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.
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.
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