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Disinhibitory Effect of Benzodiazepines

When benzodiazepines are prescribed for anxiety and the behavioral disorders of dementia, there is a well-documented risk of dizziness, sedation, falls, fractures subsequent to falls, and cognitive impairment associated with these agents in the elderly. In addition, the concept of disinhibition should be considered as a possible complication of therapy in this population. The release of previously suppressed behavior has been called the disinhibitory effect.

“Benzodiazepines dilute the controlling capacity of the ego, allowing one to lose the intensity of normal control mechanisms,” says Lucy Rea Sarkis, M.D., Executive Director, South Beach Psychiatric Center, Staten Island, NY. “The premorbid personality determines how disinhibition is expressed clinically.” Dr. Sarkis elaborates, “It depends on the normal tendencies of the individual.” For instance, in an elderly individual with a premorbid personality possessing sexual preoccupation, a benzodiazepine may precipitate sexually inappropriate behavior. If an aging adult had a premorbid personality possessing obsessive-compulsive features, an increase in anxiety and ritualistic behavior may follow the introduction of a benzodiazepine. If paranoid thinking and/or tendencies existed premorbidly, a benzodiazepine may induce an increase in verbally abusive behavior and an increase in paranoid thinking and behavior.

Furthermore, “in dementia, the area of compromise is very often the determinant of benzodiazepine response variability,” explains Dr. Sarkis. For instance, she adds, if the cerebellum is compromised, a benzodiazepine may increase the risk of falling; with a compromised hippocampus, the center of emotional response, a benzodiazepine may elicit emotional lability; alternatively, a benzodiazepine used with a compromised frontal lobe may produce significant cognitive impairment.

For treating uncomplicated, generalized anxiety in the elderly, shorter-acting benzodiazepines are recommended with scheduled dosing at lower doses than those for younger patients (Table 3). They are relatively rapid in action and effective in reducing feelings of panic, fear, and tension. They should not, however, be prescribed casually for simple situations resulting in tension and anxiety, or for those who suffer from chronic anxiety. The course of therapy is often short (e.g., up to 4 to 6 weeks) since most bouts of anxiety are short-lived, although recurrent in nature. Discontinuation after extended use is difficult due to psychologic and physical dependence; gradual tapering every few days over 3 to 4 weeks is recommended, as withdrawal may lead to rebound anxiety. In a dying patient who appears uncomfortably anxious, an assessment for treatable causes (e.g., hypoxemia, pain, fear) should be undertaken, and if necessary, a short-acting benzodiazepine is recommended.

An alternative to the benzodiazepines is buspirone, initially dosed at 5 mg BID and usually up to 10 mg BID or TID. Using the slow titration guideline of increasing by 5 mg/day every 2 to 3 days as needed up to 20 to 30 mg/day (maximum daily dose of 60 mg/day) helps to avoid or minimize side effects (e.g., dizziness, drowsiness) while providing adequate dosing for effectiveness. Response to treatment is generally seen within 1 to 2 weeks of continuous therapy, with a maximum effect after 3 to 4 weeks. Although this delay in onset of action may be perceived as a disadvantage to buspirone therapy, it should be noted that there is little potential for abuse with this agent.

Hydroxyzine — due to its potent anticholinergic properties — and meprobamate — due to its highly addictive and sedating properties — are not recommended for use in the elderly. Due to adverse effects associated with the antipsychotic drugs (noted above), they should not be used for anxiety disorders unless frank psychotic symptoms (e.g., paranoia, delusions, hallucinations) are present.

In the elderly with anxiety disorders, for whom the tricyclic antidepressants (TCAs) are indicated, imipramine and nortriptyline are well tolerated (75 mg at bedtime; range 50-150 mg/day). Due to strong anticholinergic and sedating properties, amitriptyline is rarely the TCA of choice in the elderly. The TCAs are contraindicated in patients with narrow-angle glaucoma, a frequent comorbidity in older adults. The selective serotonin reuptake inhibitors (SSRIs), also indicated in anxiety disorders, may be useful in patients at risk for sedation, hypotension, and anticholinergic effects of TCAs.The benzodiazepines are often used adjunctively for anxiety disorders, on an intermittent basis, with the TCAs or SSRIs.

Conclusion

Benzodiazepines have demonstrated their utility in relieving anxiety, including the anxiety that accompanies dementia. However, along with other documented potential adverse effects in this patient population, disinhibition may occur. In disinhibition, inappropriate social behavior such as sexual advances or verbal abuse/pananoid behavior may manifest as a side effect. The best outcome from benzodiazepine use in the elderly is obtained from short-term use (4 to 6 weeks) of smaller doses of shorter-acting benzodiazepines.

Behavioral disturbances in the elderly are probably the most important facet of dementia prompting institutionalization. The referral for pharmacologic intervention is often the result of the need for management of mood and behavior. Symptoms tend to be superficially described as “agitated,” “combative,” “depressed,” “acting out,” “inappropriately accusing,” etc., by spouses, family members, and caregivers.

Dementia may be the most common cause of anxiety in the elderly, with an increased risk of anxiety seen in patients initially transferred to a long-term care facility from the hospital or from home. Trauma or a stressful event may induce an acute, short-lived, situational anxiety. Anxiety disorders (also known as anxiety and phobic neuroses) are classified as phobic disorders, posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), and panic disorder (Table 1).

Attempts at alleviating anxiety in the elderly, and especially in those with dementia, should be attempted through nonpharmacologic intervention whenever possible. This may include providing a more structured environment with consistent routines, simplifying everyday tasks, avoiding over- or understimulation in the environment, providing soothing background music, and providing support to caregivers. Testing for adequate hearing and vision is also essential. Supportive psychotherapy, behavioral therapy, biofeedback, relaxation therapy, and paced exercise therapy may be used as nonpharmacologic and adjunctive therapy where appropriate.

Reversible etiologies of anxiety related to adverse drug effects and concomitant medical disorders should not be overlooked. When possible, eliminating medications known to contribute to or induce anxiety and treating medical conditions that may cause anxiety or similar symptoms (Table 2) may help avoid unnecessary intervention with an anxiolytic. For example, eliminating anxiety and agitation secondary to depression with the use of an antidepressant may be sufficient.

Benzodiazepines are often prescribed for elderly dementia patients with behavioral disorders because of a prescriber preference over the antipsychotics that carry a liability of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). Extrapyramidal reactions are more common in the elderly, with up to 50% of patients developing these reactions after age 60; incidence may be more common in dementia patients. The prevalence rate of tardive dyskinesia in the elderly may be as high as 40%; elderly women are especially at risk. Up to 20% of older adults take benzodiazepines, and their use is more common among women than men. Benzodiazepines are useful in treating general anxiety disorders, panic disorders, and depression, as an adjunct to antidepressants. They are also indicated in insomnia, on a short-term basis. In addition, they are useful for preprocedure/preoperative sedation (e.g., dental procedures, MRI screenings) and in cases of status epilepticus.

Challenges in Medicating the Senior Patient

Choosing an appropriate dosage form of analgesic drug is essential to successfully manage pain in the older patient. Beyond the clinical recommendations, the pharmacist can be instrumental in providing information on products that will optimize pain relief in this patient population. Swallowing difficulties secondary to other medical conditions, such as Parkinson’s disease, dementia, or stroke, may preclude the use of large tablets or sustained-release medications that cannot be crushed. Liquid medications provide an acceptable alternative for administering analgesics. Unfortunately, few analgesic preparations are available in liquid form. Ibuprofen and naproxen suspensions are the few NSAIDs available as liquids for the relief of mild to moderate pain. For moderate to severe pain, fentanyl patches provide continuous pain relief and are suitable for patients who cannot swallow sustained-release preparations, are tube-fed, or who have difficulty remembering to take their medication. The 72-hour administration interval also reduces the burden of administering medication by nursing staff in long-term care facilities or caregivers at home. The initial dose of the patch may be increased after the first three days of therapy. Additional dose increases should only occur after two cycles of patches have been applied. Morphine sulfate controlled-release capsules may be opened and the pellets mixed in applesauce or administered via a gastrostomy tube without loss of continuous pain relief. Patient controlled analgesia (PCA) through the use of a pump has not been as widely used in elderly patients, particularly those with cognitive impairment, since successful use requires active involvement by the patient.

The older patient may be taking numerous medications, some of which may induce similar side effects as pain management therapy. Constipation is frequently a side effect of narcotic analgesic administration, particularly as the dose increases, placing the patient at risk for fecal impaction. Patients may also be taking calcium supplements and psychoactive agents, which can contribute to constipation. A review of bowel management therapy is advised at the time of prescribing narcotics.

According to the World Health Organization guidelines, the basis for current pain management practices, senna is the laxative of choice for managing opiate-induced constipation. Normal peristaltic movement is inhibited by opiates, preventing movement of fecal material through the colon. Irritant laxatives, such as senna, can help stimulate bowel evacuation. Docusate or psyllium-containing products may be of additional benefit to prevent straining or to add bulk. Adequate fluid intake is essential to prevent possible bowel obstruction associated with the use of bulk-forming laxatives.

Health Care Financing Administration (HCFA) Interpretive Guidelines also influence the process of selecting drug therapy for pain management. The use of tricyclic antidepressants, especially amitriptyline and doxepin, is discouraged in elderly patients due to their increased sensitivity to adverse effects, particularly anticholinergic effects and heart rhythm abnormalities. If a tricyclic agent is to be used, particularly for neuropathic pain, nortriptyline is preferred at low doses with careful titration and monitoring. Patients currently receiving amitriptyline should be considered for conversion to nortriptyline in equipotent doses. Documentation of efficacy and absence of adverse effects should be readily available. During medication pass and meal observation, surveyors are instructed to determine whether NSAIDs are administered with a meal. If they are administered on an empty stomach, it is calculated into the facility’s medication error rate.

Analgesics that are considered unnecessary drugs with a high potential for significant adverse effects and should be avoided include pentazocine and oral meperidine. Both drugs have an increased risk of respiratory depression or central nervous system adverse effects, including seizures with meperidine, in patients over 65 years of age. Alternative agents with less serious adverse effects are readily available.

Conclusion

Successful chronic pain management in the senior patient requires the active involvement of the pharmacist in the community as well as the institution. Regulatory requirements have established a framework for a comprehensive approach to pain management and a fundamental right of patients to adequate relief of pain. Overcoming the barriers to adequate pain relief is only one of the challenges facing the patient and the clinician. Multiple opportunities exist for enhancing patient quality of life. The pharmacist can help educate patients, families and staff about pain management, provide the clinical expertise necessary to manage pain, recommend dosage forms and adjunct medications that will enhance therapy, and measure outcomes of pain management programs.

Managing Pain

Selecting an optimal therapy depends on patient-specific criteria, including medical history, previous medications utilized, drug allergies, swallowing ability, and response to therapy. A description of the pain is also useful in determining initial therapy. Nociceptive pain, often the result of chronic or other conditions arising from actual tissue damage as in osteoarthritis, can be described as aching or soreness, rather than sharp pain. Neuropathic pain, arising from damaged nerve tissue, is usually described as burning, stinging or stabbing pain. To adequately manage chronic pain, the clinician should employ a step-therapy approach that uses regularly scheduled doses of medication rather than dependence on a regimen of “prn” doses. This avoids underdosing and its resulting inadequate pain relief. Titrating the dose and managing occasional variations in pain patterns are achieved through the use of rescue analgesics. Adjunct medications and nonpharmacologic interventions enhance the efficacy of analgesics; both are useful in managing chronic neuropathic and nociceptive pain. Adjunct medications may also have a positive effect on accompanying symptoms, including insomnia and depression. Therapy should be initiated in low doses, with gradual upward titration until pain relief is achieved.

Adequate pain management is a cornerstone of both palliative care and hospice care. Palliative care, the active care of a patient whose disease is not responsive to curative treatment, may be long-term. In contrast, a patient who is receiving hospice care has a life expectancy of six months or less. Regardless of the category of care the patient is receiving, appropriate management of pain and other associated symptoms is essential to the patient’s well-being and quality of life.