- Email: [email protected]
Delirium, depression, and anxiety in the treatment of cancer pain
Techniques in Regional Anesthesia and Pain Management (2005) 9, 139-144
Delirium, depression, and anxiety in the treatment of cancer pain Ajay D. Wasan, MD, MSc,a,b Mikhail Artamonov, MD,a Srdjan S. Nedeljkovic, MDa a
From the Departments of Anesthesiology, Perioperative and Pain Medicine; and Psychiatry, Brigham and Women’s Hospital/Harvard Medical School, Boston, Massachusetts.
b
KEYWORDS: Delirium; Depression; Anxiety; Cancer; Pain; Treatment 3
Neuropsychiatric disturbances are common in cancer patients. These occur in patients with and without pain, but at a much higher rate in those with pain. The most frequent pathologies are delirium, depression disorders, and anxiety disorders. Poorly treated pain can precipitate or exacerbate these disorders. It is difficult or impossible to obtain satisfactory pain relief in cancer patients with comorbid psychopathology, and these disorders significantly lower the quality of life in of themselves. Thus, it is important to recognize the presence of these disorders as part of the assessment of pain, and treat both conditions simultaneously. This paper outlines the salient features of the most common forms of psychopathology in cancer patients and their treatment. © 2005 Elsevier Inc. All rights reserved.
Psychopathology is a common comorbidity in patients with all forms of cancer. Delirium is the most common neuropsychiatric disturbance, and almost all cancer patients will have had at least one episode of delirium during their oncological illness, particularly in the last weeks of life.1 Depression and anxiety disorders are the next most common with a prevalence rate of 30% to 50%.2 These disorders significantly interact with the treatment of cancer pain. Opioids are one of the most frequent causes of delirium,3 and depression and anxiety disorders can be precipitated or exacerbated by poorly controlled pain, as well as worsening pain treatment outcome.4,5 Interestingly, the severity of physical symptoms shows a poor correlation to the wish to die, but psychopathology is strongly correlated to a patient’s desire to hasten death.6 Unfortunately, the mistaken belief that delirium, depression, and anxiety are nothing more than natural and understandable reactions to incurable illness fuels an under-recognition and under-treatment of this reversible suffering.7 Thus, it behooves the astute pain physician to have an understanding of the psychiatric disorders afflicting patients with cancer. This discussion will provide an overview of the symptoms and treatment of delirium, depression, and anxiety disorders in cancer patients. Address reprint requests and correspondence: Ajay D. Wasan, MD, MSc, Pain Management Center, 850 Boylston Street, Suite 320, Chestnut Hill, MA 02467. E-mail address: [email protected]. 1084-208X/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.trap.2005.06.006
Delirium Historically, delirium was thought to be the inevitable consequence of end stage disease.8 But while it is expected toward the end of life, it is reversible in up to 50% of cases and usually reversible completely in those with longer life expectancies.9 Patients and their families suffer tremendously during delirious episodes, and both groups rate these periods as “extremely distressing.” Up to 50% of patients do in fact remember their delirium, and decision making is greatly impaired during the episode.1 Even in episodes near the end of life, if reversible, the patient may still have many months of good quality of life and the ability to communicate with loved ones and express their needs. Thus, it is best to approach all episodes of delirium as potentially reversible, regardless of the proximity to death. The hallmark symptom of delirium is a disturbance of consciousness: a disturbance of awareness of the environment with a reduced ability to focus, sustain, or shift attention.10 This represents a global disruption of the brain’s function, which is more pronounced in the locus ceruleus, a key subcortical brain area mediating attention and arousal. Delirium is typically described as a waxing and waning level of alertness. Patients are frequently disoriented, hallucinating or paranoid, have impaired short-term memory, disturbed sleep (drowsy by day, insomnia at night), impaired judgment, and altered mood (excited or depressed). Delirium can be either hyperactive with prominent symp-
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Table 1
Delirium etiologies
Primary brain tumor Metastases Hypoxia Electrolyte imbalance Withdrawal states (alcohol, benzodiazepines, opioids, nicotine) Drugs (steroids, opioids, anticholinergics, antiemetics, anxiolytics, antidepressants, anticonvulsants, NSAIDS) Infection/Sepsis Nutritional deficiencies (Wernicke’s encephalopathy) DIC, bleeding (subdural hematoma) Endocrine disorders Urinary retention Pain
toms of agitation, hallucinations, and myoclonus, or hypoactive with symptoms of somnolence and withdrawal.4 In evaluating symptoms suspicious for delirium it is important to distinguish delirium from dementia. While these conditions can present with the same symptoms of confusion, disorientation, and forgetfulness, dementia is a chronic condition with enduring symptoms, worsening typically over a period of time, and not reversible. Delirium on the other hand, presents as an acute disruption of the level of consciousness with greater fluctuation of symptoms during the day. It is very easy to confuse a hypoactive delirium with either a normal mental state or depression. Fluctuations in the level of alertness can help distinguish it from normal mentation, and not weeping or expressing hopelessness can distinguish it from depression. It can also be difficult to distinguish delirium from uncontrolled pain because moaning, restlessness, and writhing movements are common to both conditions. A concurrent delirium makes it difficult to manage uncontrolled pain, so it is wise to continually be aware of any delirious symptoms in patients and address them as a priority. Uncontrolled pain by itself is rarely a cause of delirium. The mental state is best assessed by clinical examination and the use of a standardized measure, such as the Mini Mental State Examination (MMSE), one of the most frequently used instruments, with high validity and sensitivity to change.3,11 This is a 30-item survey of orientation, memory, calculation skills, and the ability to follow commands, which is easily administered by any trained provider in 5 to 10 minutes. Normative scores are available for educational level and age. In general, a score below 25 raises the suspicion for dementia or delirium, and a score below 20 definitely indicates a neuropsychiatric disturbance. Possible etiologies for delirium are presented in Table 1. Specific causes for delirium are not determined in up to 75% of cases,12 and most cases of delirium are multifactorial. But, the most prevalent reversible causes are opioid toxicity, dehydration, and electrolyte imbalances (for example, hypercalcemia).9 The treatment approach is outlined in Table 2 and can be summarized as searching for the underlying cause, correction of those factors, and management of the symptoms. None of the measures actually “treats” delirium. Rather, they provide symptomatic relief until the brain’s normal function returns. In episodes caused or exacerbated by opioids, switching opioids almost always resolves the
confusional state.12 Studies of palliative care units have found that the incidence of delirium can be reduced by two thirds through instituting three easy measures: (1) use a scale to assess symptoms, (2) hydrate patients adequately, and (3) rotate opioids.3 Haloperidol is the neuroleptic most frequently used in the management delirium because it is one of the few antipsychotics that can be administered orally, subcutaneously, or intravenously. It is effective in diminishing agitation, hallucinations, and paranoia, as well as improving sleep and cognition. There are risks of extrapyramidal side effects such as Parkinsonian tremor and cogwheel rigidity, which can be improved by anticholinergic agents, such as diphenhydramine (10-50 mg, PO/IM/ IV, Q6 hours prn) or benztropine (Cogentin, 1-4 mg PO/ IM/IV twice per day prn). Caution must be heeded in using these agents because their anticholinergic side effects can worsen a delirium. Of the atypical antipsychotics, olanzapine and risperidone are now available in rapidly acting, sublingual forms, and thus are quickly becoming the agents of choice due to their improved side effect profile. Benzodiazepines can be helpful in improving agitation, but they will have minimal effect on psychotic symptoms. Particularly in older patients, benzodiazepines may be disinhibiting and a paradoxical worsening of agitation or confusion may occur. If they are used, it is best to use them in conjunction with an antipsychotic. In episodes near the end of life, 10% to 20% of patients with delirium can be controlled only by deep sedation.
Depression and anxiety disorders A comorbid depression or anxiety disorder afflicts 30% to 50% of cancer patients.2 These patients frequently have a mixture of anxious and depressive symptoms, and as a whole, these disturbances are termed affective disorders. An affective disorder can present as a more minor form which may be transient or enduring (an adjustment disorder with anxious or depressive symptoms), or as more significant psychopathology, such as a major depression, generalized anxiety disorder, or posttraumatic stress disorder.10 There is fluidity in these categories and patients can present initially
Table 2
Delirium treatment
Withhold “deliriogenic” medications Hydrate Rotate opioids Address withdrawal states Medication: Haloperidol Atypical antipsychotics Benzodiazepines if in combination with antipsychotics Environment: Safe physical environment Guard against wandering, unassisted ambulation if frail Consider a sitter Quiet and well-lighted room Minimize disturbances Repeated reassurance Physical restraint as a last resort Educate family that confusion is an organic disease
Wasan et al
Delirium, Depression, and Anxiety
with an adjustment disorder that may worsen over time to become a major psychiatric illness. Psychopathology preexisting to the cancer diagnosis may intensify as the medical symptoms worsen or the patient approaches death. While one might think that the diagnosis of cancer may induce only temporary affective symptoms, this is seldom the case and psychopathology is likely to persist.13 Multiple studies have confirmed the prevalence of comorbid psychopathology in cancer patients.14-18 They indicate that adjustment disorders are present in 10% to 30% of patients and a major depression or a generalized anxiety disorder in 10% to 20% of those studied. Several factors specific to cancer predispose patients to developing psychopathology. These include: reactions to the meanings of a cancer diagnosis (such as the loss of independence or the possibility of an early death), younger age, the severity of physical symptoms (ie, pain, breathlessness, fatigue), poor social support from family or friends, and functional impairment.7 A prior history or family history of psychiatric illness is a general factor which place anyone at greater risk for mental health difficulties. Poorly managed pain, in particular, is uniquely associated with a significantly elevated risk of developing a comorbid adjustment disorder or major depression.19 Pain both induces psychopathology and is amplified by it; that is, once a patient develops psychiatric illness in the context of poorly managed pain, it is much more difficult or even impossible to adequately control pain. Major depression, high anxiety, and overall levels of emotional distress have each been shown to be predictive of higher opioid requirements to achieve the same level of analgesia, compared with cancer pain patients with fewer psychiatric symptoms.20,21 This “positive feedback mechanism” is another reason to encourage a physician’s vigilance toward psychiatric symptoms in the evaluation of cancer pain. While effective pain treatment may significantly improve an adjustment disorder, it is unlikely by itself to cause a major depression or a generalized anxiety disorder to go into remission. In conjunction with history and mental status examination, the assessment of depression or anxiety symptoms is enhanced through the use of a standardized scale. One of the most frequently used in cancer patients is the Hospital Anxiety and Depression Scale.2,13 This 14-item scale is specific to the assessment of symptoms in patients with medical illness and is constructed to account for somatic symptoms due to medical illness. Generally, a score above 9 on either the depression or anxiety subscale is consistent with major depression or a generalized anxiety disorder.22
Depression The diagnosis of an adjustment disorder with depressed mood or a major depression is complicated by many overlapping symptoms in cancer or side effects of its treatment: fatigue, poor appetite, disrupted sleep, or normal grieving.21,23 The challenge for pain physicians, oncologists, psychiatrists, and any other care providers is to determine when psychological or somatic symptoms cannot be explained by medical illness or medical treatment alone, and thus may be caused or amplified by comorbid psychopathology. Given the high prevalence of psychiatric comor-
141 bidity in cancer patients and even more so in those with poorly controlled pain, it is best to have a low threshold for psychiatric evaluation and treatment.2 Even seemingly minor psychological disturbances deserve attention, such as strong emotional reactions during the doctor–patient visit or just the sense that the patient is having difficulty coping with cancer. Discussions with family members are crucial to determine the intensity and duration of symptoms, and if they have changed over time. In inpatient or outpatient cancer treatment settings, where there is a social worker, concerned nurse, or a palliative care team, these issues and symptoms can be elucidated before deciding to obtain a psychiatric consultation. Major depression can be distinguished from situational depression (also termed demoralization or an adjustment disorder with depressed mood), by the triad of persistently low mood, self attitude changes, and changes in vital sense, all lasting at least 2 weeks.10 Low mood refers to feelings of sadness and depression, which are frequently accompanied by tearfulness, anger, or irritability. Anhedonia, the inability to experience pleasure, is a key indicator of low mood. A diminished self-attitude is seen in patients who have thoughts of guilt or thinking that they are a bad person, spouse, or parent. Changes in vital sense refer to changes in sleep, appetite, or energy levels. These are often disrupted in patients with cancer and it is difficult whether to attribute these symptoms to psychological or medical causes. Cancer patients with major depression often feel that their thinking is slow or fuzzy and have difficulty concentrating.24 While unusual, depression can become so severe that patients become paranoid, delusional, or hallucinate (a psychotic depression). More commonly, depressed patients feel anxious, have panic attacks, or PTSD symptoms. If these symptoms occur in the presence of significant depression symptoms, they are consistent with a major depressive disorder, not a separate anxiety disorder. Depression symptoms may present as Beck’s triad, with patients feeling hopeless, hapless, and helpless.25 They see the future as bleak, they feel they cannot help themselves, and no one can help them. Hopelessness in cancer patients must be contextualized. It may be normal for patients to be hopeless about their prognosis, meaning they recognize that they will die from this disease. But it is not normal for patients to have a hopeless cognitive style.18 Patients coping appropriately with cancer feel that the time they have left is valuable, rewarding, enjoyable, and that their life has meaning up until the end. Thoughts about death reflect the severity of depression symptoms and distinctions must be made among fleeting thoughts that life is not worth living, daily thoughts that you wish you were dead (passive death wish), pervasive thoughts that you want to kill yourself (suicidal thoughts), and suicidal thoughts with a plan (suicidal intent). Chochinov and coworkers found that thoughts about death occur in up to 45% of terminally ill patients with cancer, and 8.5% had a passive death wish or suicidal thoughts.26 Interestingly, this group found that the desire to die is most significantly correlated with depression symptoms and much less correlated to the intensity of physical symptoms, such as pain. This work suggests that, while it may be reasonable to question whether life is worth living having been diagnosed with cancer, more significant thoughts about dying should
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prompt concern about a comorbid depression illness. It also questions whether the wish to die is a reasonable choice or one influenced by treatable psychopathology. As noted, identifying and classifying depression symptoms in cancer patients can be quite intricate. Fortunately, Chochinov and coworkers have found that the answers to two questions can correctly identify a case of major depression 86% of the time: (1) Are you depressed? And (2) Are there things you enjoy? This study points to the hallmark symptoms of depression being low mood and anhedonia.27 The ease of these screening questions means that any health provider can quickly get a sense of whether a patient is depressed. In treating depression, the first task is determining whether there is an underlying cause or a factor that can be modified which will improve depression symptoms.4 These include: metabolic abnormalities, sepsis, tumors of the central nervous system, radiation to the brain, constipation, and pain. Medications such as chemotherapeutic agents, opioids, and steroids can precipitate depression symptoms, which is termed “substance induced mood disorder.” Mood can improve if these agents are discontinued or significantly decreased. Because a large number of cancer patients have taken these medications, it may be difficult to assess whether use of these drugs is a factor in provoking depression. Depression is most successfully treated with both medications and psychotherapy, similar to the treatment approach in noncancer patients.28 Depression symptoms, including the wish to die,26 significantly improve with treatment in cancer patients.21 Significantly, treatment of depression improves survival time and immune function.21 Selective serotonin reuptake inhibitors (SSRIs) have shown efficacy in treating depression in patients with cancer,29 and up to 80% of cancer patients have shown a response to some medication.23 Psychological treatments are also particularly effective,23 and several methods specific to treatment of depression in cancer have been developed: spiritually centered therapy, supportive group therapy, cognitive restructuring, and coping skills training.21,30
Anxiety disorders In patients with cancer, anxiety may first appear at the time of a life-threatening diagnosis. Reactions can range from mild apprehension to even terror. Physical reactions at the time of diagnosis may include diaphoresis, dyspnea, lightheadedness, and tachycardia.4 Most patients learn to cope with their illness, but as cancer progresses, its treatments have more side effects and pain intensifies, approximately 30% of all patients will develop an anxiety disorder, most commonly either an adjustment disorder with anxiety or a generalized anxiety disorder.13 Unrelieved pain is highly correlated to the development of anxiety symptoms.31 Anxiety and worry in family members, as well, is an important aggravating factor. Other causes include medications that can provoke restlessness and agitation, such as corticosteroids, bronchodilators, and antihistamines. Withdrawal from alcohol, nicotine, benzodiazepines, and opioids may be involved. Medical conditions, such as hypoxia,
Table 3
Anxiety symptoms
Psychological Worry, apprehension Feeling wound up, “uptight,” restless, or tense Difficulty concentrating Irritable Excessively fearful of pain Unable to relax Motor Tension Muscle tightness Muscle cramps or abdominal cramps Trembling Restless Tension headache Autonomic Shortness of breath Palpitations, chest pain Lightheaded, dizzy Sweating Dry mouth Nausea or diarrhea Urinary frequency Difficulty sleeping
sepsis, thyroid abnormalities, and hypoglycemia, can produce anxiety. Anxiety symptoms can be grouped into three categories, which are outlined in Table 3 (adapted from Barraclough, 1997):7 psychological, motor tension, and autonomic symptoms. It is difficult to determine when anxiety is pathological, but one guideline for diagnosing pathological anxiety is that which interferes with normal functioning. Two types of anxiety are trait anxiety and situational anxiety. Trait anxiety is marked by excessive worry and concern, often about routine matters. The amount of worry and anxiety is out of proportion to the likelihood of the negative consequences occurring, and the patient has great difficulty controlling worry. In cancer pain patients, situational anxiety presents as anxiety about a worsening prognosis, medical condition, or pain and its negative consequences. Patients may be conditioned to be excessively fearful that activities will cause uncontrollable pain, causing avoidance of those activities, which in some patients can be extreme and almost phobic. Pain may also activate thoughts in patients that they are seriously ill,32 compounding their sense of fragility and despair. Anxiety amplifies pain perception and pain complaints through several biopsychosocial mechanisms, including sympathetic arousal with noradrenergically mediated lowering of nociceptive thresholds, increased firing of ectopically active pain neurons, excessive cognitive focus on pain symptoms, and poor coping skills. Patients with pathological anxiety are often restless, fatigued, irritable, and have poor concentration. They may have muscle tension and sleep disturbances. Their mood is often low, but not at the severity level found in major depression.33 Patients can have an acute anxiety or panic attack, either with or without a clear inciting event, which signals that there is likely an underlying anxiety disorder. Acute attacks can have a sudden or gradual onset and are characterized by fear, dyspnea, lightheadedness, tachycardia, perioral numbness, or gastrointestinal cramps. It is important to include anxiety in the differential diagnosis of these symptoms.
Wasan et al
Delirium, Depression, and Anxiety
In addition to seeking and treating an underlying cause or aggravating factor, treatment of anxiety includes pharmacological and psychological approaches. Initial stabilization of anxiety can be achieved with benzodiazepines. Long-acting forms are preferred (such as clonazepam) to avoid the rebound anxiety that is associated with short-acting forms (such as alprazolam and midazolam).28 Short-acting agents are preferred for the treatment of acute anxiety or panic attacks. After 1 to 2 months of improvement in anxiety symptoms, benzodiazepines should be tapered. Abrupt discontinuation can produce withdrawal, or even seizures. The elderly may require very gradual tapers over the course of 1 to 3 months. Concurrently, patients may also have therapy started using antidepressants, which typically require 4 to 6 weeks at the target dose before improvement is seen. Effective doses are generally higher than what are used in the treatment of major depression. Of the antidepressants, SSRIs are some of the most efficacious agents, but escalation to the target dose must be gradual because an exacerbation of anxiety may be one of the side effects. Selective noradrenergic reuptake inhibitors (SNRIs), such as venlafaxine, also have good antianxiety properties. One advantage of using this medication class is that at higher doses there are significant norepinephrine reuptake properties (similar to tricyclic antidepressants), which have been shown to reduce symptoms of neuropathic pain.34 Psychological approaches are also particularly effective in the treatment of anxiety.4 Biofeedback and relaxation therapy are mainstays of treatment, and cognitive behavioral therapy (CBT) is the most effective psychotherapeutic approach. CBT examines automatic thoughts that arise in conjunction with anxious feelings or somatic anxiety symptoms. For instance, a therapist can help a patient identify that thoughts such as “increased pain represents tissue damage” or a worsening prognosis are automatic and may precede anxious feelings. The patient can be taught how to recognize these types of maladaptive, automatic thoughts, and then learn how to break the connection between these misperceptions and anxiety feelings or bodily symptoms.
Conclusions Attention to mental health is a cornerstone of palliative care treatment. Cancer patients in general, and cancer pain patients, in particular, suffer from a high rate of neuropsychiatric comorbidity. The most common conditions are delirium, depression, and anxiety disorders. These illnesses are highly treatable and easily identifiable. Prompt recognition alleviates the suffering of both the patient and their loved ones. Treatment of psychiatric illness also improves perceptions of pain and enhances the quality of life for many of these patients.
References 1. Lawlor PG, Gagnon B, Mancini IL, et al: Occurrence, causes, and outcome of delirium in patients with advanced cancer: a prospective study. Arch Intern Med 160:786-794, 2000
143 2. Akechi T, Okuyama T, Sugawara Y, et al: Major depression, adjustment disorders, and post-traumatic stress disorder in terminally ill cancer patients: associated and predictive factors. J Clin Oncol 22: 1957-1965, 2004 3. Bruera E, Franco JJ, Maltoni M, et al: Changing pattern of agitated mental status in patients with advanced cancer: association with cognitive monitoring, hydration, and opioid rotation. J Pain Symp Manage 10:287-291, 1995 4. Paice JA: Managing psychological conditions in palliative care: dying need not mean enduring uncontrollable anxiety, depression, or delirium. Am J Nurs 102:36-42, 2002 5. Akechi T, Okamura H, Nishiwaki Y, et al: Psychiatric disorders and associated and predictive factors in patients with unresectable nonsmall cell lung carcinoma: a longitudinal study. Cancer 92:2609-2622, 2001 6. Kelly B, Burnett P, Pelusi D, et al: Factors associated with the wish to hasten death: a study of patients with terminal illness. Psychol Med 33:75-81, 2003 7. Barraclough J: ABC of palliative care: depression, anxiety, and confusion. Br Med J 315:1365-1368, 1997 8. Portenoy RK: Critical issues in the assessment of delirium, in Portenoy RK, Bruera E (eds): Topics in Palliative Care. New York, NY, Oxford University Press, 1997, pp 3-5 9. Lawlor PG, Gagnon B, Mancini IL, et al: Clinical and ethical questions concerning delirium study on patients with advanced cancer. Arch Intern Med 161:296-297, 2001 10. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders (ed 4). Washington DC, American Psychiatric Association, 1994 11. Folstein MF, Folstein S, McHugh P: Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychosom Res 12:189-198, 1975 12. Maddocks I, Somogyi A, Abbott F, et al: Attenuation of morphineinduced delirium in palliative care by substitution with infusion of oxycodone. J Pain Sympt Manage 12:182-189, 1996 13. Hopwood P, Stephens RJ: Depression in patients with lung cancer: prevalence and risk factors derived from quality-of-life data. J Clin Oncol 18:893-903, 2000 14. Okamura H, Watanabe T, Narabayashi M: Psychological distress following first recurrence of disease in patients with breast cancer: prevalence and risk factors. Breast Cancer Res Treat 61:131-137, 2000 15. Chochinov HM, Wilson KG, Enns M: Prevalence of depression in the terminally ill: effects of diagnostic criteria and symptoms threshold adjustments. Am J Psych 151:537-540, 1994 16. Fevre PL, Devereux J, Smith S: Screening for psychiatric illness in the palliative care inpatient setting: a comparison between the hostile anxiety and depression scale and the general health questionnaire-12. Palliative Med 13:399-407, 1999 17. Williams ML, Friedman T, Rudd N: And analysis of the validity of the hospital anxiety and depression scale as a screening tool in patients with advanced metastatic cancer. J Pain Sympt Manage 22:990-996, 2001 18. Breitbart W, Rosenfeld B, Pessin H, et al: Depression, hopelessness, and desire for hastened death in terminally ill patients with cancer. J Am Med Assoc 284:2907-2911, 2000 19. Spiegel D: Healthcare caring: psychosocial support for patients with cancer. Cancer 74:1453-1457, 1994 (suppl) 20. Portenoy R, Payne D, Jacobsen P: Breakthrough pain: characteristics and impact in patients with cancer pain. Pain 81:129-134, 1999 21. Speigel D: Cancer and depression. Br J Psych 168:109-116, 1996 22. Bjelland I, Dahl AA, Huag TT, et al: The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J Psychosom Res 52:69-77, 2002 23. Block SD: Assessing and managing depression in the terminally ill patient. ACP-ASIM End-of-Life Care Consensus Panel. American College of Physicians–American Society of Internal Medicine. Ann Intern Med 132:209-218, 2000 24. Grassi L, Indelli M, Marzola M, et al: Depressive symptoms and quality of life in home-care-assisted cancer patients. J Pain Sympt Manage 12:300-307, 1996 25. Alford BA, Lester JM, Patel RJ, et al: Hopelessness predicts future depressive symptoms: a prospective analysis of cognitive vulnerability and cognitive content specificity. J Clin Psychol 51:331-339, 1995 26. Chochinov HM, Wilson KG, Enns M, et al: Desire for death in the terminally ill. Am J Psychiatry 152:1185-1191, 1995
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27. Chochinov HM, Wilson KG, Enns M, et al: Are you depressed? Screening for depression in the terminally ill. Am J Psychiatry 154:674-676, 1997 28. Wasan AD, Gallagher RM: Psychopharmacology for pain medicine, in Benzon HT, Raja SN, Molloy RE, et al. (eds): Essestials of Pain Medicine and Regional Anesthesia. Philadelphia, PA, Elsevier, 2005, pp 124-133 29. Fisch MJ, Loehrer PJ, Kristeller J, et al: Fluoxetine versus placeo in advanced cancer outpatients: a double-blinded trial of the Hoosier Oncology Group. J Clin Oncol 21:1937-1943, 2003 30. Breitbart W, Gibson C, Poppito SR, et al: Psychotherapeutic Inteventions at the end of life: a focus on meaning and spirituality. Can J Psych 49:366-372, 2004
31. Payne DK, Massie MJ: Anxiety in palliative care, in Chochinov HM, Breitbart W (eds): Handbook of Psychiatry in Palliative Medicine. New York, NY, Oxford University Press, 2000, pp 63-74 32. McCracken L, Gross R, Aikens J, et al: The assessment of anxiety and fear in persons with chronic pain: a comparison of instruments. Behav Res Ther 34:927-933, 1996 33. Verma S, Gallagher RM: The psychopharmacologic treatment of depression and anxiety in the context of chronic pain. Curr Pain Headache Rep 6:30-39, 2002 34. Sindrup SH, Bach FW, Masdsen C, et al: Venlafaxine versus imipramine in painful neuropathy: a randomized, controlled trial. Neurology 60:1284-1289, 2003
Delirium, depression, and anxiety in the treatment of cancer pain Ajay D. Wasan, MD, MSc,a,b Mikhail Artamonov, MD,a Srdjan S. Nedeljkovic, MDa a
From the Departments of Anesthesiology, Perioperative and Pain Medicine; and Psychiatry, Brigham and Women’s Hospital/Harvard Medical School, Boston, Massachusetts.
b
KEYWORDS: Delirium; Depression; Anxiety; Cancer; Pain; Treatment 3
Neuropsychiatric disturbances are common in cancer patients. These occur in patients with and without pain, but at a much higher rate in those with pain. The most frequent pathologies are delirium, depression disorders, and anxiety disorders. Poorly treated pain can precipitate or exacerbate these disorders. It is difficult or impossible to obtain satisfactory pain relief in cancer patients with comorbid psychopathology, and these disorders significantly lower the quality of life in of themselves. Thus, it is important to recognize the presence of these disorders as part of the assessment of pain, and treat both conditions simultaneously. This paper outlines the salient features of the most common forms of psychopathology in cancer patients and their treatment. © 2005 Elsevier Inc. All rights reserved.
Psychopathology is a common comorbidity in patients with all forms of cancer. Delirium is the most common neuropsychiatric disturbance, and almost all cancer patients will have had at least one episode of delirium during their oncological illness, particularly in the last weeks of life.1 Depression and anxiety disorders are the next most common with a prevalence rate of 30% to 50%.2 These disorders significantly interact with the treatment of cancer pain. Opioids are one of the most frequent causes of delirium,3 and depression and anxiety disorders can be precipitated or exacerbated by poorly controlled pain, as well as worsening pain treatment outcome.4,5 Interestingly, the severity of physical symptoms shows a poor correlation to the wish to die, but psychopathology is strongly correlated to a patient’s desire to hasten death.6 Unfortunately, the mistaken belief that delirium, depression, and anxiety are nothing more than natural and understandable reactions to incurable illness fuels an under-recognition and under-treatment of this reversible suffering.7 Thus, it behooves the astute pain physician to have an understanding of the psychiatric disorders afflicting patients with cancer. This discussion will provide an overview of the symptoms and treatment of delirium, depression, and anxiety disorders in cancer patients. Address reprint requests and correspondence: Ajay D. Wasan, MD, MSc, Pain Management Center, 850 Boylston Street, Suite 320, Chestnut Hill, MA 02467. E-mail address: [email protected]. 1084-208X/$ -see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1053/j.trap.2005.06.006
Delirium Historically, delirium was thought to be the inevitable consequence of end stage disease.8 But while it is expected toward the end of life, it is reversible in up to 50% of cases and usually reversible completely in those with longer life expectancies.9 Patients and their families suffer tremendously during delirious episodes, and both groups rate these periods as “extremely distressing.” Up to 50% of patients do in fact remember their delirium, and decision making is greatly impaired during the episode.1 Even in episodes near the end of life, if reversible, the patient may still have many months of good quality of life and the ability to communicate with loved ones and express their needs. Thus, it is best to approach all episodes of delirium as potentially reversible, regardless of the proximity to death. The hallmark symptom of delirium is a disturbance of consciousness: a disturbance of awareness of the environment with a reduced ability to focus, sustain, or shift attention.10 This represents a global disruption of the brain’s function, which is more pronounced in the locus ceruleus, a key subcortical brain area mediating attention and arousal. Delirium is typically described as a waxing and waning level of alertness. Patients are frequently disoriented, hallucinating or paranoid, have impaired short-term memory, disturbed sleep (drowsy by day, insomnia at night), impaired judgment, and altered mood (excited or depressed). Delirium can be either hyperactive with prominent symp-
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Table 1
Delirium etiologies
Primary brain tumor Metastases Hypoxia Electrolyte imbalance Withdrawal states (alcohol, benzodiazepines, opioids, nicotine) Drugs (steroids, opioids, anticholinergics, antiemetics, anxiolytics, antidepressants, anticonvulsants, NSAIDS) Infection/Sepsis Nutritional deficiencies (Wernicke’s encephalopathy) DIC, bleeding (subdural hematoma) Endocrine disorders Urinary retention Pain
toms of agitation, hallucinations, and myoclonus, or hypoactive with symptoms of somnolence and withdrawal.4 In evaluating symptoms suspicious for delirium it is important to distinguish delirium from dementia. While these conditions can present with the same symptoms of confusion, disorientation, and forgetfulness, dementia is a chronic condition with enduring symptoms, worsening typically over a period of time, and not reversible. Delirium on the other hand, presents as an acute disruption of the level of consciousness with greater fluctuation of symptoms during the day. It is very easy to confuse a hypoactive delirium with either a normal mental state or depression. Fluctuations in the level of alertness can help distinguish it from normal mentation, and not weeping or expressing hopelessness can distinguish it from depression. It can also be difficult to distinguish delirium from uncontrolled pain because moaning, restlessness, and writhing movements are common to both conditions. A concurrent delirium makes it difficult to manage uncontrolled pain, so it is wise to continually be aware of any delirious symptoms in patients and address them as a priority. Uncontrolled pain by itself is rarely a cause of delirium. The mental state is best assessed by clinical examination and the use of a standardized measure, such as the Mini Mental State Examination (MMSE), one of the most frequently used instruments, with high validity and sensitivity to change.3,11 This is a 30-item survey of orientation, memory, calculation skills, and the ability to follow commands, which is easily administered by any trained provider in 5 to 10 minutes. Normative scores are available for educational level and age. In general, a score below 25 raises the suspicion for dementia or delirium, and a score below 20 definitely indicates a neuropsychiatric disturbance. Possible etiologies for delirium are presented in Table 1. Specific causes for delirium are not determined in up to 75% of cases,12 and most cases of delirium are multifactorial. But, the most prevalent reversible causes are opioid toxicity, dehydration, and electrolyte imbalances (for example, hypercalcemia).9 The treatment approach is outlined in Table 2 and can be summarized as searching for the underlying cause, correction of those factors, and management of the symptoms. None of the measures actually “treats” delirium. Rather, they provide symptomatic relief until the brain’s normal function returns. In episodes caused or exacerbated by opioids, switching opioids almost always resolves the
confusional state.12 Studies of palliative care units have found that the incidence of delirium can be reduced by two thirds through instituting three easy measures: (1) use a scale to assess symptoms, (2) hydrate patients adequately, and (3) rotate opioids.3 Haloperidol is the neuroleptic most frequently used in the management delirium because it is one of the few antipsychotics that can be administered orally, subcutaneously, or intravenously. It is effective in diminishing agitation, hallucinations, and paranoia, as well as improving sleep and cognition. There are risks of extrapyramidal side effects such as Parkinsonian tremor and cogwheel rigidity, which can be improved by anticholinergic agents, such as diphenhydramine (10-50 mg, PO/IM/ IV, Q6 hours prn) or benztropine (Cogentin, 1-4 mg PO/ IM/IV twice per day prn). Caution must be heeded in using these agents because their anticholinergic side effects can worsen a delirium. Of the atypical antipsychotics, olanzapine and risperidone are now available in rapidly acting, sublingual forms, and thus are quickly becoming the agents of choice due to their improved side effect profile. Benzodiazepines can be helpful in improving agitation, but they will have minimal effect on psychotic symptoms. Particularly in older patients, benzodiazepines may be disinhibiting and a paradoxical worsening of agitation or confusion may occur. If they are used, it is best to use them in conjunction with an antipsychotic. In episodes near the end of life, 10% to 20% of patients with delirium can be controlled only by deep sedation.
Depression and anxiety disorders A comorbid depression or anxiety disorder afflicts 30% to 50% of cancer patients.2 These patients frequently have a mixture of anxious and depressive symptoms, and as a whole, these disturbances are termed affective disorders. An affective disorder can present as a more minor form which may be transient or enduring (an adjustment disorder with anxious or depressive symptoms), or as more significant psychopathology, such as a major depression, generalized anxiety disorder, or posttraumatic stress disorder.10 There is fluidity in these categories and patients can present initially
Table 2
Delirium treatment
Withhold “deliriogenic” medications Hydrate Rotate opioids Address withdrawal states Medication: Haloperidol Atypical antipsychotics Benzodiazepines if in combination with antipsychotics Environment: Safe physical environment Guard against wandering, unassisted ambulation if frail Consider a sitter Quiet and well-lighted room Minimize disturbances Repeated reassurance Physical restraint as a last resort Educate family that confusion is an organic disease
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with an adjustment disorder that may worsen over time to become a major psychiatric illness. Psychopathology preexisting to the cancer diagnosis may intensify as the medical symptoms worsen or the patient approaches death. While one might think that the diagnosis of cancer may induce only temporary affective symptoms, this is seldom the case and psychopathology is likely to persist.13 Multiple studies have confirmed the prevalence of comorbid psychopathology in cancer patients.14-18 They indicate that adjustment disorders are present in 10% to 30% of patients and a major depression or a generalized anxiety disorder in 10% to 20% of those studied. Several factors specific to cancer predispose patients to developing psychopathology. These include: reactions to the meanings of a cancer diagnosis (such as the loss of independence or the possibility of an early death), younger age, the severity of physical symptoms (ie, pain, breathlessness, fatigue), poor social support from family or friends, and functional impairment.7 A prior history or family history of psychiatric illness is a general factor which place anyone at greater risk for mental health difficulties. Poorly managed pain, in particular, is uniquely associated with a significantly elevated risk of developing a comorbid adjustment disorder or major depression.19 Pain both induces psychopathology and is amplified by it; that is, once a patient develops psychiatric illness in the context of poorly managed pain, it is much more difficult or even impossible to adequately control pain. Major depression, high anxiety, and overall levels of emotional distress have each been shown to be predictive of higher opioid requirements to achieve the same level of analgesia, compared with cancer pain patients with fewer psychiatric symptoms.20,21 This “positive feedback mechanism” is another reason to encourage a physician’s vigilance toward psychiatric symptoms in the evaluation of cancer pain. While effective pain treatment may significantly improve an adjustment disorder, it is unlikely by itself to cause a major depression or a generalized anxiety disorder to go into remission. In conjunction with history and mental status examination, the assessment of depression or anxiety symptoms is enhanced through the use of a standardized scale. One of the most frequently used in cancer patients is the Hospital Anxiety and Depression Scale.2,13 This 14-item scale is specific to the assessment of symptoms in patients with medical illness and is constructed to account for somatic symptoms due to medical illness. Generally, a score above 9 on either the depression or anxiety subscale is consistent with major depression or a generalized anxiety disorder.22
Depression The diagnosis of an adjustment disorder with depressed mood or a major depression is complicated by many overlapping symptoms in cancer or side effects of its treatment: fatigue, poor appetite, disrupted sleep, or normal grieving.21,23 The challenge for pain physicians, oncologists, psychiatrists, and any other care providers is to determine when psychological or somatic symptoms cannot be explained by medical illness or medical treatment alone, and thus may be caused or amplified by comorbid psychopathology. Given the high prevalence of psychiatric comor-
141 bidity in cancer patients and even more so in those with poorly controlled pain, it is best to have a low threshold for psychiatric evaluation and treatment.2 Even seemingly minor psychological disturbances deserve attention, such as strong emotional reactions during the doctor–patient visit or just the sense that the patient is having difficulty coping with cancer. Discussions with family members are crucial to determine the intensity and duration of symptoms, and if they have changed over time. In inpatient or outpatient cancer treatment settings, where there is a social worker, concerned nurse, or a palliative care team, these issues and symptoms can be elucidated before deciding to obtain a psychiatric consultation. Major depression can be distinguished from situational depression (also termed demoralization or an adjustment disorder with depressed mood), by the triad of persistently low mood, self attitude changes, and changes in vital sense, all lasting at least 2 weeks.10 Low mood refers to feelings of sadness and depression, which are frequently accompanied by tearfulness, anger, or irritability. Anhedonia, the inability to experience pleasure, is a key indicator of low mood. A diminished self-attitude is seen in patients who have thoughts of guilt or thinking that they are a bad person, spouse, or parent. Changes in vital sense refer to changes in sleep, appetite, or energy levels. These are often disrupted in patients with cancer and it is difficult whether to attribute these symptoms to psychological or medical causes. Cancer patients with major depression often feel that their thinking is slow or fuzzy and have difficulty concentrating.24 While unusual, depression can become so severe that patients become paranoid, delusional, or hallucinate (a psychotic depression). More commonly, depressed patients feel anxious, have panic attacks, or PTSD symptoms. If these symptoms occur in the presence of significant depression symptoms, they are consistent with a major depressive disorder, not a separate anxiety disorder. Depression symptoms may present as Beck’s triad, with patients feeling hopeless, hapless, and helpless.25 They see the future as bleak, they feel they cannot help themselves, and no one can help them. Hopelessness in cancer patients must be contextualized. It may be normal for patients to be hopeless about their prognosis, meaning they recognize that they will die from this disease. But it is not normal for patients to have a hopeless cognitive style.18 Patients coping appropriately with cancer feel that the time they have left is valuable, rewarding, enjoyable, and that their life has meaning up until the end. Thoughts about death reflect the severity of depression symptoms and distinctions must be made among fleeting thoughts that life is not worth living, daily thoughts that you wish you were dead (passive death wish), pervasive thoughts that you want to kill yourself (suicidal thoughts), and suicidal thoughts with a plan (suicidal intent). Chochinov and coworkers found that thoughts about death occur in up to 45% of terminally ill patients with cancer, and 8.5% had a passive death wish or suicidal thoughts.26 Interestingly, this group found that the desire to die is most significantly correlated with depression symptoms and much less correlated to the intensity of physical symptoms, such as pain. This work suggests that, while it may be reasonable to question whether life is worth living having been diagnosed with cancer, more significant thoughts about dying should
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prompt concern about a comorbid depression illness. It also questions whether the wish to die is a reasonable choice or one influenced by treatable psychopathology. As noted, identifying and classifying depression symptoms in cancer patients can be quite intricate. Fortunately, Chochinov and coworkers have found that the answers to two questions can correctly identify a case of major depression 86% of the time: (1) Are you depressed? And (2) Are there things you enjoy? This study points to the hallmark symptoms of depression being low mood and anhedonia.27 The ease of these screening questions means that any health provider can quickly get a sense of whether a patient is depressed. In treating depression, the first task is determining whether there is an underlying cause or a factor that can be modified which will improve depression symptoms.4 These include: metabolic abnormalities, sepsis, tumors of the central nervous system, radiation to the brain, constipation, and pain. Medications such as chemotherapeutic agents, opioids, and steroids can precipitate depression symptoms, which is termed “substance induced mood disorder.” Mood can improve if these agents are discontinued or significantly decreased. Because a large number of cancer patients have taken these medications, it may be difficult to assess whether use of these drugs is a factor in provoking depression. Depression is most successfully treated with both medications and psychotherapy, similar to the treatment approach in noncancer patients.28 Depression symptoms, including the wish to die,26 significantly improve with treatment in cancer patients.21 Significantly, treatment of depression improves survival time and immune function.21 Selective serotonin reuptake inhibitors (SSRIs) have shown efficacy in treating depression in patients with cancer,29 and up to 80% of cancer patients have shown a response to some medication.23 Psychological treatments are also particularly effective,23 and several methods specific to treatment of depression in cancer have been developed: spiritually centered therapy, supportive group therapy, cognitive restructuring, and coping skills training.21,30
Anxiety disorders In patients with cancer, anxiety may first appear at the time of a life-threatening diagnosis. Reactions can range from mild apprehension to even terror. Physical reactions at the time of diagnosis may include diaphoresis, dyspnea, lightheadedness, and tachycardia.4 Most patients learn to cope with their illness, but as cancer progresses, its treatments have more side effects and pain intensifies, approximately 30% of all patients will develop an anxiety disorder, most commonly either an adjustment disorder with anxiety or a generalized anxiety disorder.13 Unrelieved pain is highly correlated to the development of anxiety symptoms.31 Anxiety and worry in family members, as well, is an important aggravating factor. Other causes include medications that can provoke restlessness and agitation, such as corticosteroids, bronchodilators, and antihistamines. Withdrawal from alcohol, nicotine, benzodiazepines, and opioids may be involved. Medical conditions, such as hypoxia,
Table 3
Anxiety symptoms
Psychological Worry, apprehension Feeling wound up, “uptight,” restless, or tense Difficulty concentrating Irritable Excessively fearful of pain Unable to relax Motor Tension Muscle tightness Muscle cramps or abdominal cramps Trembling Restless Tension headache Autonomic Shortness of breath Palpitations, chest pain Lightheaded, dizzy Sweating Dry mouth Nausea or diarrhea Urinary frequency Difficulty sleeping
sepsis, thyroid abnormalities, and hypoglycemia, can produce anxiety. Anxiety symptoms can be grouped into three categories, which are outlined in Table 3 (adapted from Barraclough, 1997):7 psychological, motor tension, and autonomic symptoms. It is difficult to determine when anxiety is pathological, but one guideline for diagnosing pathological anxiety is that which interferes with normal functioning. Two types of anxiety are trait anxiety and situational anxiety. Trait anxiety is marked by excessive worry and concern, often about routine matters. The amount of worry and anxiety is out of proportion to the likelihood of the negative consequences occurring, and the patient has great difficulty controlling worry. In cancer pain patients, situational anxiety presents as anxiety about a worsening prognosis, medical condition, or pain and its negative consequences. Patients may be conditioned to be excessively fearful that activities will cause uncontrollable pain, causing avoidance of those activities, which in some patients can be extreme and almost phobic. Pain may also activate thoughts in patients that they are seriously ill,32 compounding their sense of fragility and despair. Anxiety amplifies pain perception and pain complaints through several biopsychosocial mechanisms, including sympathetic arousal with noradrenergically mediated lowering of nociceptive thresholds, increased firing of ectopically active pain neurons, excessive cognitive focus on pain symptoms, and poor coping skills. Patients with pathological anxiety are often restless, fatigued, irritable, and have poor concentration. They may have muscle tension and sleep disturbances. Their mood is often low, but not at the severity level found in major depression.33 Patients can have an acute anxiety or panic attack, either with or without a clear inciting event, which signals that there is likely an underlying anxiety disorder. Acute attacks can have a sudden or gradual onset and are characterized by fear, dyspnea, lightheadedness, tachycardia, perioral numbness, or gastrointestinal cramps. It is important to include anxiety in the differential diagnosis of these symptoms.
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In addition to seeking and treating an underlying cause or aggravating factor, treatment of anxiety includes pharmacological and psychological approaches. Initial stabilization of anxiety can be achieved with benzodiazepines. Long-acting forms are preferred (such as clonazepam) to avoid the rebound anxiety that is associated with short-acting forms (such as alprazolam and midazolam).28 Short-acting agents are preferred for the treatment of acute anxiety or panic attacks. After 1 to 2 months of improvement in anxiety symptoms, benzodiazepines should be tapered. Abrupt discontinuation can produce withdrawal, or even seizures. The elderly may require very gradual tapers over the course of 1 to 3 months. Concurrently, patients may also have therapy started using antidepressants, which typically require 4 to 6 weeks at the target dose before improvement is seen. Effective doses are generally higher than what are used in the treatment of major depression. Of the antidepressants, SSRIs are some of the most efficacious agents, but escalation to the target dose must be gradual because an exacerbation of anxiety may be one of the side effects. Selective noradrenergic reuptake inhibitors (SNRIs), such as venlafaxine, also have good antianxiety properties. One advantage of using this medication class is that at higher doses there are significant norepinephrine reuptake properties (similar to tricyclic antidepressants), which have been shown to reduce symptoms of neuropathic pain.34 Psychological approaches are also particularly effective in the treatment of anxiety.4 Biofeedback and relaxation therapy are mainstays of treatment, and cognitive behavioral therapy (CBT) is the most effective psychotherapeutic approach. CBT examines automatic thoughts that arise in conjunction with anxious feelings or somatic anxiety symptoms. For instance, a therapist can help a patient identify that thoughts such as “increased pain represents tissue damage” or a worsening prognosis are automatic and may precede anxious feelings. The patient can be taught how to recognize these types of maladaptive, automatic thoughts, and then learn how to break the connection between these misperceptions and anxiety feelings or bodily symptoms.
Conclusions Attention to mental health is a cornerstone of palliative care treatment. Cancer patients in general, and cancer pain patients, in particular, suffer from a high rate of neuropsychiatric comorbidity. The most common conditions are delirium, depression, and anxiety disorders. These illnesses are highly treatable and easily identifiable. Prompt recognition alleviates the suffering of both the patient and their loved ones. Treatment of psychiatric illness also improves perceptions of pain and enhances the quality of life for many of these patients.
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31. Payne DK, Massie MJ: Anxiety in palliative care, in Chochinov HM, Breitbart W (eds): Handbook of Psychiatry in Palliative Medicine. New York, NY, Oxford University Press, 2000, pp 63-74 32. McCracken L, Gross R, Aikens J, et al: The assessment of anxiety and fear in persons with chronic pain: a comparison of instruments. Behav Res Ther 34:927-933, 1996 33. Verma S, Gallagher RM: The psychopharmacologic treatment of depression and anxiety in the context of chronic pain. Curr Pain Headache Rep 6:30-39, 2002 34. Sindrup SH, Bach FW, Masdsen C, et al: Venlafaxine versus imipramine in painful neuropathy: a randomized, controlled trial. Neurology 60:1284-1289, 2003