More on Benzodiazepines (Like Xanax).

The topic of benzodiazepines will just not go away.  At the top and bottom of this post - I include a number of book covers from my library on the topic from the last 30 years.  The publication dates are 1983, 1985, and 1990.  I wrote a brief review for the Psychiatric Times and included my unedited version  on this blog from earlier this year.  My overall message was that benzodiazepines as a group are great for very specific indications.  In fact for some indication like detoxification from alcohol or sedative hypnotic drugs and catatonia they are life saving.  The majority of benzodiazepines are not prescribed for those indications.  They are prescribed primarily as add on medications for anxiety and insomnia.  Their use is limited by tolerance and addictive properties that are expected from a medication that reinforces its own use.  It is also problematic to prescribe them to any population of patients where alcohol use is prevalent and not expect significant drug interactions or abuse.

I really wanted to include a graphic from the paper listed below (1) from JAMA Psychiatry on the prescribing rates of benzodiazepines in patients being treated for depression.  I will post it if I get permission.  That graph illustrates the growth in benzodiazepine prescribing from 2001 to 2104.  During that time the fraction of patients taking a benzodiazepine in addition  to an antidepressant rose from 6% to 12.5% of the depression treated patients.  Subgroups were analyzed and psychiatry came across as a the top prescriber of benzodiazepines across all years.  Other practitioners and specialists came in under the curve prescribed by psychiatrists. 

 A recent anxiety disorder diagnosis was a strong predictor of concurrent use of benzodiazepine use with 24.1% of patients with a recent unspecified anxiety disorder diagnosis and 39.1% or patients with a panic disorder diagnosis taking both the benzodiazepine and antidepressant.  At 6 months 45.6% of the antidepressant + benzodiazepine and 48.1% of the antidepressant monotherapy were still taking an antidepressant.  After initial adjustments 12.3% of the simultaneous benzodiazepine and antidepressant users received long term benzodiazepines with 5.7% taking them for one year.  The prescribed benzodiazepines were almost all high potency including alprazolam (43.9%), lorazepam (26.3%), and clonazepam (21.8%).  About a tenth (13.5%) of the patients got a limited supply of for only 1-7 days).

The authors generally conclude that benzodiazepine prescribing seems to be consistent with current guidelines.  These suggest that a Cochrane report that concomitant benzodiazepine use with antidepressants increased the short term antidepressant response and decreased the drop out rate attributable to antidepressant side effects.  I would think that would be offset at least as much by guidelines suggesting limited use.

The overall strength of this report is that it is a study of a very large insurance database population of 684,100 new antidepressant users and 81,020 simultaneous antidepressant and benzodiazepine users. They give a breakdown of antidepressant classes (overwhelmingly SSRIs).  Only 12.7% and 16.5% (respectively) of the patients in each class were treated by psychiatrists.  Interestingly 77.4% and 80% of each class had not received any form of psychotherapy, although it is conceivable that at least some patients were being seen by therapists outside of the database.  As noted psychiatrists were more likely to prescribe combination therapy.  The authors speculate that may be due to referral patterns and psychiatrists seeing patients with more severe anxiety and depression, training patterns in psychiatry, or more familiarity with benzodiazepine pharmacology.  I think a more likely factor is chronicity and the fact that psychiatrists tend to see more patients with chronic anxiety and temperamental forms of anxiety that are not taken into account in DSM-5 nosology.

Despite the large N, there are many drawbacks to database studies like this one.  I think it is useful in terms of the basic pharmacoepidemiology of prescriptions but it doesn't say anything about symptoms severity and many of the practical issues involved with benzodiazepine prescribing (like substance used disorders) are eliminated by the study protocol.  The authors do a good job of describing the downsides (use disorders, falls/fractures, motor vehicle accidents) of benzodiazepines in their discussion.  I would have included cognitive problems and tolerance. It also does not address the optimal way to address combined anxiety and depressive disorders. My biggest concern is the current "evidence based" fad of diagnosing anxiety and depressive disorders using symptom rating scales like the PHQ-9 (Patient Health Questionnaire-9) and the GAD-7 (Generalized Anxiety Disorder 7-item).  In a primary care setting they pass for a diagnosis.  In a psychiatric setting they short circuit any analysis of the etiological factors of anxiety or depression.  Instead these disorders are conceptualized as disorders that that require a basic medical treatment and they resolve.  That is a gross oversimplification.     

But the main limitation should be evident - we do not have a specific enough diagnostic system with reliable objective markers.  In that context a large N doesn't mean as much unless we know how many subtypes there are and the associated treatment parameters.

George Dawson, MD, DFAPA

References:

1:  Bushnell GA, Stürmer T, Gaynes BN, Pate V, Miller M. Simultaneous Antidepressant and Benzodiazepine New Use and Subsequent Long-term Benzodiazepine Use in Adults With Depression, United States, 2001-2014. JAMA Psychiatry. 2017;74(7):747–755. doi:10.1001/jamapsychiatry.2017.1273

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 21^st 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

https://www.guidelines.gov/Home/Disclaimer?id=50178&contentType=fulltextlink&redirect=https%253a%252f%252fwww.nice.org.uk%252fguidance%252fng46

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.

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.

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.

Significantly Lower Mortality With Antipsychotic Use

It is always an interesting phenomenon to see the headline grabbing news about how toxic psychiatric medications are killing people.  At first it was just  cult news, but these days it seems that some people can make a fairly good living at it.  A knowledge of psychiatry or clinical experience is never a prerequisite.  It always requires the reader to suspend their sense of reality and what they know happens in real life.  That reality is that a family member, neighbor, or friend was having some very serious problems - saw a psychiatrist and got better.  It also requires a suspension of belief in the tremendous history of what happens with untreated psychotic disorders both in terms of morbidity and mortality.  Finally it requires suspension of a belief in the usual regulatory mechanisms.  If so many people were dying from treatment - it would be obvious and somebody would be held accountable.  Every state has medical boards that basically solicit complaints against physicians.  Surely any group of physicians prescribing an inordinately toxic medication would come to light.  You have to suspend all of these realities of course because none of it has occurred.  Despite those reality factors there are any number of antipsychiatrists or people claiming to be critics who are basically using the same rhetoric warning people about the toxicities and how many people are killed by these medications each year.  Some of their estimates are astronomical and suggest a clear and biased agenda.  Actual community surveillance reveals an accurate picture and the medications with the highest complication rates are easily recognized by any psychiatrist or primary care physician.

That is not to say that the medications prescribed by psychiatrists are perfectly safe.  As I just posted - no medical decision including one that involves taking a common medication is risk free.  I spend a good deal - if not over half of my time warning people about side effects that will never happen, warning people about severe but rare side effects, managing side effects that do happen, and screening for potential side effects that might go unnoticed by the patient like electrocardiogram abnormalities or blood tests for a specific bodily systems.  In 30 years of practice, I have diagnosed the most severe problems including serotonin syndrome, neuroleptic malignant syndrome, prolonged QTc interval, various degrees of heart block, arrhythmias, myocardial infarctions, strokes, drug-induced liver disease, agranulocytosis, diabetes mellitus, diabetes insipidus, hypo/hyperthyroidism and many other that were either caused by a medication or picked up as a result of my screening for a medical complication or pre-screening for safe use.  But relative to primary care, the number of diagnoses in psychiatric practice for this reason is smaller.  The most significant cause of mortality in psychiatric populations is cigarette smoke.  The most significant number of medical conditions are pre-existing and if the psychiatric disorder is caused by an underlying medical condition - it is not common.

All of the factors in the first two paragraphs led me to read an article on the epidemiology of antipsychotics, antidepressants, and benzodiazepines in a well determined population and the effects on mortality in the June American Journal of Psychiatry.  The authors have a number of studies that appear to use a similar epidemiological approach.  For this study they identified cohort participants from national health care registers of all people 17-65 living in Sweden in 2005.  They identified anyone receiving health care for schizophrenia or psychosis (by ICD-10 codes) and anyone on disability for schizophrenia.  They also  determined all of the antipsychotics, antidepressants and benzodiazepines dispensed from 2006-2010.  They were classified by Anatomical Therapeutic Chemical Codes (ATC codes).  They calculated cumulative exposures using the WHO defined daily dose (DDD) methodology.  The WHO web site has a search engine that will let you search for the defined daily dose of medications.  Examples for antipsychotic medications would include 10 mg for olanzapine and 5 mg for risperidone.  The researchers summed the follow up days minus any hospitalization days and divided this into the sum of the dispensed medication.  That allowed the subjects with schizophrenia to be broken into four DDD groups: 1) no antipsychotics, antidepressants or benzodiazepines during the follow-up, 2) low dose -  small or occasional medications (0-0.5 DDD/day), 3) moderate doses (0.5-1.5 DDD/day, inclusive), and 4) high doses (>1.5 DDD/day).  Using the olanzapine example that would mean a dose range from 0 - >15 mg/day cross all 4 groups.  

A total of 1,591/21,492 or 7.4% of the cohort died in follow-up.  That was 4.8 times higher than a control group of age and gender matched patients.  The commonest causes of death were cardiovascular disease, neoplasms, respiratory diseases, and suicide in that order.  No interactions were noted at the level of demographic variables.  Mortality rates and hazard ratios for antipsychotic, antidepressant, and benzodiazepine use were calculated and the following observations were noted:

1.  Any exposure to antipsychotics or antidepressants was associated with a lower rate of mortality (15-40% lower) compared to no use.          

2.  High exposure to benzodiazepines was associated with a 74% higher risk of death than no exposure.  Benzodiazepine users had the highest mortality, highest risk of suicide, and more frequent visits to health care services.  

3.  In terms of cardiovascular mortality, only high dose antipsychotic use showed an equal mortality to no exposure to antipsychotics with low and moderate dose showing decreased mortality.

4.  A sensitivity analysis of first episode patients showed that there was a decreased risk of mortality with exposure to low and moderate exposure to antipsychotics and increased mortality with exposure to moderate to high dose benzodiazepines.  More striking is the fact that during the follow up period this was a cohort of 1,230 patients and 45 (4%) of them died.  Most of the patients with first episode psychosis who I treated were otherwise healthy 20 year olds, illustrating the significance of this problem.

This is an excellent study from a number of perspectives.  It looks at well defined data across a population that is generally possible only in Scandinavian populations.  By contrast studies done in the US typically look at either incomplete retail pharmacy data designed originally for pharmaceutical sales or detailed health interview data that is based entirely on self report using long and detailed questionnaires.  The study uses WHO methodology suggested for pharmacoepidemiological research.  The follow-up period is during a times when most atypical antipsychotic medications are widely available.  These are the drugs that are suggested as a source of higher cardiovascular mortality in psychiatric patients.  The authors findings are discussed in light of several other studies that show similar effects.

 The finding of this study will come as no surprise to acute care psychiatrists across the US.  It is the reason why psychiatrists cover these settings despite the hardships involved.  They know they are treating very difficult problems with very little assistance and that even in the absence of a continuum of care they can be successful.  These psychiatrists are also aware of the medication toxicity and more importantly as this article points out - they can identify high risk patients and safely treat them.  Despite the concerns about the metabolic effects of atypical antipsychotic medication there is an implication that other factors (like smoking) may be more significant in the development of cardiovascular disease (3).  The risk of antidepressant and antipsychotic medication can be seen in an appropriate context in this study and that is lowering mortality rather than causing it.

The study also provides very useful guidance on benzodiazepine use.  In my opinion, benzodiazepines should be used only briefly for the treatment of catatonia and acute agitation in patients with psychotic disorders.  They should not be used on a long terms basis.  I agree with the authors' idea that tolerance is a problem.  When dose escalation fails or results in withdrawal and panic attacks or protracted insomnia, the risk for impulsive behavior and increasing depression is much greater.  More frequent primary care visits can also occur due to tolerance and the need for dose escalation and more discussions of appropriate use.  Treating this population in the United States is problematic because at a certain point, people can be safely detoxified from benzodiazepines only in an inpatient unit, and those services are widely unavailable.   This study is a blueprint for quality assurance projects using the same methodology on electronic health records (EHR) across the country.   Every clinical population should be examined using the authors' techniques and followed for outcomes and active interventions.

The reference provides an opportunity to see the realistic risk and benefits of treatment in people with high risk psychiatric illness.  It also presents an opportunity to use this methodology to provide better treatment to people with the same illness and prescription profiles everywhere.  Instead of using the EHR to catalogue useless full text information and track physicians, the authors methods can be used with much finer tracking of details like BMI, blood pressure, smoking status and other relevant lifestyle factors.  Apart from the aspects of polypharmacy, the overall difference in mortality due to a diagnosis of a psychotic disorder needs to be addressed, and it needs the level of detail available in an EHR.  Psychiatrists in major health plans using large databases could get active feedback in a very similar manner.  The EHR could finally be used the way they advertised it a decade ago.         

George Dawson, MD, DFAPA

1: Tiihonen J, Mittendorfer-Rutz E, Torniainen M, Alexanderson K, Tanskanen A. Mortality and Cumulative Exposure to Antipsychotics, Antidepressants, and Benzodiazepines in Patients With Schizophrenia: An Observational Follow-Up Study. Am J Psychiatry. 2016 Jun 1;173(6):600-6. doi: 10.1176/appi.ajp.2015.15050618. Epub 2015 Dec 7. PubMed PMID: 26651392.

2: Robinson DG. Early Mortality Among People With Schizophrenia. Am J Psychiatry.2016 Jun 1;173(6):554-5. doi: 10.1176/appi.ajp.2016.16030334. PubMed PMID: 27245185.

3:  Newcomer JW, Hennekens CH. Severe mental illness and risk of cardiovascular disease. JAMA. 2007 Oct 17;298(15):1794-6. PubMed PMID: 17940236.

The Problem With Benzodiazepines.....

I want to thank David Allen for the inspiration for this post when he commented that as an addiction psychiatrist, I was probably seeing a skewed sample of people addicted to benzodiazepines and that might be why I have such a jaundiced view of them.  I use the above bubble diagram to illustrate how benzodiazepines are prescribed by docs like me with a strong bias toward preventing addiction compared with physicians who have no such bias.  To make sure that we are on the same page, benzodiazepines are all technically tranquilizers or sedatives.  They marked a therapeutic advance from the earlier barbiturate class  in that their therapeutic index (ratio of the drug that produces toxicity in 50% of patients to the dose that produces a therapeutic response in 50% of patients) is much greater than earlier tranquilizers like barbiturates.  The practical measure is that it takes much higher doses to produce respiratory arrest and death.  Despite the increased safety these drugs are addictive.  People can develop a tolerance and in some people they produce a euphorigenic effect, very similar to the effect of alcohol.  Some people describe benzodiazepines as "alcohol in a pill."  Unfortunately we do not know the percentage of people where that occurs or how to detect them. There are many common clinical situations where the safety margin of benzodiazepines is cancelled out by other factors.  Mixing them with alcohol and opiates are two of the most common dangerous situations and if you are treating addiction - you see that happen all of the time.

Rather than list the entire table of benzodiazepines, I am going to list the commonest ones that I see being abused.  In order from the most frequently abuse that group would include alprazolam (Xanax), lorazepam (Ativan), clonazepam (Klonopin), and diazepam (Valium).  Of those compounds Xanax Bars or 2 mg alprazolam tablets seem to be the most commonly abused by far.  The maximum recommended dose of alprazolam is 4 mg/day and I frequently have seen people taking 8-20 mg/day in combination with other street drugs.  Benzodiazepines have all been generic for a long time so they are very inexpensive to purchase if you have a prescription.  If you don't have a prescription and acquire them illegally the "street value" of a drug is a sign of abusability.  The average street value of alprazolam is about $5 for a 2 mg bar.  The immediate risk of using benzodiazepines excessively is accidentally overdosing on the single drug or in combination with alcohol and other drugs of abuse.  There is also a significant seizure risk from abrupt withdrawal when the supply of medications have been used.  The abuse of benzodiazepine like compounds that are more typically used for sleep like zolpidem (Ambien) or eszopiclone (Lunesta) does happen but it is more likely to occur in combination with alcohol for alcohol related insomnia.  A common example would be a person with alcohol dependence who takes zolpidem at night so that they can sleep through the entire night.  Without it they would predictably wake up at 2 or 3 AM from the withdrawal effects of alcohol.  Chronic use of benzodiazepines whether by prescription or acquisition from illegal sources can lead to tolerance and chronic withdrawal symptoms that can last for months if the drug or medication is stopped.  That fact alone should be considered as part of the risk of taking benzodiazepines - even in the situation where the person does not have an addiction and has anxiety that they do not believe can be treated by any other means.  In my experience, I am not sure that kind of anxiety exists.

Another common problem with benzodiazepines is that they can be psychologically debilitating, even if the person affected never takes the pill.  It is all part of the behavioral pharmacology of addicting drugs.  It usually starts out with a panic attack.  That panic attack can result in people going to the emergency department once or twice because they believe they are having a heart attack.  Somewhere along the line a physician prescribes alprazolam to take "in case of a panic attack."  That starts to happen and even if the panic attacks are rare, brief, and situational - the person affected starts to believe they need to carry alprazolam around with them wherever they go "in case" of another panic attack.  They may not have had a panic attack in years, but they are more anxious about whether they are carrying a pill when they get on a plane, cross a bridge, etc.  The pill have taken on Talisman-like features based on their using it for a condition that for most people fades away over time.  Some  who don't know the sequence of events might suggest "what's the harm" if somebody develops such a belief system around a pill.  In my estimation the harm is that the person's normal conscious state has been transformed and they have exchanged one form of anxiety for another.  The debilitating effects of anxiety depend on the illusion that your life needs to be modified in a certain way to accommodate it.  Proving to yourself that is not true is one of the best ways to adapt.        

Despite those reservations, I have prescribed a lot of benzodiazepines in my career.  They are very good medications to use in controlled environments for acute alcohol and sedative hypnotic withdrawal, acute seizures, catatonia,  akathisia, and various agitation syndromes associated with acute psychosis and mania.  The goal is typically to get the patient off the medication before they are discharged and to avoid treating patients with addiction with benzodiazepines.  Benzodiazepines are also useful for the first month in treating panic attacks, but that typically takes a lot of work.  The work involved is convincing the patient that a medication that seems to work rapidly is not a good one to take for the long haul.  The other dimension that is operating here that is rarely commented on and never explicit is whether the person receiving the benzodiazepine enjoys taking it.  Medications that are potentially addictive lead to an array of problems that are not there with drugs than are not addicting.  The main one is that they tend to be viewed as solutions for everything.  Instead of just anxiety or panic people will take them for insomnia, stress, or just to wind down at the end of the day.  Medications that reinforce their own use have the problem of inventing new uses that they were never prescribed for and that can lead to escalating doses of the medication.  In some complicated situations benzodiazepines are added to treat anxiety.  They have been used in psychiatric patients with multiple problems and been shown to add no benefit.  They are commonly added to multiple medications including opioids in patients with chronic pain with no additional benefit.

Benzodiazepines are a big problem in primary care.  The NSDUH survey illustrates that most people with an addiction are not aware of it and further that only a small minority seek treatment and find it.  That same survey suggests that about 1.5 million Americans start using tranquilizers and sedatives (they do not have a unique benzodiazepine category) for non-medical use very year.  Even if it is apparent to a primary care physician and their patient that an addiction to benzodiazepines exits, there are significant obstacles to reversing the process.  Although there are protocols for slowly tapering the medication on the Internet, it takes a very highly motivated person and ideal circumstances to accomplish this.  Outpatient detox from urgent care, the emergency department or an outpatient clinic is problematic because the same medication that the patient is not able to control is being given to them to self administer at home.  It is common that the detox medications are all taken the same day or in some cases at once.  Structured detoxification in the American health care system is practically impossible to find, especially in the case of benzodiazepines that require careful attention to seizure prevention, the prevent of withdrawal delirium, and adequate treatment of chronic withdrawal symptoms when they emerge.  Some primary care clinics are taking the preventive approach of not starting benzodiazepines in the first place.

Substance Abuse and Mental Health Services Administration, Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-46, HHS Publication No. (SMA) 13-4795. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013.

There is a lot of resistance to the ideas of addiction docs when benzodiazepines and their long term effects are discussed among physicians.  There is always a physician who claims that they have successfully treated a person with an alcohol use disorder with benzodiazepines or they have people who have stayed on low doses for decades in order to treat their anxiety.  I see the failures.  It leads to the question of how many people are capable of staying sober, not developing a tolerance to benzodiazepines, and not experiencing a negative impact on their life.

As far as I know there are no good studies that address that question and I would not expect that there will be.  Any study that allowed subjects to mix alcohol, opiates, and benzodiazepines would be unethical and should not be approved by any Human Subjects Committee.


George Dawson, MD, DFAPA


Supplementary:

This article was subsequently edited and modified for the Psychiatric Times.  The edited version reads better.