Baby’s Buprenorphine Withdrawal

This morning I responded to a woman at SuboxForum.  Her baby was taken to the NICU for ‘withdrawal’, which is better identified as neonatal abstinence syndrome.  She said that the baby is eating well, but there is concern that the baby sleep only 2 hours at a stretch.  The baby is on morphine, and mom is wondering when they both can go home.  She is kicking herself for not trying to stop buprenorphine before the delivery.  I spent a while responding, so I decided to post my response here as well, in case a mom in a similar situation stops by.

My comments:

I have written a number of posts about neonatal abstinence, and I invite you to read a post in my blog about the guilt you are feeling.

First of all, you did the right thing.  Period.  Every medical specialist, study, or text will say the same thing:  that women addicted to opioids should be maintained on a long-acting opioid until the baby is born.  Traditionally, that opioid was methadone.  But women on methadone who are pregnant often end up on very high doses of that drug– pushing their tolerance to high levels, so that virtually all their newborns have significant withdrawal.   Of course, the babies do fine in the long run— and the experience of withdrawal is not among the worst things that a baby experiences, by far.

People see a shivering newborn and somehow imagine that the baby just ‘came to be’, at that moment. In reality, a couple hours earlier the baby was in the birth canal, squeezed so tightly that shoulders are sometimes broken, probably experiencing a sensation akin to suffocation.  I say that because while oxygen is being delivered via the umbilical cord, during deliver the cord is often compressed, causing changes in oxygen and carbon dioxide that would cause the same physiologic sensations as asphyxiation. The low oxygen tension and high carbon dioxide levels stimulate the ‘preborn’ to breathe, a hopeless challenge when the baby’s face is tightly wrapped by the birth canal!

And of course before that, the baby was upside down, getting pushed, squeezed, bounced… we picture this wonderful intra-uterine environment, but in reality we have no idea what it ‘feels like’ to the fetus.  All the things we see after the birth were before birth, except perhaps the shivering.  When the baby is born, there is no ‘on switch’ that suddenly starts recording his experiences!

As buprenorphine has become more-available, the trend has been to use buprenorphine instead of methadone.  There are several advantages– the tolerance of the mother is much lower, meaning any withdrawal in the baby will likely be less severe.  According to a number of studies, about half of babies born to moms on buprenorphine show signs of neonatal abstinence syndrome, compared to almost all babies born to moms on methadone.  Studies show no benefit to tapering buprenorphine to lower doses before delivery, but I tend to think that there must be value in doing so.  I wonder if those studies truly had good control over the doses that study subjects were taking.  My patients seemed to benefit by reducing to 4- 8 mg during pregnancy– but perhaps my impressions are biased.

Another biased impression of mine is that babies have experiences largely dictated by the sensibilities of their neonatologists.  Almost all of my patients who delivered at the local, small community hospital did great, and moms and babies went home at the regular time.  If there was any withdrawal, it wasn’t noticed.   Maybe it was treated by the buprenorphine in breast milk, because all of the mothers were encouraged to breast feed.  Nursing while on buprenorphine seems to me to be the ideal way to wean a baby off the medication; the baby’s immature liver gets better and better at metabolizing medications after birth, allowing the amount of buprenorphine in the bloodstream to decrease over time.

Hospitals with neonatologists and a neonatal ICU are going to USE those things.  The regular OB nurses in those environments tend to become less-familiar and less-comfortable with anything other than ‘normal’, and watch for reasons to send babies to a higher level of care.  Every nurse on the OB unit knows that this baby’s mom is an addict.  If the baby cries along with all the other babies, the nurses will believe that ‘this’ baby is suffering from withdrawal.  And when the baby is sleeping along with all the other babies, the nurses will think ‘this’ baby is sedated from buprenorphine.
They will transfer the baby to the neonatal ICU, where the environment makes ANY baby look sick and miserable, opioid withdrawal or not.   Just look at the environment, and all of the little ways that mom’s experience changes…. instead of smiling nurses wheeling the baby into the room, congratulating mom repeatedly in front of smiling family, you have busy, serious-faced nurses and doctors bent over charts or computers.  When they take time to talk with mom, the conversations are serious, and certain to instill guilt and fear.  The baby is attached to wires or tubes, perhaps wearing oxygen, under unnatural lighting that changes skin color from healthy-looking to some type of medical specimen.

The baby will remember none of this, just as the baby won’t remember the difficult journey down the birth canal… or the circumcision!  Rest assured that all of the pain and misery will reside completely in mom, which is probably where the doctors and nurses intend for it to go.  I realize, of course, that there are good doctors and nurses out there… but I know that when you get a group of people together, the urge to look down their noses at people with addictions often becomes too powerful to avoid.

Most important of all:  a couple years ago I did a talk for a large group of public health nurses, social workers, and AODA professionals about the impact of opioid dependence on pregnancy and on children born to women addicted to opioids.  I did an extensive literature search to prepare for the talk, and I was glad—and surprised— to find that there are NO known long-term effects on children from methadone or buprenorphine treatment during pregnancy.  There ARE problems in some children born to addicted moms, but when the studies are controlled for cigarette smoking, poor or absent prenatal care, use of alcohol, and other factors, the use of opioids has no long-term developmental impact.   That is VERY good news.

Treatment? Or Murder?

I subscribe to Google news alerts for the phrase ‘overdose deaths.’  Google Alerts are a great way to follow any topic; subscribers receive headlines from newspapers and web sites for certain keywords from around the world. One thing that has become clear from my subscription is that there is no shortage of stories about deaths from opioids! Every day I see one article after the next, as news reporters notice the loss of more and more of their communities’ young people.
Along with the reports of overdoses are stories about doctors who are increasingly being prosecuted for the deaths of their patients. In an earlier post I described the case of Dr. Schneider and his wife, a nurse, who were tied to a number of overdose deaths in Kansas. That case stood out by the sheer number of deaths; the State charged the couple with the deaths of 56 patients. Cases involving fewer patients have become relatively common. The latest case that I’ve read about is a doctor in Iowa, who is accused of causing or contributing to the deaths of 8 people.
I try to present both sides of the argument when I write about this topic. I have been faced with the difficult decision over whether or not to prescribe narcotics many times, and I understand a doctor’s dilemma. The doctor sees a person who is in pain, and knows that there is a pill that will reduce that pain. But the doctor also knows, or SHOULD know, that initiating a prescription for narcotic pain medication always has unintended consequences, no matter how good the intentions of both doctor and patient.
In the Iowa case, the dilemma over narcotic-prescribing is very clear. The prosecution states that the doctor prescribed pain medication to drug addicts.  On the surface, that sounds bad, right? One gets the mental picture of dirty, lazy people, dissolving tablets in a spoon, over a candle, and then injecting the mixture. But reality is much more complicated. Patients with histories of opioid dependence do not always have track marks. And even if we tattooed the letter A across their chests, there are addicts who are in need of pain treatment. Are we to decide that every person who has become addicted to pain medication gives up the right to pain treatment?  And we know that many of the patients addicted to opioids became addicted through the course of pain treatment from their physician— so I would expect that on average, patients addicted to opioids would have a higher incidence of chronic pain, and vice versa.
I do not find it reasonable to make patients with addiction histories endure pain that would be treated in other patients.  Father than singling out some patients for ‘special non-treatment,’ we should prepare for the risks from opioids in ALL patients—a set of ‘universal precautions for opioid treatment,’ similar to the way we use a different set of universal precautions to avoid transmission of blood-borne infections.
There are times when doctors have to tolerate being the bad guys.  Some patients have been taught, through careless prescribing, that all pain should be treated with narcotics. Those patients are not happy when told, after paying several hundred dollars, that they do not ‘need’ narcotic pain medication– and so many of their doctors have a hard time saying ‘no.’ After all, doctors studied hard to do well in school, and usually receive praise for what they do. It is much easier to write a prescription and hear ‘thank you’ than to be called an unsympathetic jerk! But doctors are paid the big bucks to tolerate such things, and to keep the long-term health of patients in mind. And for many people with chronic pain, opioids will provide a good month or two, but for the price of many years of misery.
I’ve been told by patients “I don’t care about the risks, doc– I’d rather have three good months and then die, then have twenty years in pain.” I reply, “that’s why these medications require a doctor to consider things very carefully, and a good doctor would not allow someone to make that decision.” I’m sure that some people will be angered by that attitude. But the approach is similar to how we handle many other illnesses, where we encourage patients to tolerate short-term misery for long-term benefits. Many patients would refuse chemotherapy and give up on life if not pushed to move forward. And to depressed patients, suicide can appear a reasonable option. I’m a fan of free will, but I recognize that we don’t always choose our paths through life with full insight.
Even with full knowledge of the reasons to avoid narcotics, some doctors really struggle over withholding opioids.  I find it somewhat ironic that the doctors who are too ‘kind-hearted’—i.e. who want to please patients so much that they cannot deny even that which is bad for them—are the ones who end up getting into trouble.  The Iowa doctor is being sued over several of the deaths, likely by relatives of the patients who pled the hardest for pain pills!  Talk about good deeds not going unpunished!
But there are aspects of the case in Iowa that do not argue well for the doctor. Several of the patients who died were only seen once, but treated with narcotics for years. The DEA requires that patients are prescribed no more than 90 days of narcotic medication at one time (divided on three monthly prescriptions). I presume that patients were picking up scripts every three months, without having appointments each time. Such a practice is not strictly illegal (not that I am aware of, anyway), but the standard of care would be to evaluate patients on potent opioids every three months, or even more frequently. And one news article stated that the doctor had tens of thousands of pain patients. As a full-time practitioner with less than 1000 patients, I wonder how so many patients could be managed by one physician.
When I write about this topic I receive angry comments from some readers. Some attack me personally with comments like “I’m glad I’m not YOUR patient!” or “I hope YOU have to suffer with horrible pain some day!” I realize that this is a very hot topic, and my only intent is to educate and inform, to help people understand what is happening in the minds of physicians. Of course, the care of patients should not be determined by the need for doctors to protect their own interests. But at the same time, it is understandable that doctors are affected by headlines announcing the imprisonment of other doctors facing the same treatment decisions.
Bottom line– there are very good reasons to avoid using opioids for nonmalignant chronic pain. Just giving patients what they want, and ignoring the danger of opioids, will likely result in criminal and civil prosecution. But that reason is secondary to the most important thing– the promise all doctors make to first, do no harm. And patients should realize that their doctors may be withholding narcotics for that reason alone.

Hydrocodone (Vicodin) Addiction and Buprenorphine

I recently accepted a young man as a patient who was addicted to hydrocodone (the opioid in Vicodin), prompting a discussion about treatment options for someone who hasn’t been using very long, and who hasn’t pushed his tolerance all that high. Perhaps it will be informative to share my thought process when recommending or planning treatment in such cases. In part one I’ll provide some background, and in a couple days I’ll follow up with a few more thoughts on the topic.
Most people who have struggled with opioids learn to pay attention to their tolerance level—i.e. the amount of opioid that must be taken each day to avoid withdrawal or to cause euphoria (the latter about 30% more than the former). For someone addicted to opioids, the goal is to have a tolerance of ‘zero’—meaning that there is no withdrawal, even if the person takes nothing. That zero tolerance level serves as a goal, making having a high tolerance a bad thing, and pushing tolerance lower a good thing.
Tolerance is sometimes used as part of the equation when determining the severity of one’s addiction. But looking at tolerance alone can be misleading. Tolerance is a consequence of heavy use of opioids, and also a cause of heavy use of opioids. Tolerance usually goes up over time, so having a high tolerance probably correlates with length of addiction in some—- but not all— cases. Tolerance is also strongly related to drug availability. A person with a severe addiction, who only has access to codeine, will likely have a lower tolerance than a person with a more mild addiction, who has free access to fentanyl, oxycodone, and heroin.
I think it is more appropriate to measure the ‘severity of addiction’ by the degree of mental obsession that the patient has for opioids. Tolerance is one piece of information in determining that obsession, but tolerance alone can be misleading.
To get a sense of the obsession for opioids, I look at many factors. Has the person committed crimes to obtain the substance? Violent crimes? What has the person given up for his addiction? Has he been through treatment? How many times? How long did he stay clean after treatment? Have his parents or spouse thrown him out of the house, and if so, does he still use? Did he choose opioids over his career? Over his kids?
Answers to these questions provide a broad understanding about the addicted person’s relationship with the substance—an understanding that is necessary when considering the likely success or failure of one treatment or another. It is also important to consider the person’s place in the addictive cycle—i.e. early, likely in denial, cocky, with limited insight– or late, after many losses, more desperate—and perhaps more accepting of treatment.
I am a fan of buprenorphine as a long-term treatment for opioid dependence, as readers of this column know. I consider opioid dependence to be a chronic, potentially-fatal illness that deserves chronic, life-sustaining treatment— and buprenorphine, in my experience, is a very effective treatment in motivated patients. But tolerance becomes a factor, when considering buprenorphine for THIS patient.
Buprenorphine has a ‘cap’ or ‘ceiling effect’ that allows the medication to trick the brain out of craving opioids. In short, as the blood or brain concentration of buprenorphine drops between doses, the opioid effect remains constant, as long as the concentration is above the ceiling level. In order to achieve the anti-craving effects of buprenorphine, the dose must be high enough to create ‘ceiling level’ effects. If buprenorphine is prescribed in lower amounts—say microgram doses— the effect is identical to the effects of an agonist, since the dose/response curve is linear at lower levels.
Buprenorphine is a very potent opioid, and the effects of the medication are quite strong at the ceiling level. Comparisons to other opioids will vary in different individuals, but in general, a person on an appropriate dosage of buprenorphine develops a tolerance equivalent to that of a person taking 40 mg of methadone per day, or approximately 60-100 mg of oxycodone per day.
A person taking even a dozen Vicodin per day has a much lower tolerance to opioids. Such a person who starts buprenorphine treatment will obtain a very significant opioid effect from the drug— unless the dose of buprenorphine is raised very slowly over a number of days. And in that case, the person’s tolerance level would be pushed much higher.
So if our current patient starts buprenorphine, he will have a much higher opioid tolerance if/when the buprenorphine is eventually discontinued. I receive emails now and then from patients who are angry at their doctor for starting buprenorphine, feeling trapped by the considerable threat of withdrawal from stopping the drug. But at the same time, taking hydrocodone and acetaminophen in high amounts creates the risk of liver damage from the acetaminophen, as well as the considerable risks from opioid dependence.
And so the dilemma. Should buprenorphine be considered in such a case?

Jerk Counselor

Every now and then I hear about a therapist or addiction doc who is doing such a disservice to the practice of addiction medicine as to deserve special mention.  This week’s award goes to a certain counselor at a treatment program in Oshkosh, WI, who I’ll refer to as ‘This Jerk.’
I’ve made no secret, over the years, about my hope for addiction to eventually be treated with the same respect for patients and attention to medical principles as for any other illness.  I certainly try my best to work according to those ideas, and find that doing so really helps when it comes to making treatment-based decisions.  In other words, I’ll ask myself—if this person had diabetes, what would an endocrinologist do?  Or better yet—if I had diabetes, what would I want MY endocrinologist to do?

Some Jerks advocate punishing patients who struggle.
This Jerk Counselor

We all know that certain professions attract certain types of people.  Some of us have been pulled over by the cop who was the kid subject to playground taunts, now all grown up, determined to make life a living Hell for anyone with a loose seat-belt.  When I worked in the state prison system, I worked with guards who belonged in the same category; men and women who loved to carry keys to cages that held real people.  It’s the power trip, I suppose.
This Jerk apparently loves the power trip of ‘treating’ people who are sent back to jail for ‘failing’ his treatment.  He doesn’t have to worry about being a lousy therapist; he has a captive audience, and likes it that way.  One difficult aspect of being a therapist is treating patients who don’t like us for one reason or another, or who don’t kneel every time we enter the room.  But when This Jerk feels disrespected, he picks up the telephone and calls the patient’s PO to report ‘noncompliance with treatment’– then gloats about sending the patient to jail.
Treatment professionals who are in a position of unusual power over a patient must be particularly careful to empathize with their patient’s position.  In medical school, we were placed on gurneys and wheeled around by fellow students, to emphasize the vantage of patients coming to the emergency room.  We were taught to sit at the same or lower eye-level of our patients, as speaking down to people creates an unsettling power differential.
The power to prescribe or withhold buprenorphine (let alone the power to send to prison!) comes with an obligation not to abuse that power.  Withholding buprenorphine causes patients to go into withdrawal—something dreadful to people addicted to opioids.  Worse, withholding buprenorphine places patients at very high risk of relapse—which in turn places them directly in harm’s way from overdose and legal repercussions.
This Jerk, I’ve been told, takes issue with psychiatrists who continue to treat patients on buprenorphine who struggle with sobriety.  He considers it ‘good care’ to withhold buprenorphine from an addict who uses, supposedly to punish the patient into sobriety.
In case This Jerk (or a similar ethically-challenged counselor) is reading, I’ll point out the obvious:  when a doctor pulls the rug from under a patient by withholding medication, that patient might easily join the ranks of other dead addicts.  On the other hand, when I work with a patient who is struggling with sobriety, keeping the person on buprenorphine and working to identify triggers for using, that person almost always ‘gets it,’ eventually.
I’ve been working with people addicted to opioids, using this approach, for so long that the other approach—the punitive, ‘cut ‘em loose for struggling’ approach—seems barbaric.  I don’t understand how people identified as healthcare workers (nothing professional in his behavior!) rationalize the dismissive approach.  I suppose, if This Jerk views addicts as the scum of the Earth, or as people with weak characters, or people who lack ‘will power,’ punishing relapse by withholding treatment feels about right.  But most of us leave that world behind when we commit to helping people suffering from illness.
What’s This Jerk’s excuse?  Is it that he just doesn’t get it?  Or are there other motives at play?  With the current cap on patients on buprenorphine, the most lucrative way to practice is to keep turnover high, rewarding practices that hire therapist-idiots like This Jerk.
Or is it the power trip– that people with difficult addictions are an affront to therapists?  I’ve met therapists with this attitude before, who seem to have a form of codependency with their patients. They take credit for any success by their patients, but think the patients who fail are not worth their time, and should be dumped, expunged, or kicked-out to relapse and die.  I suppose This Jerk would say ‘not my problem!  I did MY job!’
Readers may suspect that this topic irritates me—and they’re right.  Maybe I’ve seen more death, up close, than the typical counselor.  I’ve attended autopsies; I’ve reviewed post-mortem photos from overdose scenes; I’ve pushed IV fluids into people with fatal injuries who presented for emergency surgery.  I have spent hours with the parents of young patients who died from overdose.  I’ve seen the parents’ faces as they struggled with the thought that they could, or should, have done something else—just one more thing to save their child.  Death, to me, is not ‘theoretical.’ It is not something to toy with, and certainly not something to invite into the life of a person who made me angry, for not recovering at MY pace.
I suspect that the Jerks of the world will continue to justify their sadistic approach to ‘treatment.’ But patients—at least SOME patients—don’t have to put up with that behavior.  People like This Jerk hold power over an individual with an addiction history, but there is power in numbers.  It is not appropriate to use one’s power vindictively, or to gloat over a patient’s struggle.  It is not appropriate to humiliate a patient in front of others.  If you see that behavior, collect witnesses, and bring it to someone’s attention.  Maybe that ‘someone’ will write a blog post about it!
Doctors in particular should treat patients with ALL diseases—including addiction—with respect.  It is not respectful, or ethical, to deprive a patient of life-sustaining medication—especially out of spite.  I look forward to the day when the thought of ‘kicking someone off Suboxone’ is viewed as similar to kicking a poorly-compliant teenage diabetic off insulin.
Would THAT make sense— even to This Jerk?

The Other Opioid Dependence Medication

Today I met with representatives from Alkermes who were promoting Vivitrol, a long-acting mu opioid antagonist that is indicated for treatment of alcoholism and opioid dependence.

Naltrexone
Naltrexone

I admit to some pre-existing bias against the medication.  I’m not certain, to be honest, whether that bias was based upon sound clinical reasoning, or whether it was based on personal, negative reactions to naltrexone in my past.  Or maybe, as a recovering opioid addict, I have negative feelings about anything that blocks mu receptors!
Vivitrol consists of naltrexone in a long-acting matrix that is injected into the gluteal muscle each month. The medication is expensive, costing about $1000 per dose (!)  That cost is usually covered by insurance, and like with Suboxone, Wisconsin Medicaid picks up the tab save for a $3 copay.  Alkermes, the company that makes Vivitrol, also has a number of discounts available to reduce or even eliminate any copays required by insurance companies.
I’ll leave the indication of Vivitrol for alcoholism for another post.  The indication for opioid dependence came more recently, and appears more obvious, given the actions of naltrexone at the mu opioid receptor.
In short, naltrexone blocks the site where opioids—drugs like oxycodone, heroin, and methadone—have the majority of their actions.  Blockade of that site prevents opioids from having any clinical effect.  There is some dose, of course, where an agonist would regain actions— an important feature in the case of surgery or injury.  But even in those high doses, the euphoric effects of addictive opioids would be muted.  People on Vivitrol, essentially, are prevented from getting high from opioids.
Back in my using days, I took naltrexone, thinking that doing so would help me get ‘clean.’  I didn’t wait long enough, however, and so I became very sick with precipitated w/d.  The makers of Vivitrol recommend waiting at least a week, after stopping opioids, before getting an injection of Vivitrol.  I suspect that a week is not long enough to prevent w/d, but I realize that it would be very difficult to expect patients to last longer, without using anything.  I would expect that any precipitated w/d could be reduced through use of comfort medications, at least for a day or two until the symptoms are mostly gone. This requirement, though, to be clean for a week or more is one of my problems with the medication.
As an aside, I was also prescribed naltrexone (oral tabs) at the end of my three months in residential treatment, and I took the medication for another three months.  I had no withdrawal or other side effects to naltrexone at that time.
Another issue was the concern that naltrexone has been connected to hepatic toxicity.  We discussed that issue today, including the studies that led to that connection—which are not compelling.  The discussion allayed most of my concerns about liver problems from Vivitrol.
Finally, I have always recommended buprenorphine over naltrexone because of the anti-craving effects of buprenorphine that result from the ‘ceiling effect’ of the medication.  I worried that naltrexone, by blocking the actions of endorphins, would actually increase cravings.  But that is not what the data shows.  In the studies with Vivitrol, cravings for opioids were dramatically reduced by the medication.  The mechanism of that effect is not entirely clear;  some of the anti-craving effect may be psychological, as addicts stop wanting something when they know there is no way to get it.  But there may be other complicated neurochemical effects at presynaptic opioid receptors that are not fully understood.
The bottom line is the result of treatment;  the very sick opioid addicts treated in the studies used by Vivitrol to gain FDA approval showed a profound reduction in opioid-positive urines, over a span of 6 months.
I suspect that I will continue to favor buprenorphine.  I do not buy into the ‘need’ some people describe to ‘get of buprenorphine as fast as possible.’  Buprenorphine is a very effective, safe, long-term treatment for inducing remission of opioid dependence.  But because of the cap, I am glad that another option is available to treat this potentially-fatal condition.  And I admit to perhaps being too quick to judge Vivitrol, which appears to be a safe alternative—particularly for people who have a lower opioid tolerance that do not want to push it higher, or for people who have been free of opioids for a week or two.
I would invite local people who are on my buprenorphine waiting list to consider Vivitrol as an option.
 

Buprenorphine for Treatment of Cocaine Dependence

This is not all that new, but it was just pointed out to me recently and I figure many of you will find it interesting.  As most readers know, the receptors that mediate the actions of cocaine are completely different than the receptors that are activated during use of opioids.  I will be posting related information in the next few days.
From DataMonitor:
Alkermes, Inc., an integrated biotechnology company, has announced positive topline results from a Phase I clinical study of an investigational combination of ALKS 33 and buprenorphine, an existing medication for the treatment of opioid addiction, for the treatment of cocaine addiction.
Data from the study showed that the combination therapy was generally well tolerated and sublingual administration of ALKS 33 effectively blocked the agonist effects of buprenorphine. Based on these positive results, Alkermes expects to initiate a phase IIa study of the combination therapy in the first half of calendar year 2011, the company said.
The phase I study was a randomized, double-blind, multi-dose,placebo-controlled clinical trial that assessed the safety, tolerability and pharmacodynamic effects of the combination of ALKS 33 and buprenorphine when administered alone and in combination to 12 opioid-experienced users.
Buprenorphine is used for the treatment of opioid addiction, despite its own potential for abuse. Combining ALKS 33, an opioid modulator, with buprenorphine, a partial opioid agonist, may block the agonist effects of buprenorphine thereby reducing the potential for the development of opioid dependence while still maintaining effective therapeutic action. Furthermore,
the pharmacologic properties and low dose of ALKS 33 required to effectively block mu opioid receptors may allow for a co-formulation with buprenorphine as a single sublingual tablet, the company added.
Elliot Ehrich, chief medical officer of Alkermes, said: “We look forward to continuing the recent momentum in our R&D efforts by initiating a phase IIa clinical trial to generate further data, as we advance the ALKS 33 and buprenorphine combination therapy as part of Alkermes’s growing pipeline of proprietary product candidates.”

The REAL Future of Partial Agonist Treatment— Pharma are you Listening?

I just wrote a note to a friend who works in the molecular sciences– she has been studying opioid receptors since the early 1980’s, when things were just getting started on a molecular level.  I’m keeping her name to myself, but I’ll share a few thoughts about what is needed to advance the treatement of opioid dependence– and make a few million dollars along the way (are you listening, RB?)
Hi ——,
(private chit chat that would bore everyone)
Anyway, today I realized what is needed in order to take partial agonist treatment of opioid dependence to the next level.
The problem with buprenorphine is that the ‘ceiling effect’ occurs at a relatively high tolerance level, approximately equal to 40 mg of methadone.  That causes at least two problems.  First, going off Suboxone is a lot of work, as the person still has a great deal of withdrawal to go through.  That may be a good thing early in the process, as it may help keep people on Suboxone, but after a year or so, when people want to try going off the medication, it is a major barrier that opens the floodgates to those old memories of using, etched in the emotions associated with withdrawal.
The second problem with the high ceiling/tolerance level is that surgery is a hassle.  People needing surgery need HIGH amounts of oxycodone to get any analgesia—I usually give 15-30 mg every 4 hours.  Pharmacists shudder to release those doses, and some surgeons and anesthesiologists balk.
The horizontal part of the dose/response curve is the essential part of buprenorphine;  that is what tricks the brain into ‘thinking’ that nothing is wearing off, and in that way eliminating cravings.  But that flat dose/response relationship could occur at lower tolerance levels and still work the same way.
Since I’m wishing for the moon, a series of molecules with progressively lower ceiling levels would be ideal, with the last molecule in the series being Naltrexone.  Although actually, naltrexone doesn’t work—it has NO mu agonism, so there is no tricking of the brain, and no reduction of cravings.  We would want something close to naltrexone, but with a tiny bit of opioid activity that does not vary with dose.
A shorter half-life would also be helpful.  Preparing for surgery requires weeks to get the buprenorphine out of the system.  Of course a shorter half-life means it is easier to get around buprenorphine by people who want to play with agonists, so again, these new molecules would be intended as ‘step down’ meds from early-stage buprenorphine treatment.
Do we know enough about molecular actions at the mu receptor to design molecules with these properties?  Or are we still at the point of making somewhat random changes and assaying the result?  Do you know of any labs doing this type of work?
I figured you’re the person to ask!
Thanks ——–
Jeff

Optimizing Absorption of Buprenorphine

I wrote this a couple years ago, and still get questions about the topic today.  Studies show that a small fraction of the amount of buprenorphine in a tablet or film strip actually gets absorbed through mucous membranes;  the rest is swallowed.  The 15%-30% amount of absorption is referred to as the ‘bio-availability’  of the drug.
People who feel like they are not getting enough buprenorphine to remove cravings can review the principles below, to see if there are ways they can easily improve the absorption of buprenorphine.  NOTE:  improving absorption is NOT an ‘addictive’ behavior, for a couple reasons…. first, because of the ceiling effect, increasing the amount absorbed will NOT cause a ‘buzz’ or high, but will only make the medication last the full 24 hours without wearing off.  Second, crushing a tablet will NOT cause a ‘rush’ or ‘high’ for two reasons– first, because of the ceiling effect as I just described, and second, because the rate-limiting step for absorption is the passage through tissue— NOT the dissolution of the tablet.  This is why, by the way, the film does not cause a ‘rush’, even though it dissolves more quickly.
Read on:
I often answer questions about Suboxone that require the qualification ‘if it is being absorbed properly’. If a person asks how long it takes for Suboxone to wear off, or at what dose does the ceiling effect occur, I need to be sure that the person is taking it in a way that maximizes absorption; otherwise all bets are off. If a person simply swallows the tablet, for example, the level of buprenorphine in the bloodstream will be much lower than if it is taken correctly.
The usual instructions for taking Suboxone are to place a tablet under the tongue and let it dissolve.  It is important that Suboxone be taken once per day, in the morning; this instruction is included in the course for physicians but is too often ignored.  I will talk another time about the philosophy for dosing once per day; the basic reason is to extinguish the behavior that has been conditioned as part of the addiction.  But the point of this post is the absorption of buprenorphine from the tablet into the bloodstream, and how to maximize that absorption.  It is important to maximize absorption, particularly if one is trying to save money by reducing the daily dose of Suboxone.
From my experiences as an anesthesiologist, as an addict**, and as a PhD chemist, I recognize that three factors will maximize absorption.  The first is the concentration of buprenorphine in the saliva, as the drug diffuses into tissue down a concentration gradient.  This gradient is maximized by having a small volume of saliva.  I recommend that a person start with a dry mouth, place the tablet in the mouth, and crush the tablet between the teeth until it is dissolved in a small volume of a concentrated solution.
The second factor that affects absorption is the amount of surface area.  Buprenorphine is absorbed through all mucous membranes (the tissue lining the inside of the mouth), passing through the surfaces and entering capillaries, the route into the bloodstream.  So the concentrated solution should be ‘painted’ repeatedly over all of the surfaces inside the oral cavity;  the inside surface of the cheeks, the tongue, the roof of the mouth, under the tongue, the back of the throat…  swished around in the mouth over and over, repeatedly bringing the concentrate into contact with new areas of mucous membranes.
The third factor is time– the longer period of time, the longer for the buprenorphine to make contact with the mucous membranes, attach to the surface, get absorbed into the tissue, and enter the capillaries.  The initial process will be the saturation of the surfaces of the mucous membranes, and the slower process will be the passage into the tissue;  that is why the amount of surface area has such an important effect on absorption.  Fifteen minutes is probablysufficient for most of the absorption to occur;  there may be drug remaining that is attached to the surface but not yet fully absorbed, and so I recommend avoiding eating or drinking within another fifteen minutes or so after swallowing the left-over saliva.
If you pay attention to these principles you will maximize absorption of the drug.  The ceiling effect will occur under these conditions at a dose of about 2-4 mg;  the long half-life of the drug will guarantee that if you take over 4 mg or so each morning, you won’t have any significant withdrawal for over 24 hours– allowing once-per-day dosing.  Yes, early in treatment patients will feel as if they need to dose more frequently– but that is not because of too little buprenorphine, but rather because of conditioned behavior.  A person early in Suboxone treatment will have feelings or minor withdrawal in the late afternoon or evening after dosing in the morning;  those minor withdrawal sensations will go away in about 15 minutes if the person takes more Suboxone, and will also go away in 15 minutes if the person doesn’t take Suboxone.  If the person takes more Suboxone, it will reinforce the sensations and the person will get stuck on dosing twice per day.  If, on the other hand, the person uses distraction and avoids dosing, those minor withdrawal sensations will completely disappear in a week or two, as the conditioned behavior is extinguished.
**I mentioned my experience ‘as an addict’;  for a period of time my preferred route of administration of lipid-soluble opioids was ‘trans-mucosal’ or ‘trans-buccal’.  Since the amount of substance available was finite (albeit a fairly large finite amount!) I did all that I could to optimize absorption, including reading about diffusion of lipid-soluble molecules through mucous membranes.

Upcoming Changes in Pain Medication Regulations

This is a repost from my blog on PsychCentral:
There are changes afoot in the use of opioid agonists for chronic pain treatment. This blog has described the epidemic of opioid dependence that has killed tens of thousands of people across the country over the past few years, and the changes are directed toward reducing the harm caused by this epidemic.
A number of interventions have been proposed. Vicodin, the number one-selling medication in the country, contains the opioid hydrocodone combined with acetaminophen, the agent in Tylenol. Hydrocodone and Vicodin are currently ‘Schedule III’ medications, and will likely move to Schedule II, where oxycodone, Oxycontin, and Percocet are currently assigned. The change will have significant impact on the use of Vicodin and hydrocodone, since medications classified as Schedule II must be ordered on written prescriptions—i.e. they cannot be called in to the pharmacy. There are a number of other limitations on Schedule II medications; the prescriptions cannot have refills for example, and a maximum of 90 days of medication can be ordered at any one time. The laws that govern diversion of Schedule II medications are more strict as well, meaning that trading or selling Vicodin or hydrocodone to a friend or relative will carry significant risk of prosecution—and incarceration.
There are proposals for additional certification and training for doctors who prescribe pain medications, beyond the current DEA licenses that typically allow registrants to prescribe all of the controlled substances, without distinguishing between classes or uses of medications. These proposals anger the ‘pain treatment lobby,’ whose members claim that additional certification requirements will lessen the availability of pain medications. And they are correct—that is, after all, the whole point of the proposed changes.
There are a couple issues that merit discussion that have no clear right or wrong answer—at least in my opinion. First, in the debate over additional certification, there is little argument that such changes would reduce the number of doctors who prescribe opioids. Many doctors will decide that it is not worth the hassle and cost to obtain the special certification. Some others will see the requirement as a golden opportunity to leave the pain med prescribing to others, as they will be able to tell their patients ‘I’m sorry—I’m not allowed to prescribe them’—an easy way to avoid confrontation with patients asking for pain pills who doctors consider to have borderline indications for them.
We don’t know, though, whether other doctors will see the changes as business opportunities—growth in a new specialty of ‘pain pill prescribing’ for example—and fill the void left by less-frequent prescribers. And if there is a reduction in pain medication prescribing, will the reduction affect the people who don’t really NEED pain medications—i.e. the patients with mild lumbar strain, who would do much better using a heating pad and ibuprofen, and perhaps learn to lift without bending at the waist? Or will people with severe pain that truly warrants opioid medication find it impossible to have their pain adequately treated?
People should be aware that there are very significant differences in opinion over the proper use of opioid pain medications between physicians. For years, doctors were taught that people with ‘real pain’ rarely become addicted to pain medications. I was stunned when I read a study a couple years ago that claimed that less than 10% of patient who are prescribed pain medications develop opioid dependence. My clinical experience, after working for ten years in pain treatment and for about 20 years as a physician, suggest a number at least five times higher.
More and more doctors are realizing that for most people, opioid pain medications do little to increase function. People become tolerant to whatever dose of pain medication they are taking, and with that tolerance, the pain relief goes away—unless the dose is increased, which only repeats the cycle at a higher tolerance level. Patients become slaves to their medications, developing severe withdrawal from missing even one dose. Their high tolerance makes it difficult to treat pain from surgery, or from other painful conditions that the patient may develop. Finally, there is more and more evidence for the phenomenon of ‘opioid-induced hyperalgesia’ where pain symptoms are ultimately increased by opioid pain medications.
But patients still want pain medications when they are in pain, no matter how many lectures they hear about ‘decreased function,’ hyperalgesia, or tolerance. Doctors are placed in the position of giving patients what they ask for, even if it is ultimately bad for them— or protecting patients and standing up to their anger. Standing up to patient anger is not what many doctors signed up for when they went to medical school, and goes against their desire to help people—and to be liked for helping people.
And I don’t know if any course or certificate will help doctors deal with THAT.

Chapter 4, Pt 2: Stages of Addiction

I am always impressed by how similar addiction progresses in one individual versus the next.  The next reader’s comments and my comments afterward demonstrate a pattern that I have observed in one opioid addict after another.  Throughout the book, comments that I receive from others will be italicized.
I started on Suboxone in Feb 08 to get off opioids. It worked very well for me, I lost 20 pounds while on it, got very active, and above all was the happiest I had been in a long time. After 7 months of taking 32 mgs a day I had to wean off it because I had no more insurance and it was very expensive.
I tried to wean the best I could and the end of Oct was it for me. I was down to taking 2 mgs a day then completely stopped because I ran out of Suboxone. About 3 days after I stopped taking it I started withdrawing. I was getting the chills, I felt weak, I had this nervous feeling in my stomach which was very annoying and caused me to not be able to sleep. So what did I do? To get rid of the withdrawal feeling I was getting I started taking opioids again.
I am now on my 3rd day of Suboxone treatment again, I am only taking 1 pill a day and by the 10th day I am going to take 1/2 a day. I will stop at 14 days and stay completely away from opioids by keeping busy, working out, and most of all living a NORMAL life. I am also planning on attending NA classes for support. I will keep you posted and to everyone else doing the same… GOOD LUCK TO ALL OF YOU!!
Early in addiction, opioid addicts believe that if they could only get past the physical withdrawal, they would be done with opioids forever.  During this first stage of opioid dependence, addicts are always fighting for that first piece of sobriety.
They hang out with each other on message boards on the internet comparing tapering plans using cocktails of amino acids or other worthless regimens, hoping to find the one that works– that gets them through withdrawal to become opioid-free.  They are not interested in meetings or rehab; they don’t consider themselves to be the kind of addicts who need THAT kind of help.  They insist that Suboxone be used only short-term, as a bridge to total sobriety.  They have no interest in accepting a life-long illness, and argue that they expect to find a ‘cure’ even as they return to opioids again and again.
Denial is huge during this stage of addiction; addicts minimize the damage opioids cause in their relationships, work, and health.  They can discount the damage in part because they consider their addiction temporary and easily corrected– once they just stop the darn opioids.  They assume– often for a long time– that the right tapering method will come along and things will be fine.  Hooked?  Not them!
Addicts enter the second stage of addiction when they have successfully discontinued opioids and made it completely through withdrawal.  From my vantage point of seeing many addicts over time, the point where sobriety is finally achieved is not associated with any particular taper method or amino acid formula, but rather occurs when addicts have had enough consequences to motivate them to tolerate the entire period of withdrawal.
More and more bad things pile up until they cannot be repressed and ignored; job(s) lost, friendships damaged or destroyed, finances in shambles, legal problems, and marital difficulties are some examples of these consequences.
During the first stage, addicts get to a certain level of withdrawal and say ‘enough of this!’ and resume using.  But during the second stage the drug-related problems are remembered throughout the entire length of withdrawal, keeping addicts motivated to get free from opioids.  Often addicts are so sick of using by this time that they don’t even use a taper, but rather just stop at a moment of self-disgust, without any plan or preparation.  Or perhaps the consequences lead to a jail cell, resulting in sudden and absolute sobriety without the luxury of medication to reduce the severity of withdrawal.
That’s great, right?  They are finally free of opioids!  Unfortunately they are about to enter the third and worst stage of opioid addiction– the stage that can last for years and that totally demoralizes addicts.  The stage begins with relapse — after a week or after a year, but the bottom line is that it almost always happens — even though NOBODY thinks it will happen to him.
I hear the comment over and over — ‘don’t worry, doc, I don’t plan to relapse!’ Or ‘I hear what you are saying — but you don’t understand how motivated I am!’ Many addicts consider themselves too smart for relapse, but I see the AA adage come true over and over: nobody is too dumb for Recovery but some are too smart for it!  The meaning is that every now and then a person will avoid relapse — and it tends to be a person who has a simple take on life who didn’t really shine in other, more competitive areas.
The lucky person who finds recovery to be easy is someone who is well aware of his own limitations, and who never got in the habit of trusting his own opinions or his own abilities.  That person can sometimes simply stop using because he accepts the idea that he has lost the fight — that opioids are much stronger than he is, and that he will never figure out how to take them without disaster.
But most people are far too smart to find easy sobriety.  As soon as things start going well their minds take off again, and at some point they return to using.  I’m not going to spend time on the triggers for relapse, as we will discuss them another time — but there are things common to all relapses, including  rationalization, denial, grandiosity, and the feeling of ‘terminal uniqueness:’ a sense that all of the dangers of relapse apply, for one reason or another, to OTHER people.
During this third stage of opioid dependence, addicts will have repeated episodes of relapse and sobriety.  There is little joy in using, because consequences occur much more rapidly now.  More and more time is spent being sick from withdrawal.  This is the stage that long-time addicts remember and fear the most.
In my case, I could stop using every weekend;  I was away from the operating room and away from the drugs, and I would start the weekend determined that ‘this was the LAST TIME–  come Monday I won’t touch ANYTHING!’  And so I was always sick; the kids would be playing outside and I would be in my bedroom curled up on the bed, hating myself for not being there for them.  And of course, on Monday I would be right back at it again, telling myself that THIS weekend didn’t work because I needed just one more day… or because I had (insert incident here) to deal with.
As I mentioned earlier, during this stage addicts become truly ‘sick and tired.’  This is a dangerous period of time for addicts for several reasons; when addicts use they feel a great deal of shame, which fuels more using — making use more impulsive and reckless and more likely to cause a fatal overdose.  Addicts in this stage become depressed — sometimes extremely depressed — and commit suicide, either actively or by not caring anymore about the risks of taking too much.
Addicts sometime feel such hopelessness or shame that they will do anything to change how they feel — swallowing any pill they come across, or shooting up unlabeled and unknown liquids — anything!  Even a hammer to the head looks good at this point!
This is the time and level of desperation when traditional treatment has been effective; addicts are at ‘rock bottom,’ and no longer feel confident about any of their own abilities.  They are ready to follow anyone or anything — after all, what do they have to lose?  Life is over anyway — so why not listen?
If an addict can keep this attitude throughout one to three months of residential treatment and then keep it into an aftercare program, he has a shot at meaningful sobriety. But if he gets into treatment and quickly finds a girlfriend, or if he tells jokes and becomes the funniest, most popular guy in the facility, or if the counselors are in awe of his wealth, education, or power and tell him how cool he is…  there is a strong chance that the treatment will prove worthless.  To get better, an addict must hold on to the attitude that he knows nothing, for only that attitude will allow change to occur.
The ‘desperation’ issue relates to why, in my opinion, young people have lower success rates in treatment.  Young people often feel too invincible for treatment to take hold.  They also have short memories for painful events; consequences are quickly forgotten and dangerous self-reliance returns.
The true wonder of AA is that the program’s founders understood all of this; the program is about humility and powerlessness, and consists of a series of steps that if practiced completely, will take people to the right frame of mind and keep them there.
The reason treatment tends to work better for older people is because first, more are at the later stage of addiction and are truly ‘sick and tired,’  and second, self-confidence tends to return a bit more slowly after a major blow in us older folks, so we hang onto our desperation a bit longer.  We also tend to remember the bad things that happen because we know that people sometimes die, and that some friendships can be lost forever.  Plus it is difficult to feel immortal when one’s body aches each morning!
In light of what you have read, go back and read the italicized comments from the reader again.  See if you can tell the stage of addiction that the person is experiencing.  I receive similar comments every day by e-mail.  I have watched over the past 16 years as addicts (including myself) repeat these stages over and over again.  Every person is convinced that he is different– only to eventually find that in regard to addiction he is the same as everyone else.
This is why I recommend seeing Suboxone as a long-term medication and seeing AA and NA as life-long programs.  In either case, the natural tendency of the untreated addict will be to relapse and return to the horrible cycle of using and withdrawal.