More than anything, it's killing Castiel to see Sam like this. Not just without a soul- although that hurts, probably more than knowing he can't retrieve it- but without the desire to get his soul back. More than that, actively fighting against it.
He thought the most painful moment, the most difficult moment, would be in that motel, his belt clenched between Sam's teeth (so familiar, a playful ritual, first done in jest, then in necessity when his skills progressed enough to send Sam howling). He thought the hardest thing would be to shove his grace in Sam's chest, forcing a connection that Sam hadn't consented to, hadn't wanted while the man he loved more than nearly everything writhed in agony he caused.
But it's not.
Because it doesn't compare to the sick, slick oily feeling of dread and despair when he finds nothing. Or, more correctly, when he finds the gaping hole where the most compassionate, caring soul he's ever touched used to be. He'd throw up, collapse to his knees, raise a hand and press it to Sam's cheek, seeking comfort or a way to deny the truth-
But Sam wouldn't care and Dean can't know.
The one thing Sam insisted on, 'Don't tell Dean. Dean can't know.'
And it's the promise he's sure to keep, no matter where his Sam's soul is.
Even if it's killing him.
When Sam calls to him, he doesn't want to go. He doesn't want to see the sum of his failures, his inability to stop Sam's sacrifice, his inability to tell wrong orders from righteous disobedience. Doesn't want to face his condemnation of a soul because it's what he was told to do, or his powerlessness to save his lover's soul from the Cage.
But he goes. And as he listens to Sam's threats, futile though they be, his heart breaks again and again and again.
He can't save anyone. So why does he even try.