Brandeis and CDC Wrong on Buprenorphine PDMP Data

I’ll share an interesting story about the data used for the prescription drug database in Wisconsin and other states.  I’ve been holding back on writing about this issue in hopes that the reason for the story would be corrected, and I would have no story to tell.  But that hasn’t happened.

A new law in Wisconsin requires all prescribers to check the prescription drug database when prescribing any controlled substance.  I’m surprised that no privacy advocates have complained about the database, which tells prescribers about the controlled substances used by their patients over the past 5 years, the pharmacies their patients used, and any suspicions of law enforcement about their patient in regard to controlled substances.  The database, or PDMP, is a significant tool for preventing doctor-shopping and diversion.  But the PDMP provides a great deal of information about activities by patients that they rightfully believed to be private just a few years ago.

But this story isn’t about privacy.  I’ll leave that for another day.  This story is about the information provided by experts at the CDC, the top health agency in the world, about buprenorphine.  A mountain of nonsense about buprenorphine permeates healthcare, law enforcement agencies, and addiction treatment programs.  But one could optimistically expect the CDC to get it right.  Right?

When a prescriber follows the new law and looks up a patient on the PDMP, the web page includes a graph that displays the patient’s use of opioids over the past three months, displayed as the oral morphine equivalence.   The graph has a blue line on the graph that represents 50 mg of oral morphine per day, and a red line that represents 90 mg of morphine per day.  Another line represents the patient’s daily opioid dose, and the entire graph is shaded red during the time that the patient also used benzodiazepines.  Neat!

For most patients, the red and blue lines are clearly visible, and the patient’s opioid use is displayed in relation to those lines.  But for patients on buprenorphine, the red and blue lines are pushed against the bottom of the graph by the line that shows the patient’s opioid usage.  Why?  Because according to the PDMP, a patient on 16 mg of a buprenorphine medication is taking the equivalent of 900 mg of morphine per day!

Anyone with a basic understanding of buprenorphine knows about the ceiling effect of the drug.  Unlike with opioid agonists, the opioid potency of addiction-sized dosages of buprenorphine cannot be directly extrapolated from the potency at lower dosages.  With oxycodone, 10 mg of the drug is ten times stronger than 1 mg of the drug.  With buprenorphine, 2 mg of the drug is about as potent as 8 mg, which is about as potent as 24 mg.  The PDMP, though, shows 16 mg of buprenorphine to be 16 times stronger than 1 mg of buprenorphine.

When I noticed the error in the data I emailed the people who developed the Wisconsin PDMP.  They responded and wrote that they appreciated the information, but Brandeis University provided the data about opioid dose equivalency, so Brandeis was responsible for the accuracy (or lack of accuracy) of the data.

So I wrote to the folks at Brandeis who provided the information for Wisconsin and other states’ PDMPs.  They responded that THEIR information comes from the CDC, and so the CDC was ultimately responsible for the dosage conversion data.  They also said that doctors shouldn’t use the information for opioid dose conversions, and there was no danger to that effect because of the fine print at the bottom telling doctors to avoid using the information in that way.

I wrote to the CDC, cc’ing everyone and their cousins to make certain that the right person received my email.  I wrote, respectfully, what I’ve written here—that the information about buprenorphine failed to take the ceiling effect into account, and that the misinformation could potentially lead to patient harm, if a doctor did what doctors tend to do, i.e. use the most readily available information about dose equivalency and trust that information, especially if it comes from an official site like their state’s Prescription Drug Database.

The CDC replied with a form-email.  Given that a genuine response takes about one minute, I can’t believe that the person who received my email saved a significant amount of time by searching out that reply, but I suppose we citizens would become spoiled if the government responded personally!  The form email thanked me for my interest in the CDC, and provided a link where I could read more about the great work they do.

I admit that I get worked up about things sometimes. And yes, I was annoyed to get a form email providing a link to more information from the CDC, after writing to correct their wrong information.  So I sent an email expressing that annoyance to everyone in the story up to this point.  I’m sure that at least a few of the people in the ‘to’ box had a good laugh, and I suspect that I annoyed a few more.  Whatever.

A couple weeks later I noticed a new paragraph under the dose-equivalence graph, telling doctors to avoid using the opioid dose-conversion information to actually convert opioid dosages.  The small print at the bottom of the page was made larger, and placed higher in the page, directly below the display of morphine equivalents.  I don’t know if the change had anything to do with my emails or was only a coincidence.

But then yesterday I received an email from one of my patients, after he consulted with his surgeon about an upcoming operation.  The patient wrote about that doctor, paraphrasing a bit: “she showed me a graph that said my tolerance is equal to 900 mg of morphine.  I don’t know what that means exactly but she will need to give me a high dose of pain medicine without killing me.”  I eventually spoke with that doctor. Guess where the graph came from?!

This the punchline by the way, in case you’re skimming the story.  The patient wrote that his doctor used the PDMP to convert the amount of morphine he would need after surgery, in spite of the ‘warning’ on the web site.  What a shock!

I shared my patient’s email with the people at the WI PDMP, Brandeis University, and the CDC, letting them know that even though they added a paragraph to their data telling doctors that their data was nonsense, doctors STILL used that data in a way that could kill somebody.

Should they be proud of that misplaced trust?  I have no idea.  But why don’t they just USE THE CORRECT DATA??!!

Where’s the Buprenorphine asked Mr. Obvious? Thanks, CDC!

A quick note tonight, hopefully with a longer post to follow this weekend…

I’ve been frustrated by the people behind the Wisconsin PDMP, or Prescription Drug Monitoring Program, for their mistakes related to buprenorphine. Whoever came up with the numbers made a rookie error when calculating the equivalent morphine dose of patients taking buprenorphine products. The error is easy to notice by anyone who works with the drug, but apparently difficult to grasp by anyone with the power to correct the database figures.

Those people include, by the way, the folks at Brandeis University who give the numbers to Wisconsin, and the people at the CDC who give them to Brandeis. I’ve written to all of them; the bright folks at the CDC skimmed my explanation of their error and responded with a form-email that provides a link to where I can get ‘answers to my questions’.

Thanks, CDC!

In short, the people doing the calculation take a low dose of buprenorphine– say 200 micrograms– and extrapolate out in a straight line to 16 mg, ignoring the ceiling effect of partial agonists like buprenorphine. The calculation causes the PDMP to display a graph showing that people on buprenorphine are on the equivalent of 1200 mg of morphine. Any physician who sees that data (and all WI physicians are required by law to use the PDMP effective April 1) will think that the buprenorphine patient needing post-op pain is on THAT dose of opioids. Talk about an April Fool’s joke– nothing like hypoxia in the recovery room to brighten everyone’s mood! Don’t worry though– in their email they pointed out the disclaimer in fine print that the site shouldn’t actually be used to compare or convert opioid doses.

Then why make the calculation and show the graph, asks Mr. Obvious?!

This is getting longer than I intended… Another annoying State tidbit is the series of letters to Wisconsin physicians warning about the severe risk of harm from prescribing benzodiazepines to patients on buprenorphine. I’ve written to those folks as well, pointing out that combinations of benzodiazepines with opioid agonists are much, much, much more dangerous than with buprenorphine. I’ve explained how somehow, sometime long ago, the phrase ‘buprenorphine can only cause death in adults if given to someone without opioid tolerance AND combined with a second respiratory depressant, to which the person also lacks tolerance’ (a true statement) was changed to ‘buprenorphine is dangerous when combined with benzodiazepines’ (mostly ‘fake news’).

I haven’t written as many letters over this second issue because I’m no big fan of benzodiazepines. But both issues annoy me greatly, maybe because the errors of logic in both cases are SO obvious. Even for government work!!

Speaking of government work, the Milwaukee County Common Council released figures about the surge in overdose deaths, including a breakdown by ethnicity, age, county region, and drugs found at autopsy. Mr. Obvious has a question for the people writing to doctors to tell them about the SEVERE risks from buprenorphine: ‘What drug is NOT on the list of the 8 most-common drugs found in toxicology tests of overdose patients?’ A hint: It starts with a ‘B’!

Benzos and Buprenorphine

The high safety of buprenorphine, except when combined with a benzodiazepine, has been twisted in comments about the drug (and in the minds of regulators) to buprenorphine being uniquely dangerous when combined with benzodiazepines, which is not true.

I’ve heard more and more from insurers, regulators, and well-meaning agencies about the dangers of combining buprenorphine and benzodiazepines.   Some insurers protest paying for buprenorphine if patients are taking benzodiazepines.  Medicaid recently sent a letter that described a ‘severe risk’ of using benzodiazepines in patients on buprenorphine.  And the state drug database contains a graph for each patient of the morphine-equivalent narcotic dose over time, and shades the data in red if benzodiazepines are also prescribed.

Readers of my blog know I’m no big fan of benzodiazepines (read this for example).  But in an era of ‘fake news’, I’m even less of a fan of incorrect statements by doctors.   The drug database also ignores the ceiling effect of buprenorphine, and extrapolates the morphine equivalency of low doses of buprenorphine as if the dose response ‘curve’ was a straight line.  That ridiculous calculation leads the graph of opioid use to show buprenorphine patients as taking the equivalence of 900 mg of morphine per day.  The harm is minor I suppose by limitations on access to the database, but the error leads to misperceptions among doctors, and could potentially lead to mistakes in treatment decisions.

Benzodiazepines are respiratory depressants, especially when added to opioids.  The combination is dangerous when patients take doses of either class of drug that are higher than their tolerance levels.  The ceiling effect of buprenorphine eliminates that risk in patients who are stable on addiction-level doses of the drug, i.e. doses above the ceiling threshold.  A patient taking a maximal amount of buprenorphine CANNOT take a dose of buprenorphine that will cause respiratory depression.  Note the word ‘maximal’, not ‘maximum’.   By maximal, I mean a dose above about 8 mg per day, beyond which further doses will have no increase in mu receptor activity.

It is very difficult, and rare, to die from buprenorphine.  A person who lacks tolerance to opioids can die from buprenorphine, but deaths in that case are rare unless a second respiratory depressant is added– usually a benzodiazepine.  The high safety of buprenorphine, except when combined with a benzodiazepine, has been twisted in comments about the drug (and in the minds of regulators) to buprenorphine being uniquely dangerous when combined with benzodiazepines, which is not true.  Benzodiazepines are much, much more dangerous when combined with opioid agonists.  That risk is almost completely mitigated by buprenorphine, providing the person is tolerant to buprenorphine.

Buprenorphine rarely causes overdose unless combined with benzodiazepines in patients who are not tolerant to opioids.  Valid questions over benzo use should not be confounded by fears over buprenorphine.

Below, I will paste a letter I recently sent to one insurer who refused to cover buprenorphine in a patient on benzodiazepines.  Comments, of course, are welcome– and encouraged.

Re: XXX XXXX

XXX XXXX is treated with Suboxone for opioid dependence, and with a combination of medication for depression and anxiety that includes clonazepam and a shorter-acting benzodiazepine, currently lorazepam.    He has a history of (a significant anxiety disorder that I won’t disclose here).

The issue of benzodiazepine use in combination with opioids is complex, but fairly predictable in people who use benzodiazepines correctly (e.g. at regular intervals, rather than taking a month’s supply in three days and then going without for several weeks).

I am experienced in the use of medications that have respiratory depressant properties.  I am Board Certified in Anesthesiology and also in Psychiatry, and I worked as an anesthesiologist for over ten years before training in psychiatry.  I also have a PhD in neurochemistry, and I teach the section on opioids at the Medical College of Wisconsin.  I will take some time to explain the interaction of benzodiazepines and buprenorphine—so I hope you will read my comments and take them seriously.

Buprenorphine has been known to be a very safe medication for the past 3 decades.  Review of the pharmacology literature will show that deaths from buprenorphine are rare. While over 30,000 Americans die from overdose each year, only about 40 of those deaths occur in people who have buprenorphine detected in the bloodstream.  Of those 40 deaths, almost all were from opioid agonists, with buprenorphine NOT acting as a contributor to the death—and in most cases the death would have been prevented had MORE buprenorphine been present in the bloodstream.

The few deaths attributable to buprenorphine each year in adults require 1. An absent or low opioid tolerance, AND 2. the presence of second respiratory depressant that the person also lacks tolerance to.  Because of the ceiling effect, which caps the CO2 response-shift from mu-receptor activation,  deaths from buprenorphine alone are rare in adults.   Death is possible in adults naïve to opioids–  but only if a second respiratory depressant is present.

The fact that death from buprenorphine can only occur in the presence of benzodiazepines has been misinterpreted at times, in warnings about opioids, as the idea that benzodiazepines and buprenorphine are uniquely dangerous when combined.   Understand that patients tolerant to buprenorphine have a partial-pressure of carbon dioxide equal to 40 mm mercury (the normal level).  Because of the ceiling effect, additional doses or amounts of buprenorphine cannot shift the carbon dioxide response curve.  For that reason, patients who have been maintained on buprenorphine doses above the ‘ceiling threshold’ for over a couple weeks have no respiratory depression from the drug.  Such patients have similar respiratory responses to benzodiazepines as those of normal patients.

Mr XXXX is fully tolerant to the cap effect of buprenorphine, so he is not at risk of respiratory depression from the drug.  Frankly, he is in a much safer position than other patients contemplating benzodiazepines, because if he used opioid agonists their effects on respiratory function would be blocked.

I am not a big fan of benzodiazepines, and for that reason have tried to taper Mr. XXXX off of them in the past.  But when we have attempted to taper them, the insomnia and anxiety symptoms become more severe, causing him to isolate from others and miss work.  I am fearful- for good reason—that attempts to reduce benzodiazepines at this point would result in another significant depressive episode, resulting in hospital admission.  My goal has been to avoid any further increase in his dosage—something we have been able to do over the past two years.

Understand that the risk of respiratory depression comes down to tolerance, for both opioids and benzodiazepines.  Mr. XXXX uses the same amount of each medication every 24 hours, and does not stockpile medications or use medications impulsively.  His tolerance to BOTH medications, along with the cap on opioid effects intrinsic to buprenorphine, provides a significant margin of safety.

Another Suboxone Argument

It has been awhile since I posted a give and take with a misguided reader. I’ve taken that interval as good news that education is winning over misinformation.

But then I read this comment.  I didn’t fix her typos, as I think they provide insight into her opinion:

My daughter was on Suboxone, because she was a heroin addict, when she could not afford this med, the withdrawal lasted for mnths, and was far worse than I have ever seen her go through Heroin withdrawal. These are a Psyhiatrist facts, I absolutely hate Suboxone, YES peple do get high on Suboxone, Yes they absolutely can and do inject this garbage. This medication may have helped people who were not addicts for pain, or addicts who truly took this drug to remain clean, and that’s o.k BUT NO THE DRUG COMPANIES are not going to put the facts out about this dug, and about the deaths caused from overdosing on this drug using it in combination with other drugs. They will not report the abuse of this drug, and the effects of this drug on the bodies organs or how it causes Bone Marrow depression. THE TRUTH WILL COME OUT NO MATTER HOW THE DRUG COMPANIES AND GOOD OLD DOCS, TRY COVER IT UP. Half these Suboxone Dr’s are addicts themselves, I took my daughter to one who’s pupils were so pinned, he was slurring and could hardly stay awake, HMMM Could it be he was abusing the same drug he was supplying. They had a great plan for getting people on it but none what so ever for getting people off of it. The Truth about Suboxone will come out. It should be used only for detox only taken no more than for 10 days. I am a Drug and ETOH detox Nurse, so I have seen not just with my own child, but with clients who, by the way do abuse the drug sell it on the street, so they can buy heroin. IT’S A MONEY MAKER FOR BIG PHARMA, AND THE MAKER OF THIS DRUG PAID DOCTORS THOUSANDS TO BECOME CERTIFIED TO PUSH THIS POISON. I will get the true facts of this drug, but Do NOT JUST PUSH THE PRETTY SIDE TELL THE TRUTH ABUT THE UGLY AND YES SOMETIMES DEADLY SIDE. DR. My daughter committed suicide January 4th 2015 overdose of heroin, among other substances. She went to heroin again because she started going through post SUBOXONE withdrawal. The withdrawal last weeks to months with post withdrawal. So please do make this sound like a miracle drug that saves lives, it also kills and that truth will come out. I am sick of these companies, hiding the facts! Facts to me because I have lived it and have seen personally the effect of this drug.

I responded as follows:

I wish you were at least partially correct, given that you work in the field, and have the potential to spread such inaccurate information.

Deaths…  in the past ten years there were about 35,000 overdose deaths in the US.  None of those people had buprenorphine in their system when they died.  What number of people had measurable amounts of buprenorphine in their bloodstream when they died from overdose?  40 per year.  Most of those 40 people would be alive if there had been more buprenorphine in their bloodstream– the only exception being the few cases each year where a young child ingested the drug.

Note that 400 people die from Tylenol each year in the US– compared to 40 deaths of people who had buprenorphine in the bloodstream.  It is very hard to die from buprenorphine;  those who die must have little or no opioid tolerance, and must also take a second respiratory depressant that they have little tolerance to.

Bone marrow depression?  Really?  Buprenorphine has been in use for almost 40 years.  It has a better safety profile than most meds out there.

‘Plans for getting people off’?  The whole point of buprenorphine is to provide chronic treatment for a chronic illness.   You apparently want something that instantly changes the brain and erases addiction, but that product is not invented yet– and I wouldn’t hold my breath for it.  Your daughter developed a condition that will last the rest of her life.  She will treat it for the rest of her life.  She can take a medication each day, or she can attend meetings several times per week. The latter approach works, mind you, only in the relatively few people who are moved by the 12-step message.  Both approaches must last for years and years, if not a lifetime.  Many people do well on buprenorphine, but some survive without it.  But if she isn’t attending meetings or doing something with similar intensiy, her prognosis off buprenorphine is not good.

The withdrawal from the partial agonist buprenorphine is less severe than from agonists.  ALL opioid withdrawal lasts for 2-3 months, and is followed by post-acute withdrawal.  On buprenorphine, a person’s tolerance is equal to 40 mg methadone per day.  Realize that heroin addicts typically have tolerance that is several times higher.  Your daughter developed a high tolerance to agonists, and then continued to have a high tolerance on buprenorphine.  Any addict, including your daughter, is facing months of detox.  Buprenorphine delayed the detox, giving her the chance to get her act together first.  Many people are successful with that approach, but some blow the chance and keep up the negative behavior.  Buprenorphine relieves cravings;  it doesn’t fix personalities all by itself.

I suspect that the reason you never saw such bad withdrawal in your daughter coming off heroin is because she could never stop heroin long enough to demonstrate 2 months of withdrawal.  Nobody just stops heroin; they stop for a couple weeks and then use again.  On the other hand, many people taper off buprenorphine, and have the chance to experience the full course of opioid withdrawal.

The cost…  The drug companies make much more money from chemotherapy, anti-hypertensives, pain pills, and other meds.  Reckitt Benckiser, the biggest maker of Suboxone products, recently spun off the drug because of the anticipated losses.  Even if buprenorphine was a blockbuster, though, I have nothing against drug companies being rewarded for the risks they take to develop new meds.  There is no doubt that the efforts to market buprenorphine have saved thousands of lives.

If your daughter sold her buprenorphine to buy heroin, that’s her bad.  Most people do not do that, but some probably do.  Understand that heroin is very addictive, and drives all sorts of bad behaviors– theft, prostitution, robberies, etc.  I guarantee you that selling her prescription of buprenorphine alone did not make enough money to pay for a heroin habit.

There are so many things you have wrong…. ‘the drug companies paid doctors to push this drug’… I’m sorry, but you are clearly a zealot, and I can’t even take you seriously with that argument.  If you know of a single doctor paid to prescribe a drug, call the Feds, as that would be a crime.  There are some doctors paid to WORK for pharma— to give lectures about new drugs, for example.  I have done that in the past for drugs I believed in.  Some people seem to hate it when doctors take any money from pharma, but when they do, it is for work–  for travelling to some cheap motel in the middle of nowhere and giving a talk to a group of doctors.  The work is highly regulated, and just like TV commercials, docs are required to stick to a very narrow script that educates, rather than promotes.

‘Detox’ has been marginalized (thankfully) because of recognition that it does nothing to treat addiction.  Likewise, non-medication treatment has very low success rates, especially if you count everyone who enters the door, instead of blaming those who fail for ‘not wanting it bad enough’.

I’m sorry about your daughter.  But one thing many parents eventually realize is that even when a kid is acting irresponsibly, buprenorphine at least keeps them alive.  Buprenorphine allows people to stay alive, even if their recovery is imperfect.  And relieved of most of the cravings to use, many of those patients eventually get it right.

Back to the present…  I’d like to think that I cleared up some misconceptions.  But two days after my comments, I received a very similar set of comments from the same person—except that most of the words were capitalized.  That is the reason I’ve tired of these types of posts….

Newborn Buprenorphine Abstinence: Standard of Care

First Posted 2/1/2014

The topic of newborn abstinence syndrome from buprenorphine provokes strong emotions.  Expectant mothers anticipate harsh attitudes from doctors and nurses.  They worry that their use of buprenorphine will cause their babies to suffer from withdrawal.  They hear about the experiences of women reported to CPS after delivery, or whose babies were kept on inpatient opioid tapers for weeks.

A member of SuboxForum recently wrote that the hospital she planned to use, in downstate NY, required mothers on buprenorphine to sign a formal policy regarding the care of their newborn infants.  The policy stated that all babies of mothers on buprenorphine must go to the NICU for at least 10 days after delivery, regardless of condition. Mothers were not allowed to refuse that level of treatment for any reason.

Last week, one of my buprenorphine patients came to her appointment with her 5-day-old baby, after both she and her baby left the hospital less than 48 hours after delivery.   Her discharge struck me as premature, not because of anything to do with buprenorphine, but because new moms are frequently anemic and sleep-deprived and can use a bit of rest before taking on an infant’s schedule.

How can the ‘standard of care’ vary so greatly?  What role does insurance coverage play in decisions about opioid tapers, NICU admissions, and discharge schedules?  After having dozens of patients go through the process uneventfully without intervention by neonatologists, I wonder if newborns are always positively served by their interventions. I also question the wisdom of using opioid agonists to taper from a long-half-life, partial agonist, i.e. buprenorphine.

In blinded studies, only half of babies born to women on buprenorphine show objective signs of ‘withdrawal’, which is a misleading word for describing the experience of an infant.  I have no doubt that in the typical non-blinded nursery, neonatal abstinence symptoms are grossly over-diagnosed.  Mothers on buprenorphine describe a biased diagnostic approach to their newborns, where babies who cry are ‘too agitated’, and babies who sleep are ‘too sedated’.

In the case of babies who truly show symptoms of NAS, do the symptoms always warrant ten days in the NICU?  Is a baby distressed by mild neonatal abstinence better off in mom’s lap nursing with breast milk containing small amounts of buprenorphine, or lying alone in a plastic incubator under fluorescent lights, with multiple IV lines? Some docs and nurses in my area allow moms on buprenorphine to nurse, a policy that makes sense from an anatomical and developmental perspective.   As the baby’s liver matures, ingested buprenorphine is eventually completely destroyed through first-pass metabolism.  The process allows for a gradual, natural taper, without the misery and cost of IV infusions and monitoring systems.

Decisions about monitoring and discharge should, of course, revolve around safety.  I question whether the various approaches to buprenorphine abstinence in the newborn are based on informed, intellectual consideration, or are instead liability-motivated rules supported by ‘best guesses’ by people who don’t understand buprenorphine.  Given the 180-degree difference between the approaches of different hospital systems, somebody is clearly doing it wrong.

I’ve griped about how research studies about drug addiction are so-often focused on demographics, where the data does more to describe the past than to improve care going forward.  The best approach to babies born to mothers on buprenorphine should be near the top of the list for research funds.  The hard part of such studies will be identifying (and following) the conclusions that are derived from science, vs. those that come from concerns about litigation, where the costliest and most-intense treatments always win out.

On Biodelivery and Norbuprenorphine

Over the past few months, I’ve read a few posts at the forum that are worth sharing.  I’ve been torn whether to share them with the general buprenorphine community, or only with doctors who prescribe the medication.  I’ve decided that since the ideas came from a layperson community, I’m not opening the floodgates to irresponsible behavior by repeating what I’ve read.  Feel free to comment if you believe I’ve made the wrong decision.

But first, a word of warning to persons taking buprenorphine:   Do NOT take steps to deliberately alter drug delivery beyond the things that your doctor approves of, such as avoiding drinking liquids right after dosing, or placing the film against your cheek instead of under the tongue—a useful step particularly for someone with dentures.  Do NOT try to increase the effects of buprenorphine by taking substances that block metabolism of the drug.  Such actions risk turning a lifesaving medication into just one more drug of abuse, putting you back into the miserable condition where you existed before buprenorphine treatment!

Bioavailability has become a significant issue for differentiating buprenorphine products.  Late-generation products have increased bioavailability— from 25% with Suboxone Film to 40% and 50% in Zubsolv and Bunavail, respectively.  One result of higher bio-availability is that lower doses of buprenorphine are needed to create identical buprenorphine blood levels.  A second result is lower blood levels of buprenorphine’s primary metabolite, norbuprenorphine, resulting in less constipation during buprenorphine treatment.

Some buprenorphine patients have learned about bioavailability, and have used the forum to describe their efforts to maximize delivery of buprenorphine to the bloodstream.  Over the past few weeks two discussions popped up that relate to different aspects of the same general issue.   And while similar discussions have come and gone over the years, there seems to be a growing sophistication to the discussions.

One recent discussion focused around the use of grapefruit juice to boost the actions of buprenorphine by delaying drug metabolism at CYP3A4, a cytochrome enzyme found in the liver.  Several writers described feeling a boost in mu-receptor activity when they dosed their buprenorphine after drinking grapefruit juice, a side effect that I considered unlikely given the ‘ceiling effect’ of buprenorphine and the rather limited impact of delaying metabolism in a medication that already has a long half-life.  But I realized, during the discussion, that grapefruit juice may be doing far more than reducing the breakdown of sublingually-absorbed buprenorphine.

When a person takes a buprenorphine product, 50% (Bunavail) to 75% (Suboxone Film) of the buprenorphine is swallowed, absorbed at the intestine, and converted to norbuprenorphine at the liver via ‘first pass metabolism.’  But blocking CYP3A4 may allow swallowed buprenorphine to escape first pass metabolism, causing swallowed buprenorphine appear in the inferior vena cava as buprenorphine rather than norbuprenorphine.  In such a case, blood levels of buprenorphine would increase not by the small factor expected from delayed metabolism of a long-half-life drug, but instead by a very large amount—doubling or even tripling the blood levels of buprenorphine.

I have not researched the issue, so I don’t know whether the effects of grapefruit juice on CYP3A4 are strong enough to eliminate or reduce the second-pass effect on swallowed buprenorphine.   But the topic is worth a look—a hint to some aspiring grad student out there!

In another discussion, a patient wrote that he is about to be kicked out of treatment because his doctor doesn’t think he is taking the buprenorphine that he is prescribed.  The patient wrote that he is not only taking the medication, he is INJECTING the medication, ‘so there should be even more buprenorphine in his system than normal.’

Lost on the patient, besides the general  folly of injecting non-sterile, non-IV-grade substances, is that many doctors measure levels of norbuprenorphine to make sure that their patients didn’t just ‘dose’ on the day of their appointments.  I suspect that this patient delivers far less buprenorphine to his liver by dosing intravenously, resulting in very little production of norbuprenorphine.

Why does he inject, by the way?  Like most people who inject buprenorphine, he says he doesn’t really know the answer to that question.  He says that injecting is a means of drug delivery that he has become used to, and that he is hesitant to give up. He is used to getting everything that he can out of heroin…. and he wants to get everything he can now, out of buprenorphine.  He says he doesn’t experience any ‘high’ when he injects buprenorphine.  I explained to him that by behaving so foolishly, he opens the door to huge risks – including the risk of losing access to buprenorphine.

Hope everyone had a nice Thanksgiving.

New Bupe News Section

Wanted to take a second or two to point out a new section to the blog, called ‘Bupe News’.  You’ll see the link at the tope of the page, along with an ever-growing list of links.  The point, of course, is to keep y’all reading, since Google knows EVERYTHING, including how many seconds each and every one of you spends on this (and every other) web site.  Understand that I don’t GIVE that information;  that information is simply that is there for the taking on the internet.  Even I can see the average time people spend on the site, the order they went to one page or another, etc.    I do not ‘collect data’ about any reader, meaning that I do not have information about who any individual is or isn’t…   but I DO get reports on my collective audience.

Check the page out, along with the other new section, and of course tell me what you think.  Positive suggestions are ALWAYS welcome!

Thank you for hanging with me,  by the way, for some tough I.T. times.  I’ve got about 3/4 of the ‘lost’ posts back, and then I’ll be back to firing off the NEW things I’m angry about, rather than replaying the things that irritated me a year ago!

J

The Ibogaine Cure

First Posted 7/28/2013

Ibogaine, a drug long-rumored to treat opioid withdrawal, has become a hot topic for those taking buprenorphine.  Ibogaine is a complex molecule that comes from a group of plants that are known, in West Central Africa, as Iboga.  In native African culture the drug is used to induce psychedelic states that are part of certain rituals.

A reduction in opioid withdrawal from Ibogaine was first described in 1962.  Since that time, anecdotes have been exchanged about the unique properties of Ibogaine, including claims that the drug does far more than reduce the symptoms of opioid withdrawal.  Some users have described trances that they claim effectively ended their addictions to opioids or other drugs.  On the other hand, some people claim to have had no positive effects from ibogaine, and others claim negative effects or bad experiences.  A list of individual experiences with Ibogaine can be found here.

Ibogaine interacts with a number of neurotransmitter receptors, including at least two classes of opioid receptors (kappa and sigma).  Ibogaine’s effects are partially mediated by NMDA receptors (where glutamate acts as neurotransmitter).  The drug also binds to multiple subtypes of serotonin receptors.

Ibogaine has been associated with a number of deaths, most commonly from arrhythmia or heart failure resulting from sympathetic hyperactivity.  There is no treatment for Ibogaine toxicity. The dangers of Ibogaine have led to classification of the drug as Schedule I by the DEA, blocking research into possible therapeutic benefits.  A recent case report in the American Journal of Addictions (Volume 22, Issue 3) highlights the risk of self-treatment with ibogaine:

A 25yearold gentleman with a past medical history of supraventricular tachycardia and chronic heroin addiction decided to try Ibogaine in an attempt at drug cessation. The patient’s mother directly supervised him and indicated that he ingested 2.5 g of Ibogaine over 3 hours. The patient started experiencing hallucinations, ataxia, muscle spasms, weakness, fever, and urinary retention. Most of those symptoms resolved over that day except for muscle spasms and ataxia. He then developed respiratory difficulty followed by cardiopulmonary arrest. He was successfully resuscitated, and brought to the Emergency Department. Physical exam revealed muffled heart sounds and coarse breath sounds bilaterally. Neurologically, the patient was in a decorticate position. A sample of the ingested substance was analyzed by the Poison Control Center, and toxicology results confirmed that Ibogaine was the ingested substance. Despite aggressive care, the patient expired after 2 days from multiorgan failure.

Ibogaine plant and active substance
Ibogaine plant and active substance

Because of the heavy interest in the ibogaine, I am adding a section about the drug at SuboxForum, where people can share anecdotes, ask questions, and place links to further information.   I encourage people to approach the discussion with a skeptical mind.  Opioid dependence creates desperation, and desperation makes us eager to chase after anything that is rumored to be a cure.

My opinion?   The whole thing reminds me of laetrile, another wonder drug that the US pharmaceutical industry supposedly withheld from US citizens.   The apricot-pit cancer cure (also known as amygdalin or ‘vitamin B-17’) spawned cancer treatment centers throughout Mexico about 30 years ago.  Steve McQueen was one of the more notable people who died during treatment with laetrile, a drug that the FDA, after decades of study, called ‘a highly toxic product that has not shown any effect on treating cancer’.  Desperate people take desperate measures.

Reducing the severity of opioid withdrawal through actions at multiple neurotransmitters is within the realm of possibility, and could perceivably lead to untold medical benefit if further study was allowed. But the idea that one or two episodes of pleasant psychosis can ‘cure’ opioid dependence sounds, from a neurochemical standpoint, too good to be true.

Addicted to Suboxone

First Published 7/23/2013

I hear from the anti-buprenorphine people now and then, less than I used to.  I also hear from fans of this blog’s early days, when I routinely lost my temper in response to those people.  Their general line was that things on heroin weren’t all that bad, but now, on buprenorphine, things are miserable.  Starting buprenorphine somehow removed an opportunity to be clean that they used to have, that they would have used if not for buprenorphine.

They somehow miss the obvious—that they could ALWAYS go back to the heroin addiction that worked so well for them.  They’ll say they could stop heroin any time they wanted (you know the joke—‘It is so easy to quit that I quit a hundred times!’), but act as if someone is forcing them to take buprenorphine.

If it is so easy to stop heroin, why not go back to heroin and stop?

For the record, I don’t advise people on buprenorphine to change to heroin.  It is difficult to wean off any opioid, including buprenorphine.  But I do have patients who have tapered off buprenorphine; something I’ve never witnessed with agonists like oxycodone or heroin (i.e. tapering outside of a controlled environment).    Most people who read my blog know that I don’t recommend tapering off buprenorphine for most people, an opinion I’ve come to after seeing many people relapse, and some people die, after stopping buprenorphine.

I received a typical anti-bupe message yesterday; the message and my response are below.  There are a few typos that I can’t decipher….

Errors of logic, anyone?

Subutex was the worst mistake I ever made. I was an off and on heroin user for 5 years. I was clean for over a year and relapsed that when I survived Subutex first I was getting it off the streets then my wife ego had the insurance got a script. She was pregnant so the doctor prescribed Subutex. She told her that her brain would never be the same from her opiate use and would need Subutex most likely for the rest of her life. We both were quickly using it IV IT killed our sex life. It made me feel like a woman or something I have no libido at all. I quit using it IV for 9 months then started again which caused me to have a full blown relapse I’m in 12 step recovery. I lost our home shortly after our new born son was born forcing her to move in with her parents and I moved into an sober living house. We are now both trying to taper off this drug that it’s overly prescribed. The doctor put her on 26mg a day mind you we shared but the doctor doesn’t know that. I do believe in short term low dose setting this drug has a therapeutic value. But I believe it’s been designed to get money lost to drug dealers into the pockets of our government. I kicked Heroin and Oxycontin more then once. Getting off Subutex has been the toughest one yet the physical and mental withdraws are horrible. The best bet for addiction treatment is 12 step meetings. All Subutex or Suboxone does is give you a crutch and prolongs actual recovery from the disease of addiction. They don’t tell you about all the terrible side effects behind this medication its marketed as a miracle drug. A wise man once said if it sounds too good to be true then it’s probably not. Rant done hopefully this helps someone. The answer to recovery is the 12 and staying sober 1 day at a time, most important a relationship with a higher power.

My Response:

An interesting comment… You’ve taken heroin for over five years as an ‘off and on user’.  You then illegally obtained buprenorphine, and injected it (!)… illegally shared what a physician prescribed for your wife… but it’s all buprenorphine’s fault that you are experiencing problems?  Part of the 12 steps that you favor includes taking responsibility for what happens in one’s life, yet I don’t hear a lot of that in your narrative.

I don’t know about ‘miracle drug’, although it probably has saved the lives of both you and your wife, since IV heroin addicts don’t tend to do well beyond 5 years.  There is nothing in your history to suggest that your ‘on and off use of heroin’ would have somehow come to an end, had you not changed your drug of choice to buprenorphine.  But one aspect of buprenorphine is the ‘ceiling effect’, which makes overdose much less likely.

Likewise, I don’t see a government conspiracy, and I disagree with your comment about ‘low dose use’.  Buprenorphine HAS been used in low dosage for treating pain for the past 30 years, but everything about buprenorphine that makes it a good addiction treatment relies on the person taking a dose that assures a high blood level, i.e. above the ceiling level for the drug’s effects.  In low doses, buprenorphine acts like any other agonist– i.e. causes the same up/down mood, cravings, and obsessive use pattern.

Your problem is that you became addicted to opioids, and your opioid addiction has cost you a great deal.  You misused buprenorphine by injecting it, but luckily for you the drug has certain safety features that helped keep you from overdosing– something heroin doesn’t have.    But now you blame buprenorphine for all your problems.

I certainly do not suggest that you do this, but for the sake of making a point—-  you could easily go right back to where you were, before you met buprenorphine, if you returned to your addiction to IV heroin.    If you started heroin tomorrow, the buprenorphine would be out of your system in a week or so, and… voila….. you would be ‘cured’ from this horrible affliction that you claim to have, i.e. an addiction to buprenorphine.  Or are you going to suggest that taking sublingual buprenorphine was somehow WORSE for you than doing what you were doing before finding a doctor, when you were injecting foul solutions of heroin into your veins?!  You were FINE with the heroin, but BUPRENORPHINE has ruined your life?

Sorry– I don’t buy it.  Most people who stop ANY opioid– buprenorphine, oxycodone, or heroin— end up using again.  Buprenorphine, as a partial agonist, relieves cravings in a way that opioid agonists can’t.  And taking buprenorphine certainly doesn’t make anything ‘worse’;  a person addicted to heroin, who doesn’t like taking buprenorphine, can always go back to heroin!  I don’t recommend it, as the overdose risk is very high with heroin, and people on heroin suffer from constant obsessions to take more and more– a life far worse than the person properly taking buprenorphine.

This is where I come in… THESE are the patients I see on a regular basis.  The doctors who used to call them ‘good patients’ now call the same people ‘drug addicts.’  And the pain doctors—the ones who create so many addicts—give lectures on ‘how to prescribe opioids.’   I can spare you the need to attend the lecture— the main message is that after you make the patient an addict, you must do everything that you can to separate yourself from the patient before the consequences of that addiction become apparent—so that your hands appear sparkly-clean!

The Pain Clinic: Your Money’s Worth?

Originally Posted 7/18/2013

Like most of you, I’m not thrilled with modern healthcare.  I miss how things were twenty years ago, when I had a sense of ‘having a doctor’ who actually knew me, who had my best interests in mind.  I remember my father, a defense attorney in a small town in Wisconsin, telling me about the state’s ban on advertising by lawyers – a once-debated issue that is hard to visualize in the current era.  He believed the ban was a positive thing, helping keep the legal profession honest and avoiding the appearance of impropriety.   I remember comparing the situation to medicine and thinking ‘of course the ban is a good thing; just think of what society would think about DOCTORS, if they hung billboards for their services!

Those debates must appear bizarre to young people now, who can’t drive a mile without hearing or seeing ads urging people to sue over work grievances, accidental injuries, discrimination, medication side effects, malpractice… while hospitals and doctors compete for space for their own ads for pain clinics, wellness centers, hip and knee replacements, or robotic surgery.

Billboards announce the next great thing that one hospital has that others don’t, one medical gimmick replacing another.  ‘Pain treatment’ is one of the biggest healthcare scams of the past 20 years, with ads promising treatment for chronic pain in an ‘advanced’ or ‘collaborative’ manner.   The scam is easy to see if one drops all positive assumptions about medicine—and health insurance– and observes what happens to patients who use pain clinics.  Follow two hypothetical patients, one with insurance and another with no money or insurance, with the exact same injury—let’s say back pain from lifting crates in a factory every night for several years. Their experiences will demonstrate why being insured is not always in one’s best interest.

Epidural injection
Are epidurals worth the money for chronic pain treatment?

Our uninsured man develops pain in his lower back that does not extend into his legs, without leg weakness or incontinence.  He goes to urgent care and pays cash for the visit, and tells the doctor that he can’t afford to be referred anywhere.  The doc tells him to avoid heavy lifting for a week, and when he returns to work, to lift with his legs and knees instead of bending his back.  He is told to stretch at least 30 minutes every morning and evening and to exercise each day.  Back pain usually comes from a combination of ‘pain generators’ in muscle, bones, tendons, ligaments, and nerves in the lower back.   But the body has amazing recuperative powers, and if our hypothetical patient stretches, exercises, and avoids repeat injury, he will get better over several weeks.  Not a bad outcome for $150!

The guy with insurance goes to his doctor, who prescribes 90 tablets of Percocet and schedules an MRI.  This doctor doesn’t explain the need for stretching, assuming that the patient will hear all that from the next doc he is referring to… or maybe he recommends stretching and exercise, but the Percocet helps the patient feel less restless while sitting in front of the TV, reducing the stretching or exercising that would have helped him feel better.  When the MRI shows ‘degenerative disk disease’ (as it always does in people over 40), the doc refers him to a neurologist for EMGs.  The patient meanwhile sees his chiropractor for 5 ‘adjustments’ per week.  The neurologist refers him to a physical medicine and rehab doc, who orders physical therapy.  All of these steps in the process extract their pound of flesh, paid by either the patient or society (through higher insurance rates).

The people who are getting rich in medicine know that it’s all about PROCEDURES.   Our insured patient already paid over $1000 for his share of the costs for a lumbar spine MRI (not to mention the plain films and a CT scan done first, just in case they might be helpful).  He or his insurer paid another grand for the EMG.  The chiropractor cost another 1-4 grand, depending on the patient’s zip code.

The money really starts to flow when the rehab doc sends him to a pain clinic.  The pain clinic starts with more x-rays, CT, and MRIs, claiming that THEIR techniques will give a better look at things that the others may have missed.   For the most common diagnoses—degenerative disc disease, lumbar strain, or facet arthropathy– treatment choices include lumbar epidural steroid injections, selective nerve root injections, and local anesthetic ‘trigger point’ injections to relax tightened muscles.  The doctor’s charge to do an epidural or nerve root injection?  About $500-$1200, for a procedure that takes about 15 minutes.  An efficient doc could easily do 10-12 injections per day.  If the doc attended one of those meetings that teach ‘maximizing reimbursement’—meetings often held on cruises or tropical islands—the doc calls his office an ‘ambulatory care center’ so that he can bill ‘facility fees’, turning a $700 epidural into a $5000 ‘short stay.’

I hear what you’re thinking—that relief from back pain is WORTH the $5,000-$10,000 cost for this patient.  What if the procedure provides only partial relief—the typical result?  Or What if the epidural steroid injection only MIGHT provide pain relief— but probably WON’T?  Is it still worth as much?  What if the pain relief won’t start for a few weeks and only lasts a month or two, and then the shot must be repeated?  What if the injection can be done only 3-4 times per year, and the patient has less than a month of relief each time.  Is 3 months of moderate reduction in pain worth $15,000?

The scam is aided by a simple fact that patients often forget: most minor injuries will heal on their own without medical intervention, as long as re-injury is avoided.   It is no coincidence that many medical procedures or treatments take ‘a few weeks’ to work, the amount of time most often associated with natural healing.  You’ve heard the joke….  With treatment, you’ll improve in 14 days; otherwise a couple weeks!  Present-day back injuries last about as long as they did 50 years ago—even though we now spend tens of thousands of dollars per injury, rather than a few weeks of ‘taking it easy.’

I’m taking care to present examples that give medicine the benefit of the doubt.  I’m not mentioning the many injections done on people despite clear evidence, on exam or MRI, that the injection will do nothing for their pain.  I’m not talking about trigger injections (done thousands of times each day throughout the US) that hurt like blazes during the shot, giving the illusion of pain relief (and nothing else) when the needle is removed.  I’m not talking about the many MRI’s, ultrasounds, CTs, and EMGs that could be replaced by a smart doctor with basic physical examination skills.

And I’m not talking (until now) about the people who suffer from iatrogenic addiction—- those who go to pain clinics for aches and pains that will either gradually go away or won’t ever go away, that in either case have a trajectory of recovery that can’t be altered by the pain clinic.  The patients are prescribed opioids, and asked to return for one procedure after another.  The patients notice that the procedures are doing nothing for the pain, but they return over and over for refills on the pain pills that they now physically depend on.

The insurer eventually balks at paying for more procedures… and at this same point the pain clinic docs decide that further attempts at pain relief would be pointless.  The doc tells the patient that since he is doing nothing but prescribing pain pills, the patient should go back to his primary care doctor and never return to the pain clinic (unless a new, reimbursable injury comes along).  The referring doctor is not comfortable prescribing the same large dose of narcotics, and tells the patient to ‘taper off the pain pills’—- something that most people just can’t do.  The patient inevitably violates the opioid treatment contract by asking for early refills, smoking marijuana, missing an appointment, running out of money to pay for visits, seeing another doctor, using the wrong pharmacy, etc…. allowing the doctor to blame the patient for breaking the rules, requiring discharge.