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Obstetrics and Gynecology
Susan W. Lehmann, MDChristina Prather, MD Erin VanMeter, PharmD Colleen Christmas, MD
This 55-minute audio lecture is part of a high-yield learning activity from AudioDigest’s Internal Medicine Library.
The goal of this program is to improve the safe use and deprescribing of benzodiazepines. After hearing and assimilating this program, the clinician will be better able to:
1. Identify appropriate and inappropriate uses of benzodiazepines.
2. Select effective modalities to treat anxiety related to cognitive dysfunction.
3. Recognize the symptoms of withdrawal from benzodiazepines.
4. Consider pharmacokinetic and pharmacodynamics factors when planning withdrawal from benzodiazepines.
5. Develop plans to taper chronic use of benzodiazepines.
Susan W. Lehmann, MD
Associate Professor, Department of Psychiatry and Behavioral Sciences
Director, Geriatric Psychiatry Day Hospital Program
Johns Hopkins University School of Medicine
Christina Prather, MD
Assistant Professor, Department of Geriatric and Palliative Medicine
The George Washington University School of Medicine & Health Sciences
Erin VanMeter, PharmD
Assistant Professor of Pharmacy Practice and Science
Clinical Pharmacy Specialist, Ambulatory Care
University of Maryland School of Pharmacy
Colleen Christmas, MD
Associate Professor of Medicine
Director, Primary Care Leadership Track
Johns Hopkins University School of Medicine,
Baltimore Johns Hopkins University School of Medicine
Highlights from the Edmund G. Beacham 47th Annual Current Topics in Geriatrics, presented by the Johns Hopkins University School of Medicine, Division of Geriatric Medicine and Gerontology
Deprescribing: is a planned and supervised process of tapering or stopping a medication that is no longer useful or is causing harm
Benzodiazepines: long-term use is common in older adults; a 2015 study of a prescription database found long-term prescriptions are common; long-term use is defined as prescriptions extending for ≥120 days; use increases with increasing age; in every age group use is higher in women than in men (by ≤2-fold); leading indications are anxiety, anxiety disorders, depression, and insomnia; use as a short-term agent to treat a specific cause of anxiety may be appropriate; prescribed in many patients for periods of years in the absence of appropriate indications; data from the National Ambulatory Medical Care Study found that rates of prescription are highest for patients >80 yr of age; a mental health diagnosis is documented for only 16% of patients given prescriptions for benzodiazepines; are often prescribed to manage symptoms more appropriately treated by other agents
Anxiety: is a common symptom of depression and should be managed by treating depression; may also be a manifestation of mild cognitive impairment or early dementia; loss of memory may also be a cause of stress and anxiety; use of benzodiazepines to treat anxiety caused by underlying cognitive impairment is inappropriate; strategies to recognize limitations and cope with difficulties of impaired cognition are the treatments of choice
Adverse events associated with benzodiazepines: include motor vehicle accidents, falls, and confusion; complications are associated with higher risk for mortality; unusual amnestic and sleep behavior disturbances may occur, especially with zolpidem (eg, driving or cooking while sleeping); meta-analysis (2005) of 24 randomized controlled trials comparing benzodiazepines with placebo for the treatment of insomnia in older adults found that sedative-hypnotic agents are associated with a slight improvement in sleep (eg, fewer awakenings, longer duration of sleep); number needed to treat was 13; number needed to harm was 6; concluded that adverse events are twice as likely as benefits; adverse events included psychomotor events, cognitive changes, fatigue, and difficulty concentrating
Case study: woman 80 yr of age presents with chronic anxiety and mild depressive symptoms; prescribed temazepam for chronic insomnia for 30 yr; recently developed back pain; reports worsening depressive symptoms for 6 mo; difficulty with concentration is her greatest concern; scored 25 of 30 on Mini-Mental State Examination (consistent with mild cognitive impairment); medications include temazepam 30 mg, eszopiclone (Lunesta), trazodone (all to treat insomnia), an opioid drug (for back pain), and gabapentin; clinical assessment—insomnia is likely secondary to unrecognized major depressive disorder; early morning awakening is a common and classic symptom of major depressive disorder; antidepressant agent rather than sedative-hypnotic agent is recommended to treat her insomnia; her insomnia and anxiety are likely due to depression; current medications are likely contributing to cognitive impairment; while trazodone has antidepressant properties, 50-mg dose is ineffective (and higher doses are not well tolerated); patient was started on selective serotonin reuptake inhibitor; eszopiclone was discontinued; temazepam was discontinued through intensive efforts over 2 yr
Case study 1: patient presents to clinic following hospitalization for a fall (fractures of radius and multiple ribs); she was a professional dancer and still enjoys dancing with friends; medical history includes compensated heart failure (medicated with furosemide), osteoporosis, and mixed urinary incontinence; takes benzodiazepine; drinks wine occasionally; a patient’s fear of falling can be an opportunity to modify risk factors and change behavior; patient lists “keeping my mind sharp” as her primary motivator; cognitive assessment (Mini-Cog) suggests mild cognitive impairment; use the patient’s priorities to engage her to change her behavior or medications
Case study 2: retired real estate agent and executive secretary 71 yr of age reports loss of memory, difficulty managing bills and learning a new computer program, and inability to organize move into a new apartment; has corrected hearing loss (hearing loss is a risk factor for progression in cognitive impairment); while patient is most concerned by her loss of memory, physician notes anxiety as the predominant clinical feature
Anxiety: an independent risk factor for Alzheimer dementia; present in ≤50% of patients with cognitive impairment; can occur at any time during course of disease; risk for progression of cognitive impairment is increased in patients with comorbid anxiety or depression; comorbid anxiety can accelerate decline of cognitive function; persons aware of their cognitive decline tend to be more anxious; anxiety is a common symptom of cognitive impairment; new onset of anxiety may indicate, eg, Parkinson disease or dementia
Treatment of anxiety in patients with cognitive dysfunction: objectives include building confidence, developing cognitive and behavioral skills, and structuring routine; speech and cognitive therapy—refer with first signs of objective deficit (reimbursable by most payers if documented by cognitive testing); develop areas of brain dysfunction and improve function; provide patients with greater confidence; structuring routine—helps compensate for memory loss; effective even as Alzheimer disease progresses; builds confidence; anxiety associated with cognitive impairment is not effectively treated by medication; assess for unmet needs—if patient is anxious about bladder or bowel function, consider presence of hemorrhoid or anal pruritus or vaginal atrophy or pruritus; restlessness may be related to excessive or insufficient mobility or engagement in community; consider each patient individually by obtaining a detailed history; identify the time of day when anxiety is worse (eg, at 3:00 PM when “sandwich” caregiver is preoccupied with caring for children returning from school); triad approach—focus on environment, caregiver, and patient; assess adequacy of environment; identify expectations of caregiver; dyad training with occupational, speech, and cognitive therapists can help to establish realistic expectations of caregiver; improves outcomes on neuropsychiatric scales; consider likes and dislikes of patient to develop nonpharmacologic interventions
Approaches to patients taking benzodiazepines long-term: conversation is often uncomfortable; use the patient’s priorities to motivate change (eg, prevention of falls, sleepiness during day); assure the patient that their medication will not be suddenly stopped; establish partnership by recognizing that the patient is in charge; warning of risks may not be helpful; cite benefits of discontinuing medication (eg, increased energy, improved cognition); assure the patient that adverse effects of withdrawal will be treated; educate patients about symptoms of withdrawal and how they will be treated (eg, maintaining use of benzodiazepine may be required for extended period); in the EMPOWER randomized controlled trial (2014) pharmacists distributed brochures; contents included risks and benefits of benzodiazepines, sample tapering schedules, and recounting of success stories; tapering was successful in 27% of patients; with the addition of clinician intervention in the second phase of the study, rate of success with tapering was 44%
Indications for tapering: timing—dependency can develop after 4 wk of use; withdrawal at this point may trigger symptoms; dose—consider in patients taking supratherapeutic doses or when used with other agents that depress the central nervous system (eg, opioid drugs, sleep aids, gabapentin); medical history—consider in patients following traumatic brain injury, in patients with cognitive impairment disorder or substance use disorders, and in patients older than 65 yr; older adults—age-related changes in pharmacokinetics and pharmacodynamics lead to accumulation of benzodiazepines and increase sensitivity to their effects; incidence of adverse effects increases as patients age (with changes in liver and kidney function); explaining risks is helpful
Symptoms of withdrawal: include altered mental status, anxiety, agitation, and insomnia; seizures are unusual (use of alcohol or illicit substances, history of seizure disorder, and use of supratherapeutic doses increase risk); most common symptoms are feeling unwell, anxiety, sweating, and palpitations; explaining potential symptoms is helpful; benzodiazepines act as allosteric modulators of GABA-A receptor that enhance neuroinhibitory effects; tolerance and dependence ensue quickly; patients often sweat or feel anxious at the end of a dosing interval (similar to symptoms accompanying worsening anxiety and insomnia); patients may erroneously conclude that benzodiazepine effectively treats anxiety and escalate dose (exacerbating symptoms at the end of a dosing interval); important to educate patient about the process of tapering
Considerations when tapering: drug interactions and pharmacokinetics; tapering schedule; some benzodiazepines are metabolized through cytochrome P450 3A4 enzyme; medications that affect 3A4 enzyme can change plasma concentration of benzodiazepines, eg, diltiazem inhibits metabolism of alprazolam and thereby increases plasma levels; clinically, tapering should be slower and longer; carbamazepine increases metabolism of alprazolam and taper can be faster than would be anticipated by dose; dosages of medications with additive effects that increase the risk for falls or sedation may require adjustment as benzodiazepine tapered; pharmacokinetics—lorazepam, oxazepam, and temazepam are the only benzodiazepines with no active metabolites; shorter half-lives result in large differences in peak and trough levels and more pronounced rebound neuronal stimulation; agents with longer half-lives have slower clearance, attenuated fluctuations in plasma concentrations, decreased neuronal excitatory stimulation, and fewer withdrawal symptoms; switching from short-acting to long-acting agents (eg, clonazepam, lorazepam) is recommended (diazepam is not recommended by speaker); diazepam has several active metabolites and an excessively long half-life (increases ~1 hr for every year after 40 yr of age) that may increase risk for adverse effects during taper (eg, sedation, falls, cognitive impairment); active metabolites accumulate in patient with renal dysfunction and further increase half-life
Tapering schedules: studies of benzodiazepine withdrawal are generally small with differing methodologies; while Australian and Canadian health organizations offer recommendations, clear guidance is lacking; taper must be individualized; consider risk factors (eg,absence of social support, duration of use); identify factors that predict more difficult taper (eg, concurrent substance use disorder, history of seizure, supratherapeutic dosage); patients taking supratherapeutic doses may tolerate a larger reduction in dose initially because GABA receptors are saturated; these patients will require smaller reductions and a longer tapering interval at the end of the taper because of greater dependency; in general, reducing the dose 10% to 25% in intervals of 1 to 2 wk is recommended; reductions should be individualized; ask the patient their opinion about appropriate dose intervals (opportunity to engage and empower them); tapering may not be possible during the first few appointments with a new patient; have the schedule prepared for when the patient is ready; schedule allows the patient to know what to expect; schedule can be changed depending on how the patient responds; for patients taking one pill, cutting pills is not recommended; consider lengthening the dosing interval; for dose reductions larger than 10% to 25%, consider a slower tapering schedule; introducing benzodiazepine-free days is not recommended (may precipitate symptoms of withdrawal because of deep drug troughs and add psychological distress in anticipation of benzodiazepine-free day); in patients who use benzodiazepines as needed (but taken on most days), switching to fixed dosing during taper is recommended
Case study: patient takes clonazepam 0.5 mg twice daily for 2 yr; returns to clinic 8 wk after beginning taper; reports withdrawal symptoms; recommended approach—maintain taper at that dose until symptoms of withdrawal pass; increasing dose should be discouraged; discuss with patient why symptoms are happening and encourage the patient to maintain dose; patient may increase dose if no plan is instituted to combat symptoms; increasing dosage intervals is recommended; goal is to continue tapering, even if it requires months or years
Resources for clinicians: deprescribing.org uses Canadian Family Physician guidelines; focuses on benzodiazepines used for insomnia; provides free brochures and patient education handouts that can be distributed in office
Questions and Answers
Role of pharmacist in clinical practice: after the physician engages the patient, the pharmacist establishes the dosing schedule and provides follow-up (both are labor-intensive); telephone call every 2 wk and clinic visit every 4 wk is recommended (may be overly burdensome for physicians)
Engaging patients: patients who deny dependence are challenging to treat; warning patients about dangers (eg, falls, motor vehicle accidents) tends to be ineffective; risk for loss of memory tends to be a better motivator (all aging individuals are concerned about loss of cognitive function)
Simultaneous dependence on benzodiazepines and opioid drugs: Dr. VanMeter—tapering benzodiazepine first is recommended; simultaneous taper is likely to cause psychological distress; benzodiazepine is more difficult to taper; benzodiazepines cause more severe withdrawal symptoms secondary to GABA inhibition; Dr. Lehmann—choice of which agent to taper first should be individualized; in patients with resolved pain, symptoms of tapering an opioid drug may be mitigated by maintaining the benzodiazepine
Anxiety exacerbated by withdrawal: in patients with an underlying anxiety disorder, treatment is appropriate; in the absence of an anxiety disorder, tapering should be initiated while finding other ways to manage the associated anxiety (eg, counseling)
Transitioning care: coordination of inpatient and outpatient care is essential; in the absence of communication, goals of care may fail; communication may be as simple as a telephone conversation
1. Which of the following prescribing scenarios for benzodiazepines is most appropriate?
(A) Prescription for anxiety caused by major depressive disorder
(B) Prescription for anxiety associated with cognitive dysfunction
(C) Short-term administration for a specific cause of anxiety
(D) None of the above
The correct answer is C. The short-term use of benzodiazepines may be appropriate to treat a specific cause of anxiety. Anxiety caused by a major depressive disorder or cognitive dysfunction should be managed by treating the underlying disorder.
2. A meta-analysis of studies of patients with insomnia found that, compared with placebo, benzodiazepine use is associated with all the following findings EXCEPT:
(A) Longer duration of sleep
(B) Increased risk for cognitive changes
(C) Greater difficulty concentrating
(D) Reduced risk for fatigue
The correct answer is D. A meta-analysis by Glass et al (2005) of studies comparing benzodiazepines with placebo for the treatment of insomnia in older adults found that sedative-hypnotic agents were associated with a slight improvement in sleep (eg, fewer awakenings, longer duration of sleep). However, adverse events were twice as likely to occur as benefits. Adverse events included psychomotor events, cognitive changes, fatigue, and difficulty concentrating.
3. In an 80-yr-old woman with chronic anxiety and mild depressive symptoms, early morning awakening is most likely secondary to which of the following causes?
(A) Age-related changes in sleep
(B) Chronic insomnia
(C) Cognitive impairment
(D) Major depressive disorder
The correct answer is D. Early morning awakening is a common and classic symptom of major depressive disorder.
4. All the following are accurate statements about the management of anxiety associated with cognitive dysfunction EXCEPT:
(A) Patients can be referred for speech therapy at the first signs of objective deficit
(B) Cognitive therapy can give patients greater confidence
(C) Structuring daily routine helps to compensate for memory loss
(D) Pharmacologic agents are effective for managing anxiety as cognitive dysfunction progresses
The correct answer is D. Speech and cognitive therapy and structuring routines are helpful in improving function and building confidence. Pharmacologic agents are ineffective for treating anxiety related to cognitive dysfunction.
5. Use of benzodiazepines for as few as _______ can provoke symptoms of withdrawal.
(A) 2 wk
(B) 4 wk
(C) 6 wk
(D) 8 wk
The correct answer is B. Dependency on benzodiazepines can develop after 4 wk of use. Withdrawal at this point may trigger symptoms.
6. Which of the following factors is associated with an increased risk for seizures during withdrawal from benzodiazepines?
(A) Younger age
(B) Cardiovascular disease
(C) Concomitant use of alcohol and illicit drugs
(D) Psychiatric disease
The correct answer is C. Risk for seizures during withdrawal from benzodiazepines is increased with concomitant use of alcohol or illicit drugs, history of a seizure disorder, and intake of supratherapeutic dosages.
7. Which of the following medications may increase plasma levels of alprazolam?
The correct answer is C. Both alprazolam and diltiazem are metabolized through the cytochrome P450 pathway. Diltiazem can increase plasma levels of alprazolam.
8. Which of the benzodiazepines has no active metabolites?
The correct answer is D. Benzodiazepines with no active metabolites include lorazepam, oxazepam, and temazepam.
9. When considering withdrawal from a short-acting benzodiazepine, switching to which of the following agents may be beneficial?
The correct answer is A. Withdrawal from a short-acting benzodiazepine is associated with lower trough levels and more pronounced withdrawal symptoms. Switching to a long-term agent may be helpful to mitigate symptoms (eg, lorazepam, clonazepam). While diazepam is a long-acting agent, its many active metabolites may worsen withdrawal symptoms.
10. Which of the following strategies is(are) recommended when tapering benzodiazepines?
1. Reducing the dose 10% to 25% every 1 to 2 wk
2. Dividing pills in half
3. Switching from an as-needed to a fixed dosing schedule
4. Scheduling benzodiazepine-free days
The correct answer is A. In general, decreasing doses 10% to 25% every 1 to 2 wk is recommended. In patients taking benzodiazepines on an as-needed basis, switching to a fixed dosage schedule is recommended. In patients taking only 1 pill, cutting pills in half is not recommended. Scheduling benzodiazepine-free days is not recommended because this may increase symptoms of withdrawal.
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