Minnesota Street Drug Bulletin - Designer Benzodiazepines

Benzodiazepine structures clonazepam (upper left) and alprazolam (lower left) are both prescription benzodiazepines.  Clonazolam (upper right) and etizolam (lower right) are not. 

Designer benzodiazepines are benzodiazepine class drugs that are not approved for therapeutic use in any country.  They are analogues that were synthesized by drug companies, and in some cases went to clinical trials and published results but never made to to market.  The name makes is seem like there are chemists out there synthesizing these drugs for a purpose, but there are not.  They are all part of the original research for benzodiazepine class medications that has not really seen any innovation in decades.  These drug are a current problem because there are online sources allow people to purchase them in tablet, capsule, powder, and blotter form.  There are several online venues where users talk about their experience and which drug creates the "best" high.  Medical staff need to realize that many of these drugs are undetectable as molecules.  They show up as "false positives" in standard toxicology testing largely due to a lack of reference material.  Drug users are often told that the drug is undetectable in standard toxicology assessments and that the drugs are also not listed as a standard prohibited substance and therefore it is a "legal" high.  That is a fairly weak argument when users are overtly intoxicated and sustain all of the consequences of intoxication.

Just as a check I looked at a list of 13 designer benzodiazepines (1) (clonazolam, deschloroetizolam, diclazepam, estazolam, etizolam, flubromazepam, flubromazolam, flutazolam, 3-hydroxyphenazepam, meclonazepam, nifoxipam, phenazepam, and pyrazolam) and compared them to the most recent posted list of Controlled Substances from the DEA.  Only one of those compounds (estazolam) is listed on the most current list dated 05-May-17.  It is listed as a Schedule IV drug.  I have no way of knowing which compounds are being considered for the list.  Just being on the list does not deter the illegal sale of controlled substances, but the designer designation generally means that there is far less known about the drug in terms of safety.  In some cases the toxicology lags behind exposures because the physicians treating intoxication, withdrawal, and overdoses with these compounds are uncertain about what they are treating.  The patient or collateral contacts of the patient may not know what the drug is and that lag time creates additional danger for the patient.     

The first time I searched for clonazolam on Medline, I was impressed with the fact that there were only 5 references in the medical literature including the analysis reference that listed 13 designer benzodiazepines.  In fact, they all had to do with analysis but also described the complications of intoxicated driving (2) while taking them and the complications of life threatening intoxication (3).  The minimal online information available suggests that it has very high potency.  There are doses suggested in the range of high potency benzodiazepines but there are no clinical applications.  As a result, there are no FDA package inserts or even reliable data from other agencies.  It is not listed in the British National Formulary (bnf.org).  Despite this lack of clinical information and application, it is immediately obvious that large quantities are available for purchase online.  On these sites it is described as a research chemical with no clinical applications.  It is also described as not for human consumption - a label I am familiar with from synthetic cannabinoids.  The current problem is that as long as this chemical or its precursors are not listed as controlled substances anyone can purchase it for any purpose.  The suggested prices quoted for this drug are far below the street price of diverted prescription benzodiazepines.  That makes these compounds ideal for illegal trafficking.

Searching etizolam on Medline resulted in 96 references and 13 clinical trials.  Some of the trials were as recent as 2009.  The trials were for anxiety disorders and based on the abstracts the results sound equivocal ranging from improvement over 4 weeks to (4) to no improvement (5).  The striking feature of the trials is the dose of etizolam being 0.5 mg BID indicating that it is a high potency benzodiazepine.  The fact that several studies were done and the drug was never approved suggests either the lack of sufficiently powered studies or some side effect that was obvious only to the pharmaceutical company or regulators.  In some cases the drug is also too difficult to use clinically.  There are several examples of benzodiazepine class medications that were determined to be problematic after use and either banned at that point or an additional warning was issued.      

One of the more disturbing trends recently in the number of benzodiazepine compounds that are involved in polypharmacy overdoses.  In the most recent analysis of overdoses by the CDC -  2 of the top 10 compounds were alprazolam and diazepam - both prescription benzodiazepines. In both cases 95% of these overdoses involved concomitant drugs.  In the US, 30% of fatal opioid overdoses involve benzodiazepines. Due to the current problems with analysis, it is highly likely that designer benzodiazepines involved in overdose deaths are not detected. This is a compelling reason to not use designer benzodiazepines.  

Reading through some of the web sites that promote the use of these compounds, it is ironic that there are messages out that that these drugs can be used safely with adequate research by the user on the Internet.  Prescription medications are understood to have qualified safety when they are approved by the FDA and prescribed by a qualified physician.  There are still completely unanticipated reactions and these approved medications are not generally tested with other addictive compounds.  There are reactions that can only be detected by pharmacosurveillance of a much larger database.  In the case of these designer benzodiazepines, they are not approved, not prescribed, and highly potent drugs being sold by sources with no responsibility to the user.

Anyone seeking to get high in that context should be questioning the value of getting high.


George Dawson, MD, DFAPA



References:

1:   Pettersson Bergstrand M, Helander A, Hansson T, Beck O. Detectability of designer benzodiazepines in CEDIA, EMIT II Plus, HEIA, and KIMS II immunochemical screening assays. Drug Test Anal. 2017 Apr;9(4):640-645. doi: 10.1002/dta.2003. Epub 2016 Jul 1. PubMed PMID: 27366870.

2:  Høiseth G, Tuv SS, Karinen R. Blood concentrations of new designer benzodiazepines in forensic cases. Forensic Sci Int. 2016 Nov;268:35-38. doi: 10.1016/j.forsciint.2016.09.006. Epub 2016 Sep 16. PubMed PMID: 27685473.

3: Łukasik-Głębocka M, Sommerfeld K, Teżyk A, Zielińska-Psuja B, Panieński P,Żaba C. Flubromazolam--A new life-threatening designer benzodiazepine. Clin Toxicol (Phila). 2016;54(1):66-8. doi: 10.3109/15563650.2015.1112907. Epub 2015 Nov 20. PubMed PMID: 26585557.

4: Savoldi F, Somenzini G, Ecari U. Etizolam versus placebo in the treatment ofpanic disorder with agoraphobia: a double-blind study. Curr Med Res Opin. 1990;12(3):185-90. PubMed PMID: 2272192..

5: De Candia MP, Di Sciascio G, Durbano F, Mencacci C, Rubiera M, Aguglia E, Garavini A, Bersani G, Di Sotto A, Placidi G, Cesana BM. Effects of treatment with etizolam 0.5 mg BID on cognitive performance: a 3-week, multicenter, randomized, double-blind, placebo-controlled, two-treatment, three-period, noninferiority crossover study in patients with anxiety disorder. Clin Ther. 2009 Dec;31(12):2851-9. doi: 10.1016/j.clinthera.2009.12.010. PubMed PMID: 20110024.

Human Brain Performance Compared To Supercomputers

For about the past year, I have been using transversed edges per second (TEPS) in my lectures about neurobiology to give a rough estimate of the computing power of the human brain and a rougher estimate of where brain power compares with artificial intelligence (AI).  I finally found the detailed information on the AI Impacts web site and wanted to post it here, both for future reference and to possibly generate more interest in this topic for psychiatrists.

I have been interested in human computer comparisons since I gave a Grand Rounds on the topic back in the 1990s.  Back then I was very interested in bandwidth in the human brain and trying to calculate it.  My basic approach was to look at the major bus systems in the brain and their fiber counts and try to estimate how much information was passing down that bus.  In engineering terms a bus is a path that the computer or processors use to communicate with other devices or processors.  The rate at which that communication passes down that pathway is a major limitation in terms of computing speed to the rate at which tasks are transmitter to peripheral devices.  Engineers typically specify the characteristics of these communication paths.  A good example are the standard USB connectors on your computer.  Today there are USB 2.0 and USB 3.0 connectors.  The USB 2.0 devices can support a data transfer rate of 480 Mbps or 60 MBs.  The USB 3.0 connection supports 5 gbps or 640 MBs.

In the work I was doing in the 1990s, I looked at the major structures in the brain that I considered to be bus-like the fascicles and the corpus callosum.  Unfortunately there were not many fiber count estimates for these structures.  It turns out that very few neuroanatomists count fibers or neurons.  The ones who do are very exacting.  The second issue was the information transfer rate.  If fiber counts could be established was there any reliable estimate of the information contained in spikes.  I was fortunate at the time that a book came out that was somewhat acclaimed at the time called Spikes.  In it the authors, attempted to calculate the exact amount of information in these spikes.  They used a fast Fourier transform (FFT) methodology that I was familiar with from quantitative EEG (QEEG).  From available data t the time I was limited to calculating the bandwidth of the corpus callosum.  I used a fiber (axon) count of 200 million.  It turns out that the corpus callosum is a heterogeneous bus with about 160,000 very large fibers.  Using a bit rate of 300 bits/sec for each spiking neuron multiplied by the entire bus results in a total of 60 Gbs.  I had a preliminary calculation but realized I had about another 11 white matter fiber tracts connecting lobes, hemispheres and the limbic system.  I did not have the fiber counts for any of these structures and the top neuroanatomist in the world could not help me.

Then I found an interesting question posted in a coffee shop.  In the process of investigating it, I found some preliminary data about a group that was using a calculation called tranversed edges per second (TEPS) and showing at least on a preliminary basis that the human brain is currently calculating at a rate that is currently on par with supercomputers.  I found additional papers from the group, just this week.  The articles can be read and understood by anyone.  They are interesting to read to look at the authors basic assumptions as well as how they might be wrong.  They give rough estimates in some cases about how large the error might be if their assumptions are wrong.  They provide detailed references and footnotes for their assumptions and calculations.  

Their basic model assumes that the human brain is comprised of interconnected nodes in the same way that a supercomputer connects with processors or clusters of processors.  This basic pattern has been described in some situations in the brain but the details are hard to find.  There is also a question about the level for analysis of the nodes.  For example are large structures the best choice and if not how many smaller networks and nodes are relevant for the analysis.  In high performance computing (HPC) several bottlenecks are anticipated as nodes try to connect with one another including bus latency, bus length in some cases, and the smaller scale of any circuity delays on the processor.  The ability to scale or divide the signal without losing the signal across several pathways is also relevant.  For the purpose of their analysis, these authors use one of the estimated numbers of neurons in the brain (2 x 10¹¹).  The authors use a figure of 1.8-3.2 x 10¹⁴ synapses.  Division yields synaptic connections for each neuron at 3,600-6,400.

The TEPS benchmark is discussed in detail on the Graph 500 web site under 8.2 Performance Metrics (TEPS).  Reference 1 contains a more basic accessible definition as the "time required to perform a breadth first search of a large random graph requiring propagating information across every edge of the graph."  The information propagation is between nodes or nodes and memory locations.  The Graph 500 site also contains a listing of top performing supercomputer system and a description of their total number of processors and cores.  The rankings are all in billions of TEPS or GTEPS in terms of the performance benchmark with 216 systems ranked ranging from 0.0214748 to 38621.4 GTEPS.

For the human brain calculation, the authors use the conversion of TEPS = synapse-spikes/second = number of synapses in the brain x average spikes/second in neurons = 1.8-3.2 x 10¹⁴ x 0.1-2 = 0.18 - 6.4 x 10¹⁴ TEPS or 18 - 640 trillion TEPS.

What are the implications of these calculations?  If accurate, they do illustrate that human brain performance is limited by node to node communication like computers.  The AI researchers are not physicians, but it it obvious that taking more nodes or buses off line will progressively impact the computational aspects of the human brain.  We already know that happens at the microscopic level with progressive brain diseases and at the functional level with processes that directly affect brain metabolism but leave the neurons and synapses intact.  The original research in this area with early estimates was performed by researchers interested specifically in when computers would get to the computational level of the human brain.  Several of these researchers discuss the implications of this level of artificial intelligence and what it implies for the future.

For the purpose of my neurobiology lecture, my emphasis in on the fact that most people don't know that they have such a robust computational device in their head.  We tend to think that a robust memory is the mark of computation performance and ignore the fact that is why humans can match patterns faster than computers and comprehend context faster than computers.  We also have a green model that is more cost effective.

These are all great reasons for taking care of it.

George Dawson, MD, DFAPA



References:

1:  AI Impacts:  Brain performance in TEPS:  http://aiimpacts.org/brain-performance-in-teps/

2:  AI Impacts:  Human level hardware:  http://aiimpacts.org/category/ai-timelines/hardware-and-ai-timelines/human-level-hardware/

3:  AI Impacts:  Brain Performance in FLOPS:  http://aiimpacts.org/brain-performance-in-flops/

4:  Rieke F, Warland D, de Ruyter van Steveninck, Bialek W.  Spikes: Exploring the neural code.  The MIT Press, Cambridge, MA 1997, 395 pp.


Attribution:

Slides below are from my original 1997 presentation (scanned from Ektachrome).  Click to enlarge any slide.  I am currently working on a better slide to incorporate the work of the AI Impacts and Graph 500 groups on a single slide with an additional explanatory slide.

Additional reference:

My copy of Spikes:

Thoroughly Read:

Minnesota Street Drug Bulletin - Carfentanil

Opioids morphine (upper left) and hydrocodone (lower left) and synthetic opioids fentanyl (upper right) and carfentanil (lower right)

I don't know how widely known the issue with potent opioids  on the street is - but I am concerned that the information is not getting out to the people who need to hear it.  There are warnings that are read mostly by health care providers.  There are politicians talking about tougher penalties and legal approaches to solving the problem.  Like many people, I don't believe that the War on Drugs has been very successful.  At the same time, there are not many readily available options, there is a historical precedent for control of narcotics, and we will never know what the outcome might have been without legal action against illicit drugs.  I don't think that a failed War on Drugs means that there should be mass legalization of drugs.  The reason is obvious.  We are in the middle of an opioid epidemic that has been initiated and sustained by legal prescription opioids.  This epidemic says more about the nature of addiction than legal deterrents.  It is very clear that people with addictions will not hesitate to obtain what once were legally prescribed medications and use them.  It is very clear that designating legal addictive drugs does not reduce the black market for highly addictive drugs or create more tax revenues for governments - both common arguments for drug legalization.  All of these abstract arguments don't reflect what happens on the street.

I have personally talked with hundreds of opioid addicts over the course of my career.  In the 1980s and 1990s - there was a small population of users largely due to limited access.  Heroin and illicit opioid prices were relatively high and the barriers to use were also high.  Widespread exposure to opioids in high school was unheard of.  Most of the people I treated were part of a small, relatively fixed population of heroin users and some were on methadone maintenance.  That has all drastically changed in the last 15 years.

Now it is common for me to talk with young people in their 20s who were exposed to opioids when they got opioid prescriptions for injuries that used to be treated with ibuprofen or acetaminophen.  In some cases their peers in high school suggested they should try taking hydrocodone or oxycodone to get high.  In many cases those drugs were scavenged from unused medications in the family medicine cabinet.  Like many people in their teens and early 20s there is a cultural movement among users that they have a special body of knowledge about these drugs.  That reinforces drug taking behavior and keeps them in contact with people who are actively using and supplying these drugs.  In some cases it leads to mistakes in how the drugs are taken and what they are mixed with.  Drug users often have illusory relationships with drug dealers that makes it seem like these dealers care more about them than their friends and family do.  With continued and progressive use, opioid users might not notice how their judgment is more and more impaired - often to the point that they don't care if they die in the process of trying to get high.  To be clear, these people will deny any intent to harm themselves but get to a situation where they are using a questionable amount of drugs and realize it could be a problem but at that point they no longer care.  Heroin overdoses and deaths are common in small towns across America.  That was unheard of in the 20th century.

Against that backdrop - carfentanil has hit the streets in Minnesota.  Carfentanil is an extremely potent opioid that was never intended for therapeutic use in humans.  It is a large animal veterinary tranquilizer.  Its toxicity in humans is not disputed.  The most significant incident was the use of a gas that probably contained carfentanil in a hostage situation at the Dubrovka theatre in Moscow.  There were 40 Chechen rebels holding 912 hostages.  Russian security forces pumped in a gas that killed all of the rebels and 130 hostages.  The gas was described as a sleeping gas and later fentanyl.  Recent research suggests that the gas was a combination of carfentanil and remifentanil.  Some authors suggest that this was an anesthetic, but I have not been able to find any clinical application of this opioid in humans.  Potent opioids like fentanyl are used as anesthetic agents as well as pain medications.  

One of the ways that drug dealers amplify their profits is by taking a relatively inexpensive but potent product and diluting it down and selling the diluted product.  I have a previous post that shows how drug dealers can take $3800 of the synthetic cannabinoid AMB-FUBINACA and produce about a half million dollars worth of product containing about 64 mg of the original compound sprayed over shredded plant material.  I am not about to post how carfentanil can be diluted.  There are media reports that talk about how much more potent the drug is relative to both fentanyl and morphine.  Anyone trying to guess about how the raw drug can be cut is making a big mistake.  The amount of drug that can lead to a lethal overdose is so small that any non-uniform distribution in a powder or tablet can result in a lethal overdose.  The drug is so potent that even touching the powder can result in an overdose and health care workers have been warned not to touch the powder for that reason.

The problem is that carfentanil is being sold as a number of different products on the street. People are being given carfentanil as powders and tablets and being told that it is heroin, oxycodone, hydrocodone, and even benzodiazepines. This is an extremely dangerous practice and several Minnesotans have already died because of it.

Don't make the mistake of even trying opioids to get high. If you are currently addicted to opioids go to detox and get treatment. Don't make the mistake that you have another 5 or 10 years to get clean.  If you need to take opioids, get Medication Assisted Treatment with buprenorphine or methadone, rather than continuing to use what is available on the street.  With FDA approved medications used under a physician's supervision - you know exactly what you are getting.  The Minnesota Department of Health recommends education in overdose prevention and naloxone administration.

I can tell you that you can't trust what you are buying on the street.

But deep down you already know that.  Carfentanil is just another clear-cut example.



George Dawson, MD, DFAPA        


References:

1:  Influx of Fentanyl-laced Counterfeit Pills and Toxic Fentanyl-related Compounds Further Increases Risk of Fentanyl-related Overdose and Fatalities.

2:  Health Advisory: Drug Overdose Deaths Linked to Carfentanil Minnesota Department of Health Mar 31, 2017 12:00 CDT

3:  Carfentanil Medline references


Attribution:

All molecules at the top of this post were downloaded from PubChem and are in the public domain.




            

Luncheon Consensus - Management Continues To Do Nothing About Hospital Violence

I had lunch last weekend with staff from several psychiatric facilities in the Twin Cities.  The group included nurses, nurse practitioners, and health unit coordinators.  Many of them were at the retirement party that I described a couple of years ago.  At one point in time we all worked on the same inpatient unit and that was the common bond.  Over the several hour long lunch the discussion gravitated to one of our favorite topics - violence and aggression in hospitals against medical and nursing staff.  There was the usual litany of injuries - concussions, a stabbing, beatings, and musculoskeletal injuries.  At one point I heard how a staff nurse in her fifties with knee replacement surgery and back problems had to interject herself between a patient she was admitting and a violent and aggressive person who walked in off the street.  In that situation she had to hope that security got there in time to protect her.  I listened to another nurse tell me how the assault charges were determined after she was assaulted - first degree assault only because she had a concussion.  The other forms of being punched and kicked that she sustained that day were all lesser forms of assault.  I also heard how some members of the hospital administration minimized the incident and how her assailant eventually was not charged with anything.

This is one of many areas where the army of health care administrators really don't seem to be able to do anything productive.  Every hospital in the country has posted non-discrimination policies.  They discuss how every patient will be treated respectfully.  These same rules do not apply to their own staff.  When staff are assaulted there is a common belief that it is an occupational hazard.  It is all part of the job.  The other crucial part of the problem occurs at the committee level in higher levels of administration.  When ever there is a potential problem resulting in injury, a standard administrative strategy is to move it to a committee or Task Force.  That is where real problems occur because there is no expertise on the committee in assessing and resolving problems with violence in medical settings.  That lack of expertise is common.  A corollary is that administrators are in the position that they do not believe that they can defer to clinical staff with much more expertise because of the chain of command.  That is a recipe for inaction and manipulation.  If a staff person brings up a concern that the administrators can't solve - the issue is tabled or the person is not asked to come back.  Even more problematic, some administrators embark on their own ideas about how to solve the problem.  I have listed some instances of this happening on this blog that have resulted in more staff injuries.  A final strategy is to bring in consultants.  I have seen situations where expensive business consultants are brought in to either tell the staff that their patients are not any more aggressive than the patients seen in other hospitals in the state.  If that doesn't work - bring in a consultant who will try to demonstrate that he or she knows more than the current staff.  Both administrative strategies fall flat when the staff is dealing with some of the more significant problems with aggression in the state and they have the most experienced clinicians.

No - the violent outbreaks that are described in most hospitals are the result of administrative failures at several levels.  A failure to recognize the issue exists.  A failure to recognize that your staff has the expertise to deal with it.  A failure to recognize that aggression toward the staff is not the result of staff failing to treat people in a particular way or due to a deficiency of the staff person.  And most of all - a failure to facilitate a team approach among the staff in the hospital or clinic with the most expertise.  It is really that easy.

In our discussion, several instances of these manipulative responses to hospital violence were noted.  Even very basic requests for additional security staff and to prevent aggressive people from walking in off the street are ignored.  There is no shortage of meetings and I have participated in many.  One of the administrative strategies is blaming physicians for the problem.  There is nothing like having a dedicated and skilled staff with as much expertise as can be found anywhere - suddenly being blamed for the problem.  In some of these situations the administrators bring in "consultants" to tell senior clinics who have been treating the problem for 20 years.  I am speculating that is right out of "Power Plays 101" in administrator school.  It is not difficult to see how all of this administrative drama and expense fails to solve the problem.  In most cases it ends up looking like nobody is even trying.  A scapegoat has been found - let's leave it at that.

There has been a laudable effort by nurses.  In my home state, the Minnesota Nurses Association (MNA) has been very vocal in terms of the number of aggressive incidents toward nurses in Minnesota hospitals very year.  A 2004 study showed that that nurses were physically assaulted at a rate of 13.2 assaults per 100 persons per year.  17% of nurses were threatened and 34% were verbally abused in the preceding 12 months of the study.  The MNA has also been active to get legislation to legally protect nurses from aggression and assault.  This link to their proposal does not indicate whether either of their proposals have been successful.  

It appears that there are no comparable efforts by the state psychiatric association or medical association.  I am sure that if this luncheon group meets again, there will be reports of further injuries and a continued lack of response to the violence and aggression toward health care workers.

It probably makes sense in terms of the American inertia in dealing with violence and aggression in general.  But it also makes sense because health care administrators really don't do anything to support clinicians or improve the environment where they work.

Replacing all of those administrators is the best place to start.



George Dawson, MD, DFAPA              


References:

1:  Phillips JP. Workplace Violence against Health Care Workers in the United States. N Engl J Med. 2016 Apr 28;374(17):1661-9. doi: 10.1056/NEJMra1501998. Review. PubMed PMID: 27119238.

2: Nachreiner NM, Gerberich SG, McGovern PM, Church TR, Hansen HE, Geisser MS,Ryan AD. Relation between policies and work related assault: Minnesota Nurses' Study. Occup Environ Med. 2005 Oct;62(10):675-81. PubMed PMID: 16169912; PubMed Central PMCID: PMC1740877.

3: Gerberich SG, Church TR, McGovern PM, Hansen HE, Nachreiner NM, Geisser MS, Ryan AD, Mongin SJ, Watt GD. An epidemiological study of the magnitude and consequences of work related violence: the Minnesota Nurses' Study. Occup Environ Med. 2004 Jun;61(6):495-503. PubMed PMID: 15150388; PubMed Central PMCID: PMC1763639



Supplemental:

Aggression and violence and their prevention is one of my interests on this blog.  A sampling of posts can be found at this link or by selecting any of the links from the right margin.

Not Taking Antidepressants

I came across this open access article on my Twitter feed that highlights some of the reality of antidepressants that I was trying to get at in my previous post.  I encourage a full reading of the article in order to understand it - specifically how patients were selected from a large commercial database.  In this retrospective study the authors selected patient with a diagnosis of major depressive disorder (MDD) who were taking and antidepressant but only in a specific time interval.  They did this for the purpose of constructing the above survival curve.  They started with a group of 6,562,955 people on antidepressants between 7/1/2003 and 1/1/2014 and ended up excluding all but 527,907.  Exclusions were based on no diagnosis of MDD in the previous 6 months, no prescription of an AD in the previous 6 months, lack of continuous enrollment in the previous 6-12 months, and pharmacological  therapies that included initiating treatment with more than one AD or 3+ ADs or augmenting agents (AA).  The final study population was 527,907 patients.

Two major endpoints were defined as measures of medication adherence - medication possession ratio (MPR) and proportion of days covered (PDC).  PDC was considered the primary measure of adherence due to previous convention.  Calculations were made at 3, 6, 9, and 12 months.  Persistence and adherence were calculated for each major antidepressant class (SSRI, SNRI, TCA, MAOI, and Other).  Adherence and persistence were calculated across all of these dimensions.  Bar graphs are available in the full text.

Adherence and persistence at 6 months was 31-36%.  SNRIs had the highest persistence and adherence rates at 6 months at 37% and TCAs the lowest at 16-17%.  Looking at the Kaplan-Meier survival above the curves were significantly different with the lowest adherence to initial TCA and MAOI therapy.  The curves also show natural break points at 30 and 90 day intervals that correspond to the typical length of prescriptions although most primary care physicians provide a significant number of refills beyond that.

A study like this has obvious limitations and the authors do a good job of explaining them. Most of them had to do with the limitations of using a database like this one with limited granularity.  For example - no data about the status of the prescriber or practice context.  I would have the question of whether adherence was any different among those given and antidepressant based on a screening questionnaire versus more detailed assessment and follow up.  It would also be interesting to see if subjects seeing psychiatrists were any more adherent than than what I am guessing are the majority of patients being see in primary care.  Surrogate markers for psychiatric care could have been devised based on AD and AA combinations but that would be an imperfect marker since most primary care depression guidelines incorporate these strategies.   There was a very minor erratum (2) essentially a typographic error that does not change the main paper.                      

When I look at a study like this, I always ask myself if the study group resembles the people I am currently seeing or have seen.  In this case 64% of the population was female and 81% were covered by commercial insurance.  Twenty-four percent had comorbid anxiety, 24% had comorbid chronic noncancer pain, and 6% had both.  Sertraline has the largest percentage of prescriptions at 18.7% with only about 5.4% of people on bupropion extended release.  I currently see a large number of people on sertraline or citalopram +/- bupropion augmentation.  Despite the FDA warning about maximum doses of citalopram - I still see people on 60 mg/day or > 40 mg/day who are 62 years of age or older.  Both of those situations were flagged in the FDA warning.

I do find that SNRI medication are better tolerated than SSRI and do not hesitate to make that change sooner than later.

Give the limitations this is an interesting study.  At several levels it matches my experience.  At least 20-40% of people do not tolerate SSRIs very well.  I have also found that  SNRIs are effective and more well tolerated than SNRIs.  The major limitation from my perspective is that without the data that the authors refer to - it is really not possible to design a clinical program that optimized adherence or that provides much of a foundation for the differences.  Many psychiatrists have the experience that they see the same people with severe depression for years.  In many cases plasma levels of antidepressants are measure to optimize dosing but they also confirm adherence.  In other cases, the patients are in settings where medications are administered.  A critical dimension in psychiatric practice is the ongoing relationship with the patient.

Looking at how the relationship with the patient and how that effects adherence is needed, but it is obviously a more difficult study to capture in a retrospective database.              


George Dawson, MD, DFAPA



References:

1:  Keyloun KR, Hansen RN, Hepp Z, Gillard P, Thase ME, Devine EB. Adherence and Persistence Across Antidepressant Therapeutic Classes: A Retrospective Claims Analysis Among Insured US Patients with Major Depressive Disorder (MDD). CNS Drugs. 2017 May;31(5):421-432. doi: 10.1007/s40263-017-0417-0. PubMed PMID: 28378157.


2: Keyloun KR, Hansen RN, Hepp Z, Gillard P, Thase ME, Devine EB. Erratum to:Adherence and Persistence Across Antidepressant Therapeutic Classes: A Retrospective Claims Analysis Among Insured US Patients with Major Depressive Disorder (MDD). CNS Drugs. 2017 Apr 27. doi: 10.1007/s40263-017-0435-y. [Epub ahead of print] PubMed PMID: 28451963.

Attribution 1:

The above graphic is directly from reference 1 reposted per terms of the Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license.  No changes were made to the graphic.  Click on the graphic to enlarge.


Thanks:

To Barney Carroll for putting this reference on his Twitter feed.

Burnout Industry Just Doesn't Get It

I was sent a long list of burnout interventions from a colleague today.  It was quite amazing.  Opinion pieces on Burnout. TED talks on burnout.  Books, videos, and web-based resources on burnout.  All with the message: "Physicians - in the event that you could not figure this out yourself - here is what you can do to alleviate burnout."   The disease model of burnout, except in this case we are not treating with with medication or surgery we are using life style modification.  What is wrong with this picture?

It turns out there is plenty wrong with this picture.  The biggest problem of course is that all of the factors that lead to burnout flow from incompetent management.  We have had a surplus of that in the past 30 years with no end in sight.  I would venture a guess that in all of my time in practice, I have seen about 1 manager who I would consider to be competent.  Nobody working for him was at risk for burnout.  More importantly, the most important protective factor against burnout has also become a casualty of bad management.  That factor is collegiality.  I could regale the reader with stories from my past on how much work I and my teammates did in various medical and surgical settings.  But I think that most people in working settings realize how much better the job and the day goes if they are working with bright, knowledgeable and highly motivated people.  A sense of humor is always a plus and I am convinced that at least some of the physicians I worked with were some of the funniest people I have met anywhere.

Rather than more stories, I will get right to the point about how bad management subverts collegiality.  Very early in the process, managers sold the idea that "there are some slackers in the group and therefore we need to introduce a way to measure productivity."  I was skeptical.  I looked around the room and did not see any slackers.  The statement appeals to those who are competitive by nature or anyone who wants to make sure that everyone is working as hard as they feel they are.  The next part of the process was adapting a very crude systems and after several missed starts applying it to everyone.  Even then I was quick to point out that it looked like 95% of the group was working hard and the only difference were the correction factors applied to the work units.  At that point I was told that this was not an academic exercise and we were now on this system whether I liked it or not.  Over the years, the calculations fluctuated and everybody did the same job, but now we were all cast as competitors rather than  colleagues.  In the end the productivity system was just a manipulation, more hoops to jump through as management made us less and less efficient with a series of roadblocks.

The second step is to set some arbitrary rules about how individual productivity affects the entire group.  In other words, penalize everyone up front and let the group know that this "holdback" in earned wages would be paid out only if everyone  made their productivity requirements.  I have never seen that rule applied to any other group of employees.

The next step is to set up some kind of arbitrary and meaningless employee evaluations.  Solicit random anonymous comments from any staff working with the physician employee and have them defend this one-sided criticism in their annual evaluation as if it is  true.  Have the physician who is working 60-70 hours a week, teaching, and doing independent educational activities select some goal at work that they will quickly forget until the next annual review.  All of the steps so far have served to isolate physicians and create a general paranoia about who might be making negative comments about them.  Paranoia is never good for collegiality.

Top this entire mess off with a primary school disciplinary system with a very low threshold.  Nurse Cratchett says that a physicians was too "curt" with her and suddenly that physician is called into the Chief of Staff's office and told that they are a disruptive physician.   Furthermore, that physician is advised that they have "one strike" against them and if they accumulate two more strikes they are "out".  There is no appeal process or due process.  If Nurse Cratchett complains - it must be legitimate and that conclusion based solely on the opinion of one person and supported by the Chief of Staff - stands.

At this point collegiality is gone and the physicians are further isolated from other non-physician staff.   Anyone can "report" them and that report will be taken seriously whether it is true or not.  The physician-administrators are no longer colleagues but hostile flunkies of the business hierarchy.

The final step was a stroke of genius by the incompetent managers.  For about 30 years managed care companies have had physicians reviewers sitting in a different state - remotely viewing records and telling the physician who is actually treating the patient - that patient must be discharged from the hospital or in some cases treatment for substance use disorders or outpatient psychiatric treatment.  In the last 10 years managers decided to have their own on site case managers, sitting in rounds and team meetings telling the physicians when to discharge patients.  If the physician doesn't go along with them they are reported to the medical director.  That creates additional problems and possibly another accusation of being a disruptive physician.

I have been talking about this sequence of events since I started writing this blog.  I recently encountered some resistance for the first time.  A colleague suggested that since burnout in physicians in other countries exists - there must be more to it than managed care.  I think that misses the point at a couple of levels.  First, it is possible that there are other bad managers - managed care companies certainly don't have a monopoly but they are highly standardized so that the onerous management practices that you find in one will certainly exist in another.  The literature on burnout in other cultures is small at this point and in some cases non-specific.  In other cases there is clear overlap.  But as I think more about this argument it seems lacking.  It seems like finding burnout and bad management practices in other countries can be used to rationalize the existence of ultimate bad management or managed care.  Secondly, bad management of personnel is just one aspect of bad management in general.  Does management ever do anything positive from an intellectual or creativity perspective?  Apart from one physician manager, I have not seen a single positive management outcome after observing a significant number of these people.

In fact,   if managed care administrators could not treat physicians like production workers they would have absolutely nothing going for themselves.  Nothing at all.



George Dawson, MD, DFAPA



References International Physician Burnout:

1: Jesse MT, Abouljoud M, Eshelman A, De Reyck C, Lerut J. Professional interpersonal dynamics and burnout in European transplant surgeons. Clin Transplant. 2017 Apr;31(4). doi: 10.1111/ctr.12928. Epub 2017 Mar 19. PubMed PMID: 28185307.

2: Głębocka A. The Relationship Between Burnout Syndrome Among the Medical Staff and Work Conditions in the Polish Healthcare System. Adv Exp Med Biol. 2016 Dec 31. doi: 10.1007/5584_2016_179. [Epub ahead of print] PubMed PMID: 28039665. 

3: O'Kelly F, Manecksha RP, Quinlan DM, Reid A, Joyce A, O'Flynn K, Speakman M, Thornhill JA. Rates of self-reported 'burnout' and causative factors amongst urologists in Ireland and the UK: a comparative cross-sectional study. BJU Int. 2016 Feb;117(2):363-72. doi: 10.1111/bju.13218. Epub 2015 Jul 30. PubMed PMID: 26178315. 

4: O'Dea B, O'Connor P, Lydon S, Murphy AW. Prevalence of burnout among Irish general practitioners: a cross-sectional study. Ir J Med Sci. 2016 Jan 23. [Epub ahead of print] PubMed PMID: 26803315. 

5: Tomljenovic M, Kolaric B, Stajduhar D, Tesic V. Stress, depression and burnout among hospital physicians in Rijeka, Croatia. Psychiatr Danub. 2014 Dec;26 Suppl 3:450-8. PubMed PMID: 25536981. 

6: Misiołek A, Gorczyca P, Misiołek H, Gierlotka Z. The prevalence of burnout syndrome in Polish anaesthesiologists. Anaesthesiol Intensive Ther. 2014 Jul-Aug;46(3):155-61. doi: 10.5603/AIT.2014.0028. PubMed PMID: 25078767. 

7: Kravitz RL. Physician job satisfaction as a public health issue. Isr J Health Policy Res. 2012 Dec 14;1(1):51. doi: 10.1186/2045-4015-1-51. PubMed PMID: 23241419; PubMed Central PMCID: PMC3533582. 

8: Putnik K, Houkes I. Work related characteristics, work-home and home-work interference and burnout among primary healthcare physicians: a gender perspective in a Serbian context. BMC Public Health. 2011 Sep 23;11:716. doi: 10.1186/1471-2458-11-716. PubMed PMID: 21943328; PubMed Central PMCID: PMC3189139. 

9: McKinlay JB, Marceau L. New wine in an old bottle: does alienation provide an explanation of the origins of physician discontent? Int J Health Serv. 2011;41(2):301-35. Review. PubMed PMID: 21563626.

Wait A Minute - Is Psychiatry Less Unhinged Than Most Other Specialties?

For the past decade psychiatry has taken far more than its share of hits on conflict of interest from both within and outside of the profession.  There are any number of bloggers that claim their reason for existence is to keep the profession honest.  Needless to say - a smug attitude like that rubs people like me and the majority of my colleagues the wrong way.  But I will go beyond that in terms of conflict of interest and have in many posts on this blog.  Unlike managed care administrators and US Senators, I believe that even physicians are entitled to be paid for the work that they do.  That includes providing CME presentations and doing consulting work - whether or not that includes payment by pharmaceutical companies or medical device manufacturers.  The only reason I do not do that, is to keep my name off the corruption list (implicit) that is currently compiled by an agency of the US government.  That list is episodically analyzed by consumer agencies who think that they are doing somebody a favor by naming any physician who gets reimbursed by industry.  My reasoning is simple - businesses and governments already have a painfully large amount of leverage against physicians -  why provide them with more?  Especially when it involves a good faith effort on your part and somebody is distorting  that effort and doing their best to make it seem like you have done something wrong. More importantly there is the frequent suggestion that a physician is aligned against the interests of their own patients.  I don't think that happens, even if a name is on that list.

This decade long campaign to compile the information has resulted in a difficult to decipher database with many errors.  It takes time to go through the data and sort it out.  It is impossible to try it on a casual basis.  It is a full time job.  The first of these disclosures came out in July of 2015 from ProPublica.   In the article, they looked at the number of days per year that a physician would receive industry payments.  They also looked at the top 20 MDs in each state in terms of payments received and in my home state there were no psychiatrists?  Wait a minute - weren't psychiatrists maligned in the press at the national level by a US Senator and also at state levels as being frequent recipients of pharmaceutical money?  In the most popular post on this blog - I point out that erroneous assumption used by a reporter to criticize the DSM-5 process at the peak of DSM-5 hysteria.  In an attempt to suggest that the DSM-5 may be swayed by the fact that the APA received money from the pharmaceutical industry the author fails to point out that the money received was less than half of what another specialty organization received.  I pointed out in a separate post that the theory that pharmaceutical company money to physicians is tied to pharmaceutical prices is equally flawed.  Taking physicians totally out of the loop results in the most expensive pharmaceuticals in the world in the USA.  That suggests that the monetary influence occurs at the level of Congress and not physicians.

The May 2, 2017 edition of JAMA has a conflict of interest theme.  Many of the articles are editorials with very predictable conclusions.  For the past decade conflict of interest in medicine has been simplified on the one hand in terms of definitions and solutions and politicized on the other.  I abstracted the table at the top of this post from one of the data driven articles (1).  They analyzed data from the CMS National Plan & Provider Enumeration System (NPPES), a database of all allopathic or osteopathic physicians with a national provider number (NPI).  The NPPES records input of all general payments, research payments, and ownership interests of these physicians.  General payments were described as all forms of payments (like speaking fees, food, beverages) other than research payments done under a written protocol.  The ownership interest was presumably in medical concerns but that was not really specified in the article.  The specific listing of specialties is available in the full text of the reference below.  My only focus here is on psychiatry.  I don't think the rankings or specific amounts have any particular meaning.

The abstracted table lists two of the end points in the article -  the percentage of physicians receiving some kind of general payment and the percentage of physicians receiving more that $10,000 per year.  The $10,000 amount was flagged by the the US Department of Health and Human Services as representing "significant conflicts of interest".  In fact, for most physicians who do consulting - it represents about 2 weeks of work.  The news for psychiatry reflected the reality that I am aware of.  Psychiatry was mentioned just twice in the article and both of those mentions were in the above highlighted table.  None of the headlines from the past decade that psychiatrists were getting more money from pharmaceutical companies than anybody else.  A little more than a third of psychiatrists got some kind of general payment with a median value of $171 (median interquartile range of $34 - 442.)  For perspective - I purchase 2 or 3 new textbooks a year that typically range $300-400 apiece.  I also subscribe to the standard online internal medicine text at a cost of $500/year.  I am not saying that the transaction involved textbooks but many do involve educational materials and I am not sure they are not added into this figure.

The second endpoint is the $10,000 figure and psychiatry is lower on this metric with 3.6 % of psychiatrists getting this level of payments.  For context, the upper end of the range for these payments is 11-12% for some specialists and the lower end is at about 1%.   Proceduralists (surgeons and interventionalists like cardiologists) tended to get the highest level of payments usually due to substantial licensing fees and ownership interests in the industry like medical imaging facilities and surgical facilities.

The authors do not draw many conclusions about the data.  They point out that there have been some concerns about accuracy.  In their conclusion section they point to other studies about connections between payments and prescribing patterns that suggest a "subconscious bias" in their decision-making.  In other words, accept a free lunch and start prescribing the medication of the pharmaceutical rep that bought the lunch.  One of the reasons I continue to read these articles is to see if the "subconscious bias" argument has any more evidence to back it up than speculation and rhetoric.  I continue to not see very much.  I have pointed out the flaws in one of their references in a previous post.  In other words there are a number of explanatory factors operating here other than "subconscious bias".  I have not seen any Manchurian candidates among my colleagues.  Physicians use a lot more discretion in prescribing medications than whether or not somebody bought them a piece of pizza.  The easiest way to avoid the brainwashing accusation is to not accept the pizza or payment for an educational presentation.  That is what I and two-thirds of my colleagues do.  When you are squeaky clean according to the US government/CMS, it is easy to develop an unrealistic idea about yourself - as if this hall of shame approach means anything.

The downside of course is that industry and medical education suffers unless there are incentives out there for physicians to do additional work.  If you happen to be a national expert in demand - will you fly back and forth across the country to educate your peers for nothing?  Maybe a time or two but not much beyond that.  If the pharmaceutical or medical device industry needs consultation from an expert - will you go to a multi-billion dollar a year business and provide your expertise for nothing?  There are no academics from any other department in any university that are expected to do that.  Another piece of the equation that is never mentioned is how physicians are reimbursed relative to the pharmaceutical industry.  An asthma specialist can see a patient once or twice a year and during that time prescribe $4,000 to $6,000 worth of inhalers.  That specialist might bill $200-300 for their professional time, but that will be discounted by insurance companies.  An argument can be made that physicians are seriously underpaid for managing expensive products and working for the industry is one way around that.  In other words - if physicians were paid for all of the high volume work that they do - they may be less interested in outside consultation with industry.

There are additional arguments about conflict of interest that nobody seems to talk about.  Physician owned medical facilities are often described as being significant sources of self referral conflict of interest.  But what are the advantages of physician ownership?  Not being managed by non-physicians would seem to be the clear cut advantage.  Would these environments provide higher quality and more professional services?  Would they be more likely to treat physicians fairly and cause less burnout?  Would they be more likely to be able to provide the full spectrum of services that their patients need?  Who has the greater conflict of interest - a physician employee of a managed care company who is paid to ration health care for the company's interest or a physician who owns the business and can provide services based on his or her idea of medical quality?  The evidence that these differences exist is widespread.                      

Finally, how much of this conflict of interest rhetoric focused on physicians is designed to control them and keep them in line?  Although there are always qualifiers about this data including its accuracy, the federal government seems to have upped the ante by their description of the $10,000 marker.  Is this the 21st century equivalent of billing and coding violations from the 1990s?  Those investigations were driven more by politics, convention and rhetoric than any wrongdoing.  I can't think of a better example of that than doing $10,000 worth of consulting work and finding out that your name is now on a list produced by the federal government and some media outlet is implying wrong doing or quid pro quo with pharmaceutical companies.

Those are the facts of the list as I see them.  There has not been much discussion of the article or the theme of this edition.  The data within psychiatry confirms what I have seen and it has never been as shocking to me as it has been typically portrayed either in the media or by groups interested in influencing physicians.

It is not shocking at all.


George Dawson, MD, DFAPA



References:

1:  Tringale KR, Marshall D, Mackey TK, Connor M, Murphy JD, Hattangadi-Gluth JA. Types and Distribution of Payments From Industry to Physicians in 2015. JAMA. 2017 May 2;317(17):1774-1784. doi: 10.1001/jama.2017.3091. PubMed PMID: 28464140.

2:  JAMA May 2, 2017, Vol 317, No. 17, Pages 1707-1812.  This entire issue is about conflict-of-interest and the link is here.


Supplementary 1:

Before sending any inflammatory comments please remember that I don't eat the free lunch or accept industry money from anybody.  Feel free to look that up on any list.

Supplementary 2:

Original form of the table.  I had to convert it to a graphic version at the top of this post.

Per Physician Value of General Payments to Allopathic and Osteopathic Physicians by Specialty in 2015
Percentage of physicians receiving general payments	Percentage of physicians receiving >$10,000
1.	1.
2.	2.
3.	3.
4.	4.
5.	5.
6.	6.
7.	7.
8.	8.
9.	9.
10.	10.
11.	11.
12.	12.
13.	13.
14.	14.
15.	15.
16.	16.
17.	17.
18.  Psychiatry (37.3)	18.
19.	19.
20.	20.
21.	21.  Psychiatry (3.6)
22.	22.
23.	23.
24.	24.
25.	25.
26.	26.

Supplementary 3:

Some additional points of interest from other articles in this supplement:

589,042 of 850,000 active physicians in the US received some type of general payment in 2015 with a mean value of $400 and a median value of $138.

Any physician registered at a sponsored CME event is considered to have received a payment whether they consume provided food or beverages or not.

from:  Steinbrook R. Physicians, Industry Payments for Food and Beverages, and DrugPrescribing. JAMA. 2017 May 2;317(17):1753-1754. doi: 10.1001/jama.2017.2477. PubMed PMID: 28464155.

The threshold for reporting is a $10 transfer to the physician.

"At the same time, most physicians have essentially no meaningful COI."

from:  Lichter AS. Conflict of Interest and the Integrity of the Medical Profession. JAMA. 2017 May 2;317(17):1725-1726. doi: 10.1001/jama.2017.3191. PubMed PMID: 28464163.