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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").

Monday, February 21, 2011

"Less" is not always "More"



Demystifying the pharmacological properties of buprenorphine

A common belief of buprenorphine in the context of maintenaince is that: High doses commonly prescribed by Physicians are completely overkill and hardly ever close to being necessarry. It is common for patients to cut their doses to the 1-2 milligram range claiming they feel better - the term "feeling better" typically in the case of opiate addicts typically means "feeling buzzed". They believe that taking their miniscule single milligram dose of Suboxone or Subutex causes stronger binding and mu opioid activity than an 8 to 12 milligram dose. This misconception makes sense, after all, mini doses of buprenorphine do tend to result in an agonist-like glow, however this is quite misleading. Ultra low doses of buprenorphine do not cause stronger mu opioid activation relative to larger doses in the 8 to 16 milligram range.

One first must understand the basic properties of buprenorphine as an agonist-antagonist or partial agonist opioid. Most users know of the ceiling effect - some have a basic but lacking understanding of it and some have simply heard the term.

The dose respone curve for buprenorphine is unique from that of the typical opioid agonist. When taking an opioid agonist such as morphine for instance, the effect and response to the dose increases (intensifies) at a steady rate as the dose is increased, in some cases, curving upward even more-so as higher levels are reached. Any increase in dose results in a proportionate increase in response and effect - A 60 mg dose of morphine will cause much more response than a 30mg dose. This as most of you know, is not (entirely) the case with buprenorphine. In low doses of bupe, the dose response curve is indeed the same as an opioid agonist - as dose is increased, response will increase at a proportionate rate, until of course, it reaches a point where it gradually levels of - meaning as dose keeps increasing, the relative response begins to slow down at a disproportionate rate - note that the response does not actually decrease or decline in a literal sense, but simply levels off to a point at which the increasing dose causes no more increase in effect.

Note the differences (Below) with the dose-response of an agonist vs that of the mixed/partial agonist buprenorphine:



This leveling off in response with buprenorphine occurs at different points depending on whether the purpose is analgesia or mitigation of opioid withdrawal/craving - We are dealing with the latter, and this level-off is generally observed to occur between the 4mg and the 32mg dose range - response does not drastically cease, but gradually levels off between these points; the end of that flattening off is variable between individuals but may go as high as 32mg, after which point there is no longer any response in most patients. Note, that once a person is stabilized on a dose which keeps one's blood level higher than that FLATTENING point, will barely be felt or noticed . If one is stabilized on a dose which is adequate to control symptoms but is below the flattening, one will effectively remain "well" as well as experience some degree of "glow" with each dose.

With buprenorphine, the (approximate) 4mg point at which the response begins its level-off is equivalent to roughly 120mg of morphine oral, or 90mg oxycodone oral; with buprenorphine generally being taken once daily, meaning 4mg is roughly similar to a tolerance to the equivalent of 120mg oral morphine daily.

Many opioid dependent individuals or opiate addicts have developed a moderate to heavy, or extreme tolerance - those in the higher range are far beyond a 120mg morphine equivalent per day - Thus make no mistake, a switch from - a bundle a day heroin habit or IV OxyContin habit, to 4mg Suboxone or Subutex each day is not going to be whatsoever practical, and will likely leave one in moderately severe withdrawals for a while.

There are many folks who proudly preach that "Less IS More! It worked for me", and indeed they may be doing okay; At these low doses ranging from micrograms to a couple milligrams a dose of buprenorphine will indeed provide a buzz, and feel in some cases indistinguishable from a full fledged opioid agonist - The catch is, one must vastly train-down their opioid tolerance to the level which permits this to be effective. One with a bundle-a-day habit of quality heroin must lower their tolerance to roughly a level of 120mg morphine/daily, or around 50mg IV.

In the case of addicts and opioid dependent patients, a very high tolerance is typical at the time of induction to buprenorphine. Realistically, most will respond well to a dose in the general range of 4 to 24 mg, with most falling somewhere near the middle. This is all dependent on their frequency of use, extent of use, level of use, etc; all of which factors in to their overall tolerance to opioids. In some cases, a heavily tolerant subject may warrant increases up to the concrete ceiling of 32 mg or so. And in some cases, a heavily tolerant subject may find buprenorphine doesn't cut it, and may require methadone.

Within this wide dose range, there is always some degree of response, up to a certain point which varies between individual - When moving up from 8 milligrams, an increase to 12 mg may be necessarry to compensate for this lesser degree of response, and this may be done all the way up to around 32 mg for some highly tolerant individuals.
In the days following induction, the individual becomes tolerant to the daily dose level of buprenorphine, during this period, adjustments can be made to effect.

Dosing is approached in one of two ways, each of which may cater to a particular patient:

  • Some Doctors select a daily dose that is slightly higher than the dose which actually "holds" them; not everyone knows this, however most subjects are placed on doses which are just higher of those required to hold them, however somewhere short of the ceiling dose - in frank terms, this means that each dose may still cause some degree of response, hence, the slight glow. This is not as dramatic of an agonist-like property as the utra low-dose range but does elicit positive response, i.e reinforcement.

  • Even more ideal thought for a commited "recovery" patient in the context of buprenorphine's purpose is a dose that is slightly higher than that of the absolute ceiling of response for the individual - the idea being that the patient's blood level of buprenorphine stays above their ceiling of tolerance to the buprenorphine, effectively avoiding withdrawal - In this instance, as long as blood levels consistently remain above the "brick ceiling", not only is the dose more than sufficient to mitigate withdrawal, but no subjective 'high' is experienced. In addition, a supra-ceiling bupe dose leads to better control of opioid craving and no non-compliant behavior relating to the buprenorphine.

Regardless of induction dose, which will vary greatly, most users turning to suboxone should not fool themselves; realistically one will cross over with a tolerance level requiring these Doctor recommended doses (8mg, 12mg, 16mg, 24mg, etc) After all, Literature indicates the 8 to 16 mg target induction for a reason. The 8 mg tablet/film was chosen for a reason. The Doctor starts these initial doses for a reason. It's no conspiracy theory. If one wants to feel a buzz with each dose - it's going to take difficult work to get there, and one may of course gradually taper down from the point of induction, eventually reaching the "agonist-like" area of the dose-response curve.

Some doctors with a better understanding of the drug, will however select a dose which is more than enough to hold you, with the intention of ensuring you remain above ceiling levels between dosing, leading to better control over opioid cravings and in hopes that a patient is not "feeling" the medication - As much as this may be overkill, in the case of most with any real tolerance, micro doses are UNDER-kill - Until the point that you ease your tolerance down to that level.

Do not make any mistakes, higher doses of buprenorphine will effectively 'feel good', so long as they remain between level of tolerance, and point of the concrete ceiling (and no, not the 4 mg early level-off).

5 comments:

  1. To 'dislike' (i.e. disagree with) this information without a well thought out explanation which is actually supported by science and literature, reeks of arrogance... Probably a 'junkie-forum snob' who simply believes what 'peers' say without question, like the catchy sounding 'less is more' idea that has been misinterpreted, completely oversimplified and raped of any legitamacy, at least in its new defenition... Some actually interpret the word of their drug-seasoned peers as divine insight and fact... Based on nothing but subjectivity. Stop challenging legit info and go write up a 'trip report' ;)

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  2. I actually firmly believe that junkies know better when it comes to this type of stuff, simply because they have experience. Doctors (most anyways) have no experience. They base everything on science which isnt always accurate for everyone.

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  3. There's always a margin variation in how tissue (body and brain) responds to a compound in biological terms; but the pharmacodynamic properties of a given compound (such as EC50 and intrinsic characteristics) at a given receptor subtype of a particular species never change. Science is objective, Personal interpretation & psycho-subjective response is not. Plus, The published literature on buprenorphine maintenance for opioid dependence is based on years of extensive controlled studies in many "junkies" (studies which incorporate subjective reporting & objective measures of physiological response).

    Larger blood concentrations of buprenorphine produce greater mu-receptor response and greater suppression of abstinence for longer periods (up to a ceiling of anywhere from 4-32mg) - which is optimal in terms of maintenance treatment. Low dosing, in the right particular context, may be more rewarding in terms of a rush-like effect (subjectively speaking), but these low dose levels are not practical in the context of anyone with a considerable opioid tolerance, and therefore generally lead to physical discomfort & withdrawal - therefore, without a gradual taper in these cases, micro-dose bupe (say, less than 1 or 2mg) is certainly not "more", and does not do more. Just as many "junkies" will attest to this as will subscribe to the "less is more" notion.

    I am weary of the phrase because it grossly oversimplifies the properties of this drug so much as to be meaningless.

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    1. i can relate to your exasperation in trying to combat the "junkie lore" out there. You are correct about the "less is more" meme. To the anonymous comment above, God forbid we actually base these things on science as opposed to subjective experience, although many doctors are also shockingly ignorant when it comes to science.

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  4. 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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