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Management of the
Dual-diagnosed Patient
Alan D. Valentine, MD
Address care of the cancer patient. Taken together, they can present
The University of Texas M.D. Anderson Cancer Center, Psychiatry even greater challenges, but also some opportunities in
Section, Department of Neuro-Oncology, 1515 Holcombe Blvd, attempts to palliate suffering and improve quality of life.
Unit 431, Houston, TX 77030, USA.
E-mail: avalenti@mdanderson.org
Current Pain and Headache Reports 2003, 7:262–269
Current Science Inc. ISSN 1531-3433 Depression in Cancer
Copyright © 2003 by Current Science Inc. Psychiatric illness is a common, but by no means obligate
part of the cancer experience. In the often-cited Psychoso-
Depressive disorders and pain syndromes are very com- cial Collaborative Oncology Group study of ambulatory
mon in the experience of cancer patients and may be expe- and hospitalized cancer patients [1], 47% met the criteria
rienced simultaneously. There is an intuitive association for a psychiatric disorder. Adjustment disorders with
between cancer pain and cancer depression, both of which depressive or anxious features and major depression were
are multidimensional entities. Research has suggested, but the diagnoses made most often (Table 1).
not conclusively proven a cause-effect relationship. Suicidal Depression is a term that has different meanings in differ-
ideation is a common concern in cancer patients with ent settings, ranging from the emotional state of sadness com-
severe depression or pain. Antidepressant therapy is a monly experienced in life, to a maladaptive psychologic
mainstay of management of depression. That some antide- response to a stressor (adjustment disorder, or reactive depres-
pressants have use in the management of cancer pain may sion; Table 2), to a persistent disorder with characteristic psy-
influence choice of drug selection in depressed patients. chologic and physical symptoms (major depression; Table 3)
Antidepressant side effects and the patient’s drug history [2]. Adjustment disorders with depressed mood and major
are relevant variables. Because antidepressants that are depression are associated with levels of distress that warrant
effective as coanalgesics may not be tolerated at doses intervention. In both of these depressive disorders, the patient
effective for depression, the clinician must be familiar with experiences significant dysphoria or anhedonia and often
newer classes of antidepressants and psychostimulants. other psychologic and physical symptoms.
Combination drug therapy may be required. Psychotherapy The 1-month prevalence of major depression in the gen-
also is common to the treatment of cancer pain and eral population has been estimated to be between 1.8% and
depression. With or without the intervention of pain and 4.9% [3]. The reported prevalence of major depression in can-
mental health specialists, ongoing supportive therapy from cer patients varies from less than 5% to more than 50% [4].
the primary clinician is essential. Many factors appear to contribute to differences in preva-
lence. In their review, DeFlorio and Massie [4] attributed most
of the variance to differences in study methodology and diag-
nostic criteria. Higher rates of depression generally are seen in
Introduction studies using less stringent diagnostic criteria. Other factors
Cancer, with notable exceptions, is not a curable disease. influencing prevalence include use of observer v self-report
However, with commitment of massive effort and resources, rating scales and the sensitivity and specificity of those scales.
remarkable progress is being made such that is reasonable to Increased rates of depression are seen with advanced disease
begin to look at cancer as a chronic disease that patients may [1,5–7], decreased performance status [7], and with involve-
expect to live with for years while curative therapies are being ment of different organ systems and treatment modalities (eg,
developed. It follows that patients may expect to live longer interferon, corticosteroids). In the discussion that follows, the
with morbidities associated with the disorder. There is an influence of pain on cancer-related depression is developed in
intuitive relationship between cancer pain and depression, detail. When all of the factors are considered, Massie and Pop-
each of which would reasonably exacerbate the other. Taken kin [8] have concluded that approximately 25% of all cancer
by themselves, each is a major obstacle to effective supportive patients experience significant depression.
Cancer Pain and Depression: Management of the Dual-diagnosed Patient • Valentine 263
Table 1. Rates of Diagnostic and Statistical Manual-III psychiatric disorders and prevalence of pain observed
in 215 patients with cancer from three cancer centers*
Patients with
Diagnostic class significant pain
Psychiatric
Diagnostic category n % diagnoses, % n %
Adjustment disorders 69 32 68 N/A N/A
Major affective disorders 13 6 13 N/A N/A
Organic mental disorders 8 4 8 N/A N/A
Personality disorders 7 3 7 N/A N/A
Anxiety disorders 4 2 4 N/A N/A
Total with psychiatric diagnoses 101 47 N/A 39 39
Total with no psychiatric diagnoses 114 53 N/A 21 19
Total patient population 215 100 N/A 60 28
*Score higher than 50 mm on a 100-mm visual analogue scale for pain severity.
Adapted from Deragotis et al. [1] and Breitbart and Passik [19], with permission.
more with activity and mood than did nondepressed Although study designs, assessment instruments, and
patients. Depression also did not predict response to study results have not been consistent, the evidence for the
treatment of pain. Using research diagnostic criteria, existence of a relationship between cancer pain and depres-
Spiegel et al. [20] found higher rates of depressive disor- sion is sufficient to suggest that clinicians should always
ders and anxiety, but a significantly lower history of consider pain as a contributing factor in the depressed can-
depression in patients with severe pain than in those cer patient. The possible presence of depression (and psy-
with less severe pain, suggesting a relationship in which chologic distress in general) should always be considered
pain is more likely to cause depression than the con- in a cancer patient in pain.
verse. Ciaramella and Poli [21] found increased rates of
depression in pain patients compared with those not in
pain, but they found increased intensity of pain (using a Management
visual analog scale) in those who were depressed. The cancer patient who is depressed and in pain can
Depressed patients did not have higher lifetime rates of present significant management challenges. Some difficul-
depression, leading to an argument for pain as the more ties are practical, others may be more philosophic.
causal entity [21]. Although the goal of adequate pain relief for all cancer
Spiegel and Bloom [22] found that level of mood distur- patients has not been achieved, few would argue that the
bance, use of analgesics, and belief about the meaning of goal is inappropriate. With regard to depression, this may
pain were major factors contributing to variance in pain not be the case. Some clinicians assume that depression is
experienced by women with metastatic breast cancer. a “normal” part of the cancer experience and thus need not
Observing bone marrow transplant patients, Syrjala and be addressed. Chochinov [25] describes this as “therapeu-
Chapko [23] found that psychologic distress (although not tic nihilism,” which absolves the caregiver for failing to
frank depression) contributed (to some extent) to the experi- respond to the patient’s suffering. The stigma associated
ence of mucositis pain. A bidirectional relationship in which with mental illness is such that patients may not volunteer
depression could be a cause and effect of cancer also has that they are in distress because of shame or fear of com-
been suggested [24]. promising treatment. Failure of the clinician to inquire or
Cancer Pain and Depression: Management of the Dual-diagnosed Patient • Valentine 265
screen for psychologic distress can serve as an unfortunate [29•]. These drugs have been employed effectively against
reinforcement to such beliefs. several different pain syndromes, but especially neuropathic
The question of order of treatment also can cause diffi- pain, making them of considerable potential value in the
culties. Some authors assert that the psychiatric symptoms cancer setting. Unlike mood-elevating effects, the initial
of patients in pain must first be considered consequent to analgesic effects of TCAs occur rapidly, often within a few
unrelieved pain and that this must be addressed first with doses. Antidepressant effects of TCAs can be correlated with
re-evaluation of mental state after pain control is achieved serum levels, which generally is not true of other antidepres-
[12,26]. Others assert that patients who meet diagnostic sants. There are data indicating that TCA-induced analgesia
criteria for depression should be treated concurrently with also can be correlated with serum levels [32]. These drugs
pain management [23]. As a practical point, patients in have the added advantage of modest cost, compared with
severe pain are likely to be in such distress that they cannot newer antidepressants.
be engaged, making adequate pain control a prerequisite The side-effect profile of TCAs can make their use
to psychiatric evaluation and treatment. In unfortunate, problematic, especially in cancer patients who are seri-
but not uncommon cases in which adequate pain control ously ill. The anticholinergic, antihistaminic, and α-adr-
is difficult to achieve, it is not reasonable to defer treatment energic blockade effects of TCAs are greatest for the tertiary
of depression and attempted management of both prob- amines (eg, amitriptyline, doxepin, imipramine), which
lems should be simultaneous. are more potent analgesics than secondary amines
(nortriptyline, desipramine). Sedation, constipation, uri-
nary retention, and orthostatic hypotension can be caused
Antidepressants by these medications or exacerbated in the setting of use
Antidepressants are used frequently to treat moderate to with opioid analgesics and other drugs. In seriously ill
severe depression in cancer patients. Clinical and patients, this can make the use of TCAs difficult even at
research experience is such that they are now a recom- low doses let alone at doses necessary for therapeutic
mended component of the management of cancer serum levels. In such cases, the use of secondary amines is
patients who meet diagnostic criteria [27]. Antidepres- preferred. These drugs must be used cautiously, if at all, in
sants are effective coanalgesics that are recommended for cardiac patients, especially those who have had postmyo-
use against pain of all levels of intensity and appear to be cardial infarction. They are potentially lethal in overdose
especially useful for management of neuropathic pain and thus must also be used cautiously in patients with
[26,28,29•,30]. Oncologists and supportive care special- unstable or severe psychiatric disorders.
ists who take care of cancer patients need to have a
working knowledge of these medications. Their pharma- Selective serotonin reuptake inhibitors
cology, especially with regard to the management of The drugs in this class are likely the antidepressants pre-
pain, has been thoroughly reviewed [31•]. scribed most often in clinical practice for the manage-
No antidepressant or class of antidepressants has been ment of depression. Selective serotonin reuptake
shown to have superior efficacy in the management of the inhibitors (SSRIs) specifically influence reuptake of sero-
depressed cancer patient. Variables relevant to the selection tonin at different receptor-binding sites. Within the class,
of an antidepressant include the drug’s side-effect profile, differences in effects on 5-HT binding may provide some
the patient’s clinical status and particular depressive symp- guidance in the selection of a drug. However, similar to
toms, a history of response to antidepressants, and poten- other antidepressants, the side-effect profile of the SSRI
tial drug interactions. The considerable data on the efficacy is matched most often against particular symptoms (eg,
of antidepressants as analgesics may make drug selection severe insomnia, fatigue) of the patient’s depression. The
easier when the depressed cancer patient also is in pain SSRIs have been studied for treatment of several types of
(Table 4). pain, including that associated with diabetic neuropathy,
fibromyalgia, and migraine headache [31•]. Although
Tricyclic antidepressants SSRIs have demonstrated significant relief of pain in
The introduction of these drugs began the modern era of some studies compared with placebo, they do not per-
pharmacotherapy of depression. They are the most well- form well when compared with TCAs. The review of stud-
studied antidepressants with regard to analgesia [29•,31•]. ies by McQuay et al. [30] of antidepressant treatment of
In oncology, they are used most often as coanalgesics with neuropathic pain revealed a rate of SSRI-induced major
opioids. There are several possible mechanisms contributing side effects 50% that of TCAs.
to analgesia, including the variable effects of tricyclic antide- Side effects of the SSRIs include nausea, anxiety,
pressants (TCAs) on norepinephrine and serotonin levels. insomnia (especially with the use fluoxetine), weight loss
Although equally efficacious against depression, the TCAs or gain, and sexual dysfunction (especially, but not exclu-
with more serotoninergic effects (eg, amitriptyline, doxepin) sively fluoxetine). Thrombocytopenia is not common,
appear to be the most effective analgesics and amitriptyline but does occur and is of obvious concern in patients
is generally considered the adjuvant analgesic of first choice undergoing chemotherapy or who have undergone a
266 Cancer Pain
bone marrow transplant. The drugs do not affect cardiac Third generation and atypical antidepressants
conduction and are relatively safe in intentional overdose There are few available studies of these drugs, which include
situations, which is one reason why they are so popular in combined serotonin/norepinephrine reuptake inhibitors
general clinical practice. Serotonin syndrome is poten- (venlafaxine, nefazodone), noradrenergic/specific serotonin-
tially dangerous and occurs with increased serum seroto- ergic antidepressants (mirtazapine), and noradrenergic/
nin levels caused by dose escalation or combination dopaminergic agents (bupropion). All of these drugs are
therapy with other serotoninergic drugs. It is character- potentially useful in the management of the depressed cancer
ized by anxiety, autonomic hyperactivity, hyper-reflexia, patient. Most of the few studies to date have involved ven-
diaphoresis, tremor, and hypertonicity. In worst cases, lafaxine, which appears to have some use in the treatment of
altered mental status and life-threatening hyperpyrexia neuropathic pain [35,36] and hot flashes [37]. Very early
may occur. Patients who are very sensitive may experience studies of mirtazapine suggest it also may be useful against
serotonin syndrome at normal medication doses. pain in cancer patients [38].
Cancer Pain and Depression: Management of the Dual-diagnosed Patient • Valentine 267
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