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Providing straightforward information pertaining to drugs, drug use & drug policy. The Grey Pages promotes drug-related literacy and advocates a system of viable and tolerant drug policies. This is my personal collection of commentaries, essays, tid-bits, and other such writings on everything ranging from drug use, drug policy and drug-myths, to drug-science, addiction, human behavior, and the workings of the human brain. I started this blog with a particular focus on opioids, and over the past year have found my interest gravitate toward the intriguing, ever-changing world of designer intoxicants (i.e. "research chemicals" or "designer drugs").

Thursday, July 14, 2011

A Followup to the "Less is More" Buprenorphine Myth

http://www.nature.com/npp/journal/v23/n3/full/1395518a.html


A brain-scan demonstrating mu-opioid receptor availability (vacancy) at various dose-levels; placebo, 0mg, 2mg, 16mg . The brightened areas represent vacant or unoccupied mu-receptors

Above is the link to an interesting study which supports my disapproval of a common myth regarding buprenorphine dose. Furthermore, buprenorphine has not been proven to exhibit a bell shaped dose response curve in humans in terms of mu activation; and if this even was the case, a net-DECREASE in mu-opioid stimuli would appear at doses well in excess of the ceiling or plateau range of ~2mg to 32mg.

You can find the original entry exploring the "Less is more" myth here

I explained the flaw in the 'less is simply more' notion in a forum post today:

Buprenorphine has NOT been proven in humans to have a bell-shaped dose response curve; also, this bell-shaped response shown in lab-studies was shown for only certain effects. Even assuming that bupe indeed does produce an actual DECREASE in intrinsic activity at higher doses, this pattern would take place beyond the 0 to 8mg level, more likely in doses well in excess of the clinically observed (many times over, in hundreds of subjects) ceiling range of buprenorphine's intrinsic ceiling (roughly the 24 to 32mg range) for tolerant/dependent maintenance users.

Again, there is no solid evidence in humans that buprenorphine's intrinsic activity actually DECREASES at higher doses , rather than simply level off with no further increase.

Also; I think some folks are misinterpreting the context in which the term "mixed agonist-antagonist" is used in reference to buprenorphine; this refers to its ability to produce positive analgesic & reinforcing agonist acvtivity in post-detox  opioid users or opioid naiive individuals while at the same time, playing the role of an antagonist with its tighly bound blocking of full agonists from associating with mu-receptors (this indeed is an antagonizing property) - additional properties earning it the antagonist reference include its tendency to precipitate withdrawal  via its competitive binding in place of full agonists in dependent individuals, leading to a net-decrease in intrinsic activity, thus, acute opioid withdrawal (a property similar to naloxone).

It may also be taken in part to reference the kappa antagonist effect of buprenorphine. Considering the aforementioned properties along with its limited agonist properties, bupe can be referred to as an agonist/antagonist, or an opioid partial agonist with individual antagonist traits under certain conditions.

This is not at all to say that I am refuting the possibility of a bell shaped dose response curve in humans, particularly in the maintenance context, but to try and explain what I believe is misunderstood by some; it doesn't help with people all over the web perpetuating the phrase "less is more" as if it's really so simple.. Indeed many have actually listened to this type of anecdote and end up either sick, or "craving" (i.e. inadequately medicated) 

Yes, with low doses of bupe, if one's tolerance permits, one will experience pronounced euphoric/anxiolytic and opiate-type effects and actually FEEL each dose, as opposed to feeling no lift, no glow, and no increase in effect as with higher maintenance range doses (4 to 16mg) and I believe this is leading some to believe that the higher (plateau-level doses) are in fact providing a LESSER intrinsic agonist effect than these fun little micro-doses.
Believe it or not - though a higher dose (8 to 12mg for instance) may not produce the obvious glow you feel at .5 to 1mg, you are in fact MORE stimulated than you are with the micro-dose (which is indeed why you feel so little). That's right, an 8mg dose will keep withdrawal at bay longer, and more effectively than a 1mg dose.

There's much more to it than "less is more", and this statement is almost senseless in a way, and comes riddled with assumptions which have never been proven clinically in the human-maintenance setting; and even if it were, this particular myth still would not apply.  as this mythological NET-DECREASE in mu-stimulation would take place in double digit doses well beyond the typical maintenance range.. (opposed to a 0 to 2mg range)

So, micro dosers; by all means continue low dose bupe, I am happy you are able to keep yourself in that low range and am not surprised you "feel" more, but what alot of these folks suggest to someone such as this OP who in fact do not find these low doses effective (and won't unless they taper themselves to this level of tolerance), is a bit misleading, very misleading actually. I say that with all due respect.

I'm just weary of hearing this already somewhat strangely chosen -and more methaphorical than factual - phrase taken far out of context in a way that simplifies and distorts the true understanding of bupe's pharmacological properties.














7 comments:

  1. I realize this is a fairly old original post but I came across your article looking for more information on the subject and was somewhat confused on a few points. I'm unclear on where you got your information for the myth itself. The way you speak on the less is more theory it appears you are claiming the proponents of this theory are asserting the Buprenorphine produces stronger effects at lower doses. While this is technically not wrong, I am quite sure that believers (at least those who intelligently defend their beliefs on the subject) insist it more specifically involves the competition of the 2 chemical resultants, i.e. Buprenorphine effects vs Nor-Buprenorphine (full agonist) effects. I just wanted to mention this because if using scientific studies as support for your criticism, you might want to consider looking up studies on Nor-buprenorphine for further understanding.

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  2. Interesting theory but I'm thinking you misunderstand the concept of less is more dosing idea. It is true that buprenorphine has mixed agonist/antagonist properties. However the blockade effect is actually an agonist effect as it is orchestrated by the bupe binding very tightly to the mu receptor. Precipitated withdrawal is also an agonist effect of bupe because it happens as a result of bupe, a partial agonist, displacing a full agonist from the mu receptor. The antagonist effects of bupe are only on the kappa receptors. The less is more theory confuses some because yes of course the more you take the longer the receptors will stay filled and the longer it takes to fill withdrawal effect so in that sense more is definitely more. However, as an above commenter stated, due to bupe metabolizing into nor-buprenorphine which is a full agonist if one were to take a small enough dose to leave a good amount of receptors empty, one would get more of an opiate effect because of this metabolite. Pretty cool stuff and I definitely agree with less is more idea in terms of stimulation, but I can see where you are coming from with the more is more idea in terms of duration of effect. Just don't confuse drug duration with level of stimulation.

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  3. If Bupe doses of 0.2 - 0.4 mg are used on opiate naive patients as "temgesic" brand in the hospital for severe pain, including post-surgically, then yes something weird is up with this drug. We know that even these patients would not have life-threatening respiratory depression at 4, 8, 16 mg. But it is indicated for moderate and severe pain at 0.2 mg. I don't think the 16mg dose would work for them. I agree with you that it's not simple, but there is a dosing regime providing more analgesia at micro doses, and this is one type of less is more. But this regime does not provide as much blockade and does not treat cravings on addicts as well. Btw Butrans patch operates at these tiny doses. It's for pain. Says right on there that it doesn't treat addiction.

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