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Keyboard hook is the more reliable way and if you hadn't it checked, then try it. Just tested it with LoL and it worked straight away. If it doesn't help, let the keyboard hook option checked and start Soundpad after the game. That way Soundpad's hotkeys get precedence.
If it still doesn't work, then it looks like the game/application is deliberately blocking global hotkeys and there's really not much one can do about it.
See details at FAQ - Why are my hotkeys not working?[www.leppsoft.com]
Can you try it with Mouse4, Mouse5 or Mouse Mid in League of Legends?
you should have the same problem if you use push to talk in teamspeak.