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Manipulating opioid pharmacokinetics – Thinking out loud

<- Just got back from the hospital and have thus obtained (3) boxes of;
* Promethazine hydrochloride injection; 28.2 mg/ml (base 25mg) 50mg.
Phenergan 50 ampoules (10 / box). (I.M) or (I.V) Sterile Injection.

There are considerable amounts of medical literature and clinical notes regarding the synergy between opioid + phen administration. Especially post-op; with regards to there potentiation of each other, and side effect alleviation. Since all my supplement goods; 5-HTP, AA, nootropics; are still in the midst of transit - they might not get here by this weekend. Hence I will just experiment with the Promethazine; which will most definitely have a pronounced effect.

________________ Anti-Histamine (incl. Promethazine) + Opioid studies..;

The potentiation of narcotic analgesics with phenothiazines.

Potentiation of narcotic analgesics with phenothiazines have been used for preoperative and postoperative analgesia for a number of years by the podiatric community. The agents most frequently cited in studies are the combination of meperidine with either the phenothiazines chlorpromazine, trimeprazine, or promethazine.

No development of tolerance to analgesia by repeated administration of H1 antagonists.

The effect produced by repeated administration of the H1-antihistaminics diphenhydramine, promethazine and pyrilamine on their ability to induce antinociception was evaluated in the mouse hot-plate and abdominal constriction tests. Contrary to morphine, baclofen and oxotremorine, the three H1 antagonists investigated did not promote the development of tolerance to the analgesic effect after 14 days of repeated treatment. H1 antagonists could, therefore, represent a promising pharmacological approach to the management of chronic pain.

Morphine and promethazine as intravenous premedicants.

Two hundred seventy patients received morphine 5 mg or 10 mg alone or with promethazine 6.25 mg, 12.5 mg, or 25 mg. Promethazine 25 mg alone also was studied. All drugs were given intravenously. Anxiety relief, sedation, patient acceptance, lack of recall, and side effects were the variables examined. Promethazine improved relief of anxiety, sedation, and patient acceptance when added to morphine. Doses of promethazine larger than 12.5 mg intravenously failed to improve these effects. Memory remained unaffected by any of the drugs.

Analgesic effects of antihistaminics.

The literature provides considerable evidence indicating that several, but not all antihistaminics, are indeed analgesic agents and some are analgesic adjuvants as well. Those for which effectiveness is reported includes diphenhydramine, hydroxyzine, orphenadrine, pyrilamine, phenyltoloxamine, promethazine, methdilazine, and tripelennamine.

The literature suggests that more than one mechanism of action exists for them. There is considerable evidence suggesting that histaminergic and serotoninergic central pathways are involved in nociception and that antihistaminic drugs can modulate their responses (1). The evidence for a role for norepinephrine and dopamine and the effects of antihistaminics on them are less well established. Still other pathways have been proposed. A greater understanding of pain mechanisms will aid in elucidating the role of antihistaminics in analgesia.

Reduction of postoperative vomiting in high-risk patients.

Twenty-eight patients who had a history of severe postoperative vomiting were divided into two groups. The first group received various anaesthetic drugs and the second group received a pethidine promethazine premedication and thiopentone, alcuronium, fentanyl and droperidol. There was a significant reduction in postoperative vomiting as assessed by vomiting score in both groups of patients, with the second group having a greater reduction in vomiting score than the control group. Nine of the patients in the second group have received the same anaesthetic uneventfully on a subsequent occasion. We propose that reassurance and the anaesthetic technique described can significantly reduce the incidence of postoperative vomiting in a high risk group.

Effects of second generation of histamine H1 antagonists, cetirizine and ebastine, on the antitussive and rewarding effects of dihydrocodeine in mice.

CONCLUSION: Taken together, the potentiation of place preference of dihydrocodeine with ebastine may be due, at least in part, to stimulation of the central dopaminergic system via D(1) receptors. However, combination of dihydrocodeine with cetirizine does not potentiate place preference at all, nor does it potentiate the central dopaminergic system. Thus, it is likely that cetirizine may be a useful constituent in opioid-containing, antitussive preparations that would not potentiate the development of psychological dependence.

* (Cetirizine) = Zyrtec

The influence of histamine receptor antagonists on antinociceptive action of narcotic analgesics.

The influence of some antagonists of histamine receptors on morphine-, fentanyl-, and pentazocine-induced analgesia was studied in rats and mice.
...
Thus, H1 and H2 antagonists potentiate the antinociceptive effects of morphine and fentanyl but the action of pentazocine is not changed by H1 antagonists and is affected in an inconsistent manner by a H2 antagonist cimetidine. It seems that the potentiating effect of H-antagonists is related to the opioid mu receptors.

Diphenhydramine potentiates narcotic but not endogenous opioid analgesia.

The analgesic effect of morphine in rats, as reflected in elevated thresholds for tail shock induced vocalizations, was markedly potentiated by the antihistamine, diphenhydramine. Intrinsic to the behavioral test paradigm employed are stressors which mobilize endogenous opioid activity as verified by the hyperalgesic effect of naloxone. Diphenhydramine failed to potentiate the analgesic effect of such endogenous opioid activity. The potentiating effect of antihistamines may therefore be mediated by mechanisms whose influence is restricted to systemically administered opiates.
________________

The ginsengs opioid antagonism is very interesting. When I have the time, a new thread will probably be made on the topic. "If" the ginseng does mimic narcan (regarding opioid receptor occupation) even in a minor way, it could be a great method to lower tolerance, by administering it in low doses daily on drug "off" days. I would never use or recommend it though for emergency / overdose protection, its onset would be way to slow and have nowhere near narcans effectiveness.

ChillsH2o - Formal education has mostly contributed to my knowledge of basic scientific principal, biochemistry and anatomy. I'm also taking a couple of neuropharmacology courses this semester. Research methods are self-learned.

Now I'm going to use the Promethazine [I.M inject @ 25mg (standard/max dosage)] to check my individual responsiveness to the compound for later this week, while watching and writing a film report.
 
So if I am understanding this correctly you are purporting that benzos would decrease the euphoria of opiates because of their actions on the Gabanergic (is that a word?) system? Dimenhydrinate increases sedation in me I have found but didn't really notice any difference in euphoric effects.
I use a benzo/strong opioid/dimenhydrinate mix fairly regularily but I am building a tolerance even with infrequent use so I am interested in this. Have not tried 5HTP. I am currently on Remeron so that should potentiate them then. Not that I've noticed really though. In fact my tolerance is growing and I use once or twice a week. If I am misunderstanding this then please enlighten me.
 
Bamboozle said:
Promethazine [I.M inject @ 25mg (standard/max dosage)]

Promethazine - Interesting compound - very noticeable effect. Less than 15 minutes after administration I felt some symptoms of onset; respiratory, mental and physical. Mild but noticeable change of breathing, a moderate sedated buzz, yet obviously absent of any kind of euphoric properties alone, heavier limbs and some comfortable movement induced vertigo (identical to opioid induced). Lots of sedation and tiredness < important to note, I indulged on a powerful lust for sleep just after an hour/30 min. Ridiculously long half life; I unexpectedly woke up with the same heavy sleepy demeanor I went down with, and over 12 hours later am still feeling. Dosage will need adjusting coinciding w/; <Morphine and promethazine as intravenous premedicants>. The most prevalent risks associated with this drug would be; respiratory depression and lethargy. So anyone considering using it should consider this, and starting at the regular dosage unit of 25mg, gauge themselves from there. It's light sedation, buzz and anti-nauseating & anxiety effects should compliment opioids nicely. Plus any form of undocumented euphoric synergy.

_____________

Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines).

This article reviews clinical pharmacokinetic data on the H1-receptor antagonists, commonly referred to as the antihistamines. Despite their widespread use over an extended period, relatively little pharmacokinetic data are available for many of these drugs. A number of H1-receptor antagonists have been assayed mainly using radioimmunoassay methods. These have also generally measured metabolites to greater or lesser extents.

Thus, the interpretation of such data is complex. After oral administration of H1-receptor antagonists as syrup or tablet formulations, peak plasma concentrations are usually observed after 2 to 3 hours.

Bioavailability has not been extensively studied, but is about 0.34 for chlorpheniramine, 0.40 to 0.60 for diphenhydramine, and about 0.25 for promethazine.

Most of these drugs are metabolised in the liver, this being very extensive in some instances (e.g. cyproheptadine and terfenadine). Total body clearance in adults is generally in the range of 5 to 12 ml/min/kg (for astemizole, brompheniramine, chlorpheniramine, diphenhydramine, hydroxyzine, promethazine and triprolidine), while their elimination half-lives range from about 3 hours to about 18 days [cinnarizine about 3 hours; diphenhydramine about 4 hours; promethazine 10 to 14 hours; chlorpheniramine 14 to 25 hours; hydroxyzine about 20 hours; brompheniramine about 25 hours; astemizole and its active metabolites about 7 to 20 days (after long term administration); flunarizine about 18 to 20 days].
 
edarrin said:
So if I am understanding this correctly you are purporting that benzos would decrease the euphoria of opiates because of their actions on the Gabanergic (is that a word?) system? Dimenhydrinate increases sedation in me I have found but didn't really notice any difference in euphoric effects.
I use a benzo/strong opioid/dimenhydrinate mix fairly regularily but I am building a tolerance even with infrequent use so I am interested in this. Have not tried 5HTP. I am currently on Remeron so that should potentiate them then. Not that I've noticed really though. In fact my tolerance is growing and I use once or twice a week. If I am misunderstanding this then please enlighten me.

First realize that most the medical literature on the topic is hypothesized. The dopamine angle is one of the only semi-confirmed explanations of its euphoric effects. Hence any compound that potentiate gaba, or in the case of benzodiazepines potentiate the GABA receptors - than from the dopamine angle hamper the opioid compound. There are no doubt more pathways involved in the action of opioids, but benzos may specifically hamper dopa. My personal experience with benzo + opioids have just equated to less euphoria and more sedation. I feel a lot of people may mis-diagnose, potentiation with sedation.

Consider > individual results may vary, namely if you actually have an authentic chemical imbalance - than the restoration of normal function would more than likely be ideal for you. I do not, so realize that my response to benzo's may be different.

Tolerance should be most avoided for obvious reasons; most notably the un-desired and serious side effects of the drug not being down-regulated, while the euphoria is. Plus the long term potential damage to the natural reward/pain system. I will look into tolerance more in depth when I have time. The easiest way to bring it down is a opioid antagonist or simply time off.

Remeron, mirtazapine, I believe is also very mentally, not physically sedative - though that loses effect with time. Remerons true mechanism of action is unknown - so I couldn't tell you much. What is known; R enhances central noradrenergic and serotonergic activity. It also is a antagonist of the histamine receptors (sedation). If the tiredness is alleviated, I think that it may in fact be a nice addition - assuming seratonergic activity enhances euphoria | and the (above) histamine angle.
 
Results: 320mg Codeine + 18mg Promethazine.

Took the promethazine (Phenergan) injection 1 hour prior to the codeine, as it peaks in 1-2 hours. Note that the 18mg phenergan is almost the equiv to 25mg oral.

The results were quite excellent. You can actually feel the phen kick in after about 20 minutes - you feel more relaxed and any kind of nausea is alleviated. Even the codeine, which personally is the worst thing I have ever tasted, didn't even get close to making me gag as it normally does. The opioid euphoria came on slow, as it always does with something as weak as codeine. Nothing like the warm rush I get from oxy. Once both drugs were in full effect I noticed that the breathing depression that I expected was not apparent at all. Higher non-drowsy sedation was achieved ( heavy / warm body, not sleepy). The euphoria was a slight bit different though- hard to describe, as if it had all the pleasure of previous uses, but enabled me to think slightly clearer. Was easy to ignore this effect, but noticeable. < I’m going to have to describe it better next time, I’m evidently forgetting things. The high seemed to last a slight bit longer at just past 6 hours.

This is where lately I always seem to get some nausea, oxy's and morphine are the worst, 90% of the time I have to move very slowly to the bed and lie down with overwhelming nausea and occasional throwing up. This time I had not even the slightest inclination to do so. I was walking, tried running, around fine. At some point was also waving around a samurai sword, put two slice marks in the paint on the wall, decided to put it away until my balance returned. During the evening I had also eaten 3 rather gigantic bowls of fruit and drank a 2 liter bottle of diet ginger ale, felt fine. Urinated at least four liters that night, peeing took forever - got leg & ass cramps from standing so long. If the phen had no euphoric accentuating effects I would still use it for anti-nausea effect alone. The next day, where normally with opioids I can always still feel some residual nice warm after-effects, was noticeably enhanced also (phen / long half-life) - nice.
 
Also, quinine is widely over-looked, and as i've said many times before, 250mg capsules are available at aquarium stores with the brandname "quinsulex". It works suprisingly well.

what exactly does quinine do? is it a potentiator?
 
With regards to quinine, I only have time to post this study before class.

It appears to asert its primary action through enzymatic manipulation.

_________


The influence of pharmacogenetics on opioid analgesia: studies with codeine and oxycodone in the Sprague-Dawley/Dark Agouti rat model.

Cleary J, Mikus G, Somogyi A, Bochner F.

Department of Clinical and Experimental Pharmacology, University of Adelaide, Australia.

In the Sprague-Dawley (SD) rat, the O-demethylation of codeine to morphine is catalyzed by cytochrome P4502D1 (CYP2D1), which is absent in the female Dark Agouti (DA) rat. Oxycodone is similar in structure to codeine but, in contrast, has an analgesic potency in humans similar to morphine.

The aim of the study was to test whether the DA rat and the SD rat pretreated with the CYP2D1 inhibitor quinine showed attenuation in analgesia to codeine and oxycodone.

With the use of the tail flick model, dose-response curves were constructed to codeine, morphine, oxycodone and oxymorphone (the O-demethylated metabolite of oxycodone) in both rat strains. Codeine did not induce analgesia in the DA rat and there was a 60% reduction in codeine analgesia in the SD rat pretreated with quinine in comparison to the untreated SD rat. In the DA rat, the ED50 to oxycodone was increased 10-fold but there was a significant (P = .0001) prolongation in the duration of analgesia in comparison to that in the untreated SD rat. In the quinine-pretreated SD rat, there was no reduction in oxycodone analgesia but the duration of analgesia was also prolonged. It was concluded that

1) codeine-mediated analgesia requires the formation of morphine through the functional activity of CYP2D1 and

2) oxycodone-mediated analgesia may only be partly dependent on CYP2D1.
 
Yeah, why bother worrying until you get to the stronger opiods. Just use better drugs. Then you can worry about how to potentiate.
 
edarrin said:
Yeah, why bother worrying until you get to the stronger opiods. Just use better drugs. Then you can worry about how to potentiate.

I already replied to why I'm using that particular drug earlier. More dosage room for error, morphine potentiating, easy to make comparisons with low strength, heavy literature .. I will use oxycodone and morphine later. Once ideal dosages for any effective potentiators has been established.
 
I know you did. I was implying that although I admire your keen interest in the scientific analysis of medline etc. the fact remains that codeine sucks and your sort of wasting your time. You will never get the same effect from codeine as OXY or H regardless. So unless you are investing in a future narcotic addiction then why waste your time. Just get better drugs. Thats what the rest of us (at least many) did. If you want to get high, get high. Just don't let it control you. Just stating an opinion. No malintent.
 
Bamboozle, keep up the excellent research! Potentiating opioids is a very interesting subject that stands on its own and should not be squashed by the "get better drugs" objection.

For the doubters, here are some good reasons for potentiating opioids:

1) A very large number of people cannot legally or comfortably get OC or H. However most of us can easily get weaker opioids. So this research is practically useful for thousands of people reading this board. And I don't mean just those of us looking for the high, but also those of us looking to kill chronic pain more effectively than the weak pills the doctor prescribes are able to do.

2) OC and H are very expensive. If there is a way to take half a dose plus a potentiator to get the same effect, but all means we need to know about it.

3) Some potentiators slightly change the high and might have other useful properties such as nausea reduction. So doing (2), somebody might actually have a better experience than a person taking a full dose of the "good" drug.

4) When you are a regular user, normal does of OC or H don￾ft really get you as high as they used to, and going up in dose might be prohibitive due to side effects or cost. Again, here is where this research comes in handy. Especially when it comes to reversing tolerance.

TH
 
Potentiators have a unmistakable role, and i have done many experiments on my self in search of potentiation. I understand the reason to explore. But what i learned more, is that the best thing for potentiating opiates, is by taking more opiates. Or you could take drugs that are already powerfull, like oxycontin or heroin. Ok say you want to find the way to get the most out codeine, the best your going to get is more codeine metabolized into morphine, which in itself isnt all that great. If you shoot a nice taste of some heroin #4, potentiation will easily slip the mind...........
 
Good responses. Again, this has nothing to do with codeine. I've already stated the reasons for its use. TokyoHigh also mentioned some excellent points. Taking more, at least in my opinion, is not the answer. That just leads to way more side effects and a much higher tolerance. I will try to post some studies on quinine later tonight. A great potentiator could be the ginseng, if it lowers tolerance, will report back on that tomorrow. If I can get quality quinine that will probably be next. Followed by some Nootropic drugs like vinpocetin and dmae.
 
The 5-HTP is great for coming down off all opioids, as sometimes they are serotonin depleting. I hypothesize that some of the nausea, headache and dysphoria (if any) may be somewhat alleviated by 5-HTP . Also pre-loading 5-HTP with morphine in some studies indicated higher analgesia potentiation. It would be safe to try, and is useful, but does not (personally) have a very profound effect, more of a subtle one. If post-opioid you often feel the symptoms of serotonin depletion, than it is perhaps your best bet.
 
Yeah, this thread is one I've referred to a lot/am really interested in, but it seems to've fallen off...

:(
 
TokyoHigh wrote 05-11-2003 21:48

Especially when it comes to reversing tolerance.



i agree wholeheartedly

to me this is the most interesting and most valuable aspect of this research

thanks for all the great work guys
 
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