I switch/add/remove extra monitors daily, sometimes even multiple of times daily, at least for my part, I've never encountered this issue, not even once. For the record, I use Qubes 4 as well, since RC-2.
I do however encounter this issue on Windows 7, both on Qubes 3.2. and Qubes 4.0, but it's relatively easy to fix by clicking the middle-mouse button, which immediately returns the usage of mouse-1 and mouse-2 buttons. Could it be something similar, perhaps? In Win7, this only happens to me when I navigate the GUI Windows in non-seamless mode. It sounds very, very similar to your description too. It's possible it's a similar issue, and if so, maybe it can be used to track down the core issue.
Extra questions that may help troubleshot the issue:
- For those experiencing something similar as OP, are you using Qubes 4 or Qubes 3.2.?
- How frequent do you experience this issue? Daily? Weekly?
- Is the frequency between when it happens somewhat evenly distributed, or is it more random like in the frequency pattern?
- When did it start to happen? Did you update dom0 or templates at the time?
- Is it only an issue in certain VM's, or is it universal for all windows in dom0?
- If only happening inside certain VM's, then which ones? Are other VM's behaving differently?
- Do you sync updates between dom0 and template updates?
- If you use current-testing updates, do you run current-testing in both dom0 and templates?
- and other possible scenarios like the above, try track it down bit by bit in a detective kind of fashion, to be a bit cliché and cite: "When you have eliminated the impossible, whatever remains, must be the truth". Essentially, limit and narrow down the issue, until there is few or nothing left to pick from. You can start with the list above, but try go beyond it.