Tottenham boss Mauricio Pochettino believes Manchester United's Champions League disappointment may be doubled when they realise the difficulties of playing in the Europa League.
United will drop into Europe's second tier competition after Tuesday's defeat to Wolfsburg ended their hopes of reaching the Champions League knockout stages.
Europa League football may harm United's Premier League prospects too, with Thursday night fixtures notoriously difficult to juggle with domestic matches.
Tottenham have already felt the struggle, most recently when a Sunday lunchtime kickoff against Chelsea followed a six-hour trip to Qarabag in Azerbaijan, from which the squad returned to London at 5 a.m. on Friday morning.
Spurs are hoping to beat United to a place in the top four this season and Pochettino has warned his rivals they may be in for a shock in the Europa League.
"For sure Manchester United will feel very disappointed after last night because they had the possibility to go into the next round," Pochettino said on Wednesday.
"It is difficult to guess what will happen to them in the future. It is a different competition and you have to change your strategy -- to play Thursday instead of Tuesday or Wednesday. It is true it can affect your game.
"I think it is a big, big difference. When you play Thursday and you play Sunday it affects the mentality.
"Always Thursday night, big travel, you need to play Sunday in the afternoon. Always for the players it affects the psychology because football is Saturday 3 'o clock, or it used to be."
United's exit continues a worrying trend for English teams, who have struggled in recent years to keep pace with Europe's elite.
Premier League clubs have managed just one semifinal appearance in the last three Champions League tournaments while in the past five years, only Chelsea have made the Europa League last four.
"It is difficult to find the solution," Pochettino said.
"The good thing for the Premier League is the teams at the bottom have the capacity to improve because the Premier League has more money, the teams are in a good financial condition.
"From zero you can improve -- one, two, three, four, five -- but when you're are at the top it is difficult to improve. The step from eight to nine, nine to 10 is more difficult.
"The teams around the bottom, the gap is bigger to improve. If we want a tough competition, and the Premier League is very, very tough, you need to compete.
"It is true competing in the Europa League or the Champions League is not easy.
"A team like Barcelona, or Real Madrid or Paris Saint-Germain in France -- the gap between them and second is maybe 10, 12 points.
"They can rest and prepare for the Champions League in the best condition."
Tottenham have already qualified for the Europa League's last 32 but need a draw against Monaco on Thursday to guarantee top spot in Group J and earn a seeding for the knockout phase.
Nabil Bentaleb and Nacer Chadli are both available after recovering from foot and ankle injuries respectively but Mousa Dembele is out as he is sick.
Ryan Mason and Alex Pritchard are also missing with ankle injuries while Pochettino may take the chance to rest players ahead of Sunday's home game against Newcastle.