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PostPosted: Sun Apr 23, 2017 3:22 pm 
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Wanted to know if someone could clarify that point for me. I am very experienced, college-plus educated in this kind of stuff.. pharmacology, drugs, etc. I read one of his posts on his blog that subs at low dose like <1mg behave as if they have a shorter half life, and thus he recommends dosing twice a day at those levels.

I'm not talking about subs acting like full agonist opiates at the mu receptor once the dose drops below the ceiling effect dose... I understand that perfectly. I just don't understand his point in that the half-life of subs seems to change and become shorter at low doses thus leading to his recommendation of twice a day dosing at low levels of sub.


Could someone clarify this point for me? Why is that? Seems to me like if 2mg has a, say, 36 hour half life, then 0.125mg should also have a similar half life. (I am currently at day 2 of 0.125mg in my taper, dosing once a day, plan for about 3-4 more doses before my final jump.) I guess I would rather dose twice a day if that will steady out my blood levels a bit more. I don't want a big peak after the AM dosing to undo my tolerance just a tiny bit each time I dose in the AM daily.


The taper is starting to catch up to me, definitely feeling it in the mornings before dosing and at night when I try to sleep. Was wondering if perhaps I should switch to twice a day dosing than the once a day morning dose I am currently doing in order to avoid some of these peaks and valleys I've been happening... feeling fine after taking my morning dose and afternoons go really well, but at night start having issues with insomnia; had diarrhea for the first time this AM, and briefly had RLS for the first time last night since the entire taper.


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PostPosted: Sun Apr 23, 2017 6:21 pm 
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Hey DSH, best of luck with your tapering. I forget exactly why this happens, something to do with the enzyme that metabolizes buprenorphine. The medicine is slowly converted and the enzyme can only metabolize so much at a time. The reason patients are prescribed doses of suboxone that are higher than the ceiling threshold is so the drug will stay in their system longer and not drop below said ceiling between doses. There are anecdotal reports that doses above the ceiling can increase the effect of the medication, but many of these experiences are likely psychological in nature.


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PostPosted: Sun Apr 23, 2017 8:11 pm 
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I'll try and take explaining this on. I'm usually quite good at explaining this idea, but given my head has been a bit sketchy lately I'll do my best. Obviously Dr. J can explain it better if he has time.

Buprenorphine is unique for a couple of reasons. The main reason is its partial agonist effect that creates a ceiling effect at higher doses. The ceiling effect means that once you hit a certain dose, which is for most people around 4-8mg (body weight and metabolism depending), all mu receptors are saturated with buprenorphine, so taking any more has no extra stimulation of the mu-opioid receptors. However taking increasing doses over the ceiling effect does have the nifty effect of increasing the length of time the mu-opioid receptors are saturated. So say if your body type and metabolism leads to receptors being saturated for 24 hours, taking 16 or 24 mg can significantly increase that duration. This is why some parts of the world permit double dosing, of taking twice the dose and dosing every 48 hours instead of 24.

When you're on a really low dose of Suboxone, say 1-4mg, often the PEAK level of buprenorphine in blood/plasma don't even hit the ceiling at all. This leads to noticeable peaks and troughs throughout the day. Every time you dose the receptors are forced to upregulate and downregulate, which is exactly what happens a person takes short acting full agonist opioids like heroin, oxy, morphine etc. This can lead to a person actually feeling a bit "stoned" every time they take their dose, and potentially feeling mild withdrawal as the dose wears off.

It's kind of like the difference between wearing a nicotine patch and smoking a cigarette (if you're a smoker). A nicotine patch delivers steady state nicotine throughout the day with no "satisfaction". Just a curbing of cravings. Whereas a person who smokes cigarettes gets heavy peaks and troughs of nicotine throughout the day, leading to a feeling of relief whenever a person smokes, leading to addictive reinforcement.

In that way doses of Sub that are too low, taken for a significant duration, can actually lead to more addictive reinforcement, only this time the reinforcement is to Suboxone rather than oxy or heroin.

Here's a really good video Dr. J did on the subject:



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PostPosted: Sun Apr 23, 2017 9:08 pm 
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TeeJay,

Thanks for that. I'm not all that bright, so if i get the feeling I'm grasping
something, it means the guy doing the explaining did a good job simplifying.

I'm slowly getting a much better understanding of buprenorphine and why it works.
Do you know anything about the history of the development of this drug? Were they
trying to synthesize something that would work this way....that is something that would
have as a unique property this ceiling effect, so that it might be used in MAT? Or was it
one of those serendipitous things whereby they realized over time that it might be used
in this way?

Best,
Godfrey


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PostPosted: Mon Apr 24, 2017 4:41 am 
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I think it was created in the 70's by Reckitt Benckiser's chemists while looking for a long acting synthetic opioid they could market as a painkiller. It was shelved for a couple of decades before its potential as an addictive medicine was realised, mainly owing to its long half life. It was actually used in the early 1990's as Subutex as an alternative to methadone in the UK and Australia, before it was marketed in America in its Suboxone formulation with naloxone added in an attempt to curb diversion.


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PostPosted: Mon Apr 24, 2017 5:42 pm 
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TeeJay wrote:
I think it was created in the 70's by Reckitt Benckiser's chemists while looking for a long acting synthetic opioid they could market as a painkiller. It was shelved for a couple of decades before its potential as an addictive medicine was realised, mainly owing to its long half life. It was actually used in the early 1990's as Subutex as an alternative to methadone in the UK and Australia, before it was marketed in America in its Suboxone formulation with naloxone added in an attempt to curb diversion.



Hey guys thanks for the quick answers. The first reply seems to be a good explanation for why half life changes... the kinetics of things like enzymes working on substrate can be altered at different concentrations.... so that can make sense.

TeeJay, also thanks for the response. It seems that is the explanation for why bup acts like a full agonist below the ceiling threshold, but not why the half life changes. However, that does make a good point about twice a day dosing at lower doses regardless of half life...... At small doses like <1mg, you wanna avoid the peaks and valleys as much as you can period so in that regard twice a day dosing at lower doses where you are definitely below the ceiling dose should help level out the blood levels a bit more. It's much easier to get off somethign that gives you slow and steady, as opposed to sudden peaks of relief followed by valleys of discomfort that leave you craving the next dose.


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PostPosted: Mon Apr 24, 2017 10:04 pm 
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Here is what I was thinking: http://suboxonetalkzone.com/graph.jpg

The thin horizontal line is the concentration needed to create the maximum opioid effect at the mu receptor. The red line is dosing once per day, and the similar black line is dosing twice per day.

The lines are intended to refect blood levels of buprenorphine for each type of dosing, for the same daily total dose. Dosing twice per day, the concentration stays above the ceiling level, and prevents withdrawal. Dosing once per day allows blood level to fall below that threshold for part of the day.

Hopefully you get the idea-- the exact placement of the lines differs.


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PostPosted: Tue Apr 25, 2017 2:50 pm 
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suboxdoc wrote:
Here is what I was thinking: http://suboxonetalkzone.com/graph.jpg

The thin horizontal line is the concentration needed to create the maximum opioid effect at the mu receptor. The red line is dosing once per day, and the similar black line is dosing twice per day.

The lines are intended to refect blood levels of buprenorphine for each type of dosing, for the same daily total dose. Dosing twice per day, the concentration stays above the ceiling level, and prevents withdrawal. Dosing once per day allows blood level to fall below that threshold for part of the day.

Hopefully you get the idea-- the exact placement of the lines differs.



Thank you for the response. The link says I am forbidden to access it! But, that's OK. I am getting the idea here, and everyone's responses combined has given me a decent picture of what is going on.


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PostPosted: Fri Apr 28, 2017 11:58 pm 
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Now THAT'S frustrating! I was proud of the crude little drawing. Can other people see it? It pulls up when I click on it-- anyone else?

I'll try a different site- try clicking here: http://www.suboxforum.com/graph.jpg

Or I'll see if I can get it to pull up in the next post.


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PostPosted: Sat Apr 29, 2017 12:09 am 
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Image


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PostPosted: Sat Apr 29, 2017 12:54 am 
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I took a screenshot of the error message for the first link if that would be helpful, but it was due to "hotlinking not being allowed for that resource" in short.

Thanks for reposting, that's a good visual aid for those that are tapering their dose and getting close to the ceiling.


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PostPosted: Mon May 01, 2017 9:24 pm 
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Thanks- I'm not sure why my server blocks that.

As for the crude drawing.... the main issue is that dosing more often results in less variability of the blood level throughout the day. The mean blood level of buprenorphine is the same with both types of dosing. But the red line, dosing once per day, results in higher highs and lower lows regaring the blood level. The blood level is higher at the peak-- no big deal because of the ceiling effect. But it is also lower at the 'trough', or lowest point-- taking the blood level below the critical ceiling threshold. Dosing more often causes the swings in blood level to be smaller, whether they are up or down... which keeps the blood level above the ceiling threshold. Note that drug testing would also vary a bit between the different types of dosing, making the time of the test much more important in patients who dose once per day, than in patients who dose 2 (or more) times per day.


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