Incidental use of pregabaline as an (atypical) anxiolytic

[Solipsis]

Lyrica is pretty much the only thing that alleviates ASD related anxieties, rigidity and 'stuckness' in (negative) emotional states for me. However I was quite done taking it daily so I tapered off it months ago and I don't think it is smart to take it most days and then not for a couple of days, this seems to destabilize me and that is probably not a surprise withdrawal-wise although pregabalin is not so overt for me. How it exerts effects (including withdrawals) feels mostly hidden from me compared to other substances, even if they can be dramatic.

When I mention daily vs incidental use of pregabalin my shrink has concerns that there isn't really any proper data on taking Lyrica more incidentally even if I attest that it certainly does work acutely. While I have not tried any blind experiments I do remember this from long before I had any preconceptions of what pregabalin and gabapentin do (other than that they were supposed to help with getting off G), which I think makes placebo much more unlikely as it is also a form of blind experimenting IMO.
He did note himself how, remarkably, pregabalin seems to help so specifically for certain ASD problems - there is no official medication for any that I know of.

Anyway, I personally don't even know how much pregabalin has been investigated as an anxiolytic, what is even required for it to be used off-label? How off-road do shrinks go anyway when they prescribe off-label?

I would like to get a pregabalin script again but only if it is for incidental use to alleviate the worst shit occasionally, personally I think it is justified and all things considered I don't see any real risks. It doesn't have a MOA anyway that suggests it should be taken chronically like SSRI's to be efficacious although I admit VDCC's aren't something most people in the field seem to know all that much about.

Does anyone have any info on using pregabalin like that? What do you think are pro's, con's, risks... any speculation?

 

[Hodor]

Anyway, I personally don't even know how much pregabalin has been investigated as an anxiolytic, what is even required for it to be used off-label? How off-road do shrinks go anyway when they prescribe off-label?

I don't see any problem with incidental use of Pregabalin, except maybe that the capsules don't allow you to split doses in case your tolerance goes down. As you said, it certainly is effective acutely, if maybe too slow-acting and subtle to stop a panic attack. But when you're experiencing a sort of "diffuse" anxiety every now and then, it might be reasonable that a single dose of Pregabalin could get you out of your "rut" on those days.

Anyway, there is extensive data on the use of Pregabalin as an anxiolytic in the treatment of Generalized Anxiety Disorder, and at this point (having gone generic in Europe a few years ago) doctors seem to hand it it out pretty liberally - next to quetiapine, pregabalin is probably the most popular add-on treatment for depressed patients struggling with anxiety issues.

 

[Cotcha Yankinov]

Antagonism at alpha2delta seems to have significant effects on glutamate release, and if you're familiar with the phenomenon of kindling with GABAergics (which has to do largely with glutamate rebound), there is some concern with regards to kindling. Kindling is especially an intermittent dosing/uneven CNS levels type phenomenon. There is evidence that AMPA antagonists actually help decrease tolerance/withdrawal associated with GABAergics, and I'll point out here that AMPAr's largely influx calcium.

Its possible that the GABAergic portion of pregablin/gabapentin are contributing to withdrawals as well, the GABAergic effects are thought to at least play a role in their efficacy for bipolar mania.

With regards to a chronic MAO of pregablin similar to SSRIs, there is the matter of thrombospondin and excitatory synaptogenesis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791798/

Calcium influx plays a critical role in the expression of anxiety during GABAergic withdrawal -
https://www.ncbi.nlm.nih.gov/pubmed/17762513

"CA1 neuron AMPAR-mediated hyperexcitability is a central component of a functional anatomic circuit associated with the expression of withdrawal anxiety.

~ injection of an L-type voltage-gated calcium channel antagonist, nimodipine (10 mg/kg, intraperitoneally) averted AMPAR current enhancement and anxiety-like behavior, suggesting that these manifestations may be initiated by a voltage-gated calcium channel-dependent signal transduction pathway"

https://www.ncbi.nlm.nih.gov/pubmed/18812492
https://www.ncbi.nlm.nih.gov/pubmed/12724155

The L-type VDCCs (Cav1.2 especially) seem to be considered a target for neuropsychiatric diseases by many authors but research seems to have somewhat halted. High blood pressure aside, they seem to be used primarily in migraine as it currently stands.

 

[Solipsis]

I wasn't planning on taking so much so often that I would develop a lot of tolerance although it does seem to go up pretty fast with pregabalin at least part of the effects. Sporadic use of benzos isn't *that* bad for kindling either?

Logically if AMPA antagonists help decrease tolerance it doesn't seem like calcium channel blockage is such a bad thing... and I am not sure what GABAergic withdrawals even have much to do with any of this although it happens to be I drink a bit much. Something I did not tend to do when I took pregabalin.

That pregabalin over time reduces synaptogenesis I have known for a long time and both peppersocks and me have observed an apparent dumbing down effect after chronic pregabalin use. Hardly comparable to SSRI effects as they are not even positive let alone part of the therapeutic action?

Also AFAIK there is an effect on glutamate decarboxylase but I haven't heard of significant direct effects on GABA or glutamate release or that pregabalin is considered to be a significant GABAergic agent in any traditional sense.

That VDCC blockers are able to attenuate GABAergic withdrawals - if a lot of your post addresses what I said about coming off G: yes that is nice info to help explain some of that. Also: hyperexcitability perhaps just like nootropic irritability seem to be something I suffer from a lot. Part may be from ASD but it is made worse by dexamphetamine (irritability is a known side effect). Something that helps attenuate such hyperexcitability seems ideal to me, especially over more 'broad-spectrum' sedatives which are typically not direct or selective in the way they could achieve that.

I guess 'diffuse anxiety' is a way to put it, it is not for panic attacks. If pregabalin is handed out liberally I would be interested to know how the regimen and length of prescription compares to that of benzos or other anxiolytics. Benzos are in some places in the world handed out liberally, and that should not be taken as evidence for anything. However the habits of healthcare professionals in their prescription of pregabalin could be very interesting regarding infrequent use.
Again for the record: intermittent is not supposed to mean here 'on for a month off for a month'... that does not seem like a great idea at all.

 

[adder]

Sporadic use of benzos isn't *that* bad for kindling either?

Recently I've been wondering about this as well. I took benzodiazepines daily for 9 years, mostly clonazepam at 6mg a day. After I quit 4 years ago, the withdrawal was pure hell despite tapering but within months I got better enough to start functioning normally, I thought I was done with benzos for the rest of my life. But no, for the last several months my anxiety has been getting worse and worse until eventually I started getting panic attacks during obligatory classes at the university. I visited my GP, told my situation and got prescribed trazodone for sleep and alprazolam for panic attacks. Needless to say trazodone even at 25mg is too dulling to be of any use when you have several tests to pass every week and need to be sober enough to work in the lab with chemicals, besides it does very little for anxiety unless taken in a dose that knocks me out. So I started taking alprazolam before those 3-4-hour long classes that had been inducing extreme anxiety. It worked like a charm at only 0.5mg, got rid of most of the anxiety and didn't make me drowsy. Often I had to take it 3 days in a row, soon I started needing it even on weekend days at home, within a month I went from 0.5mg to 1.0mg for a single dose that helps enough so I don't skip classes I'm obliged to attend. I never took more than 1.0mg on a single day, yet if I take 1.0mg per day for 2-3 consecutive days, then on the following day when I don't take it (and don't need it because I'm at home), I start feeling weird, of course the usual anxiety comes back but I can also feel pretty specific symptoms like insomnia that got much worse, dark thoughts (it's hard to describe, it's the feeling as if you were surrounded by the evil and something bad was going to happen), hints of depersonalization, changes in the perception of touch, smell, taste, and vision, my back hurts more and my legs feel restless when I'm lying in bed. It's hard to say what will happen on day 2 without it as I don't think I went for 2 days without it since I first noticed these rebound effects. It actually makes me frightened as hell because I can't function without it during the week and I've got a lot of tests and exams coming up next month, and at the same time nothing is worth risking going through benzodiazepine withdrawal again.

 

[Neithman]

try exercising this also helps reducing anxiety in public settings,instead of starting to use benzos again,you managed to quit for 4 years why risking getting addicted again,it would be insanely stupid.
Also try a lower dose of trazodone

 

[adder]

Like I wrote trazodone is useless for me, at the dose it does something for anxiety, it feels like it's blocking adrenaline too much and I basically can't wake up next morning. It's not just about anxiety in public settings, that's where it gets the worst and where it accumulated to give me a panic attack for the first time, but it's there all the time due to having too much stuff on my mind, not getting enough sleep and doing only duties. When you have to get too many things done at the same time no matter what, that's what happens. You lose control, your judgement fails. What I really need is some time off, a lot of time off without having to think about what to do next and how, every decision I need to make feels like it requires tons of mental energy. I used to meditate regularly, but I can't do that any more, I can't stop thinking. Before I get that time off, I need to finish the studies, I've lost too much time due to depression, anxiety, and drugs taken to fix/escape that. A few years ago I did take those extra duties upon myself, I didn't think it'd be so tiring then, but I really don't want to get stuck where I am right now, so if I were to go back, I would have made the same decision, that's why I'm pushing myself and risking it, I guess. Exercising would help a lot if only I had enough motivation to make myself do that, but I will try to squeeze that motivation out of somewhere. I did ask myself multiple times why I would risk getting dependent again before I took the first pill, then tortured myself many times more before taking a pill even though I was on the edge and really needed it. Also, quitting any addiction is one step to accomplish, everyone does have a reason why they got addicted, I took opioids and benzos to numb certain emotions for years and even though I managed to quit benzos and stabilize on buprenorphine, I didn't work through all those numbed emotions which I believe is a great part of the reason for what's going on. On the other hand taking benzodiazepines for years certainly leaves you more susceptible to stress, in many other ways it feels like you're changed for good.

 

[Cotcha Yankinov]

I am not sure what GABAergic withdrawals even have much to do with any of this although it happens to be I drink a bit much.

Sorry if I wasn't clear - I meant to say that both GABAergic withdrawal and gabapentinoid withdrawal are largely due to glutamate rebound, therefore the relevance of the benzo literature

That pregabalin over time reduces synaptogenesis I have known for a long time and both peppersocks and me have observed an apparent dumbing down effect after chronic pregabalin use. Hardly comparable to SSRI effects as they are not even positive let alone part of the therapeutic action?

I should have been more clear - the effects on astrocytic thrombospondin are thought to play a role in gabapentinoid's efficacy for neuropathic pain, as too many excitatory synapses (often induced by nerve injury related astrocyte activation) is a large cause of neuropathic pain sensitization - I think I'm wrong now but I thought you might have had some nerve injury. I'm probably thinking of someone else...

But anyways I am curious if the effects on thrombospondin can play a role on gabapentinoid's actions on the brain, rather than peripheral nerve injury related synaptogenesis.

Also AFAIK there is an effect on glutamate decarboxylase but I haven't heard of significant direct effects on GABA or glutamate release or that pregabalin is considered to be a significant GABAergic agent in any traditional sense.

Its a bit hazy for me but IIRC one paper showed that the effects on GABA metabolism likely played a role in gabapentinoid's efficacy for mania

The gabapentin/pregablin GABA-B agonist thing is quite the enigma. While most studies have found no affinity for GABA-B, there was one group that found gabapentin had some affinity for a rather specific subunit containing GABA-B receptor.

The other groups that found negative results with regards to GABA-B agonism seemed to have mostly used different cell types expressing different GABA-B receptors, although one study attempted to replicate the same GABA-B receptor (subunits wise) and found negative results. There is still some chance in my mind that gabapentin/pregablin have some GABA-B agonism. Interesting with regards to previous use of GHB.

(paper supporting the GABA-B agonism hypothesis)
https://www.ncbi.nlm.nih.gov/pubmed/11408520 - " ~ gabapentin activation of neuronal GABA(B) gb1a-gb2 receptors negatively coupled to VD-CCs can be a potentially important therapeutic mechanism of action of gabapentin"

(negative findings paper)
https://www.ncbi.nlm.nih.gov/pubmed/11747901

The positive findings paper used several controls, including cells that only expressed GABA-B receptors, baclofen to compare to, antagonists of GABA-B to block the effects of gabapentin, and knockdown of the necessary GABA-B subunit in question to nullify efffects. Things seem to go all sorts of wrong when it comes to affinity findings, but I wouldn't 100% dismiss the GABA-B hypothesis quite yet

CY

 

[Solipsis]

@Adder: I have experienced something very similar but with etizolam at night (I too take very low doses, often below 1 mg). Kindling in the past or not, I have grown more sensitive to GABAergics and dependence and with the etizolam I realized that you mustn't push it with the 3~ times a week which is roughly where the maximum lies but probably not if you have gotten more sensitive like us. Plus: short-acting anxiolytic benzos can cause more acute and pronounced dread as withdrawal effect. While you should keep an eye out for seizures (haven't had them myself), I recommend that you are not scared too much by the dread and other withdrawal effects and that you go through them and tone it down with the benzos. If you do this in an early stage the worst of it may not last too long and it would be a small sacrifice compared to going deeper and deeper into it again.
It's not insanely stupid though as was said so bluntly. It can put on a lot of pressure to have to withdraw in a sort of schedule if you have to be functional, you need the faith that you can manage and it will be okay soon enough again and make a lot of correct decisions with that while you are being influenced by the effects / fears / withdrawals / panic attack type stuff. But anyway it would be a damn shame indeed for both of us.

I realize it is playing with fire and my belief is that it is a pretty bad plan to use benzos (again) on a structural basis, so for a problem that is recurrent / anticipated and in a way scheduled. Of course a continuous problem is worst to treat with benzos, that was my major mistake in the first place. So I reserve it only for exceptions where it would be worse for my functioning etc if I didn't take it.

I think mania happens with GHB and its withdrawal too, Cotcha... not quite sure what is behind that but it is interesting. Yeah I imagine that glutamatergic rebound to be quite bad for you, isn't it?

No I don't have neuropathy other than some chronic neuropathy caused by slightly herniated vertebrae - so that is quite unrelated.

I agree that the nature of the rebound is interesting, but I'm not sure if any of this says much about how quickly this might happen and thus how pregabalin must be taken. With benzo's and other simpler GABAergics you might pretty much say to take as little as possible whereas for now the message is unclear what is true for pregabalin. I guess it's manageable to go on a stable regimen, it seems like a bad idea even just based on my experience to take it a lot but too randomly, but I guess I am really wondering about something like 1-2 days per week (tops).
I have trouble gleaning it from the data, would probably be easy for me to misinterpret something as potentially dangerous (based on inappropriate parallels drawn with GABAergics - even if they share some properties) which is not the plan.

Thanks for the info! The GABA-B controversy could indeed turn out to be based on an oversimplification, that seems like a typical outcome to be clarified after some sophistication. I guess not yet in this case.