If you want to go for range, a significant factor is getting the ac to fly straight (I'm serious). By keeping the wings dead level and watching the heading, if you get any creep, then you've got a twisted airframe or the rudder trim is not set right. Set it all up and watch the speed creep up.
The Nimrod endurance technique called for shutting down outboard engines; the crew checked the fuel flow at the endurance speed on all 4 engines. One engine was throttled back and the 3 remaining spooled up to maintain the speed. The fuel flow was then compared and if it was less than the 4-eng case, the engine was shut down. The same procedure was repeated some time later to check if 3/2 was more economical. This technique considerably increased the time on task.
Clearly, drag is a serious factor - it is obviously more significant where the engines are wing mounted, as opposed to buried in the wing root.