OMTh is not free of costs but is plausibly characterized by fewer contraindications and adverse events than conventional pharmacological treatments, and particularly indicated for patients not compliant with drug regimens and those at increased risk of adverse drug effects. Notably, there is disparity between patient perceptions and clinical definitions of adverse events, as a conceptual model with four inter-related components (expectation, personal investment, osteopathic encounter and clinical change) has suggested. Patients might report mild effects following OMTh and in general all forms of manual therapy, but these effects should not be strictly regarded as adverse events. Our previous pilot trial did not observe adverse events among ETTH patients belonging to both arms of the study (treatment and sham). Exceedingly rare serious adverse events may be observed after spine manipulation, only one of many different techniques usually administered in osteopathic clinical field and recommendations have been already published to meet the requirements of the principles of prevention and precaution. For example, minor unwanted effects of prior manipulation should be searched routinely and taken as contraindication for future spinal manipulations. Great care should be taken when particular anatomic conditions such as cord encroachment or increased vertebra-basilar risk are present. Certainly, besides effectiveness, still to be completely proven, the financial impact of OMTh on subjects and health systems could be also a topic of appraisal for future comparative studies.