Thursday, April 8, 2021

A Psychiatrist Takes An Overly Detailed Look At Endoscopy

 


I started typing this shortly after completing an esophagoduodenoscopy (EGD) and a screening colonoscopy. Starting at age 25 I have probably had a total of 4 EGD’s and 4 screening colonoscopies. About three weeks ago I started to experience dysphagia. During those episodes food fails to pass through the esophagus and causes pain.  In the extreme food does not pass at all and that leads to all the symptoms associated with esophageal obstruction. It is an extremely uncomfortable sensation that can lead to esophageal perforation and the need for emergency surgery. The last time that happened to me was about 25 years ago. Over the years I have had a couple of close calls but two recent episodes of near obstruction led me to going to see my primary care physician who set up the test.

My immediate association and worry was that I may have esophageal cancer. Three second-degree relatives and one first-degree relative had pancreatic cancer. It is rumored that my maternal great great grandfather died of stomach cancer. 2 second-degree relatives died of stomach cancer. All of the second-degree relatives had risk factors primarily cigarette smoking, but you can certainly develop cancer in the absence of risk factors and aging alone is a risk factor for cancer.  Since my first esophageal obstruction, I have not eaten beef (the source of the acute obstruction) and have also tried to avoid foods that have been implicated in G.I. cancers such as smoked and preserved foods as well as excessively hot beverages. I have never used tobacco products and do not drink alcohol. I have also tried increase foods that may be protective such as vegetables and tree nuts. The nuts were easy but vegetables require much more of an effort. I am one of those people that has an aversion to the taste of most vegetables, but for the past ten years I have been eating 2-3 vegetables per day.

Over the years of the screening colonoscopies, I always asked the gastroenterologist whether or not I should also have an EGD to see if there any after effects from the initial obstruction and dilatation. They all said that there was no reason to repeat it unless I had additional symptoms but that was never very satisfying response. Cancers of the esophagus and gastroesophageal junction are difficult to diagnose. Symptoms often do not appear until the cancer is advanced and not treatable.  One of the gastroenterologists seemed more concerned about the dilatation procedure. He advised me that the anatomy of the esophagus is multiple layers of transverse fibers and that dilatation procedures can disrupt that anatomy. He gave me a tip sheet on how to avoid dysphagia and esophageal obstruction by changing eating habits in some cases making sure that a mouthful of food is chewed at least 40 times.

The screening colonoscopies have generally been uneventful yielding one or two small noncancerous polyps per screening. That result led to the recommendation for screening every five years instead of every 10 years. Since the last screening I decided to greatly increase my fiber intake to 40 to 50 g per day and take additional wheat dextrin – 18-24 g/day.

As a psychiatrist who is as neurotic as the next person, I always reflect on how the neurosis affects my medical encounters. As a kid I had a high degree of death anxiety. I was always concerned that I had a fatal illness and that I would die within a year or two. In retrospect it is easy to think about how the family environment was the origin of those thoughts. I was exposed to relatives who are also very neurotic and preoccupied with health concerns. I had an aunt who died of pancreatic cancer in those days the entire family was involved in treatment largely because there was no coordinated blood banking and she needed transfusions from her siblings. At some point in my mid-to-late teens I realized my worries about dying were excessive because of the obvious fact that I was still alive. But old habits die hard. I am still very safety conscious about every possible hazard to the point that my wife says I am “paranoid.”  On an ongoing basis, I pay attention to every reference in the medical literature that might apply to my somatic concerns. The most recent examples are a commentary and an article in the New England Journal of Medicine (1,2) on the immunotherapy of esophageal cancer that was described as a major advance.  Over the years I have also tracked the complications in this area that were not related to cancer but more to scarring or fistula formation. None of this keeps me awake at night, it is what I do as normal activity.

The prep for screening colonoscopy is an ordeal. It seems to have become more of an ordeal over the years. By that I mean the prep went from an oral stimulant laxative and two sodium phosphate enemas to very large amounts of oral osmotic laxatives like polyethylene glycol 3350 ± additional salts (sodium sulfate, sodium chloride, sodium bicarbonate and potassium chloride).  Any Internet search for colonoscopy preps yields a wide range of recommendations and volumes. The clinic I was going to had the prep for people with chronic constipation that involved consuming the polyethylene glycol over two days (and additional osmotic and stimulant laxatives) and the one that I used started on 5 PM the night prior to a morning procedure.  I prepared 4 liters of a solution of Gatorade + polyethylene glycol 3350 (476 g). The instructions were to drink the first 3 liters at a rate of 237 ml (8 oz) every 10 minutes until gone and then wake up at 4:00 AM and drink the remaining liter – 4 hours before the procedure.

I describe this as an ordeal because just anticipating consuming that much salty fluid can create some anxiety, disgust, and anticipatory nausea. I typically drink fluid volumes every day right around 4 L, but the instructions here were to maintain additional fluid intake on top of the laxative.  I probably consumed an additional 5 L on top of the laxative (per the instructions).  The biology and chemistry of this procedure is interesting. For example, creating solutions rarely produces the original volume. The final solution can be smaller or greater than starting volume, but the difference is generally not factored into the final concentration. In this case, I found that final solution of polyethylene glycol 3350 and Gatorade was about 300 ml greater than 4 L so I discarded it to maintain the recommended volume.  There is also the question of the impact that osmotic laxatives have on fluid and electrolyte balance. Interestingly, the two main products used consist of one product with a combination of polyethylene glycol 3350 and additional electrolytes and one product that is pure polyethylene glycol 3350 mixed with sports drinks containing the additional electrolytes.  The former product contains warnings about use in patients who may have sensitivity to electrolyte imbalances like patients with seizures or arrhythmias.  I received some information about products that are more recent and easier to use including MOVIPREP® and SUPREP®. Both require the ingestion of much lower fluid volumes.

The main thing to remember about preparation for the colonoscopy is that the goal is to induce diarrhea and continue that until it is clear of fecal material. In my case that happened at about 1 AM following the initial 3 L ingestion. I seriously contemplated not drinking the additional leader at 4 AM but did not want to risk having to repeat the whole procedure again if the preparation was inadequate. As a result, I had diarrhea until about 8 PM the next night - about 10 hours after the procedures were completed.

The procedure itself was well coordinated and pandemic precautions remained in place. I had a negative COVID-19 screen two days prior to the procedure.  I was accompanied to the gastroenterology clinic and had to wear a mask throughout the entire procedure with the exception of the EGD. They placed the nasal prong oxygen cannula under my mask. All the nursing staff was masked. The gastroenterologist was wearing a large helmet like face shield in addition to a mask.  That reminded me of my positive affiliation with gastroenterologists. For years, I ate lunch with a group of 3-4 gastroenterologists and the occasional infectious disease specialist.  We typically discussed movies but at times the conversation would wander to hastas (the plant), politics, or medicine. They all had a good sense of humor. Whenever another gastroenterologist was brought up their humorous seal of approval was "He/she really knows their way around the colon!" They were all very likeable and had a great sense of humor.     

The endoscopy suite contained a wall of high-tech equipment. I was advised that the gastroenterologist would talk with me about informed consent. I reflected on that for a minute and realized that the last 10 surgeons and proceduralists that I have had contact with spend less time in aggregate talking about risks and benefits then I typically spend talking about antidepressant risks and benefits with the average patient. I don’t consider that to be a problem because as I have written before, desperate situations in medicine require desperate probability-based decisions and procedures. There are no guarantees.  In addition, I have treated patients who have had most of the known complications of both EGD and screening colonoscopy including perforations and the need for emergency surgery. I have also treated patients who have had spontaneous perforations of the esophagus for unclear reasons. My conversation with the gastroenterologist went something like this:

GE: “The risks of this procedure involve perforation and the need for emergency surgery, but that is rare. There is also some discomfort if we have to perform a dilatation. We will let you know what we find today and what the follow-up needs to be. Do you have any questions?”

Me: “My primary care doctor wanted me to let you know about my family history of G.I. cancer especially pancreatic cancer. He wanted to know if there was any additional screening that needed to be done?”

GE: “We generally do not do screening for pancreatic cancer. With your family history you might want to try to find a geneticist to see if you need any genetic screening. Your primary care doctor might consider a one-time CT scan of the pancreas.”

Me: “Regarding the dilatation, I saw gastroenterologist about 15 years ago who talked to me in detail about the anatomy of the esophagus and how repeat dilatations can disrupt the layered fiber structure of the esophagus. Is that a problem?”

GE: “Well I don’t know about that. If you have to eat-you have to eat. We have some patients who need to get the dilatation procedure every week.”

As we completed our conversation, the nurse advised me that she was going to induce “conscious anesthesia”. I clarified with her that was fentanyl and midazolam that I have taken many times in the past for these procedures. With my interest in consciousness, the idea of conscious anesthesia is something that I pay close attention to.  I missed the key opportunity with this session to ask the nursing staff what I behaved like under conscious anesthesia.  As soon as the anesthesia took effect the only recollection I have over the next 90 minutes was a nurse asking me about bradycardia and my reply was “it’s the beta-blocker”.  I woke up groggy and mildly ataxic. I put my clothes on and walked out to the elevator and left the clinic. The post procedure instructions said not to do anything that required a high level of thought or coordination for the next 12 hours. That is about how long it took the “brain fog” of the anesthesia to wear off. I always compare the current anesthesia to the first round I got at age 25. That combination of medication produced a paradoxical euphorigenic effect and about two hours of continuous laughter. It would be unwise of me to disclose that combination medications.

I can’t recall whether the gastroenterologist discussed the results with me or not but I was provided with two different sets of discharge instructions that read as follows:

Instructions after upper endoscopy (EGD) with biopsy:

Findings:

-Mild Schatzki ring - dilated

-Normal middle and upper third of esophagus. Biopsied to rule out eosinophilic esophagitis

-Normal stomach

-Normal examined duodenum

Instructions after colonoscopy:

-The entire examined: is normal

-The examined portion of the ileum is normal

-Repeat screening is recommended in 10 years

I could not have asked for a better result. No evidence of gastroesophageal reflux or Barrett’s esophagus. No significant esophageal strictures or ulcers. An upper and lower G.I. examination that is fairly unremarkable. That is very reassuring, but I doubt that it will have much impact on my focus on doing everything possible to prevent G.I. cancer and more esophageal problems. The colonoscopy result might indicate that my conscious move to a more high-fiber diet had some impact, but at this point I am questioning the issue of soluble versus insoluble fiber from the standpoint of metabolic and microbiome effects. Like most medical research there are no clear answers and so I am left with myself as an N=1 study and I have the help of an excellent internist.

As I recover, I am thinking about the afferent sensory innervation of the gut and the unusual sensations that it might be producing. I thought I might post a detailed synopsis here but will hold off for now. I think that many neurotic people adapt to some degree by what is currently described as mindfulness.  You get to a point in life where you realize you are probably excessively cautious and that you have to focus on and do many other things in a day. And you are able to do those things.  You adapt to the somatic concerns and there is no significant associated affect. In many ways it might just be another aspect of being goal directed or conscientious.

So I will take a break on that line of thought while I wait for a more detailed genomic analysis of possible risk factors for pancreatic cancer.

 

George Dawson, MD, DFAPA

 

References:

1:  Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, Mendez G, Feliciano J, Motoyama S, Lièvre A, Uronis H, Elimova E, Grootscholten C, Geboes K, Zafar S, Snow S, Ko AH, Feeney K, Schenker M, Kocon P, Zhang J, Zhu L, Lei M, Singh P, Kondo K, Cleary JM, Moehler M; CheckMate 577 Investigators. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N Engl J Med. 2021 Apr 1;384(13):1191-1203. doi: 10.1056/NEJMoa2032125. PMID: 33789008.

2:  Ilson DH. Adjuvant Nivolumab in Esophageal Cancer - A New Standard of Care. N Engl J Med. 2021 Apr 1;384(13):1269-1271. doi: 10.1056/NEJMe2101983. PMID: 33789017.


Graphic Credit:

That is the actual stuff that I drank in addition to another 4 liters of water, tea, and white grape juice.


Additional Credit:

I thank the gastroenterologist and staff involved in my care.  The experience was first rate.

Monday, April 5, 2021

Airborne Transmission - Once Again!

 


I thought I would take time for a rare celebration on this blog.  Most of my writing is about probabilities and uncertain outcomes. In many cases I am responding to the same tired arguments from people who don’t understand science, biology, medicine or psychiatry. Those positions generally result in some political attacks based on that lack of understanding or some specific political agenda. The position I am referring today is the airborne transmission of viruses. Although it seems like a straightforward scientific issue it has led to as much controversy as any psychiatric topic. Despite a significant amount of literature out there on airborne spread, there has been nothing but resistance to the concept.

Nowhere was the resistance more evident than the advent of the current SARS-CoV-2 pandemic. Initially the message was that the virus was spread by fomites or intermediate size droplets that fall within a few feet following a cough or a sneeze.  Accordingly, social distancing at more than a few feet, decontaminating hands and surfaces were recommended to counter this mechanism of transmission. Many experts claim that most respiratory viruses with very few exceptions are transmitted this way. Those same experts claim that airborne transmission of viruses in smaller droplets travelling much longer distances was controversial at best. All of those conflicting ideas led to recommendations for no masks in February of 2020 followed by recommendations for masks in the next two months.  The mask recommendations occurred in the context of widespread shortages of personal protective equipment (PPE) for health care workers.   

I posted my qualifications on the matter (2 Avian Influenza Task Forces earlier in this century, being subjected to multiple respiratory virus epidemics at work despite rigorous hand washing, and studying the available engineering and viral data, and lengthy discussions with HVAC experts) and began to write about it on this blog.  My perspective is clearly that respiratory viruses are airborne and therefore will not be stopped by handwashing alone, that there are clearly engineering approaches to stop respiratory viruses that will work much better than just handwashing, and that there should be a major research and development effort on environmental designs to minimize and even stop respiratory viruses in homes and public building. In fact, as I type this I have selected a UVC device to be installed in my home HVAC system and it will probably be installed in the next month or two.  Many of those posts on this blog can be found here or by using the search term “airborne” in the search box.

The victory lap today occurs with a press release from the CDC today that I consider a bombshell in terms of the airborne transmission concept.  The press release is a quick read but it highlights why surface contamination is unlikely to be a significant factor:

“Quantitative microbial risk assessment (QMRA) studies have been conducted to understand and characterize the relative risk of SARS-CoV-2 fomite transmission and evaluate the need for and effectiveness of prevention measures to reduce risk. Findings of these studies suggest that the risk of SARS-CoV-2 infection via the fomite transmission route is low, and generally less than 1 in 10,000, which means that each contact with a contaminated surface has less than a 1 in 10,000 chance of causing an infection.”

And further:

“The principal mode by which people are infected with SARS-CoV-2 is through exposure to respiratory droplets carrying infectious virus.”

This information has been slowly presented over the course of the past several months.  For example, Dr. Fauci mentioned on several news outlets that cleaning all of the mail and groceries was not necessary because it was not considered a main route of transmission. A logical inference from that statement is why there is a concern about any surfaces at all unless there is a person with a known infection close by.  And by extension, if surface contamination is not that much of a problem why the concern about accidentally touching your face?  As Dr. Fauci typically states we now have the science behind the transmission and the recommendations can be adapted to the new findings.

The CDC press release does not come right out and say airborne transmission.  They continue to say respiratory droplets are the predominate mode of spread and the old document on respiratory droplets says nothing about differentiating between moderate sized droplets that typically fall to the ground within a 6-foot radius of where they are generated or airborne droplets that are lighter, spread past 6 feet from the generation site and remain suspended for longer periods of time.

Some of the comments on the press release have been much more definitive. The only reference to this post has a good timeline on the airborne controversy and this quote from atmospheric chemist Jose-Luis Jimenez: “If we took half the effort that’s being given to disinfection, and we put it on ventilation, that will be huge.”  In the same reference Germany has invested a half billion dollars in improving ventilation and indoor air quality.

Overall, it appears that the CDC is slowly coming around to the idea that respiratory viruses are transmitted via airborne routes, but some resistance is still evident in the press release they link to an earlier non-descript respiratory droplet transmission document.  There are many potential advantages to fully backing the airborne transmission concept (in addition to the available science).  Research and development is at the top of the list. In an early blogpost, I pointed out that UV decontamination was routine in buildings when I was a kid in a small town in northern Wisconsin.  The currently available UVC is much safer and very effective for killing airborne biological particles. From a clinical trials perspective, deployment of these systems on a large scale and following the number of respiratory infections in facilities with and without the technology seems like a fairly basic experiment.

It is also interesting to consider the resistance. There is undoubtedly politics in science and that can be a factor. There may be a medical intervention bias. In other words, we need some magical intervention like a vaccine, antiviral medication, or general polypharmaceutical modality that can either cure or prevent the excessive morbidity and mortality from respiratory viruses.  The track record there is some wins and many losses.  Every year various populations around the world are subjected to significant effects from flu-like illness that are nowhere as lethal as SARS-CoV-2.  Remarkably – everyone accepts this state of affairs until a more lethal virus comes around and affects a larger group of people.  There is politics as usual leading to irrational attitudes about viruses and physical interventions.  The appropriate environmental interventions may make mask refusers irrelevant at some point in the future.

The bottom line of today’s release is good news for all of the airborne virus crowd and I definitely consider myself in that crowd. I would still like to see the CDC modify their position on transmission in respiratory droplets and I think that is coming.  But most of all, I would like to see us get serious about using environmental measures to limit the exposure and spread of all respiratory viruses including the current one that has killed far more Americans than any influenza epidemic since 1918.

 

George Dawson, MD, DFAPA

 

References:

1:  Lewis D. Why indoor spaces are still prime COVID hotspots. Nature. 2021 Apr;592(7852):22-25. doi: 10.1038/d41586-021-00810-9. PMID: 33785914.

 

Friday, April 2, 2021

Medical Library Access For Everyone

 



Medical library access is a critical issue for physicians because only a few physicians have access to all of the literature that they need.  For as long as I have practiced medicine and psychiatry life long learning has been a stated goal of the profession.  That forms not only professional behavior but it is also incorporated into the medical practice laws of each state.  In order to be relicensed each year, medical practitioners also have to fulfill the continuing medical education (CME) requirements in each state.  That typically requires a combination of self-study and CME courses sponsored by various medical education organizations typically departments of psychiatry or professional organizations.

When I first came to the Twin Cities in 1989, I worked for a large multi-disciplinary clinic in St. Paul, MN.  We were the second largest hospital-based practice in the Twin Cities and a Level 1 Trauma Center and Burn Unit.  We had the most psychiatry beds in the East Metro area. I did a rotating internship at this hospital and liked the practice and the attendings well enough to return there and stay for the next 22 years. We also were a teaching hospital and trained medical, surgical, and psychiatric trainees from the University of Minnesota.  As a result of that position, I was expected to train resident physicians and medical students. At some point we were given electronic access to the Biomedical Library at the University of Minnesota and could access a wide array of biomedical journals online at that facility.  Up to that point, I had to go to the library and make copies of articles that I wanted to study and keep for future reference.  I was also able to access interlibrary loan articles through my hospital library that I would get via mail or fax in 2-3 days.  All of this reference material was relevant to my clinical work, teaching, and research at the hospital.

In general, University training programs depend on their affiliated or adjunct staff and facilities for teaching residents.  These affiliations result in broader clinical exposure to both patients and practitioners as well as different work environments. Good examples of the necessity of these affiliations is the amount of individual and psychotherapy supervision residents require.  Much of that training is provided by practitioners in the community who are doing the work every day.  In some cases a University training program may lack a critical component like an addiction service or a community psychiatry service and these affiliations provide those resources.  In return for the services provided to the training program, the affiliated practitioners get University titles and electronic access to the library.  In todays work environment stressing excessive productivity, there is generally no break in the work of the day.  For example, the adjunct teachers are still required to put in a full day’s work in addition to their teaching and supervisory role.  All of the work for the training program is uncompensated with the exception of the access to the library perk.

In my case, the other physicians in my group had negotiated with the University so that we all had regular Assistant Professor titles. We understood our role was critical to the components of the educational program and that these titles had nothing to do with regular track university titles.  As time went by our group was acquired by a managed care company and the teaching role diminished.  There was some turmoil at the University and a non-psychiatrist was appointed temporary department head. He ended up sending out letters firing numerous adjunct faculty – myself included.  The letter stated that we were "costing the department too much" as the rationale for the “firing”.  Since I was curious about how much I could be costing, when I had not ever been compensated – I called the University and asked them that question.  The answer was a $1,000/year library access fee. When I got that figure I called the University library and asked them if I could retain library access by paying them $1,000/year and they declined giving no good reason other than "it is policy".

To establish how much an individual physician may expend on journal resources – I include my subscriptions below.  The total cost is $2,640/year for a very inefficient way to access articles of interest.  Some are more inefficient than others. For example, my APA membership includes 1 of a possible 5 journals.  Just a few years ago it included at least an additional journal, but now the other journals are all for addition fees.  By comparison – the AMA membership includes access to 11 journals for only slightly more money.  Getting all of these journals to read only a fraction of the articles is also very inefficient.  The educational and self-improvement goals of individual physicians depend a lot on medical specialty and current practice environment as well as how much interest they have in the biology relevant to that specialty. Early in my career I was in a research position where we all got a hard copy of Current Contents, checked off the articles of interest and got the reprints within a day or two.

Another level of inefficiency is introduced at the level of publishers.  If you think about it medical publishing is a relatively low-cost endeavor.  Publishers are not paying for content. All of the submissions to their journals are generated for free by scientists and physicians wanting them published.  The peer reviewers who expend significant amounts of time reviewing these articles are not reimbursed.  The costs are basically for a small editorial staff, maintaining an information technology (IT) infrastructure and Internet presence, and printing paper journals.  Ideally, paper journals could be eliminated and readers could access the electronic copies and read and print what they want. We are not in the ideal world at this point. Many if not most publishers do not provide access to electronic only journal copies.

Licensing agreements between publishers and services that aggregate publications is also a controversial area. Publishing has become a very high margin business, particularly if that publisher has a number of widely read journals. In some of these cases, the annual licensing fees are easily in the millions of dollars per year for large university facilities.  That has led some library facilities to refuse or threaten to refuse agreements with major publishers so that their journals cannot be accessed.

Given this landscape, is there a possible solution that resolves the physicians need for eclectic reading, the state’s interest in physicians with life long education, the library’s interest in providing a useful service to its patrons, and the publisher’s interest in being paid.  I think there is and that is to make the University medical library electronic services available to anyone willing to pay an agreed upon fee. I was willing to pay $1,000/year 12 years ago and I am clearly paying much more for limited individual access to the journals listed in the table below.  Basically, the state and the library’s ability to negotiate group access will makes it more widely available to more physicians or for that matter anyone in the state who wants the equivalent access to electronic journals.


There are alternatives to paid journals for access.  Some grant recipients need to provide a free copy of their paper that is posted as open access on the National Library of Medicine web site (in their PubMed search engine). There are open access journals, many of which charge the authors a publication fee.  I was an editor for one of these journals and came away from that experience with the perspective that it adds significant conflict of interest for the publisher and may encourage the publication of low-quality research for profit. There are many high-quality journals that have added a smattering of open access papers for one reason or another. During the current pandemic many high-quality journals have offered articles relevant to the pandemic as open access. There are also research sites where authors can be contacted to request papers and pre-print servers where you can read the unedited versions. All of these indirect measures assure some level of access to articles that might be behind a paywall, but it is no guarantee.  For example, my requests to researchers are successful about 50% of the time and in many cases, they tell me they are prohibited from sharing their research due to copyright constraints.  The only way that you can review the literature for writing or research purposes is with complete access to what is out there.

At some point I am hopeful that physicians and/or their professional organizations advocate for these services.  



George Dawson, MD, DFAPA


Graphic Credit - Shutterstock per their standard agreement.  Click on any graphic to expand.

Monday, March 29, 2021

The New Black Box Warnings On Benzodiazepines

 


 

The FDA started communicating that there was going to be a new black box warning in the package inserts of benzodiazepines starting last fall.  Black box warnings are defined as applying to potential problems with medications that can lead to serious or life-threatening complications.  These warnings have been around since 1979 and they are included in the package insert or detailed prescribing information included with every medication. They are also available on line by searching “[drug name] FDA package insert”.  The changes in the package insert for benzodiazepines (in this case diazepam and clonazepam) are shown in the graphic at the top of this page. In this case the old package insert is on the left and the new one that I received in the mail on March 18, 2021 is on the right.

Benzodiazepines are controversial medications and have been over most of their 60-year existence.  Current benzodiazepines and z-drugs that are primarily used for sleep and their release dates are listed in the graphic below:


At the time of their original release the primary indication for the medication was anxiety (although current diagnostic nomenclature was not in use at the time) and that continued to be the main indication until the advent of higher potency benzodiazepines like clonazepam, lorazepam, and alprazolam. Higher potency benzodiazepines were used for panic disorder and panic attacks. As clinical use expanded it became clear that these medications also reinforced their own use and that people could develop a substance use disorder with all medications in this class.  They were also noted to be cross tolerant with alcohol and other sedative hypnotics so that the use of benzodiazepines expanded to detoxification applications.

When it became apparent that some people were not able to stop using benzodiazepines, escalated the dose, or began acquitting them from non-medical sources strategies were developed to minimize their use as much as possible.  The following timeline looks at how the treatment guidelines for anxiety and panic changed over the years with the goal of minimizing benzodiazepine exposure.


The graphic illustrates that benzodiazepines have gone from a primary role (and in some case very high dose role) in the treatment of panic disorder to a secondary and time limited role.
  Clinical prescribing typically expands on the original FDA approved indications. In the case of benzodiazepines, it is common to see them prescribed for various types of situational anxiety like public speaking or air travel.  It is also very common to see them prescribed for both transient emotional disorders (from a time limited stressor) and ongoing emotional disorders from chronic stressors.  In society today there is always a performance enhancement aspect. A common example is the person who consumes a lot of caffeine in the daytime to stay energetic and alert at work and in the gym who needs to take a benzodiazepine to treat the expected insomnia.  The main problem in prescribing the medication to a benzodiazepine naïve patient is that it is not possible to predict with certainty how they will respond.  With any medication that reinforces its own intake a substantial number of people will stop taking to due to side effects – typically excessive sedation or cognitive problems. Patients at risk with notice a euphorigenic effects that is very reinforcing.  A large number of people will take it as prescribed. In my experience, fewer people will take benzodiazepines if they receive informed consent that they are a potentially addictive medication.

The move to benzodiazepines by psychiatrists and primary care physicians came after decades of using medications with a much lower therapeutic index – primarily barbiturates but also meprobamate (Miltown) and ethchlorvynol (Placidyl). For the initial decades of use, it was taught that it was nearly impossible to ingest a lethal overdose of benzodiazepines unless they were combined with alcohol.  

Withdrawal effects with benzodiazepines can also be significant.  They depend on the duration of use, dose of medication, and pharmacological properties of the medication. In the most severe case, withdrawal delirium or withdrawal seizures can occur and both are potentially life-threatening situations compounded by the lack of effective treatment facilities.

From an epidemiological standpoint, one question is what is the current level of benzodiazepine use and is it changing over time?  Are there any direct measures of prescriptions rather than proxies like overdose deaths or benzodiazepine-based office visits?  There is a business that does collect prescriptions in retail pharmacies and has done that for the past 60 years. That data is proprietary and tends to be available only in glimpses where it is referenced by the purchaser.  In all of my searches on this subject, I located an FDA presentation on prescription patterns of controlled substances (3).  In the benzodiazepine section of that presentation there are a fairly consistent 20 million prescriptions per year between 2009 and 2015.  The commonest prescribed benzodiazepines were alprazolam (50-60%), lorazepam (25%), and diazepam (10-15%).  Further analysis shows that about 75-80% of all these prescriptions were from non-psychiatric physicians and 15% by psychiatrists and 15% by nurse practitioners and physician assistants.  67% of all benzodiazepine prescriptions were for women.  By age demographics 80% of all prescriptions were to people who were 40-59 (41.4%) and 60+ (38.2%).  This information is interesting because there is a life stage correlation with increased benzodiazepine use and use by the oldest demographic that has been flagged in the geriatric literature as being higher risk because of falls and cognitive impairment.

A global perspective on benzodiazepine use is available from INCB (International Narcotics Control Board) who estimates global supply and demand for controlled substances across the world.  According to that report, global production in 2018 was 199 tons and increase of 24% from 2017 (p. 36). The INCB also estimates the total benzodiazepine use by country for clinical and scientific use.

Additional resources in this area include this post that looks at a selective study of several states that agreed to disclose prescription levels for the purpose of this study.  There is significant variation in both opioids and benzodiazepine use from state to state.  My initial thoughts about pharmacosurveillance and pharmacovigilance still apply.  A robust system of following medication side effects and utilization can no longer depend on inadequate snapshots and voluntary reporting.

With regard to the specific change in black box warning the three main bullet points are all very reasonable and I would be shocked if any physician is not aware of these problems.  The first bullet point, highlights that the epidemiology of overdoses clearly shows a correlation of deaths with concurrent use of benzodiazepines and a shift to more potent fentanyl based illicit opioids.  A trend that has not received any comment yet is the use of fentanyl to produce counterfeit benzodiazepine tablets.  The second bullet point is necessary for the informed consent discussion with any patient.  Unless the addictive potential is openly discussed patient concerns about their past experience with addictive drugs and their family history is never mentioned.  The severity of addiction and withdrawal effects including the potential for protracted withdrawal also need to be openly discussed. The third bullet point is basically a necessary extension of the warning about tolerance and withdrawal. In clinical practice it is common to talk with patients who decided that they wanted to discontinue benzodiazepine on their own and experienced seizures and/or severe withdrawal after abrupt discontinuation.

The associated concern about the black box warning is whether it will change physician behavior or not. The experience with the black box warning on antidepressants and suicidality in patients less than 25 years of age had a significant effect on decreased prescriptions in that age group. The black box warning on benzodiazepines is really nothing new and it will be interesting to see if there are any effects. The lack of comprehensive prescription information restricts any study of that phenomena to local effects. A useful outcome may be a more comprehensive discussion of the risks and benefits before benzodiazepines are prescribed.        

 

George Dawson, MD, DFAPA

 

References:

1:  Silberman E, Balon R, Starcevic V, Shader R, Cosci F, Fava GA, Nardi AE, Salzman C, Sonino N. Benzodiazepines: it's time to return to the evidence. Br J Psychiatry. 2021 Mar;218(3):125-127. doi: 10.1192/bjp.2020.164. PMID: 33040746.

2:  Balon R, Starcevic V, Silberman E, Cosci F, Dubovsky S, Fava GA, Nardi AE, Rickels K, Salzman C, Shader RI, Sonino N. The rise and fall and rise of benzodiazepines: a return of the stigmatized and repressed. Braz J Psychiatry. 2020;42(3):243-244. doi: 10.1590/1516-4446-2019-0773. Epub 2020 Mar 9. PMID: 32159714; PMCID: PMC7236156.

3:  Jones CM.  The latest prescription trends for controlled prescription drugs. FDA presentation. September 1, 2015

4:  International Narcotics Control Board.  Psychotropics 2019 Statistics for 2018 Assessments of Annual Medical and Scientific Requirements.  Link.


Graphics:

All graphics made by me.  As far as I know package inserts are public information. Click on any graphic to enlarge.


Thursday, March 25, 2021

Brain Fog

 


“Brain fog” or “brain-fog” is a popular term that has penetrated the medical literature fairly recently.  In talking with hundreds of patients who have used the term in my evaluations most of them mean an actual fogginess to their mentation.  That typically occurs in two ways. The first is an underwater feeling and noticing that both the speed and content of thought is not quite up to par.  The second is more of a problem in concentration and focus where it takes a noticeable effort to sustain both.  I have personally had these experiences during illness and probably on a developmental basis.  In the case of the illness, I was running my usual team meeting at about 8AM, and suddenly realized my thoughts were clouded. I developed chills and knew that there was a mini-epidemic of influenza in my staff. I told my team members that I had to stop due to illness and went home.  It took about 48 hours for that to clear.  Since that time, I have been very interested in how infectious diseases and diseases in general have that effect on the brain.

The closest term that I could think of that might approximate brain fog is “clouding of consciousness”.  This term from descriptive psychiatry and psychopathology is commonly associated with neurocognitive disorders. It is typically a criterion for delirium but in most texts, it is also associated with other anatomical and functional brain disorders.  The best review of the psychopathology and phenomenology of clouding of consciousness is from Lipowki’s text (1).  Lipowski reviews the 2500 year history of delirium and how confusion and clouding of consciousness became critical concepts in advancing research in this area.

A lot of the current psychopathology texts have very little to say about clouding of consciousness and symptoms of delirium.  There are a few exceptions.  Sims discusses it in a chapter “Consciousness and Disturbed Consciousness”.  He starts with defining consciousness by three components an inner awareness of experience, intentional reaction to objects, and knowledge of the conscious self.  He also has an excellent diagram (Fig 3.1 p. 40) that ties together the medical use of the term, clinical context, and changes that can occur in that context.  Since I cannot get permission to post the diagram I will describe it.  Normal consciousness is the central component and it is transitioned to reduced wakefulness, sleep, and stages of sleep and deep sleep.  There is another transition to the unconscious mind (via preconsciousness).  The final transition is to clouding of consciousness, drowsiness, stupor, and coma. The latter transition is obviously the only pathological one, but in terns of psychopathology there is obvious overlap between reduced wakefulness transitioning to normal sleep and drowsiness that may be a prelude to neurocognitive disorders.  That is also a critical decision point in thinking about brain fog.  Is the underlying mechanism one of reduced wakefulness or a focal or global decrease in brain metabolism seen in neurocognitive disorders?  Sims also defines clouding of consciousness as: “most intellectual functions are impaired including attention and concentration, comprehension and recognition, understanding, forming associations, logical judgement, communication by speech and purposeful action”. (p. 41).  Sims definition is most consistent with an early delirious state but not “brain fog” described by a person who is going to work every day and subjectively feels that their work performance could be better.

I have followed the evolution of Neuropsychiatric Systemic Lupus Erythematosus (NPSLE) across the last 3 versions of Lahita’s text on SLE.  There are generally 2 chapters dedicated to this topic in each text.   Over the years, there has been much more specificity in terms of the biological mechanisms involved in NPSLE.  There are 19 separate neuropsychiatric syndromes involving neurocognitive symptoms and constellations of more pure psychiatric symptoms like anxiety and depression.  From a purely cognitive standpoint, an interesting concept is that many of the mechanisms that are thought to moderate cognitive function like long term potentiation (LTP), synaptic plasticity, and neurogenesis are immune cells and inflammatory molecules.  The diagram below illustrates some upstream perturbations in the cytokine system that can result in impaired learning and memory.  There are additional immune systems affecting neurogenesis.


     

In the review that I constructed this diagram from, the author states: “‘‘Lupus brain fog’’ is an extremely common patient complaint that refers to periods of forgetfulness and confusion that are related to impaired cognition.”  She cites the range of 21-80% of SLE patients having some degree of cognitive impairment leading to some degree of disability or impaired quality of life.  NPSLE and the associated studies of how inflammation and immune function impair learning and memory is an excellent example of how various disease processes can have effects on cognition. It is also a good example of how the term “brain fog” has developed recently in this clinical population with clear CNS pathology.  It also suggests a lack of specificity for the term given the range of impairment.

At this point – a few clinical vignettes of “brain fog” can be considered as additional examples:

Vignette 1:  60-year-old man referred for assessment and treatment of mania and possible bipolar disorder.  He gives a history of drinking 750 ml/day of alcohol and appears intoxicated at the time of the evaluation.  As part of the initial evaluation, he is given a standard cognitive exam and scores a perfect 30/30 points indicating no deficits in orientation, attention span, short term memory or language skills (comprehension, repetition, or naming).  He has no subjective cognitive symptoms.  He returns a week later for reassessment and does not recall meeting the same physician or doing any cognitive testing. He does not believe he was ever at the clinic in the past.

This patient essentially blacked out or was amnestic for the initial interview with the psychiatrist.  Like many heavy drinkers he has a sustained mood disturbance at times that resembles manic episodes, but these symptoms resolve after detoxification and abstinence from alcohol. Patient with these problems are likely to described brain fog during episodes of intoxication, withdrawal, detoxification, sleep deprivation from the effects of alcohol, decreased attention span and concentration that is probably multifactorial and during mood changes that are alcohol induced.  Heavy alcohol consumption can lead to profound and persistent cognitive changes, most notable from untreated Wernicke encephalopathy the result of Vitamin B1 deficiency that can accompany persistent alcohol use.

Vignette 2: 40 yr old woman referred for assessment of severe anxiety and panic. She attributes both symptoms to “chronic Lyme disease” despite extended course of antibiotic treatment by experts and extended treatment by non-medical personnel using more atypical types of treatment.  She was previously very vigorous and physically active but that is no longer the case.  She describes fatigue, hypersomnia, and “brain fog” that puts her job at risk because of decreasing productivity and performance. She is being treated with benzodiazepines for anxiety and z-drugs for sleep.

This is a familiar scenario for psychiatrists. In this case the patient is diagnosed with a controversial illness and has not recovered despite very aggressive treatment.  She is anxious because of the decrease in her level of functioning and describes fatigue, hypersomnia, and brain fog.  It is often difficult to determine the progression of symptoms without detailed records – depending only on the patient’s recollection of what happened over a number of years.  In these cases I have found that it is best to track all of these symptoms and see how they fluctuate with logical changes based on the patients current clinical status. In these cases I would typically proceed with tapering and discontinuing the benzodiazepines and z-drugs and monitoring the fatigue, hypersomnia, and brain fog while simultaneously providing psychotherapy that I thought would be most effective for the target symptoms.

Vignette 3: 50 yr old man being seen for severe alcohol use disorder, persistent depression disorder, major depression, chronic insomnia, and possible attention- deficit/hyperactivity disorder. He has had lifelong insomnia, onset of chronic depression at age 18, and heavy daily drinking for the past 15 years. He describes inattentiveness, distractibility, procrastination, and “brain fog”.  He is requesting that treatment for the “brain fog” be prioritized since it is currently his most significant problem.

Very common scenario in treatment settings.  The ADHD diagnosis is more controversial lately based on the idea that some people may develop it as an adult.  I always ask adults about childhood sleep problems and it is a very common finding.  Childhood sleep disturbance also results in erroneous diagnoses of ADHD, but it is often difficult to establish that diagnosis in generations where it was not emphasized on school.  The diagnosis of alcohol use disorder is a complicating factor. In the case of heavy drinkers, they are often drinking all day long, in a state of intoxication or withdrawal, and typically wake up in the middle of the night and need to decide whether to drink in order to fall back asleep or tolerate withdrawal until the morning and then drink to reduce more severe withdrawal symptoms.  Clearly, every one of those transitional states is associated with some cognitive impairment and some have described it as “brain fog”.  An additional patient-based bias is wish that a medication can correct all of this cognitive impairment.  That wish is complicated by the fact that many heavy drinkers have used cocaine or amphetamines to drink more and improve their concentration and attention.  They have also used benzodiazepines as a way to treat insomnia and withdrawal symptoms, especially withdrawal symptoms in the morning that could otherwise lead driving to work with high blood alcohol levels and risking legal problems.  In all of these cases, the patient needs to be followed and serially reassessed up to the 60-day mark.  In my experience, the transient cognitive symptoms should be clear at that point and the baseline symptoms and their severity can be determined.

If brain fog exists can it be phenomenologically separated from other psychiatric diagnostic terms?  Sedation or excess somnolence is a common form of clouding of consciousness.  There is a temporal aspect to both related to a combination of both alerting mechanisms and circadian rhythms and the biological basis of both has been grossly determined (6).  I would anticipate that sedation or somnolence would fluctuate over the course of the day, with the exception excessive sleep deprivation or external sources of sedation like a sleeping agent.  Most people tend to describe brain fog as unrelenting.

In the final analysis, is brain fog a useful term?  Is it a colloquialism rather than a technical term that should be used in medicine? My argument suggests that it may be a useful descriptor of a sub delirious state or very early clouding of consciousness.  There are multiple associated etiologies and conditions including some that are just a temporary disruption in normal physiology.  Based on my clinical experience it is clearly a word that patients frequently use. From the PubMed search, it is also being used more frequently in the medical literature, just over the past 20 years. 

 


A word of caution is needed before it is adopted on any widespread basis. Lipowski points out how 19th century psychopathologists advanced the field by specifying a class of disorders based on clouding of consciousness and confusion arising in the context of acute brain dysfunction.  What followed was a proliferation of terms that set back further research for decades (p. 27).  Time will tell if the term becomes more widely adapted or it is fitted into existing nomenclature.  Based on the recent tightening of the nomenclature for delirium (7) it is not likely.  Since most people seem to be using it to cover both mild and moderate subjective cognitive impairment - it does not add much precision. On the other hand psychiatrists are focused on the patient’s subjective state and use of language so it is undoubtedly useful for beginning the early exploration of the problem that led to the consultation.

 

George Dawson, MD, DFAPA

 

References:

1:  Lipowski ZJ.  Delirium: Acute Confusional States.  New York: Oxford University Press, Inc; 1990.

2:  Sims A.  Symptoms in the Mind: An Introduction to Descriptive Psychopathology. 3rd ed. Amsterdam: Elsevier Limited; 2003.

3:  Mackay M, Ulug AM, Volpe BT.  Neuropsychiatric Systemic Lupus Erythematosus: Mechanisms of Injury.   In:  Lahita RG, Tsokos G, Buyon J, Kolke T.  Systemic Lupus Erythematosus. 5th ed. London: Academic Press; 2011. p. 491- 512.

4:  Hanley J.  The Nervous System and Lupus. In:  Lahita RG, Tsokos G, Buyon J, Kolke T.  Systemic Lupus Erythematosus. 5th ed. London: Academic Press; 2011. p. 727-746.

5:  Mackay M. Lupus brain fog: a biologic perspective on cognitive impairment, depression, and fatigue in systemic lupus erythematosus. Immunol Res. 2015 Dec;63(1-3):26-37. doi: 10.1007/s12026-015-8716-3. PMID: 26481913.

-Reference 5 is an excellent open access review of the relationship between inflammation, immune systems, and cognition (especially memory and learning).

6:  Valentino RJ, Volkow ND. Drugs, sleep, and the addicted brain. Neuropsychopharmacology. 2020 Jan;45(1):3-5. doi: 10.1038/s41386-019-0465-x. Epub 2019 Jul 16. PMID: 31311031; PMCID: PMC6879727.

7:  Slooter AJC, Otte WM, Devlin JW, Arora RC, Bleck TP, Claassen J, Duprey MS, Ely EW, Kaplan PW, Latronico N, Morandi A, Neufeld KJ, Sharshar T, MacLullich AMJ, Stevens RD. Updated nomenclature of delirium and acute encephalopathy: statement of ten Societies. Intensive Care Med. 2020 May;46(5):1020-1022. doi: 10.1007/s00134-019-05907-4. Epub 2020 Feb 13. PMID: 32055887; PMCID: PMC7210231.

 

 

 

Graphic Credit:

Graphic was downloaded from Shutterstock per their standard agreement.  The artist in this case had many similar brain fog graphics and these depictions are probably an indication of how common this term has become.

 


Sunday, February 28, 2021

Another Round of Addiction As A Brain Disease

 



A new open access article looking at the issue of addiction as a brain disease was recently published by Neuropsychopharmacology.  The authors point out that since this original claim as made 20 years ago (7) and subsequently reinforced (8) there have been a flurry of critical articles. On this blog I have examined several of these articles in the past. They parallel typical arguments that are used against psychiatric diagnoses, particularly the concept of psychiatric disorders as diseases.  Interestingly, in this paper that entire issue was summarily addressed:

“Few, if any healthcare professionals continue to maintain that schizophrenia, rather than being a disease, is a normal response to societal conditions. Why, then, do people continue to question if addiction is a disease, but not whether schizophrenia, major depressive disorder or posttraumatic stress disorder are diseases?”  (p. 3)

Any casual observer of the constant arguments on this issue will note a constant flux of how psychiatric disorders are described.  Disorders, conditions, and constructs come to mind.  I always like to point out that actual surveys of both the general public and health care professionals finds that both groups typically classify severe mental illnesses and substance use disorders as diseases, but to varying degrees.  The best surveys of this problem have been done in Finland (4,5) with large sample of doctors, nurses, psychiatrists, laypersons, and politicians included.  In two separate studies the authors asked respondents to consider 60 general conditions and 20 psychiatric conditions.  Respondents were asked to rank the disorders according to which were more similar to disease conditions and different cut offs were used for both samples. In the larger survey of 60 medical and psychiatric conditions – schizophrenia and autism met the survey requirements for disease.  In the second survey, 75% of the respondents considered schizophrenia and autism as diseases and 50% considered Depression, Anorexia, Panic disorder, Generalized Anxiety Disorder, Bulimia, Attention deficit hyperactivity disorder, and Personality disorder to be diseases.  There was more disagreement on Alcoholism and Drug Addiction but 64% of physicians and 74% of psychiatrists considered alcoholism to be a disease.  On the issue of drug addiction 50% of physicians and 65% of psychiatrists considered that condition to be a disease. The authors generally discuss the implications of these opinions from a practical and public policy perspective rather than a medical or philosophical one. The common arguments that persist is that disease status confers social legitimacy on a disorder leading to more treatment resources and hopefully decreasing stigma.  In the case of addictions there are longstanding moral defect or choice theories that essentially equate addiction to willful misconduct. Since large corporations have taken over the healthcare systems in the United States many of these biases are less visible since proprietary rules determine who gets treatment resources and how they are treated. A recent court ruling details how these rules are seriously flawed (6).  An important perspective from the discussion and that is personal experience with the illness by the patient, family members, friends, and employers– a subject I will elaborate on further.

The previous posts on this blog addressed a New England Journal of Medicine article suggesting that addiction was a problem in learning rather than a disease in two separate posts.  Before that I addressed a 2015 article that listed 10 reasons why addictions were not a disease. Responding to these articles highlighted their rhetorical aspect.  Many of the arguments against a disease model of addiction have three basic flaws.  First, they consider the concept of disease to be clearly defined and it is not. Second, they use their more precise definitions for comparison and as a way to prove addiction is not a disease.  And third, they suggest that psychosocial variables are relevant only if the condition in question is not a true disease.  They suggest that real diseases are self-contained and self-perpetuating and that interpersonal relationships and environmental factors cannot modify diseases.  By extension only a medication or a surgical intervention can modify or cure a real disease.  There are many examples of diseases that illustrate why that premise is not true.  In my practice over the past 30 years the most common examples have been diabetes mellitus Type 2, hypercholesterolemia, and hypertension. I have seen many people with extreme cholesterol elevations who were “cured” by a simple dietary change and starting to exercise.  My two previous articles discuss these lines of argumentation.

Another disease feature of substance use disorders is that they can occur in discrete epidemics.  Although epidemics are typically thought of as being associated with infectious diseases, the CDC description is careful to point out that they can also occur as a result of non-infectious diseases like obesity and diabetes mellitus. They also describe 5 conditions that lead to epidemics including an increase in exposure in terms of total amount or increased virulence, introduction of a novel agent, enhanced transmission, a chance in host response, or increased host exposure that can occur by new portals of entry.  All 5 of these factors are relevant in drug epidemics.  Substance use disorder epidemics have these features as evidenced by the 20-year opioid epidemic that started with excessive availability of prescriptions opioids and transitioned to more potent illicit opioids. The widespread availability of these compounds come from illicit importation and supply chain proliferation often by opioid users selling these compounds in order to assure that they have an adequate supply.  Over the past 25 years there have been a clear pattern of increased geographic availability of multiple drug classes – leading to increased morbidity and mortality from substance use disorders in these areas.  

Does the current paper add anything to the argument for addiction as a brain disease?  The authors review the history of the more public airing of the concept – an original article by Leshner (7) asserting “addiction is a brain disease” and a follow up article by McClellan (8). The fact that both of these declarations are only about 20 years old should not be lost on anyone. The authors get derailed from the basic concept of disease in the very next paragraph by suggesting “To promote patient access to treatments, scientists need to argue that there is a biological basis beneath challenging behaviors of individuals suffering from addiction.”  The social utility of a diagnosis is separate from its medical and scientific utility. All three are conflated at times (even to the point of suggesting that laypersons should have input into what is a diagnosis), but in my opinion without medical and scientific utility – there is not social utility.

They review the definition of disease – starting with Jellinek’s “The Disease Concept of Alcoholism”.  Jellinek made the argument that diseases were not self-contained “entities” but it is more of an agreed upon label “to describe a cluster of substantial deteriorating changes in the structure or function of the human body and the accompanying deterioration in biopsychosocial functioning”.  That definition is very close to the one I came up with reviewing the work of philosophers Munson and Resnick who defined disease as a “failure of normal functioning”. The main difference is that these two philosophers predicated the definition on the premise that biological systems were programmed processes and those processes failing is what causes the disease.  Adaptive reward based learning can certainly be considered a programmed process in brain biology.  

They take a close look at the idea that any definition of addiction should account for spontaneous remission and non-relapsing states. One of the typical arguments against addiction as a disease is that a significant number of heavy drinkers (and probably cannabis smokers) stop after they graduate from college.  In many ways, excessive alcohol and drug use in college is considered a rite of passage by many Americans.  That rite of passage has a considerable mortality and morbidity on its own that is usually not considered by the addiction as disease critics.  The vast majority of these people are not the people seen by addiction specialists later in life. The people seen in their 40s or 50s will typically give a history of knowing that their pattern of drinking was problematic.  As an example: “I knew from the very first time that I drank a lot more and I drank faster than anyone else. I drank more in college and I did not stop after I graduated”.  And they elaborate on the consequences of excessive alcohol use at every life stage.  Binge use or even fairly continuous use of drugs or alcohol in college is not the same as an addiction.  

The authors point out that some of the epidemiological data used to justify the remission argument is dependent on methodology and population.  For example, a population recruited from a residential treatment facility and interviewed with a standardized interview will yield much different results than a community sample. The diagnosis of addiction (or severe alcohol use disorder) will be stable in the former case but not the latter.  They reference NESARC (National Epidemiological Survey on Alcohol and Related Conditions) as the community sample and using that methodology the baseline lifetime prevalence of non-remitting alcohol dependence was 10% (p. 9).  They also point out that opioid use disorder when observed for 10-30 years has a stable abstinence rate of < 30%.  The fact that some people stop using excessive amounts of drugs or alcohol is not an argument that there is not a large population of people who clearly have a chronic relapsing course and incur significant mortality and morbidity along the way.

The authors proceed to the genetic argument and point out that family and adoption studies point to a heritability of ~50% for addictive disorders. They highlight typical misunderstandings of genetics, specifically the concept of polygenic risk and that fact that some polygenic disorders lead to pathological states – addiction being one of them.  An additional argument is that although the first 20 years of human genome study have been very productive for Mendelian disorders, it has been far less productive for more complex disorders (11). Understanding the human genome is far from complete at this point and some research groups are just beginning to understand the relationships between genetics, addiction, and medication effects (12, 13, 14).

The lesion argument is the next disease straw man to fall. It should be obvious to anyone that diseases do not necessarily produce a discrete lesion either on imaging studies or autopsy.  An yet it remains a favorite to anyone who claims that addictions or psychiatric disorders are not diseases.  They review how imaging is currently used clinically.  This is a reality that most of the critics seem to miss.  If I see brain imaging consistent with small vessel ischemic disease – that alone is insufficient to make the diagnosis. It also requires an adequate history and examination of the patient. The critics apparently have not see radiology reports that point out “clinical correlation is necessary”.  The authors briefly review the functional imaging of alcohol and stimulant use disorders that point to problems with frontal-striatal circuitry, structural changes with alcohol, and demonstrable and expected changes in dopamine signaling. Brain imaging in addiction at this point (apart from the necessary clinical imaging) is useful from a heuristic standpoint – looking for relevant mechanism and treatments, but there is no imaging of addictive disorders per se. 

A popular viewpoint these days is that there is not enough of an investment in psychosocial factors in funded research. Many of those critics make the argument that the trade off should be reduced funding for biological research and those funds should be diverted to psychosocial research. The authors here acknowledge the importance of social factors, their incorporation in more complex research designs, and the fact that a view of addiction as a brain disease in no way negates the importance of other environmental factors. 

The authors address the issue of reductionism.  They use the term determinism instead. Over the past two decades molecular biologists have moved firmly away for the idea that all complex biological systems can be reduced to the basic laws of chemistry and physics. The does not mean that with the appropriate tools biological complexity can not be understood and explained.  Many physicists see the brain as deterministic.  In other words because the brain is made up of particles and those particles must follow the laws of physics, the future (or past state) of any brain can be determined by the right differential equation. Deterministic states can be chaotic and in that situation they are not predictable.  If you believe the brain is deterministic based on physical laws – it follows that there is no free will and that free will is an illusion.  The real limiting factors with describing the brain as deterministic include the following problems:

1.  There are known stochastic factors that introduce random events – some of which are relevant for the addiction.

2.  Complexity – as noted above.  There is so much structure and so many particles that must be considered in these complex systems that there is a clear measurement problem and the most difficult problems are solved by computer modeling approximations rather than mathematically.  I have not seen it discussed but whenever I consider the complexity of biological systems, I see them as an almost infinite set of microenvironments - each with their own physical and chemical parameters. If there was an equation to describe all of those microenvironments acting at one - it would be exceedingly complex.

3.  Brain changes occurring during the addiction process (a large number of which are unknown at this time) alter the deterministic nature of the system.  I suppose the response by the physical determinists would be that the new altered system would be determined by the laws of physics and chemistry. That does not alter the fact that it is a new system with different physical and chemical componenets.

The authors contend that the system is indeterministic because of these factors and therefore free will is allowed.  An associated physics and philosophical question is whether it is really deterministic but unpredictable and why.  Overall, these philosophical arguments do not really seem to add much to the debate.  The critical piece is whether either deterministic or reductionist is used in a pejorative manner.  That use is typically coupled with arguments that other social or psychological theories is what is really happening.  Scientists and physicians are generally interested in knowing all of the details and mechanisms of action. The is the real driver of knowing what is happening at the molecular level.  This paper does a good job of explaining why people who use that approach do not exclude everything else that is going on in the environment.

They end on the issue of compulsivity (or more accurately uncontrolled use) in addiction. It is not the case that this does not happen, but the degree at which it happens.  In the people who I work with practically all of the negative outcomes are associated with uncontrolled use/compulsivity.   That does not mean that people with addictions are automatons. The major treatment modality anywhere is some form of group therapy.  Those groups would not exist if there was an assumptions that people with substance use disorders could not choose to change their thought patterns and behavior.  They continue to have some flexibility, but the probabilities during an active addiction is that the substance use will continue despite negative and in many cases life threatening outcomes. Intact decision making in other areas or even in the focal area of continued substance use with episodes of abstinence does not mean that normal decision making occurs in all areas of life.

In their conclusion, the authors suggest that progress can occur from integrating a number of scientific perspectives including those outside the field of neuroscience.  They advocate for consilience and input from a plurality of disciplines. They also suggest that no single discipline has exclusive ownership of the field.

As a clinician who is used to constant criticism of psychiatry from people who don’t know anything about it – I have a different position.   First, we need to acknowledge the severity of addictions specifically that they kill and disable large numbers of people.  Family members trying to help an afflicted persons know that as well as the difficulty in trying to help them stop.  Second, in rankings of disability compared with other disease states – addictions are consistently in the top 10.  When combined with psychiatric diseases they are ranked second.  There are few other diseases as disabling or lethal.  Third, there have been treatments that are based on the underlying biological factors that are thought to be relevant to addiction that have worked.  Four, it is very clear that individuals with addictions are no longer functioning normally – defined as their normal baseline.  That can start at any point in the life cycle – and at some point most people are aware that they have a severe problem and cannot stop.

All of those factors point to a disease state and it is good to see a paper supporting that opinion.   But even beyond this opinion, consider the people you have known with addictions and make up your own mind based on that experience.  Carefully consider how you interact with people if you consider addiction to be a disease or intentional decision-making.

 

 George Dawson, MD

 

References:

1:  Heilig M, MacKillop J, Martinez D, Rehm J, Leggio L, Vanderschuren LJMJ. Addiction as a brain disease revised: why it still matters, and the need for consilience. Neuropsychopharmacology. 2021 Feb 22. doi: 10.1038/s41386-020-00950-y. Epub ahead of print. PMID: 33619327.

2:  Heilig M, Augier E, Pfarr S, Sommer WH. Developing neuroscience-based treatments for alcohol addiction: A matter of choice? Transl Psychiatry. 2019 Oct 8;9(1):255. doi: 10.1038/s41398-019-0591-6. PMID: 31594920; PMCID: PMC6783461.

3:  Venniro M, Banks ML, Heilig M, Epstein DH, Shaham Y. Improving translation of animal models of addiction and relapse by reverse translation. Nat Rev Neurosci. 2020 Nov;21(11):625-643. doi: 10.1038/s41583-020-0378-z. Epub 2020 Oct 6. PMID: 33024318.

4:  Tikkinen KA, Leinonen JS, Guyatt GH, Ebrahim S, Järvinen TL. What is a disease? Perspectives of the public, health professionals and legislators. BMJ Open. 2012 Dec 2;2(6):e001632. doi: 10.1136/bmjopen-2012-001632. PMID: 23204142; PMCID: PMC3533011.

5:  Tikkinen KAO, Rutanen J, Frances A, Perry BL, Dennis BB, Agarwal A, Maqbool A, Ebrahim S, Leinonen JS, Järvinen TLN, Guyatt GH. Public, health professional and legislator perspectives on the concept of psychiatric disease: a population-based survey. BMJ Open. 2019 Jun 4;9(6):e024265. doi: 10.1136/bmjopen-2018-024265. PMID: 31167856; PMCID: PMC6561450.

6:  Wit v. United Behavioral Health.  Full text of ruling.

7:  Leshner AI. Addiction is a brain disease, and it matters. Science. 1997 Oct 3;278(5335):45-7. doi: 10.1126/science.278.5335.45. PMID: 9311924.

8:  McLellan AT, Lewis DC, O'Brien CP, Kleber HD. Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA. 2000 Oct 4;284(13):1689-95. doi: 10.1001/jama.284.13.1689. PMID: 11015800.

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