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Agitation Executive Summary APreferred Treatments by Clinical Situation(bold italic = first line) CHAP = conventional high potency antipsychotic SSRI = selective serotonin reuptake inhibitor
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Overall Management |
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| Mild agitation | environmental intervention + medication; consider environmental intervention alone | ||
| Severe agitation | medication + environmental intervention; consider medication alone | ||
Choice of Environmental Intervention |
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| Both mild and severe agitation | education and support for family and caregivers | ||
| Mild agitation | structured routines, reassurance, socialization | ||
| Severe agitation | supervision and environmental safety | ||
Selecting Medications for Specific Presentations of Agitation | |||
| Delirium (other than medication toxicity) | CHAP | ||
| Psychosis | long-term | risperidone; CHAP | |
| acute | CHAP | ||
| Depression | without psychosis | antidepressant alone: sertraline or paroxetine | |
| with psychosis | antidepressant + antipsychotic; or electroconvulsive therapy | ||
| Anxiety | long-term | buspirone | |
| acute | benzodiazepine (lorazepam; consider oxazepam) | ||
| Insomnia | long-term | trazodone | |
| acute | trazodone; consider benzodiazepine (zolpidem, lorazepam) | ||
| "Sundowning" | long-term | trazodone; consider risperidone, olanzapine, or CHAP | |
| acute | trazodone; consider CHAP, risperidone, olanzapine | ||
| Aggression or anger | severe, long-term | divalproex, risperidone, or CHAP | |
| severe, acute | CHAP, risperidone | ||
| mild, long-term | divalproex, SSRI, trazodone, buspirone | ||
| mild, acute | trazodone | ||
| Osteoarthritic pain | tricyclic antidepressants, SSRIs, trazodone | ||
IM Medications for Acute Interventions |
haloperidol alone; consider lorazepam alone | ||
Managing Inadequate Response to Initial Medication |
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| Mild agitation | no response | switch to a second medication | |
| partial response | switch or combine | ||
| Severe agitation | no response | switch to a second medication | |
| partial response | combine with a second medication | ||
Selecting the Next Medication after an Inadequate Response to: |
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| Conventional antipsychotic | atypical antipsychotic; consider divalproex, trazodone, another conventional antipsychotic | ||
| Atypical antipsychotic | conventional antipsychotic, another atypical antipsychotic; consider divalproex, trazodone, carbamazepine | ||
| Benzodiazepines | atypical antipsychotic, conventional antipsychotic, divalproex, trazodone | ||
Length of Trial to Determine Response |
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| For long-term treatment | antipsychotics and benzodiazepines: a few days to a few weeks.
buspirone, divalproex, antidepressants: minimum of 1�2 weeks up to 6 weeks |
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| For acute treatment | antipsychotics and benzodiazepines: approximately 2 days up to 1 week | ||
When to Try Tapering If Good Response (approximate range of minimum and maximum treatment): |
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| Mild agitation: | antipsychotics and benzodiazepines: after 1�6 months other medications: after 2�8 months |
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| Severe agitation | benzodiazepines: after 1.5�6 months other medications: after 3�9 months |
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Safest Medications for Long-Term Use |
SSRIs, buspirone | ||
Safest Medication Choices for Patients with High Medical Comorbidity |
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| Antipsychotics | risperidone | ||
| Anxiolytics | buspirone | ||
| Anticonvulsants | divalproex | ||
| Antidepressants | SSRIs | ||
| For sleep | Trazodone | ||
Medication Least Likely to Cause Drug-Drug Interactions |
buspirone | ||
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Geriatric Agitation Executive Summary BConsensus Recommendations by Somatic Treatments(bold italics = first line) |
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Antipsychotics |
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| Conventional high potency antipsychotics | Delirium (other than medication toxicity)
Long-term and acute management of agitation with psychosis Long-term and acute management of agitation with severe anger or aggression Inadequate response to an atypical antipsychotic Inadequate response to a benzodiazepine Consider for long-term and acute management of agitation with "sundowning" Consider for inadequate response to another conventional antipsychotic |
| Atypical antipsychotics | Inadequate response to a conventional antipsychotic
Inadequate response to another atypical antipsychotic or to a benzodiazepine |
| Risperidone | Long-term management of agitation with psychosis
Consider for long-term and acute management of agitation with sundowning Consider for long-term and acute management of agitation with severe anger or aggression |
| Olanzapine | Consider for long-term and acute management of agitation with sundowning |
Antidepressants |
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| SSRIs (sertraline and paroxetine preferred) | Safe for long-term use in comparison with most other types of medication
Agitation with nonpsychotic depression; combine with antipsychotic for psychotic depression Long-term management of agitation with mild anger Management of agitation due to osteoarthritic pain |
| Trazodone | Long-term and acute management of agitation with insomnia
Long-term and acute management of agitation with sundowning Long-term and acute management of agitation with mild anger Management of agitation due to osteoarthritic pain Inadequate response to a benzodiazepine Consider for inadequate response to a conventional or atypical antipsychotic |
| Tricyclic antidepressants | Management of agitation due to osteoarthritic pain |
Other Treatments |
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| Benzodiazepines (lorazepam; consider oxazepam) | Acute management of agitation with anxiety
Consider for acute management of agitation with insomnia |
| Buspirone | Safe for long-term use in comparison with most other types of medication
Long-term management of agitation with anxiety Long-term management of agitation with mild anger |
| Carbamazepine | Agitation in a patient with comorbid seizure disorder
Consider for inadequate response to an atypical antipsychotic |
| Divalproex | Treatment of choice when using an anticonvulsant to control agitation
Agitation in a patient with comorbid seizure disorder Long-term management of both mild and severe agitation with anger and aggression Inadequate response to a benzodiazepine Consider for inadequate response to a conventional or atypical antipsychotic |
| Electroconvulsive therapy | Agitation with psychotic depression |
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Guideline 1: Assessment of Agitation in Dementia |
1A. Differential Diagnosis |
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| Introduction: Patients with dementia often have general medical illnesses and/or neuropsychiatric syndromes that may be responsible for their agitation. Therefore, before a treatment plan can be developed, it is crucial to conduct a systematic differential diagnosis focusing on teh common causes of agitation in this context. |
Agitation in Dementia | ||||
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Causes of Agitation (appropriate guideline to consult shown in parentheses) |
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| Onset or exacerbation of a general medical condition superimposed on dementia? |  Yes |
Change from baseline mental status; impaired consciousness and cognition; and fluctuating course? | Yes |
Delirium (4A) |
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Also consider |
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Also consider |
Is there pain? |
Yes |
Pain (4H) |
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| Also consider | |
Other distress or discomfort due to medical problems (1B) | ||
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| Is patient receiving medication or using substances? | |
Yes | |
Medication induced or substance induced agitation (4A) |
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Drug-drug interaction (9A) | ||
| Also consider | |
Medication or substance withdrawal (4A) | ||
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| Environmental or psychosocial problems? | |
Yes | |
Environmental stressors (3), e.g.,
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Also consider |
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Psychosocial stressors (3), e.g.,
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| Prominent neuropsychiatric syndromes? | |
Yes | |
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No | |
Agitation (e.g., agression) as a direct result of dementia (4G) | |
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Guideline 1: Assessment of Agitation in Dementia, continued |
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1B. Medical Causes of Agitation in Dementia1 |
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| Summary: The experts recommend an exhaustive differential diagnosis to pursue potential underlying medical causes of change in mental status. The following conditions often cause delirium or agitation in patients with dementia. | ||
| Priorities in Evaluation | Other Possibilities to Consider | |
| General medical conditions to consider | Medication-caused:
Urinary tract infection Poor nutrition, decreased oral intake of food and fluid Respiratory infection Recent stroke Occult head trauma if patient fell recently Pain* Constipation* |
Congestive heart failure
Orthostatic hypotension (e.g., low CNS blood flow if sitting for a long time) Chronic obstructive pulmonary disease Hypothyroidism Diabetes Current alcohol/substance-induced disorder Alcohol/substance withdrawal Occult long bone fracture if patient fell recently |
| Editors� Comment: It is also important to remember that agitation is often caused by more than one problem. The initial improvement following treatment of one underlying condition may not be sustained if another problem is also contributing. For example, a patient may be delirious due to a combination of congestive heart failure, drug-induced hyponatremia, and a drug-drug interaction between an anti-arrhythmic and an antidepressant medication. | ||
| 1Question 1 *Editors� addition |
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Guideline 1: Assessment of Agitation in Dementia, continued |
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1C. Assessments and Diagnostic Tests2 |
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| Summary: In the assessment of agitation, the top priority of the expert panel is a careful bedside evaluation of the patient�s psychiatric, general medical, neurologic, and cognitive status. The panel also recommends routine laboratory studies and serum drug levels for commonly used medications that can cause agitation if present in toxic levels. Additional more specific and specialized testing is recommended as needed after evaluation of the results generated from these screening efforts. (Note that this guideline is directed toward comorbid medical problems that may cause agitation, but does not cover the diagnostic workup for dementia itself.) | ||
| Priorities to Perform
(bold = assessment of choice |
Consider as Needed | |
| Assessment | At the bedside:
Routine laboratory:
Serum drug levels if patient is taking:
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| *Editors� Comment: The Mini-Mental State examination (see Appendix, p. XX) provides a quick, quantitative measure of cognitive function and its change over time. Selected behavioral rating scales can also be useful (see Suggested Readings, p. XX, for references). | ||
| 2Question 2 | ||
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Guideline 2: Overall Management Strategies3 |
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| Introduction: Throughout the survey, we asked the experts to consider their strategies for treating agitation in four contexts: short- and long-term management of both mild and severe agitation. We used the following definitions: | ||||
| Acute management | A drug or environmental intervention you would use for rapid symptom control over a period ranging from one time to a few weeks | |||
| Long-Term management | A drug or environmental intervention you would use continuously for more than a few weeks (including chronic maintenance) | |||
| Mild agitation | Behavior that is somewhat disruptive to others, but is nonaggressive and poses little risk of danger
Caregivers feel taxed by the frequency of the behaviors and constant need for redirection Examples: patient moans, cries, argues, paces, speaks inappropriately to strangers, asks repetitive questions, makes repetitive movements, uses telephone inappropriately, wanders but can be redirected |
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| Severe agitation | Aggressive or endangering behavior that is very disruptive and/or poses a threat of physical harm to self or others
The agitation is a major source of difficulty to caregivers; commonsense verbal limit-setting and simple redirection by caregivers are ineffective Examples: patient screams, insists on trying to leave dwelling or often gets lost in public places, makes feeding difficult, throws objects, grabs and scratches caregivers, bangs head or injures self |
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| Summary: After pertinent medical conditions have been identified and managed (see Guideline 1), significant agitation may still be present and require intervention. The experts recommend that the treatment for agitation in dementia combine both medication and environmental intervention in almost all situations, regardless of the severity of the presentation or the length of treatment. This recommendation is especially important because there is often a tendency to neglect environmental interventions in formulating a treatment plan for such patients. For patients with mild agitation, the experts consider environmental intervention alone as sometimes sufficient (e.g., when there is no danger to safety; when the family or caregiver prefers to avoid medication; when the agitation is environmentally induced and the environment can be improved; or in patients at high risk for drug side effects or interactions). In severe agitation, medication alone is sometimes appropriate (e.g., if the patient is in danger or the environment cannot be changed). | ||||
| Mild Agitation | Severe Agitation | |||
| Long-Term Management | Acute Management | Long-Term Management | Acute Management | |
| First line | Environmental intervention plus Medication |
Environmental intervention plus Medication |
Medication plus Environmental intervention |
Medication plus Environmental intervention |
| Highly rated second line | Environmental intervention alone | Environmental intervention alone | Medication alone | Medication alone |
| 3Question 3 | ||||
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Guideline 3: Selecting Environmental Interventions4 |
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| Summary: As indicated in Guideline 2, the experts recommend that most patients receive some sort of environmental intervention. Agitated patients at any severity level may benefit from structure, individually targeted behavioral interventions, and education and emotional support for family and caregivers. Some interventions are more suitable depending on the degree of agitation. In mild agitation, several of the preferred strategies require active participation by the patient. In patients with severe agitation, interventions are more external, promoting safety and control of the environment. Behavioral interventions can be viewed as careful experiments: caregivers must often make educated guesses as to circumstances that trigger agitation, and sequential efforts to change selected elements in the environment may be necessary before the right formula is determined. Note that physical restraint is to be used very cautiously, generally only when agitation is severe and other efforts have failed. For a more detailed discussion of the types of behavioral intervention and education that may be helpful, refer to the Guide for Families and Caregivers (p. XX). | |
| Preferred Strategies (bold = intervention of choice) | |
| For both mild and severe agitation | Helping the family and caregivers
Structuring the physical and psychosocial environment
Behavioral interventions
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| Most important in mild agitation; sometimes consider in severe agitation | Structuring the environment
Behavioral interventions
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| Most important in severe agitation |
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| 4Question 4 | |
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Guideline 4: Selecting Medications for Specific Syndromes of Agitation |
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| Organization of Guideline 4: Guideline 4 is divided into eight sections that address medication choices for different neuropsychiatric presentations of agitation in dementia. We emphasize that the first consideration should always be treatment of comorbid general medical conditions (see Guideline 1B).
Clinicians should keep in mind that patients may have more than one cause for agitation. Treatments may need to be carefully sequenced, or sometimes combined, if multiple causes are present. |
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4A. Delirium5 |
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| Introduction: Delirium is a change in the patient�s baseline mental status caused by a general medical condition, in which there is an impairment in the level of consciousness and cognition, often with a course that fluctuates rapidly over minutes or hours. Delirium indicates the presence of a medical emergency that can lead to death or worsening dementia. The underlying medical condition that is causing the delirium requires urgent identification and treatment. The agitation that accompanies delirium should receive separate treatment when it threatens the patient�s safety, interferes with medical treatment (e.g., pulling out intravenous lines), or causes significant subjective distress. Unless agitation was present before the onset of delirium, the treatment for agitation in delirium is usually brief and the medication may be tapered when the medical condition has improved.
Summary: For delirium caused by common medical disorders, the experts prefer conventional high potency antipsychotics, followed closely by the atypical antipsychotics risperidone and olanzapine. Conventional antipsychotics may be preferred because they can be administered parenterally. |
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| Common Causes of Delirium | First Line Medications | Also Consider |
| Congestive heart failure
Urinary tract infection Upper respiratory infection Chronic obstructive pulmonary disease (COPD) * Pneumonia* Diabetes Dehydration or electrolyte imbalance Postoperative delirium� |
Conventional high potency antipsychotic (e.g., haloperidol) | Risperidone
Olanzapine |
| Medication (or substance) toxicity or interaction� | Reduce or stop offending medication; address substance use |
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| Benzodiazepine withdrawal� | Prescribe a benzodiazepine that has a short half-life and is metabolized well in older adults (e.g., lorazepam) | Prescribe a lower dose of whatever benzodiazepine the patient was previously using and taper slowly |
| *Further Recommendation: The experts strongly recommend avoiding benzodiazepines in COPD or pneumonia. | ||
| 5Question 5
�Editors� recommendations |
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Guideline 4: Specific Syndromes of Agitation, continued |
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4B. Psychosis6 |
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| Introduction: Psychotic symptoms in patients with dementia are often manifested as delusions related to forgotten recent events. For example, patients may misplace or forget where they put things and believe that someone has stolen them, or may believe that their spouse is having an affair because they don�t recall seeing him or her for periods of time. Another common delusion is believing that family members or caregivers have been replaced by impostors. Hallucinations are less common and are not the same as confabulated delusional memories, such as reports of having seen nonexistent visitors or burglars at night (see Guideline 4F, "Sundowning").
Summary: For long-term treatment, the experts recommend risperidone, followed by conventional high potency antipsychotics. Extrapyramidal reactions and long-term risk of tardive dyskinesia are potential concerns with conventional antipsychotics, especially at higher doses. The risks may be lower with risperidone. Olanzapine, divalproex, and trazodone are highly rated second line alternatives. For short-term treatment, the experts recommend conventional high potency antipsychotic medications, such as haloperidol, which have the advantage of being available in parenteral form for emergencies or for patients who cannot take oral medication. Atypical antipsychotics are highly rated second line choices for short-term use and are especially preferred in patients at high risk for extrapyramidal side effects. It should be noted that this expert survey was done before quetiapine and other newer atypical antipsychotics were available. |
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| Medication | ||
| Long-Term Management* | Acute Management | |
| First line medications |
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| Also consider |
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| *See Guideline 6B for information on HCFA regulations regarding long-term use of antipsychotics.
Further Recommendations:
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| 6Question 6
7Question 7 �Editors� recommendation |
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Guideline 4: Specific Syndromes of Agitation, continued |
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4C. Depression8 |
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| Introduction: Depressive symptoms in a patient with dementia are usually the same as those in younger patients but may be missed because they resemble the symptoms of a general medical illness (e.g., weight loss, sleep disturbance, fatigue) or dementia (e.g., flat affect, loss of interest, poverty of speech). In addition, depressive symptoms in a patient with dementia may fluctuate widely over short periods of time and may not meet the full criteria for a major depressive episode. Depression can be very hard to separate from apathy and anhedonia secondary to dementia, a picture where the role of antidepressants is less clear. The presence of depressed mood is often what makes the syndrome clearer. The clinician should evaluate for vegetative symptoms (e.g., poor sleep or appetite), nonverbal signs of depressed mood (e.g., facial expression of suffering and sadness, sobbing), and verbally expressed feelings of hopelessness, helplessness, or guilt. Depression with psychosis may be characterized by delusions of guilt, impoverishment, jealousy, and persecution.
Summary: The treatment of prominent depressive symptoms in an elderly patient with dementia and agitation will vary depending on the severity of the depression and whether psychotic symptoms are present. For mild to moderate depression, the experts first line choice is an antidepressant alone, but there is also modest support for adding psychotherapy. For severe depression without psychosis, the treatment of choice is an antidepressant alone, but electroconvulsive therapy (ECT) should also be considered. For severe depression with psychosis (often called delusional depression), the combination of antidepressant and antipsychotic medication is the treatment of choice, and ECT is also a first line option. |
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| Mild to Moderate Depression | Severe Depression, No Psychosis | Severe Depression with Psychosis | |
| First line strategies | Antidepressant alone* | Antidepressant alone* | Antidepressant* + antipsychotic
ECT** |
| Also consider | Some experts suggest adding psychotherapy to the antidepressant | ECT** | |
| *See Guideline 7 for details on selecting specific antidepressants.
**Editors� Comment: ECT may cause more severe and persistent memory loss and other cognitive impairments in a patient with dementia than in a nondemented patient; however, this complication eventually subsides. |
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| 8Question 8 | |||
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Guideline 4: Specific Syndromes of Agitation, continued |
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4D. Anxiety9 |
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| Introduction: Generalized anxiety presents with verbal or facial expressions of worry, nervousness, or fear and/or somatic symptoms such as palpitations, stomach problems, or feelings of tension. Patients may repeatedly request reassurance or complain of somatic symptoms. Worries are often related to memory loss, such as needing repeated assurance that loved ones are safe or are planning to visit, that belongings have not been lost, or that plans and schedules will be kept.
Summary: For long-term management, the experts prefer buspirone, with trazodone and the selective serotonin reuptake inhibitors SSRIs as alternatives. For acute treatment, the experts prefer benzodiazepines. However, for safety reasons, benzodiazepines are not recommended for long-term use (see also Guideline 7). |
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| Long-Term Mangement* | Acute Management | |
| Preferred medications (none were first line) | Buspirone | Benzodiazepine� |
| Also consider | Trazodone
Selective serotonin reuptake inhibitor (SSRI)** |
Trazodone |
| *See Guideline 6B for HCFA regulations.
�See Guideline 7 for details on selecting a specific benzodiazepine or a specific SSRI. Further Recommendation: Buspirone and the SSRIs have a gradual onset of action. If the initial acute treatment is a benzodiazepine and the clinician then wishes to continue long-term treatment with buspirone or an SSRI, either can be added while the benzodiazpine is tapered.� |
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| 9Question 9
�Editors� recommendation |
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Guideline 4: Specific Syndromes of Agitation, continued |
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4E. Insomnia10 |
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| Introduction: Insomnia is a common source of distress in the elderly who often sleep less and have reduced sleep efficiency as part of the aging process. Insomnia may also be due to an identifiable cause that should be treated appropriately, such as pain or distress associated with a general medical condition, psychosis, depression, or anxiety.
Summary: The experts prefer trazodone for both long-term and acute treatment of nonspecific insomnia. Benzodiazepines are acceptable as second line only for short-term use. |
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| Long-Term Management | Acute Management | |
| First line medications | Trazodone* | Trazodone* |
| Also consider | (Other medications very cautiously) | Benzodiazepine** |
| *Some expert panel members suggested nefazodone as well, a related compound that we did not include in the survey as an option for insomnia.
**See Guideline 6B regarding HCFA regulations and Guideline 7 for details on selecting a specific benzodiazepine or other sedative-hypnotic medication. Editors� Recommendation: Clinicians should also consider the principles of sleep hygiene (e.g., reduce daytime caffeine; avoid nocturia by reducing fluid intake in the evening; reduce noise level; adjust lights up or down as needed; provide a soothing activity before bed; have the patient spend less time in bed to match the actual need for sleep). |
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| 10Question 10 | ||
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Guideline 4: Specific Syndromes of Agitation, continued |
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4F. "Sundowning"11 |
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| Introduction: Sundowning consists of agitation, confusion, and disorientation that often start in the late afternoon and become especially severe at night. It may be the result of a number of causes, including fatigue, loss of visual cues in the dark, and instability in circadian rhythm. Sundowning may result in dangerous behavior such as falls from wandering or climbing over bed rails. It may be helpful to use orienting environmental interventions such as night-lights or reassuring check-ins from caregivers. Medication can help promote sleep and diminish confusion.
Summary: The experts recommend first trying trazodone for both long-term and acute management. Should this fail, antipsychotics are recommended. If long-term use is necessary, atypical antipsychotics are preferred over conventional antipsychotics.. |
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| Long-Term Management | Acute Treatment | |
| Preferred medications (none were first line) | Trazodone | Trazodone |
| Also consider | Risperidone
Olanzapine Conventional high potency antipsychotic |
Conventional high potency antipsychotic
Risperidone Olanzapine |
| 11Question 11 | ||
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Guideline 4: Specific Syndromes of Agitation, continued |
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4G. Aggression or Anger Not Due to Other Causes (e.g., Psychosis, Depression, Anxiety, Insomnia)12 |
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| Introduction: This guideline deals with aggression or anger that is not primarily explained by another syndrome such as psychosis or anxiety. Mild anger (i.e., without physical aggression) may be limited to specific situations (e.g., bathing, getting out of bed) or may be continuous. Severe anger with physical aggression is characterized by acts directed at caregivers and other people (e.g., forcefully pushing away a hand offering food; pushing, slapping, or scratching; extremely loud and disruptive yelling for extended periods).
Summary: The experts made no first line recommendations. For mild anger, the experts prefer divalproex or serotonergic medications (SSRIs, trazodone, buspirone) for long-term treatment and trazodone for acute treatment. For the long-term treatment of severe anger with physical aggression, they favor divalproex, followed by risperidone or conventional high potency antipsychotics. For acute treatment, they favor conventional high potency antipsychotics or risperidone, both of which work rapidly. |
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| Mild Anger, Not Aggressive | Severe Anger with Physical Aggression | |||
| Long-Term Management | Acute Management | Long-Term Management | Acute Management | |
| Preferred medications (none were first line) | Divalproex
Selective serotonin reuptake inhibitor (SSRI)* Trazodone Buspirone |
Trazodone | Divalproex
Risperidone� Conventional high potency antipsychotic� |
Conventional high potency antipsychotic
Risperidone |
| Also consider | Only modest support for:
Carbamazepine Risperidone� Olanzapine� |
Only modest support for:
Benzodiazepine Conventional high potency antipsychotic Risperidone |
Olanzapine�
Carbamazepine Trazodone SSRI* |
Olanzapine
Trazodone |
| *See Guideline 7 for details on selecting a specific SSRI. �See Guideline 6B regarding HCFA regulations for long-term use of antipsychotics. Further Recommendations:
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| 12Question 12
�Editors� recommendation |
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Guideline 4: Specific Syndromes of Agitation, continued |
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4H. Prominent Pain13 |
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| Introduction: Musculoskeletal pain from chronic osteoarthritis is a common problem that is often resistant to drug therapy. Comfortable positioning, physical therapy, local heat, and other pain management techniques can be helpful. Treatment with acetaminophen or nonsteroidal anti-inflammatory drugs should also be tried. Despite these measures, patients may become agitated due to continued pain and may benefit from treatment with certain psychotropic medications.
Summary: The experts had no first line recommendations, but preferred tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and trazodone over codeine compounds when dealing specifically with agitation. |
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| Preferred medications (none were first line) | Tricyclic antidepressants Selective serotonin reuptake inhibitors (SSRIs) Trazodone |
| 13Question 13 | |
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Guideline 5: Managing Inadequate Response to Medication |
| Introduction: Before changing or adding medication in a patient who is having no response or only a partial response, it is important to consider the following questions and take appropriate action:
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5A. Should You Switch Medication or Combine? |
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| Summary: The experts usually avoid polypharmacy in this vulnerable patient group, preferring to use drugs one at a time in most situations. In mild or severe agitation with no response to the first drug, the experts clearly prefer switching to a new medication. In severe agitation, however, the experts support adding a second medication if the patient has had a partial response to the first, since the recurrence of full-blown agitation may be more dangerous than the potential risk of drug interactions. In mild agitation with partial response to the first drug, the experts have no first line recommendation and support either switching or combining. When combinations are chosen, care should be taken to select new medications that will not interact negatively with those already being taken (see Guidelines 5B and 9A for safer combinations).
Editors� Comment: Should a drug combination be needed, the clinician can lessen the risk of drug interactions by trying lower doses of each agent rather than the usual "full" doses for single-drug therapy. |
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| Mild Agitation | Severe Agitation | |||
| No Response14 | Partial Response15 | No Response14 | Partial Response15 | |
| First line | Switch to a second medication | No first line recommendation | Switch to a second medication | Combine with a second medication |
| Second line | (Combinations generally not preferred) | Switch to a second medication
Combine with a second medication |
Combine with a second medication | Switch to a second medication |
| Editors� Recommendation: Should a patient improve when two drugs are combined, the clinician may wish at some future point to taper one of the medications slowly to find out if a single medication alone will be sufficient. | ||||
| 14Question 14
15Question 15 |
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Guideline 5: Managing Inadequate Response to Medication, continued |
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5B. Selecting the Next Medication |
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| Summary: For patients who have not responded adequately to conventional antipsychotics (e.g., haloperidol), the experts recommend switching to an atypical antipsychotic. Divalproex, trazodone, or another conventional antipsychotic are second line alternatives. For patients who have not responded adequately to an initial trial of an atypical anitpsychotic, the experts recommend switching to a conventional antipsychotic, if this has not been previously tried, or to another atypical antipsychotic (e.g., risperidone to olanzapine or vice versa). For patients who have not responded adequately to a trial with a benzodiazepine, the next step would be an antipsychotic, divalproex, or trazodone. When the clinician wishes to add a second drug to an antipsychotic, either to augment a partial response or because single-drug trials have failed, divalproex or trazodone is generally preferred as an add-on. If a patient is receiving ongoing treatment with a benzodiazepine and a second drug is needed, the preferred choice is an antipsychotic or divalproex. The experts recommend using benzodiazepines for immediate p.r.n. use when extra sedation is needed in patients on antipsychotics. Antipsychotics are recommended for p.r.n. use in patients on benzodiazepines.
Editors� Comment: In choosing the second medication, it can be helpful to focus on the main symptoms being treated (e.g., switch to antipsychotics for prominent psychosis, divalproex for prominent aggression, trazodone for uncomplicated insomnia). If the initial switching strategy fails, the other choices may be tried. |
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| If Switching | If Combining | |||
| Previous Medication | Preferred Agents (none were rated fist line except where indicated) | Also Consider | Consider for Ongoing Treatment* | Preferred for p.r.n. Use� |
| Conventional antipsychotic16 | Atypical antipsychotic (first line) | Divalproex
Trazodone Another conventional antipsychotic |
Divalproex
Trazodone |
Benzodiazepine |
| Atypical antipsychotic17 | Conventional antipsychotic
Another atypical antipsychotic |
Divalproex
Trazodone Carbamazepine |
Trazodone
Divalproex |
Benzodiazepine |
| Benzodiazepine18 | Atypical antipsychotic
Conventional antipsychotic Divalproex Trazodone |
Carbamazepine
Antidepressant |
Conventional or atypical antipsychotic
Divalproex |
Antipsychotic |
| *There was little consensus on combination strategies. Their main use is in severe agitation when there has been a partial response to the first medication (see Guideline 5A).
Further Recommendations: When switching from an antipsychotic, if there has been a partial response, the antipsychotic should be tapered while starting the new agent. However, if there has been no response to the antipsychotic, it may be stopped altogether when the new drug is started.� Benzodiazepines should be tapered when switching to a new drug, unless they have been prescribed at extremely low doses (e.g., lorazepam 0.25�0.5 mg at bedtime).� |
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| �Editors� recommendations, adapted from Question 19
�Editors� recommendation 16Question 16 17Question 17 18Question 18 |
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Guideline 5: Managing Inadequate Response to Medication, continued |
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5C. Defining Inadequate Response: How Long to Try a Medication |
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| Introduction: Agitation in dementia is often a chronic problem requiring long-term management and it may take many weeks of treatment at gradually adjusted doses to determine if a given medication and dosage schedule are useful. Sometimes, very brief use of medication may be helpful to stabilize a patient during an acute crisis. | ||
1. For longer-term management19Summary: Among medications used to treat agitation, some work rapidly while others have a delayed onset of action. The experts generally recommend trials of 2 weeks or longer for divalproex, buspirone, and antidepressants. Antipsychotics, trazodone, and benzodiazepines may produce a response in 1 week or less. |
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| How Long to Try a First Medication Before Switching to or Adding Another Medication If Response Inadequate | ||
| Medication | Shortest | Longest (weeks) |
| Antipsychotic (atypical or conventional) | 4�7 days | 2�4 |
| Benzodiazepine | 3�4 days | 1�3 |
| Buspirone | 1.5�2.5 weeks | 4�6 |
| Divalproex | 1�2 weeks | 3�6 |
| SSRI antidepressant | 10�14 days | 4�6 |
| Tricyclic antidepressant | 10�14 days | 4�6 |
| Trazodone | 7�10 days | 3�4 |
2. In an acute situation20Summary: To determine if a medication will be helpful in an acute situation, the experts recommend trying an antipsychotic for at least 2 or 3 days and a benzodiazepine for at least 1 or 2 days. If the response to the initial treatment is not adequate, the clinician should wait no longer than 1 week before deciding on the next step. |
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| How Long to Try a First Medication Before Switching to or Adding Another Medication If Response Inadequate | ||
| Medication | Shortest (days) | Longest (days) |
| Antipsychotic (atypical or conventional) | 2�3 | 6�8 |
| Benzodiazepine | 1�2 | 4�6 |
| 19Question 20
20Question 21 |
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Guideline 6: Long-Term Treatment Issues |
6A. Medications for Long-Term Safety21 |
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| Summary: It is important to monitor the long-term safety of continuous psychotropic medication use in elderly patients, both as general practice and specifically to comply with HCFA requirements for long-term care facilities. The experts indicated that selective serotonin reuptake inhibitors and buspirone are least likely to cause serious problems with continued long-term use. Other drugs require more careful monitoring. The experts rate the newer antidepressants, such as buproprion, nefazodone, and venlafaxine, as less safe than the SSRIs but considerably safer than the tricylic antidepressants (e.g., amitriptyline). Among anticonvulsants, divalproex is preferred over carbamazepine. Atypical antipsychotics are viewed as considerably safer than conventional antipsychotics. | ||
| Medication | Comment | |
| First line |
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| Second line |
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| 21Question 22 | ||
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Guideline 6: Long-Term Treatment Issues, continued |
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6B. When to Taper Medication If the Patient Has Had a Good Response |
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Summary: Although some patients require long-term treatment, it is important periodically to taper and try to discontinue medication following a period of satisfactory improvement. In general, the experts suggest attempting to taper medication as soon as 2 to 3 months, particularly in milder agitation, and certainly within 6 to 9 months even in a patient who had severe agitation. The recommended period of treatment tends to be somewhat shorter for antipsychotics and especially for benzodiazepines. Repeated relapses suggest the need for continuing medication indefinitely. Editors� Comment: In deciding whether to continue or taper medication for agitation, the editors recommend considering the following factors:
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| Length of Time to Treat Before Trying to Taper and Discontinue22 | ||||
| Medication | Milder Agitation | Severe Agitation | ||
| Fewest Months | Most Months | Fewest Months | Most Months | |
| Antidepressant (not for depression) | 2�3 | 6�8 | 3�4 | 7�9 |
| Antipsychotic (atypical or conventional) | 1.5�2 | 4�6 | 2�3 | 6�8 |
| Benzodiazepine | 1�2 | 3�6 | 1.5�2 | 4�6 |
| Buspirone | 2�3 | 5�8 | 2.5�4 | 6�9 |
| Divalproex | 2�3 | 6�8 | 3�4 | 7�9 |
Trazodone |
2�3 | 6�8 | 2.5�4 | 7�9 |
| Further Recommendations: Tapering should be done gradually (e.g., 25% every week or two). Most of the experts do not recommend continuing medication indefinitely, especially in milder agitation. | ||||
| 22Question 23
aDepartment of Health and Human Services, Health Care Financing Administration. Long Term Care Guidelines. Transmittal No. 274, June 1995 |
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Guideline 7: Selecting Specific Medications within Different Classes of Drugs |
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| Summary: Individual medications even within a given group may vary considerably in tolerability, efficacy, and the risk of interaction with other drugs. Among antidepressants, the experts recommend sertraline or paroxetine as first line choices, with nortriptyline, venlafaxine, and fluoxetine as the top-rated second line alternatives. Lorazepam and buspirone are preferred over the other anxiolytics for agitation. Zolpidem and lorazepam are preferred among sedatives for sleep�both have intermediate half-lives (8�12 hours) and simple metabolism. Divalproex is the treatment of choice among anticonvulsants for use in agitation. | ||
| Class of Medication | Preferred Agents | Also Consider |
| Antidepressant23 | Sertraline (first line)
Paroxetine (first line) |
Top second line choices bordering first line:
Nortriptyline Venlafaxine Fluoxetine Other highly rated second line choices: Nefazodone Desipramine Trazodone Bupropion Fluvoxamine |
| Anxiolytic for generalized daytime agitation (none were first line)24 | Lorazepam
Buspirone |
Oxazepam |
| Sedative-hypnotic or anxiolytic to promote sleep (none were first line)25 | Zolpidem
Lorazepam |
Temazepam
Oxazepam Chloral hydrate |
| Anticonvulsant26 | Divalproex (treatment of choice) | Carbamazepine (highly rated second line)
Gabapentin |
| Further Recommendation: The choice of a specific antipsychotic agent is dependent on the nature of the presentation and whether the management situation is acute or long-term. Refer to Guideline 4 for recommendations about factors that influence this selection. | ||
| 23Question 24
24Question 25 25Question 25 26Question 26 |
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Guideline 8: Dose27 and Side Effects |
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| Summary: Manufacturers� dosing recommendations are usually intended for younger patients. Dosages for the drugs shown below are much lower for elderly than for younger patients. The starting doses recommended by the expert consensus panel may be sufficient in many cases, but doses can be gradually increased toward the target dose based on the clinician�s judgment of how well the patient is responding to and tolerating the medication. The highest doses should be reserved only for patients who have not responded to lower doses but are tolerating those doses well. The editors list the most common or important side effects and refer readers to comprehensive references such as the Physicians� Desk Reference and Drugs of Choice from the Medical Letter (see p. XX) for more complete information. | ||||
| Recommended Oral Doses (mg/24 hr) | Most Important Side Effectsa | |||
| Medication | Starting Dose | Average Target Dose | Highest Final Dose | |
| Buspirone (Doses usually divided b.i.d.) | 10 | 30 | 50�60 | Headache, dizziness, nausea; rarely overstimulation |
| Divalproex (Doses usually divided b.i.d.) | 250�375 | 625�825 | 1250�1750 | Nausea, tremor, weight gain, hair loss, thrombocytopenia, drowsiness, rarely hepatic dysfunction |
| Divalproex blood level | 45�60 mcg/ml | 60�70 mcg/ml | 90�100 mcg/ml | |
| Carbamazepine | 100�200 | 400�600 | 800�1000 | Rash, drowsiness, blurred or double vision, headache, ataxia, nausea, mild leukopenia, rare agranulocytosis |
| Carbamazepine blood level | 2�5 mcg/ml | 7�8 mcg/ml | 10�11 mcg/ml | |
| Haloperidolb | 0.5�1.0 | 1.5�2.0 | 5�7 | Drowsiness, postural hypotension, extrapyramidal effects (EPS), tardive dyskinesia, weight gain, anticholinergic effectsc |
| Lorazepamb | 0.5�1.5 | 1.5�2.5 | 3�5 | Drowsiness, ataxia, amnesia, disinhibition, paradoxical excitement, depression, dizziness, withdrawal symptoms, rebound insomnia or excitement |
| Olanzapine | 2.5�5.0 | 5.0�7.5 | 12.5�15 | Drowsiness, weight gain, dizziness, anticholinergic effects, postural hypotension, EPS (rare) |
| Risperidoned | 0.25�0.5 | 0.5�1.5 | 2�3 | Blurred vision, dizziness, drowsiness, postural hypotension, headache, nausea, EPS (occasional), weight gain (occasional) |
| Trazodone | 25�50 | 50�100 | 250�300 | Drowsiness, headache, GI upset, occasional postural hypotension and ventricular arrhythmias, priapism in men (rare) |
| Editors� Note: Antidepressants are not covered in this table because of the complexity of the subject. Appropriate doses of selective serotonin reuptake inhibitors for elderly patients vary widely. Tricyclic antidepressants should only be used with careful monitoring of blood levels. | ||||
| aAbramowicz M, ed. Drugs of Choice from the Medical Letter. New Rochelle, NY: Medical Letter, Inc, 1997
bFluphenazine is also frequently used, with approximately the same dose ranges as for haloperidol. For IM injection of haloperidol alone, the experts recommend a dose of 0.7�2.4 mg. For IM injection of lorazepam alone, they recommend a dose of 0.5�1.5 mg. Although not generally recommended, when the clinician feels it is necessary to combine haloperidol and lorazepam in an IM injection, the experts recommend using the lower end of the IM dose range for both drugs.28 cAnticholinergic effects are defined by the Drugs of Choice from the Medical Letter as dry mouth, mydriasis, cycloplegia, urinary retention, constipation, tachycardia, memory impairment, and delirium. dEditors� recommendations; doses shown are lower than those suggested by the expert panel, reflecting new data that became available after the survey was conducted (Janssen Pharmaceutica, on file). |
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| 27Question 27
28Questions 27 and 28 |
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Guideline 9: Safety and Tolerability |
9A. Medications Least Likely to Cause Drug Interactions29 |
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| Introduction: Watching out for drug interactions is a high priority in older patients for at least four reasons: 1) older patients usually metabolize drugs more slowly than younger patients; 2) this population is often on multiple medications, increasing the likelihood of having an adverse interaction; 3) older patients are often more frail and therefore may be more sensitive to the adverse consequences of an untoward interaction; and 4) ironically, drug-drug interactions may be misidentified and mistakenly attributed to an underlying medical illness. There are two types of interactions. A pharmacokinetic interaction is the alteration by one drug of the absorption, distribution, metabolism, or elimination of another drug. A major example is the inhibition of hepatic cytochrome P450 (CYP) isoenzymes by various selective serotonin reuptake inhibitors (SSRIs), which may increase the levels of other medications metabolized by these enzymes. A pharmacodynamic interaction is the alteration by one drug of the nature or magnitude of the response to another drug because of the first drug�s effects on the second site of action. An example would be additive diarrhea in a patient receiving both an SSRI and a laxative.
Summary: The experts rated buspirone as the first line choice to avoid drug-drug interactions. Highly rated second line choices are the antidepressants sertraline, bupropion, venlafaxine, paroxetine, and nefazodone; atypical antipsychotics; high potency conventional antipsychotics; and divalproex. We have highlighted a few key interactions for each medication; clinicians are advised to check the Physicians� Desk Reference or other similar sources for comprehensive lists of specific interactions caused by and to each medication. |
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| Medication | Editors� Comment | |
| First line | Buspirone | Metabolized by CYP3A; its level may be raised by CYP3A inhibitors (e.g., ketaconazole, macrolide antibiotics, nefazodone). Does not appear to alter CYP enzymes itself. Use cautiously with other drugs that may cause nausea. |
| Higher second line, less problematic (drugs in each class are listed in order of mean scores; differences were not statistically significant) | Antidepressants | |
| Sertraline | Modest inhibition of CYP2D6 at higher doses. Examples of substrates whose levels may be increased: tricyclic antidepressants, many opiates, antiarrhythmics, and beta blockers | |
| Bupropion | Lowers seizure threshold; use cautiously with other drugs that do the same. Levels of hydroxybupropion (major active metabolite) may be raised by CYP2D6 inhibitors (e.g., fluoxetine). Does not appear to alter CYP enzymes itself. | |
| Venlafaxine | Modest inhibition of CYP2D6; also potential for increased venlafaxine level if combined with other inhibitors of CYP2D6. May raise blood pressure so that increased dose of antihypertensive medication may be needed | |
| Paroxetine | Substantial inhibition of CYP2D6; will increase levels of 2D6 substrates | |
| Nefazodone | Substantial inhibition of CYP3A at higher doses. Examples of substrates whose levels may be increased: tricyclic antidepressants, sertraline, acetaminophen; many calcium blockers, antiarrhythmics, benzodiazepines, and opiates | |
| Atypical and high potency conventional antipsychotics | May exacerbate sedation or hypotension caused by other medications; potential additive akathesia or extrapyramidal symptoms with SSRIs. Haloperidol (and perphenazine, a medium potency antipsychotic) moderately inhibits CYP2D6. Effects of atypical antipsychotics on CYP enzymes are not well known. | |
| Anticonvulsant Divalproex |
Dissociates in the stomach to valproic acid, which can cause the following interactions: level may be raised by aspirin; can potentiate sedative effects of other medications. Use cautiously with highly protein-bound drugs, since valproic acid can displace them, raising their free fraction. Use cautiously with medications that may cause hepatotoxicity. | |
| Lower second line, more problematic | Fluoxetine | Inhibits many CYP enzymes: substantial inhbition of CYP2D6 and CYP2C9/10, moderate inhibition of CYP2C10, mild inhibition of CYP3A/4. Therefore, may raise levels of many other antidepressants, and of many benzodiazepines, antipsychotics, antiarrhythmics, antihypertensives, and analgesics. Drug interactions persist many weeks after discontinuation due to prolonged half-life of elimination. |
| Fluvoxamine | Effects similar to those of fluoxetine except without prolonged half-life. | |
| Carbamazepine | Induces several CYP enzymes; reduces levels of a variety of other medications | |
| Tricyclic antidepressants and low potency conventional antipsychotics | Both have a wide variety of potential pharmacodynamic interactions and should be used with careful monitoring in patients receiving multiple medications | |
| Benzodiazpines | May cause greater sedation, confusion, and ataxia in combination with other medications | |
| Further Recommendations: Do not combine monoamine oxidase inhibitors (MAOIs) (including selegiline [Eldepryl] used in Parkinson�s disease and Alzheimer�s disease) with SSRIs, venlafaxine, buspirone, or tricylic antidepressants. A washout time of 1 to 2 weeks is recommended between stopping MAOIs and beginning these other medications, and 5 weeks or more between stopping fluoxetine and beginning an MAOI.* | ||
| 29Question 29
*Editors� recommendation |
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Guideline 9: Safety and Tolerability, continued |
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9B. Safest Medications�Least Likely to Cause or Exacerbate Specific Complications30 |
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| Summary: Sometimes preferred medications for agitation (Guideline 4) are problematic for patients with serious comorbid conditions. Table 9B lists potentially effective alternatives for agitation that are less likely to exacerbate comorbid conditions as well as medications that are more likely to cause difficulty. | |||||||||||
| Likelihood of causing or exacerbating problem: | +++ = preferred; unlikely to cause problems
++ = usually not a problem but possible + = more likely -- = often |
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| Complicating problem | Antipsychotics | Anxiolytics | Anticonvulsants | Antidepressants | |||||||
| RSP | OLZ | HP | LP | BSP | BNZ | DVP | CBZ | SSRIs | TCAs | TRZ | |
| Falling due to gait problem other than parkinsonism | ++ | ++ | + | -- | ++ | -- | ++ | + | +++ | -- | + |
| Very poor memory | ++ | ++ | ++ | -- | ++ | -- | ++ | ++ | +++ | -- | ++ |
| Nausea or poor appetite | ++ | ++ | ++ | ++ | ++ | ++ | ++ | + | + | ++ | ++ |
| Lethargy | ++ | + | + | -- | ++ | -- | + | + | ++ | + | -- |
| Constipation | ++ | ++ | ++ | -- | ++ | ++ | ++ | ++ | +++ | -- | ++ |
| Concern over weight gain | ++ | + | ++ | -- | ++ | ++ | ++ | ++ | ++ | -- | ++ |
| Prostatic hypertrophy | ++ | ++ | ++ | -- | ++ | ++ | ++ | ++ | +++ | -- | ++ |
| Potential drug abuse or dependence | +++ | +++ | ++ | ++ | ++ | -- | ++ | ++ | ++ | ++ | ++ |
| Congestive heart failure | ++* | ++* | ++ | -- | ++ | ++ | ++ | ++ | ++ | --� | ++ |
| Orthostatic hypotension | ++* | ++* | ++ | -- | ++ | + | ++ | ++ | ++ | -- | -- |
| Cardiac conduction disease | ++* | ++* | ++ | -- | ++ | ++ | ++ | + | +++ | -- | + |
| Angina | ++* | ++* | ++ | -- | ++ | ++ | ++ | ++ | ++ | --� | ++ |
| Liver disease -- elevated liver function tests | ++ | ++ | ++ | + | ++ | + | -- | -- | ++ | + | ++ |
| Renal insufficiency | ++ | ++ | ++ | + | ++ | ++ | ++ | ++ | ++ | + | ++ |
| Seizure disorder | ++ | ++ | ++ | -- | ++ | ++ | +++ | +++ | ++ | + | ++ |
| Chronic obstructive pulmonary disease | ++ | ++ | ++ | + | ++ | -- | ++ | ++ | ++ | ++ | ++ |
| Insomnia� | +++ | +++ | ++ | +++ | + | +++ | +++ | +++ | -- | +++ | +++ |
| SSRIs: selective serotonin reuptake inhibitors; TCAs: tricyclic antidepressants; NT: nortriptyline; HP: conventional high potency; LP: conventional low potency; Atyp: atypical; RSP: risperidone; OLZ: olanzapine; TRZ: trazodone; BSP: buspirone; BNZ: benzodiazepines; DVP: divalproex; CBZ: carbamazepine; LFT: liver function test; COPD: chronic obstructive pulmonary disease | |||||||||||
| *Atypical antipsychotics asked about as a class in these conditions
�Nortriptyline low second line in this condition �Editors� recommendations 30Questions 30�33 |
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