Novel pharmacological approach to psychotherapeutic hypnolepsy prescribing?

[Geaux Tigers!]

I apologize if this is more appropriate for Neuroscience and Pharmacology Discussion; moderators have my permission to move it there if appropriate.

Hello, Bluelight community!

I am treating a patient that I diagnosed with narcolepsy featuring minor episodes of cataplexy. It has been 17 months now, and she is satisfied with my prescribed medicine cocktail, but doses continue to escalate because she claims tolerance at diminutive doses.

I have her "maintained" currently, but I feel like I have her consummated on every option. She desires perfection, and I am doing the best I know how; however, psychopharmacology may not alleviate every symptom of narcolepsy. I want her to be satisfied with her medical treatment.

I am infamous as being the "most interesting" psych in town. I believe in off-label too, and I go by my own judgement when it comes to prescribing the doses because I always keep the patient's response and tolerance to medication in my mind.

In this case, I suppose that this is more neurology than psychology, but I digress.

What augmentation would you suggest with this regiment below?

7.5g at night of Xyrem (sodium oxybate)
#180 Zenzedi (dexamphetamine IR) 10mg. [60mg.]
#120 Provigil (modafinil) 200mg. [800mg.]
#120 Vivactil (protriptyline) 10mg. [30mg.]
#90 Wellbutrin SR (bupropion) 100mg.

The patient's most problematic symptom is excessive daytime sleepiness. As you can tell, the doses are capacious, and there is really no more proliferation. She is satisfied right now with her treatment, but I am anxious about her tolerance aggrandizing leading to dissatisfaction with treatment that was once effacious. I make it my goal to not have to see every patient every month (just come in for script) because they are stable so this is something I'm concerned with; essentially, this is my professional impetuosity.

She claims that the most effective medication is the GHB which makes sense to me. She stated that it helps her get the type of sleep she needs thus reducing the severity of her EDS. She is on the third tier of the FDA recommended dosage, however.

The Zenzedi (dexamphetamine), you may be questioning why I chose it over Adderall (amphetamine salts), a drug that might be more stimulating due to the l-amp. Zenzedi is specifically indicated for narcolepsy via a brand name. The highest dose is 10mg., just like the generic Dexedrine IR. The patient has very good insurance. Also, I believe this is better for her blood pressure than amphetamine salts.

For months, she said the modafinil was worthless yet "had potential". It took awhile, but she is now on 800mg. and it is no longer placebo. I do not believe modafinil is very toxic at high doses, but according to the FDA, it is not proven to be any more effective over 400mg. I believe this an atypical case.

The protriptyline was initiated with the cataplexy specifically in mind. It seems to be rarely used. (I find it to be a great augmentation agent for ADHD as well.) I thought the cataplexy suppressing effects of its TCA properties and its stimulation, unique among TCAs, made it a felicitous selection for this patient.

The bupropion is sort of a desperation attempt due to its relevant reuptake inhibition. I was concerned with it due to the cataplexy. She takes her medicine throughout the day; therefore, I thought that having higher plasma levels of bupropion would make its negligible stimulation more active. I need to monitor bupropion more closely.

So, there ya have it, Bluelight.

What approach should I take pharacologically to best ameliorate this patient's narcolepsy?

Thanks!

 

[Snakevillon]

Xanax

 

[Geaux Tigers!]

Xanax

Snakevillon, I must disagree with your suggestion of alprazolam. This addictive benzodiazepine would give an already heavily sedated patient more possible lethargy. Also, she is not indicated for any anxiety disorders.

 

[klekip]

a doctor asking for advice on a harm reduction site? wut?

 

[cwake18]

I think he was joking. Those are some pretty generously high dosages, I was on nuvigil 150mg once for depression induced lethargy and my dr had me only take half the pill and that would have me stimulated all day, as did 50mg vyvanse. But 800mg of provigil and the dex is generous as it is. You could keep exploring stimulants and such but it seems like this pt has a serious narcolepsy condition. I know nuvigil is indicated for narcolepsy, although it's pretty much the same as provigil, but comes in a 250mg dose. What does the patient think she needs?

 

[Geaux Tigers!]

I know nuvigil is indicated for narcolepsy, although it's pretty much the same as provigil, but comes in a 250mg dose. What does the patient think she needs?

Yes, I'm aware of the availability of armodafinil at that dose since 250mg. is what I am prescribed personally for myself to take everyday.

The patient has no idea what she needs. She has no complaints right now, but I bet she will say she's feeling really, really tired soon. She will almost fall asleep during the visit, and I can tell it isn't bullshit. She has a serious case of it, and I am surprised that she went to me instead of a neurologist. Well, I'm not too surprised since I am regarded to be well versed on all aspects of brain physiology. My medical knowledge of narcolepsy, which requires medication that I have extensive experience with, makes me a well-suited choice to treat her condition. I want her to be satisfied, but I am not sure what else I can do psychopharmacologically in this case.

 

[Geaux Tigers!]

I think this thread is more suited for the advanced drugs discussion forum. Moderators, can you please move my thread? Thank you!

 

[pasha]

moved

 

[atara]

Bupropion and modafinil can inhibit the dopamine releasing effect of amphetamine. I'm not sure why you would combine these, though I would love to hear sekio's opinion. It's possible that by removing these two, amphetamine will be able to work at full effectiveness and you'll see an improvement! The short version is that bupropion blocks the function of DAT whereas amphetamine reverses it, but you can't reverse something that isn't running. Modafinil is also a DRI, with additional action as a D2R partial agonist (the highest efficacy at the schizophrenia receptor that medicine is willing to fuck with).

Anywho, an effect which every psychedelic drug user is familiar with is can't-sleep-elves-will-eat-me: psychedelics, which act by activating the 5-ht2a receptor, are extremely potent antihypnotics. Inversely, trazodone, a potent 5-ht2a antagonist, is also a powerful hypnotic. The implication for 5-ht2a agonism's effect on sleep is clear.

In this light, I suggest first lisuride, a 5-ht2a partial agonist with no psychedelic action, a result of its functional selectivity. Unfortunately, this drug is not available in the US anymore. It would be of course of profound convenience to simply prescribe a small amount of DMA or a similar nonpsychedelic 5-ht2a agonist, as it seems to be an effective stimulant with little psychedelic action due also to functional selectivity. However the only available drug similar to lisuride is ergometrine, which is out of the question because it causes heart problems (among other things). Fenfluramine is technically on the list too, but... well... you know.

I would, as stated, probably withdraw bupropion. The reason bupropion is not stimulating is suspected to be antagonism at some subtypes of the nicotine receptor (nAChR). Conversely, though with a break in between, I would suggest a nicotine patch. These are well-tolerated and known to be used safely in combination with the drugs listed, and nicotine is an effective stimulant with a separate (in fact synergistic) mechanism of action.

[Note: I am not a doctor! See my custom title.]

 

[checktest]

What an oddly timed thread. I actually just heard from a friend whose family had a weird kind of hypersomnia-narcolepsy thing going on. They all had really weird sleep studies, with varying levels of sleep apnea and odd spikes, and varying diagnoses. More relevantly, his sister finally found a big difference in a trial for some GABA-modulating drug, after years of stimulants, anticonvulsants, and modafinil. Wikipedia lists Flumazenil and Clarithromycin, but I don't know if it was one of those. That family was on a similar line, though. I remember seeing him fall asleep readily after taking 80 of IR amphetamine, and never being really all that more awake on any of the drugs.

Hopefully she has had a few sleep studies, some daytime EEGs, and a holter to cross off a few other problems. Autonomic dysfunction as well. Likely that has been covered. And you can't really try out any of the other major REM-affecting drugs like an MAO inhibitor because of the degree of interaction already.

On the other hand, with that kind of dose escalation, calling drugs worthless, and perfectionism, maybe there could be something else or additional going on that could be better suited by a different kind of treatment. [Summarizing a quick story from a neuropsych- long term patient was taking doses of seroquel before visits and encounters to get more drugs. Didn't go so well. Dealing with chronic pain is bad enough.]

 

[Geaux Tigers!]

prescribe a small amount of DMA or a similar nonpsychedelic 5-ht2a agonist ... I would, as stated, probably withdraw bupropion. ... I would suggest a nicotine patch.

atara, thank you so much for your apropos counsel! Great information like this is the reason I joined and asked this wonderful community.

Your suggestion of a 5-ht2a agonist is novel indeed-- just the type of thing I was looking for. I know the theory behind it, but you really brought this idea to the surface. I read your links, very interesting-- what a great idea! I love reading things like this.

I've always seen bupropion augmented over and over again with patients concomitantly on psychostimulants, but I was not aware that it actually attenuates amphetamines. I will definitely have to see how she does off of it. I will definitely withdraw it.

I've thought about suggesting a nicotine patch, but the idea feels so "wrong", lol. I feel like she would follow my advice about it for sure and develop an addiction. Maybe if things get worse, I will have to for sake of her quality of life.

Thanks, atara!

GABA-modulating drug ... Hopefully she has had a few sleep studies, some daytime EEGs, and a holter to cross off a few other problems. Autonomic dysfunction as well. Likely that has been covered. ... something else or additional going on that could be better suited by a different kind of treatment.

Hey, checktest! Thanks for providing another SUPERB, well thought-out response!

The GABA-modulating drug is a fascinating-- novel-- suggestion. Just the kind of thing I was wanting to read about. I see some drugs in development that use this function. I can not believe I've never read into this! I did find the Wikipedia article you mentioned, good stuff. In terms of flumazenil, I am wary about that one; however clarithromycin-- there is a 500mg. extended-release version of it, very interesting. Just so off the wall and theoretical, but it's the type of thing I'm known to do.

I have sent her for all relevant tests including hypocretin. It reminds me of a pain management doctor dealing with a patient that has fibromyalgia pain with no MRI evidence. I'm doing the best I can to make her life better, but there comes a point where something is up.

Thanks, checktest!

Anyone else, please feel free to contribute input!

 

[BallsStapledToLeg]

Hey,

You might want to be careful with how specific you are with your information regarding yourself especially on a site like this. A specific profession and location is enough to narrow down your identity significantly without me bothering to do any kind of identification past that.

url goes here

Best,

Some paranoid guy on the internet

 

[Geaux Tigers!]

Thanks, I thought I had checked some sort of box where my location wasn't public, but I was obviously thinking of something else. Really glad you're looking out for me! Cheers.

 

[Hammilton]

Wasn't modafinil supposed to be an orexin agonist? I would think that alone would benefit the cataplexy.

What symptoms are you most concerned about?

Have you considered a daytime dose of the sodium oxybate? Its efficacy and the relative ease of treating the induced sedation with amphetamines would make me think that if the cataplexy is a serious problem, it would be a good way to go.

I disagree with the decision to go with a dextro-amphetamine over the more common adderall because the addition of the l-isomer is certainly more stimulating, and here the goal isn't mental focus, it's simple stimulation and I don't think there's much reason to think it's any more dangerous. Is the indication that important?

I would agree with atara that the bupropion probably isn't helping.

The modafinil may still be helpful, but I'd switch to armodafinil if the doses need to be so high for activity. Need the insurance for it, though, I am prescribed it, but it's damn expensive.

 

[yaesutom]

In my experience Adderall causes much greater tolerance... after a while on it massive doses wouldn't wake me up. When I switched to Dexedrine I still got a tolerance in the end but it was never as bad as Adderall.

Even better... why not Desoxyn? After I had been off all stimulants for years I started taking d-meth (but confirmed to be near pharma grade so basically Desoxyn) and even after many months I never needed to raise the dose over 20mg/day and that worked better than 60mg Dexedrine after being on it for a long time. Also, when I ran out, I didn't NEED to take it to wake up in the morning. There was barely any withdrawal (going off Adderall or Dexedrine, I can't even get out of bed for a week or two).

Another good thing with Desoxyn is you will still be able to raise the dose higher because there's less side effects.. A friend told me about some guy she knows who needs 120mg Desoxyn to stay awake (narcolepsy).. you wouldn't be able to push Dexedrine that high without terrible side effects.

 

[Limpet_Chicken]

Clarithromycin doesn't strike me as a good idea at all, breeding resistant infections isn't something anybody wants, either for the patient, or for the wider range of people living in the area.

 

[checktest]

Yeah, I'm pretty nervous seeing antibiotics as off-label adjuncts. Having people be on maintenance doxycycline for acne is pretty scary as well. Clarithromycin is even a pretty bad one for C. Diff as well. Seeing wide ranging antibiotics like Minocycline and clarithromycin, or backup TB drugs like Cycloserine used in mental disorders kind of speaks to the lack of progress made to treat those disorders, though. Hopefully research will guide understanding for more selective drug development.

Moreover, clarithromycin has decently strong effects on liver enzymes (3A4?), so drug interactions would have to be watched closely and doses balanced. Especially with Tricyclics in the mix. (Having been on fluoxetine and desipramine before, I know psychiatrists deal with that a lot, but still, another factor to consider.)

http://jop.sagepub.com/content/early/2013/12/02/0269881113515062.abstract