With most new backpacking footwear you're told to break in the boots before you go; with these you're advised to break yourself in first. Based on my experience so far I'd say definitely take that advice.
I've done quite a bit of biking for the past few years, but only started running (strictly treadmill stuff) last September. I've never liked even the thought of running, but was surprised to find myself on there 5 days a week doing 5Ks, 10Ks, and 13.1 miles on Fridays, about once a week with a small backpack. This was all in running shoes. Well, "regular" shoes -- nothing fancy, just what I had lying around.
After mail ordering 2 separate orders for a total of 3 pairs of KSOs from REI I settled on the 43s with Injinji socks and started running in those. While I was waiting for those to come in I consciously started walking around the house barefoot more often, trying to toughen up my soft feet a little.
I wish I had done some documentation to better track the process of getting myself used to them, but it went something like this. I started running in the KSOs mid-November, knowing beforehand I would be cutting back on the mileage; The skin on my feet threatened to blister, something deeper in the soles of my feet was sore, the muscles in my feet were sore, and my calves were killing me. That was probably after only a 5K. Needless to say I didn't rush to up the mileage much.
I think it was after about a week the threats of blistering went away, and about 2 or 3 weeks after that the soreness in the soles disappeared. At that point, 10Ks were again no problem, and I started adding an 18lb pack once or twice a week, which brought back a little of the sole pain, but not for long. Surprisingly (to me, anyway), my calves adjusted the the new running style (more forward on the foot) before my foot muscles have; I'd say they stopped being any more sore than normal after a run sometime just after the 1-month mark.
It's been about 2 and a half months of pretty consistent running in them and my feet still sometimes feel like they've had their own little workout, independent of my heart and legs, but it's getting less and less. I haven't done any half-marathons in them yet, concentrating more on adding hills and weight, but have managed 10 miles a couple of times in the past month.
A few points potentially worth consideration:
1 - This is all indoor work; there aren't many ankle-twisting obstacles on the treadmill belt.
2 - The treadmill surface is softer to run on than concrete, but most of us don't backpack on sidewalks much anyway.
3 - My experience so far has only included fairly low miles with a fairly low load; I'm not sure yet what 25 miles with 25 pounds would feel like in these (anyone?).
4 - Little rocks and sticks underfoot under load could be a whole 'nother ballgame. I've only day-hiked with about 10 pounds so far (no problem).
It's just my limited experience, but I hope it helps someone. If not -- hey, I'm an unemployed automotive engineer in Michigan; what else do I have to do besides write long posts and stare at a white basement wall for 13 miles?