Wasting Resources on Suboxone

Readers of this blog know that I have often questioned whether there is any clinical difference between Suboxone and generic buprenorphine.  Naloxone is an opioid-blocking chemical added to buprenorphine, supposedly in order to reduce intravenous diversion of the medication.  The combination of buprenorphine plus naloxone is branded as Suboxone. I’ve pointed out over the years […]

Does Suboxone Cause SIDS?

In a recent Google search about Suboxone and pregnancy, one of the top links included the frightening statement that Suboxone and buprenorphine have been linked to SIDS or sudden infant death syndrome, commonly called ‘crib death.’ The statement was from a health forum where a woman wrote about taking Suboxone during pregnancy.  She wrote that her […]

Suboxone and Tooth Decay

I have received a several emails over the past few years from people who experienced deteriorating dental health while taking buprenorphine or Suboxone.  I also have patients in my practice who have had extensive dental work, and wonder if Suboxone is to blame for their cavities or other problems.

I wrote about this issue several years ago.  At that time I wrote that there was no evidence that sublingual buprenorphine or Suboxone cause or accelerate tooth decay.  After writing the article I received a number of angry emails from people who insisted that I was wrong.

Let’s step back for a moment to highlight the difference between thinking something vs. proving something.  Some people misunderstood my comments about tooth decay and Suboxone, thinking that I was arguing that Suboxone does not harm teeth.  That was not what I wrote.  My point was that as of that time, there was no evidence that Suboxone or buprenorphine caused tooth decay.  When I write about the science of buprenorphine, I try my best to distinguish between what I think is true vs. what was established through scientific study.

I recently met with a patient who has had extensive dental work over the past few years, the same time that she was taking sublingual buprenorphine.  She asked if I thought that the two were related.   I made a few comments (that I’ll be getting to), but also promised her that I would do a literature search, to see whether any connection has since been established.  Ironically, a case report of a woman on Suboxone who required extensive dental work was just published yesterday.  The case report is in the latest issue of The American Journal on Addictions, and the same case is cited in the October 20, 2012 edition of Reactions Weekly.  This latter citation is a newsletter that follows multiple sources for any report of adverse drug reactions, described in more detail here.

The world of science is not efficient.  Knowledge moves forward slowly, based on findings amassed from many studies, often repeated multiple times.  Case reports are not intended to prove something.  In fact, case reports are often unusual clinical examples that defy the norm.  They are often published to point out an area that deserves more study.

I cannot copy the case report here because of copyright laws.  But the case described a 35-y-o woman who used oxycodone for about a year at doses up to 160 mg per day, and then went on buprenorphine/naloxone.  After 18 months, her dentist told her that she had extensive decay of 4 molars requiring root canal.  She reportedly had minimal history of dental problems before starting opioids or buprenorphine.

The author of the case report hypothesized that if there is a connection between Suboxone and tooth decay, one reason could be xerostomia, i.e. dry mouth, caused by buprenorphine.  The lack of saliva was my thought, too, as a mediator of any possible effects of buprenorphine on teeth.  Saliva serves an important role in dental health, including rinsing away food particles and acting as a buffer.  The patient in the case report did not report a dry mouth, so the author pointed out that all opioids have some ability to suppress the immune response, and perhaps buprenorphine and/or naloxone reduce the immune response, allowing for greater destruction of teeth by bacteria.

The case report, surprisingly, did not say which buprenorphine product(s) the patient had used, e.g. tablets, film, or generic buprenorphine.

What needs to happen next is for someone to do a case-control study of patients on buprenorphine, to see if they are more or less likely to have tooth decay.  The most valuable study is usually a prospective, randomized clinical trial;  that would not be proper here, since it would not be appropriate to randomize subjects to buprenorphine vs. no buprenorphine.  But a close second would be a case controlled study, where patients on buprenorphine are matched to ‘controls’ with similar characteristics— age, sex, eating habits, income level, education, etc.– and the dental outcomes are followed forward over a number of years.  A less-costly, less-reliable study is one that looks backward, comparing patients on buprenorphine with those not on buprenorphine to see which group has a higher incidence of dental caries.

We are not much better off at this point in our knowledge of whether Suboxone or buprenorphine predispose toward tooth decay.  The case report only mirrors what I see in my practice.  But as I often tell patients, I have other patients who are not on buprenorphine or Suboxone, who have tooth problems.  I also have patients on Suboxone with great teeth.  Hopefully some ambitious PhD candidate will sort through the issue soon.

$uboxone Clinically Identical to Buprenorphine??

As I give my last post more thought….  I wonder if there is ANY clinical difference between $uboxone at $7 per dose, vs. generic buprenorphine at $2.33 per dose?  Researchers out there– can anyone send me a reference?

Read my last post for details– but the essence is that naloxone is destroyed when Suboxone is taken properly (orally, sublingually), and has no action whatsoever– on that issue there is scientifc agreement (although there is a great deal of ignorance among prescribers about this fact).  The ONLY think naloxone does, is to supposedly serve as a deterrent to IV injection of buprenorphine.

Sounds good, but…  we know that people divert Suboxone intravenously, naloxone and all.  Buprenorphine binds opioid receptors very tightly- so tightly that the naloxone doesn’t effectively compete with buprenorphine.

The State of WI requires Medicaid patients to take expensive Suboxone Film, whereas in other cases they require prescribing the generic.  What is the argument for requiring the film?  RB would argue (now that the tablet has lost the luster of being on-patent) that the film is harder to ‘divert’– i.e. to inject.  But frankly, the intravenous diversion of buprenorphine is a tiny issue compared to things like heroin addiction and a budget crisis.  Most of the diversion of buprenorphine, either Suboxone or generic, is not injected, but rather taken orally to ward off withdrawal– and the film makes no difference in that case.

Insurers, likewise, are wasting millions of dollars (literally) by paying for Suboxone— sometimes exclusively(!)  Have the bean counters fallen asleep on this issue?

I have nothing personal against Reckitt-Benckiser, beyond the fact that they refuse to engage in conversation with me.  If the good Brits at RB have discovered a way to suck millions of dollars from the weakest members of society, more power to them.  But I am a big fan of intellectual honesty, particularly in regard to the science behind medical practice.  So if someone has evidence that $uboxone is clinically different than generic buprenorphine, whether used properly or injected, please send it my way.

The Suboxone Business Fix

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

Suboxone Doctors act dumb with buprenorphine
Dumb about naloxone?

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

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

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

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

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

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

 A few examples of intellectual laziness: 

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

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

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

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

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

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

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

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

 

 

Buprenorphine for Treatment of Cocaine Dependence

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.”

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

I just wrote a note to a friend who works in the molecular sciences– she has been studying opioid receptors since the early 1980′s, when things were just getting started on a molecular level.  I’m keeping her name to myself, but I’ll share a few thoughts about what is needed to advance the treatement of opioid dependence– and make a few million dollars along the way (are you listening, RB?)

Hi ——,

(private chit chat that would bore everyone)

Anyway, today I realized what is needed in order to take partial agonist treatment of opioid dependence to the next level.

The problem with buprenorphine is that the ‘ceiling effect’ occurs at a relatively high tolerance level, approximately equal to 40 mg of methadone.  That causes at least two problems.  First, going off Suboxone is a lot of work, as the person still has a great deal of withdrawal to go through.  That may be a good thing early in the process, as it may help keep people on Suboxone, but after a year or so, when people want to try going off the medication, it is a major barrier that opens the floodgates to those old memories of using, etched in the emotions associated with withdrawal.

The second problem with the high ceiling/tolerance level is that surgery is a hassle.  People needing surgery need HIGH amounts of oxycodone to get any analgesia—I usually give 15-30 mg every 4 hours.  Pharmacists shudder to release those doses, and some surgeons and anesthesiologists balk.

The horizontal part of the dose/response curve is the essential part of buprenorphine;  that is what tricks the brain into ‘thinking’ that nothing is wearing off, and in that way eliminating cravings.  But that flat dose/response relationship could occur at lower tolerance levels and still work the same way.

Since I’m wishing for the moon, a series of molecules with progressively lower ceiling levels would be ideal, with the last molecule in the series being Naltrexone.  Although actually, naltrexone doesn’t work—it has NO mu agonism, so there is no tricking of the brain, and no reduction of cravings.  We would want something close to naltrexone, but with a tiny bit of opioid activity that does not vary with dose.

A shorter half-life would also be helpful.  Preparing for surgery requires weeks to get the buprenorphine out of the system.  Of course a shorter half-life means it is easier to get around buprenorphine by people who want to play with agonists, so again, these new molecules would be intended as ‘step down’ meds from early-stage buprenorphine treatment.

Do we know enough about molecular actions at the mu receptor to design molecules with these properties?  Or are we still at the point of making somewhat random changes and assaying the result?  Do you know of any labs doing this type of work?

I figured you’re the person to ask!

Thanks ——–

Jeff

Long-term opioid analgesia without tolerance, respiratory depression, or euphoria

I have been kicking these observations around for the past year, and have been unable to find a big fish willing to ‘bite’.  I truly believe that the observations below have the potential to dramatically change the approach to opioid treatment of chronic pain.  Since I have a blog, I have a soapbox– so I’ll share the idea, and welcome comments in return.  I do ask that proper attribution be provided if this article is shared.

Introduction:

Long-term opioid analgesia without tolerance, respiratory depression, or euphoria?  Introducing the Holy Grail for chronic pain treatment!

Premise:

The miracle of opioid pain relief is fatally limited by tolerance, addiction and respiratory depression.  Buprenorphine, when combined with a mu agonist, results in game-changing effects.  Patients experience potent, dose-related analgesia from the agonist, but have NO euphoria.  The therapeutic window is widened.  Patients unable to control their use of a mu agonist alone gain that control when on buprenorphine. And most exciting, buprenorphine indefinitely anchors tolerance, maintaining analgesia WITHOUT DOSE ESCALATION. This finding offers huge implications for pain management.

Discussion:

Use of opioids for chronic pain has severe limitations.  Tolerance removes the benefits of opioid analgesics over time.  Worse, tolerance is associated with dependence and withdrawal.  Many patients use additional doses of their prescription early in the month, then suffer through withdrawal while awaiting refills.  Others find opioids through less-reliable, non-clinical sources.

At the same time, addiction to mu opioids is a nationwide epidemic.  Reformulation Oxycontin has pushed many opioid users toward diacetylmorphine—brand name Heroin.  Some physicians recommend avoiding mu opioids altogether for chronic pain (e.g. Physicians for Responsible Opioid Prescribing), while pain treatment advocates argue to ease narcotic restrictions.

Over the past six years I have treated over 500 patients using buprenorphine, mostly for opioid dependence.  Buprenorphine, a partial mu agonist, is the active ingredient in Suboxone, a medication used for treating opioid dependence. The majority of my patients began their addictions with narcotics prescribed by doctors for back pain, knee pain, shoulder pain, fibromyalgia, chronic headaches, and other conditions.

Many of my patients found their pain reduced or gone after stopping mu agonists and substituting buprenorphine.  Buprenorphine has the mu activity of 40 mg of daily methadone, but this activity is unlikely responsible for significant analgesia, since patients rapidly become tolerant to the agonist actions of buprenorphine. Instead, their pain while on mu agonists was likely maintained by psychological forces.

Patients on buprenorphine occasionally need opioid analgesia, just like other patients.  My patients have had knees replaced, gallbladders removed, hysterectomies and c-sections, rotator cuff repairs, and in two cases, cardiac surgery.  In all cases, sufficient analgesia was provided by maintaining daily buprenorphine at 4-8 mg per day, and using potent mu agonists, usually oxycodone, in doses ranging from 15-45 mg every 4-6 hours as needed.

Several patients have severe chronic pain from avulsion of the brachial plexus, failed spinal fusion, or other conditions, where prior opioid use resulted in rapid tolerance that prevented effective analgesia. These patients are now successfully maintained on combinations of buprenorphine plus mu agonists.

The combination of buprenorphine plus mu agonists has provided perioperative analgesia for patients on buprenorphine.  Patients universally describe adequate pain relief, even after major surgeries.  They also described the absence of euphoria, and to their surprise, the ability to control their use of pain medication—something impossible before taking buprenorphine.

But it is the effects on chronic pain that suggest a ‘game-changer’ for pain treatment.  Even after over a year on combination buprenorphine/oxycodone, my patients 1. have no euphoria;  2. are often able to manage their own narcotic medication; and most important, 3. describe stable analgesia WITHOUT agonist dose escalation.

The ability to treat pain long-term without tolerance or dose-escalation is as exciting a development as was the initial discovery of opioids for pain relief!

Properties of a combination agent

Buprenorphine is administered sublingually, and could be prescribed as a separate medication, and use verified through urine monitoring.   But greater safety benefits would come through regulations requiring buprenorphine (or a similar partial agonist) to be an inseparable part of every opioid prescription.  Such a policy would dramatically lower the addictiveness and reduce the respiratory depression of mu agonists WITHOUT removing efficacy.  The most obvious formulation would be a transdermal system that delivers buprenorphine and fentanyl, since both are already available in separate transdermal systems.

There may be situations, for example hospice care, where euphoria would be a desirable part of opioid treatment.  But for other cases, analgesia without euphoria has obvious benefits.

I have written to several pharmaceutical companies with this idea, and have heard back that while the idea is interesting and scientifically sound, the generic nature of the component medications reduce the potential for profit that would motivate development.  But given the potential value of this approach for multiple problems– addiction and chronic pain among them—I have to think that there is money to be made—not to mention the advances in treatment that the approach offers.

Reference:

Some supporting background information can be found in:  Alford, D., P Compton, and J Samet, Acute Pain Management for Patients Receiving Maintenance Methadone or Buprenorphine Therapy.  Ann Intern Med. 2006 January 17; 144(2): 127–134.

I also discuss this approach to pain treatment in my ‘Users Guide to Suboxone’, sold on Amazon and at bupeguide.com

Jeffrey T Junig MD PhD

Please do not reproduce without attribution.

Recommended Reading

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

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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.