From the Guidelines
Fentanyl works by binding to opioid receptors in the brain and spinal cord, primarily the mu-opioid receptors, which blocks pain signals and produces intense feelings of euphoria. As a synthetic opioid, fentanyl is a highly lipid-soluble mu-opioid receptor agonist that can be administered by various routes, including parenteral, spinal, transdermal, transmucosal, buccal, and intranasal routes 1. When used medically, fentanyl is typically administered in controlled doses for severe pain management, particularly in surgical settings or for cancer pain. The drug works by mimicking natural endorphins, but with much greater potency, causing not only pain relief but also respiratory depression, sedation, and decreased consciousness.
Some key points to consider when using fentanyl include:
- Transdermal fentanyl is not indicated for rapid opioid titration and should be recommended only after pain is adequately managed by other opioids in opioid-tolerant patients 1.
- Findings from a Cochrane Database review support the efficacy of transdermal fentanyl for relieving moderate to severe cancer pain and suggest a reduction in opioid-related constipation compared with oral morphine regimens 1.
- Conversion from intravenous fentanyl continuous infusion basal rate via patient-controlled analgesia to transdermal fentanyl can be accomplished effectively using a 1:1 conversion ratio 1.
- Transmucosal fentanyl may be considered in opioid-tolerant patients for brief episodes of incident pain not attributed to inadequate dosing of an around-the-clock opioid 1.
Overall, fentanyl's high potency and rapid onset of action make it a valuable tool for managing severe pain, but its use requires careful consideration of the potential risks and benefits, as well as close monitoring of patients to minimize the risk of adverse effects 1.
From the FDA Drug Label
Fentanyl is an opioid analgesic. Fentanyl interacts predominately with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, fentanyl exerts its principal pharmacologic effects on the central nervous system
- Key points about how fentanyl works:
- Fentanyl is an opioid analgesic that interacts with opioid mu-receptors in the brain, spinal cord, and other tissues.
- It exerts its effects on the central nervous system, producing analgesia, as well as alterations in mood, euphoria, dysphoria, and drowsiness.
- Fentanyl depresses the respiratory centers, depresses the cough reflex, and constricts the pupils.
- The mechanism of action is primarily related to its binding to opioid mu-receptors, which are involved in pain perception and regulation. 2 2
From the Research
Mechanism of Action
- Fentanyl works by binding to the μ-opioid receptor, which is responsible for its analgesic and respiratory depressant effects 3, 4, 5.
- The binding of fentanyl to the μ-opioid receptor is characterized by high affinity and rapid association, with a dissociation that is biphasic, suggesting the existence of high and low affinity binding sites 5.
- Fentanyl's high lipophilicity allows it to quickly cross the blood-brain barrier, resulting in rapid onset of action 3, 5.
Respiratory Depression
- Fentanyl depresses respiration by reducing both respiratory rate and tidal volume, which can lead to respiratory failure and death 3, 6.
- The depression of respiration by fentanyl is more rapid than that of heroin or morphine, and is not reversed as easily by naloxone, a commonly used opioid antagonist 3.
- Prolonged treatment with morphine can induce tolerance to respiratory depression, but the degree of cross-tolerance to fentanyl is less than the tolerance to morphine itself 3.
Signaling Mechanisms
- Fentanyl recognition and signaling of the μ-opioid receptor involves dual interactions with both the TM3 and TM6/7 regions of the receptor, which is different from other opioid agonists 4.
- Mutations at the TM6/7 interface can abolish arrestin recruitment of the μ-opioid receptor promoted by fentanyl, and ligands designed to reduce TM6/7 interactions can display preferential G protein signaling 4.