It's 1-of-3 things...so far. The first one is temporary and moderators can't explain. The cable-box becomes "sluggish" to any command from the remote. For example, if you press Guide, it'll take 4-5 seconds to display the Guide menu. It's happened to me twice with Controur-2 and both disappeared after a couple days.
The second happened with Rovi and it sounds like the OP's problem: wear-and-tear. The Guide button went from requiring another press to harder-and-harder presses to eventually becoming a dead chunk of rubber. However, the rarely-used buttons also became unresponsive. Reboots to fix other problems had no effect.
The third on is new: reboot the cable-box. Do instruction sets become corrupt? I've never seen that. Beginning with a LaserDisc player, I've had lots of components and lots of remotes but never had one lose its codes.