Treatment of chronic noncancer pain (CNCP) with high-dose opioids (HDOs) has burgeoned over the past 2 decades in the United States. Characteristic domains and features of the failed CNCP management patient using long-term HDOs are described herein as the/an opioid syndrome (Schreiber AL, personal communication. 2013). Reversing or even modulating HDO use in patients with CNCP requires a paradigm shift on the part of physician, patient, and the societal “quick fix” medical culture. This review offers measures, agents, and strategies to consider in management of this pervasive, erosive medical and societal challenge.