Poor social cohesion, poverty traps, excessive materialism and individualism.
I blame Cold War domestic propaganda tactics. Americans stigmatized and undermined cultural values for a generation, the societal equivalent of an autoimmune disease, and ever since we have been shifting further towards a brutal, cold, almost purely economic system with sparse and weakly connected communities made up of individuals constantly bombarded by news and ads (propaganda).
Extraordinary wealth & extremely high disposable incomes (very large profit magnet), by far the largest pharma economy, a pharmaceutical culture you won't find anywhere else, a many decades long history of general persecution of drug addicts, and a healthcare system that doesn't take good care of the homeless or drug addicts.
That covers both the prescription abuse and blackmarket issues.
The wealth & income in the system acts as a huge magnet. If you're going to sell drugs somewhere (legal or illegal), you want to do it in the US. The US has nearly double the median personal disposable income of the EU, under one big roof. The culture encourages a drug-solution approach to everything. The doctors, nurses, admin, hospitals, pharma companies and healthcare system overall have been very happy accomplices, feeding the problem for decades to great personal profit. A lot of prescription writers should be in prison for playing assist in murdering tens of thousands of Americans. The persecution of drug addicts makes everything worse on the back-end once a person has become an addict; it pushes them away from treatment, it isolates them from society. The poorly constructed healthcare safety net in combination with the cultural & legal / political persecution, then finishes them off, leaving them little to no proper safe recourse or way back out - ending far too often in death.
https://www.theatlantic.com/magazine/archive/2019/05/opioid-...
I feel that's the root of the problem and where the US should invest heavily.