I've rarely, if ever, ran into a drive so long in between Plains chase targets (during a multi-day trip) that required an all-nighter. The trek from and back to home is another story, if you live outside of the Plains.
Before I lived in St. Louis, I routinely chased the Plains from West Virginia. Most targets were 14-18 hours from home, so this meant leaving the day before a setup. I usually waited for the 12z model runs and the new Day 2 outlook. If I left at 4PM EDT from Charleston, WV, I could make any Plains target the next day with at least a 5-hour window for roadside sleep. On the trip out from home, I rarely got a hotel unless I was so certain of a Day 2 setup as to leave before the 12z models came out. There really wasn't any reason for me to depart so late that I'd have to pull an all-night drive. Waiting for the 00z models wasn't an option as it was too late for even an all-nighter. The short night's sleep on the way out was no issue as long as I got a good night's sleep at a hotel the following night.
On the way home from the Plains, I would just pull over whenever I felt tired and sleep until I woke up (sometimes the full 8 hours).
I have never nodded off while driving, but the thought terrifies me. I'll always pull over at the first hint of an episode of sleep deprivation getting to be too much.
I'd say leave as early as you possibly can to avoid the all-nighters, and prepare your vehicle in advance for roadside naps (for me it's a pillow, blanket and a way to cover the windows). An hour nap can work wonders. Scout out spots you know you can safely park for a while and not be bothered (truck stops are the best for this IMO). I'd be pretty nervous to rely on caffeine for alertness - at least for me, even it has limited utility when you're really sleep deprived.