Despite concerns, FDA approves new opioid 10x more powerful than Fentanyl
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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!
I hope you are successful getting a generic auto-injector approved, but I don't think your biggest hurdle will be design or engineering.
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.
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.
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!
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...
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.
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.
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.
(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.
What, exactly, does "10x more powerful" mean?
Potency? Presumably it'd then be prescribed in lower doses?
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?...
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.
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.
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.
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.
Non opioid pain killers like ibuprofen are usually 1/200-1/300th of morphine.
Marketing's probably up there.
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 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.
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.
People demonizing these drugs have obviously never known anyone living with severe, chronic pain.
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
ED50 LD50 Theaputic Index
Fentanyl 0.01 3.1 277
Sufentanil 0.007 18 26716
The therapeutic index is the ratio of LD50:ED50.
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?...
https://en.wikipedia.org/wiki/Moscow_hostage_crisis_chemical...
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.
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.
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.
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?
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.
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!
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.
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.
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.
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.