Over the course of several years teaching students how to alternate pick, I’ve noticed a lot of issues arising from the way many of them had been holding their pick. More specifically, it was down to the way their thumb was positioned.
A lot of people find that they have to wrestle the pick through the strings, forcing it through with an iron grip. Sometimes this happens as a reaction to not wanting to drop the pick or have it slip around in their grip, so they tighten their hold onto the pick and keep the thumb locked out straight.
The trouble with this is that it can put the pick in a position that isn’t conducive to gliding through the strings. With the widest edge of the pick facing the strings, each down or up stroke feels more like a push.
Now, for certain tonal characteristics in our phrasing, this is sometimes what we want. For slower and mid-tempo playing, this can be fine. But when you want to ramp up the tempo for something a little… busier… then this "pushing the pick through the strings" business can be pretty energy consuming. Not only that, but the locked thumb position makes it harder for players to feel out and find a relaxed wrist motion because the pick doesn’t glide over the strings easily, and this can lead them toward a stiff-armed approach, which then leads to more tension and a frustrating lack of progress.
The fix is simple. Just relax your thumb and watch as it retracts slightly into its natural position. You might get a slight bump where the knuckle is, but don’t force this. Also try not to worry too much about dropping your pick or having it move about as you play.