Chronic daily headache is a complex pain disorder that encompasses many diagnostic and therapeutic challenges. Our understanding of the pathophysiologic processes of intermittent migraine has improved over the past decade, but the biologic basis of chronic daily headache remains obscure. Some of the more common issues confounding management of patients who experience chronic daily headache are medication overuse, psychiatric comorbidity, refractoriness to pharmacologic treatments, and disability. Long-acting opioid analgesics would appear to provide a viable treatment option for those patients who remain refractory to other treatment interventions; however, clinical experience often does not support this belief. Current concepts of the pathophysiologic basis of chronic pain and associated neural plasticity may elucidate a biologic basis for the general inefficacy of opioids in the management of chronic daily headache. This article explores the models of pathophysiology for migraine and chronic daily headache, the concept of chronic daily headache as a neuropathic pain syndrome, neural plasticity in the context of neuropathic pain states, the physiologic basis for opioid tolerance and opioid-induced hyperalgesia, and how each of these conditions interact to provoke the general lack of opioid efficacy often observed in the management of chronic daily headache.