The pair both had scans today after limping off during Saturday’s spirited 2-2 draw at Shrewsbury Town.
Butler suffered a hip injury and is likely to be out for at least a month, while there are fears Ben Khemis could miss the rest of the season with ligament damage.
Speaking ahead of his side’s rearranged M180 derby at Scunthorpe United tomorrow, Ferguson said: “Speaking to the physio, given the nature of what he’s seen and the injuries, you’re probably looking at a minimum of a month each.
“But I think that would be very optimistic, unfortunately.
“It’s part and parcel of the game but it’s come at a bad time for us, there’s no doubt about that.
“It’s really unlucky for Issam, coming on and scoring and then getting injured.
“He had an impact with his energy and we’re maybe starting to think about using him a bit more.
“Andy Butler has obviously been so consistent for us over the course of the season.”
Mathieu Baudry will return to the starting line-up at Glanford Park but Ferguson is considering playing a back three in Butler’s absence.
“We’re just going to have to cope, someone else has got to step up,” he said.
“I’ve got two very capable centre halves in Joe Wright and Mathieu Baudry.
“They’ve not had a great amount of games together but I thought they did fine on Saturday, in the second half anyway.
“If Craig Alcock stays he can play as a centre half so we’ve got the option of going back to back three, which I have to say would come more into my thinking now given what’s happened.
“We have to get on with it and other people have to step up.
“This is why you have a squad, and then obviously we’ll have to have a sit down and have a look if we can bring one or two in.”