Crazy Week for Suboxone

Originally Posted 3/3/2013
What a crazy week for buprenorphine.  I’ve written about the FDA slapping the face of Reckitt Benckiser by denying their Citizens’ Petition.  Adding insult to injury, the FDA then approved two generic formulations of Suboxone tabs (actually, the correct name is buprenorphine/naloxone combination tabs).  Stock in RB dropped about 5%, but shares regained most of their price within a couple days, reflecting the balance of pessimism vs. optimism in the company’s ability to maintain stellar profit growth going forward.
In case anyone is wondering, I do not own shares in Reckitt Benckiser, and I have never owned shares in Reckitt Benckiser.  One nice thing about NOT having significant savings, I supposed, is that I can report my holdings (or lack of holdings) without too much effort!
If I WAS an investor, though, I’d wonder about the future of Reckitt Benckiser’s Suboxone, now that two generic competitors are hitting the market.  Some patients clearly prefer the tablet over the film;  will state medicaid agencies go back to covering the tablet, which will likely be cheaper than the film?  Will insurers cover the tabs?  Or will both groups continue to buy into the marketing scheme of Reckitt-Benckiser, and the company’s claim that only the film is ‘safe’?
Many patients strongly favor the tablet over the film, and if given the opportunity to choose would definitely choose generic tablets over film.  So here is where things get interesting…..   if the generic tablets become popular, will RB go back to making tabs?  After their RADARS-assisted claim about the danger of tabs, such a move would be a clear indicator of the company’s truthfulness on the issue.

Reckitt Benckiser Citizen Petition for Suboxone: DENIED

Posted 2/23/2013
For those who missed my explanation, I’m adding these old posts to reconstruct the archive.  The site’s database was damaged by something, somehow… New posts coming soon.
Find a copy of the response here, or at this url:www.suboxonetalkzone.com/cpresponse.pdf

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?

Cost of Suboxone

A Reader Writes:
Message:
The State of XXXXXX prescription price list noted Target Pharmacy as the cheapest for Suboxone at $6.99/Suboxone pill, 8mg-2mg, qty. 30. So I started getting my prescriptions filled at Target.
Well, needless to say they raised their prices twice since then and I am now paying $8.158333/Suboxone pill, 8mg-2mg, qty. 30, Nov. 12, 2011.
My question: How can they be alowed to jack their prices up so fast and so high in a short period of time? What can I do? It’s like they pulled a bait and switch on me.
Please write back Dr. Junig
My Reply:
I sympathize with you.  The best thing you can do is have an educated and educatable doctor– someone who has enough humility to recognize when he/she is wrong, and adjust accordingly.  Somebody who recognizes that as physicians, we are constantly sorting through new data, responding clinically to phenomena according to science.  Most importantly, someone who recognizes that in medicine, as in all fields, people make assumptions about things with partial data, and sometimes later learn that their assumptions were wrong.
I realize that is difficult in the current era when people with addictions are considered ‘manipulative’ for simply raising appropriate questions. The truth is also competing with the marketing and persuasion tactics by Reckitt-Benckiser– a company that has found a way to influence policy-makers in government and addiction societies.  I am generally a fan of corporate greed, as I believe that the marketplace is the best stage for ideas to rise or fall (mixing several metaphors, I know!)  But I am appalled by the extent of involvement of Reckitt-Benckiser, the British corporation that makes Suboxone, with physician societies– the groups that are supposed to be advocating for policies that save lives that are being lost to addiction.
The generic tablet of orally-dissolving  buprenorphine, 8 mg, is FDA-indicated for treating opioid dependence.  In Wisconsin, some pharmacies have it for as low as $2.35 per tab;  the more expensive places sell it for $3.00.  It is CLINICALLY IDENTICAL to Suboxone;  the naloxone in Suboxone is not absorbed sublingually (actually, 3%-5% is absorbed, but does nothing clinically), and after being swallowed the naloxone is completely destroyed at the liver by first pass metabolism.
Suboxone is supposedly safer then generic buprenorphine because naloxone supposedly causes withdrawal if injected.  This is the only justification (initially put forth by the folks at Reckitt-Benckiser) for the need for Suboxone.  The justification is flimsy, since many people who would benefit from the lower price of buprenorphine have very little risk of injecting the medication.  But worse, the flimsy justification is a lie. People who have injected Suboxone intravenously (I have met and heard from many of them) report NO withdrawal from naloxone-containing Suboxone.  What’s more, people who wrote to me who have injected both buprenorphine and Suboxone, at different times based based on availability, have all reported the same thing– that the subjective experience from injecting either substance is identical.
I must point out here that there are MANY reasons to avoid injecting any substance– but particularly a substance made to be taken orally.  These compounds contain fillers that destroy the capillary beds of the lungs, where oxygen is absorbed– potentially leading to severe lung damage.  And infection is always a huge risk, when placing poorly-sterilized material directly into the bloodstream.  Please– don’t do it.
Back to taking buprenorphine properly… the high cost of Suboxone is an unfair burden for patients without insurance coverage, when a much cheaper, idential alternative is available.
I am going to remove your name and location, and put up your question on my blog;  you are then welcome to bring a copy of the post to your doctor. You can also tell him/her to read prior posts, where I explain all of this in greater detail.
For Doctors and Insurance Formulary Committees:
I implore you to look into the facts of this situation with an open mind.  I have a PhD in Neurochem, besides 10 years of experience as an anesthesiologist and training and experience in psychiatry.  Some insurers cover buprenorphine;  they are, of course, the smart ones.  Your company can save a great deal of money by simply allowing the generic equivalent to be covered.  States that mandate the use of Suboxone or Suboxone Film could save large sums of money for their taxpayers.  And doctors–  your cash-paying customers could really use the break, especially in this economy.  If you are concerned that a patient is injecting medication, I understand your hesitancy— even though, frankly, it is misplaced, given that BOTH Suboxone and buprenorphine can be injected.  If your patient pays cash, and never injected medication, do you REALLY think that person is going to start injecting buprenorphine– since doing so would not create any effects?  The ‘ceiling effect’ is in place for ANY route of administration, so a patient taking sublingual Suboxone, who injects buprenorphine, will feel… NOTHING.
Give your patient the gift of affordable treatment as a Christmas present.  You may be saving someone’s life.
JJ

$uboxone Clinically Identical to Buprenorphine??

As I give my last post more thought….  I wonder if there is ANY clinical difference between $uboxone at $7 per dose, vs. generic buprenorphine at $2.33 per dose?  Researchers out there– can anyone send me a reference?
Read my last post for details– but the essence is that naloxone is destroyed when Suboxone is taken properly (orally, sublingually), and has no action whatsoever– on that issue there is scientifc agreement (although there is a great deal of ignorance among prescribers about this fact).  The ONLY think naloxone does, is to supposedly serve as a deterrent to IV injection of buprenorphine.
Sounds good, but…  we know that people divert Suboxone intravenously, naloxone and all.  Buprenorphine binds opioid receptors very tightly- so tightly that the naloxone doesn’t effectively compete with buprenorphine.
The State of WI requires Medicaid patients to take expensive Suboxone Film, whereas in other cases they require prescribing the generic.  What is the argument for requiring the film?  RB would argue (now that the tablet has lost the luster of being on-patent) that the film is harder to ‘divert’– i.e. to inject.  But frankly, the intravenous diversion of buprenorphine is a tiny issue compared to things like heroin addiction and a budget crisis.  Most of the diversion of buprenorphine, either Suboxone or generic, is not injected, but rather taken orally to ward off withdrawal– and the film makes no difference in that case.
Insurers, likewise, are wasting millions of dollars (literally) by paying for Suboxone— sometimes exclusively(!)  Have the bean counters fallen asleep on this issue?
I have nothing personal against Reckitt-Benckiser, beyond the fact that they refuse to engage in conversation with me.  If the good Brits at RB have discovered a way to suck millions of dollars from the weakest members of society, more power to them.  But I am a big fan of intellectual honesty, particularly in regard to the science behind medical practice.  So if someone has evidence that $uboxone is clinically different than generic buprenorphine, whether used properly or injected, please send it my way.

The Suboxone Business Fix

I have shared my thoughts about ‘Suboxone Film,’ a product that serves only one purpose:  to block generic competition from entering the Suboxone market.  Below I’ve copied a Bloomberg article that discusses the current nature of the buprenorphine/naloxone business, and the efforts by RB to prevent market penetration by generics– something that would lead to price reductions for healthcare consumers.

Suboxone Doctors act dumb with buprenorphine
Dumb about naloxone?

Unfortunately, the Bloomberg article overlooks the most significant threat to the profits of Reckitt-Benckiser.  This threat is mitigated only by the ignorance of many of the physicians who prescribe Suboxone.  The threat to profits consists of a simple fact that RB does not want anyone to realize:  that the generic equivalent of Suboxone is already available, in the form of orally-dissolving tablets of buprenorphine.

I encourage physicians who doubt my comments to do their own ‘due diligence’ and break out their old pharmacology textbooks.  I have a hard time understanding how people who graduated from accredited medical schools can get things as wrong as they do with this issue.  I sometimes present opinions, but not with this post.  The facts about buprenorphine and naloxone that I’m about to describe are described in any pharmacology textbook— e.g. Goodman and Gilman—and are not in dispute in any way.

Suboxone consists of buprenorphine plus naloxone.  Naloxone is an opioid antagonist that is added to reduce diversion of Suboxone in the form of intravenous injection of a dissolved tablet.  Naloxone is NOT ACTIVE when not injected.  The molecule is poorly absorbed through the oral mucosa because of the molecule’s size and poor lipid-solubility.  Instead, naloxone is swallowed, absorbed from the small intestine, and totally destroyed at the liver before reaching the systemic circulation through a process called ‘first pass metabolism.’

I suspect that some physicians confuse naloxone with the similarly-named substance naltrexone, an opioid antagonist (blocker) that IS orally active. There is NO naltrexone in Suboxone.

All of the beneficial aspects of Suboxone come from the partial agonist buprenorphine.  The ceiling effect of buprenorphine causes a reduction in cravings through a process that I’ve described in earlier posts.  Naloxone, on the other hand, does absolutely nothing to reduce cravings, to increase safety, to reduce euphoria, etc, provided that the medication is not injected.

The confusion surrounding buprenorphine essentially consists of intellectual laziness or intellectual dishonesty by the physicians who prescribe the medication and the pharmacists who dispense it.  I realize that not all doctors are cut out to be ‘physician scientists’ who understand pharmacology in great detail.  But I am particularly disappointed that the large organizations that supposedly oversee the science of addiction treatment have dropped the ball on this issue. I don’t know why groups like ASAM and SAMHSA don’t get it– whether the problem is ignorance, or whether there are mutually beneficial relationships between these organizations and RB that encourage the organizations to foster ignorance among
patients and doctors.  I don’t belong to the organizations primarily for this reason– and I blame ASAM and SAMHSA for the current status of addiction treatment as the ‘no science zone’ of modern medicine.

 A few examples of intellectual laziness: 

Example 1:  Physicians who prescribe Suboxone often say that one shouldn’t use buprenorphine ‘because it doesn’t have the opioid blocker and therefore….’ (add whatever here– it causes euphoria, it is addictive, it isn’t safe– any or all of these comments). The statement is partially correct. Generic buprenorphine does not have the opioid blocker naloxone— but naloxone is irrelevant to the actions of Suboxone!

There are TWO opioid blockers in Suboxone, but only one is clinically relevant—the one that is in both Suboxone and generic buprenorphine.  What is the relevant ‘opioid blocker’ that IS
in both Suboxone and generic buprenorphine?  Buprenorphine!   As a partial agonist, buprenorphine has antagonist properties that are responsible for ALL of the effective clinical properties of Suboxone.

Example 2:  Refusing to consider the cost of medication as a factor that determines access to treatment.  Some docs make ‘fear of diversion’ the only factor in determining what to prescribe.  Discussions with hundreds of opioid addicts over the years have convinced me that buprenorphine is rarely a drug of choice.  Rather, it is used by addicts who are sick and tired and want a break from using without withdrawal, or by addicts who have no money or access to agonists.  In such cases, buprenorphine or Suboxone are equally effective– and equally diverted.  When I ask addicts new to treatment about their injecting habits, I often ask whether they injected buprenorphine or Suboxone.  The typical response is either ‘can you do that?’ or ‘why would I do that, since heroin is cheaper?’

In my area, an 8 mg tab of buprenorphine costs as low as $2.33.  This low cost should be part of the equation for choice of medication, just as it is for other illnesses.  Does anyone doubt that there are some people kept from treatment by a price differential of 300%?!  Is it ethical to fear diversion so greatly that treatment is effectively withheld– for a condition with the fatality rate of opioid dependence?!   I’m sure readers know my answer, especially when there are effective ways to reduce diversion, such as close monitoring of prescribed doses, a ‘no replacement’ policy, and drug testing, among others.

Example 3:  There is some question whether the naloxone in Suboxone does anything to reduce diversion. Buprenorphine patients on my forum  who have injected Suboxone in the past have claimed that they did not experience withdrawal from either Suboxone or buprenorphine, consistent with what I would expect from combining a low-affinity antagonist with a high-affinity partial agonist.

Note: Injecting ANYTHING is in essence taking your life in your hands, and I strongly encourage anyone in such a position to seek treatment immediately.   Really—don’t do it.

Example 4:  Insurers generally refuse to cover generic buprenorphine (the generic form of the RB drug Subutex), even though it is much cheaper than Suboxone.  The one time they WILL cover Subutex or buprenorphine is for women who are pregnant or nursing.  The argument is that we shouldn’t expose the fetus/infant to one more drug (naloxone), since that drug isn’t necessary to the actions of Suboxone.  I agree with the argument, and wonder why it is extended only to the fetus?  Why does mom or dad have to be exposed to an extra substance(naloxone) that isn’t necessary to the actions of Suboxone?

I struggle to understand the insurance issue, as I would expect that someone at some major insurer would know enough about pharmacology to save money on Suboxone by favoring gen
eric buprenorphine.

The ultimate of silliness is that the State of Wisconsin requires that people on Medicaid use only Suboxone FILM.  Getting Abilify for a patient is virtually impossible without first using a variety of older, cheaper medications… but the squishy arguments in favor of Suboxone Film push the med up the formulary chain past an alternative that sells at a fraction of the cost.  The film/Medicaid situation is doubly dubious, as we have the arguments for buprenorphine over Suboxone, and the even less-sound argument for Suboxone Film being favored over the tablet.

RB apparently convinced the state that for Medicaid patients, only the film was safe– and that the film should be required instead of the tablet form of Suboxone, placing future generics at a great disadvantage.  It is especially impressive that RB accomplished this feat after selling a million units of the tablets themselves!  I can picture the person making the point:  ‘the tablet is unsafe…. Starting NOW!’

I’m going to write all night if I don’t wrap this up.  To summarize, the Bloomberg article below describes why RB is winning the battle with generics, but the writers of the article, along with most doctors, miss the bigger issue– that misplaced fears, intellectual laziness, and misinformation have protected Suboxone sales from a much greater foe-– generic buprenorphine.  If doctors, states, and insurers ever get their acts together and prescribe according to science, brand name Suboxone profits will go down the toilet faster than the cleaning products made by RB.

The Bloomberg piece:

Reckitt Benckiser Kicks Heroin Tablet Habit With Film: Retail

By Clementine Fletcher

Reckitt Benckiser Group Plc may be kicking its heroin problem.

After losing U.S. patent protection in 2009 for its Suboxone tablet, designed to help heroin users quit, Reckitt Benckiser has said that the entrance of a generic competitor could erode pharmaceutical sales and profit by 80 percent (note by JJ:  What a shame?!  Consider the benefit of such a price reduction for addicts in need of treatment!).

Reckitt Benckiser, which gets most of its revenue from selling home and personal-care products like Lysol cleaners and Durex condoms, has faced calls to sell the business before a generic comes to market. Instead, the London-based company aims to divert the showdown by switching users to a film form of the drug — one whose last patent doesn’t run out until 2025 (note by JJ:  NOW do you see why they made the film?!)

To get people to make the switch, Reckitt Benckiser is thinking more like a consumer company than a pharmaceutical one. It’s drawing on a marketing technique first pioneered by Coca- Cola Co. more than 100 years ago: coupons. By offering up to $45 a month toward a user’s co-payment in the U.S., the company is making the film version, which looks like a Listerine Pocketpak, close to free. That offers patients who get part of the bill subsidized by health insurance little incentive to transfer to a generic pill once it appears on the market.

“They’ve done a good job of making a silk purse out of a not very compelling situation,” said Martin Deboo, an analyst at Investec Securities Ltd. in London.

Reckitt Benckiser’s shares have risen 55 percent in the last five years, outpacing Unilever and Procter & Gamble Co. Under Chief Executive Officer Bart Becht, who stepped down last month, the company more than doubled sales in a decade. The stock has dropped 3.7 percent this year, compared with Unilever’s 4.7 percent gain and P&G’s 1.2 percent gain.

Drugs Growth

The company is due to report third-quarter results tomorrow and will probably say revenue adjusted for purchases and asset sales rose 7 percent at the drugs division, analysts led by Andy Smith at MF Global in London estimate, compared with a 3.9 percent increase for the rest of the business. Profit likely rose 0.9 percent to 430 million pounds, they said.

The film version of Suboxone, introduced in September 2010, accounted for 41 percent of the drug’s U.S. sales by the end of the first half (note by JJ:  Thanks, Wisconsin Badgercare!). That surpassed the company’s own expectations, Becht said on an Aug. 30 conference call arranged by Sanford C. Bernstein. Becht was succeeded by Rakesh Kapoor, a company veteran.

Generic Delay

The film “has been a phenomenal success,” Becht said, according to a transcript of his remarks. “To make the business completely sustainable, we would like to have a share which is clearly much higher than where we are.” He added that the company aims to grow that share every month.

Right now, time is on his side. Teva Pharmaceuticals Industries Ltd., the world’s biggest maker of generics, began the year saying it might launch a Suboxone copy in 2011. Now the company has backed off, saying it no longer expects the product to win regulatory approval this year.

Biodelivery Sciences International Inc., another drugmaker going after Suboxone, said a study comparing its own version of the drug to a placebo failed to show a statistical difference in the treatment of chronic pain. A test in patients addicted to opioids, which include heroin and codeine, is scheduled to begin
later this year. Titan Pharmaceuticals Inc. on Aug. 31 said it’s preparing to seek approval of an upper-arm implant that would deliver buprenorphine, one of
the active ingredients in Suboxone, directly into the bloodstream (note by JJ:  the ONLY active ingredient in Suboxone!)

‘Massive Benefit’

“This delay has been a massive benefit,” said Andrew Wood, an analyst at Sanford C. Bernstein. “With every day that goes by, RB has an extra day to convert users.” Suboxone is either harder-than-expected to copy or generic-drug makers are having second thoughts about targeting addicts, according to Bernstein.

About 1 million people in the U.S. are addicted to heroin, the National Institute on Drug Abuse estimates. As many as 325,000 people use Suboxone to quit the drug or painkillers, says Pablo Zuanic, an analyst at Liberum Capital in London.

The medicine combines buprenorphine, a painkiller derived from the opium poppy that shares some of its properties, with naloxone, a chemical that blunts
withdrawal symptoms (note by JJ:  This is simply WRONG.  BLATANTLY WRONG.  Really–  an opioid antagonist BLUNTING withdrawal symptoms?  Shame on the writers!). The film sells for about $4.63 to $8.23 a dose at Walgreens stores, according to Liberum, depending on its strength and pack size. That means the strongest dose costs about $247 a month.  (note by JJ—a pharmacy near my practice sells generic buprenorphine dissolvable tabs, 8 mg, for $2.33 per tablet—a medication that works EXACTLY the same way IF NOT INJECTED INTRAVENOUSLY)

More than half of people on Suboxone use private insurance with co-pay, Zuanic says. Reckitt Benckiser offers $45 towards co-pay for the film, he said, meaning an insured patient who’d contribute $50 to the cost of the drug may end up spending $5.

‘Near Zero’

“The actual cash cost for some patients buying the film with private insurance could be near zero,” Zuanic said in a note to clients this month. (note by
JJ:  but we are all paying the cost in higher insurance premiums, and some insurers, notably Humana, have draconian policies that stop covering—forcing instant withdrawal- if a patient receives a prescription for a sleep medication such as Ambien, so many people are left paying cash).

Meantime, Suboxone is only becoming more important to Reckitt Benckiser. The drugs division, whose sales grew five times as quickly as the main business last year, accounted for almost 9 percent of sales and 24 percent of profit, up from 7.6 percent and 20 percent in 2009. Sales a
t the unit will probably rise 12 percent to 829 million pounds ($1.3 billion) this year, according Nomura International Plc estimates.

The maker of French’s mustard is even considering making an injectable Suboxone and developing new products for cocaine, alcohol and cannabis addicts.
The plan has met skepticism.

“We’re quite a long way from having any visibility on these products,” said Julian Hardwick, an analyst at Royal Bank of Scotland Group Plc in London. “Are they products that will work? Which will get approval?”

Prescription drugs are perceived as a bit of a misfit in the home of Vanish stain removers and Finish dishwasher tablets.

Misfit

“Reckitt Benckiser is basically a home and personal-care company with over-the-counter pharmaceuticals,” said Carl Short, an analyst at Standard & Poor’s in London. The drugs unit is “always going to be something that looks like it doesn’t fit with the rest.”

Reckitt Benckiser may look at selling the unit, which Becht himself has said is “not the No. 1 strategic part” of the company, once a generic form of Suboxone reaches pharmacy shelves, analysts said. (note by JJ:  i.e. after all of the profit has been wrung from suffering addicts).  But the company’s marketing savvy, coupled with delays in the launch of a generic, are giving Kapoor time to settle into his new job.

“This is a big job and he is coming in after someone’s done it for some considerable time and very well,” said Julian Chillingworth, who helps manage about 16 billion pounds in shares at Rathbone Brothers Plc, including Reckitt stock. “You wouldn’t want to come in as a CEO into a very successful business and start selling things off on the cheap.”

Not Time

Analyst valuations range from 2 billion pounds to 6.3 billion pounds, according to four estimates compiled by Bloomberg News. Estimates diverge because it’s hard to value the business without knowing how Suboxone sales will resist the generic challenge and whether the shift to film can counter some of that impact.

“Until you get generic competition for the tablet, I think it’s unlikely that prospective buyers would give you the full value for the business,” said Hardwick of RBS. “Now is not the time to sell.”

–With assistance from Naomi Kresge in Berlin. Editors: Celeste Perri, Marthe Fourcade.

 

 

The REAL Future of Partial Agonist Treatment— Pharma are you Listening?

I just wrote a note to a friend who works in the molecular sciences– she has been studying opioid receptors since the early 1980’s, when things were just getting started on a molecular level.  I’m keeping her name to myself, but I’ll share a few thoughts about what is needed to advance the treatement of opioid dependence– and make a few million dollars along the way (are you listening, RB?)
Hi ——,
(private chit chat that would bore everyone)
Anyway, today I realized what is needed in order to take partial agonist treatment of opioid dependence to the next level.
The problem with buprenorphine is that the ‘ceiling effect’ occurs at a relatively high tolerance level, approximately equal to 40 mg of methadone.  That causes at least two problems.  First, going off Suboxone is a lot of work, as the person still has a great deal of withdrawal to go through.  That may be a good thing early in the process, as it may help keep people on Suboxone, but after a year or so, when people want to try going off the medication, it is a major barrier that opens the floodgates to those old memories of using, etched in the emotions associated with withdrawal.
The second problem with the high ceiling/tolerance level is that surgery is a hassle.  People needing surgery need HIGH amounts of oxycodone to get any analgesia—I usually give 15-30 mg every 4 hours.  Pharmacists shudder to release those doses, and some surgeons and anesthesiologists balk.
The horizontal part of the dose/response curve is the essential part of buprenorphine;  that is what tricks the brain into ‘thinking’ that nothing is wearing off, and in that way eliminating cravings.  But that flat dose/response relationship could occur at lower tolerance levels and still work the same way.
Since I’m wishing for the moon, a series of molecules with progressively lower ceiling levels would be ideal, with the last molecule in the series being Naltrexone.  Although actually, naltrexone doesn’t work—it has NO mu agonism, so there is no tricking of the brain, and no reduction of cravings.  We would want something close to naltrexone, but with a tiny bit of opioid activity that does not vary with dose.
A shorter half-life would also be helpful.  Preparing for surgery requires weeks to get the buprenorphine out of the system.  Of course a shorter half-life means it is easier to get around buprenorphine by people who want to play with agonists, so again, these new molecules would be intended as ‘step down’ meds from early-stage buprenorphine treatment.
Do we know enough about molecular actions at the mu receptor to design molecules with these properties?  Or are we still at the point of making somewhat random changes and assaying the result?  Do you know of any labs doing this type of work?
I figured you’re the person to ask!
Thanks ——–
Jeff

I'm On Suboxone; Can I Have Surgery?

I recently resumed writing for the expert forum on addiction at MedHelp.Org. One result of writing for MedHelp is that I receive a number of e-mails from people with questions about specific issues related to buprenorphine. The most common questions are from people on buprenorphine undergoing surgery, asking about the safety of anesthesia and about postoperative pain control.
There are very significant problems with medical coverage for patients on buprenorphine undergoing surgery. Patients on buprenorphine will occasionally need surgery, and in such cases there are often no doctors willing and/or competent to manage postoperative pain. Psychiatrists, frankly, have little knowledge or experience in this area. Before psychiatry residency, medical school graduates generally complete a medical internship that provides little or no training in critical care or surgery. Making matters even worse, the medical students who go into psychiatry tend to be those who have the least interest in the surgical specialties.
And then there are surgeons. Where psychiatrists lack courage to provide effective pain relief for addicts, surgeons simply lack interest or concern. Surgeons enjoy being in the operating room, cutting things apart and sewing things together. The last thing they want to do is have a heart-to-heart talk about someone’s addiction to pain pills. To a surgeon’s way of thinking, addiction doesn’t even exist. You can’t cut it off or sew it on, so why even talk about it?
Hopefully, those of you who take buprenorphine will slip this article under the door of your psychiatrist to drop a hit about this problem. I cannot provide medical recommendations for people who I do not know, but I will at least provide some general information so that readers of my blog will know when they are being fed a line of nonsense.
Speaking of nonsense, the silliest and most potentially harmful advice that I hear about in e-mails is that buprenorphine will cover a person’s postoperative pain; that the person should simply take his/her normal dose of Suboxone and everything will be fine. Nonsense! People taking buprenorphine quickly become tolerant to the pain-relieving properties of buprenorphine, and therefore will not get adequate pain relief from buprenorphine for anything but the most minor surgical procedures. Buprenorphine has complex actions at opioid receptors, including partial agonism at mu receptors and mixed effects at kappa opioid receptors. The actions at kappa receptors are less subject to tolerance and provide some long-term effects on mood and analgesia, but these effects are not even close to what is required to cover postoperative pain.
There are several articles that have been published that describe various approaches for treating postoperative pain in patients on buprenorphine. I cannot post the articles here because of copyrights, but the general recommendation in the literature for treating post-op pain is to reduce the daily dose of buprenorphine starting several days before the surgery, and to use potent opioid agonists in addition to buprenorphine. Another option is to stop buprenorphine completely before surgery. But buprenorphine has a long half-life, and must be stopped for a week or more in order to significantly lower the level of buprenorphine in the body.
It is important to understand that there are two things that get in the way of pain relief in patients on buprenorphine; the antagonist actions of buprenorphine at the mu receptor, and the patient’s high tolerance to opioid agonists. Even if buprenorphine is stopped a week or two in advance of surgery, the person still has a high tolerance to opioids, and still requires significant doses of opioid agonists for adequate post-operative pain control. And if buprenorphine is stopped completely, the person must go through a period of withdrawal before eventually restarting buprenorphine in order to avoid precipitated withdrawal.
I have found it easiest to keep the person on a small dose of buprenorphine, perhaps 4 mg per day, throughout the entire operative period, until postoperative opioids are no longer needed. I’ve had good success treating post-operative pain with high doses of oxycodone while continuing buprenorphine, even after major surgeries. Interestingly, patients report good pain relief but the complete absence of the euphoria that they used to get from opioids. At the point after surgery when opioid agonists are no longer necessary, patients simply stop the agonists and resume their full dose of buprenorphine.
Whether or not buprenorphine is discontinued, high doses of opioid agonists are required to provide adequate pain relief for major surgery. An oxycodone equivalence of about 60 mg per day is required just to ‘break even’ with the tolerance of a typical person on buprenorphine maintenance. You can understand, then, why psychiatrists are wary of treating postoperative pain. Such high doses of oxycodone could easily cause fatal overdose in patients not taking buprenorphine. I am board certified in anesthesiology, but even I get nervous in such situations. But what is the alternative? I have had patients who required coronary bypass, hysterectomy, and total knee replacement, as well as minor surgeries. Dental work in particular is quite common in patients with a history of addiction. Should people on buprenorphine simply go without the necessary procedures that other people are allowed to have?
If psychiatrists or surgeons are unwilling to provide adequate postoperative analgesia for patients to take as outpatients, patients should allowed to stay in the hospital, even the intensive care unit, if that is what it takes for the doctor to feel safe providing adequate analgesia. Surgeons should provide adequate care, even if they have to fill out paperwork and battle insurers to obtain the necessary coverage for hospitalization. They would do the same for patients with brittle diabetes who need close monitoring following surgery. Opioid addicts are people too!
As for general anesthesia, buprenorphine does not pose significant problems, provided that the anesthesiologist is aware that the patient takes buprenorphine and has a high opioid tolerance. Opioids are often used during anesthesia to blunt changes in blood pressure and heart rate, and larger doses of opioids would be required for people taking buprenorphine. The amnesia component of an anesthetic is generally provided by medications not blocked by buprenorphine, such as anesthetic vapors or benzodiazepines.
Another reason that anesthesiologists must be made aware if a patient is taking buprenorphine is so that sufficient opioids are ‘on board’ when the patient awakes. As patients emerge from anesthesia, anesthesiologists often use respiratory rate to gauge whether sufficient doses of narcotics have been provided to cover postoperative pain. Without the knowledge that a patient is on buprenorphine, the anesthesiologist may be confused by the patient’s lack of response to narcotics, causing the anesthesiologist to give too little pain medication—meaning that the patient will awake with considerable pain.
Medications with combined actions (such as tramadol and the newer agent Nucynta) or of little value for post-operative pain control. These medications have actions at mu opioid receptors that are blocked by, and cross-tolerant with, buprenorphine– completely nullifying that component of their action. The other component of their action is through effects on serotonin or norepinephrine pathways, and these actions are insignificant for post-surgical pain. Because of mu receptor tolerance, Nucynta essentially becomes as useful for treating post-op pain as Cymbalta— i.e. worthless!
I must stress that everything I have written here is intended to serve as a basis for discussion between patients and their doctors. Every case has unique variables that must be taken into account, and so my comments must not be taken as medical recommendations or advice. Taking high doses of opioid agonists can be dangerous, particularly in combination with other respiratory depressants.
One final comment… I recently received letters from two different health insurers about ‘buprenorphine policies’ citing situations where Suboxone would not be covered. These situations have included cases where patients are prescribed opioid agonists. I want to point out that there are times when patients on buprenorphine require surgery, and every patient undergoing surgery deserves adequate pain control. There are also patients on buprenorphine maintenance who have chronic pain; pain that in some cases justifies the relief afforded by opioid agonists. I hope that those with the power to influence policy, including Reckitt-Benckiser, the American Society for Addiction Medicine, NIDA, and SAMHSA, will direct attention to this important gap in medical coverage.