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Benzodiazepines II: Waking Up on Sedatives: Providing Optimal Care When Inheriting Benzodiazepine Prescriptions in Transfer Patients

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This review discusses risks, benefits, and alternatives in patients already taking benzodiazepines when care transfers to a new clinician. Prescribers have the decision—sometimes mutually agreed-upon and sometimes unilateral—to continue, discontinue, or change treatment. This decision should be made based on evidence-based indications (conditions and timeframes), comorbidities, potential drug-drug interactions, and evidence of adverse effects, misuse, abuse, dependence, or diversion. We discuss management tools involved in continuation (e.g., monitoring symptoms, laboratory testing, prescribing contracts, state prescription databases, stages of change) and discontinuation (e.g., tapering, psychotherapeutic interventions, education, handouts, reassurance, medications to assist with discontinuation, and alternative treatments).
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Journal of
Clinical Medicine
Review
Benzodiazepines II: Waking Up on Sedatives:
Providing Optimal Care When Inheriting
Benzodiazepine Prescriptions in Transfer Patients
Jeffrey Guina 1,2, *ID and Brian Merrill 2
1Department of Psychiatry, University of Michigan Medical School, Ann Arbor, MI 48109, USA
2Department of Psychiatry, Wright State University Boonshoft School of Medicine, Dayton, OH 45417, USA;
brian.merrill@wright.edu
*Correspondence: jeffguina@yahoo.com; Tel.: +1-937-223-8840
Received: 17 November 2017; Accepted: 5 January 2018; Published: 30 January 2018
Abstract:
This review discusses risks, benefits, and alternatives in patients already taking
benzodiazepines when care transfers to a new clinician. Prescribers have the decision—sometimes
mutually agreed-upon and sometimes unilateral—to continue, discontinue, or change treatment.
This decision should be made based on evidence-based indications (conditions and timeframes),
comorbidities, potential drug-drug interactions, and evidence of adverse effects, misuse, abuse,
dependence, or diversion. We discuss management tools involved in continuation (e.g., monitoring
symptoms, laboratory testing, prescribing contracts, state prescription databases, stages of
change) and discontinuation (e.g., tapering, psychotherapeutic interventions, education, handouts,
reassurance, medications to assist with discontinuation, and alternative treatments).
Keywords:
benzodiazepine; sedative; hypnotic; anxiolytic; psychopharmacology; alprazolam;
clonazepam; evidence-based; taper; monitor
1. Introduction
Benzodiazepines (BZDs) are some of the most commonly prescribed medications in the world [
1
,
2
].
The risks and benefits of these medications have been widely debated [
3
,
4
]. Many patients take BZDs
long-term without ever receiving evidence-based first-line treatments such as psychotherapy or
serotonergic agents. Many clinicians are very cautious in prescribing BZDs, and some even have
clinic policies against their prescription, but it is not uncommon for these same clinicians to have
patients transferred to them from other clinicians who are less reluctant to prescribe BZDs. Many
clinicians are comfortable continuing BZD prescriptions in some patients for months or even years
and, when these patients transfer to a new clinician who is loath to prescribe BZDs, it can put the
gaining clinician in a quandary. Is it the new prescriber’s responsibility to continue the prescription?
To provide a taper? Or, is the clinician legally and ethically able to refuse to continue the prescription
they did not start and do not think is indicated, even if it risks withdrawal? This review discusses risks,
benefits, and alternatives in patients already taking BZDs when transferring care to a new clinician.
A few years ago and after treating several patients with posttraumatic stress disorder (PTSD)
who were “inherited” from other providers with BZD prescriptions, the authors of this study began
questioning if any good was being done by continuing the prescriptions. These patients had long
histories full of distress, dysfunction, and hopelessness. Moreover, they did not seem to improve
like other PTSD patients. The authors began hypothesizing that the medications may be inhibiting
improvement. Which came first: the severity and chronicity, or the BZD? Many of these patients had
been taking BZDs for decades, many of them had never been treated with another medication class or
psychotherapy, and almost all of them firmly believed that their PTSD could never improve. When
J. Clin. Med. 2018,7, 20; doi:10.3390/jcm7020020 www.mdpi.com/journal/jcm
J. Clin. Med. 2018,7, 20 2 of 18
provided education about prognosis and evidence-based treatments, most were reluctant to change
and some even reacted with hostility when it was suggested that other treatments could improve their
lives. Those that accepted evidence-based treatments almost universally improved.
If avoidance is a poor prognostic factor for anxiety and BZDs are inherently avoidance-producing
(i.e., inhibit cognitive processing and promote numbing), could BZDs prolong or worsen anxiety?
Due to frequent resistance to alternatives and many claims that BZDs were helping (despite
the persistence of severe symptoms), the authors were reluctant to change treatments against
patients’ desires. When there was evidence of harm (e.g., excessive sedation, falls, delirium) or
misuse (i.e., use other than as prescribed—e.g., presence of illicit substances in urine-drug-screens,
prescriptions from multiple providers, early refills), treatment changes were often made unilaterally.
For others, the authors were reluctant to make changes based on instinct and anecdote without a basis
in evidence. When initially looking for evidence about BZDs for conditions like PTSD, it was common
to find articles lamenting the lack of studies on the subject, or recommendations for or against BZDs
without referencing studies. However, there are several studies in existence, and we review them here.
2. Deciding the Recommendation
A particularly challenging clinical scenario occurs when one encounters a patient that has been
maintained on BZDs for an extended period of time (months to years). In these situations, the clinician
must first assess the need for ongoing BZD maintenance. If it is determined that the patient is at risk
of adverse consequences of BZDs or that the indication for benzodiazepines no longer exists, then
weaning is prudent.
While the decision to forgo initiating a BZD in favor of evidence-based first- and second-line
treatments is easy, it can be very difficult to decide how to manage a patient transferred from another
prescriber who was prescribing BZD. BZD dependence is preventable with short-term use (i.e., less than
2–4 weeks) [
1
], but even more preventable by using other of the various medications for anxiety. Once
BZDs are used, patients are often reluctant to change medications or may not find replacement
medications as subjectively pleasing. Prescribers have the decision—sometimes mutually agreed-upon
and sometimes unilateral—to continue, discontinue, or change BZDs. This decision should be made
based on evidence-based indications (conditions and timeframes), risk of adverse effects and misuse,
comorbidities, and potential drug-drug interactions.
This decision should not be taken lightly. Continuing a harmful treatment violates the primum
non nocere principle, but removing a treatment perceived as helpful could risk the therapeutic alliance.
Some prescribers may oppose continuing BZDs even when the potential for harm is high even in the
absence of adverse effects or misuse, while others argue for vigilant monitoring. Some prescribers may
push for unilaterally discontinuing BZDs when contraindications are present but no definitive harm,
though others may decide to continue BZDs when patients protest their discontinuation all the while
providing psychoeducation and working through the stages of change to move a patient away from
BZDs and towards evidence-based treatments. “Unwilling patients should not be forced to withdraw.
It is unwise and unkind to compel withdrawal. Enforced withdrawal is usually unsuccessful and
leads to unnecessary distress” [
5
]. Nevertheless, many clinicians do not want to assume the risks and
responsibilities associated with continuing to prescribe BZDs.
There are great ethical concerns and legal liability/criminal responsibility [
6
] when BZDs are
continued in the presence of clinical risks, but there are also great clinical and ethical concerns when
unilaterally discontinuing medications against a patient’s wishes. These include withdrawal, but also
simply losing a disgruntled patient, either preventing them from getting any care, leading them to
seeking self-treatment from illegal sources, or leading them to seek care from a less scrupulous or
less evidence-based prescriber. Seeking BZDs elsewhere and relapse rates after BZD discontinuation
range from 8–57% [
1
,
7
9
]. “Quality patient focused care involves weighing up the balance between
the modest benefits of benzodiazepines with the substantial risks and harms in some patients” [
10
].
Prescribers must weigh the risks of continuing treatment (e.g., adverse effects, misuse, and delaying
J. Clin. Med. 2018,7, 20 3 of 18
definitive treatment and recovery) and the risks of discontinuing treatment (e.g., withdrawal, fleeing
treatment, seeking inappropriate alternative sources).
With patients taking BZDs, the initial goals of treatment should be to determine diagnosis and
to establish a therapeutic alliance. “The art of treatment is knowing when the therapeutic alliance is
sufficiently established to institute drug withdrawal, and knowing when outpatient treatment is not
progressing adequately” [11].
2.1. Assessing Proper Indication
In patients taking BZDs, providers need to make an accurate diagnosis. This includes differentiating
primary disorders from BZD-induced disorders, and eliciting a thorough course of illness via interview
and collateral sources (certain symptoms may have worsened or only developed after initiation of
BZDs). Once an accurate diagnosis is made, the patient’s treatment history can be assessed to determine
if they received adequate courses of first- and second-line evidence-based treatments for that diagnosis.
If the variety of evidence-based treatments were not exhausted before BZDs were initiated (e.g., a PTSD
patient tried prolonged exposure (PE) but not cognitive processing therapy (CPT) or eye movement
desensitization and reprocessing therapy (EMDR), and a selective serotonin reuptake inhibitor (SSRI)
but not a serotonin norepinephrine reuptake inhibitor (SNRI)), adding or changing to unexplored
evidence-based treatments should be encouraged.
2.2. Assessing Effectiveness
Frequently, both clinical and research assessments of improvement of mental disorders are based
on self-reported levels of symptoms. However, most clinicians, researchers, and patients would
agree that level of functioning is more important than level of symptoms. Anxiety and insomnia are
very simple symptoms to treat: one only need provide enough of a central nervous system (CNS)
depressant—whether diazepam, midazolam, fentanyl, alcohol, or heroin—until someone is calm
or asleep. This is not functional recovery. Many patients report a sedative “helps” their anxiety,
yet their lives are no better. The aims of clinicians should not be to treat anxiety but to treat functional
impairment. If a rare BZD allows an individual to fly on a plane, or if someone was unable to sustain
steady employment before BZDs and has steady employment since being prescribed BZDs, then
BZDs are effectively treating impairments in functioning. However, if despite BZDs, they continue
to have difficulty leaving their home, working, and interacting with their family, than BZDs may be
effective for anxiety but they are not effective for their functioning. In the absence of obvious harms,
the presence or absence of effectiveness should be the principal determinant of BZD continuation
or discontinuation.
2.3. Assessing Harms
When patients present with problems, clinicians’ first instinct is to be active—to provide or
increase treatment rather than remove or decrease treatment. However, one of the first questions
a clinician should always ask themselves is, “what have other providers or I done to potentially cause
this” before ruling in or ruling out iatrogenic effects and proceeding with assessment. After all, “first,
do no harm.”
A thorough history, review of systems, review of collateral information, and laboratory testing
(e.g., for the presence of other substances which indicates misuse or the absence of BZDs which
indicates diversion) should be used to determine the presence of adverse effects (which patients
often fail to connect to their medications on their own), contraindicated conditions and medications,
and misuse. Signs that patients are not appropriately using prescribed BZDs include the fabrication of
psychiatric or medical symptoms, signs of intoxication, using BZDs more than prescribed, early refills,
doctor shopping (which is most easily verified by prescription monitoring systems), negative blood or
urine tests for BZDs (indicative of diversion), and positive tests for other substances.
J. Clin. Med. 2018,7, 20 4 of 18
Contraindications, significant adverse effects, drug-drug interactions, and evidence of misuse
(including diversion) should lead to unilateral discontinuation (by outpatient taper, inpatient
admission, or immediate discontinuation, when appropriate). Minor adverse effects or physical
dependence (i.e., tolerance and/or withdrawal) in the absence of misuse should lead the prescriber
and patient to engage in discussions that weigh the risks and benefits of continuing BZDs, or changing
to more effective and/or safer alternatives (see Table 1) [12].
Table 1. Benzodiazepine risks, benefits, and alternatives.
Risks Benefits Alternatives
Physical adverse effects (e.g.,
commonly dizziness, slurred
speech, and psychomotor
impairment; most seriously
overdose, withdrawal, falls,
autonomic instability, seizures,
hepatotoxicity, respiratory
depression, and death)
Cognitive adverse effects (e.g.,
commonly drowsiness, inattention;
most seriously confusion, amnesia,
hallucinations, delirium and coma)
Emotional adverse effects (e.g.,
commonly depression, irritability,
anxiety; most seriously lability)
Behavioral adverse effects (e.g.,
commonly disinhibition, insomnia
and avoidance; most seriously
suicidality, violence and abuse)
Other (e.g., teratogenicity,
breast-feeding risks,
drug-drug interactions)
Short-term anxiolytic effects
Short-term hypnotic effects
Fast-acting
Can be prescribed as needed
Acute/Fast-acting Treatment
Behavioral techniques
Psychotherapy
Sedating antidepressants (e.g.,
trazodone, mirtazapine, tricyclics)
Adrenergic inhibitors (e.g.,
prazosin, propranolol)
Antihistamines (e.g., hydroxyzine)
Anticonvulsants (e.g.,
gabapentin, pregabalin)
Antipsychotics (e.g., quetiapine,
olanzapine, risperidone)
Chronic Treatment
Behavioral techniques
Psychotherapy
Serotonergic agents (e.g.,
antidepressants, buspirone)
Antipsychotics
Anticonvulsants (e.g., lamotrigine)
3. Continuation
Though steeped in controversy and clearly not without potential hazards, BZDs remain viable
treatment options for multiple anxiety disorders and insomnia. Below we will discuss relevant
evidence for the use of benzodiazepines and provide practical guidance in deploying these agents
in the treatment of anxiety and insomnia. Any prescription of BZDs—including initiation and
continuation—should be preceded by thorough discussion of possible risks and benefits, including the
potential for abuse (i.e., continued use despite harms) and dependence.
When patients refuse evidence-based treatment trials and the benefits are deemed to outweigh the
risks, clinicians at times choose to continue prescribing BZDs outside of evidence-based and/or
FDA-approved indications. Physical dependence on BZDs may be acceptable if psychosocial
functioning is improved with BZDs due to the effective treatment of disabling anxiety [
11
]. However,
continued monitoring, education, and the use of additional treatments should be utilized. Tannenbaum
et al.’s EMPOWER (Eliminating Medications Through Patient Ownership of End Results) trials have
demonstrated that when patients are educated about the potential harms of BZDs, they often want
to taper from them [
13
,
14
]. The authors have frequently observed this phenomenon in their own
clinical experience.
3.1. Monitoring
When a prescriber makes the decision to continue BZDs, there are a variety of steps they can and
should consider. Close patient monitoring is recommended [
15
]. Clinical and risk management tools
should be used on a regular basis, and not just the first time BZDs are prescribed.
J. Clin. Med. 2018,7, 20 5 of 18
Regular education is important to assure proper use of BZDs. For example, elderly patients should
regularly be warned about the increased risk with BZDs for falls, hip fractures, cognitive impairment,
and dementia that can persist beyond BZD discontinuation [
15
17
]. All patients taking BZDs should
regularly be advised not to use alcohol on the same day (or even within days or weeks for elderly
patients or those with hepatic impairments) [
7
9
,
15
,
18
]. Prescribers should warn patients about the
risks of driving while taking BZDs. Prescribers should advise all patients of the risk of dependence,
adverse effects, and drug-drug interactions (including regular reminders and regular assessments of
medications prescribed by other sources).
The easiest and likely most common tool is simply monitoring symptoms and vital signs.
Prescribers should regularly assess for stability of underlying symptoms, development of adverse
effects, and functional impairment. Functional impairment is often under-evaluated, but is arguably
the most important marker of treatment effectiveness. Clinicians often tend to focus on self-reported
subjective distress rather than objective dysfunction. It is important to eliciting levels of, changes of,
and examples about various domains of functioning: academic, occupational, social, interpersonal,
recreational, effective communication, self-care, and safety. Optimization of functioning is more
indicative of recovery and treatment effectiveness than reduction of symptoms. Additionally, remission
and not simply symptom management (e.g., daily anxiety attacks aborted with BZDs with reoccurrence
each day).
Some providers find contracts to be helpful tools with patients when using agents with high
potential for abuse and addiction such as BZDs. These contracts can specify parameters for both
parties and serve to codify expectations in the doctor-patient relationship as they relate to the
prescribed medication and other elements of the treatment plan (e.g., attending psychotherapy aimed
at addressing anxiety). Prescribers should advise all patients of the risk of dependence, adverse effects,
indication(s) for continued use, that the lowest dose for the shortest period of time to achieve the
desired outcome will be provided, that they will be monitored closely (e.g., weekly reviews, urine
drug screens), that the treatment of anxiety and insomnia should rely largely on nonpharmacological
interventions (e.g., psychotherapy, sleep hygiene, relaxation techniques), and that they must obtain
all prescriptions from the same provider and pharmacy (and inform the provider of changes) [
10
].
These agreements should be clearly explained to the patient who signs the agreement, a copy is
provided to the patient, and it is clearly documented in the record.
Laboratory tests (e.g., blood and/or urine) can help detect mixing of drugs and diversion.
Potential pitfalls include false positives/negatives and knowing which specific drugs are tested
for (e.g., it is common for “benzodiazepines” to only refer to diazepam, temazepam, and oxazepam;
alprazolam and clonazepam are high-potency BZDs commonly preferred by people with substance
use disorders (SUDs) but are often undetected in drug screens due to being excreted in small amounts
in urine; long half-life BZDs like diazepam and chlordiazepoxide that are taken long-term or in
high doses may be detected for weeks). Different laboratories have different cut-offs, detection
times, and drugs included in screening panels [
11
]. For these reasons, prescribers should consult
their laboratories directly to learn about variations and obtain lists of specific drugs tested and of
potential false positives/negatives for each drug. Additionally, the use of quantitative—rather than
qualitative—testing (universally or only on samples for which the qualitative drug screen is positive)
can confirm that the initial screen was positive, and can differentiate specific drugs and metabolites.
However, some laboratories may dispose of the sample before a quantitative test can be performed.
Considering the risk and prevalence of mixing BZDs and alcohol, blood alcohol tests (which are subject
to zero-order metabolism) and urine ethylglucuronide/ethylsulfate (which detects ethanol metabolites
1–3 days following use, similar to most urine drug testing). Toxicology tests can be useful to confirm
substance use.
In addition to laboratory tests, another tools to detect misuse, diversion, and doctor shopping is
prescription databases. Some states (e.g., Ohio) require all prescribers to check their state’s controlled
substance database at the time of every controlled substance prescription. These systems can be
J. Clin. Med. 2018,7, 20 6 of 18
useful for determining what controlled substances a person has access to, how much is dispensed,
how many prescribers are dispensing, and frequency of refills. Potential pitfalls include patients
who cross jurisdictions (e.g., multiple states, federal systems like the Department of Defense and/or
Veterans Affairs) for which all of a particular patients’ prescriptions may not be recorded in a specific
database (although many states share data).
Just as important as education about proper usage is education about gold standard treatments
and the lack of evidence for long-term BZDs. Just as with SUD patients, prescribers should frequently
assess BZD patients for readiness for change using the change continuum (e.g., pre-contemplation,
contemplation, preparation, action, maintenance), and work towards moving the patient away from
long-term BZDs and towards evidence-based treatments.
3.2. Changing Benzodiazepines
Expected onset and duration of action and metabolic properties for individual patients are
important considerations when selecting amongst particular benzodiazepines. Considerations should
be based on the indication, pharmacokinetics, and pharmacodynamics of each particular agent.
The pharmacodynamic considerations for prescribing benzodiazepines are largely relevant in the
context of abuse and addiction, as higher potency and shorter-acting agents have higher potentials
for abuse.
Even within the individual disorders, the clinical phenomena of anxiety can be episodic
or continuous (e.g., a patient with generalized anxiety disorder (GAD) can experience episodic
intense worry with an increase in somatic symptoms and a patient with panic disorder (PD) can
experience continuous worry about another panic attack). BZD regimens should be selected so
that the pharmacokinetic properties of the selected agent correspond to the expected duration of
symptoms. For example, continuous, gnawing anxiety that lasts all day may be best treated with
longer-acting, whereas briefer and more pulsatile anxiety experiences might be best treated with short-
or intermediate-acting agents. APA guidelines suggest that long-term treatment with BZDs is helpful
to some with PD, though this is based on clinical experience, as opposed to randomized controlled
trials or other rigorous study designs [19].
3.3. Adding Psychotherapy
Psychotherapy is the gold standard treatment for anxiety (including PTSD) and insomnia.
Psychotherapy is a “mainstay in the treatment of all anxiety disorders; exposure to feared situations is
necessary to move beyond phobic avoidance and functional impairment to full recovery, the ultimate
goal of therapy” [
20
]. BZD monotherapy is not recommended in anxiety disorders nor PTSD, but may
be useful when very anxious PTSD patients have poor responses with other medications [
15
]. However,
in these cases, it is incumbent on providers to recommend psychotherapy as a potential alternative
or—at least—additional treatment. This is important not just for those prone to medication side effects,
but for all patients. Just as stress and trauma can negatively change the brain, neuroimaging studies
demonstrate that psychotherapy can positively change the brain [
21
,
22
]. “The most effective and
promising therapeutic approach to PTSD employs medication in combination with cognitive behavioral
interventions” [
23
]. In fact, many would argue that medication alone—without psychotherapy—is not
appropriate treatment for anxiety or insomnia.
Prescribers who do not provide psychotherapy themselves should refer patients for psychotherapy
that is evidence-based for the indicated condition. Cognitive behavioral therapy (CBT), including
exposure therapies such as systematic desensitization and flooding), psychodynamic, acceptance,
and commitment therapy, mindfulness-based, relaxation, feedback, interpersonal, assertiveness
training, and dialectical behavioral therapies are each efficacious for anxiety [
24
27
]. These and
trauma-focused psychotherapies (e.g., CPT, PE, EMDR) are efficacious for trauma/stressor-related
disorders such as PTSD [
28
,
29
]. For insomnia, CBT, CBT-I, stimulus control, relaxation, and sleep
restriction are efficacious [
30
]. While not every type of evidence-based therapy are accessible in all areas,
J. Clin. Med. 2018,7, 20 7 of 18
there is a high likelihood that at least one of these modalities will be available. For those with limited
funds/insurance, free clinics, community mental health clinics, and universities/colleges/training
programs (e.g., psychiatry, psychology, clinical social work, licensed counselor) may be sought out.
Unfortunately, BZDs can inhibit the therapeutic effects of psychotherapy by promoting avoidance,
inhibiting cognitive processing, and inhibiting fear extinction upon exposure [
31
35
]. Nevertheless,
most clinicians agree that it is better to provide psychotherapy to patients who refuse to stop
BZDs—even if they will have more modest effects—than to deny treatment.
3.4. Adding Additional Pharmacotherapy
Psychotherapy is the preferred first-line treatment for anxiety disorders, but pharmacotherapy
is also an important treatment option, especially when there is limited availability of psychotherapy
or to comply with patient preference. Pharmacotherapy can not only improve symptoms, but in an
empathic setting, can improve patient engagement in their treatment [
36
]. While BZDs are effective for
some anxiety disorders, other medications such as serotonergic agents are more effective and safer,
especially in the long-term. When patients refuse to stop BZDs and prescribers deem that it is safe to
continue them, BZD monotherapy should be avoided. In addition to psychotherapy, evidence-based
medication trials should be used to improve symptoms and help work towards transitioning away
from long-term BZDs—due to lack of efficacy and significant risks. The downsides of prescribing
BZDs with SSRIs is that there is a greater risk of drug–drug interactions with multiple medications
(e.g., synergistic sedating effects) and it can make it difficult to discriminate side effects that may occur
from each medicine [
15
]. The benefit of starting another medication in the presence of BZDs is that
there is typically less resistance to, and less likelihood of attributing withdrawal/rebound symptoms
to, the evidence-based medication.
Table 1displays some evidence-based alternatives for BZDs for both short-term/fast-acting and
long-term uses. Serotonergic agents (e.g., SSRIs, SNRIs, tricyclics, mirtazapine, monoamine oxidase
inhibitors, trazodone, nefazodone, buspirone) have the strongest evidence of greater therapeutic
effects and less adverse effects than BZDs, but adrenergic inhibitors (e.g., propranolol, prazosin,
clonidine, guanfacine), antihistamines (e.g., hydroxyzine, diphenhydramine), anticonvulsants
(e.g., gabapentin, pregabalin, lamotrigine, topiramate, valproate), antipsychotics (e.g., quetiapine,
olanzapine, risperidone), memantine, and triiodothyronine all have stronger evidence for certain
anxiety/insomnia disorders than BZDs [
25
,
28
,
29
,
36
45
]. Consideration for unique adverse effects and
comorbidities should be given. For example: hydroxyzine may be particularly effective for people
with anxiety, insomnia, nausea/vomiting, and/or allergies (all indications); amitriptyline may be
particularly effective for people with anxiety, insomnia, depression, neuralgias, and/or migraines
(all indications); clonidine may be particularly effective for people with anxiety, insomnia,
inattention
±
attention-deficit hyperactive disorder, tics, cancer-related pain, and/or hypertension
(all indications); lamotrigine may not be first-line, but may be used earlier in the course of successive
medication trials for people with anxiety, bipolar disorder (especially bipolar depression), and epilepsy
(both indications), and/or obesity (lack of weight gain effects); and it may be prudent to avoid
(or try later in the course of medication trials) olanzapine in those with obesity and/or diabetes
(metabolic risks), but useful to try it earlier in those with anxiety, insomnia, depression, psychosis,
and/or bipolar disorder.
Psychological and behavioral therapies are standard for insomnia (e.g., stimulus control therapy,
relaxation therapy, CBT/CBT-I, sleep restriction therapy, sleep restriction, paradoxical intention,
biofeedback therapy) [
30
]. However, some pharmacological treatments are weakly evidence-based.
Non-BZD gamma-Aminobutyric acid (GABA) receptor agonists (i.e., zolpidem, zaleplon, eszopiclone)
have weak evidence for insomnia, but have similar risks as BZDs [
1
,
46
]. The non-sedative-hypnotics
with the strongest—though still relatively weak—evidence for insomnia include: ramelteon, trazodone,
amitriptyline, doxepin, mirtazapine, gabapentin, tiagabine, quetiapine, and olanzapine [
30
]. Sedating
antidepressants are especially encouraged when used in conjunction with depression/anxiety [30].
J. Clin. Med. 2018,7, 20 8 of 18
Regardless of which medications are prescribed (BZDs and/or anything else), prescribers should
recommend medications “preferably in combination with non-pharmacological treatments such
as cognitive behavioral therapy” [
38
] because appropriate care “involves not only providing the
best initial evidence-based pharmacotherapy, but also ideally delivering it collaboratively with
a psychotherapist” [
36
]. Comprehensive treatment approaches involving both psychotherapy
and pharmacotherapy are especially important for chronic treatment-refractory anxiety and
insomnia patients.
4. Discontinuation
Mental health treatment should aim to reduce symptom severity, prevent and treat comorbid
disorders, decrease functional impairment, modify pathogenic fear schemas, prevent relapse, build
resilience, and improve the quality of life [
45
]. Often, prescribers focus on the first goal to the detriment
of the others. When patients are self-reporting symptom reduction with BZDs, but have evidence
of adverse effects, misuse, contraindicated comorbidities (e.g., depression, SUDs, neurocognitive
disorders) and/or—most importantly—persistent functional impairment despite of or because of
BZDs, many prescribers will choose to cease BZD prescriptions even against patients’ requests.
Discontinuation of BZDs is appropriate for those experiencing breakthrough symptoms that were
previously well-controlled, neurocognitive side effects, and abuse of other substances (e.g., alcohol,
cocaine, other prescription medications) [11].
Decreasing and discontinuing BZDs can be terrifying for patients. Approximately one-third
of patients have difficulties during managed BZD withdrawal [
5
], and even more likely have high
anticipation anxiety even before starting the discontinuation process. It is difficult to study BZD
discontinuation because of high rates of patients refusing to participate in and of dropping out of
BZD withdrawal studies [
1
]. This is a testament to how powerful BZD dependence is. Dropping
out of a BZD-tapered discontinuation study is associated with not being married, short-acting
BZDs and extraversion. Successful discontinuation is associated with low baseline neuroticism,
low behavioral inhibition due to anxiety, higher number of positive life events, and higher level
of social support satisfaction. Self-efficacy in coping during the tapering period is associated with
decreased relapse. “Psychological differences might explain why some patients do and others do not
experience difficulties stopping BZDs” [
47
]. Even with education, it is often difficult to transition
patients from BZDs—which they have potentially been using for years—to evidence-based treatments.
Psychotherapeutic interventions and replacement pharmacotherapy to target the symptoms which
these patients are most afraid of can be helpful in the transition.
While symptom relapse after BZD discontinuation is high only for a brief period of time during
acute withdrawal, there is a high risk of relapse—perhaps as high as 50%—on BZDs often with patients
seeking the medications from other prescribers and/or illegal sources [
8
]. Relapse (i.e., resumed use)
after BZD discontinuation is associated with abrupt withdrawal (i.e., without taper), insomnia severity,
psychological distress (e.g., anxiety, major life changes such as divorce, retirement, or death of a spouse),
snoring partner, hospitalization, or surgery and chronic pain [
8
]. Elderly patients are significantly
less likely to stop BZDs than younger patients. Many do not see an advantage to withdrawal and
believe BZDs are effective. However, the cognitive advantages to withdrawal and lack of effectiveness
of long-term BZDs may be persuasive [
7
]. To reduce relapse risk, there are several tools to assist in
discontinuation: education, handouts, psychotherapeutic interventions, tapering, medications to assist
with discontinuation, and alternative medications. The keystones of BZD discontinuation are gradual
tapering, psychological support, and judicious individual management [
1
]. When BZD discontinuation
is managed judiciously and individually, success rates can be 70–80% [1,7,48].
4.1. Education and Support
Education and handouts can improve successful discontinuation. Prescribers should continuously
discuss the proper indications of BZDs, the alternative evidence-based indications, and the risks
J. Clin. Med. 2018,7, 20 9 of 18
of continuing BZDs. Because it is difficult to determine whether or not distress and dysfunctional
behaviors are the result of BZDs, and because providers, patients, and patient families may disagree
on the cause of these symptoms, the patient may need to be observed medication-free for a time.
Symptoms may then be reframed as the result of “addictive medications” or “dependence” rather than
the underlying psychiatric disorder [
11
]. Prescribers should prepare patients for rebound/withdrawal
symptoms, reassure that anxiety/insomnia will improve after days–weeks, and make a plan to
work towards reducing any residual anxiety/insomnia with evidence-based treatments. Written
withdrawal schedules and information sheets are more effective than verbal instructions. Calendars
or charts allow patients to record their progress, increasing incentive to continue. Useful support
of patients with withdrawal anxiety includes written information about what to expect with BZD
withdrawal aimed at patients (including books and pamphlets, prescriber-screened website referrals,
and material individualized by the prescriber for the patient), keeping a diary to pinpoint precipitating
factors and other alternative explanations for panic attacks other than simply the absence of
BZDs, and reassurance [
1
,
5
]. Protocols for BZD-related education based on randomized trials are
available
[13,14]
. Several studies (including randomized controlled trials) have demonstrated that
primary care consultations and receiving a letter signed by a primary care provider advising gradual
reduction in BZD use can facilitate BZD discontinuation [
49
]. It may be helpful to explain BZD physical
dependence and discontinuation as processes of “neuroadaptation” [11].
Since patients “remain vulnerable to stress for some months” after BZD discontinuation [
1
],
individual support via the therapeutic relationship can greatly improve treatment adherence and
successful transitions towards evidence-based treatment. BZD withdrawal is most likely to be
successful with a combination of gradual dose reduction and psychological support. When managed
well, success rates for stopping BZDs are approximately 90%, with the majority feeling better after
withdrawal than when they were taking BZDs [
5
]. Psychological support should be available both
during tapering and for some months after discontinuation. Some patients may do better with
weekly contact—by phone and/or face-to-face—in the initial stages, usually to assess causes of
anxiety and provide reassurance. Support includes provision of information about BZDs, general
encouragement, and psychotherapeutic interventions. Useful support of patients with withdrawal
insomnia includes reassurance, social support, referrals to support organizations and 12-step recovery
programs, family psychoeducation, accurate evaluation of the social and interpersonal context,
physical examination, sleep hygiene, relaxation techniques, and constant telephone availability of
a clinician [
1
,
5
,
18
,
48
]. Support organizations and self-help groups such as 12-step recovery programs
(e.g., Narcotics Anonymous, Alcoholics Anonymous) are important treatment adjuncts. Providers
should warn patients that groups vary significantly in philosophy, with some groups opposing the
use of all psychotropic medications [
11
]. Self-help groups run by ex-BZD users may be helpful,
but psychotherapy is more effective, especially when individual rather than group psychotherapy [
5
].
Involving spouses or family can increase support. Many patients only require minimal support, though
a few may need formal psychotherapy. During withdrawal, it is important that patients are provided
individual counseling with specific advice, options for self-help support programs, and referrals when
necessary [10].
Psychotherapeutic interventions—whether formal or brief, and by referral or the prescriber—can
be helpful. It is often useful to separate medical management from psychotherapy to prevent
medication discussions from dominating psychotherapy sessions [
11
]. However, psychotherapists
and prescribers can both recommend and/or utilize anxiety management techniques, coping skills
(to cope with stress without BZDs), relaxation techniques, breathing exercises, counseling, physical
exercise, massage therapy, motivation enhancement, chemical dependence counseling, and CBT
techniques. Cognitive behavioral interventions have been found to help facilitate the discontinuation
of BZDs and reduce risk of relapse—especially in combination with a supervised taper
[1,8,11,38,50,51]
.
Psychotherapies should remain supportive and cognitive-behavioral, focusing on “coping with
protracted withdrawal symptoms, repairing relationships and learning to function without reliance on
J. Clin. Med. 2018,7, 20 10 of 18
psychoactive drugs.” In early BZD abstinence or fragile patients, insight-oriented and psychodynamic
psychotherapies risk mobilizing strong affects, memories, and emotions that may increase the risk
of relapse [
11
]. CBT plus tapering has been studied the most and has the strongest evidence,
and motivational enhancement also has some evidence [
51
]. CBT techniques focus on evaluating
stressors and physical/emotional/behavioral consequences, and replace unhealthy/unrealistic
thoughts (e.g., “BZDs are the only thing that will work,” “nothing else will help,” “if you take
away my BZD, I’ll have a panic attack and die”) with healthy/realistic thoughts (e.g., “there are many
healthy ways that can improve my sleep,” “even if the next treatment fails, my doctor will work with
me until my anxiety is controlled,” “I know my anxiety will worsen somewhat at first and panic attacks
are uncomfortable, but I can get through them and master my feelings”). “The discovery that a panic
attack can be controlled without resorting to a tablet is a great boost to self-confidence” [
5
]. While most
CBT techniques can be helpful during BZD withdrawal, exposure therapy is less effective during BZD
use than after withdrawal, likely due to BZD-induced cognitive effects [5].
4.2. Withdrawal
When BZDs are suddenly discontinued in tolerant patients, they become exposed to hypoactive
inhibition of GABA and hyperactive excitation of glutamate [
1
,
18
]. This combination causes
withdrawal symptoms, which often leads to the perception that baseline anxiety is worse without
BZDs. Most patients who take BZDs long-term will experience clinically significant withdrawal
symptoms [
15
,
52
]. Even patients who use low doses short-term (even as few as 3 weeks) may
experience mild withdrawal [
15
,
18
]. There is also evidence to suggest that sporadic, non-continuous
BZD use may sensitize patients to future withdrawal [18].
There are three types of BZD discontinuation symptoms: recurrence, rebound, and withdrawal.
Recurrence symptoms are identical to the symptoms for which BZDs were originally prescribed.
It is common for both patients and providers to misinterpret rebound and withdrawal symptoms to be
recurrence symptoms, leading patients to mistakenly believe these symptoms make up their permanent
baseline condition without BZDs. Other than a few symptoms (e.g., seizures, delirium, paresthesia,
hypersensitivity to light or sound), there are few withdrawal symptoms that are distinguishable from
common anxiety symptoms [11,18].
Rebound symptoms are “the mirror image” of therapeutic effects of BZDs (e.g., worse anxiety,
insomnia, and restlessness) [
53
]. These symptoms occur shortly after discontinuation, including
between doses (especially with short half-life BZDs) [
50
]. This generally causes patients to be
acutely aware of their next dose. Such craving is common, and may itself exacerbate symptoms
of anxiety [1,52,5456].
Withdrawal symptoms are idiosyncratic to drug classes, and are not present before the particular
drug was first used. For BZDs, severe symptoms usually occur after abrupt discontinuation
(e.g., seizures, arrhythmia, death), but more mild symptoms may also occur with gradual tapering
(e.g., anxiety, insomnia, tremors) [
53
,
54
]. The course of withdrawal is different depending on half-life,
and may be slower with elderly or liver disease patients [
11
,
15
,
18
,
54
]. Withdrawal symptoms
(particularly protracted withdrawal) may be due to individual constitutional and psychological
factors in addition to GABA-A receptor changes. “Determining whether symptoms that emerge during
[BZD] taper are actually a recurrence of anxiety or are related to a withdrawal syndrome is often
difficult” [50].
While most patients taking long-term BZDs experience withdrawal symptoms upon
discontinuation, short half-life BZDs can cause earlier and more severe withdrawal [
50
]. Table 2
summarizes the characteristics of various common BZDs [
1
,
15
,
39
,
57
]. Short half-life BZD withdrawal
usually starts within 6–24 h, peaks in intensity at 1–4 days, and significantly improves by 4–5 days.
Long half-life BZD withdrawal usually starts within 1–7 days, peaks in intensity at 5–14 days,
and significantly improves by 3–4 weeks. In some patients, mild withdrawal symptoms may last
J. Clin. Med. 2018,7, 20 11 of 18
for months to years (i.e., protracted withdrawal syndrome) [
48
,
58
]. With gradual reduction (over
2–4 months), the withdrawal of short-term and long-term BZDs are more similar and less severe [
50
].
Table 2.
Approximate benzodiazepine characteristics and equivalent doses (therapeutic equivalent
doses are approximate due to clinical potency varying between individuals).
Onset (hours) Action Duration Half-Life
(hours) Potency Equivalent
Doses (mg)
flurazepam 1 Long * 40–250 low 15–30
chlordiazepoxide
1.5 Long * 36–200 low 10–25
diazepam 1 Long * 36–200 low 5–10
clorazepate 1 Long * 36–200 low 7.5–15
clonazepam 1 Long 18–50 high 0.25–0.5
temazepam 0.5 Intermediate 8–22 low 30
lorazepam 2 Intermediate 10–20 high 1
oxazepam 3 Short 4–15 low 15–20
alprazolam 1 Short 6–12 high 0.5
triazolam 0.5 Short 2–5 high 0.25–0.5
* active metabolites.
Severe withdrawal symptoms are associated with higher doses, higher potency, shorter action
and/or half-life, more rapid discontinuation, the elderly, organic brain damage (even minimal brain
damage, which may be common in the elderly), SUDs, anxiety disorders, personality disorders,
higher neuroticism, more baseline psychological distress, more baseline behavioral inhibition due to
anxiety, less social support satisfaction, lower quality of life, and lower education level [
1
,
11
,
18
,
47
].
Unfortunately, some of these factors (e.g., comorbid substance use, anxiety and personality disorders)
also correlate with increased BZD prescriptions (see above). Though rare, complicated BZD withdrawal
(like with alcohol) may cause psychosis, tonic-clonic seizures (occurring in 20–30% of patients with
untreated withdrawal), delirium, and/or death [11,15,53,54].
In a study [
55
] of 79 PTSD patients receiving long-term alprazolam (2–9 mg/day for 1–5 years)
who attempted tapering or discontinuing the medication, 34 had withdrawal symptoms and 8 had
severe withdrawal symptoms. Severe withdrawal symptoms included anxiety (8/8), sleep disturbances
(8/8), nightmares or intrusive thoughts (8/8), rage reactions (6/8), homicidal ideations (6/8), suicidal
ideations (4/8), and dissociative reactions (4/8). All 8 participants had symptoms that had never
occurred before alprazolam treatment or were rebound symptoms of a severity never experienced
before. Of note, all 8 patients with severe withdrawal had a prior history of alcohol and/or BZD use
disorders. Because severe withdrawal reactions occurred even with gradual tapering, the authors
suggested that the withdrawal syndrome with alprazolam may be more severe than with other BZDs.
The study cautioned against starting BZDs without considering the risk of withdrawal, even with
gradual taper.
There are three strategies for preventing life-threatening or distressing withdrawal when
discontinuing BZDs: slowly decrease the dose (tapering), substitute a long-acting BZD then slowly
decrease the dose, and substitute a long-acting barbiturate then slowly decrease the dose.
4.3. Tapering
A taper is necessary for safe and successful BZD discontinuation. Weaning from benzodiazepines
should be done systematically with a full appreciation of the potentially-fatal consequences of abrupt
cessation. Providers should reduce BZDs with patients’ consent and cooperation when possible [
10
],
though unilateral decisions to taper BZDs may be appropriate when the risks of continued prescriptions
outweigh the benefits. A tapering schedule plan should be made initially and then modified according
to frequent evaluation. Those that reduce their BZD dose slowly often deny any withdrawal symptoms,
and have improvements in mental health (including sleep and cognition) and physical health (including
requiring fewer medical consultations) [1,49].
J. Clin. Med. 2018,7, 20 12 of 18
Hospitalization may be appropriate is cases with severe panic, suicidal ideation, or confusion [
18
],
those with a history of complicated withdrawal (i.e., hallucinosis, seizures, delirium), or with
compounding comorbidities (e.g., epilepsy, arrhythmias). While inpatient BZD withdrawal is typically
easier and more rapid (usually days, or at most a few weeks), outpatient withdrawal is more likely to
allow patients to build alternative coping skills gradually [5], which can improve future success.
Withdrawal symptoms can be lessened or avoided entirely with gradual tapering that considers
dose, potency, duration of BZD use, duration of taper, rate of taper, frequency/timing of dosing,
and psychosocial factors (e.g., lifestyle, personality, stressors, and support). For example, because
withdrawal insomnia is a major concern, taking higher doses or the total BZD dose at night can increase
discontinuation tolerance [
1
,
5
]. A long duration of taper is generally thought to best, with many
recommending tapering over at least 2–4 months [
24
,
50
]. The whole process of BZD withdrawal
may take months. Rapid withdrawal can increase distress and decrease success, but some argue that
withdrawing at too slow of a rate may prolong distress. During withdrawal, symptoms commonly
wax and wane, varying in severity and type. “Patients need not be discouraged by these wave-like
recurrences; typically ‘windows’ of normality, when the patient feels well for hours or days, appear
after some weeks, and over time these ‘windows’ enlarge while discomfort slowly regresses” [5].
Regarding rate of tapering, there are varying recommendations. Length of time of tapering
is unpredictable, ranging from a few weeks to months depending on dose, duration, type of drug,
patient’s physical health, and concomitant psychopathology. Usually the rate of discontinuation
decreases over time as most withdrawal symptoms occur in the last half of tapering. Patients are
usually able to tolerate gradual tapering without withdrawal symptoms until they are at 10–20%
of their highest dose [
11
]. For the most effective and safest (especially in outpatient settings), most
recommend tapering no faster than 25% of the total daily dose per week [
1
,
49
,
59
]. Because the end of
the taper can often be most difficult, some recommend 25% daily dose reductions per week until (1)
there is a 50% reduction in the original total daily dose, after which slow the rate even further [
50
];
(2) there is a 75% reduction in the original total daily dose, after which decrease the remaining dose
one-eighth to one-tenth per week until discontinued; or (3) 4 weeks have passed, after which space
out the further reductions for a total discontinuation period of 12 weeks [
47
]. While tapering one half
tablet daily every 2 weeks can be effective for those who have taken BZDs for less than a year, more
rapid tapering can be effective for those who have taken BZDs for over a year (e.g., 0.5 mg/week
for alprazolam, 1 mg/week for lorazepam) [
15
]. Ideally, the patient should be in control of the
reduction rate with informed consent and support from the provider [
1
,
8
]. A useful technique is to
offer 2–3 reasonable options for rate/dose/frequency changes (but not an option for no change) and
allow the patient to choose.
Original dose may influence tapering rates. For those with therapeutic dose dependence, a slow
tapering rate of one-eighth to one-tenth of the daily dose every 1–2 weeks with optimal time for
withdrawal from 6–8 weeks up to 1 year is helpful. For those taking less than 20 mg of diazepam
equivalents daily, patients usually tolerate decreases of 1 mg every 1–2 weeks. For patients taking
20–40 mg, patients usually tolerate decreases of 2 mg every 1–2 weeks until the daily dosage is 4–5 mg,
after which decreases of 0.5 mg every 1–2 weeks are better tolerated. Stopping the last 4–5 mg are
often particularly difficult for patients (usually because of fears about how they will cope without the
medication), but they are generally surprised by how easy it actually is. For patients taking larger
doses (some abusers take over 0.5 g of diazepam equivalent dose daily), patients usually tolerate
decreases of 10 mg every 2–3 weeks. For those with high-dose BZD dependence in the presence
of polysubstance use, Ashton recommends inpatient detoxification for the primary drug and BZD
conversion to diazepam with withdrawal over 2–3 weeks [1,5].
During tapering, withdrawal severity can be measured with the Benzodiazepine Withdrawal
Symptom Questionnaire (BWSQ), which has demonstrated high test–retest reliability, construct validity,
and predictive validity for monitoring BZD withdrawal. Low BWSQ scores during the end of tapering
predict less or no use of BZDs during the year after discontinuation [
11
]. BWSQ assesses multiple
J. Clin. Med. 2018,7, 20 13 of 18
signs/symptoms, including: dissociation; noise, light, smell, and touch sensitivity; peculiar taste in the
mouth; muscle pain and twitching; paresthesia; dizziness; lightheadedness; feeling sick; dysphoria;
sore eyes; motion sickness; hallucinations; feeling unable to control your movements; loss of memory;
and loss of appetite [60].
4.4. Substitution or Adjuvant Pharmacotherapy for Withdrawal
To increase safety and decrease distress during discontinuation, many prescribers substitute one
BZD for another longer-acting cross-tolerant sedative-hypnotic and/or add additional medications
to control withdrawal symptoms. Tapering the current BZD may be useful for long-acting agents,
for those without other substance use and for those who are likely to adhere to dosing regiments.
However, in other cases, substitution of a long-acting BZD or a barbiturate can be particularly useful.
Because withdrawal is worse with short-acting BZDs, transition to long-acting BZDs (e.g.,
diazepam, clonazepam, chlordiazepoxide) can facilitate eventual discontinuation of all BZDs.
Long-acting BZD substitution increases BZD discontinuation successfulness, especially for those
with both alcohol and BZD dependence. Discontinuation of BZDs can be facilitated by
changing to long half-life BZDs (e.g., diazepam) and slowly tapering the dose [
10
]. For some
patients taking a high-potency BZD, Ashton recommends converting to diazepam due its slow
elimination. This conversion can be done in stages by cross-tapering based on equivalent doses [
1
].
It is recommended to convert to diazepam and reduce the dose by about 10 mg every 2–3 days or
as the patient tolerates and, when the daily dose is about 20 mg, the rate of taper can be decreased
to about 5 mg every few days [
61
]. It then becomes more tolerable and safer for the patient to taper
off the lower potency, longer acting diazepam. Diazepam is useful for withdrawal due to available
formulations of scored tablets of 2, 5, and 10 mg [
5
]. Another advantage of diazepam is that it is
more lipophilic than chlordiazepoxide, and therefore has a more rapid onset of action (which makes it
favorable to prevent severe withdrawal) [
61
]. Conversion to diazepam is usually sufficient to prevent
seizures, but some recommend carbamazepine [
1
]. One disadvantage of diazepam is that it is low
potency. While both will prevent severe withdrawal, for high potency BZD substitution, clonazepam
may be better tolerated than low-potency long-acting BZDs. Just as long-acting opioid methadone is
used to transition patients off short-acting heroin, long-acting clonazepam can be used to transition
patients off short-acting alprazolam.
Substitution of long-acting barbiturates can replace BZDs to facilitate discontinuation due to
slower clearance [
18
]. Table 3summarizes BZD to barbiturate dose conversions. Barbiturates have
the advantages of little fluctuation of blood levels between doses and of being effective on GABA-A
receptors that have become BZD-insensitive due to long-term BZD use. Low-dose BZD discontinuation
can be facilitated by discontinuing the BZD, starting phenobarbital 200 mg/day on the first day,
and slowly tapering as tolerated. High-dose BZD discontinuation can be facilitated with conversion
to phenobarbital which can then be tapered 30 mg/day. Before receiving each dose of phenobarbital,
the patient should be examined for signs of barbiturate toxicity: sustained nystagmus (the most
reliable), slurred speech or unsteady gait. If nystagmus is observed, the scheduled dose should
be withheld. If all three signs are observed, the next two doses should be withheld and the total
daily dosage for the next day should be decreased by 50%. If there are signs of sedative-hypnotic
withdrawal, the daily dose is increased 50%. If there are no signs of intoxication or withdrawal,
the phenobarbital taper is again continued at a rate of 30 mg/day. The major disadvantage of
barbiturates is a lower therapeutic window that may make clinicians nervous about prescribing and
monitoring it as outpatients. However, phenobarbital intoxication is not known to produce euphoria
or behavioral disinhibition, which may make patients more likely to view it as a medication [
11
].
Nevertheless, barbiturate substitution is typically reserved for inpatient BZD discontinuation.
Adjuvant medication may be helpful during BZD withdrawal, but no medications have
consistently demonstrated relief of general withdrawal. No adjuvant medications have been proven
effective in attenuating BZD withdrawal symptoms. Among those medications studied have
J. Clin. Med. 2018,7, 20 14 of 18
been antidepressants, beta blockers, buspirone, anticonvulsants (e.g., gabapentin, carbamazepine),
flumazenil, captodiamine, and progesterone. Of these, carbamazepine has the strongest—though
still relatively weak [
5
]—evidence of promise for BZD withdrawal [
62
,
63
]. While non-BZD GABA
receptor agonists (e.g., zolpidem, zaleplon, eszopiclone) have proven to relieve BZD withdrawal
symptoms, they are contraindicated due to having the same disadvantages as BZD (i.e., dependence
and abuse) [
1
]. Nevertheless, some occasional adjuvant medications may be helpful during
discontinuation [
1
,
5
]. Several medications have been used for temporary symptom relief during
BZD withdrawal: propranolol, non-BZD hypnotics, TCAs, clonidine, and analgesics. These drugs help
control certain symptoms but do not alleviate overall withdrawal [
48
]. If autonomic hyperactivity is
present (e.g., tachycardia), beta blockers (e.g., propranolol) or 2-adrenergic agonists (e.g., clonidine)
may be useful adjuncts [
11
]. Antidepressants can help with dysphoria [
48
]. Low doses of TCAs may
help for anxiety, insomnia, and depression. However, SSRIs may precipitate acute anxiety in some
cases. Beta-blockers such as propranolol may help with palpitations, tremors, and muscle twitches but
have little effect on overall states. Buspirone, clonidine, nifedipine, and alpidem have demonstrated
no benefit, and may sometimes worsen withdrawal symptoms [5].
Table 3.
Phenobarbital withdrawal equivalents of benzodiazepines (withdrawal equivalent doses are
not the same as therapeutic equivalent doses).
Dose Equal to 30 mg of Phenobarbital (mg) Phenobarbital Conversion Constant
flurazepam 15 2
chlordiazepoxide 25 1.2
diazepam 10 3
clorazepate 7.5 4
clonazepam 2 15
temazepam 15 2
lorazepam 2 15
oxazepam 10 3
alprazolam 1 30
triazolam 0.25 120
4.5. Replacement Pharmacotherapy for Anxiety and/or Insomnia
See Section 3.4 for evidence-based alternatives to sedative-hypnotics. Again, psychotherapy is the
gold standard treatment for either anxiety or insomnia. As far as pharmacological agents, serotonergic
agents and a variety of non-sedative-hypnotic agents have the strongest evidence for anxiety and
insomnia, respectively. When prescribers and patients find the need for fast-acting medication, Table 1
presents several alternatives. However, treatments that enhance patient coping skills and build
confidence should always be emphasized and preferable to exogenous means of sedation. While the
lack of immediate response/remission can frustrate patients and providers, prescribers should not
resort to prescribing ineffective or harmful medications just to satisfy their own feelings of helplessness.
5. Conclusions
A risk-benefit analysis of continued BZD use should be examined by providers before prescribing
BZDs. In patients where there is evidence of dangerous side effects, misuse (e.g., drug screen positive
for other substances, BZDs obtained from multiple providers, early refills, taking more than prescribed,
suspicious claims of lost or stolen prescriptions), or diversion (e.g., drug screen negative for BZDs),
providers should discontinue BZDs as rapidly as safely possible, whether the patient agrees or not.
However, when there is lack of harm and patients refuse to decrease or discontinue BZDs despite
education about evidence of inefficacy and harm, different prescribers have different philosophies and
may implement different plans on a case-by-case basis. Some would argue that the medication should
be discontinued, whether the patient agrees or not, to prevent harm (which is often insidious, hidden
from both patients and providers) from occurring and because providers should not support treatments
that they themselves believe to be ineffective (non-maleficence). However, others would argue for
J. Clin. Med. 2018,7, 20 15 of 18
approaching the problem as they would approach patients who engage in other harmful behaviors
(e.g., smoking, unhealthy eating), with building of a therapeutic alliance, continued psychoeducation,
and supportive promotion of stages of change. Some argue that this is a different situation because
with behaviors like smoking or unhealthy eating, providers are not prescribing the cigarettes or junk
food. The counterargument is that if a provider does not work through the stages of change, the patient
is simply apt to find another provider without qualms about prescribing BZDs—one who is likely
not going to help the patient eventually decrease or discontinue BZDs. Debates like this can go on
in perpetuity, but it is important that prescribers always discuss with the patient and document their
reasoning. If stipulations are used (e.g., provider will not prescribe BZDs if the patient does not get
random or regular drug screens, tests positive for other substances, does not engage in evidence-based
treatments like psychotherapy and SSRIs), they should be discussed with the patient and documented.
Author Contributions:
J.G. and B.M. conceived and performed this review, analyzed the data, and wrote
the paper.
Conflicts of Interest: The authors declare no conflict of interest.
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... ANN NEUROL 2022;00: [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] H undreds of thousands of people with coronavirus disease 2019 (COVID -19) have been or are currently being treated for acute respiratory distress syndrome (ARDS) in intensive care units (ICUs) worldwide. 1 However, for survivors of severe COVID-19, 2 the reemergence of consciousness is often prolonged, 3 leading to clinical and ethical uncertainty surrounding neurologic prognosis and goals of care. ...
... Pooled data are presented without weighted pooling methods, given the nearly equal sample size at each of the 3 sites. [14][15][16] Statistical Analysis Demographics, clinical factors, laboratory tests, and medications were compared between cohorts and between hypoxemia thresholds (PaO 2 ≤55 mmHg, ≤70 mmHg) using t tests for continuous data that were normally distributed, Wilcoxon rank-sum tests for non-normally distributed continuous variables, and chi-square or Fisherʼs exact test for categorical variables. ...
Article
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Objective: Estimate time to recovery of command-following and associations between hypoxemia with time to recovery of command-following METHODS: In this multi-center, retrospective, cohort study during the initial surge of the United States' pandemic (March-July 2020) we estimate the time from intubation to recovery of command-following, using Kaplan Meier cumulative-incidence curves and Cox proportional hazard models. Patients were included if admitted to one of three hospitals with severe COVID-19, endotracheal intubation for at least seven days, and impairment of consciousness (Glasgow Coma Scale motor score <6). Results: 571 patients of the 795 patients recovered command-following. The median time to recovery of command-following was 30 days (95%-confidence interval [CI]:27-32). Median time to recovery of command-following increased by 16 days for patients with at least one episode of an arterial partial pressure of oxygen (PaO2 ) value ≤55mmHg (p<0.001), and 25% recovered ≥10 days after cessation of mechanical ventilation. The time to recovery of consciousness was associated with hypoxemia (PaO2 ≤55mmHg hazard ratio (HR):0.56; 95%-CI:0.46-0.68; PaO2 ≤70 HR:0.88; 95%-CI:0.85-0.91), and each additional day of hypoxemia decreased the likelihood of recovery, accounting for confounders including sedation. These findings were confirmed among patients without any imagining evidence of structural brain injury (n=199), and in a non-overlapping second surge cohort (N=427, October-April 2021). Interpretation: Survivors of severe COVID-19 commonly recover consciousness weeks after cessation of mechanical ventilation. Long recovery periods are associated with more severe hypoxemia. This relationship is not explained by sedation or brain injury identified on clinical imaging and should inform decisions about life-sustaining therapies. This article is protected by copyright. All rights reserved.
... For assessing total exposure and exposure per day of admission, benzodiazepines were converted to lorazepam equivalents. 15,16 Descriptive statistics were reported as means and standard deviations or medians and interquartile ranges (IQRs) for continuous data, and as frequencies and percentages for categorical data. Univariate and multivariable logistic regression were used to assess the association between patient factors, medication factors, and readmission. ...
Article
Full-text available
Objective To investigate medication factors and patient characteristics associated with readmissions following alcohol-related hospitalizations. Patients and Methods Adult patients admitted from September 1, 2016, through August 31, 2019, who had an alcohol-related hospitalization were identified through electronic health records. Patient characteristics and medications of interest administered during hospitalization or prescribed at discharge were identified. Medications of interest included US Food and Drug Administration–approved medications for alcohol use disorder, benzodiazepines, barbiturates, gabapentin, opioids, and muscle relaxants. The primary outcome was to identify medications and patient factors associated with 30-day alcohol-related readmission. Secondary outcomes included medications and patient characteristics associated with multiple alcohol-related readmissions within a year from the index admission (ie, two or more readmissions) and factors associated with 30-day all-cause readmission. Results Characteristics of the 932 patients included in this study associated with a 30-day alcohol-related readmission included younger age, severity of alcohol withdrawal, history of psychiatric disorder, marital status, and the number of prior alcohol-related admission in the previous year. Benzodiazepine or barbiturate use during hospitalization or upon discharge was associated with 30-day alcohol-related readmission (P=.006). Gabapentin administration during hospitalization or upon discharge was not associated with 30-day alcohol-related readmission (P=.079). Conclusion The findings reinforce current literature identifying patient-specific factors associated with 30-day readmissions. Gabapentin use was not associated with readmissions; however, there was an association with benzodiazepine/barbiturate use.
... We hypothesized that the following variables affect discordance in the HRV-and breathing-based models: 1) specific features from cardiac and respiratory signals; 2) daily dosing of opioids, benzodiazepines, and antipsychotics; 3) SOFA score, a measure of a patient's illness severity. HRV and breathing features of interest were: RR interval, RR root mean square of successive differences (RMSSD), HRV very low frequency power (VLF), HRV low frequency power (LF), HRV high frequency power (HF), inter-breath-intervals, respiratory rate, respiratory variability index, ventilation CVar, cardiopulmonary coupling (42) (43)), benzodiazepines (in Midazolam milligram (44,45)), antipsychotics (DDD method (46)) and the SOFA score were associated with discordance, we computed Pearson and Spearman correlations between each of these variables and the proportion of discordant sleep for each 24-hour segment. ...
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Background. Full polysomnography, the gold standard of sleep measurement, is impractical for widespread use in the intensive care unit (ICU). Wrist-worn actigraphy and subjective sleep assessments do not measure sleep physiology adequately. Here, we explore the feasibility of estimating conventional sleep indices in the ICU with heart rate variability (HRV) and respiration signals using artificial intelligence methods. Methods. We used deep learning models to stage sleep with HRV (through electrocardiogram) and respiratory effort (through a wearable belt) signals in critically ill adult patients admitted to surgical and medical ICUs, and in covariate-matched sleep laboratory patients. We analyzed the agreement of the determined sleep stages between the HRV- and breathing-based models, computed sleep indices, and quantified breathing variables during sleep. Results. We studied 102 adult patients in the ICU across multiple days and nights, and 220 patients in a clinical sleep laboratory. We found that sleep stages predicted by HRV- and breathing-based models showed agreement in 60% of the ICU data and in 81% of the sleep laboratory data. In the ICU, deep NREM (N2 + N3) proportion of total sleep duration was reduced (ICU 39%, sleep laboratory 57%, p<0.01), REM proportion showed heavy-tailed distribution, and the number of wake transitions per hour of sleep (median = 3.6) was comparable to sleep laboratory patients with sleep-disordered breathing (median = 3.9). Sleep in the ICU was also fragmented, with 38% of sleep occurring during daytime hours. Finally, patients in the ICU showed faster and less variable breathing patterns compared to sleep laboratory patients. Conclusions. Cardiovascular and respiratory signals encode sleep state information, which can be utilized to measure sleep state in the ICU. Using these easily measurable variables can provide automated information about sleep in the ICU.
... Such an increase would not only highlight the psychological impact of the event but would also have health consequences of its own. 10 Short-term use of benzodiazepines is associated with negative side effects such as an increased risk of accidents due to altered psychomotor and cognitive performances. 11 12 These negative outcomes of benzodiazepine use are of particular concern in older people. ...
Article
Full-text available
Objectives To determine whether the terrorist attacks occurring in Paris on November 2015 have changed benzodiazepine use in the French population. Design Interrupted time series analysis. Setting National population-based cohort. Participants 90 258 individuals included in the population-based CONSTANCES cohort from 2012 to 2017. Outcome measures Benzodiazepine use was evaluated according to two different indicators using objective data from administrative registries: weekly number of individuals with a benzodiazepine delivered prescriptions (BDP) and weekly number of defined daily dose (DDD). Two sets of analyses were performed according to sex and age (≤50 vs >50). Education, income and area of residence were additional stratification variables to search for at-risk subgroups. Results Among women, those with younger age (incidence rate ratios (IRR)=1.18; 95% CI=1.05 to 1.32 for BDP; IRR=1.14; 95% CI=1.03 to 1.27 for DDD), higher education (IRR=1.23; 95% CI=1.03 to 1.46 for BDP; IRR=1.23; 95% CI=1.01 to 1.51 for DDD) and living in Paris (IRR=1.27; 95% CI=1.05 to 1.54 for BDP) presented increased risks for benzodiazepine use. Among participants under 50, an overall increase in benzodiazepine use was identified (IRR=1.14; 95% CI=1.02 to 1.28 for BDP and IRR=1.12; 95% CI=1.01 to 1.25 for DDD) and in several strata. In addition to women, those with higher education (IRR=1.22; 95% CI=1.02 to 1.47 for BDP), lower income (IRR=1.17; 95% CI=1.02 to 1.35 for BDP) and not Paris residents (IRR=1.13; 95% CI=1.02 to 1.26 for BDP and IRR=1.13; 95% CI=1.03 to 1.26 for DDD) presented increased risks for benzodiazepine use. Conclusion Terrorist attacks might increase benzodiazepine use at a population level, with at-risk subgroups being particularly concerned. Information and prevention strategies are needed to provide appropriate care after such events.
... Despite the growing problem of benzodiazepine (BZD) addiction, the treatment principles remain unstructured, and as argued [1,2], most studies on detoxification procedures do not meet the criteria for clinical trials. This results in a multitude of reviews, confirming the eclectic state of the art [3][4][5]. In turn, data are scarce regarding actual treatment efficacy and frequency of dropouts or early relapses. ...
Article
Full-text available
Objective Rapid relapses after successful withdrawal occur even in apparently motivated benzodiazepine (BZD)-dependent patients. Regardless of known personality or biological (re-adaptation) issues, the aim of this open-label, single-arm, seminaturalistic study was to search for any detoxification errors contributing to failures. Methods The data came from 350 inpatients. Based on serum-BZD evolution criteria, the procedure was divided into four stages: substitution, accumulation, elimination and post-elimination observation. After switching the patients to a long-acting substitute (diazepam), to prevent data falsification due to unwanted overaccumulation, the doses were expeditiously reduced under laboratory feedback until accumulation stopped. With the start of effective elimination, the tapering rate slowed and was individually adjusted to the patient’s current clinical state. The tracking of both serum-BZD concentration and the corresponding intensity of withdrawal symptoms was continued throughout the entire elimination phase, also following successful drug withdrawal. Detoxification was concluded only after the patient's post-elimination stabilization. Results Regardless of various initial serum-BZD concentration levels and the customized dose-reduction rate, and despite the novel lab-driven actions preventing initial overaccumulation, elimination was systematically proven to be protracted and varied within the 2- to 95-day range after the final dose. Within this period, withdrawal syndrome culminated several times, with varying combinations of symptoms. The last crisis occurrence (typically 2–3 weeks after withdrawal) correlated with the final serum-BZD elimination. The factors that prolonged elimination and delayed the final crisis were patient age, duration of addiction, adjunct valproate medication and elimination stage start parameters growing with former overaccumulation. Conclusions The low-concentration detoxification stage is critical for patients’ confrontations with recurring withdrawal symptoms. Underestimated elimination time following drug withdrawal and premature conclusions of detoxification expose patients to unassisted withdrawal crises. Concentration tracking defines proper limits for medical assistance, preventing early relapses.
... 23 Hypnotics are widely prescribed for adult psychiatric in-patients suffering from poor sleep. 24 They can be effective and necessary for acute insomnia, 25 but if insomnia persists the benefits of hypnotics may wane while the risk of sideeffects increases. 26 Hypnotics have the potential to worsen outcomes for sleep apnoea, anxiety, cognitive function and depression, 27 and pose a significant risk of dependence and harm with long-term use. ...
Article
Full-text available
Aims and method: In-patients on mental health wards are commonly prescribed hypnotics for the long-term management of disturbed sleep. Specific sleep disorders remain underdiagnosed and effective behavioural interventions are underused. We developed a suite of three educational interventions (a video, poster and handbook) about sleep, sleep disorders, the safe prescribing of hypnotics and use of psychological strategies (sleep hygiene and cognitive-behavioural therapy for insomnia, CBTi) using co-design and multiprofessional stakeholder involvement. This controlled before-and-after study evaluated the effectiveness of these interventions across seven in-patient psychiatric wards, examining their impact on hypnotic prescribing rates and staff confidence scores (data collected by retrospective drug chart analysis and survey respectively). Results: A marked reduction was seen in the percentage of patients prescribed hypnotics on in-patient prescription charts (-24%), with a 41% reduction in the number of hypnotics administered per patient (mean reduction -1.142 administrations/patient). Clinical implications: These simple educational strategies about the causes and treatment of insomnia can reduce hypnotic prescribing rates and increase staff confidence in both the medical and psychological management of insomnia.
... In other words, the deprescribing conversation is likely very different with someone who has never considered reducing than with a patient who raises the concern themselves. Although the transtheoretical model (TTM; that is, 'stages of change') is recommended to guide deprescribing, 30 at present only one study has validated the efficacy of BZD interventions when aligned with the patients' stage of change. 31 Broader consideration is therefore required to understand how patient barriers and facilitators vary over time according to their level of motivation and capacity for change. ...
Article
Full-text available
Background: Given the prevalence of long-term benzodiazepine (BZDs) prescribing, increased monitoring through the implementation of prescription monitoring programs (PMPs) may be the necessary impetus to promote BZD deprescribing. Despite evidence promoting the importance of patient-centred care, GPs have not been sufficiently supported to implement these principles through current deprescribing practice. Aim: To investigate patients' perception of their prescriber's influence on ceasing BZD use, including their willingness to take on their advice, and to understand how a patients' stage of change influences the barriers and facilitators they perceive to discontinuing BZDs. Design and setting: An online survey and qualitative interviews with 22 long-term BZD users (≥6 months), aged 18-69 years, recruited from the general population in Victoria, Australia. Method: Two groups of BZD users participated, one in the process of reducing their BZD and one not reducing, and were categorised according to their stage of change. Data underwent thematic analysis to identify barriers and facilitators to reducing BZDs both at the patient-level and prescriber-level. Results: BZD patients' perceptions of the prescriber influence were characterised by prescribing behaviours, treatment approach, and attitude. Barriers and facilitators to reducing their BZD were mapped against their stage of change. Irrespective of their stage of change, participants reported they would be willing to try reducing their BZD if they trusted their prescriber. Conclusion: This study illustrates that with a few key strategies at each step of the deprescribing conversation, GPs are well-positioned to tackle the issue of long-term BZD use in a manner that is patient-centred.
Article
Benzodiazepine and related sedative use has been increasing. There has been a growing number of unregulated novel psychoactive substances, including designer benzodiazepines. Benzodiazepines have neurobiological and pharmacologic properties that result in a high potential for misuse and physical dependence. Options for discontinuing long-term benzodiazepine use include an outpatient benzodiazepine taper or inpatient withdrawal management at a hospital or detoxification facility. The quality of evidence on medications for benzodiazepine discontinuation is overall low, whereas cognitive behavioral therapy has shown the most benefit in terms of behavioral treatments. Benzodiazepines may also have significant adverse effects, increasing the risk of overdose and death.
Article
Purpose Claustrophobia remains a challenging barrier for a significant number of patients to successfully complete a Magnetic Resonance Imaging (MRI) examination. While use of wide-bore machines and pre-exam administration of a low-dose benzodiazepine are commonly employed, there is little published research to determine which modality is the most efficacious based on the patient's specific degree of claustrophobia. This retrospective case-control study examines the efficacy of using a low-dose oral benzodiazepine and wide-bore magnet to successfully aid the claustrophobic patient in completing an MRI Brain examination. Methods 3966 non-contrast MRI brain examinations were considered for this study. The sample was filtered to include only patients who were older than 18 years of age, not currently experiencing symptoms which may hinder MRI examination, and did not undergo any additional MR studies at the time of their exam, resulting in a final sample of 2358 examinations for analysis. Patients were then sub-divided based on severity of claustrophobia and analyzed using logistic regression analysis. Results Use of wide-bore magnet increased odds of successfully completing the MRI Brain examination in mild, moderately, and severely claustrophobic patients (OR: 1.79, 95% CI: 1.17–2.75). The administration of pre-examination low-dose oral benzodiazepine increased odds of successfully completing the MRI Brain examination in severely claustrophobic patients (OR: 6.21, 95% CI: 1.63–19.28). Conclusion Use of a wide-bore magnet is effective in assisting mild, moderately, and severely claustrophobic patients in completing an MRI Brain exam. However, the efficacy of low-dose oral benzodiazepine is limited to severely claustrophobic patients.
Article
Despite the lack of evidence on the long-term effectiveness of benzodiazepines and their potential harmful effects, prescriptions of the drug have significantly increased in the US over the past decade. This article reviews best practices regarding primary care benzodiazepine prescriptions and how providers can best prevent and treat benzodiazepine use disorder and other harmful effects.
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Benzodiazepines are some of the most commonly prescribed medications in the world. These sedative-hypnotics can provide rapid relief for symptoms like anxiety and insomnia, but are also linked to a variety of adverse effects (whether used long-term, short-term, or as needed). Many patients take benzodiazepines long-term without ever receiving evidence-based first-line treatments (e.g., psychotherapy, relaxation techniques, sleep hygiene education, serotonergic agents). This review discusses the risks and benefits of, and alternatives to benzodiazepines. We discuss evidence-based indications and contraindications, and the theoretical biopsychosocial bases for effectiveness, ineffectiveness and harm. Potential adverse effects and drug-drug interactions are summarized. Finally, both fast-acting/acute and delayed-action/chronic alternative treatments for anxiety and/or insomnia are discussed. Response to treatment—whether benzodiazepines, other pharmacological agents, or psychotherapy—should be determined based on functional recovery and not merely sedation.
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Introduction: The purpose of this guideline is to establish clinical practice recommendations for the pharmacologic treatment of chronic insomnia in adults, when such treatment is clinically indicated. Unlike previous meta-analyses, which focused on broad classes of drugs, this guideline focuses on individual drugscommonly used to treat insomnia. It includes drugs that are FDA-approved for the treatment of insomnia,as well as several drugs commonly used to treat insomnia without an FDA indication for this condition. This guideline should be used in conjunction with other AASM guidelines on the evaluation and treatmentof chronic insomnia in adults. Methods: The American Academy of Sleep Medicine commissioned a task force of five experts in sleep medicine. A systematic review was conducted to identify randomized controlled trials, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used to assess the evidence. The task force developed recommendations and assigned strengths based on the quality of evidence, the balance of benefits and harms, and patient values and preferences. Literature reviews are provided for those pharmacologic agents for which sufficient evidence was available to establish recommendations. The AASM Board of Directors approved the final recommendations.
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Objective To determine whether higher cumulative use of benzodiazepines is associated with a higher risk of dementia or more rapid cognitive decline. Design Prospective population based cohort. Setting Integrated healthcare delivery system, Seattle, Washington. Participants 3434 participants aged ≥65 without dementia at study entry. There were two rounds of recruitment (1994-96 and 2000-03) followed by continuous enrollment beginning in 2004. Main outcomes measures The cognitive abilities screening instrument (CASI) was administered every two years to screen for dementia and was used to examine cognitive trajectory. Incident dementia and Alzheimer’s disease were determined with standard diagnostic criteria. Benzodiazepine exposure was defined from computerized pharmacy data and consisted of the total standardized daily doses (TSDDs) dispensed over a 10 year period (a rolling window that moved forward in time during follow-up). The most recent year was excluded because of possible use for prodromal symptoms. Multivariable Cox proportional hazard models were used to examine time varying use of benzodiazepine and dementia risk. Analyses of cognitive trajectory used linear regression models with generalized estimating equations. Results Over a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia, of whom 637 developed Alzheimer’s disease. For dementia, the adjusted hazard ratios associated with cumulative benzodiazepine use compared with non-use were 1.25 (95% confidence interval 1.03 to 1.51) for 1-30 TSDDs; 1.31 (1.00 to 1.71) for 31-120 TSDDs; and 1.07 (0.82 to 1.39) for ≥121 TSDDs. Results were similar for Alzheimer’s disease. Higher benzodiazepine use was not associated with more rapid cognitive decline. Conclusion The risk of dementia is slightly higher in people with minimal exposure to benzodiazepines but not with the highest level of exposure. These results do not support a causal association between benzodiazepine use and dementia.
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Background: Benzodiazepines (BZDs) have a sedative and hypnotic effect upon people. Short term use can be beneficial but long term BZD use is common, with several risks in addition to the potential for dependence in both opiate and non-opiate dependent patients. Objectives: To evaluate the effectiveness of psychosocial interventions for treating BZD harmful use, abuse or dependence compared to pharmacological interventions, no intervention, placebo or a different psychosocial intervention on reducing the use of BZDs in opiate dependent and non-opiate dependent groups. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL- the Cochrane Library issue 12, 2014) which includes the Cochrane Drugs and Alcohol Group Specialized Register; PubMed (from 1966 to December 2014); EMBASE (from 1988 to December 2014); CINAHL Cumulative Index to Nursing and Allied Health Literature (1982 to September 2013); PsychINFO (1872 to December 2014); ERIC (Education Resources Information Centre, (January 1966 to September 2013); All EBM Reviews (1991 to September 2013, Ovid Interface); AMED (Allied & Alternative Medicine) 1985 to September 2013); ASSIA (Applied Social Sciences Index & Abstracts (1960 to September 2013); LILACS (January 1982 to September 2013); Web of Science (1900 to December 2014); Electronic Grey Literature Databases: Dissertation Abstract; Index to Theses. Selection criteria: Randomised controlled trials examining the use of a psychosocial intervention to treat BZDs versus pharmacological interventions, no intervention, placebo or a different psychosocial intervention on reducing the use of BZDs in opiate dependent and non-opiate dependent groups. Data collection and analysis: We used the standard methodological procedures outlined in Cochrane Guidelines. Main results: Twenty-five studies including 1666 people met the inclusion criteria. The studies tested many different psychosocial interventions including cognitive behavioural therapy (CBT) (some studies with taper, other studies with no taper), motivational interviewing (MI), letters to patients advising them to reduce or quit BZD use, relaxation studies, counselling delivered electronically and advice provided by a general practitioner (GP). Based on the data obtained, we performed two meta-analyses in this Cochrane review: one assessing the effectiveness of CBT plus taper versus taper only (575 participants), and one assessing MI versus treatment as usual (TAU) (80 participants).There was moderate quality of evidence that CBT plus taper was more likely to result in successful discontinuation of BZDs within four weeks post treatment compared to taper only (Risk ratio (RR) 1.40, 95% confidence interval (CI) 1.05 to 1.86; nine trials, 423 participants) and moderate quality of evidence at three month follow-up (RR 1.51, 95% CI 1.15 to 1.98) in favour of CBT (taper) for 575 participants. The effects were less certain at 6, 11, 12, 15 and 24 months follow-up. The effect of CBT on reducing BZDs by > 50% was uncertain for all time points examined due to the low quality evidence. There was very low quality evidence for the effect on drop-outs at any of the time intervals; post-treatment (RR 1.05, 95% CI 0.66 to 1.66), three month follow-up (RR 1.71, 95% CI 0.16 to 17.98) and six month follow-up (RR 0.70, 95% CI 0.17 to 2.88).Based on the very low quality of evidence available, the effect of MI versus TAU for all the time intervals is unclear; post treatment (RR 4.43, 95% CI 0.16 to 125.35; two trials, 34 participants), at three month follow-up (RR 3.46, 95% CI 0.53 to 22.45; four trials, 80 participants), six month follow-up (RR 0.14, 95% CI 0.01 to 1.89) and 12 month follow-up (RR 1.25, 95% CI 0.63 to 2.47). There was very low quality of evidence to determine the effect of MI on reducing BZDs by > 50% at three month follow-up (RR 1.52, 95% CI 0.60 to 3.83) and 12 month follow-up (RR 0.87, 95% CI 0.52 to 1.47). The effects on drop-outs from treatment at any of the time intervals between the two groups were uncertain due to the wide CIs; post-treatment (RR 0.50, 95% CI 0.04 to 7.10), three month follow-up (RR 0.46, 95% CI 0.06 to 3.28), six month follow-up (RR 8.75, 95% CI 0.61 to 124.53) and 12 month follow-up (RR 0.42, 95% CI 0.02 to 7.71).The following interventions reduced BZD use - tailored GP letter versus generic GP letter at 12 month follow-up (RR 1.70, 95% CI 1.07 to 2.70; one trial, 322 participants), standardised interview versus TAU at six month follow-up (RR 13.11, 95% CI 3.25 to 52.83; one trial, 139 participants) and 12 month follow-up (RR 4.97, 95% CI 2.23 to 11.11), and relaxation versus TAU at three month follow-up (RR 2.20, 95% CI 1.23 to 3.94).There was insufficient supporting evidence for the remaining interventions.We performed a 'Risk of bias' assessment on all included studies. We assessed the quality of the evidence as high quality for random sequence generation, attrition bias and reporting bias; moderate quality for allocation concealment, performance bias for objective outcomes, and detection bias for objective outcomes; and low quality for performance bias for subjective outcomes and detection bias for subjective outcomes. Few studies had manualised sessions or independent tests of treatment fidelity; most follow-up periods were less than 12 months.Based on decisions made during the implementation of protocol methods to present a manageable summary of the evidence we did not collect data on quality of life, self-harm or adverse events. Authors' conclusions: CBT plus taper is effective in the short term (three month time period) in reducing BZD use. However, this is not sustained at six months and subsequently. Currently there is insufficient evidence to support the use of MI to reduce BZD use. There is emerging evidence to suggest that a tailored GP letter versus a generic GP letter, a standardised interview versus TAU, and relaxation versus TAU could be effective for BZD reduction. There is currently insufficient evidence for other approaches to reduce BZD use.
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Importance Benzodiazepines have been prescribed for short periods to patients with depression who are beginning antidepressant therapy to improve depressive symptoms more quickly, mitigate concomitant anxiety, and improve antidepressant treatment continuation. However, benzodiazepine therapy is associated with risks, including dependency, which may take only a few weeks to develop. Objectives To examine trends in simultaneous benzodiazepine and antidepressant new use among adults with depression initiating an antidepressant, assess antidepressant treatment length by simultaneous new use status, estimate subsequent long-term benzodiazepine use in those with simultaneous antidepressant and benzodiazepine new use, and identify determinants of simultaneous new use and long-term benzodiazepine use. Design, Setting, and Participants This cohort study using a US commercial claims database included commercially insured adults (aged 18-64 years) from January 1, 2001, through December 31, 2014, with a recent depression diagnosis who began antidepressant therapy but had not used antidepressants or benzodiazepines in the prior year. Exposures Simultaneous new use, defined as a new benzodiazepine prescription dispensed on the same day as a new antidepressant prescription. Main Outcomes and Measures The proportion of antidepressant initiators with simultaneous new use and continuing antidepressant treatment for 6 months and the proportion of simultaneous new users receiving long-term (6-months) benzodiazepine therapy. Results Of the 765 130 adults (median age, 39 years; interquartile range, 29-49 years; 507 451 women [66.3%]) who initiated antidepressant treatment, 81 020 (10.6%) also initiated benzodiazepine treatment. The mean annual increase in the proportion simultaneously starting use of both agents from 2001 to 2014 was 0.49% (95% CI, 0.47%-0.51%), increasing from 6.1% (95% CI, 5.5%-6.6%) in 2001 to 12.5% (95% CI, 12.3%-12.7%) in 2012 and stabilizing through 2014 (11.3%, 95% CI, 11.1%-11.5%). Similar findings were apparent by age group and physician type. Antidepressant treatment length was similar in simultaneous new users and non–simultaneous new users. Among simultaneous new users, 12.3% (95% CI, 12.0%-12.5%) exhibited long-term benzodiazepine use (64.0% discontinued taking benzodiazepines after the initial fill). Determinants of long-term benzodiazepine use after simultaneous new use were longer initial benzodiazepine days’ supply, first prescription for a long-acting benzodiazepine, and recent prescription opioid fills. Conclusions and Relevance One-tenth of antidepressant initiators with depression simultaneously initiated benzodiazepine therapy. No meaningful difference in antidepressant treatment at 6 months was observed by simultaneous new use status. Because of the risks associated with benzodiazepines, simultaneous new use at antidepressant initiation and the benzodiazepine regimen itself require careful consideration.
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Objective: This article addresses some of the controversies about the role of benzodiazepines in the treatment of posttraumatic stress disorder. Conclusions: Benzodiazepines have been admonished in treatment guidelines for posttraumatic stress disorder, but this is based on very little solid evidence. Although benzodiazepines do not seem to be effective in the treatment of the core posttraumatic stress disorder symptoms, their careful use as adjunctive agents for the symptoms such as anxiety and sleep disturbance may be useful. Future research needs to identify predictors of improved treatment outcomes in posttraumatic stress disorder with use of benzodiazepines.
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Benzodiazepines are advantageous treatments for anxiety disorders because they work quickly. However, benzodiazepines can vary in terms of efficacy across anxiety disorders. Benzodiazepines have been found to be a superior treatment in social anxiety disorder. While benzodiazepines are effective in the treatment of generalized anxiety disorder, other treatments such as selective serotonin reuptake inhibitors may be more effective. Also, research indicates that benzodiazepines may not be effective in the treatment of postraumatic stress disorder. Therefore, physicians need to consider the type of anxiety disorder before prescribing a benzodiazepine as a treatment.
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Objective: Although benzodiazepines (BZDs) are commonly used in the treatment of posttraumatic stress disorder (PTSD), no systematic review or meta-analysis has specifically examined this treatment. The goal of this study was to analyze and summarize evidence concerning the efficacy of BZDs in treating PTSD. Methods: The review protocol was undertaken according to the principles recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and is registered with the PROSPERO international prospective register of systematic reviews (http://www.crd.york.ac.uk/PROSPERO, registration number CRD42014009318). Two authors independently conducted a search of all relevant articles using multiple electronic databases and independently abstracted information from studies measuring PTSD outcomes in patients using BZDs. Eighteen clinical trials and observational studies were identified, with a total of 5236 participants. Outcomes were assessed using qualitative and quantitative syntheses, including meta-analysis. Results: BZDs are ineffective for PTSD treatment and prevention, and risks associated with their use tend to outweigh potential short-term benefits. In addition to adverse effects in general populations, BZDs are associated with specific problems in patients with PTSD: worse overall severity, significantly increased risk of developing PTSD with use after recent trauma, worse psychotherapy outcomes, aggression, depression, and substance use. Potential biopsychosocial explanations for these results are proposed based on studies that have investigated BZDs, PTSD, and relevant animal models. Conclusions: The results of this systematic review suggest that BZDs should be considered relatively contraindicated for patients with PTSD or recent trauma. Evidence-based treatments for PTSD should be favored over BZDs.