An Unusual Molecule

Fenethylline

In the course of addiction practice it is common to run across unusual compounds typically being used for their intoxicating properties.  That happened to me recently when I encountered the compound fenethylline.  Fenethylline was apparently invented for use as a stimulant in Attention Deficit-Hyperactivity Disorder and some of the conditions that were precursors to this diagnosis.  I have read a lot of that literature and had never encountered it.  The interesting property of this chemical is that it is cleaved in vivo to theophylline and amphetamine.  Theophylline is one of a class of coumpounds called methyl xanthines that most physicians in my era were familiar with from the treatment of asthma and exacerbations of chronic obstructive pulmonary disease.  They proved to be weak medications and although some sources list them as tertiary agents today use is not very likely.  This medication is proof that medicine evolves based on what happens with real world applications.  This pill for the most part has been replaced by inhaled corticosteroids alone or inhaled corticosteroids in combination with long acting inhaled beta agonist medications.  Theophylline is a non-addicting medication that can produce side effects very similar to excessive caffeine use in a number of patients.

Amphetamine is different and is in a number of preparations for ADHD.  Many of these preparations are FDA approved for that application.  Amphetamine is a potentially addicting drug and is a Schedule II N stimulant on the schedule of controlled substances indicating a high high potential for abuse or dependence.  Fenethylline is a Schedule I compound meaning that there is no accepted medical use, high risk for abuse and a lack of safety when used under medical supervision.  It has been a Schedule I compound since 1981.

In the medical literature problems with fenethylline were noted as early as the the 1960s with the first paper on addiction published in 1965 (1).  It was apparently synthesized in 1961.  It was listed as a substance of concern by the World Health Organization in 1986 (2).  There was a paper the same year pointing out that it had been in use for 21 years at that point and it appeared to have less abuse potential than amphetamine. More recent case reports have been published on the issue of psychosis and myocardial infarction from using the drug.  The real issue that has surfaced in the last several years has been the addictive potential and the use of revenues generated from this drug being used to fund terrorist operations and possible the war in Syria.

Van Hout and Wells (7) track the illicit manufacture of fenethylline and synthetic amphetamine type stimulants (ATS) in the Middle East.  The manufacture of Captagon ( a former brand name for fenethylline) started in the early 2000s in Southeastern Europe and it was transported to the Arabian Peninsula.  The name branded medication did not contain fenethylline but an array of amphetamine and caffeine like stimulants as well as antibiotics.  Lebanon became a major supplier of the drug but eventually Syria took over in about 2013.  In 2015 about 48 million pills of Captagon were confiscated en route from Syria to various Middle Eastern locations.

The Captagon tablets themselves sell for $3 to $20 each and are thought to serve two purposes - a stimulant for soldiers engaged in the military who need to be alert and aggressive and as a revenue source for funding the war.  They are widely available on the Arabian Peninsula.

A brief review of the pharmacology of fenethylline (6) suggests that the compound is more lipid soluble and have better brain access than amphetamine products.  All of the currently available medical sources seem to suggest that it is less toxic than amphetamine, but also considerably weaker.  The literature is limited but the reasons for why it has attained a great deal of value in the Middle East do not seem perfectly clear.  The rationale for synthesizing the original compound is also not very clear.  There has always been some folklore that methylxanthines like caffeine and theophylline would have a stimulant like effect on persons with ADHD.  Reviews of that phenomenon have found very little to back it up (8,9).          

I post this here as another curious note in terms of another addictive drug that appears to be unique to a certain part of the world.  As usual, wherever an addictive compound is found there will be people there to profit from it.      

George Dawson, MD, DFAPA



References:




1: Grahmann H, Reimer F.  Captagon as an addicting drug.  Nervenarzt.  1965 May; 36: 227-8. German. PubMed PMID: 14305717.

2: Keup W. Use, indications and distribution in different countries of thestimulant and hallucinogenic amphetamine derivatives under consideration by WHO. Drug Alcohol Depend. 1986 Jun;17(2-3):169-92. PubMed PMID: 2874968.

3: Kristen G, Schaefer A, von Schlichtegroll A. Fenetylline: therapeutic use,misuse and/or abuse. Drug Alcohol Depend. 1986 Jun;17(2-3):259-71. PubMed PMID: 3743408.

4: Al-Imam A, Santacroce R, Roman-Urrestarazu A, Chilcott R, Bersani G, Martinotti G, Corazza O. Captagon: use and trade in the Middle East. Hum Psychopharmacol. 2016 Oct 21. doi: 10.1002/hup.2548. [Epub ahead of print] PubMed PMID: 27766667. 

5: Khanra S, Sen S. Pharmacoterrorism: We should be worried. Asian J Psychiatr. 2016 Aug;22:83. doi: 10.1016/j.ajp.2016.05.002. PubMed PMID: 27520902. 

6: Katselou M, Papoutsis I, Nikolaou P, Qammaz S, Spiliopoulou C, Athanaselis S. Fenethylline (Captagon) Abuse - Local Problems from an Old Drug Become Universal. Basic Clin Pharmacol Toxicol. 2016 Aug;119(2):133-40. doi: 10.1111/bcpt.12584. Review. PubMed PMID: 27004621. 

7: Van Hout MC, Wells J. Is Captagon (fenethylline) helping to fuel the Syrian conflict? Addiction. 2016 Apr;111(4):748-9. doi: 10.1111/add.13262. PubMed PMID: 26787140.

8: Hughes JR, Hale KL. Behavioral effects of caffeine and other methylxanthines on children. Exp Clin Psychopharmacol. 1998 Feb;6(1):87-95. Review. PubMed PMID: 9526149. 

9: Stein MA, Krasowski M, Leventhal BL, Phillips W, Bender BG. Behavioral and cognitive effects of methylxanthines. A meta-analysis of theophylline and caffeine. Arch Pediatr Adolesc Med. 1996 Mar;150(3):284-8. PubMed PMID: 8603222.




Attributions

Fenetylline structure was obtained from ChemSpider.

Exploitation Of Opiate Addicts - Same Song Different Century

Most people don't know or care about the past history of addictive drugs in America.  The best examples of this are the people who want to legalize all drugs and don't realize that there was a long history before regulation and that there were legal over-the-counter forms of opium and cocaine.  Contrary to the Utopian way that it is portrayed today, regulation of addictive drugs occurred because of problems and not the other way around.  The only way that you can think that the legal aspects of drug control created the problems rather than the drugs themselves is if you completely ignore what really happened.  The quote by Osler is particularly poignant with regard to that history.  The quote is from his classic text The Principles and Practices of Medicine and a chapter he wrote in that text on opiate addiction.  The year was 1894.  It occurs in the context of a marked increase in opium use.  The isolation of morphine from opium in 1804 and the commercial production of morphine in 1826 as well as the invention of the hypodermic needle in 1855 were thought to be contributors to the opiate epidemic of the late 19th century.  Although morphine had been injected into areas close to nerves previously, the hypodermic needle allowed unprecedented ability to inject morphine very close to affected nerves.  Within a short while morphine injections to treat various forms of neuropathic pain were common.  The statement about women being higher risk may reflect the estimated risk that women were twice as likely to become addicted to opiates from precriptions by their doctors.

The new method of treating nerve pain with injected morphine was thought to be a major advance in the treatment  of chronic pain.  Despite frequent injections it took some time for physicians to recognize the fact that people were getting addicted to morphine.  Musto in one of his excellent texts titles a chapter:  "The Belated Recognition of Addiction to Hypodermically-Administered Morphine" (1)  Although that title may seem laughable today the historical mistakes have been repeated again.  Just a few examples include "tamper proof" addictive medications that turn out to not be tamper proof, tramadol as a "non-addictive" option to opioids. and the idea that benzodiazepines are safe and non-addicting.  All have all been disproved on a historical basis.  The historical approach to addictive drugs has been a naive one - even before the era of intense marketing to physicians, massive lobbying efforts and direct to consumer advertising.

There seem to be very few people who are knowledgeable about the regulatory landscape for narcotics in the United States over the past 150 years.  It is an interesting parallel to the origins of the current opioid epidemic and it rests on the principle that increasing access to addictive compounds will result in more members of society with addiction.  It also has implications for the disease concept of addiction well before there was any established neuroscience.  The argument in those days was whether opiate addiction permanently altered the physiology of the nervous system to the point where the need for ongoing drug was inevitable.  There has been plenty of evidence to support that and the evidence has been there for a long time.  As early as 1875, a German physician Eduard Levinstein collected follow up data on patients he had weaned off opiates and found a relapse rate of 75% (ref 1 p 74).  In 1914, physicians at the Tombs prison in lower Manhattan estimated that it would take two months to get opiate addicts off drugs and unless they were isolated from drugs for another year the prospects for cure were low (ref 1 p 107).  That sums up my experience with opioids even today.  The main difference is that people are now on maintenance opioids for at least that long and get the message that they need to take these drugs for the rest of their life.

In the early 20th century, some American physicians looking to "cure" opiate addicts were fairly pessimistic about the prospects.  By 1920 there was one estimate that there were a million opiate addicts in the United States.  The population at the time was about 107 million people.  Two options were considered at the time - indefinite maintenance on opioids and the elimination of all non-medical use.  There was a relatively small number of physicians referred to as dope doctors whose practices consisted of maintaining large numbers of people in addiction by ongoing opiate prescriptions.  As regulations proceeded from the belief that federal control over narcotics and prescription practices of doctors was unconstitutional in 1900 to the enactment of the Harrison Act on March 1, 1915 outlawing the non-medical prescription of opiates - there were a small number of physicians engaged in the practice of maintaining addiction.  That practice was declared illegal by the Harrison Act until it was modified years later to allow methadone maintenance.  The evolution of medical practice over that time was interesting.  In less than a generation, opiates and cocaine went from being over-the-counter medications to being highly regulated.  Medical and pharmacy practice was impacted and there were political battles along the way.  Post Harrison Act there are still physicians engaged in the now illegitimate practice that are described in the popular culture in the 1950s and 1960s.  Legitimate and illegitimate prescribing of controlled substances is always a fine line.  In the 21st century, the main problem is the number of patients who are trying to game the system and get opioids and stimulants.

It is still illegal to prescribe addictive medications to an addict.  The only exceptions are methadone and buprenorphine.  Methadone prescriptions for addiction treatment can only occur in licensed methadone clinics.  Buprenorphine can occur in outpatient medical practice but a special license it required and the total number of patients treated is regulated.  But what about the patient who claims that they can take an addictive medication in a controlled manner?  It may not be the primary addiction, but there are many patients with alcohol use disorders and opioid use disorders who believe that they have Attention Deficit~Hyperactivity Disorder (ADHD) and claim that they can take stimulant medications.  There are many people with stimulant use disorders who claim that they can take prescription stimulants in a controlled manner and insist on it.  How many doctors continue to prescribe these medications to patients who they know are addicted?  My speculation is that there are currently millions if not tens of millions of people being maintained in addiction by physicians who think that they are being helpful as their primary motivation.

I started this post with the intent to comment on a the specific practice of buprenorphine maintenance.  I commented recently on the problems with buprenorphine maintenance and why it is a far from ideal solution to the centuries old problem of opioid addiction.  Since that post I have become aware of a new problem.  In many areas there are very few buprenorphine prescribers and many opioid addicts.  There are many excellent physicians who are addictionologists and addiction psychiatrists out there trying to make a difference.  Running a buprenorphine clinic is a fairly intensive exercise that typically involves counseling and frequent toxicology screens.  Many of these patients have significant medical and psychiatric comorbidity.  That said, there are apparently some buprenorphine prescribers that are motivated to make a significant profit from this practice by charging patients $500 to $1,000 for brief monthly visits with additional charges for the toxicology and counseling.  These charges are all in cash and in my opinion are problematic.

The problem with these charges is that they directly impact the relationship with the physician.  A straight economic argument is often made.  That argument goes something like this: "What would this person be spending if they were still using heroin?"  That number is highly variable based on individual physiology and geographic location but a rough cost estimate would be $1200 - $5,000/month.  On straight cost basis an expensive buprenorphine clinic comes in at the low end of the estimated monthly cost of daily heroin use.  But that misses the point.  When people are in recovery, many of them are working at low paying jobs with minimal or no insurance.  They need a cost effective solution to opioid treatment and that includes buprenorphine maintenance.  If they see a physician and need to pay $500-1,000 cash essentially for a prescription it will lead to immediate thoughts about why they are bothering to stay sober.  It will lead to resentment toward the physician or at the minimum a loss of physician credibility.  It leads to a question about physician motivation.  People with addictions are no different than anyone else seeing a physician.  They have to realize at some point that the physician is interested in them and helping them rather than just making a profit.  There are clearly some physicians out there who don't get that point.  The outcry has been palpable with a backlash on buprenorphine prescribing that is visible on several social media groups.  The toal membership of these groups is over 10,000 people.  Many of these people are clearly interested in tapering off buprenorphine at some point rather than life-long maintenance.

The dynamic of taking advantage of people with addictions in the US goes back to the early 20th century.  The landscape  has changed based on what is considered to be a legitimate prescription to people with addictions. In the 21st century we are currently operating under the premise that we may have a treatment for opioid addiction, but there are many limitations.  Physicians would do better heeding Osler's warning at the top of this post. modifying his quote about hypodermic syringes to include the equivalent today - high potency opioids.  In the case of people with know addictions, treatment needs to be ethical and patient focused.  We have seen a rapid move to "evidence based" treatment for opioid addiction based on medications and little else.  That is really not a solution to the problem of known addiction or the ongoing drug epidemics in the US.

Prevention is the best current approach to addiction.
    



George Dawson, MD, DFAPA


References:

1:  Musto DF.  The American Disease: Origins of Narcotic Control.  3rd ed.  Oxford University Press.  New York, 1999.

2:  Musto DF.  Drugs In America: A Documentary History.  New York University Press.  New York, 2002.

The Best Strategy To Address The Proliferation Of Prescribers

MPS Newsletter Ideas of Reference 2017, Number 1, Volume XLX

When I got home this evening I opened up a copy of the Minnesota Psychiatric Society newsletter Ideas of Reference.  I was greeted by the above graphic and an accompanying story on the differences between psychiatrists and psychologists.  There were even some bar graphs on the relative biomedical training comparing psychiatrists, nurse practitioners, physician assistants, and a proposed trivial training period for psychologist prescribers.  I can only surmise that there is some initiative to create psychologist prescribers.

It should be obvious to any casual reader of this blog that as a medical psychiatrist and neuropsychiatrist, I don't think that anyone has better training than psychiatrists to prescribe medications and diagnose mental disorders and associated medical and neurological disorders.  My first letters on this matter date back to 1988 with the CAAP v. Rank legislation in California that proposed that psychologists should have admitting privileges to hospitals.  The same national group was getting active in trying to convince state legislators to allow psychologists to prescribe medications.  To somebody who has been steeped in biomedicine, why somebody with no training would want to take a crash course to prescribe a niche of medications while knowing nothing about general pharmacology or physiology is a mystery to me.  The early advocates were explicitly concerned about making money.  There is nothing wrong with that, but it should be equally understandable why a highly trained person might find that approach somewhat appalling.

Over the years, I tried with no success to rally the troops not so much against any political group but always arguing for a tight professional organization whose goals was to bring all psychiatrists up to speed in order to practice state-of-the-art psychiatry.  As a professional organization that is all you can do.  The American Psychiatric Association tries to pull it off, but there are too many political conflicts of interest.  For years the APA has clearly been more aligned with managed care organizations and the American Board of Medical Specialties and the American Board of Psychiatry and Neurology against the membership.  People may deny it but that has been the net effect.  Instead of the goals of independent life long learning and state-of-the-art psychiatry, the vigor of the organization has been dissipated on shaky political alliances and special interest politics.  Instead of defending the organization and its members there have been concessions to people grandstanding in Congress.  There have also been concessions to the cost rhetoric of both the government and managed care organizations and the current collaborative care rhetoric as psychiatric reimbursement from those organizations has become trivial and the infrastructure required to treat severe disorder - destroyed.

For the last 30 years, there has been a constant war of attrition in state legislatures everywhere against the idea that you probably should have medical training in order to prescribe medications.  There is a break with reality in that physicians with the highest level of training also have the highest levels of accountability.  Any interested citizen living in a state where there are a lot of nonphysician prescribers should ask themselves if all of those prescribers are held to the same standard or not?  What level of training does it take in a crash course to equal my 8 years of medical training?  How do politicians with no knowledge of medical training themselves make these decisions?  Is the decision based on public safety - their usual standard for investigating physicians - or is it something else?  I would submit that it is always something else?

Getting back to the title of this post I will comment on a few strategies that are probably too little and too late at this point.  These are things I have been talking about for 30 years frequently to the annoyance of colleagues who prefer a head-in-the-sand approach:

1.  State-of-the-art psychiatry:  I was buoyed by a presentation on neuropsychiatry at the Madison conference this year and think that teaching and talking about these concepts needs to be more widespread.  There is no better way to up your game than to take the thinking in the field to an entirely different level.

2.  Politics:  Physicians in general depend far too much on the kindness of strangers.  The amount of money that physicians have given to politicians looking for a modest break (like maybe there should be a limit on who is qualified to prescribe medication) is legendary at this point.  That is billions of dollars wasted just so the Obama administration could sit physician representatives down in a room and tell them their job was to sit there, shut up and support Obamacare.  Physicians and psychiatrists cannot afford to squander blood, sweat, and treasure on people who only know how to exploit physicians.  That includes anyone supporting maintenance of certification (MOC), maintenance of licensure (MOL), managed care organizations, or pharmaceutical benefit managers.  That includes anyone supporting  the various reasons why physicians have to sit down at the end of a busy day and spend another 3 to 4 hours on paperwork before they can go home.      

3.  Know who your friends are: Any manager who suggests that you need to be on a team comprised of nonphysicians when you are perfectly fine practicing independently is not your friend particularly when some of these people with no accountability start to tell you how to practice medicine.  They can do that because they have the full support of the administration.  Managed care companies that burn physicians out and hire more and more "prescribers" are not your friend.  In this case the focus is on a nonmedical profession prescribing.     While shocking it is also the logical conclusion of decades of more and more non-physicians who are often practicing in specialty clinics and seeing patients in regular rotation with subspecialists.  The entire trend is driven not by expertise but by the managed care mantra of how to ration care but still make money.  The current collaborative care model supported by the APA is a recipe for getting rid of psychiatrists either entirely or replacing them with somebody who can sit, look at a guideline and say something on the phone.

The team approach is also a management tool to make it seem like all team members are equal.  If one of the specialists with a particular skill set is gone the patient can be seen by anyone.  The encouraged egalitarian approach by management is clearly biased away from any particular expertise and toward generic and presumably less expensive prescribers.

4:  Competition:  When all of the geniuses in state legislatures max out the number of "prescribers" any psychiatrist out there needs to ask themselves: "Now what?"  Well if anyone had been listening 30 years ago, psychiatry would be in a much better place right now.  Instead, everyone jumped on the managed care bandwagon and three decades of decidedly poor quality care.  The only hope that I see is doing what every other successful specialty does to survive managed care - get out and form your own specialty groups that compete on quality rather than the lack of competition.  There are some physicians groups who become independent and try to out managed-care the managed care companies.  By that I mean that they optimize billing, hire their own non-physician prescribers, and when the patient's financial resources are depleted - send them back to the managed care company.  That is not a quality approach that will allow physicians to distinguish themselves from the typical managed care model. 

5: High ethical standards:  You can't impress anyone sitting in an office and prescribing Prozac.  You are even less impressive if you are charging a lot of money for a brief appointment.  You are least impressive if that appointment involves the prescription of an addictive drug.  You can't get by with the managed care assembly line approach and do good work.  Offer a high quality product for reasonable value and nobody can compete with that today - because there are few (as in hardly any) high quality products.  Do not be surprised if no managed care company wants to contract with you.  Do not be surprised if government payers will not reimburse you at levels that allow you to stay in business.  It is definitely more ethical to work on your own than accept trivial reimbursement for stereotypical poor care.    

6:  Understand rhetoric:  Physicians as a group really don't understand rhetoric or politics very well.  They think that they are insulated from the fray and avoid confrontations.  They never understand that bullshit and fake news works by leveling the playing field at some level for anyone who is arguing that they have equivalent knowledge or skill.  In the worst case scenario, I have heard many physicians praising prescribers for some quality or another that generally had nothing to do with technical skill.  The only way to preserve the integrity of a profession is to not engage in these pointless arguments and invest that time, energy, and mental work in advancing the profession at the national and local level.  How many district branches have journal clubs, scientific meetings, and clinical discussions on state-of-the-art treatment on a routine basis?  Not many I would guess and yet there is always time for these political squabbles.  The commonest reason I hear that these learning activities don't occur is that everyone is "busy" and doesn't have enough time.  Everyone is busy because their time is wasted managed care companies, the federal coding and reimbursement scheme, the mandatory and inefficient electronic health record, redundant maintenance of certification exercises, and pharmaceutical benefit managers.  

7:  The myth of the "prescriber" shortage:  There should be no doubt in anyone's mind that the most commonly prescribed classes of psychiatric medications are overprescribed.  The idea that we need more "prescribers" to provide even more of these medications flies in the face of that very fact.  Do we need more ADHD experts to provide more stimulants or more anxiety experts to provide benzodiazepines?  The answer is clearly no.  There are only two interests being served by the prescriber shortage myth at this time and those are the health care systems that would prefer to equate all mental health treatment with the prescription of medications and the people manufacturing and selling the medications.  A health care system that is flush with prescribers can certainly do a lot of billing and it is good for public relations, but it is unable to provide any quality psychiatric treatment.

 Psychotherapy services and practically all psychiatric services have been adversely affected by the prescriber shortage myth.  Right now there is a far greater shortage of behavior therapists for anxiety and post-traumatic stress disorders than there is of prescribers.  In the case of patients with severe psychiatric illnesses and addictions these same health care systems that advertise prescribers do not provide adequate treatment environments for the psychiatric treatment of severe disorders and addictions.  All care is funneled into a 10 or 15 minute appointment every three months focused on initiating or maintaining a medication - whether that is the best course of action or not.

Psychological testing is also discriminated against.  The clearest example is the association of learning disorders with ADHD.  Most studies show that at least 1/3 of people with ADHD have associated learning disorders.  There are currently some managed care companies that not only have no psychologists to do this testing, they only allow for testing based on "medical necessity" whatever that might be.  Psychologists that do testing are essentially managed right out of managed care companies or are so unavailable that it takes months or longer to do the testing.  My speculation is that any quality improvement program on this issue for any managed care company would indicate either inadequate levels of testing and/or overdiagnosis of ADHD.  It could easily be accomplished by looking at the number of ADHD prescriptions and determining if any testing had been done.  It turns out managed care companies are the worst at determining the level of prescribing, psychotherapy and psychological testing needed to treat any population of people with mental illness.

Those are a few of my ideas just looking at the graphic.  I am sure that I will have some more posts on this in the future.  My main point this evening is that it is certainly understandable to try to fight this battle with special interest politicians but it is generally a battle that cannot be won at that level. Politicians will deplete time and money and give you nothing in return.  There are just too many people who think that they should be able to prescribe medications irrespective of their training relative to the training of physicians.  The only way to beat them is to excel and pull away looking at them in the rear-view mirror.

One thing is for sure -  if I come to your clinic to see a Cardiologist - I better be seeing a Cardiologist and not a prescriber.


George Dawson, MD, DFAPA



Supplementary:

In thinking a little bit more about the current MPS approach, I came up with an alternative.  I would ask MPS members to send in all of the medical problems and diagnoses they have made in the course of their practice on a month to month basis and compile them on the web site.  That would go a long way toward differentiating medical and psychiatric practice from non-medical mental health practice.  I would include diagnosing and treating complications of medical treatment.  That would make more of an impact than the current infographic.


Attribution:

The graphic at the top is from the referenced source.  I am a member and Past President of the MPS and a Distinguished Fellow of the APA.  Use of this graphic is for commentary purposes and does not imply endorsement of me by the MPS or APA, although that should be fairly obvious.

As far as the graphic goes I realize that I am not the target audience here, but even with that premise the graphic appears to seriously dumb down what I do on a daily basis.  That is one of the central problems in trying to condense and compare 8 years of education and training to someone with essentially no training at all in medicine.










  

Managed for Mediocrity - Corporate Medicine in the 21st Century

I had in interesting conversation with a colleague the other day.  The focus was on the concept of population based medicine.  It has been a buzzword in managed care and HMOs for the past 20 years.  I have seen many physicians who were promoted to administrators in these organizations who had to start talking the population based medicine hype as part of their role as administrators.  Looking at Medline references the definition goes back to 1995, but I heard it long before that.  If you Google the term you will find a definition that is attributed to the American Medical Association:

An approach that allows one to assess the health status and health needs of a target population, implement and evaluate interventions that are designed to improve the health of that population, and efficiently and effectively provide care for members of that population in a way that is consistent with the community’s cultural, policy, and health resource values.

In trying to confirm that definition for the past three days through AMA staff and their web site - I have been unable to locate the specific document.  The problem with this definition should be apparent to any physician.  Physicians are trained to assess and treat individuals.  They are trained to treat people with diseases and illnesses.  They spend the majority of their time doing this.  The idea that this kind of approach is going to be implemented by a physician or even a group of physicians is overreaching and absurd.  It is very convenient for managed care companies, pharmaceutical benefit managers, and governments who want to ration resources across communities and intentionally discriminate against others.  What could be a better rationale for having fewer and fewer people being seen by physicians and more people taking inexpensive screenings or just being told that there are no resources.  It is also useful to mass market very expensive pharmaceuticals to people who will get minimal to no benefit from them.  Corporate management removes physicians from those decisions, but in some cases makes it seem like the physicians approve.  The best example is a corporation limiting choices and then making it seem like the physician is approving the course of action.

The business and government led movement to homogenize medicine has additional fall out that I am sure few people outside of medicine know very much about.  Physicians are managed to see a number of billing codes per day and those codes are typically optimized to collect the maximum billing per encounter.  They need to be because the payers are already gaming the system to pay the lowest possible amount per billing code.  That tension between the non-medical forces on three sides: payers, coding specialists, and physician managers creates a pathological assembly line of brief expensive visits where not much happens.  Have you ever been told by a physician or nurse that you can be seen for only one problem at a time and if you have a second or third problem you will need to set up new appointments? This is the pathological assembly line approach taken to its absurd conclusion.  Any slight glitch in appointment times or a patient suddenly requiring more intense treatment than anticipated throws a wrench into the works.  Some patients in the waiting areas can be backed up for hours.

Homogenization has another intended consequence - it makes it seem like all of the physicians in the clinic are the same.  That is always true to some extent, but there are always major unappreciated differences.  Some physicians gravitate toward specialty areas based on their interest and experience.  Some physicians have a natural talent to deal with certain problems and procedures.  Other physicians know that they should avoid certain areas of medical practice and for that reason stay out of specialty areas.  On this blog, I have posted that many physicians have told me over the years that they really like psychiatry but that they could never tolerate treating a certain type of personality or trying to determine the level of suicide risk when seeing patient with that problem.  There are differences within the same specialty.  Some psychiatrists are better at handling the medical aspects of psychiatry.  Others do a better job with psychotherapy.  Prior to homogenization, those differences were allowed to exist and they were developed across the entire professional lifespan of physicians.  When that happens in any group of specialists, these skills are recognized and patients with those problems are directed to the physician with those skills.   Today billing codes, patient visits, and electronic health record templates  preclude any differences between physicians and have them all producing the same rapid low quality product.

Physician evaluations are often set up to not recognize the unique contribution of the physician to the department and to insist instead on some kind of meaningless corporatized individual improvement plan.  The maintenance of certification (MOC) and maintenance of licensure (MOL) in some states is way to send the message that individual physicians don't have any particular expertise and in fact have to pass an arbitrary general exam in order to maintain certification - even if they have specialized in the area for 20 years, are recognized for their expertise, and know more about it than the physicians who designed the exam.

Physicians themselves know that I am speaking the truth about specialization because in many cases they still have this inside information.  They try to get at this information and use it to recommend care to family members and other patients.  If my spouse needs surgery, you can bet I am going to find the surgeon who does the most procedures and the one recommended by his or her colleagues.  Non-physicians do the same thing to some extent by talking to relatives and neighbors who have had surgery and asking them if they would recommend that surgeon.

There is probably no better term for this corporate tactic than suppression.  Current health care management actively suppresses physicians at multiple levels.  That is obvious in the initial interview in any health care organizational if the physician is savvy enough to ask directly about the expectations of the corporation.  They may discover unrealistic productivity and call expectations.  They may find out that although they were hired for some administrative, research or teaching position that there will also be at least a half time productivity expectation that involves seeing a lot of patients.  The associated administrative time cuts into their other role.  They will find that there is no time for the necessary phone calls for pharmacy and insurance hassles, documentation, or even meetings with an administrative agenda that are of no benefit to the physician.  Annual reviews are another place to observe corporate suppression in action.  One of the greatest tools ever created to suppress physicians and give them the message that they need active guidance by the less accountable is the 360 degree evaluation.  Today that typically involves soliciting anonymous negative comments from fellow employees and including that in the physician's review.  Many solid performing physicians many find it disquieting to put in a solid performance both in terms of productivity and other functions like teaching and presentations and leave their annual evaluation feeling like they have just been slandered.  In some cases, administrators may go as far as suggesting a performance improvement plan based on the fiction in the anonymous comments.

All of that is a far cry from the professionalism that used to exist among physicians practicing in groups and hospitals.  The current tactics certainly create more than enough leverage against physicians to keep the businessmen and politicians firmly in control.  The price is clearly a less vibrant, creative, and enthusiastic physician workforce.  The burnout syndrome has been written about extensively in the past several years and the single-most important cause of that burnout is bad management.

There is of course an asymmetry to the management tactics.  They are never applied to the managers themselves.  How would you manage the productivity of managers - the number of bad ideas they can come up with in a month?  Some of them make mistakes that approach a legendary scope in terms of losing money by restructuring employee schedules or signing licensing agreements with electronic health record companies.  They can make decisions that lose millions of dollars and shrug it off like nothing happened.  They can solicit employee complaints because it is currently the corporate ethos to do so and solve none of the problems.  There is no shortage of health care companies that hemorrhage professional employees because of their cookie cutter bad management approach.  It is probably logical from management's perspective because they see physicians and other professionals as production workers who could not survive without active guidance.  They fail to recognize that all of this active interference removes the best minds for treating the problem and relegates them to a secondary role.  In some cases, it appears that the administrators are practicing medicine.
     
These days bad management is about the only management that is out there.                      



George Dawson, MD, DFAPA




Attribution:

Graphic is from Shutterstock (Grayscale Town by Ganzaless) per their standard licensing agreement.   The use of the image does not imply any endorsement of this blog.

Allen Brain Atlas Is A Serious Upgrade

© 2010 Allen Institute for Brain Science. Allen Human Brain Atlas. Available from: human.brain-map.org

I have been studying neuroanatomy for the past 37 years.  When I started out there was no Powerpoint.  All of the presentations and lectures were projections of actual sectioned or stained specimens, photographs, or combinations of images from journal articles.  The lecture notes were generally a patchwork of similar figures.  The texts were a self study manual by Sidman and Sidman (2) and Carpenter's Human Neuroanatomy (1).   My original neuroanatomy course focused primarily on functional neuroanatomy that focused on clinical syndromes that had to do with identifying cranial nerve, midbrain, and hindbrain lesions and the general organization of the central and peripheral nervous systems.  Some systems were discussed.  Papez version of the limbic circuit for example but there was very little aphasiology or behavioral neurology.  There was very little cortical localization for that matter.  Mt speculation is that the neuroanatomists of the time thought that most medical students would pick it up in clinical neurology.  In terms of motor function, there was an emphasis on the dorsal striatum and a discussion of the usual clinicopathological correlates - Wilson's Disease, Huntington's Disease and Parkinson's Disease.  There was not discussion of the broad array of movement disorders.

Those early days of neuroanatomy were far from perfect.  There was no focus on the ventral striatum. despite the fact that Olds had discovered the median forebrain bundle and the reward system about 20 years earlier.   Diagrams about mesolimbic dopaminergic systems, even in pharmaceutical company literature were labelled according to conventions established in laboratory rats rather than the human brain.  There were a lot of deficiencies for anyone who learned neuroanatomy in the last two decades of the 20th century.  That is at least as far as I can tell.  I routinely teach a course on the neurobiology of addiction to physicians and residents where I usually say something like: "When I was in medical school most of the focus was on the dorsal striatum and the disease correlates.  Now we know that there is a ventral striatum that hang off the anterior and inferior aspect of the dorsal striatum.  I assume that you all have learned about these structures?"  That is generally followed by dead silence.  I am still uncertain about what that silence means.          

You can't really study neuroscience as it relates to psychiatry without knowing a great deal of neuroanatomy.  Finding the right sources is critical.  There was a progression of neuroanatomy texts  for medical school but in my opinion none of them is better than Hal Blumenfled's text (3).  His text has excellent graphics that are organized to illustrate concepts.  The best example I can think of is Figure 14.10 in this text entitled Dopaminergic Projection Systems.  The diagram illustrates the striatum (dorsal striatum), limbic system, and prefrontal cortex and their connections to the midbrain structures via the mesolimbic, mesostriatal and mesocortical pathways.   The origins of these pathways in the substantia nigra pars compacta, ventral tegmental area, and ventral tegmental area plus ventral tegmental area are illustrated in the same diagram.  It is one of the best conceptual diagrams I have seen in the field.  When it comes to illustrations of the ventral striatum and nucleus accumbens the text depends on a photograph of a coronal section (fig. 18.4) through the nucleus accumbens very similar to the one illustrated below from the University of Michigan.

The anatomy of this area of the brain is critical.  There are connections to the limbic system and hypothalamus.  Most medical school neuroanatomy texts lack both granularity and specific detail when is comes to the connectivity in this area.  A lot of the lack of granularity is based on the photographs and staining characteristics of the sections.  Blumenfeld's text talks about important structure in the area, neurotransmitter characteristics of some of those nuclei

Paxinos, Mai, and co-authors offer a detailed text (4), a detailed human brain atlas (5), and an online site (6).  I am still using the second edition of the text and the atlas and there are third and fourth editions available at this time.  These texts were recommended to me by Dr. Heimer when I corresponded with him after taking his course on brain dissection.  There is probably no better paragraph illustrating the significant advance in the neuroanatomy of this area than in Chapter 21 of this edition on page 682.  It is the only page in the text that refers to the nucleus accumbens:

".....The ventral region, which has been included in the term, the "substantia innominata," has now been histochemically identified as the ventral extension of the striatum.  In addition, the olfactory tubercle and the rostrolateral portion of the anterior perforated space adjacent to the lateral olfactory tract in primates are also included in the ventral striatum (Heimer, et al., 1999).  The remainder of the anterior perforated space appears to be a mixed area with elements of the putamen, extended amydala, the corticopetal cell complex, and the ventral extension of the pallidum."

There have been some major developments along the way such as Heimer's formulation of the extended amygdala (8).  His work was based on an advancement in technology that allowed for clearer visualization of the connections between the basal forebrain and the amygdala (9).

Enter the Allen Brain Atlas.  I have my favorite coronal section displayed at the top of this page per the Allen Brain Atlas terms of non-commercial use.  It is section 21 of 106 (numbered from the frontal pole).  I encourage anyone with an interest in human brain anatomy to go to the web site and look at coronal sections of the human brain.  Every coronal section has a smaller image of the location of the section on a lateral view of the brain. The image here is a standard image file (.jpg) and does not have the functionality of the web site.  As an example, on the web site there is a rollover feature that tells the exact structure under the cursor.  This is a very useful feature when studying the basal forebrain area and relationships between the nucleus accumbens, amygdala, and hypothalamus.

The only other text that I have found to be very useful in the clinical applications of neuroanatomy is Scott Atlas text on the MRI of the brain and spine (10).  The graphics on the accompanying CD are excellent and very useful as orientation to MRI scanning.

One of the problems with expensive texts is that they are not very useful or practical for teaching purposes.  I have tried to get permission from several texts to use the occasional graphic on this blog or for teaching purposes only to be confronted with very steep fees.  By steep, I mean on the order of a thousand dollars per graphic.  I consider that to be outrageous based in some cases on the publication date and the use for noncommercial not-for-profit teaching purposes.  In the case of reasonable fees, the licensing arrangement seems impractical.  As an example, I had a licensing arrangement at a reasonable rate but it involved me counting the number of PowerPoint slides for the number of students and submitting that fee on a regular basis.  I have no doubt that many lecturers are more organized than I am, but at 15-20 neuroanatomy based lectures per year to groups of various sizes I eventually gave it up and used publicly available material.

The good news for psychiatrists is that neuroanatomy has never been more relevant.  It has become a clear basis for addiction psychiatry and neuropsychiatry.  The amount of material that is openly accessed for teaching purposes has never been better.  In clinical work, one of the few good features of the electronic health record (EHR) has been access to imaging in the digital format.  I used to have to go down to Radiology and trace abnormal images on note cards and occasionally reproduce them in the handwritten record.  In many systems it is possible to cut and paste the image of interest into EHR progress notes.



George Dawson, MD, DFAPA



References:


1:  Carpenter, Malcolm B.  Human Neuroanatomy.  7th ed.  Baltimore, MD: The Williams & Wilkins Company, 1976.

2:  Sidman RL, Sidman M.  Neuroanatomy A Programmed Text: 1st ed. Baltimore, Maryland: Lippincott, Williams, and Wilkins, 1965.

3:  Blumenfeld, Hal. Neuroanatomy Through Clinical Cases: 1st ed. Sunderland, MA: Sinauer Associates, 2002: p 595.

4:  Paxinos G, Mai JK, eds. The Human Nervous System: 2nd ed. San Diego, California: Elsevier Academic Press, 2004.

5:  Mai JK, Assheuer J, Paxinos G.  Atlas of the Human Brain: 2nd ed.  Amsterdam, Netherlands: Elsevier Academic Press, 2004.

6:  Mai JK, Paxinos G, Voxx T.  Atlas of the Human Brain: 3rd ed.  Elsevier Science, 2007.
This text is listed as the source material for http://teaching.thehumanbrain.info/ an open access neuroanatomy site that uses photographs from the book and other materials and is licensed for non-commercial use and teaching purposes by a Creative Commons 3.0 license - Attribution Non-Commerical - No Derivatives 3.0 Germany.

7:  Haber SN, Gdowski MJ.  The basal ganglia. In: Paxinos G, Mai JK, eds. The Human Nervous System: 2nd ed. San Diego, California: Elsevier Academic Press, 2004:  676-738.

8:  Heimer L. A new anatomical framework for neuropsychiatric disorders and drug abuse. Am J Psychiatry. 2003 Oct;160(10):1726-39. Review. Erratum in: Am J Psychiatry. 2003 Dec;160(12):2258. PubMed PMID: 14514480.

9:  Elias WJ, Ray DK, Jane JA. Lennart Heimer: concepts of the ventral striatum and extended amygdala. Neurosurg Focus. 2008;25(1):E8. doi: 10.3171/FOC/2008/25/7/E8. PubMed PMID: 18590385.

10:  Atlas SW, ed.  Magnetic Resonance Imaging of the Brain and Spine.  3rd ed.  Philadelphia, Pennsylvania: Lippincott Williams, and Wilkins, 2002.

Insights From the UK: Prescribing Addictive Drugs

From the British National Formulary (BNF): under the heading prescribing drugs likely to cause dependence or misuse (p. 9):

1.   To avoid creating dependence by introducing drugs to patients without sufficient reason (2).

2.  To see that that the patient does not gradually increase the dose of the drug, given for good medical reasons, to the point where dependence becomes more likely (2).

3.  To avoid being used as an unwitting source of supply for addicts and being vigilant to methods for obtaining medicines (2).


I was asked to write a piece about benzodiazepines last week.  In the process, I went to look at guidelines in the UK, specifically the NICE guidelines.  In the process, I ended up getting a copy of the British National Formulary because it had some commentary on prescribing addictive drugs.  The section starts with three paragraphs that start with the above sentences.  I don't know how long these sentences have been included in this book but I took a few moments to ponder whether anything like this is written in papers or texts that American physicians read.  Americans may go about the prescription of addictive drugs in an entirely different manner.

Medical training in the US often matches trainees with a lot pf people on complicated polypharmacy for a lot of different conditions.  In a typical resident's clinic there will be people taking benzodiazepines, sleep medications, antidepressants, and in some cases pain medications including opioids.  There people generally expect to see a resident and get these prescriptions refilled.  In supervising residents, they generally have the same questions about this process from 30 years ago: "Wouldn't it be a good idea to see if we can get people off these medications?"

The only difference in my approach from that of my supervisors was to suggest an informed consent approach.  In other words, advise the patient about current guidelines that suggest time-limited use and open up a potential dialogue about how to taper and discontinue a drug.  Even that position can be controversial.  There are three main attitudes that I have encountered in that area.  The first is: "Maybe the patient needs it."  In the case of benzodiazepine maintenance, there is really no research guidance at all in this area - there rarely is for chronic medication use.  The underlying assumption is that here is the rare person that needs maintenance use of this medication - typically a benzodiazepine or sedative hypnotic.   

The second attitude is "As physicians we need to be able to help the patient and that is my orientation when prescribing these drugs."  The underlying assumption here is that this medicine is the only possible way to help the patient.  There is a more insidious underlying assumption that if you don't want to prescribe this addictive drug that maybe you as a physician don't want to help as much as the physician who does.  The other obvious limitation that if the patient believes the only way he or she can be helped is with a specific medication that will define what the physician does in this case.

A third attitude is more nihilistic and that is the patient has been on this medicine for years and seen new residents every one of those years.  What are the odds that they want to change it?  There may be a rational basis for the nihilism.  People are generally very resistant to tapering and discontinuing an addictive drug even if there is no indication that it is doing anything for them. In my days in resident clinic many people were taking triazolam at two and three times the maximum recommended dose for sleep.  They still complained of insomnia - often to the same degree before they started using this medication.  Any attempts to taper them off were fraught with problems.  It was often possible to get them down to maximum recommended dose only to find that they went back to the higher dose after a new resident came into the clinic.

The three lines from the BNF assume that the physician being advised is going to prescribe the addictive drug initially rather than maintain it.  That is a lesson that should not be lost on residents in these clinics or attending physicians in the field.   Every physician prescribing addictive drugs needs to have a plan in their head that incorporates the BNF guidelines.  There is plenty of evidence that is not the case.  Wide variability of prescribing patterns by physicians in the same setting provides a good illustration.   In a recent study (1) the range of opioid prescriptions across physicians varied from about 7 to 25% of emergency department visits with the odds of long term use correlating directly with the quartiles based on those frequencies.

There is another implicit dimension to the BNF guidelines and that has to do with neutrality.  There is generally far too much heat around the issue of addictive drugs in American training and practice.  That ranges all the way from the physicians just being uncomfortable with prescribing the drugs and transmitting that emotion to the patient to overt threats by the patient in order to get the drugs.  In the case of the former, I have had people who were both reliable and unreliable tell me that they felt they were being treated like a drug addict.  In the case of the latter, physicians (including myself) have been threatened with physical attack or blame for a patient's demise (suicide or accident due to recklessness) if they do not supply the desired addictive drug in the right dose and quantities.  There are the "dog ate my alprazolam calls"  to on-call physicians who typically are not seeing the caller as a patient.  All of these factors often lead to a contentious relationship between physicians in training and attending physicians and the people on addictive medications.  As these few pages in the BNF point out - that emotional intensity is really unnecessary.

I have found that to be a mistake in the training of American physicians.  We learn how to prescribe addictive drugs and come to dealing with the problem of addiction much later.  The most important aspect of those prescriptions is the personal relationship and emotional reaction to the patient.  Some physicians never really learn to deal with it.  We could learn a lot earlier by the basic focus that is in the BNF.    


George Dawson, MD, DFAPA



References:

1: Barnett ML, Olenski AR, Jena AB. Opioid-Prescribing Patterns of Emergency Physicians and Risk of Long-Term Use. N Engl J Med. 2017 Feb 16;376(7):663-673. doi: 10.1056/NEJMsa1610524. PubMed PMID: 28199807.    

2:  British National Formulary.  Published Jointly by the Pharmaceutical Press; Division of the Royal Pharmaceutical Society; 66-68 East Smithfield, London E1W 1AW, UK and BMJ Group; Tavistock Square, London, WC1H 9JK, UK; 2016: p. 9.


Attributions:

The cover of the BNF is the cover of my copy that I purchased from Amazon.  I consider the three lines that are quoted and referenced to this book to be fair use for scientific discussion on a non-commercial and not-for-profit blog.

I have no personal or business connection with the BNF.  Any references to it here are just for the scientific discussion of its content and potential importance in medical training.

Why Buprenorphine Is No Panacea for Opioid Addiction - An Insider View

That's right - I am an insider in the current opioid epidemic.  I only treat people with addictions.  I am licensed to prescribe buprenorphine and have been for 10 years, but in my current position my role is to do independent psychiatric assessments and treat associated psychiatric comorbidity.  Opioid detox is done by addictionologists and the maintenance decision is made by a multidisciplinary committee.  In that capacity I see a wide variety of people who end up addicted to opioids and eligible for opioid maintenance treatment.  I see them in various stages of detoxification/withdrawal and maintenance.  I know what works and what does not work.  Forget what you read about from all of the politicians and administrators - buprenorphine containing products (Suboxone, Subutex, etc) are not a panacea for opioid addiction.  It takes more than a pill to stop an addiction to opioids and more importantly assist in long term recovery.  Forget what you hear about how cravings to use a substance not predicting future use.  I can predict who will be able to remain abstinent from a drug with a high degree of certainty.  Anybody who suggests that is not possible does not know what they are talking about.

What follows is a discussion of some of the factors that limit the utility of buprenorphine based products in the treatment of opioid addiction and the reasons for these limitations.  Before getting into it it I want to clarify that I do support the use of buprenorphine for the treatment of opioid addiction.  People on medication assisted treatment with buprenorphine are about twice as likely to remain off opioids as people without this treatment.  They are more likely to remain in treatment and are less likely to develop Hepatitis C seroconversion.  But there are a lot of factors that are not discussed along the way when politicians talk about widespread use of buprenorphine as the best way to address the current opioid epidemic.  I had thought about including a comprehensive table on results to look at the limitations but decided against it - due to complexity.  If you would like to see what that table looks like - let me know and I will finish it.  For now here are a few of the issues as I see it.

1.  Indefinite maintenance:  Nobody wants to be on indefinite maintenance medication - even people with known chronic medical conditions like hypertension and asthma much less opioid addiction.  The first consideration is that the person with an opioid addiction needs to view it as a chronic medical problem and most addicts do not.  That is especially true for addicts in their 20s who may have started using as early as their teenage years.  Their general attitude is that they will quit some day, but not before they have acquired enough time getting high.  That is nothing particularly unique in terms of the rationalizations that accompany addictions, but at this point in time mapped onto this demographic it may be a unique problem.  It certainly is not conducive to realizing the need to take a maintenance medication every day.  It is common in clinical practice to see a number of patients who stay on buprenorphine for a few months at a time and "go back to using heroin for a while."  The attitude about prescribing buprenorphine seems to be just to keep prescribing it and at some point a stable maintenance situation will result.  I don't think there is any evidence that will happen.  Since opioid addiction is generally a chronic condition going on and off maintenance would seem to be more likely than indefinite maintenance.  There is confusion among some prescribing physicians whether or not repeated relapses is a relative contraindication to future opioid buprenorphine use or it it means referral to a methadone maintenance clinic.  The real life problem is the patient who cannot tolerate withdrawal symptoms, may have a history of buprenorphine diversion, and has no easy access to a methadone program.    

2. Buprenorphine has definite street value:  Every opioid user knows this to be true.  Buprenorphine can generally be sold and the proceeds will result in being able to purchase 3 - 4 times the equivalent amount of heroin.  The other option is just to resume heroin and use the buprenorphine to cover heroin withdrawal when the drug is in short supply or there are not any reliable street sources.  As previously indicated this sort of diversion is a contraindication if the patient is using it as a consistent way to cover withdrawal from other opioids or to acquire other opioids. 

3. There are a small but significant number of users who can abuse the drug:

The original buprenorphine/naloxone combination preparation was designed to prevent intravenous use of the crushed buprenorphine tablets.  Since then, there has been some evidence that the naloxone component also reduces the euphorigenic component from buprenorphine and makes increased self administration less likely (1).  Patients maintained on low dose buprenorphine alone report positive subjective ratings with both additional intravenous and intranasal buprenorphine indicating potential abuse liability (2).  The combination buprenorphine/naloxone occurred after a number of overdoses in Europe and it confers decreased intravenous abuse liability, but it does not eliminate it (3).  In an earlier high dose study of intravenous and sublingual buprenorphine doses up to 16 mg in experienced opioid users produced consistently positive but variable mood effects.   In morphine maintained heroin users intravenous buprenorphine was the only opioid not administered at levels greater than placebo compared with intravenous fentanyl, oxycodone, or heroin (4).  That is an expected effect due to the partial antagonist effect of buprenorphine.  The authors comment that in research setting buprenorphine inconsistently precipitates withdrawal in opioid dependent subject in research settings.  For example moderate to severe withdrawal occurs in subjects taking 60 mg/day of methadone but no to mild withdrawal (from 2 and 8 mg buprenorphine doses) in subjects taking 25-30 mg/day of methadone.  Other studies  looking at rapid dose induction in heroin dependent men resulted positive ratings and experiencing the buprenorphine as an opioid agonist rather than an antagonist.  This same variability is noted clinical, largely by patient history and there seem to be a small number of patients who can escalate the dose beyond the theoretical ceiling due to opioid antagonism.  There is limited information on escalating the oral dose of buprenorphine or buprenorphine/naloxone.  In one study (5), 19 subject were maintained on 4 mg/day of buprenorphine alone and then were given 2 mg increments at 2 hour intervals for a total of three doses of buprenorphine alone.  In this study the authors thought that abuse liability based on subjective ratings was low.   All of this variability can be observed at the clinical level and it is very important that the prescribing clinicians know the individual and their response patterns very well.  

4. The existential condition of 20 year olds:    

One of the unique aspects of the current opioid epidemic is the number of young people that it affects.  Unused medicine cabinet opioids have been identified by the CDC as an important gateway drug to heroin use.  Using prescription opioids increased the likelihood of heroin use 55 times.  This same cohort is caught in a culture that is swinging toward increased permissiveness of substance use with broadened legalization of cannabis and excessive stimulant prescriptions for attention deficit~hyperactivity disorder and a subculture of performance enhancement in colleges and universities.  One of the logical extensions of these cultural currents is to see drugs as a solution to a problem and opioids are viewed as being no different.  A unique aspect of alcohol and drug taking in American culture has been that the early twenties is a time to do it and get it out of your system.  A large number of young opioid addicts who continue to use and routinely go off and on buprenorphine maintenance will say that they felt like they were too young to stop using.  They wanted to keep on going for a while before they stopped.  Most 20 year olds have a sense of invulnerability and that also plays a role in the use of dangerous drugs and alcohol.              

5.  Inadequate dosing

One of the main lessons that an addiction psychiatrist learns early on is that opioid use and withdrawal is a great mimic of psychiatric conditions specifically insomnia, anxiety and depression.  Practically everyone in withdrawal experiences these syndromes at one point or another.  There is a natural tendency during a psychiatric interview to describe practically all of the recent history as being dominated by the withdrawal symptoms.  Conversely, when the correct dose of buprenorphine is prescribed all of the insomnia, depression, and anxiety clears and it clears completely.  There are no associated psychiatric problems and the patients does not need any additional pharmacological therapies.  This cannot be emphasized enough because opioid users will naturally end up on benzodiazepines and z-drugs for sleep and anxiety and both are contraindicated with opioids.  Even antidepressants are a potential problem due to case reports of buprenorphine based products and antidepressants causing serotonin syndrome.  That is an admittedly rare syndrome, but potentially very serious if it occurs.        

The second issue is dose adequacy in terms of cravings about opioids.  By definition cravings are an intense urge to use opioids.  At the height of opioid withdrawal they occur with the withdrawal symptoms.  As buprenorphine maintenance is established they may occur at times during the day when there are breakthrough withdrawal symptoms.  Eventually even when the acute withdrawal symptoms are treated cravings can persist.  The ideal response is that cravings to use are eliminated as well as any thoughts about using or acquiring opioids.  This is possible during treatment but results vary from person to person especially as the physician attempts to establish the proper maintenance dose of buprenorphine.  In my experience cravings and intense thoughts about using are poor prognostic factors due to heightened relapse potential.    

The subpopulation of people addicted to opioids from chronic pain treatment can generally benefit from seeing physicians with expertise in pain management with buprenorphine preparations.  It may require split dosing and other adjustments.

6.  The lack of appropriate prescribing 

This can occur in several ways.  There can be a lack of physicians who are licensed to prescribe buprenorphine.  There can also be physicians available to prescribe it who are not able to maintain patients on the drug.  Finally there are physicians who are overcharging for the services they provide and that leads to patient dissatisfaction and discontinuing the buprenorphine strictly on that basis.

All of these problems can be addressed.  They can be addressed by providing good medical care.  They can also be addressed by addressing the 30 year old problem of rationing services for addiction and mental health services.  Any person going in to be seen by a physician for opioid use problems needs to feel like they are understood.  They have to be able to communicate with that physician about their addiction.  They have to know that their physician understands addiction and is not just there to provide prescriptions.

Treating opioid addiction is more than prescribing a medication.  It requires a relationship  with a competent physician.  That competent physician needs to be technically competent to prescribe the drug and discuss all of the above issues with every patient with an opioid addiction and every one of those patients who will take buprenorphine.

That is the same as the general plan for just about any complex medical problem.      

George Dawson, MD, DFAPA

References:

1: Jones JD, Sullivan MA, Vosburg SK, Manubay JM, Mogali S, Metz V, Comer SD. Abuse potential of intranasal buprenorphine versus buprenorphine/naloxone in buprenorphine-maintained heroin users. Addict Biol. 2015 Jul;20(4):784-98. doi: 10.1111/adb.12163. PubMed PMID: 25060839.

2:  Jones JD, Madera G, Comer SD. The reinforcing and subjective effects ofintravenous and intranasal buprenorphine in heroin users. Pharmacol Biochem Behav. 2014 Jul;122:299-306. doi: 10.1016/j.pbb.2014.04.012. PubMed PMID: 24793093; PubMed Central PMCID: PMC4094364.

3: Comer SD, Sullivan MA, Vosburg SK, Manubay J, Amass L, Cooper ZD, Saccone P,Kleber HD. Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusers. Addiction. 2010 Apr;105(4):709-18. doi: 10.1111/j.1360-0443.2009.02843.x. Erratum in: Addiction. 2010 Jul;105(7):1332. PubMed PMID: 20403021.

4: Comer SD, Sullivan MA, Whittington RA, Vosburg SK, Kowalczyk WJ. Abuse liability of prescription opioids compared to heroin in morphine-maintained heroin abusers. Neuropsychopharmacology. 2008 Apr;33(5):1179-91. PubMed PMID: 17581533.

5: Singhal A, Tripathi BM, Pal HR, Jena R, Jain R. Subjective effects ofadditional doses of buprenorphine in patients on buprenorphine maintenance. Addict Behav. 2007 Feb;32(2):320-31. PubMed PMID: 16814937.

6: Umbricht A, Huestis MA, Cone EJ, Preston KL. Effects of high-dose intravenous buprenorphine in experienced opioid abusers. J Clin Psychopharmacol. 2004 Oct;24(5):479-87. PubMed PMID: 15349002.

Cannabis and Causation

Cannabis use is highly politicized in the US at this time largely due to legalization rhetoric that has spilled over into scientific research on the topic.  Despite the broad movement to legalize cannabis across the US, only a minority of the population are regular cannabis users.  More widespread use will undoubtedly lead to increased problems associated with wider exposure, especially wider exposure in populations with vulnerabilities to the toxic effects of cannabis.  The toxic effects of interest include addiction and psychosis.  It is common in clinical practice to encounter daily cannabis smokers who stopped using the substance after several years because they started to get panic attacks, paranoia, or both.  The people I see have all moved on to something else, but there are also a substantial number of chronic smokers who are addicted.  That number is about 9% of users, and that is comparable to the amount of people who have problems from drinking alcohol.  Inpatient psychiatrists commonly see people with florid psychotic episodes from smoking significant quantities of cannabis.  They also see repeat admissions from people who are either detoxified or treated for these psychotic episodes, are discharged and smoke more cannabis to the point of a repeat psychotic episode.  The longstanding controversy among people who are not doing the work and just speculating is whether any good observational studies can be done to show that cannabis does cause psychosis or if this is an artifact of observational methodology.  In other words,  could a reverse causality bias exist that makes people who are prone to schizophrenia or psychotic episodes more likely to smoke cannabis.  In my opinion, there have been excellent observational studies showing the association between cannabis use and psychosis, but as long as that is the technology these studies will always contain the old association is not causation qualifier.

A recent paper (1) in Molecular Psychiatry may have just illustrated the causation that psychiatrists have been experiencing firsthand for decades.  The authors use a novel genetic appraoch to look at the issue of causation.  The main assumption of this study is that using specific genotypes as the independent variable rather than observed individuals gets rid of the confounding demographic and environmental variables that could be casual.  They point out that any actual clinical trial looking at the issue of whether cannabis causes psychosis would be unethical, but that a model that looks at whether causation can be established by looking at single nucleotide polymorphisms (SNPs) from a Genome Wide Association Study (GWAS) looking at the any cannabis use phenotype.  They looked at the top 10 SNPs from that data that were used to calculate gene-exposure (SNP-cannabis) estimates.  SNP-risk of schizophrenia exposure estimates were calculated from available data from the Psychiatric Genomics Consortium.  Instrumental variable estimates were made by dividing the risk of schizophrenia/risk of any cannabis use.  The instrument variable analyses were pooled across SNPs and analyzed with fixed effect meta-analysis.  The authors provide a detailed discussion and rationale for their statistical calculation in the full text of the article and supplementary material.  At this point I am going to post their main graphics.  Click on any graphic to enlarge it.

The first graphic looks at prospective observational studies.  The authors were interested in determining whether their genetically based analysis was in the same direction of this meta-analysis. Ever use cannabis use was associated with a 43% increase in schizophrenia or psychosis.

Figure 1. Meta-analysis of prospective observational studies reporting an association between use of cannabis and risk of schizophrenia or related disorders. Meta-analysis uses a random-effects model. Studies are sorted by type of outcome (schizophrenia only vs schizophrenia and related outcomes). Odds ratios (ORs) and 95% confidence intervals (CIs) express the risk of schizophrenia or psychotic symptoms for ever use of cannabis (compared with never use). For additional information on each study, see Supplementary Table S1. Dunedin, Dunedin Multidisciplinary Health & Development Study; ECA, Epidemiologic Catchment Area; EDSP, Early Developmental Stages of Psychopathology Study; NEMESIS, Netherlands Mental Health Survey and Incidence Study; SC, Swedish Cohort.

Figure 2 looks at the Mendelian Randomization analysis of 34,241 cases of schizophrenia and 45,604 cases of ever use cannabis.  This shows a 37% risk of cannabis users versus non-users for schizophrenia/psychosis risk.  The authors did a sensitivity analysis of this same data by removing each SNP from the analysis to calculate a summary causal effect of 1.33 across all 10 SNPs or 1.88 when restricted to 2 functional SNPs.

Figure 4 is included here to illustrate the authors' sensitivity analysis showing a summary casual effect of about 1.37 (red line).

All things considered this may be a compelling story for causation.  I qualify that of course in a couple of domains.  First. there are a lot of statistical models and calculations operating here.  In my experience mapping complex statistical estimates onto the most complex object in the universe has not worked out very well.  My first hand experience was statistical modeling of quantitative EEG and claims that is was predictive of psychiatric diagnosis.  Those compelling calculations published in Science (4) did not pan out at all in the long run.  It will be interesting to see if the authors applications are more widely applied to other SNPs to determine disease causation from other risk factors.  The second potential problem is a slight variation on that theme and that is the overall imprecision of meta-analysis.  The known  approximate prediction/concordance rates of meta-analyses for clinical trials (2.3) suggests that it may not be good predictor of a reproducible result.  The authors themselves suggest that the potential limitations of their study start with the fact that none of the chosen SNPs met conventional genome wide significance thresholds.  The specific dose effect of cannabis could not be investigated in the study.  The age at exposure is may be a developmental variable of interest and that was unknown.  The Mendelian Randomization techniques may have not been powerful enough to detect pleiotropic (one gene affecting more than one trait) effects, but they discuss how an alternate analysis applies in this situation.

The other question I had was about epigenetic effects on this model.  The authors were certainly aware of smoking as a confounding variable.  The known epigenetic effects of nicotine on brain chromatin would seem to cloud SNPs as pure genetic risk factors.  But this is nonetheless one of the more interesting models and concepts I have seen in a while.

They conclude that their study is "the closest approximation to a randomized trial on the effect of ever use of cannabis and risk of schizophrenia" when such a clinical trial is unethical.   That is an interesting take on their method and causation.  Hopefully it will open up the way for other studies of causation using these techniques.  If that is the case, it is a good idea to study this paper and the supplementary material (26 pages) and have a good idea about its difference from observational/association studies.  The supplementary material is also very useful for the calculations used in the study, a Venn diagram of the overlap between the schizophrenia-GWAS group (N=79,845) and the ever-use cannabis GWAS group (N=37,957), and their review methods of the best observational studies of cannabis use and  schizophrenia/psychosis.  



George Dawson, MD, DFAPA



References:

1: Vaucher J, Keating BJ, Lasserre AM, Gan W, Lyall DM, Ward J, Smith DJ, Pell JP, Sattar N, Paré G, Holmes MV. Cannabis use and risk of schizophrenia: a Mendelian randomization study. Mol Psychiatry. 2017 Jan 24. doi: 10.1038/mp.2016.252. [Epub ahead of print] PubMed PMID: 28115737.

2: LeLorier J, Grégoire G, Benhaddad A, Lapierre J, Derderian F. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997 Aug 21;337(8):536-42. PubMed PMID: 9262498.

3: Ioannidis JPA, Cappelleri JC, Lau J. Issues in Comparisons Between Meta-analyses and Large Trials. JAMA. 1998;279(14):1089-1093. doi:10.1001/jama.279.14.1089

4:  John ER, Prichep LS, Fridman J, Easton P. Neurometrics: computer-assisted differential diagnosis of brain dysfunctions. Science. 1988 Jan 8;239(4836):162-9. PubMed PMID: 3336779.

"The standard for psychiatric diagnosis and categorization in the United States and Canada is now DSM-III and soon will be DSMIIIR. The categories defined therein have often been criticized as nothing more than a compilation of symptoms. The results obtained with neurometrics have shown that at least the categories studied are much more than arbitrary groupings of symptoms. ............. Validity-the great deficiency of psychiatric nosology - is beginning to emerge and, thus far, to reveal an impressive concordance with biology." p. 169

5: Smith GD, Ebrahim S. Mendelian Randomization: Genetic Variants as Instruments for Strengthening Causal Inference in Observational Studies. In: National Research Council (US) Committee on Advances in Collecting and Utilizing Biological Indicators and Genetic Information in Social Science Surveys; Weinstein M, Vaupel JW, Wachter KW, editors. Biosocial Surveys. Washington (DC): National Academies Press (US); 2008. 16. Available from: https://www.ncbi.nlm.nih.gov/books/NBK62433/

Selected References on Mendelian Randomization

Attributions:  All graphics except my home-made one at the top are from reference 1 per a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.




Supplementary 1:

With today's publicly available genetic technology it is possible for a person to search their own DNA for the SNPs found in this study.  When I do that using a database where my DNA analysis resides I found the following SNPs from this study from chromosomes 15, 4, and 12 respectively.  I have linked them  to the dbSNP database at NLM:

rs4984460

rs7675351

rs2099149

It is interesting to speculate on what it means to have 3/10 genetic markers for schizophrenia/psychosis susceptibility if any cannabis exposure.


Supplementary 2:  Click on my homemade graphic to see how beautiful it is.  Blogger does not do it justice.