I have made several rag quilts with cotton on top and flannel on the back. I did not prewash any of the fabric. Once the rag quilts were completed I washed them several times prior to giving them away. They turned out very nice. One quilt had batiks on top and flannel on back. The other two had 100% cotton on top and flannel on back.
Also, I put the completed rag quilt in the dryer on timed dry prior to washing them. That actually removes a lot of the lint before putting it into the washer.