High Dose Buprenorphine (HDB) and Toxicity Concerns

Several weeks ago an article with a provocative title was posted at Suboxone Forum.  I don’t remember the exact title, but it was something like ‘Toxicity from High Dose Buprenorphine (HDB).  Before everyone gets too excited, there was nothing all that new in the article, which consisted of three case reports about deaths of people taking buprenorphine.  One case consisted of a suicide from very large doses of buprenorphine, one was a death from combining buprenorphine with other respiratory depressants, and the third death was in a person with liver failure who took buprenorphine with other psychotropic medications.  There are a couple issues brought up in the article that are worth mentioning.
First, I appreciate their use of the term ‘high dose buprenorphine,’ and this was the first time I came across the distinction between the historical use of buprenorphine in microgram doses for treating pain and the more recent use of milligram doses for treating addiction.   Buprenorphine is an extremely potent opiate; the ceiling effect protects from overdose in the absence of other respiratory depressants (with some exceptions– see below) and places a ‘cap’ on tolerance to the medication, but buprenorphine reaches maximal effect at a very low dose.  The potency of buprenorphine is more similar to that of fentanyl or sufentanil than to morphine or oxycodone.  Transdermal formulations of buprenorphine used for pain release doses of buprenorphine between 5 and 75 MICROgrams per hour.  The most popular dose of buprenorphine used for opiate dependence in the US is the 8 mg Suboxone tablet, which contains 8000 micrograms of buprenorphine!  It is likely that one reason for the occasional death from buprenorphine ingestion relates to fact that a fraction of an 8 mg tablet is about as potent as an entire 8 mg tablet, and novices to buprenorphine make the mistake of thinking that a very small piece will be less likely to kill them than taking an entire tablet.  Because of the ceiling effect and high potency, there is little if any protection in taking a small piece of a tablet.
While the ceiling effect offers some protection against overdose from buprenorphine, there is no protective ceiling effect to the actions of the drug’s primary metabolite, norbuprenorphine.  There have been deaths attributed to the ingestion of very large doses of buprenorphine where the metabolite accumulated to levels that caused respiratory arrest.  It appears that norbuprenorphine does not accumulate to levels sufficient to cause respiratory arrest in people with intact liver function who are taking standard, FDA-approved doses of Suboxone.  But there are a number of medications that inhibit certain liver enzymes, and it is conceivable that the right combination of medications and a large dose of buprenorphine could result in potent respiratory depression.  A number SSRI’s interfere with liver enzymes, the most potent perhaps being fluoxetine or Prozac, but in the case of SSRI’s the enzyme affected converts buprenorphine to norbuprenorphine.  Fluoxetine may in fact then offer a protective effect by preventing conversion of buprenorphine to the more-dangerous metabolite norbuprenorphine.
The respiratory depression potentially caused by norbuprenorphine again draws attention to the fact that very high doses of buprenorphine are used when treating opiate dependence.  We know much about the metabolism and actions of microgram doses of buprenorphine, as the medication has been around for over three decades.  But a number of attributes of the medication change at very high doses.  One very significant change is in the half-life of the medication.  Microgram doses are metabolized in several hours, but at milligram doses the metabolizing enzymes become overwhelmed, increasing the half-life to one to three days.  This increase in half-life is very useful when using buprenorphine to treat opiate dependence… but can be cumbersome when trying to rid the body of buprenorphine, say before elective surgery.
The most frightening question about HDB is whether there are toxic effects from such use that have not been apparent after years of microgram dosing of the medication.  Because of this blog I receive a number of messages from people who take buprenorphine.  I have heard of several cases of neurological illness in people taking buprenorphine, but I have no idea whether the reports represent higher frequencies of illness than would be expected in the general population.  Specifically, I have heard about a person with dementia, a person with encephalopathy, and a relatively young young person who developed symptoms of Parkinson’s Disease.  In all cases, the person was taking buprenorphine for several years.
At this point I must say DON’T HAVE A COW.  To date, several hundred thousand patients have been treated with HDB;  we would expect a number of those people to come down with these conditions in the ABSENCE of any connection between buprenorphine and neurological illnesses.  I continue to prescribe buprenorphine, and I believe WITHOUT RESERVATION that the medication is the best, most appropriate treatment for MOST cases of opiate dependence.  I think it is probably clear to most readers by now that I am not in bed with Reckitt-Benckiser;  I will always write about any concerns that I come across about the medication without delay.  I regularly scan the literature for articles about buprenorphine, and I run literature searches in response to any serious concerns by people in my practice or on the forum.  I also ask that if anyone is aware of a case of neurological illness in a patient who takes buprenorphine, that they contact me so that I can report the information to the FDA.
JJ

How dangerous is opiate dependence?

I frequently point out the lack of outrage over the epidemic of opiate dependence and the consequence of that epidemic.  I live in ‘middle America,’ and sometimes it seems that everyone I know has some connection to opiate dependence– a relative who is an addict, a friend who died, a parent who is in prison.  My perceptions are admittedly distorted by the work that I do, but I don’t know who has the more accurate perceptions; me or the people who seem surprised to hear that most high school kids know where they could get heroin.  Addicts who I treat who come down from the U.P. of Michigan tell me that heroin is very easy to get up there now, even cheaper than oxycodone.  I guess that’s to be expected, given the horrible economic situation up there.  One thing is certain though– SOME people are making money!  In my part of Wisconsin, oxycodone generally sells for 60-80 cents per milligram;  the average user that I see tries to find one or two ’80’s’ per day, ending up with a habit that costs over $100 per day.  Given the number of people actively using, there is a LOT of money going into someone’s pockets!  Of course much of the oxycodone on the street is bought by insurance coverage and then stolen from grandma’s medicine cabinet by her granddaughter, who replaces them with plain tylenol tablets…  but the herion money is probably leaving town, eventually finding its way back to Chicago.  Sorry, Chicago.  We have to blame SOMEBODY.
Many diseases have prominent celebrities who put on pink ribbons and fight for funding.  Not so for opiate dependence, even though the deaths from opiate dependence must rival those from breast cancer.  I’ll have to look at the numbers.  But celebrity opiate addicts tend to end up like Kurt Cobain or Michael Jackson– or slink off to rehab and later proclaim themselves cured.  Anyone who watches knows that there is no cure for opiate dependence, and the celebrity addicts only go back to rehab again as society goes ‘tsk tsk’.  Society doesn’t say ‘tsk tsk’ when someone’s breast cancer comes back.
I found an interesting web site called ‘informationisbeautiful.net’ where information about a variety of topics is presented in visual form.  Below I have a couple images from the site using data from the UK on deaths from overdose of a number of substances.  The images are relevant to the current discussion, as he compares the death rates to the reports about deaths due to the substances in the National media.  At the web site he discusses data collection;  I won’t make conclusions on the data but rather simply let is provide ‘food for thought.’  After viewing the first image be sure to contine to the next image down.
Opiates have the highest death rate of a range of substances.
In the next image he manipulates the data slightly to add a denominator to the information– he provides the number of deaths per user of the substance.  Again, I will let people truly interested in his findings visit his web site to look into whatever assumptions were made and which data sources were used.  I would like to again leave the data without much comment, in part because I don’t really know how to explain the high rate of fatalities among methadone users.  I will point out that use of methadone in the UK may be quite different than in the US, because in the US the medication is prescribed in two ways– as a cheap opiate for chronic pain management, and as a maintenance agent for opiate dependence.  In the latter case, prescriptions for the medication are regulated very closely (actually ‘prescription’ is not even the right word, as addicts must personally pick up their dose of methadone each morning for at least the early part of their management by a particular clinic).  I should also point out that Heroin is a pain medication in the UK that is prescribed by physicians (as well as a ‘black market’ substance), whereas in the US all Heroin is illegal and cannot be prescribed for ANY indication.  Finally, paracetamol is the Brit’s term for acetominophen, or Tylenol.  The graphic:
Methadone deaths per user lead the pack for deaths from substances in the UK.
I do have a couple final comments.  On other blogs or in response to my videos I sometimes come across remarks by people who are ‘anti-suboxone’ that ‘the problem with treating addicts with buprenorphine is that you then can’t get them off buprenorphine, and you have another problem to deal with’– that the addicts are ‘addicted to buprenorphine.’   I find that argument to be faulty for a couple reasons.  First, ‘addiction’ is not so much about the taking of the substance as it is about the obsession with the substance.  An addict who is properly treated with buprenorphine loses the obsession for opiates– something that is amazing to witness at the first follow-up appointment, when the addict sometimes cries over how wonderful it is to be freed from the obsession to use.  So I don’t see buprenorphine as a ‘replacement’, and I don’t see the physical dependence on buprenorphine as ‘addiction’ any more than people taking effexor or propranolol are ‘addicted’ to those medications (which also have withdrawal symtoms of stopped abruptly).   But even beyond that consideration, given the high mortality rate for opiate dependence, when people complain about taking buprenorphine I am always tempted to say ‘compared to what?’   People are DYING from this disease– frankly I don’t CARE if they get dependent on buprenorphine.  I am on the record here over and over with my opinion– that buprenorphine should be a long-term medication.  Use it to keep a person alive during his or her 20’s, and then worry about tapering off– and if the person cannot taper off, so be it!  It beats death.   And any parent of an addict in his or her 20’s knows that a string of ‘sober’ treatment centers and repeated relapses is NOT a great life… assuming the person even manages to stay alive.  We are left with comparing the two options of taking buprenorphine and living or avoiding it– and likely dying.   A pretty easy choice to make in my opinion.    I have to wonder what the people making arguments about ‘the problem with buprenorphine’ think about all of the problems with chemotherapy…   if a person’s child develops leukemia, if you treat him with chemotherapy he may end up sterile, and with an increased risk of a different cancer years later.   Would you recommend avoiding using chemotherapy to save his life now?  What’s the difference?
As always I am interested in your comments here and over on the forum.  We’ll talk again in 2010!
JJ
http://suboxonetalkzone.com