How Will Electronic Pill Monitoring Be Accepted In A Post-Orwellian Society?

Pretty well I would say.

That is by definition.  Orwellian is a term that captures the world George Orwell described in his classic book 1984.  Free society no longer exists as the people are manipulated by state propaganda, surveillance, and overt coercion.  As Orwell put it (1): "Political language is designed to make lies truthful and murder respectable and to give an appearance of solidity to pure wind."  More contemporary authors like Nunberg(2) have pointed out that somewhere along the way - what were considered classic Orwellian terms like jackboot have been replaced with less emotionally loaded terms that nonetheless have the same value as propaganda or misinformation.  Recent events illustrate that the Internet is a veritable firehose of misinformation from a wide range of parties that have to gain from misdirecting the public.  Nunberg points out that political language these days is less stark and intimidating than Orwell proposed - but the intent is undeniable.

A parallel process has been the gradual loss of privacy ever since the monitoring with Social Security numbers became widespread.  There is an associated acceptance that the government and even businesses should have wide spread access to personal information of most if not all citizens.  Forty years ago, no physician would have predicted that medical care in the US would be dictated by governments and businesses.  Health care in America is definitely post-Orwellian.  Patients don't complain.  The physicians that do are typically squelched by the big tent philosophy of medical societies and businesses that have an affinity for the physician executive.

That brings me to the topic of electronic monitoring of medication compliance or adherence.  No matter what you call it - it involves the percentage of medications taken as prescribed.  I am often in the situation where I am seeing a patient in an initial consultation and I have to determine what medications they were taking from a list of medications labelled as their medications.  In addition to the specific medications, I ask them what percentage of the medications they have been taking in the past month.  I get estimates from 0% to 50% in many cases.  Not taking medications is a significant cause of morbidity and mortality not only in psychiatry but also in populations taking antihypertensives, cardiac medications, antibiotics, and medications for diabetes mellitus.

Enter the new idea in pharmaceuticals.  Put a chip in the pill and use it to monitor the pills taken.  More advanced applications include monitoring of physiological parameters or in the case of electropharmaceuticals deliver a therapeutic electric current to an organ or system in the body to treat disease.  The first device to be sold in an FDA approved medication is the the Abilify MyCite preparation (aripiprazole-sensor) sold by Otsuka Pharmaceutical Company.  The system consists of a small (1 mm) chip in the pill.  The system was designed by Proteus Digital Health.  The chip consists of a small silicon microcircuit that transmits a unique identification code when the pill hits gastric acid.  The chip is not powered by a battery, but an electrochemical reaction that occurs when the cuprous chloride and magnesium strips on the chip meet stomach acid and that triggers a brief electrochemical reaction that transmits the code to a patch the patient wears on the skin.  From there the data is transmitted to a Smartphone App and a provider portal on the Internet.  Continuous Positive Airway Pressure (CPAP) machines use a similar data transmission systems so that the machine does not have to be taken into a physicians office for the SD card to be read.  The Smartphone app in this case allows the patient to decide to release the data.

There are several stories about this technology written from the Big Brother perspective.  In other words trusting corporations or governments with this data is just asking for trouble.  The opposition will say that your data is already out there in social media, copies of critical data (text messages, emails, phone logs, travel routes, GPS locations, etc),  and there is plenty of evidence that even secure accounts can be hacked.  What difference does some information about medication taking make?

As a psychiatrist, I can't envision much demand for this technology on a clinical basis.  The best way to document medication taking is to just ask a person and check a plasma level of the drug.  The most common scenario is that the person is just not getting any better and I need to know if it is due to inadequate levels of the medication or the medication is just not effective.  Practically all guidelines suggest doses and time frames to demonstrate medication nonreponse.  Psychiatrists have had long acting injectable medications available for some time.  They work in the context of a good working relationship.  The patient has to show up very two to four weeks for an injection.  In the case of nonresponse it may still be a good idea to check plasma levels.

The pill checking technology may be an adjunct to plasma levels to document that the medication has been taken reliably enough to produce a steady state of medication in the therapeutic range.  This may be valuable in clinical trials where pills counts have been used as evidence of pill taking.   In clinical research and practice the patient would need to be informed and consent to taking the pill.

Forensic applications may occur in the case of coerced care.  For example, a patient may be under a court order to take the medication and may prefer to take an oral medication.  This would allow the court to follow the patient's medication taking to document compliance with the court order.

There are several post-Orwellian scenarios that I am concerned about.  The first is patent extension.  The pill-sensor preparation is a distinct product and I would not be surprised that it results in another extension of the Abilify patent for this preparation.  It would allow for a high medication cost even when the original Abilify preparation can be sold as generic aripiprazole.  Secondly, if the electronic patent does extend the patent,  the patent may be much longer than a pharmaceutical patent based on the electronic device.  This is analogous to the situation with Advair inhalers where the mechanical apparatus of the inhaler prevented the pharmaceutical portion of the inhaler from going generic and extended the patent on a billion dollar drug.                         

A third potential problem occurs at the level of what physicians will be forced to do to justify this medication.  Will it be just the usual prior authorization or will it be more than that?  I could see a scenario very similar to the current CPAP scenario used by a number of healthcare organizations.  Many organizations currently rent out CPAP machines to patients with diagnosed sleep apnea and then download the electronic data about usage.  If the patient has not used the machine at the level they expect, they insist that the machine be given back and the patient must pay a resterilizing and restocking fee.  Will that be a new standard for expensive pharmaceuticals?  Can we expect that the patient will only take an expensive drug on a trial basis?  If the pill monitoring system says they are missing too many days - they will have to take a less expensive generic drug in the same class.

What will the physician's role be in all of this?  They will need to get data from the Smartphone portal.  Are there fees associated with that?  How much staff time will be involved?  Will this system require human support like the electronic health record?     

There are a lot of unanswered questions. Post-Orwellian medicine assumes that there will be widespread acceptance of gadgetry and further privacy intrusions.  But that is the practice of medicine we are left with when it is run by businesses and government - not physicians.

The design of a medication like this also has a distinctive propharmaceutical bias.  It assumes that medications that generally have diffuse effects on multiple organ systems in the body are producing a highly selective and effective medication response.  The "cure" is the pill.  Take the pill and you will be all right.  In fact, we have seen that when patients are actively engaged in their care taking pills is not that much of a problem.  For example, one of the most potent interventions for the chronically hypertensive patient is to have him or her monitor their own blood pressure at home.  In many cases, they can take less medication, fewer classes of medication and have better blood pressure control.

In the case of Abilify MyCite one of the suggestions about the need for this medication is that patients with schizophrenia have high rates of not taking their medications.  There are psychosocial interventions like public health nursing and ACT teams that work quite well to assist people with their medication.  There are long acting injectable forms of medication.  There is a large body of work on cognitive deficits and lack of insight in schizophrenia that is untapped at a clinical level today.  Clearly - all of the healthcare companies and governments funding treatment of schizophrenia want to keep it as simple as possible.  That involves pretending that all of these other problems don't exist and that the real problem is that the patient won't take their medications every day.  Medications that have been suggested by a psychiatrist they see 3 or 4 times a year who hardly knows them.

That myth may be one of my biggest objections to this system.


George Dawson, MD, DFAPA



References:


1:  George Orwell.  Politics and the English language. (see the send to the last sentence)  Full text

2:  Geoffrey Nunberg. Going Nucular: Language, Politics, and Culture in Confrontational Times.  Public Affairs Press. 2014: p 121-125.

3:  Prachi Patel.  Gulp! Electronics go down the hatch.  Chemical Engineering News.  October 16, 2017. p 20 - 22.



Attribution:

The Chip on a pill download is from Shutterstock per their licensing agreement.   Stock illustration ID: 763524688  Chip on pill with medicine box. 3D Render by haryigit.

Psychiatry or Anti-Psychiatry Blog How Do You Tell?

I was recently e-mailed a graphic that declared "Top 100 Psychiatry Blog" and encouraged me to display it on my blog.  I was contacted again a week later and asked why I was not displaying the graphic.  My first question was whether there really were 100 psychiatry blogs on the Internet.  My second question was whether there was any advertising hype associated with this offer.  The Internet seems like one big ad these days.  What appears to be a reasonable site often degenerates into more mouse clicks than an electronic health record in order to get viewers close to ads so that they count as advertising revenue.  There are plenty of sites out there that just link to other sites and try to get advertising revenue without producing any original content.

I visited the list of blogs and several were familiar.   I have a number of blogs written by the psychiatrists who I follow attached to this web site in my profile - along with a number of scientific blogs.  I don't think that ranking them serves any useful purpose, but I will say that they seem very reasonable to me.  At the same time there were also blogs listed there that were more antipsychiatry than anything.  Are antipsychiatry blogs psychiatry blogs?  What if they are implicitly rather than explicitly antipsychiatry blogs?  Does that make a difference?  I think that if you are writing from a strictly or even loosely antipsychiatry vantage point it probably has very little to do with psychiatry.  These sites exist and you can certainly go there.  You can read them exclusively.  But I would not equate them to a psychiatry blog that is written by someone who knows the field and is interested in scientific discussions about the field.   

So what are the red flags if you are wondering about a psychiatric blog that you might be reading? Here are a few guideposts:

1.  They are not written by psychiatrists -

Believe it or not there are a multitude of people on the Internet writing about subjects that they have no knowledge of at all.  It turns out that psychiatry is a complex subject that requires a great deal of scholarship in training and on an ongoing basis.  It is not generally amenable to lay interpretations of the meaning of brain imaging studies or clinical trials.  Some of the top viewed posts on this blog are excellent examples.  Some of the major Internet sites have writers that clearly do not know the subject material but do not hesitate to provide a heavy handed analysis that is often miles away from reality.  Fake news is an overused term that can't easily be applied to opinion.  I had a couple of readers ask the question: "Well - aren't we entitled to our opinion?"  Of course you are entitled to your opinion - but your opinion really does not apply to the real treatment of psychiatric illnesses or what is really happening in psychiatry.  There are blogs out there who bombastically target about "reforming" psychiatry when the opinions expressed on those sites clearly indicate that none of the authors knows anything about the practice of psychiatry or the influence of business and government on the care of mental illnesses.         


2.   They are written by psychiatrists -

Curiously - psychiatry itself has produced some world class antipsychiatrists who in some cases affiliated themselves with more notorious antipsychiatry organizations.  For me Thomas Szasz is a clear case in point.  In fact, some of his antipsychiatry rhetoric has become so mainstream that it is even used by psychiatrists when they wax rhetorical.  I recommend a skeptical approach to any blog - even if it is written by a psychiatrist that is a blanket condemnation of the field or that makes it seem like every conceivable problem with mental health diagnosis and treatment can be blamed on psychiatry or psychiatrists.  There is generally an air of superiority in the writing as in "Most other psychiatrists have these problems but I don't, because either I am intellectually superior or my methods are superior."  To my knowledge that condition has never existed in the history of the field.

3.  They may be the remnants of the newspaper business selling the news -

Every week I get one and sometimes two large newspapers in my driveway whether I want them or not.  The newspaper business is so desperate that they have to give papers away. They have stopped cold calling every week with some promotion that everyone knows these days is just a scheme to rapidly escalate the charges to the point that you cancel the subscription and start over.  It is obvious that nobody wants to buy a newspaper anymore.  I don't even want it littering my driveway for free.  I feel badly for another industry gone obsolete - but not bad enough to buy a newspaper.  That unhealthy atmosphere drives all manner of provocative headlines.  What used to be a discussed and edited product is now like anything else on the Internet - provocative and looking for mouse clicks and advertising revenue. The spin offs of these newspapers are generally as bad.  Some of them are "Top 100" sites. Not the best sources to consider for unbiased news about psychiatry - especially in the context of a well documented pre-existing media bias against psychiatry.

4.  They are uniformly negative about psychiatry and psychiatric practice-

One of the main reasons for this blog is to simply point out that most media is biased against psychiatry and psychiatrists - if anything the blogs are much worse.  I wrote an early post on this blog about how a writer has to adopt an overly negative view of psychiatry in combination with an overly positive view of the rest of medicine to be that negative about psychiatry.  In the real world, the demand for psychiatry has greatly exceeded the supply.  Non-physician specialists are now being hired en masse to fill unfilled psychiatric positions.  Psychiatrists are consulting in collaborative care models with primary care physicians to enable them to treat more psychiatric problems and prevent closed practices that occur when psychiatrists provide individualized care.  All of this hiring is being done by organizations that would just as soon not hire any psychiatrists if they could get away with it.  That is strong economic proof that psychiatrists and psychiatry has a lot to offer tens of thousands of patients in these health plans. 

5.  They are basically fronts for antipsychiatry cults-

As a psychiatrist with limited resources I am not about to name names and end up in some endless cycle of ridiculous litigation.  You really have to do your homework on this one, because nobody can afford to stick their neck out and name names.  Sites on the Internet that were set up to follow and characterize these groups have been intimidated into removing material or in some cases just shutting down.   These sites are often obvious by over the top rhetoric about psychiatry or psychiatrists, but many are now taking a more subtle approach.  They can give the appearance of being legitimate - right up to the point that they may offer services or request donations.  The services often cost very large amounts of money.  The legitimate psychiatry blogs I read are not looking for patients or funds.  They also point out they are not handing out medical advice and that they are generally for educational or scientific purposes.  One of the best ways to investigate questionable clinical services or requests for donations is to make sure that they have appropriate site licenses and professional licenses by state regulatory agencies.   

6.  They are written by somebody who claims they have been wronged by a psychiatrist-

I am always skeptical of this approach, basically because if you have been wronged by physicians in American society there are generally more remedies than there are in any place in the world.  I have repeatedly pointed out that the boards of medical practice in any state have a very low threshold for investigating physicians and assigning punishment that can include license forfeiture.  Practically all physicians these days are employees in healthcare organizations and there are administrators in those organizations who may be even more eager than medical boards to discipline physicians right up to firing them.  All three of these entities - medical boards, employers, and malpractice attorneys have very strong incentives for going after physicians.  In fact, any physician caught in that cross fire does not stand a chance - even if they have done nothing wrong.  American society is renowned for being litigious and medical malpractice is one of the cash cows.  There are 3 ready solutions for people who feel they have been wronged by any physician.  When I compare the time it takes to write a vituperative blog for no real gain to these cash, justice, or revenge solutions - the logical question is why?  There are not many good answers to that question.  I can think of maybe one or two - but even then extrapolating from an isolated case to thousands of doctors requires an illogical leap - especially while maintaining an equal level of contempt.

Keep all of this in mind.  A "Top 100" site may include sites that are there to bash psychiatrists or the profession.  It may be written by someone with absolutely no knowledge of psychiatry or (potentially worse) a psychiatrist who thinks that they know more than any other psychiatrist who was ever born.

Like most things on the Internet - let the reader beware.



George Dawson, MD, DFAPA

Koch's Book On Consciousness

I was pleasantly surprised to find this book.  I have been following the work of Guilio Tononi for some time and that involves reading articles co-authored by Christof Koch as one his main collaborators.  There also have several excellent videos available on YouTube where they discuss consciousness and Integrated Information Theory (IIT) of consciousness.  In this book we learn about Koch's personal and professional trajectory in the field and several of his influences.  He is currently the President and Chief Scientific Officer of the Allen Institute for Brain Science and a Professor of Biology and Engineering at Caltech.  His academic credentials are available at the link to his web page and they are reviewed in this book as a backdrop to how he came to the field of consciousness studies.     

The layout of the book is 10 chapters over 166 pages.  It is well written in that it contains technical terms but they are well explained for the novice.  On the other hand there are also higher level concepts pertaining to consciousness that will probably not be obvious to many readers that are well explained and worthwhile reading for anyone who is not an expert in the field.  The text reminds me of a slim guide to neuropathology that one of my med school professors claimed was the only book he studied to pass his subspecialty boards exams.  In other words, the more you bring to a book like this, the more you may take away.  At the same time it is interesting reading for a novice.   

A typical chapter is organized around clinical and scientific observations, associated philosophy and the personal experience and meaning to the author.  I thought about characterizing the writing as a very good blog, but this writing by one of the top neuroscientists of our time is several levels above that.  Koch writes from the perspective of admiration of some of the best scientists in the world when it is clear that he is among them.  He adds a unique perspective referencing his training, his family and social life, and the relationships he has with colleagues and mentors.  In the final chapter he describes how his career and experience has impacted on his belief system and personal philosophy.

I will touch on a couple of examples of what he covers and the relevance to consciousness.  Chapter 5: Consciousness in the Clinic is a chapter that is most accessible to clinicians specializing in the brain.  He briefly summarizes achromatopsia and prosopagnosia or face-blindness.  He discusses prosopagnosia from the perspective of clinical findings and associated disability, but also consciousness.  For example, patients with this lesion do not recognize faces but they do have autonomic responses (galvanic skin resistance) when viewing faces that they know (family or famous people) relative to unknown people.  This is evidence of processing that occurs at an unconscious level that he develops in a subsequent chapter.  He describes the Capgras delusion - as the "flip-side" of prosopagnosia in that they face is recognized but the patient believes the original person has been replaced by an impostor.  In this case the expected increase in galvanic skin resistant is lacking because there is no autonomic response to unconscious processing.

In the same chapter he details the problem of patients in a coma,  persistent vegetative state (PVS) and minimally conscious state (MCS) and how some new developments in consciousness theory and testing may be useful. From a consciousness perspective coma represent and absence of consciousness - no arousals and no sleep transitions.  Persistent vegetative state result in some arousals and sleep-awake transitions.  In the minimally conscious state there are awakenings and purposeful movements. The minimally conscious person may be able to communicate during the brief arousals.  At the clinical level being able to distinguish between the persistent vegetative state and the minimally conscious state is important from both a clinical and medico-legal perspective. He discusses the use of fMRI in the case of apparently unresponsive patients who are able to follow direction to think about very specific tasks and produce the same brain pattern of activation seen in controls.  In a subsequent chapter Tononi and Massimini use transcranial magnetic stimulation (TMS) and electroencephalography (EEG) for the same purpose.  This technique is considered proof of IIT as well as a clinical test to differentiate PVS from a minimally conscious state.  In normal awake volunteers the TMS impulse results in brief but clear pattern of reverberating activation that spreads from the original stimulation site to surrounding frontal and parietal cortex.  The pattern can be viewed in this online paper (see figure 1).  In the patient who is in non-REM sleep there is no cortical spread from this impulse and the total impulse duration is less, illustrating a lack of cortical integration required for a conscious state.  When applied to PVS versus MCS patients, the MCS patients show the expected TMS/EEG response that would be seen in conscious patients.  The PVS patients do not.  He describes the TMS/EEG method as a "crude consciousness meter" but obviously one that probably has a lot more potential than traditional clinical methods.

There are many other clinical, philosophical and scientific issues relevant to consciousness that are discussed in this book that I won't go into.  I will touch on a recurring theme in the book that gets back to the title and that is science and reductionism.  Philosophical perspectives are covered as well as the idea that the origin of consciousness may not be knowable by scientific methods. Koch's opinion is that most everything is knowable by science and that science generally has a better track record of determining what is knowable.  That is certainly my bias and I am on record as being an unapologetic reductionist rather than a romantic one.                           

This is a book that should be read by psychiatrists and residents.  These concepts will hopefully be some of the the mainstays of 21st century psychiatry.  It can be read at several levels.  I was interested in the development of Koch's ideas about consciousness.  I wanted to learn about his relationship with collaborators.  I was pleasantly surprised to learn that we had similar thoughts about popular media, philosophy, and and psychodynamic psychiatry.  I have had career long involvement in neuropsychiatry and behavioral neurology so the description of cortical localization and clinical syndromes was second nature to me.  But even against that background, he makes it very clear where consciousness comes in to play.  One of my concerns about psychiatric training is that there is not enough emphasis on neuroscience and consciousness.  Condensed into this small book there are number of jumping off points.  Each chapter has a collection of annotations and there is a list of about 100 scientific references at the end.  It may take some work, but this book is a brief syllabus on how to get up to speed in this important area and greatly extend your knowledge of how the brain works.


George Dawson, MD, DFAPA


Reference:

Christof Koch.  Consciousness: Confessions of a Romantic Reductionist.  First MIT Press Paperback.  Cambridge, Massachusetts, 2017.  Copyright 2012.   

Attribution:

Figure 1 above used with permission of the publisher.  The complete reference is:

1:  Massimini M, Ferrarelli F, Sarasso S, Tononi G. Cortical mechanisms of loss of consciousness: insight from TMS/EEG studies. Arch Ital Biol. 2012 Jun-Sep;150(2-3):44-55. doi: 10.4449/aib.v150i2.1361. Review. PubMed PMID: 23165870.  Open Access Free Text.

What Are The Implications Of The Suboxone Versus Vivitrol Study For Treating Opioid Use Disorder?

A major study came out in the Lancet last week that was a head-to-head comparison of  Suboxone (buprenorphine-naloxone or BUP-NX) and Vivitrol (extended-release naltrexone or XR-NTX).  I am beginning with the product names here because they were the actual medications used in the study and nobody uses the generic names at this point other than physicians.  This is an important study for a couple or reasons.  The first is that oral naltrexone tablets have already been tried for the treatment of opioid use disorder (OUD) and that approach failed.  XR-NTX used in this study is a long acting intramuscular injection that is given every 28 days.  The second is that many people with OUD do not want to take BUP-NX for many reasons.  They may be philosophically opposed.  They may have the experience that they know they will relapse on it, using heroin and then covering heroin withdrawal with BUP-NX.  They may not be able to tolerate the medication either because of side effects or the possibility of cognitive side effects.  The cognitive set of the patient is also important in the decision.  It is common to find patients who benefit from XR-NTX because using the medication makes heroin ineffective and therefore using it is a waste of money.

The study design is relatively straightforward.  This is a 24 week open-label randomized trial comparing BUP-NX to XR-NTX.  There is no placebo arm and I hope that at this point there are no human subjects committees suggesting that there should be.  OUD is just too dangerous to be considering a placebo group.  The protocols for starting treatment with either medication make blinding impossible. Eight study sites of the National Drug Abuse Clinical Trials Network (CTN) were used.  One of the non-uniform aspects of this trial was that the detox protocols varied by site:

1:  Two sites used no opioids, but used clonidine or "comfort meds" a term that I really don't like to see. Other comfort meds typically include an NSAID like naproxen for muscle and joint pain, hydroxyzine for anxiety and insomnia, methocarbamol for muscle spasm, and dicyclomine for abdominal cramping.

2:  Four sites used 3-5 day methadone tapers.

3:  Two sites used 3-14 day buprenorphine tapers. 

If a subject was going on to the XR-NTX group they had to be off all opioids for three days, have negative toxicology for the presence of opioids, and have a negative naloxone challenge test.  The authors don't explicitly state this but all of these detox protocols favor BUP-NX in the induction phase or initial dosing toward maintenance.  That is basically because most moderate to heavy users of heroin will be experiencing withdrawal symptoms at the end of these protocols.

Random assignment of 283 subjects to the XR-NTX group and 287 subjects to the BUP-NX group occurred.  Early termination occurred for a number of reasons in 78 of the XR-NTX group and 62 of the BUP-NX group.  A total of 283 and 287 subjects respectively were assigned in the final intent to treat analysis.

The primary outcome variable was time to relapse.  Relapse was defined as self report of use and either provided positive urine toxicology for any non-study opioid or failed to provide a urine sample.  The subjects were seen weekly for monitoring of cravings, self reported use, reports of adverse events and report of other substance use.  Standard physician or nurse led office based medication management was described as happening at these visits.  It is not clear to me what that is but they described a standard medication focused visit.  Psychosocial counseling was recommended and available but it was not a variable for this research. 

Secondary outcome variables included portion of subjects getting through the induction phase and into the active study, adverse events (including overdoses), frequency of non-opioid study use, and opioid cravings (rated on a 0-100 visual analogue scale).

In terms of results, they were broken down across several variables.  The intent-to-treat analysis showed that relapse-free survival was 8.4 weeks in the XR-NTX group and 14.4 weeks in the BUP-NX group but 20.4 weeks in the XR-NTX group and 15.2 weeks in the BUP-NX group when the protocol group rather than treatment intent was used.  The difference in these results was due to induction (starting of either medication at the end of detox) failures in the XR-NTX group.  The rates of successful XR-NTX induction varied site from 95% at an extended stay opioid free program to 52% at the methadone detox programs.  Self reported opioid abstinent parallels these results.  The graphical representations of these data (survival curves) show essentially parallel curves after an initial drop due to differences in the induction protocol.  The authors conclude that the drugs are equally safe and effective in preventing opioid relapse.

A separate interesting survival curve was the rating of opioid cravings over time.  The authors interpretation of these curves was that that the BUP-NTX group had fewer cravings initially but that by 24 weeks the ratings converged.  There may be some additional data in that graph showing that the low point in cravings was reached about 5 weeks earlier in the BUP-NX group and therefore it persistent longer.

The other important secondary outcome measure was the number of overdose deaths.  If analyzed just by the protocol there were 10 overdose events in the XR-NTX group and 9 overdose events in the BUP-NX group.  Including the failed induction subjects in the intent-to-treat analysis increases these number to 18 and 10 respectively.  There were 2 fatal overdoses in the XR-NTX group and 3 fatal overdoses in the BUP-NX group. The fatal overdose group was due to failed induction and premature termination of treatment.

As a physician involved in the treatment of OUD the implications here are:

1.  BUP-NX and XR-NTX are equivalent treatments and should be recognized as such - there has been some press about XR-NTX not being an "evidence-based" treatment despite the fact that it has been in use for some time.  Those articles either ignore the fact that it had the FDA approved indication or they ridicule the study used to get that approval. Here is the additional evidence.

2.  There is a need for standardized opioid detox protocols that are optimized for patient safety and efficacy for treating withdrawal symptoms - the three options used in the treatment center in these trials are representative of what is available in the community.  One of the goals of detox is to optimize  the transition to medication assisted treatment (MAT) to prevent relapse to opioid use.  As the authors point out the lack of a smooth transition to XR-NTX was the main reason for treatment failures and poorer outcomes in that group in the intent-to-treat  analysis.

3.  Besides the detoxification protocol other resources to facilitate the transition from detox to MAT maintenance are unknown -  It is clear that transitioning the patient from detox to MAT is a critical step in the treatment process. That not only involves the medication but the structure of the program and individual patient support at that time.  People leave treatment for sustained and untreated withdrawal symptoms and that include severe psychiatric comorbidity including severe anxiety +/- panic attacks, insomnia that often involves days of no sleep and drenching night sweats, and depression.  There is often a lot of confusion over which symptoms are due to an associated psychiatric disorder and which symptoms are due to withdrawal.  The confusion can be heightened if the patient comes in being treated for anxiety, insomnia, or depression with a maintenance medication.  The current paper does not describe an optimal path for treating those patient characteristics (psychiatric disorders and other substance use disorders were an exclusion criteria).   

4.  Optimal patient selection for the BUP-NX versus XR-NTX are unknown - In additional to significant psychiatric symptoms there are a number of other factors that will influence patient selection not the least of which are cost and logistics.  In many parts of the country it is still extremely difficult to find a BUP-NX provider.  Even when a physician is found, many do not accept insurance and the out of pocket cost for patients for both the visits and associated lab tests is prohibitive.  XR-NTX is a very expensive injection that may not be covered by insurance companies or patient assistance programs.  This study may increase the likelihood of coverage despite the fact that XR-NTX has had an FDA approved indication for "the prevention of relapse to opioid dependence, following opioid detoxification" since 2010. 

5.  Clinicians should use this information to discuss realistic treatment with their patients - as I have previously pointed out BUP-NX is no panacea and neither is XR-NTX.  Contrary to the idea that antagonist therapy prevents overdoses, there was no significant differences in overdose deaths in this study.  That should lead to a very serious informed consent based discussion about these medications with patients.  The idea of how long the medication should be taken or whether it should be taken indefinitely should not be part of that initial discussion.  The focus needs to be on completing detox and transitioning onto one of these medications.  The patient's capacity to make a realistic decision and what their preferences are with regard to these medications are all part of that process.  Life is not a randomized clinical trial.  Part of the skill set of the physician is the ability to have these discussions. It takes more than the ability to prescribe these medications.

That's my take on the head-to-head comparison of Vivitrol (XR-NTX) and Suboxone (BUP-NX).  Even with effective treatments to prevent relapse to opioid use - many more elements need to be in place.  The practical issue most frequently discussed is the availability of prescribers. Nobody seems to be talking about the fact that some treatment programs offer neither option.  There is also very little discussion about the fact that some treatment programs lack the atmosphere or expertise to provide patients with a shot at being successful and getting off opioids. 

We have come a long way with agents to treat OUD  compared to the days when I would see hospitalized heroin addicts who wanted to stop but had no realistic options.  I could only offer the 3 days methadone detox, continuing their methadone maintenance dose, or covering the sympathetic symptoms of withdrawal with clonidine. I could tell them where the closest methadone maintenance program was but that did not assure them an appointment or a place in that program.  Federal Law at the time prohibited the active treatment of OUD unless you happened to be in a licensed methadone maintenance program. Now that the legal and regulatory landscape has improved - it is up to treatment programs everywhere to get up to speed and offer state of the art care.  It is up to state licensing agencies to not allow treatment centers to take care of these patients if they don't.


George Dawson, MD, DFAPA



References:


1:  Joshua D Lee, Edward V Nunes Jr, Patricia Novo, Ken Bachrach, Genie L Bailey, Snehal Bhatt, Sarah Farkas, Marc Fishman, Phoebe Gauthier, Candace C Hodgkins, Jacquie King, Robert Lindblad, David Liu, Abigail G Matthews, Jeanine May, K Michelle Peavy, Stephen Ross, Dagmar Salazar, Paul Schkolnik, Dikla Shmueli-Blumberg, Don Stablein, Geetha Subramaniam, John Rotrosen.  Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial.  The Lancet
Published: November 14, 2017.