I think the biggest block is making things non-magical. You'd definitely have to use inherent bonuses. Perhaps lasers could give masterwork bonuses to hit and damage but obviously be very rare.
You'd have to account for fights with whatever is on hand, whether it be a chair leg or a pistol, the characters will most likely rarely have their favourite weapons on hand.
I think you'd also have to have some sort of agreement in place in regards to hand-to-hand fighting. A monk character would suit a River character very well, but any strong hand-to-hand class is going to have a keen advantage in such a setting simply due to always having their weapons 'on hand' so to speak.