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NITPICK compares two frames, and identifies features which are more than a specified significance level away from the value in one and replaces these pixel values with the corresponding values from the other. Photon noise is automatically allowed for, using known CCD statistics. Sky subtraction software automatically allows for cosmic ray removal, so this is only run if the object spectrum is affected. NITPICK only corrects one frame, so you have to apply the first frame vs the second, and then the second frame vs the first to correct both frames.
As a general guide, 4 sigma is a good starting level. Care should be taken not to try to remove too many small variations. NITPICK produces a map of which pixels have been affected. This image should be displayed; if you don't and there is a shift between the two images you are comparing, you will be unaware that part of your spectrum has been cleaned away.