Liverpool fans are sure to already be feeling sufficient hurt from Saturday's 2-0 defeat to Everton.
The Reds came into this Merseyside derby having not lost to their rivals in over a decade, while you had to go back as far as 1999 for a loss at Anfield.
But this is a result that held significance beyond local bragging rights - it could well be the one that condemns Jurgen Klopp's side to Europa League football next term.
It is not necessarily that the gap is too big, with Liverpool still just three points behind fourth place despite their recent woeful run.
Nor is it that the opposition are too good - Chelsea also dropped points on Saturday, Everton still trail their neighbours, and Leicester City showed last year that they are capable of a late-season collapse.
Yet it is almost impossible to imagine the reigning champions making any of that pay as they contend with injury problems that simply refuse to ease.
Klopp started this game with his 17th different centre-back partnership of the season in defence, none of whom had made it through three consecutive games.
And that dreadful record was extended in the first half as Jordan Henderson limped off to be replaced by Nat Phillips.
The long-term absences of Virgil van Dijk, Joe Gomez and Joel Matip have not just left a hole in the defence, they have also put too much demand on their replacements.
It is no coincidence that two of them - Henderson and Fabinho - are both now sidelined with muscle problems.
Throw in the fact they are also being desperately missed in midfield and that the acquisition of the inexperienced Ozan Kabak now looks like little more than desperation and it does not add up to a solid foundation.
Of course, the problems don't just stop there, as one goal in almost nine hours of football at Anfield underlines.
The loss of Diogo Jota as a rotational option during a season more relentless than any other is no doubt part of that - again, it comes back to injuries.
Things may ease slightly on that front in the coming days, with Jota, James Milner and Fabinho close to returning, though Klopp must now wait nervously on Henderson.
Still, these players will come back into a Liverpool team that has just lost four on the bounce in the league at home for the first time since 1923 and is well short of confidence.
Only a huge change in fortunes on the fitness front will allow the Reds to put together the sort of turnaround in form that would make a top-four finish a possibility.
But supporters won't be holding their breath, and the consequences of that are sure to be far-reaching.
The reluctance of the club's owners, Fenway Sports Group, to spend during a pandemic was evident in the buy-now-pay-later deals agreed for Jota and Thiago Alcantara over the summer.
There was a notable lack of risk, too, attached to the mid-season loan of Kabak, who arrived from Schalke only with an option to buy attached.
And the Americans are unlikely to be willing to sanction any big-money deals if Champions League money is not present on next season's accounts.
If there is one upside for Liverpool, it is that clubs across Europe who might covet the likes of Mohamed Salah and Sadio Mane are unlikely to be able to finance such moves themselves.
But either way, it is likely that more pain awaits, not just across the remainder of this season, but into the summer as well.