I never had a problem with MP:H after I got a case for my DS. The increased size helped the ergonomics. I remember back in the day, Double Dragon II really got to my thumbs more than any other game had for me at the time. The NES controller was shit anyways, so it's no wonder.
Modernly though, only the PSP has any lack of ergonomics. I can almost be guaranteed a sore appendage when playing that. The Wii has been a little of a problem if I feel I need to hold my arm out in a Nazi salute to aim. I've learned how to just face the controller at the screen while resting my elbow on my knee, so it hasn't been a problem more than once or twice.