I have a New 3DSXL. For some reason, the form factor really made my hands cramp up if I played too long, despite never having the problem with the DS Lite. So, one of the first things I did was get a grip. Mine is the Cyber Gadget brand. There may be better ones now. Or not, I dunno, the 3DS is basically finished as a platform, right?

Anyway, the second part is trickier, and that's simply finding some method of playing. For me, I sort of rotate frequently from side to side, to back to belly, like every 20-30 minutes.