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").

Sunday, October 3, 2010

The Idiot's Guide To Buprenorphine Treatment

To understand the theory behind the use of buprenorphine, let alone it's basic effects, one must familiarize themselves with the basic function of an opioid agonist versus an opioid partial agonist, and an opioid antagonist. These principles apply not only to opioid receptors, but to all neuro-receptor sites to which neurotransmitters and exogenous compounds bind or attatch. Opioid receptors are located within the dendrite portion of nerve cells, within the synaptic cleft which works as a conjunction between nerve cells.

There are several distinct types of opioid receptors, though the most relevant for our purpose here is the mu opioid receptor (i.e. the morphine receptor); which is responsible for the analgesic (pain relieving) properties as well as the euphoric and addictive properties of opioids.

Agonist: A compound that will bind with a receptor site and positively activate some form of a cellular response. Opioid agonists include morphine, heroin, methadone, and oxycodone.

Antagonist: A compound that merely binds with a receptor, but doesn't elicit any biological response; as if the receptor were unoccupied. In other words, antagonists simply take up space at the receptor sites with which they bind, thus blocking other compounds (i.e. agonists) from interacting with these receptors. Naloxone and Naltrexone are opioid antagonists.

Partial Agonist: A compound that binds to a receptor and elicits a relatively limited biological response. It activates the receptor but not to the same degree as a typical agonist. Opioid partial agonists include butorphanol and buprenorphine. Many partial agonists are also referred to as mixed agonist-antagonists; this is because a) they are attracted to receptors with such a high affinity that they may displace other compounds already bound with the receptors, or block traditional agonists from binding with these receptors, and b) their binding induces a cellular response. So in other words, many opioid partial agonists (best example being buprenorphine) share both agonist-like properties (similar to morphine), and antagonist-like properties (similar to naloxone).

Buprenorphine acts as a partial agonist at mu opioid receptors (or, a mixed agonist/antagonist); with actions similar to either morphine or naloxone, depending on the specific setting in which it is used. Buprenorphine stands out from other partial agonists in that its morphine-like agonist properties are for the most part predominant to its antagonistic properties (the latter of which only dominate in certain situations).

Buprenorphine is very potent and is therapeutically active in microgram doses (1 microgram = 1/1000th of a milligram). It exhibits extremely strong binding affinity for mu opioid receptors (the morphine receptor) but exhibits limited intrinsic activity; it's narcotic effects are dependent on blood concentration and increase with dose until leveling off once a certain dose is reached. For example, a dose of 8 mg will cause greater effect than a dose of 4 mg; however a dose of 40 mg may be no more effective than a dose of 32 mg. 

In understanding this ceiling effect, one must understand the relationship between dose and receptor activation. As the concentration of buprenorphine in the blood increases, more mu receptors in more areas become saturated and therefore activated (the greater the number or proportion of receptors activated, the stronger the opioid effect). So bearing this in mind, can you guess what happens once the body's mu receptors are completely saturated, filled at maximum capacity? That's right. When this occurs, greater systemic concentrations of buprenorphine will have no additional effect (at least not through the mu receptor); simply put, increasing the dose will do little to potentiate the morphine-like effects.

In doses of 200 to 300 micrograms (0.2 to 0.3 mg), buprenorphine is clinically effective in relieving moderate to severe pain; and is used in a similar manner to most opioid agonists for this purpose. In this dose range, buprenorphine acts the same as a full agonist such as morphine or methadone, eliciting a steady, dose-proportionate response. In the past, buprenorphine was assumed to have a limited analgesic response due to its ceiling effect, but more recent experience has shown that buprenorphine exhibits a steady, dose-dependent increase in pain relief at levels up to at least 7 milligrams a day.

In the last decade, High Dose Buprenorphine has been succesfully marketed as a therapeutic for opioid dependent individuals, for both short term detox (where the dose is gradually reduced to zero) and for long term opioid substitution (i.e. maintenance treatment), lasting anywhere from several months to several years, or a lifetime if necessary), allowing struggling opioid users to avoid the struggles associated with maintaining an illicit and sometimes problematic narcotic habit. For this purpose, the drug is available in sublingual preparations (suboxone or subutex) containing 2 mg and 8 mg of buprenorphine, with or without naloxone (added for the theoretical purpose of deterring misuse and diversion). Sublingual buprenorphine products can be administered discretely only once daily (though this may vary from twice daily to once bi-daily).

It is in the milligram level doses present in the sublingual preparations that buprenorphine exhibits its unique characteristics. As mentioned previously, buprenorphine binds with very high affinity to mu opioid receptors. Because its affinity is greater than most opioid agonists including morphine and heroin; the morphine-type effects of these drugs are significantly reduced or blocked altogether while buprenorphine is occupying receptors, making the use of such opioid agonists less appealling for subjects who are taking suboxone or subutex at the time. 

When bound to mu receptors, buprenorphine produces typical morphine-like effects, increasing in intensity with dose until the point where mu receptors become saturated, and thus no further increase in effect can be acheived. This ceiling level will vary between individuals depending on their own physiology, receptor quantity and receptor density; for some it may be 8 milligrams, for others it may be 24 milligrams; the proper dose for any individual being:

The lowest possible dose needed to sufficiently eliminate and avoid opioid withdrawal, while at the same time producing minimal side effects such as sedation and somnolence (nodding).

Once the correct dose is reached; blood plasma levels of buprenorphine stabilize over the course of the next several days; with the ideal goal being  maintaining the plasma level of buprenorphine high enough so that even at the end of the dosing interval, the opioid activity remains above the ceiling level (i.e. mu receptors remain fully saturated). If this level of dosing is achieved and maintained for several days, one will develop a tolerance to the morphine-like effects - the presence of buprenorphine at mu receptors will no longer produce the level of reward or euphoria that it did initially, assuming plasma concentrations remain at a level beyond the aforementioned ceiling.

Once a tolerance is reached; the regular dosing of buprenorphine will no longer produce any discernable subjective effects (i.e. an opiate buzz). So basically not much of anything is felt with each dose. Many describe this stage of maintenance as "feeling just the way they did before they had become addicted to opioids". 

With proper dosing and an individualized regimen, sublingual buprenorphine is an effective long term maintenance tool for those who are addicted to narcotics and don't want to be completely drug free, or simply can't afford to continue an illegal drug habit. Bupe has been reported to be a sufficient narcotic substitute (in terms of suppressing withdrawal and obsessive craving) for around 70 percent of the opioid dependent population, with the remaining 30 percent requiring full agonist treatment with methadone.

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