How does medicinal chemistry or structure activity relationship impact opioid tolerability?
Medicinal chemistry can absolutely be used to a clinician’s advantage when predicting how a patient may respond to a specific opioid. There are five chemical classes of opioids: phenanthrenes, benzomorphans, phenylpiperidines, diphenylheptanes, and phenypropylamines.
Semisynthetic dehydroxylated phenanthrenes such as hydrocodone, hydormorphone, levorphanol, oxycodone, buprenorphine, butorphanol, and others lack the 6-OH group contained in the morphine molecule. This seems to diminish side effects otherwise seen with morphine and codeine, such as pruritis and nausea. More importantly, if a patient has a true allergy (which is extremely rare) to one phenanthrene, they will be allergic to the entire phenanthrene class. Conversely, it is not possible to be allergic to one dehydroxylated phenanthrene and not another. For example, if a patient claims to be allergic to oxycodone but not hydrocodone, or vice versa, this is in fact impossible and is more likely a result of a pseudoallergy. The distinction between a pseudo-allergy versus a true allergy is that a pseudoallergy is related to histamine release and therefore not life threatening, while a true allergy is related to immunoglobulin activity and could be life threatening. If a patient is grossly intolerant to one opioid chemical class, they may tolerate another. For example, if a patient claims only to tolerate meperidine, then fentanyl may be a viable option because both are phenylpiperidines, especially given fentanyl is the only opioid with little to no histaminergic activity.