We derive and factorize the fourth-order difference equations satisfied by orthogonal polynomials obtained from some modifications of the recurrence coefficients of classical discrete orthogonal polynomials such as: the associated, the general co-recursive, co-recursive associated, co-dilated and the general co-modified classical orthogonal polynomials. Moreover, we find four linearly independent solutions of these fourth-order difference equations, and show how the results obtained for modified classical discrete orthogonal polynomials can be extended to modified semi-classical discrete orthogonal polynomials. Finally, we extend the validity of the results obtained for the associated classical discrete orthogonal polynomials with integer order of association from integers to reals.