I personally have done it with Joy2Key, and xpadder will work the same. It took time, but once I got the hang of it, I was able to get most of my c64 games to run on my controls with no problems. I would just create a joystick profile for each game that had unique controls, create a batch file to load that profile and boot the game, then have the emulator boot the batch file.
I think that will only work if you have a joystick encoder. If you have a keyboard encoder, like a ipac, you would probably need to use autohotkey. I have never dived into autohotkey, but I think you can create a script to remap your buttons on each game boot. Maybe an autohotkey pro can chime in on how to do that exactly.
Also, as you know a bunch of c64 games have crack screens and trainers on them. They usually require a bunch of buttons to bypass and get to the actual game. You can create bypass this by creating snapshot files (save states) of the the game after you get to the title screen, and have the frontend open the snapshot files instead of the game itself. You will also not need to wait for the game to load when you fire it up with this method as well.
Sorry I don't know more about how to use autohotkey. I think that will be the best route if you are not using a joystick encoder.