A question was asked about the last post that warrants top billing:

“Buprenorphine acts similar to opioid agonists in lower doses, with the same addictive potential as oxycodone or heroin. In higher doses—doses above 8 mg or 8000 micrograms per day—the ‘ceiling effect’ eliminates interest and cravings for the drug.”

Ceiling Effect

I’m not sure I followed this. Can you explain more? What would you think about someone who is taking 1-2mg of Suboxone twice a day without a prescription, and says they want to stay on that dose once they find a prescriber? Are they better off on 8mg or more per day, or would it be ok for a prescriber to keep them at the lower dose? Is the answer the same if they hope to taper off the medication completely within a year (they don’t feel able to do this on their own right now, but hope to be able to when some life circumstances change). Thanks!

This gets a bit complicated, but I’ll do my best. A couple background issues; buprenorphine has a ‘ceiling’ to its effect, meaning that beyond a certain dose, increases in dose do not cause greater opioid effect. That is the mechanism for how buprenorphine blocks cravings.

If the blood level of buprenorphine is ABOVE that ceiling, the opioid receptors are maximally, 100% stimulated. If the person takes more buprenorphine, and the blood level increases, the opioid receptors don’t feel the increase, as they cannot be stimulated more than 100%. But more importantly: when the person takes less, and the blood level of buprenorphine goes DOWN, the receptors also sense nothing– as long as the level stays above the ‘ceiling’ level.

Read the above paragraph, and think on it until you grasp it– as it explains buprenorphine and Suboxone. If you understand that paragraph, you will know more about Suboxone than most doctors!

Below that ceiling level, the opioid effect from buprenorphine varies directly with dose—just as with oxycodone, hydrocodone, heroin, etc. Medications that have effects that increase with dose are called ‘agonists’. Buprenorphine is a ‘partial agonist;’ it acts like an agonist up to point, the ceiling effect, beyond which increases in blood level have no greater effect.

The level of this ‘ceiling’ varies from one person to the next, depending on efficiency of absorption (on average, only a third of a dose is absorbed from under the tongue), body size, liver function, differences in regional blood flow, and the presence of other medications that affect buprenorphine metabolism. In order for buprenorphine to have the unique, craving-blocking effects, the blood level of buprenorphine must stay above the ceiling level, for the reasons described above.

Lower levels (blood levels of buprenorphine below the ceiling level) still have SOME effects on cravings. Buprenorphine has a long half-life, an that alone reduces the desire to take more—especially if the medication is taken more than once per day– since the blood level drops very little between doses. For agonists or for buprenorphine below the ceiling level, drop in blood level equals drop in opioid effect, equals sense of things wearing off, equals cravings.

But the classic method for treating with Suboxone, as described in the certification course, is for it to be given at a high enough dose to stay above the ceiling level… and dosed only ONCE per day. If the blood level stays above the ceiling level, once-per-day dosing covers cravings completely. Yes, people still want to take more, especially initially, but that desire is not driven by chemical effects; the desire is instead based on psychological factors, like habit, or from being accustomed to feeling better after a dose, and getting a placebo ‘lift’ from taking a second dose.

A person can eliminate that second dose fairly easily, providing that the morning dose is high enough, i.e. usually 8-16 mg. To eliminate the second dose, the person should distract him/herself as soon as the thought about taking the second dose comes to mind. Immediately, do anything else—the dishes, call a friend, wrestle with the dogs… and the thought will pass. If the person does the distraction method for a few days, the need to take the second dose will go away—a psychological process called ‘extinguishment.’

Dosing every other day, and even every third day, has been studied; people cannot tell the difference, if the dose is raised enough to keep the blood level above the ‘ceiling’ (providing the person is given a placebo that tastes the same).

As for as the writer’s friend… I’m not a fan of any illicit use, but I am aware of the shortage of physicians. When the person has a physician, in my opinion the person should be prescribed a dose that allows for once per day dosing. Realize that buprenorphine wears off VERY slowly; it takes over three days for half of a dose to leave the body! So that ‘need’ to take more is almost always entirely learned or ‘conditioned.’ The medication does not wear off in that short period of time.

Even if the person has withdrawal symptoms, the sensations are almost surely imagined. How to tell? Use the distraction method, and note that a couple hours later, when the person remembers that the dose was skipped, note that the withdrawal went away. That doesn’t happen with ‘real’ withdrawal!

The sense of withdrawal that drives the second dose is simply a memory; a conditioned response that the body has that triggers the person to take more opioid. We become conditioned by drug use, just like the salivating dogs from science books! In the case of opioids, whenever we feel down, we think that an opioid will lift us up, as it has hundreds of times before. And even if what is taken is not a real opioid, the mind ‘feels’ a boost, just from expecting what has always happened in the past.

As for tapering, I look at many factors in order to recommend, or not recommend, stopping buprenorphine—things like age, presence/absence of using friends or contacts, physical health, mood, support network, personal motivation to stop buprenorphine, ability or lack thereof to dose once per day, consistently, number of relapses and personal ‘recovery’ plan, etc.

Realize that EVERYONE looks forward to a day when life circumstances will change for the better—but most of the time, life becomes more, not less challenging. Yes, it is nice to have a reliable job… but it is much more stressful being the sole breadwinner for a family with children, than working to pay for one’s self! Marriages settle down in some ways over time, but they also lose the intense infatuation that can gloss over personal differences.

As I have often written, it is VERY hard to stop opioids. It is a little easier to stop buprenorphine; I am convinced of that fact because I have seen opioid addicts taper off buprenorphine, but I know of no opioid addict who tapered off an agonist. But SOME people cannot taper of ANY opioids—including buprenorphine. I do not consider those people ‘addicted’ to buprenorphine, because they lack the constant obsession for opioids that is so destructive to the mind of an active addict. But they ARE physically dependent on buprenorphine— a fair trade, in my opinion, for a life of chaos, broken relationships, legal problems, and death.

I often talk to my patients on buprenorphine (aka Suboxone) about the need to fill their minds with new ideas, plans, and experiences.  For years, those of us with addictions were focused on one thing– finding a way to avoid being sick for the next few hours.  That one issue became the center of our Universe, pushing out every other interest in our lives.  Treatment with buprenorphine removes that obsession, leaving room behind for interests to re-develop.  The challenge for patients on buprenorphine, particularly young patients, is to seize the initiative, and to fill their minds with healthy interests, relationships, and activities.

Many treatment professionals completely miss the point of buprenorphine treatment.  The unique action of buprenorphine at the mu receptor results in a constant level of opioid effect, even as the brain level of buprenorphine varies throughout the day.  This constant stimulation disappears through the phenomenon of tolerance; a process that allows the mind to ignore ANY input or stimulus that never varies.

The mind, then, has no evidence that the person is on a medication– so the person ‘feels’ normal, and IS normal– as normal as anyone can be, in a world with caffeinated beverages and wifi networks.  All of the mental activity that was spent fretting over opioids is removed during buprenorphine treatment– a process that really should be called ‘remission treatment,’ given what is occurring in the mind and brain.

I’m getting far afield here… my point is that the removal of all that ‘fretting’ allows for the interests of the person to return. The relationships pushed out and neglected by cravings can be restored, and hopefully repaired.  Hobbies can be taken up again.  Athletic interests can return.

But people who became attached to opioids at a very young age may have missed the normal opportunity to develop those relationships and interests.  Young people must develop interests in other things, once they are stabilized on buprenorphine. As an older person, I am not ‘hip’ to all of the things that younger people do these days (as evidenced by saying ‘hip’!), so I have to leave much of that to the creative energy of those patients!  But as an example of the things one can get interested in, this morning I had a few minutes of ‘do nothing’ time… and after watching one of the stars of ‘The Artist’, the silent movie that one all the Oscars, I Googled ‘silent movies’ and started reading.  Eventually I somehow ended up at a site for a college Asian Student Association (would LOVE to visit at least one Asian country some day…) where I viewed beautiful photos from Taiwan, including the countryside, the cities, the food…. and eventually the YouTube video below, of the Taiwan 2010 New Year firework display, at the world’s SECOND tallest building (for now) – Taipei 101.  (before clicking the link you just past, do you know the first?)

Watch in HD if possible–  turn  of the volume, listen to the people around you, and you’re almost there!

Wow. I just read an email about a story that I was vaguely aware of– about a doctor in Kansas and his wife, who were together linked to scores of overdose deaths. But that is just the beginning. The doctor was supported, during his trial, by Siobhan Reynolds, founder of a nonprofit advocacy group called ‘Pain Relief Network.’  She started the group back in 2003, when her ex-husband was suffering from severe pain from a congenital connective tissue disorder.

He (the ex-husband) found relief in combinations of high-dose opioids and benzodiazepines, at least until his doctor, Virginia pain specialist William Hurwitz, was convicted on 16 counts of drug trafficking.  The ex died, by the way, in 2006.  Are you still with me?

The trial of the Kansas doctor, Stephen Schneider, went on for years.  During the trial, Ms. Reynolds apparently helped support what she considered to be a ‘dream team’ of attorneys.  She used the case as an opportunity to increase her visibility, encouraging the Schneiders to aggressively fight the charges against them on the basis of ‘patient rights.’  Ms. Reynolds, through the Schneiders, argued that suffering patients are being denied appropriate care because of a war, waged by overly-aggressive prosecutors, against doctors who prescribe pain medication.

Ms. Reynolds even paid for a billboard adjacent to the road to the courthouse, so that jurors could see, en route, the statement “Dr. Schneider Never Killed Anyone.”  Some might see the billboard as ‘free speech’, but the judge presiding over the case was not amused.  At the eventual sentencing, the judge gave both Dr. Schneider and his wife over 30 years in prison, hoping that the sentences would “curtail or stop the activities of the Bozo the Clown outfit known as the Pain [Relief] Network, a ship of fools if there ever was one.”

We already have enough drama for a made for TV movie.  Actually there already is one, made by Ms. Reynolds, about her ex’s struggle over finding appropriate pain treatment.  The hour-long film is called ‘The Chilling Effect,’ and can be found here– along with a number of vignettes about the efforts of the Pain Relief Network.

Make that the former Pain Relief Network.  Ms. Reynolds was investigated by a Grand Jury, led by the same prosecutor who led the efforts against Dr. Schneider.  After years of what she considered to be ‘vindictive efforts,’ she closed down Pain Relief Network, saying that the organization’s finances ‘were in shambles.’

Within weeks of closing PRN, Ms. Reynolds lost her life in a plane crash.  Piloting the plane, and also killed, was Kevin Byers– Ms. Reynold’s romantic partner and also– get this– attorney for the wife of Dr. Schneider.

Our story ends in typical, made for TV fashion, with all of the loose ends tied up.  The Pain Relief Network is gone, tragically missed by some, and considered ‘good riddance’ by others.  Ms. Reynolds, tireless advocate or misguided fanatic, has left this world for the next.  Left behind are the story-tellers;  I will provide links to both sides, so that readers can have a true, balanced perspective.  From the PRN side, simply go to their former web site, and you will find links to the archives.  The archives contain links to stories in a number of publications, including Slate and the NYT– places where David and Goliath stories are repeated without much challenge, particularly for the Davids.

On the other side is a woman named Marianne Skolek, writer for the Salem News online site, who has little positive to say about Ms. Reynolds and PRN.  For years she has chronicled the epidemic of deaths from Oxycontin, and she has also written a number of articles about the Schneiders, Reynolds, and PRN.  One of the most chilling points in a story by M. Skolek is a a list of the patients who saw Dr. Schneider and who died shortly afterward.  The pattern is clear; people in sudden possession of large numbers of pain pills, who took amounts sufficient to end their lives:

The story is not quite over.  The Schneiders are now appealing their convictions, claiming insufficient counsel– namely that the romantic involvement of one of their attorneys with Ms. Reynolds created a conflict that led to poor counsel.  In other words, they may have asked for mercy, had Ms. Reynolds not been cheering them and their attorney to place everything on the line.

As I’ve written many times, the use of opioids for chronic pain is a complicated issue, with no clear ‘good’ or ‘bad’ side. As in most of life’s challenges, the extremes of each position appear…. extreme.  Ms. Reynolds believed that the Controlled Substances Act should be repealed;  I find it difficult to understand how any educated person would adopt such an approach.  But the extreme opposite side leads to enough fear, in physicians, to stifle the use of narcotic pain relievers in people who truly need such relief.  As for me, I keep trying to straddle the wide middle.

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

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.

This post is from a couple years ago;  I think it is important for people to have a basic understanding of how buprenorphine removes opioid cravings, so I’m republishing the post.

Note that naloxone has NOTHING to do with the effects of Suboxone.

In this video I explain why the ceiling effect is so important to the effects of buprenorphine for treating opiate dependence.

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.

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 generic 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 at 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.

This is not all that new, but it was just pointed out to me recently and I figure many of you will find it interesting.  As most readers know, the receptors that mediate the actions of cocaine are completely different than the receptors that are activated during use of opioids.  I will be posting related information in the next few days.

From DataMonitor:

Alkermes, Inc., an integrated biotechnology company, has announced positive topline results from a Phase I clinical study of an investigational combination of ALKS 33 and buprenorphine, an existing medication for the treatment of opioid addiction, for the treatment of cocaine addiction.

Data from the study showed that the combination therapy was generally well tolerated and sublingual administration of ALKS 33 effectively blocked the agonist effects of buprenorphine. Based on these positive results, Alkermes expects to initiate a phase IIa study of the combination therapy in the first half of calendar year 2011, the company said.

The phase I study was a randomized, double-blind, multi-dose,placebo-controlled clinical trial that assessed the safety, tolerability and pharmacodynamic effects of the combination of ALKS 33 and buprenorphine when administered alone and in combination to 12 opioid-experienced users.

Buprenorphine is used for the treatment of opioid addiction, despite its own potential for abuse. Combining ALKS 33, an opioid modulator, with buprenorphine, a partial opioid agonist, may block the agonist effects of buprenorphine thereby reducing the potential for the development of opioid dependence while still maintaining effective therapeutic action. Furthermore,
the pharmacologic properties and low dose of ALKS 33 required to effectively block mu opioid receptors may allow for a co-formulation with buprenorphine as a single sublingual tablet, the company added.

Elliot Ehrich, chief medical officer of Alkermes, said: “We look forward to continuing the recent momentum in our R&D efforts by initiating a phase IIa clinical trial to generate further data, as we advance the ALKS 33 and buprenorphine combination therapy as part of Alkermes’s growing pipeline of proprietary product candidates.”

Weeks ago I posted a few new ideas—things like a memorial wall for victims of opioid dependence, and a ‘wall of shame’ for doctors who are known for reckless prescribing of opioids.  I mentioned these ideas over at SuboxForum as well.

I received good feedback from readers here, and from members there.  Sometimes the best feedback is the hardest to hear;  I’ll get excited about a certain plan of action, and like anyone, I don’t like it when someone rains on my parade.

One of my addiction docs from years ago was big on ‘sober thinking.’  Back then, it seemed as if anything I came up with that pushed the boundaries was in need of more ‘sober thinking.’  I wondered if ‘sober thinking’ was simply code for ‘I don’t want to say yes to your idea, and maybe that was the case in SOME instances.  But I now recognize a part of myself that acts quickly, impulsively, with great optimism, and with little regard for risks.  ‘Sober thinking’ is simply letting an idea sit in one’s mind for a few days or even weeks, and keeping a truly open mind to the comments that one receives about the idea.

Beats Death--- Barely

I won’t spell out who wrote to me, but I’ll thank the people who did—who risked my ire by giving their honest opinions.  I mentioned a memorial page;  some people pointed out that a memorial on an addiction-related web page may add to the pain and shame felt by family members.  As for my ‘doctor wall of shame’, I was reminded that every story has two sides, and it may be more useful to simply provide referenced information that would allow readers to make up their minds without my own coloring of the facts.  I want to thank the people who wrote, and let them know that they made a difference—and the site will be better because of their efforts.

Instead of the earlier ideas, I added what I am calling the ‘consequences’ page.  The page will contain news stories identified to Google as having ‘drug overdose’ in their tags.  The information will be replaced every 24 hours or so.  I experimented with a couple different intervals and found that no day went by without a significant amount of news under that tag—a rather compelling statistic!

Click on ‘consequences’ to check it out, and let me know what you think!

More than ever, patients have easy access to information once read only by scientists and medical professionals.  And at the same time, doctors have reduced the time spent with patients during appointments.  The result has been an increase in internet-educated patients, who come to appointments armed with data from package inserts, information from internet health forums, and stacks of questions from net-savvy relatives.

There is a good side to this process, of course.  Patients are wise to take greater interest in their personal health, and to be knowledgeable of medications that they are taking.  And whether good or bad, the situation is necessary, given the abdication by many physicians of their roles as educators.

But there are downsides to the situation as well.  Package inserts provide studies and odds ratios for the risks from medications, but interpreting the studies and odds ratios requires education and experience. Some data is reported in a way that a person without considerable education in statistics would have a hard time deciphering what is or isn’t relevant.  Some patients struggle under the burden of calculating and weighing risks, and prefer to have a careful, caring doctor provide his/her opinion whether a medications is safe or not.  Speaking from my role as physician, I am frustrated when patients choose to follow advice from an online forum over a recommendation based on medical knowledge or a careful literature search..

Doctors sometimes add to the problem.  I am frustrated when doctors make claims that are not supported by best medical practice or by medical science.  Distinctions between sources of information are blurred, so that some ‘facts’ are based on nothing but rumor.  The process is like the old ‘telephone line’ game; a doctor reads a question about a medication or illness, and responds with his/her opinion.  Another doctor then hears or reads that answer, adopts it as fact, and shares it with other doctors—who then reinforce the ‘factual’ nature of the information.

People tend to take information from physician educators/writers verbatim, as if the act of putting information online, in writing, guarantees that it to be true.  People are confused when they read conflicting ‘facts’ or recommendations from people with comparable credentials.

I try, when writing here, to differentiate between facts, best medical practice, and personal opinion.  If someone asks ‘how long should I stay on Suboxone?’, I’ll reply that several studies show high relapse rates in people who stay on Suboxone for less than 6 months (fact), that more and more physicians are keeping patients on the medication long-term (medical practice), and that in my opinion, many people are best off staying on the medication for an extended period of time.  You get the idea.

I think it is because of my PhD training that I tend to take a closer look at things that everyone ‘knows’ and ask, ‘says who?’  History has given us many examples of things that everyone knew that turned out to be wrong—from the connection between autoimmune disease and breast implants that wasn’t, to global cooling, the impending disaster when I was a kid (read here)—and we all know how THAT turned out!

The treatment of opioid dependence with buprenorphine/Suboxone appears to be particularly vulnerable to misinformation.  Some examples:

The naloxone in Suboxone prevents the person from getting ‘high’: Naloxone is not active orally or sublingually, and is added to Suboxone to prevent intravenous injection of the medication.  Confusion comes in part from mistaking naloxone, an IV medication, with naltrexone, an orally-active medication that is NOT part of Suboxone.

People will abuse Subutex because it doesn’t have the opioid blocker in it: Subutex or the generic equivalent—buprenorphine—works just like Suboxone when taken correctly.  Doctors and pharmacists are mistaken when they believe that buprenorphine is more addictive if naloxone is not included.  In reality, the subjective effects of Suboxone and Subutex are identical.  There IS a relatively low incidence of intravenous abuse of buprenorphine;  Suboxone in theory causes withdrawal if injected because of the presence of naloxone.  Realize, though, that the effects of buprenorphine or Suboxone are similar, whether injected or taken correctly.  Injected buprenorphine has the same ‘ceiling effect’ as does sublingual buprenorphine, and so people on buprenorphine maintenance would NOT experience an opioid ‘high’ after injecting their medication—any more than they do when taking it sublingually.

The tablet should not be crushed or chewed: The package insert recommends that Suboxone tablets should be taken sublingually, without crushing the tablet.   I am guessing that the recommendation comes out of an attempt to standardize the bio-availability of buprenorphine.  Studies show that as little as 15% of a dose of buprenorphine is absorbed, and in my opinion, the high cost of the medication warrants efforts to reduce the amount that gets wasted.  The bio-availability is affected by the concentration of buprenorphine in saliva, the surface area available for absorption, and the time that the medication is in contact with absorptive surfaces.  Passage of buprenorphine through mucous membranes is the rate-limiting step for absorption–NOT dissolution of the tablet.  In other words, crushing or chewing the tablet does NOT cause a ‘high’, and is NOT a sign of drug-seeking behavior.  Neither does crushing or chewing hasten the onset time of a dose of Suboxone.

Discussions about chewing or crushing buprenorphine provide examples of the doublespeak that only confuses people.  My own recent discussion with another Suboxone prescriber went like this: “I don’t want patients to crush or chew the tablet because that will make it get absorbed too quickly.  In fact,  I usually recommend the film, because it dissolves much more quickly than the tablet.”  Say what?  Do we want it to dissolve more quickly or not?  The truth is that it really does not matter.  The dissolving of buprenorphine— or the film– is the LONG part of the process.

The veins under the tongue absorb the drug in Suboxone. Actually, buprenorphine passes through all of the surfaces in the mouth, eventually entering capillaries under the surface.  The veins under the tongue absorb little or no buprenorphine.

You must stop smoking cigarettes if you are on Suboxone: I have searched the literature and I have talked to folks at Reckitt Benckiser, and I can find no evidence to back up this claim.  Scientifically, I cannot think of a reason that cigarette smoking would affect the absorption of buprenorphine, except perhaps to increase production of saliva, diluting the buprenorphine in solution and reducing diffusion into tissues.  I doubt this would have any significant effect on the bio-availability of buprenorphine, and my clinical experiences backs that up.  Patients in my practice who smoke have had normal responses to buprenorphine or Suboxone.

You can’t take pain pills if you are on Suboxone: Actually you can, but they will only reduce pain if the dose is sufficient.   I often use this approach to treat people on buprenorphine who undergo surgery.  But problems ARE caused if a person does things in the opposite order.  In that case—if someone taking opioid agonists then takes buprenorphine– there is risk that the person will develope precipitated withdrawal, depending on the amount of opioid agonist that was being used.

The longer you are on Suboxone, the harder it is to stop: I have read no studies supporting this oft-read comment, and I can think of NO reason that it would be true.  The tolerance to buprenorphine is set by the ceiling effect of the drug, and once tolerance develops, typically by several weeks on the medication, longer periods of time do not push tolerance higher.

The film formulation is safer than the tablet. Says who? If we are worrying about kids getting their hands on Suboxone, yes—the little orange tablets look like candy to a toddler.  But little red strips of flavored material appear appetizing as well. ALL medications should be kept away from children.  If the safety concerns are directed toward patients—for example one doctor told me he prescribes the film because it cannot be crushed—remember that crushing Suboxone is not a problem.  I SUSPECT (only my opinion) that the change in formulation was a marketing ploy aimed toward preventing acceptance of generic buprenorphine tablets.  Reckitt Benckiser apparently convinced the state of Wisconsin to cover the film exclusively, rather than allow addicts the choice of taking generic buprenorphine—a medication that works exactly the same as Suboxone, at about half the cost.

I think you get the idea.  Whether thinking about Suboxone or another medication, I urge readers to always ask the question, ‘says who?’  There are MANY experts out there on the internet—and some exhibit more restraint in their comments than others.  Ask yourself, what is the mechanism for what is being described?  And if it doesn’t seem to make sense, consider that just perhaps, you’re the right one.