"When a movement is repeated over time, a long-term muscle memory is created for that task, eventually allowing it to be performed without conscious effort. This process decreases the need for attention and creates maximum efficiency within the motor and memory systems." -- Wikipedia
Are you talking about something which was once muscle memory, but has become uncomfortable over time? Or are you referring to a motor activity that was so uncomfortable from the start that it was never repeated enough times to become so? In the case of the former, I would definitely recommend learning a new method that doesn't risk causing harm to oneself (the discomfort may be a sign of more serious health issues). In the case of the latter, I would similarly recommend an alternate muscular action that avoids the discomfort.
However, in my case (and the case for what I suspect is 99.999% of keyboard users out there), things like Ctrl on the bottom row present no noticeable discomfort at all, and so having muscle memory tied to it isn't a problem. Moreover, thanks to muscle memory, that layout is yielding the benefits of "maximum efficiency within the motor and memory systems." Changing to something else would be patently counter-productive, and recommending that folks do so would be doing them a disservice.