There are several difficulties in researching the effects of spinal manipulation. Most of the conditions that are treated (i.e., back and neck pain) do not have a well-defined pathophysiology. Therefore, it is not possible to study treatment by evaluating the effects of treatment on physiological variables. The lack of a proven pathophysiology also leads to heterogeneous study populations with large variability in response to treatment. This makes it necessary to use large experimental populations in order to detect any effects of treatment. There is heavy reliance on subjective outcome measures in neck and back pain research, making these clinical trials particularly sensitive to placebo or "nonspecific" effects. The use of blinded subjects is the accepted method of dealing with these issues, but blinding is particularly difficult to achieve when investigating physical interventions, particularly those where the therapist can't be blinded as to whether s/he is delivering an actual or sham treatment.