I've been trying different bikes, and different configurations of the same bike (Norton) for the last several years, trying to find something I could ride for a longer round trip than 100 -150 miles. I'm 74 and have some damaged lower vertebrae, as well as severe neck arthritis, and am also subject to leg and hand cramps from long rides. As they say, getting old isn't for sissies. I've been weaning myself from pain meds because of the bad side effects, and have found that they don't really help that much anyhow. As an aside, the single most helpful thing I've done to reduce pain is lose a little weight. It's amazing how much difference just 10 lbs can make. But back to the bikes, I've found that the only style I can ride any distance at all is a conventional sit-up configuration with "normal" bars. Two other critical items are foot pegs more or less centered below my body center of gravity, and some sort of rear support from the seat. It doesn't have to be a full back rest, just enough that I don't have to use leg muscles to keep from sliding rearward. At the moment, the most comfortable bike I have for longer rides is a Kawasaki Ninja 650 that has had higher bars fitted. I can do a comfortable 150 miler on it, as long as I stop and stretch my legs a bit once in a while. For the Nortons, after riding a MK3 Interstate for a number of years, I'm converting it to roadster configuration. I've been lately riding the MK3 roadster we built for my grandson, and it's much easier on me than the Interstate was. The interstate seating position is just too far back for me to ride comfortably. The standard roadster configuration, with the stock "Western" bars is pretty good for me. I think a little seat modification to put some support behind my butt will make it even better. Of the other bikes I've tried in the last few years, the most comfortable one was a 1980 Honda CX500C with Corbin seat, but it really didn't corner all that well, so I sold it. But it did show me how significant the seat design is for long term comfort.
Another consideration is some sort of fairing to reduce the wind blast at higher speeds. I find that pretty fatiguing at anything over 65 mph for any significant distance. Fortunately, in the type of rides I usually do, there's not much sustained high speed. We might get up to 90 mph now and then, but only briefly. Most of my riding is in the 45 mph to 70 mph range, so most of my bikes don't have fairings. If I wanted to do highway riding at higher speeds (80 mph seems to be the normal speed on local freeways now!), I'd fit a fairing. The kind of riding comnoz and grandpaul are talking about really dictates some sort of wind protection.
In case you haven't figured it out already, age is a significant factor here. When I was 30, and had just acquired my Norton Production Racer, I could do several hundred miles on it with no problems, clip-ons, rear sets, and race seat included. Now, if I still had it, I couldn't ride it around the neighborhood without severe neck pain!
Ken