Ceilings

A question was asked about the last post that warrants top billing:
“Buprenorphine acts similar to opioid agonists in lower doses, with the same addictive potential as oxycodone or heroin. In higher doses—doses above 8 mg or 8000 micrograms per day—the ‘ceiling effect’ eliminates interest and cravings for the drug.”

Buprenorphine Ceiling Effect
Ceiling Effect

I’m not sure I followed this. Can you explain more? What would you think about someone who is taking 1-2mg of Suboxone twice a day without a prescription, and says they want to stay on that dose once they find a prescriber? Are they better off on 8mg or more per day, or would it be ok for a prescriber to keep them at the lower dose? Is the answer the same if they hope to taper off the medication completely within a year (they don’t feel able to do this on their own right now, but hope to be able to when some life circumstances change). Thanks!
This gets a bit complicated, but I’ll do my best. A couple background issues; buprenorphine has a ‘ceiling’ to its effect, meaning that beyond a certain dose, increases in dose do not cause greater opioid effect. That is the mechanism for how buprenorphine blocks cravings.
If the blood level of buprenorphine is ABOVE that ceiling, the opioid receptors are maximally, 100% stimulated. If the person takes more buprenorphine, and the blood level increases, the opioid receptors don’t feel the increase, as they cannot be stimulated more than 100%. But more importantly: when the person takes less, and the blood level of buprenorphine goes DOWN, the receptors also sense nothing– as long as the level stays above the ‘ceiling’ level.
Read the above paragraph, and think on it until you grasp it– as it explains buprenorphine and Suboxone. If you understand that paragraph, you will know more about Suboxone than most doctors!
Below that ceiling level, the opioid effect from buprenorphine varies directly with dose—just as with oxycodone, hydrocodone, heroin, etc. Medications that have effects that increase with dose are called ‘agonists’. Buprenorphine is a ‘partial agonist;’ it acts like an agonist up to point, the ceiling effect, beyond which increases in blood level have no greater effect.
The level of this ‘ceiling’ varies from one person to the next, depending on efficiency of absorption (on average, only a third of a dose is absorbed from under the tongue), body size, liver function, differences in regional blood flow, and the presence of other medications that affect buprenorphine metabolism. In order for buprenorphine to have the unique, craving-blocking effects, the blood level of buprenorphine must stay above the ceiling level, for the reasons described above.
Lower levels (blood levels of buprenorphine below the ceiling level) still have SOME effects on cravings. Buprenorphine has a long half-life, an that alone reduces the desire to take more—especially if the medication is taken more than once per day– since the blood level drops very little between doses. For agonists or for buprenorphine below the ceiling level, drop in blood level equals drop in opioid effect, equals sense of things wearing off, equals cravings.
But the classic method for treating with Suboxone, as described in the certification course, is for it to be given at a high enough dose to stay above the ceiling level… and dosed only ONCE per day. If the blood level stays above the ceiling level, once-per-day dosing covers cravings completely. Yes, people still want to take more, especially initially, but that desire is not driven by chemical effects; the desire is instead based on psychological factors, like habit, or from being accustomed to feeling better after a dose, and getting a placebo ‘lift’ from taking a second dose.
A person can eliminate that second dose fairly easily, providing that the morning dose is high enough, i.e. usually 8-16 mg. To eliminate the second dose, the person should distract him/herself as soon as the thought about taking the second dose comes to mind. Immediately, do anything else—the dishes, call a friend, wrestle with the dogs… and the thought will pass. If the person does the distraction method for a few days, the need to take the second dose will go away—a psychological process called ‘extinguishment.’
Dosing every other day, and even every third day, has been studied; people cannot tell the difference, if the dose is raised enough to keep the blood level above the ‘ceiling’ (providing the person is given a placebo that tastes the same).
As for as the writer’s friend… I’m not a fan of any illicit use, but I am aware of the shortage of physicians. When the person has a physician, in my opinion the person should be prescribed a dose that allows for once per day dosing. Realize that buprenorphine wears off VERY slowly; it takes over three days for half of a dose to leave the body! So that ‘need’ to take more is almost always entirely learned or ‘conditioned.’ The medication does not wear off in that short period of time.
Even if the person has withdrawal symptoms, the sensations are almost surely imagined. How to tell? Use the distraction method, and note that a couple hours later, when the person remembers that the dose was skipped, note that the withdrawal went away. That doesn’t happen with ‘real’ withdrawal!
The sense of withdrawal that drives the second dose is simply a memory; a conditioned response that the body has that triggers the person to take more opioid. We become conditioned by drug use, just like the salivating dogs from science books! In the case of opioids, whenever we feel down, we think that an opioid will lift us up, as it has hundreds of times before. And even if what is taken is not a real opioid, the mind ‘feels’ a boost, just from expecting what has always happened in the past.
As for tapering, I look at many factors in order to recommend, or not recommend, stopping buprenorphine—things like age, presence/absence of using friends or contacts, physical health, mood, support network, personal motivation to stop buprenorphine, ability or lack thereof to dose once per day, consistently, number of relapses and personal ‘recovery’ plan, etc.
Realize that EVERYONE looks forward to a day when life circumstances will change for the better—but most of the time, life becomes more, not less challenging. Yes, it is nice to have a reliable job… but it is much more stressful being the sole breadwinner for a family with children, than working to pay for one’s self! Marriages settle down in some ways over time, but they also lose the intense infatuation that can gloss over personal differences.
As I have often written, it is VERY hard to stop opioids. It is a little easier to stop buprenorphine; I am convinced of that fact because I have seen opioid addicts taper off buprenorphine, but I know of no opioid addict who tapered off an agonist. But SOME people cannot taper of ANY opioids—including buprenorphine. I do not consider those people ‘addicted’ to buprenorphine, because they lack the constant obsession for opioids that is so destructive to the mind of an active addict. But they ARE physically dependent on buprenorphine— a fair trade, in my opinion, for a life of chaos, broken relationships, legal problems, and death.

The Buprenorphine Ceiling Effect

This post is from a couple years ago;  I think it is important for people to have a basic understanding of how buprenorphine removes opioid cravings, so I’m republishing the post.
Note that naloxone has NOTHING to do with the effects of Suboxone.
In this video I explain why the ceiling effect is so important to the effects of buprenorphine for treating opiate dependence.

The REAL Future of Partial Agonist Treatment— Pharma are you Listening?

I just wrote a note to a friend who works in the molecular sciences– she has been studying opioid receptors since the early 1980’s, when things were just getting started on a molecular level.  I’m keeping her name to myself, but I’ll share a few thoughts about what is needed to advance the treatement of opioid dependence– and make a few million dollars along the way (are you listening, RB?)
Hi ——,
(private chit chat that would bore everyone)
Anyway, today I realized what is needed in order to take partial agonist treatment of opioid dependence to the next level.
The problem with buprenorphine is that the ‘ceiling effect’ occurs at a relatively high tolerance level, approximately equal to 40 mg of methadone.  That causes at least two problems.  First, going off Suboxone is a lot of work, as the person still has a great deal of withdrawal to go through.  That may be a good thing early in the process, as it may help keep people on Suboxone, but after a year or so, when people want to try going off the medication, it is a major barrier that opens the floodgates to those old memories of using, etched in the emotions associated with withdrawal.
The second problem with the high ceiling/tolerance level is that surgery is a hassle.  People needing surgery need HIGH amounts of oxycodone to get any analgesia—I usually give 15-30 mg every 4 hours.  Pharmacists shudder to release those doses, and some surgeons and anesthesiologists balk.
The horizontal part of the dose/response curve is the essential part of buprenorphine;  that is what tricks the brain into ‘thinking’ that nothing is wearing off, and in that way eliminating cravings.  But that flat dose/response relationship could occur at lower tolerance levels and still work the same way.
Since I’m wishing for the moon, a series of molecules with progressively lower ceiling levels would be ideal, with the last molecule in the series being Naltrexone.  Although actually, naltrexone doesn’t work—it has NO mu agonism, so there is no tricking of the brain, and no reduction of cravings.  We would want something close to naltrexone, but with a tiny bit of opioid activity that does not vary with dose.
A shorter half-life would also be helpful.  Preparing for surgery requires weeks to get the buprenorphine out of the system.  Of course a shorter half-life means it is easier to get around buprenorphine by people who want to play with agonists, so again, these new molecules would be intended as ‘step down’ meds from early-stage buprenorphine treatment.
Do we know enough about molecular actions at the mu receptor to design molecules with these properties?  Or are we still at the point of making somewhat random changes and assaying the result?  Do you know of any labs doing this type of work?
I figured you’re the person to ask!
Thanks ——–
Jeff

Optimizing Absorption of Buprenorphine

I wrote this a couple years ago, and still get questions about the topic today.  Studies show that a small fraction of the amount of buprenorphine in a tablet or film strip actually gets absorbed through mucous membranes;  the rest is swallowed.  The 15%-30% amount of absorption is referred to as the ‘bio-availability’  of the drug.
People who feel like they are not getting enough buprenorphine to remove cravings can review the principles below, to see if there are ways they can easily improve the absorption of buprenorphine.  NOTE:  improving absorption is NOT an ‘addictive’ behavior, for a couple reasons…. first, because of the ceiling effect, increasing the amount absorbed will NOT cause a ‘buzz’ or high, but will only make the medication last the full 24 hours without wearing off.  Second, crushing a tablet will NOT cause a ‘rush’ or ‘high’ for two reasons– first, because of the ceiling effect as I just described, and second, because the rate-limiting step for absorption is the passage through tissue— NOT the dissolution of the tablet.  This is why, by the way, the film does not cause a ‘rush’, even though it dissolves more quickly.
Read on:
I often answer questions about Suboxone that require the qualification ‘if it is being absorbed properly’. If a person asks how long it takes for Suboxone to wear off, or at what dose does the ceiling effect occur, I need to be sure that the person is taking it in a way that maximizes absorption; otherwise all bets are off. If a person simply swallows the tablet, for example, the level of buprenorphine in the bloodstream will be much lower than if it is taken correctly.
The usual instructions for taking Suboxone are to place a tablet under the tongue and let it dissolve.  It is important that Suboxone be taken once per day, in the morning; this instruction is included in the course for physicians but is too often ignored.  I will talk another time about the philosophy for dosing once per day; the basic reason is to extinguish the behavior that has been conditioned as part of the addiction.  But the point of this post is the absorption of buprenorphine from the tablet into the bloodstream, and how to maximize that absorption.  It is important to maximize absorption, particularly if one is trying to save money by reducing the daily dose of Suboxone.
From my experiences as an anesthesiologist, as an addict**, and as a PhD chemist, I recognize that three factors will maximize absorption.  The first is the concentration of buprenorphine in the saliva, as the drug diffuses into tissue down a concentration gradient.  This gradient is maximized by having a small volume of saliva.  I recommend that a person start with a dry mouth, place the tablet in the mouth, and crush the tablet between the teeth until it is dissolved in a small volume of a concentrated solution.
The second factor that affects absorption is the amount of surface area.  Buprenorphine is absorbed through all mucous membranes (the tissue lining the inside of the mouth), passing through the surfaces and entering capillaries, the route into the bloodstream.  So the concentrated solution should be ‘painted’ repeatedly over all of the surfaces inside the oral cavity;  the inside surface of the cheeks, the tongue, the roof of the mouth, under the tongue, the back of the throat…  swished around in the mouth over and over, repeatedly bringing the concentrate into contact with new areas of mucous membranes.
The third factor is time– the longer period of time, the longer for the buprenorphine to make contact with the mucous membranes, attach to the surface, get absorbed into the tissue, and enter the capillaries.  The initial process will be the saturation of the surfaces of the mucous membranes, and the slower process will be the passage into the tissue;  that is why the amount of surface area has such an important effect on absorption.  Fifteen minutes is probablysufficient for most of the absorption to occur;  there may be drug remaining that is attached to the surface but not yet fully absorbed, and so I recommend avoiding eating or drinking within another fifteen minutes or so after swallowing the left-over saliva.
If you pay attention to these principles you will maximize absorption of the drug.  The ceiling effect will occur under these conditions at a dose of about 2-4 mg;  the long half-life of the drug will guarantee that if you take over 4 mg or so each morning, you won’t have any significant withdrawal for over 24 hours– allowing once-per-day dosing.  Yes, early in treatment patients will feel as if they need to dose more frequently– but that is not because of too little buprenorphine, but rather because of conditioned behavior.  A person early in Suboxone treatment will have feelings or minor withdrawal in the late afternoon or evening after dosing in the morning;  those minor withdrawal sensations will go away in about 15 minutes if the person takes more Suboxone, and will also go away in 15 minutes if the person doesn’t take Suboxone.  If the person takes more Suboxone, it will reinforce the sensations and the person will get stuck on dosing twice per day.  If, on the other hand, the person uses distraction and avoids dosing, those minor withdrawal sensations will completely disappear in a week or two, as the conditioned behavior is extinguished.
**I mentioned my experience ‘as an addict’;  for a period of time my preferred route of administration of lipid-soluble opioids was ‘trans-mucosal’ or ‘trans-buccal’.  Since the amount of substance available was finite (albeit a fairly large finite amount!) I did all that I could to optimize absorption, including reading about diffusion of lipid-soluble molecules through mucous membranes.

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.