Ronaldo has been substituted in his past two appearances for Juventus and reportedly left the stadium before full-time against AC Milan last time out, as replacement Paulo Dybala struck the winner.
The suggestion Ronaldo was unhappy dominated the agenda as Portugal faced the media on Thursday (AEDT), with Ruben Neves insisting his team-mate was "fine".
But Santos was not willing to similarly answer questions on the forward, believing the profile of the player meant too much was being read into the Juventus substitution.
"Everybody wants to talk about Cristiano Ronaldo, everybody wants to give their opinion on Cristiano Ronaldo," he said ahead of the Euro 2020 qualifier against Lithuania.
"Because if this thing [the substitution] was with any other player, nobody would be talking about it. We are only talking about this because it's Cristiano Ronaldo.
"There are millions of players out there and it seems that this only happens to him and maybe another two or three players. To nobody else.
"Cristiano is here, he was called up, he's fine, he'll play, I have no doubts about it. So, for me, there's no issue here."
Santos clearly felt he had made his stance clear, as he replied to the next question on Ronaldo: "Cristiano Ronaldo again? No, sorry, sorry.
"On Cristiano Ronaldo again, I'm talking about Portugal. You are talking to me about Cristiano. Cristiano, no. I won't talk about Cristiano anymore.
"For me, the theme of Cristiano Ronaldo ends here."
Portugal will qualify for next year's European Championship finals if they beat Lithuania while Serbia fail to defeat Luxembourg.