Buprenorphine Diversion: Beyond a Superficial Understanding

First Posted 11/19/2013
In ‘Addiction Treatment with a Dark Side’, Deborah Sontag of the New York Times shared her observations of the clinical use of buprenorphine for treating opioid dependence, warts and all.  Readers of the Talk Zone know my bias—that buprenorphine/Suboxone is one of the only effective treatments for opioid dependence, and many patients are best-served by long-term, perhaps life-long treatment with buprenorphine.   But I read the article the article with interest because I know that Ms. Sontag ‘did her homework’, including visiting a number of practices, speaking with a number of patients, and reviewing hundreds of studies about buprenorphine and Suboxone over the course of many months.

From my perspective, the article overstates the diversion problem.  In my last post I asked if the fear of diversion should be a factor in whether buprenorphine-based medications become the leading edge of addiction treatment.    I stated my opinion—that if overdose deaths don’t pull acetaminophen from pharmacy shelves and diversion doesn’t keep hydrocodone off the market, then diversion of buprenorphine deserves little discussion relative to the value of buprenorphine treatment for addiction.

With the wave of stories describing buprenorphine as ‘controversial’, every discussion of the medication seems to revolve around diversion.   Do the numbers support the association? Deaths from Suboxone—deaths where buprenorphine was one of the drugs that caused death—amounted to several hundred over the past ten years, compared to 38,000 drug overdose deaths in 2010 alone.  The magnitude of the difference is so staggering that it deserves repetition; 400 deaths in ten years, vs. 38,000 deaths in one year.  The total number of deaths linked to buprenorphine over the past ten years is about equal to the number of people who die from acetaminophen– EACH year.

Diversion of buprenorphine is a complex issue.   Words like ‘diversion’ and ‘overdose’ are loaded with so much emotion that one word seems to tell the whole story.   A Google search of Suboxone brings up news reports such as ‘Suboxone found at overdose scene’, or ‘man arrested with cocaine, heroin, and three Suboxone tablets.’  The stories create an ugly image, with buprenorphine/naloxone as one more drug of abuse, found at ‘an increasing rate’, according to other headlines. But a superficial look at diversion yields a superficial understanding of the diversion problem.

Take as example a patient has not used illicit substances for 3 years while taking prescribed Suboxone, who relapses to heroin and dies from overdose.  News stories will describe a scene littered with needles, heroin, and Suboxone tablets.  That description creates a misleading impression of the patient’s history, and a misleading impression of buprenorphine.  Even if the story provides more detail, the headline alone will fill the tweet—the ‘news’ of the modern era.

Is the nature of diversion, the reason for diversion, or the consequence of diversion relevant to discussions about the diversion of buprenorphine?  If someone tries to hold life together by purchasing street Suboxone in a geographic region void of certified physicians, should that ‘diversion’ be included in the category as the sale of oxycodone?

What if the powerful mu-receptor blocking effects of buprenorphine have positive effects?  What if studies found a lower rate of overdose deaths in communities with greater diversion of buprenorphine?   Would that be relevant to the diversion discussion?

I do not know of any evidence that diversion of buprenorphine correlates with fewer overdose deaths.  But many public health experts predict that encouraging ‘street use’ of naloxone would reduce overdose deaths, so expecting the same from buprenorphine, a stronger and longer-lasting mu antagonist, is not unreasonable.

Patients on buprenorphine awaiting elective surgery discover that the blocking effects of buprenorphine last for weeks.  The same patients report that even after several weeks off buprenorphine, significant doses of oxycodone will relieve post-op pain, but won’t provide the ‘euphoria’ oxycodone used to provide.  Patients who could never make a week’s script for oxycodone last longer than a day can often control use of opioid agonists after surgery if kept on a small dose of buprenorphine.    Considering these findings, it is not unreasonable to wonder if there is a lower risk of death by overdose in people who ‘divert’ buprenorphine.  Buprenorphine has a much longer half-life than oxycodone or heroin, so diverted buprenorphine intended for use ‘in between’ acts as a blocker during periods of active heroin use.  Is it possible that traces of diverted buprenorphine in the bloodstream saves lives?  If so, is that relevant to discussions about diversion?

The worst diversion scenario is if opioid-naïve people take buprenorphine or Suboxone and becoming addicted to opioids as a result, i.e. diverted buprenorphine serving as a gateway drug to opioid dependence.  Nobody should take that situation lightly.  But stories from the streets bring to mind biological programs where sterile males of an invasive species are released into the wild in effort to eliminate the invasive mosquito, lamprey eel, or fruit fly.  What if the spread of buprenorphine functions as an ‘addiction moderator’ where the more buprenorphine in a community, the lower the rate of overdose deaths?

I realize that I am out on a limb— but as the saying goes, that’s where the fruit is.   If buprenorphine diversion is investigated in a superficial manner, we will collect nothing but superficial results.  The diversion of a medication with the potential to save as many lives as buprenorphine deserves a deeper level of understanding.

Pregnant Taking Suboxone: Should Social Services be Involved?

First Posted 11/4/2013
I recently saw a new patient who described treating her own opioid dependence with diverted Suboxone.  She sheepishly described reading everything she could find about buprenorphine and meticulously using half of her friend’s medication to avoid other opioids, without fail, for four years. She would likely be treating herself now, if she hadn’t become pregnant and  told her OB and a hospital nurse what she was doing.  Her disclosure prompted a call to CPS, leading to the assignment of a caseworker and the threat to remove her baby from her home.  CPS eventually allowed her to keep her baby providing that she stop using medication illegally—prompting her to call my office.
My first reaction was that everything worked out well, and justice had been served.  But since the visit I’ve thought about some of the inconsistencies in how HIPAA is applied, and in the general attitude toward doctor/patient confidentiality.
I’ve also given thought to how things could have worked out, had my patient count been at 100 rather than 99.  There are not many buprenorphine-certified prescribers in my area, and she very likely would have been unable to find a doctor if my practice was full.  Had that been the case, what would have happened?  Would CPS have backed off and told her to go back to doing what she had been doing?  More likely she would have been given the choice of stopping buprenorphine or going to the methadone/buprenorphine clinic an hour’s drive away.    In the latter case, how would that work, exactly, traveling an hour at 6 AM each day as the single mother of a newborn infant?
I suspect that if my practice had been full she would have stopped buprenorphine or Suboxone, and joined the ranks of either the 4% of people who remain clean after stopping buprenorphine or the 96% who relapse within a year.  Would anyone at CPS have noticed which group she became part of?
Her case is an example of how complicated the ‘diversion’ issue has become.  And perhaps I’m paranoid, but I feel the need to say that I am against diversion of buprenorphine.  I’m saying so because I know the righteous attitudes of some physicians who claim to be more careful than others.  So to avoid confusion…. diversion is bad.  I’m on THAT side.
But death is bad too.  And breaking patient confidentiality is bad.  My new patient is someone’s daughter, and I found myself wondering what I would have recommended had she been MY daughter?  What would the reader recommend for his/her daughter?  She is 22 years old.  She became addicted to opioids at 16, when her best friend shared Vicodin that she found in her mother’s medicine cabinet.  By 18 had tried to quit a number of times on her own and with the help of meetings.  She failed intensive outpatient and residential treatment, like the vast majority of patients who take those paths, before her parents asked her to move out.
She tried calling numbers on the NAABT and SAMHSA databases but found that all listed practices within an hour’s drive were full, or more often were out of the ‘Suboxone business.’  She went on methadone for a few months but had trouble making the 50 mile drive to the clinic in the middle of January—an understandable problem for people who know the area.
At some point she met someone who agreed to share a prescription of Suboxone, splitting the script if she picked up most of the cost.  Compared to a buck per mg for oxycodone, she thought she found a bargain.
I’m usually able to let go of conflict in such cases by arguing for the common good, or by pointing out the things that she should have done to avoid her current problems.  But those positions are more difficult when one imagines the hypothetical case of a son or daughter.
I was going to make a number of points, but it is getting late, the Packers lost, and I’m in the mood to just call it a night.  I was going to ask whether or not her isolated case truly threatens the ‘public good.’  I was going to ask if it is appropriate to call CPS about someone who has done all that she can to create a better environment for her baby.  I was going to ask if breaking her confidence for the good of the child would be a bit paternalistic by modern medical standards.  I was going to ask if there are different types of ‘diversion’, and if self-treatment, in the absence of any other option, should always be condemned?
But I think I’ll just leave it here, and ask people to imagine their own daughter in the situation that I described.  Would you be angry that she met someone who shared Suboxone?  I know that some will claim that there must be other options— an argument that I’ve already heard from several people claiming the doctor did the right thing to turn her in.  But if there were any options I didn’t mention, I am not aware of them.
What would you have recommended for your child?  Things worked out this time, but I have a waiting list of 90 people who are looking for a doctor who prescribes buprenorphine, and I had just discharged a patient the day before her call.  Nobody was out there making certain that after the call to CPS, she would find a reasonable option.  With that in mind, how was the call to CPS consistent with the thought of ‘first, do no harm?’
A few comments from the original post:
WisdomQ:
What is a pregnant woman taking buprenorphine supposed to do? Stop being addicted to opioid’s for 11 months?
A 2010 study (http://www.nih.gov/news/health/dec2010/nida-09.htm) found bupe to be less problematic than methadone. Perhaps the most powerful tool is to never tell the child about it unless the child starts to abuse opioid’s on their own; considering the power of suggestion.
Tic:
This patient had been diverting suboxone for four years. I doubt that she was looking for a provider for four years without any success.
Me:
I don’t know what things are like in your area, but patients in northern Wisconsin have no access to buprenorphine-certified physicians. Some are listed– but they are all people who either signed up but never actually prescribed buprenorphine, or who shut down that aspect of their practice.
I’ve been at the 100-patient limit since shortly after the limit went from 30 to 100. My waiting list has 90 patients. Note that I do no accept any insurance panels– not just for the 30% of my practice that comes for addictive disorders, but for all patients– but patients wanting buprenorphine have no choice (the other patients choose to see me because I provide much longer appointments, guarantee to start on time, provide easy access, etc). There were two other docs in the county that at least prescribed the medication; one left a year ago, leaving one person.
Even in areas where there are more doctors, many doctors arbitrarily discharge patients after one year (or Medicaid in a state may stop covering the medication after one year). Studies show 94% relapse rate in people treated with buprenorphine for a year– i.e. the medication is best considered as similar to most other medications, as a TREATMENT, not a CURE. There are also practices who abandon the people who struggle the most– a cruel way of practicing medicine that is unique to addiction. So again, I imagine there are places where a patient has been kicked out of the practice of the only provider, perhaps for taking a benzodiazepine– instead of seeing the illicit use as one more aspect of her ILLNESS that deserves better treatment. Perhaps you consider it fair to give a 17-y-o woman one chance– and if she fails, tough luck—- and if that is the case, I hope you’re not someone’s doctor.

Who Pays For Health Care? (Hint: We ALL Do)

First Published 4/20/2013
I realize that practice patterns differ between practices, even those treating the same condition (opioid dependence) with the same medication (buprenorphine).  Differing patient characteristics result in different regional standards of care, for example.  And some areas have access to services (e.g. group treatments or laboratory testing) that may not be as available somewhere else.
Is Anyone Trying to Reduce Costs?
Physicians also have differing opinions and attitudes toward relapse and personal responsibility.  Some docs are more paternalistic than others. Some are quicker to dump ‘difficult’ patients. For most medical problems, patients are able to find doctors whose practice patterns match their personal preferences.
Shortages of buprenorphine prescribers in some parts of the country force patients onto waiting lists, and to take whatever open space comes along, whether or not they consider the physician to be personable or competent.  I resist finding fault in how other docs run their practices, as I have no way of knowing the considerations that any physician takes in regard to his/her patients.  But I sometimes hear about practice styles that make me wonder if patients need a wider range of options.

Per Capita Healthcare Costs
Per Capita Healthcare Costs

A patient in my buprenorphine program is trying to find treatment for his wife.  I’m at the cap, so I can’t take more patients.  At a recent visit, he described the practice where his wife receives buprenorphine treatment.  I realize that I’m hearing only ‘his side’, but he had little to gain by misleading me…. beyond, I suppose, having an interesting story.
He said that his wife has done well on buprenorphine/Suboxone for over two years.  She hasn’t relapsed or missed appointments, and she hasn’t tested positive for any other psychotropic substances.
She is required to attend weekly psychotherapy sessions with a counselor employed by her physician.  If she misses a psychotherapy appointment, she is subject to discharge from treatment.  Even after two years of doing well, she is required to continue weekly psychotherapy.  She must attend at least one AA or NA meeting per week.  She must see the prescribing physician every month.  And every month she undergoes urine testing.
Her prescriber accepts Medicaid, so her financial burden is not all that high, other than needing to take time off from work five times per month for appointments.  But her husband described the invoices that she receives for charges to Medicaid.  The charges for doctor appointments are significantly discounted, so they make up less than half of the total bill.  But the lab bills add up.
The clinic charges Medicaid a couple hundred dollars for each ‘point of care’ urine test.  Without Medicaid, the charge is paid by the insurer or by patients themselves.  I showed her husband the kits I use that test for the presence or absence of amphetamines, cocaine, buprenorphine, THC, methadone, oxycodone, mixed opioid (e.g. heroin), and PCP.  I purchase the test kits through internet suppliers, complete with collection vials, for about $5 per test— total, for a test that measures simultaneously for all of the substances.  The $5 kits are just as sensitive and accurate as the $200 tests. The only difference is that I do the testing myself in about 3 minutes, rather than send the urine to the lab.
People with ‘indeterminate’ tests at his wife’s clinic— something that he says occurs about 30% of the time— undergo ‘quantitative’ drug testing.  I’ve written about the boondoggle of quantitative urine testing in the past, about why the tests are not an accurate reflection of blood levels of substances.  In short, blood is filter at the kidney through sieve-like structures.  That filtrate goes through a series of tubules where water is re-absorbed in varying amounts, depending on the balance between fluid intake and fluid loss through sweating, respiration, etc.  Because of the varying concentration of urine, the concentration of a drug in the urine is not directly related to the concentration of that drug in the bloodstream.  Further confounding the tests, some substances are specifically transported out of the filtrate, and others are specifically excreted into the filtrate.
Quantitative tests measure the amount of each substance in the patients’ urine, but tell little about the amount of each substance in the bloodstream.  Labs try to correct for concentration effects by measuring the specific gravity and applying a correction factor.  But the resulting value must be taken with a grain of salt (no pun intended) because of the essential flaw in using urine to determine drug levels.
I have used quantitative testing, and I understand the value in knowing, for example, the ratio between excreted buprenorphine and excreted norbuprenorphine, the chief breakdown product.  But in an era of limited resources, I cannot rationalize making a patient, insurer, or taxpayer pay the $800 – $1200 charged for EACH test!
I dropped the quantitative test company that I was using after I learned about their charges.  The reps for the company paid me a visit over lunch, and asked me why it mattered.  ‘Everybody else is using us,’ they said.  ‘Besides— the patient never even sees it.  We just take it from the insurance company, or from Medicaid.  The patients don’t really pay for it.’
Then one of them added a comment that summarizes why healthcare costs are out of control:  ‘I see your point about the problems with the test, but if you don’t use it, you could get in trouble with the state.’
To translate, the $1000 test adds very little information to the $5 test, but the people on state medical boards doesn’t necessarily understand the reasons why the tests are not worth the money, so I should order them just to make sure that I LOOK like I’m doing as much testing as everybody else.
When I was in med school (way back in the mid-1980’s), my professors at the University of Rochester made a big deal about healthcare costs.  We were taught to know the price of tests that we ordered, and to consider the value of each test, in light of the cost. With everybody bemoaning the cost of health care, seems to me that now would be a good time to get back to some of those considerations.

Suboxone Makes Me Fat and Boring and Stupid

Originally posted 3/6/2013
A late post tonight, since my new exercise program has pushed my blogging back by an hour or so each night.  My suspicions about exercise were correct, by the way; it is much easier to suggest exercise to other people than it is to actually exercise.  I’ve been at it since the beginning of the year, and I at least feel a bit less hypocritical.
While I’m on the topic…  I’ve received many comments over the years from people complaining that they’ve been taking Suboxone or buprenorphine for X many years, and they have no energy, they feel stressed, they have gained weight, they don’t sleep well or they sleep TOO well… and concluding that all of the problems are from Suboxone.
Suboxone causes… everything!
They aren’t (from Suboxone).   Not at all.  But I wonder, at this point, if regular readers of my blog know EXACTLY what I’m going to say.  I’m tempted to stop typing and ask people answer so I get a sense of how predictable I’ve become.    But then I’d have to wait and then come back, read, and assess the situation….  I really can’t imagine much positive to come out of THAT experience, so I’ll just finish my thoughts, about the problems that people often blame on Suboxone.
The problems are the result of other things, including things that tend to occur naturally as our lives become less chaotic and more outwardly-secure.  The problems I mentioned above, for example, come from inactivity.  They come from thinking that we’ve ‘paid our dues’ at the age of 30, and it’s time to coast in life.  They come from failing to seek out challenges, and from failing to do our best to tackle those challenges.  They come from letting out minds be idle, smoking pot or watching American Idol  instead of responding to the naggings sense of boredom that ideally pushes people to join basketball, tennis, or bowling leagues.
Our minds and bodies are capable of SO much.  I (honestly) am not a network TV viewer, but I love the contrast of ‘before and after’ scenes on ‘Biggest Loser.’  People magazine (it sits in my waiting room) had a section a while back about people who lost half their body size, by exercise and dieting.  The part I found most interesting was the deeply personal answer that each person had to the question, ‘what was your turning point?’  Each cited an episode of humiliation or shame that lifted the veil of denial, and helped them do what they knew, all along, needed to be done.
We are not all capable of ‘Biggest Loser’ comebacks. But it is important for people to understand that feeling good, physically or mentally, takes work.   That incredible feeling of a ‘sense of accomplishment’ only comes when we accomplish something.  We don’t need to eliminate global hunger or cure cancer; sometimes we just need to shovel the driveway, mow the lawn, or do a crossword puzzle.  I’ve learned, as a psychiatrist, that the people who walk around with smiles on their faces usually did something that made the smile happen.  I’ve learned that ‘feeling happy’ does not just happen for most people.  And I don’t think I’ve ever met a person who answered, when asked about stress, ‘no—I don’t have anxiety.’
Once someone blames Suboxone for their problems, it becomes less likely that the real causes of those problems will become apparent. For example, If I think that my glasses are giving me headaches, I’m less likely to make changes in my diet that might make the headaches better.  Once we have something to blame, our problems become more and more engrained, and the real solutions become less and less evident.
I’m truly sorry if I am coming across as ‘preachy’; understand that I’m just trying to make my way through life like everyone else.  But I now take note of all those people power-walking at 6 AM, and I understand why they do it.  Some of them might be on Suboxone.  Some of them might not be.  But I respect all of them for opening their minds, and for their willingness to do the hard work that brings happiness—or at least points in that general direction.

Reckitt Benckiser Citizen Petition for Suboxone: DENIED

Posted 2/23/2013
For those who missed my explanation, I’m adding these old posts to reconstruct the archive.  The site’s database was damaged by something, somehow… New posts coming soon.
Find a copy of the response here, or at this url:www.suboxonetalkzone.com/cpresponse.pdf

Suboxone Maker's Petition Denied by FDA

Originally Posted 2/23/2013
I’ve written in detail about the bold move by Reckitt-Benckiser, maker of Suboxone, that few people outside the company saw coming.  In brief, the company has been cruising across the Atlantic for the past ten years, fueled by stellar growth of its flagship medication, even as the expiration of the patent on Suboxone loomed ahead (y’know– like an iceberg).
But unlike the Titanic, RB had a secret plan to deal with icebergs.  A couple months ago, the company hired a company that investigates bad drugs to look into its OWN product, Suboxone tabs, and used those findings to tell the FDA that the source of their profits for the past ten years is a BAD DRUG.  In fact, it is SO bad that they insisted on doing the right thing—file a Citizens Petition with the FDA to make sure that NOBODY ever makes that bad drug again.
By coincidence, RB happened to have a DIFFERENT drug with a fresh, new patent expiration date that they promised was much safer than the drug they used to make.  And by coincidence (insert more sarcasm), this all happened a year or so after the patent on the bad drug ran out, so RB was willing to just get rid of the bad drug completely.    Never mind that a bunch of other companies were about to make less-expensive generic forms of Suboxone; RB asked the FDA to protect the American people by banning those awful Suboxone tabs that used to make them so much money.
But on Friday, the FDA essentially told RB ‘thanks for the warning… but we’re cool.’  They denied RB’s request to block the tablets, opening the door to generic manufacturers to consider making less-expensive forms of buprenorphine/naloxone, what RB calls ‘Suboxone.’
RB (stock symbol RBGPF) has been dodging icebergs for ten years.  I’ve wondered over the years how they would navigate through some very treacherous passages.  How did they get everyone to buy into the idea that Suboxone is significantly different than plain, cheap buprenorphine?  How did they get state Medicaid agencies to cover ONLY the branded product, when the generic buprenorphine is clinically identical to Suboxone?  A glance at the price of shares in RB shows that they have been doing it well—at least up to now.

Reckitt-Benckiser Stock Price
Reckitt-Benckiser Stock Price

But the seas are getting choppy.  There are two lawsuits directed at the company, accusing RB of running a grand scheme to block generic manufacturers from entering the buprenorphine market.  And in denying of the Citizens Petition the FDA adds credence to the lawsuits, even writing that they will refer concerns over anti-competitive business practices to the FTC.  Amazing how quickly things can change; one minute you’re sitting in a deck chair, whistling a happy tune with the wind in your hair… the next, everyone is looking for a lifeboat.
I’ve been writing for years that the company that wants to be viewed as a shiny rescue vessel has been acting more like a pirate ship.  Hopefully last week’s collision will give them pause, and help then realize that it’s not about being the first ship to get to those in need;  it’s more about making sure, once there, that other ships are on the way—and that everybody gets a seat in a lifeboat.

Urine Drug Testing on Suboxone

First Posted 2/15/2013
A recent exchange with a reader:
I have been on buprenorphine for 5 yrs.  Recently my doctor stated that my u/a t looked like I have been ‘loading my meds.’  He said my levels where ‘backwards’ and that would happen if I took just a few doses just before my appt.   My doc had me come back in two weeks to go over my next u/a, and again it came back funky.  So my doc starts having me take my meds in front of the nurses on a daily basis.  Two weeks later with supervised u/a’s, my urine comes back the same.  My doc looked perplexed but kind of ignored the results like I was still doing something to mess with the results.  I had to come in again for another urine test and it finally came back normal.  My numbers were fine after that, and all was good until last week.
I went to my normal monthly check up and the u/a showed NO buprenorphine in my system.  My doc looked at me like I am the biggest liar.  I am perplexed.  I am taking my meds daily.  I don’t know what is going on and I need to figure it out soon before my doc kicks me out of the program. What could be wrong with the test, that is says that I have no buprenorphine in my body?
My response:
There are several directions we could go with this issue.  One aspect is whether it is always fair to believe the results of drug tests over the word of our patients.  I understand the reasons for testing, but I think that doctors sometimes lose the forest (the patient’s addiction problem) on account of the trees (quantitative testing).  This patient has been on buprenorphine for five years; I would hope to have sufficient trust established with patients after that period of time, such that the lab results wouldn’t be seen as the only answer.  There can be problems with any laboratory test.  Drug tests are one tool– not the ultimate arbiter of truth.
Most people metabolize buprenorphine a certain way, leading to the build-up of a chemical called norbuprenorphine.   I assume that by ‘backwards’ the doctor is saying that the buprenorphine level is higher than the norbuprenorphine level, whereas with daily use of buprenorphine the opposite would be true. As your doctor said, if a person takes one dose of buprenorphine and is tested an hour later, buprenorphine would be present, with only small amounts of the metabolite norbuprenorphine.
Urine tests for any substance are affected by many variables, including the actions that different parts of the kidney have on certain substances.  Some substances are concentrated at the kidneys, making urine testing more sensitive than blood testing.  But other substances might be re-absorbed by the kidneys to a varying degree, depending on hydration status, nutritional and dietary factors, hormonal factors, and personal genetics.  Because of concentration and reabsorption effects, the drug levels from urine tests are not accurate indicators of drug levels in the bloodstream.
In addition, the metabolic pathways for certain substances might be changed by the presence of other substances.   For example, if the enzyme that turns buprenorphine into norbuprenorphine is blocked or occupied by other substances, the pathway may change such that metabolites other than norbuprenorphine are formed—- including metabolites that won’t show up unless they are specifically tested for.
I asked the patient:
Are you taking any other medications?  Are you able to get the actual lab results showing the details of the test?
She replied:
I thank you for responding to me.  I am on many medications because I have fibromyalgia among many other things.  My list of meds:
Prozac 20 mg; Provigil 200 mg; Clonidine 0.1 mg 4x’s a day; Amlodipine 5mg once a day; Nabumetone 500mg 2x’s a day; omeprazole 20mg once a day; Ambien 10mg per day; Relpax when I have a migraine; Buspirone 10mg about 2x’s a day; Subutex 16 mgs per day. I also take diphenhydramine 50 mgs at bedtime when needed to help sleep, and Vitamin D3-1000 iu once per day.  I take this because my blood tests showed it was low.
I asked to see my results and my doctor told me that I didn’t need to see them; that he had told me what it said and that it should be enough for me to know.
The receptionist in the office is getting the number to the lab for me.  Do you have any questions that I should ask?  What should I know?  I am going to ask for a copy of my labs at my next visit.  I am nervous that my doc will just stop prescribing.  This medication has saved my life and I don’t know where I would be without it.  Please help me make my doctor believe in me again.  I know that is a lot to ask but I’m in trouble.  Where can I turn?  There aren’t any Suboxone docs in my area taking new patients.
(A couple thoughts)
Over my 20 years as a physician, I’ve come across times when tests were mistakenly trusted over the word of patients.  At a maximum security prison for women where I worked as a psychiatrist, for example, many women were disciplined for diverting clonazepam, until a call to the lab revealed that testing wasn’t reliable for that medication.
Over time, we learn more and more about how the metabolism of one medication impacts other medications.  One such interaction was apparent in this person’s case.
My comments:
The most obvious interaction from your list is that Provigil is an ‘inducer’ of cytochrome 3A4, the enzyme that breaks down buprenorphine.  A person taking Provigil develops greater amounts of that enzyme in the liver, which results in faster metabolism of buprenorphine.  The first step in metabolism of buprenorphine is conversion to norbuprenorphine, so levels of buprenorphine and norbuprenorphine would be affected by Provigil, in unpredictable ways.
From the program that I use to search for interactions: buprenorphine ↔ modafinil
Coadministration with modafinil (the racemate) may decrease the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. Modafinil and armodafinil are modest inducers of CYP450 3A4, and pharmacokinetic studies suggest that their effects may be primarily intestinal rather than hepatic. Thus, clinically significant interactions would most likely be expected with drugs that have low oral bioavailability due to significant intestinal CYP450 3A4-mediated first-pass metabolism (e.g., buspirone, cyclosporine, lovastatin, midazolam, saquinavir, simvastatin, sirolimus, tacrolimus, triazolam, calcium channel blockers). However, the potential for interaction should be considered with any drug metabolized by CYP450 3A4, especially given the high degree of interpatient variability with respect to CYP450-mediated metabolism. Pharmacologic response to these drugs may be altered and should be monitored more closely whenever modafinil or armodafinil is added to or withdrawn from therapy. Dosage adjustments may be required if an interaction is suspected.
That is just one of many possible interactions. When a person takes multiple medications, there are often other, less predictable interactions.  Some medications also interfere with the testing of other medications.  You may know that there are chemicals available on the internet to block the testing for certain compounds;  some medications do the same thing.
She answered:
I can’t thank you enough for even responding to me……  You are a very kind man!  I hope this helps me.  I am very scared my doctor will take me off my meds.
But then she wrote again:
I wanted to send you an update.  My doctor wouldn’t even look at the conversation we had.  I guess for whatever reason, he refuses to look deeper into the issue.  It is sad when a doctor has had a patient for over 5 yrs and he won’t look into this further.  I don’t ever have dirty u/a’s.  I don’t drink, I don’t smoke marijuana, I only take what he prescribes to me.  He refuses to look further into the matter so much that it is clouding his judgment.  He won’t even test me another way.  He states urine test are the most accurate but there is something wrong because I know that I take my meds.  He refuses to do another supervised dosage week because he doesn’t have the manpower.  
I know in his eyes that all I am is a drug addict but I deserve respect. Why would a man who believes in science have such a closed-minded view?  I would think he would at least want to discover what is happening.  There has to be more patients like me that are being thrown away because we don’t fit a certain mold.  When he throws me out of treatment on Monday, I have nowhere to go.  There are large waiting lists to see a doctor in my area. I can’t go back on the streets for medication.  I don’t have any of those friends left in my life.  I am in so much trouble.
I don’t know why I felt the need to vent to you but my hope was to find one person that believes me in hopes that this problem could be addressed someday, somehow.  Thank you for listening.  I do appreciate it.

Wasting Resources on Suboxone

Originally posted 1/26/2013
Readers of this blog know that I have often questioned whether there is any clinical difference between Suboxone and generic buprenorphine.  Naloxone is an opioid-blocking chemical added to buprenorphine, supposedly in order to reduce intravenous diversion of the medication.  The combination of buprenorphine plus naloxone is branded as Suboxone. I’ve pointed out over the years that the high affinity of buprenorphine at the opioid receptor is too great to be overcome by the amount of naloxone in a tablet or two of Suboxone, making naloxone unnecessary for anything except to create profits from Suboxone.
Because of the low number of doctors who obtain certification to prescribe buprenorphine and the limits on number of patients per doctor, many people who want treatment with buprenorphine are unable to find it.  While sitting on wait lists, some people opt to treat themselves with ‘street Suboxone, rather than continue to use oxycodone or heroin.
When taken through the proper sublingual route, about 25-33% of the buprenorphine in Suboxone reaches the bloodstream.  Because of the scarcity and high cost of Suboxone, patients who engage in self-treatment sometimes choose to inject the medication, since doing so reduces their costs by 70%.
I have treated patients who described injecting buprenorphine or Suboxone while waiting for a treatment spot to open up.  The patients always claim the same thing; that they could detect no difference between injecting Suboxone, with the medication’s naloxone component, vs. injecting plain buprenorphine.
I am not advocating injecting Suboxone by any means; injecting any substance not intended to be used intravenously is very dangerous, particularly in people who are not clinically monitored, by people who are not trained in aseptic techniques.  My point is that in an era of limited healthcare resources, should insurers and state health agencies use a medication that costs four times more than the clinically-identical generic?
The reasoning behind Suboxone makes sense on the surface.  Naloxone is poorly absorbed from the mouth, whereas buprenorphine dissolves through cell membranes and enters the circulation when Suboxone is placed under the tongue.  Naloxone is swallowed, absorbed by the intestine, and destroyed at the liver.  But if injected, the naloxone is not destroyed, and instead binds to opioid receptors, blocking the effects of buprenorphine.
But what if naloxone doesn’t do what everybody thinks?  I’ve done binding studies of other neural receptors back in my grad school years, and I’ve wondered, from those experiences, just how well a loose-binding drug like naloxone would interfere with the binding of a very tightly-binding drug like buprenorphine?
A study in human volunteers from 2006 does nothing to reduce my curiosity (1).  In the study, adult volunteers received 0.2 mg of intravenous buprenorphine and the respiratory effects were measured.  The volunteers then received different doses of intravenous naloxone, and the ability of varying doses of naloxone to block the effects from buprenorphine were measured.
The study found that 2 mg of naloxone, the amount in a standard tablet of Suboxone, blocked the respiratory effects of 0.2 mg of buprenorphine. But the study found that lower ratios of naloxone had no effect on buprenorphine.  A tablet of Suboxone contains 40 times more buprenorphine than was used in the study.
According to the 2006 study, naloxone had no effect on buprenorphine when administered intravenously in the ratio of 4:1.  In fact, naloxone became effective only at doses over 10:1.   But when a person injects Suboxone, the ratio of naloxone to buprenorphine is much, much smaller— equal to 0.25:1.   According to the 2006 study, a dose of Suboxone would have to include 80 mg of naloxone in order to block the respiratory effects of 8 mg of buprenorphine!
To restate the findings, blocking the effects of buprenorphine requires a dose of naloxone ten times higher than the dose of buprenorphine.  Suboxone contains only 2.5% of the naloxone that would be necessary—-an amount that isn’t even in the ballpark of what is needed to block the effects of buprenorphine.
If naloxone isn’t doing anything, why do insurers demand that people spend the insurers’ money on it?

  1. Van Dorp E, Yassen A, Sarton E, et al. Naloxone reversal of buprenorphine-induced respiratory depression. Anesthesiology. 2006;105(1):51–57

Does Suboxone Cause SIDS?

Originally posted 1/13/2013
In a recent Google search about Suboxone and pregnancy, one of the top links included the frightening statement that Suboxone and buprenorphine have been linked to SIDS or sudden infant death syndrome, commonly called ‘crib death.’
The statement was from a health forum where a woman wrote about taking Suboxone during pregnancy.  She wrote that her child went through opioid withdrawal after delivery, recovered, and then died two months later from SIDS.  She then claims that her doctors told her that Suboxone was a possible reason for her child’s death.
Suboxone and SIDS?
I don’t know if the woman’s story is true. If it is, I hope my comments do not cause her pain, and I’m sorry for her loss.  But someone should comment on the information, given the number of young women on Suboxone who become pregnant and frantically search the internet for reassurance that their baby will be OK.  I know that pregnant women in my practice lose a great deal of sleep because of guilt over taking buprenorphine.  I am not a SIDS specialist, obstetrician, or pediatrician, and I do not actively follow the SIDS literature.  But I have done some reading to prepare for this post, and I’ll do my best to address the issue.
While the causes of SIDS are not completely understood, a number of factors have been associated with sudden infant death, including maternal age and socioeconomic status (higher rates in infants of poorer, younger mothers), maternal smoking, air pollution, low birth weight, season of birth (higher in infants born in the winter), too high or too low room temperature, male sex, history of premature birth, and bottle feeding (instead of breastfeeding).
One of the biggest risk factors is the easiest to correct: sleeping position. The incidence of SIDS is thought to be about twice as high for babies who are placed prone (face-down).  Since 1992, when 4895 deaths were attributed to SIDS in the US, a public relations campaign to encourage parents to place infants on their backs may have reduced the incidence of SIDS by 50%.  I write ‘may have’ because some experts attribute the decrease to changes in how infant deaths are coded and reported, rather than to a true decrease in cases.
SIDS is a leading cause of death among healthy US infants.  But the actual risk is very low, estimated at about one death from SIDS per 2000 infants.  Deaths from prematurity or from congenital disorders are far more common than SIDS.
When I started this post, I planned to write that the link about buprenorphine causing SIDS was nonsense.  And it may be nonsense.  Realize that it is very difficult to determine the risk factors for things that rarely occur. Only relatively common factors like smoking or prematurity are identified as risks for SIDS in controlled studies.  Unless the connection is very strong (and it isn’t), there are not enough pregnant women on buprenorphine to cause a detectable rise in deaths from SIDS, even in the largest studies.
So what about the link in search engines about SiDS and Suboxone?  From what I can tell, the connection between buprenorphine, Suboxone and SIDS comes from a 2007 study in Finland that prospectively followed 67 women who had babies while prescribed buprenorphine.  In that study, 2 of the 67 infants were reported to have died from SIDS, an incidence of 3%.  A number that high is certainly frightening. But at the same time, an effect that strong would be evident in the larger SIDS studies—- especially those including thousands of women.
A closer look at the Finnish study reveals that the two infants who were thought to have died from SIDS were born to women who were not compliant with the buprenorphine program, i.e. who were using other opioids including heroin.  The associations between SIDS and other risk factors—risk factors that are common among active drug users, such as smoking, low socioeconomic status, low birth weight, and prematurity— confound the results of the study.  Are women struggling with active opioid dependence as likely to know that infants should be placed on their backs? Some SIDS researchers have questioned the numbers from the Finnish study, The forensic uncertainties often associated with SIDS, the significant risk of death associated with co-sleeping, and the challenge of monitoring women who are actively using opioids further confound the Finnish study.
One possible cause of death in SIDS is the accumulation of carbon dioxide in soft blankets or clothing, close to the mouth and nose of a baby sleeping prone (face down).  That cause of death suggests danger for an infant who is for some reason administered opioids, since opioids reduce respiratory response to carbon dioxide.  Opioids are secreted in breast milk, including buprenorphine.  The infants of mothers on Suboxone/Subutex would be tolerant to any buprenorphine in breast milk, since the exposure would be less, if anything, than the exposure during pregnancy.  But mothers who are noncompliant, i.e. intermittently dosing with high-potency opioid agonists, could in theory expose their infants to levels of opioids higher than the infants’ opioid tolerance.  I did not find any reported associations between opioid use, SIDS, and breast feeding.
My take on the data is that the safest situation for any infant is to develop in the womb of a woman who is not drinking alcohol, smoking cigarettes, taking prescription medications, or using illicit opioids.  Out of all of these things, being compliant with a stable dose of buprenorphine or Suboxone likely carries the least amount of risk.  If there was certainty that pregnant women could remain free from opioids after stopping buprenorphine maintenance, then stopping buprenorphine during pregnancy would be a good idea.
But unfortunately, far more women PLAN to remain opioid-free after Suboxone, than actually remain opioid-free.  The intermittent use of illicit opioids, and the malnutrition, cigarette smoking, poor sleep, poverty, needle-sharing, and other risky behaviors that come with opioid dependence create the worst-case-scenario, making the stable use of Suboxone or buprenorphine far safer in comparison to ‘planned abstinence.’
As with everything, there is the world we want, and the world we live in.  I encourage women addicted to opioids to do all in their power to maintain compliance in a Suboxone/buprenorphine program.  I also encourage these women to look forward to a life of doing the ‘next right thing’ for their children— and cutting themselves some slack over taking buprenorphine.  Efforts to stop Suboxone would be better used to avoid alcohol, tobacco, and illicit substances, and to maintain appropriate prenatal care.

Suboxone Side Effects Pt. 2

Originally posted 1/2/2013
We can now leave naloxone out of the discussion, and focus on the side effects of Suboxone that are caused by buprenorphine.
Side effects are symptoms caused by a given medication that are not part of the therapeutic benefit of that medication.  Whether a symptom is a side effect depends on the reason for taking the medication.  For example, decreased intestinal motility is the desired effect of opioids used to treat diarrhea, but a bothersome side effect when taking opioids for pain.  The term ‘side effect’ is not on the package insert for medication, the symptoms and actions instead referred to as ‘adverse reactions.’  Package inserts also have a section entitled ‘warnings and precautions’ where the most dangerous adverse reactions are listed.
Some medications have a ‘black box warning’ for adverse reactions that are particularly common or particularly dangerous, consisting of a frightening statement at the start of the package insert (enclosed, naturally, by a black box). Black box warnings in psychiatry include the warning for increased suicidal ideation in children and adolescents treated with antidepressants, and the increased risk of death in people with dementia treated with atypical antipsychotics.
Increased risk of cancer or mutations, and effects on fertility or fetal development, are listed in yet another section entitled ‘nonclinical toxicology.’  They are listed as ‘nonclinical’ because the events do not involve the intended physiologic system or pathway targeted by the medication.  For example, slowing of intestinal activity by opium is either treatment of diarrhea or unwanted constipation, but in either case the outcome is caused by actions of opioids at opioid receptors.  If the opium molecule happened to bind to DNA and cause cancer, the cancer would be nonclinical toxicology, not a side effect.  Carbamazepine decreases the excitability of neurons to prevent seizures, and the sedation caused by the slowing of neurons is considered an adverse reaction. Carbamazepine impairs fetal development through different actions, considered nonclinical toxicology.
All of these divisions can be picked apart so that division of symptoms to one category or another will appear arbitrary.  The system is not precise, by a long shot.  But it may be helpful to be aware that one person’s ‘adverse reactions’ are another person’s intended therapeutic effect.  Some people find the mood stabilizer quetiapine too sedating;  others find the sedation critical to a good night’s sleep.
Allergic reactions are yet another issue.  To put it simply, medication allergies are not something that the medication does to the body, but rather something that the body (the immune response) does to a medication—and the inflammatory fall-out from that reaction.  While the distinction sounds like splitting hairs, the true nature of a reaction can be important.  Nausea is a common adverse event from the action of opioids, used for pain control, at opioid receptors.  Through intellectual laziness, a patient with nausea from morphine in a hospital is often incorrectly labeled as having a morphine allergy. Because of the bureaucracy of modern medicine, the patient has had a very useful medication removed from the armamentarium of treatment options, in essence forever.  Analogous situations are ‘allergies’ to antibiotics like erythromycin.  Allergies tend to become worse with each medication exposure, whereas adverse reactions often go away over time.
Am I going to need a part 3?
Things actually get pretty simple from here. Buprenorphine, like other opioids, has a range of predictable effects that occur along the dosage spectrum— a spectrum that is relative to the person’s opioid tolerance.  Doses of buprenorphine low on the person’s tolerance spectrum fail to have the desired action of preventing withdrawal.  Doses that are close to a person’s tolerance level have the desired therapeutic effect, i.e. blocking withdrawal and a reduction in cravings for opioids.  Doses in this range commonly cause ‘ileus’, i.e. disruption of the normal movement of the intestine.  Ileus in turn causes a number of symptoms, including constipation, cramping, bloating, loss of appetite, and nausea.  Constipation can lead to increased intestinal pressure, leading to hemorrhoids or diverticular disease.
Apart from ileus, buprenorphine and all opioids have direct actions at the base of the brain, at the ‘area postrema’.  Actions at the area postrema cause nausea as an adverse reaction, or in other cases the desired therapeutic effect of induced vomiting.  Nausea is very common when doses of opioids are taken that are at the upper end of tolerance, making nausea particularly common with potent opioids like buprenorphine.  Impaired coordination, slow reflexes, sedation, slurred speech, and somnolence are also caused by strong opioid effects.  Combinations of these effects are obviously quite dangerous.
Opioids reduce the tone of the ‘gastroesophageal sphincter’, increasing the chance of acid reflux, heartburn, hoarseness, and theoretically even esophageal cancer in severe cases.
Cough suppression by opioids might be a therapeutic benefit, but can be an adverse reaction if gastric contents are aspirated into the lungs.
Opioids reduce the response of the brain’s respiratory centers to carbon dioxide, resulting in less drive to breathe.  Carbon dioxide level therefore goes up, and the rise in CO2 increases brain blood volume and in turn, intracranial pressure.  The increased brain pressure reduces the flow of fresh, oxygenated blood into the brain.  Because of this potentially-disastrous sequence of events, opioids must be used with caution in people with head injuries.
Respiratory depression is a common reason for overdose, but even that adverse event can be a desired therapeutic benefit in some cases, for example in patients who are on a ventilator and triggering the machine to cause hyperventilation.  Respiratory depression is even used therapeutically to reduce ‘air hunger’ in people at the end of their lives, to relieve suffering in patients and patients’ family members who are witnessing the death.
I realize that a simple list of side effects would have been easier to read, but like the proverb says about giving a man a fish, I’m hoping that running through the processes will help people figure out, for themselves, what their medications are doing.
What else…  pruritis or ‘itching’ is a common side effect of potent opioids, that doesn’t respond very well to the usual anti-itching treatments like diphenhydramine or steroids.  All common opioids except meperidine (Demerol) constrict pupils, which often makes daytime vision sharper, but impairs night vision by allowing less light to fall on the retina.
Opioids reduce immune function through a number of physiologic interactions, including the presence of opioid receptors on immune tissue. Opioids can have a range of effects on mood and mood disorders.  All opioids, including buprenorphine, have the potential to reduce testosterone levels in men, which in turn can affect mood, libido, and sexual performance.  Opioids alter the release of vasopressin, changing how much water is conserved by our kidneys—which in some people results in more trips to the bathroom at night.
Buprenorphine and other potent opioids interfere with the initiation of ‘micturition’, i.e peeing, particularly in men who are already struggling from an enlarged prostrate.
I know that I’m missing something, and I invite people to write and help me out.  I also realize, as I write this, that I don’t have a package-insert category for a particularly common worry about Suboxone, that it is hurting one’s teeth.  Such a reaction, were it found to be attributable to Suboxone, would probably be considered nonclinical toxicology, although a recent case report proposed that buprenorphine could increase cavities by reducing the immune response in teeth, which sounds more like an adverse reaction.  In either case, I’ve written about the lack of evidence for tooth damage from Suboxone, but the topic still appears on my forum now and then.
That’s all for now…