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| alprazolam |
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)
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Benzodiazepines
alprazolam
lorazepam
clonazepam
diazepam
chlordiazepoxide
temazepam
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Benzodiazepine-like
imidazopyridines
zolpidem
cyclopyrrolone
eszopiclone
pyrazolopyrimidine
zaleplon
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Table 2. The Use of
Benzodiazepines In Patients With Substance Use Disorders
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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.
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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.
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Table 3. Tips for Benzodiazepine Prescribing
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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.
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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).
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