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.

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.

Blame Suboxone!

First Posted 3/24/2014
I recently came across the blog of a person who has dedicated his life to trashing buprenorphine treatment.  I won’t provide the name or link, as I don’t want to waste my own ‘page rank’ on supporting his misplaced anger.  But I suspect many readers of my blog have stumbled across that one as well, given the similarity of our keywords.    His blog doesn’t contain personal comments, I suppose because there are only so many ways to say ‘darn that Suboxone’.  Instead he auto-posts stories from across the country from newsfeeds, with keyword combinations of ‘Suboxone’ or ‘buprenorphine’ plus ‘robbery’, or ‘death’, or ‘overdose’, or ‘real bad person.’  I made the last one up, but you get the idea.
The person lost his son several years ago, a tragedy that would usually keep me from adding my own commentary.  But in the several years since his son’s death, he has written a number of diatribes on other anti-buprenorphine web sites.  In other words, he has contributed to the deaths of enough young people that by now, counterpoints are long overdue.
In his ‘about me’ section, he writes that his son took Suboxone for about 18 months, and died over two years after stopping buprenorphine/Suboxone.  He explains, in twisted logic, how the death is not the fault of his son’s drug addiction, or the drug dealers, or easy prescribing of prescription opioids or diversion of opioid agonists, or poppy policy in Afghanistan… but because of Suboxone.
He argues that his son’s Suboxone treatment was a ‘waste of time.’  I don’t understand that argument.  Suboxone added 18 months to his son’s life—and if his son had continued taking it, would likely continue to keep his son alive.  Hardly a waste of time.
I’m always impressed by how two people can see the same information and come to opposite conclusions.  He writes that during his son’s time on Suboxone, his son was prescribed over 13,000 pills, including opioid agonists and benzodiazepines.  He doesn’t say who it was who prescribed those 13,000 pills, and doesn’t apparently hold any ill will toward the people who did.  Instead, he blames Suboxone for not keeping his son from doctor shopping, for not keeping doctors from being duped by his son, and for his home state not having the type of database that tells doctors about problem patients.  If a ‘good medication for addiction’ is going to have to do all of those things, I wouldn’t hold out much hope for a new drug approval anytime soon!
The logic he uses on the web site brings to mind a recent encounter with a patient who has successfully stopped opioids, but who is struggling with other addictive substances.  Suboxone (or buprenorphine) is one piece of a person’s recovery, and does that one thing remarkably well.  Suboxone reduces cravings for opioids, making it much more likely that a person willing to do his part of the work will be successful in stopping opioids.   But it doesn’t do everything!  It doesn’t create an interesting life. It doesn’t keep a person from lying.  It doesn’t CURE addiction.  Buprenorphine is a tool that helps people who are ready to help themselves.  Our job as doctors is to try to match the limited treatment slots with the people who are serious about sobriety.  If the doctor treating his son was wrong about anything, it was in that regard—for taking in a patient who was not serious about staying clean.
The other thing that Suboxone or buprenorphine does, remarkably well, screams out from the tragic story.  His son stayed alive while taking buprenorphine, despite taking over 13,000 doses of other dangerous, controlled substances.  Despite the reckless drug use, buprenorphine kept his son alive.  As I’ve written many times, it is very difficult for someone taking buprenorphine or Suboxone to die from overdose.  But when the medication is stopped, that protection goes away.  Should we blame nitroglycerin for NOT stopping heart attacks because a patient chose not to take it?  When a person refuses chemotherapy and then dies from cancer, do we blame the chemotherapy?
The person with the blog writes that he is ‘all about detox and abstinence’.  Who isn’t?!  I’m ‘all about having shorter winters in Wisconsin.’  Should I blame the heating oil companies for the weather we’ve had?   He is angry that doctors who prescribe buprenorphine are not more interested in STOPPING the medication.   He is angry at RB for their lack of interest in detox, and their goal to maintain compliance with their medication.  He wants more people to be in his son’s position—fighting opioid addiction without the benefit of a medication that reduces interest in opioids and prevents overdose!
Those of us who prescribe buprenorphine know the value of the medication for keeping people alive.  I have known a number of family members who bullied patients over their use of buprenorphine.  In at least six cases, those family members won out, and the patients stopped buprenorphine.  In at least six cases, they stayed off buprenorphine, all the way up until their overdose death was announced in the obituary section.  I’m not pointing any fingers…. but I certainly wouldn’t blame the outcome on Suboxone.

Suboxone Side Effects

I’ve received questions over the years from people claiming a range of symptoms from Suboxone or buprenorphine, from back or muscle pain to fatigue, depression, or irritability. I didn’t invent Suboxone, so I don’t take it personally when people blame commonly-occurring symptoms on the drug. But I get bored by the non-scientific thinking behind such claims— that since they started buprenorphine at some point in the past ten years, every symptom or illness that comes along must somehow be related to buprenorphine. No matter, apparently, that people who DIDN’T start buprenorphine often develop the same symptoms. And no matter that they themselves have done a number of things over the past few years BESIDES start buprenorphine. But over and over, people insist that they know, without a doubt, that buprenorphine has to be the problem.
I also get frustrated answering questions about these symptoms when people who complain about them are closed off to other explanations. When I point out that many non-buprenorphine patients have the same complaints, my comments provoke anger. Sometimes I’m accused of having a vested interest to keep people on buprenorphine (I don’t-beyond wanting to provide good medical care).
I have a long waiting list of patients and buprenorphine is only a small part of my practice, so I have no reason to compel use of buprenorphine. But I don’t like the risk that my own patients, or others, might be swayed by faulty logic and fret over problems that have no logical basis.
To the people who have written to ask about feeling depressed, anxious, irritable, numb, sleepy, wakeful, or dulled by buprenorphine, my answer is that in almost all cases, people on buprenorphine feel the same way they would feel if they were not on buprenorphine. People develop full tolerance to the effects of buprenorphine at the mu opioid receptor, so from a scientific standpoint, people on stable doses of buprenorphine should feel ‘normal’. Beyond the science, I can say that after treating over 800 patients with buprenorphine over the past ten years, I have seen no evidence that buprenorphine causes depression, irritability, chronic pain, emotional numbness, lack of interest in things, or personality changes. Honest.
Whenever I answer an email or forum post about buprenorphine I try to think of an explanation for the person’s perception. I try to give the person’s history the benefit of the doubt. I might have a couple of explanations for why someone might feel different on buprenorphine.
One case would be a person who is taking too little buprenorphine to stay above the ceiling threshold. Many doctors, and some patients, apply constant downward pressure to the dose of buprenorphine, I assume because of thinking that less buprenorphine is closer to total abstinence than a full dose of buprenorphine. But the benefits of buprenorphine are lost in doses insufficient to reach the ceiling effect of the medication. People taking too little buprenorphine will experience irritability, fatigue, sweating, and depression when the drug concentration drops below that level. The solution is to increase the dose enough for blood levels to stay above the ceiling threshold.
Another possible cause of irritability requires some speculation on my part. Actively-using addicts have very straightforward problems, which boil down to having enough narcotic to avoid getting sick every few hours. I’ve noticed that my own patients sometimes feel stressed or anxious in early buprenorphine treatment, as they become aware of all of the problems that were less-visible during active addiction. Most of that anxiety is only temporary, resolving as patients catch up with bills, settle legal issues, and feel less shame about behavior during active addiction.
Along the same line, active addiction sometimes allows people to postpone changes that really should be made, but were not possible during active addiction. Bad marriages seem less bad when surrounded by misery and chaos. But when a person finds happiness and moves forward in life, a miserable or abusive partner becomes more noticeable. Or maybe a marriage seemed ‘healthier’ when the partner was making the money necessary to support a drug habit. Effective treatment of opioid dependence empowers patients to make positive changes. But even positive changes come at the cost of emotional pain.
The people who remain convinced that buprenorphine is causing side effects would be best served by an open mind. Most of the complaints that I read about are identical to the complaints of my non-buprenorphine patients, and the most successful interventions include healthy living, stress reduction, and moderate exercise. Stopping buprenorphine is not going to be helpful in the absence of these interventions.
There is also the risk that the symptoms are caused by something other than buprenorphine—something more serious. An extreme example would be blaming buprenorphine for fatigue that in reality is caused by anemia, thyroid dysfunction, or heart disease. That situation is made even worse by the common behavior of doctors, who tend to blame any unexplainable symptom on the medication the patient is taking that the doctor knows the least about. Too often I’ve told patients to go to their GP because of unexplained muscle weakness, numbness, headaches, fatigue, or weight loss, only to have the doctor send them out without any tests or treatments, other than telling them to ‘stop Suboxone!’
Anyone reading this post, who truly suffers from adverse effects from buprenorphine, should report the side effects to the FDA web site so that clusters of symptoms, if present, can be identified.

Hot Flashes from Suboxone and Buprenorphine Treatment

First Posted 1/13/2014
A viewer on YouTube commented on my video about hot flashes  from Suboxone, but I don’t know if that is because the symptoms dissipate, or if people learn to deal with the symptoms.  I suspect that both are true.  But for some people, the sweating and heat are no small matter:
Here is what I wrote back, and a few more thoughts:
There seems to be a form of tolerance that develops more slowly than tolerance to the analgesic and euphoric effects of buprenorphine.  At least in the patients I’ve followed, complaints about constipation and hot flashes only go away over a period of months– after the other subjective effects of buprenorphine are long-gone.
Those who struggle with hot flashes may find relief by reducing the daily dose to the lowest amount that keeps blood levels above the ceiling threshold, around 4-8 mg per day. I think that in some case, people make the mistake of blaming withdrawal for the sweats and taking more and more buprenorphine, when the problem is too much opioid effect, not too little.
I recommend that patients carry a damp cloth or folded paper-towel, to use to create a chill when hot flashes start by touch the cloth to the face or neck. Another trick is to find a sink, and run cold water over the backs of the hands.  Anything that creates a chill—a blast of air conditioning to the face in the car, or an ice-cube touching the neck– will turn hot flashes off before they get started.
Nerves release acetylcholine to activate sweat glands in the skin, so medications that block acetylcholine reduce sweating.  But acetylcholine is also the neurotransmitter for salivary glands, so medications that block sweating will cause dryness of the mouth.  Many medications with unrelated primary functions have blocking effects at the acetylcholine receptor, causing ‘anticholinergic side effects.’   Anticholinergic effects are so common that medical students use a mnemonic as a reminder to keep the side effects in mind, when patients present with a certain pattern of symptoms:  dry as a bone, red as a beet, blind as a bat, hot as a hare, and mad as a hatter.  The symptoms are particularly common in the elderly, but can occur in younger patients taking high doses of anticholinergic medications.
The goal is to take an amount of an anticholinergic medication that reduces the worst of the sweating, without causing other anticholinergic effects.  Oxybutynin and glycopyrrolate are two medications used off label to reduce perspiration.  Sweating serves a valuable function by cooling the body, particularly in warm atmospheres.  Anticholinergic medications have the potential to cause hyperthermia, and even death.  Anticholinergic medications can also cause memory problems, particularly in older people.
Most of my patients have found that hot flashes, like constipation, become less severe over time.