Medical Cannabis Does Not Prevent Opioid Overdoses

The political aspects of medical cannabis are undeniable. The legalization of cannabis for recreational purposes had no traction with American politicians or voters until it was promoted as a miracle drug.  With that widespread promotion medical cannabis is now legal in 33 states and recreational cannabis is legal in ten.  The legalization arguments also suggested that the US was behind other countries of the world when there are only two countries – Canada and Uruguay – where it is completely legal for medical or recreational sale and purchase.  In the world, 22 of 195 countries have legalized medical cannabis with widely varying restrictions on its use. The Netherlands is often cited as an example of recreational cannabis use, but most Americans don’t realize that it is illegal for recreational use and tolerated for use and sale only in specially licensed coffee shops.  The promotion of cannabis as a solution to the opioid overuse and chronic pain problems can be seen as an extension of the political arguments for legalization that outpace any science to back them up.

There was probably no greater hype about the purported benefits of medical cannabis than early data suggesting that it might decrease the rate of opioid overdoses (1). The sequence of events was supposed to be opioid users tapering off of opioids or using lower equivalent amounts because of medical cannabis use.  The original study covered the time period from 1999-2010 and suggested that states with medical cannabis laws had a lower mean opioid overdose mortality and that the annual rates of overdose progressively decreased over time.  The authors conclusion was:  “Medical cannabis laws are associated with significantly lower state-level opioid overdose mortality rates.”

Despite the usual caveats suggested by the authors in the original study the results of that study were heavily hyped by all cannabis promoters as was the discussion of many Internet forums.  The lay press, public, and politicians saw it as another reason to promote medical cannabis and recreational cannabis by association.

A study came out today in PNAS (2), that is an extension of the original data and it no longer comes to the same conclusion.  In this new study the authors replicated the opioid mortality estimates from the original study but when the data was extended from 2010 to 2017 – the improved opioid overdose mortality rates not only did not stay constant but they reversed themselves to that they were now on the average from -21% to +23%.  They provide an even more valuable analysis of this effect as spurious rather than a true positive or negative effect based on the low penetration of medical cannabis in the population at large (2.5%).  The authors focus on the problem of ecological fallacy – that is conclusions about individuals are drawn from aggregate data across the entire population.They point out that the states with the medical cannabis laws have a number of characteristics separating them from other states.  A recent good example of this fallacy was the New England Journal of Medicine (3,4) report that per capita chocolate consumption correlated with the number of Nobel Laureates in a particular country.  

This is a valuable lesson in scientific analysis. The political approach to the problem is all that most of the public sees. That approach is to grab any information that seems to agree with your viewpoint and run with it.  Big Cannabis and cannabis promoters have been doing this for almost 20 years now. The process of science on the other hand is slower and more deliberate.  It is not a question of a right answer but a dialogue that hopefully produces the right pathway. The authors of this study have added a lot to the dialogue about cannabis but also statistics and how statistical descriptions may not be what they seem to be. 

George Dawson, MD, DFAPA

References:

1: Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999-2010. JAMA Intern Med. 2014;174(10):1668–1673. doi:10.1001/jamainternmed.2014.4005 (full text)

2:  Shover CL, Davis CS, Gordon SC, Humphreys K.    Association between medical cannabis laws and opioid overdose mortality has reversed over time.  First published June 10, 2019 https://doi.org/10.1073/pnas.1903434116  (full text)

3: Messerli FH. Chocolate consumption, cognitive function, and Nobel laureates. NEngl J Med. 2012 Oct 18;367(16):1562-4. doi: 10.1056/NEJMon1211064. Epub 2012 Oct 10. PubMed PMID: 23050509.

4:  Pierre Maurage, Alexandre Heeren, Mauro Pesenti, Does Chocolate Consumption Really Boost Nobel Award Chances? The Peril of Over-Interpreting Correlations in Health Studies, The Journal of Nutrition, Volume 143, Issue 6, June 2013, Pages 931–933, https://doi.org/10.3945/jn.113.174813


Attribution:

Above figure is from the original article (reference 2): "This open access article is distributed under Creative Commons Attribution-Non Commercial No Derivatives License 4.0 (CC BY-NC-ND).y"  See this link for full conditions of this license.

LinkedIn Headline Throws Psychiatrists Under the Bus

There is was - plain as day on my LinkedIn feed:  "Psychiatric drugs killing more users than heroin, cocaine, say health experts".  Seems like a headline more fitting for one of the large antipsychiatry web sites out there.

What?  Addictive drugs and the current overdose situation is something that I know more than a little about.  I lecture about it.  I treat the addicted.  I was in the medical school pharmacology classes where they taught us it is practically impossible to kill yourself with benzodiazepines unless you mix them with alcohol.  Of course today we know that it is very easy to kill yourself by mixing benzodiazepines with opioids.

My first problem was the characterization that benzodiazepines are psychiatric drugs when 80% of the prescriptions are from non-psychiatrists (1).  This is a common tactic used to impugn monolithic psychiatry.  Some authors try to link the ills of all antidepressant, antipsychotic, and mood stabilizing medication to psychiatrists.  The only medication that psychiatrists prescribe more of than primary care physicians is lithium.  Most primary care physicians consider lithium to be a weird little niche drug that they would prefer psychiatrists handle.  For a while psychiatrists were also reluctant and prescribed a number of less effective medications.  Part of that was based on hype, but I am sure there was at least a partial unconscious motivation that the burden of lithium prescribing could be avoided.

The secondary argument of course is that psychiatrists are thought leaders in this area and convince the poor unthinking primary care physicians to prescribe benzodiazepines and add them to opioids!  There are no Key Opinion Leaders (KOLS) advocating for the widespread use of benzodiazepines. Instead I am asked to write about reasons to avoid prescribing them.  Since the entire class has been generic for some time there is no pharmaceutical marketing.  No - you really don't have a leg to stand on if you are making that argument.  Although antipsychiatrists don't generally have a leg to stand on - let's assume there is at least one person who is interested in the facts rather than hum-drum antipsychiatry fake news.

It turns out there is actual data out there.  Thoughtful analyses from both NIDA and the CDC that look at the issue of overdoses on various forms of opioids and cocaine, but also the various combinations of opioids plus either cocaine or benzodiazepines.  All of the data I am posting here is available at this link.  It is all public domain from employees of the US Government and they have done an excellent job with the details of the current drug epidemic.

       
The  first two slides are total death from all opioid overdoses and heroin overdoses.  Looking at 2015 those numbers are 33.091 and 12,989 respectively.  The next slide looks at total cocaine deaths.  And in 2015 that number was 6,784.

The final slide looks at benzodiazepines on their own (1,306) and benzodiazepines plus opioids (7,485).  Note that concomitant benzodiazepine use with opioids is a major risk factor for death from that combination.  The annual benzodiazepine deaths have remained relatively constant until the onset of the opioid epidemic.  It is well known that some opioid users take benzodiazepines to enhance the effects of opioids.  

To recap, if the heroin deaths in 2015 were 12,989, the cocaine deaths were 6,784 and the benzodiazepine deaths were 1,306 the headline is glaringly inaccurate.  The only way that benzodiazepines are as lethal is if they are mixed with opioids - a fairly common occurrence.  That is not a combination prescribed by psychiatrists.  The overwhelming number of deaths due to drug overdose are from opioids - 33,091/year.

These combinations have been studied in persons on maintenance opioids (methadone and buprenorphine) who are also prescribed benzodiazepines, sedative hypnotics and in a recent study (4) - pregabalin.  The authors of that study found that of their sample of 4501 patients - 32.8% were prescribed benzodiazepines, 40.8% z-drugs (zolpidem,  zopiclone, eszopiclone, and zaleplon) and 22.2% were prescribed pregabalin.  In their study, the pregabalin and z-drug prescriptions were associated with more overdose deaths and the benzodiazepines were associated with more overall deaths.

That combination accounts for the common experience of opioid and heroin overdose deaths in small towns across America.  Those overdose deaths in small town American were unheard of before the current epidemic.

It doesn't hurt to get the facts straight when attempting to throw psychiatrists under the bus, even though in the majority of cases - facts are the last thing any of the critics seem to consider.



George Dawson, MD, DFAPA



References:

1:  Cascade E, Kalali AH. Use of Benzodiazepines in the Treatment of Anxiety. Psychiatry (Edgmont). 2008; 5(9): 21-22. Link

2: Olfson M, King M, Schoenbaum M. Benzodiazepine Use in the United States. JAMA Psychiatry. 2015;72(2):136-142. doi:10.1001/jamapsychiatry.2014.1763

3: Kjosavik SR, Ruths S, Hunskaar S. Psychotropic drug use in the Norwegian general population in 2005: data from the Norwegian Prescription Database. Pharmacoepidemiol Drug Saf. 2009 Jul;18(7):572-8. doi: 10.1002/pds.1756. PubMed PMID: 19402032.

4: Abrahamsson T, Berge J, Öjehagen A, Håkansson A. Benzodiazepine, z-drug andpregabalin prescriptions and mortality among patients in opioid maintenance treatment-A nation-wide register-based open cohort study. Drug Alcohol Depend. 2017 May 1;174:58-64. doi: 10.1016/j.drugalcdep.2017.01.013. Epub 2017 Feb 28. PubMed PMID: 28315808.

Attribution:

All slides from NIH/NIDA and are assumed to be public domain.

POTUS Tweets Measures To Address Opioid Epidemic

In 2014, nearly 21,000 deaths in the U.S. involved prescription opioids. Here's what @POTUS is doing about it: https://t.co/M2HgnDDN6a

— The White House (@WhiteHouse) March 29, 2016

I happened to be on Twitter last night when I caught the above Tweet from POTUS.  Having a professional interest, I decided to follow the link at the White House blog to look at the proposed measures.  They were listed as:

1.  Increasing a key drug for medication assisted treatment.  That key drug is buprenorphine in a number of formulations for treating severe opioid dependence.

2.  Preventing opioid overdose deaths.  This appears to be $11 million in funding for various forms of treatment and increasing access to naloxone to reverse the effects of an acute overdose.

3.  Addressing substance use disorder parity with other medical and surgical conditions.

These are very modest and in some cases unrealistic proposals about about trying to stop a drug epidemic that is killing 20,000 people a year.  Let me tell you why:

1.  Increasing a key drug for medication assisted treatment.  That key drug is buprenorphine in a number of formulations for treating severe opioid dependence.

Buprenorphine as Suboxone and Subutex have been available for the treatment of opioid addiction in the US since 2002.  The current evidence suggests that buprenorphine has superior efficacy for abstinence from opioids and retention in treatment.  There is also evidence that patients on buprenorphine have fewer side effects and that they is a less severe neonatal abstinence syndrome in mothers maintained on buprenorphine versus methadone.   Buprenorphine is also used for acute detoxification and treatment of chronic pain.  One of the limitations of maintaining opioid addicts on buprenorphine is that a special license is required to prescribe it.  Physicians can obtain that license by by attending CME or online courses.  Even then, expansion to primary care physicians has been slow because they may have no colleagues in their practice with similar certification and that makes on call coverage problematic.  In addition, many clinics that are medically based are reluctant to provide this type of service to people who have opioid addictions.  Apart from the technical requirements of prescribing the various preparations of buprenorphine certain physician and patient characteristics may also be important.  Physicians have to be neutral and not overreact in situations where the patient exhibits expected addictive behaviors that may include relapse.  As an example, younger opioid users are frequently ambivalent about quitting and in some cases, use other opioids and reserve the buprenorphine for when their usual supply dries up.  They may sell their buprenorphine prescription and purchase opioids off the street.  It may not be obvious but physicians prescribing this drug need an interpersonal strategy on how they are going to approach these problems.    On the patient side,  there is the biology of how the opioids have affected the person.  Do they have severe withdrawal and ongoing cravings?  What is their attitude about taking a medication on an intermediate or long term basis in order to treat treat the opiate addiction?

In clinical trials, buprenorphine seems to be ideal medication for medication assisted treatment (MAT) of opioid dependence.  Like most medications, there are issues in clinical practice that are not answered and possibly may never be answered.  The issue of life-long maintenance is one.  Many people with addictions are concerned over this prospect.  Long term maintenance with buprenorphine has advantages over methadone in that it is easier to get a prescription rather than show up in a clinic every day to get a dose of methadone.  Most addicts are aware of the fact that withdrawal from both compounds can be long and painful.  This deters some people from trying it and relapse risk is high if a person attempts to taper off of it.  Despite the current consensus about use. there is still the problem of young addicts who feel that they are "not done using" and who go between using heroin and other opioids obtained from non-medical sources and buprenorphine.  

2.  Preventing opioid overdose deaths.  This appears to be $11 million in funding for various forms of treatment and increasing access to naloxone to reverse the effects of an acute overdose.

Naloxone kits that would allow for rapid reversal of opioid overdoses have been shown to be effective in partially decreasing the death rate.  At some treatment and correctional facilities opioid users are discharged with naloxone kits for administration in the event of an overdose.  Opioids are dangerous drugs in overdose because they suppress respiration and that can lead to a cardiac arrest.  There are several properties of opioids that heighten the overdose risk.  Tolerance phenomena means that the user eventually becomes tolerant to the euphorigenic and in some cases therapeutic effects of opioids and needs to take more drug.  If tolerance is lost when the user is not taking high doses for a while, using that same high dose can result in an overdose.  Taking poorly characterized powders and unlabelled pills acquired from non-medical sources compounds the problem.  The exact quantity of opioid being used is frequently unknown.  Adulterants like fentanyl - a much more potent opioid can also lead to overdoses when users do not expect a more potent drug.

In addition to the pharmacology of the drugs being used there is also a psychological aspect to overdoses.  Users often get to the point where they don't really care how much they are using in order to get high.  They will say that they are not intentionally trying to overdose, but if it happens they don't care.

The available literature on making naloxone available suggests that it is effective for reversing overdoses in a fraction of the at risk population that it is given to.  I would see at as the equivalent of an Epi-pen in that the majority of patients with anaphylactic reactions get these pens refilled from year to year but never use them.  When they are required they are life-saving.  The problem with a naloxone kit is that it assumes a user or bystander can recognize an overdose and administer naloxone fast enough to reverse the effects of opioids before the user experiences serious consequences.  Unfortunately addiction often leads to social isolation and not having a person available makes monitoring for overdoses much more problematic.  Naloxone kits should always be available opioid users, first responders, family members, and anyone involved in assisting addicts.  Detailed long term data on the outcomes over time is needed.  

3.  Addressing substance use disorder parity with other medical and surgical conditions.

The is the most critical aspect of the President's tweet.  One of the main reasons for this blog is to point out how people with addictions and severe mental illnesses have been disproportionately rationed since the very first days of managed care - now about 35 years ago.  Some of the first major changes involved moving medical detoxification out of hospitals.  So-called social detoxification was available with no medical supervision.  These non-medical detox facilities were very unevenly distributed with only a small fraction of the counties in any state running them.  Any admissions to hospitals were brief and "managed" by managed care companies.  In the case of addictions some of the management practices were absurd.  A standard practice was to determine how many days a person could be in residential treatment.  That often required a call to an insurance company nurse or doctor who had never seen the patient.  They could determine that the patient could be discharged at any time based on arbitrary criteria.  In some cases that involved just a few days and the patient was leaving with active cravings and in some cases an an active psychiatric disorder.  This practice continues today, despite party legislation that suggests that addictions and mental disorders should be treated like any other medical problem.

This is where the President's tweet is on very shaky ground.  His legislation  focuses on large systems of health care and yet these systems don't seem to be able to supply adequate treatment with either buprenorphine or naloxone kits.  The President is fully aware of the The Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 (MHPAEA).  That act was supposed to provide equal treatment for mental illnesses and addictions that was on par with medical and surgical conditions.  I think it is no secret that special interests have shredded the intent of this bill to the point that it is useless.  Managed care systems still ration care for these disorders in their best financial interest.  The resources for treating these disorders are still not equal to the task. In the case of prescription painkillers the same system of care not providing adequate treatment for addiction is often where that addiction started.

All three of the President's points could be addressed by forcing health care companies to provide adequate care for addictions and mental illnesses instead of grants to provide services that they should be doing in the first place.  In an interesting recent twist the President (1) suggested that this discrimination was based on race.  He implied that as a result the police rather than doctors have been used to address the problem.

Let me be the first to say that President Obama is wrong.  There is no doubt that racial discrimination exists.  There is no doubt that it occurs in systems of health care (2,3).  There is also no doubt that all it takes is a diagnosis of addiction or mental illness to trigger highly discriminatory health care coverage - irrespective of a person's race.  It is all about how health care businesses make money in this country by rationing or denying treatment for these disorders.

To reverse that discrimination,  the government needs to take the MHPAEA seriously.  So far they have failed miserably and that is the problem on the treatment side in trying to address the opioid epidemic.  

George Dawson, MD, DLFAPA

References:

1:  Sarah Ferris.  Obama: 'We have to be honest' about race in drug addiction debate.  The Hill March 29, 2016.

2:   Eddie L. Greene, MD and Charles R. Thomas, Jr, MD.  Minority Health and Disparities-Related Issues: Part I.  Medical Clinics of North America July 2005; 89(4).

3:   Eddie L. Greene, MD and Charles R. Thomas, Jr, MD.  Minority Health and Disparities-Related Issues: Part II.  Medical Clinics of North America July 2005; 89(5).

  

Opiates And Moral Dilemmas For Physicians

I became aware of an article from Reason magazine written by a physician Jeffrey A. Singer titled Physicians Face A Moral Dilemma In Conscription on War on Drugs (1). In keeping with the main theme, the subtitle was “In the government’s new war on opiates, physicians and their patients find themselves caught in a crossfire.”  Physicians are generally in the crossfire of any number of government healthcare reforms. The opening lines of this essay should not surprise any physician.  We have been in the crosshairs for thirty years.  There is a tangible difference in the War on Drugs.  In the 1990s, I can recall a vague threat about incarceration for not doing my notes properly.  That wasn’t a threat to me specifically but an entire clinic of physicians than I belonged to at the time.  In retrospect it sounds absurd, but that the was pre-911 days when the FBI spent a lot of time reading physician notes and deciding whether or not they had committed health care fraud by not doing enough documentation.  These days physicians can be prosecuted and incarcerated for the way that they prescribe opiates. The threat is much more real.

Dr. Singer’s introductory paragraph points out that when any health crisis occurs politicians are eager to step up and offer their solutions and throw a lot of money at the problem.  In this case President Obama is building new drug addiction centers and “training” government physicians on opioids to the tune of $100 million.  Hillary Clinton is promising $10 billion as a criminal justice initiative as grant for drug treatment centers and training for first responders to administer opiate antidotes.  I have never seen a single politician or government bureaucrat acknowledge that the reason why the opiate epidemic exists has to do with policy initiatives that occurred right around the year 2000.  At that point, physicians were encouraged to treat pain more aggressively and with fewer checks and balances than they had in the past.  The cumulative effect of these policy changes was a lower threshold for prescribing opiates for chronic noncancer pain and a removal of some of the gatekeeper mechanisms – like getting second opinions from pain specialists on this practice.

The First War on Drugs was described as the initial prohibition of opiates and cocaine by the Harrison Act in 1914.  Singer describes a scenario where a physician who would prescribe an opiate to help a patient “cope with their addiction” as being in conflict with the law.  The Harrison Act prohibited physicians from prescribing opiates to maintain an addiction.  He cites this example as being the first moral dilemma.  It is more complicated than depicted.  There have always been a number of physicians who consciously or unconsciously maintained large numbers of patients in addiction and that was their medical practice.  That practice does not pass current conflict of interest considerations much less the ethical obligation of physicians to do no harm.  It is a given that legal interventions are generally blunt instruments for protecting people from their problematic decision-making and that a complete picture of all of the data (the number of people addicted by medical treatment versus non-medical sources) is never clear.  Is there a problem with suggesting that physician themselves should not be a primary source for creating and maintaining addiction?  The main problem is that even the most well-informed and well-intentioned physician can end up with a patient who is addicted to a medication.  There is currently no known way to prevent that.  Are those physicians criminals in any way?  I don’t think so.  At the same time, should there be a prohibition against physicians setting up a practice that maintains high number of patients in addiction, does nothing to facilitate their recovery from addiction, and has no other purpose – of course there should be such a prohibition. 

The next argument in the essay has to do with the safety of opiates versus alcohol.  This is a common argument by people who see nothing wrong with the legalization of drugs.  I am not suggesting that Singer is making this argument; he is trying to point out that opiates are relatively safer than alcohol and alcohol is a legal drug.  I think that he is wrong on several counts in this argument.  The first point has to do with the overall toxicity of alcohol.  He cites a number of diseases that have to do with the long-term toxicity of alcohol.  Alcoholic cirrhosis for example is typically the fifth or sixth leading cause of death in middle-aged men.  The estimated dose required in most cases is 15-pint years or drinking one pint of whiskey per day for 15 years (2).  Doing a quick calculation shows that this is about 143.26 grams of ethyl alcohol per day.  The progression to cirrhosis will vary based on sex, genetic factors, and rates of metabolism.  The overriding point is that alcohol consumption at this rate is limited to a small percentage of drinkers and the population exposure to alcohol is relatively stable based on current legal and cultural factors.  A related issue is that if you are alcohol dependent tolerance and withdrawal phenomena may lead to a marked increase in consumption – up to 750-1,500 ml/day in order to maintain blood levels high enough throughout the day to prevent withdrawal.  The exposure of multiple tissues over time causes the damage.

The primary mechanism of injury and death from opiates is respiratory ataxia and arrest by the direct action of the drug on small clusters of cells in the midbrain and medulla.  Opiates have a direct effect on the center that determines respiratory rhythm and the center that responds to chemical changes due to oxygen deficiency and carbon dioxide accumulation.  Benzodiazepines, alcohol and sleep medications are often involved in these situations and have a combined effect.  Alcohol in high enough doses can have a similar effect in depending on the individual and their state of tolerance.

Looking at the acute mortality related to alcohol and opiates, I don’t think that there should be any doubt that opiates are probably more lethal than alcohol.  The CDC states that about 2,200 people die every year from acute alcohol poisoning (3).  The population at risk appears top be 38 million binge drinkers.  Men ages 35-64 are at highest risk.  In 2014, there were 18,893 overdose deaths from prescription painkillers and 10,574 deaths from heroin overdose (4).  In this case the estimated populations at risk include 1.9 million people with a prescription painkiller problem and 586,000 heroin users.  Furthermore the death rate from prescription painkiller and heroin use parallels the availability.  I am puzzled by the author’s suggestion that opiates are “much safer” and that there is “honest disagreement among health care practitioners over just how harmful long term opiate use can be…”.

I guess that I am one of those disagreeable health care practitioners.  Anyone can fact check the above argument for acute toxicity and I would encourage a close look at the trendlines over the past 15 years.  If you look at this lines, you will find that the rate of deaths due to heroin overdose was relatively stable for at least a decade before a sizable number of prescription painkiller users decided to start using heroin.  The decision is a strictly economic one.  The most commonly abused prescription painkiller costs a dollar per milligram on the street.  Addicts are typically using 120-240 mg per day.  The equivalent amount of heroin can be purchased for about ¼ as much.  The end result is that stable rate of heroin overdose deaths has quadrupled in the last 5 years.  It is stark to contemplate that the total opiate death rate is based on a population at risk that is about 10% the size of the drinking population at risk.

Dr. Singer describes the movement that led to increased opiate prescribing at the beginning of the 21^st century as “enlightened” and “compassionate.”  He uses the term opiophobia as the irrational fear that doctors and patients have about these medications.  I think it is very clear that these advocacy groups and bureaucrats had no clue that increased access would lead to an epidemic of addiction and overdose deaths.  The moral dilemma for physicians is not colluding with law enforcement in the War on Drugs and “cutting patients off.”  The moral dilemma is practicing sound medicine in a system that blames them for not prescribing enough opioids and then ten years later blames them for prescribing too many.  All of this occurs against the backdrop of a culture that has an insatiable appetite for intoxicants in a country that has one of the highest per capita opiate consumption rates in the world.  The moral dilemma for physicians is recognizing that they can’t predict who will or not become addicted to an opiate and that many physicians do not have the skills necessary to not prescribe to patients who either really don’t need the drug or are probably addicted to it.

There is more than one moral dilemma in the opiate epidemic.  On the patient side should you let your doctor know if you have an addiction before the opiate prescription is written?  Should you let your doctor know that the first pill from the prescription left you feeling euphoric, energetic, confident and like you have never felt before in your life?  Should you let your doctor know that you are continuing to take prescription painkillers even though they don’t work for the pain or because the pain is gone?  Should you tell your doctor or pharmacist know that you suddenly have access to all of the opiates from a deceased family member who was in hospice care and ask how to keep them off the street?

There are many moral dilemmas associated with opiates for everyone and very little moral guidance.

      

George Dawson, MD, DLFAPA


Supplementary:

To calculate the mg alcohol in a pint of whiskey:

1 pint = 473.18 ml

473.18 ml x 0.4 (percent alcohol) x 0.757 g/ml (specific gravity of alcohol) = 143.26 g ethyl alcohol

References:

1:  Singer JA.  Physicians Face Moral Dilemma In Conscription on War on Drugs.  Reason.com  March 23, 2016.  Accessed on March 25, 2016.

2:  Lefton HB, Rosa A, Cohen M. Diagnosis and epidemiology of cirrhosis.  Med Clin  North Am. 2009 Jul;93(4):787-99, vii. doi: 10.1016/j.mcna.2009.03.002. Review. PubMed PMID: 19577114.

3:  Centers for Disease Control and Prevention.  Alcohol Poisoning Deaths.  CDC Vital Signs, January 2015.

4:  American Society of Addiction Medicine.  Opioid Addiction 2016 Facts and Figures.  ASAM web site accessed on March 26, 2016.   

       

Some Arguments on Drug Tolerance and Prohibition

I have extensive experience treating people with alcohol and drug use problems.  I am always amazed at the lack of knowledge about addiction and alcoholism in the general public and how that impacts public policy.  As a result I occasionally get involved in public forums to argue a few points.  As a matter of disclosure I am thoroughly independent and vowed not to vote for any major party candidates a long time ago.  That doesn't prevent people from sending me heated e-mails accusing me of either being a Democrat or a Republican.  Of course you can also be attacked for being a independent and being too much of an elitist to not accept the fact that only major party candidates can be elected.  I have never found that to be a compelling argument.  My latest post to the quoted excerpt follows.  You can read the entire sequence of posts by clicking the link at the bottom.  There are obvious limitations to engaging in this exercise and that should be evident by reading the exchange right up to the last post where I get the expected shot for being a psychiatrist.  Tiresome isn't it?

“Come again...Politicians are pushing for legalization?  Politicians have been spewing the “war on drugs” “tough on crime” protecting the “fabric of society” bullshit for the last 40-plus years.”

Sorry – I try just to stay to the facts.  If you read the actual history of drug use in this country we swing from periods of prohibition to drug tolerance.  We are currently swinging into a period of drug tolerance and I fully expect to see drugs legalized in some way or another in most states.  So I really don’t have a stake in this fight either way.  So you can lighten up.  I am not “on your side” but I can predict with certainty that it will happen.  You can Google “politicians who support drug legalization” as well as I can.  As more of them get on board you will hear an escalation in rhetoric on how they will tax and control it.

You can put any type of spin on it you want – more freedom, freedom from the war on drugs, ability to generate more taxes, ability to treat any problem you might have with medical marijuana, you name it – history shows the outcome will be the same.  If you are still serious about legalizing heroin and coca like you previously stated that experiment has already been done and the outcome will be the same.  That experiment is being done right now with diverted legal opioids (the source of synthetic heroin) and according to the CDC we are in about year ten of an opioid epidemic that is killing more people in many states than motor vehicle accidents – about 15,000 people a year.  If you consider that the drugs typically called synthetic heroin on the street are usually pharmaceuticals with known safe doses, that also illustrates the nature of the problem.  If you think that nobody will be looking for synthetic marijuana if marijuana is legalized – I know that is false per my previous post.  No matter how free you are to smoke marijuana, there are very few employers I know of that will tolerate it at work and none if you are in a job where your decision making can lead to substantial liability. 

The problem with the “war on drugs” and excessive incarceration of people with drug charges in many ways parallels the excessive incarceration of the mentally ill because we have a health care system that is politically managed.  The politicians realized a long time ago that you can save health care costs by incarcerating the mentally ill instead of treating them in medical settings.  It may not have been a conscious decision up front but they have done little to stop it after it was clearly underway.  The three largest mental hospitals in the US right now are county jails.  Addicts in many cases are treated even more poorly if they are incarcerated because they do not get medically supervised detoxification and go through acute withdrawal.

In any “war” somebody has to be blamed and denied resources.  I prefer Musto’s analysis of the US tending to blame other countries for our drug problems:  “That analysis avoids the painful and awkward realization that the use of dangerous drugs may be an integral part of American society.”  That is reminiscent of Mexico’s Past President Vincente Fox pointing out that Mexico’s problem with cartel violence is fueled by America’s massive appetite for drugs supplying the money.  On that basis he was a proponent of the legalization and control of marijuana argument.  That doesn’t address the massive appetite for drugs problem.

The problem with the politics of addictive drugs is that people generally don’t know much about addiction.  There is a significant portion of the population that is vulnerable and the only thing it takes in increased availability for them to start having significant problems.

So good luck with the new temporary American dream of increased access to intoxicants and enjoy it while you can.  Depending on exactly what gets legalized – I would predict that would be the next 20 – 40 years.  That is the usual time it takes to complete a cycle.

Minnesota Politics and Issues Forum

George Dawson, MD, DFAPA

David F. Musto.  The American Disease: Origins of Narcotic Control.  Third Edition.  New York, Oxford University Press, 1999: p 298.  

Additional Clinical Note 1: A couple of graphs from my other blog that show alcohol use patterns over time are available on my other blog for the United States and the United Kingdom.  Graphs of opioid consumption over the past decade by the UN drug control agency shows a linear increase in consumption and production.

Additional Clinical Note 2:  If you had the patience to follow the political thread you probably notice the marijuana advocate trying to tell me that I was saying there was an epidemic of synthetic marijuana abuse that occurred with the legalization of marijuana.  My argument was simply that marijuana users if they are screened for THC at work will switch to synthetic marijuana in order to avoid positive toxicology screens and job loss.  Now in the February 5, 2014 edition of JAMA a report from the CDC it turns out that there was an "outbreak" of synthetic marijuana use in Colorado in August and September that involved about 200 people.  There was a similar outbreak in Georgia in August of 2013.  In addition  to the medical characteristics I would encourage the CDC to collect data on how many people were smoking marijuana to avoid toxicology testing and how many people were unable to stop smoking marijuana in order to achieve that same goal. I sent the CDC a note on how to refine their methodology. 

Supplementary Material Note 1:  My response from the CDC.

Why Has Suboxone Turned Into A Problem?

The short answer is that it is like very other drug and there was always the potential for a problem.  Any practicing physician realizes that when a drug is approved by the FDA for general release to the public there are all kinds of unintended consequences that are possible.  That is the basis of post marketing surveillance by the FDA.  There is invariably a lot of hype associated with the release of a drug, but as I have previously pointed out the FDAs approval process is not in place to guarantee a drug that is safe for everyone.  It is focused on a releasing a drug that is a potential tool for responsible practitioners.  That means any drug can potentially cause a small number of serious unexpected reactions (liver failure, cardiac arrhythmia)  that even the most experienced practitioners will not be able to predict.  There is also an implicit understanding that the practitioners prescribing the drug have a thorough understanding of its pharmacology, indications and contraindications.  Many practitioners advise against trying out a product that has just been released but that advice is tempered by the severity of individual circumstances and the hope of relief and also the general bias that new drugs are somehow better than the old ones.  That bias has been repeatedly disproven.

Suboxone prescribers have to take a special course in order to get a prescriber number in addition to their usual DEA number.  I took the Suboxone prescriber course about 7 years ago.  It was a total of 8 hours of lectures given in a convention center room in a hotel.  It was jointly sponsored by state medical association.  The morning sessions were largely a review of the pharmacology of the drug and the scope of the opioid addiction problem at the time.  The afternoon session focused on vignettes of patients with addictions of varying complexities and the exercise was to determine of Suboxone should be prescribed to that person and how the induction would be done.  That was the first suggestion that something was problematic.  There apparently were no contraindications to Suboxone.  The clear message was that it should be given to anyone with an opioid addiction no matter what their social circumstances or comorbid psychiatric diagnoses and addictions.  There was a definite implication that this was a drug that would revolutionize the treatment of opioid addiction.

 
Suboxone is a combination of buprenorphine and naloxone.  Buprenorphine is the active ingredient in terms of treating addiction.  In this post I will use Suboxone and buprenorphine interchangeably.  The pharmacological properties of buprenorphine that were interesting in terms of potential use for addiction included the fact that it was a opioid mu receptor partial agonist and antagonist at the kappa receptor.  The partial agonist effects relevant for addiction such as euphoria and sedation occur at the lower doses and the antagonist effects occur at higher doses.  The antagonist effects like preventing respiratory depression were thought to put a ceiling effect on this side effects and make it safer than pure mu receptor agonists that would produce dose related toxicities.  In the Suboxone course the mixed agonist/antagonist effects were described as producing less toxicity and less risk of abuse.  The naloxone component of Suboxone is a pure mu receptor antagonist.  In the course I took, the explanation for the combination of buprenorphine and naloxone was that it reduced the risk of intravenous drug use and that this had occurred in Europe and it resulted in several deaths.  The company also sold Subutex which was buprenorphine only and indicated for use in pregnant women.

The pharmacodynamics and pharmacokinetics in real life can differ quite a bit from the idealized cases that the initial marketing and advertising was based upon.  Like many medications it can be a life changing drug.  People can recover and break the cycle of addiction, recovery and relapse and go on to productive lives.  It is the outliers that physicians need to be most concerned about.  In real life there are always going to be people who get significant side effects even at low doses and cannot tolerate the drug.  There are also people who tolerate the drug at high doses and do not experience the ceiling effect of mu receptor antagonism.  The people are probably very low in number but they are significant because they are not protected by the ceiling effect that is supposed to be there from the drug.  Drug addiction always attracts or produces a significant number of people who become amateur pharmacologists and use the drug to facilitate their addiction.  The word gets out and suddenly buprenorphine has street value (about $1,000 for a 1 month prescription) and opioid addicts can use it when they run out of heroin or oxycodone.  In a few people it is their preferred opioid because it has a longer half life.

The politics of Suboxone are as complicated as you will find in the pharmaceutical industry.  There are plenty of conflicts of interest in terms of how the drug was initially marketed and plenty of crossover between regulators and the company who developed, marketed and sold it - Reckitt-Benckiser.  According to a New York Times article last fall, the company was granted a period of exclusive sales that ended in 2009.  After that they went on the offensive to suggest that their new product - a Suboxone film was superior to the generic tablets especially in the area of child safety.  They stopped selling the Suboxone tablets at that point.  Insurance companies can work any controversy to their advantage and people on buprenorphine maintenance have been cut off based solely on the amount of time they have been taking the drug.  There are no scientific guidelines for how long a person should take buprenorphine and like most drugs used for maintenance therapy there will never be a study that looks at that question due to the expense.  Most experts would agree that if you have a severe addiction and have recovered based on buprenorphine there is no reason why you would be cut off.  In fact discontinuing buprenorphine seems to present a more significant problem as dose is tapered to 2 mg and  lower.   We also have a familiar political theme in the issue of opioids with the government seeming to create the problems in the first place and now saying: "Trust us we have the solution."  That may have explained the desperation in the descriptions of how public health officials were trying to increase Suboxone prescribers to address a public health opioid epidemic that was a likely result of government initiatives to improve the treatment of pain.

Suboxone has become a problem for the same reason that every other drug becomes a problem - unrealistic expectations, conflicts of interest, and a knowledge deficit on the part of the practitioners.  The title of the New York Times article illustrates how the press can look at the dual nature of drugs and imply that there is a larger problem.  I don't know of two many drugs that do not have a "Dark Side".  The negative trends in buprenorphine use can be reversed but it will take more than the suggested strategy in the NY Times article.  Here are a few ideas:

1.  The CDC needs to get involved and look at Suboxone/buprenorphine related deaths and study it in the same manner that they studied methadone.  It would be very instructive to see exactly where Suboxone/buprenorphine falls on the spectrum of deaths/100 kg MME (milligram morphine equivalents).  The expectation of some in the article is that it is much safer, I would prefer to see the numbers.  Only the CDC has access to the detailed data to look at this issue.  I would take it a step farther and suggest that the CDC recalculate this table on an annual basis as a key metric in reversing the significant public health problem of accidental opioid overdose deaths.

2.  The physicians prescribing the buprenorphine need to be highly motivated and well versed in prescribing medications to individuals with addictions.  The NY Times article suggests that there are many who take an entrepreneurial approach to the prescription of buprenorphine with cash only practices that vary from $100 - $250 a visit.  I have no problem with cash only practices if there is a quality approach.  By definition that involves a lot more than handing someone a prescription in 5 minutes.  The problem is the rest of what happens during that time is poorly defined.  The original prescribing information said that the physician needed to refer the patient to counseling services.  In many presentations of research that I have seen there is a clear movement to illustrate that - counseling adds little to nothing to outcomes when buprenorphine is prescribed.  There are problems drawing that conclusion about this research given the modest outcomes of the buprenorphine treatment.

3.  At least part of the interview of any patient recovering from the severe addiction that occurs with opioids is assessing their functional capacity.  What are they doing on a day to day basis and is that routine consistent with both recovery and a lack of cognitive side effects from the buprenorphine?  Being able to corroborate that improvement with a third party makes it even more reliable.

4.  A big part of the unconscious aspects of addiction is the behaviors that are present to continue the addiction despite the best conscious efforts of the person affected.  Good examples include craving, lying, and hiding use from others.  That requires prescribing physicians to engage their patients at this level and not develop a law enforcement transference.  A lot of physicians don't know how to respond to an accusation of: "You don't trust me!" when there is a question of the need for a toxicology screen or a discussion of a positive toxicology.  The interpersonal aspect of treatment is very important and it received no attention in the standard Suboxone prescribing course.

5.  Continued work on a model of treatment looking at all of the potential positive factors is needed.  There is nothing worse in medicine than to treat a scientific topic like a political one and not have a rational approach to the person with the problem.  Like the original course I took, there are  people out there who say that buprenorphine prescribed out of a physicians office is all that is needed.  Is that the case when you have a person who takes two to three times the prescribed amount to get high?  Or the person who is crushing it and snorting or injecting it?  Or the person who is selling it on the street to get purchase heroin?  Or the person who can't function due to cognitive problems at 2 mg a day?  Or the person who is hospitalized for recurrent bowel obstructions due to severe constipation?  As the prescribing physician - are  you confident that you can accurately screen for these problems?  What about competing approaches like the long acting mu antagonist naltrexone injections?  Where does 12-step recovery like Narcotics Anonymous fit in?  Where do sober housing and residential treatment fit in?  And finally - where can a person get detoxified and should anyone be forced to go through acute opioid withdrawal when they are incarcerated?

All of these questions are currently unanswered.  But like most treatments in medicine, the solution is typically a lot more than a pill.  Drugs with addictive potential always add the complication of significant financial gain from a captive audience.        

George Dawson, MD, DFAPA

Deborah Sontag.  Addiction Treatment With A Dark Side.  New York Times. November 16, 2013.

SAMHSA.  Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction.  A Treatment Improvement Protocol.  TIP 40.

NICE.  Naltrexone for the management of opioid dependence. 2010.

NICE.  Methadone and buprenorphine for the management of opioid dependence.  2010.