For clarity: I'm referring to all the previous attempts to "fix" the synthetic opioids, each of which ended up making a stronger, more dangerous opioid.

The crisis is one created by policy and cannot be eliminated on the pharmaceutical end. This isn't a case of methanol being sold as ethanol or SSRIs having less than ideal efficacy rates while causing widespread sexual dysfunction at a rate much higher than originally thought, or Zolpidem leading to over a hundred observational notes published in medical journals describing dangerous activity performed even on small doses followed by anterograde amnesia that certainly is a real thing that is also potentially dangerous, but incredibly difficult to study. Those effects are happening when the medication is taken as prescribed Do people take those without prescriptions? Of course, but one assumes the risk, and also, anyone ever seen a Zoloft pill mill?

Fentanyl had been diverted in small quantities onto black market supply chains for as long as it has been available. You can absolutely get an Actiq Pop in 2006 if you really wanted it, and the thing is a lollipop for crying out loud. It didn't cause widespread overdoses, it didn't even cause any significant black market demand. It was at best a curiosity. It's hard to quantify a subjective experience, but generally it was regarded as "not fun" anecdotally. Heroin is fun. Hydromorphone is even more fun but the best ROA leaves you with a 5-10 minute high at best and takes about that much time to prep. Oxycodone was fun but since the DEA made sure that it was as difficult to obtain as possible all of a sudden and what was available was spiked with enough APAP so that your liver might give out before you overdosed, well, what does cutting off the supply but leaving the demand in place do? The crisis as we know it today was inevitable in some form. It's created by policy, which is not set by scientists, and in fact when hydrocodone/APAP was rescheduled for Schedule II a specific reply to patient access concerns was "we don't take that into account", according to the DEA. Thanks for the candor, sadly we've gotten very little of it in the years since.

But of course, even on the black market, people overdose in a manner that is to a degree predictable. Long term users with steady supplies - say, everyone who's on a benzodiazepine long term - aren't overdosing regularly (yes, the LD50 of benzodiazepines generally makes overdosing on it alone very difficult if not impossible, but kicking it cold turkey does actually cause deaths from seizures and when mixed with another depressant like alcohol it becomes almost trivial to overdose on it, arguably making it at least in theory a more dangerous drug if one takes the view of the DEA). They are mostly able to obtain legitimate, low cost, and frequently entirely legal versions of, well, name the variety. From Triazolam (3 hour half life) to Midazolam (water soluble) to Etizolam (scheduled into schedule I based on 4 cases in Norway where when mixed with another depressant patients ended up in the ER. All survived and were discharged almost immediately. The reason why the DEA laundered cases in Norway through the FDA to justify at first an emergency scheduling and then turned it into a permanent one? Because they couldn't find any cases that demonstrated the purported danger in the US or Canada.) Overdoses happen when someone takes too much of a substance, but "too much" is difficult to determine when you don't have a reliable supplier in terms of quality and adulteration, but also, because tolerance gets built up so that long term users can use prodigious amounts and be just fine. But how do we make sure that nobody knows where their tolerance is at? Non-medically assisted, pseudoscientific "sobriety help" like AA or its variants that are ordered by the court, and of course, probation, testing, in-patient medicaid fraud mills, you name it. Since none of these actually do anything except use homebrewed aversion therapy or even less efficient, shame, to achieve what is basically not even a real goal but is tied to the criminal justice system, congrats, you have the perfect storm of demand not knowing how much to actually demand for. Fentanyl being the adulterant made this last inevitable easier, but it only hastened what had been happening for quite some time. When heroin supply on streets increased, fentanyl related deaths began decreasing. Wonder why? It's correlative, but observational studies take a lot more data and a lot longer time periods, although it would certainly follow previously observed patterns.

This may be interesting as a scientific venture, but treating it as anything but that is foolhardy and misguided. We know how to control pain. We know how to reduce the harmful externalities that form part of the definition of substance use disorder since we, as in society and lawmakers elected by us, are responsible for those harmful externalities in the first place. Fentanyl is not the problem. Making sure that there's no safe way to reduce potential harm associated with, ultimately, a personal choice favored by some but certainly not all as recreation, killed the hundreds of thousands since Lou Reed sang Heroin and put it onto the Velvet Underground and Nico. Why are we still acting brand new?

I've found low dose naltrexone to be somewhat effective for severe chronic pain. Not as good as opiods.

THC can also help somewhat, but its action seems so dissociative. At an effective level for chronic pain, I'm sleepwalking though the day.

Opioids or their analogues cause or complicate bowel issues. Four years of 200mg/day Tramadol really helped me, but it shredded my gut. Getting off Tramadol wasn't hard for me. I'd stay on it were it not for the gut issues.

As an aside, lacing hydrocodone with acetaminophen is truly a horrific practice. Doctors prescribe this to patients on hepotoxic drugs and are shocked when they get liver damage.