I've found that safes cost around five lockpicks for 261 or 287ish in loot. This doesn't seem like an even trade. Are there any safes that include gear or something else rare/valuable, or are they always just money and consumables? If the former, which? If the latter, I'd prefer to just skip them. Or are they as random as other containers?
Safes are containers, and containers (corpses, lockboxes, crates, trashcans, etc) can only contain certain types of loot:
Safes have a very high probability of containing a large amount of money (100+ coins), but they will never contain Gear, Infusions, weapons, or voxophones.
There are some locked objects that require keys, and some pickable doors that have these items behind them, but they will never be in safes.
There are enough lockpicks to be found in the game to unlock every safe and door found, but (especially early on) you'll have to scour around to find enough.
So cash for free really, as long as you've done enough scavenging. So, yes safes are always worth picking.
So another question: are lockpicks worth paying for?
This is a tougher. Occasionally Dollar Bill machines have lockpicks for sale for around $48. They never have more than two or three and they're pretty rare.
Here I'd say it depends on how many lockpicks you've found so far. Late game there are levels with lots of 3 and 5 pick locks, but they also have more picks to be found. I'd say it's probably worth buying picks if you have fewer than about 10.
I finished the game having opened every lock and with about 20 picks left over, so you shouldn't need to buy any.
However, from a cash proposition - 5 x $48 = $240, while safes usually net $250+ so it is worth buying picks to open safes.