It is well appreciated that excessive use of medication in the treatment of severe headaches may result in a paradoxical increase in intensity and frequency of the headaches, along with changes in the subjective qualities of the headaches themselves. A parallel development is found in the increasing appreciation for the observations that development of paradoxic abnormal pain can occur in response to prolonged exposure to opioids. In both of these situations, no clear mechanisms have yet been established. The increase in opioid use for clinical management of chronic, nonmalignant pain, including recurrent headache syndromes, over the past two decades has resulted in increased interest in the study of this phenomenon. Recent studies have indicated that prolonged opioid exposure results in several neuroplastic changes that ultimately lead to the establishment of descending facilitation arising from the RVM and in spinal sensitization. These changes have been associated with increased activity of CCK in the RVM that likely results in increased expression of spinal dynorphin, which itself promotes increased afferent inputs. Activation of a descending pain facilitatory system along with increased spinal dynorphin promote the release of excitatory neurotransmitters from primary afferent neurons. Together with increased release of PGE2 from spinal neurons, the increased outflow of neurotransmitters from the primary afferent fibers sensitizes projection neurons that in turn activate descending pain facilitatory systems. Ultimately, knowledge of the mechanisms of possible deleterious actions of opiates may allow the development of new chemical approaches that can prevent these effects. Importantly, evidence is emerging that medication-induced enhanced pain is not unique to opioids, but may be generalized to other analgesic classes acting through G-protein coupled receptor systems. An understanding of these mechanisms would lead to improved therapeutic management of long-term painful conditions, including recurrent headache.