorders can develop reactions that are clinically indistinguishable from IgE-mediated perioperative allergy/anaphylaxis, but are triggered by non-specific mechanical triggers such as temperature, stress, or some histamine-releasing drugs 1 If a patient does experience histamine-like reactions while taking oxycodone, they should inform their healthcare provider. In such cases, an antihistamine like diphenhydramine (25-50 mg) may be recommended to manage symptoms if needed. The low histamine-releasing property of oxycodone is one reason it may be preferred in some clinical situations over other opioids, particularly for patients with a history of opioid-induced histamine reactions or those with mast cell disorders.

From the FDA Drug Label

Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension Oxycodone may cause histamine release, as evidenced by potential manifestations such as pruritus, flushing, and orthostatic hypotension. Key points include:

• Histamine release is not the only possible cause of these symptoms, as peripheral vasodilatation may also contribute.
• The clinical significance of histamine release associated with oxycodone is not explicitly stated in the label. 2

From the Research

Histamine Release and Oxycodone

• Oxycodone is a semi-synthetic opioid analgesic that has been studied for its potential to cause histamine release 3, 4.
• A study published in 1991 compared the reactivity of five opioid analgesics, including oxycodone, on mast cell suspensions obtained from porcine heart, kidneys, liver, and lungs, and found that oxycodone caused histamine release, particularly from cardiac cells 4.
• However, a more recent review article published in 2021 stated that oxycodone has an advantage over other opioids due to its lack of histamine release or ceiling effect 5.
• Another study published in 2021 discussed the toxicities of opioid analgesics, including histamine release, but did not specifically mention oxycodone as a histamine releaser 6.

Mechanism of Action and Pharmacokinetics

• Oxycodone exerts its analgesic effect via the µ-opioid receptor and is primarily metabolized in the liver by the cytochrome P450 (CYP) enzymes 3, 7.
• The pharmacokinetics of oxycodone can vary between individuals due to genetic differences, particularly in the CYP2D6 and CYP3A enzymes 7, 5.

Clinical Implications

• The clinical efficacy of oxycodone is similar to that of morphine, and it may be associated with less toxicity in long-term administration 3.
• Oxycodone may be beneficial in patients with severe hepatic cirrhosis due to its higher and less variable bioavailability compared to morphine 7.