Tapering off Buprenorphine or Suboxone, Pt 2

In the last post we discussed some of the misconceptions about tapering off opioids.  Today we will discuss a couple basic principles, and then describe the approach I recommend for my patients tapering off buprenorphine.

Opioids act at receptors that normally bind endorphins, which are released by neurons in response to a range of stimuli including trauma and rewarding behaviors such as eating a good meal or using addictive drugs.  Endorphin pathways elevate mood, reduce sensation of pain, and impact urine production, immune function, intestinal motility, and other bodily functions.  Endorphin pathways have a certain baseline activity or ‘opioid tone’ that is directly related to opioid tolerance.   When opioid stimulation is greater than one’s tolerance, opioid tone is increased.  When opioid stimulation drops below one’s tolerance, opioid tone is reduced, causing withdrawal symptoms.

The goal of any taper off opioids is to recover original or native opioid tolerance.  Some people focus on getting rid of the opioid, and even use substances or behaviors to ‘flush buprenorphine from the body’.   Products marketed as detox agents have minimal impact on the clearance of buprenorphine or other substances.  And even if they could increase the rate of clearance,  they would only make detox harder by increasing the severity of withdrawal symptoms.  The relatively slow metabolism and clearance of buprenorphine provides a cushion by slowing the loss of opioid tone.

Prolonged use of any opioid changes opioid receptors.   The changes are not fully understood but include a decrease in number of receptors and changes in binding properties that reduce receptor sensitivity to opioids, including endogenous opioids (endorphins).  Recovery from a state of tolerance takes 2-3 months, and is initiated by reduced opioid tone.  Withdrawal symptoms reflect the reduced opioid tone that provokes eventual recovery of native tolerance.

Recovery of native tolerance is the rate-limiting step when tapering off any opioid, including buprenorphine.  When the dose of buprenorphine is reduced, the amount of buprenorphine at opioid receptors decreases over the next 5 days and then stabilizes at a lower level.  In response, opioid tone (the summation of current flow through opioid receptors) drops below normal.   If the dose of buprenorphine is maintained at that level, opioid tone will recover to normal in about 2-3 months.  If buprenorphine is suddenly and completely discontinued, opioid tone will decrease to very low levels and cause severe withdrawal that lasts for 2-3 months.  If buprenorphine dose decreases more slowly, opioid tone will decrease more slowly, lessening the severity of withdrawal.  But it still takes 2-3 months for opioid tone to return to normal.  So for any taper, patients must decide whether to decrease their dose quickly and be done in 2-3 months, at the cost of greater withdrawal, or instead to taper more slowly to reduce the severity of withdrawal.

The relationship between buprenorphine dose and opioid activity is linear up to about 2-6 mg.  Beyond that point further increases in dose have less impact on opioid tone.   The reverse occurs when tapering, so that opioid tone decreases only slightly as dose is reduced from 16 mg per day to 4 mg per day.  The non-linear dose/response relationship allows for rapid decreases in dose early in the taper process with limited or no physical withdrawal symptoms. Since the early challenge is mostly psychological, I use the early part of a taper to help assess whether a patient is truly ready to take on the tapering process.

I like to have patients lead the way in tapering off buprenorphine.  I’ve found that if I lead and reduce the amount of prescribed buprenorphine for the next month, patients often fail to make reductions and end up out of medication before the end of the month.  So instead I ask patients to tell me when they are certain that they are ready to stay at the lower dose.

During a taper, I recommend dosing buprenorphine twice per day.  Patients start by removing 2 mg from the evening dose.    After at least two weeks 2 mg can be removed from the morning dose.  This sequence is repeated at intervals of at least 2 weeks until the total dose is 4 mg per day. In my experience patients who get to that point are usually in a good mental position to begin the second, more difficult part of the taper.

Most people will be able to continue working when opioid dose is reduced by 5% or less every 2 weeks, or 10% every month.  That number is a good general guideline when deciding how fast to taper.  Suboxone film makes tapering relatively easy.  Patients purchase a weekly med organizer, and start the week by opening and stacking 7 films.  A scissors or razor is used to cut a millimeter from the end of the stack, and one film is placed in each compartment of the organizer for that day’s dose.  When the patient is comfortable with that dose, slightly more is removed for the next week.  The process continues every 2-4 weeks, eventually changing to the 2 mg films.  I recommend that patients continue tapering until the dose is 300 micrograms (0.3 mg) per day or less before stopping buprenorphine completely.  It is fairly easy to guesstimate where to cut the film in order to reduce by 10%;  just measure half, then half of that, then half of that.

Buprenorphine tablets, of course, are much harder to divide.  Zubsolv did people a favor by coming out with a range of doses, and hopefully other brand and generic manufacturers will eventually follow suit. For now I usually have patients use the tablets to taper as far as possible, using the 2 mg tablets in the lower dose range, and then pay the extra cost for the film for the final month or so.   A 12 mg film can be divided into 24 half-milligram pieces without too much effort, so the cost doesn’t have to be prohibitive.

I have had many patients taper successfully off buprenorphine.  Fear is common and normal for a number of reasons, but the fear usually gives way to a sense of confidence and optimism when a taper is done correctly.

Things to keep in mind:

  • Be patient.  Tapering by too much, or too quickly, causes withdrawal symptoms that lead to ‘yo-yos’ in dose.
  • Buprenorphine products are very potent.  A sliver of Suboxone Film may contain enough buprenorphine to harm or kill an animal or small child.  Take care to divide the medication in a well-lit setting, and clean up very carefully.
  • Buprenorphine is used to treat pain in microgram doses.  If you jump from 1 mg, you will have considerable withdrawal symptoms.
  • If you are still running out of medication early, it is not time to taper off the medication.
  • People on buprenorphine for a year or less have rates of relapse over 90%.  In my experience patients are more successful tapering off buprenorphine if they have been on the medication for 2-5 years or more.
  • If you struggle in tapering down to 8 mg, consider going back to your stable dose, waiting 6 months, and trying again.
  • People addicted to opioids often substitute other drugs for their drug of choice.  Do not start a new addictive substance in order to get off buprenorphine.

Good luck!

Addiction Treatment ‘Science’ and Dead Rats

In my last post I teased that I would write about fake science.  I’ll try to make it interesting.

The internet allows everyone to do research about symptoms and treatments for any condition. If not for need for prescriptions, people could act as their own doctors.  But a huge dose of caution is necessary before anyone takes that path.

Realize first that doctors don’t treat themselves or even their family members.  The saying that ‘a person representing himself in court has a fool for a lawyer’ applies double in healthcare.  Treating someone close to one’s self introduces a bias that is hard to explain, but easy to notice.  As an example, I see a doctor annually to monitor a progressive condition that threatens my vision.  I would like to know the answer to a simple question:  how bad is it?  If I have a patient with that condition I can look at images of his/her retina and have an immediate, rough sense about what the person is facing.  But when I look at my own images and test results I sense nothing beyond fear or relief.  The problems with self-assessment are of course greater in the field of psychiatry and addiction.  After my relapse in 2001 I was told I needed treatment, and my assessment called for a brief refresher course on the twelve steps.  Three months later, still in residential treatment, I recognized how wrong I was.

A larger problem is that research on the internet is nothing like the research used by doctors or scientists.  There are a few sites that offer true research, such as Pub Med, where you can search my name and see the articles from my PhD work in the 1980s.   Doctors at academic hospitals or institutions often have access to an electronic database including thousands of peer-reviewed journals.  In grad school I spent time each morning in the library, reading the Science Citation Index for new stories about vasopressin and then searching the stacks for the article (medical libraries have so many journals that they take up 4 or 5 floors or more of a large building, with narrow halls between floor-to-ceiling shelves).  In the stacks I sometimes realized I was standing amidst the results of the hard work of millions of scientists over the past 50 years.

The information on the internet is useful because it helps patients ask the right questions.  But it is a mistake to consider it as research, or even to assume it is correct.  Doctors and scientists (and any good health practitioners) rely only on peer-reviewed literature.  And even then, a good scientist gathers a sense, over time, of the better peer-reviewed journals vs. the ones with less credence.  What is peer review?  When a scientist submits research for publication, the article is sent to 3 or 4 independent reviewers who work in the same field but have no connection to the author of the study.  I am a peer-reviewer for a couple of journals.  When I receive an invitation to review a study I have to disclose any bias or connection to the study or authors.  If I accept the invitation I have several weeks to carefully review the study, noting if the findings are valuable, whether the groups were sufficiently randomized and blinded, whether the statistics are correct or if a statistician should be involved, and whether the findings support the conclusions.  I then tell the journal editor my opinion, including whether the study should be accepted, rejected, or accepted with certain revisions.  Peer reviewers are not paid;  they provide the service because they recognize that the process is necessary and valuable.

The FDA regulates medications based on the results of research studies.  Some of the studies reviewed by the FDA are already published, and some may never end up in a formal publication.  But their process for evaluating medications is similar to the work of a peer-reviewer in that they determine whether the science is ‘good’ – double blinded, properly randomized, good statistics, etc.  Any claims about a medication MUST be deemed accurate by the FDA.

This post was inspired by an ad for Declinol, a supplement marketed to ‘treat’ alcoholism.  Supplements are not medications, and not subject to the same rules. Read the FAQ on the Declinol web site and note the answer about FDA approval.  Declinol is not subject to FDA approval because it is a nutrient, not a medication.  The FDA allows greater latitude for promotional claims about nutrients, but even makers of supplements are not allowed to lie.  The acrobatics of marketers of such products are sometimes funny, at least to us nerds, and Declinol is a classic example.  Note that the web page doesn’t say that it treats alcoholism or cravings;  it is a ‘SUPPORT for physical cravings, calmness, and overall well-being’.  What is a ‘support’?  Your guess is as good as mine.

Instead of making claims that can be found to be false, nutrients often show quotes by ‘satisfied customers’.  If the FDA believes that the quotes are misleading, that’s on ‘Bob from California’, not on the marketer of the nutrient.  Instead of describing how the nutrient works, nutrient marketers provide citations about the nutrient that support whatever the marketers want you to think.  So with Declinol we see ingredients like folic acid, with broad generalizations about the value of that substance.  Yes, Folic acid is valuable.  You can’t live without it.  But that’s a far cry from saying that taking extra folic acid has any value, let alone value in reducing alcohol intake.  We give folate to alcoholics in detox because they sometimes have dietary deficiencies caused by consuming nothing but alcoholic beverages.  If you eat meals a couple of times per day you almost surely have plenty of folic acid in your body, and any extra is metabolized and excreted..

Must nutrient ‘treatments’ or supplements contain a blend of vitamins.  It is very easy to write reassuring and positive statements about vitamins because by definition, vitamins (the term comes from ‘vital amines’) are molecules critical to normal function.  But many studies have shown that a typical diet provides adequate amounts of vitamins, even if that diet includes fast food.

Many nutrient ‘treatments’ also contain a couple special ingredients we’ll call ‘secret sauce’.  One secret sauce in Declinol is Kudzu, and support for Kudzu in reducing alcohol consumption can be found on Pub Med.  Like similar products, Declinol’s marketers take a finding about a substance and grossly generalize the findings to create an impression that was never part of the original finding.  According to the study about Kudzu, 20 people in a ‘natural settings laboratory’ (is that an oxymoron?) were given water, juice, and up to six beers, and told to drink at will.  And (wow) when people were given 2 grams of Kudzu first, they drank beer more slowly, and opened fewer bottles.

A couple of problems, though, in concluding relevance to treating alcoholism.  Were the 20 subjects alcoholics? It doesn’t say, but I would guess not because I don’t know if a study giving beer to alcoholics would pass the ethical review board.  Beyond that, WHY did they drink less alcohol?  If I gave you syrup of ipecac, you would probably drink less alcohol.  If I gave you a tablet of oxycodone, you would probably drink less alcohol.  That doesn’t mean that the substances are useful in treating alcoholism or alcohol cravings.  Why did the Kudzu group drink less alcohol? Did it truly reduce interest in alcohol in a study with very few subjects who may or may not have alcohol problems? Or did it leave a nasty taste in their mouths or destroy their taste buds?  Did it cause nausea or dizziness that made alcohol less enticing? Did it reduce vision so they couldn’t find the beer bottles as easily?

As for the title of this post, when I researched vasopressin one hot idea was that vasopressin enhanced learning and memory.  We measured that improvement in studies using ‘passive avoidance.’  We placed rats in a cage that had dark cubbies in one corner, and when rats invariably went into a certain cubby they received an electric shock.  We repeated the task with or without putting vasopressin into the rats’ brains and some rats ‘learned’ to avoid the electric cubby, supposedly by remembering the shock better than other rats.  There is a major flaw in the study that can often be applied to other ‘experiments’, including the one I cited about Kudzu:  the best performer in a passive avoidance task is a dead rat.

I have no idea whether Declinol reduces cravings or generates ‘well being’, whatever that is.   But nothing on their website pushes me toward that conclusion.  I hope readers will keep some of these comments in mind when the next big cure comes along.

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’!

Buprenorphine Overdose After Naltrexone Treatment

Naltrexone induces mu-receptor hypersensitivity.  Buprenorphine’s protective ‘ceiling effect’ may not prevent overdose in patients with this ‘reverse tolerance’.

A new patient described his recent history of respiratory failure several days into buprenorphine treatment.  He was told by his doctors that he experienced an allergic reaction to Suboxone. The rarity of buprenorphine or naloxone allergy led me to look deeper into his history, and my conclusion differs from what he was told by his last treatment team.

The patient, a man in his mid-50s, has a history of significant opioid use over the past 20 years.  He used a variety of opioid agonists over the past year, mostly prescription opioids, with an average daily dose greater than 200 mg of oxycodone per day.

Three months ago he went through hospitalization and detox, and after a week he was discharged on oral naltrexone.  He sought further treatment at a different institution that offered buprenorphine.  He was told to stop the naltrexone two weeks before induction with buprenorphine.

He avoided all opioids for that two weeks, and then started buprenorphine, 2 mg twice per day as directed by his physician.  The patient became progressively sleepier after each dose of buprenorphine, and after 24 hours could barely maintain wakefulness.  His complaints resulted in his admission to the hospital intensive care unit.

In the ICU he had a rocky course that included several episodes of apnea, hypoxemia and bradycardia.  The patient does not currently have the records from the hospitalization, so the course of events is based only on his recollections from several weeks ago.  He blacked out several times, and was told by doctors and nurses that his ‘heart stopped on the monitor’ during those times.  He says that his oxygen level was very low at those times according to the monitors, and according to what he was told.

After the episodes when he lost consciousness, he was told that since his heart stopped he needed emergency implantation of a pacemaker.  He said that a short time later those concerns were dropped, and no pacemaker was inserted.  He was discharged from the hospital in good condition after several days.  Follow-up with a cardiologist was not deemed necessary. He was told by his hospital physician that the episodes of lost consciousness were caused by an allergic reaction to Suboxone.  He had no rash or pruritus (itching).

I’m writing about this patient’s care in the form of a ‘case report’.  The patient does not have access to his records.  If he did, I would review them and write a formal case report for publication.  Since I’m relying on the patient’s perceptions and memories, I’ll use this blog.  I will say that I have no axe to grind, and my purpose in sharing this case is to help people avoid a similar situation.  And, of course, to keep readers of this blog entertained!

As the patient shared his story, I assumed that he had an opioid tolerance well-below the ceiling actions of buprenorphine.  When I mentioned my hypothesis, the patient smiled, and told me he had been using over 200 mg of oxycodone each day, blowing that theory to pieces.

But I returned to the same theory when he said that he followed the doctor’s orders very closely, including avoiding opioids completely for two weeks before induction.  I wondered, could a 2-week interval of abstinence lower tolerance so dramatically that buprenorphine resulted in overdose? Then the patient mentioned, in an offhanded way, that ‘he even stopped the naltrexone’.

I’ve written about the increased incidence of opioid overdose following treatment with naltrexone, a risk that is unreported and largely unknown beyond brief reports from Australia cited in the linked post.   Opioid antagonists, including naltrexone (the drug that makes up Vivitrol injections), induce ‘reverse tolerance’ in mu opioid receptors to cause a heightened response, and heightened respiratory depression, from subsequent exposure to opioid agonists.  Anyone close to the field of opioid dependence notices the increased frequency of overdose in patients newly released from confinement, whether in jail or in abstinence-based treatment.  The increased risk of death after a period of abstinence is related to the resetting of tolerance during abstinence.  A return to ‘normal’ use creates significant risk of overdose.

That risk is multiplied if the period of abstinence includes treatment with naltrexone.   Imagine a person who is using six ‘30s’ of oxycodone—180 mg—every 24 hours.  If that person waits a week and then goes on naltrexone, tolerance drops to zero and then to negative levels.  After a couple of weeks on naltrexone, a tablet of Vicodin has the potency of a tablet of Percocet.  That 180 mg of oxycodone now has the potency to cause respiratory arrest and death.

Buprenorphine is a partial agonist with a ceiling effect that prevents overdose in almost all patients who have even small degrees of opioid tolerance.   Almost all deaths from buprenorphine occur in people with limited or no tolerance to opioids.  In the presence of inverse or negative tolerance, the ceiling on buprenorphine’s opioid effect has less protective value.  Such was the case in the patient who is the subject of this discussion.

So what would have been a better plan?  Buprenorphine induction is always more dangerous in patients with low opioid tolerance, so careful patient selection will mitigate that risk.  In patients with low tolerance, reducing the starting dose buprenorphine to low-milligram levels does little to reduce the risk of respiratory depression because of the ceiling effect, which reflects the minimal difference in strength between 2 or 16 mg of buprenorphine.   Much lower doses of buprenorphine, on the order of 0.5-1 mg, are required to reduce risk of respiratory depression and overdose in patients with inverse tolerance to mu opioid agonists.

A second option would be to continue naltrexone through the induction process, and afterward gradually reduce the dose of naltrexone over a week or two.  As the block from naltrexone decreases, buprenorphine bound to mu receptors would gradually increase, allowing opioid tolerance to grow more slowly.  Precipitated withdrawal would not be a problem, as PW occurs when bound agonist is suddenly displaced by buprenorphine—  not when antagonists are displaced by agonists or partial agonists like buprenorphine.

Thankfully, the patient is now doing well, with no lingering problems caused by his course of treatment.  But the incident also relates to another common problem, i.e. the erroneous blaming of symptoms on medication ‘allergies’.  In an era of electronic medical records, that mistake often removes, permanently, a patient’s access to medication that may someday be helpful—and in the case of buprenorphine, irreplaceable.

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.

Cannabinoid Hyperemesis: How Rare?

Marijuana might cause pain and vomiting in the people who value the drug the most. Doctors should learn more about cannabinoid hyperemesis syndrome.

I recently read a CBS news story about CHS, or Cannabinoid Hyperemesis Syndrome, describing a 100% increase in cases in Colorado since the legalization of marijuana there.  A search for ‘THC’ and ‘CHS’ pulls stories from a range of sources including High Times, Wikipedia, Fusion.net, and Current Psychiatry.  A broader search reveals articles calling the disorder ‘fake news‘.

Most articles about CHS describe the condition as rare, but becoming less rare as the legalization movement takes root and grows.  The syndrome occurs in heavy, long-time users of marijuana who first notice reduced appetite, mild nausea, and sometimes weight loss.  Those symptoms, and the symptoms that follow, are relieved by smoking marijuana, leading those with the condition to become heavier users who come to see marijuana as beneficial to their health.

Over time the symptoms worsen to include paroxysms of severe abdominal pain, nausea, and vomiting.  Patients often seek help from a number of health practitioners, including alternative health treatments.  Tests come up negative, and patients continue to turn to marijuana to treat the symptoms– along with hot baths and showers, which for some reason make the pain and nausea more-tolerable.

Since we live in an era of social media I’ll point out that I have no strong feelings toward marijuana.  I don’t kick people off buprenorphine products for testing positive for THC, as it makes little sense to stop treating a potentially fatal disease because the patient smokes pot.  I doubt doctors would withhold cancer treatment because of marijuana use either.  I’m describing my observations only to get the word out about something that doctors are missing.  Over the past 2-3 years I’ve had several patients with symptoms identical to those described in stories about CHS, so I suspect the condition is more common than thought.

The Current Psychiatry article describes possible mechanisms for symptoms of CHS.  The nausea and vomiting may be caused by accumulation of cannabinoids in the lipid tissue of the gut, causing activation of the CB1 receptor in the intestine to override the anti-emetic effects of CB1 activation in the hypothalamus.  Activation of CB1 receptors in the gut slows peristalsis (the motion of the intestines that propels food forward) and dilates the blood vessels to the intestinal system. Hot baths and showers may provide relief by dilating blood vessels in the skin and redirecting blood flow away from the gut.  Other possible causes relate to the effects of specific cannabinoids, or perhaps herbicides or pesticides.

One of my patients had classic symptoms of CHS for several years.  A year ago I had not yet heard of the condition, but noticed that he repeatedly talked about marijuana being a ‘wonder drug’ for disabling stomach pain and nausea, even as he lost weight and his general health deteriorated.  When I asked if he considered that marijuana may actually be harming his health he became angry and defensive, and never returned for follow-up.

Another patient talked about his spouse’s health problems, hoping I would have ideas about the cause of her symptoms that weren’t found through visits to many specialists. Marijuana wasn’t even part of the discussion as he described her severe pain and nausea over the past year that caused her to go to the ER several times each month.  At his last appointment, armed with new knowledge about CHS, I asked him if his wife smoked marijuana.  He said that she not only smoked it, she recently got her ‘medical marijuana’ card because smoking was the only thing that relieved her nausea.  I asked if she ever felt better after a shower, and he said “oh my  gosh, she is in the shower for three hours or more every day with the hot water turned up!”

The big question, of course, will be whether people with similar symptoms will try going without pot for a month, the length of time required for symptoms to fade, and whether clearing their systems of THC actually relieves their symptoms. But other heavy marijuana users with pain and nausea should read up on CHS, and consider a trial off THC.  One month without pot isn’t going to kill you.

Make Sleep Meds Work For You

I’ve been busier than I like, and haven’t had as much time for posting.  But I spend a lot of time answering emails from my patients, and some of my responses may be useful for others.  Below I’ll share my answer to a patient who has been unable to get quality sleep.  Next week I’ll find another answer to share with readers.

This patient asked whether her insurance would cover Lunesta.  She wrote at 2 AM that she is up most of the night tossing and turning. She now takes 10 mg of Ambien, and wrote that it ‘stopped working’.  She doesn’t think 20 mg of Ambien would be covered by insurance (although Ambien is very inexpensive when purchased for cash).  She takes gabapentin for a pain condition and wonders if increasing it would help with sleep.

My response:

Before getting into a discussion about insurance I want to make sure you have a good understanding about the issues you’re facing when you take sleep medications.  Most sleep medications are subject to tolerance, and some share ‘cross tolerance’.  Lunesta (s-zopiclone) and Ambien (zolpidem) act at the same receptor and have the same actions, so if a person is used to one, she is used to the other.  The situation is analogous to opioids, where a person tolerant to a significant dose of oxycodone will find little effect from morphine.

I have taken Lunesta but stopped it for the same reason you are unhappy with Ambien:  it just didn’t do much.  Lunesta also causes a very bitter taste in the mouth, not from the pill touching taste buds, but from the drug circulating in your bloodstream.  The taste is unpleasant but goes away aftef a few weeks in most people.  If you are not responding to Ambien, you won’t likely respond to Lunesta.

Some people change from an ‘ultrashort’ to a benzodiazepine, typically temazepam.  That change will often offer some benefit, but tolerance will eventually match the effects of temazepam just as with the shorter medications.  Patients often ‘chase’ tolerance higher until their doctor refuses to prescribe larger amounts.  The exercise only deepens the plight of the insomniac, making it harder and harder to sleep without medication.

What is your current dose of gabapentin?  Pain docs sometimes taper that drug up to a total of 3 grams per day, and higher doses cause some degree of sedation.  But again, step back and look at the big picture.  With any sedating substance, including gabapentin, you are only  addressing the short-term.  Your body will adjust to any dose of sedative, just as with opioids, and you will eventually need to address the same symptoms on even higher doses of sedatives.

I am willing to look at the gabapentin, but understand what you are up against.   Patients tend to focus on the short-term at 2 AM.  My job is to know that you will be around for years, even decades!  I often see new patients whose doctor prescribed benzodiazepines for years, repeatedly raising the dose.  At some point the patient ran out too early, prompting discharge.  At that point there is little to be done for such patients beyond helping them through several weeks of severe insomnia caused by benzodiasepine withdrawal.  Sometimes questiapine, clonidine, or hydroxyzine will help patients find some restless sleep while lowering their tolerance to benzodiazepines, but that sleep is usually poor in quality and associated with significant daytime sedation.

My best advice:  When taking sleep medications, the most important point is to NEVER ‘double up’.  If you take two tablets instead of one of any medication, you will never get the same benefit from taking one again.  You will only run out early, and the doctor, pharmacist, and state will all prevent early refills  The second point is that newer sleep meds will not just make a person fall asleep.  For the first few nights a new medication might feel more potent, but over time, the best thing a sleep med will do is HELP a person fall asleep.  Patients must do everything else correctly, including sleep hygiene measures such as using a dark, somewhat cool room, using white noise to help the mind avoid focusing on creaking boards or other noises, avoiding significant alcohol use, avoiding caffeine after noon, avoiding eating or smoking right before bed,  calming down at the end of the day (some people can’t  sleep if they exercise late in the day), dimming lights, avoiding watching football right before bedtime, etc.

If you do all those things, a sleep medication will help ease the transition to sleep.   But the shorter meds like Lunesta and Ambien work best when they take effect in people who are in bed already, working on getting to sleep.  People often make the mistake of taking a sleep medication and wating to go to bed until they feel sleepy.  The newer sleep meds don’t cause the sleepiness that came with the older drugs, and they don’t last near as long.  Waiting ‘until they work’ can also cause amnestic behaviors like sleep-eating, sleep-sexting, sleep-driving, and worse.

Give these issues some thought and tell me the amount of gabapentin you take.  Beyond the controlled substances, consider trazodone or clonidine, two medications that work differently than benzodiazepine and Ambien.

The best sleep, of course, is found in the unmedicated condition desiged by evolution.  Evolution is not fast enough to keep up with changes in communication and the social media phenomenon, so it is often useful to think about the sleep environment of our ancestors, 40,000 years ago.  If I knew how to use twitter, I’d hashtag ‘sleep like a caveman.’

This Suboxone Doesn’t Work!

Today on SuboxForum people were writing about their experiences with different buprenorphine formulations.  Doctors occasionally have patients who prefer brand medications over generics, but buprenorphine patients push brand-loyalty to a different level.  The current thread includes references to povidone and crospovidone, compounds included in most medications to improve bioavailability.  Some forum members suggested that their buprenorphine product wasn’t working because of the presence of crospovidone or povidone.  Others shared their experiences with different formulations of buprenorphine and questioned whether buprenorphine products are interchangeable, and  whether buprenorphine was always just buprenorphine, or whether some people respond better to one product or another.

My comments, including my observations about patient tolerance of specific buprenorphine products, are posted below.

Just to get some things straight about povidone and crospovidone (which is just another synthetic formulation of povidone),  both compounds are NEVER absorbed, by anyone.   They are part of a group of compounds called ‘excipients’, and are included in many medications to help with their absorption.  They act as ‘disintegrants’– meaning they allow the medication to ‘unclump’ and dissolve in liquids, such as saliva or intestinal secretions.

Molecules tend to clump together, sometimes into crystals, sometimes into other shapes.  A pile of powdered molecules molded, packed, and dried into pill form wouldn’t dissolve in the GI tract if not for povidone or other disintegrants.  I remember reading somewhere about cheap vitamins that could be found in the stool, looking much the same as they did when they were swallowed.  Not sure who admitted to doing the research for that article..

Buprenorphine IS buprenorphine.  Period.  The absorption isn’t affected much by excipients, because nobody ever complains that their Suboxone or buprenorphine won’t dissolve.  Povidone or crospovidone are also added to increase the volume, because an 8 mg tab of buprenorphine would be the size of 100 or so grains of salt.  Excipients like povidone and crospovidone also help some drugs dissolve, especially drugs that are fatty and don’t usually dissolve well in water-based solutions.   This last purpose does NOT apply to buprenorphine, since buprenorphine is very water-soluble.  Zubsolv is supposedly absorbed more efficiently in part because it dissolves very quickly, and maybe that is due to excipients.

I realize that when I write ‘bupe is bupe’ it sounds like I don’t believe those who complain about their medication.  But honest, I work with people over this issue every day…  I have an equal mix of people who insist Suboxone doesn’t work for them and people who insist ONLY Suboxone works for them.    Today I was reading TIP 43–  a guide about medication-assisted treatment put out by SAMHSA and the Feds that is over 300 pages long, very well-cited– in a section that cited studies about the psychological triggers for withdrawal symptoms.  TIP 43 and other TIPs can be downloaded for free… just Google them.  TIP 43 is primarily about methadone, but some of the information applies to methadone and buprenorphine.  The pertinent section was around page 100, if I remember correctly.

The TIP information mirrored what I see in my practice.  For years, I’ve noticed that patients will complain about withdrawal symptoms even at times when their buprenorphine levels are at their highest.  Patients also report that their withdrawal symptoms go away ‘right away’ after dosing, when in fact buprenorphine levels won’t increase significantly for 45-60 minutes.  People who have been addicted to opioids may remember how even severe withdrawal mysteriously disappeared as soon as oxycodone tabs were sitting on the table in front of them.   The bottom lline– withdrawal experiences are remembered, and those memories are ‘replayed’ in response to triggers or other memories.

In my experience as a prescriber, I’ve come to believe that patients with an open mind will learn to tolerate any type of buprenorphine (the exception being the 1 patient I’ve met who developed hives from meds with naloxone– hives that appeared consistently on three distinct occasions).  But withdrawal symptoms seem to be triggered, in many people, by the expectation of withdrawal symptoms.  So someone convinced he will never tolerate Zubsolv, Bunavail, or Suboxone Film will probably never tolerate those medications.

As for buprenorphine, it IS just buprenorphine.  Molecules with a certain name and structure are always identical to each other.  They are not ‘crafted’ products like bookcases or tables;  some buprenorphine molecules aren’t made with a quality inferior to other buprenorphine molecules.  And once a molecule is in solution, I don’t see much role for excipients.  Of course a tablet or strip could contain too much or too little active drug, but that is an FDA issue, not an excipient issue.

Drug Court Organization Lobbied Against Suboxone

For years, people familiar with the benefits of buprenorphine have wondered– who is the idiot standing in the way of increasing access to this life-saving treatment?  One of the idiots was recently identified, when an open-records request by the Huffington Post uncovered a letter to HHS Secretary Sylvia Burwell from West Huddleston, then-CEO of the National Association of Drug Court Professionals.

In the letter, Huddleston wrote that allowing doctors to see more than the current limit allows ‘will result in the expanded use of buprenorphine in a manner that is less responsible and presents greater risk to the health and safety of the individuals and communities we both serve.’   The Huffington Post correctly points out that over 28,000 Americans died from opioid overdose in 2014, when the letter was written.

People familiar with buprenorphine know that the medication virtually eliminates the risk of death by overdose– even when taken incorrectly.  The anti-medication lobby, fueled by the large profits of revolving-door ‘abstinence-based’ treatments, has used fear of diversion of buprenorphine as a weapon against greater access to the medication.  But stories about diversion always fail to mention key facts about buprenorphine– for example that of the 30,000 US opioid overdose deaths last year, only about 40 had buprenorphine identified as one of the drugs in the bloodstream at the time of death.  And of those 30,000 deaths, none were CAUSED by buprenorphine.

There have been overdose deaths that were in-part due to buprenorphine or buprenorphine/naloxone medications (i.e. Suboxone, Bunavail, and Zubsolv).  But such deaths are rare.  In order for buprenorphine to contribute to overdose, the victim must 1. Have a low tolerance to opioids, and 2. Have a low tolerance to a second respiratory depressant, taken around the same time in sufficient amount.   In other words, someone physically dependent on opioids cannot overdose on buprenorphine.  In fact, buprenorphine products would precipitate severe withdrawal if taken by opioid addicts within a few hours of heroin, oxycodone, or other opioid use.

Drug courts in my area tend to avoid medication assisted treatments, with the exception of Vivitrol or IM Naltrexone.  There is no evidence that blocking opioid receptors for a year has any effect on death rates from opioids.  Studies have reported that patients who stay compliant with treatment, who return each month for another injection of naltrexone, don’t waste their money on agonists that would have no effect on them.  But what happens 6-12 months later, when probation ends and those patients are no-longer required to take naltrexone?

I wish I could tell you what happens– but I can’t, because nobody has done the studies to find out.  The cynic in me takes it further, wondering if anyone even cares what happens when people are temporarily maintained on naltrexone and then allowed to stop the medication?  I’ve asked physicians, prosecutors, and law enforcement the same question:  what happens to the person when the naltrexone is discontinued?  In response I usually hear ‘what do you mean?’  Or ‘how would I know, since I don’t see them anymore?’, or ‘I assume they do fine… don’t they?’

I don’t see much concern when I explain that people who stop naltrexone are in a state of ‘reverse tolerance’ making them more susceptible to death by overdose.   So I remind them of the large number of overdose deaths in people who were recently released from a controlled environment, such as residential treatment or incarceration, after tolerance dropped to normal levels.  Maybe I’ll point out the Australian studies that show a 12-fold higher death rate in addicts who were maintained on naltrexone.   But by that time I’ve lost the person’s attention– just as their attention leaves each addict when his/her probation expires.  ‘Not my problem anymore.’

Huddleston is no longer the CEO, but the NADCP continues to express a muddled message about buprenorphine medications.   If you have a minute, you might consider educating the NADCP staff about the value of buprenorphine treatment.

Meanwhile, HHS Secretary Burwell says changes to the cap are coming.  I received 12 calls last week from people looking for help.  I’ll keep telling them to try to be patient.