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Barcelona have fitness doubts over Gerard Pique and Andres Iniesta, while Real Madrid must decide who will take the role of playmaker and striker.
The position in which Barcelona have the most uncertainties is undoubtedly at the back, with Gerard Pique being a doubt for the clash. The centre-back suffered a sprained foot against Spartak Moscow in September, and has been racing to return to fitness in time for the game. If he fails in his bid, Alex Song will step in to replace him. Javier Mascherano will also have to be drafted into the backline to replace the injured Carles Puyol, and Jordi Alba is expected, although not certain, to start ahead of Adriano at left-back.
Barcelona have one big question for midfield, which is whether Ballon D'Or winner Andrés Iniesta will be fit to take over from Cesc Fabregas. The former Arsenal midfielder may be in form, but Iniesta's record against Real Madrid cannot be ignored, and his experience may be preferred in a game of such magnitude. Sergio Busquets and Xavi are certain to line up in the other two positions in midfield.
Few doubts for Barcelona here, and a front three of Alexis Sánchez, Lionel Messi, and Pedro are expected to start the game. Tito Vilanova may toy with the idea of deploying Cesc Fabregas or Andres Iniesta on the left, but with the latter not at full fitness and the former enjoying a good run in midfield, it would be unlikely and an unnecessary gamble.
Madrid look a more settled team overall going into the game, and are almost certain to continue with their back four of Marcelo, Pepe, Sergio Ramos, and Alvaro Arbeloa. The quartet have come together to give Real Madrid a calmer appearance in recent games, and Mourinho will need to be sure that his back four can hold out against the inevitable Barcelona onslaught.
Xabi Alonso will surely be certain to start in one position of Real Madrid's double pivot, and Sami Khedira is likely to get the nod over Michael Essien for the other, particularly with the Ghanaian having suffered a recent minor injury. The real question is over whether Luka Modric or Mesut Özil will line up in an advanced position in the hole. Mourinho may opt for the more defensively-aware Croatian, but equally he may decide that Özil is the man to make the most efficient use of the limited possession Madrid are likely to enjoy. Kaka is a third option, but it would be a major surprise if he were to be trusted to start in a game of this importance.
Cristiano Ronaldo and Angel Di Maria will be certainties to occupy the wide positions here, but there is doubt over who will lead Los Merengues' attack. Karim Benzema is expected to start, but Gonzalo Higuain has a better goalscoring record so far, and already has one goal against Barcelona to his name this season, in the second leg of the Supercopa.
Barcelona predicted lineup (4-3-3): Victor Valdes; Jordi Alba, Javier Mascherano, Alex Song, Daniel Alves; Sergio Busquets, Cesc Fabregas, Xavi; Pedro, Lionel Messi, Alexis Sánchez.
Real Madrid predicted lineup: (4-2-3-1): Iker Casillas; Marcelo, Sergio Ramos, Pepe, Álvaro Arbeloa; Xabi Alonso, Sami Khedira; Angel Di Maria, Mesut Özil, Cristiano Ronaldo; Karim Benzema.
Real Madrid have probably been heartened by Barcelona's injuries, but on paper they barely look a weaker side at all. Whether Barcelona's weakened defence can remain strong remains the key question for the game, and one on which the result and La Liga title could hinge, but Real Madrid will have to find a way to dispossess the Blaugrana midfield before they can think about it.
One thing that is clear is that Real Madrid are likely to have better options off the bench. In their two contested positions, playmaker and striker, they have two equally good options and therefore two big changes that can be made it things are not going to plan. Combined with the additional defensive cover, it makes them less error-prone: Barcelona's decision not to purchase a centre-back in the summer looks questionable now, but if they are forced to begin the game with Alex Song and Javier Mascherano at the back and suffer another injury, it will look positively suicidal.
Despite all the question marks over form and fitness, it seems little has changed. Indeed, if Real Madrid line up as above, Álvaro Arbeloa will be the only player who did not start the 5-0 humiliation in 2010. That may speak volumes about Mourinho's struggles to improve his starting eleven, but it shows that the key for Los Merengues has not changed: if they can get at Barcelona's defence, they have a chance, but that will require coping with the Blaugrana midfield. Easier said than done.