The Buprenorphine FAQ - Version 2.91 WIP
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs2.5 License,
(c) 2006 Nephalim.
1)
Introductory
Notes
All of the
practical information in this FAQ is relevant only to the
Nephalim may be
reached for questions at nephalim@heroindiaries.com
Disclaimer:
I (the writer) am
not a doctor. I am not a pharmacist. I am not a scientist. I am not a licensed
professional of any kind, nor do I possess any relevant degree. I have
absolutely no qualifications to provide medical advice. This FAQ is for
informational purposes and should not be treated as medical advice. All medical
advice should come from your doctor, and if the case is such that you doubt
what he is saying for whatever reasons, then a second opinion is the next step,
not disobeying his orders to follow anything in this FAQ. You may, however,
discuss what you may have found in here with him/her, and I encourage you to
try to find as much evidence of what you are trying to tell him/her as
possible, and try to do this as gently as possible, as no doctor enjoys being
told he is wrong (nevermind by a layman), and may even react impulsively.
Note on common nomenclature and
slang:
Buprenorphine is
commonly abbreviated “bupe” (or “bup” in medical/technical language -
“bupe” isn’t an actual abbreviation of buprenorphine), and methadone
is commonly abbreviated “mdone”, “done”, or “meth” (”meth” is also slang for
Crystal Meth / methamphetamine).) Just as Methadone Maintenance Treatment is abbreviated
MMT, Buprenorphine Maintenance Treatment is abbreviated BMT. Subutex and
Suboxone are both abbreviated “Sub” occasionally. Detoxification is often
abbreviated “detox”. Methadone clinics are commonly called “klinics.”
Important Notice:
Opioids
are can be extremely individualized in their subjective and even sometimes
objective, effects. Some work for some, other work for others, all with
different effects. With buprenorphine this is multiplied exponentially. Every
aspect of the drug can be very
individualized (even the science of opioids is to this day poorly understood in
a large regard, especially so in buprenorphine’s case). One of the large
reasons for this is the fact that the drug is a “partial agonist”, as well as a
mixed agonist/antagonist for that matter. This only makes matters that much
more complicated, and the fact that buprenorphine is a partial agonist which
binds very tightly to the opioid receptors in the body is what is responsible
for many of buprenorphine’s (non)actions in the body.
Nothing said in this FAQ is or will be necessarily be
true for you. Please keep
this in mind at all times.
2) What is Buprenorphine? What is the DATA?
Buprenorphine
(FDA approved in the brand names of Subutex and Suboxone, manufactured by Reckitt Benckiser), exactly like methadone
(Dolophine, Methadose), is a medication given to keep (via maintenance) or wean
(via detoxification) people off of heroin or other opioids and improve their,
and society in general’s, quality of life – and out of pocket cost (i.e. via
taxes).
Buprenorphine is
properly labelled as a mixed partial
agonist/antagonist. With that said, buprenorphine’s major clinical importance
is as an agonist of classic opioid receptors. Buprenorphine is not like naloxone (Narcan) or naltrexone
(Revia) in terms of a treatment for opioid addiction. For clinical/treatment
purposes, buprenorphine is a partial agonist, not a mixed agonist/antagonist.
It is the fact that buprenorphine is a partial agonist in addition to the fact
that it binds tightly to and has a long half-life at the classic opioid receptors
in the brain and elsewhere that cause it to have an antagonistic-like effect in
those dependent on or attempting to use classic opioid drugs – causing
withdrawals in people with a moderate or severe opioid dependence and blocking
other opioids from working much like methadone’s effect (this effect varies greatly
– the original claim was that it was almost an ideal blocker from allowing
other opioid drugs from working and thus allowing the patient to get high, but
further study has indicated this claim to be exaggerated.)
The reason
buprenorphine is labelled a mixed antagonist
is because of its action at the kappa opioid receptors. The kappa receptors
cause dysphoria and this antagonist
effect has no clinical importance except in that buprenorphine doesn’t have the
kappa-based side effects that other mixed (partial) agonist/antagonists do.
For the reason
it’s a “partial agonist,” which in buprenorphine’s case equates to a very low
ceiling effect for euphoria/analgesia and less danger of overdose, and that it
will cause withdrawals in those physically dependant on opioids, buprenorphine
is regarded with less abuse, addiction, and diversion potential. For these
reasons buprenorphine is Schedule III under the controlled substances act,
which, due to it’s FDA approval in the form of Subutex and Suboxone for
treatment of opioid addiction, allows it to be prescribed by qualified
physicians out of their offices as per the Drug Addiction Treatment
Act of 2000 (abbreviated as DATA, and called as such for the
rest of this FAQ.)
What the DATA is, Quoted
From SAMHSA (the Substance Abuse and Mental Health Services
Administration):
“The Drug
Addiction Treatment Act of 2000 (DATA of 2000) expands the clinical
context of medication-assisted opioid addiction treatment by allowing qualified
office-based physicians to dispense or prescribe specially approved schedule
III, IV, and V narcotic medications for the treatment of opioid addiction. In
addition, (the) DATA reduces the regulatory burden on physicians who choose to
practice opioid addiction therapy by permitting qualified physicians to apply
for and receive waivers of the special registration requirements defined in the
Controlled Substances Act.”
What this means
is that drugs approved for treatment of opioid addiction in the form of medical
maintenance or detoxification (which currently only includes methadone, LAAM,
and buprenorphine) that are in schedule III or above (which only includes buprenorphine,
in the Subutex and Suboxone formulations,) can be prescribed by qualified
physicians (usually psychiatrists and certain clinics) directly out of their
office (via regular albeit usually “secure” prescriptions that can be brought
to your pharmacy of choice). This law was enacted (in 2000!) in order to help
get more addicts into treatment by loosening some of the clinic restrictions
(of methadone clinics), by eliminating the clinic completely in certain
situations.
As of this
publishing, LAAM is no longer produced in the
3) Eliminating the Fat
Can any doctor
prescribe buprenorphine? What are the requirements?
No. Only doctors who meet the (fairly simple)
qualifications, and then apply to SAMHSA
(who then follows through with the DEA,
whom issue the doctor a second, special DEA
number (which in all cases I have seen it is the same one with the first letter
being replaced with “X”) may prescribe maintenance medications. See the “Practical
Information” section for more practical information, including finding
a doctor. The qualifications are more of a red tape then anything else. All
that is necessary at minimum is an 8 hour course (if the doctor meets none of
the other requirements) and a short application. If you have a doctor or
psychiatrist you know and like whom isn’t a part of this program, perhaps you
can convince him or her to sign up. There is a short waiting period, which the
doctor can waive by checking a box on the sign-up form. Finally, there is a 30
patient limit – for individual physicians only as of 08/02/2005. Prior to this,
it applied to group practices as well.
Rep. Souder
(R-IN), the ultimate drug war bureaucrat, was first to sponsor an amendment to
the DATA to get rid of the 30 patient
limit (which has since passed into law as of August 2005.) Debate led to
keeping the limit for individual physicians but removing it for group
practices. There are two reasons why there was reason to remove the limit, the
first being that there is no such rule applicable to doctors in any other way,
and many doctors did not appreciate it. The second is that there was a lot of
"patient shuffling" going on. That means that some of the less
reputable group clinics, in an attempt to make money, would keep offering only
"detox" to people, making them pay enormous sums over and over, using
the 30 patient rule as an excuse.
Does this mean that qualified doctors can prescribe methadone or LAAM?
No. Both
methadone and LAAM are in Schedule II (of the Controlled Substances Act.) Only
Schedule III, IV, or V drugs may be prescribed by office physicians under the
rules of the DATA. The drug must also
be FDA approved for opioid dependence. Buprenorphine
is the only drug that meets these criteria. There is no other drug your doctor
may legally prescribe for maintenance. LAAM is no longer manufactured in the
It is possible,
and eventually likely, that other drugs will come forth in the future that will
meet these criteria, although most likely not anytime in the immediate future.
Perhaps even methadone or LAAM will be rescheduled. That is fairly unlikely for
a conservative country such as the
At the time of this
writing, the differences between Subutex/Suboxone and methadone in
4) Buprenorphine vs. Methadone
A lot of heroin
addicts or methadone maintenance patients have preconceived notions that buprenorphine
won’t work, largely due to the fact that it is a partial agonist and thus “weaker”.
That is simply not true. Buprenorphine is not in general inferior to Methadone.
That is a widely believed myth. It’s different, but not generally inferior. It depends
on the individual. For some people methadone will work better, for some
buprenorphine will work better, it’s that simple. Buprenorphine, once your body
has a period of time to adjust to it, is just as effective as 90mgs of
methadone or more as a treatment for heroin addiction. While the ceiling level
for buprenorphine is only equivalent to roughly 30mg methadone, you can get it
so that you dose that twice a day or more,
and it even reduces your tolerance. This is mostly due to its
antagonistic/partial agonist nature. Because of this, it makes what would be
equal to 30mg of methadone much more effective, in some people. The other major
downside to buprenorphine is that in most cases of serious heroin addiction,
you will have to go through at least some withdrawals. If you are switching
from methadone you can expect withdrawals, and the typical cut-off dose for
switching from methadone to buprenorphine is 30mg.
Personal Notes:
I am not
saying buprenorphine could ever be more potent than a full agonist. I am saying
due to other factors it can in some cases work better, especially over
time Granted, it is likely very
rare that buprenorphine will get someone “higher” than methadone in general. It
can work better though, if you
give it time, and it gives you more flexibility. If you are on it long term and
you are successful with it I was nearly positive you will get a buzz (similar
albeit weaker than the “methadone buzz” that clinical literature tells us doesn’t
exist), given the fact that you were successful with it. However, I was proven
wrong in this regard: It seems much more common not to receive a buzz than I
thought, but oddly enough these people are happy with that, that was their aim
(very little side-effects seem to go along with not getting a buzz). While you
shouldn’t rule out buprenorphine because of this, if getting a buzz is of the
most importance to you, then that should definitely affect your choice negatively
towards buprenorphine. I strongly believe either it’ll work or it won’t, once
you give it time and find the right dose. Struggling on buprenorphine therapy
is unlikely. If it doesn’t work, it doesn’t work. Switching to methadone is a
fairly simple process if buprenorphine isn’t your cup of tea, the clinic will
probably be happy to have you. Luckily there have been a lot of addicts in the
community who have had good experiences with buprenorphine now as compared to
the first publishing of this FAQ, and they have shared those experiences, so
that the community is more informed. Street addicts, however, are not, and buprenorphine
is still grossly underused in those communities. There is also the prevailing
belief that buprenorphine is for pill addicts not for heroin addicts, and this
is totally bogus, minus the fact that I wouldn’t recommend a hydrocodone addict
to get on methadone, of course.
From personal experience, I have found that
getting on buprenorphine from a heavy heroin habit involves 1-3 days of
withdrawal (3 days from a heavy habit without waiting through a lot of hell),
much more tolerable than straight heroin of course.
A simple example of the
possibilities of maintenance treatment: 4 possible scenarios of dependence,
not including the scenario where the addict succeeds at abstinence the first
time, which is incredibly rare.
Person A
has an “ordinary” opioid dependence. He needs a dose of agonist to keep him
maintained. Methadone works, at doses most likely anywhere in the double
digits, and he is happy. Buprenorphine works, and he is happy. He is the most
likely to succeed with abstinence, but not necessarily so. Don’t rule yourself
out of this spot so quickly. This also includes the person who wants the least
“opioid” necessary, he doesn’t want to get a buzz or get high, and he doesn’t
want side effects. (If that’s the case, while it is totally possible buprenorphine
can give you a buzz and give you side effects equal to methadone, the chances
of it not doing so warrant it being your first choice IMO).
Person B
has an “ordinary” opioid dependence, but her tolerance and addiction level is
sky high. She needs a high dose of agonist to keep her happy. Methadone at
normal levels isn’t enough. She needs a dose (most likely) of 100mg or more to
be happy on methadone. Had she tried buprenorphine, it would have never reached
her level of opioid dependence. She would have failed, and she would have
relapsed or switched to methadone.
Person C
has a “special” opioid dependence. Methadone at any dose doesn’t work.
Buprenorphine doesn’t work. Hopefully she will one day be able to have heroin
or morphine maintenance, as they have in
Person D
has a “special” opioid dependence. He has a certain predisposition that makes
him a good candidate for buprenorphine. He is likely to have a high level of addiction, although this
could depend on how long he has been using opioids, and which ones. He also is
quite likely (but far from definitely, it’s individualized like everything
else) would have failed on methadone. Buprenorphine lowers his tolerance and
addiction level, and seems to fit right, and gives him the proper maintenance
that he needs.
Now, the Person
A and Person B scenarios I gave you are very typical. It’s what you would
expect. Person C is less typical, but is still there. However, the Person D
scenario tends to be overlooked. While it can’t be proven that certain people
have a predisposition to having success on buprenorphine, I don’t see how you
could argue against it. Just look at how individualized opioid use is in
general, and the responses people have to which drugs. What could be argued is
just how often Person D comes strolling along. Exactly what criteria Person D
is likely to fall into is guesswork at best. It is entirely possible that they
would have failed on methadone. Don’t rule out buprenorphine because methadone
didn’t work. Also, it is completely possible tolerance has little or nothing to
do with it. I can say this from personal experience among other things.
Hopefully future research will give us answers to these questions. I will give
reasons for my beliefs as to what people would fall into the “Person D”
category throughout this FAQ. See my personal experience and partial agonist
(in pharmacology) sections especially for more information.
Effectiveness of treatment:
In many studies
done, 8mg SL (sublingual) buprenorphine (a low-average maintenance dose) was
shown to be slightly less effective as a maintenance drug than ~90mg methadone
(measured by keeping people in treatment and having clean urine). It was shown
to be much more effective than low dose methadone (~20mg.) It was also,
interestingly, shown to be more effective than LAAM, which is a full agonist. Given
that 8mg is basically the lowest line in terms of dose for maintenance (4mg for
maintenance is possible, even lower is possible but not ideal generally
speaking,) it can be fairly safely assumed that buprenorphine is generally as
effective as 90mg of methadone in terms of effectiveness as a maintenance
medication, and can also be somewhat safely assumed that buprenorphine, once it
your body adjusts to it, at an optimal dose, is equal to about 90mgs methadone
in potency for the user vs. potency for someone on 90mgs methadone; this however
is a major simplification.
From personal experience, I have found that
increasing the dose to 16-32mg, while not increasing any buzz, has an enormous
additional effect on cravings and of course has additional blocking effects,
and would easily bet that the higher dose would prove as effective as a higher
dose of methadone than 90mg in most people.
The 48 hour rule(?):
There is one
other difference to be noted. As previously mentioned, buprenorphine has an
extremely high affinity for the classic opioid receptors, which means it
effectively blockades them, not allowing other opioid drugs to bind to them and
forcing other opioids that do bind to them off pretty quickly and unpleasantly
as buprenorphine is only a partial agonist with a low ceiling. Originally it
was believed that a dose as low as 8mg will cause an effective blockade for
about 72 hours. This has recently found to be largely untrue. If you are on a
dose of 16mg or more, you really can’t get high on opioids for about 48
hours-72 hours, this is true as it was written. You often will get what is
called an “attenuated rush”: you get a small rush, and then feel dysphonic/opioid
withdrawal. It’s like the methadone blockade, but with an antagonistic backlash
that is reportedly very unpleasant.
However, if your dose is 12mg or less, more-so with 8mg or less, and extremely
so with 4mg or less, you can get a solid 75% effect from stronger opioids,
namely Heroin or Oxycontin, about 24 hours later, as little as 2-4 hours with
strong heroin. It is possible the reason this holds true is after being on
buprenorphine for a long period of time, which the studies regarding this do
not properly account for, your tolerance is lowered to such a large extent that
you can get high easily. This is merely hypothetical, however. If you do this
however, there is the potential for an antagonistic backlash that must be mentioned
in warning. Even after those 24 hours, that buprenorphine will be sitting there
in your system for a solid week, even after taking other opioids. Occasionally
it will push the other opioid off the receptors and retake its space. This
causes nausea mainly, and other unpleasant symptoms, although they usually do not clearly resemble opioid withdrawal.
This scenario can easily be fixed by returning to your buprenorphine regime,
with antagonistic effects fading almost immediately. Finally, I will mention
that if you do this (use other opioids to get high), which I am not suggesting, I am merely providing
information, switching back to buprenorphine is fairly easy, if you
binge for 2-3 days, my suggestion is wait until you are sick (WAIT!) and then
take your buprenorphine, and hopefully
the transition back will be smooth, but there are no guarantees. I have
personally found that quite ironically the higher your tolerance is, up to a
point, the better buprenorphine works. Of course, this, again, is
individualized, and your tolerance and metabolism will play a large role in all
of this.
Less than daily dosing?
With recent
data, it seems that buprenorphine can be given with less than daily dosing,
with every other day to tri-weekly (three times a week) still being effective
in some people. However, as always, this is very individualized, and with the
recent laws in the US there seems to be no reason to attempt such a dosing
schedule unless for some reason you want to (having a very slow metabolism for
buprenorphine for instance, which could possibly lower your ability to be maintained on buprenorphine (more
!= better once you reach that ceiling level,) in which case less than daily
dosing would be a good idea.) Discuss it with your doctor.
There is
currently a depot formulation of buprenorphine in stage 3 clinical testing. It
seems to be doing well, and you can expect it to be available in a few years.
It is a little pill that gets injected under your skin (like the naltrexone
depot) and keeps you with a steady state of buprenorphine for a month. This,
most certainly, is not for everyone, and there will be a bare minimum of a year
before it’s available commercially.
Should I switch from methadone to
buprenorphine?
In my opinion, probably
not. You will go through at least
some withdrawals, and it won’t be worth it, unless you really want out of the clinic
or want to detox. If one clinic doesn’t suit your needs, perhaps another will.
If methadone isn’t working for you though, then that doesn’t mean buprenorphine
won’t, and in that case also it’s worth a try. However, a methadone -> buprenorphine
conversion can be tricky, and if buprenorphine just doesn’t work for you, you
are in for a very rough week or so.
Should you
switch from methadone to buprenorphine if you are going to detox? Again, in my
opinion, Absolutely! I see absolutely no reason why this should not be done.
Buprenorphine detox has been shown to be very effective. Methadone withdrawals
are downright terrible. Buprenorphine withdrawals generally are far milder,
albeit just as long lasting. On top of that, it will work sort of like an UROD
(Ultra Rapid Opioid Detoxification - buprenorphine will force the methadone out
of your system,) while giving you enough opioid stimulation in your brain to
help the withdrawals, at the same time. See the withdrawals section for more
information.
To further sum up – author’s opinion
If you want to
get off of Heroin, and have not been in maintenance, should you try buprenorphine?
Of course! It’s very likely to work just fine on you. And if it doesn’t, there
is always methadone. It’s your call, of course, but it isn’t something that
should be ruled out without at least a full investigation.
Does buprenorphine
give you a “buzz”? Usually it does, dependent on dose, but it may not. Can you
get high off of it? Yes, you can (and if you think the answer is no, explain
the gigantic population in
Buprenorphine is
a very individualized experience. I strongly believe that it works the best on
people with a certain type of predisposition to heroin use. It seems to fix
certain broken indigenous opioid systems. Some people will love buprenorphine, and some people will find it
ineffective. This is the way it goes.
5) General rules for starting buprenorphine
Try to cut down
as much as you can before being inducted with buprenorphine. If it’s just for a
day or two, it won’t make much of a difference, however, unless it’s major.
You must wait
until you are in withdrawals
before taking your first dose of buprenorphine. If you don’t, you will be in withdrawals after taking it, and it will be much less
pleasant than if you wait. In general, with the short acting opioids, including
Heroin, this means (from your last dose) waiting at minimum 8 hours, but 12-24
hours is strongly recommended (sleeping some of it out is a good idea). This is
the most important thing when
starting buprenorphine. The longer you wait before taking that first dose, the
better off you will be and the less the chances of withdrawals. The only
potential downside is the rare case where buprenorphine doesn’t work for you at all, then it’ll be longer before you
can get a working dose of another agonist.
When starting
buprenorphine, lower is better. Start with a dose of 4mg (SL), and work up
slowly from there, with 2 additional doses of 2mg to a maximum first day dose
of 8mg (just a general recommendation.) Exceeding 8mg during the first day will
most likely just make you regret it, and is not recommended in any case. Its
effective action as an antagonist will overwhelm its action as an agonist.
Your doctor will
be in control the first three days (ideally, at least), and give you your
doses. Be completely honest with him/her and do what he/she says.
In the case of methadone
It is strongly
recommended that you lower your dose to 30mg or less. I think this is a little
on the conservative side, but until further data is available, you shouldn’t
stray from this number. Methadone has a nasty backlash, as you probably know,
so it’s much better safe then sorry.
It is strongly
recommended that you wait 48 hours minimum before taking your first buprenorphine
dose, and that estimate I do not believe to be conservative.
What to expect
This part is the most individualized. It
depends on four things:
1. Your level of
opioid addiction
2. The current level
(amount) and state (time since your last dose) of your opioid of choice in your
body
3. Your reaction to
buprenorphine
4. Dose of
buprenorphine (remember, less is best)
Now, I honestly
can’t tell you what to expect. It varies far too much. Unfortunately since not
only is it individualized it’s weighing on a combination of four different things,
it makes it nearly impossible to predict. I can promise you almost definitely
you will go through at least some withdrawals, unless you really shouldn’t be
on buprenorphine in the first place. These withdrawals will either come before
or after your first buprenorphine dose, depending on the above four things (see
the guidelines for further info.) It most likely will be a mixture of both, but
will weigh more to one side, and this will be mostly your choice.
These
withdrawals could last anywhere from 4 hours to 4 days. It is possible that you
could have mild lingering withdrawal after this period. It is also possible
that you could decide to wait it out and keep trying, making the withdrawals
last longer.
How long should
you wait it out if you are struggling? My opinion - if you are still having
major withdrawal symptoms after 4 days since your first buprenorphine dose it’s
time to move on. It is unlikely that you will find buprenorphine to work for
you if you are suffering greatly
after 4 days. If you are still having mild symptoms, this is normal. This is my
opinion, and I will search for more information on this.
In the case of
switching over from methadone the above is not necessarily true as was already
pointed out earlier. Dose (and your level of addiction that comes along with
that) weighs in much heavier than with short acting opioids, and withdrawal
time could be longer. See the guidelines for more information. Once again, this
does not strictly depend on
tolerance by any means.
Side effects of treatment
There have only
been 3 confirmed side effects from long term methadone maintenance treatment:
Constipation, Sexual dysfunction, and Sweating. With buprenorphine, you can
expect the same. The constipation is still there, but not as bad as Heroin (from
personal experience buprenorphine is far from the ideal opioid for the
digestive track.) The sexual dysfunction is definitely still there, I can
unfortunately say that personally. I have never experienced the sweating, but
there is no reason to believe it is not part of buprenorphine maintenance. Its
importance, however, is practically nothing. Unfortunately tolerance does not
develop, or develops very little, to these three side effects of opioids.
These are the major
side effects according to the product literature: Headache (36%, placebo 22%), Withdrawal
Syndrome (25%, placebo 37%), Pain (22%, placebo 19%), Nausea (15%, placebo
11%), Insomnia (14%, placebo 16%), and Sweating (14%, placebo 10%). These are
short-term side effects.
Warning: Cytolytic Hepatitis and Hepatitis with Jaundice have
been observed in the population taking buprenorphine for narcotic addiction.
Whether this is due to the addicts contracting Hepatitis beforehand, which is
very common, or a cause of the drug itself is currently unknown. It is possible that buprenorphine, notably in
large doses, can cause liver problems.
6) Buprenorphine Pharmacology
There is a lot of conflicting data about buprenorphine. (Miller et al., 2001) It likely has to do with many factors, dose being the most major. On top of that, the concept of a “partial agonist” is poorly understood. This further emphasizes how buprenorphine can be very individualized, and even have a different effect every time you take it. A lot of the pharmacological information you may find may be outdated and incorrect.
By the Textbook
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Buprenorphine |
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17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,
5-epoxy-18, 19-dihydro-3-hydroxy-6-methoxy- α -methyl-6,
14-ethenomorphinan-7-methanol, hydrochloride [5α, 7α(S)]- |
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CAS number |
ATC code |
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504.10 |
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31%
(sublingual, varies) |
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Metabolism |
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37
hours |
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C
(USA) |
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Buprenorphine is
a semi-synthetic narcotic opioid, derivative of thebaine. It is a mixed partial
agonist-antagonist. It is a mu partial agonist and a kappa antagonist (Subutex
full prescribing information). At low doses (~100mcg-1mg,) it works as a full
agonist, and is slightly selective for mu. At higher doses, the antagonistic &
partial agonist properties become more dominate, and it is competitive.
(Buprenex full prescribing information, (1), (Miller et al., 2001)
Buprenorphine
hcl is a white powder, weakly acidic with limited solubility in water
(17mg/ML). Chemically, it is 17-(cyclopropylmethyl)-α-(1,1-dimethylethyl)-4,
5-epoxy-18, 19-dihydro-3-hydroxy-6-methoxy- α
-methyl-6, 14-ethenomorphinan-7-methanol, hydrochloride [5α, 7α(S)]-.
It has a molecular formula of C29 H41 N04 Hcl
and the molecular weight is 504.10 (Subutex full prescribing information).
Note about Suboxone:
Naloxone is present in a 4:1 ratio in both dosage strengths (8mg/2mg and
2mg/0.5mg). See “Subutex vs. Suboxone”
for further information on the naloxone component.
Receptor Affinities & Efficacies
Buprenorphine
has a high affinity at all 3 major opioid receptor types and the ‘Orphan
Receptor’, opioid receptor-like 1 (nociceptin) (mu, delta, kappa, and ORL1/NOP)
(Miller et al., 2001, (1))
Order of
affinity (How much attraction to and how tightly it binds to each receptor): mu
> kappa > delta > ORL1 (Miller et al., 2001) (delta has about 30 fold
less affinity than mu) (Negus et al., 2002)
Buprenorphine is
a partial agonist at mu, delta*, and
ORL1. It is a full and potent antagonist at kappa. (Miller et al., 2001) It’s efficacy at
the receptors is related to dose. The higher the dose, the less efficacious it
works, (1) until it reaches a dose (~32mg SL) where increasing it any more
would make it work less efficacious, although more data is necessary. (See Buprenorphine and Dose)
Order of
Efficacy (how much activation it causes at the receptors): ORL1 (34%) > mu
> delta* (Miller et al., 2001)
The fact that it
is efficacious at ORL1 is significant, as I am unaware of any other traditional
opioids that can stimulate ORL1 (this includes morphine and Heroin.) ORL1, the
opioid receptor-like 1 orphan receptor is a G-protein coupled receptor with
functional and structural homology to opioid receptors, namely mu.
Unfortunately buprenorphine has a very low affinity for ORL1, which would appear
to require large doses to create a significant effect there despite its high
efficacy. Fairly large doses have been attempted in limited studies with no
interesting results, other than the eventual apparent complete reversal of
agonist effects. There is also evidence that the ORL1 effect is significant in
the fact that naloxone/naltrexone both are unable to fully reverse overdose
with buprenorphine (Suboxone Full Prescribing Information). ORL1 has been shown
to have anti-anxiety effects as well (Jenck et al., 2000). The information is constantly growing on this
subject.
·
There is a lot
of conflicting studies in regards to kappa. Some say that buprenorphine does
indeed produce kappa agonism. This isn’t the case, but I’d like to know why
this is. It possibly has something to do with in vitro testing, however the in
vitro testing summary (Miller et al., 2001) has determined buprenorphine to be
a kappa antagonist.
·
* I have been
told by very reliable sources (two pharmacologists) that buprenorphine has no
effect at delta. Why these studies say it does, I do not know. Apparently it
does, at least have an antagonistic effect, but its agonism is so low as to be
non-existent, in layman’s terms.
Buprenorphine
has an extremely long half-life at the receptors. It takes about a month for
the drug to be completely removed from your system.
Finally,
buprenorphine has a major active metabolite, norbuprenorphine, which has
activity at the receptors. See metabolism for more information.
General Pharmacological Information
Buprenorphine
has a slow onset of action, with peak effects taking place in approximately 100
minutes (Suboxone full prescribing information). The peak effects for methadone
take place in approximately 120 minutes. The onset of action for buprenorphine
is approximately 30-60 minutes.
The duration of
action depends heavily on the dosage. At a low dose (~<4mg), it is
approximately 8-12 hours. At a high dose (~>16mg), it can last approximately
24-72 hours (and thus the reason less than daily dosing is possible.) Buprenorphine
readily crosses the blood brain barrier, and is highly lipophillic. Buprenorphine
is about 10x more potent IM than
Sublingual
absorption varies greatly, and can be anywhere from 25%-75%, with an average
around 40%. However, in most people, their personal variation from one dose to
another is low. (Subutex full prescribing information)
A comparison of
buprenorphine to methadone for respiratory effects found that buprenorphine had
a much higher incidence of respiratory depression not requiring medical intervention. Buprenorphine can cause
respiratory depression, but very
rarely anything resembling life threatening. Both drugs decreased 02
saturation to the same degree. The chances of severe respiratory depression are
increased via the injection route. (Suboxone full prescribing information) Buprenorphine
is a very safe drug for an opioid. Overdose is very difficult, even for opiate
naive individuals. (Subutex full prescribing information) See “Buprenorphine
and Dose” for further information on this topic.
Distribution and Elimination
Buprenorphine is
approximately 96% plasma bound, primary to alpha and beta globulin (Subutex
full prescribing information)
Buprenorphine
has a mean half-life plasma elimination of 37h (this can greatly vary between
people) (see metabolism for further information) (Suboxone full prescribing
information.) The half-life of methadone is 15-22 hours, although recent data
suggested this could increase with repeated administration, and be as high as
150 hours.
Metabolism
Buprenorphine
undergoes N-dealkylation into norbuprenorphine and glucuronidation. This is
done by the cytochrome P-450 3A4 isozyme (Subutex full prescribing
information.) Norbuprenorphine is an active opioid. It is similar to buprenorphine
in its profile of action, but more potent. From one in vitro test, it has very
similar affinities to buprenorphine. Norbuprenorphine is a full agonist at
delta and ORL1 with a low potency, but buprenorphine antagonizes its effects.
This study also states that at the ?- (mu?) and Kappa- receptors, both buprenorphine
and norbuprenorphine are potent partial agonists, with buprenorphine having a
low efficacy and norbuprenorphine having a moderate efficacy, which we know is
not true (in terms of kappa), and makes me doubt this study. (Huang et al.,
2001) Norbuprenorphine however does appear to be a potent
opioid agonist, superior to buprenorphine. (Mégarbane et al., 2002)
The nonlinear
disposition in the clearance and volume of distribution of buprenorphine can be
attributed, in part, to the increasing concentration of norbuprenorphine (Gopal
et. al., 2002)
Note: Whether you take it orally or sublingually,
approximately the same amount of norbuprenorphine is bioavailable. If, for some
reason, you would want to maximize norbuprenorphine and minimize buprenorphine,
oral would be the way to go. This shows that the first-pass liver breakdown is
responsible for the low oral availability of buprenorphine, quite similar to
morphine.
Further studies
are necessary, or more access to information for me, for more information on
norbuprenorphine.
Inhibiting/Inducing
P450 3A4 will cause differences to you personally on how buprenorphine works.
What those changes would be are impossible to say without further investigation.
Unfortunately, this includes HIV protease inhibitors, just like with methadone.
It is doubtful any significant differences/problems would arise that dose
adjustment wouldn’t solve.
Pregnancy
Buprenorphine is
very similar to methadone when it comes to pregnancy. The good part, however,
is that neo-natal withdrawals are less, for obvious reasons. (Fischer et al.,
1998) Buprenorphine also being the unique drug that it is that very rarely
causes tolerance would be less likely to cause problems related to neo-natal
addiction later in life if such problems do indeed exist. I have not backed
this up, nor has problems later in life have been confirmed (making this
impossible to back up,) this is mostly assumption and logic. I am fairly
certain if you become pregnant or are planning on becoming pregnant it will be
recommended you switch to buprenorphine, if this didn’t require a major dose
reduction. This, however, is 150% better told to you by a doctor, and a
decision made with his advice.
Partial Agonist / Mixed
Agonist-Antagonist
Buprenorphine
best classified as a mixed partial agonist-antagonist. The fact that buprenorphine
is a mixed –antagonist is if anything a good thing (that it antagonizes, or
rather doesn’t agonize, kappa.) The fact that it’s a partial agonist is what makes it a “weaker”
opioid comparatively. They are two different things as far as Buprenorphine’s
classification is concerned. Buprenorphine is a very bizarre drug, mostly due to the fact that it’s a
partial agonist with a fully active metabolite to boot. I can’t emphasize this
enough. It has a ceiling for agonist effects (due to its partial agonist
nature), and, for example, 16mg is not twice as strong as 8mg.
Buprenorphine
can also be classified a mixed antagonist at mu because it has a very high
affinity, which means it pushes whatever is there off of the receptor and takes
it’s place, and it’s partial agonist nature (low efficacy, to put it simply)
means it can’t do the job that was just being done. This can cause it to be
classified as having mixed -antagonistic effects, however partial agonist is a
better classification as long as the dose is proper. It doesn’t simply have a
“low efficacy”, its better put as a “partial agonist.” Read on for more
theories on this.
Taking a large
enough dose of buprenorphine, out of proper clinical dosing, can be enough to
do a UROD, as it pushes all the opioids out of your brain. This is what causes
the problem with starting buprenorphine. You have to go through some
withdrawals. See the part on starting buprenorphine and methadone vs.
buprenorphine for further information.
So what exactly
does all this mean? It is easiest (and still largely accurate) to describe
buprenorphine as a normal opioid agonist with a sliding ceiling (by sliding I
mean different in every person, and dose and effects aren’t linearly linked.)
Buprenorphine and dose
Buprenorphine is
a very unique drug in regards to dose. As already explained, double the dose
doesn’t double the effects. The reason for this is because as the dose goes up
the efficacy goes down. (1) The reason for this is (fair to say) unknown, and
related to its partial agonist nature. Dose for highest efficiency: 0.3mg (IM.)
At this dose, its effects are maximized and it behaves almost completely like a
full agonist, acting equal to 10mg IM morphine in opiate naive individuals.
(Buprenex full prescribing information) 32mg is about the ceiling level. This
ceiling level is different in every person (see bottom of this section.) For
this reason, it is possible
that in people who have a very low ceiling are those that would likely fail at
buprenorphine, but further information is necessary. Increasing the dose higher
than this will have the loss in efficacy overtake this increase in amount in
your system. Taking doses higher than the ceiling will eventually lower its
effects, and taking very high doses will function as a straight up antagonist,
(1) although again more information is necessary. (See below)
There is one
study to this regard available; in rats a dose of about 1mg/kg caused an end to
increase in agonist effects and a linear reversal in efficacy. In the average
human this would be a dose of about 80mg, which is way more than ~32mg. obviously,
since it’s a different species, the numbers can’t be applied. It does seem
however that this same mechanism happens in humans, but at a lower dose.
Further information is necessary.
An 8mg-24mg dose
is highly suggested for maintenance, depending on your personal reaction to the
drug and dose. If you go over 16mg, it is strongly suggested you take it more
than once a day. It is also important to say that 32mg is the GENERAL ceiling. This depends on the
individual, but in every individual a ceiling was reached, and usually above
8mg. (Subutex full prescribing information.) So please remember, more doesn’t
necessarily mean better with buprenorphine. If this is the drug for you, you
will find the proper dose, and don’t feel like you are getting gypped because
you are only on 8-24mg.
Tips for getting the most out of buprenorphine:
1.
First and
foremost, see “buprenorphine and dose” in the above section.
2.
Cut your dose in
half, and take it twice a day. This is because of efficacy as I just explained.
By taking it twice, you get more bang for your buck, and it’s long half-life
makes sure that it’s effects are cumulative the second time you take it. I
strongly believe this makes a big difference. However, for you, as always, it
could be different. Certainly worth a try, and definitely if your dose is over
16mg daily, or if it’s just not working and you’ve reached the ceiling.
3.
Take your dose
in the evening. I have personally found that when I take it in the morning, it
leaves me wanting more and having very little effect. If I wait it out and take
it later in the day, it works great. Granted, I have to be a little sick for about an hour or two, but
it’s nothing really, for me at least.
4.
Hold it under
your tongue for longer than 15 minutes. At first it didn’t take as long as it
does now, it took about a half hour (to ABSORB, not to DISSOLVE.) Nowadays it
takes at least an hour for it to absorb as best as it will. SL absorption
varies greatly from individual to individual, which is one possible reason why buprenorphine
works for some people and not for others. How can I tell that it’s absorbing
and how long it takes? I have been taking this drug for several years. I can
feel it tingle on my tongue. I can taste the drug in my mouth. If my tongue is
in it, it will tingle. If I take my tongue out before it’s done, it will stop
tingling to some extent. This is how I can tell. You have nothing to lose by
trying.
Buprenorphine Withdrawals and Detox
There are two
aspects to this, withdrawals when switching to buprenorphine and withdrawals
from quitting buprenorphine.
Withdrawals from switching to buprenorphine
You do have to
go through at least a little withdrawal if you are addicted to opioids. This is
unavoidable. Now, if you are switching from heroin, it really isn’t that bad.
See “General rules for starting buprenorphine” for further information.
Buprenorphine withdrawals
Buprenorphine
withdrawals were believed to be mild at best (in comparison to other opioids.)
For this reason, it is a great thing for people wanting to get off methadone
but unable to deal with the withdrawals. However, recent experience has shown
this to also be untrue, and in certain individuals the withdrawals can be just
as bad as methadone. Unfortunately, due to its long receptor half-life like
methadone, the withdrawals will last at least a month (although this too is
individualized, and can be shorter.) Buprenorphine has one major unique symptom
of withdrawal that will be the centrepiece: this unbeatable fatigue that will
outlast all the other symptoms. All of the other symptoms, except a few minor
and not worth mentioning unique ones such as stomach grumbling, are similar to
other opioids. I have been told that the withdrawals are the worst during the
first week and then proceed to lighten up a lot. I have also been told that
withdrawals don’t even begin until the third day. Once again, individualized.
It is strongly recommended you do not
taper your dose really low before quitting. It doesn’t work, and doesn’t help.
It’ll make the withdrawals linger much longer. It is not a good idea. Reports
of withdrawals cold turkey have been much more positive than taper attempts.
(PROVIDE REFERENCE) The suggested dose to go cold turkey from is 2 to 4mg. Your
body will take care of the rest (via the slow disassociation of the drug from
the receptor, lasting quite a long time, creating an auto-taper.) I must say
however, as I have in just about every other section, this is individualized.
If the withdrawals from buprenorphine are very bad, in this case a different
strategy is likely warranted, possibly
involving a longer and lower taper.
Treatment with
Naltrexone (although strongly frowned upon by myself) is possible very early
after the cessation of low-dose buprenorphine treatment, within days, and does
not cause severe withdrawal symptoms. (Bell et al., 1999) This certainly is
individualized, and if you are in the rare situation of having bad withdrawals
after stopping low-dose buprenorphine, it is a very bad idea.
Buprenorphine for detox
Coming soon.
Subutex vs. Suboxone
Many addicts
hear “naloxone” and get scared. The fact of the matter is that naloxone is not
absorbed sublingually (however recent studies have discovered one in three
people are hypersensitive to it.) It is added so that people don’t inject it.
If you inject Suboxone, you will get very sick and will deeply regret it. There
is no clinical difference between sublingual Subutex and sublingual Suboxone.
OK, now to get a little more technical. A tiny tiny amount of naloxone is
absorbed. Picograms. So little in fact, it wouldn’t even qualify for ULD
antagonist therapy (as told by my doctor, and Mike Strates, a pioneer of ULD
Naloxone therapy, as I can’t personally make sense of the numbers.) Why then I recently learn that one in three
people are hypersensitive to naloxone I don’t know, and must research.
Practical
Information
Suboxone and
Subutex are both fully available in the
Here is a link
to the doctor locator: (Note: Not every doctor authorized is listed here. Not
every doctor listed here is competent.)
http://buprenorphine.samhsa.gov/bwns_locator/index.html
Sadly, even
though Suboxone is available, and the DEA numbers are issued, that doesn’t mean
getting into the program will be easy. Doctors have little clue of what they
are doing, nevermind what is going on. Pharmacies are sceptical of catering to
heroin addicts. Let me address some of this.
Pharmacies are
not going to have Suboxone in stock. They will most likely order it on a per
prescription basis. This is even more the case because of its price, nevermind
its use. Be sure to keep this in mind. Almost all pharmacies have next day
delivery, provided that it’s not backordered (which it’s not at the current
time.) You should have your doctor call in this induction dose the day before
so it will be available. Then we come to the next problem. Pharmacies don’t
want to cater to junkies. Most will be very sceptical. In major cities, this
really isn’t an issue, but in rich/suburban communities, this can pose quite a
problem. Be sure to call around and try to find a good pharmacy. A good
pharmacy will make your life a whole lot better, and you should not quit until
you find one. I suggest you try and find one before finding a doctor, as he may
bring this up.
Pricing Information
Here is some very
approximate pricing information. I have no idea whether your insurance will
cover it, call them and ask. As of my last (and only) script for ‘buprenorphine,
it came up as drug not found on my insurance. When further information is
available regarding information I will provide it. (These prices are for a
month supply (30 days) at the specified daily dose. I have roughly extrapolated these numbers from
the price of the 8mg daily monthly supply, and as such the other numbers are
far from perfect. This can also vary regionally, and by pharmacy. Some
pharmacies offer discounts, 10% for such a large cost is not uncommon.)
8mg - $175 12mg
- $250 16mg - $340 24mg - $510 32mg - $650
The average
daily dose is 16mg. 32mg is NOT necessarily
the best dose, due to pharmacological reasons, regardless of whatever your
tolerance may be. (See “Buprenorphine and dose” in the “Buprenorphine
Pharmacology” section) Buprenorphine comes in bottles of 30 and is available in
2 strengths: 8mg and 2mg, in both Subutex and Suboxone formulations. They will
likely come in the original bottle for as much as your dose is divisible by 30.
The procedure
for switching to buprenorphine is simple. You go to the doctor’s office the
first 3 days where he administers a dose of most likely Suboxone. (S)he will
likely have you in the office for 2 hours during the first dosing. The second
and third days will be shorter. You will then go once or twice a week for the
first month, and it is unknown how large a script you will be given. After the
first month is up, you will get monthly supply scripts, once a month (obviously,)
and will see your doctor (most likely) once a month for maintenance and once a
week if you are receiving psychotherapy. Psychiatric fees are usually in the
$200-300 range for one visit, at least in
Buprenorphine is
a schedule III (not V) narcotic
under the controlled substances act. This was changed recently. Buprenorphine
most definitely deserves to be a CIII, and I believe the prior scheduling (via
Buprenex) was automatic due to it’s relation to thebaine, and has not been
examined directly.
Other Formulations
There is one
other formulation that exists: Buprenex. (as was just mentioned) They come in
0.3mg injection vials for injection (possibly 0.6mg but I’m not sure.) They are
very expensive I hear. It is important to note that Buprenex is not FDA approved for maintenance, it is
approved for pain, and it is illegal
for that use (for your doctor (Special rules apply to opioid maintenance, see
the first section). If you had a legit script, it’s not illegal for you.)
People have used it in desperation in the past, with mixed results, although
generally the results are surprisingly favorable for such a small dose.
Overseas
In some
countries Subutex comes in 0.4mg strength as well. This has no practical use
except for PRN (as needed) use during induction (or, obviously, for pain in
opioid naïve individuals). This will not be happening in the
There is also
another formulation, Temgesic, but it isn’t available in the
Getting high
YES, it IS
possible to get high off of buprenorphine. In
There have
120-something or so deaths from buprenorphine in
It should be
noted that respiratory depression is increased when the drug is injected. This
shows that injection probably increases the euphoria aspect of buprenorphine.
The euphoric
aspect of Buprenorphine appears to be increased by injection/sniffing. The drug
IS highly lipophillic, which means it rushes the brain like heroin (and
theoretically should provide a rush if not for its partial agonist nature,)
however, and also due to its partial agonist nature (?), it has a very long
onset of action, of approximately 100 minutes to peak effects.
I feel 100%
confident in saying that buprenorphine works just fine for getting opioid naive
individuals high. It’s quite potent in that case, actually. The downside is its
long onset of action, which can take 1-2 hours if taken SL. In this case, a
dose from 0.2mg to 1mg SL works wonders, however even in opioid naive
individuals overdose is difficult. Don’t try it out, though! People HAVE died,
and it will most likely be unpleasant at an extremely high dose. If you don’t
have a tolerance, 0.2mg SL should be your first dose. And give it time!
Getting high while
on buprenorphine (on other opioids) is difficult to say the least. The drug can
work with a fairly similar efficacy to oral naltrexone in blocking opioid
agonists. See the “48 hour rule” in Buprenorphine vs. Methadone for further
information.
Buprenorphine is
clearly not as good a euphoriant as other opioids in many regards.
Experiences Getting High
A personal
report of getting high on 0.3mg via IV in an opioid tolerant/non-dependent
individual:
http://www.erowid.org/experiences/exp.php3?ID=15694
He compares it
to Vicodin and Xanax all rolled into one, mild (without the rush, nod, or
intense euphoria), yet glorious. This is just one account, however, and is far
from what you will experience if you try.
Another one:
http://www.erowid.org/experiences/exp.php3?ID=13581
This one uses
Temgesic 0.2mg SL tabs. He had a very strong reaction to the 1mg he took the
first time, and enjoyed the rest of the bottle of 30, taking only one at a
time. He takes them SL, as they are designed for.
Nephalim’s Experience on Buprenorphine Maintenance
I personally am
fairly certain I would have failed on methadone. My tolerance was so high that
ANY dose of anything other than good heroin (1 bag minimum) going straight into
my vein did absolutely nothing.
This was good quality dope,
trust me. There was only one brand that I liked, the rest were no comparison. I
took my last dose of H in the evening. The next morning I was sick as a dog (I
smoked some opium later that night (the one before) to try hold the withdrawals
longer. I didn’t wait long enough. BAAAAD idea.) By the end of that day, I received
my buprenorphine dose and was a hell of a lot better. Those were the worst
withdrawals I have ever experienced (before taking the buprenorphine.) I was
puking every 3-5 minutes, cramped so bad I couldn’t hold a thought, kicking and
screaming…it was actually like the movies. Anyway, the withdrawals were over by
the end of day 2. In about a week, I started feeling REALLY high (I hadn’t felt high in ages.)
One night I was so high I nearly OD’ed (I was barely breathing and couldn’t
move,) it was the best high I’ve ever felt. Obviously, that ended fairly
quickly, but it shows clearly that tolerance doesn’t necessarily mean that buprenorphine
won’t work for you. In fact IMO I think they will find it to be the opposite. I
still get a buzz off ‘buprenorphine, and sometimes a fairly strong sedative
effect, but rarely anything really nice, usually just a buzz. HOWEVER, it’s
different every day. It holds me every day, but some days are much better than
others. That is my experience with buprenorphine and my opinion.
Notes
(1) Dum JE, Herz
A. In vivo receptor binding of the opiate partial agonist, buprenorphine,
correlated with its agonistic and antagonistic actions. Br J Pharmacol. 1981;
74:627-33.Heel RC, Brogden RN, Speight TM et al. Buprenorphine: a review of its
pharmacological properties and therapeutic efficacy. Drugs. 1979; 17:81-110.
(IDIS 121541)Kareti S, Moreton JE, Khazan N. Effects of buprenorphine, a new
narcotic agonist-antagonist analgesic on the EEG, power spectrum and behavior
of the rat. Neuropharmacology. 1980; 19:195-201.Sadée W, Richards ML, Grevel J
et al. In vivo characterization of four types of opioid binding sites in rat
brain. Life Sci. 1983; 33:187-9.
Bibliography
G Fischer, P
Etzersdorfer, H
Miller W;
Hussain F; Shan S; Hachicha M; Kyle D; Valenzano K J (2001). In Vitro
pharmacological profile of buprenorphine at mu, kappa, delta, and ORL-1
receptors.
Dum JE, Herz A.
In vivo receptor binding of the opiate partial agonist, buprenorphine,
correlated with its agonistic and antagonistic actions. Br J Pharmacol. 1981;
74:627-33.
Heel RC, Brogden
RN, Speight TM et al. Buprenorphine: a review of its pharmacological properties
and therapeutic efficacy. Drugs. 1979; 17:81-110. (IDIS 121541)
Kareti S,
Moreton JE, Khazan N. Effects of buprenorphine, a new narcotic
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rat. Neuropharmacology. 1980; 19:195-201.
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ML, Grevel J et al. In vivo characterization of four types of opioid binding
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GB, Cowan A, Liu-Chen LY (2001) Comparison of Pharmacological Activities of
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Mégarbane
B, Gueye PN, Risède P, Monier C, Borron SW, Baud F Effects of single intravenous doses of
norbuprenorphine on arterial blood gases in rats XXII International Congress of the EAPCCT, Lisbon,
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330-1
Buprenex full
prescribing information (
Subutex/Suboxone full
prescribing information (USA)
Links
The Official Subutex/Suboxone Website
Erowid
Buprenorphine Vault
SAMHSA’s
buprenorphine qualified doctor locator
Subutex and Suboxone
are a trademark of Reckitt Benckiser Pharmaceuticals.
Dolophine
is a trademark of Eli Lilly Pharmaceuticals. Methadose is a trademark of Mallinckrodt Pharmaceuticals.