Neuroscience The science of cross tolerance in opioids

[Opiophiliclab]

Maybe some of you know that some doctors use a practice known as opioid rotation to prevent both an increase in tolerance as well as prevent a gradual loss of the analgetic effect in their patients. I personally experienced this when I stopped taking morphine after years of use and started taking Methadone instead. In the first two days I didn't notice anything besides having no withdrawals, but from the third day onward I started to feel a strong sense of euphoria and generally the whole spectrum of positive effects associated with opioids. I felt like I was back in my opioid naive days. This lasted two weeks after which I switched back to morphine and had the same effect. Rinse repeat. I have no idea why this works but here is my theory: could it be that opioid agonists' cross tolerance directly correlates with their structural similarity? What I mean by that is this: imagine you rotate between morphine and oxycodone every three days. Your tolerance still increases because they are both part of the same "family" so to speak, that is they are both 4,5-epoxymorphinans and therefore structurally too similar in order to not be cross tolerant. Now compare this with Methadone. Methadone as a 3,3-diphenylpropylamine is structurally completely different to morphine. In fact it is so different that just by looking at the structure one could assume that those are two completely different substances with completely different effects. So I'm thinking maybe the body interprets it that way when it gets this totally different molecule that works like an opioid but has a very different structure and hence the lack of cross-tolerance.
I also noticed this with Levorphanol that I am taking since a year. Whether I was previously on methadone or morphine, I feel good effects when I switch to an opioid from a different class.

Or is the cause somewhere else entirely? Do you guys have similar experiences? Is there maybe some list with opioids that share little to no cross-tolerance to each other? Studies are welcome.