What is the mechanism of action (MOA) of Fentanyl?

Fentanyl Mechanism of Action

Fentanyl is a synthetic opioid agonist that exerts its pharmacologic effects by binding predominantly to mu-opioid receptors distributed throughout the central nervous system, spinal cord, and peripheral tissues. 1

Primary Receptor Interaction

• Fentanyl interacts primarily with the mu-opioid receptor, which is the principal mechanism responsible for its analgesic, sedative, and respiratory depressant effects 1
• The drug also demonstrates weak activity at kappa-opioid receptors 2
• These opioid receptors are widely distributed in the brain, spinal cord, and other tissues throughout the body 2, 1

Key Pharmacologic Effects Mediated by Mu-Receptor Binding

Central Nervous System Effects

• Produces respiratory depression through direct action on brain stem respiratory centers, reducing responsiveness to both increased carbon dioxide tension and electrical stimulation 1
• Causes miosis (pinpoint pupils) even in total darkness, which is a characteristic sign of opioid activity 1
• Provides potent analgesia by modulating pain perception at multiple levels of the nervous system 2

Gastrointestinal Effects

• Reduces motility and increases smooth muscle tone in the antrum of the stomach and duodenum 1
• Delays digestion in the small intestine and decreases propulsive contractions 1
• Decreases propulsive peristaltic waves in the colon while increasing tone to the point of spasm, resulting in constipation 1
• May cause spasm of the sphincter of Oddi and transient elevations in serum amylase 1

Cardiovascular Effects

• Produces peripheral vasodilation, which may result in orthostatic hypotension or syncope 1
• May cause a small reduction in arterial blood pressure and heart rate in response to vagal stimulation 2
• Has relatively little direct effect on the cardiovascular system compared to other opioids 2

Unique Pharmacologic Properties

• Fentanyl is highly lipid-soluble, which allows it to rapidly cross the blood-brain barrier and reach opioid receptors quickly 2
• This high lipophilicity enables multiple routes of administration including transdermal, transmucosal, buccal, intranasal, and parenteral delivery 2, 3
• The onset of action after intravenous administration is 1-2 minutes with a duration of effect of 30-60 minutes 2
• Fentanyl is approximately 80 times more potent than parenteral morphine due to its high receptor affinity and lipid solubility 2

Clinical Implications of Mechanism

• Unlike morphine, fentanyl has no known active metabolites that accumulate in renal insufficiency, making it safer in patients with kidney disease 2, 4
• The drug demonstrates minimal histamine release compared to other opioids, resulting in less pruritus and allergic-type reactions 1
• In large doses, fentanyl may induce chest-wall rigidity resulting from centrally mediated, generalized hypertonicity of skeletal muscle, which can make assisted ventilation difficult 2