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Volume XVII, Issue 4
Editorial Board
Editor-in-Chief
Jane C. Ballantyne, MD, FRCA
Anesthesiology, Pain Medicine
USA
Advisory Board
Michael J. Cousins, MD, DSC
Pain Medicine, Palliative Medicine
Australia
Maria Adele Giamberardino, MD
Internal Medicine, Physiology
Italy
Patricia A. McGrath, PhD
Psychology, Pediatric Pain
Canada
M.R. Rajagopal, MD
Pain Medicine, Palliative Medicine
India
Maree T. Smith, PhD
Pharmacology
Australia
Claudia Sommer, MD
Neurology
Germany
Harriët M. Wittink, PhD, PT
Physical Therapy
The Netherlands
Production
Elizabeth Endres, Associate Editor
Kathleen E. Havers, Programs Coordinator
Rich Boram, Marketing and
Communications Manager
Upcoming Issues
Coping with Pain
Opioids in Cancer Pain
Prescription Opioid Abuse
September 2009
The Cancer Patient with Anxiety and Chronic Pain
Clinicians working with patients with chronic cancer-related pain are
familiar with the experience of pain having both somatic sensory and psychological
components. With adequate pain management, we often see a lessening of anxiety
and a return to emotional equilibrium, which allows patients to process the loss
inherent in the cancer experience. But in some of our patients we see persistence of
psychological suffering and of a maladaptive anxious response that interrupts this
processing and worsens outcome. While most anxiety develops after the onset of
cancer, a smaller subset of patients with anxiety represent those with preexisting
conditions.1,2 This issue of Pain: Clinical Updates addresses the complex and
bidirectional relationship of chronic pain and anxiety in cancer patients, the
dilemmas inherent in adequately diagnosing the underlying cause of this prolonged
suffering, and the multimodal treatment approach necessary to improve adaptation
and quality of life.
Anxiety
Anxiety can be described as an emotional state characterized by feelings
of unpleasant anticipation and a sense of imminent danger. Anxiety has both
physiological and psychological components. Autonomic hyperarousal with
acceleration of heart rate and respiration, tremor, sweating, muscle tension and
gastrointestinal changes are common physiological experiences. Apprehension,
feeling powerless, and fearing loss of control are psychological aspects. There are
many types of anxiety disorders, and all are relatively common in the population,
with prevalence data varying from 7% to 18%.3,4 Anxiety is a common, though
not universal, symptom that affects 13–16% of patients with cancer.5,6 The high
prevalence of anxiety disorders in those with chronic pain is also well documented,
with prevalence data of 20–40%.7 Characteristics of anxiety disorders are listed
in the American Psychiatric Association’s Diagnostic and Statistical Manual
(DSM)8 and include acute stress disorder, post-traumatic stress disorder (PTSD),
generalized anxiety disorder, obsessive compulsive disorder, panic disorder,
and phobias. PTSD occurs in 25% of the general population after exposure to
a traumatic event that threatens an individual’s life and causes intense fear and
helplessness.9 The American Psychiatric Association expanded its DSM criteria
for a PTSD stressor to include diagnosis with life-threatening illness in 1994.
PTSD can thus exist prior to cancer and its treatment and can also be caused or
exacerbated by cancer and its treatment. Acute stress disorder and PTSD involve
re-experience of trauma in the form of intrusive thoughts or nightmares, efforts
to avoid reminders of the trauma, and increased arousal that causes disturbances
in sleep and attention. When the disorder lasts 2–4 weeks and resolves, it meets
the criteria for acute stress disorder; when these symptoms persist for more than 1
month, they meet the criteria for PTSD. Essential to both acute stress disorder and
PTSD is impaired functioning at home and work. Other anxiety disorders include
generalized anxiety disorder, which involves excessive worry along with motor
Supported by a grant from Endo Pharmaceuticals, Inc., USA
greater in those with lower scores on measures of helplessness
and higher scores on measures related to self-efficacy and
rational thinking.20 Keefe has found that interventions that
teach coping skills and enhance patients’ perception of
control over their pain lessen psychological distress and lower
perception of pain.21 Sullivan, Keefe, and others have done
much to further the understanding of catastrophizing and its
contribution to pain-related fear avoidance and enhanced
disability. Catastrophizing is a cognitive style that incorporates
excessive focus and worry about negative aspects of pain,
underestimation of ability to cope effectively with pain, and
helplessness in the face of pain. Catastrophizers report more
negative pain-related thoughts, enhanced emotional distress,
and greater pain intensity.22,20
tension and restlessness, irritability, autonomic hyperarousal,
sleep disturbance, and inattention, with onset typically in early
adult life. Panic disorder involves episodes of sudden high
anxiety accompanied by fear of loss of control, by activation
of the sympathetic nervous system, and by the urge to escape,
which can result in abrupt termination of cancer treatment.10
Phobias usually have a childhood onset and are characterized
by extreme anxiety when exposed to a feared situation
or object and by efforts to avoid them. Phobias involving
exposure to the medical environment (needles, blood, enclosed
spaces found in the intensive care unit, diagnostic scanners,
and radiation therapy devices) are common.11
Anxiety in Pain Research
Anxiety in Cancer
Modern concepts of chronic pain incorporate more
than just an understanding of transduction, transmission,
and modulation effects of direct tissue damage or invasion.
Pain perception also involves genetics, psychological state,
social situation, cognitive variables such as expectations and
memories, personality, and culture.12 Keefe found in 1987
that coping variables powerfully predict perception of and
adjustment to pain.13 The 1980s also brought exciting research
into the cognitive-behavioral model of disease-related pain and
new roles for intervention involving altering ones thoughts,
beliefs, expectations, and behavioral patterns to enhance
adjustment to pain.14 More recently, studies involving brain
imaging and psychosocial aspects of pain and its psychological
management have provided new findings indicating that
cognitions, emotions, and behaviors can influence pain.15,16
Research into the psychological factors associated
with chronic pain has blossomed in the past two decades. The
fear-avoidance model, as proposed by Vlaeyen, incorporates
learning theory and cognitive-behavioral perspectives to
explain how pain-related fear can lead to chronic disability.
Pain-related fear can produce avoidance of movement and
activity in a misguided attempt to preempt further pain. These
avoidance behaviors occur in anticipation of pain and can
ultimately lead to disuse syndromes and depression, further
lowering pain tolerance and promoting pain-related disability.17
Asmundson and others have described the phenomenon
of “anxiety sensitivity.” Anxiety sensitivity has to do with
fear as a consequence of feeling the physical manifestations
of anxiety. It is a trait that involves interpreting anxiety as
having to do with an underlying danger or threat (e.g., cancer
recurrence). Asmundson looked at 259 patients with chronic
pain and found that anxiety sensitivity led to an increase in
pain avoidance behavior.18 Anxiety sensitivity has been a
fruitful area of research, and evidence has mounted to show
that it may be a cognitive vulnerability factor for negative pain
experiences. Keogh found that subjects who are highly fearful
of pain exhibit a selective attentional bias toward pain-related
stimuli compared with those with low fear of pain. Further,
those with high anxiety sensitivity misinterpret innocuous body
sensations as threatening.19
In a review of studies of patients with arthritis, Keefe
found three variables in pain coping that predicted improved
adjustment to chronic pain: (1) pain control and rational
thinking (the perception that one has control over pain); (2)
self-efficacy (confidence in one’s ability to cope with pain);
and (3) helplessness (the perception that one lacks control over
outcome). Psychological distress and perception of pain were
For most patients, cancer requires facing uncertainty,
worries about cancer treatment effects, fear of cancer
progression and death, guilt, and spiritual questioning.23 In
the cancer treatment trajectory, anxiety tends to increase
at nodal crisis points: initial diagnosis, initiation of cancer
treatment, cancer recurrence, failure of treatment, and
perception of dying.10 Massie and Holland have described a
“normal” response to cancer diagnosis and recurrence that
resolves in days to weeks and is characterized by a period of
initial shock and disbelief as well as emotional distress with
anxiety, irritability, sadness, and disturbed appetite and sleep.
Concentration impairment often temporarily reduces function
at home and work. Patients can describe ruminative worry
and fear about the future.24 This type of short-term anxiety
reaction can facilitate a patient’s anticipation and preparation
for what is to come, motivate a patient to seek support, and
mobilize previously successful coping strategies, thus lessening
the likelihood of sustained helplessness. Maladaptive,
pathological, and persistent anxiety responses exist as well.
While less common, these responses can precipitate anxiety
disorders characterized by persistent social and/or occupational
functional impairment and helplessness.
The Psychosocial Collaborative Oncology Group
looked at the prevalence of psychiatric disorders in adult
cancer patients in all stages of disease receiving treatment
at three major cancer centers and found pre-existing anxiety
disorders to be present in 4% of these patients. More common
were psychiatric disorders that developed after the cancer
diagnosis.1 In studies of women with breast cancer, rates
of psychiatric disorders after diagnosis and at the time of
recurrence range between 14% and 38%.1,25,26 The prevalence
of PTSD in all stages of breast cancer is reported to be
between 3% and 19%.27–32 Research has supported the clinical
finding that precancer mental disorders worsen cancer-related
distress.23,28,33 Smith et al. conducted a review of published
studies of PTSD in cancer patients and found that a prior
history of trauma, low levels of social support, and prior
history of a psychiatric disorder to be predictive of PTSD
occurrence following cancer diagnosis and treatment.34
Anxiety in Chronic Cancer Pain
Patients often come to cancer with much fear
about pain, and pain is common among cancer patients.35
In a recent review of the literature, the prevalence of pain
2
in all cancer types was more than 50%.35 Cancer pain
can result from direct tissue invasion, from biopsy and
other diagnostic procedures, and from treatment (surgery,
radiation, chemotherapy) and untoward consequences of
treatment (infections, gastrointestinal tract ulcerations).
Cancer pain can be treated with long-acting analgesics and
shorter-acting rescue medications for breakthrough pain
along with adjuvant therapies according to the World Health
Organization guidelines.36 Cancer pain can be complicated by
the psychological distress inherent in the experience of cancer
pain itself, with its associated fear and helplessness, often
precipitating mood and anxiety disturbances.37,38 Portenoy
found significant pain to be a causal factor in an ovarian
cancer patient’s report of increased anxiety.39 Further, cancer
pain can trigger a reactivation of prior emotional trauma and
can exacerbate underlying anxiety disorders.40,41 Precancer
emotional trauma increases a sense of vulnerability that both
cancer and pain reinforce.28 A prior history of trauma taxes the
patient’s capacity to cope with illness and pain.42 More research
is needed in this area because few studies in the cancer pain
literature have examined pain as either a trigger or symptom of
PTSD. In looking at patients with cancer of mixed etiologies,
Gold found a significant association between the presence of
PTSD and the degree of pain severity reported.43
As with noncancer pain, the relationship between pain
catastrophizing and increased experience of pain and anxiety
in cancer patients has been demonstrated.30,44–46 In addition,
an enhanced sense of control over pain is associated with a
reduction in cancer pain perception.44,46 Early identification and
treatment of anxiety reactions, especially those involving low
self-efficacy and high tendency to catastrophize, are likely have
the potential to enhance cancer treatment compliance, recovery,
and survival.
Table I
Key components of anxiety evaluation in cancer patients
1.
Obtain history of precancer anxiety disorder (generalized
anxiety disorder, panic disorder, phobias, post-traumatic
stress disorder, obsessive compulsive disorder)
2.
Rule out drug effects (corticosteroids, interferon-α) and
underlying medical conditions (brain metastasis, pulmonary
embolism, hypoxia, delirium, electrolyte disturbances,
anemia, hormone-secreting tumors)
3.
Treat pain adequately
4.
Once pain is controlled, reassess for anxiety disorder
helplessness. PTSD symptoms recurred at the time of cancer
diagnosis and worsened after surgery, when she experienced
severe postoperative pain. Over the 2 years since her surgery,
she had had brief periods of improvement in function. Episodes
of improvement ended with the onset of worsened pain, which
she believed signified cancer recurrence. Much of the fear
and ruminative worry she described during the day involved a
hypervigilance for pain cues. She described herself as “frozen
with fear,” unable to function, relentlessly pursuing reassurance
from her oncology team. Despite having 2 years of being
cancer free, she had been unable to recover a meaningful sense
of purpose and enjoyment to her life.
This case highlights the reactivation of underlying
psychopathology linked to earlier emotional trauma by
postoperative pain in the context of high-risk cancer. The
patient experienced fear, terror, helplessness, and anticipation
of doom, which she linked to her current condition but
which was probably fueled by her past trauma experience.
The resulting disabling anxiety affected all aspects of her
functioning, including her interpersonal relationships and her
work, and interfered with her cancer treatment. She became
overwhelmed, unable to cope, and unable to process and
adapt to the loss, the fear, and the uncertainty she was facing.
In patients like Ms. A., pain can trigger a flashback to an
earlier trauma. We can suspect that Ms. A.’s hypervigilance
with respect to her pain is in part a sign of PTSD and that her
attentional bias toward pain cues links the present and past
traumas and taxes her underdeveloped and insufficient capacity
to cope with the emotional fallout of cancer.
Case History
The pain and symptom management team of a large tertiary
care center was asked to perform a consultation on Ms. A.
She is a 35-year-old, married, successful businesswoman
who 2 years previously had undergone a bilateral mastectomy
with reconstruction for initial treatment of locally advanced,
invasive, node-positive breast cancer. Chemotherapy followed
by radiation therapy was completed, but targeted cancer
therapy with monoclonal antibody treatment was terminated
secondary to complaints of pain for which oxycodone was
prescribed. Ms. A. also experienced persistent pain in her right
axilla and across her upper back. Opioid tolerance developed,
necessitating escalating doses and leading to the referral to the
pain and symptom management team. On initial assessment
by the team, Ms. A described her pain as continuous and
interfering with most daily activities. It was not relieved by
trials of physical therapy, acupuncture, or escalating doses of
opioids, both with and without gabapentin. She also reported
feeling highly irritable and worried, spending much of her time
ruminating about the possibility of recurrence. She was unable
to return to work, was unable to shop or do household chores,
and isolated herself from friends and other family. Further
evaluation revealed a history of early childhood abandonment
by her father and neglect and emotional abuse by her mother.
In her adult life, she had experienced untreated depression
and anxiety as well as episodes of PTSD with hyperarousal,
nightmares, avoidance, and overwhelming fear and
Diagnosis
Diagnosis of anxiety in the context of cancer and
chronic pain is difficult for many reasons. First, there is an
overlap of anxiety symptoms, cancer symptoms, and adverse
effects of cancer treatment. Problems with concentration,
fatigue, shortness of breath, sleep, and appetite are common
and nonspecific. All can be caused by anxiety, and all can be
worsened by anxiety. Second, any medication or other organic
factors producing an ongoing anxiety state must be identified
(e.g., involvement of the central nervous system; systemic
factors such as anemia, abnormal glucose levels, or atrial
fibrillation; endocrine factors such as thyroid, pituitary, and
parathyroid abnormalities; medications such as corticosteroids
and interferon- ; withdrawal syndromes; and substance
abuse). Third, one must differentiate an acute anxiety reaction
associated with pain from a more maladaptive anxiety reaction
that may become chronic. Psychiatric symptoms in patients
3
Table II
Psychopharmacological agents helpful in the treatment of anxiety in cancer patients with pain
Medication
Starting Dose
Daily Dose
Positives
Possible Side Effects
ANTIDEPRESSANTS
Selective Serotonin Reuptake Inhibitors (SSRIs)
Citalopram
10 mg q.a.m.
20–40 mg
Few side effects
Escitalopram
5–10 mg q.a.m.
10–20 mg
Few side effects
Sertraline
25 mg q.a.m.
50–100 mg
Few side effects
Paroxetine
10 mg q.h.s.
20 mg
Generic
Fluoxetine
5–10 mg q.a.m.
20–40 mg
Stimulating
All SSRIs: Gastrointestinal
stimulation, sleep disruption,
sexual dysfunction, restlessness
(uncommon), headache, increased
risk of bleeding; paroxetine is also
anticholinergic
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
Venlafaxine
37.5–75 mg q.a.m. or
q.h.s.
150–300 mg
Neuropathic pain
Duloxetine
20 mg q.a.m. or q.h.s.
40–60 mg
Neuropathic pain
All SNRIs: Blood pressure
elevation, constipation, nausea,
withdrawal reactions, sedation
Tricyclic Antidepressants (TCAs)
All TCAs: Sedation; anticholinergic,
α1-adrenergic, and antihistaminic
effects; prolonged QT
Amitriptyline
25–50 mg q.h.s.
50–100 mg
Neuropathic pain
Nortriptyline
25–50 mg q.h.s.
50–100 mg
Less sedating than
amitriptyline
Mirtazapine
7.5–15 mg q.h.s.
30–45 mg q.h.s.
Increased appetite; improved
sleep; antinausea
Oversedation; weight gain
Bupropion
150 mg q.a.m.
300–450 mg q.a.m.
Stimulating; no sexual
dysfunction; smoking cessation
Lowers seizure threshold;
occasional overstimulation
Lorazepam
0.25–0.5 mg b.i.d.–
t.i.d.
1–2 mg per day
Anti-nausea; no active
metabolites
Clonazepam
0.25–0.5 mg b.i.d.
0.5 mg b.i.d. and
0.5–1 mg q.h.s.
Longer length of action
All benzodiazepines: Sedation,
anterograde memory impairment,
motor impairment, high abuse
potential, withdrawal reactions
Other Antidepressants
BENZODIAZEPINES
ATYPICAL ANTIPSYCHOTICS
Quetiapine
12.5–25 mg b.i.d.
12.5 mg b.i.d. and
50–100 mg q.h.s.
Low EPS
Risperidone
0.25–0.5 mg b.i.d.
0.25 mg b.i.d. and
0.5 mg q.h.s.
Low EPS
All atypical antipsychotics:
Metabolic syndrome, sedation,
quetiapine contraindicated with
methadone (QT prolongation)
Abbreviations: b.i.d. = twice a day; EPS = extrapyramidal side effects; q.a.m. = every morning; q.h.s. = at bedtime; t.i.d. = three times a day.
Treatment
with severe pain must be considered a direct result of pain and
must be treated before an accurate psychiatric assessment can
be made. Once pain is adequately addressed, psychopathology
can be assessed. Table I outlines the key components of the
psychiatric evaluation of patients with persistent cancer pain.
Several scales have been used to detect pathological
anxiety states: The Hospital Anxiety and Depression Scale
(HADS),47 the Hamilton Rating Scale for Anxiety,48 and the
State-Trait Anxiety Inventory.49 Payne and others at Memorial
Sloan Kettering Cancer Center found the HADS to be an easy,
inexpensive, and convenient scale for use in the clinic setting,
with a high predictive value when screening breast cancer
patients for anxiety and mood disorders. The HADS is a 14item self-report scale designed for use in the medically ill. It
eliminates the somatic symptoms of anxiety and depression,
which are poor indicators of psychological distress in this
population. Each item is rated from 0 (“not at all”) to 3 (“very
much”). A score greater than 13 has a positive predictive value
of 75%.50
The complexity of cancer patients with chronic
pain underscores the potential benefit of a multidisciplinary
approach, with psychiatry and psychology assuming major
roles within the treatment team. However, many cancer
treatment settings cannot offer this breadth of service within
their own facility. Health care professionals should be
aware of local and wider community resources available for
psychoeducation,21 psychotherapy, and psychopharmacology
interventions aimed at enhancing compliance with cancer
treatment, coping, function and quality of life. Hutchinson
and colleagues have developed a tiered model of psychosocial
intervention for cancer patients incorporating referral to
community-based clinical interventions based on the level of
the patient’s distress.51 Patients with mild distress (difficulty
coping emotionally, social isolation, and problem-solving
and decision-making issues) are referred for supportive
care through cancer support websites, organizations that
4
provide group support and psychoeducation, and tele-based
cancer help lines. Those with moderate distress (high stress
around adjustment to cancer) are referred for group and
individual therapy by trained health professionals (e.g.,
a social worker, nurse counselor, or psychologist) in the
community. Those with moderate to severe distress (anxiety
disorders, acute stress disorder, PTSD, or mood disorders)
are referred to psychologists or psychiatrists with oncology
experience for psychological treatment and consideration of
pharmacotherapy.51 It cannot be overemphasized, however,
that adequate analgesia by itself can improve emotional
and functional response and must be maintained in concert
with any psychiatric intervention. Table II is an overview
of common psychopharmacological agents helpful in the
treatment of anxiety in cancer patients with pain.
promote psychological adaptation. Psychotherapy can lessen
fears about disease progression, help problem-solve associated
psychosocial difficulties, and explore worries about increased
dependence.56 Exploratory psychotherapy, especially where
precancer trauma is involved, can be helpful in understanding
antecedents of anxiety, in changing maladaptive coping
styles, and in working through issues around grief and loss.
Forming a therapeutic relationship can be invaluable in
discussing existential and spiritual issues that arise around
cancer as well as exploring meaning in both life and in death.
Cognitive-behavioral therapy has been shown to be helpful
both in chronic pain57 and in anxiety disorders.58 It helps
elucidate patterns of maladaptive attitudes toward illness,
encourages alternative coping strategies, and allows for
earlier recognition of triggers for anxiety and somatization.
Growing evidence indicates that behavioral interventions such
as hypnosis, progressive muscle relaxation, and acupuncture
have roles in the treatment of anxiety and chronic pain in these
patients.52,59–61
Psychopharmacology
Benzodiazepines are potent anxiolytics and are
relatively safe in the treatment of anxiety in the cancer
patient.52 Their antiemetic effect is an added bonus for many
cancer patients. Adverse effects include dose-dependent
sedation, psychomotor impairment (which can result in
falling), memory deficits, and the potential for dependence. In
patients with liver dysfunction, lorazepam and oxazepam are
chosen over other benzodiazepines because of their lack of
active metabolites.
Tricyclic antidepressants and the newer serotonin/
norepinephrine reuptake inhibitors (SNRIs), duloxetine and
venlafaxine, have long been used for their positive analgesic
effects in neuropathic pain. They have a proven history of
anxiolytic effects as well. Adverse effects for tricyclics include
anticholinergic, histaminic, and 1-adrenergic reactions.
Venlafaxine and duloxetine can cause strong withdrawal
reactions. Selective serotonin reuptake inhibitors (SSRIs) are
also efficacious in the treatment of all anxiety disorders. The
literature on analgesic properties for SSRIs is less robust than
for SNRIs. Side effects include gastrointestinal activation,
sleep dysfunction, and appetite changes. Mirtazapine is an
antidepressant particularly well suited for the cancer patient in
that it has antinausea and potentially weight-promoting side
effects, as well as sedating effects that are helpful in reversing
sleep disturbance.
Antipsychotics are especially useful with severe
anxiety when maximal doses of benzodiazepines are
insufficient, with agitation related to delirium, and with
patients intolerant of benzodiazepines. Atypical antipsychotics
such as quetiapine and risperidone may have a better sideeffect profile than older antipsychotics such as haloperidol and
chlorpromazine, but they are more expensive.
Conclusions
Anxiety in cancer patients with pain must first be
regarded as a consequence of inadequate pain control.62
Along with adequate pain management, a multimodal
approach to anxiety treatment is critical to achieving a return
to function and improving quality of life. Psychological
assessment and intervention with psychopharmacological
and psychotherapeutic modalities is an essential part of the
comprehensive treatment approach to ongoing cancer pain.
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Ruth H. Steinman, MD
Cancer Counseling Service
Abramson Cancer Center
University of Pennsylvania
Philadelphia, PA 19104, USA
Tel: +1-215-615-0534
[email protected]
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