Napoli and Olympiacos face an uphill battle to create Europa League history and avoid elimination from the competition on Thursday.
Napoli went down 3-0 to Viktoria Plzen in the opening leg of their last-32 tie, while Levante accounted for the Greek side by the same score.
No team has ever bounced back from a three-goal first-leg deficit in the competition's current format, leaving Plzen and Levante in the box seat to advance to the round of 16.
Olympiacos are one of two Champions League sides playing catch-up in the second leg. The other, CFR Cluj, trail Inter Milan 2-0.
Cluj's fellow Romanian club Steaua Bucharest are also up against the odds, needing to overturn a 2-0 loss to stop Ajax from moving a step closer to the final in Amsterdam.
Zenit St Petersburg boast a two-goal advantage for their trip to Liverpool, while another Russian outfit, Anzhi Makhachkala, take the same lead to Hannover.
Bayer Leverkusen start the second leg in arrears, looking to turn around a 1-0 defeat to Benfica, while Atletico Madrid, winners of two of the past three Europa League titles, trail Rubin Kazan 2-0.
Meanwhile, Lazio and Borussia Moenchengladbach are locked at 3-3 in one of eight ties to be either level or separated by a solitary goal at the halfway point. Tottenham Hotspur travel to Lyon hoping for more wizardry from Gareth Bale, whose two goals earned the London club a 2-1 advantage.
Metalist Kharkiv and Newcastle United will look to break a goalless deadlock, while Dynamo Kiev and Bordeaux resume at 1-1.
Stuttgart and Genk are tied at 1-1, and European champions Chelsea lead Sparta Prague 1-0.
BATE Borisov and Fenerbahce are equal at 0-0, with Dnipro Dnipropetrovsk 2-0 down against Basel.