Category: Suboxone

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!

Tapering Off Buprenorphine or Suboxone pt. 1

Many patients taking buprenorphine live in fear of a dark world around the corner where they will have to taper off the medication.  They see horror stories on YouTube posted by people who, for some reason, abruptly stopped the medication and kept a video log of their experiences.   My own patients sometimes ask, nervously, if I plan to retire some day.  Some have asked what they should do if I ever, say, drop dead.

It needn’t be all that bad.  Yes, sudden discontinuation of a typical dose of buprenorphine will result in withdrawal symptoms.  But if you taper correctly, your body will slowly reset your tolerance without putting you through the wringer.   In this post I’ll describe my typical approach to helping a person through that process.  But first we should correct some of the misconceptions about buprenorphine and opioid dependence.

It does NOT get harder and harder to stop buprenorphine the longer you take the medication.  I have heard that idea over and over in one form or another, and I presume it comes from the experience people have with active addiction where use tends to grow with time, and other facets of life gradually fade away.   But the opposite occurs in patients treated with maintenance agents like buprenorphine or methadone, where use of the medication does not trigger a reward or relieve the ‘punishment’ of withdrawal.   The conditioning that occurred during active addiction is slowly extinguished, and most people gradually lose the desire to use opioids.   I’ve witnessed this process literally hundreds of times over the past 12 years in patients on buprenorphine or methadone. Patients of successful treatment also develop interests and accomplishments that help them avoid returning to opioids.  And after a few years away from ‘using friends’, people no longer see themselves as part of the using scene.  Patients get to a point where they have too much to lose to get close to that world again.

Opioid withdrawal has physical and psychological dimensions.  During short-term detoxes, minor physical symptoms trigger fears that magnify the perception of those symptoms.  A bead of sweat on the neck signals that hot flashes, diarrhea, and depression are on the way.  Patients who have been away from the cycle of using and withdrawal don’t seem to have as many emotions about their physical symptoms.  I see the change very clearly in methadone-assisted treatment, where the minor withdrawal at the end of the day is a big deal to people starting treatment, but a minor inconvenience in patients tapering off methadone after several years of treatment.

Does buprenorphine ‘get in your bones’?  YES, of course!  Bones are living tissue, so anything in the bloodstream gets in the bones.  Glucose gets in your bones.  Aspirin gets in your bones.  But so what? When you taper off buprenorphine, the buprenorphine in your body will be metabolized and removed.  It does not accumulate or stay in bones or other tissues beyond what occurs with other fat-soluble molecules.

Is buprenorphine or Suboxone ‘the hardest opioid to stop’?  No.  The brain keeps no record of the molecules that pushed opioid tolerance higher.   The challenge during a taper is that opioid receptors have become down-regulated by opioid stimulation, resulting in reduced endorphin tone as the opioid is removed.   Opioids that leave the body quickly tend to have more-intense discontinuation effects than those that leave more slowly because the latter mimics a taper, where opioid activity decreases over time.  The longer half-life of buprenorphine also slightly extends the total period of withdrawal by a few days.

I’ve heard people claim that ‘heroin was much easier to stop’, and rather than tell people what they should think I’ll let them have their opinions on the issue.  But that opinion is not supported by studies comparing withdrawal from different opioids.  Usually the claim is followed by the comment that ‘with heroin I was fine after 4 days’ or something along that line.  But it takes longer for tolerance to reset, after ANY opioid.  I suspect that perception comes from the severity of early heroin withdrawal, making subsequent weeks easier by comparison.  Again, the brain doesn’t care which opioid you used to take;  it only cares that the opioid stimulation that was there is now gone.

In a few days I’ll share the approach I recommend to patients tapering off buprenorphine.

Buprenorphine, Not Subbies

I’ve been writing longer and longer posts on SuboxForum so maybe I need to write more here.  This blog archives twelve years of frustration over the ignorance toward buprenorphine, at least until I ran out of steam a year ago.  I grew used doctors refusing to treat people addicted to heroin and other opioids.  I became used to the growth of abstinence-based treatment programs, even as relapse rates and deaths continued to rise.  It isn’t all bad news; I enjoyed the past couple meetings of AATOD, where people openly spoke about medication-assisted treatments without hushed voices.  I feel like I’m the conservative one at those meetings!

I don’t remember where I heard first – maybe in an interview with some reporter about addiction- that I was an ‘influencer’ with buprenorphine.  The comment surprised me, because from here I don’t see the influence.  My supposed influence is from this blog, although I may have changed a couple of minds in my part of my home state among my patients, who had to sit across from me and hear me talk. For an ‘influencer’ I’m not very happy about how many buprenorphine-related things have gone over the years.  I still see the same reckless spending of resources, for example. A couple million people in the US abuse opioids, and only a fraction receive treatment.

Those are big things, and anyone reading my blog knows all the big things.  I want to write about the little things.  The easiest way to have influence is to write about the things that nobody else writes about.  After all, that’s what made me an influencer in the first place, back when I had the only buprenorphine blog out there. Here’s what I want to influence:  If you’re trying to leave opioid addiction behind, do not call buprenorphine ‘subs’ or subbies.

On the forum I try to keep things real – not in a cool way, but in a medical or scientific way.  I want people to use .  I know I sound like some old guy frustrated by all of the new words and acronyms on social media.  YES, dammit, I AM frustrated by those things!  But communication has become so…. careless in the era of Twitter and texting.  Find an old book and notice the words and phrases used by educated people 100 years ago.  Or look in the drawer at your mom’s house where she kept letters from your dad, or from her friends.  Does anyone communicate in sentences anymore?

I’m not crazy (always pay attention when you catch yourself saying that!), so I realize this isn’t the start of a wave (what color would THAT one be?)   But I might show a couple people how loose language is used to take advantage of healthcare consumers. In the next post I’m going to show an example of ‘fad-science’ masquerading as alternative medicine, promoting substances that avoid FDA scrutiny by identifying as nutrients and not drugs.  Some large scams benefit from the informal attitudes toward health and medicine;  attitudes that might encourage more discussion about health, but also lead people to think that medical decisions are as easy as fixing a faulty indicator on the dashboard with the help of a YouTube video.  As in ‘I can treat it myself if I can find the medicines somewhere.’

The point is that common talk about medicines is helpful unless it isn’t.
Many people in my area addicted to opioids treat themselves with buprenorphine, either now and then or in some cases long-term.  Is ‘treat’ the right word?  From my perspective I’d say yes in some cases, and no in others.  Last year I took on 4 patients who were taking buprenorphine medications on their own, paying $30/dose, for more than a year.  They said (and I believe them) that they hadn’t used opioid agonists for at least that long.  I’ve also taken on patients who used buprenorphine but also used heroin, cocaine, and other illicit substances.  There is a big difference between the two groups in regard to level of function, employment, relationship status, emotional stability, dental and general health status, and finances.  Another difference between them is that people in the first group talk about taking buprenorphine or Suboxone or Zubsolv.  Those in the second group talk about finding subbies.

I also have patients in my practice to whom I prescribe buprenorphine, who sometimes talk about subbies, or subs, or ‘vives’, or addies.  I correct them and tell them that I have a hard time trusting patients who talk that way.  After all, those are street terms.  A pharmacist doesn’t say ‘here’s your subs!’

So here’s the rub.  Should I discharge these patients? Should I assume from their language that they are part of the street scene, and maybe selling medication I’m prescribing?  Or should I just watch them closer and be more suspicious, doubling the drug tests and pill counts? Should I tell the police?
No, of course not.  I took it that far to make a point about slippery slopes, and the struggle to find a foothold while sliding.

But I will continue to correct them, and let them know that their words create a certain impression.  Getting that point across would be enough influence for one day!

Missing the Point of Buprenorphine Treatment

A forum reader wrote about concerns over a partner on buprenorphine.  Her concerns pointed out a common misperception about the goals of treatment of opioid use disorder using buprenorphine, or using methadone for that matter.

Her question, amended for privacy:
I married the love of my life.  He is still he love of my life but has been an addict for 15 of them. Our children have been greatly affected by his addiction.  He made promise after promise that he was clean, and I dove back in with complete faith time after time only to get burned.

His addiction started with recreational pills increasing over time, but now he is abusing Suboxone.   He was taking up to 12 mg depending on the day, but no pain pills for the last year. I suggested a Suboxone doctor and a plan to get off, and my husband called one and was able to get right in.

At the visit the doctor did a half ass intake and called in a prescription for an 8 mg tab for induction.   After induction they called in prescription for 20 mg/day.   My husband stayed with 4 mg once a day and was “blah” in the afternoon and irritable but not physically sick.  On his next visit to the doctor he was proud, but when he told the doctor he had only take 4mg in the mornings she got angry. She told him she wouldn’t see him anymore if that’s what he was going to do. He asked how long he would be on it and she wouldn’t give any kind of answer. I asked again before we left and she snapped at me.

I see a profound change in him after each time we see her and she tells him to take more. We walked away last time with another prescription for 16 mg a day which is just about double what he’s been taking for the last year and a half. So my question is, how does it make sense to treat someone taking 8 mg as their addiction with the same medication at double the dosage? Since seeing her he has decided he needs to take it more than once a day as well as up the dosage.  Is this right? Is it right to treat Suboxone addiction with Suboxone? A heroin addict isn’t treated with more heroin and a pill addict isn’t treated with more pills.  While I understand the concept of treating his original pill addiction with Suboxone, I am having a very hard time wrapping my head around what’s happening.

Me again… 
The writer raises interesting questions.  Regarding the ‘drug for a drug’ questions, buprenorphine has significant pharmacologic differences from heroin or pain pills. Those differences, including the long half-life and ceiling on agonist effects, allow the medication to create a level degree of mu-receptor agonism across the dosing interval.  Tolerance to that level mu agonism allows patients on the medication to feel ‘normal’ throughout the day, or at least normal from an opioid standpoint.

But her broader point provides an example of the basic misunderstanding many people have about medication assisted treatment, in focusing on the same short-term goals that their addicted loved ones have focused on: controlling the dose of opioid and tapering off.  That goal is natural, of course;  anyone who loves a person addicted to opioids wishes and hopes that the person will reverse the using behavior and climb down from opioid use.  Those hopes are bolstered by ads for rapid detox, even as studies show that detox is mostly useless.

My response to her:
I would not be concerned about increasing the dose of buprenorphine, because there is no increase in effect after a dose of about 8 mg per day.  A higher dose might reduce mild withdrawal symptoms at the end of the dosing interval, and sometimes provides a reduction in cravings through a placebo effect.

So why increase? Because the goal with buprenorphine treatment is to put cravings into remission for a considerable length of time. If your husband is still having cravings as he gets by on 8 mg, then his dose is not high enough. Buprenorphine is a safe medication that is used as a tool to extinguish the conditioning that was part of your husband’s addiction.

One of my patients saw a different buprenorphine physician for years, and her dose was constantly lowered over the past year. She would run out of medication after 24 days each month and then go without for 6 days, craving opioids and experiencing wtihdrawal during that time.  In some ways, her entire time in treatment was a waste.  She could boast, I suppose, that she was prescribed less buprenorphine over time. But in most ways she is just as far from stopping opioids as when she entered treatment, still lying to her husband, lying to her doctor, and feeling ashamed of herself.   All of those things  keep her addiction in the dark, where it stays active.

When I started treating her my goal was to promote legitimate behavior. I increased her dose to 12 mg per day, from 8 mg.   After a month she still ran out early, So I raised the dose to 24 mg per day. Now, after 6 months, she has taken the medication as prescribed. Her focus on buprenorphine is going down, as we want it to do. She isn’t lying, and she isn’t craving pain pills or buprenorphine. My goal is for her to take the medication like she would take a vitamin or blood pressure pill, without any special attention or interest.

How long will we do this? I can’t say now. We know from research that the longer a person stays on medication, the less risk of relapse after stopping. I don’t like to push anyone off buprenorphine, because I’ve seen so many people who have relapsed after being pushed off by their former doctors.  I find that many people eventually decide that the time has come to taper off buprenorphine, and those efforts are usually successful.  From my perspective, people forced to taper off buprenorphine do not generally do well.  That perspective is just an opinion, but an opinion based on treating 800 people with buprenorphine over the past 11 years.

Opinions aside, the goal is not about getting off opioids as fast as possible. Your husband can accomplish that in a couple weeks with a remote hotel room and a bottle of clonidine, or a couple weeks in jail. But those experiences rarely lead to prolonged abstinence, and they sometimes precede overdose, when people return to using with a lower tolerance.

I can’t tell whether your husband’s doc is on the right track or not– but she might be. She is a better doctor telling you that she can’t give a time estimate, than a doctor telling you he will be off in 3 months.  Ideally, your husband will be in a state of ‘remission’– on a dose of buprenorphine that virtually eliminates interest in opioids– for a year or more. He can taper for some of that time, but the taper should be slow enough that he doesn’t return to using.  If he returns to active use, he starts over in many ways.

Try to drop the focus on ‘how much’ or ‘how long’. Those things are not important; what is important is to get his interest back on you and the family, not on buprenorphine or other opioids. That will be easier if you let him know that he has your support, even if he takes a medication, and even if he needs that medication for a long time. You would want the same from him if you ever needed a medication for hypertension, diabetes, or anything else.

Ten Gripes of Buprenorphine Doctors

I recently gave a lecture to medical students about opioid dependence and medication assisted treatment using buprenorphine, methadone, or naltrexone. I was happy to see their interest in the topic, in contrast to the utter lack of interest in learning about buprenorphine shown by practicing physicians. In case someone from the latter group comes across this page, I’ll list a few things to do or to avoid when caring for someone on buprenorphine (e.g. Suboxone).

1. Buprenorphine does NOT treat acute pain, so don’t assume that it will. Patients are fully tolerant to the mu-opioid effects of buprenorphine, so they do not walk around in a state of constant analgesia. Acute pain that you would typically treat with opioids should be treated with opioids in buprenorphine patients. Patients on buprenorphine need higher doses of agonist, usually 2-3 times greater than other patients. Reduce risk of overuse/overdose by providing multiple scripts with ‘fill after’ dates. For example if someone needs opioid analgesia for 6 days, use three prescriptions that each cover two days, each with the notation ‘fill on or after’ the date each will be needed.

2. Don’t say ‘since you’re an opioid addict I can’t give you anything’. There are ways to provide analgesia safely. If you do not provide analgesia when indicated, your patient will only crave opioids more, and may seek out illicit opioids for relief. Unfortunately nobody will criticize you for leaving your patient in pain, but they should!

3. Don’t blame the lack of pain control on laws that don’t exist, for example “I’d like to help you but the law won’t let me.” Patients deserve honesty, even when the truth makes us uncomfortable. We get paid ‘the big bucks’ for tolerating the discomfort that sometimes comes from frank discussions with our patients.

4. Don’t assume your patient can or cannot control pain medications. If a patient has been stable on buprenorphine for years, he/she may have a partner or family member who you can trust to control pain medications. Some patients stable on buprenorphine can control agonists used for acute pain, but I wouldn’t stake my life, or theirs, on that ability. A useful compromise is to prescribe enough pain medication to cover 1-2 days of analgesia on each of several prescriptions, each with a ‘fill after’ date, to reduce the amount of agonist controlled by the patient at one time.

5. Don’t tell your patients that ‘opioids don’t work for chronic pain.’ I see stories on such great medical sources as the ‘Huffington Post’ explaining that ‘opioids never help chronic pain’. In reality, your patients know that opioids DO treat chronic pain, so they will consider you a liar or an idiot if you clam they don’t. The challenge is explaining the risk/reward equation to your patients, and explaining why treating chronic pain with opioids often leads to greater problems, as the risk/benefit equation is changed by tolerance.

6. I know this will cause heads to explode, but don’t assume that chronic pain is always less severe than acute pain. What if your patient’s chronic pain is worse than the typical pain after cholecystectomy or ACL repair? Most doctors would gasp at the idea of recovering from major surgery without opioids. What if the pain from failed back syndrome is worse?! I have had a few patients who, I’m certain, experience a great deal of suffering, and have gone so far as to have brain or spinal cord implants to get relief. I’m not arguing that we treat chronic pain in the same way as acute pain. But we shouldn’t jump to the conclusion that chronic pain isn’t severe enough to warrant opioids in order to dismiss those complaints more easily.

7. Don’t tell your patient to stop taking buprenorphine unless you’ve talked with the doctor who is prescribing that medication, and realize that the doctor you are calling knows more about buprenorphine and addiction than you do.

8. Don’t ask patients ‘how long are you going to take that stuff’ or criticize patients’ use of buprenorphine medications. Likewise psychiatrists shouldn’t tell patients scheduled for knee arthroscopy that the procedure is controversial, or talk patients out of hernia surgery.

9. Don’t assume that the doctor prescribing buprenorphine knows what YOU are doing. Too often patients will tell me about surgery that they failed to discuss in advance, even calling about pain hours after getting home from a procedure they failed to mention. Some people seem to believe that doctors regularly collaborate on their care, even though the opposite is closer to the truth.

10. Don’t assume that unusual or atypical symptoms come fromo buprenorphine. One truism of medicine is that doctors tend to blame unexplained symptoms on whatever medication they know the least about. Fevers of unknown origin, mental status changes, or double vision are not ‘from the buprenorphine!’

Those are the gripes at the top of my list. Did I miss one of yours? Or for patients, have you suffered from breakdowns in the system?

Addendum: 11. When treating post-surgical pain in buprenorphine patients, choose one opioid and stick with it. What often happens is that doctors will use one opioid, say morphine… and when nurses call a few hours later to say the patient is still screaming, they change to a different opioid, then another after that. As a result, the patient is placed on insufficient doses of several opioids, rather than an adequate dose of one medication.

There are two critical issues in treating such patients effectively. First, providing pain relief comes down to competition at the mu receptor. A certain concentration of agonist in the brain and spinal fluid will out-compete buprenorphine and provide analgesia. You cannot get there by adding other opioids together. If you use oxycodone for an hour and then change to dilaudid, you are starting over. Instead, choose one drug, preferably something that can be given intravenously, and stick with it. Morphine is not a good option btw, because of the low potency and histamine releasing properties of that drug.

Second, remember that analgesia and respiratory depression travel together, both mediated by the mu receptor. Anesthesiologists know this principle well… opioid medication can be titrated to respiratory rate, providing that the medication is given IM or IV. If a patient is breathing 28 times per minute, he/she is in pain. If the patient is breathing 6 times per minute, pain is not a problem, and the patient should be monitored for respiratory depression and possible overdose. When treating pain, doctors should aim for a respiratory rate of 14-18 breaths per minute, making sure that the medication is actually getting into the bloodstream (the risk comes when patients are given SQ injections or oral doses of narcotic that enter the bloodstream later, causing toxic blood levels).

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.

Opioid Induced Hyperalgesia Prevented by Buprenorphine?

“Buprenorphine is a kappa receptor antagonist. For these reasons, buprenorphine might be unique in its ability to treat chronic pain and possibly OIH.”

The opioid crisis has been fueled by the use of opioids to treat chronic pain.  Practice patterns have changed, but doctors are still criticized for their roles in the overuse of opioids.  I’ve sat through community ‘heroin forums’ (sometimes on stage) as sheriffs, politicians, and ‘recovered addicts’ firmly pointed fingers at health professionals.  I, meanwhile, kept my finger under the table, but had the thought that some of the people pointing would be the first to complain if they were forced to stop pain medication prematurely for their own good or ‘for the good of the community.’
Doctors can’t see into the future.  I suspect most cases of opioid overuse began with well-intended efforts to provide temporary pain relief.   But then for a variety of reasons things didn’t go as planned.  Maybe the planned knee or back surgery never took place because of patient indecision or insurance problems.  Maybe the lumbar strain didn’t heal after 6-8 weeks the way it was supposed to.  In any case, doctors who work with pain patients know what happens next.  Before the next appointment, the doctor plans to tell the patient that the time has come to stop opioids.  But after that suggestion, the patient replies that the pain is even worse now than when the pain meds were started.  “Actually (says the patient) I was going to ask you to increase the pain medication!”
Some doctors hold fast to their plan and initiate a taper.  Some doctors argue over the issue, and some manage to create enough fear in the office that no patient would dare talk back. Too often, patients are suddenly cut off high doses of opioids, precipitating withdrawal symptoms that drive them toward illicit pills or heroin.  Patients who manage to maintain scripts for opioids embark on a miserable journey that often ends badly.
I’ve converted many pain pill patients to buprenorphine patients over the years.  I could save time using a rubber stamp to document their histories:  (blank)-year-old man was started on pain pills after (blank) injury (blank) years ago; dose was increased over time using oxycodone then OxyContin then fentanyl patches; patient lost the ability to control the medications and ran out early, resulting in discharge from treatment.  Patient presents asking for treatment with buprenorphine.
Many past patients fit this description, riding the gray area between opioid dependence and pain.  Lawmakers and policy-writers seem to believe that most patients are either addicts or pain patients.  Doctors who work in the field know that most patients sit in the middle, with smaller groups on each side. **
I’ve been surprised at how well those pain patients do after changing to buprenorphine.  They usually feel much better overall, which is no surprise given the misery of living according to a cycle of relief and withdrawal.  More surprising is that their pain is reduced, sometimes completely.  I assume the reduction in pain relates to stopping the cycle of relief and withdrawal, although I don’t know the mechanism beyond that idea.  People who take opioids become more ‘somatic’ over time, more and more focused on symptoms including those that warn of impending withdrawal; perhaps buprenorphine reduces that tendency toward somatization.
Which brings us to opioid-induced hyperalgesia or ‘OIH’, where prolonged use of opioids makes pain symptoms worse.  I’m reluctant to go ‘all in’ on OIH, just as I reserved full judgement of the full range of symptoms blamed on TMJ, EBV, IBS, CFS, FM, MCS, WPW, PMS, PMDD, RSD, CRPS, RLS, GAD, SAD, DID, IED, and other ‘initialed diseases’ that have garnered headlines over the years.   (Can you name them all? *** Try THESE )   Attention on OIH has waxed and waned over the years, and is gaining attention now as PROP, the CDC, and SAMHSA talk down opioid use.
LOL.
But seriously, my problem with OIH starts with awareness that pain sensation is very complicated.  Different people describe varying pain intensity for the exact same stimulus.  And even within one patient, intensity varies according to mood, fear, the duration of the pain (expected and actual), the perceived reason for the pain, the perceived harm from the stimulus, the setting (e.g. home vs. laboratory), and many other variables.  It is one thing to see how long it takes a rat to flick its tail when placed over a heat lamp, but another when a human fills out a pain scale.
I also take note of selection bias, a phenomenon that occurs whenever science bumps into political forces where studies citing the occurrence of a phenomenon are more likely to get government funding and editor approval than studies denying the phenomenon.  And no, I’m not a denier—of anything.  But I know bias when I see it. I’ve seen articles that conclude ‘there is not enough evidence to rule OUT the existence of OIH’, which is the opposite of how good science is supposed to be conducted.
You’ll find a great review of OIH here: http://www.painphysicianjournal.com/current/pdf?article=MTQ0Ng%3D%3D&journal=60
A cautious reader of the literature will note that at best, OIH is more of a ‘basic science’ phenomenon than a ‘clinical phenomenon.’   Increased pain sensitivity in response to opioids is subtle.  If it wasn’t, it would have been described decades, even centuries ago.  The linked material references older comments that the authors suggest came from observations of OIH, but to my reading the comments more likely referred to the withdrawal that follows opioid use.  You’ll also notice, if you read the linked article, that most of the studies of OIH in humans look at pain sensitivity in long-term methadone patients.  But you’ll also read that in theory, methadone is one of the least-likely opioids to cause OIH.
Interestingly, the other opioid agent with lower likelihood to cause OIH is… buprenorphine.  From the link above:  Buprenorphine has been shown to be intermediate in its ability to induce pain sensitivity in patients maintained on methadone and control patients not taking opioids. Buprenorphine showed an enhanced ability to treat hyperalgesia experimentally induced in volunteers compared to fentanyl. And spinal dynorphin, a known kappa receptor agonist, increases during opioid administration, thus contributing to OIH. Buprenorphine is a kappa receptor antagonist. For these reasons, buprenorphine might be unique in its ability to treat chronic pain and possibly OIH.
In short, long term use of opioids appears to increase pain sensitivity.  But we are a long way from understanding the extent of that phenomenon.  Some studies suggest that all opioids are not equal in regard to OIH, and I wonder if the reported decrease in pain from relatively minor injuries such as lumbar strain, when people change from opioid agonists to buprenorphine, is caused by a decrease in opioid-induced hyperalgesia.
But then again, maybe those patients just thought they had pain because of a subconscious (or conscious) desire to get pain pills.
For whatever reason, people with chronic pain seem to do well on buprenorphine.  Hopefully all of the concerns over opioids will leave us at least that one treatment option.  Give the extreme safety of buprenorphine, that should be a no-brainer!
**At least that was the case until several years ago, when I began seeing more and more patients who ‘started heroin recreationally’- an oxymoron if there ever was one.
***TMJ = temporomandibular join disorder, blamed for chronic headaches and other symptoms; EBV = Epstein Barr Virus; IBS = irritable bowel syndrome; CFS = chronic fatigue syndrome; FM = fibromyalgia; MCS = multiple chemical sensitivity; WPW = Wolf Parkinson White; PMS = premenstrual syndrome; PMDD = premenstrual dysphoric disorder; RSD = reflex sympathetic dystrophy;  CRPS = complex regional pain syndrome; RLS = restless leg syndrome; GAD = generalized anxiety disorder; SAD = seasonal affective disorder; DID = dissociative identity disorder; IED = intermittent explosive disorder.

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.

Congress Acts on Opioid Dependence (ugh)

I won’t weigh in on the upcoming election, for fear of being barraged with insulting tweets by one candidate or ‘offed’ by the other.  But the current opioid dependence crisis provides a great chance to learn whether you stand on the side of ‘limited government’ or the alternative.
The TREAT Act takes 5 minutes to read, that would have increased the cap on buprenorphine patients.  President Obama undermined the TREAT Act by announcing his own plans to raise the cap soon after the TREAT Act was presented in the Senate.  After 7 years without mentioning heroin or opioid addiction, it’s hard to believe Obama’s actions were a coincidence.   Only a master politician can ignore 200,000 deaths, and then claim to solve the problem single-handedly despite a do-nothing Congress!
As I wrote earlier, few doctors will make use of Obama’s lousy offer.  Today Congress approved a bipartisan bill that will reportedly signed ‘begrudgingly’  by President Obama– who complained that the Bill ‘doesn’t go far enough.’  I wonder how many pages HIS Bill would be.
I invite readers to check out the language of the TREAT Act in regard to the buprenorphine cap– and then read the language of the ‘Comprehensive Addiction and Recovery Act of 2016‘.  And then, please, tell me how many patients doctors will be able to treat with buprenorphine.  The new law will provide treatment authority for nurse practitioners and physician assistants– I think.  How?  When?  How many?  I see a number of details that are left to the HHS Secretary–  a post that changes a couple times during a 4-year Presidential term.
How do we set up practices based on rules that change every couple years?!
I’m no political scientist, so I’m just reading the Bill and trying to figure it out– and I encourage you to do the same.  Myself, I prefer the language of the TREAT Act, but hopefully the attorneys will get this new thing figured out and let us know how many people we get to help with buprenorphine.

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.