When I first got a keyboard with a thumb cluster that had 6 keys I was originally a bit overzealous and had a bunch of relatively frequently used keys assigned to them. I actually ended up developing a little bit of what I think was some tendonitis in my thumbs when I first started using it quite a bit.

Ever since then, I primarily only use two of the keys of each thumb clusters with frequency, and they both require very little movement to reach (the two large keys on a kinesis 360). The others that require a little bit more extending of the thumb are more infrequently used keys that don't ring all the time.