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Opioids Other CYP2D6 inducers combined with codeine (Not glutethimide)

kaosisallwesee

kaosisallwesee

Bluelighter
Joined
Aug 14, 2007
Messages
796
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uk
I've been aware of glutethimides past use to vastly potentiate codeine for a while, however as I'm sure you all know glutethimide is near impossible to find. What about other CYP2D6 inducers? Dexamethasone and rifampicin are also known CYP inducers, with rifampicin being the most known about. In fact during rifampicin treatment drug interactions are extremely common and monitored closely.
I am aware that abuse of antibiotics is not a good thing, however I'm still curious if anyone has tried codeine combined with either of the drugs I've mentioned or any other CYP inducers I'm unaware of.
I should also point out that I am NOT planning on taking any of these combinations as I ended my run with opioids years ago and have no intention of returning. Its purely out of curiosity.
 
Hey. I know it's been since you asked the question but I'll answer it incase you are still interested. So yes you are right Rifampin is a CYP2D6 inducer. However, Codeine is tricky. Codeine is metabolized in 2 different methods.

Method number 1: Through CYP2D6 which essentially metabolizes the codeine into morphine (Thought to be the main mechanism of pain relief)

Method number 2: Through CYP3A4 which metabolizes the codeine to nor codeine which is thought to be inactive.

Technically you are right, Rifampin would induce CYP2D6 and cause the conversion from codeine to morphine to happen a lot faster. However, Rifampin is also a CYP3A4 inducer so it would also speed up the metabolism of codeine to its inactive form. Basically, the end result here is a weaker effect of codeine.

Also, unlike enzyme inhibition which can happen in hours, enzyme inducing takes weeks to happen (a person would have to be on rifampin for at least 2-3 weeks in order to have CYP induction)

To answer questions: Because codeine is a pro-drug it is kind of hard to potentiate it unlike other opiates like oxy. Theoretically though if someone uses a CYP3A4 inhibitor , the metabolism of codeine to its inactive form would be slowed down and thus, more codeine would be available to be converted into morphine, thus potentiating the drug. However this is just theoretical because codeine's pharmacokinetics are typically hard to predict and highly differs from one person to the other.

Cheers!
 
It may take a long time to reach a stead state, but isn't that just down to the required build up time to reach that steady peak of enzyme levels. While rifampicin takes a while, if all inducers required this build up time that would render Glutethimide and codeine a useless combination. Interestingly it's now believed that the glucuronide is actually the primary active metabolite (codeine-6-glucuronide) rather than morphine, which is a pathway glutethimide also induces. So that might be a reason for it working better than other inducers when taken in acute doses.
 
You are right the time to induction differs from drug to drug. However for Rifampin it won't be less than a week for sure. Also, I don't believe glutethimide has an effect on codeine pharmacokinetics at all. I have never done the stuff so this is just a theory but I am an expert in pharmacokinetics. I strongly believe that the added effect with glutethimide is strictly due to the effects of glutethimide which has a great potential of abuse itself. I think the 2 drugs have a synergistic affects but unless taken together for a long duration of time, I doubt that they have an effect on each other's metabolism. Especially keeping in mind that glutethimide has a half life of 10-12 hours which would mean it would take even more time to induce the enzymes than rifampin would. Also even though Codeine-6-glucuronide does have some activity, it's affinity to mu receptors doesn't come close to morphine's at all.

cheers!
 
KPharmD said:
I have never done the stuff so this is just a theory but I am an expert in pharmacokinetics.
Click to expand...
You gotta back your shit up bro. Just scratch pubmed and at least pull up a half assed reference. This is the internet, you can't appeal to authority.

Anyway you are also wrong. Glutethemide increases morphine blood levels when taken with codeine.

www.sciencedirect.com

The study of codeine–gluthetimide pharmacokinetic interaction in rats

A high-performance liquid chromatographic (HPLC) assay with native fluorescence detection was developed for the simultaneous quantification of codeine…
www.sciencedirect.com www.sciencedirect.com
 
What I have never understood is why grapefruit, despite being a CYP3A4 inhibitor, raises serum levels of opioids. (?)

Also, high serum levels = better high, right?
 
CYP3A4 tends to remove the methyl group on the nitrogen of opiates. This renders them pretty much inactive.

CYP2D6 demethylates the codeines and turns them into the morphines making them stronger typically.

Inhibiting CYP3A4 will pretty much always increase blood levels of opiates. Inducing CYP2D6 only increases potency of codeine type prodrugs for the corresponding morphine/ -morphone.
 
@Skorpio Honestly man, I don't understand nothing. I don't know anything about chemistry. I hated in school in fact. :ROFLMAO:

Skorpio said:
inhibiting CYP3A4 will pretty much always increase blood levels of opiates. Inducing CYP2D6 only increases potency of codeine type prodrugs for the corresponding morphine/ -morphone.
Click to expand...

This where I am confused "increasing blood levels" means "better high"? Or not necessarily?
 
Yeah, it means you will be higher and possibly for longer.

Meds that block CYP3A4 can cause normal pain folks to od on their typical dose for example.
 
Skorpio said:
You gotta back your shit up bro. Just scratch pubmed and at least pull up a half assed reference. This is the internet, you can't appeal to authority.

Anyway you are also wrong. Glutethemide increases morphine blood levels when taken with codeine.

www.sciencedirect.com

The study of codeine–gluthetimide pharmacokinetic interaction in rats

A high-performance liquid chromatographic (HPLC) assay with native fluorescence detection was developed for the simultaneous quantification of codeine…
www.sciencedirect.com www.sciencedirect.com
Click to expand...
Exactly. This is the internet. I am just offering my professional opinion not writing a research paper so no I don't have to list references for every single thing I post. Also, not sure if you read the full version of the half assed reference you posted or just went with the abstract or not, but rats do no have CYP2D6, which is the highly polymorphic enzyme I was talking about earlier. You can't compare codeine metabolism in rats and humans and base the conclusion on blood concentrations because its just not the same thing.

Cheers!
 
The low receptor affinity of c-6-g would explain the significantly reduced effect of codeine compared to morphine. Also while rats don't have cyp2d6 they do have cyp2d2 which follow the same mechanism. So I'm not too sure what your point is there, or with a lot of the other pointless information you've provided. Other than to flex your apparent expert level of knowledge.
Cheers!
 
Enzyme inducers actually lower blood concentration of the substance whose metabolism they're inducing as the substance gets metabolised and cleared faster. Inhibitors make it so plasma levels of the substance increase as metabolism of the substance is slowed down and so also its clearance.
This is how I understand things to work and I have said it in a simplified way.
 
OpialiciouslyMe said:
Enzyme inducers actually lower blood concentration of the substance whose metabolism they're inducing as the substance gets metabolised and cleared faster. Inhibitors make it so plasma levels of the substance increase as metabolism of the substance is slowed down and so also its clearance.
This is how I understand things to work and I have said it in a simplified way.
Click to expand...
It's would all depend on which enzymes are induced or inhibited, and the subtance that has been consumed.
 
nohandsjoe said:
Data on dexamethasone is mixed; some sources claim it reduces codeine concentrations in the blood, and some sources claim that it increases morphine conversion rates (others still claim that it's reduces the analgesic efficacy of morphine).

In my own experience, it seemed to potentiate the codeine I was using to treat a rotting tooth. That could have also been due to the antiinflammatory properties of dexamethasone, though.

It's been postulated that it has utility in paliative cancer care, where opioids are also often Rx'd, which gives me a hunch that any interaction is not major?

But yeah, worth mentioning it. Wish there wasn't so much contradictory evidence about codeine potentiation (finicky drug, codeine...)
Click to expand...
To be honest I find codeine useless. They should just prescribe low dose morphine. Some people cannot even metabolise it into morphine at all.
 
nohandsjoe said:
Agreed. Though I sure do miss being able to buy asparin with codeine and caffine over the counter; it was the only formulation I could reliably get all the caffeine out of (the aspirin too, obviously)
Even with my citalopram killing the effects, a good 400+mg usually had me nice and float-y

Now I vape brorphine and never look back :v
Click to expand...
Definitely better to vape that than ingesting all that aspirin to get 400mg of codeine! It's really damaging to the stomach and so on. I hope you were doing a CWE. That doesn't get rid of caffeine though.
Sorry... Didn't mean to go all harm reduction on you.
I'm in the UK and we still have the low dose codeine otc with paracetamol or ibuprofen or aspirin. Are you in Australia?
 
@nohandsjoe Yes, you can get codeine with just paracetamol (it's called cocodamol and it's very cheap for a box of 32 tablets). 8mg of codeine and 500mg of paracetamol. Then you have the version with also caffeine. You can buy the Nurofen Plus or generic with just codeine and ibuprofen. The codeine is slightly more in this one. They also do one with aspirin only and no caffeine (brand name Codis).
There's a large variety really. We also have Paramol, brand name for otc dihydrocodeine with paracetamol.

Caffeine is very water soluble so it cannot be removed with a cold water extraction. You need a different solvent to get rid of it but then that solvent wouldn't work with the paracetamol etc. It's a lot of work to do multiple extractions with different solvents for just codeine IMO.
 
dus_aster said:
Agreed. Though I sure do miss being able to buy asparin with codeine and caffine over the counter; it was the only formulation I could reliably get all the caffeine and NSAID out of.

Even with my citalopram killing the effects, a good 400+mg usually had me nice and float-y

Now I vape brorphine and never look back :v
Click to expand...
Can I ask a random question? Is it possible to vape liquid morphine?
 
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