Per AS' Robbie Dunne, the defender had to be substituted in added time against the Partenopei after an awkward fall. Despite being in the final minutes of the match Pique "immediately" reached out to the Barca dugout and was replaced by Clement Lenglet.
As football writer Dermot Corrigan observed, the injury appeared painful:
He did not need crutches or a protective boot to leave the Stadio San Paolo, though:
Meanwhile, the centre-back's team-mate, Sergio Busquets, said he hopes "Pique's thing is nothing," per Sport.
After the Blaugrana loaned Jean-Clair Todibo to Schalke in January, the club only have three senior centre-backs to see them through the remainder of the season.
If Pique is unable to feature against Real Madrid, Setien can still turn to Lenglet and Samuel Umtiti, but if anything were to happen to either of them, he may be forced to use Busquets as an emergency defender.
Per Transfermarkt, the Spaniard has been used in such a role on 19 occasions over the course of his Barcelona career, but he wouldn't be as effective as a natural defender and moving there would deprive the team of his presence in midfield.
A victory for Barcelona on Sunday would be a significant step in La Liga's title race. The Catalan side are two points ahead of Real, so the opportunity is there to open up some breathing room.
It would also give them the advantage in their head-to-head record, as the pair played out a 0-0 draw at the Camp Nou.