Editor’s Note: This is the third part of an ongoing series on what emergency physicians can do to combat the opioid epidemic. The series will continue in the August issue.
I feel cheated! After all that time in pharmacology classes and the tests in undergraduate, graduate school, medical school, and residency all oversimplify the concept of the difference between a partial agonist and full agonist. When you dig deep into the pharmacology literature, you find only one true full agonist, DAMGO (ie, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin), which is not even a medication used in humans.
In fact, all the opioid pain medications we give patients are only partial agonists to varying degrees. And as if that wasn’t enough, the ceiling effect of buprenorphine seems to be a myth regarding pain control.
Partial or Full?
As a quick review, we conventionally determine if a medication has partial agonist or full agonist activity based on its intrinsic activity Kappa (Ki). The Ki tells us how much an opioid, or any drug for that matter, activates a receptor when it binds. The strict definition of a full agonist would be any substance that binds to the receptor and activates it 100 percent.
But as stated earlier, there are no clinically available opioids that activate the mu receptor 100 percent. Some get close, such as fentanyl and sufentanil, which activate at about 90 percent. However, others such as hydromorphone and morphine only activate the receptor in the high 80 percent or high 70 percent range, respectively. Buprenorphine effectively reduces the receptor activation to 50 percent. Relatively speaking, opioids have the hierarchy of intrinsic activity shown below in Figure 1.
Why does all of this matter? It matters because buprenorphine is possibly the most important medication in the fight against opioid-use disorder and its close cousin, overdose death. Think about a patient who is physically dependent on opioids, either morphine or hydromorphone. If you give this patient a dose of buprenorphine, you may be called to the bedside and read the riot act because they’re now in acute precipitated withdrawal!
It turns out this is not just about the IA of buprenorphine, but also the strength in which buprenorphine binds to the mu receptor, or what’s known as its affinity. For all you molecular biologists out there, we know the receptor affinity data are based on cell culture experiments and mostly in Chinese hamster ovary (CHO) cells at that, not human cells. We therefore must take the absolute numbers of both IA and affinity with a grain of salt.