The Pharmacology of Fentanyl and Its Impact on Pain Management

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Lipid Solubility

Lipid Solubility of Commonly Used Opioids

Of the clinically available pure mu agonists, fentanyl and sufentanil are the most lipid-soluble and morphine is the least lipid-soluble.^[6] The octanol-water partition coefficient is a classic way of looking at the lipid solubility of drugs. The octanol-water partition coefficient for morphine is 6 and 9550 for fentanyl, thereby showing that fentanyl is highly lipid-soluble.^[6] This difference in lipid solubility has profound effects on how we can use these 2 drugs in clinical practice.

Effects of Lipid Solubility on Drug Behavior

We normally think of fentanyl as short-acting and morphine as long-acting. However, the 2 drugs have similar elimination half-lives: 2-4 hours for morphine and 3-7 hours for fentanyl.^[6] We often think of drug elimination as determining the duration of effect. However, morphine does not last longer than fentanyl because it is eliminated more slowly from the body; it lasts longer because once it enters the central nervous system it has a difficult time exiting the cellular lipid barrier (blood-brain barrier). It is this retention in the central nervous system that makes morphine longer-acting than fentanyl.^[7] Because morphine is not very lipid-soluble, it takes a long time to cross the blood-brain barrier both going into and out of the brain. This produces what one might call a "slow-in, slow-out" drug. Indeed, when compared with lipid-soluble drugs, morphine is noted to be slower in onset. Fentanyl, on the other hand, is lipophilic and crosses the blood-brain barrier rapidly in both directions; it is a "fast-in, fast-out" drug. Therefore, fentanyl acts quickly and has a short duration of action because of its lipid solubility.

Another factor that can play a role in how a drug behaves clinically is receptor affinity. If an opioid binds tightly to a mu receptor, it may have a surprisingly long duration of action. The mu receptor dissociation constant for fentanyl is 1.9 and 2.0 for morphine, indicating that they are very similar.^[6] Because their elimination half-lives, as described above, and their mu receptor binding affinities are very similar, it is primarily differences in lipid solubility that govern the different behaviors of these 2 drugs.