Addiction Treatment, Science, and Dead Rats

In my last post I teased that I would write about fake science.  I’ll try to make it interesting.

The internet allows everyone to do research about symptoms and treatments for any condition. If not for need for prescriptions, people could act as their own doctors.  But a huge dose of caution is necessary before anyone takes that path.

Realize first that doctors don’t treat themselves or even their family members.  The saying that ‘a person representing himself in court has a fool for a lawyer’ applies double in healthcare.  Treating someone close to one’s self introduces a bias that is hard to explain, but easy to notice.  As an example, I see a doctor annually to monitor a progressive condition that threatens my vision.  I would like to know the answer to a simple question:  how bad is it?  If I have a patient with that condition I can look at images of his/her retina and have an immediate, rough sense about what the person is facing.  But when I look at my own images and test results I sense nothing beyond fear or relief.  The problems with self-assessment are of course greater in the field of psychiatry and addiction.  After my relapse in 2001 I was told I needed treatment, and my assessment called for a brief refresher course on the twelve steps.  Three months later, still in residential treatment, I recognized how wrong I was.

A larger problem is that research on the internet is nothing like the research used by doctors or scientists.  There are a few sites that offer true research, such as Pub Med, where you can search my name and see the articles from my PhD work in the 1980s.   Doctors at academic hospitals or institutions often have access to an electronic database including thousands of peer-reviewed journals.  In grad school I spent time each morning in the library, reading the Science Citation Index for new stories about vasopressin and then searching the stacks for the article (medical libraries have so many journals that they take up 4 or 5 floors or more of a large building, with narrow halls between floor-to-ceiling shelves).  In the stacks I sometimes realized I was standing amidst the results of the hard work of millions of scientists over the past 50 years.

The information on the internet is useful because it helps patients ask the right questions.  But it is a mistake to consider it as research, or even to assume it is correct.  Doctors and scientists (and any good health practitioners) rely only on peer-reviewed literature.  And even then, a good scientist gathers a sense, over time, of the better peer-reviewed journals vs. the ones with less credence.  What is peer review?  When a scientist submits research for publication, the article is sent to 3 or 4 independent reviewers who work in the same field but have no connection to the author of the study.  I am a peer-reviewer for a couple of journals.  When I receive an invitation to review a study I have to disclose any bias or connection to the study or authors.  If I accept the invitation I have several weeks to carefully review the study, noting if the findings are valuable, whether the groups were sufficiently randomized and blinded, whether the statistics are correct or if a statistician should be involved, and whether the findings support the conclusions.  I then tell the journal editor my opinion, including whether the study should be accepted, rejected, or accepted with certain revisions.  Peer reviewers are not paid;  they provide the service because they recognize that the process is necessary and valuable.

The FDA regulates medications based on the results of research studies.  Some of the studies reviewed by the FDA are already published, and some may never end up in a formal publication.  But their process for evaluating medications is similar to the work of a peer-reviewer in that they determine whether the science is ‘good’ – double blinded, properly randomized, good statistics, etc.  Any claims about a medication MUST be deemed accurate by the FDA.

This post was inspired by an ad for Declinol, a supplement marketed to ‘treat’ alcoholism.  Supplements are not medications, and not subject to the same rules. Read the FAQ on the Declinol web site and note the answer about FDA approval.  Declinol is not subject to FDA approval because it is a nutrient, not a medication.  The FDA allows greater latitude for promotional claims about nutrients, but even makers of supplements are not allowed to lie.  The acrobatics of marketers of such products are sometimes funny, at least to us nerds, and Declinol is a classic example.  Note that the web page doesn’t say that it treats alcoholism or cravings;  it is a ‘SUPPORT for physical cravings, calmness, and overall well-being’.  What is a ‘support’?  Your guess is as good as mine.

Instead of making claims that can be found to be false, nutrients often show quotes by ‘satisfied customers’.  If the FDA believes that the quotes are misleading, that’s on ‘Bob from California’, not on the marketer of the nutrient.  Instead of describing how the nutrient works, nutrient marketers provide citations about the nutrient that support whatever the marketers want you to think.  So with Declinol we see ingredients like folic acid, with broad generalizations about the value of that substance.  Yes, Folic acid is valuable.  You can’t live without it.  But that’s a far cry from saying that taking extra folic acid has any value, let alone value in reducing alcohol intake.  We give folate to alcoholics in detox because they sometimes have dietary deficiencies caused by consuming nothing but alcoholic beverages.  If you eat meals a couple of times per day you almost surely have plenty of folic acid in your body, and any extra is metabolized and excreted.

Must nutrient ‘treatments’ or supplements contain a blend of vitamins.  It is very easy to write reassuring and positive statements about vitamins because by definition, vitamins (the term comes from ‘vital amines’) are molecules critical to normal function.  But many studies have shown that a typical diet provides adequate amounts of vitamins, even if that diet includes fast food.

Many nutrient ‘treatments’ also contain a couple special ingredients we’ll call ‘secret sauce’.  One secret sauce in Declinol is Kudzu, and support for Kudzu in reducing alcohol consumption can be found on Pub Med.  Like similar products, Declinol’s marketers take a finding about a substance and grossly generalize the findings to create an impression that was never part of the original finding.  According to the study about Kudzu, 20 people in a ‘natural settings laboratory’ (is that an oxymoron?) were given water, juice, and up to six beers, and told to drink at will.  And (wow) when people were given 2 grams of Kudzu first, they drank beer more slowly, and opened fewer bottles.

A couple of problems, though, in concluding relevance to treating alcoholism.  Were the 20 subjects alcoholics? It doesn’t say, but I would guess not because I don’t know if a study giving beer to alcoholics would pass the ethical review board.  Beyond that, WHY did they drink less alcohol?  If I gave you syrup of ipecac, you would probably drink less alcohol.  If I gave you a tablet of oxycodone, you would probably drink less alcohol.  That doesn’t mean that the substances are useful in treating alcoholism or alcohol cravings.  Why did the Kudzu group drink less alcohol? Did it truly reduce interest in alcohol in a study with very few subjects who may or may not have alcohol problems? Or did it leave a nasty taste in their mouths or destroy their taste buds?  Did it cause nausea or dizziness that made alcohol less enticing? Did it reduce vision so they couldn’t find the beer bottles as easily?

As for the title of this post, when I researched vasopressin one hot idea was that vasopressin enhanced learning and memory.  We measured that improvement in studies using ‘passive avoidance.’  We placed rats in a cage that had dark cubbies in one corner, and when rats invariably went into a certain cubby they received an electric shock.  We repeated the task with or without putting vasopressin into the rats’ brains and some rats ‘learned’ to avoid the electric cubby, supposedly by remembering the shock better than other rats.  There is a major flaw in the study that can often be applied to other ‘experiments’, including the one I cited about Kudzu:  the best performer in a passive avoidance task is a dead rat.

I have no idea whether Declinol reduces cravings or generates ‘well being’, whatever that is.   But nothing on their website pushes me toward that conclusion.  I hope readers will keep some of these comments in mind when the next big cure comes along.

A New Way to Stop Suboxone?

Originally Posted 10/27/2013
I usually have my wife/business partner review my posts and provide her opinion whether my arguments are sound.  For the record, she tells me that this post is technical and boring.  I disagree, but we aren’t planning to separate over the issue.  A valid criticism, I think, is that I’m doing a lot of guessing and wondering in this post.  This post is an example of the things I waste time wondering about.   I try to avoid writing things that are somewhat speculative, but I wanted to give it a shot for two reasons.  First, because there may actually be something to the idea I am about to describe.  But more important, I wish to point out some of the many ideas in the addiction world worth exploring…. And I hope that pharma continues to search for answers (i.e. spend money) in this area of medicine.
So I’ve been thinking more about ALKS 5461, the Alkermes pipeline medication that is a combination of buprenorphine and ALKS 33, which is a mu opioid antagonist also called Samidorphan with the structure shown at the left. ALKS 5461 is being developed by Alkermes for the treatment of major depression.  I don’t know much about the clinical actions of ALKS 33, (a proprietary molecule), except that it comes from a family of drugs that bind with high affinity and specificity to mu or other opioid receptors.  Samidorphan, a mu receptor antagonist, allows investigation of buprenorphine’s potential therapeutic effects at kappa and delta opioid receptors by blocking effects at the mu receptor.  Drugs with actions at other opioid receptors have be developed, and in some case patented.Until recently, theories about depression revolved around abnormalities in brain monoamine pathways or deficiencies of monoamine neurotransmitters.  Monoamines include serotonin, melatonin, and the catecholamines (noradrenaline, dopamine, and adrenaline). Most modern antidepressants act at serotonin or catecholamine receptors or reuptake sites. The new Alkermes medication ALKS 5461 is the first serious effort that I am aware of to treat depression from the opioid perspective.
Our brains contain natural opioids called endorphins and enkephalins.  Endorphins and enkephalins are neurotransmitters in pathways with a wide range of actions, including blocking pain and raising mood during injury or sexual activity. Pain pills such as oxycodone displace endorphins and hijack the natural endorphin pathways, providing euphoria without the trouble of buying flowers.  Of course, a relationship with self-administered opioids always becomes more destructive than even the most codependent partnership!
As an aside, when I presented for addiction treatment 13 years ago I told the addictionologist about my background in neurochemistry, and went on to explain that I was fairly certain that I suffered from a deficiency of natural opioids.  That doctor got a kick out of my story, and I would enjoy a sense of justification if my hypothesis someday proved to be correct.
When one considers using treating depression with buprenorphine, the obvious deal-breaker is the same issue that has prevented every other serious consideration of treating depression with opioids, namely the development of tolerance at the mu opioid receptor.  Because of tolerance, anyone who finds relief from depression with buprenorphine would be cursed by the need for eventual withdrawal, as well as other consequences of opioid dependence. I assume that Samidorphan is added to ALKS 5461 to prevent mu activation and tolerance.  Beyond partial agonist effects at the mu receptor, buprenorphine antagonizes (blocks) delta and kappa opioid receptors.  These blocking actions are not subject to tolerance, and may provide avenues for treating pain and/or depression.
Depression causes significant morbidity throughout the world, so there are huge profit incentives for new antidepressant medications. Addiction creates a large market as well, but companies rarely go as far out on a limb for addiction products as they do for other diseases. The need for new antidepressants is acute, but in an alternate universe where pain and addiction treatment take priority, Samidorphan and related opioid molecules might have a number of benefits. I’ve posted, for example, about my experience treating severe chronic pain by combining buprenorphine with an opioid agonist.  I expect the combination to be exploited eventually given the need for effective pain treatments, perhaps using an analog of Samidorphan.
Doctors use buprenorphine to treat opioid dependence.  The goal of buprenorphine treatment is to block the cycle of use and reward for some period of time, and to allow patients to create support systems, establish self-sufficiency, regain self-esteem, and practice living ‘life on life’s terms.’  The amount of time that it takes to accomplish these goals likely varies depending on the individual’s premorbid function, life experiences, insight, genetics, and other factors, but studies suggest that a year is not long enough to make meaningful headway.   It is possible that for some people, opioid dependence is a relatively permanent condition that is best controlled with life-long maintenance treatment.   But for those who would like to try to maintain sobriety off buprenorphine, the tapering process reignites the circuits that were set up by the initial addiction, causing cravings, withdrawal, and the constant obsession to delay the taper and resume the prior day’s dose of opioid.
If ALKS 33 has a long half-life and blocks buprenorphine in a dose-dependent manner, I could picture an alternate strategy for stopping buprenorphine where the antagonist (ALKS 33) is introduced to buprenorphine patients at a gradually-increasing dose.  The goal would be to eventually have the person on a daily dose of Samidorphan sufficient to block all of buprenorphine’s effects at the mu receptor, at which point the person could discontinue buprenorphine without withdrawal.  I suspect that the patient would experience withdrawal in response to each increase in dose of Samidorphan, although withdrawal would be reduced by introducing the drug at a measured pace.
What is the value in tapering in such a ‘reversed’ way?  Why would adding an antagonist be preferable to the current process, i.e. simply reducing the dose of buprenorphine over time?  The answer comes from an understanding of the nature of addiction.  A person stopping buprenorphine by gradually adding Samidorphan would face the decision once per day, whether to take the next dose of Samidorphan.  Compare that once-per-day decision to the current method of tapering buprenorphine, where the person must decide, thousands of times per day, to NOT take more buprenorphine.  I would expect that deciding to take an antagonist once per day would be more likely to succeed then CONSTANTLY deciding NOT to take buprenorphine all day long, throughout all of life’s ups and downs—times when the patient was conditioned to take opioids.
We will learn more about Alkermes new medication in coming months. I hope that someone in a power position will consider some of the other diseases that might respond to these interesting chemicals, including opioid dependence.

New Bupe News Section

Wanted to take a second or two to point out a new section to the blog, called ‘Bupe News’.  You’ll see the link at the tope of the page, along with an ever-growing list of links.  The point, of course, is to keep y’all reading, since Google knows EVERYTHING, including how many seconds each and every one of you spends on this (and every other) web site.  Understand that I don’t GIVE that information;  that information is simply that is there for the taking on the internet.  Even I can see the average time people spend on the site, the order they went to one page or another, etc.    I do not ‘collect data’ about any reader, meaning that I do not have information about who any individual is or isn’t…   but I DO get reports on my collective audience.
Check the page out, along with the other new section, and of course tell me what you think.  Positive suggestions are ALWAYS welcome!
Thank you for hanging with me,  by the way, for some tough I.T. times.  I’ve got about 3/4 of the ‘lost’ posts back, and then I’ll be back to firing off the NEW things I’m angry about, rather than replaying the things that irritated me a year ago!
J

Suboxone Maker's Petition Denied by FDA

Originally Posted 2/23/2013
I’ve written in detail about the bold move by Reckitt-Benckiser, maker of Suboxone, that few people outside the company saw coming.  In brief, the company has been cruising across the Atlantic for the past ten years, fueled by stellar growth of its flagship medication, even as the expiration of the patent on Suboxone loomed ahead (y’know– like an iceberg).
But unlike the Titanic, RB had a secret plan to deal with icebergs.  A couple months ago, the company hired a company that investigates bad drugs to look into its OWN product, Suboxone tabs, and used those findings to tell the FDA that the source of their profits for the past ten years is a BAD DRUG.  In fact, it is SO bad that they insisted on doing the right thing—file a Citizens Petition with the FDA to make sure that NOBODY ever makes that bad drug again.
By coincidence, RB happened to have a DIFFERENT drug with a fresh, new patent expiration date that they promised was much safer than the drug they used to make.  And by coincidence (insert more sarcasm), this all happened a year or so after the patent on the bad drug ran out, so RB was willing to just get rid of the bad drug completely.    Never mind that a bunch of other companies were about to make less-expensive generic forms of Suboxone; RB asked the FDA to protect the American people by banning those awful Suboxone tabs that used to make them so much money.
But on Friday, the FDA essentially told RB ‘thanks for the warning… but we’re cool.’  They denied RB’s request to block the tablets, opening the door to generic manufacturers to consider making less-expensive forms of buprenorphine/naloxone, what RB calls ‘Suboxone.’
RB (stock symbol RBGPF) has been dodging icebergs for ten years.  I’ve wondered over the years how they would navigate through some very treacherous passages.  How did they get everyone to buy into the idea that Suboxone is significantly different than plain, cheap buprenorphine?  How did they get state Medicaid agencies to cover ONLY the branded product, when the generic buprenorphine is clinically identical to Suboxone?  A glance at the price of shares in RB shows that they have been doing it well—at least up to now.

Reckitt-Benckiser Stock Price
Reckitt-Benckiser Stock Price

But the seas are getting choppy.  There are two lawsuits directed at the company, accusing RB of running a grand scheme to block generic manufacturers from entering the buprenorphine market.  And in denying of the Citizens Petition the FDA adds credence to the lawsuits, even writing that they will refer concerns over anti-competitive business practices to the FTC.  Amazing how quickly things can change; one minute you’re sitting in a deck chair, whistling a happy tune with the wind in your hair… the next, everyone is looking for a lifeboat.
I’ve been writing for years that the company that wants to be viewed as a shiny rescue vessel has been acting more like a pirate ship.  Hopefully last week’s collision will give them pause, and help then realize that it’s not about being the first ship to get to those in need;  it’s more about making sure, once there, that other ships are on the way—and that everybody gets a seat in a lifeboat.

Reckitt Benckiser is Smarter than I Thought

Originally published 10/14/2012
Regarding a prior post, I carefully read through the entire Citizens Petition’ filed with the FDA by Reckitt-Benckiser.  I have a better understanding of what, exactly, was accomplished by that action by the manufacturer of Suboxone.
The document explains that the company hired an independent group, RADARS (Researched Abuse, Diversion, and Addiction-Related Surveillance), to investigate the exposure of small children to Suboxone tabs and Suboxone Film.  The results are spelled out in detail in the Citizens Petition.
They show an increase in exposure to Suboxone Tabs over the past ten years.  They also show an increased rate of exposure, i.e. number of exposures, divided by the number of tabs prescribed.  Reckitt-Benckiser wrote that they instituted REMS over the past few years to counter that increase. What are REMS, you ask?
From the FDA site:  ‘The Food and Drug Administration Amendments Act of 2007 gave FDA the authority to require a Risk Evaluation and Mitigation Strategy (REMS) from manufacturers to ensure that the benefits of a drug or biological product outweigh its risks.’
To meet that requirement, RB claims that they instructed their sales force to be double, extra-especially careful to tell doctors to remind patients to avoid giving Suboxone tablets to their children.  No, I’m not making this stuff up… although the ‘double, extra-especially’ part is my own hyperbole.  I don’t remember exactly how it was worded in the petition.
RB wrote that the warning is actually part of their mitigation strategy—that they expect an impact on pediatric exposure, if their salespeople tell doctors to tell patients to keep the pills out of the hands of children.  Gosh—good thing they did that!  I’m picturing all those people who having their 2-year-old kids managing their Suboxone!
But telling doctors to tell patients this ridiculous bit of information did not solve the problem, so RB claims they needed to do more.  They decided that every dose of Suboxone must be individually packaged.  But they had problems with the stability of naloxone while producing individually-packaged Suboxone Tabs, leading them to make the Film form of the drug.
To read the petition, the expiration of their patent on the tabs had nothing to do with anything.  And the long, new patent on the Film has nothing to do with anything.
I have a couple questions at this point.  First, the obvious one—did RB REALLY have a discussion about having their salespeople remind doctors to remind patients to protect their children?  Do they really think that patients and doctors are that stupid—that their salespeople can make a difference in that regard?
Second, do they really find it necessary to individually wrap each dose of Suboxone, a combination of an opioid partial agonist plus an opioid antagonist, when oxycodone, hydromorphone, hydrocodone, and other potent opioid agonists are sold by the bottle?  I could go on and on about this issue… most patients on Suboxone guard each tablet carefully, as they are prescribed to match up with the number of days in each month… whereas opioid agonists are usually prescribed to take ‘as needed’, meaning the tabs are much more likely to end up in kitchen cupboards or otherwise unaccounted for.
Why would a company hire another company to find fault with their product?  One might think that the manufacturer of a substance would be, if anything, pointing out the safety of their product—not arguing that it is unsafe.  This is where cynicism starts to set in; where I wonoder if they are really just ‘Here to Help.’ I’m supposed to believe that RB discovered a problem with their product, hired a company to assess that problem, and then voluntarily withdrew the product from the market.
To believe the RB line, I have to accept a number of coincidences.  They wrung profits out of the tabs for almost ten years, and just happened to figure out this danger within a year after patent expiration—just when generic pharmaceutical companies were able to manufacture cheaper forms of buprenorphine.  The company has been dreading the flow of generics for years;  heck, their reps spend more time talking about THAT issue than they do about pediatric exposures!  It is also an odd coincidence that RB just happened to be pushing the Film like crazy to insurers and Medicaid agencies, well before their ‘discovery’ of the danger of pediatric exposure to tablets.
To really understand the situation, you must read all the way to the top of page 29 of the Citizens Petition.  There, the attorneys for RB point out to the FDA that if a manufacturer voluntarily withdraws a medication for safety reasons, the FDA is not allowed to approve any new drug application for a generic that is based on the withdrawn medication.
Wow.  They have some darn good attorneys at RB.

Dear CEO

This is a repost of an article from 10/2/2012
I’m going to start by paraphrasing John Le Carre’s comments in his book The Constant Gardener: “Nobody in the letter below is based upon an actual person or outfit in the real world. But I can tell you this; as my knowledge of the pharmaceutical world increases, I come to realize that, by comparison with the reality, my letter is as tame as a holiday postcard.”
Dear Fictional CEO,
I have a question about your company.
Over a decade ago, you took an action unprecedented among cleaning-supply companies by gaining FDA approval to market a combination of two generic compounds. I do not know if you thought that compound N was necessary to gain approval of the medication, or if someone at your company had the prescience to know how things would eventually play out in your marketing department.  Kudos if it was the latter.
You now know, I suspect, that compound N is irrelevant to the use of Product S to treat opioid dependence. You are aware that many people, even prescribers, often confuse the actions of compound B and compound N, mistakenly thinking that compound N does something to reduce cravings or improve the safety of Product S. It isn’t your fault that people get it wrong. True, you spent only fractions of your huge profits on educating psychiatrists, surgeons, ER doctors, and nurses. But just because their ignorance plays into your marketing strategy does not prove that you WANTED them to remain ignorant. Perhaps you figured that education about your product was the responsibility of someone else.
Speaking of education, 12 years ago you fooled the FDA by showing cases of several French people who died from improperly using compound B, and used the cases to justify adding compound N to your product. Never mind that those deaths would not have been prevented by compound N, a low-affinity, short half-life opioid antagonist with little ability to out-compete compound B at the mu receptor— the idea– that the compound N would precipitate withdrawal if Product S is injected, yet do nothing when taken properly, was pretty cool– especially compared to the drudgery of making rat poison!
Maybe the FDA needs more cynics, because they didn’t notice that adding compound N was an effective way to turn a cheap, generic compound– B– into Product S, a cash cow for your company. Even if they had noticed, would anyone really expect you to save opioid addicts WITHOUT the huge profits? I don’t think so!
So I cannot blame you for how things have played out up to now.  Almost all is fair, in the world of business.  And I understand how horrible it must have been over the last five years, as generics threatened to kill off that cash cow.  You needed a strategy to protect Product S.  That unfair Patent Office only gave you a few (well, 8 or 10) years to rake in profits, before going back to the unglamorous, less-profitable world of cleaning supplies.  No limos for those guys!  Time flies when you’re making money… and next thing you know ANYONE can make Product S!  How uncool is that– suddenly you would have to live on only typical profit margins, or even invent a new product like other companies have to do to keep the cash flowing.  Bummer.
I get a bit confused at this point.  Let me get this straight…  after making tons of money off Product S, knowing that someone ELSE is going to make their own cheaper version of Product S, you decide to kill off Product S for EVERYONE?  You make Product S-F, and go back to the FDA (heck, they covered your back once!), and say that the product that made us ALL THAT MONEY is a BAD PRODUCT.   And you just figure this out now, at the same time your patent expired—just when other people are able to make Product S.  Am I getting it right?
Correct me if I’m wrong, but it looks like you somehow got a whole bunch of people—insurance companies, state Medicaid agencies, etc— to require the use of  ONLY Product S-F.  You told everyone that Product S (that you were still selling tons of) wasn’t as ‘safe’ as Product S-F, so they should only use S-F.  It somehow worked; you got close to 70% of those people to require patients to take Product S-F… even though your claims about safety were pretty silly.  Never mind—they actually believed you!
I admit that I do not understand why those insurers and Medicaid agencies were so short-sighted.  Surely they knew what was going on—that you were only trying to destroy Product S for everyone, and take away a market for generic competitors.  Didn’t they recognize that whatever discounts you bribed them with, would be peanuts compared to the savings they would eventually get from generics?  How did you pull it off?
The icing on the cake… I read last week that you are PULLING Product S and ONLY selling Product S-F.  You hired a company (YOU hired THEM!) to show that Product S was unsafe, to justify pulling it.  Again, you did this just as other companies were in a place to make Product S themselves… at a much lower cost than YOUR product.  Your people are saying that 4 kids died from Product-S over the past 5 years.  They didn’t mention that Product-S saved tens of thousands of teenagers over the same time, and they didn’t say that the companies about to make it so much cheaper would save tens of thousands more.  I guess that is a tough calculation— I mean, who is worth more, 4 young kids or 20,000 teenagers?
Most people would be satisfied with the sequence of events and call it a day.  In fact, most people would feel a bit shameful, knowing that they just completed a strategy that 1. Mislead medical science into buying your product for ten years, when plain old compound B would have done the same thing all that time—at a fraction of the cost; 2. Prevented effective education about compound B that could have saved many thousands of those who died from overdose over the past ten years; 3. Bypassed the usual conditions in the world of pharma where a company can make billions of dollars for years, but eventually allows generics to make the product, so that poor people and people without insurance get a chance to save THEIR lives too; and 4. Tricked insurers and agencies into forcing patients to use not the cheaper drug, like they usually do, but your EXPENSIVE drug—causing those same groups to limit life-saving use of the drug to only a year or two, since they can’t afford to cover your expensive one indefinitely.
You’ve accomplished quite a bit.  But I just read that you aren’t resting on wilted laurels.  Even though insurers and agencies are forcing people to buy your expensive product, there are people with no insurance and no Medicaid who have the gall to buy a generic form of compound B.  Sales of the generic are only a fraction of your sales, and some reasonable people would say that even poor people have the right to take life-saving medication, just like the rest of us.   But you are filing a ‘citizens’ petition’ with the FDA to have that medication—the affordable one that is saving all those poor people—taken OFF THE MARKET.
And now my question:
Are you SERIOUS?

Short-Timers

Another question from a reader:
The current blog brings up the notion of long term use of Bupe or short term detox.  You say you are a fan of long term use, and that is clearly a good thing when the patient is one headed back to a drug culture of life of crime or is obsessed with the drug.  But-  what about patients like me and I think many others who have zero contact with the drug world, have never taken an illegal drug, and yet have taken Ocy C over the years for pain and find it all but impossible to stop the Ocy C.  
 The Suboxone helps with the W/D and just getting through with that is all we want.  NA meetings and the like are like being on Mars, it makes no sense.  There are no drug cravings at all and the goal is just normal.  Or rather, the goal is to make it through the W/D which is so harsh with Oxy C as to be dangerous for older people, whose only source of drugs indeed is the doctors Rx for them  And now that too is unavailable.  This group does not need Suboxone to become a new problem for them.  They just want the help.  It is not critically  important to determine “who” is being treated.  The certification training materials seem to brush over this so lightly that there is only one induction method allowed.  One that a drug company would love, but not always a patient —  pleading, do no harm.
My Thoughts:
I hear you, and watch for those patients.  Frankly I wish I had more of them, so that I could get some movement through my practice—- instead of being stuck with 100 chronic patients and a long wait list.   The financial motivation for the DOCTOR is to push people through, for that same reason.  Of course the drug company gets paid in either case.
The first question is whether buprenorphine even helps in the case you describe.   It is easier, in many ways, to taper with methadone than with buprenorphine, as you don’t have to divide such tiny pills.  It has been suggested that it is easier to taper off a partial agonist than an agonist—and I believe that to be true, simply because I have seen people do the former and not the latter.  But I don’t know HOW much easier it is—or if psychological aspects of the taper were more responsible than the person’s state of misery.
There were several studies a few years ago that showed relapse rates of 100% in people treated with Suboxone for less than a year;  those findings, it seems to me, put a damper on the idea that buprenorphine could be useful for short-term detox.  But I don’t know where those people would have fallen on the spectrum that you are presenting.  I do know that they were people with a primary diagnosis of ADDICTION— NOT chronic pain– so maybe they are not relevant here.
My caveat would be that I HAVE met many people over the years who are convinced that they fall in the pain camp you describe, but who turn out to be just as ‘addicted’ as anyone else.  They describe the process in different terms;  instead of admitting to ‘relapsing on opioids’, they describe ‘deciding the pain was worse than they expected, and that it was a mistake to go off opioids.’  They will claim to be different…. But an objective observer would see the same growing attachment to opioids, the same gradual dose escalation, the same excitement and activity when opioids are ‘on board’, and the same depression and misery if a day passes without using.
I agree with your thoughts, and get your point.  I just don’t know if very many people are as clearly-defined as you describe. One reason is because there are few conditions that cause pain severe enough to require high-dose opioid agonists for an extended period of time– say, a few months– that then go away.  Most pain conditions have residual symptoms—- from chronic inflammation, or even from the set-up of central pain circuits.  In a sense the pain is remembered, even after the original injury is repaired.  The severity of that residual pain is affected by the person’s emotional state, dependency, motivation, genetics…..  and the residual pain becomes a expressway back to using opioids— an expressway that is used often by many people.
Thanks for your comments!

Children Deserve Pain Treatment Too

I hope that people recognize the tongue-in-cheek nature of the title. After working as a physician in various roles over a period of 20 years, I can state with absolute confidence that the answer to the question is ‘yes’.
I’ve written numerous times about the writer/activist for the Salem-News.com web site, Marianne Skolek. I don’t know if she writes for the print edition as well, but at any rate I somehow was planted on a mailing list that provides constant updates on what she calls the battle against Purdue and ‘big pharma’.
People with a stake in the outcome of this battle may want to stay current, and even see if their Senators are involved in the process. The investigation was launched in early may, by the Senate Committee on Finance, and at this point has asked for documents from several pharmaceutical companies, including Purdue, the manufacturer of oxycontin– a medication that has become the focus for most of the wrath of those affected by opioid dependence. The investigation will include a number of groups whose missions are (or in some cases, were) to advocate for pain relief, including the American Pain Foundation, the American Pain Society, the American Academy of Pain Medicine, the Federation of State Medical Boards, the University of Wisconsin Pain and Policy Studies Group and the Joint Commission.
I consider it part of the human condition, the way we push in one direction for some period of time, and then realize (with surprise!) that we pushed too far, and need to push back. Years ago a  Newsweek article warned that an emerging ice age doomed the Earth. Suggestions for saving the planet included covering the polar ice caps with soot, in order to absorb more of the sun’s precious heat– although the article pointed out that growing seasons had already been severely limited in most parts of the world, and famine was just around the corner.
We all know what happened to THAT disaster. And then last week, Dr. James Lovelock, a leading doomsayer of the global warming movement, pointed out that many of the disastrous outcomes predicted by himself, featured in Al Gore’s movie, um…. haven’t happened… and to the chagrin of many, he wrote that most of the disasters that were predicted are unlikely to occur. Read for yourself. Never before were so many people so disappointed by good news.
I’m running off topic, I know, but it is hard to observe the dramatic swing on pain relief without recognizing the broader pattern. For those confused about the pain isssue, you have reason to be confused. About 15 years ago I worked as an anesthesiologist, when the Joint Commission on Accreditation of Hospitals made their 3-year site visit to our hospital. Hospital administrators hired consultants to find out what THAT year’s big issue was— e.g. hospital acquired infections, patient privacy, rights of those with disabilities…. and found that the hot-button issue was ‘undertreatment of pain.’ Little diagrams were dispensed to every patient room, showing the smiley-face guy with an expression ranging from happy to miserable, in case a person was experiencing pain but unable to speak– allowing the person to point to the appropriate picture instead. Key personnel were told to make it abundantly clear that we all take pain VERY seriously, and we do all in our power to avoid undertreatng because of, for example, fear of addiction. Studies were widely cited that claimed that only 7% of people with true pain become addicted to opioids.
One or two textbooks became the authority on opioid prescribing, introducing a new term– pseudoaddiction– which refers to a condition of drug-seeking behavior caused by under-treating pain, rather than by true addiction.
I know that I have to pull all of this together at some point. The easiest way for me to do that is by directing people to the latest article by Ms. Skolek, where she suggests that doctors have been influenced to promote narcotics because of grants from the pharmaceutical industry. Similar accusations have been made by others, including a series of articles by the Milwaukee Journal Sentinel that accused the University of Wisconsin School of Medicine of promoting opioids in return for millions of dollars.
I respect the efforts of another group I’ve described– PROP, or Physicians for Responsible Opioid Prescribing. Their efforts have been promoted by Ms. Skolek to some extent, and vice versa. I do not know of any formal relationship between PROP and Ms. Skolek. But I hope that PROP’s efforts take a more reasoned approach than the latest article by Skolek, where she compares Purdue Pharma to Adolf Hitler. Why? Because among the many clnical trials by Purdue is one that studies the use of potent opioids like Oxycontin in children and teenagers. Some of the most sobering experiences of my medical training were at Childrens Hospital of Philadelphia, providing care for brave, hairless children, knowing the years of pain that awaited them– if things went well.
I think I’ve provided enough background and links to start interested parties off on their own holiday reading. Yes, there is an epidemic of opioid dependence in this country and elsewhere. There are many reasons for this epidemic, and MOST of the reasons have nothing to do with the marketing tasks used by Purdue decades ago– for which they have paid dearly. While there are clearly areas where opioids are overprescribed, and in some cases grossly overprescribed, it would be a shame if the current swing in regulatory sentiment takes us to the point where doctors are afraid to provide pain relief for people who are suffering. This is already the case in some instances; people labelled as ‘addicts’, no matter the length of their remission, are likely to wait a long time for their first dose of narcotic, should they be unlucky enoough to develop a kidney stone.
I’ve spent a great deal of time and energy defending those poor souls, and discovered, sadly, that most doctors just don’t care about the pain experienced by recovering addicts. But there is a saying, also often referenced to the Holocaust, referring to mistreatment of others being ignored, until eventually similar mistreatment is directed at those who didn’t care about others. There are times when attempts to ‘cure’ go too far. Suggesting that methods of pain relief should not be investigated, clarified, and perfected for children is going a bit too far.

Size Matters?

I’ve received several complaints from patients and readers about one of the current buprenorphine formulations.  The primary complaint is that the tablet is ‘not ‘working as well as the other formulations;’ that it seems to wear off earlier, or that people feel compelled to take more than what is prescribed.

buprenorphine formulations
Buprenorphine 8 mg tabs

My understanding, admittedly based only on what people have told me, is that there are three current formulations of buprenorphine.  The brand form, Subutex, comes as a relatively-large, flat-oval tablet, white or off-white in color.  The Roxanne version is a round white tablet, with a diameter of about 0.5 inch.  The tablet people have complained about is from Teva, and is smaller;  about the size of a tic-tac.
In general, I think that generics are as good as brand name medications.  I have never come across a reliable instance, in my practice, of generics being less potent or less active.  I recognize that particularly for psychiatric medications, the placebo effect accounts for significant portions of the actions of medications—so if a person BELIEVES that generic fluoxetine is less likely to work, it IS less likely to work.  But take away the placebo issue, and a molecule of fluoxetine is a molecule of fluoxetine—regardless of where it comes from.
That said, I realize that the delivery of molecules can be affected by the design of capsules and tablets.  I remember a study, years ago, that showed that many of the vitamins sold in the US passed through the intestinal system without even dissolving, let alone getting into the bloodstream. If the active substance is encased inside insoluble resin, there is little to be gained from taking it.
The delivery issue is less of a concern with a medication that is delivered through the oral mucosa, as with buprenorphine.  There are several factors that affect absorption of buprenorphine;  the concentration of buprenorphine in saliva,  the amount of surface area that buprenorphine is allowed to pass through, and the time allowed for that passage to occur.  If the smaller tablet dissolves more slowly, molecules of buprenorphine may have less actual contact-time with oral mucosa, thereby reducing absorption.
On the other hand, I am well aware of the psychological reward that people describe from taking buprenorphine or buprenorphine-naloxone, even in the absence of any subjective sensation.  The fear of withdrawal is relieved by taking buprenorphine—making the dosing experience ‘rewarding.’  It may be that the smaller tablet provides less reward, as the small size engenders less confidence in those unfelt ‘effects.’
In any case, I invite readers to share their experiences, just in case those who have already written are truly onto something.  Please leave comments below—and thanks for sharing!

The Other Opioid Dependence Medication

Today I met with representatives from Alkermes who were promoting Vivitrol, a long-acting mu opioid antagonist that is indicated for treatment of alcoholism and opioid dependence.

Naltrexone
Naltrexone

I admit to some pre-existing bias against the medication.  I’m not certain, to be honest, whether that bias was based upon sound clinical reasoning, or whether it was based on personal, negative reactions to naltrexone in my past.  Or maybe, as a recovering opioid addict, I have negative feelings about anything that blocks mu receptors!
Vivitrol consists of naltrexone in a long-acting matrix that is injected into the gluteal muscle each month. The medication is expensive, costing about $1000 per dose (!)  That cost is usually covered by insurance, and like with Suboxone, Wisconsin Medicaid picks up the tab save for a $3 copay.  Alkermes, the company that makes Vivitrol, also has a number of discounts available to reduce or even eliminate any copays required by insurance companies.
I’ll leave the indication of Vivitrol for alcoholism for another post.  The indication for opioid dependence came more recently, and appears more obvious, given the actions of naltrexone at the mu opioid receptor.
In short, naltrexone blocks the site where opioids—drugs like oxycodone, heroin, and methadone—have the majority of their actions.  Blockade of that site prevents opioids from having any clinical effect.  There is some dose, of course, where an agonist would regain actions— an important feature in the case of surgery or injury.  But even in those high doses, the euphoric effects of addictive opioids would be muted.  People on Vivitrol, essentially, are prevented from getting high from opioids.
Back in my using days, I took naltrexone, thinking that doing so would help me get ‘clean.’  I didn’t wait long enough, however, and so I became very sick with precipitated w/d.  The makers of Vivitrol recommend waiting at least a week, after stopping opioids, before getting an injection of Vivitrol.  I suspect that a week is not long enough to prevent w/d, but I realize that it would be very difficult to expect patients to last longer, without using anything.  I would expect that any precipitated w/d could be reduced through use of comfort medications, at least for a day or two until the symptoms are mostly gone. This requirement, though, to be clean for a week or more is one of my problems with the medication.
As an aside, I was also prescribed naltrexone (oral tabs) at the end of my three months in residential treatment, and I took the medication for another three months.  I had no withdrawal or other side effects to naltrexone at that time.
Another issue was the concern that naltrexone has been connected to hepatic toxicity.  We discussed that issue today, including the studies that led to that connection—which are not compelling.  The discussion allayed most of my concerns about liver problems from Vivitrol.
Finally, I have always recommended buprenorphine over naltrexone because of the anti-craving effects of buprenorphine that result from the ‘ceiling effect’ of the medication.  I worried that naltrexone, by blocking the actions of endorphins, would actually increase cravings.  But that is not what the data shows.  In the studies with Vivitrol, cravings for opioids were dramatically reduced by the medication.  The mechanism of that effect is not entirely clear;  some of the anti-craving effect may be psychological, as addicts stop wanting something when they know there is no way to get it.  But there may be other complicated neurochemical effects at presynaptic opioid receptors that are not fully understood.
The bottom line is the result of treatment;  the very sick opioid addicts treated in the studies used by Vivitrol to gain FDA approval showed a profound reduction in opioid-positive urines, over a span of 6 months.
I suspect that I will continue to favor buprenorphine.  I do not buy into the ‘need’ some people describe to ‘get of buprenorphine as fast as possible.’  Buprenorphine is a very effective, safe, long-term treatment for inducing remission of opioid dependence.  But because of the cap, I am glad that another option is available to treat this potentially-fatal condition.  And I admit to perhaps being too quick to judge Vivitrol, which appears to be a safe alternative—particularly for people who have a lower opioid tolerance that do not want to push it higher, or for people who have been free of opioids for a week or two.
I would invite local people who are on my buprenorphine waiting list to consider Vivitrol as an option.