I think a solution to a lot of this would simply be to make the manufacturers of such be responsible for the costs of getting people off them. And the cleanup costs for cities that have to deal with the results.
Of course it is. Regulatory capture is a real thing. While the courts are far from perfect, judges don't routinely "retire" to take multi-million dollar positions with the companies they rule on the way that regulators do.
The DoD does have that much influence. If they want it, they'll get it. And if they can't get it through normal channels they'll bend over backwards to try to get Congress to carve out an exception.
This is probably a stupid question but is it possible for this or for any drug to be absorbed and take effect via the eye? Or does it have to get into the circulatory/digestive system to take effect?
No question is stupid! For fentanyl at least that can totally happen. On of the common ways to administer it is via a transdermal patch. It’s one of the major selling points of fentanyl and why people that need ridiculous amounts of opioids because of burns or cancer like it.
Especially in this context. I have a modest understanding of just a couple of these compounds. And that comes by way of chronic pain people in my life.
Over time, doing the work to better undestand these things has paid off. They, at times, get contradictory or just bad advice, or see something that makes them worry, or think they are in danger somehow.
It can be hard to get clarity, and know a change is thearaputic vs compliance related, for example.
Anyway, I just liked that you said that and followed up with super easy to understand information.
Do they actually dispense drugs in the pure form (i.e. would anyone outside of a pharmacy have access to the drug in a medical setting), or are they diluted in liquid or maybe in a painkilling patch?
To my knowledge, all legal formulations are diluted for administration and only the manufacturer handles the substance in its pure form.
Illicit fentanyl and its derivatives are usually distributed in their pure form, to people who have no training in handling hazardous substances.
Sometimes first responders to fentanyl overdoses will not even be able to enter the room of the victim without hazmat suits, because accidentally breathing in fentanyl dust or touching a surface in which the dust has settled could kill them.
Opioids are measured in binding strength (and so pain relief) with morphine as the baseline which ranges from x0.5-x1 for light opioids like Codine to x100 for Fentanyl.
Non opioid pain killers like ibuprofen are usually 1/200-1/300th of morphine.
It’s the the binding strength which has direct impact on addiction and withdrawal which is a bit scary since Fentanyl is 100 times stronger than morphine already, heroine is only 5 times as strong for comparison.
Are you talking about binding affinity? Do you have a cite for the relationship between this and the relative addictiveness of opioids given at their normal effective doses?
Everything I'm turning up suggests that, in the clinical setting, the "strength of opioids" is a statement about the relative size of the effective dose (in mg). Presumably that's correlated with molecular properties like the affinity, but I don't think that's what the article is talking about.
Edit: Since you edited your question I think you might want to look at opioid agonism across the range of receptors you should probably be able to find quite few NIH studies.
I don't think that article answers my question. This seems to be the entire contents that might directly address the issue:
> The new, deadlier drugs are altered opioids that bind in more powerful ways to the brain’s receptors and get to the brain more quickly. The combination of factors can make them thousands of times more deadly.
> All opioids connect to particular brain and nervous system receptors that exist for the body’s natural painkiller, endorphins...
That is the only mention of the word "bind" and the article doesn't contain the word "affinity". It doesn't discuss the relationship between effective-dose-size and potential for addiction, except in cases where it seems to go in the opposite direction of what you suggested:
> Methadone is about three times stronger than morphine, but it does not produce a strong euphoric effect. It also lasts much longer and can address physical dependence on other opioids, making it the most common choice for treating opioid addiction.
It did when you only had “do you have a cite for this” check my edit look at opioid agonism studies especially around addiction treatments where weak/partial agonists opioids are used to ease widthrawal symptoms without prolonging addiction.
Which of receptors the opioids can bind to and at what level also has impact on their addiction as many of these receptors regulate different functions iirc the ones that cause the most physical dependence are the strong Mu receptor agonists.
> It did when you only had “do you have a cite for this” check my edit
Oh gotcha, sorry about that. I edited my top-level comment fast, so I just assumed you hadn't had time to read the initial version.
> opioid agonism studies especially around addiction treatments where weak/partial agonists opioids are used to ease widthrawal symptoms without prolonging addiction.
OK, I spend 10 minutes Googling. I found a few authoritative lists of addictiveness that didn't seem to correlate with effective dose (which I am pretty confident is the measure of "power" being discussed in the article). And I couldn't find anything that asserted a reasonably robust correlation between effective dose size and addictiveness, whether mediated by agonism strength or otherwise. But I understand if you don't want to spend a bunch of time on this. Thanks.
Now I understand what are you looking for no at the “effective” dose it likely won’t matter the problem is that effective dose is irrelevant in this case because we are talking about substance abuse.
All full Mu receptors agonists can cause severe physical dependency, the stronger the affinity the more they also can push out other opioids and natural occurring ones and as over time the opioids can actually affect the “shape” of the receptor this is essentially what causes the addiction since what your body produces like endorphine is no longer good enough for you.
So if this will be prescribed like fentanyl and other opioids this will be a problem the opioid epidemic didn’t happen because opioids were tightly prescribed and administered in controlled conditions it happened because you sprained your back and instead of some physiotherapy and a sauna you’ve been given a bottle of pills to chew on like candy.
Not a primary source, but see slide 11 [0]. In this case, for the "10X" I think they're looking at the binding affinity to the u-receptor.
Edit: realized that doesn't answer your question about the relationship between binding affinity, relative effective dose in mg/kg, etc. At least when medicinal chemists I work with say "10X stronger" they're referring to the binding affinity. Not sure about what it means in a person.
I’m pretty sure it does the “potency” is derived by the Ki value of the opioid to the Mu receptor which is the affinity while they aren’t identical (the lower the Ki the higher the potency) they are interchangeable at these levels unless you are looking for much more complex pharmacology where agonism and multiple receptors come into play.
Since pain relief opioids are full Mu receptor agonists the rest doesn’t really matter in the context of these articles this is accurate enough to be technically correct while not being generalized to all opioids such as low Ki opioids which are mixed agonists or antagonists which can be used to treat addiction and even overdose since they bind to they receptors but don't activate them fully or not at all which means that they block other opioids.
> no at the “effective” dose it likely won’t matter the problem is that effective dose is irrelevant in this case because we are talking about substance abuse.
Do you disagree with either of these?
1. In popular news coverage, or doctors talking with lay patients, the term "power" or "strength" of an opioid is shorthand for it's potency on normal (non-addicted) patients. That is, it is inversely related to the number of milligrams that must be administered to get effective pain relief for some fixed reference injury.
2. The potency of a drug is only weakly correlated with its potential for addiction. There are several opioids that are less potent than average but have a higher propensity for addiction than average, and vice versa.
Ok "affinity" it's how strongly it would bind to a receptor.
Then there is agonism or antagonism which can be partial or full.
Full agonism is the "strongest" activation that doesn't have anything to do with affinity because it just means it fully activates the receptor, the affinity is how likely it will be bound to the receptors.
For opioids that are full agonists potency and affinity can be used essentially interchangeably these are all primary pain relief opioids and fully bind to the receptors in the same manner essentially, opioids which are mixed agonists or even antagonists such as those used to treat addiction or withdrawal can have very high affinity but low potency because while they bind to the receptor very strongly they don't fully activate it or even deactivate it but as their affinity is high they can beat other opioids to the binding and block the receptors.
As this drug is a replacement for fentanyl it's a full agonist opioid which means that if it's more potent it has to have a lower Ki value which means higher affinity at a matching ratio.
Isn't one of the big issues with the opioid addiction the fact that oxycontin was marketed as being able to control pain for 12 hours when in reality it didn't last that long?
So, with oxycontin, you got a big effect at beginning, wearing off too soon, and craving another--all actions which are really good at reinforcing addiction.
If your binding strength is much better, wouldn't you get lower doses (less big effect at start), which are more effective (less craving), further apart in time (actually controlling the pain like it was supposed to). This seems like a huge win.
I’m not an expert on opioids but there are other factors when it comes to how long it lasts the binding strength is just one of them, the delivery method is also important so are other factors such as how quickly it can pass the brain blood barrier, which other receptors it can bind too and what is the half life of the drug in vivo.
Fentanyl for example can administrated with a topical patch due to its relative strength to enable longer duration of pain relief, morphine would require an injection to be as effective.
No way that’s true. Buprenorphine has a much higher binding affinity than all the worst opiates yet you don’t see people trying to do that over heroin and all the others.
The strengths you’re speaking of are potency. And even then, most addicts I know would rather have an unlimited supply of oxymorphone than fentanyl or any of the others. At a certain point, cost outweighs all of that.
There’s so much misinformation out there about these drugs.
Buprenorphine is a partial agonist of the Mu receptor (the one which causes the most physical dependency) and is antagonist for the rest, it’s also has a very high affinity which displaces other opioids which is why it’s used in addiction treatment.
Yes is more to this than just affinity the type and level of the binding to each receptor is also important but on the grand scheme of things in this context it’s not because all the opioids which are primarily used for pain relief are full Mu receptor agonists which is when the simple affinity strength estimate is pretty much sufficient to estimate potency and potential harm.
Also last time I checked the potency is derived directly from the Ki value of the Mu receptor which represents the affinity (regardless of agonism) of the opioid, so these are essentially interchangeable.
That picture is misleading. Although the pain relief effect of carfentalin is ~35 times higher than fentanyl, the lethal dose of both drugs is about the same. So carfentanil is actually safer, in the sense that it has a higher therapeutic index.
Botox is lethal at ~1ng per kg of body weight. It takes 20,000 times that amount of the compound in question to kill you. (These are both using LD50 numbers).
Botox is a refined form of one of the most lethal substances to humans, it is a poison, and most of all it’s not a recreational drug of abuse commonly smuggled around the world. You also can’t absorb it through your skin like fentanyl and carfentanil. Brief contact with botulinum toxin won’t kill you, but brief contact with a rice-grain sized particle of carfentanil can and will.
>Sufentanil (R30730, brand name Sufenta) is a synthetic opioid analgesic drug approximately 5 to 10 times more potent than its parent drug, fentanyl, and 500 times as potent as morphine. Structurally, sufentanil differs from fentanyl through the addition of a methoxymethyl group on the piperidine ring (which is believed to reduce duration of action[2]), and the replacement of the phenyl ring by thiophene. Sufentanil first was synthesized at Janssen Pharmaceutica in 1974.[3]
>Sufentanil is marketed for use by specialist centers under different trade names, such as Sufenta and Sufentil. Sufentanil with and without lidocaine or mepivacaine is available as a transdermal patch similar to Duragesic in Europe under trade names such as Chronogesic. It is available as a sublingual tablet under the trade name Dsuvia.[4]
>Currently sufentanil is the strongest opioid painkiller available for use in humans. Although stronger narcotic pain medications do exist, all medications stronger than sufentanil are approved for veterinary use only.
This dissipates any doubt I had about the influence of lobbying.
FDA, a federal agency that is fully aware of the harmful and addictive nature of opioids (and its impact on the public health system) approves one of the most powerful opioids ever, disregarding the fact that its unique advantage is the fact that this is a non-intravenous administered opioid...
Ohh, and the argument for approving is basically that they believe is good to have more alternatives to existing opioids. Really? Like is not fentanyl strong enough to address every possible medical use case for a powerful opioid?
Many years ago my friend doctor patented a brilliant but simple device for holding on broken joints together. Because he seen so many open joints, he took advantage of this knowledge and it was light years comparing to other devices that were made from bulky material, expensive and painful to wear. All other doctors-friends tap him on the back and looked in his eyes like he's already a billionaire. "You only have to file with FDA and you good to go!", they say.
Seven years later and $450,000 in FDA fees and lawyers, he did not get anywhere! But he was lucky enough to stop there, as he met some lawyer that used to work for FDA before. That layer told him even back in 70s everyone within agency knew the goal of FDA is NOT to protect citizens and their health; but rather to protect big pharma, or pretty much every corporation with big enough pockets, from disrupting market and as a result messing around with their bottom line.
This lawyer told my friend that this is as hard-core "capitalism Americana" as it can ever get!
Maybe we don't have Standard & Oil and Rockefeller in full charge taking advantage of capitalism's cons, but indeed it shakes you to the core when you educate yourself how broken the system IS.
Edit: to expand on FDA goal - when you file for approval for a big enough disruptive product, they will find all sort of downsides to drag your feet. The good rule of a thumb is if you are rejected the second time, you most likely won't get anyway ever. So FDA's job is to come up with good enough excuse to put your product/approval down with as sounded reason as possible.
Followup: if you love these kind of stories and dirty rabbit holes, lookup how Aspartame was initially approved by FDA. Goosebumps and head shakes guaranteed!
I can't speak for this drug, but different opioids are processed by different liver pathways. Some people don't properly metabolize something like Oxycodone, but handle morphine just fine. So that's part of it.
The other issue is that in specific cases (for instance, in battlefield medicine) you may need something that hits harder and faster than fentanyl. Again, I don't know this particular drug, but it may also last longer than fentanyl, which wears off quite quickly.
> This dissipates any doubt I had about the influence of lobbying.
Who are you accusing of lobbying here? It's pretty clear from the article that the primary advocate for this drug is the military (DoD).
> Like is not fentanyl strong enough to address every possible medical use case for a powerful opioid?
Strength is not something that's assessed along a one-dimensional axis, much as popular reporting on opiates and pharmaceuticals would have you believe.
AcelRx, the pharmaceutical company that produces and distributes DSUVIA. You understand how lobbying works right? Even if the Department of Defense is advocating for the use of a drug, they don't have any input on the safety of whatever they are advocating for. This is the role of the FDA. AcelRx happens to have something that the DoD wants so they lobby for its approval. In this case, DoD, FDA, and AcelRX are all different parties but is clear that AcelRX is the only party that will benefit financially from this.
Just from an anectodical perspective, so you can understand how this works, check ACRX stock closing price today. It closed 16% up today.
Just because the DoD is advocating for this drug, that doesn't mean that there's no pharmaceutical lobbying behind this. By that logic then all defense contractors and weapon manufacturers wouldn't have to lobby as much as they do.
> clear that AcelRX is the only party that will benefit financially from this
The DoD benefits as well.
> Just because the DoD is advocating for this drug, that doesn't mean that there's no pharmaceutical lobbying behind this.
Thr converse applies too. Just because FDA approved a drug that the military wanted, that doesn't mean that the approval was the result of their lobbying.
Yes but the doctor prescribes it first. When addicted, and the doctor doesn't want to prescribe it anymore, the street becomes the supplier. Most likely some politician or lobbyist out there is gaining on this whole chain of supply and demand, how else would a stronger drug get approved in the light of the opioid crisis we already can't handle.
fentanyl sold on the street is generally not diverted from prescriptions. fentanyl that you can actually take home tends to come in something like a patch where the drug is suspended at very low concentrations in a gel. illicit fentanyl sold at scale usually comes from illicit labs overseas.
> how else would a stronger drug get approved in the light of the opioid crisis we already can't handle
in this context, "stronger" simply means more potent by weight. you shouldn't assume that more potent opiates are more addictive; fentanyl is not the drug of choice for most opiate addicts.
That's not true. Fentanyl gets stolen in medical facilities all the time.
There were some pharmacists in Canada some years ago that were stealing the fentanyl themselves and reporting they were being robbed. Of course that was a stupid scheme and they got caught.
If you are interested in learning more the general name for this drug (outside of the US) is ARX-04.
The maker has some data that compares it to Fentanyl [1]. Their numbering states that is closer to 100x, and crosses the blood brain barrier in around 6 minutes.
Interesting. I'm a bit confused about slide 6, which says that it has a theraputic index which is 100 times better than fentanyl. It cites the reference [1], which indeed has those numbers in it, but the full table there is:
ED50 LD50 Theaputic Index
Fentanyl 0.01 3.1 277
Sufentanil 0.007 18 26716
The therapeutic index is the ratio of LD50:ED50.
This clearly makes no sense, someone must have moved a decimal point, and got a number which is wrong by a factor 10.
EDIT: Ok, it seems that it is indeed an error in the cited paper, but the typo is for the ED50 number. In the original source[2] it's given as 0.00071, which agrees with the "10 times stronger than fentanyl" claim in the original article, and gives the correct theraputic index.
All the negativity aside, my mom had a very aggressive cancer. Found in October, she passed in May. She was getting doses of fentanyl and it was the only thing numbing the chronic pain. I'm pretty sure it was a patch like a bandaid. That said I'm glad it was available because she would have suffered even more without it.
For those of us that have had to use opioids for cancer treatment to the point of being addicted, then kicked the habit after treatment, all of the asinine demonization of opioids is absolutely infuriating. I used ate percs like candy during treatment and rehab, then used fentanyl patches to wean off. It was hard, like really hard, but life is hard.
It's not worth it to try and convince anyone that hasn't knocked on deaths door that sometimes you need palliative care in the form of narcotics to make it to your destination, recovery or otherwise.
I'm sorry about your mother, she wasn't bad for using fentanyl or anything else. She did great things with her life, you're proof. Don't let the stupid media or internet SJWs try influence you. After my ordeal I haven't watched TV or the news in years and am much happier for it. Family, work, and video games (or hobby of choice) is all a person needs IMO.
I agree with this. FDA approval shouldn’t be the issue since it’s safe when administered correctly and has medical purposes. Controlling distribution should be the issue. There almost needs to by a super controlled substance drug class
> For those of us that have had to use opioids for cancer treatment to the point of being addicted, then kicked the habit after treatment, all of the asinine demonization of opioids is absolutely infuriating. I used ate percs like candy during treatment and rehab, then used fentanyl patches to wean off. It was hard, like really hard, but life is hard.
I guess you're going to ignore the actual issue of doctors handing this crap out like candy to people who don't need it and companies selling these drugs directly to doctors with promises that they weren't anywhere as addictive as previous opioids? There actually is an opioid epidemic, and they're not talking about terminally ill patients who actually need the shit.
> Family, work, and video games (or hobby of choice) is all a person needs IMO.
I hate listing credentials in online forums, but as someone who lost two grandparents to painful cancer, yes opioids are useful medicine. Additionally as someone who lost 2 cousins, a best friend and more than a couple acquaintances, there is a very real issue with opioids, and "a hobby of choice" is _NOT_ all a person needs. I'm extremely glad you kicked it, but please don't anecdotally shrug off an issue that is currently killing young people at an unprecedented rate. My home town looks like it had a draft for a war that was lost terribly - there are no young people left, we either fled or died.
> "a hobby of choice" is _NOT_ all a person needs.
That's why he said family, work AND a hobby. He missed one, too: a close relationship with God goes a long way. Family, community and faith are the most effective ways of dealing with addiction.
Before you rage against this; fentanyl has been an immense asset to medicine, and when dosed correctly it offers much more manageable side effects (and greater control) than many other opioids. Just because the drug is more potent per microgram, that doesn't mean there's some sort of moral failing involved in bringing it to market.
When you're in immense pain, and the only safe way to relieve that for you is some potent opioid, I guarantee you will thank people for bringing these things to market.
I don't understand, the article states the distribution is very controlled and geared towards the military. The problem with Fentanyl is its widespread prescription by family doctors.
If the US doesn't allow its distribution through mainstream channels, it's no big deal. I'm pretty sure that stuff is weaker than morphine, yet morphine is quite available in hospitals...
EDIT: ah, apparently it's quite stronger than morphine. The argument still holds. Hospitals do have stronger stuff :)
Yeah, but what does "strong" mean in this context? If it means you can get the same effect with 1/10th the dose, then you just put 1/10th as much active ingredient in each pill and nothing effectively changes.
There's some discussion at the top of the thread that suggests it's more complicated than that, and may make it either more or less dangerous, depending.
The other problem with fentanyl is that it is much "stronger" than morphine, and much easier to smuggle into the US. It was until recently legal to produce it in China.
This means heroin dealers were buying fentanyl and cutting it with sugars.
If they correctly cut it - dilute it - it's bad, but not as bad as when they incorrectly cut it and release product that is too strong. This is one of the reasons fentanyl is killing so many Americans.
Naloxone is the drug used to block the effects of opioids. LE carry them, but at the cost of $4500 for two injectors. The Narcan spray is slightly lest costly iirc. I'm a uni student working on designing an auto-injector that could be used instead (the medicine itself is very cheap) and potentially to administer epinepherine too (also a case of cheap medicine - expensive administration device).
I've made some progress but have no mechanical design experience. I'm not optimistic about the time period needed for FDA approval so I'm really doing it for the learning experience. I'd love some help!
My suggestion, keep a journal about the process you go through (design, manufacture, ip, regulatory) and publish that when you’re done.
This whole area of portable medical devices is in serious need of disruption. Knowledgeable people should be able to enter into this area. Check out the insulin pump hackers if you haven’t already to get a peek at what is possible.
It is absolutely criminal that a <$20 drug can be sold for $4500... Auto-injectors have been a solved problem for decades, and there is nothing special about naloxone vs any other drug. Treating auto-injecting tech as different for each drug only helps drive up prices and keep out competition by making FDA approval very expensive.
I hope you are successful getting a generic auto-injector approved, but I don't think your biggest hurdle will be design or engineering.
>(3) In the Emergency treatment of anaphylactic reactions Guidelines for healthcare providers the preferred needle length is 25 mm for adrenaline injectors to access muscle in most people. I heard during expert evidence that Epipen needle length was 16mm - suitable according to the UK Resuscitation Council for “pre-term or very small infants”. The use of needles which access only subcutaneous tissue and not muscle is in my view inherently unsafe. An alternative autoinjector, Emerade has a 24 mm needle.
>(4) The dose of adrenaline in Epipen is 300mcg. The UK Resuscitation Council recommends a standard emergency dose of 500mcg. Emerade contains a dose including 500mcg. The combination of what my expert told me was an inadequate dose of adrenaline for anaphylaxis and an inadequate length needle raises serious safety concerns.
-Depending on her weight 300mcg may be an appropriate dose for US guidelines (listed at 0.01mg/kg).
The listed issues may be from a company taking a 'one-size-fits-most' approach. They also do not update their product with respect to new guidelines and recommendations (new doses, new needle lengths, etc) Possibly to avoid further FDA approval processes? With such large profits and so little competition there is no incentive to innovate/update.
For the record, a large part of anesthesia worldwide is done with that molecule. Potency is not everything, and using sufentanyl in hospital contexts is very much justified.
The tablet formula of course makes it far more prone to misuse, though...
I can also add that iv remifentanyl is on the market in the US, prescribed routinely, and is much more powerful than even sufentanyl. In fact, so powerful that getting high on it would most certainly kill you, making it pretty much useless to drug users. So again, potency is not everything.
> The tablet formula of course makes it far more prone to misuse, though...
The primary danger of fentanyl is accidental use - ie, people consuming lethal doses of fentanyl because their heroin (which is much less potent, by weight) is cut with fentanyl.
It's unclear from this article whether that's a risk here, which depends (among other things) on how readily Dsuvia is absorbed through other means.
The problem is that with high potency, you also get more side effects for the same "painkiller" effect (also depending on absorption velocity). Therefore, using something such as remifentanyl in the mix would almost certainly be counterproductive if you are looking for the "high". It would displace fentanyl, and be more risky.
And first of all, it is far more expensive than fentanyl.
It's worth noting here that not every opioid is metabolized the same. I can't speak for this medicine, but different metabolic pathways are used to process opioids.[1] Having more tools in your toolkit means that you are more likely to be able to treat a patient's pain.
That being said, I think that one of the major uses for this drug will be to treat acute pain in chronic pain patients. Those patients aren't opioid naive and may need something that will "override" the tolerance these patients have developed. I'm guessing that they'd also work for patients on the opioid agonist/antagonist Buprenorphine, which is used for chronic pain, but tends to block other opiates.
Lastly, while potent, this drug appears to wear off very quickly. That's going to be key here, because it's simply not useful unless you're able to administer a high quantity of the medicine.
To boot, I believe that the manufacturer claims that this drug has less cognitive side effects than other opioids. [2]
To boot, I believe that the manufacturer claims that this drug has less cognitive side effects than other opioids
I'd take manufacturer claims with a grain of salt, since their goal (actually pretty much a requirement for a public company) is to sell drugs and earn money, not heal people.
The last time these companies promised it wouldn't be as addictive as previous opioids, they were pulling numbers out of their ass and straight lying about it. I think we should all be alarmed if they're releasing a new drug that's even more potent.
It's definitely concerning, but that doesn't mean that it shouldn't be released. It's the sort of drug that will find an appropriate use, though pretty much only in edge cases.
> It's the sort of drug that will find an appropriate use, though pretty much only in edge cases.
You're way too trusting. While I do think drugs like this should exist for those who really need it (particularly terminally ill patients), I'm incredibly worried about how these drug companies intend to profit from the drug (by selling these drugs to doctors in a way that encourages their use in circumstances that in no way warrant it). Their profit motive and the incredible expense of developing a new drug directly contradicts the need for restrictive and sparing use of the drug to appropriate contexts.
Look here's the issue. In people with chronic pain, there's a medical issue.
Treating the medical issue ... is very expensive (I believe spinal operations would be pretty common).
Giving them opioids ... "treats" the issue. Cheaply, even though yes, these people are from that point on dependent on opioids. They are of course addicted FIRSTLY because they went untreated, and SECONDLY because the medicine is addictive.
Eliminating one of those reasons for addition is pointless.
You cannot give these people nothing. You can't actually treat them (that's WAY too expensive). So what is your suggestion, exactly ? You can't leave them untreated and in sometimes incredible pain.
>I think that one of the major uses for this drug will be to treat acute pain in chronic pain patients
(Assuming you're talking about long-term non-organic chronic pain here).
Opioids are no more effective than Nonopiod painkillers for treating chronic pain [1] and the risks of addiction (8-12% of patients become addicted [2]) mean that the risks don't really outweigh the benefits. Psychosocial treatments seem to be more effective for chronic pain than opioids.
They're not, but they can cause depression and/or anxiety. Also, euphoria, agitation, et. al. In one person I noticed that she had developed terrible memory problems. She used to be an academic, but there's no way she could function in an academic environment now.
The most pernicious side effects-- in my opinion-- that have fairly scary mental health ramifications are hyperalgesia [1] and uncontrollable itching [2].
I saw a girl afflicted by hyperalgesia and the itching and it was terrible. The solution was to take her off of the morphine, but she wouldn't consider it. Paradoxically, she resorted to self harm to control the issue. Unfortunately, I don't know how the story ended. The last I heard a dermatologist was talking about THC creams being investigated for this type of thing. But I have no knowledge of that. I only mention it because it sounds intriguing.
Note: I'm not a doctor. I work in the US government and my job gives me a lot of experience working with pain management doctors and their patients.
> I saw a girl afflicted by hyperalgesia and the itching and it was terrible. The solution was to take her off of the morphine, but she wouldn't consider it. Paradoxically, she resorted to self harm to control the issue.
You know, why did she take morphine in the first place. That's the big missing link here. People's actions make sense.
If, for instance, she had a hernia and couldn't treat it (too expensive, even with insurance, or just no insurance), that would explain her behavior. Same with any other painful or degenerative condition, and in fact quite a lot of untreated conditions.
More generally that is the problem there. Addiction, yes, but in the sense of psychological addiction, not substance abuse. If you're in chronic pain you've either got the willpower of an olympic athlete or you're "addicted".
Then she is not a substance abuser, and cannot be helped with less addictive pain medication. She will be addicted to pain medication, and probably not really care which one, beyond effectiveness arguments. She is not addicted to morphine (or if she self-medicates, cocaine or ...). She cannot deal with the amount of pain she's subjected to without such substances. These are not drug addicts, even if they are substance addicted that's a secondary problem at best.
There are many people like this (with much pain, not so much with degenerative genetic conditions).
And I would argue this medication will actually help them, because if you've ever had morphine (I don't wish kidney stones on anyone, but that's why I've had morphine, and probably a lot, I don't remember particularly well), you know that it puts this "cloud" over your mental state. Something that helps with the pain but leaves you fully conscious, unlike morphine, would be welcome.
The FDA approves things based on the purpose they were presented to the FDA/market for.
It isn't based on danger, it is based on evidence backed disclosure of the danger.
In the specific use the company told the FDA about, it passed, and that will usually happen with some objections or outright denial. The denial didn't happen and that isn't article worthy.
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[ 2.8 ms ] story [ 188 ms ] threadI think a solution to a lot of this would simply be to make the manufacturers of such be responsible for the costs of getting people off them. And the cleanup costs for cities that have to deal with the results.
What, exactly, does "10x more powerful" mean?
Potency? Presumably it'd then be prescribed in lower doses?
Hear, hear!
Especially in this context. I have a modest understanding of just a couple of these compounds. And that comes by way of chronic pain people in my life.
Over time, doing the work to better undestand these things has paid off. They, at times, get contradictory or just bad advice, or see something that makes them worry, or think they are in danger somehow.
It can be hard to get clarity, and know a change is thearaputic vs compliance related, for example.
Anyway, I just liked that you said that and followed up with super easy to understand information.
Illicit fentanyl and its derivatives are usually distributed in their pure form, to people who have no training in handling hazardous substances.
Sometimes first responders to fentanyl overdoses will not even be able to enter the room of the victim without hazmat suits, because accidentally breathing in fentanyl dust or touching a surface in which the dust has settled could kill them.
Non opioid pain killers like ibuprofen are usually 1/200-1/300th of morphine.
Marketing's probably up there.
Everything I'm turning up suggests that, in the clinical setting, the "strength of opioids" is a statement about the relative size of the effective dose (in mg). Presumably that's correlated with molecular properties like the affinity, but I don't think that's what the article is talking about.
Edit: Since you edited your question I think you might want to look at opioid agonism across the range of receptors you should probably be able to find quite few NIH studies.
> The new, deadlier drugs are altered opioids that bind in more powerful ways to the brain’s receptors and get to the brain more quickly. The combination of factors can make them thousands of times more deadly.
> All opioids connect to particular brain and nervous system receptors that exist for the body’s natural painkiller, endorphins...
That is the only mention of the word "bind" and the article doesn't contain the word "affinity". It doesn't discuss the relationship between effective-dose-size and potential for addiction, except in cases where it seems to go in the opposite direction of what you suggested:
> Methadone is about three times stronger than morphine, but it does not produce a strong euphoric effect. It also lasts much longer and can address physical dependence on other opioids, making it the most common choice for treating opioid addiction.
Which of receptors the opioids can bind to and at what level also has impact on their addiction as many of these receptors regulate different functions iirc the ones that cause the most physical dependence are the strong Mu receptor agonists.
Oh gotcha, sorry about that. I edited my top-level comment fast, so I just assumed you hadn't had time to read the initial version.
> opioid agonism studies especially around addiction treatments where weak/partial agonists opioids are used to ease widthrawal symptoms without prolonging addiction.
OK, I spend 10 minutes Googling. I found a few authoritative lists of addictiveness that didn't seem to correlate with effective dose (which I am pretty confident is the measure of "power" being discussed in the article). And I couldn't find anything that asserted a reasonably robust correlation between effective dose size and addictiveness, whether mediated by agonism strength or otherwise. But I understand if you don't want to spend a bunch of time on this. Thanks.
All full Mu receptors agonists can cause severe physical dependency, the stronger the affinity the more they also can push out other opioids and natural occurring ones and as over time the opioids can actually affect the “shape” of the receptor this is essentially what causes the addiction since what your body produces like endorphine is no longer good enough for you.
So if this will be prescribed like fentanyl and other opioids this will be a problem the opioid epidemic didn’t happen because opioids were tightly prescribed and administered in controlled conditions it happened because you sprained your back and instead of some physiotherapy and a sauna you’ve been given a bottle of pills to chew on like candy.
Edit: realized that doesn't answer your question about the relationship between binding affinity, relative effective dose in mg/kg, etc. At least when medicinal chemists I work with say "10X stronger" they're referring to the binding affinity. Not sure about what it means in a person.
https://www.ctsi.ucla.edu/education/files/view/training/docs...
Since pain relief opioids are full Mu receptor agonists the rest doesn’t really matter in the context of these articles this is accurate enough to be technically correct while not being generalized to all opioids such as low Ki opioids which are mixed agonists or antagonists which can be used to treat addiction and even overdose since they bind to they receptors but don't activate them fully or not at all which means that they block other opioids.
> no at the “effective” dose it likely won’t matter the problem is that effective dose is irrelevant in this case because we are talking about substance abuse.
Do you disagree with either of these?
1. In popular news coverage, or doctors talking with lay patients, the term "power" or "strength" of an opioid is shorthand for it's potency on normal (non-addicted) patients. That is, it is inversely related to the number of milligrams that must be administered to get effective pain relief for some fixed reference injury.
2. The potency of a drug is only weakly correlated with its potential for addiction. There are several opioids that are less potent than average but have a higher propensity for addiction than average, and vice versa.
Then there is agonism or antagonism which can be partial or full.
Full agonism is the "strongest" activation that doesn't have anything to do with affinity because it just means it fully activates the receptor, the affinity is how likely it will be bound to the receptors.
For opioids that are full agonists potency and affinity can be used essentially interchangeably these are all primary pain relief opioids and fully bind to the receptors in the same manner essentially, opioids which are mixed agonists or even antagonists such as those used to treat addiction or withdrawal can have very high affinity but low potency because while they bind to the receptor very strongly they don't fully activate it or even deactivate it but as their affinity is high they can beat other opioids to the binding and block the receptors.
As this drug is a replacement for fentanyl it's a full agonist opioid which means that if it's more potent it has to have a lower Ki value which means higher affinity at a matching ratio.
So, with oxycontin, you got a big effect at beginning, wearing off too soon, and craving another--all actions which are really good at reinforcing addiction.
If your binding strength is much better, wouldn't you get lower doses (less big effect at start), which are more effective (less craving), further apart in time (actually controlling the pain like it was supposed to). This seems like a huge win.
Fentanyl for example can administrated with a topical patch due to its relative strength to enable longer duration of pain relief, morphine would require an injection to be as effective.
The strengths you’re speaking of are potency. And even then, most addicts I know would rather have an unlimited supply of oxymorphone than fentanyl or any of the others. At a certain point, cost outweighs all of that.
There’s so much misinformation out there about these drugs.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2581407/
Yes is more to this than just affinity the type and level of the binding to each receptor is also important but on the grand scheme of things in this context it’s not because all the opioids which are primarily used for pain relief are full Mu receptor agonists which is when the simple affinity strength estimate is pretty much sufficient to estimate potency and potential harm.
Also last time I checked the potency is derived directly from the Ki value of the Mu receptor which represents the affinity (regardless of agonism) of the opioid, so these are essentially interchangeable.
https://www.statnews.com/wp-content/uploads/2016/09/Heroin-F...
http://mediad.publicbroadcasting.net/p/wosu2/files/styles/me...
https://twitter.com/davidjuurlink/status/859227636400349184?...
This is the drug the article is talking about.
>Sufentanil (R30730, brand name Sufenta) is a synthetic opioid analgesic drug approximately 5 to 10 times more potent than its parent drug, fentanyl, and 500 times as potent as morphine. Structurally, sufentanil differs from fentanyl through the addition of a methoxymethyl group on the piperidine ring (which is believed to reduce duration of action[2]), and the replacement of the phenyl ring by thiophene. Sufentanil first was synthesized at Janssen Pharmaceutica in 1974.[3]
>Sufentanil is marketed for use by specialist centers under different trade names, such as Sufenta and Sufentil. Sufentanil with and without lidocaine or mepivacaine is available as a transdermal patch similar to Duragesic in Europe under trade names such as Chronogesic. It is available as a sublingual tablet under the trade name Dsuvia.[4]
>Currently sufentanil is the strongest opioid painkiller available for use in humans. Although stronger narcotic pain medications do exist, all medications stronger than sufentanil are approved for veterinary use only.
FDA, a federal agency that is fully aware of the harmful and addictive nature of opioids (and its impact on the public health system) approves one of the most powerful opioids ever, disregarding the fact that its unique advantage is the fact that this is a non-intravenous administered opioid...
Ohh, and the argument for approving is basically that they believe is good to have more alternatives to existing opioids. Really? Like is not fentanyl strong enough to address every possible medical use case for a powerful opioid?
Seven years later and $450,000 in FDA fees and lawyers, he did not get anywhere! But he was lucky enough to stop there, as he met some lawyer that used to work for FDA before. That layer told him even back in 70s everyone within agency knew the goal of FDA is NOT to protect citizens and their health; but rather to protect big pharma, or pretty much every corporation with big enough pockets, from disrupting market and as a result messing around with their bottom line.
This lawyer told my friend that this is as hard-core "capitalism Americana" as it can ever get!
Maybe we don't have Standard & Oil and Rockefeller in full charge taking advantage of capitalism's cons, but indeed it shakes you to the core when you educate yourself how broken the system IS.
Edit: to expand on FDA goal - when you file for approval for a big enough disruptive product, they will find all sort of downsides to drag your feet. The good rule of a thumb is if you are rejected the second time, you most likely won't get anyway ever. So FDA's job is to come up with good enough excuse to put your product/approval down with as sounded reason as possible.
Followup: if you love these kind of stories and dirty rabbit holes, lookup how Aspartame was initially approved by FDA. Goosebumps and head shakes guaranteed!
The other issue is that in specific cases (for instance, in battlefield medicine) you may need something that hits harder and faster than fentanyl. Again, I don't know this particular drug, but it may also last longer than fentanyl, which wears off quite quickly.
Who are you accusing of lobbying here? It's pretty clear from the article that the primary advocate for this drug is the military (DoD).
> Like is not fentanyl strong enough to address every possible medical use case for a powerful opioid?
Strength is not something that's assessed along a one-dimensional axis, much as popular reporting on opiates and pharmaceuticals would have you believe.
AcelRx, the pharmaceutical company that produces and distributes DSUVIA. You understand how lobbying works right? Even if the Department of Defense is advocating for the use of a drug, they don't have any input on the safety of whatever they are advocating for. This is the role of the FDA. AcelRx happens to have something that the DoD wants so they lobby for its approval. In this case, DoD, FDA, and AcelRX are all different parties but is clear that AcelRX is the only party that will benefit financially from this.
Just from an anectodical perspective, so you can understand how this works, check ACRX stock closing price today. It closed 16% up today.
Just because the DoD is advocating for this drug, that doesn't mean that there's no pharmaceutical lobbying behind this. By that logic then all defense contractors and weapon manufacturers wouldn't have to lobby as much as they do.
Yes, I do. There's no need to be condescending.
> clear that AcelRX is the only party that will benefit financially from this
The DoD benefits as well.
> Just because the DoD is advocating for this drug, that doesn't mean that there's no pharmaceutical lobbying behind this.
Thr converse applies too. Just because FDA approved a drug that the military wanted, that doesn't mean that the approval was the result of their lobbying.
fentanyl sold on the street is generally not diverted from prescriptions. fentanyl that you can actually take home tends to come in something like a patch where the drug is suspended at very low concentrations in a gel. illicit fentanyl sold at scale usually comes from illicit labs overseas.
> how else would a stronger drug get approved in the light of the opioid crisis we already can't handle
in this context, "stronger" simply means more potent by weight. you shouldn't assume that more potent opiates are more addictive; fentanyl is not the drug of choice for most opiate addicts.
The maker has some data that compares it to Fentanyl [1]. Their numbering states that is closer to 100x, and crosses the blood brain barrier in around 6 minutes.
[1] http://www.acelrx.com/technology/publications/arx-04/MHSRS%2... here
https://en.wikipedia.org/wiki/Moscow_hostage_crisis_chemical...
EDIT: Ok, it seems that it is indeed an error in the cited paper, but the typo is for the ED50 number. In the original source[2] it's given as 0.00071, which agrees with the "10 times stronger than fentanyl" claim in the original article, and gives the correct theraputic index.
[1] https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1440-1681.... [2] https://twitter.com/davidjuurlink/status/859227636400349184?...
It's not worth it to try and convince anyone that hasn't knocked on deaths door that sometimes you need palliative care in the form of narcotics to make it to your destination, recovery or otherwise.
I'm sorry about your mother, she wasn't bad for using fentanyl or anything else. She did great things with her life, you're proof. Don't let the stupid media or internet SJWs try influence you. After my ordeal I haven't watched TV or the news in years and am much happier for it. Family, work, and video games (or hobby of choice) is all a person needs IMO.
People demonizing these drugs have obviously never known anyone living with severe, chronic pain.
I guess you're going to ignore the actual issue of doctors handing this crap out like candy to people who don't need it and companies selling these drugs directly to doctors with promises that they weren't anywhere as addictive as previous opioids? There actually is an opioid epidemic, and they're not talking about terminally ill patients who actually need the shit.
I hate listing credentials in online forums, but as someone who lost two grandparents to painful cancer, yes opioids are useful medicine. Additionally as someone who lost 2 cousins, a best friend and more than a couple acquaintances, there is a very real issue with opioids, and "a hobby of choice" is _NOT_ all a person needs. I'm extremely glad you kicked it, but please don't anecdotally shrug off an issue that is currently killing young people at an unprecedented rate. My home town looks like it had a draft for a war that was lost terribly - there are no young people left, we either fled or died.
That's why he said family, work AND a hobby. He missed one, too: a close relationship with God goes a long way. Family, community and faith are the most effective ways of dealing with addiction.
https://www.youtube.com/watch?v=ao8L-0nSYzg
When you're in immense pain, and the only safe way to relieve that for you is some potent opioid, I guarantee you will thank people for bringing these things to market.
If the US doesn't allow its distribution through mainstream channels, it's no big deal. I'm pretty sure that stuff is weaker than morphine, yet morphine is quite available in hospitals...
EDIT: ah, apparently it's quite stronger than morphine. The argument still holds. Hospitals do have stronger stuff :)
There's some discussion at the top of the thread that suggests it's more complicated than that, and may make it either more or less dangerous, depending.
This means heroin dealers were buying fentanyl and cutting it with sugars.
If they correctly cut it - dilute it - it's bad, but not as bad as when they incorrectly cut it and release product that is too strong. This is one of the reasons fentanyl is killing so many Americans.
I've made some progress but have no mechanical design experience. I'm not optimistic about the time period needed for FDA approval so I'm really doing it for the learning experience. I'd love some help!
This whole area of portable medical devices is in serious need of disruption. Knowledgeable people should be able to enter into this area. Check out the insulin pump hackers if you haven’t already to get a peek at what is possible.
I hope you are successful getting a generic auto-injector approved, but I don't think your biggest hurdle will be design or engineering.
https://www.nejm.org/doi/full/10.1056/NEJMp1609578
And yet we still have stuff like this: https://www.judiciary.uk/publications/natasha-ednan-laperous...
>(3) In the Emergency treatment of anaphylactic reactions Guidelines for healthcare providers the preferred needle length is 25 mm for adrenaline injectors to access muscle in most people. I heard during expert evidence that Epipen needle length was 16mm - suitable according to the UK Resuscitation Council for “pre-term or very small infants”. The use of needles which access only subcutaneous tissue and not muscle is in my view inherently unsafe. An alternative autoinjector, Emerade has a 24 mm needle.
>(4) The dose of adrenaline in Epipen is 300mcg. The UK Resuscitation Council recommends a standard emergency dose of 500mcg. Emerade contains a dose including 500mcg. The combination of what my expert told me was an inadequate dose of adrenaline for anaphylaxis and an inadequate length needle raises serious safety concerns.
-For over 10 years, It well documented in literature that even in normal BMI women the needle is not long enough to reach muscle. https://www.ncbi.nlm.nih.gov/pubmed?term=15945556
- Prior to around 2003 IM and subcutaneous routes were both listed as valid treatments for anaphylaxis. (See https://www.aafp.org/afp/2003/1001/p1325.html)
-Depending on her weight 300mcg may be an appropriate dose for US guidelines (listed at 0.01mg/kg).
The listed issues may be from a company taking a 'one-size-fits-most' approach. They also do not update their product with respect to new guidelines and recommendations (new doses, new needle lengths, etc) Possibly to avoid further FDA approval processes? With such large profits and so little competition there is no incentive to innovate/update.
FDA typically takes ~10 years to get through (though this WILDLY varies).
Make sure to put your contact info in your bio so HNers have a way to contact you!
The primary danger of fentanyl is accidental use - ie, people consuming lethal doses of fentanyl because their heroin (which is much less potent, by weight) is cut with fentanyl.
It's unclear from this article whether that's a risk here, which depends (among other things) on how readily Dsuvia is absorbed through other means.
To be fair, this is what we used to say about fentanyl until recently.
That being said, I think that one of the major uses for this drug will be to treat acute pain in chronic pain patients. Those patients aren't opioid naive and may need something that will "override" the tolerance these patients have developed. I'm guessing that they'd also work for patients on the opioid agonist/antagonist Buprenorphine, which is used for chronic pain, but tends to block other opiates.
Lastly, while potent, this drug appears to wear off very quickly. That's going to be key here, because it's simply not useful unless you're able to administer a high quantity of the medicine.
To boot, I believe that the manufacturer claims that this drug has less cognitive side effects than other opioids. [2]
[1] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704133/ [2] http://www.acelrx.com/technology/publications/arx-04/MHSRS%2...
I'd take manufacturer claims with a grain of salt, since their goal (actually pretty much a requirement for a public company) is to sell drugs and earn money, not heal people.
You're way too trusting. While I do think drugs like this should exist for those who really need it (particularly terminally ill patients), I'm incredibly worried about how these drug companies intend to profit from the drug (by selling these drugs to doctors in a way that encourages their use in circumstances that in no way warrant it). Their profit motive and the incredible expense of developing a new drug directly contradicts the need for restrictive and sparing use of the drug to appropriate contexts.
Treating the medical issue ... is very expensive (I believe spinal operations would be pretty common).
Giving them opioids ... "treats" the issue. Cheaply, even though yes, these people are from that point on dependent on opioids. They are of course addicted FIRSTLY because they went untreated, and SECONDLY because the medicine is addictive.
Eliminating one of those reasons for addition is pointless.
You cannot give these people nothing. You can't actually treat them (that's WAY too expensive). So what is your suggestion, exactly ? You can't leave them untreated and in sometimes incredible pain.
(Assuming you're talking about long-term non-organic chronic pain here).
Opioids are no more effective than Nonopiod painkillers for treating chronic pain [1] and the risks of addiction (8-12% of patients become addicted [2]) mean that the risks don't really outweigh the benefits. Psychosocial treatments seem to be more effective for chronic pain than opioids.
1. https://jamanetwork.com/journals/jama/fullarticle/2673971?fo... 2. https://dtb.bmj.com/content/56/10/118
In any case, I only have experience in palliative care environments, where opioids are de rigueur and with good reason.
The most pernicious side effects-- in my opinion-- that have fairly scary mental health ramifications are hyperalgesia [1] and uncontrollable itching [2].
I saw a girl afflicted by hyperalgesia and the itching and it was terrible. The solution was to take her off of the morphine, but she wouldn't consider it. Paradoxically, she resorted to self harm to control the issue. Unfortunately, I don't know how the story ended. The last I heard a dermatologist was talking about THC creams being investigated for this type of thing. But I have no knowledge of that. I only mention it because it sounds intriguing.
Note: I'm not a doctor. I work in the US government and my job gives me a lot of experience working with pain management doctors and their patients.
[1] https://www.ncbi.nlm.nih.gov/pubmed/21412369 [2] https://www.jpsmjournal.com/article/S0885-3924(98)00115-8/fu...
You know, why did she take morphine in the first place. That's the big missing link here. People's actions make sense.
If, for instance, she had a hernia and couldn't treat it (too expensive, even with insurance, or just no insurance), that would explain her behavior. Same with any other painful or degenerative condition, and in fact quite a lot of untreated conditions.
More generally that is the problem there. Addiction, yes, but in the sense of psychological addiction, not substance abuse. If you're in chronic pain you've either got the willpower of an olympic athlete or you're "addicted".
There are many people like this (with much pain, not so much with degenerative genetic conditions).
And I would argue this medication will actually help them, because if you've ever had morphine (I don't wish kidney stones on anyone, but that's why I've had morphine, and probably a lot, I don't remember particularly well), you know that it puts this "cloud" over your mental state. Something that helps with the pain but leaves you fully conscious, unlike morphine, would be welcome.
It isn't based on danger, it is based on evidence backed disclosure of the danger.
In the specific use the company told the FDA about, it passed, and that will usually happen with some objections or outright denial. The denial didn't happen and that isn't article worthy.
Potency doesn't matter; pills are mixed with fillers to adjust dosage.
Now, if street drugs start being cut with this new drug, that's another story, if the mixing is poor.