PRESCRIPTION DRUGS, INCLUDING AMPHETAMINES, OPIoids, and benzodiazepines, provide therapeutic value to millions of Americans. At the same time, there are increasing concerns about the skyrocketing rates of prescription abuse and overdose deaths. The annual number of fatal drug overdoses in the United States now surpasses the annual number of motor vehicle deaths, and overdose deaths attributable to prescription opioids—nearly 15 000 in 2008—exceed those attributable to cocaine and heroin combined. These trends have co-occurred while clinicians and policy makers have attempted to improve the undertreatment of chronic pain through efforts such as the “Pain as the 5th Vital Sign” campaign and the promulgation of quality measures by professional organizations. Many of these initiatives do not specifically advocate greater opioid use. However, the initiatives have coexisted with, and in some cases been supported by, a pharmaceutical industry in which increasing sales of opioids have grossed billions of dollars. A recent senatorial inquiry hints at the opaque flow of funding from industry to consumer and advocacy organizations that promote increased use of pain medication. To address the increasing epidemic of opioid abuse, a variety of strategies have been implemented, including limits on the number of opioid prescriptions covered by insurers, requirements that these drugs be supplied through a single physician or pharmacy, and state prescription drug monitoring programs. Despite these efforts, reduction of opioid abuse may not succeed until there is a broader clinical shift from such widespread use of these medicines. There are clear correlations between national trends for prescription opioid sales, admissions for substance abuse treatment, and deaths. Between 1999 and 2010, each of these has steadily and inexorably increased in parallel with the others. This suggests that substantial increases in the nonmedical use of opioids is a predictable adverse effect of substantial increases in the extent of prescriptive use. Under current regulatory and market conditions, it is likely that a significant and increasing amount of opioids produced to meet clinical demand will be misused or diverted from the legal to illegal markets, leading to more addiction and death. This has important implications for policy makers, because it highlights the difficulty of selectively decreasing abuse and diversion while keeping the overall supply of opioids for legitimate use constant or increasing. To curtail the current epidemic of opioid abuse, overdoses, and related deaths, regulatory and enforcement measures to prevent nonmedical use and diversion should be complemented by changes to clinical guidelines to treat chronic pain that are less reliant on opioids. A public health approach to the treatment of pain in the context of an epidemic of abuse would place greater weight on considering the harmful effects, or what economists consider to be negative externalities, that clinicians’ treatment decisions have on other individuals beyond the individual patient being treated. There are sources of diversion of opioids at every step in the supply chain, and some observers have argued that because the majority of opioid addicts report that their access to the drugs is through friends or family rather than physicians, the misuse of these therapies may not be considered a “clinical problem.” Publicity regarding robberies of warehouses storing opioid medications serves to reinforce the perception that physician practices, aside from “pill mills,” are not of concern. Such reasoning fails to consider that increased access of opioids through friends and family is due, in part, to the increasing prescribing of medications commonly diverted for illicit use. Greater clinical judiciousness is especially warranted given the limited evidence to support many clinical applications in which opioids are used. For example, although opioids may be efficacious for acute lower back pain, the safety, efficacy, and abuse data are limited for chronic back pain. There are serious gaps in the knowledge base regarding opioid use for other chronic nonmalignant pain as well, including a lack of randomized trials that have active treatment groups or that examine major harms and benefits of