Monday, June 19, 2017

Benzodiazepines in patients with substance use disorders: cautions, strategies, and rationale.


alprazolam


Note:  This article came out in the Psychiatric Times today as an edited version.  I am posting the unedited version here to  provide more details.  I have not seen the printed version yet.  I will add a link later to download a PDF version.

For the past 30 years, there have been widely discrepant views on the use of benzodiazepines (Table 1) varying from avoiding their use entirely to moderate to high dose maintenance benzodiazepines for certain anxiety disorders.  Reviews in the early 21st century suggested that high potency benzodiazepines were the preferred agents for treating anxiety disorders and panic disorder due to rapid onset of action and the fact that older low potency benzodiazepines were considered ineffective for panic disorder.  These same reviews discussed the side effects due to tolerance (rebound anxiety), direct effects on memory, and dependence.  Over that same time frame, treatment guidelines for treating anxiety disorders recommended shorter periods of use.   Benzodiazepines are no longer regarded as first line treatment.  There was a parallel evolution of thought on the addictive potential of benzodiazepines, ranging from the view that there was a low abuse potential to current observations that benzodiazepines are frequently seen being used in combination with other drugs of abuse and are commonly seen in polydrug overdose scenarios.  Benzodiazepines are Schedule IV compounds and according to the Controlled Substances Act that means as a group they have a low potential for abuse.  Despite that assessment alprazolam is the third most common diverted drug.    

Epidemiology

Practical data of the extent of use of benzodiazepines in the population is available from the National Survey On Drug Use and Health (NSDUH) from SAMHSA.  The most recent data from 2015 (1) breaks out benzodiazepine preparations from other compounds.  29.7 million people (11.2% of the population) used benzodiazepine tranquilizers.  Of that group 17.6 million (6.6% of the population) used alprazolam containing products.   

An additional category of sedatives was designated.  There were 18.6 million sedative users.  Sixty percent of the sedative users used zolpidem type sedatives and this represented 11.5 million people or 4.3% of the population. 2.5 million or 0.9% of the population used benzodiazepine type sedatives.  The NSDUH survey estimates the degree of misuse in addition to total use.  A total of 6.1 million people were estimated to have misused sedatives.  Of that group 5.5 million misused benzodiazepines and of that group 4.1 million or 1.5% of the population misused alprazolam.  An additional 1.1 million people misused zolpidem products and 205,000 misused benzodiazepine sedatives.  More specific estimates of misuse of individual products both in terms of total number and percentage of the population are included in the report.

Survey estimates of the use and misuse of benzodiazepines do not give any measure of morbidity or mortality.  Some of those measures are available from pharmacovigilance projects.  A project over 6 years in England and Wales reported that in the group of patients that sustained severe harm or death from medication related incidents, benzodiazepines ranked sixth after opioids, antibiotics, warfarin, heparin, and insulin (2).   A recent report by the Centers For Disease Control (CDC), analyzed the drugs most frequently involved in overdoses between the years 2010-2014 (3).  Two of the top ten drugs involved in overdoses were the benzodiazepines diazepam and alprazolam.  In the deaths involving diazepam and alprazolam 95% involved the use of concomitant drugs.  In the US, 30% of fatal opioid overdoses involve benzodiazepines (4). 

The CDC and the FDA developed the Prescription Behavior Surveillance System (PBSS) to look at the trends in the prescriptions of controlled substances (5).  The PBSS categorizes all of the data into three categories: benzodiazepines, stimulants, and opioid analgesics.  Zolpidem is classified in a miscellaneous category rather than with the benzodiazepines.  In the system, benzodiazepine prescribing rates were noted to vary from 324.3 to 580.7 prescriptions per 1,000 residents.  The highest rates occurred in the patient segment that was 65 years of age or greater.  The number of overlapping days of treatment between benzodiazepines and opioids varied from 11.7 to 19.3.  The study illustrates common problems in benzodiazepine prescribing to geriatric patients and patients being maintained on opioids as well as the benefits of a pharmacovigilance system. 

Clinical guidelines:

Guidelines on benzodiazepine use have evolved over the years.  A series of texts like Principles and Practice of Psychopharmacology (6) provides some idea of the authors conclusions in reviewing the literature in the updates from the publication dates ranging from 1993 to 2011.  The authors of this text provide an algorithmic summary for anxiety disorders based on severity and chronicity.  In examining their successive chapters on the treatment of panic disorder, benzodiazepines were reserved for inadequate response to behavior therapy, selective serotonin reuptake inhibitor (SSRI) plus behavior therapy, or tricyclic antidepressants (TCA) and behavior therapy.  At that point the initial recommendation was alprazolam/clonazepam.  If the entry point into the algorithm was at the severe level the authors recommended alprazolam plus TCA or SSRI for the first month or if that was insufficient “indefinite” alprazolam.  There are additional therapies with or without benzodiazepines if that level of treatment is inadequate.  By the second edition, clonazepam was added to the algorithm as another option for refractory anxiety.  In subsequent editions, other antidepressant (venlafaxine, TCA), alprazolam XR, serotonin and norepinephrine reuptake inhibitors (SNRI), and anticonvulsant (valproate, gabapentin) were all factored in at decision points.  The basic position on benzodiazepines has been unaltered – limited use for the first month until the SSRI starts to work is preferred unless there is insufficient response and in that case benzodiazepines are added at the level of various therapies as maintenance therapy for insufficient response.

Other opinions are available from specialty texts on the treatment of anxiety disorders.  One of these sources on the treatment of panic disorder (7), echoes the Janicak, et al text by listing SSRI and SNRI antidepressants with cognitive behavioral therapy as first line treatment.  Benzodiazepines are listed as treatment for refractory cases with a long list of other options.  Standard psychiatric references do not list benzodiazepines a first line treatment for anxiety disorders.  Using the example of generalized anxiety disorder, typical problems described include the need for frequent dosing, rebound anxiety, difficulty transitioning off the medication, inability to address comorbid depressive states and cognitive side effects (8). 

One property is not mentioned in non-addiction literature is that in a subgroup of patients, benzodiazepines will reinforce their own self administration.  That can occur in a number of ways.  Some patients will notice either a euphorigenic or calming effect that is reinforcing.  If the calming effect occurs in the case of social anxiety disorder both the effect of the drug and the secondary effects of social affiliation will be reinforcing.  In the case of patients with phobias, the medication can take on a magical talisman effect and a person may find it difficult to confront the feared situation.  The medication needs to be in their possession whether they take it or not.  These are all important but understudied aspects of the behavioral pharmacology of benzodiazepines.       

An additional consideration in the use of benzodiazepines is the problem of chronic use.  Most anxiety disorders are chronic conditions.  Some studies show that subgroups will require pharmacotherapy for only a part of the time at intervals after the initial diagnosis.  There is no objective guidance on who should receive indefinite maintenance therapy and it is a decision that is complicated by several potential problems.  Short term tolerance and dose escalation can occur.  The behavioral pharmacology issues previously mentioned can be part of the dose escalation and complicate a plan for stopping them at any point.  Benzodiazepines also complicate the use of other medications most notably opioids.  Social drinking can be a problem if a person is maintained on benzodiazepines.  There has been increasing concern about geriatric complications including falls and cognitive impairment as any cohort on benzodiazepine treatment ages (9). 
           
There are several patterns of benzodiazepine use in addictive disorders that explain why these drugs are frequently found as secondary medications.  Moderate to heavy drinkers frequently wake up in the middle of the night from withdrawal and have additional withdrawal symptoms in the morning.  Benzodiazepines and sleep medications are taken to maintain sleep and treat early morning withdrawal symptoms.  Opioid users use benzodiazepines to treat withdrawal.  There are also several studies that suggest benzodiazepines are used to augment the effect of opioids in an attempt to create a euphorigenic effect including during methadone maintenance.  Stimulant users obtain benzodiazepines to stop the continuous insomnia associated with stimulant use.  One groups uses intoxicants primarily for their amnestic effect and can use benzodiazepines and a number of other agents to induce and intoxication delirium and escape perceived stressors.  In each of these scenarios it is important to assess the person for secondary use of benzodiazepines and discuss the high risk that is created.

Despite the long-term concerns and behavioral pharmacology related concerns about benzodiazepines, they are indispensable medications in a number of situations.  They have been first line medications for catatonia in inpatient settings and greatly reduce the morbidity associated with that condition.  They are used in inpatient settings for treating acute agitation associated with manic and psychotic states.  They are also used for various forms of anesthesia.  Benzodiazepines are the preferred medications for detoxification from alcohol and sedative hypnotic drugs due to their wide safety margin in acute dosing.  There is no doubt that in a supervised setting these medications can clearly be the preferred agents for some conditions.  As a quality concern, length of stay considerations play an important part in these uses because the inpatient physician may find that their patient is being discharged before the benzodiazepine can be tapered and discontinued.  In that case, a plan needs to be developed if it is clear that the patient cannot take the medication in a controlled manner.  Table 2. Lists a number of applications in patients with substance use problems.

From a purely diagnostic perspective the treatment of substance use disorders (SUD) complicates the assessment and treatment of co-occurring psychiatric disorders at several levels.  The comorbidity of anxiety and depression with substance use disorder is high.  A recent study (10) looking at pooled odds ratios (OR) across carefully selected studies showed strong associations for both alcohol dependence ( OR 3.094, 95% CI 2.377-4.027) and drug dependence (4.825, 95% CI 3.013-7.725) with major depression.  For any anxiety disorders, the associations were alcohol dependence ( OR 2.532, 95% CI 2.243-2.859) and drug dependence (OR 4.194, 95% CI 3.447-5.104).  A more recent study (11 ) looking at DSM-5 criteria for 12-month drug use disorders found associations with bipolar 1 disorder, dysthymia, major depressive disorder and posttraumatic stress disorder.  Looking at lifetime estimates added additional associations with anxiety disorders including generalized anxiety disorders, panic disorder, and social phobia.    These studies are generally based on cross sectional survey data and have limitation in terms of data collection.  The critical aspect of care is being able to differentiate primary psychiatric disorders from intoxication, withdrawal, and induced states and whether treating clearly defined co-occurring disorders makes a difference in outcome.  In a review that looked at the issue of treating co-occurring mood disorders and substance use disorders, the authors conclude that while mood stabilization is possible, it does not lead to decreased substance use (12).     

A typical flow diagram of how diagnosis might proceed in patients with co-occurring disorders is illustrated in Figure 1. There is very little literature on treating the demarcated disorders and in clinical practice intoxication, withdrawal, and substance induced states may be difficult to determine in an outpatient setting.  There are a number of problematic scenarios from a purely psychiatric perspective that are difficult to treat such as severe anxiety and bipolar disorder, chronic refractory insomnia as a primary diagnosis before any psychiatric diagnosis was established, and anxiety and depression.  When these disorders occur with one of more substance use disorders and are approached in a systematic manner, the need for long term use of benzodiazepines is rare.  But it can happen at a very low frequency.  In my current practice, we estimate about 1 in 500 admissions to residential care for substance use disorders.

One of the main problems in using benzodiazepines is that there have been no advances in their evidence-based use in populations with SUD.  After it was determined that there was an addiction risk and that more potent short acting benzodiazepines presented a higher risk, not much research has been done since the 1980s and 1990s.  Major guidelines for sleep (13) and substance use disorders (14) do not include guidance that is any more specific for their use than the previously mentioned guidelines for treating sleep and anxiety disorders in the context of addiction.  The APA guideline cautions that it is more than 5 years old and cannot be considered to reflect “current knowledge and practice” but there has been minimal relevant clinical benzodiazepine related research since.  There are guidelines available that provide a detailed discussion of how to approach the prescription and overall handling of controlled substances (15) that can be applied to benzodiazepines.  This guideline contains a number of checkpoints in the system of care and assessment and treatment of the patient.  The prescribing plan includes a detailed informed consent discussion, the goals and duration of treatment, the specific indication and instructions to the patient. 

The British National Formulary (16) also provides basic guidance on the responsibilities of the prescriber of controlled substances.  The three basic areas suggested include that the drug is given for a sound medical reason, that the dose is not escalated, and that the physician does not become an “unwitting source of supply for addicts.”  A structured approach to prescribing benzodiazepines may be useful but there is some evidence that there is a significant interpersonal component.  A study of general practitioners (17) found that they were overwhelmed by the psychosocial problems of their patients and the prescriptions were driven by wanting to help the patient.  Additional biases noted in this study were the limited availability of psychological services, personal use of benzodiazepines for stress relief, perceiving the benzodiazepine as benign, and the time constraint for counseling by the physician.  In a follow-up, meta-synthesis of studies on benzodiazepine prescribing (18) some of the same authors synthesized findings from 8 qualitative studies and found very ambivalent attitudes about long term benzodiazepine prescribing.  They characterized the decisions as “complex, demanding, and uncomfortable”.  The decisions varied by individual physician and at times interaction between patient attributes and physician values influenced the prescribing decision.

Those decisions are more complex and demanding in the setting of a substance use disorder and a patient who may be seeing the physician to get a prescription to use primarily to get intoxicated, to treat the effects of a primary addiction, or to potentiate the effects of another addictive drug.  They are complicated when the original prescription was made by a different physician and the patient is asking for a refill.  I have included a list of practical tips on both the interpersonal dimension and details about what can be useful in optimizing the safe prescription of benzodiazepines (Table 3) in that population.  

George Dawson, MD, DFAPA


References:

1. Arthur Hughes, Matthew R. Williams, Rachel N. Lipari, and Jonaki Bose; RTI International: Elizabeth A. P. Copello and Larry A. Kroutil.  Prescription Drug Use and Misuse in the United States:  Results from the 2015 National Survey on Drug Use and Health.  SAMHSA.  September 2016.

2.  Cousins DH, Gerrett D, Warner B. A review of medication incidents reported to the National Reporting and Learning System in England and Wales over 6 years (2005-2010). Br J Clin Pharmacol. 2012 Oct;74(4):597-604.

3.  Warner M, Trinidad JP, Bastian BA, et al. Drugs most frequently involved in drug overdose deaths: United States, 2010–2014. National vital statistics reports; vol 65 no 10. Hyattsville, MD: National Center for Health Statistics. 2016.

4. Sun EC, Dixit A, Humphreys K, Darnall BD, et al. Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis BMJ 2017; 356 :j760

5.  Paulozzi LJ, Strickler GK, Kreiner PW, Koris CM.  Controlled Substance Prescribing Patterns — Prescription Behavior Surveillance System, Eight States, 2013. Morbidity and Mortality Weekly Report (MMWR)  October 16, 2015/ 64 (9): 1-14.

6.  Janicak PG, Marder SR, Pavuluri MN.  Principles and Practice of Psychopharmacology: 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2011.

7. Bandelow B, Baldwin DS.  Pharmacotherapy for panic disorder.  In: Stein DJ, Hollander E, Rothbaum BO, eds.  Textbook of Anxiety Disorders.  2nd ed.  Arlington, VA: American Psychiatric Publishing, Inc, 2010: 339-416.

8. Van Ameringen M, Mancini C, Patterson B, Simpson W, Truong C.  Pharmacotherapy for generalized anxiety disorder.  In: Stein DJ, Hollander E, Rothbaum BO, eds.  Textbook of Anxiety Disorders.  2nd ed.  Arlington, VA: American Psychiatric Publishing, Inc, 2010: 194.

9.  Short- and Long-Term Use of Benzodiazepines in Patients with Generalized Anxiety Disorder: A Review of Guidelines [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2014 Jul 28. Available from http://www.ncbi.nlm.nih.gov/books/NBK254091/

10.  Lai HM, Cleary M, Sitharthan T, Hunt GE. Prevalence of comorbid substance use, anxiety and mood disorders in epidemiological surveys, 1990-2014: A systematic review and meta-analysis. Drug Alcohol Depend. 2015 Sep 1;154:1-13.

11: Grant BF, Saha TD, Ruan WJ, Goldstein RB, Chou SP, Jung J, Zhang H, Smith SM, Pickering RP, Huang B, Hasin DS. Epidemiology of DSM-5 Drug Use Disorder: Results From the National Epidemiologic Survey on Alcohol and Related Conditions-III.  JAMA Psychiatry. 2016 Jan;73(1):39-47.

12. Pettinati HM, O'Brien CP, Dundon WD. Current status of co-occurring mood and substance use disorders: a new therapeutic target. Am J Psychiatry. 2013 Jan;170(1):23-30.

13.  Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2017;13(2):307–349.  Available from http://www.aasmnet.org/Resources/pdf/PharmacologicTreatmentofInsomnia.pdf

14.  American Psychiatric Association. Practice guideline for the treatment of patients with substance use disorders, 2nd edition. In American Psychiatric Association Practice Guidelines for the Treatment of Psychiatric Disorders: Compendium 2006. Arlington, VA: American Psychiatric Association, 2006 (pp. 291–563). Available online at http://www.psych.org/psych_pract/treatg/pg/SUD2ePG_04-28-06.pd

15.  National Institute for Health and Care Excellence (NICE). Controlled drugs: safe use and management. London (UK): National Institute for Health and Care Excellence (NICE); 2016 Apr 12. 29 p. (NICE guideline; no. 46).  Available from

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

16.   Anthierens S, Habraken H, Petrovic M, Christiaens T. The lesser evil? Initiating a benzodiazepine prescription in general practice: a qualitative study on GPs' perspectives. Scand J Prim Health Care. 2007 Dec;25(4):214-9.

17.  Sirdifield C, Anthierens S, Creupelandt H, Chipchase SY, et al. General practitioners' experiences and perceptions of benzodiazepine prescribing: systematic review and meta-synthesis. BMC Fam Pract. 2013 Dec 13;14:191




Table 1.  Selected benzodiazepine and benzodiazepine-like compounds (allosteric modulators of GABAA receptor)


Benzodiazepines

alprazolam
lorazepam
clonazepam
diazepam
chlordiazepoxide
temazepam



Benzodiazepine-like

imidazopyridines

zolpidem

cyclopyrrolone

eszopiclone

pyrazolopyrimidine

zaleplon


 


Table 2.  The Use of Benzodiazepines In Patients With Substance Use Disorders

Acute/Subacute

1.  Detoxification:  Benzodiazepines remain the drugs of choice for alcohol and sedative hypnotic detoxification.  Many treatment facilities have withdrawal protocols that use anticonvulsants or phenobarbital, but benzodiazepines have the widest safety margin and may address some symptoms of the withdrawal syndrome like anxiety better than non-benzodiazepine options.  Benzodiazepines with long half-lives are generally preferable to other agents, but familiarity with options for patients with severe liver disease is also necessary.

 2.  Short term bridging to a more effective long term plan for treating anxiety or anxiety and depression:  Withdrawal syndromes in patients with a chronic and complicated history of use can be more difficult to treat than textbook scenarios based on the pharmacological properties of the medications being used.  In many situations, it is difficult to know if the withdrawal syndrome has been adequately treated, whether the underlying anxiety or sleep disorder is surfacing, whether there is a new substance induced disorder, or some combination of these processes. 

 3.  Short term bridging in the case of a polypharmacy situation where alternative medications are less safe:  Many of the non-benzodiazepine medications that are used to treat depression, sleep, and anxiety disorders have risk in a polypharmacy environment.  A common flag is problems with cardiac conduction. In many of these situations it is best to avoid any medications that target the patient’s anxiety or insomnia but potentially complicate other problems and use benzodiazepines temporarily.

4.  Acute catatonia, agitation, akathisia, transient anxiety due to brief severe stressors. In residential treatment centers that agitation is more likely associated with complex withdrawal states that include severe anxiety states.  Benzodiazepines are useful medications to alleviate akathisia that can be the result of treatment with SSRIs or antipsychotic medications.


Long-Term

1.  Severe treatment refractory insomnia.

2.  Severe treatment refractory anxiety disorders including mixed anxiety and bipolar states and mixed anxiety and depressed states.

3.  1 and 2 only in situations where the abuse potential (dose escalation, multiple prescribers, additional illegal intoxicants) can be contained.

  



Table 3. Tips for Benzodiazepine Prescribing


Interpersonal Dimension

1.  Avoid emotional prescribing based on the stress of the situation or patient characteristics.

2.  Have a well thought out general approach to prescribing and do not deviate from that plan.

3.  Be aware of how prescribing a controlled substance can affect your decision making and the relationship with the patient.

4.  Maintain a conservative prescribing bias in general and especially in the case of a suspected substance use disorder based on the risks and scenarios presented here.

5.  Maintain a teaching role with the patient that includes a detailed risk benefit discussion and the rational for prescribing or not prescribing the benzodiazepine.  That includes an informed consent discussion of the addiction risk and how to prevent it.

6.  Consult with colleagues in difficult situations and avoid professional isolation.  Solicit feedback on how colleagues would make similar decisions.  In group practices controlled substance prescribing can be the basis of a quality improvement initiative and process.


Technical Considerations

1.  Carefully assess patients requesting treatment with benzodiazepines especially if they are new to your practice.  The diagnosis being treated and the rationale needs to be clear.  Reevaluating the diagnosis and response to therapy over time is equally important.

2.  Consider urine toxicology in search of other drugs especially compounds that are often used with benzodiazepines (methadone, opioids, alcohol, stimulants).  If a benzodiazepine is prescribed urine toxicology also confirms adherence rather than diversion.

3.  Consult a prescription drug monitoring program (PDMP).  Rules vary by state and some states require checking the PDMP before the prescription of any controlled substance.

4.  Consult with collateral contacts who know the patient well.  If the patient is in a structured environment – know the procedures for monitoring and dispensing the medication.

5.  Have a clear plan and indication for the benzodiazepine including a plan for discontinuing it and discuss it with the patient at the time of the initial prescribing decision.

6.  A written document on the expectations of the patient may be a good idea as an anchor point in treatment.  Although treatment contracts do not necessary improve outcomes, the expectations in terms of a single prescriber, precautions, expected outcomes and what must be avoided is generally better than a rushed conversation about the same topics.  That document can be a reference point for the future decisions.

7.  Close monitoring is generally necessary with collateral contacts to assure that the patient is doing well and not experiencing complications from the benzodiazepine.  An important consideration in the collateral information is the patient’s functional capacity on the medication. 

8.  Dose escalation can be an early sign of a problem, prescriptions be counted pill counts at each visit to determine the rate at which the patient is taking the medication.

9.  Develop referral patterns for non-pharmacological approaches to problems that are commonly addressed by benzodiazepines like insomnia (referral to CBT for sleep) and chronic pain (pain specialist or physical therapy referrals).



Supplementary:

Here is a link to the final Psychiatric Times version of this article.



Sunday, June 18, 2017

A Circular Ethics Argument About Psychiatric Services





I attended the Minnesota Psychiatric Society MPS spring meeting yesterday.  The current American Psychiatric Association (APA) President  Anita Everett, MD was there and gave a presentation on ethics.  The title of her presentation was Ethical Issue Management in Team Care.  The conference was focused on collaborative care and innovative ways to extend psychiatric practice out into areas where there is little to no coverage.  The afternoon was dedicated to an APA sanctioned presentation called Applying the Integrated Care Approach: Practical Skills for the Consulting Psychiatrist.

The central theme in Dr. Everett's presentation involved streamlining the 9 dimensions of the AMA code of ethics annotated for psychiatry to 4 dimensions from Principle of Biomedical Ethics.  Those dimensions include beneficence, non-maleficence ("do no harm"), autonomy and justice.  There was not a good 1:1 translation largely because in her formulation autonomy seemed to apply to patients but there was a question mark regarding physician autonomy.  Some of the AMA/APA dimensions applied to two of the 4.  For example, commitment to medical education was seen as applying to both beneficence and non-maleficence.

Dr. Everett is a community psychiatrist and has studied various community mental health centers.  She makes the distinction between simple and complex systems and how applying ethical principles to complex system. She gave some examples of how this might apply like integrated care in a medical shared ACO and meeting a patient in a coffee shop as part of an ACT team intervention.  She  poses the the ethical analysis as a series of questions pertaining to the 4 dimensions.

The open discussion was instructive.  There was a psychiatric administrator present who talked about the ethical issue of emergency department congestion.  In his hospital there are 80 ED beds.  There has a chronic problem with psychiatric patients stranded in the ED sometimes for days.  The problem is basically a systems problem because most Minnesota acute care hospitals do not have psychiatric units, and very few (2 or 3) in the Metro area are equipped to treat patients with aggressive behavior.  As a result practically all of the police and paramedic related acute admissions in a 5-county area are brought to this hospital.  At the same time acute care beds in Minnesota are rationed to the point that there are fewer beds available than in practically all OECD countries including Mexico.  One of the other attendees at the conference also made a statement consistent with what I have put on this blog many times: the state of Minnesota has systematically dismantled the state hospital system and came up with an inadequate secondary system that they no longer use.  That participant was an expert in the state hospital system.  In the meantime, individual counties have essentially eliminated supervised housing for people with severe mental illnesses.  I really don't know what people expect when all of the resources to treat severe mental illnesses are rationed away and emergencies continue to happen.  What occurs is a large steady state population of mentally ill people who are rooted partially on the street or in very suboptimal housing, inpatient units, the ED, or (worse case scenario) jail.  In what was probably the most illogical approach to a solution, the ED reported the Psychiatry Department to the ethics committee for not solving the problem of ED congestion with psychiatric patients!

The ethical conflict in this situation was discussed from the perspective of turf (ED physicians versus psychiatrists) and patient autonomy.  Physician autonomy was touched on only so far as the question of whether physicians need to sacrifice autonomy for the greater good. Does the sacrifice of autonomy lead to resources to treat more people in the long run?  That argument was advanced by a managed care physician-administrator.

Any reader of this blog knows that I view ethics as basically political arguments.  Most ethics seem relative to the political arguments that carry the day.  For example if you think doctors aren't paying enough attention to costs and you are a health care administrator - make cost effective care the new definition of professionalism.  In this case, it comes down to blaming psychiatrists for severely rationed services.  The technical argument basically transfers blame directly away from the rationers to psychiatrists who are left with a huge problem.  That ethical argument carries the compounding problem negatively impacting all of the ethical elements as outlined by Dr. Everett and leaving the psychiatrists in a totally untenable situation.  It also illustrates how a dissection of a complex system - in this case the entire universe of mental health care in Minnesota - results in a ethical argument that only applies to one environment - in this case the emergency department.  Even there it should be painfully obvious that these problems selectively apply to psychiatric patients.  There is no backlog of patients with chest pain waiting for 2 or 3 days in the ED or being transferred to a remote hospital 200 miles away.  All of the illogical approaches to psychiatric care that apply in the ED can be traced back to decisions by politicians - not the least of which is to hire managed care proxies to ration access to care.  It is obvious that sacrifices in physician autonomy to managed care administrators has only made the problem far worse and not better.

In the state of Minnesota. there is no justice for psychiatric patients.


George Dawson, MD, DFAPA


References:

Anita Everett, MD, DFAPA.  Ethics in complex systems of care.  Minnesota Psychiatric Society Spring Scientific Meeting.  June 16. 2017.      





               

Saturday, June 17, 2017

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.


Sunday, June 11, 2017

The EMTALA Paradox




I wanted to add a post here about EMTALA or Emergency Medical Treatment & Labor Act.  The definition can be found  on the CMS web site:

"In 1986, Congress enacted the Emergency Medical Treatment & Labor Act (EMTALA) to ensure public access to emergency services regardless of ability to pay. Section 1867 of the Social Security Act imposes specific obligations on Medicare-participating hospitals that offer emergency services to provide a medical screening examination (MSE) when a request is made for examination or treatment for an emergency medical condition (EMC), including active labor, regardless of an individual's ability to pay. Hospitals are then required to provide stabilizing treatment for patients with EMCs. If a hospital is unable to stabilize a patient within its capability, or if the patient requests, an appropriate transfer should be implemented."


There are numerous links on the web site about what that all means.  From a practical standpoint in many states the law has been disruptive to psychiatric care for persons going to an emergency department with a psychiatric emergency.  The law in effect makes it seem like there are plenty of resources to treat anyone with a serious problem, but on the other had the receiving services are seriously rationed.  There is no better example than psychiatric services where most hospitals have no inpatient services and practically no hospitals have psychiatrists working in their emergency departments (ED).  That results in a triage system based on dangerousness and the two pronged deficiencies of no treatment unless you are dangerous and a frequently contentious determination of dangerousness.  Dangerousness here is basically a managed care term to facilitate discharges in patients who have been partially treated and still symptomatic.  A person can be determined to be ready for discharge if they are no longer saying that they are having suicidal or aggressive thoughts that day.  That means at the time of admission there can be a lot of dishonesty by others to get people in the hospital and in many cases a desperate person who is not able to function will say they are "suicidal" when they are not.  The main problem is people who are uncertain for one reason or another and end up on legal holds for psychiatric assessment.  In the state of Minnesota that hold is for 72 hours excluding weekends and holidays.

The EMTALA law generally creates a massive backlog of patient in the ED waiting to be admitted for psychiatric indications. If they cannot be admitted to the hospital they initially present to, they can be transferred to any hospital in the state.  Transfers of several hundred miles are common.  The receiving hospital is at a disadvantage because they have no records and any transferred electronic health records (EHR) are typically devoid of useful information.  They also no longer have access to psychiatrists who know them and their family has to travel much greater distances to see them.  The combination of rationed inpatient services, rationed housing and residential services, and EMTALA basically keeps a large population or partially stabilized people with psychiatric disorders rotating in an out of the ED, inpatient units, shelters, and in many cases local jails.  EMTALA makes it seem like politicians are doing something while they are allowing insurance companies to ration services and make money.

In health care policy discussions, there has been an excessive focus on ED services.  I have heard many people say that we don't need wider access to health care because of EMTALA: "Whether I have any insurance or not - I can always go to the ED and get treated." That is a rather naive statement about the evaluation and treatment of most medical problems.  

What about the situation where patients have reached American healthcare nirvana and are insured?  In this case rather than getting default rationed treatment because of an inadequate system they have the opportunity to receive proactively rationed care for the sake of maintaining their insurance company's profits.  To make matters worse quality of care in both scenarios is very poor.  Since these scenarios are only obvious to psychiatrists working in either acute care or residential care settings - I will provide a few examples of how being insured works against the patient.  The outcomes are factual, the case specifics are not.

Case 1:  36 year old man admitted with alcohol use disorder and a recent suicide attempt.  He requires detoxification and during that process it is discovered that he is also taking alprazolam 2 mg bars - 4 -5 a day that he acquires off the street.  The detoxification is difficult for many reasons with poor response to benzodiazepines and on day 5 the decision is made to change the detox agent to phenobarbital.  The patient remains depressed, hopeless, and is non-disclosing about suicide potential despite continuing on high doses of two antidepressants, one of which (venlafaxine ER 150 mg/day) was effective prior to escalating alcohol and benzodiazepine use.  A managed care company reviewer calls on day 3 and 4 and says the patient must be discharged by day 5.  When provided with the new data about the change in detox protocol - he says the patient can take the medication with him and complete it as an outpatient.

Case 2: 75 year old man with diabetes mellitus Type II, hypertension, and atrial fibrillation.  He has an alcohol use problem but was admitted because of cognitive concerns and declining cognitive function.  The family doubts that he is taking any of his ten medications accurately due to the cognitive problems.  They are also concerned about the number of empty vodka bottles found at his home and the fact that he has numerous firearms.  The managed care company reviewer calls the day after admission and states that the patient is not covered because there is no "dangerousness" - translation - he is not making any suicidal remarks or threatening to harm other people. He must leave the hospital or pay for his own treatment.

Case 3:  22 year old man with depression and heroin addiction.  He was dropped off outside the ED following an accidental overdose.  The ED staff are familiar with the patient because this is the fifth overdose he has had in the last 3 months all from excessive use of intravenous heroin.  During the interview he says: "Look I am not trying to kill myself, I just get  to the point when I am trying to get high that I don't care if I live or die."  The plan is to detox the patient and get him on buprenorphine-naloxone in a controlled setting to reduce the risk of another overdose and provide the additional counseling necessary to do that.  The managed care reviewer calls on day 2 and says the patient must be discharged and the buprenorphine-naloxone can be started on an outpatient basis.      

These are a few of the many examples of people with insurance who are denied emergency psychiatric care based on the subjective impression of a managed care reviewer.  The reviewer has clear conflict of interest since they are charged with saving the company money.  In all of the examples there is a clear need for the patient to be in a protected environment until effective and maintenance treatment can be established.  There is a clear need for the patient to be detoxed on an inpatient unit.  Why would anyone think that giving a large supply of addictive medications to a person with an addiction to managed their own detox would be a good idea?  In all cases the managed care reviewer does not care.  There used to be an appeal process, but it was to another reviewer hired by the same company.  There is no appeal to anyone who is neutral and there has not been for 20 years.  The system has worsened in the past ten years.  Now the hospitals being reviewed by these managed care companies have their own internal case managers who pressure physicians to make the same low quality decisions. 

The result is clear.  Very poor quality of care.  Burned out physicians scrambling to pull together very shaky discharge plans for unstable patients.  Politicians and regulators making it seem like they are doing something and bragging how they are improving access and quality of care while containing costs.

That is the real product of the EMTALA paradox.


George Dawson, MD, DFAPA    
   









  

Lithium and Pregnancy - The Latest From the NEJM




Lithium and pregnancy have always been a major concern for psychiatrists, obstetricians, and of course women who need to take the medication for mood stabilization.  In the Lithium Encyclopedia (published in 1983) - there is a chapter on the physiological effects of pregnancy and how that potentially affects lithium balance and a separate chapter on teratogenesis.  That chapter describes the Lithium Baby Registry that was established in 1970 to collect information on the effects of lithium in pregnancy.  In the first 10 years, 225 infants exposed to lithium were described and 25 had congenital malformations.  Of these births 18/25 had cardiovascular abnormalities including Ebstein's anomaly, 7 were stillborn, 2 had Down's syndrome and 1 had intracerebral toxoplasmosis.  The results suggested that lithium was a cardiovascular teratogen, but there was a question of reporting bias.  That is, results consistent with the study concern about lithium being a teratogen were more likely to be reported than normal births.  

Those references set the knowledge about lithium and  pregnancy for all residents trained in my era in the late 1980s.  The standard question by attendings and on examinations was: "What is the cardiac anomaly associated with intrauterine exposure to lithium?".  The answer was Ebstein's anomaly.  The follow up question was expected: "And what is Ebstein's anomaly?"  In those days the short answer was downward displacement of the tricuspid valve into the right ventricle.  Today Ebstein anomaly (no longer a possessive) is described in greater detail. A modern reference describes the extension of the tricupsid valve into the right atrium to the extent that most of the functional chamber chamber is collapse to a very small volume.  In some cases it is collapsed to the right ventricular outflow tract.  The downward valve displacement is due to a number of morphological abnormalities in the tricuspid valve.  The myocardium is also abnormal because the valve tissue has failed to completely separate from the myocardium during fetal development - a process called delamination.  That is associated with a thin and poorly contractile myocardium and poor right ventricle performance. There are several associated cardiac abnormalities including ventricular septal defect, patent foramen ovale, patent ductus arterious, and accessory conduction pathways that can lead to arrhythmias.  The associated clinical syndromes of cyanosis, congestive heart failure and arrhythmia can occur in infancy to adulthood depending on the degree of anatomical disruption.  The complications can be fatal at any age (2).

Ebstein abnormality is a preventable complication and one that must be avoided.  In real life that is easier to say than do.  In a controlled hospital or clinic environment it is a very straightforward process to take a history and determine the obstetric history and last menstrual period.  Urine and serum pregnancy tests can be done for confirmation.  The best advice to physicians in this situation is to treat very woman of childbearing age as if they were pregnant until proven otherwise.  In my experience life is less regimented.  There are lapses in contraception and planning that lead to pregnancies in women taking lithium who know that exposure to the infant is an avoidable risk.  Many of these women are on lithium maintenance.  Since lithium remains a mainstay of treatment for bipolar disorder and may be a superior agent in postpartum psychosis - the question of teratogenicity remains an important one.

There have been a number of estimates of congenital malformations due to psychiatric medications and I recently reviewed a few of them and cited extensive database references.  In one of the reviews very large databases were examined looking for major congenital malformations to lithium exposed women especially Ebstein anomaly.

The New England Journal of Medicine published another large retrospective database study of the question of lithium exposure in pregnancy and risk of cardiac malformations.  Their database involve a Medicaid cohort of 1,325,563 pregnancies over the ten year period between 2000 and 2010.  In this cohort there were cardiac malformations noted in 16 of 663 (2.4%) lithium exposed infants.  Lower rates of cardiac malformations were noted in nonexposed infants (1.15%) and lamotrigine exposed infants (1.39%).  In addition there appeared to be a dose related effect with increasing risk ratio noted with increasing doses of lithium.  For example at the dose of 600 mg or less/day the risk ratio was 1.11 but the risk ratio increased to 1.11 and 3.22 for doses of 601-900 mg/day and greater than 900 mg respectively.

The authors have a detailed report on how the cardiac malformations were determined.  They make an interesting point that a misclassification bias can occur with Ebstein anomaly.  Some clinicians may make the diagnosis of right ventricular outflow tract obstruction defects or Ebstein anomaly based on whether or not there has been a history of exposure to lithium.  That may make it more likely to misclassify Ebstein anomaly.  They provide data for the total prevalence of all cardiac malformations and cardiac malformations classified as right ventricular outflow obstruction.  They were focused on "major cardiac defects that were likely to be consequential for the infant."  The diagnostic codes had to be listed several times or associated with surgery.

The calculated prevalence of Ebstein abnormality in unexposed pregnancies was 7 cases per 100,000 live births.  They did not provide the prevalence of Ebstein anomaly in the lithium exposed due to the low number.  After a detailed analysis and analysis of possible sources of error like terminate pregnancies where lithium exposure occurred the authors conclude that lithium had a modest effect in terms of increased risk of cardiac malformations.  Their final estimate was an increased risk of 1 additional case per 100 live births if the exposure occurred early in the pregnancy.  They describe this as a modest increase in risk of cardiac malformations due to lithium.  The difference in the ratio of cardiac malformations in this study (16/663) compared with the Lithium Baby Registry (18/225) is probably due to a more rigorous methodology.

The authors looked at five sources of error in their final discussion of the results.  For clinical psychiatrists the most relevant point was that other factors affecting treatment decisions in pregnancy were not investigated.  They are considerable given that it is highly likely that the women being treated with lithium have severe mood disorders and suicide in the postpartum period in the number one cause of death.  This study can best be viewed as a study that supports current clinical practice to avoid first trimester exposure to lithium by careful screening and then planning if additional adjustments need to be made for planned pregnancies based on the trimester.  In those cases of accidental exposure, consultation with high risk obstetrics and a decision based on a detailed discussion with the patient is usually the preferred option.                 




George Dawson, MD, DFAPA




References:

1.  Jefferson JW, Greist JH, Ackerman DL. Lithium Encyclopedia for Clinical Practice.  Washington, DC; American Psychiatric Press, Inc., 1983: 264-265.

2.  Connolly HM, Qureshi, MY.  Clinical manifestations and diagnosis of Ebstein anomaly. In UpToDate,  Greutmann M, Fulton DR, Yeon SB (Accessed on June 9, 2017).

3.  Patorno E, Huybrechts KF, Bateman BT, Cohen JM, Desai RJ, Mogun H, Cohen LS, Hernandez-Diaz S. Lithium Use in Pregnancy and the Risk of Cardiac Malformations. N Engl J Med. 2017 Jun 8;376(23):2245-2254. doi: 10.1056/NEJMoa1612222.


Saturday, June 3, 2017

Enhancing The Volkow-Collins Approach To The Opioid Epidemic






Nora Volkow, MD - Director of the National Institute on Drug Abuse and Francis S. Collins, MD, PhD - Director of the National Institutes of Health co-authored a paper on the role of science in the current opioid crisis.  Full text of the article is available free online from the New England Journal of Medicine at the reference given below.  In the article the authors review the scientific interventions at three levels of care in treating opioid addiction and use, treating and preventing overdoses, and the treatment of chronic pain.  The treatment of chronic non-cancer pain (CNCP) with opioids can be realistically viewed as the precipitant of this epidemic.  The brief 4 page review is a good rapid review of the science behind these interventions.  The level of cooperation between NIDA and NIH with private industry may surprise a few people but as the authors point out -  the level of mortality with the current epidemic needs to be approached with urgency at all levels.

At the level of opioid overdose prevention and reversal - more potent and long lasting opioid antagonists are being developed to counter exposure to fentanyl and carfentanil appearing at an increasing rate on the street.  Narcan Nasal Spray is probably the most effective and practical outcome of the industry-NIDA partnership.  A wearable device that can detect signals of an impending overdose and administer a μ-opioid receptor antagonist is mentioned.  At the level of addiction treatment methadone, buprenorphine, and extended-release naltrexone are all mentioned as current treatments for opioid use disorder.  Access to providers is discussed as a limiting factor.  vaccines and novel receptor approaches are discussed as potentially new pharmacological approaches to the problem.  New approaches to chronic pain are discussed in greater detail.  Cooperation between the NIH and industry is emphasized again in terms of getting these approaches to market and clinical use.  In the concluding section - the emphasis on NIH-industry partnerships is a central theme.  The argument makes imminent sense, but after two decades of rancorous debate about the effects of pharmaceutical company pizza on prescribing - this level of access to the highest level of taxpayer funded research is somewhat stunning.

But what else might be immediately useful?  I can concentrate just on buprenorphine and come up with a couple.  Anyone working with this compound and people who are addicted to opioids routinely encounters problems with its use.  It is common to treat people who still have withdrawal symptoms and cravings on the  recommended doses and remain at high risk for relapse even after being treated with what is described as one of the best current therapies.  Taking a look at the recommended dose range from the package insert:

The upper limit of the recommended dose is 24mg/6mg buprenorphine/naloxone per day for SUBOXONE. The reported lack of significant increase in brain mu‐receptor occupancy between doses of 16 mg and 32 mg implies that there should be little difference in clinical effectiveness at doses between 16 mg and 24 mg in most patients. When a patient expresses a need for a higher dose, consider the possible causes (e.g., environmental stressors or psychosocial issues that increase cravings or possible drug interactions). Before increasing the patient’s dose, explore other alternatives. Also consider the possibility that the patient may be exaggerating symptoms to obtain additional medication for diversion. (p 34-35).

And:

The recommended target dose is 16 mg buprenorphine/4 mg naloxone per day. Clinical studies have shown that this is a clinically effective dose. Although lower doses may be effective in some patients, for most patients, a 16 mg dose should alleviate withdrawal symptoms and block or attenuate the effects of other opioid agonists for at least 24 hours. (p. 34)

In clinical practice there is a wide range of effects to buprenorphine doses.  The FDA approved considerations show the subjectivity involved in adjusting the dose.  But that is even an understatement.  There needs to be a much greater investigation of the causes of continued craving and withdrawal symptoms when the patient is taking a recommended dose of buprenorphine.  This may be a genetically determined phenomenon either at the pharmacokinetic or pharmacodynamic level.  That is only partially accounted for by drug interactions.

Investigation of withdrawal symptoms and continued craving is more than just a passing concern.  It potentially determines who will be able to remain on maintenance therapy and stay off of heroin.  It is important because a significant number of these patients are being actively treated for psychiatric disorders with antidepressants, anxiolytics, atypical  antipsychotics and mood stabilizers.  How much of that medication use is due to inadequate treatment with buprenorphine and the common symptoms of insomnia, anxiety, and depression associated with opioid withdrawal.  These are all very complex clinical situations.  Many of these patients have a life long history of stress intolerance and there can be a reluctance on the part of clinicians especially if they have no mental health training to explore and treat those problems.  Once the patient has been indoctrinated into the idea that a maintenance medication is going to help them stay off heroin - it is a difficult transition to now say that all of these other factors are now important and need to be addressed.  That is especially true when some of the existing buprenorphine studies minimize counseling or are publicly presented as "counseling adds nothing to the results obtained with buprenorphine."  Finally, there is a large social media movement of people who want to stop buprenorphine and are warning others about it.  What is behind this widespread dissatisfaction and what needs to be done to resolve it?  The overall impression that all of the issues in this paragraph leaves is that buprenorphine is another heavily hyped medication that does not live up to the claims.  All of these areas could use much clearer input from NIDA through additional scientific investigation.

Additional studies on drug interactions with buprenorphine are critically needed.  I use a standard commercially available drug interaction software package.  Any time I enter a psychiatric medication I get a warning to consider to modify therapy and a list of 230 potential drug-drug pharmacodynamic interactions at the CNS level.  Since there is a high prevalence of patients on maintenance psychiatric medications this represents a deterrent to some physicians, especially if they are not psychiatrists and they are in a state with an unfavorable malpractice environment.

The next issue is determining who is susceptible to opioid overuse and dependence.  In my mind the phenotype is very clear.  The person who takes the first opioid tells me that they either "fall in love with it" or they experienced an intense euphoric and almost hypomanic effect.  They felt transformed by the medication into a person that they had always wanted to be.  Side effects are modestly effective deterrents, but I have been told that side effects and a complete lack of analgesia are acceptable in order to get the intense, euphoric high.  How can these people be identified?  The authors discuss biomarkers for pain and pain relief - but the single-most important biomarker would identify this high risk group of patients for addiction.  There are currently commercial databases out there that poll their members on various traits and symptoms.  Can NIH or NIDA design the polling questions and look for markers in these existing databases?

Even before that marker is identified, is there a simple strategy that could be used in clinical practice? Could a clinician tell a patient to self monitor for the intense euphoria and report back to the physician as soon as possible if it occurs?  Could the patient be told to just dispose of the pills by bringing them in to the pharmacy if euphoria and thoughts of dose escalation occur?

These are some thoughts that come to mind that might be immediately useful.  They would address both the limitations of medication assisted treatment and identifying the at-risk population for primary prevention of opioid use problems.                
    
     
George Dawson, MD, DFAPA




1: Volkow ND, Collins FS. The Role of Science in Addressing the Opioid Crisis. N Engl J Med. 2017 May 31. doi: 10.1056/NEJMsr1706626. [Epub ahead of print] PubMed PMID: 28564549.



Wednesday, May 31, 2017

Lawyers, Libertarians, and Journalists On the Opioid Epidemic





It was a perfect confluence of events today.  At one point or another I heard or read about somebody's theory of why there was an opioid epidemic, deaths from drug use, and who was to blame.  Although some of the discussants were quite heated they all had one thing in common - they were all dead wrong.

Let me start with the lead story - the Attorney General of the State of Ohio suing drug manufacturers for the massive opioid problem in that state.  I say massive because there are an estimated 200,000 opioid users in the state and an associated mortality.  If you listen to the story (1) many local coroners and morgues are overwhelmed by the body count.  I heard the story on Minnesota Public Radio on the drive home tonight.  Ohio Attorney General Mike DeWine is suing Purdue Pharma, Johnson & Johnson, Teva Pharmaceuticals, Endo Health Solutions and Allergan for their role in the opioid epidemic.  Apparently the state of Mississippi filed the first law suit in the area.  The AG alleges that these companies basically convinced physicians through their questionable marketing efforts that these drugs were much safer than they really were and more effective for the conditions that they were supposed to treat.  Robert Siegel the reporter made an attempt to blame physicians instead and asked why they were not named in the law suit.  The AG's position was that the culture of medicine was affected by the false promotion and that it will take a while to change things around.  See the press release here for the exact position of the AG.  A copy of the entire complaint by the AG is available here.

The second story (2) came to my attention on my Facebook feed.  This was a case of  Ross Ulbricht - who was apparently convicted and sentenced to life in prison based on operating a darknet market that he created called Silk Road.  The conviction was apparently for money laundering, conspiracy to traffic narcotics, and computer hacking.  My interest in this case has nothing to do with the charges, the defendant himself, the conviction or the sentencing but the reaction on various web sites about the case.  There is a consensus on some of these web sites that he was offering valuable service for adults who want to come together and freely exchange items that it might be difficult for them to exchange in other places.  The associated arguments are that competent mature adults should be able to do this, that any interest the state has in suppressing such activity is an inappropriate intrusion on individual rights, and that in fact a service like this was essentially competing against cartels and may put them out of business. Some suggested that there was a conspiracy between the state and cartels to put sites like this out of business.  

All of these arguments fall flat to an addiction psychiatrist like me.  They seriously underestimate the effect that an addiction has on the brain and conscious state of an addicted individual.  Imagine what it is like to get out of bed in the morning and the very first conscious thought is: "How can I score some dope today so that I can function?" At that stage you are no longer a competent adult able to weigh decisions and make them in your best interest.  All of your decisions are weighted in the direction of ongoing drug use and addiction.  That is true if you are on the darknet looking for drugs or standing on a street corner in Ohio.  That is true if you are sitting in a physician's office and telling them what you think they need to hear to enable them to prescribe you more opioids.

The second aspect of opioid addiction that is difficult to understand is the genetic predisposition to addiction.  There are still a lot of pop psychology theories about addiction being just a bad habit or a lack of moral character that seem to explain the differences between people with addiction and people without addictions.  The fact is a substantial part of the population is genetically vulnerable to addiction and it is just a matter of whether or not they are exposed to a highly addictive drug.  If I had to estimate, my best guess would be that number is at least 40% of the population.  By that I mean that 40% of the population will get an extremely euphorigenic response to opioids (whether or not they work for pain).  They will remember that response and if exposed to more opioids are much more likely to use them than not use them.

That is what makes it so hard to stop this epidemic.  Without those two basic features of addiction there is no unlimited demand for addictive medications from pharmaceutical companies.  There is no need to go to a part of town that a person would never typically travel in to purchase diverted prescription opioids or heroin.  There is no need to search out opioids or other addictive drugs on the Internet or the dark net.

Doctors don't get off the hook.  All physicians are taught about controlled substances and the schedule of controlled substances.  All physicians know that opioids are scheduled according to their addictive potential.  The problem is that most physicians do not know how to interact with people who have significant addictions, and even experts can be fooled.  Most physicians have an incredibly naive approach to addiction and how they can prevent it or approach it once it is established. The cultural norm that physicians help people by prescribing them medications, combined with the fact that physicians are trained to help people, creates a powerful force to continue to prescribe addictive pain medications.  The absence of competent detox facilities is another.  

Pharmaceutical companies, doctors, judges and prosecutors - the pro and anti-blame rhetoric around this issue is intense and unrelenting.   It is not any easier to stop the current opioid epidemic when lawyers, libertarians, and reporters are spreading the blame around to anyone or anything other than the real cause of the problem - the addiction itself.

Start there - treat it as a public health problem and start to make progress.


George Dawson, MD, DFAPA      


References:


1:  Ohio Sues Drug Companies Over Role In Creating Opioid Epidemic.  All Things Considered; may 31, 2017.  Transcript and audio clip.

2:  Brian Doherty.  Ross Ulbricht Loses His Appeal Over Conviction and Sentencing in Silk Road Case.  Hit and Run Blog.  Reason.com  May 31, 2017.


Supplementary:

A reminder about the Ross Ulbricht case.  I am not focused on the case per se or the War on Drugs.  I am solely focused on the argument that anything can be openly traded on a market between consenting adults.  I do not dispute the argument that the sentence was excessive or any other arguments for that matter.

Minnesota Street Drug Bulletin - Designer Benzodiazepines


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



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

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

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

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

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

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

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


George Dawson, MD, DFAPA



References:

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

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

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

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

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