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.

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.”

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 have a few interesting books to recommend– the first mostly just for people interested in history and science, and the second two out of the ‘self help’ section.  I’ve read the latter two books and think they are valuable for people in recovery, to help grow into a new life of sobriety.  I receive a buck if you purchase through the links, and the proceeds help to support the site– so if you check them out, thanks!

More and more addicts presenting to my practice are reporting addictions to heroin.  I wrote a post a month or two ago, wondering if the change in the Oxycontin formulation would have the unintended consequence of increased use of heroin– and with it, the increased use of needles.  I’m sorry to say that my concerns were justified.  I’m seeing kids in high school with needle marks, and hearing about more and more deaths– the increase because of the less-predictable potency of a bag of H compared to a pharmaceutical tablet of OC.

For people interested in the history of this resurgent killer, this book describes the history and pharmaceutical properties of heroin.  And since it comes from Hazelden, it does not glamorize the drug:

Heroin – $ 12.76

Retail Price: 15.95

You Save: $3.19

I work with people who are on buprenorphine maintenance, who like everyone will sometimes feel ‘stuck.’  Addicts who use ‘the steps’ have a ready-made program of self-discovery right in front of them, but people on buprenorphine do not have the desperation that is often required to motivate a suffering addict to give him/herself to the steps.  So instead, I often talk about mindfulness.  I have read a number of  books about mindfulness over the years; one of my favorites is ‘Wherever you go, there you are’ by Kabat-Zin.  Here is another, more current book about mindfulness that I recommend:

Awakening to Mindfulness – $ 11.96

Retail Price: 14.95

You Save: $2.99

Another issue for people on buprenorphine is the shame that they feel, left over from the days of lying and using.  Again, AA and NA have steps dedicated to processing this shame;  steps that people on maintenance buprenorphine would benefit from.  Shame is a particular issue in people who have to deal with loved ones who don’t ‘get it’ about buprenorphine;  who contribute to a feeling of guilt for what happened in the past– and even for their current means of treatment.  I try, during sessions with patients, to address the shame that they are feeling– and to help them realize that they have a disease that they do not deserve, and that they have no reason to feel shame over.  The following book is a classic for dealing with shame;  I read it myself years ago, as I was trying to put my own shame to rest, and I recommend it for any recovering addict who suffers from that heavy feeling that they did something wrong, and that they will never forgive themselves.  Get the book, forgive yourself, and move on.

Healing the Shame that Binds You – $ 11.96
Retail Price: 14.95
You Save: $2.99

By the way– I notice that my page is often covered with ads for Withdrawal-Ease (not sure if I am spelling that correctly).  I know nothing about the product; it is just coming up from the keywords on my site, assigned by Google adwords.  I do not endorse the product.  If you have tried it, you are welcome to comment about the product in response to this post– and I will leave your comment, whether it is good or bad.  I receive NOTHING if you purchase the product.

Every now and then I receive an e-mail  or comment that is sufficiently long to warrant a post of it’s own.  Below is the comment without interruption;  a bit lower I repeat parts of the comment, interspersed with my own responses.  I hope you find it interesting.

The comment:

I am a strange case: vegetarian, healthy, Pilates instructor, good-looking– NEVER A DRUG ADDICT — but i had a secret-  I was badly depressed for years- treatment resistant to over 30 meds, only some helped to a point… I did extensive research into the brain and opiate systems and i wondered if it was possible my endorphin system may be the culprit ( check this primer: http://www.prohibitionkills.blogspot.com/)

 I was desperate enough to try out opiates as a final solution ( and I monitored myself- I have brakes yet I was always scared of tolerance– and forever afraid to keep on that track) then i found my holy grail… i learned about Suboxone’s other use-  ( and it is now being studied for depression)

I was forced to lie to get on Suboxone, i pretended i was an Oxycontin addict etc.. i know that is wrong, but i was trying to save my life ( i was already at the point of suicide attempts)…not only did i get better, i brought my  mother in who was also treatment resistant and she was made better also within a week when even ECT failed her and messed up her brain for a good year…..she still takes what i took- 1mg in morning, 1mg in afternoon ( we both sensed that was when we needed a second dose not uncommon believe it or not for other depression sufferers that noticed a drop in the afternoon that Suboxone was again needed)

Anyway she is doing great on it to this day…saved her.

Me after intense meditation for one month- seriously no joke – i sensed i was ready to go off it.

 i do everything the hard way- so i went cold turkey off my 2mg a day after being on it for 5 years.

lucky for me- no depression- although the withdrawal did a real number on me– i was so sick from flu and withdrawal , horrible coughing, sore throat, dizzy and weak i wound up at the ER – thought i had H1N1. lol !  I was bed-ridden for almost 2 weeks; i ate nothing for a whole week but soups.

it was NO walk in the park, i was so weak i could not brush the tangles from my hair, even talk much to anyone. and the sweats were out of this world.

i am now at one month and 2 weeks.  i still feel  kind of weak and sickly, swollen glands, and sometimes a sore throat a little, my face is pale and i have huge dark circles under my eyes… the sweats have almost stopped….but my pupils still dilate… when i exercise i tend to feel worse not better — why is that?  

but my real question is this:  why does it make me look so pale and dark circles- ??? is it the interrupted sleep?? or low blood pressure or vitamin deficiencies?? Anemia – i take lots of vitamins and 3 iron pills a night (always did as a vegetarian).   i only wake up once or twice a night and i take a quarter of sleeping pill – unfortunately- every night still- otherwise i will be up forever..

And is there any nutritional things i can do to make me look less ghastly??  i look like a heroin addict and feel like people will see me that way as i can’t keep saying i have a flu forever !! ! What puts color back in the face ??

* before u lecture me about my terrible lie to the Suboxone doctor ( i think he knows anyway as he had to fudge my notes to make me a worse addict than  i claimed)  but u know what?? When i was in ER , and could hardly walk straight from my flu + withdrawal–i told the doctor while i felt like i was dying – that even then…  i was so happy i took Suboxone – it cured me and my mom FROM A LIFETIME of DEPRESSION. 

there IS NO withdrawal that is worth depression, let alone years of it, so please don’t lecture me on what i did, i saved 2 peoples’ lives by lying and i would do it again in a heartbeat…( in fact i was so angry when i found they have a cure for treatment resistant depression i tried in vain to contact media sources to publish a story on it- but who would touch that??)

edie

Wow.  I am exhausted.  I’m not sure why- but some comments take so much energy to get through—and this was one of those comments.  Is it just me? 

First things first: Never hesitate to call drug addiction hotlines for help in drug emergency cases.

Some of my answers will likely come across as harsh, and for that I apologize in advance.  I don’t wish Edie any bad will, but my comments will probably show that I think she has gotten a bit carried away with some of her ideas.  Besides, some of the readers LIKE it when I get obnoxious.  Admit it!

My responses—for those of you who still have some energy left:

I am a strange case: vegetarian, healthy, Pilates instructor, good-looking– NEVER A DRUG ADDICT — but i had a secret-  I was badly depressed for years- treatment resistant to over 30 meds, only some helped to a point… I did extensive research into the brain and opiate systems and i wondered if it was possible my endorphin system may be the culprit (check this primer: http://www.prohibitionkills.blogspot.com/)

Most of my friends are drug addicts.  Most are not good-looking.  They all eat meat—lots of it—and laugh at people in Pilates classes.  And they AREN’T depressed.  I’m not drawing any conclusions—just pointing out an inverse correlation with an ‘n’ of about 6.  I’m also suspicious of the ’30 meds’ comment;  it would take a lifetime to give 30 meds adequate trials, even if there were 30 different meds for depression.  But I exaggerate too, so no big deal.

The primer is interesting, mainly for the collection of links to articles about the effects of opioids on mood and depression.  Edie describes doing ‘extensive research into the brain and opiate systems.’  I don’t know exactly what she did, but the long treatise at the url above is in no way scholarly, but rather is a collection of scattered, mostly-minor studies and comments with many, many incorrect statements, all intended to make the reader believe that there is a unique type of depression caused by deficiencies in the body’s endorphins.  I hardly know where to start—but the article, for example, claims that Effexor (venlafaxine) is a good antidepressant in part because of its similarity to the actions of tramadol— and that implies that venlafaxine effects the endogenous opioid system.  This is all nonsense.  Venlafaxine is an SNRI.  Tramadol has effects on norepinephrine reuptake as well.  But tramadol has entirely SEPARATE effects on the mu receptor that are NOT shared by venlafaxine.

The comments about acupuncture… there are a host of studies that show a failure of opioid antagonists to block the analgesia produce by acupuncture—evidence for an effect that does NOT involve endogenous opioids (which are blocked by naltrexone).

I honestly could go on and on and on… we know the mechanism of capsaicin on the release of substance P;  the effects are a very long shot from thinking that using (or eating!) capsaicin will somehow increase a person’s endorphins.  The writer describes a type of patient—a combination of cluster B traits from the DSM, along with assorted personality traits like ‘crying easily.’  Evidently somebody wrote a book.  Understand that the current distinctions between mood disorders, while not perfect, are based on hundreds of studies and years of input from psychiatry thought leaders—who then have their opinions examined and tossed around by more thought leaders.  Comparing the list of symptoms for ‘endorphin deficiency syndrome’ in the article with the longstanding and scientifically-validated diagnoses from the DSM is like someone writing a poem off the top of his head and saying it belongs in the Bible.

The problem is that there is such a thing as REAL science.  I actually DID study neurochemistry and neuroscience during my work for my PhD, and despite that four years of intensive labwork, lectures with distinguished scientists, searching through literature to write and defend my 150-page thesis—despite ALL of that and then my medical school training—I learned about a tiny, tiny bit of how the brain works.  The actions of receptors, neurotransmitters, and their relationships to mood and other subjective states encompasses a vast amount of knowledge, much of which contradicts itself from one study to the next.  One cannot extract a few studies out of ten thousand and use them to draw conclusions.  I’m searching for an analogy… it is like measuring the temperature during one minute from one hour of one day, in a town in Southern Wisconsin, and saying that you therefore understand the climate of the US—and that the US is a rainy and cold place.  You would be ignoring all of the other towns, times, and temperatures—and thinking that your point about the US was still valid.

I’m never going to finish this…

I learned about Suboxone’s other use-  ( and it is now being studied for depression)

I do recommend that people periodically check www.clinicaltrials.gov to see the interesting studies involving buprenorphine.  I would expect other partial agonists to appear on the scene in due course.

I was forced to lie to get on Suboxone, i pretended i was an Oxycontin addict etc.. i know that is wrong, but i was trying to save my life

I’m sorry to interrupt, but this sure sounds like something an addict would say, doesn’t it?  Nobody can be ‘forced to lie;’  we CHOOSE to lie because we like what the lie does for us.  Maybe it was justified… but ‘forced’?  C’mon.

i am now at one month and 2 weeks.  i still feel  kind of weak and sickly, swollen glands, and sometimes a sore throat a little, my face is pale and i have huge dark circles under my eyes… the sweats have almost stopped….but my pupils still dilate

So much for being good looking!  Sorry—just another bitter, bad-looking bald guy…

why does it make me look so pale and dark circles- ??? is it the interrupted sleep?? or low blood pressure or vitamin deficiencies?? Anemia – i take lots of vitamins and 3 iron pills a night (always did as a vegetarian).  

Shoot—I was just going to suggest a good T-Bone, medium rare.  But seriously, the dark circles can be caused by tiny hemorrhages around capillaries, which tend to be very fragile under the eyes… and the pallor of the skin from vasoconstriction in that part of the body—which is part of opioid withdrawal, along with the ‘goose flesh’ that is so common. 

And is there any nutritional things i can do to make me look less ghastly??  i look like a heroin addict and feel like people will see me that way

There you go again, dissing addicts!  I’m sorry, but heroin addict don’t all look the same, and they don’t  all look ‘ghastly.’  I have patients in my practice who were opioid addicts—some oxycodone, some heroin, most whichever was around— who look like the other people they work with on the job as teachers, carpenters, attorneys, nurses, and CEOs.   And no—the thing that will make you look and feel better is TIME.

* before u lecture me about my terrible lie to the Suboxone doctor

Oops—did that already!

please don’t lecture me on what i did, i saved 2 peoples’ lives by lying and i would do it again in a heartbeat…( in fact i was so angry when i found they have a cure for treatment resistant depression….

I NEVER lecture people, but I don’t know if you would get the Nobel prize in Medicine for what you did—although didn’t Al Gore get it for something already anyway?

I’ll stop here.   There is no conspiracy, and buprenorphine is not a ‘cure’ for treatment resistant depression.  Yes, it does seem to improve mood for SOME people.  But there are big downsides—for example the state that you currently are in.  You may be positive that you are not an addict, but I’m not;  your lie to get yourself on buprenorphine for a while MAY have placed something in you that you cannot yet see, that you will regret some day.  If, in five years, you are free of depression and also free of opioids, then it appears that at least in YOUR case, the experiment worked.  But frankly, the odds are against you.  You will tell me all of the reasons why you are different, and special, and why you will never use again…. But I suspect that if the depression returns, you will have a hard time avoiding another lie for another trial of opioids.  If you can’t get buprenorphine but instead buy opioids on the street, you are looking pretty similar to every other opioid addict—ghastly or not.

I have written about this topic before, and included links to some of the things linked on the url that Edie provided.  My bottom line?  If a person has a history of depression and is an opioid addict, there is one more reason to stay on buprenorphine long-term.  But I would have to think very long before conditioning a person to crave opioids—which is essentially what Edie has done.  As my treatment-roommate said (about regretting making porno movies with his wife while using), ‘there are some things that we learn, that we cannot unlearn.’    The warm, fuzzy feeling provided by opioids is one of those unlearnable things, and the lesson comes at a steep price—especially in a person who is prone to episodes of depression that only respond to opioids!

I hope I wasn’t too rough, Edie—I do wish you the best.

I’m not sure about the make-up of readers of this blog.  I know that there are about 20,000 page views each month, but I don’t know how many are by people addicted to opioids, people taking buprenorphine, family members of addicts, or physicians who prescribe buprenorphine.  If you fall into that latter category– i.e. if you prescribe buprenorphine, or if you prescribe other medications to treat opioid dependence such as Vivitrol or methadone– consider joining the group at linkedin.com called ‘Buprenorphine and other medication-assisted treatment of opiate dependence.’  If you already belong to LinkedIn, you can simply follow this link to join: http://www.linkedin.com/groupRegistration?gid=2710529

I have always resisted separating those who prescribe buprenorphine from those who are prescribed the medication.  I have avoided, for example, placing a ‘doctors’ section’ at SuboxForum, as I don’t want there to be two separate discussions.  Clearly, each group would benefit from the wisdom of the other.  But there are some physicians who want to discuss prescribing habits, techniques, and science with other docs, who are not comfortable discussing some topics in the ‘presence’ of their patients.

Non-docs, please don’t flame me for this decision;  I’ve wrestled with it, and have made this decision, at least for now.   Frankly, the discussions at SuboxForum are far more interesting than anything that has come up so far at the linked in site!    But some docs who prescribe buprenorphine are isolated out there, perhaps even looked down on by their peers for working with addiction– and that is a crying shame.    I want to get those docs some support.  My goal ultimately is to bring the two sides together, so that docs can talk to addicts and realize that they are the same species as the rest of their patients!

Thanks all,

JJ

It i salways humorous when companies do what Reckitt-Benckiser recently did– make a small change in their product, then trash the old product in favor of the new, more expensive product.  “The OLD formulation is GARBAGE!  It poses huge risks! It is reckless and irresponsible to prescribe that tablet (the one that we’ve been marketing for years, that is…)”

The orange rectangle is buprenorphine film

For people who are confused, here is what happened…. Reckitt-Benckiser, the makers of Suboxone and Subutex, used to have a stranglehold on the market for buprenorphine.  Profits poured in from selling buprenorphine at ridiculous prices;  $6 per tablet in the Midwest for Suboxone, and over $11 per tablet for Subutex.  The prices were particularly obnoxious given that the company didn’t invent buprenorphine– in fact, buprenorphine has been around for 30 years, and could be purchased cheaply in bulk quantities.  All that RB did was come up with a sublingual formulation, and from that point forward they were essentially printing money.  Suddenly a cleaning product company is raking in the big bucks!

Of course at some point, patents expire.  Companies often sue to stretch out patents– and profits– as far as possible, but at some point the party comes to an end, and such is now the case with Reckitt-Benckiser and Suboxone.   The generic version of Subutex costs as little as $2.80 in my area;  RB has been stemming the bleeding from that generic by warning doctors that patients will dissolve and inject buprenorphine if naloxone is not mixed in– something that is exceedingly rare, given the long half-life of the medication, the aversion that most addicts have for needles, and the fact that most diversion of buprenorphine is by people seeking a way to stop using– not by people looking for a ‘buzz.’  But more recently Teva, a large manufacturer of branded and generic medications, received approval for their version of sublingual buprenorphine.  I have not seen it in pharmacies in the Midwest, at least not yet, but it will be more difficult for RB to deal with this form of buprenorphine– which will essentially be the same as branded Suboxone, only cheaper.

Some states, including Wisconsin, REQUIRE pharmacists to substitute less-expensive generics unless specifically blocked by the prescriber.  Insurers, both private and government, also require use of generics in the absence of a compelling reason to use the branded product.  That means that to get brand Suboxone, doctors will have to fill out paperwork explaining their reason for requesting the brand.  Doctors, of course, hate paperwork, and so I anticipate a huge shift to the generic product once it appears in pharmacies.

RB, then, is in a pickle.  So some marketing guy gets the idea to put buprenorphine in a listerine-style breath strip, sell it indiviually packaged, and tell everyone that individual tablets of Suboxone are a huge risk to the public.  They tell us that little kids put them in their mouths, that the packaging isn’t safe enough, or that the tablets absorb moisture, making their sublingual dissolution rate unpredictable.  Better use the strips intead, they say.

I tried one of the strips– one that was a ‘dummy strip’ that did not contain buprenorphine.  The instructions are to put it under your tongue, but as I have written here many times, there is nothing special about the under-the-tongue space, and they can be put on top of the tongue if that is easier;  the point is to get the molecule in contact with the mucous membranes that line the mouth.  I like the idea of the strip in theory;  the absorption of buprenorphine is driven by the concentration gradient of the molecule, and the film helps deliver a highly concentrated dose of buprenorphine to the surface of the oral mucosa.  The film could also conceivably be cut into small pieces using an exacto knife, to help with tapering the drug.  But in practice, the film was unpleasant to use.  It was thicker than I expected, sort of like a cross between a Listerine strip and a gummy worm.  It took longer to dissolve than I expected, and the taste was nasty.

So what is the conclusion?  Is the strip a leap forward in safety and convenience?  Or is it just an attempt to hang onto a brand?  I suppose that answer depends on how you see the world, and how you see a cleaning products company from the UK that struck it big on the backs of US opioid addicts.

One of my patients sent me a link to a Kentucky newspaper article that described the recent surge in cases of opioid dependence and treatment with buprenorphine. The article described the increased costs for medicaid programs because of the need to pay for buprenorphine. The reporter said that the problem was that people are being placed on buprenorphine and only ‘maintained,’ instead of receiving ‘definitive treatment’ to fix the problem.

The reporter’s perspective and conclusions are not unusual, but they are, to put it bluntly, a crock– for a couple reasons. The first problem with the story is the reporter’s bias, caused by stigma. I left a comment after the article asking why the reporter wrote about rising costs for buprenorphine, instead of an article about the rising costs for medications for ALL of the many new diagnoses and conditions treated these days? To name a few, we have new medications for bipolar disorder, for elevated cholesterol, for coronary disease, for impotence and ‘low T,’ for diabetes, and for asthma– and all of those medications have resulted in higher costs as well. Why single out buprenorphine?

In fact, opioid dependence has become the second leading cause of death for young adults in many parts of the country, and if you look at the cost of buprenorphine over a denominator consisting of the number of lives saved by the medication, buprenorphine becomes a real bargain! Medications for other fatal diseases, for example chemotherapy for breast cancer, are much more costly than the $5 per day cost for treating opioid dependence. We also spend hundreds of thousands of dollars for EACH victim of a serious motor vehicle accident, and similar amounts for every transplant recipient– even when most transplants eventually fail, just as many addicts eventually relapse. Why is only ONE chronic illness– one with a relatively inexpensive cost per life saved– singled out? Are some lives less valuable than others?

What about the suggestion that buprenorphine is only a band-aid, and avoids ‘definitive treatment?’ I have written about this situation many times, and (thankfully) more and more data lends support to my position. I have struggled with my own opioid dependence for 18 years, and over that period of time have come to know a great many addicts; people who were colleagues, friends, patients, and acquaintenances. I have worked in residential treatment settings, and have referred patients to treatment programs ranging from one month to over a year in length, costing from $4,000 to $70,000 per month. The simple, shocking truth is that for opioid dependence, residential treatment RARELY WORKS. The issue of ‘addiction treatment’ is an incredible, sad, shameful ruse that has been spoon-fed to the lay-public, and even to medical and AODA treatment professionals. On TV, Dr. Drew does his thing with addicts– and yet nobody ever seems to question why his patients KEEP ON USING! We read that Lindsay Lohan just failed another drug test, and people assume she is pathologically stupid– when the truth is that she is only like so many others. She probably has an ignorant doc, pushing her off buprenorphine and blaming her when her ‘treatment program’ failed…. when in reality her DOCTORS failed, and her COUNSELORS failed, by not reading the literature and saying ‘duh– this residential stuff never works!!’ At the residential treatment center where I worked for the past few years, the counselors get excited when the patients look all shiny and clean after six weeks in the program… but completely ignore the fact that almost all of those same patients are using by the end of the next year. And what REALLY angers me is that many of the patients who the counselors consider ’cured’ end up dead from their addictions… and instead of looking at themselves in the mirror with shame, they blame the ADDICTS for not following the program. That would be fine if a small percentage failed treatment. But when EVERYONE fails, it is the TREATMENT that deserves criticism, NOT the PATIENT.

Sorry for shouting.

Over 600 people taking buprenorphine were followed in a recent study that you can read about here. The study showed more of the same– that patients taken off buprenorphine universally relapse. But the study showed something that I found interesting, but not all that surprising. You see, everyone always loves to say that buprenorphine is fine, but ‘only if there is counseling too.’ I always get a kick out of how many people think ‘counseling’ is a good idea– as long as it is for someone else! This study of people on buprenorphine compared a control group that had a quick med check each week during the study period, with a ‘counseling group’ that had two one-hour sessions per week throughout the period, talking about interpersonal issues, personality problems, trauma and stress in the patients’ lives, and other feel-good issues. Guess what? There was NO DIFFERENCE in relapse rates between the control group and the addicts that received intensive counseling. None. Nada. Zero.

I have stated many times that opioid dependence deserves treatment as a MEDICAL ILLNESS, a chronic illness, a potentially fatal illness that finally has a chronic and effective treatment available. But now that this life-saving treatmennt is finally here, the insurers have the gall to limit access to treatment for only a year?! The newspapers have the gall to whine about the cost of a day’s medication– all of five bucks?!! And AODA counselors and some misinformed doctors have the gall to mislead patients by talking down the medication that will help people, even while knowing that their own meal-ticket/treatment programs are ineffective?!!

It even appears that the docs who ‘get it’ about buprenorphine are not doing what good medical science usually does– which is to keep an open mind about treatments and follow the data, not ‘PC’ assumptions. One assumption has been that addicts are so ‘faulty’ inside that they cannot be treated without ‘counseling;’ that surely they all need counseling to truly get better. Where is that assumption when it comes to treating other illnesses? And now that we have evidence that counseling was of no value in the latest study, will minds be open to change?

One of the study’s authors summed it up like this:  

“Does putting people on a short period of buprenorphine maintenance combined with counseling lead to reductions in relapse? It’s a great idea, and a wonderful hypothesis, because if it does work then this would be a huge win. We would not have to use extended maintenance. Unfortunately, it did not work, but the study needed to be done.”

I have written about this topic multiple times, but perhaps a summary is appropriate.  More and more evidence and clinical experience suggest that buprenorphine is best considered a long-term ‘remission agent’ for opioid dependence.  Such a conclusion would have been obvious years ago if not for the hesitancy to do what has been suggested by addictionologists for decades, and treat opioid dependence as a DISEASE.  While many people pay lip service to addiction being a chronic illness, the reluctance, particularly by AODA counselors, to fully accept a medication for the condition is clear evidence of the stigma that continues to force addiction into the realm of ‘character.’   AODA counselors would do well to do some serious soul-searching on this issue– at least in my opinion.

While remission therapy with buprenorphine will likely become the standard treatment for opioid dependence, there will be some cases where tapering off buprenorphine is appropriate.  The problem in such cases is that the taper process causes withdrawal, which stirs up all of the self-disgust, fear, and shame that predispose an addict toward relapse.  As I have discussed, a long-term injectable formulation (such as Probuphine, currently in the FDA approval process) would be useful for tapering off buprenorphine.  The final piece of the equation would be effective treatments for opioid withdrawal. 

A number of medications are rumored to help reduce the symptoms of opioid withdrawal.  I’ll mention a few of the medications that I have used to treat withdrawal, or that I have read about in scientific studies or case reports.

- Clonidine is the ‘standby’ agent for treating opioid withdrawal.  The medication reduces CNS excitation by effects at alpha-2 adrenergic receptors, causing less release of epinephrine and norepinephrine by central and peripheral nerve terminals.  Symptoms of withdrawal are reduced by about a third, and the primary side effect is sedation.

- Some medications target specific components of withdrawal;  Imodium (generic name loperamide) reduces bowel cramping and diarrhea; benzodiazepines reduce anxiety (but are themselves addictive); ibuprofen and acetaminophen reduce muscle aches and headache; stimulants or wellbutrin reduce fatigue (perhaps for severe symptoms, but use of stimulants would be considered controversial at best).

- Proglumide is an antagonist of two classes of receptors for a gastro-intestinal hormone called ‘cholecystokinin’, or CCK.  Proglumide used to be used in the US and elsewhere to treat gastric ulcers, before more effective medications like histamine blockers were developed (e.g. cimetadine).  There are a number of chemicals structurally related to proglumide that have similar actions, that include enhancing analgesia caused by opioids, treating Parkinsons disease, and enhancing the release of growth hormone.  Proglumide appears to ‘reset’ tolerance to opioids in people who are physically dependent, and also to reduce symptoms of withdrawal.  Proglumide appears to have dropped of the face of the planet;  if you search for the medication you will find it available in chemical supply houses in China, but not available through pharmaceutical companies.  I recently received contact from a person claiming that  proglumide is available through a company based in Pakistan, but I have not yet verified the information.  Stay tuned.

- I recently came across an article with some fairly convincing evidence that symptoms of withdrawal are reduced by the anti-anxiety medication buspirone.  A study found that self-reported withdrawal symptoms of opioid addicts were greatly reduced by treatment with buspirone, which is a pretty safe, inexpensive medication that is not itself addictive.

- Ondantreson is an anti-nausea medication used during chemotherapy and surgery.  I have seen several studies demonstrating a reduction in opioid withdrawal from the medication, which like buspirone is fairly safe and is not addictive.  Ondantreson is, however, more costly.

I have treated patients in withdrawal using gabapentin, specifically to reduce sweating and hot flashes.  I do not know if it works, or if the people who liked it were getting a placebo response.  I have not seen reports in the literature showing this benefit.

- I have mentioned the recent approval of transdermal buprenorphine, called ‘BuTrans.’  This formulation provides a lower range of doses of buprenorphine, in the tens to hundreds of micrograms (one tablet of Suboxone contains 8000 micrograms of buprenorphine).  This lower dosed formulation may find usage for tapering.

Do you have other suggestions for treating opioid withdrawal?  If so, please share them in the comments below or over at SuboxForum.  Of course, these medications must NOT be taken ‘on the street,’ but rather should be discussed with your physician if and when the time comes to taper off buprenorphine.

Thanks all,

JJ