Can Fentanyl or Versed Cause Headaches?
Headache is not a recognized adverse effect of fentanyl, but midazolam (Versed) can cause headache, occurring in approximately 1.3-1.5% of patients receiving intravenous administration. 1
Fentanyl and Headache
Fentanyl does not cause headache as a direct adverse effect. The major adverse effects associated with fentanyl are:
- Respiratory depression (the most significant concern, which may persist longer than the analgesic effect) 2
- Nausea and vomiting (similar incidence to other opioids, resulting from stimulation of the medullary chemoreceptor trigger zone) 2
- Chest wall rigidity in large doses (from centrally mediated skeletal muscle hypertonicity) 2
- Cardiovascular effects (small reductions in blood pressure and heart rate from vagal stimulation) 2
Importantly, the AGA Institute review explicitly distinguishes fentanyl from meperidine, noting that unlike meperidine, fentanyl has not been implicated in drug interactions with monoamine oxidase inhibitors that can cause headache 2. This suggests headache is not a characteristic adverse effect of fentanyl.
Midazolam (Versed) and Headache
Midazolam causes headache in 1.3% of patients following intramuscular administration and 1.5% following intravenous administration 1. The FDA drug label for midazolam explicitly lists headache as an adverse reaction observed in clinical use.
Other common adverse effects of midazolam include:
- Respiratory depression (decreased tidal volume/respiratory rate in 23.3% IV and 10.8% IM; apnea in 15.4% IV) 1
- Cardiovascular effects (variations in blood pressure and pulse rate) 1
- Drowsiness and oversedation (1.2-1.6% of patients) 1
- Nausea and vomiting (2.6-2.8% of patients) 1
Critical Safety Consideration: Synergistic Respiratory Depression
When fentanyl and midazolam are used together—a common practice in procedural sedation—they produce a potent synergistic effect on respiratory depression that significantly increases the risk of hypoxemia and apnea:
- Combined use produces hypoxemia in 92% of patients (11 of 12 subjects) and apnea in 50% (6 of 12 subjects) 3
- Fentanyl alone produces hypoxemia in only 50% of subjects and no apnea 3
- Midazolam alone produces no significant respiratory effects 3
- 78% of deaths associated with midazolam were respiratory in nature, and in 57% an opioid had also been administered 3
The concomitant use of a benzodiazepine with an opioid has a synergistic effect on the risk of respiratory depression 2. This is the primary safety concern with these medications, not headache.
Clinical Bottom Line
If a patient develops headache after receiving fentanyl or midazolam, consider alternative causes rather than attributing it to fentanyl. Midazolam may be responsible in approximately 1-2% of cases, but headache is not a characteristic adverse effect of either medication. The far more important clinical concern is monitoring for respiratory depression, particularly when these agents are used in combination.