Benzos Possible risk involved w/ sublingual administration of oral benzodiazepines

[The.Ghost]

If you want to soften the pills up, put them in a bottle with a few drops of water. The water vapor will absorb into the pills, taking them from rock-hard to soft and chalky. Unless it's an allergic reaction / dehydration as others have suggested, this should make the pills SL-able.

 

[ReversiblePulpitis]

I'd like to interject on a tangent.

As a 4th year Dental School student whom is nearing imminent graduation, I have a patient whom also chooses to administer his benzos (Xanax and Klonopin) via the sublingual path. Neither of these meds are designed to be dissolved this way, but obviously it works.
My comment and question:
On more than one occasion I have noticed rampant diffuse erythema throughout his sublingual soft tissues including the ventral and dorsal surfaces of his tongue, as well as his anterior mandibular gingiva both lingual/facial sides.
The erythema is coincident with slight-moderate edema (and in the case of his gums, it would there be referred to as gingivitis).
These findings are less so on the buccal mucosa, as well as the maxillary tissues but at the same time are not unaffected; they just aren't quite the same intensity in color of the erythematous lingual/mandibular tissues (bright fire-truck red beyond that of even the color that severe gingivitis may bring).

These findings SEEM to be coincident with: timing and dose of the medication in relation to the appointment, and then also of course his oral hygiene. The Xanax also subjectively but clinically seems to be the greater irritant of the two, and incase I haven't made myself clear enough yet, I believe (some/all with variance) these benzos to be a mild-moderate irritant when consumed sub-lingual.

Now this can be the case with other medication obviously, but there aren't many other meds that people willingly choose to use via this unintended ROA.

Now I do believe that superb oral hygiene would probably negate or prevent some if not all of these signs, especially if use could be followed by vigorous water rinse at least and in tandem with soft bristle soft-tissue brushing (no toothpaste) at best.

I also found it interesting that the signs were worse with the Xanax. However considering this was no sort of official experiment, there have been many variables out of my own recognition or supervision. But he also is a regular patient with a set of average hygiene habits that I am familiar with as I see him often.

Anyone else notice/experience this with a SL placed benzo meant to be consumed orally (swallowed)?

This may deserve it's own thread, especially when it's preceded by such a confusing OP. But reading the thread is what sparked the memory.

 

[tricomb]

I'm going to go ahead and move your post into it's own thread since I believe it merit's it's own discussion thread.

However, in response, as someone who has been taking my oral benzodiazepines sublingually for the better part of a decade with no problems to speak of (as directed by my physician), I'm a bit confused about what you're saying. I'm not an oral surgeon nor am I a trained healthcare professional, would you mind rephrasing your concern about using the sublingual ROA for oral benzodiazepines such as alprazolam (Xanax), lorazepam (Ativan), clonazepam (Klonopin), diazepam (Valium), etc.

This peer reviewed article proved that taking the oral formulation tablets via the sublingual ROA is therapeutically equivalent, neigh, even slightly more effective (faster onset and higher peak plasma concentrations) for alprazolam....

"Thirteen healthy volunteers received 1 mg of alprazolam, as the commercially available oral tablet, by sublingual and oral routes on two occasions in random sequence. Plasma alprazolam concentrations during 48 hours after each dose were measured by electron-capture gas-liquid chromatography. The peak plasma concentration after sublingual dosage was higher than after oral administration (17.3 vs. 14.9 ng/ml), and the time of peak concentration/b] following sublingual administration was reached (1.17 vs. 1.73 hours after dose). However, these differences did not reach statistical significance. The mean total area under the plasma concentration curve for sublingual administration was slightly but not significantly larger than that following oral dosage (203.7 vs. 194.4 hr. ng/ml) and no significant differences between sublingual and oral dosage were found for elimination half-life (11.7 vs. 11.8 hours) or for clearance (86.4 vs. 92.4 ml/min). Thus, alprazolam absorption following sublingual administration is as rapid as after oral dosage on an empty stomach, and completeness of absorption is comparable. In clinical terms, sublingual and oral dosages of alprazolam are likely to be therapeutically equivalent. The sublingual route may be a useful alternative for panic disorder patients who cannot swallow pills or for those who do not have access to a liquid at the time of dosing. (J Clin Psychopharmacol 1987;7:332-334)"

http://www.ncbi.nlm.nih.gov/pubmed/3680603

 

[Znegative]

What I wonder, is whether this could be the cause of using other drugs (including other benzodiazepines) through sublingual administration. I know for instance that the z-drugs, which are similar in action to benzo's are absolutely horrific to take sublingually, as are some antihistamines (I'm thinking Promethazine specifically). Another possibility could be what generic versions of clonazepam theatre m&t is using. Xanax almost always disintegrates as if it was made to be taken sublingually, but clonazepam, depending on the generic-does not. Some pills are much harder than others and I remember screwing up the bottom of my tongues few times from swishing some of the harder generics around down there

 

[Dagda Mochta]

Well there must be a reason that there are are specific formulations designed for subligual use. The insoluble inactives in the pills meant to be swallowed could be irritating the mucosa. The sublinguals also probably contain some kind of buffer. I know upsetting your oral pH can cause some problems.

 

[tricomb]

Well there must be a reason that there are are specific formulations designed for subligual use. The insoluble inactives in the pills meant to be swallowed could be irritating the mucosa. The sublinguals also probably contain some kind of buffer. I know upsetting your oral pH can cause some problems.

I'm pretty damn sure that the only reason they created specific sublingual formulations was further profit, kind of like Evergreening that is so common in Big Pharma, (for example, citalopram's patent almost runs up, all of a sudden they release the pure enantiomer Escitalopram, market it as the coolest NEW thing since sliced bread, flood the market with Lexapro tablets and oh-look-its-not-a-pill liquid solution). In other words, $$$$$

The only difference I have ever found between oral alprazolam (Xanax) and the sublingual dissolving version (Niravam) was the texture of the decomposition of the pill. The sublingual formulations break down much faster, and honestly I prefer using the oral alprazolam because it breaks down SLIGHTLY slower, and I'm able to keep it in the perfect spot under my tongue, unlike SL benzos which tend to dissolve all over the place in your mouth.

The only other significant difference between oral (Xanax) and SL (Niravam) version of alprazolam is price.

edit:
The inactive ingredients in my xanax bars are as follows:

docusate sodium (interesting, quite possibly irritating to mucosa, this is the active ingredient in many stool softeners)
lactose monohydrate (not surprising, can't imagine it being irritating)
magnesium stearate (typical of most pills)
microcrystalline cellulose (typical of most pills)
pregelatinized starch (probably for texture?)
sodium benzoate (as a preservative, I'd imagine)

Does anyone else see anything that I don't in terms of inactive ingredients in Alprazolam that could pose irritation to the sublingual ROA?

 

[Dagda Mochta]

I'm pretty damn sure that the only reason they created specific sublingual formulations was further profit, kind of like Evergreening that is so common in Big Pharma.

Hmmm, I wouldn't put it past them. But I've had both types of clonazepam, and the SL ones do dissolve better, and seem to hit me faster (although I admit that could be placebo).

I know you've never had a problem with sublingual benzos, and neither have I, but apparently it has caused some individuals some minor issues. Isn't there another thread about benzo mucosal damage floating around OD?

 

[tricomb]

^Yes there is, there might be a couple actually, I am working on finding them. I seem to recall someone experiencing irritation after sublingualling a new generic form of their alprazolam, if you find the links before I do feel free to post em up in here and I may merge it all together if it's appropriate.

It's very interesting since I have never heard of anyone having difficulties sublingualling benzodiazepines until recently and only on BL.

 

[Dagda Mochta]

Here's the thread I was referring to: http://www.bluelight.ru/vb/threads/...n-under-tongue-when-trying-to-sublingual-them

Also, the docusate sodium is interesting. Used as a stool softener? I wonder why it's used as a pill additive. Don't most stool softeners work by pulling water into the stool through the intestinal walls? Thats how magnesium laxatives work. If the same is true of docusate sodium, it could definitely cause some problems by dehydrating the mucous membrane. Im just speculating though.

EDIT: After reading a little bit about docusate sodium, I my presumption above seems to be incorrect, but it appears to be an irritating substance none the less.

 

[Swimmingdancer]

Perhaps it depends on the benzo, the inactive ingredients and the person's unique sensitivity, but personally I've taken various benzos sublingually (that were not marketed as sublingual formulations) and have never had a problem, and I have a very sensitive easily-irritated mouth. Obviously some people do ocassionally have problems though.

Did this discussion stem from this thread? Generic 1mg Xanx tearing up skin under tongue when trying to sublingual them

It's interesting that ReversiblePulpitis says their patient had more mouth irritation from the Xanax than the clonazepam. Maybe it's something to do with Xanax? I can't recall if I've even actually had brand-name Xanax before, but I've definitely had no problem with clonazepam. Clonazepam is actually soothing to my mouth and is sometimes given as a treatment for burning tongue/mouth syndrome.

 

[tricomb]

I merged that thread into this one.

 

[pasha]

Well there must be a reason that there are are specific formulations designed for subligual use..

Benzodiazepines are poorly soluble in water, so it takes time for them to infuse into the blood vessels under the tongue, but they will eventually as they remain there. Sublingual formulations of benzodiazepines on the other hand are water soluble.

 

[Swimmingdancer]

^Really?? How does one make a poorly-water-soluble/insoluble benzo water-soluble? I thought the only difference was in some cases the inactive ingredients used in sublingual formulations made the tablets disintegrate faster (depending on the formulation, some pills meant for oral use disintegrate very rapidly in the mouth), but that the actual drug itself was still poorly soluble in water. The drug names are no different, it's not like the ingredients say "lorazepam hydrochloride" or something. I am confused

Here's an example of the ingredients list for oral vs sublingual Ativan (lorazepam was just the easiest to find)

ATIVAN

Oral Tablets:
1 mg: contains: lorazepam, lactose, magnesium stearate, microcrystalline cellulose and polacrilin potassium.

Sublingual Tablets:
1 mg: contains: lorazepam, cornstarch, lactose, magnesium stearate and microcrystalline cellulose.

Unless you have evidence/knowledge that the chemical makeup somehow makes a poorly water soluble benzo water soluble I am with tricomb here, I think the only reason there are special sublingual versions is for profit on the part of the pharmaceutical companies. I have had excellent absorption from taking benzos intended for oral use sublingually.

 

[pasha]

^Mostly an inference based on kinetics of sublingual administration and sublingual administration of other specific medications such as Suboxone (buprenorphine HCL).

Tablets that are administered sublingualy need to be degraded by saliva (which is 99.5 percent water) in order to permeably pass through the blood vessels under the tongue. The only thing that allows regular formulations of benzodiazepines to degrade is that they can be effectively held under the tongue.

You maybe correct in that sublingual formulations are also not fully soluble in water but I'm still inclined to believe that they have better water solubility than regular formulations, as you mentioned the quicker disintegration/degradation in water alone may possibly serve as an indicator of improved solubility as essentially solubility is how well a substance can disintegrate/dissolve in water. This is also a clear advantage in terms of absorption.

I didn't have time to read the whole thread, but other advantages to bear in mind for sublingual tablets and oral liquids for sublingual administration is the ability to administer them were one is unable to swallow tablets, such as in the case of trying to control someone having a seizure, or a child.

Benzodiazepines can be made to be water soluble fairly easily.

Here's a case in point with Ketotifen (an anti-histamine) effectively prepared for sublingual administration only through the use of water soluble binders and different methods of assembly which showed improved permeability and bioavailability:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2902300/

 

[tricomb]

Benzodiazepines are poorly soluble in water, so it takes time for them to infuse into the blood vessels under the tongue, but they will eventually as they remain there. Sublingual formulations of benzodiazepines on the other hand are water soluble.

Source please? I doubt this. I don't think that Niravam is alprazolam hydrochloride. Benzodiazepines have been proven multiple times to work effectively via the sublingual route in their oral freebase non-water soluble formulation. This is due to their lipid solubility characteristics.

 

[tricomb]

The source you quoted isn't really as relevant to the topic hand as I think proper evidence should be.

Orally disintegrating tablets do not require any water to dissolve. They require the slightly acidic pH in saliva to dissolve (this is from the Niravam package insert). Orally disintegrating tablets / sublingually formulated benzodiazepines are absolutely no more water soluble than their non-SL, standard oral counterparts. I checked the active ingredients and unlike water soluble benzos like midazolam which are formulated most often in hydrochloride salt form to make it water soluble, because by nature the vast majority of benzodiazepines are water insoluble due to their existing in freebase form. For example, Xanax contains alprazolam base. But this is implied so they don't need to say so, unlike say, the hydrochloride version of a benzo like midazolam hydrochloride which adds the HCL part to specify that it has been modified from it's original freebase form to be water soluble because it's more convenient for it's most common application in anesthesiology and surgery. Form vs. Function.

 

[pasha]

The source you quoted isn't really as relevant to the topic hand as I think proper evidence should be.

The source was purely in regards to turning a substance into a water soluble one without the requirement of hydrochloric acid as I was directly asked how a insoluble compound can turn into one which is soluble, as presented in the case study with polyethylene glycol, which IIRC is the same substance that is used to create clonazepam oral solution, whilst also stating that the water soluble drug exhibited stronger absorption and permeation.

As far as your pharmacokinetics go you're correct on most parts except in that benzodiazepines are not dependent on water to be broken down.

Orally disintegrating tablets do not require any water to dissolve.

I've stated nothing different then the following:

The reason BZDS and other poorly water soluble drugs can be absorbed sublingually is because they actually have a trace of water solubility, and as you hold them on your gums they will diffuse through to the blood vessels on the other side. In addition they have affinity for the fats that form cell walls.

As for the first statement in regards to sublingual formulations having better water solubility, I clearly rectified it by saying it was purely an inference based on kinetics of other sub-lingual formulations of drugs which are water soluble and rely on that for their metabolism as in the case of olanzapine or suboxone.

I was also under the impression that polyethylene glycol would be used to create sub-lingual formulations of benzodiazepines, as in the case of oral solutions or benzodiazepines prepared for IV administration. If you're correct in the respect that water plays no part in the degradation of benzodiazepines, then that inference goes out the window.

What can't be outlooked though is that sublingual formulations of any medicine have practical applications.

 

[Dagda Mochta]

I have been under the impression that benzodiazepines readily penetrate membranes because of their high lipophilicity, and that it has nothing to do with water solubility.

 

[tricomb]

The source was purely in regards to turning a substance into a water soluble one without the requirement of hydrochloric acid as I was directly asked how a insoluble compound can turn into one which is soluble, as presented in the case study with polyethylene glycol, which IIRC is the same substance that is used to create clonazepam oral solution, whilst also stating that the water soluble drug exhibited stronger absorption and permeation.

As far as your pharmacokinetics go you're correct on most parts except in that benzodiazepines are not dependent on water to be broken down.

What do you mean? The piece of information you're questioning was copied from the package insert for Niravam (sublingual formulation of alprazolam).

NIRAVAM® is an orally administered formulation of alprazolam which rapidly disintegrates on the tongue and does not require water to aid dissolution or swallowing.
.....
Drugs Effecting Salivary Flow and Stomach pH

Because NIRAVAM® disintegrates in the presence of saliva and the formulation requires an acidic environment to dissolve, concomitant drugs or diseases that cause dry mouth or raise stomach pH might slow disintegration or dissolution, resulting in slowed or decreased absorption.

The part of my pharmacokinetics that you doubted is supported almost word for word by the package insert.

I retain that the sublingual properties of benzodiazepines are a result of their lipophilicity, their fat solubility is what allows the water insoluble benzos to permeate the oral mucosa. I mean, out of all the benzodiazepines, alprazolam is about the least water soluble benzodiazepine out there, or at least, it is almost completely insoluble at physiological pH, and yet..... I have plenty experiences to verify that alprazolam works VERY well via the sublingual ROA, I daresay it may even work better via the sublingual ROA than other more water soluble benzodiazepines.

Also, I have experience with midazolam hcl via multiple ROAs (PO, SL, IV, IM, IR), and honestly via the sublingual route, the onset of alprazolam is pretty much just as fast as sublingual midazolam hcl. (from my experiences) leading me to highly suspect the lipid solubility factor being the key player here.

http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=34860

I've stated nothing different then the following:



As for the first statement in regards to sublingual formulations having better water solubility, I clearly rectified it by saying it was purely an inference based on kinetics of other sub-lingual formulations of drugs which are water soluble and rely on that for their metabolism as in the case of olanzapine or suboxone.

I was also under the impression that polyethylene glycol would be used to create sub-lingual formulations of benzodiazepines, as in the case of oral solutions or benzodiazepines prepared for IV administration. If you're correct in the respect that water plays no part in the degradation of benzodiazepines, then that inference goes out the window.

What can't be outlooked though is that sublingual formulations of any medicine have practical applications.

Absolutely, I have been a strong advocate for the sublingual ROA with benzodiazepines, it's really ridiculous that anyone would try to inject them when the effects of sublingual dosing are just as good without the risk of IV drug abuse.

Most benzodiazepines are already formulated pretty much in their best form, yet people constantly rush to tamper with it, as if it were a tamper resistant time released opioid analgesic..... It's a purely instant release, nothing-to-stop-abuse-mechanism, don't-broke-don't-fix-it pill.

 

[pasha]

Thanks for the clarification, but I still have a few questions because I've looked extensively and you seem to have more information regarding the subject than what's out there. I'm not doubting the information you've provided, and I know that benzodiazepines are lipophilic (hence why they're stored in fat tissues in the body) I'm just interested in the somewhat exclusive sublingual kinetics of benzodiazepines as I ingest them through this route almost always, alprazolam included.

I comprehend what you mean and I agree with you on everything you've said, that benzodiazepines are purely lipophilic and don't explicitly depend on water, but rather the acidity in saliva to metabolize.

However, I've seen some evidence that clearly indicates that some benzodiazepines such as diazepam are lipophilic and ones such as lorazepam are hydrophilic.

Could you explain this?

Also, if benzodiazepines are reliant on the acidic nature of saliva, then how does that translate into other routes of administration such as intranasal?

Another thing that's confusing me is when they say:

does not require water to aid dissolution or swallowing

Does this mean it doesn't require drinking water, or saliva? Isn't saliva water anyways?

I've also seen a study indicating that orally disintegrating alprazolam is superior to regular alprazolam through the sublingual method, as it reaches steady peak plasma states quicker. Could I be correct that somehow these formulations have better permeability?

Appreciate you taking the time.