Opioids Converting Codeine into more Morphine

[Anon54]

I'm aware there's a "Codeine potentiation and synergy thread" but I'm only interested in true inducers which convert more Codeine to Morphine. Not, Valium goes well with Codeine or smoke some pot or whatever.

So does anyone have the REAL facts about whether or not any of these Antihistamines help convert Codeine to Morphine?

Here is a lost of Antihistamines from:
http://en.wikipedia.org/wiki/Antihistamines

I suppose the most sedating & atleast synergizing would be:
Diphenhydramine (Benadryl)
Doxylamine (Restovit)
Promethazine (Phenergan)
Quetiapine (Seroquel)

There is so much conflicting information.
Whether or not to take before, or after or whether or not they increases or decreases the conversion and I don't know what to believe.
Here is some examples of some different opinions with there sources also available:

This following paragraph stating Diphenhydramine reduces or even completely blocks the conversion of Codeine to Morphine is quoted from:
http://en.wikipedia.org/wiki/Codeine#Pharmacokinetics

Some medications are CYP2D6 inhibitors and reduce or even completely block the conversion of codeine to morphine. The most well-known of these are two of the selective serotonin reuptake inhibitors, paroxetine (Paxil) and fluoxetine (Prozac) as well as the antihistamine diphenhydramine and the antidepressant, buproprion (Wellbutrin, also known as Zyban). Other drugs, such as rifampicin and dexamethasone, induce CYP450 isozymes and thus increase the conversion rate.

So this webpage says Diphenhydramine is a bad idea.

This folowing post stating that Promethazine DOUBLES Codeine to Morphine by Suboxer is quoted from:
http://www.drugs-forum.com/forum/showthread.php?p=842159

Promethazine is not used, like cyclizine and diphenhydramine, to synergize with codeine, however horrible a term that may be when applied to anti-histamines, with anti-histamines.

Promethazine, like glutethimide, is a true potentiator of codeine, as well as having what some view - spuriously (at least in the case of anti-histamines) - synergistic effects.

Promethazine is a moderately strong CYP450 IIDVI enzyme inducer. CYP450 IIDVI is the enzyme that converts inactive codeine - methylmorphine, a prodrug for morphine - in to morphine by demethylation. In most people about 10% of the oral dose of codeine is converted in to morphine, so: 90mg codeine = 9mg morphine. Promethazine increases the amount of codeine converted to morphine in vivo by a factor of two, so the same 90mg of codeine is now equal to roughly 18mg of morphine, and, in addition, is made more sedative, less itchy (the itch is the best part of an opioid high besides the nod), and a slightly more effective painkiller (some anti-histaminics have what is called "analgesic sparing" properties, meaning, combined with an opioid, they increase the analgesia it provides synergistically) by the anti-histaminic and mild anti-psychotic effects of promethazine (promethazine is roughly 1/10 the potency of chlorpromazine [Thorazine, Largactil]).

The drug, codeine, has no effects. It is converted to morphine by first-pass metabolism in the liver after it has been absorbed by CYPIIDVI. Taking the drug AFTER you've ingested the codeine does nothing but add an anti-histaminic effect on top of the codeine - it acts synergistically.

If you take the promethazine one to two hours before you take the codeine, it is a true potentiator in addition to whatever "synergistic" effects it might have - it increases the maximum plasma concentration and area under the curve of morphine itself, increasing the actual height and duration of the opioid high - not just adding the effects of a sedative anti-histamine to it. So, for Christ's sake, take the promethazine BEFORE you take ANY of the codeine, and you'll get more of an opioid effect - if you take it after the codeine, YOU WONT! - you'll just have the effects of a sedating anti-histamine/anti-psychotic added to it.

Now, the above information will get you more opioid bang for your buck - any one who says to take the promethazine after the codeine will not increase the opioid concentration in your blood one bit, but will just add promethazine "buzz" on top of it. Taking the promethazine with the first dose will work, albeit less well than taking it an hour before. For maximum effect, you should always take all your doses together (but be wary of risk of overdose) - all you're getting by taking one-half a dose every thirty minutes is about 55% of the high you would taking it all at once, and 200% the tolerance per "unit of high."

Note: Promethazine effectively doubles the limit of codeine a person can metabolize, and thus benefits users of low to low-midrange tolerance as well. Normally 300mg of codeine can be metabolized in to only 30mg of morphine, and the liver enzymes are "saturated" in a sense - they can convert no more. This becomes 60mg while taking promethazine around one to two hours before use of the codeine.

Note 2: Caution: I am unsure of the metabolism of tramadol, but tramadol itself is an extremely weak opioid, that, like codeine, must be demethylated, in the case of tramadol, in to o-desmethyltramadol (the "M1 metabolite" of tramadol) before it is active at the mu-opioid receptors (900x increased affinity compared to tramadol). Tramadol, before being metabolized, is merely a norepinephrine reuptake inhibitor and serotonin releasing agent. If the metabolism of tramadol to o-desmethyltramadol is also catalyzed by CYPIIDVI, you may be putting yourself at risk of opioid overdose by taking promethazine before the codeine and tramadol, because, in essence, you could be effectively doubling your active dosages.

Here is a quote stating GFJ converts more Codeine to Morphine from:
http://en.wikipedia.org/wiki/List_of_drugs_affected_by_grapefruit

Codeine and Tramadol.[8] It reduces the amount of codeine converted by CYP3A4 into norcodeine thus increasing the amount metabolised into morphine.[citation needed] Morphine itself, however, is not affected by grapefruit juice, as it is not metabolised by the cytochrome P450 system

I would have thought an inhibitor would slow the conversion of Codeine to Morphine.

Here is another interesting website for those who know a bit about pharmocology:
http://psy.psychiatryonline.org/cgi/content/full/44/6/515

Despite the case reports that would follow these studies, some researchers have had difficulty accepting that codeine's conversion to morphine by 2D6 is the reason for its efficacy as an analgesic.

They postulate that it is the main metabolite of codeine created by UGT 2B7, codeine-6-glucuronide, that is responsible for most of codeine's analgesic and µ receptor activity

Here is a typical P450 drug interaction table:
http://www.ildcare.eu/Downloads/artseninfo/CYP450_drug_interactions.pdf

This table does not state Promethazine as an inducer conflicting with what Suboxer claims.

Conclusion:
As you can see from all the websites I've listed above the information is extremely conflicting. The only real inducers for Codeine I've ever seen on one of these tables are carbamazepine, ethanol, phenobarbital, phenytoin, primidone, rifampin, ritonavir & St John’s wort.
I've never seen Promethazine as an inducer like Suboxer claims & Inhibitors such as Grape fruit juice are said by some to slow the conversion of Codeine to Morphine but many disagree with this, yet what wikipedia says is it helps the conversion & at the same time says the inhibitor diphenhydromine slows or even completely blocks the conversion. So I don't have a clue what to think of the whole "potentiating Codeine" theorys!

 

[Znegative]

that would be pretty wild if promethazine doubled the conversion of codeine>morphine.

 

[Nexius]

I had a theory of something similar to the trypsin method for vyvanse.

I wonder if this is possible with codeine assuming you had the correct enzyme

 

[brasil]

Just had 300mgs o codeine + 50 mgs promethazine + 40mgs valium + 4 cans of beer. Great, great combo.

 

[Mr Blonde]

Promethazine is actually an inhibitor of CYP2D6.

That wikipedia quote about morphine 'not being metabolized by the CYP450 system' is bullshit. Morphine is metabolized by the CYP3A4 enzyme, amongst others, and grape fruit juice will work to slow down this metabolism.

To be honest with you OP, most of these antihistamines are not incredibly potent inhibitors of the enzymes so I would not worry too much about them. There are some SSRIs that are potent inhibitors of CYP2D6 though which would have an effect on the metabolism of codeine to morphine.

As for inducing CYP2D6 to produce more morphine, the most readily available inducers are ethanol and St Johns Wort. One or two standard drinks 45 minutes before codeine should help. I'm not sure about dosing for St John's Wort, but there might be something about it here on Bluelight. Try out a dose or two before your codeine.

The rest of the inducers I am aware of are scheduled and probably hard to get... phenobarbital is one. Some of the others are steroids, NSAIDS or heavy-duty antibiotics. They should be listed on a CYP450 chart somewhere out there. I can't be bothered to reference mine right now.

 

[hexxx]

^ what he said. You need inducers to make your dose more efficient, inhibitors will slow them down. Codeine is a prodrug and needs to be processed by those enzymes you are trying to inhibit causing the metabolism of codeine to morphine to be less efficient.

 

[brasil]

Right now i just had 2 doses (4 hs betewen doses) of 300mgs... had a feel beers and joints, but i don't know if i should mixture it with one lsd blotter. right now i'm feeling great I LOVE CODEINE. i think i'm going to wait, 4 more ours... if i still want to o get high then....

 

[brasil]

Here in Brazil (prescriptions in hand) 30 pills of 60mgs pure codeine phosfate will cost: <snip> dollars.
Really sheap. And any doctor here give any precription you want (if i was going to buy it without prescription, i would pay usd : 80 (on the black market) 30 pills with 60mgs each).feeling great right now!
Love you all!!!
Ps: justa had 600 mgs
"walking on the moon"

*mod edit*
no prices!!!

 

[What was it?]

Just had 300mgs o codeine + 50 mgs promethazine + 40mgs valium + 4 cans of beer. Great, great combo.

i'd be calling an ambulance after that

 

[Jabberwocky]

i'd be calling an ambulance after that

no need for the smart arse comments, thanks.