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Misc Codeine and CYP2D6

kleinerkiffer

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This post is intended to help you understand the connection between the CYP2D6 polymorphism and codeine metabolism.

Codeine is considered a Prodrug, meaning that codeine itself isn't active (it is active to some really small extend but not enough to produce the analgesic effects you want) but the metabolite(s) is/are. The two major active metabolites of codeine are Morphine (via Phase-I metabolism by CYP2D6) and Codeine-6 -glucuronide (via Phase-II metabolism by UGT2B7). Now the research into which one has the major effect isn't clear, as there are papers claiming that C6G is the more important metabolite seen as around 80% of codeine is metabolized into C6G and only around 5-10% is metabolized into morphine (given that you are an extensive metabolizer). But there are good points to the other side as well, so the mystery isn't fully solved afaik.


Now to get into the CYP2D6 polymorphism:
As I said, the CYP450 family (this family includes a bunch of enzymes responsible for Phase-I metabolism) isozyme CYP2D6 is responsible for metabolizing codeine into morphine and given that morphine is way more potent you want as much codeine metabolized into morphine as possible.
You might remember the term allele. If not a quick recap on genetics. You have 46 chromosomes, 23 each from your father and mother respectively. Of those 46 44 chromosomes are called autosomes and the other 2 are called allosome. The two allosomes are responsible for your sex and the remaining 44 are homologue meaning the copy from your father and mother of say chromosome 1 are pretty much identical (they aren't identical to the base-pairs, but they each have the same genes on the same spot) so you have 2 so called alleles for each gene. Now this is important for the polymorphism. Your phenotype is determined by the genotype (the genes you have) and CYP2D6 has a lot of different genotypes.
I'll try to explain it with this graphic:

https://imgur.com/a/a6C6tTB


Here you can see the 4 important genotypes of CYP2D6.

1. Let's start with the poor metabolizer:
In this case you inherited an inactive/faulty allele each from your mother and father. This can happen in a few different ways. The CYP2D6*3 allele for example means that you miss the nucleotide in position 2549, because of this the reading frame shifts and you get a non-functioning enzyme. With this polymorphism your enzyme doesn't work at all (prevalence is around 1-4% in Caucasians). The CYP2D6*4 allele means that at position 1846 the base G was switched to A, this leads to problems with splicing which in turn leads to the loss of enzyme activity (prevalence is around 12-21% in Caucasians). The CYP2D6*5 allele means that the gene just isn't there at all, so no gene no enzyme (prevalence is around 1-7% in Caucasians).
With all these mutations your enzymes aren't working and inducing them will most likely fail to work at all.
2. Intermediate metabolizer:
In this case you either have one functioning and one non-functioning allele (see poor metabolizer for examples) or two mutated genes that have limited function. In this case inducing the enzyme will most likely help to a certain extend.
3. Extensive metabolizer:
This one is the one most people have. Here you have two functioning alleles, also called wild type alleles. This means that your enzymes are working as they should. In this case inducing your enzymes will help.
4. Ultrarapid metabolizer:
In this case you have more than the usual 2 functioning alleles, like 3 or even more. This genotype is called CYP2D6UM allele. In this case you have more functioning enzymes than normally. This can lead to problems as even a therapeutic dose of codeine might be metabolized into more morphine than you can take without risking an overdose. Because of that its advised to try a small dose of codeine first if it's your first time taking codeine, to rule out that you're an ultrarapid metabolizer. Here inducing your enzyme will only lead to more side effects and is really dangerous.

Now what's all the fuzz about inducing enzymes?
Normally your genes are expressed (not sure if that's the right term, in German it's called "exprimieren") at a set rate, let's call it the basal rate. So in a certain amount of time, an hour for example you produce 100 enzymes.
When you induce an enzyme by taking a drug you increase the basal rate. This will lead to more enzymes being produced in a set amount of time, like 200 enzymes instead of the 100 in an hour. Normally this isn't something you want as enzymes metabolize the drugs you take and will decrease the duration of action, so more enzymes = faster metabolism.
But in the case of codeine you want it as you want as much codeine metabolized into morphine as possible.
Drugs that induce CYP2D6 and thus increase the metabolism of codeine into morphine are:


- Glutethimide, this one is a strong inducer, meaning that a lot of CYP2D6 will be expressed leading to an increase of morphine production. But the drug itself is classified as a hypnotic sedative thus increasing the side effects and dangers of codeine. In the worst case this can lead to respiratory depression and death so proceed with caution and start with extremely low doses and have a friend around in case you overdose.

- Dexamethasone, this one has an unspecified potency, meaning that we don't know how strong it induces CYP2D6. The drug is classified as corticosteroid and imo that's a class of drug you shouldn't take if you don't have to as they come with a bunch of serious side effects.

- Rifampin, this one has an unspecified potency as well. Another drug you shouldn't fuck with as it's an antibiotic and popping antibiotics for fun will lead to nasty side effects and bacterial resistance (this is an important problem as we are currently running out of antibiotics, so please don't add to it!).

- Haloperidol, this one has an unspecified potency as well. It's an antipsychotic and imo another drug you shouldn't take if you don't have to as antipsychotics and especially strong ones like haloperidol come with serious and sometimes life threatening side effects (those are rare, but can happen, like torsade de pointes, a kind of arrhythmia that can lead to sudden death; neuroleptic malignant syndrome that can lead to high fever and can lead to your muscles breaking down etc.)

Now to conclude all this, if you really want to induce CYP2D6 the only way imo is with Glutethimide, but even this drug comes with dangers like increased respiratory depression and afaik is really hard to get. So really, there's not much you can do to increase the metabolism of codeine into morphine.
 
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kleinerkiffer

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So how harm reductive is this actually Kiffer?
On a scale of 1 to harm reduction I'd give it a proper 3.753. While it has no immediate harm reduction effects like MDPV_Psychosis said, it helps to educate people and every now and then we get a thread about this topic so now we can guide everyone to this thread instead of them making a whole new thread thus leaving more space for real harm reduction questions on the front page.
 

emkee_reinvented

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It's definetily educational just wondering if the specific naming of the last 3 substances was necessary as they seem dangerous when used for the purpose of potentiation. Putting the info out carry's a risk if it was not commonly known at this point.

But I am totally unknowledgable about what is known about Codein and if there are people who are allready contemplating using corticosteroids, anti-biotics or anti-psychotics for the potentiation of Codein. I wouldn't but some might. Like some are huffing glue and kerosine. If this is allready common knowledge then this wouldn't apply and naming them wouldln't carry the risk of giving someone bad ideas. But that is the point I am making.

Glutethimide is allready wellknown. As potentiator with added sedative effects. Would like to try that one without Codein for curiousity's sake. A non benzo sedative.
 

kleinerkiffer

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^Good point!
Well, if you google CYP2D6 inducer you will find the 4 drugs I mentioned, even on Wikipedia, so imo it's better to mention them and talk about the risks involved, but you made a valid point too. I'll report this so that my fellow mods can give me some feedback. Thanks for your concern!
 

Jabberwocky

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does tamoxifen potentiate codeine and tramadol or not? I've read mixed stuff around the forums but I did not try it. I have some tamoxifen left from when my pharmacist gave me a box accidentally instead of dhc (lol), in the end he gave me the dhc too and let me have the tamoxifen for free. as I do not have breast cancer or hormonal issues the only use I may have for it would be for potentiation but I am not sure.
 

kleinerkiffer

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Tamoxifen is a substrate of CYP2D6 (and is considered a prodrug as well), so combining codeine and tamoxifen will lead to the drugs competing for CYP2D6 metabolism, resulting in less morphine (and less of the far more potent tamoxifen metabolites) production
 

Jabberwocky

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thanks kk, considering tramadol and codeine are both pro drugs, taking them together would lessen the metabolisation in morphine and o-demethyltramadol or would just delay it?

as I relapsed 2 days ago, I took a combination of tramadol and codeine togheter, I pretty much know how to distinguinsh the feeling between them and it felt that codeine kicked in after the tramadol with an hour let's say. separately it takes both about 20-30 minutes to kick in in my experience, would taking codeine and 1 hour after tramadol help avoiding this issue?
 

kleinerkiffer

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That's a tough question and I don't think that there's a study I could look up so this is just an educated guess that should be taken with a grain of salt.
As both codeine and tramadol aren't only metabolized by CYP2D6 I'd think that it could lead to a shift in metabolism, i.e. more codeine into norcodeine via CYP3A4 and/or more tramadol into M2 via CYP3A4. Depending on which drug has the higher affinity for CYP2D6, plus it'll depend on the drug concentration and your enzyme concentration as well.
Taking them an hour apart should help.
 

emkee_reinvented

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^Good point!
Well, if you google CYP2D6 inducer you will find the 4 drugs I mentioned, even on Wikipedia, so imo it's better to mention them and talk about the risks involved, but you made a valid point too. I'll report this so that my fellow mods can give me some feedback. Thanks for your concern!
Thanks for acknowledging it.
 

Forever Changes

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Thanks for the detailed info, Kleinerkiffer

(apologies, I just posted in another thread asking this question before I saw this thread)

as I'm pretty sure I'm a poor or very poor metaboliser of codeine, would I also be a poor metaboliser of Dihydrocodeine? The two drugs have different metabolic pathways, but DHC still relies on CYP2D6 for the conversion into dihydromorphine? Do you know if this is correct?
 
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kleinerkiffer

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^ no worries, I unapproved your comment in the other thread, hope that's alright with you :)

From my understanding DHC was designed for CYP2D6 poor metabolizer and while it has at least one far more potent metabolite (dihydromorphine) the production is so miniscule that it doesn't matter. It might be a 'problem' if you're a ultrarapid metabolizer as this can lead to respiratory depression with therapeutic doses as you'd produce more metabolite, but int the case of a poor metabolizer it shouldn't make a difference.
I'll look it up after my exam later today to verify what I just wrote.
 

kleinerkiffer

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Sorry for taking so long to verify what I said
OBJECTIVE:
The metabolism of dihydrocodeine to dihydromorphine, a high affinity mu-opioid receptor ligand in membrane homogenates, is catalyzed by CYP2D6. However, it is not clear whether an active CYP2D6 enzyme is required for opioid receptor-mediated effects in man after standard dihydrocodeine doses.

METHODS:
Whole cell opioid-receptor affinity and effects on cAMP accumulation of dihydrocodeine and its metabolites were determined in differentiated SH-SY5Y neuroblastoma cells. In a double-blind, 2-period, placebo-controlled randomized crossover pilot study the pharmacokinetics of dihydrocodeine (60 mg single dose) and its metabolites were examined in 5 phenotyped extensive (EMs) and 4 poor metabolizers (PMs) for CYP2D6, and pharmacodynamics were evaluated using a pain threshold model and dynamic pupillometry.

RESULTS:
Displacement binding and cAMP accumulation experiments showed clearly higher affinities (100- and 50-fold) and activities (180- and 250-fold) of dihydromorphine and dihydromorphine-6-glucuronide, respectively, whereas the other metabolites had similar or lower affinities and activities as compared to dihydrocodeine. The clinical study revealed no significant difference in plasma or urine pharmacokinetics between EMs and PMs for dihydrocodeine and its glucuronide. Dihydromorphine and its glucuronides were detectable in EMs only. A clear reduction of initial pupil diameters was observed up to 6 hours postdose in both PMs and EMs, with no obvious differences between CYP2D6 phenotypes. In the pain threshold model no effects were observed in either group.

CONCLUSION:
CYP2D6 phenotype has no major impact on opioid receptor-mediated effects of a single 60 mg dihydrocodeine dose, despite the essential role of CYP2D6 in formation of highly active metabolites.
https://www.ncbi.nlm.nih.gov/pubmed/12665158
 
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