Optimizing Absorption of Buprenorphine

A ‘quick one’…  I have written before about getting the most buprenorphine from a God-awfully expensive tablet of Suboxone, and will repeat myself for newcomers.  Note that my description is based on an understanding of pharmacology, organic chemistry, and physiology– NOT on the recommendations of Reckitt-Benckiser or the FDA.  My suggestions also come from knowledge of other, similar medications that are absorbed through mucous membranes– for example fentanyl, which is dispensed with a trans-mucosal delivery system for cancer pain.
A bit of background…  the reason you can’t just swallow a tablet of buprenorphine and expect it to work is because of something called ‘first pass metabolism.’  The liver is very good at breaking down buprenorphine in MOST people.  Buprenorphine and other medications, if swallowed, pass through the lining of the small intestine into the ‘portal vein’, which delivers them very efficiently to the liver, where they are effectively metabolized.  Some medications including fluoxetine (Prozac) will interfere with liver metabolism; I have not seen studies showing the levels of buprenorphine in such cases, but I would presume that levels of buprenorphine would be higher in general in people taking fluoxetine, especially comparing levels in people who swallow buprenorphine tablets whole.  As an aside, naloxone, the other ingredient in Suboxone, is also rapidly destroyed by ‘first pass metabolism.’  Because of first pass metabolism, little naloxone or buprenorphine accumulates in the bloodstream after oral ingestion.

Buprenorphine diffusion
Schematic of Oral Mucosa

Suboxone is therefore designed to be taken ‘trans-mucosally’, i.e. via absorption through the lining of the oral cavity into the bloodstream (the lining of the oral cavity is called ‘mucosa.’  The passage of molecules through the oral mucosa is affected by a number of things– the size of the molecule, the lipid solubility of the molecule, the concentration of the molecule, etc.  Buprenorphine is a lipid-soluble molecule that passes through the mucosa relatively easily, whereas naloxone is more water-soluble, and crosses the mucosa very poorly.  THAT is the basis for why the naloxone in Suboxone is not active;  only buprenorphine enters the bloodstream in significant amounts through the oral mucosa, and BOTH buprenorphine and naloxone are destroyed after being swallowed.
The goal with buprenorphine is to keep a level of the medication in the bloodstream that is above the ‘ceiling’ level– the level where the maximum opiate effect is obtained, above which no more effect can be gained with higher levels.  If the blood level stays above that ceiling level during the entire interval between doses, there will be no drop-off in opiate effect, i.e. no withdrawal, and no cravings for opiates (except for psychological cravings that can be quite intense initially, but that can be reduced through proper use of the medication.)  A constant level above the ‘ceiling’ is also necessary to prevent feeling ups and downs while on the medication.  If the level remains above the ceiling point, the person feels ‘normal’ all of the time, and gets no ‘high’ from taking the medication. 
Suboxone is, of course, too expensive;  the generic form of Subutex was initially priced at about $2.50 per 8 mg tablet, but the price is now approaching the price of brand-name Suboxone.  Some people require higher doses of medication than others, depending on body size, liver function, other medications, and other factors.  Most of my patients take around 12 mg of buprenorphine per day;  some take 8, some take 16, and some take doses as low as 2 mg per day.  In my experience the need for doses above 16 mg is rare, and if a person is getting ‘withdrawal’ at 16 mg I consider ineffective dosing as a potential problem.  In some cases the ‘withdrawal’ is actually psychologically-based, and would not respond to any dose of buprenorphine without an intervention to correct the patient’s perceptions.   But when the problem is ineffective dosing, I have seen very good results by making some changes in the way the person takes the buprenorphine, in order to optimize absorption.  Here was my suggestion to optimize absorption for a person who wrote to me the other day:
Absorption of buprenorphine is affected by a number of factors.  The three things that affect absorption that you can control are the concentration of buprenorphine in solution, the amount of surface area for buprenorphine to pass through, and the time allowed for absorption to occur.  So start with a dry mouth (swallow first), then crush an entire tab between your teeth to get it dissolved right away, in a very small amount of saliva.  That will increase the concentration of buprenorphine in solution, driving the diffusion of the molecule down the concentration gradient, into tissue.  Then ‘paint’ all of the surfaces in your mouth using your tongue as the paintbrush.  Try to spread the concentrated mixture over every surface;  there is nothing special about the tissue under the tongue.  The buprenorphine molecule will stick to the fresh surfaces, then pass through the mucosa, eventually diffusing into the bloodstream at a capillary.  After painting and re-painting the oral surfaces for 10-15 minutes, you can swallow the rest;  most of the absorption will have occurred by that time.   Be sure not to eat or drink for at least 10 minutes, though, so that buprenorphine molecules that are bound to the mucosa are not rinsed away, and rather can be absorbed.
I have seen good responses to this technique.  I have also been told that taking buprenorphine in this way shortens the time that it takes to dose.  For those who hate the taste, try putting an Altoid or half of a Life Saver in your mouth while dosing;  just avoid increasing the volume to a large extent, as that will reduce diffusion and absorption of buprenorphine.  You could also try sucking on an ice cube and then dosing, as the cold will reduce the function of your taste buds;  I would have a little concern, though, that absorption of buprenorphine will be slowed down by the cold as well, since blood flow through capillaries will be reduced after chilling the mucosa.
I expect there eventually to be a number of options for taking buprenorphine.  Hopefully we will eventually have some ‘American-style competition’ that gets the price per tablet out of the stratosphere!

Is My Suboxone Dose Too High to Have Surgery?

Thanks, all of you who wrote comments to my last post.  I remind everyone once again to consider taking your comments here and after writing them, also taking them to SuboxForum.com.  I am going to put up a new category to discuss topics that were initiated here;  it would be great to get a spirited, respectful ‘give and take’ on some of these topics.  As I have mentioned before, the only thing that I will block on that site would be debating whether people on Suboxone are ‘in Recovery’– just because there are plenty of other sites for that, and I want the forum to be for people who have made their decision– and don’t want to be harassed over it.  I will be upgrading that site shortly and changing the hosting account;  hopefully I will pull it off without erasing everything!
OK, tonight’s topic: I am taking my post from a different forum and posting it here also to save wear and tear on my keyboard…  I responded to a person who is taking 32 mg of Suboxone daily and who is concerned that the relatively high dose will raise her tolerance higher than she would like.  She has surgery coming up, and is concerned that the high tolerance will get in the way during or after the surgery.    My reply addresses the level of opiate tolerance in relation to dose of buprenorphine.  Incidentally though I will quickly say that buprenorphine poses little problem during an anesthetic;  it does not interfere to a large degree with general, epidural, or spinal anesthesia.  But buprenorphine DOES interfere with the treatment of post-operative pain.  I will also comment that I consider 32 mg of daily Suboxone to be a waste of money;  my experiences treating people with Suboxone have only reinforced my opinion that there is no benefit, and often considerable harm, in taking more than 16 mg of Suboxone per day,  and in dosing more than once per day.  But that discussion will have to wait.
My Response:
I will talk about buprenorphine, the active medication in Suboxone, just to simplify things a bit– although Suboxone will have the same effects. First, when talking about the dose, it is important that the method one takes it is identified– as that is what determines how much active drug ends up in the bloodstream. I will assume that the person is taking steps to get maximal absorption of Suboxone; for example keeping it exposed to mucous membranes for a long-enough time, and not rinsing the mouth with liquid for at least 15 minutes after dosing, to avoid rinsing away drug that is attached to the lining of the mouth but not yet absorbed. As an aside, there is a post somewhere on this blog entitled ‘maximizing absorption of Suboxone’ for those who want more info.

When a person takes Suboxone, he is taking a ‘supra-maximal’ dose of buprenorphine. Buprenorphine is used to treat pain in microgram doses; the BuTrans patch is used in the UK to treat pain, and it releases buprenorphine at a rate of 5-20 MICROGRAMS per hour! One tablet of Suboxone containes 8000 micrograms! So whether a person is taking one, two, three, or more tabs of Suboxone per day, he is taking a very large dose of buprenorphine— a dose large enough to ascertain that he is up on the ‘ceiling’ of the dose/response curve. It is important to be on the ceiling, as this is the flat part of the curve (I know– a silly statement) so that as the level of buprenorphine in the bloodstream drops, the opiate potency remains constant, avoiding the sensation of a decreasing effect which would cause cravings.

I have read and heard differing opinions on the dose that gets one to the ‘ceiling’ but from everything I have seen the maximal opiate effect occurs at about 2-4 mg (or 2000-4000 micrograms), assuming good absorption of buprenorphine. I base this on watching many people initiate Suboxone; if a person with a low tolerance to opiates takes 2 mg of buprenorphine, he will have a very severe opiate effect; if he takes that dose for a few days and gets used to it, and then takes a larger dose, there is no significant increase in opiate intoxication– showing that once he is used to 2 mg, he is used to 16 mg— and is ‘on the ceiling’ by definition. I see the same thing in reverse; there is very little withdrawal as a person decreases the dose from 32-24-16-12-8 mg, but once the person gets below 4 mg per day, the real withdrawal starts. This again shows that the response is ‘flat’ at those high doses, and only comes down below about 4 mg of buprenorphine.

The flip side of all of this is that tolerance reaches a maximum at about 4 mg of buprenorphine, and further increase in dose of buprenorphine does not cause substantial increase in tolerance. Tolerance and withdrawal are two sides of the same coin; the lack of withdrawal going from 32 to 8 mg of buprenorphine is consistent with no significant change in tolerance across that range.

So in my opinion, being on 32 vs 4 mg of Suboxone doesn’t raise your tolerance. But in regard to upcoming surgery, there is an additional concern. One issue with surgery on buprenorphine is the high tolerance, but the second issue is blockade of opiate agonists by buprenorphine– and this effect is directly related to the dose of buprenorphine. A person on 32 mg of Suboxone will need much, much higher doses of agonist to get pain relief than will a person on 4 mg of Suboxone– not because of tolerance but because of the blocking effect, which is competitive in nature at the receptor. When people are approaching surgery I recommend that they lower their dose of Suboxone as much as possible– to 4-8 mg if possible. Because of the very long half-life (72 hours), this should be done at least a week before the surgery. Then I have them stop the Suboxone three days before the surgery; it usually takes 2-3 days for significant withdrawal to develop. I say all of this to give a general sense of the issues involved; people should discuss the issue with their physician rather than act on what I am describing here.