I too suffered from wrist pain and fatigue in the past. The experimentation with different layouts helped a little but it felt like micro-optimization. What actually resolved the problem was switching to an unorthodox ergonomic keyboard where none of the keys required straining or unnecessary effort (kinesis advantage, using a different one these days). Also, most common problems were caused by placement of special keys (shift, ctrl, backspace, enter) and that's not something colemak, dvorak or their friends seem to be addressing.
I see analogy to guitar playing here. No matter how well you figure out finger positioning for a complex passage, you won't be playing with ease unless your elbow, wrist and spine are also positioned properly.
Indeed, I like the thumb keys (2 per thumb would be enough for me though), the tap/hold feature and the central special keys on ergodox for instance.
I have not found anything like that for laptops. Not even a split space bar. The tap/hold feature is possible at the os level, with caveats.
I usually map the key left to the space bar to Enter.
What is tap/hold?
I believe some people have done portable kinesis builds, which could be an option in tandem with a laptop.