The Cancer Patient with Pain: Psychiatric Complications and Their Management

Cancer Pain

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The Cancer Patient with Pain: Psychiatric Complications and Their Management

Mary Jane Massie, M.D.,* and Jimmie C. Holland, M.D.t

The diagnosis of cancer induces stresses that are caused by the patient's perceptions of the disease and its manifestations and by the stigma commonly attached to cancer. For most individuals, the primary concern is the fear of a painful death. In addition, all patients with cancer fear becoming disabled and dependent, having altered appearance and changed body function, and losing the company of those close to them. Although such fears are similar in all p;ltients, the level of psychologic distress is highly variable. This variability is accounted for by three factors: medical factors (site, stage, treatment, and clinical course of the cancer, and the presence of pain); psychologic factors of prior adjustment, coping ability, emotional maturity, the disruption of identified goals, and ability to modify plans; and social factors such as the availability of emotional support offered by family, friends, and co-workers. 12 Emotional distress is a normal response to the catastrophic event that a cancer diagnosis represents. However, by understanding the factors outlined above, one can better predict and manage the distress that exceeds what we arbitrarily define as "normal." The presence of an intolerable level of distress, which prohibits usual function of the patient, requires evaluation, diagnosis, and management. This review outlines the normal responses to cancer and the frequently encountered psychiatric disorders, as well as how they are influenced by pain in their clinical picture and incidence.

NORMAL RESPONSES TO THE STRESS OF CANCER When individuals receive a diagnosis of cancer or learn that a relapse has occurred or that treatment has failed, they show a characteristic

*Assistant Attending Psychiatrist,

Memorial Hospital; Associate Professor of Clinical Psychiatry, Cornell University Medical College, New York, New York tChief, Psychiatry Service, Memorial Hospital; Professor of Psychiatry, Cornell University Medical College, New York, New York

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emotional response: a period of initial shock and disbelief, followed by a period of turmoil with anxiety and depressive symptoms, irritability, and disruption of appetite and sleep. The ability to concentrate and carry out usual daily patterns of life is impaired, and intrusive thoughts about the diagnosis as well as fears about the future are present. These normal responses to crisis or transitional points in cancer resemble the response to stress that has been described in relation to other threatened or actual losses.ll, 14, 16, 17 Symptoms usually gradually resolve in seven to ten days with support from family and friends and from the physician, who outlines a treatment plan that offers hope, Intervention beyond that provided by empathic physicians, nurses, social workers, and clergy is generally not required unless symptoms of emotional distress interfere with function or are prolonged or intolerable. Prescribing a hypnotic to permit normal sleep and a daytime sedative (a benzodiazepine) to reduce anxiety can help the patient through crisis periods. Some patients, however, continue to have high levels of anxiety and depression (both are usually present, although one may predominate) that persist for weeks or months, This persistent reactive distress is not adaptive and frequently requires psychiatric treatment. These disorders are classified in the current Diagnostic and Statistical Manual-IIF as "adjustment disorders with depressed, anxious or mixed mood" depending on the major symptoms. Psychiatrists working in oncology utilize short-term supportive psychotherapy based on a crisis intervention model, which includes offering emotional support, providing information to assist the patient in adaption to the crisis, emphasizing past strengths, and supporting previously successful ways of coping. Patients and their families are seen at least weekly, and we prescribe anxiolytic or antidepressant drugs as indicated. As symptoms improve, medication can be reduced and discontinued. Having the patient talk with a "veteran patient," who has been through the same treatment, is often a helpful adjunct. 22 PREVALENCE OF PSYCHIATRIC DISORDERS Disorders in Cancer Patients

There are many myths about the psychologic problems of cancer patients, which vary from "all patients are distressed and need psychiatric help" to "none are upset and no one needs help." One of the first efforts in the new field of psycho-oncology was to obtain objective data on the type and frequency of psychologic problems to plan for provision of services and utilization of support staff in cancer centers and on oncology units. Using criteria from the Diagnostic and Statistical Manual-Ill classification of psychiatric disorders, the Psychosocial Collaborative Oncology Group in three cancer centers determined the psychiatric disorders in 215 randomly accessed hospitalized and ambulatory adult patients with cancer.6 Slightly over half (53 per cent) the patients evaluated were adjusting normally to stress; however, nearly half (47 per cent) had clinically apparent psychiatric

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PSYCIIIATRIC COMPLICATIONS AND THEIR MANAGEMENT

Table 1. Rates of DSM-III Psychiatric Disorders Observed in 215 Cancer Patients From Three Cancer Centers* IN SPECIFIC

PER CE!,;T OF

NU~IBER

DIAG!,;OSTIC CATEGORY

CATEGORY

Adjustment Disorders Depressed mood Mixed emotional features Anxious mood Emotion and conduct

26 29 12 2

(12%) (13%) (6%) (1%)

Major Affective Disorders Unipolar depression Bipolar depression Atypical depression Dysthymic disorder

8 1 3 1

(4%) (0.5%) (1.5%) (0.5%)

Organic Mental Disorders Presenile dementia Dementia with depression Organic affective syndrome Dementia Atypical organic brain syndrome Organic personality syndrome

1 (0.5%) 1 (0.5%) 2 (1%) 1 (0.5%) 2 (1%) 1 (0.5%)

Personality Disorder and Alcohol Abuse Schizoid Compulsive Histrionic Dependent Other Alcohol abuse (in remission)

1 (0.5%) 2 (1%) 1 (0.5%) 1 (0.5%) 1 (0.5%) 1 (0.5%)

Anxiety Disorders Generalized anxiety disorder Simple phobia Obsessive-compulsive disorder

1 (0.5%) 1 (0.5%) 2 (1%)

Total Psychiatric Diagnoses Psychiatric Diagnosis Absent

NUMBER IN DIAGNOSTIC CLASS

PSYCHIATRIC DIAGNOSES

69 (32%)

68

13 (6%)

13

8 (4%)

8

7 (3%)

7

4 (2%)

4

10l (47%) 114 (53%)

*Adapted from Derogatis LR. et al: The prevalence of psychiatric disorders among cancer patients. JAMA 249:754, 1983. disorders. Of this 47 per cent with psychiatric disorders, over two thirds (68 per cent) had reactive anxiety and depression (adjustment disorders with depressed or anxious mood); 13 per cent had a major depression; 8 per cent had an organic mental disorder; 7 per cent had a personality disorder; and 4 per cent had a pre-existing anxiety disorder (Table 1). It is interesting to note that nearly 90 per cent of the psychiatric disorders observed were reactions to or manifestations of disease or treatment. Only 11 per cent represented prior psychiatric problems, such as personality and anxiety disorders. Therefore, the physician treating patients with cancer is largely treating psychologically healthy individuals who have emotional reactions to the stresses posed by cancer and its treatment.

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Table 2. Prevalence of Psychiatric Diagnosis Among Patients Experiencing Pain* Total population Psychiatric diagnosis No psychiatric diagnosis

1\

x

S.D.

%2:50t

215 101 114

33.01 38.29 28.33

28.86 31.83 25.18

28 39 19

*Data collected in the study reported by the Psychosocial Collaborative Oncology Group. Derogatis LR, et al: The prevalence of psychiatric disorders among cancer patients. JAMA 249:751-757, 1983. tWO = worst possible pain.

Disorders in Cancer Patients with Pain In the Psychosocial Collaborative Oncology Group study described above, each of the 215 patients rated the severity of their pain (Table 2). Of the patients who received a psychiatric diagnosis, 39 per cent indicated the severity of their pain was greater than 50 mm on a WO-mm visual analogue scale (rated from anchor points of no pain = 0 to worst possible pain = 100 mm). In contrast, only 19 per cent of patients who did not receive a psychiatric diagnosis had significant pain. The psychiatric diagnosis of the patients was predominately "adjustment disorder with depressed or mixed mood" (69 per cent), but, of note, 15 per cent of patients in significant pain had symptoms of a major depression. This finding of increased frequency of psychiatric disturbance in patients with pain has been reported by others. Ahles, Blanchard, and Ruckdeschel compared cancer patients with and without pain and found that patients with pain obtained higher scores on measures of depression, anxiety, hostility, and somatization. 1 Sternbach noted that anxiety symptoms often accompany acute pain, whereas patients with chronic pain are depressed. 35 Treating both these emotional states usually has a salutary effect on pain; thus, the emotional states may represent both a consequence of and a contribution to pain in patients with cancer. 27 These data confirm the clinical observation that the psychiatric symptoms of patients who are in pain must initially be considered as a consequence of uncontrolled pain. Acute anxiety, depression with despair (especially when the patient believes the pain means disease progression), agitation, irritability, uncooperativeness, anger, and inability to sleep are common emotional and behavioral symptoms of pain. These symptoms in a patient in pain are not labeled as a psychiatric disorder unless they persist after pain is adequately controlled. Psycho-oncologists should first assist in pain control and then reassess the patient's mental state after pain is controlled to determine whether the patient has a psychiatric disorder. The cancer patient with pain has an enhanced risk of developing the common psychiatric disorders in cancer. Clearly, in terms of frequency, depression, anxiety, or mixed symptoms of depression and anxiety are the most common problems. In this chapter, depression is reviewed first, followed by anxiety and delirium. DEPRESSION IN CANCER PATIENTS Depression has been studied in cancer patients using a range of assessment methods. 3 , 6, 15, 28, 33 In general, the more narrowly the term is

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Table 3. Reason for Consultation Among 546 Patients Referred to the Memorial Sloan-Kettering Cancer Center Psychiatry Service REASON

Depression or Suicidal Risk Depression Suicidal risk Organic Mental Disorder eNS dysfunction Behavior management Evaluation of behavior Anxiety Medication management Other Total

N

313 281 32 93 14 54 25 82

10

48 546

PER CENT OF TOTAL REQUESTS

59 18

16 2 5 100

defined, the lower the prevalence of depression that is reported. The difficulty of studying depression stems in part from the fact that depressive symptoms represent a spectrum of mood change ranging from sadness to major affective disorder. When a patient is confronted by major threat to life by cancer, the evaluation of these symptoms becomes difficult. Several studies utilizing patient self-report and observer rating report that approximately one fourth of hospitalized cancer patients have major depression. 3, 8, 28 Factors associated with greater prevalence of depression are a higher level of physical disability, more severe illness, and presence of pain. One study has shown that patients with pancreatic cancer in advanced stages have more severe depression and anxiety than do comparably ill patients with advanced gastric cancer. 13 The incidence of depression in cancer patients is similar to that in comparably ill patients with other medical diagnoses,25, 34 suggesting that degree of illness, irrespective of its underlying cause, is its primary determinant, not the cancer diagnosis per se. When severe depression is present in cancer patients, it should be treated as aggressively as in other medically ill patients. In a recent review, Rodin and Voshart note the challenge of detecting a treatable psychiatric disorder when boundaries between normality and pathology are blurred by the circumstances of illness and in which, as yet, clinically relevant and valid rating scales for medically ill patients do not exist. 33 Yet, despite these research difficulties, the clinician must diagnose and manage the spectrum of depressive symptoms. We have reviewed data on 546 patients referred for psychiatric consultation at Memorial Hospital. 21 Of these consultations, 59 per cent had been requested for evaluation of depression or suicidal risk, or both (Table 3). When the consultants' actual impressions were reviewed, depressive symptoms were by far the most common, with adjustment disorders accounting for 54 per cent and major depression 9 per cent (Table 4). The following sections outline the clinical picture of depression and management approaches.

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Table 4. DSM -Ill Diagnosis Among 546 Patients Referred for Evaluation at the Memorial Sloan-Kettering Cancer Center Psychiatry Service N

PER CENT

295

Adjustment Disorder Depressed Anxious Mixed

140

62 93 49 39

Major Depression

Single episode Recurrent episode

10

III

Organic Mental Disorder

Delirium Dementia Organic affective syndrome

78

54

9

20

24

9

Major Psychiatric Disorder

26

5

Anxiety Disorders Other

5 22 22 2 2 21

4 4

546

100

21

Schizophrenia Manic-depressive

Mental retardation Somatoform

No Mental Disorder Total

4

CLINICAL PICTURE Diagnosis of depression in physically healthy patients depends heavily on the presence of somatic symptoms of anorexia, fatigue, and weight loss. These indicators are, however, of little value as diagnostic criteria for depression in a cancer patient, since they are common to both cancer and depression. In cancer patients the diagnosis of depression must depend on psychologic, not somatic, symptoms. These psychologic symptoms are dysphoric mood, feelings of helplessness, loss of self-esteem and feelings of worthlessness or guilt, and thoughts of "wishing for death" or suicide. Presence of suicidal ideation requires careful assessement to determine if a patient has a depressive illness or whether talk or suicide is one way the patient expresses his wish to have ultimate control over intolerable symptoms. Thoughtful clinical judgment is required, especially in the patient with advanced disease, to make this differentiation. If a patient is suicidal, we arrange for a 24-hour companion to provide constant observation, to monitor the suicidal risk, and to provide reassurance to the patient.

TREATMENT OF DEPRESSION PSYCHOLOGIC

Before planning an intervention, the psychiatrist obtains a history of previous depressive episodes, family history of depression, concurrent life stresses, and availability of social support. An assessment of the meaning of illness to the patient and his understanding of his medical situation is

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Table 5. Medications Used in Cancer Patients GENERIC NAME

Tricyclic Antidepressants Amitriptyline Doxepin Imipramine Desipramine Nortripty line Second-Generation Antidepressants Trazodone Maprotiline Amoxapine Bupropion Monoamine Oxidase Inhibitors Isocarboxazid Phenelzine Tranylcypromine

STARTI!\G DAILY

THERAPEUTIC DAILY

DOSAGE (PO)

DOSAGE (PO)

25 50 25 25 50

mg mg mg mg mg

50 25 25 100

mg mg mg mg

75-150 75-150 75-150 75-150 100-150 tid qd tid tid

mg mg mg mg mg

150-250 mg 50-75 mg 100-150 mg 300-450 mg

10 mg bid 15 mg bid 10 mg bid

20-40 mg 30-60 mg 20-40 mg

Lithium Carbonate

300 mg bid

600-1200 mg

Sympathomimetic Stimulants Dextroamphetamine Methylphenidate

2.5 mg bid in the morning 5 mg bid in the morning

Benzodiazepine Alprazolam

0.25-1.00 mg qd

0.75-6.00 mg

essential. If a patient has a medical condition or is being treated with medications known to cause depression, attempt is first made to treat these disorders. Depressed patients are usually treated with a combination of supportive psychotherapy and antidepressants. Antidepressants There are several reports of the efficacy of antidepressants in depressed patients with serious physical disorder. 19.32 Our clinical experience supports the usefulness of antidepressants in cancer patients with major depression. The antidepressant agents that can be considered for use in cancer patients are (1) the tricyclics; (2) "second-generation" antidepressants; (3) monoamine oxidase inhibitors (MAOIs); (4) sympathomimetic stimulants; (5) lithium carbonate; and (6) benzodiazepines. Table 5 shows the starting dose and range of therapeutic daily doses for these drugs.

Tricycle Antidepressants (Amitriptyline, Imipramine, Doxepin, etc.).

The antidepressants most frequently used in the oncology setting are the tricyclic antidepressants (TeAs). They are started at a low dose, especially in debilitated patients, beginning with 10 to 25 mg given at bedtime and increasing the dose by 25 mg everyone to two days until beneficial effect is achieved. For reasons that are unclear, depressed cancer patients often show a therapeutic response to a tricyclic at much lower doses (25 to 125 mg qd) than are usually required in physically healthy, depressed patients (150 to 300 mg). Patients are usually maintained on a TeA for four to six

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months after symptoms improve, after which time the dose is gradually lowered and discontinued. The choice of tricyclic depends on the nature of the depressive symptoms, medical problems present, and side effects of the TeA. The depressed patient who is agitated and has insomnia will benefit from the use of a TeA that has sedating effects, such as amitriptyline or doxepin. Patients with psychomotor slowing will benefit from use of the compounds with the least sedating effects, such as protriptyline or desipramine. The patient who has stomatitis secondary to chemotherapy or radiotherapy, or who has slow intestinal motility or urinary retention, should receive a TeA with the least anticholinergic effects, such as desipramine or nortriptyline. Amitriptyline, imipramine, and doxepin can be given intramuscularly to patients unable to take medications by mouth. Although TeAs have not yet been approved for intravenous use in the United States, several studies from Europe indicate their efficacy and safety by this route. 5. 26. 36 Imipramine, doxepin, and amitriptyline are increasingly used in the management of pain in cancer patients with a starting dose of 10 to 25 mg at bedtime. While the initial assumption was that analgesic effect resulted indirectly from the effect on depression, it is now clear that these tricyclics have a separate specific analgesic action probably mediated through several neurotransmitters, most prominently serotonin. Second-Generation Antidepressants. If a patient has been given a trial of tricyclic antidepressants without therapeutic effect, or if he cannot tolerate side effects, one of the "second-generation" antidepressants should be considered: trazodone, amoxapine, maprotiline, or bupropion. The starting dose and daily therapeutic dosage of these agents vary depending on the compound (see Table 5). Like the tricyclic compounds, the secondgeneration antidepressants vary in their antihistaminic and anticholinergic effects. Early clinical experience with bupropion suggests it may be useful for medically ill patients because of its activating effect in withdrawn patients. 30 Lithium Carbonate. Patients who have been receiving lithium carbonate prior to cancer should be maintained on it throughout cancer treatment, although close monitoring is necessary in the preoperative and postoperative periods when fluids and salt may be restricted. Maintenance dose of lithium may need reduction in seriously ill patients. Lithium should be prescribed with caution for patients receiving cis-platinum due to potential nephrotoxicity of both drugs. Several authors have reported possible beneficial effects from the use of lithium in neutropenic cancer patients;4. 20 however, the functional capabilities of these leukocytes have not been determined. The stimulation effect appears to be transient; no mood changes have been noted in these patients. Monoamine Oxidase Inhibitors. If a patient has responded well to a monoamine oxidase inhibitor for depression prior to treatment for cancer, its continued use is warranted. However, most psychiatrists are reluctant to start depressed cancer patients on MAOIs because the need for dietary restriction is poorly received by patients who already have dietary and nutritional deficiencies secondary to cancer illness and treatment. Psychostimulants. The psychostimulants, dextroamphetamine and

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251

methylphenidate, are sometimes prescribed for depressed medically ill patients in whom TCAs are contraindicated. 37 Dextroamphetamine also is used to potentiate the analgesic effect and counter the sedative effects of narcotics. A common starting dose is 2.5 mg of dextroamphetamine or 5.0 mg of methylphenidate given at 8:00 AM and noon. Psycho stimulants in low dose stimulate appetite and promote a sense of "well-being." Benzodiazepines. The triazolobenzodiazepine alprazolam has been shown to be an effective antidepressant as well as an anxiolytic. g, 31 Alprazolam is particularly useful in cancer patients who have mixed symptoms of anxiety and depression. Starting dose is 0.25 mg tid; effective doses are usually in the range of 4 to 6 mg daily. ELECTROCONVULSIVE THERAPY

Occasionally, it is necessary to consider electroconvulsive therapy (ECT) for depressed cancer patients who have depression with psychotic features or in whom treatment with antidepressants poses unacceptable side-effects. The safe and effective use of ECT in the medically ill has been reviewed by others. 2 ANXIETY Types of Anxiety Seen in Cancer Patients The types of anxiety seen in the oncology setting are (1) episodes of acute anxiety related to the stress of cancer and its treatment and (2) chronic anxiety disorders that antedate the cancer diagnosis and that are exacerbated during treatment. Most patients are anxious (1) while waiting to hear their diagnosis; (2) before procedures (bone marrow aspiration, start of chemotherapy or radiotherapy, wound debridement, dressing changes) or before major diagnostic tests; (3) before an operation; and (4) while awaiting test results. Although we consider anxiety "normal" at these times, many patients can be made more comfortable during these stressful times with reassurance and support from the physician and if given adequate doses of hypnotics on the night before surgery or before a painful procedure. If a patient describes fearfulness, if he seems too anxious to cooperate or to understand the description of procedures, or if he has symptoms of sympathetic hyperactivity (tachycardia, sweating, or hyperventilation), we prescribe an antianxiety drug to help reduce symptoms of anxiety to tolerable levels. Anxiety Symptoms Related to Medical Problems Patients in acute pain and those with acute or chronic respiratory distress usually appear anxious. The anxiety that accompanies acute pain is best treated with analgesics; the anxiety that accompanies severe respiratory distress is usually relieved by oxygen and judicious use of mild sedation. Many patients on corticosteroids have insomnia and symptoms of

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anxiety that vary from mild to severe. Since steroids prescribed as part of cancer therapy usually cannot be discontinued, anxiety symptoms are often relieved with benzodiazepines or low-dose antipsychotics. Patients who are developing encephalopathy (delirium) or are in early stages of dementia can appear restless or anxious. Anxiety symptoms are also features of withdrawal from narcotics, alcohol, benzodiazepines, and barbiturates. Since patients who abuse alcohol usually inaccurately report alcohol intake prior to admission, the physician needs to consider alcohol withdrawal in all patients who develop otherwise unexplained anxiety symptoms during early days of admission to the hospital. Other medical conditions that may have anxiety as a prominent feature or as the presenting symptom are hyperthyroidism, pheochromocytoma, carcinoid, primary and metastatic brain tumor, and mitral valve prolapse. Phobias and Panic The anxiety disorders that antedate cancer diagnosis are phobias and panic disorder. Occasionally but rarely, patients have their first episode of panic while being treated in a medical setting. It is important to request a psychiatric consultation in patients with a history of panic disorder or phobia when they begin treatment, since they are likely to have difficulty. Patients who are claustrophobic may have extreme anxiety in the confined spaces of diagnostic scanning devices or radiotherapy treatment rooms. Patients who have needle phobia often report having avoided medical evaluations for years because of their fears. Recently much attention has been given to the treatment of both panic and phobias on news programs and in magazines. Patients who in years past were embarrassed to report these fears now ask for help more readily. Many patients with phobias find relaxation therapy or distraction techniques helpful. Often, however, the need for diagnostic procedures or treatment for cancer is urgent. In these urgent situations, benzodiazepines (e.g., alprazolam, 0.5 mg) are helpful to allow phobic patients to tolerate venipuncture, intravenous chemotherapy administration, scanning procedures, or radiotherapy treatment. Classes of Antianxiety Medications Used in the Oncology Setting The classes of drugs that can be useful for the treatment of anxiety are the benzodiazepines, antipsychotics, antihistamines, beta blockers, and antidepressants (Table 6). Both acute and chronic anxiety states are usually treated with benzodiazepines. Barbiturates and meprobamate were once the mainstay of treatment of anxiety, but because they are highly addictive and lethal in overdose, their use has been supplanted by the benzodiazepines. The barbiturates occasionally are used for preoperative sedation. Antipsychotic medications are indicated for patients with severe anxiety that is not controlled with the maximal therapeutic dose of a benzodiazepine. Their primary usefulness is for anxiety or agitation of psychotic disorders and organic brain syndromes. The low efficacy of the antihistamines for anxiety limits their general usefulness; however, they are prescribed for anxious patients with respiratory impairment. The tricyclic antidepressant imipramine, the triazolobenzodiazepine alprazolam, the beta blocker propranolol,

PSYCHIATRIC COMPLICATIONS AND THEIR MANAGE~1E:'>IT

253

Table 6. Classes of Drugs Used to Treat Anxiety in Patients with Cancer BENZODlAZEPINES

Alprazolam Oxazepam Lorazepam Triazolam Diazepam Chlordiazepoxide Flurazepam Clorazepate dipotassium

ANTIPSYCHOTICS

Thioridazine Trifluoperazine Haloperidol Perphenazine

ANTIHISTAMINES

Diphenhydramine Hydroxyzine

Al'iTIDEPRESSANTS

Imipramine Phenelzine

(Xanax) (Serax) (Ativan) (Halcion) (Valium) (Librium) (Dalmane) (Tranxene) (Mellaril) (Stelazine) (Haldol) (Trilafon) (Benadryl) (Atarax, Vistaril) (Tofranil) (Nardil)

BARBITURATES

Phenobarbital Butabarbital sodium

BETA BLOCKERS

Propranolol

(Inderal)

and the monoamine oxidase inhibitor phenelzine are all useful in the treatment of panic disorder. Benzodiazepines are prescribed for acute panic; imipramine is the drug of choice for maintenance treatment of panic disorder. Clinical Use of Antianxiety Agents Diazepam and clorazepate, both benzodiazepines with rapid absorption rate and rapid onset of action, have long been prescribed for patients with acute anxiety. Increasingly, however, alprazolam, lorazepam, and oxazepam, short-acting benzodiazepines, are being prescribed for medically ill patients. These medications are rapidly metabolized and are better tolerated by patients with impaired hepatic function and by those taking other medications with sedative effects (e.g., analgesics). Dosage. The starting dose of anxiolytic is determined by the severity of the anxiety, the patient's physical state (respiratory and hepatic impairment), and the concurrent use of other medications (antidepressants, analgesics, antiemetics). Table 7 lists the commonly used starting dose of benzodiazepines, elimination half-life, and presence or absence of active metabolites. The dose schedule depends on the patient's tolerance and the duration of action of the anxiolytic. Diazepam, a long-acting benzodiazepine, often needs to be given to patients with chronic anxiety states no more than twice a day because of its long duration of action. Time-release forms of

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Table 7. Commonly Prescribed Benzodiazepines in Cancer Patients APPROXIMATE DRUG

ELIMINATION HALF-LIFE OF

DOSE

ORAL

DRUG

ACTIVE

EQUIVALENT

DOSAGE

Y1ETABOLlTES

METABOLlTES

0.25-0.5 mg tid 10-15 mg tid 0.5-2.0 mg tid

10-15 hr 5-15 hr 10-20 hr

Yes No No

10-25 mg tid

10-40 hr

Yes

5-10 mg bid 7.5-15 mg bid

20-100 hr 30-200 hr

Yes Yes

Short-Acting Aiprazolam Oxazepam Lorazepam

0.5 10 1

Moderately Long-Acting Chlordiazepoxide

10

Long-Acting Diazepam Ciorazepate

INITIAL

5 7.5

diazepam are available; however, we avoid prescribing this preparation when drug metabolism is impaired because of hepatic dysfunction. The shorter-acting benzodiazepines (alprazolam, oxazepam, lorazepam) are best given three to four times a day. If anxiety does not appear to be responding to a benzodiazepine, it is best first to increase the dose to the drug's maximal recommended dose that is well tolerated before switching to another drug in the same class or to another class of drug. Patients who experience anxiety only before a procedure (i.e., anxiety before chemotherapy administration) often take an anxiolytic only immediately prior to the procedure. Patients with chronic anxiety states will often need to take anxiolytics daily or intermittently for months or years. In our experience, cancer patients, even those with chronic anxiety, usually do not take more medication than they absolutely require and eagerly discontinue medications as soon as their symptoms remit. Side Effects. The most common side effects of the benzodiazepines are drowsiness, confusion, and motor incoordination. These dose-dependent effects disappear when the dose is lowered; uncomfortable sedation often disappears while the antianxiety effects continue. Sedation is most common and most severe in patients with impaired liver function. Physicians should be aware of the synergistic effects of the benzodiazepines when used with other medications with central nervous system depressant properties such as narcotics.

DELIRIUM (ORGANIC MENTAL DISORDER) Delirium, the second most common psychiatric diagnosis among cancer patients, is due both to the direct effects of cancer on the central nervous system (CNS) and the indirect eNS complications of the disease and treatment. Posner has reported that 15 to 20 per cent of hospitalized cancer patients have abnormalities of cognitive function that are not related to structural disease. 29 Approximately one fifth of all consultation requests made to our psychiatry service are requests for assistance in the management of symptoms of delirium. Early symptoms of delirium are often

PSYCHIATRIC COVlPLICATIO"lS AND TT-IEIH ;vIANAGEI\IE1\T

255

unrecognized or misdiagnosed by medical and nursing staff as symptoms of depression. Recognition of delirium is important since the underlying cause may be a treatable complication of cancer. Any patient who shows acute onset of agitation, impaired cognitive function, altered attention span, or a fluctuating level of consciousness should be suspected of having delirium. Delirium is usually due to one or more of seven causes: medications, electrolyte imbalance, failure of a vital organ or system, nutritional state, infections, vascular complications, or hormone-producing tumors. 18 In a study of delirium in terminally ill cancer patients, we found that over three fourths of the dying patients studied developed a delirium and that the etiology was most often a combination of factors (e.g., analgesics, infection, hypoxia, or hemorrhage).25 Many analgesics can cause acute confusional states. Levorphanol, morphine sulfate, and meperidine, all commonly used in the treatment of cancer pain, also commonly cause delirium. Among the more than sixty chemotherapeutic agents now available for cancer, CNS symptoms are not generally a prominent feature. Those that have been reported to cause delirium are methotrexate, fluorouracil, vincristine and vinblastine, bleomycin, BCNU, cis-platinum, asparaginase, procarbazine, and the glucocorticosteroids, prednisone and decadron.·38 All the steroid compounds may cause psychiatric disturbances ranging from minor mood disturbance to a frank steroid psychosis. 10. 18 Disturbances may include affective changes (emotional lability, euphoria, depressed mood), anxiety, fears, or paranoid interpretation of events and suspiciousness of others, with illusions, delusions, and hallucinations. Symptoms often develop four to five days after beginning high-dose steroids or when the dose is rapidly tapered, but psychiatric symptoms can also develop while patients are on maintenance dose. No relationship has been shown between the development of steroid psychosis and premorbid personality or psychiatric history. Management of Delirium

It is often necessary to treat a patient's agitated or disturbed behavior while simultaneously trying to determine its cause. When agitation is severe or the patient is delusional or hallucinating, one-to-one nursing observation is indicated. 24 Pharmacologic intervention is often indicated for the delirious patient. Patients with delirium with psychotic symptoms and agitation need a medication that is rapidly effective and easily administered. If the presenting symptoms include suspiciousness with refusal to take medications by mouth secondary to agitation or poor compliance, an antipsychotic should be administered in parenteral form. Antipsychotic drugs vary in their sedating properties and likelihood of producing orthostatic hypotension, neurologic side effects (acute dystonia, extrapyramidal symptoms), and anticholinergic effects. The acutely agitated cancer patient requires a sedating medication; the patient with hypotension requires a drug with least effect on blood pressure. The delirious postoperative patient who has mechanical ileus or urinary retention and who requires treatment with medications with anticholinergic activity (e. g., meperidine, diphenhydramine, atropine) should receive an antipsychotic

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with the least anticholinergic effects. Haloperidol is most commonly prescribed in our setting for patients with delirium because of its useful sedating effects and low incidence of cardiovascular and anticholinergic effects. Haloperidol can be given orally in tablet or concentrate, or by intramuscular or intravenous injection. Peak plasma concentrations are achieved in two to four hours after an oral dose and measurable plasma concentrations occur in 15 to 30 minutes after intramuscular administration. Although not yet approved by the Food and Drug Administration for intravenous use, haloperidol is commonly and safely administered by this route for the agitated patient. Haloperidol causes less orthostatic hypotension and has fewer anticholinergic effects than the low-potency antipsychotics (e.g., chlorpromazine, thioridazine). It can unfortunately produce strong extrapyramidal effects that can usually be well controlled by use of antiparkinsonian medications. The initial dose of haloperidol varies widely. In cancer patients it is best to start with a low dose (0.50 to 1.0 mg) administered by mouth (or 0.25 to 0.5 mg parenterally), repeating the dose at frequent intervals until symptom control is achieved.

SUMMARY The psychiatric complications most often seen in cancer are depression, anxiety, and delirium. All are more likely to occur in the cancer patient who has pain. It is important for patient comfort and quality of life to evaluate and intervene to manage the psychologic distress in the patient with cancer, especially if pain is a complication.

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