March/April 2017

Medication Monitor: Antianxiety Medications
By Mark D. Coggins, PharmD, CGP, FASCP
Today's Geriatric Medicine
Vol. 10 No. 2 P. 9

Anxiety and insomnia are common in older adults, with the two conditions overlapping for many patients. The prevalence of generalized anxiety disorder (GAD) in adults aged 65 and older ranges from 1.2% to 7.3% in community settings to as high as 80% in primary care settings. About 44% to 52% of older adults with GAD also have insomnia.1

Benzodiazepines (BZDs) such as alprazolam (Xanax), diazepam (Valium), and lorazepam (Ativan) are widely used to treat anxiety and insomnia despite guidelines advising against their use due to significant risks. Nonpharmacologic approaches and antidepressants are recommended over BZDs as first-line treatment for anxiety. Also, while rates of insomnia increase with age, practice guidelines recommend health care providers consider behavioral interventions as first-line treatment over medications.1,2

Although anxiety is common in older adults, the prevalence of anxiety disorders declines with increasing age. Despite this reduction in prevalence, BZD prescribing has been shown to increase steadily with age. This is troublesome as older adults are the age group most vulnerable to negative effects associated with BZDs due to reduced drug elimination, increased polypharmacy with potential for significant drug interactions, and comorbid medical conditions. A study from 2014 found BZD use to be more than three times greater in patients aged 65 to 80 vs those aged 18 to 35. When comparing the same age groups, patients aged 65 to 80 were found to be two times more likely to receive BZDs long term, defined as more than 120 days. In all age groups, women were about twice as likely to receive BZDs as men. One in 10 women aged 65 to 80 was prescribed a BZD, with nearly one-third of those receiving long-term prescriptions.2

BZD Risks
Older adults taking BZDs are particularly susceptible to the risks of dependence, excessive sedation, cognitive decline, and psychomotor impairment. There is a strong correlation between BZD use and falls, which frequently result in hip and other skeletal fractures, head injury, and loss of independence. BZDs have been shown to cause a substantial risk of increased mortality even when use is limited to only a few doses per year.1,2 Also of concern is the fact that 10% of geriatric hospitalizations have been shown to be related to the use of BZDs.3

Withdrawal Symptoms and Dependence
Rapid dependence development and withdrawal symptoms make limiting BZD use essential to patient safety. Continuous use of BZDs for as short a period as two weeks can result in withdrawal symptoms when the medication is stopped. To help reduce withdrawal symptoms, patients who have been receiving long-term treatment with BZDs must have their doses slowly tapered. Additionally, abruptly stopping BZD use in chronic users may result in seizures.3

Systematic Approach to Treating GAD
A systematic approach including the following considerations can improve anxiety for patients while minimizing the inappropriate use of BZDs:

• Address comorbid medical conditions as potential causes of anxiety and maximize treatment. For example, patients with COPD experiencing anxiety should be treated per Global Initiative for Chronic Obstructive Lung Disease guidelines for COPD. An aggressive COPD treatment plan may improve respiratory status and, in turn, reduce anxiety.

• Rule out delirium. The treatment plan for delirium will look much different from treating anxiety. Keep in mind that BZDs can induce delirium in older adults and individuals with medical illness.

• Evaluate medications as a potential cause of anxiety and adjust as appropriate. Caffeine, amphetamines, other stimulants, thyroid medications, glucocorticoids (eg, prednisone), some antidepressants, and highly anticholinergic medications (eg, antihistamines) can worsen anxiety symptoms.

• Nonpharmacological interventions are recommended as first-line treatment. Increased exercise, relaxation techniques, increased social activity, and meditation alone or with medications are recommended interventions.

• Consider cognitive behavioral therapy (CBT).

Antidepressants for First-Line Pharmacological Treatment
For anxiety not controlled with nonpharmacological interventions, antidepressants are considered the first-line pharmacological treatment. Although antidepressant use is not without some risks, selective serotonin reuptake inhibitors (SSRIs) such as escitalopram (Lexapro) and sertraline (Zoloft) have been shown to be the best tolerated medications, and response rates are significantly higher than placebo for panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, social anxiety disorder, and GAD. Some improvement should be noted within three or four weeks, with the dose being increased in the absence of improvement. SSRIs should be started at low doses and gradually titrated up to therapeutic levels to avoid an initial exacerbation of anxiety.2

BZDs continue to be useful in the short-term management of symptoms until acceptable reduction of symptoms is achieved with an SSRI or CBT. The tolerability and lack of addiction potential make the SSRIs more desirable for long-term management, but the delay in response makes short-term symptom relief with a BZD desirable for those with the greatest impairment. Because of the risk for rebound anxiety when withdrawing from BZDs with short half-lives such as alprazolam (Xanax), many psychiatrists prefer the longer acting BZDs, such as clonazepam (Klonopin).2

If a patient does not respond to the combination of CBT and medication, a reevaluation of symptoms may reveal a comorbid disorder that was missed on the initial examination. Consider switching between SSRIs before implementing BZDs. A referral to a psychiatrist for further evaluation and management may be necessary if none of these strategies works.2

Indications for Short-Term Treatment With BZDs3
The principal recommended indication for BZDs is for short-term treatment (from two to six weeks) of anxiety that is severe and debilitating.

Continuing BZDs beyond four to six weeks may result in the loss of effectiveness, the development of tolerance, dependence with potential for withdrawal syndromes, persistent adverse side effects, and interference with the effectiveness of other medications and counseling.

Using BZDs on an as-needed (PRN) basis is advisable. Continuous use for more than two weeks increases concerns related to withdrawal effects. If used continuously for two weeks or more, the dose should be tapered rather than abruptly discontinued.

Insomnia
While there is some evidence supporting the effectiveness of BZDs and other hypnotics for the relief of short-term insomnia (one to two weeks duration), there is less evidence supporting long-term insomnia treatment. The treatment period for insomnia should not exceed two weeks.

The primary significant clinical difference between older BZD hypnotics and newer "Z" benzolike ones such as zolpidem (Ambien), zaleplon (Sonata), and eszopiclone (Lunesta) is the shorter half-life. All three have similar risks of dependence and tolerance. A search for an etiology of the insomnia should be undertaken. Sleep hygiene and other nonpharmacological measures are preferable.

Additional Considerations2,3
A key to optimizing the use of BZDs is to ensure patients are not started on these medications if at all possible.

Before BZD treatment is started, always consider that some patients will have significant difficulty discontinuing the medication at the end of even acute treatment periods. Patients should clearly understand the side effect risks and the potential for dependence. Patients should be advised explicitly regarding the planned duration of therapy, exit strategies such as short taper, or initiation of alternative treatments.

Contraindications to BZDs
BZD use is contraindicated during active substance abuse, including alcohol. A number of medical conditions may be aggravated with BZD use including fibromyalgia, chronic fatigue syndrome, depression (except short term use up to four weeks to treat associated anxiety), bipolar disorder (except for urgent sedation in acute mania), ADHD, and impulse control disorders. While BZDs are often used for short-term treatment of insomnia in acute grief, they should otherwise be avoided in treating grief reactions, as they may suppress and prolong the grieving process.

BZDs can decrease the respiratory rate, especially in conditions where the rate is already compromised. These medications may worsen hypoxia and hypoventilation in asthma, sleep apnea, COPD, congestive heart failure, and other cardiopulmonary disorders.

BZD Use With Opioid Black Box Warning4
In 2016, as part of its Opioids Action Plan to better inform prescribers and protect patients, the FDA began requiring stronger warnings for opioid analgesics, prescription opioid cough products, and BZD labeling related to serious risks and death from combined use.

An FDA review found the growing combined use of opioids with BZDs or other drugs that depress the central nervous system (CNS) has resulted in serious side effects, including slowed or difficult breathing and deaths. Opioids are used to treat pain and cough; BZDs are used to treat anxiety, insomnia, and seizures. In an effort to decrease the concurrent use of opioids and BZDs or opioids and other CNS depressants, the FDA added boxed warnings to the drug labeling of prescription opioid pain and opioid cough medicines, and BZDs.

Safe Prescribing Practices
In an effort to increase safety in prescribing, health care professionals should keep in mind the following:

• Limit prescribing opioids with BZDs or other CNS depressants only to patients for whom alternative treatment options are inadequate.

• If prescribed together, limit the dosages and duration of each drug to the minimum possible.

• Warn patients and caregivers about the risks of slowed or difficult breathing and/or sedation, and the associated signs and symptoms.

• Avoid prescribing opioid cough medicines for patients taking BZDs or other CNS depressants, including alcohol.

Summary
BZD use should be limited and accompanied by clear documentation describing the rationale for their use, including risk to benefit. Use a PRN BZD only if symptoms of acute anxiety are severe or debilitating or if required during the implementation of antidepressant therapy to treat anxiety.

Avoid the use of BZDs with opioids and other CNS depressants. Limit prescribing orders to a maximum of 14 days. Orders should not be extended without further practitioner evaluation.

— Mark D. Coggins, PharmD, CGP, FASCP, is vice president of pharmacy services for Diversicare, which operates skilled nursing centers in 10 states. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
1. Ivan MC, Amspoker AB, Nadorff MR, et al. Alcohol use, anxiety, and insomnia in older adults with generalized anxiety disorder. Am J Geriatr Psychiatry. 2014;22(9):875-883.

2. Markota M, Rummans TA, Bostwick JM, Lapid MI. Benzodiazepine use in older adults: dangers, management, and alternative therapies. Mayo Clin Proc. 2016;91(11):1632-1639.

3. Maine Benzodiazepine Work Group. Guidelines for the use of benzodiazepines in office practice in the state of Maine. http://www.benzos.une.edu/documents/prescribingguidelines3-26-08.pdf

4. FDA requires strong warnings for opioid analgesics, prescription opioid cough products, and benzodiazepine labeling related to serious risks and death from combined use. US Food and Drug Administration website. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm
518697.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery. Published August 31, 2016.