Butalbital; used with baclofen- pharmacological interactions?

[AlphaOdure]

First; I am on high doses of butalbital which I have been trying to slowly taper off, with not much success (now at just about 1500 mg/d). These doses are dangerous; & I’d like to stop. So, I was prescribed baclofen to help with this. Before I go on & explain my experience causing me to ask this question- i will say that I took baclofen as directed & did not notice much cross tolerance/additive CNS depression (as you'll see below)

I know butalbital is chiefly a GABA-a agonist (through mechanisms I admittedly am not too familiar with; the GABAergic complex can be somewhat intricate for my understanding of pharmacology); and baclofen is a GABA-b agonist. However, I assumed there would be cross tolerance. I took the max prescribe dose of baclofen ; 100 mg in 24 hours. It certainly helped initially with my intake of butalbital, only needing roughly 1/2-2/3 (~750mg-1000mg/day). But, then came the horrific & infamous “after-effects” of baclofen—that is, almost 24 hours of no fluids, no eating, & profuse vomiting. Needless to say, I was unable to take my butalbital & was put into slight withdrawal; although the baclofen—which I wasn’t taking during this time obviously—still helped w/ *some* of the anxiety.

I then slowly tapered up to ~1300-1500mg of butalbital after roughly starting 3 days after my 24-dosing period of baclofen. Stabilizing back on 1500mg of butalbital by day 4 (since baclofen intake); On day 6, I resumed baclofen but at ABSURDLY small doses; only 10-20 mg a day—through to day 8; today, June 16th (evening). I am not noticing any ill-effects from the baclofen, aside from some gastrointestinal disturbances (nothing major though) & irregular sleep patterns. Only now am I noticing most of the typical effects from butalbital. The baclofen seems to be helping to avoid using higher amounts of butalbital (>1500 mg in a day; which I would commonly do as needed)—but I assume I’ll need to slowly titrate my baclofen dose upwards before it will have any noticeable impact on lowering my butalbital dosage. But, I am concerned b/c there seems to be some reduction in butalbital’s efficacy. (Side note: I am also on buprenorphine/naloxone formula, 4mg/day—but this seemed to have no relation to each other).


So my main question to help resolve the above issue is this:
I know baclofen is supposed to be selective for GABA-b; but is there any sort of antagonist action (either direct or indirect) baclofen has on some GABA-a receptor sites that barbiturates/butalbital act on? Or is there any other sort of effect baclofen has on general GABAergic PAM activity at -A receptor sites? …That anyone is aware of? Or perhaps, is there an interaction with indirect dopamine stimulation butalbital might otherwise cause? Or is this all a result of the high doses (and "hangover") of my initial baclofen dosages? Any theoretical inquiry, speculation into this; and/or information on baclofen & barbiturate interactivity would be helpful!!

I would love to use baclofen safely to hopefully wean down off of the butalbital—but as of now, I am still feeling very “flat” & am sort of stuck trying to taper down. But for health's sake (and for harm reduction's sake), any relevant answers would be very helpful so I can reduce, or eventually get off, butalbital.


~~~


(Apologies in advance if this would be more appropriate for the OD forum—but after thoroughly searching google many times over, I haven’t found anything remotely related to this subject. & apologies for any overtly obvious naivety in my pharmacological nomenclature)

 

[AlphaOdure]

EDIT: in absence of any information on these two drug's interactions between each other.. any general GABAergic information between -A & -B selective agonists would also be helpful...

 

[ebola?]

Some of the effects that you attribute to overdose with baclofen could be due to the effects of barbiturate withdrawal. There should be some cross-tolerance between the two, insofar as tolerance to GABAnergic receptors is mediated via general downregulation of GABAnergic receptors and decreased endogenous synthesis of GABA. I currently lack access to journal articles, but it is my understanding that baclofen is pretty selective for GABA-B. I would titrate up with baclofen slowly as you titrate down with butalbital, ideally under medical supervision.

ebola

 

[AlphaOdure]

Thank you for responding, Ebola (I see you & i have both been here since the early days too! eh? although you got 2-3 years on me!)... Anyway, yea, I was assuming it was a result of my lack of intake of butalbital during the "overdose" period when I was unable to take my typical doses for a few 2-3 days. But, the half-life of baclofen is very low- which is why i did not attribute it to an overdose, but perhaps a hangover of sorts?

And yes, I assumed baclofen would be pretty selective; but it seemed to cause a neurological blockade effect (even during the first day or so when I took the baclofen... when I didn't have any adverse effects; I didn't have the need to take nearly as much as my typical butalbital dosage, although this probably complicated matters during my adverse reaction period since it came out to some 5 days, give or take, where I was taking very low amounts)

I have noticed some very similar "dulling" off the effects of other GABAergic drugs (carisoprodol, meprobamate; and--while not a surprise--also benzodiazepines) w/ the use of butalbital. But, since baclofen is metabolized by the kidney's & *NOT* via hepatic metabolism & CYP enzymes ulike the other drugs mentioned, especially butalbital (& especially w/ CYP hepatic interactions), I assumed there was some pharmacological and/or neurological action going on here. And seeing as though baclofen is an older drug, with no money to be made here in the U.S. by a healthcare system more concerned w/ being a business than by abiding by the Hippocratic oath.. surprise surprise! There are VERY little double blind studies done w/ it (its not patentable, no money to be made!).. & thus very few HUMAN studies on neurological interactions! (thus prompting me to post here for just ANY help/support.)

But, thankfully, I am starting to feel back to normal, I'm back on my normal intake of butalbital & haven't used baclofen in at least 24 hours. So, I think i'll give it some time here... take 20mg in a day MAX; see how i react to it w/in a few days... then go from there.

 

[AlphaOdure]

^^^^
...CONTINUED: I still welcome any further discussion, hypotheses, etc for anyone else w/ any knowledge on these drugs! Or any knowledge w/ ANY concurrent use of GABA-A & GABA-B agonists (such as barbiturates--even benzodiazepines--with GHB type drugs, although admittedly GHBergics w/ GABA-B affinity are much less selective than baclofen)????? Seeing as though baclofen is metabolized via kidneys & butalbital is metabolized via the liver, i'm just assuming its an issue w/ neurological interactions... but, i definitely did NOT foresee some sort of blockade effect (although, as i said, admittedly, this may be b/c of barbiturate w/d?) since concurrent use of CNS depressants of the GABAergic type are usually additive rather.

Side Note: I noticed quite similar blockade, or "dulling", effects w/ GABAPENTIN in respect to butalbital, although not as severe & w/o the similar hangover, overdose, or whatever the fuck it was. But all in all, concurrent use of GABAPENTIN (around ~1000mg give or take, over 1-2 months) had more additive effects than it did long term blockade effects. But then again, it didn't prevent me from taking my butalbital as usual, at typical doses.. but it also didn't help me in lowering doses

 

[sekio]

It is my understanding that GABA-A and GABA-B are two seperate inhibitory pathways that share a common ligand. This accounts for the rather varied pharmacology of 'GABA-mimicing' drugs. GABA-A is rather special because directly agonistic compounds (muscimol) have rather undesirable effects such as freaky hallucinations and blackouts. Thus, most drugs we consider to "act at GABA-A" act as positive allosteric modulators (increasing the affinity & opening time when GABA binds) rather than being directly agonistic, and show no activity at GABA-B. There are also at least 5 currently known subtypes of GABA-A receptors that pose pharamcological significance, due to the receptor being a pentamer formed from 5 individual protien units - this explains the different effects of the various benzodiazepines, nonbenzodiazepines, and barbiturates.

As for for drugs like GHB and phenibut - though they resemble GABA structurally, they lack affiity for GABA-A and instead have only affinity for GABA-B as direct agonists. Somewhat confusingly, the classes of drugs do share some effects due to both being inhibitory pathways, though they do not neccesarily substitute for one another.

If you are currently trying to detox off of barbiturates, I suggest trying to find a comparable benzodiazepine dosage and use that to titrate off. Barbiturates do not act at only GABA-A - they are dirty drugs that have actions at e.g. ion channels, much like the arylcyclohexylamines. If you do use GABA-B agonists, be aware they may not fully substitute for a GABA-A PAM.

Addendum: Gabapentin (and also pregabalin) is a third, totally different class of drug - neither GABA-A nor GABA-B agonist. It instead acts at a subtype of the calcium channel.

 

[AlphaOdure]

Thanks Sekio! Here's my responses... (and please, ANYONE keep the conversation going too if they have anything to add)

It is my understanding that GABA-A and GABA-B are two seperate inhibitory pathways that share a common ligand. This accounts for the rather varied pharmacology of 'GABA-mimicing' drugs. GABA-A is rather special because directly agonistic compounds (muscimol) have rather undesirable effects such as freaky hallucinations and blackouts. Thus, most drugs we consider to "act at GABA-A" act as positive allosteric modulators (increasing the affinity & opening time when GABA binds) rather than being directly agonistic, and show no activity at GABA-B. There are also at least 5 currently known subtypes of GABA-A receptors that pose pharamcological significance, due to the receptor being a pentamer formed from 5 individual protien units - this explains the different effects of the various benzodiazepines, nonbenzodiazepines, and barbiturates
....
If you are currently trying to detox off of barbiturates, I suggest trying to find a comparable benzodiazepine dosage and use that to titrate off. Barbiturates do not act at only GABA-A - they are dirty drugs that have actions at e.g. ion channels, much like the arylcyclohexylamines. If you do use GABA-B agonists, be aware they may not fully substitute for a GABA-A PAM.

First, I am attempting a slow detox; & turned to baclofen to aid, b/c this "slow" detox has been at a standstill. & my experiences w/ benzos w/ barbiturate w/d is minimally helpful at best, unless at absurd doses (despite my dose isn't really *that* high, considering barbs affinity to rapidly induce tolerance!)- My understanding is benzos are less effective for barb w/ w/d due to needing GABA NT availability; & the whole efficacy vs. frequency thing- PLEASE, correct me if i'm wrong. B/c I don't quite fully understand this difference.

& yea, i am aware of the quite extensive medical knowledge known on GABA-A subtypes- unfortunately I wish there were similar understandings of GABA-B subtypes (but of course, no money there, no patented drugs like the newer Z-drugs/non-benzos)- so they're left unnoticed! I also realize the different mechanism between barbiturates & benzodiazepines--albeit, i don't entirely understand the mechanics, other than barbiturates are more broadly impacting, in a way.

& as well, also i'm aware of the opposing receptor-effects of muscimol & the amanita relative to the inhibitory effects of benzos, barbs, alcohol, etc; Although perhaps quite a juvenile, or simplistic statement, my understanding is substances such as muscimol affect GABAergic complexes similar to how PEA-stimulants stimulate dopamine NT... (correct me if i'm wrong! anyone? )

As for for drugs like GHB and phenibut - though they resemble GABA structurally, they lack affiity for GABA-A and instead have only affinity for GABA-B as direct agonists. Somewhat confusingly, the classes of drugs do share some effects due to both being inhibitory pathways, though they do not neccesarily substitute for one another.

Uggh, I know! Very paradoxically!

Gabapentin (and also pregabalin) is a third, totally different class of drug - neither GABA-A nor GABA-B agonist. It instead acts at a subtype of the calcium channel.

Yea, very true. & again I was aware of this, although i have absolutely no common knowledge on how this may indirectly affect GABAergic receptors. I was merely pointing out (probably irrelevantly so...) a very similar psychological response I experienced between baclofen & Gabapentin (it was *very* GABAergic in nature, for me at least; & it definitely displayed no cross tolerance to butalbital either).. But the difference being, I didn't get deathly ill after high doses of gabapentin.. & gapapentin was more friendly to concurrent use! BUT.. unfortunately, quite worthless for helping me reduce my butalbital intake.

 

[sekio]

You seem very confused on the pharmacodynamics of barbiturates versus benzodiazepines. Here's a little excerpt that should help -

While both benzodiazepines and barbiturates bind to GABAA receptors to augment GABA-mediated responses, they do so in different ways. Barbiturates have dual actions to enhance GABAA receptor-mediated Cl- ion conductance (42, 45). At low (subanesthetic) concentrations, barbiturates augment the affinity of the GABAA receptor for GABA and increase the mean channel opening time induced by GABA. At higher (anesthetic) concentrations, barbiturates directly increase channel openings, even in the absence of GABA. Benzodiazepines, on the other hand, have no direct effects on channel opening but only increase the affinity of the receptor for GABA as well as the frequency of GABA-activated channel openings (28, 45). This is an important distinction because it means that benzodiazepines will markedly augment GABA's actions at low intrasynaptic GABA concentrations, but will have little to no effect at saturating concentrations of GABA (i.e., benzodiazepines "shift" the concentration–response curve for GABA slightly to the left) (54). These differences undoubtedly contribute to the relatively low toxicity of benzodiazepines compared to barbiturates.

The binding site for benzodiazepines is distinct from the binding site for barbiturates and GABA on the GABAA receptor, and also produces different effects on binding,[11] with the benzodiazepines causing bursts of chloride channel opening to occur more often, while the barbiturates cause the duration of bursts of chloride channel opening to become longer.[12] Since these are separate modulatory effects, they can both take place at the same time, and so the combination of benzodiazepines with barbiturates is strongly synergistic, and can be dangerous if dosage is not strictly controlled.

Also note that some GABAA agonists such as muscimol and gaboxadol do bind to the same site on the GABAA receptor complex as GABA itself, and consequently produce effects which are similar but not identical to those of positive allosteric modulators like benzodiazepines.

I must point out here that simply because of its structural nature, being comprised of 5 possibly different subunits, there are intriniscally more possible GABA-Ar's than there are GABA-Br's. GABA-B receptor is actually a whole different type of receptor that is only one protien, although it has 2 subtypes (GABA-B is a G protien receptor - other famous ones are the cannabinoid and serotonin 1/2 receptors)

Muscimol does not "oppose" the effects of GABAergic drugs - it is a direct agonist at GABA-A that causes the receptor to activateand cause the cell to inhibit firing. A more appropriate analogy would be that amanita intoxication is closer to being improperly anesthetised with propofol, or being blackout drunk.

The best option for your treatment remains titration downwards with barbiturates until you can safely switch to a BZD. The 'switching point' will depend on which benzo you choose and the dose. Good luck with whatever your choice may be.

 

[AlphaOdure]

^ thanks! Yea, I actually did some catching up earlier this morning on the GABAergic complex. It is my understanding with say muscimol (was reading on that exact same article you referenced), that it actually plugs into the same receptors as endogenous GABA NTs do; causing different effects.. whereas BZDs & barbiturates bind to different receptors (still confused on PAM action though) & merely increase frequency or potency of GABA in the synapses. & yes, I read on the different fundamentals of GABA-B receptors relative to GABA-A receptors.. although I don't entirely understand the implications here; it seems reasonable to think this would be some source of little cross tolerance? I don't know, i still may be off the mark.

At higher (anesthetic) concentrations, barbiturates directly increase channel openings, even in the absence of GABA.

Yes, i've read this time & time again; but i can't seem to grasp the concept entirely. I would think (correct me if i'm wrong), this would imply barbiturates would still have some effectiveness (since they don't depend on GABA presence) in cases of generalized GABA-A agonist withdrawal? no? yes? maybe? Whereas BZPs wouldn't, for example, be nearly as effective in treating withdrawal in equatable dosages to a barbiturate? no? yes? maybe? ...i somewhat assumed this to be the mechanism for why one can't necessarily substitute BZPs for barbiturates (if used at higher doses)? Unless i'm totally off here..? B/c this article always seems to conclude with "this is why barbiturates are more toxic" -- while, I partially *get* why this is; I don't know if the assumptions I also made would apply?


Anyway, thank you so far for your responses. I just want to discuss further implications between concurrent GABA-A & GABA-B drugs, in general. I just don't get how.. GABA-B drugs, such as GHB or GHL can have additive effects. Yet, baclofen, also a GABA-B agonist did NOT have additive effects, almost the opposite (and i don't see GHB-receptor affinity playing a role in this? if anything, this would cause a problem! But baclofen has no affinity for the GHB receptor).. unless, again, my initial experience was a result of an overdose/hangover effect; inducing some unknown mechanism causing the blockade. (Its now day 8-9 since my initial/first baclofen dosage, i believe, and i am just now regaining nearly typical effects from butalbital, with only ~10 mg of baclofen at night.. so now i'll be able to start titration downwards)

 

[alkap555]

Here is an interesting paper from Nature Neuro regarding the strx elucidation of the GABAb receptor, which is IMO has largely been ignored as a pharmacological target (except for the obvious baclofen, GHB agonists). To my knowledge this is the first paper that characterizes the strx, fxn, and interaction of different subunits of the GABAb receptor.

Inhibitory neurotransmission is mediated primarily by GABA. The metabotropic GABAB receptor is a G protein–coupled receptor central to mammalian brain function. Malfunction of GABAB receptor has been implicated in several neurological disorders. GABAB receptor functions as a heterodimeric assembly of GBR1 and GBR2 subunits, where GBR1 is responsible for ligand-binding and GBR2 is responsible for G protein coupling. Here we demonstrate that the GBR2 ectodomain directly interacts with the GBR1 ectodomain to increase agonist affinity by selectively stabilizing the agonist-bound conformation of GBR1. We present the crystal structure of the GBR2 ectodomain, which reveals a polar heterodimeric interface. We also identify specific heterodimer contacts from both subunits, and GBR1 residues involved in ligand recognition. Lastly, our structural and functional data indicate that the GBR2 ectodomain adopts a constitutively open conformation, suggesting a structural asymmetry in the active state of GABAB receptor that is unique to the GABAergic system.

http://www.nature.com/neuro/journal/...l/nn.3133.html

The paper is pretty comprehensive, including X-ray strxs, electrophys, and some ligand binding-conformational change assays. They highlight the strxural and fxnal differences between the GABAbR and related GPCRs such as the mGluRs. Very cool.

 

[AlphaOdure]

Here is an interesting paper from Nature Neuro regarding the strx elucidation of the GABAb receptor, which is IMO has largely been ignored as a pharmacological target (except for the obvious baclofen, GHB agonists)

Well.. I do agree the neuropharmacology of GABA-B is not as fully understood relative to GABAergic drugs of the -A subtype, nor are they as well studied (thus prompting this thread!); and this is most likely due to the lower variance of and/or distribution of endogenous metabotropic GABAergic receptors (as I've taken from Sekio's response, although i'm dancing dangerously close to the edge of my knowledge on this matter). HOWEVER, Although from anecdotal case-studies & worthless studies on RATS, I wouldn't say baclofen & GHB are exempt from lack-of-study.. Not by a long shot!

And really, is all of this much of a surprise? Not really. All current psychoactives that have primary affinity and/or selectivity for GABAergic metabotropic receptors (like baclofen) aren't patentable... or they've been around for a while. There aren't any new drugs on the horizon; so, SURPRISE SURPRISE! ..No intensive or broad double-blind studies have been and/or ARE being performed on these drugs in humans (specifically in regards to baclofen; and even more so in relation to their interactions with GABA-A agonists. And for example, in issues of possible blockade of GABA-A agonists--which was my own experience w/ baclofen).. All b/c there's no money to be made.

Angers me just thinking about it (i have a fetish for politics & economics; especially w/ drug, prohibition, & healthcare policy, in case you haven't noticed )! Drugs are only developed for a profit motive. While this isn't necessarily a bad thing.. merely profit motive as a means for an ends isn't a good thing either if its the "end-all-be-all", as it is here in the US. Medicine & health shouldn't be purely a private-enterprise at the mercy of the market & its irrational demands! We've gotten away from the Hippocratic Oath. Big time! Anyway; I'm off topic here on my own thread. SO, I digress....

Anyway, thanks for the link alkap; i'll take a look as soon as I have some extra time!

 

[sekio]

I'm not going to elaborate on it here, but medicine and drug discovery is not always all profit-driven. Drugs may be marketed and sold for profit motives, but they are developed to solve biological problems. Nobody designs a drug for the sole purpose of getting filthy rich - the money is all in the production. (It just so happens that the executives like it when both halves of the Venn diagram overlap.)

 

[AlphaOdure]

^HA... i can agree with that. But after all, It is the executives & COs who are in charge of the direction of a particular firm (and they aren't pharmacologists.. they're about the bottom line; they may be developed to solve biological problems, but this is merely a commodity, a tool- just like selling corn or speculating on equity-markets).

But, Like i said; no doubt there is some value in having profit as an incentive to produce medications. Sometimes it is a hindrance, sometimes not. But, my own economic philosophy finds something disturbing in mixing typical economic incentives to a much higher degree w/ pharmaceutical development relative to finding adequate treatment! (Mind you, this is all in the context of the American healthcare system, err business, where capital is pumped at exponentially higher rates into developing boner-medications for $20 a pop & for patentable medications; rather than medications to treat AIDS & malaria--which do in fact exist--but they are not distributed & produced on mass scale due to low capital return)

Anyway, sorry, didn't mean to derail my own thread 8( ...back to business!

 

[alkap555]

Although from anecdotal case-studies & worthless studies on RATS, I wouldn't say baclofen & GHB are exempt from lack-of-study.. Not by a long shot!

I never said baclofen and GHB were under-studied. I said the opposite, in fact, as quoted in your post: "...has largely been ignored as a pharmacological target EXCEPT for the obvious agonists, baclofen and GHB (revising my grammar a little)." Also, the VAST majority of behavioral pharmacology is conducted on rodents, and I would hardly call that "worthless." Any modern drug you've ever taken was first tested in rodents and other mammals for toxicology, absorption, metabolism and excretion, and w/o these "worthless" rats, they would never have made it to human trials.

So please don't denigrate the sacrifices of our furry little rodent friends--many of them paid the ultimate price so we could use the lifesaving and recreational drugs we take for granted.

And really, is all of this much of a surprise? Not really. All current psychoactives that have primary affinity and/or selectivity for GABAergic metabotropic receptors (like baclofen) aren't patentable... or they've been around for a while. There aren't any new drugs on the horizon; so, SURPRISE SURPRISE! ..No intensive or broad double-blind studies have been and/or ARE being performed on these drugs in humans (specifically in regards to baclofen; and even more so in relation to their interactions with GABA-A agonists. And for example, in issues of possible blockade of GABA-A agonists--which was my own experience w/ baclofen).. All b/c there's no money to be made

You are forcing me to further derail your thread! First of all, there are only a handful of these "unpatentable" GABAb agonists in common usage, the most notable being phenibut and GHB. However, GHB, under the trade name Xyrem, is currently patented by Jazz pharmaceuticals!! And for anything to get through the FDA's approval process these days, there must be extensive double-blind studies on efficacy, adverse effects, toxicology etc.

So really you are talking about one compound, phenibut, which for all intents and purposes is a dirtier version of baclofen that would have no real uses in clinical practice.

Baclofen has no affinity for GABAa receptors, so it is highly unlikely that you are experiencing direct competitive antagonism of butalbital; I'm sure if you scoured the literature you could find studies comparing/contrasting barbiturates and baclofen, and there have likely been many experimental protocols involving their concomitant use. It seems a bit over-the-top to expect researchers to study the effects of combining baclofen with jaw droppingly LETHAL-high doses of butalbital, don't you think?

But more to the point, who is to say there is no money to be made off of novel GABAb agonists? If they can characterize novel binding sites on the GABAb receptor, then there sure is the potential to develop interesting new drugs for anything ranging from muscle spasticity to cocaine addiction (yes, baclofen shows anti-addictive qualities--a HUGE possible money maker, BTW). So honestly, I don't know where you are getting this idea that Big Pharma (or academia) has decided to abandon all research into GABAb receptor agonists and allosteric modulators, especially when this exciting new paper has just been published?

Yes, drug development is often profit-motivated, by why shouldn't it be? Can you think of any major diseases lacking pharmacologic treatment modalities b/c there is "no money in it"? For the most part, profit-driven drug development is mutually beneficial: if 10 million people suffer from condition X, then there is a large $ incentive for pharma to develop a treatment to help those 10 million people. And in cases where the prevalence, and thus incentive is much lower, that is where the Orphan Drug Act comes into play. Case in point: Xyrem (GHB; Sodium Oxybate).

In the hey-day of Big Pharma, this profit-driven market model may have posed a more significant threat than it currently does. In recent times, however, an increasing majority of new drugs are initially discovered in academia and developed by biotech start-ups. If you can provide me with any concrete examples of how the pharmaceutical industry has somehow "let down" mankind, I am honestly very curious to hear.

When I tell people that I plan to work in the pharmaceutical industry, I have gotten the same question half a dozen times: "how could you work in an industry that only cares about their revenue and doesn't help people?" And my response is always "can you give me an example of this?" Invariably, the topic of conversation changes rather quickly.

NOTE: I agree that it shouldn't all be about money, but everything in this world is. To expect anything else from private corporations is a bit silly. If anyone can propose alternative solutions, I am all ears. Sorry for derailing your thread, but you can't provoke me like that and expect to get away without it

 

[AlphaOdure]

but you can't provoke me like that

its all good! Uggh, its hard for me NOT to respond either, haa. But i'll refrain! ..Aside from a few points:

In regards to Jazz pharmaceuticals; it very well has patented GHB; but not making much money (RARELY prescribed!)... & its patent will run out by 2018ish.

& read my post (i edited it) above yours... in regards to production of drugs like Viagra in favor of widely available AIDS treatments (most of which aren't patented- i need a source, but this discussion is for another post, for another day, & another forum anyway).. all b/c there is more profit to be made in these drugs, at the hands of PHRMA & the pharmaceutical companies it represents here in the states. But, again, there are upsides to profit incentives (btw, there is a better way.. w/ a mix of private & public healthcare systematic drug development; private industry must make ever-accelerating returns, this is good for some areas; where as the state must only break even, perhaps make a little profit, in relation to revenue-and-expenditure ratio, which is wonderful for drugs that are poorly inductive to revenue, but fulfill a huge medical need)

Anyway- I really don't wont to get this thread closed down; so your points are well taken alkap & hope I didn't provoke you too much! SO! ....back to topic!

 

[alkap555]

K. Lets continue this discussion another time. Agreed there prob is a better way. Who knows. I am not an economist.

 

[sekio]

Nobody's going to close the thread as long as there's intelligent discussion going on. Plenty of threads have derailed before and mods can always split threads apart.

From my point of view, it seems that with most pharmaceuticals, cost has 3 rough factors: complexity, age since discovery, and worldwide demand. Biologics like antibodies etcetera are very complex, relatively new, and must be carefully matched to the disease and person who is recieving them. Small-molecule drugs like GHB and phenibut that have been around for 50+ years are going to cost intrinsically less because they can be produced en masse very easily, and there's often wide demand for things like selective small-molecule protien ligands (i.e. SSRIs, antipsychotics)

 

[AlphaOdure]

^^^^
Definitely!.. Although i'd view your last two factors "age since discovery" & "worldwide demand" as much less of importance (at least to PHRMA clients & their benefactors, here in the US)... i'd say. again- viagra = more profit margin (& its relatively complex! ...i'm sure it'll be abandoned for widespread use once its patent runs out in favor of newer drugs, but that's just in my opinion).

Whereas similarly complex drugs that save lives (rather than cause erections within a healthcare system tailored to rich, healthy individuals in the US & foreign nationals, for that matter) = very low perpetuation. Same w/ non-patentable drugs and/or older drugs! But again, i'm just expressing my opinion, there are many dangers in a system mostly based on patent rewards for private-development of drugs (like that of ours, in the US.. by your statements, i'm assuming you live here). Of COURSE these industries--who are in business to make money--will gravitate to lower cost intensive drugs; relative to profit margin! In all cases, of course this isn't a bad thing among all drugs & their development.

My personal opinion is just that there needs to be a balance between a profit-based industry & a state-sponsored entity (i.e., the gov't) who acts on our behalf (although, unfortunately, most the electorate I live in is quite ignorant on the complexities of most issues (look at the prison state? prohibition? etc)... as I said; there is something to be said between a private industry that depends on ever-accelerating net-profit margins & equity centralization; whereas a government must only need to break even, thus making development & distribution more common (not to mention preventative care!)

BUT.. w/ phenibut & GHB... they're really only available on black markets; not as medications; nor are they studied to the extent of SSRIs, newer & patented drugs, etc... But of course, you my apply this to the wonders of a totally private, profit-driven market? But from my point of view, I see this as detrimental (for the record, i'm a libertarian socialist: anti-prohibitionist, decentralized socialized gov't w/ federal oversight, like of the Scandinavian type, particularly Sweden being a model of Social Democracy I look to... but thats just me)

 

[AlphaOdure]

ANYWAY
Sekio- Did you read any of my posts on GABAergic mechanics? ...Especially relative to -A & -B subtypes & their interactions? Any corrections? Anything I missed, or anything I confused? I know the GABAergic complex is very intricate, but trying my best; & i'd like to try & relearn it to higher degree than I do now. It was some 7 years ago since I was a pre-pharmacy major for some one & a half years (although most of which wasn't remembered since this is when my opioid addiction first started to severely manifest itself)!

 

[ebola?]

So this thread has taught me a good bit about relevant details of GABAnergic agonism. I have two main questions:

1. How wide is the gulf between GABA-A and GABA-B mediated inhibition? To the extent that the relevant processing pathways are entirely separate or profoundly downstream, we should expect concurrent GABA-A and GABA-B agonism (or positive allosteric modulation thereof, as is usually the case with GABA-A 'agonism') to be additive in effect. But to what extent is it synergistic? How do we account for such synergy?

2. To what extent is neural adaptation to exogenous GABAnergic agonists specific to these ligands' effects? That is, to what extent will there be cross-tolerance between GABA-A and GABA-B agonists? To the extent that tolerance is limited to receptor downregulation, I would expect tolerance to be highly specific. But to what extent are other mechanisms, eg downregulation of the endogenous conversion of glutamate to GABA, involved?

Nobody designs a drug for the sole purpose of getting filthy rich - the money is all in the production. (It just so happens that the executives like it when both halves of the Venn diagram overlap.)

Honestly, it is more that no one DESIGNS drugs per se. Rather, chemists tinker with what they can synthesize, informed limitedly via biochemists (and biophysicisits' and microbiologists' intuitions into SARs), make new compounds, and then those novel ligands expected to be profitable enter clinical trials.

Yes, drug development is often profit-motivated, by why shouldn't it be? Can you think of any major diseases lacking pharmacologic treatment modalities b/c there is "no money in it"? For the most part, profit-driven drug development is mutually beneficial: if 10 million people suffer from condition X, then there is a large $ incentive for pharma to develop a treatment to help those 10 million people.

My primary qualm is that the criterion of profitability often diverges from efficacy of treatment. This occurs mainly because individuals and insurance providers will pay similar sums for modestly effective treatments in a field composed entirely of modestly effective treatments as they would for highly effective treatments in a field composed mostly of highly effective treatments. eg, ask yourself why we have developed 437890254732 SSRIs in the last two decades while the pursuit of alternative avenues has for the most part stagnated.

ebola