Regarding causation, three issues are important. First, the opioid crisis clearly grew out of the confluence of several important contributing factors, each contributing a part of the “perfect storm” that lead to growth in the rates of prescription opioids. Literature, reports, and commentary from experts consistently point to nine factors consisting of a mix of “supply push” and “demand-pull” factors that can also be thought of as “enabling” or “causative” factors, the influence of which combined in synergistic and additive ways to increase the volume of opioids on the market, including regulatory failure, medical need, public policy, medical advocacy, ratings and accreditation, manufacturer marketing, socioeconomic factors, and advisor advocacy. The overall supply of opioids in the U.S. has also been driven by an increase in illegally trafficked illicit opioids; thus, drug trafficking is identified as the tenth contributing factor. Second, regarding medical need, about a third of the differences in physician prescribing patterns is attributed to normal variation in practice patterns. Another third has been shown to vary based on a combination of medical need, patient characteristics, and socioeconomic factors. This leaves another third to distribute across the remaining contributing factors. Third, the West Virginia case study illustrates, in a descriptive and conceptual way, how these factors have been featured in a state broadly impacted by the opioid crisis.