From the Guidelines
Fentanyl and morphine are both opioid analgesics that work by binding to mu-opioid receptors in the central nervous system, but they differ in several important ways, with fentanyl being 50-100 times more potent than morphine due to its greater lipid solubility, leading to a faster onset of action and shorter duration of action. The mechanism of action of fentanyl and morphine involves binding to mu-opioid receptors, which are highly expressed in brain regions that regulate pain perception, such as the periaqueductal gray, thalamus, cingulate cortex, and insula 1.
Similarities in Mechanism of Action
- Both fentanyl and morphine are full mu-opioid agonists, producing analgesic effects by activating mu-opioid receptors in the central nervous system 1.
- Both drugs can cause respiratory depression, which may persist longer than the analgesic effect, and can result in overdose-induced death 1.
- Both fentanyl and morphine can cause nausea and vomiting, with similar incidence rates 1.
Differences in Mechanism of Action
- Fentanyl has a faster onset of action (1-2 minutes for IV fentanyl versus 5-10 minutes for IV morphine) due to its greater lipid solubility, which enables it to cross the blood-brain barrier more rapidly 1.
- Fentanyl has a shorter duration of action (0.5-1 hour) compared to morphine (3-4 hours), making it useful for brief procedures and easier to titrate 1.
- Fentanyl demonstrates greater selectivity for mu receptors with minimal activity at other opioid receptor subtypes, whereas morphine has some activity at kappa and delta opioid receptors 1.
- Morphine causes more histamine release than fentanyl, which explains why morphine more commonly causes pruritus and hypotension 1.
- Fentanyl undergoes primarily hepatic metabolism, while morphine produces active metabolites (particularly morphine-6-glucuronide) that can accumulate in patients with renal impairment, potentially prolonging its effects in these patients 1.
From the Research
Mechanism of Action of Fentanyl and Morphine
The mechanisms of action of fentanyl and morphine, both opioid analgesics, have been studied extensively. Key similarities and differences are outlined below:
Similarities
- Both fentanyl and morphine bind to the μ-opioid receptor (μOR) and activate G protein and arrestin signaling pathways 2.
- They both induce analgesia and unwanted side effects through these pathways 2.
- Both drugs are agonists at μ, κ, and δ opioid receptors 3.
Differences
- Fentanyl and morphine have different binding interactions with the μOR. Fentanyl forms interactions with both TM3 and TM6/7 regions, while morphine also interacts with both regions but with different preferences 2, 4.
- Fentanyl has a higher affinity for non-opioid receptors and transporters, such as α1A and α1B adrenoceptor subtypes and dopamine D4.4 and D1 receptor subtypes, compared to morphine 3.
- Fentanyl induces different clinical effects, including rapid onset muscular rigidity and vocal cord closure, which may be attributed to its non-opiolo receptor pharmacology 3.
- The efficacy of fentanyl is higher than that of morphine, which may be due to differences in ligand-receptor interaction landscapes and induced conformational changes in the μOR 4.
- Fentanyl and morphine have different onset and offset profiles, with fentanyl having a more rapid onset and offset due to its faster transfer to the receptor site 5.
Receptor Pharmacology and Signaling
The receptor pharmacology and signaling mechanisms of fentanyl and morphine have been studied using various techniques, including molecular dynamics simulations and receptor binding assays.
- Fentanyl and morphine elicit different activation patterns in the μOR, with fentanyl preferentially activating TM6 and TM7 and morphine preferentially activating TM3 and TM5 4.
- The differences in receptor activation patterns may contribute to the greater efficacy of fentanyl over morphine 4.
- Fentanyl's higher affinity for non-opioid receptors and transporters may also play a role in its different clinical effects compared to morphine 3.