I was wondering if there are any precautions or things I should do to ensure no damage is done to my outboard on long runs? Pretty long runs like 50 or 60 miles one way... Should I have the outboard set lower to get more water?

I have a 21' Triton with a 225 Opti-Max, both are 2000's

I assume you're talking trim angle, unless you have a hydraulic jack plate.  The key is your water pressure, you don't want to get it below 16 psi.   As for trim and engine height, you want it up and trimmed out from max speed at the rpm you're wanting to cruise at so there is as little hull drag as possible.  Just don't let water pressure get below 16 psi.

Now, if you're talking WOT for 50 mile runs on an OPTI-POP, good luck.

Then their's this equation, 70 mph for 60 miles one way = 120 miles round trip = approx 40 - 60 gallons of gas @ $3.5 = $150 - $200 per trip.

I have ther TR21x with a Mercury 250 XS I run 18psi water pressure at about 5700 RPM about 63 MPH I make runs up to 20-30 miles never had a lick of trouble water pressure is the key keep it above 15 psi and my manual says

K thanks,

Yeah, if you've ever fished the Ohio River you'd know that sometimes you've gotta make one hell of a run to get some fish, but if it pays off that $200 in gas will win me $6000.

How many locks are in that 60 miles? I run at the river and have locked through two locks, man that eats up the time. 2 locks 20 minutes each to lock down and back up on a good day 2 hours driving. Thats like 3 1/2 hours. There are good fish in most pools. Thats seems like a huge waste of time there. I have an Opti with the extra intake on the nosecone of my gearcase. I rarely drop below 20# of pressure. At the highest setting on my jackplate my prop is above my hull. No problems. My farthest runs are usually 35-40 miles but I have made a couple much longer at close to WOT.

This perhaps belongs on a different thread and I don't know the Ohio River but with that long of a run, is it possible to put in at a different (closer) ramp?  But I'm sure you would've thought of that.