Are there any penalties for using a reliever as an opener beyond the normal fatigue? It’s small n right now but my early relievers are getting absolutely shelled and I’m wondering if it is bad luck or some hidden engine thing.

Is your "small n" the team that has played 3 games and has had exactly 1 of your 3 SP get shelled?

The short answer to your question is: No.

The longer answer to your question is: make sure you understand how in-game fatigue works, and how to set your pitch counts appropriately.
At a cursory glance, your PC for your entire staff are set way too high.

My pitch counts are mostly 20ish for pitchers I calculated have at least 20 pitches a game using the formula in the forums. My pitchers are mostly not getting to extremely low fatigue and I rotate a lot. My players with 80+ innings have slightly higher pitch counts but still quite low. The highest pitch count on my whole staff was 30/35 although I’ll try lowering it to 25/30. The low inning guys are generally on 15/20.

The other two games show where my pitch counts are set. I think weird things happened in the third game (three players exceeded maximum pitch counts) because it was a 241 pitch game and my maximum pitch count for non-starters is close to 250.

Kuo threw 38 pitches; I would have him at 15/15
Gagne threw 35 pitches, I would have him at 15/15
Nathan threw 33 pitches, I would have him at 15/15.
Etc

Kuo was set to 20/25 when the minimum is 20/20 for a starter. Like I said that game was weird because how many pitches there were.

Gagne was also set to 20/25 again in part because of starter minimums. I’m mostly trying to find settings that get people to pitch one inning unless they get shelled because I only have 10 relievers and need to get through a game. I stopped using a LHS because he was never pitching. I am using a 2 man starting rotation and sending starters up and down as needed to get a large enough bullpen.

For what it’s worth Kuo finished that game at 85% stamina and would have recovered for a start in two days but I had better options so sent him down.

If I run into problems I’ll probably take away one option on my bench to get an extra reliever slot for more pitch count. New at this so still learning.