5. Travel Fatigue
Something that would make the game far harder than it currently is. If you are Manchester United and you play Rubin Kazan away on a Wednesday and then have the Manchester Derby at the weekend, I wouldn't expect the whole squad to be fully fit for that game. Have them be extremely tired and possibly jet lagged, forcing you to change your team/tactics for either the European away game or the big game at the weekend. It would make European draws in the game that more meaningful.