Loperamide Safety

[clubcard]

I am becoming increasingly concerned about the use of large doses of loperamide. Just because it's an OTC drug does not make it inherently safe. It has been attributed as the sole cause of fatal poisonigs in the last few years and the amounts involved are the same as doses mentioned on BL. US Patent 3714159 '2,2-diaryl-4-(4'-aryl-4'-hydroxy-piper-idino)-butyramides' details a lot of related compounds and the 25th compound in table 1 is the title drug:

Ar1 Ar2 -N=Z Ar3 A B C

Ph Ph -N(CH3)2 4-C-Ph 0.13 80 615

A LOT of effort went into ensuring that loperamide would not be subject to abuse. A is the ED50 as an Anti-Diarrheal, B is ths ED50 as an analgesic & C is B?C.


https://academic.oup.com/jat/article/40/8/677/2445880
http://www.thepoisonreview.com/2016/04/29/cardiac-effects-of-loperamide-overdose/
https://www.japha.org/article/S1544-3191(16)31028-7/pdf


I have avoided the sensationalist news reports and just listed a few of the reports in academic journals.


http://dmd.aspetjournals.org/content/32/9/943


The above is another consideration. Their logic seems reasonable and like so many of the medicines of the past, the true risks are slow to be identified.

On a personal note, reports suggest that the dose-response curve is biphasic. Loperamide is actively removed from the brain:


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879961/


Until the ATP is overwhelmed. At this point the dose-response curve suddenly gets steeper. Someone who might have taken 250mg for months without acute toxicity showing up could end up in hospital or worse if they increase to 300mg for example. This dose regime was never envisioned so not a lot of research has taken place so far. The predecessor of loperamide, diphenoxylate was similarly (ab)used until atropine was added to prevent people from taking high doses. From the original patent we can clearly see that the absence of the chloro grouping (example 29 in list 1) is an order of magnitude more potent as an analgesic but also more than a magnitude more potent as an anti-Diarrheal.

I cannot think of a kitchen sink protocol for removing that chlorine (and anyway I couldn't post it) so it looks like the decision to go with the 25th analogue was with abuse resistance in mind. If people look at the patents that cite the title patent they will repeatedly see the term 'peripheral opioid' so I believe Janssen thought very carefully about the drug.

I think it is important for people to consider possible alternatives. Racecadotril (France brand-name Tiorfan, Italian brand-name Tiorfix, Indian trade-name Redotril) is available on the internet without prescription and as far as I know it is legal everywhere. It's mode of action is somewhat different and it MAY prove to be a superior agent in it's utility as well as it's safety.

In short, loperamide is simply substituting one opioid for another; a potentially more dangerous one. I can see manifold reasons WHY it is used but at the end of the day, the (ab)user is still dependent on opioids. Racecadotril is a enkephalinase inhibitor so it prevents the bodies natural opioids being broken down. The outcome is the same - you don't get opiate abstinence syndrome but it does at least mean that the bodies own opioids that don't seem to mess with the b-arrestins so may prove a good way to reduce dependence.

Now I haven't checked US law or prices but I hope it at least gives some people an idea for a possible alternative. I believe viminol has helped some people but that isn't something I would choose to import into the EU let alone the US.

 

[Pomzazed]

I like your way of thinking. It is very concerned about user safety.

Just one thing, Racecadotril is nearky instantly cleaved to thiorphan
And the resulting thiol is way to hyprophilic to cross the BBB.

There are analogs of it which is slower to get cleaved and may exhibit mu and delta opioids centrally, the RB-101
There are much more similar analogs to this but it is non commercially available.
synth of them can be easily done in proper lab not home kitchen, but it cannot be discussed here.

But a little warning that these similar structure may have cardiac effect. Eg. Candoxatril.
So no random modification and test blindlessly even if you can make them.

 

[clubcard]

There are analogs of it which is slower to get cleaved and may exhibit mu and delta opioids centrally, the RB-101
There are much more similar analogs to this but it is non commercially available.
synth of them can be easily done in proper lab not home kitchen, but it cannot be discussed here.

But a little warning that these similar structure may have cardiac effect. Eg. Candoxatril.
So no random modification and test blindlessly even if you can make them.

Central or peripheral - the enkephalinase inhibitors still increase the levels throughout the body as the natural opioids can cross the BBB (or so is my understanding).

Synthesis of them is not practical and if someone isn't held by high doses of those, loperamide dosing would be verging on the suicidal (and I am given to believe that an antidepressant is also an opioid - another option.

Removing the -Cl isn't too complex but of course, no details. If you live somewhere that even SMALL doses of codeine can be obtained (I believe even in the US paracetamol + 5mg of codeine is available) so swapping the 6-OH for a 6-Cl is quite simple (but again no details).

I'm just trying to find alternatives to loperamide. It IS killing people and it it looks like it may end up being removed from the market [P] so people should be thinking ahead of time.


In my heart of hearts, I know agents with an ED50 around that of etorphine with an LD50 around that of codeine. The fact fentanyl is everywhere is due to certain suppliers ensuring novel analogues keep appearing that fall just outside the MoDA. After all, fentanyl is class A so LIFE whereas the 3-F derivative falls outside the MoDA so PDA with a maximum of 5 years. The SAFE compounds are neither hard to make nor hard to dose. When I read of $2 fentanyl caps I realized we had entered a 'crack' style of market. The low cost is keeping people dosing dozens of times a day - each time potentially being fatal.

I cannot condone people breaking the law but it is fairly common knowledge that 14-methoxy nor-N-(S)-β-OH 2-furanylethyl levorphanol has a T1/2 of 7 hours and from UNODC documents from 1959 (look on their pages, they give a QSAR of about 50 analogues), 180 x 240 = 2400 BUT the LD50 is 1/8th that of morphine giving a TI of 144,000. The LD50 of the N-methyl is no different from the (S)-β-OH-2-furanylethyl so the TI is 19200. Signs of toxicity are not depression of respiration but seizures but it means that even an eyeballed dose won't hurt.

I've covered the synth in other places and what makes me so angry is that it's structure is significantly different so it remains to be seen if the CsA laws even count and I should imagine that in a setting where nobody is dying or committing violent or acquisitive crime to prevent withdrawal is a win for society as a whole and gives people the breathing space to get their lives back together. I DO know that it feels like. After my last hip ops I was on 175ug/h fentanyl patches with 40mg oxycodones for breakthrough pain and the day after surgery a noctor (nurse practitioner) told me after 18 months that I could just stop taking the analgesics. OK I demanded the registrar who told me to reduce slowly but even when you are making the running, a LOT of stress is heading your way and I don't want to see others in that position.

Those Russians making desomorphine (well, desoxymorphine C/D in fact) were suddenly cut off and I cannot imagine the hell from that. I'm also VERY keen to get
(3S)-6-{3,4-dihydro-2H-spiro[naphthalene-1,4'-piperidine]-1'-yl}-4,4-diphenylhexan-3-yl acetate approved for substitution therapy. It IS expensive but then it is x212 methadone in potency (so actually same price per dose) because it doesn't suffer the long-QT problems with ORLAAM but it's T1/2 is 20.5 hours so 3 oral doses per week replaces daily methadone pick-up (with all of that inconvenience), the onset and duration means it has no 'fun' value to the extent that the Methadone-bus type of access (as seen in Amsterdam) means that someone just has to turn up every 3rd day to get a dose and it's potent enough to blockade even fentanyl.

I'm not saying it's the whole of the answer but people being able to get normal jobs, not to be using pins and having their health checked every month has to be a win for everyone. I've lost far, far too many friends to opioids or the alcohol they replace the opioids with. I'm in the UK and it isn't THAT hard to get onto methadone and now they even accept that in the first 14 days (while they are getting the dose right), they don't throw you out for pissing dirty.

A less well known alternative is 8-[(1S)-1-(furan-2-yl)ethyl]-1-(2-methylphenyl)-1,3,8-triazaspiro[4.5]decan-4-one which is some x414 methadone with a T1/2 of 17 hours so every 48 hours and I defy anyone to say that it's covered by the CsA. Simple question - what is it the analogue OF? Nothing. It's totally novel. It was discovered by Jenssen when he was developing fluspiriline and it's similarly safe and gives people a chance to get their life back......


I'm sorry, it's just makes me angry to know we can do MUCH better but somebody somewhere obviously thinks that a certain number of people dependent on opioids is a GOOD thing. Like it's a punishment. Nothing like the punishment to family, friends and society as a whole but evidently it's worth harming a lot of people because 1 person made 1 mistake. If only we could get Trump hooked on opioids..... I mean a 240mg oxyM per day type of thing...............

 

[Limpet_Chicken]

As far as being suddenly cut off, the russians I mean, yeah, it must have been hell on earth, especially since, is it not the case there, is opioid replacement therapy not illegal? the desomorphine addicts must have suffered greatly first, but they had not long to live to begin with, once they began to inject the desomorphine derivative-based garbage pile of slops and filth (well, phosphorus isn't filth, nor iodine, SOCl2, I find them every one, to be most useful indeed, but if they are to be mixed in with a shot, then they count as filthy enough). If I remember reading rightly, the lifespan of the average user of krokodil is between 4-6 months and one year at most after they begin to inject that abominable slop of phosphorus, iodine, SOCl2, phosphorus halides and nonpolar solvents, plus god only knows what acidic or basic swamp-slime.

What an awful thought, and an awful way to go, refused even the most basic compassion and medical help that might save, if not their rotted limbs, then their lives, and at the very least, palliative care, going through the horrors of uncontrolled withdrawal before finally dying in the most abysmal manner imaginable.

And I agree with you, not only is the medical system broken, and has been made so by the filthy politician scum sticking their dirty little ignorant piece of shit fingers in the pie, but that someone, somewhere, obviously WANTS opiate addicts, wants a threat to society to present to the sheeple and keep them compliant, fearful and stupid, people like that, wherever they are, I can only hope that wherever they may be, and whoever is guilty of it, shall be rooted out and themselves and their vile power base dug up, exposed to the light and left to wither and die, for such foulness cannot in the thrive in the sight of those who are not themselves evil filth.

That, and work, where possible, to create such long acting, potent opioids with a high TI, and to at least try to help get the knowledge out to other hobbyist chemists of a like mind, so that others too, may further such interests for the benefit of humanity.

 

[Coolwhip]

What an awful thought, and an awful way to go, refused even the most basic compassion and medical help that might save, if not their rotted limbs, then their lives, and at the very least, palliative care, going through the horrors of uncontrolled withdrawal before finally dying in the most abysmal manner imaginable

QFT. Just reading that made me shudder.

And you must be an eternal optimist Clubcard, to actually believe any of your proposals have even the smallest chance of coming to fruition. And I mean that as a compliment, it is inspiring. I've become quite the cynic myself. The fact that neither the masses nor those in charge will admit the OBVIOUS logic of your argument and deny the benefits to society that would result from prescribing to the point of view found within your posts makes it impossible for me to hold any optimism regarding the human race. I used to think people were too stupid to see the truth, now I just think we are too evil.

 

[clubcard]

A few years ago some H users I know came across a gram of AH-7921. Their opinion was enlightening. They found it odd. It certainly stopped their abstinence syndrome and kept it at bay for many long hours but they found that larger doses did no more. In fact, all it did was blunt the effect of H! Now to me that sounds like a useful agent. I've tried swallowing and snorting the stuff (this was in about 2004) and I found the same. No buzz, no high... I just had to eat lots of fruit if you know what I mean. Now 3 people isn't statistically useful but I did see it briefly turn up as an RC but for the life of me I cannot fathom who would take it from choice.

For a few months we toyed with various different HR options. It's a VERY cheap compound. I mean it's 2 quantitative-yield steps from (cheap) commercially available materials so the cost of the stuff makes methadone look pricey. Now I cannot compare oral to nasal to IM to IV but they just said it stopped them feeling sick. I understand why methadone (mostly) comes as linctus and suboxone as films. Anything to stop it feeding the needle. But in retrospect, how much harm does a pure material in a sterile format cause?

Our minds went to where F dealers in some areas of the US are. Since almost all opioid users in the UK are known to a HR group (it isn't like the mark of Cain over here), we considered ID cards and like the HR kits available from vending machines in some forward-thinking countries like Spain, we considered 30mg capsules sold for ?1. That price would cover all the costs. The thing is, to buy you need to insert your card and that has a time-out of 60 minutes. Why so complex? Well, getting ?1 isn't going to takes someone long and compared to hanging around for dealers, just walking upto a machine and buying makes life simple.

The lockout also means people are more hard put to buy to sell on and the effects of the stuff being as disappointing as they are, who else but other people dependent on opioids would want it? We quite regularly hear of people buying someones friday pickup (3 days), washing it down with beer and dying. Well, while that would still be possible, given the subjective effects, would there be a market?

I'm not saying that this is the answer but starving dealers and ensuring sterile substitution material would let people get clean in their own good time. 30mg stopped these guys rattling and no more. I don't know the duration and obviously if it's designed to IV then you cannot add an SR formulation but does anyone else know? I was seriously underwhelmed by the stuff. On the other hand, after trying U-47700 I saw the writing on the wall. The stuff was too nice, too potent and too popular. It goes to prove that it doesn't take super-potent fentanyl analogues to cause a spate of deaths.

I suppose that an oral formulation would be possible. No clever binders - just make the thing the size of an APAP tablet (or bigger). The US went down complex highways and byways to stop oxycodone abuse... when we ran into problems with temazepam, the pills just got HUGE. Duration is another issue but in fact, Mark P. Wentland et all have made a silent revolution. Phenolic opioids can have the phenol swapped for a carboxamide and just as an example, while the T1/2 of pentazocine in mice was 90 minutes, with the -OH --> C(O)NH2 analogue had a T1/2 of 8.5 hours. That means that phenanthracene (think morphine or hydromorphone for example) opioids become orally much more active (almost as active as IV) but their durations become HUGE. While methadone is a 1-size-fits-few model, oral morphine that can be taken once a day?

But I digress. Loperamide is bad news on so many levels. It really is worth taking the time to read about what materials are OTC in your neck of the woods. I have often been surprised to discover odd little items forgotten by everyone (including the government). While opioids aren't my thing, I was truly amazed to discover that cyclizine is still technically a [P]. My local pharmacist is a friend so I wouldn't attempt to get anything untowards out of him but if an oral dose streaches opioids.... that's one more brick.... one more tiny tool to make things easier.

 

[Limpet_Chicken]

Coolwhip-stupid vs evil? whoever said they were mutually exclusive. Granted the smart stupid ones are the more dangerous type than the generic cretin, at least, when it gets beyond the scale of a crowbar and a dark alley for some little old lady's purse. But still, stupid and fucking bag of steaming shit, are not mutually exclusive.

Although not necessarily a pair either, Putin is anything but a moron, IMO, but still a psychotic murderous bastard who crawled out of the devil's own arse ring, he just planted the resultant nuggets of shit on the first poor git to disagree with him and swapped places. All his assassinations aside, do you really think somebody that can allow opioid treatment to be illegal in a region where the poverty-stricken most desperate are driven to cook up slop I wouldn't dump in a chromic acid bath and inject the stuff, resulting in a shambling horror that would give H.P.Lovecraft nightmares and make most other folk reach for a shotgun and shout 'you've got to hit them in the head if you want them to fucking stay dead!' to their nearest friends; could be anything other than a honking great heap of stagnant ordure?

When it gets to the point that its kinder to take a human to the vet and put them down, or even kinder just to shoot them in the face, somebody is to blame, and whoever it is, is in my book, someone that deserves to get what they have given.


Interesting about the carboxamide, is that a 1,6-disubstitution, akin to the well known, loved, loathed and currently having me royally fucked up diesters? And is this a generalization, as with say, sticking an N-cyclopropylmethyl on the phenanthrene opioid agonists makes for at best a partial agonist and at worst something downright unpleasant?

Interested particular in dihydrocodeine from this point of view, if its a single carboxamide substitution your talking of, since the 6-OMe can be persuaded to leave, rather than with codeine, have to be ripped off with about as much enthusiasm for leaving as most men have for their dangly bits to meet the same fate.

The temazepam problem here, came about really when they were available as 'jelly eggs', which were filled with more or less what they sound like, and caused massive vascular damage when injected.

As for loperamide, the long QT, possible noxious dopaminergic neurotoxin metabolite, I should think that never mind repeatedly using such high doses, once, you'd not shit until you learned how to defaecate via your ears. Hmm...makes me wonder if loperamide was/is a govt. experiment part way through, only this time they decided for once, not to abuse their own citizens, MK-ULTRA style, and they just haven't got to the point where it doesn't stick mid-way through the ear canal. Although they seem to have mastered oral waste-disposal of solids.

In the UK at least we have codeine products of if not great, not utterly insipid potency. The 600mg/200ml linctus is near extinct, aside from online sales, and anywhere but with a damn naive new pharmacist to be exploited, won't sell you more than one bottle or box of much of anything. Shit, in the UK, at least in this city, they claim its the law they can't sell more than 1x50ml bottle of clean, if not anhydrous, and at least, odor- and EtOAc-free acetone at a time, never mind the fact they have it in 200ml bottles with a funky smell, some bitrex, colorants and brand-variant, whatever other garbage the manufacturer feels ought to go in nail polish remover. I don't want to pay for water, bitrex and fucking perfume. And when challenged, they change their story, repeatedly, on the spot. I've had (from the same shithead at the same time) 'you might drink it', followed by 'a child might drink it' (then when told (I am obviously at least a middle aged fart) that there aren't any kids either in the house, or being expected) then 'oh, but its flammable', and when pointed out so is the mixture of ethyl acetate and acetone and assorted shite (yes, I was beginning to have my temper fray a little, I don't have much of a tolerance for abject and insistent stupidity), which comes in 200-250ml bottles, 'but this bottle is glass, you could break it and cut yourself', followed by finally, 'its flammable' and then 'but its a SOLVENT! BAAAWWWWW'. At that, I ended up probably being barred from the place forever more, after first pointing out I'm an organic chemist with 5 fucking liter cans of THF, white phosphorus, ether that needs peroxide testing like the THF if you don't want to end up in little pieces, ICl, and in the end, despite that, relatively politely, albeit obviously getting more pissed by the second, it ended up with 'drink bleach and die of cancer, have a nice fucking day'. Forget what I left them with, but it wasn't very nice.

'because I might DRINK it? and because a child, who they are informed, both does not exist and that none ever visit the house might do so...I think 9 months at a theoretical (ish) maximum/minimum length of time, is more than long enough for your average chemist to use more than 50ml of bloody acetone. Had it been some psychoactive, I probably would have cut them slack, and gone off with one. But that, that just pushed things too far. My patience for deliberate cretinism, had been left somewhere back in the pleistocene. And if I'd have had my way, so would the idiot in question, with a boot print in their groin.

Still liquid codeine cough mixtures around though, along with a 20mg morphine/100ml bottle one, and gee's linctus, based on tincture of opium, and actually respectable in strength.

Cyclizine isn't rx only here, although its pharmacy sale only. Although whether or not I'd get it is probably down to luck. In the pharmacy that gave me ten tons of lies and dogshit over a snivelling trifling little quantity of acetone, even pre-roasting, I doubt it. The place I pick up my scripts from has it on the shelf on display for sale, although I go there regularly, and they might ask why I need more cyclizine when if they are short some in stock, I'll just tell them not to bother, just give me what you've got and forget the rest, although they'd probably serve me anyway. More local place has it listed as an 'ask the pharmacist' on a big red card along with various other technically non-prescription meds that nobody will ever actually be sold. Varies, some pharmacists can be alright, some, and it seems too many, way too many, are not just uppity shitspeaking liars, but perhaps worse, obnoxiously snooty about it, as if they were looking at something they wouldn't suffer a beggar to lick off their shoe for a penny. Some are worse, just poster children for the biopreparat. In the sense of 'this is an advertisement in favour thereof, lets get out the Y.pestis'

My neck of the woods..it might be, but why, then, do I so often feel the urge to throttle it from behind in a back alley as it walks home?

I bet the pharmacist who denied calm, polite logic, repeatedly changing his story, and always obviously to another transparent lie, could have toured my home, and looked in my non-foodstuffs fridge, been told just what the reason for the teflon-sealed bottles in there was, and had an empty 10-liter acetone jug waved in his face, and still refused to sell 100ml to one person at once.

I don't know if its just because I have long hair, a piercing and more often than not, wear a leather trench or bomber jacket, spiked collar, chains and spiked bracers..or if its just people being cunts. But I've tried many times going in wearing nothing more out of the ordinary than lazy ass black tracksuit kecks and a generic t-shirt (although I draw the line at doing anything to my hair for some uppity NT swine of that ilk, and the piercing doesn't come out, I'd probably need a pair of bolt cutters if I wanted it out), and still..I've had other pharmacists here refuse to sell a bottle of lavender oil and a pack of valerian tablets. Refused even to sell the lavender oil alone. Why? 'because I felt like it'.

It really is a wonder that there are no charred corpses behind any local pharmacy counters, busy causing the brickwork to burst into flames on contact.

 

[novaveritas]

cayman

 

[Limpet_Chicken]

No, I neither brought with me, nor went quite so far to bite the bastard as a small-to-medium sized crocodile would have. Although you might just have given me certain considerations to make about returning to a particular pharmacy, the pharmacist there being distinctly unpopular with me (and doubtless he doesn't much like me either. certainly seemed the have an aversion to logic)

No, I know what you mean. And I have my sources for the chemical items I need, acetone certainly is not so large a problem as even to turn up on my radar. Only reason I'd ever go OTC for it, is if I have something like a dual-solvent recrystallization to perform, something insoluble in acetone and a lack of willingness to wait the time between ordering and receiving when I can pick enough up from a couple of pharmacies and get it done same day, after drying time is taken into account.

Might check them out some time, I haven't as of now, more or less to see if they are willing to do business. I do need some carbon disulfide after all, for something I had/have in mind involving diphosphorus tetraiodide (and yes I did mean P2I4, not the PI3 evolved as a transient in RP/I2 type meth cooks, just need the solvent for it that ought to give high yields based on the main reactant)

 

[GQ_chill]

I have a sneaking suspicion that the decision to go with the 25th analogue was not driven by anti-abuse potential, but by the desire to introduce a new, unique, less risk-adverse single active pharmaceutical ingredient (API) opioid for diarrheal suppression.
As you correctly pointed out (thank you for doing so) Diphenoxylate is the precursor to Loperamide, & was 1st synthesized in 1956. Further research and experimentation into the medicinal efficacy of opiods, Loperamide was 1st tested against placebo in late 1972, with the 1st clinical published in 1973.
In 1973 the Drug Enforcement Agency was established. As a result of this single unified command, not only were federal drug laws actively enforced but the governments drug control activities were consolidated and coordinated as well.
As a result, Janssen started actively promoting Loperamide in lieu of Diphenoxylate to treat diarrhea. A closer look at the incredibly quick FDA approval process for Loperamide and its subsequently fast reclassification from a Schedule II narcotic in 1970, to a Schedule V controlled substance in 1977, to its ultimate decontrolled status in 1982.