Do you play with three fingers?
I find that if I play really intense material for 5 minutes straight, my right hand gets very sore and it's quite hard to keep up the speed.
PAIN IN THE ASS!!!
You also need to warm up before speed picking. John Myung of DT, for instance, is well known for warming up two hours before every show, without fail. And that's the entire two hour period, just warming up. No wonder he can play 3-4 hours on every show, and he hardly flubs a note.