It's about action, reaction and pivot points.
With handguns the barrel is higher than your wrist. When the handgun is fired the forces pushing the bullet down the barrel also push the pistol against your hand. Your wrist become a pivot point for these forces. Since the barrel is above your wrist the firearm will tend to flip up, trying to "roll around" your wrist. Hold a pistol sideways, "gangsta style," and you may note the barrel tends to flip to the side.
Similar holds true for long guns, however the shoulder becomes the pivot point.
Firearms designed to direct the forces into major muscle groups or bones tend to exhibit less flip. Think of the AR platform. While there is a considerable amount of force propelling the projectile, the barrel tends to be low with a higher sightline than many other designs. This directs the reactive forces more
into the shoulder instead of over or around it, resulting in less muzzle flip.
Similarly in handguns, there's been recent talk of a new thumb-operated single shot pistol intended for senior citizens (the
Palm Pistol). People with limited mobility in their hands are likely to find a design which directs the forces into the palm of the hand (and thus along the line of the bones in the forearm) to be more comfortable to shoot. With such a design there is less "flip" or rolling of the wrist, which can be painful.
Of course, this is just the way I see it. Maybe I'm wrong and a kinesiologist or physicist will be along to better explain it.