I agree that a new toy or book can make a big difference. Never tried drugs or a DVD player, but may soon consider the latter. We've got 3 1/2 year-old boy-girl twins and have not had any terrific problems taking them on half a dozen long flights. They went over to England when they were 8 months and slept through most of it -- tip: try to get bulkhead seats, then you're right there with the pull-down basinets.
They and we endured a 20-hour nonstop from New York to Hong Kong just before they turned 2 (and would need their own seats!) I think we may have bought one extra seat for the two, and counted on somebody to move, which is a sure thing when they see them coming, I tell you. There was some trouble in the "morning" somewhere over Siberia, but for the most part they were awed enough (and still are when we travel) that scenes were short-lived. The 12-hour time change was a chore for all of us for about 3 days, and we tended to end up bolt upright in our beds at 3 a.m. for awhile, but that soon passed.
Last summer they did quite well on a flight to Ireland, followed by short flight to Paris, then a TGV to the South. All the transfers, the crowded ride in the hot Metro, really seemed to keep them too entertained to get too upset, it seems. Then they were in tent in Provence for 10 nights ... again they gave us very little trouble, no more than the usual afternoon tired grumpiness, really.
And just a couple of weeks ago we all went on a 7-hour trip from NYC to Guadeloupe, with a transfer in San Juan, and it was the easiest yet. They looked out the window some, slept a fair amount, and were absorbed with books and coloring the rest of the time.
A lot of how they take it might have to do with how you handle it, and maybe how regular you are with naps, etc. We play it a little loose with that stuff (they also eat out a fair amount) and I find they adjust well to changes in their sked because of it. I'd say plunge in with a sense of adventure and it'll be way more fun than difficult.
