Superfluous

Superfluous

...
Mar 16, 2019
973
I was initially going to post this when I was ready to start the regimen. However, as I have been allowed some time to consider my options, I've decided to post it beforehand to give others an opportunity to review and comment on it, and maybe even help to improve it.

Disclaimer: I am not a medical professional, and I will/may be conducting this trial purely based on my own investigations. I am neither proposing nor recommending this as a reliable regimen.

This 'ahead' regimen differs somewhat from any of the recommended ahead regimens described in any of the literature currently available (Five Last Acts, PPeH March 2019, Wikibooks).

The purpose of this regimen is to achieve higher plasma concentrations of domperidone in the body without introducing risk.

The reason why I have chosen to try a slightly different regimen is that most of the current literature focuses on metoclopramide as the anti-emetic of choice, and domperidone is known to be weaker. I feel, therefore, that it's more important to try and achieve higher plasma concentrations of domperidone to provide the same or similar success levels when it comes to reducing the risk of vomiting. I am, of course, assuming that higher plasma concentrations will reduce the risk of vomiting.

It's broken up into sections to make it easier to read.
I have found what I consider to be a reliable study published on eMC (electronic Medicines Compendium) that provides some detailed information on domperidone plasma concentration levels. You can check the link as to who they are if you like.

The specific study is this:

You don't need to read through the complete article as I will be referencing the appropriate sections as I go, but feel free to do so if you prefer.
The primary purpose of the study was to prove the safety of domperidone as a treatment for various conditions, nausea included, specifically in relation to the risks of QT prolongation. In doing so, it also monitored concentration levels of domperidone in blood plasma, and it's this specific data I am using. It also 'proves' (and I use this term loosely) the lack of risk of QT prolongation with the dosages used in the trials.
There are no specific values relating to plasma concentrations in either the study or my post. Also, I have no comparative data between the effectiveness of metoclopramide over domperidone for the purpose of reducing the risk of vomiting. All references to plasma concentrations of domperidone are relative.
This is always a difficult question to answer. I've read and have copies of Bad Pharma and Bad Medicine, both written by Ben Goldacre MBE, so I have a basic grasp of how to identify good studies from bad. However, I am not an expert.

In my opinion, the first indication that's it's a good study is the level of detail included.

Next, it is recent (or was at least recently updated on 14th June 2019 last time I checked).

In section 4.8 Undesirable effects, it outlines the details of the trials.
The safety of domperidone was evaluated in clinical trials and in postmarketing experience. The clinical trials included 1275 patients with dyspepsia, gastro-oesophageal reflux disorder (GORD), Irritable Bowel Syndrome (IBS), nausea and vomiting or other related conditions in 31 double-blind, placebo-controlled studies. All patients were at least 15 years old and received at least one dose of domperidone. The median total daily dose was 30 mg (range 10 to 80 mg), and median duration of exposure was 28 days (range 1 to 28 days).

On the positive side, the 31 trials were all double-blind and placebo-controlled, which is good. 1275 patients isn't a lot, but it's better than some. It also covers a wide range of conditions.

On the negative side, it was conducted by a pharmaceutical company testing their own product.

As the median duration of the 31 trials was 28 days and the maximum trial length was 28 days, we can deduce that at least 16 of the trials had a duration of 28 days.

No such deduction can be made regarding daily dosages.
My plan is to take 20mg domperidone 4 times daily at 5 hour intervals over 4 days. The reason for this is based on information in section 5.2 Pharmacodynamic Properties, in the Absorption subsection.
Domperidone is rapidly absorbed after oral administration with peak plasma concentrations occurring at approximately 1 hr after dosing. The Cmax and AUC values of domperidone increased proportionally with dose in the 10 mg to 20 mg dose range. A 2- to 3-fold accumulation of domperidone AUC was observed with repeated four times daily (every 5 hr) dosing of domperidone for 4 days.

I plan to eat something small before each dose due to the following information also in the same section (irrelevant part omitted):
The low absolute bioavailability of oral domperidone (approximately 15%) is due to an extensive first-pass metabolism in the gut wall and liver. Although domperidone's bioavailability is enhanced in normal subjects when taken after a meal...The time of peak absorption is slightly delayed and the AUC somewhat increased when the oral drug is taken after a meal.

Enhanced bioavailability and increased AUC are the objective of this regimen.

As I only eat 2 small meals a day, I'll have to time these meals accordingly, and for the other 2 doses I'll eat a small snack (I'm thinking a small Snickers bar).

Additional useful information in the same section under the heading Excretion:
The plasma half life after a single oral dose is 7-9 hours in healthy subjects...

Please feel free to comment. Any and all thoughts or ideas are welcome, and any links to other similar studies would be very useful.

If I receive more data (or can find more myself) that could improve this regimen, then I will incorporate it and create a new post if/when I plan to start.

If I receive data that would invalidate this regimen, then I will obviously not attempt to use it and will request that the thread be deleted.

Otherwise, if/when the time comes, then I will resurrect this thread and provide feedback on progress and success/failure as is appropriate.
 
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bilamajina

bilamajina

Member
Jun 7, 2019
42
@Superfluous, how do you plan to test your hypothesis?
 
Superfluous

Superfluous

...
Mar 16, 2019
973
If I decide to go, then I will follow the above regimen and report if any side effects are noticed over the 4 days. I think this unlikely, but anything is possible as everyone reacts differently.

If I don't experience any side effects by the time I'm ready to take my final dose, then I'll post. My plasma concentration will definitely be higher than that based on ahead regimens as defined in current literature due to the 5 hour interval between doses, increased daily dosage, the 7-9 hour half life and the 4 day regimen.

Then it comes down to the actual taking of the drugs. This will obviously be the most difficult part to report back on. My method will be the amitriptyline cocktail version #2. If I experience any nausea or vomiting early on, then I'll need to abort and try to vomit up as much as possible. In this case, I should be able to report back, although it may take some time as I may be unconscious for a period of time.

If any problems occur later or my attempt is successful, then I don't know. I'm open to ideas though.
 
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phoenitic_riser

Member
Jun 10, 2019
51
If I decide to go, then I will follow the above regimen and report if any side effects are noticed over the 4 days. I think this unlikely, but anything is possible as everyone reacts differently.

If I don't experience any side effects by the time I'm ready to take my final dose, then I'll post. My plasma concentration will definitely be higher than that based on ahead regimens as defined in current literature due to the 5 hour interval between doses, increased daily dosage, the 7-9 hour half life and the 4 day regimen.

Then it comes down to the actual taking of the drugs. This will obviously be the most difficult part to report back on. My method will be the amitriptyline cocktail version #2. If I experience any nausea or vomiting early on, then I'll need to abort and try to vomit up as much as possible. In this case, I should be able to report back, although it may take some time as I may be unconscious for a period of time.

If any problems occur later or my attempt is successful, then I don't know. I'm open to ideas though.

Thank you for detailed and informative post.

I found below article helpful to get some basic understanding of NV

Recommended management of nausea and vomiting

Looks like oral bio-availability of Domperidone is quite low at 13-17% compared to >90% for Metochlopramide. Maybe that is why it is weaker.

The study you referenced says

"Oral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 minutes of 21ng/ml after two weeks oral administration of 30 mg per day was almost the same as that of 18 ng/ml after the first dose "

This seems to suggest ahead regimen does not help much with Domperidone?

Metoclopramide also has 5-HT3 antagonist action which Domperidone does not. I don't know how essential that is to prevent vomit from toxins but have you considered also using Zofran?
 
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Superfluous

Superfluous

...
Mar 16, 2019
973
Thank you for detailed and informative post.

I found below article helpful to get some basic understanding of NV

Recommended management of nausea and vomiting

Looks like oral bio-availability of Domperidone is quite low at 13-17% compared to >90% for Metochlopramide. Maybe that is why it is weaker.

The study you referenced says

"Oral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 minutes of 21ng/ml after two weeks oral administration of 30 mg per day was almost the same as that of 18 ng/ml after the first dose "

This seems to suggest ahead regimen does not help much with Domperidone?

Metoclopramide also has 5-HT3 antagonist action which Domperidone does not. I don't know how essential that is to prevent vomit from toxins but have you considered also using Zofran?
Excellent information in the linked pdf. Thanks.

Late here so bedtime, but will review and respond tomorrow.
 
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SinisterKid

SinisterKid

Visionary
Jun 1, 2019
2,113
What about managing your stomach acidity levels?
 
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B

Bentham

Member
Feb 21, 2019
45
I hope DOM be effective for your choice of the lethal substance. It could be helpful to read the antiemetic drug history. Chapters 1 and 2 of Serotonin and the scientific basis of anti-emetic therapy (caution: a heavy pdf file) is also a good read.


Apomorphine: D2 antagonists (both MCP and DOM)
5-HT3 antagonists not effective

Copper sulfate: MCP (maybe BBB penetrable D2 antagonists)
DOM and 5-HT3 antagonists not effective

Cisplatin: 5-HT3 and NK1 antagonists
DOM slightly effective but not used

Alcohol: NK1 antagonists and some other substances
5-HT3 antagonists not effective
 
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Superfluous

Superfluous

...
Mar 16, 2019
973
Looks like oral bio-availability of Domperidone is quite low at 13-17% compared to >90% for Metochlopramide. Maybe that is why it is weaker.

The study you referenced says

"Oral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 minutes of 21ng/ml after two weeks oral administration of 30 mg per day was almost the same as that of 18 ng/ml after the first dose "

This seems to suggest ahead regimen does not help much with Domperidone?

Metoclopramide also has 5-HT3 antagonist action which Domperidone does not. I don't know how essential that is to prevent vomit from toxins but have you considered also using Zofran?
Just woken up so need more time to digest the pdf info, but thought I would give a quick reply to the other parts.

I agree that the low bioavailability may (and probably does) play a part in it being weaker than metoclopramide, as may other factors such as the fact that metoclopramide crosses the blood brain barrier for example. Unfortunately, as I don't have any quantative data on how effective each drug is as a dopamine antagonist (and the fact that I'm not a pharmacologist), I've avoided making any comparisons between the 2 drugs. I'm simply trying to increase the plasma concentrations of domperidone compared to the current recommended ahead regimens based on an assumption that domperidone itself will be more effective at higher concentrations.

I remember reading the part of the study you quoted

Oral domperidone does not appear to accumulate or induce its own metabolism; a peak plasma level after 90 minutes of 21ng/ml after two weeks oral administration of 30 mg per day was almost the same as that of 18 ng/ml after the first dose

The reason I dismissed it (rightly or wrongly) is because it appears to relate to single 30mg daily dosages. Considering that the half life of domperidone is 7-9 hours and the doses are taken 24 hours apart, it's not surprising that little accumulation is observed.

Regarding Zofran (ondansetron - trade name Onsia here), I was planning on taking either 8mg or 16mg with my last dose as per the Wikibooks guide for antiemetics:


Thanks again for the pdf link and I'll get back to you if I can decipher it :shy:
 
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phoenitic_riser

Member
Jun 10, 2019
51
From below,

Pharmacokinetic interaction between domperidone and ketoconazole leads to QT prolongation in healthy volunteers: a randomized, placebo-controlled, double-blind, crossover study.

"Ketoconazole tripled the plasma concentrations of domperidone ". It elongates the Qt interval which is not good I think but still may be better than risking EPS from MCP...

Also, Piperine supposedly can help improve bio-availability of Domperidone...

 
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Superfluous

Superfluous

...
Mar 16, 2019
973
What about managing your stomach acidity levels?
All the test subjects had preexisting conditions that required them to take the domperidone before meals. As I don't have any of those conditions (to the best of my knowledge), I'll be taking my doses after meals, which should provide a more acidic environment.
I hope DOM be effective for your choice of the lethal substance. It could be helpful to read the antiemetic drug history. Chapters 1 and 2 of Serotonin and the scientific basis of anti-emetic therapy (caution: a heavy pdf file) is also a good read.


Apomorphine: D2 antagonists (both MCP and DOM)
5-HT3 antagonists not effective

Copper sulfate: MCP (maybe BBB penetrable D2 antagonists)
DOM and 5-HT3 antagonists not effective

Cisplatin: 5-HT3 and NK1 antagonists
DOM slightly effective but not used

Alcohol: NK1 antagonists and some other substances
5-HT3 antagonists not effective

From below,

Pharmacokinetic interaction between domperidone and ketoconazole leads to QT prolongation in healthy volunteers: a randomized, placebo-controlled, double-blind, crossover study.

"Ketoconazole tripled the plasma concentrations of domperidone ". It elongates the Qt interval which is not good I think but still may be better than risking EPS from MCP...

Also, Piperine supposedly can help improve bio-availability of Domperidone...


Wow. Thanks for all those links. I'll need time to digest all this information (if I'm able). What have I let myself in for? I could really do with a pharmacologist right now.

:love:
 
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Superfluous

Superfluous

...
Mar 16, 2019
973
Just a quick update based on the the links so far provided.

From the first link from @phoenitic_riser regarding the Recommended management of nausea and vomiting, i thought the following image may be useful:

12442

Due to a recent update, images may not display correctly on your device, so click/touch to view if this is the case.

In the case of drugs, chemicals and toxins (which is what concerns us here), it''s the red bit we're interested in, specifically dopamine D2 and 5HT3 antagonists.

Next, from the Anti-emetic drug history link provided by @Bentham, I found the following table:

12443

From the limited editing tools I have at my disposal, I've managed to highlight the 2 recommended drugs: metoclopramide and domperidone. What's interesting here is the dopamine D2 antagonist values for both. Domperidone has slightly higher values than metoclopramide, albeit that the metoclopramide values are for mice and domperidone for humans. I believe this strongly suggests that the reason domperidone is weaker is, as previously suggested, down to the low bioavailability of domperidone compared to metoclopramide.

I did follow the source for this table, but couldn't find this exact one on the source site. I did find the following table on D2 receptors (the link jumps to the list of antagonists):


I haven't attempted to read the heavier article yet though.
 
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phoenitic_riser

Member
Jun 10, 2019
51
Just a quick update based on the the links so far provided.

From the first link from @phoenitic_riser regarding the Recommended management of nausea and vomiting, i thought the following image may be useful:

View attachment 12442

Due to a recent update, images may not display correctly on your device, so click/touch to view if this is the case.

In the case of drugs, chemicals and toxins (which is what concerns us here), it''s the red bit we're interested in, specifically dopamine D2 and 5HT3 antagonists.

Next, from the Anti-emetic drug history link provided by @Bentham, I found the following table:

View attachment 12443

From the limited editing tools I have at my disposal, I've managed to highlight the 2 recommended drugs: metoclopramide and domperidone. What's interesting here is the dopamine D2 antagonist values for both. Domperidone has slightly higher values than metoclopramide, albeit that the metoclopramide values are for mice and domperidone for humans. I believe this strongly suggests that the reason domperidone is weaker is, as previously suggested, down to the low bioavailability of domperidone compared to metoclopramide.

I did follow the source for this table, but couldn't find this exact one on the source site. I did find the following table on D2 receptors (the link jumps to the list of antagonists):


I haven't attempted to read the heavier article yet though.

Looks like any CYP3A4 inhibitor will help increase bio-availability of Domperidone


Grapefruit juice looks like an easy option.

Please keep us posted. You are a pioneer in this area ;)
 
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Mbound

Experienced
Apr 29, 2019
255
I am planning on doing the same due to fear of EPS from meto so I really appreciate this thread

I also appreciate anyone trying to break down the science for us-- I feel like Jesse Pinkman and I really need a Walter White but for ctb not meth lmao
 
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Superfluous

Superfluous

...
Mar 16, 2019
973
Looks like any CYP3A4 inhibitor will help increase bio-availability of Domperidone


Grapefruit juice looks like an easy option.

Please keep us posted. You are a pioneer in this area ;)
Thanks for all the ideas. I'm not going to add ketoconazole into the mix due to the increased risks involved, although I do like black pepper so will add that to meals where possible (although not with the chocolate bars). I read something about avoiding grapefruit juice somewhere, but can't remember where or with which substance. I also hate the taste.

I'm also starting to question the usefulness of posting all this information for a couple of reasons.

Whilst I do find it strange that all the current literature specifies the same dosages for both metoclopramide and domperidone when it's known that domperidone is weaker, the reason for this may simply be it's lack of affinity to the 5HT3 receptor and not related in any way to its much lower bioavailability. In addition, I won't be able to prove the effectiveness or otherwise of following this regimen. All I can do is confirm what's already been stated in the trials I initially linked to in that it's safe to take at these dosages over this time frame, assuming I have no negative side effects.

Having reread the history of anti-emetics linked to by @Bentham, it's clear that even the medical profession don't fully understand all the mechanisms behind vomiting and nausea to this day as it incorporates multiple body organs. I did download and open the heavy pdf, but quickly closed it again as I knew I was well out of my depth.

It's looking more likely that I will go through with my second attempt and if so I will follow this regimen as, if it is safe, then I see no disadvantage to (potentially?) having higher concentrations of domperidone in my system - at least not at this time based on the data I currently have. What I can't do is prove if it's more advantageous.
 
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Soul

Soul

gate gate paragate parasamgate bodhi svaha
Apr 12, 2019
4,704
Maybe the "avoid grapefruit juice" advice was related to SN, since vitamin C is contraindicated for that method (it's sometimes given as an antidote).

This impressive and valuable document billowed beyond my poor powers of biochemical comprehension almost from the get-go, but if I could make a tiny suggestion: I think it would be helpful to put your intended exit method into the title. A lot of this can probably (?) be applied to other methods, but not to all of them. I think. Maybe?

Carry on. Oh and if any of you pharmaceutical/biochemical/medical types could have a look at my questions here I'd be very grateful: https://sanctioned-suicide.net/threads/salicylate-poisoning.17653/
 
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Superfluous

Superfluous

...
Mar 16, 2019
973
Looks like I may not have the time to do the full 4 days I was planning. Unless things change, I'm currently working to a date of Saturday 29th. I'll probably start the ahead regimen later today, but as timing is key I'll miss the first 2 doses. This allows for a 3 day regimen.

I've set my alarms for taking the domperidone at the following times during the day:
  • 09:00
  • 14:00
  • 19:00
  • 00:00
Meals and snacks will precede each dose by 30mins. I'll report any side effects should they arise.

If I have the time, I'll try and compose a new thread summarising all the above information. Can't promise anything though as time is limited.

One more note. As domperidone only has affinity to the dopamine receptors and not the 5HT3 receptor as metoclopramide has, I'll be taking a single 16mg dose of ondansetron with the final dose. This is a 5HT3 antagonist and does not require an ahead regimen.
 
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ProhibereDolor

ProhibereDolor

Cloak and Dagger
May 21, 2019
88
Ondansetron was actually what I was going to suggest. While BA of a drug is certainly important, it's really the half-life that you have to worry about. You would also have to see if BA goes down with how saturated your systems are. Gabapentin has this issue because it has saturable non-linear absorption kinetics i.e. not dose proportional. If you had the time you could go to a doctor and tell them about the badass fishing trip you're going on but you have horrible motion sickness and don't want to be seasick the whole time so you wanted to know if there is something you can take for it. Meclizine is an option. Hell, just add dramamine to the mix. But first find out if there's any interactions. I am not a pharmacist and don't work on pharmaceuticals. I do not know entirely what interactions there are as well as the plethora of meds there are out there with more added every day. I'm just trying to remember stuff I had to go through during school and training. I try to give people the best advice I can. Sorry if this wasn't much help. And if I don't talk to you before you go to the bus stop then I hope your journey is peaceful and you find the rest you deserve. I will try to be back before you go. Good luck and best wishes my friend.
 
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Superfluous

Superfluous

...
Mar 16, 2019
973
@ProhibereDolor Thanks for taking the time to reply.

I've decided to have this last 'normal' day. I'll start my regimen tomorrow morning, which will effectively make it a 48 hour regimen, but with an additional dose every day. 20mg doses.

I'll try to post something tomorrow with regards to my method. Thanks again to everyone who has contributed. I've learnt a lot.
 
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phoenitic_riser

Member
Jun 10, 2019
51
@Superfluous Good luck and thank you for sharing
 
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Theon

Theon

Experienced
Jun 20, 2019
241
@ProhibereDolor Thanks for taking the time to reply.

I've decided to have this last 'normal' day. I'll start my regimen tomorrow morning, which will effectively make it a 48 hour regimen, but with an additional dose every day. 20mg doses.

I'll try to post something tomorrow with regards to my method. Thanks again to everyone who has contributed. I've learnt a lot.
Thank you for all the info. Can't take meto so this seems to be my option.
 
Theon

Theon

Experienced
Jun 20, 2019
241
@ProhibereDolor Thanks for taking the time to reply.

I've decided to have this last 'normal' day. I'll start my regimen tomorrow morning, which will effectively make it a 48 hour regimen, but with an additional dose every day. 20mg doses.

I'll try to post something tomorrow with regards to my method. Thanks again to everyone who has contributed. I've learnt a lot.
Did you begin the regimen?
 
Superfluous

Superfluous

...
Mar 16, 2019
973
I completed almost 3 days (11 doses) of the regimen last week. The reason for terminating was mostly due to a delay in my planning.

I did experience a minor side effect, namely 'nervousness'. I didn't attribute this immediately to the regimen as I felt it was normal to be nervous leading up to such an event. However, on reflection, I believe it was. It was mildly unpleasant but nothing more. The nervousness didn't manifest itself externally (voice, muscles) but was more of a feeling inside my chest, accompanied by a sensation of coldness. Very difficult to put into words. This feeling disappeared within 2 days of ending the regimen.

No other side effects were apparent, although I was unable to monitor QT intervals.

I'm planning to take my cocktail tomorrow morning, and will be taking a stat dose of 40mg together with 16mg ondansetron 45 mins prior, although I decided to take 2 doses of 20mg at 8 hour interval the day before (today @ 4pm and midnight). I'm already feeling nervous and a little extra shouldn't do any harm and may help reduce the risk of vomiting.

I'll be around briefly later tonight to check if there are further questions.
 
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H2H2

Specialist
May 31, 2019
320
I completed almost 3 days (11 doses) of the regimen last week. The reason for terminating was mostly due to a delay in my planning.

I did experience a minor side effect, namely 'nervousness'. I didn't attribute this immediately to the regimen as I felt it was normal to be nervous leading up to such an event. However, on reflection, I believe it was. It was mildly unpleasant but nothing more. The nervousness didn't manifest itself externally (voice, muscles) but was more of a feeling inside my chest, accompanied by a sensation of coldness. Very difficult to put into words. This feeling disappeared within 2 days of ending the regimen.

No other side effects were apparent, although I was unable to monitor QT intervals.

I'm planning to take my cocktail tomorrow morning, and will be taking a stat dose of 40mg together with 16mg ondansetron 45 mins prior, although I decided to take 2 doses of 20mg at 8 hour interval the day before (today @ 4pm and midnight). I'm already feeling nervous and a little extra shouldn't do any harm and may help reduce the risk of vomiting.

I'll be around briefly later tonight to check if there are further questions.
Thanks for sharing , Superfluous. I wish you the best.
 
Superfluous

Superfluous

...
Mar 16, 2019
973
I had to delay again. Should be today. Just wanted to update.

I've now taken 4 doses of 20mg at 8 hour intervals and haven't noticed the same side effects as before. Maybe I was pushing it too much with the 4 daily doses at 5 hour intervals. On reflection, for the ahead regimen I'd recommend the suggested 3 daily doses for 48 hours. As everyone reacts differently, I'd also follow the advice given and do a small test at a low dosage beforehand just to make sure you don't have any bad reactions.
 
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phoenitic_riser

Member
Jun 10, 2019
51
I had to delay again. Should be today. Just wanted to update.

I've now taken 4 doses of 20mg at 8 hour intervals and haven't noticed the same side effects as before. Maybe I was pushing it too much with the 4 daily doses at 5 hour intervals. On reflection, for the ahead regimen I'd recommend the suggested 3 daily doses for 48 hours. As everyone reacts differently, I'd also follow the advice given and do a small test at a low dosage beforehand just to make sure you don't have any bad reactions.
Thank you again for your valuable input. Good luck.
 
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