Brompton Cocktail - The Magical Qualities of Addictive Drugs....

I was talking to a colleague today about problems in the addiction field.  She was referring to problem with opioids and suddenly I had the association: "Brompton Cocktail."  The Brompton Cocktail was a mixture of alcohol, cocaine, morphine and other ingredients that had purported superior pain alleviating qualities compared with any other available medication at the time.  I first encountered the term on a medicine rotation as a medical student.  Our attending physicians at the time were two very bright hematologist-oncologists.  One was older and more cerebral with many publications.  The other was younger, outspoken and generally edgier.  He had just completed his fellowship.  When the conversation turned to pain relief for patients with cancer pain he made it very clear that his preference was "Brompton's Cocktail" but that it was not available in the United States.  He railed against the regulations in this country that prevented him from providing Brompton's to his American patients.

That piqued my interest at the time.  The natural question is why Americans were being denied a superior analgesic?  The second question was - why all of the polypharmacy?  Alcohol was an analgesic out of the old west - why would it need to be mixed with morphine and cocaine?  And why the cocaine?  It could certainly be a local anesthetic that could restrict blood flow in ENT procedures - but would it really provide widespread pain relief if it was ingested and systemically absorbed?  Further research in the matter showed that in addition to gin - vodka and whiskey were being used as the alcoholic beverage.  Some people added tincture of cannabis.  Others added anti-nausea medication like phenothiazines or antihistamines.

These combinations in elixir form were popular in Europe where their original use was in mainstream surgery in the late 1890s.  They became widespread in the 1920s and 1930s when many formulations were listed in the medical literature and practitioners often had their own custom formulations.  One of the references I read suggested that the patient could be given a choice in terms of the alcohol component (vodka, whiskey, or gin) and it gave them a sense of control over their medication.  There were some modifications of the original formula based on economic considerations - like the cost of cocaine.  The most striking feature of this mixture is that it persisted in use in medical facilities for nearly 100 years!  My medical school professor was telling me it was the ultimate pain medication in 1982.  Available evidence accumulating in the 1970s eventually illustrated that for pain relief there was no advantage of an exotic mixture over morphine monotherapy (1).   And that (in addition to more permissive use of opioids) brings us into the current period of opioid and nonopioid treatment of chronic pain, although the Brompton mixture was used almost exclusively for severe postoperative pain or pain associated with malignancy.

One of the strong themes in medical care as in the rest of American culture is the lack of appreciation of how past history factors into current medical care.  Although there were probably two biases in the early 20th century leading to the use of Brompton - the lack of manufactured pharmaceuticals and the potent effects of both cocaine and morphine, the same biases exist today.  The common bias noted on this blog has been the idea that opioids are universally effective for acute and chronic pain.  We are seeing an emphasis on cannabis as a treatment for pain and tincture of cannabis was an element of Brompton a century ago and it was eventually eliminated.  Unusual combinations of prescription medications are combined with the hope that they will provide some pain relief including opioids, sedative-hypnotics for sleep, benzodiazepines for anxiety and muscle spasm, muscle relaxants, gabapentinoids, and antidepressants.  I see patients who are taking extended release forms of opioids who are also given immediate release forms of the same opioid and told that they are "rescue" medications in the event that they have breakthrough pain not treated by their maintenance extended release medication.  I see people with implanted opioid pumps who are given immediate release medications for the same reason.  In both cases they tell me that their pain is the same but they continue using the rescue medication.

In a previous post on medical cannabis, I posted that some physician advocates talk about the entourage effect and why the whole plant needs to be smoked for pain relief.   The uniting thread in all of these approaches is that there is a predominance of potentially addictive drugs.  Addictive drugs always seem to be imbued with magical qualities - whether it is pain relief or the recent push to use psychedelics for whatever ails you. That always leads me to ask - is this medication working for pain or is it just reinforcing its own use?

All of these approaches strike me as being not much more scientific than Brompton Cocktail.  Like all historical lessons about addictive drugs and their purported effects - Brompton is nearly forgotten.

I nearly forgot it myself.


George Dawson, MD, DFAPA




References:

1: Melzack R, Mount BM, Gordon JM. The Brompton mixture versus morphine solution given orally: effects on pain. Can Med Assoc J. 1979 Feb 17;120(4):435-8. PubMed PMID: 376079.








   

I Was Compassionate Today ........

I attended the Minnesota Psychiatric Society (MPS) Spring Scientific Meeting today entitled "Reclaiming Our Joy and Wonder as Healers."  The full program of that venue is available online at this site.  In the registration process I noted that a lot of the content seemed to be experiential and that is my least favorite kind of conference.  To make sure I did not miss anything I compared notes with a long time colleague and she agreed and had the same selection process - try to avoid the experiential components of the program.  I was generally successful, but more about that later.

The program did begin with three lectures and ample audience participation.  The presentations on happiness and burnout seemed to be an uncritical look at happiness and gratitude science.  The lead off speaker talked about his personal experience in a health care system that sustained 2 physician suicides in less than a year and how he led the effort to reduce physician burnout.  He discussed some straightforward exercises in gratitude and happiness as well as the importance of human relationships.  He encouraged psychiatrists at one point to help out their nonpsychiatric colleagues in this area.  He provided extensive resources for physicians to use through a web site.

I worked with the second physician for over a decade in my previous position.  He discussed the clash of professional values and expectations with what happened in the family and intrapsychically and how he negotiated some of those transitions including going to a clinical track from an academic- research track.  He read part of this piece by Jamie Riches, DO - an Internal Medicine resident at Sloan Kettering and the impact of resident suicides.  It contained the familiar refrain: "The work does not stop!"  No matter what catastrophe you encounter as a physician (and there are many) you are expected to take a deep breath and get back to it - immediately.  A resident I worked with completed his shift and the final admission note on 15 patients he had seen that night despite an upper GI bleed.  He did not seek medical attention until he had signed out at 8AM the next day.  Any bystander can look at these occurrences and other problems listed by Dr. Riches and see how physicians are shooting themselves in the foot.  You can't provide good care to patients if you can't take care of yourself.

The third morning lecturer was on the state hospital association and he discussed their attempts to address physician burnout.  They had graphed the degree of burnout in various medical organizations and concluded that interventions could be useful for decreasing burnout in general and burnout specifically due to the EHR.  I have seen first hand how survey data can be manipulated by health care organizations and I am skeptical that this data means much - especially when there was acknowledgement that the EHR itself has either not changed or the organization implemented the usual unhelpful EHR teams as the primary intervention.         

I was able to propose a thought experiment in an afternoon session on Compassion Training.  I am no stranger to Buddhism, meditation, or mindfulness techniques.  As a psychiatrist trained in the theory and maintenance of therapeutic neutrality, I was skeptical of emotionally loaded terms like "happiness" and "compassion" being used in the context of a therapeutic relationship.  Just about every definition of compassion includes terms like sympathy, pity, concern, and or sorrow for the plight of another person.  That seems a lot less precise than empathy.  The definition of empathy that I use is the technical version from Sims (1) : ".....empathy is a clinical instrument that needs to be used with skill to measure another person's internal subjective state using the observer's own capacity for emotional and cognitive experience as a yardstick.  Empathy is achieved by precise, insightful, persistent, and knowledgeable questioning until the doctor is able to give an account of the patent's subjective experience that the patient recognizes as his own."  Some definitions confuse empathy with passive understanding of another person's emotional state and compassion with understanding and a willingness to take action to help that person.  Psychiatrists trained like me use empathy to explore the person's subjective state for the purpose of understanding it and trying to help them.  It is anything but passive.  In the course, the various stages of meditations were also focused on developing a baseline compassion toward oneself.

I asked the instructor to consider the following thought experiment:

1.  In Room 1:  I am interviewing a patient with borderline personality disorder and proceeding by using the guiding concepts of therapeutic neutrality and empathy.

2.  In Room 2: A psychiatrist with compassion training is interviewing a patient with similar problems.

Question:  How would an observer compare the psychiatrists in Room 1 and Room 2?  Would there be any discernible differences between the two?

The response I got was quite interesting.  She suggested that the main difference would be after the interview was terminated - the compassion trained clinician would be less distressed after the interview than I would.  The problem with that response is that I am not distressed at all interviewing patients.  I have plenty of experience across a wide array of scenarios.  At some level, I am much more comfortable talking to people in my office than just about anywhere else.  The expectations are clear.  I know what I have to do and have done it tens of thousands of times in the past.  I can talk about anything a person wants to talk about including how they perceive me in that  situation.  In the interest of time and not wanting to appear argumentative, I did not bring that up.  It does raise the issue of whether the new interventions for burnout have much to add over appropriate training from the past.  I have practiced mindfulness techniques and meditation and like a lot of the patients  I see - they don't seem to add much.

In the summary session I requested the microphone.  I don't come across well in a potentially contentious environment.  When I speak people think that I am irritated or angry and that probably affects my message.  I consider myself to be passionate - but I am not really angry about anything.  It would be foolish to be angry about various things that haven't changed in 20 years.

At the micro level my emphasis was on direct connections. I described a scene from my internship, where another intern and I were responsible for a patient on a balloon pump in an ICU setting.  At one point we looked at one another and realized there was nothing more we could do.  I knew from the look on his face at 4AM that he was as distressed about the situation as I was. We did not know enough at the time to realize that there was nothing anyone could do - but it would have been very useful to have somebody tell us that.   In those days, there was an implicit rule that attending physicians should probably not be called at night and that everything in the hospital could be resolved by you and your Internal Medicine PGY3.  I only heard one attending ever give us explicit instructions and that was "I don't want to be surprised in the morning."  My resident had to translate it for me: "We need to call him if somebody is going down the tubes."  As an attending physician myself, I wanted to make  sure that never happened.  I got called by a resident who had a very confusing patient presentation and went in and made the diagnosis of serotonin syndrome and had the patient transferred to the ICU.  My emphasis at the micro level was that there has to be clear communication that you don't mind discussions and consultations about cases even when you are out in practice.  I am consulted by and consult many psychiatrists by phone and email on an ongoing basis and any time of the day and it has been a great source of professional development and peer support.

At the macro level, my message was politics.  The speaker touched on the EHR as a burnout factor and what they might need to do about it.  Nobody mentioned maintenance of certification.  Some people seemed irritated that I mentioned either politics or MOC in this course that was supposed to be about preventing burnout and creating a more resilient workplace.  I don't know what a more resilient workplace is.  The workplace is resilient simply because it is out of physician control and completely resistant to change.  There are more ways to get the EHR and MOC changed than hope that a hospital association will do it with survey data.  I proposed that physicians consider political activism at the level of the practice environment and the government level and that they consider defeating MOC.

At the end one of my colleagues told me she appreciated the approach to providing residents support and wished she had it in her training program.  I was glad I got that message out.  No takers on the EHR or MOC.

I will keep going and adding my two cents - even though my anxiety seems to be getting higher and higher every time.  At some level I probably realize that there are very few people who see the psychiatric world the way I do - and I know my time is limited.  I also know that I don't see anybody coming along who is prepared to challenge the status quo that seems to keep dictating our deteriorated practice environment.


George Dawson, MD, DFAPA


References:

1:  Sims A.  Symptoms in the Mind, 3rd Edition.  Elsevier Limited, London (2003): p 3.



Graphic Credit:

Incense burner is from Shutterstock per their standard licensing agreement.

A Second Look At Recreational Cannabis - Already?

I don't know how many other people are weary of the onslaught of pro-cannabis propaganda over the past two decades.  The goal was clear to me at the outset - legalize marijuana.  I have previously posted that I think there will be legalized marijuana in every state in the United States.  I have also posted that "medical" marijuana or cannabis is basically a front for the legalize recreational marijuana movement.  I am very weary of all of the arguments about how cannabis is a miracle drug, how it will lead to stunning new discoveries, how it will lead to less opioid use and misuse, and all of the permutations of these pseudoscientific arguments.  Many of the legal arguments are just straight off-the-wall.  Those include put all the cannabis dealing cartels out of business, create jobs, and tax it as a great source of tax revenue.  The considerable downsides of adding another intoxicant to the culture seems to be mentioned only by a few psychiatrists who are familiar with a great many of the downsides from treating patients who have been using it for a lot longer than the legalization arguments have been in vogue.

A few of those problems became more evident last week. Colorado Governor John Hickenlooper came on CNN and discussed several correlates of cannabis legalization in Colorado.  Property crimes and violent crimes are up.  The number of homeless in Denver is up and some believe this is a correlate of increased crime.  The number of lethal motor vehicle accidents involving cannabis are up.  He did not mention health care related phenomena including a doubling of cannabis related hospital billing codes, a five-fold increase in cannabis related mental health codes, and an 80% increase in cannabis related calls to poison control centers (3).  Unintentional pediatric exposure to cannabis was also observed (4) to increase.  None of the costs of this medical care has been calculated as an offset of the tax revenue from the cannabis.  Gov. Hickenlooper made the point that recent tax revenues were about $200 million relative to a state budget of $30 billion and about 1/3 of that revenue goes for associated law enforcement and educational activities.  He advised against any state making the decision to legalize cannabis based on a tax revenue argument (5).  The articles in the popular press seem to emphasize the need for flexibility with the great social experiment of recreational cannabis and the Governor seems all for that up to a point.  That point is if it is apparent that the social costs in terms of crime and motor vehicle accidents is really up. At that point he suggests that the current cannabis laws can be reversed. 

Rather than get caught up the old causation versus correlation argument, I can say unequivocally that it is naive to assume that the legalization of another intoxicant would not lead to more problems.  The suggestion that problems would be less and that society will be improved overall by the use of more intoxicants can only be seen as a blatant political ploy.  There will be more accidents, more acute toxicity, and more psychiatric morbidity due to cannabis.  I don't know if Colorado is adding up those costs and trying to compare them to any advantages of legalized cannabis, but I would not be surprised at all if Colorado taxpayers don't incur more liability from cannabis than revenue.

Before any cannabis promoters attempt to teach me about the costs of alcohol - read this blog.  There is more posted here on the costs of alcohol than you will find in most places.  My point is not that alcohol doesn't cost more.  My point is fairly obvious and that is every time you add an intoxicant to society it costs you something.  It is not free or a net benefit.   Once cannabis is legal in all 50 states it will be easier to estimate the total damage.

The other article that came out last week had to do with the 420 holiday and a very interesting plot by Staples and Redelmeirer (see Figure 1).  In this essay the authors look at the 420 holiday which is a celebration of cannabis.  The celebrants gather for mass consumption of cannabis. They studied 25 years of fatal crash data between the hours of 4:20PM and 11:59PM on April 20 and compared the crashes at that time to crashed on control days (April 13 and April 27 during the same time interval).  The Forest Plot below shows the findings across a number of comparisons.

The risk of fatal crashes was higher on 420 and significantly higher for younger drivers. On geographic analysis absolute risk of a fatal crash was highest in New York, Texas, and Georgia.  Relative risk (see original article) was decreased only in Minnesota.  The authors comment that even though the majority of the population does not celebrate 420 (or even know that it exists) the traffic accident risk is similar to what is seen on Super Bowl Sunday and policy makers might want to take this into consideration.  So might anyone interested in the drunken driving issue.  Is it possible that cannabis intoxicated drivers as a population are more impaired than alcohol intoxicated drivers?

Those are the considerations from last week.  I am sure that more will occur as the United States legalizes cannabis in very state and as it becomes a legitimate industry.  An issue flagged by the CDC several years ago was the use of synthetic cannabinoids in order to avoid occupation related drug screens, but their initial data was from a time before cannabis was legalized in Colorado.  And once again this post is not an argument for or against legalization.  I hope that I have been quite explicit in saying that I anticipate widespread legalization of cannabis.

This post and most of the posts on this blog are to document the expected fall out from increasing the amount of intoxicants consumed by the population. It is neither benign or beneficial as suggested by the advocates.   


George Dawson, MD, DFAPA



References:

1: Staples JA, Redelmeier DA. The April 20 Cannabis Celebration and Fatal Traffic Crashes in the United States. JAMA Intern Med. 2018 Apr 1;178(4):569-572. doi: 10.1001/jamainternmed.2017.8298. PubMed PMID: 29435568; PubMed Central PMCID: PMC5876802.

2: Colorado Attorney General Announces Indictment of Massive Illegal Marijuana Trafficking Conspiracy. June 28, 2017.

3: Wang GS, Hall K, Vigil D, Banerji S, Monte A, VanDyke M. Marijuana and acutehealth care contacts in Colorado. Prev Med. 2017 Nov;104:24-30. doi: 10.1016/j.ypmed.2017.03.022. Epub 2017 Mar 30. PubMed PMID: 28365373; PubMed Central PMCID: PMC5623152.

4: Wang GS, Le Lait MC, Deakyne SJ, Bronstein AC, Bajaj L, Roosevelt G.Unintentional Pediatric Exposures to Marijuana in Colorado, 2009-2015. JAMA Pediatr. 2016 Sep 6;170(9):e160971. doi: 10.1001/jamapediatrics.2016.0971. Epub 2016 Sep 6. PubMed PMID: 27454910.

5: All Things Considered.  Colorado Gov. On How Federal Marijuana Decision Could Affect State.  January 4, 2018.



Graphics Credit:

1.  Photo at the top is a commercial cannabis grower from Shutterstock per their standard licensing agreement.

2.  Figure 1 above is reproduced with permission from [JAMA Intern Med. 2017. 178(4):569-572. doi: 10.1001/jamainternmed.2017.8298. Copyright©(2017) American Medical Association. All rights reserved." from reference number 1. License number 4335700705440.

American Academy of Sleep Medicine versus Minnesota Medical Cannabis Program

The American Academy of Sleep Medicine (AASM) came out with a position statement about the use of medical cannabis for obstructive sleep apnea (OSA).  In brief they think it is not a good idea.  The entire statement can be read at the link.  I think that it is important to keep in mind that they concerns about safety and efficacy are generally dependent on the fact that like most of the conditions on the Minnesota list,  there is minimal to no scientific data to back up the suggested uses.

The AASM is not the first professional society to take a position on medical cannabis.  One of the first purported applications of medical cannabis was for glaucoma.  The American Academy of Ophthalmology has a position statement on Cannabinoids for Glaucoma  that reviews the history of this application and concludes that although cannabinoids can lower intraocular pressure, the duration of this effect is too short and the side effect profile too problematic for cannabinoids to be used for this application.  The statement points out that long acting cannabinoids for this application were recommended by the Institute of Medicine in 1999, but as of 2018 statement - there has been not suitable cannabinoid derivative.

That brings me back to the familiar refrain on this blog and that is the fallacy that cannabinoids or any street drug for that matter represents some form of miracle drug. Humans have been aware of cannabis for many applications for about 5,000 years.  A reasonable question is why some miracle application or even one less than a miracle has not been found at this point in time.  Why for example, were opioids developed as effective pain medications from the natural compounds over the same period of time?  I have attended the lectures on physicians who advocate for medical cannabis.  Some of them invoke Chinese medicine and quasi-scientific explanations like the entourage effect  about why the whole plant needs to be smoked. I don't really see a need for physicians to certify people to access these largely unproven treatments, especially when medical colleagues are describing them as potentially unsafe and ineffective.

I have no problem with the state of Minnesota supplying medical cannabis to people with a condition that has no clear cut treatment. I have no concerns about the state supplying cannabis to people who are terminally ill.  I do have a problem when cannabis is listed as a treatment when in fact there is little to no evidence that it is effective and vastly superior treatments exist.  Glaucoma and obstructive sleep apnea are two of these conditions.  From a purely psychiatric standpoint post traumatic stress disorder, and autism have existing treatments and autism has a newly approved treatment.  In the case of Tourette's syndrome and other movement disorders - the data remains very preliminary.     

As a prescribing physician, I have serious doubts about the thinking that goes into prescribing cannabis as an actual medication.  I prescribe medications every day.  These medications are all approved for use by the FDA.  There are specific indications and off label uses. There are potentially serious side effects.  The medications have to be prescribed to take the patient's chronic illnesses into account.  For example, I would not prescribe a sedative to a patient who I thought might have obstructive sleep apnea.  Prescribing cannabis, even in a special program that eliminates smokable cannabis continues to not make any sense to me. 

The list at the top of this page is directly from the Minnesota Medical Cannabis program as of today.  It lists all of the current conditions that qualify a person to take it.  I see the list as a political compromise to delay and potentially thwart the recreational marijuana movement.  It should not be a surprise that medical cannabis has always been a mainstay of the strategy to legalize recreational marijuana.  While that drama plays out - I hope that people in Minnesota don't forgo effective medical treatment for medical cannabis.  Today that means CPAP for obstructive sleep apnea and glaucoma drugs and surgery for glaucoma.

There is no evidence that medical cannabis can come close to the medical effectiveness of those options. At the political level - this is also a great example of how politics negatively impacts quality medical care.


George Dawson, MD, DFAPA


References:

1:  Ramar K, Rosen IM, Kirsch DB, Chervin RD, Carden KA, Aurora RN, Kristo DA, Malhotra RK, Martin JL, Olson EJ, Rosen CL, Rowley JA; American Academy of Sleep Medicine Board of Directors. Medical cannabis and the treatment of obstructive sleep apnea: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2018;14(4):679–681.

2:  Petitions to Add Qualifying Medical Conditions to the Medical Cannabis Program.  This document documents the review process for adding qualifying conditions to the list.  Link 



Graphic: 

The table at the top of this post is directly from the Minnesota Medical Cannabis web site and is used here as a public document.

First FDA Approved Cannabis Product - Epidiolex

Cannabidiol (CBD)

Headlines yesterday were that the FDA Peripheral and Central Nervous System Drugs Advisory Committee approved a cannabis product for the treatment of seizures.  The draft agenda for that meeting is available on the FDA web site but no vote or minutes of the meeting.  This has been a widely hyped application of medical cannabis since the term was first used to try to start the legalization of cannabis products.  Ironically the first example of a patient used as an example for this application did not have the syndrome in question.

At the  time I am typing this post there is no FDA approved package insert for the compound and no prescribing information available on the manufacturer's website.  There is a considerable amount of detail in the patent that is available online.  The patent focuses on the use of cannabidiol in treatment resistant epilepsy including Dravet syndrome; myoclonic absence seizures or febrile infection related epilepsy syndrome (FIRES). The patient states that when  cannabidiol is used for these disorders the total reduction in seizure frequency is 50-70% but as high as 90-100%.  The product is formulated to be used separately or with other anti-epileptic drugs (AED).  The patent suggests that the formulation is comprised of highly purified cannabidiol extract (98% w/w) with most of the psychoactive components - tetrahydrocannabinol (THC) removed.

The epidemiology and treatment of epilepsy especially Dravet's syndrome is reviewed in the patent.  It is clear from that data that there are no good treatments for these disorders and that conventional AEDs are partially effective at best.  The four treatment scenarios (non of which are randomized controlled clinical trials) all demonstrate efficacy for CBD in intractable epilepsy.  These results are included in the table below.

Trials	Treatment	General Response	Best Response
N=27 children and young adults Dx: severe childhood onset treatment resistant epilepsy (TRE)	Initial dose: CBD 5mg/kg/day titrated to a max of 25 mg/kg/day in addition to baseline AEDs	-after 3 months of therapy, 48% of patients had an equal to or greater than >50% reduction in seizures. -	- 2 patients were seizure free at three months - 6 patients had a 90% reduction in seizures at three months
N=9 children and young adults with treatment-resistant Dravet syndrome	- as above	- after 3 months of therapy, 56% of patients had an equal to or greater than 50% reduction in seizures,	- 2 patient were seizure free at three months -3 patients has a 90% reduction of seizures at three months
N=4 patients with myoclonic absence seizures who were taking at least two concomitant anti-epileptic drugs	-as above	after 3 months of therapy, 2 of the patients had an equal to or greater than 50% reduction in seizures, 1 patient (25%) had a 90% reduction at the three month stage.	-0 patients were  seizure free -1 patients with a 90% reduction of seizures at three months
N=3 patients with FIRES (febrile infection related epilepsy syndrome)	-as above	- 2/3 children has a 90% reduction in seizures	-2/3 children had a 90% reduction in seizures and regained some motor and intellectual functioning.

In these studies no patients were withdrawn because of side effects.  Common adverse events were somnolence, fatigue, decreased appetite, increased appetite and diarrhea.  Given the degree of polypharmacy it is probably difficult to determine what side effects are due to CBD and either the other compounds or interactions with the other compounds.   All patients had severe epilepsy with hundreds to thousands of seizures per month and in many cases required episodic aggressive treatment to stop status epilepticus.  In this population, placebo response would be expected to be very low.  The use of CBD in this population could easily be justified on a compassionate use basis because of illness severity and the lack of any severe complications from the CBD.  The results of these open label trials appear to be complied in reference 1.  Some of the authors have also published a review and  randomized, placebo controlled dose ranging study of the safety of CBD.  I cannot imagine that there was not an efficacy arm to that study.  There is also a 2017 commentary that looks at the general question about whether there is adequate evidence that CBD is effective for epilepsy(4).

A mysterious part of the patent process is that this is a simple organic chemistry extraction of CBD from cannabis plants and then resuspending for oral dosing.  The authors specify that THC is essentially removed.  The dosing is done in a standard mg/kg dose that would be expected for any medication. That dose range appears to be part of the patient. Does this patent mean that any CBD extracted from cannabis is the intellectual property of this company or is there more to it than that?  If that is the case then any product with a CBD/THC ratio could be patented and there are currently 11 of these compounds prepared by a similar extraction process in the Minnesota Medical Cannabis Program.  Is each one of these compounds patentable? Or is there some additional information about the formulation that is not included in the patent that would make this formulation more unique? At one point the patent states that the CBD can be synthesized as well as extracted.

The market for this product is potentially significant, if it works in less severe forms of epilepsy. Will it work for example in the case of a person who has a few seizures per month after their AEDs have been optimized?  Can that person take the necessary dose of CBD and not experience significant side effects?  Will the company or other companies try to get another FDA approved indication for CBD related products from the FDA? I suspect the standard will be higher in patients where there are compounds of equal or better efficacy.  Will physicians prescribe CBD derived drugs off-label to people requesting them for philosophical reasons (eg. I want to be treated with a substance derived from a botanical)?  Will the positive effects noted in these small trials persist as more and more people with epilepsy are exposed to the drug?  Will there be more significant side effects with post marketing surveillance and maintenance use? There are still a significant number of people who do not appear to respond very well to CBD.  Those are some of the questions I had considering the implications of this product release.

On theoretical grounds, a key question is whether the utility of this compound in severe epilepsy will lead to additional drug discovery of more compounds for this difficult to treat problem.  For now, the FDA has made a sound decision getting this compound into the hands of the physicians who treat these disorders on a day to day basis.


George Dawson, MD, DFAPA


References:


1:  Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016 Mar;15(3):270-8. doi: 10.1016/S1474-4422(15)00379-8. Epub 2015 Dec 24. Erratum in: Lancet Neurol. 2016 Apr;15(4):352. PubMed PMID: 26724101.

2:  O'Connell BK, Gloss D, Devinsky O. Cannabinoids in treatment-resistant epilepsy: A review. Epilepsy Behav. 2017 May;70(Pt B):341-348. doi: 10.1016/j.yebeh.2016.11.012. Epub 2017 Feb 8. Review. PubMed PMID: 28188044.

3: Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, Greenwood S, Morrison G, Sommerville K; GWPCARE1 Part A Study Group. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018 Apr 3;90(14):e1204-e1211. doi: 10.1212/WNL.0000000000005254. Epub 2018 Mar 14. PubMedPMID: 29540584

4:  Perucca E. Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last? J Epilepsy Res. 2017 Dec 31;7(2):61-76. doi: 10.14581/jer.17012. eCollection 2017 Dec. Review. PubMed PMID: 29344464.

5:  FDA Briefing Document Peripheral and Central Nervous System Drugs Advisory Committee Meeting April 19, 2018 NDA 210365Cannabidiol

A Report From The Minnesota Medical Cannabis Program

I have described the Minnesota Medical Cannabis Program in a previous post.  It is a unique program because it does not provide smokable cannabis for medical purposes.  All of the cannabis is in a form that is vaporized, edible, absorbed through the oral mucosa, or transcutaneously after application to the skin.  It is produced by two companies and made into products of varying amounts of  tetrahydrocannabinol (THC), cannabidiol (CBD) .  In the original matrix from the first post there appeared to be a total of about 11 products based on the THC and CBD ratios. For the purpose of this report the cannabis products were classified base on ratios of cannabinoids and route of administration according to the following table:

The program came out with a report on the experience of patients with chronic intractable pain using the program this week.  They produce frequent reports and this is the latest. Although it is not a scientific study of the associated issues of pain relief it is interesting because of a number of considerations not the least of which is what happens when a state starts to manage a CSA Schedule 1 drug on their own and come up with their own process for certification and use.

The report details the cohort of patients who were qualified on the basis of intractable pain according to the following definition:  “pain whose cause cannot be removed and, according to generally accepted medical practice, the full range of pain management modalities appropriate for this patient has been used without adequate result or with intolerable side effects.” (p 4).

The report focused on the results and side effects of 2245 patients certified by various practitioners for intractable pain between August 1, 2016 and December 31, 2016. It contains basic demographics of the patients and practitioners as well as a breakdown of the possible origins of their chronic pain.  All of these details are available in the original report and I encourage any interested reader to find the details there.  I am interested in the type of medical cannabis being used and the outcomes.

These details are fairly interesting from a descriptive standpoint. For example, just using the product definitions there is a distribution of how the products are purchased.  The following bar graph illustrates the distribution of purchased products by THC and CBD content:

 
The report gets into more specific details about the types of THC and CBD products in each category and the average ingestion of these products per day in milligrams (mg). I am reproducing the first of a 4 page table here that contains progressively fewer patients in each strata:

It is apparent that very high THC products that are inhaled or ingested predominate the product distribution.  Although the largest single group of patients were averaging 81.5 mg/day THC and 0.6 mg/day CBD the range is significant from 4.4 to 553.8 mg/day THC and 12.2 to 1,439.2 mg/day CBD.

Patient and treatment providers were asked to rate their degree of benefit from the medical cannabis program on a Likert scale where 1 = no benefit and 7 - great deal of benefit.  Using that system 61% of the patients rated their experience as a 6 or 7 compared with 43% of the healthcare professionals rating the patient benefit as a 6 or 7.  Specific benefits were rated and the top three included pain relief (56%), sleep improvement (10%), and reduction in pain medications and side effects (7%). 

An area of interest in the report is whether or not the patient is reducing the amounts of other pain medications used in response to the use of medical cannabis. This question is asked to the certifying health care professionals.  For this report, 586 responses of a total of 692 were used to determine that pain medications were reduced in 58% of the cases and not reduced in 48% of the cases.  221 reduced an opioid with 127/221 reducing the opioid by 50% or more.  In addition, 16 reduced a benzodiazepine and 128 reduced a pain medication "other than an opioid or benzodiazepine" - but benzodiazepines are not pain medications.  The full list of medications reduced or discontinued are available in Appendix E.  Minnesota does have a Prescription Monitoring Program for controlled substances making it possible to quantify and confirm all of this data rather than depending on survey results.

The section of the report that I found most interesting was the section on a standard group of 8 symptoms followed in this patient group for improvement or no improvement.  These symptoms are listed in the tables below.

The response options are on a standard analogue scale where 10 is the worst possible symptom and 0 is the symptom is not present.  The report listed the results of this scale applied to intractable pain patients as shown in the table below.

It is an interesting report in that it gives improvements in symptoms over 4 months as well as the percentage of patients a 30% improvement in symptoms at some point in the initial 4 months, the percentage of patients who had a 30% symptoms improvement in the 4 month follow-up period, and the percentage of patients who had the 30% symptoms improvement and maintained it for at least 4 months.  Only 11% of the pain patients maintained a 30% improvement in pain symptoms over the 4 month follow up despite higher ratings of initial pain relief.  The most significant improvements were in nausea and vomiting.

Side effects were reported in the final section with about 10% of patient reporting severe side effects.  These side effects included somnolence, sedation, headaches, dizziness, lightheadedness, confusion, fatigue, abdominal pain, mental fogginess, inability to concentrate, anxiety, panic attacks, and insomnia.  Physical side effects were reported roughly twice as often as mental side effects and most were in the mild to moderate range.  A typical metric found in clinical trials - medication discontinuation because of side effects was apparently not determined.  In a series of statements included in the report, one patient stopped because of a lack of efficacy and there was a suggestion that stopping could occur for that reason or financial reasons but the data was not clear.

Although the current report is focused on intractable pain a couple of things seems clear.  First, these reports are not scientific.  There are no comparison drugs or placebos.  Medical cannabis is added in many cases to a combination of existing opioid pain medications and benzodiazepines.  In a purely qualitative sense, they do show what products are preferred by customers and these products contain significant amounts of THC.  Second, in the case of the 8 symptom rating pain relief from medical cannabis appears to be modest at best.  A significant number of patients acknowledged severe side effects, but were these side effects of the same level of severity that might be seen in a clinical trial?  In those patients who replaced opioids or to a lesser extent benzodiazepines - was that because the initial medications were ineffective for pain or because cannabis has superior effects on pain?

The most interesting part of the data to me is that fact that medical cannabis is highly promoted for chronic pain.  That promotion was initially political - for the purpose of legalizing medical cannabis.  Currently it takes the form of cannabis saving people from opioid overdoses and this report makes an attempt to record reduced amounts of opioids use due to the cannabis. The problem is that it is all survey data.  There are no standardized doses of cannabis and no attempt to determine a placebo effect.  Physicians used to reading clinical trials need to ask themselves: Is a patient interested in using medical cannabis in Minnesota capable of answering the questions in an unbiased manner?  Will their interest/belief in medical cannabis influence survey results? And if that is true - what does it mean that medical cannabis ends up with such a poor result for pain relief over a period of 4 months?  I have concerns about the survey results based on my interviews with thousands of cannabis smokers.  Although I am seeing people with significant addiction problems, I don't see the side effect frequency of insomnia, anxiety, panic, and paranoia that I am used to hearing hearing about.  And in this group, I can't help but wonder how many of them have significant addictions? I also don't see a discussion of the fact that many opioid users commonly switch to cannabis when the opioid supply runs low or they make an attempt to stop using. There are potentially several mechanisms occurring in this population in addition to pain relief and side effects.

Another issue indirectly addressed by this report is what happens when you do an end run around the FDA?  I have certainly been a critic of the FDA and its regulatory processes, but in the end there is always a study available for public discussion.  That study typically has much more information content about drug efficacy and tolerability than the current Minnesota study because of the scientific design.  This report is the type of data that you get when that regulatory hurdle is ignored.

The direction and legacy of medical cannabis in Minnesota seems to be contingent on the status of recreational cannabis.  The program has been criticized for being too expensive compared with smokable cannabis.  If Minnesota legalizes recreational cannabis, that may be the preferred route by many of the people in this program. Questions about the efficacy of cannabis in intractable pain remain unanswered despite all of the details in this report.



George Dawson, MD, DFAPA


References:

1:  Minnesota Department of Health Office of Medical Cannabis.  Intractable Pain Patients in the Minnesota Medical Cannabis Program: Experience of Enrollees During the First Five Months. Report

2: Desrosiers NA, Ramaekers JG, Chauchard E, Gorelick DA, Huestis MA. Smoked cannabis' psychomotor and neurocognitive effects in occasional and frequent smokers. J Anal Toxicol. 2015 May;39(4):251-61. doi: 10.1093/jat/bkv012. Epub 2015 Mar 4. PubMed PMID: 25745105.


Graphics:

All tables excerpted from reference 1 as a public document with no copyright.

Sensational Antidepressant Article from the New York Times

Take some quotes taken out of context, the suggestion that doctors know less about the problem than the New York Times does, and the suggestion that you may be "addicted to antidepressants" and what do you have - the latest article on antidepressants by the New York Times.  Although the New York Times has never been an impressive resource of psychiatric advice they continue to play one and the latest article  Many People Taking Antidepressants Discover They Cannot Quit is a great example.

The reader is presented with numbers that seem to make the case "Some 15.5 million Americans have been taking the medications for at least five years. The rate has almost doubled since 2010, and more than tripled since 2000." and "Nearly 25 million adults, like Ms. Toline, have been on antidepressants for at least two years, a 60 percent increase since 2010."  Guaranteed to shock the average reader, especially in a culture that systematically discriminates against the treatment of mental illness.

Adding just a little perspective those figures translates to 15.5M/254M = 6.1% and 25M/254M = 10% of the adult population in the US.  Looking at the most recent epidemiological estimates of depression in the US 1990 - 2003 shows one year prevalences of 3.4 - 10.3% of the adult population.  The lifetime prevalences from some of those studies 9.9-17.1%.  It seems that the claims of antidepressant utilization may be overblown relative to the epidemiology of depression and the number of people disabled by it.  The authors go on to quote a study on the overutilization of antidepressants on data obtained from the National Health and Nutrition Examination Survey (NHANES) study.  These same authors have quoted an increase of antidepressant use of 10.4%.  This same study estimated a lifetime prevalence of depression of 9.5%.

Depression alone is not the sole indication for antidepressants. Anxiety disorders is another FDA approved indication.  Anxiety disorders can add an additional 3% 1 year prevalence and 5-6% lifetime prevalence.  About 16.5% of the population has headaches and antidepressants are used to treat headaches.  Another 6.9-10% of the population have painful neuropathies that are also an indication for antidepressant treatment.  Over a hundred million Americans have chronic back pain another indication for a specific antidepressant.  The main reference points to a study (3) that suggests only about 7.5% of antidepressants are prescribed for nonpsychiatric conditions.  Only 65.3% of the prescriptions were for "mood disorders. A study looking at antidepressant drug prescribing in primary care settings in Quebec Canada (5) provides specific data and concludes that  29.4% of all antidepressant prescriptions were not for depression or anxiety but for insomnia, pain, migraine, menopause, attention-deficit/ hyperactivity disorder, and digestive system disorders. Those same authors go on in a subsequent paper to provide a detailed analysis of the off-label use of those antidepressants.

The number of antidepressant prescriptions is far less drastic when taken in that context.  I am not arguing that every person with an eligible condition should be on antidepressants.  I am definitely saying that given the large numbers of people who will potentially benefit - the number of antidepressant prescriptions is not as outrageous as portrayed in the article.

What follows is a brief descriptions of antidepressant discontinuation symptoms and the fact that the medical profession doesn't know what to do about it.  This is certainly not the case in any setting where I have practiced. Discontinuation symptoms are well know to occur with SSRI and SNRI medications.  I routinely describe them and their varying intensity as part of the informed consent procedure when I prescribe these medications. The reality is that 20% of people will stop taking antidepressants in the first month after getting a prescription. Many will just get the prescription and never start.  An additional 20-30% will stop in the next 3-4 months.  Stopping antidepressants without medical guidance is so common that I routinely ask patients if they have abruptly stopped at any point when I am making any changes in their medications.  The majority have stopped without getting any of the discontinuation symptoms.  I qualify that by the fact that I have not prescribed paroxetine in 30 years because I considered it to be a problematic medication and I have a very low threshold for stopping antidepressants if I don't believe they are tolerated.  Even in their referenced study (2) the authors state: "In one national study, for example, only about one-quarter of adults initiating antidepressants for new episodes of depression continued to take their medications for 90 days...".  Does that sound like it is a medication that is difficult to stop?

They don't stop there.  After making it seem like we are in the midst of an antidepressant epidemic and that people are unable to stop antidepressants they make an even more absurd argument - doctors are unable to help patients get off antidepressants.  Before I go into their details consider this.  I work at a facility where we routinely detox people off high doses of the most addictive drugs in the world.  If we are able to do that, why would a doctor not be able to figure out how to discontinue a non-addictive antidepressant?  This specific statement really had me rolling my eyes:

"Yet the medical profession has no good answer for people struggling to stop taking the drugs — no scientifically backed guidelines, no means to determine who’s at highest risk, no way to tailor appropriate strategies to individuals."

Do I really need a study to do something that I have been doing successfully for 30 years?  Tapering people off of medications is something that every physician has to do.  Successfully using antidepressants means being able to taper and discontinue one and start another or taper and discontinue one while starting another or starting another and eventually tapering and discontinuing the original antidepressant.  That is not innovation - that is standard psychiatric practice.

I can only hope that the quotes from family physicians that follow were totally out of context.  Statements about "parking people on these drugs for convenience sake." and that the "state of the science is absolutely inadequate" are ludicrous.  I would say if you have to park somebody on a psychiatric drug or have questions about how it is used - it is time to send that patient to see a psychiatrist.  Nobody should ever be "parked" on a drug.

These physicians seem to have lost sight of the fact that they do not have similar problems prescribing equal amounts of antihypertensive medications and leaving people on them indefinitely.  There is no rhetoric about "parking" somebody on an antihypertensive medication or a cholesterol lowering drug or a medication for diabetes.  The fact that depression is the leading cause of disability in the world seems to be ignored.  The fact that up to 15% of people with depression die by suicide is not mentioned.  The suggestion is that this disabling and potentially fatal condition should not be addressed as rigorously as other chronic illnesses.

In the midst of all of the confusion created in this article, the authors fail to point out the likely cause of increased antidepressant prescriptions but they quote one psychiatrist who comes close.  He points out that the increase in antidepressants is due to primary care physicians prescribing them after brief appointments and (probably) not being able to follow the patient up as closely as a psychiatrist.  This was one of the main findings in the paper by Mojtabi and Olfson (2).  The specific quote "...the increase in long-term use (of antidepressants) was most evident among patients treated by general medical providers."

What is really going on here?  This blog has repeatedly pointed out that mental health care and treatment by psychiatrists has been rationed for about 30 years.  The result of that rationing is that there are few reasonable resources to treat all kinds of mental illnesses.  With that end result, the argument is now being made that we really don't have to build the infrastructure back up - we just need to shift the burden to primary care clinics.  In order to make it more simple for them we can just screen people with a rating scale for depression (PHQ-9) or anxiety (GAD-7) and treat either symptoms with a medication.  That way we can not only ration psychiatrists, but we can also ration psychologists and social workers who could possibly treat many of these patients with psychotherapy alone and no medication. For that matter, we could treat a lot of these patients with computerized psychotherapy - but managed care organizations will not.  State governments and managed care organizations will screen people, make a diagnosis based on a rating scale, and put that person on an antidepressant medication as fast as possible.

That is a recipe for high volume and very low quality work.  A significant number of those patients will not benefit from a medication because they do not have a compatible diagnosis.  A significant number will not benefit from the medication because it is not correctly prescribed.  In order to compensate for that inadequacy, a model of collaborative care exists that provides a psychiatric consultant to the primary care clinic.  That psychiatrist never has to directly see the patient.  The collaborative care model depends on putting patients on antidepressants as soon as possible and even more classes of psychiatric medication.

That is the real reason for increased antidepressant prescriptions and people taking them.  It is not because nobody knows how to prescribe them or stop them.  It is not because they are "addictive". It is because there is a lack of quality in the approach to diagnosing and treating depression in primary care settings and that is a direct result of federal and state governments and managed care organizations.


To be perfectly clear I will add a series of rules that will not question the current business and political rationing of mental health resources but will address the problem of antidepressant over prescribing and antidepressant discontinuation:

1.  Stop screening everyone in primary care clinics with rating scales - there is no evidence at a public health level that this approach is effective and it clearly exposes too many people to antidepressants and other medications.  I am actually more concerned about the addition of atypical antipsychotics to antidepressants for augmentation purposes when nobody is certain of the diagnosis or reason for an apparent lack of response and nobody knows how to diagnose the side effects of these medications.

2.  Provide any prospective antidepressant candidate with detailed information on antidepressant discontinuation syndrome - including the worse possible symptoms. While you are at it give them another sheet on serotonin syndrome as another complication of antidepressants.  It is called informed consent.  I encourage the New York Times not to write another article about serotonin syndrome.

3.  Triage depressed and anxious patients with therapists rather than rating scales - brief, focused counseling, CBTi for insomnia, and computerized psychotherapy all have demonstrated efficacy in addressing crisis situations and adjustment reactions that do not require medical treatment.

4.  Refer the difficult cases of discontinuation symptoms to psychiatrists who are used to treating it.

5.  Don't prescribe paroxetine or immediate release venlafaxine - both medications are well know to cause discontinuation symptoms and they are no longer necessary.

6.  Every physician who starts an antidepressant needs to have a plan to discontinue it - the idea that a patient needs to be on a medication "for the rest of their life" in a primary care setting is unrealistic.  If that determination is to be made - it should be made by an expert in maintenance antidepressant medications and not in a primary care clinic.

7.  Every patient should be encouraged to ask to see an expert if either their medication prescribing or treatment of depression is not satisfactory.  The standard for treating depression is complete remission of symptoms - not taking an antidepressant.  If you are still depressed - tell the primary care clinic that you want to see an expert.

In an ideal world, people with severe depression would be seen in specialty clinics for mood disorders, by psychiatric experts who could address every aspect of what they need.  That used to happen not so long ago.  It still happens in every other field of medicine.

But quality care like that is no longer an option if you have depression.


George Dawson, MD, DFAPA

References:

1: Carey B, Gebeloff R. Many People Taking Antidepressants Discover They Cannot Quit. New York Times April 7, 2018.

2: Mojtabai R, Olfson M. National trends in long-term use of antidepressant medications: results from the U.S. National Health and Nutrition Examination Survey. J Clin Psychiatry. 2014 Feb;75(2):169-77. doi: 10.4088/JCP.13m08443. PubMed PMID: 24345349.

3: Mark TL. For what diagnoses are psychotropic medications being prescribed?: a nationally representative survey of physicians. CNS Drugs. 2010 Apr;24(4):319-26. doi: 10.2165/11533120-000000000-00000. PubMed PMID: 20297856.

4: van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain. 2014 Apr;155(4):654-62. doi: 10.1016/j.pain.2013.11.013. Epub 2013 Nov 26. Review. Erratum in: Pain. 2014 Sep;155(9):1907. PubMed PMID: 24291734.

5: Wong J, Motulsky A, Eguale T, Buckeridge DL, Abrahamowicz M, Tamblyn R.Treatment Indications for Antidepressants Prescribed in Primary Care in Quebec, Canada, 2006-2015. JAMA. 2016 May 24-31;315(20):2230-2. doi: 10.1001/jama.2016.3445. PubMed PMID: 27218634.

6: Wong J, Motulsky A, Abrahamowicz M, Eguale T, Buckeridge DL, Tamblyn R.Off-label indications for antidepressants in primary care: descriptive study of prescriptions from an indication based electronic prescribing system. BMJ. 2017 Feb 21;356:j603. doi: 10.1136/bmj.j603. PubMed PMID: 28228380.