Fentanyl and Histamine Release
Fentanyl does not cause clinically significant histamine release, making it a preferred opioid in situations where hemodynamic stability is important or in patients at risk for histamine-mediated reactions. 1, 2
Evidence on Fentanyl and Histamine Release
Fentanyl stands apart from many other opioids in its relationship with histamine:
- The FDA label for fentanyl specifically states that "histamine assays and skin wheal testing in clinical studies indicate that clinically significant histamine release rarely occurs with fentanyl administration" 1
- Multiple controlled studies have demonstrated that fentanyl does not cause significant histamine release:
- A double-blind study comparing four narcotics found that none of the patients given fentanyl had clinical signs of histamine release or elevations of plasma histamine levels, while meperidine and morphine did cause histamine release in some patients 3
- Laboratory studies have confirmed that fentanyl does not induce histamine and tryptase release or the de novo synthesis of inflammatory mediators from mast cells 4
Comparison with Other Opioids
The histamine-releasing properties of opioids vary significantly:
- Meperidine and morphine reportedly induce increases in histamine levels in humans more frequently than fentanyl and sufentanil 5
- In clinical studies, histamine release occurred in 31% of patients given meperidine and 10% of patients given morphine, but in none of the patients given fentanyl 3
- This difference in histamine-releasing properties contributes to fentanyl's popularity in clinical practice, as it provides "minimal cardiovascular effects, does not result in increases in plasma histamine, is relatively short in onset of action and duration of effect" 2
Clinical Implications
The lack of significant histamine release with fentanyl has important clinical implications:
- Fentanyl is often preferred in hemodynamically unstable patients or those at risk for histamine-mediated reactions
- For patients with mastocytosis (a condition with increased mast cell burden), fentanyl and sufentanil are preferred over morphine and meperidine due to their lower risk of triggering mast cell degranulation 5
- Dose and rate-related histamine release does not occur with fentanyl analogues, making them safer options when rapid administration is necessary 5
Special Considerations
Despite fentanyl's favorable histamine profile, clinicians should be aware of:
- One study suggested fentanyl may enhance histamine release in airways through indirect mechanisms, potentially contributing to cough reflexes 6
- A German study reported histamine release with both nalbuphine and fentanyl, though this contradicts most other research findings 7
- While fentanyl itself doesn't cause significant histamine release, it's still an opioid with potential for other adverse effects including respiratory depression, which should be monitored 5, 8
Practical Applications
When selecting an opioid for clinical use, consider:
- For patients with history of allergic reactions or hemodynamic instability, fentanyl offers advantages over morphine or meperidine
- For procedures requiring rapid administration of opioids, fentanyl's lack of histamine release makes it a safer choice
- In patients with mastocytosis or other mast cell disorders, fentanyl or sufentanil should be preferred over other opioids 5
The evidence consistently shows that fentanyl is among the opioids least likely to cause clinically significant histamine release, making it a valuable option in many clinical scenarios where hemodynamic stability is crucial or where patients may be at increased risk for histamine-mediated adverse effects.