I am not sure what "it", "setting" or "normal" refer to here. Can you give more detail on that?
Some more things that might be relevant to tracking it down:
Which file display mode are you using?
Which button event(s) are you seeing the problem with?
Have you tried assigning it/them to a different command (e.g. Help ABOUT) in case there's something specific to the command? (E.g. A script that never finishes or takes a long time could block subsequent events from starting, maybe. Or the script, if that's still what you're using, may not be seeing the keyboard state and not running the expected command, even though the script is being run. We may be looking in the wrong place here, until we know that.)
Any mouse/macro software that might be changing what the mouse button does sometimes?
Random thought: Does it depend whether Opus is the active window before clicking?
Those two shouldn't really affect each other. The first one only affects clicking on files and folders to run the middle button double-click filetype events. The second one only affects clicking on the background to run the configured background events.
Either way, setting it up as you have said, single middle-click on background in thumbnails mode still runs the configured command.
Maybe something to do with your mouse drivers? For example, I've often found the Logitech drivers have a habit of occasionally forgetting their configuration and have to be restarted.