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Overview of anxiety in palliative care

Overview of anxiety in palliative care
Authors:
Scott A Irwin, MD, PhD
Jeremy M Hirst, MD
Section Editor:
Susan D Block, MD
Deputy Editors:
Jane Givens, MD, MSCE
Michael Friedman, MD
Literature review current through: Dec 2022. | This topic last updated: Jan 03, 2022.

INTRODUCTION — For most patients in palliative care, symptoms of anxiety are normal and are expected consequences given the uncertainties of living with serious illness and the possibility of approaching death. Anxiety is generally described as a feeling of helplessness or fear, often related to a sense of losing control that frequently accompanies life with illness, as well as being generated by death-related factors. A patient’s distress may also be related to physical, psychological, social, spiritual, practical, end-of-life, and loss issues [1,2]. They express fears about what their death will look and feel like and what events will lead up to it. They frequently voice concerns about religious beliefs, spiritual issues, existential matters, or how to achieve a good death. Some people with anxiety may require intervention and some may not. Often reassurance, presence, addressing their concerns directly, and controlling symptoms are all that is needed.

While many patients with serious illness have worries, fears, and apprehensions, they do not usually rise to the level of an anxiety disorder. That is, anxiety disorders should not be assumed to be an inevitable part of serious illness [3]. However, for other patients, symptoms of anxiety can be severely debilitating and require intensive treatment. At the most extreme, out-of-control anxiety can sometimes lead to a heightened interest in a hastened death [1].

The detrimental impact of untreated, persistent anxiety was demonstrated in one multicenter study of over 600 patients with advanced cancer that evaluated associations between anxiety disorders and multiple endpoints, including physician-patient relationships [4]. Patients with anxiety disorders had less trust in their clinicians compared with those without anxiety. In addition, patients with anxiety reported being:

Less comfortable asking questions about their health

Less likely to understand the clinical information

More likely to believe that their clinicians would offer them futile therapies

Less certain that they would have adequate symptom control at the end of life

Persistent, high levels of anxiety are not adaptive and require aggressive intervention, including psychotherapy, anxiolytics, and/or antidepressants [5]. Intervention by providers skilled in working with anxiety is needed whenever anxiety significantly worsens, interferes with the patient’s ability to function, or persists for more than seven days [6].

This topic will discuss the approach to diagnosis and management of anxiety in palliative care patients. Other topics in palliative care and specific discussions on anxiety in other patient populations are discussed separately:

(See "Benefits, services, and models of subspecialty palliative care".)

(See "Overview of managing common non-pain symptoms in palliative care".)

(See "Overview of comprehensive patient assessment in palliative care".)

(See "Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis".)

(See "Comorbid anxiety and depression in adults: Epidemiology, clinical manifestations, and diagnosis".)

(See "Generalized anxiety disorder in adults: Cognitive-behavioral therapy and other psychotherapies".)

(See "Generalized anxiety disorder in adults: Management".)

EPIDEMIOLOGY — Although exact figures are not available, symptoms of anxiety are thought to occur in more than 70 percent of medically ill patients, especially those approaching end of life [7,8]. However, anxiety that rises to the level of a disorder likely impacts less than 10 percent of patients in palliative care. For example, in the Coping with Cancer study, 635 patients underwent a prospective evaluation to determine the presence of anxiety disorders using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV) criteria [9]. The main results were that:

An anxiety disorder was present in less than 8 percent of patients

Anxiety disorders were more common among subgroups, including women, physically impaired patients, and in younger patients

While only a small percentage has experienced any symptoms of anxiety beyond normal prior to diagnosis or treatment [10], reports suggest that these patients may go on to develop symptoms of posttraumatic stress related to their diagnosis, prognosis, or treatment regimens [11-13].

CLINICAL MANIFESTATIONS — In hospice and palliative care settings, anxiety is generally described as a feeling of helplessness or fear, often generated by death-related issues. However, anxiety may be related to other quality of life areas, including the physical, psychological, social, spiritual, and practical domains [1,2]. A feeling of losing control in relation to the great uncertainty that accompanies many aspects of living with serious illness frequently heightens anxiety for many patients seen by palliative care.

Although the symptoms may vary in palliative care patients, common manifestations of anxiety include the following [14,15]:

Emotional symptoms – Edginess, feelings of impending doom, or terror

Cognitive difficulties – Apprehension, dread, fear, obsession, uncertainty, or worry

Behavioral problems – Avoidance, compulsions, or psychomotor agitation

Autonomic symptoms – Diaphoresis, diarrhea, nausea, dizziness, tachycardia, or tachypnea

Expressions of fears about what their death will look like and what events will lead up to it

Concerns about religious beliefs, spiritual issues, existential matters

Worries about how to and if they will achieve a good death

Noticing how the patient presents to the team or even what responses the patient evokes from the treatment team can be useful indicators of underlying patient distress. Patients with anxiety may seem inattentive, confused, and unable to take in information. These patients may ask the same questions over and over, or demonstrate difficulty making decisions, both of which may cause frustration for the treatment team. In addition, patients may also appear inconsistent or even suspicious [16].

Anxiety can accompany the fear of uncontrolled symptoms or concerns about loss of independence, and for some patients, their response may be expressed as a heightened interest in hastened death [1].

Assessment — Although patients with serious illness often experience anxiety [7,17], many patients may not directly express these symptoms to care providers or articulate their experiences. As a result, it is important that clinicians listen for key words that can often signal underlying anxiety. This was shown in one study where the audio recordings of 415 visits between patients with advanced cancer and oncologists were reviewed [18]. Both anxiety and fear were the most common types of emotion expressed, and patients most frequently used the words “concerned,” “scared,” “worried,” and “nervous” to convey them. Being aware of these key words and noticing whether they occur during conversations with patients can aid clinicians in pinpointing the presence of anxiety.

Routine screening of anxiety should be carried out in palliative care patients, given the high prevalence of symptoms. For patients with cancer, the American Society of Clinical Oncology (ASCO), along with the American College of Surgeons Commission on Cancer and the National Comprehensive Cancer Network (NCCN), have issued recommendations for assessment and diagnosis of anxiety disorders, based upon Canadian practice guidelines [19]. The recommendations state that every patient with cancer should be screened for anxiety when the initial diagnosis of cancer is made and periodically thereafter as clinically indicated, especially with changes in cancer or treatment status (eg, posttreatment, recurrence, or progression), as well as at transitions in care focus (treatment and/or palliative versus end-of-life/hospice care). (See "Clinical features and diagnosis of psychiatric disorders in patients with cancer: Overview", section on 'Anxiety disorders'.)

All palliative care patients should be screened for both anxiety and depression, and a reasonable initial tool is the brief Patient Health Questionnaire for Depression and Anxiety (PHQ-4) (table 1) [20]. If the PHQ-4 screen is positive for anxiety (or if additional symptoms exist that suggest underlying anxiety), the seven-question Generalized Anxiety Disorder scale (GAD-7) (table 2) is suggested [21,22]. The GAD-7 can be used to inform the diagnosis of an anxiety disorder, the diagnosis of which is made on the basis of DSM-5 criteria [23], and to monitor severity of symptoms over time. (See "Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis", section on 'Assessment and Diagnosis'.)

If a patient screens positive for depression on the PHQ-4, they should be assessed for major depression or dysthymia using DSM-5 criteria for these disorders. If major depression is present, the nine-item Patient Health Questionnaire (PHQ-9) can be used to monitor its severity over time (eg, in response to treatment) (table 3). (See "Assessment and management of depression in palliative care", section on 'Tools for assessment and diagnosis' and "Unipolar depression in adults: Assessment and diagnosis", section on 'Diagnostic criteria and classification'.)

The symptoms of anxiety may occur due to physiological derangements rather than from an anxiety disorder or psychological state (eg, due to heart failure, anemia, respiratory compromise, or hyperthermia), and this should not be overlooked. Good history taking and physical examination are both important in the assessment of anxiety (table 4) [24]. Physiological causes are particularly common if the symptom onset of symptoms are after age 35, there is a lack of personal or family history of anxiety, and/or if there is a poor response to anxiolytic treatment [25]. Interventions to ameliorate underlying physiological causes should be undertaken. For example, patients with dyspnea can be very anxious; however, remarkable relief can usually be obtained with opioid therapy [26]. (See "Assessment and management of dyspnea in palliative care", section on 'Opioids'.)

Important aspects in the assessment for anxiety include [14,15]:

A detailed history and physical exam in order to attain a thorough sign and symptom profile [1] and to discern psychological versus physical contributing factors, including medications and/or lifestyle contributions (eg, steroids, alcohol, caffeine, nicotine, lack of exercise)

Laboratory testing, including the measurement of electrolytes, blood cell counts, relevant hormones (eg, thyroid and adrenal), and toxicologies

Corroborative history obtained from family, friends, and other members of the interdisciplinary care team

DIFFERENTIAL DIAGNOSIS — In hospice and palliative care settings, anxiety is common and can be a part of the normal reaction to a progressive, potentially life-limiting illness or the end of life. However, many symptoms of anxiety overlap with the symptoms associated with other psychiatric disorders, particularly depression, delirium, and dementia. For example, symptoms such as loss of appetite and insomnia are often associated with depression but can be a part of a patient’s anxiety state or their physical illness [6].

Depression — The symptoms of anxiety can be difficult to distinguish from depression, and the two can co-occur. For patients who may have a depressive disorder rather than (or in addition to) anxiety, a diagnostic assessment using the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria can distinguish between conditions [23]. The anxiety and depression symptom scales discussed previously, the nine-item Patient Health Questionnaire (PHQ-9) and the seven-question Generalized Anxiety Disorder scale (GAD-7), can be useful to inform the diagnosis. (See 'Assessment' above and "Unipolar depression in adults: Assessment and diagnosis", section on 'Diagnostic criteria and classification' and "Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis", section on 'Assessment and Diagnosis'.)

Individuals with depression tend to brood self-critically on prior events and circumstances, may be agitated and perseverative, and may express feelings of hopelessness, helplessness, and worthlessness. By contrast, patients with anxiety worry more about what might happen in the future. In addition, early morning awakening, diurnal variation in mood, and suicidal ideation are not typically present in anxiety and are usually associated with a primary depressive disorder. (See "Comorbid anxiety and depression in adults: Epidemiology, clinical manifestations, and diagnosis" and "Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis".)

Delirium — Delirium and anxiety may be manifest by poor sleep and difficulty with attention or concentration. However, unlike patients with anxiety, psychotic behavior, delusions, disturbance in consciousness, and altered cognition are common in delirium [27]. (See "Diagnosis of delirium and confusional states".)

Dementia — Dementia can be distinguished from anxiety due to the cognitive decline that accompanies it, which is absent in anxiety, and efforts to hide deficits from others; dementia is typically characterized by insidious and progressive cognitive changes which occur over a protracted period of time. This may be either mistaken for or comorbid with anxiety. (See "Diagnosis of delirium and confusional states".)

DIAGNOSIS — For patients in palliative care, clinically significant anxiety may or may not meet diagnostic criteria for an anxiety disorder or trauma-related disorder. However, the symptoms may be sufficiently distressing to merit clinical attention and possibly treatment despite the absence of a formal disorder. (See 'Clinical manifestations' above.)

Adjustment disorder with anxious features — An adjustment disorder is a psychological response to an identifiable stressor which results in the development of clinically significant emotional or behavioral symptoms that do not, taken as a whole, qualify for a diagnosis of an anxiety disorder [28]. Many people with serious medical illness may have trouble psychologically adjusting to their diagnosis, prognosis, or treatment regimens and develop significantly distressing adjustment (or coping) issues that deserve attention from the care team. (See "Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis".)

Generalized anxiety disorder — GAD is characterized by excessive and persistent worrying that is hard to control, causes significant distress or impairment in day-to-day activities, and occurs more days than not for at least six months. Patients, and their family members, often describe a lifelong history of “living on the anxious side of life” beginning far before their illness. Other features include psychological symptoms of anxiety, such as apprehensiveness and irritability, and physical (or somatic) symptoms of anxiety, such as increased fatigue and muscular tension. The prevalence of generalized anxiety disorder in patients with advanced cancer appears to be 0.4 percent [9]. (See "Generalized anxiety disorder in adults: Epidemiology, pathogenesis, clinical manifestations, course, assessment, and diagnosis".)

Panic disorder — Panic attacks most often present with classic, discrete episodes of intense fear that begin abruptly and last for several minutes to an hour. Patients also often present with autonomic symptoms such as chest pain or shortness of breath. In panic disorder, patients experience recurrent, unexpected panic attacks, have significant impairments in psychosocial functioning, and one month or more of at least one of the following:

Worry about future attacks

Phobic avoidance of situations that could trigger an attack

Other changes in behavior due to the attacks

In patients with progressive, potentially life-limiting illnesses, panic may arise from fear of treatment, treatment related symptoms (eg, nausea), prognosis, and fears about impact on family. The prevalence of panic disorder in patients with advanced cancer appears to be 0.4 to 0.7 percent [9]. Further discussion of panic disorders is covered separately. (See "Panic disorder in adults: Epidemiology, clinical manifestations, and diagnosis".)

Posttraumatic stress disorder — Posttraumatic stress disorder (PTSD) is characterized by intrusive thoughts, nightmares and flashbacks of past traumatic events, avoidance of reminders of trauma, hypervigilance, and sleep disturbance, all of which can lead to considerable social, occupational, and interpersonal dysfunction.

In patients receiving palliative care, PTSD can arise from receiving the diagnosis, being given a poor prognosis, and treatment-related events, such as receiving chemotherapy. The prevalence of PTSD in patients with advanced cancer appears to be 0.4 to 1.1 percent [9]. Aspects of PTSD may be present in palliative care patients, such as avoiding treatment center visits or becoming hypervigilant regarding physical symptoms, no matter how mild, worrying they may be a sign of worsening disease or recurrence; yet full diagnostic criteria for PTSD may not be met. Further discussion on PTSD is covered separately. (See "Posttraumatic stress disorder in adults: Epidemiology, pathophysiology, clinical manifestations, course, assessment, and diagnosis".)

TREATMENT APPROACH — Symptoms of anxiety should be addressed when they are interfering with function or quality of life. 2015 recommendations from the American Society of Clinical Oncology (ASCO) suggest intervention for those with moderate to severe symptomatology (score ≥10 on the seven-question Generalized Anxiety Disorder scale (GAD-7) (table 2)) [19].

An individualized approach is warranted which takes into account multiple factors, including [14,15]:

Underlying illness and prognosis

Presence of comorbidities

Medical frailty

General psychological and physical status

Patient (and family) wishes

A multilayered treatment paradigm consisting of a combination of supportive care, psychotherapy, and, when necessary, pharmacotherapy, is best. In addition, complementary or alternative therapies may be helpful.

Psychotherapy — Psychotherapy is useful for patients and their families as a way to explore issues that may be causing or exacerbating their anxiety. Issues amenable to psychotherapy may be related to, among many others, feelings about or fears of medical interventions, physical symptoms, social impacts, finances, family conflicts, future disability, dependency, being a burden, spiritual issues, existential suffering, grief and loss, end-of-life issues, and dying [14,15]. Importantly, such issues cannot be resolved with medications alone. (See "Overview of spirituality in palliative care", section on 'Spiritual distress and existential suffering'.)

Formal psychotherapy can be employed with individuals, couples, families, and groups. A number of psychotherapeutic modalities designed specifically for patients with serious medical illness may improve symptoms of both anxiety and depression [29], including brief individual approaches [30,31], cognitive-behavioral therapies [32,33], supportive-expressive group therapy [34], dignity therapy [35,36], and meaning-centered psychotherapy [37]. (See "Assessment and management of depression in palliative care", section on 'Psychosocial interventions'.)

As an example, in the Managing Cancer and Living Meaningfully (CALM) trial, 39 patients with advanced cancer underwent a semi-structured individual psychotherapy program to evaluate its impact on depressive and other symptoms, including death anxiety and spiritual wellbeing [30]. Assessments were made at baseline, three months, and six months. The intervention was associated with reductions in all three of these endpoints. However, the data were limited by attrition; of 39 patients assessed at baseline, only 16 completed evaluation at six months. Despite this limitation, these data point to a potential role for psychotherapy in these patients.

When possible, psychotherapy should always be utilized and, when necessary, augmented with pharmacotherapy. The role of psychotherapy for anxiety disorders in the general population is discussed separately. (See "Overview of psychotherapies", section on 'Indications for psychotherapy'.)

Complementary therapies — In addition to psychotherapy, numerous alternative therapies can be utilized when attempting to decrease anxiety among patients with serious illness, including:

Hypnotherapy [28]

Music therapy [38]

Relaxation training [39]

Acupuncture [10]

Mindfulness meditation [11]

Aromatherapy

Massage [12]

Art therapy [13]

Of these, music therapy appears to show considerable promise for decreasing anxiety and improving quality of life specifically in patients receiving hospice and palliative care [38]. Relaxation training and mindfulness meditation are widely applied, particularly since they can often be provided at relatively low cost and have long-term effects, if the techniques are practiced consistently over time [40].

Exercise — Physical exercise may prove beneficial, even among the seriously ill. Exercise can decrease worry and anxiety while improving overall functioning. Exercise may also serve an important role in providing a sense of autonomy, control, or success.

Even patients who are bedbound can engage in activities that provide exercise, even it if is only practicing passive range of motion.

Lifestyle factors — Patients with serious illness who are experiencing anxiety may also benefit from a detailed assessment of their daily caffeine and alcohol intake or other anxiety-producing activities. Learning about such activities and modifying them can help diminish concomitant anxiety and may serve to educate the patient about the implications of such lifestyle behaviors and potential coping mechanisms.

In addition, a sleep hygiene protocol may be implemented to help regulate anxiety without the use of pharmacologic intervention. (See "Insomnia in palliative care", section on 'Lifestyle modifications'.)

Pharmacotherapy — For patients entering palliative care in whom symptoms warrant the initiation of medication [14,15], standard treatment utilizing benzodiazepines may be indicated. For patients with a history of chronic anxiety or a mix of anxiety and depression, a selective serotonergic reuptake inhibitor (SSRI) is also indicated. (See 'Benzodiazepines' below and 'Selective serotonin reuptake inhibitors' below.)

For patients in whom symptoms are refractory to standard treatment or concerns for increased susceptibility to adverse events from benzodiazepines are present for whatever reason, alternative agents can be utilized. (See 'Alternative agents' below.)

Due to the limited data available to guide the treatment approach to anxiety for patients in palliative care, there is no consensus on what constitutes the most effective treatment [41]. Therefore, much of the discussion below reflects the clinical experience of the authors/experts at UpToDate.

Benzodiazepines — Benzodiazepines are the medications of choice for the management of acute anxiety reactions. However, caution should be used when using them in the palliative care and hospice populations, as benzodiazepines are associated with many adverse events in the medically ill. (See 'Treatment approach' above.)

In general, multiple agents of this class should not be administered together. The exception to this may be the treatment of complicated situations. For example, a patient with known GAD who also experiences panic attacks may require a long-acting benzodiazepine for the GAD and the use of a short-acting agent only as needed for the panic attacks.

Choice of benzodiazepine and dosing — In most instances, benzodiazepines are selected based on the desired half-life. The longer the half-life, the more sustained the effect of the medication. Medications with a half-life that extends beyond a day or two, such as clonazepam or diazepam, may accumulate, causing mounting side effects and toxicity, and should be used with caution.

Shorter-acting benzodiazepines, such as lorazepam, can be dosed more frequently and are useful not only for anxiety but for nausea and panic attacks.

Benzodiazepines with very short half-lives (eg, alprazolam, oxazepam, triazolam) are not suitable for treating anxiety in that they remain effective for very limited periods of time and are associated with a higher risk of rebound anxiety and withdrawal syndromes.

Patients with compromised hepatic functions may do better with lorazepam, oxazepam, or temazepam, given these drugs are metabolized by conjugation and have no active metabolites.

Whichever medication is chosen, the lowest dose should be used with careful titration to the desired effect with the least burden of adverse effects. Benzodiazepines might need to be tapered if they are causing adverse effects, such as over-sedation, delirium, falls, or cognitive impairments. As disease states progress, especially during the last six months of an illness, these adverse events are more likely and benzodiazepines may need to be avoided, cross-titrated to longer-acting agents, or discontinued [14,15,27,42-46].

As patients receiving palliative care may require discontinuation of benzodiazepines due to side effects or treatment-related toxicity, if indicated, benzodiazepines should be tapered, when practically and medically possible. For patients who have been on them for more than a few days or at moderate to high doses, benzodiazepines should not be tapered faster than 25 percent per week. The longer someone has taken a benzodiazepine, the slower the taper should be.

Side effects — The main side effects of benzodiazepines include:

Sedation

Memory loss

Delirium

Confusion, particularly in patients with preexisting cognitive impairment

Gait instability

Selective serotonin reuptake inhibitors — SSRIs are indicated to manage chronic anxiety or to treat mixed symptoms of anxiety and depression. (See "Comorbid anxiety and depression in adults: Epidemiology, clinical manifestations, and diagnosis".)

Paroxetine is often chosen because it tends to be more sedating and can provide a calming effect, but it can be problematic due to increased drug-drug interactions, frequency of withdrawal symptoms, or anticholinergic properties that require medication discontinuation. The risk for withdrawal is particularly of concern in this population who may lose the ability to take oral medications as they progress to later stages of illness [14,15].

For patients who experience new-onset anxiety, treatment should be initiated at a low dose and titrated slowly, because these medications, while treatments for anxiety, can also induce anxiety. However, higher doses of SSRIs are often needed to manage anxiety (as opposed to depression).

SSRIs tend to have fewer autonomic and anticholinergic side effects than tricyclic antidepressants, which should be avoided in most medically ill patients. Side effects common to SSRIs include transient nausea, gastrointestinal upset, and headache, and most of these agents can cause significant sexual side effects. Some of these drugs, particularly citalopram, may carry a dose-dependent propensity to cause sodium abnormalities and/or cardiac rhythm disturbances, clinically manifested on electrocardiogram as a prolongation of the QT interval.

Alternative antidepressants — Serotonin-norepinephrine reuptake inhibitors (SNRIs) are also effective for anxiety disorders and have efficacy in reducing neuropathic pain. As a class, SNRIs share a similar side effect profile with the SSRIs. The three that target anxiety are venlafaxine, desvenlafaxine, and duloxetine.

Finally, several other agents with unique mechanisms of action, notably bupropion [47-50] and mirtazapine, may have anxiolytic effects. Bupropion has mild stimulant properties and is frequently used in patients with significant fatigue or anergia; like the other antidepressants, it can also stimulate anxiety. Mirtazapine can improve anorexia, nausea, and insomnia at the low end of its dosage range, and many patients experience it as sedating.

The administration of antidepressants for depression and/or anxiety in the general population is discussed separately. (See "Unipolar depression in adults: Assessment and diagnosis" and "Unipolar major depression in adults: Choosing initial treatment" and "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects" and "Pharmacotherapy for social anxiety disorder in adults" and "Pharmacotherapy for specific phobia in adults" and "Generalized anxiety disorder in adults: Management".)

Choosing an antidepressant agent — Several factors should be considered in choosing an antidepressant for anxiety. However, as with any medication, it is important to review medication lists for potential drug-drug interactions before starting an antidepressant.

Predictors of response include whether or not a patient had a good response to a particular antidepressant in the past. If there is no history of prior antidepressant use, knowing if any first-degree relative had been treated previously, and which agent they responded to, may also be useful [51,52].

Agents with a longer half-life (eg, fluoxetine) might expose patients to side effects that take longer to remit upon discontinuation, whereas agents with a shorter half-life (eg, paroxetine) can expose patients to withdrawal syndromes if suddenly discontinued.

Some agents tend to be more sedating (eg, mirtazapine and paroxetine) and may help with sleep. Others tend to be more activating and may help with energy (eg, fluoxetine, bupropion, duloxetine, venlafaxine). The non-SSRIs and non-SNRIs, such as bupropion and mirtazapine, tend to not have sexual side effects. SNRIs, bupropion, and SSRIs (in that order) can all help with neuropathic pain to some degree and might be good choices if neuropathic pain is contributing to anxiety.

Combination therapy — For some patients with severe anxiety, often both a benzodiazepine and an SSRI are initiated. Once the therapeutic effect of the SSRI is achieved, the benzodiazepine may be slowly discontinued, as tolerated.

If there is a question about the appropriate treatment, or if initial treatments are not working in a timely manner, consult a psychiatrist.

Alternative agents — While controversial and without solid evidence, in the authors’ experience with hospice populations, often standard anxiolytic pharmacotherapies either carry significant risk of adverse events, such as memory loss, delirium, falls, and disinhibition (eg, benzodiazepines) or do not work fast enough (eg, SSRIs [53,54]).

We have used gabapentin [55-59] (100 mg PO every hour pro re nata [PRN], to a maximum daily dose of 3600 mg/day) and trazodone [60-62] (25 mg PO every hour PRN for anxiety or agitation; 25 to 100 mg PO at bedtime for insomnia) for thousands of patients as effective, rapid-acting alternatives that appear to carry less risk of adverse events [14,15]. The most common side effects of trazodone are blurred vision, confusion, dizziness, faintness, lightheadedness, sweating, and unusual tiredness or weakness. Priapism is a concern in men. For gabapentin, the most common side effects are sedation, blurred vision, cold or flu-like symptoms, delusions, dementia, hoarseness, lack or loss of strength, lower back or side pain, swelling of the hands, feet, or lower legs, trembling or shaking, and unsteadiness.

Once it is determined how many doses are needed daily, that dosage can be scheduled on a daily basis, with PRNs still available for any breakthrough symptoms. Unfortunately, solid evidence beyond clinical experience is lacking for these approaches.

For patients with extreme anxiety that is unresolved with the above maneuvers, respite or palliative sedation may be an option. However, this is a controversial indication for its use and requires a thoughtful and interdisciplinary discussion with the primary and consultative teams, the patient, and family. (See "Palliative sedation", section on 'Respite sedation'.)

Investigational agents: MDMA and psilocybin — Interest in the therapeutic use of these substances has been increasing, although both drugs are schedule I and are not available for prescription use outside of research trials. Early therapeutic trials of 3,4-Methyl​enedioxy​methamphetamine (MDMA) were performed in the United States between 1977 and 1985 [63]. In 2017, the FDA designated MDMA as a "breakthrough therapy" based on its use in assisting psychotherapy for the treatment of posttraumatic stress disorder (PTSD), and in 2018, psilocybin was designated a "breakthrough therapy" for treatment-resistant depression, both designations allowing for further research to occur.

Overall, while there are some positive data to suggest that both MDMA and psilocybin may have beneficial effects for patients with cancer plus anxiety and/or depression, the studies are small, these substances have known negative impacts on psychological states, and they are not available outside of research trials. Further, the possible need for multi-hour psychotherapy sessions utilized in some of the trials may limit the practicality of delivering this treatment within health care settings.

MDMA — Small trials with MDMA suggest that it might be an effective adjunct to psychotherapy for treating individuals with anxiety [64-69]. However, MDMA taken in isolation, without therapy, does not appear to produce beneficial effects.

The psychotherapeutic mechanism for its potential benefit is thought to be through strengthening therapeutic alliances, decreasing avoidance behaviors, and improving tolerance for the recall and processing of painful memories [64-66]. The effects of MDMA may depend on patient characteristics (biologic sex, genetics, medical and psychiatric history, general health) as well as the dose [70]. MDMA starts to work within 45 minutes. Effects can last up to six hours, depending on the amount taken.

In a small pilot randomized double-blind study among patients with anxiety related to a life-threatening illness, participants in an MDMA group (n = 13) demonstrated a greater mean (standard deviation [SD]) reduction in State-Trait Anxiety Inventory (STAI) scores, -23.5 (SD 13.2), indicating less anxiety, compared with the placebo group (n = 5), -8.8 (SD 14.7) when combined with two eight-hour psychotherapy sessions; however, results did not reach a significant group difference. The MDMA was found to be well-tolerated [71].

MDMA may cause anxiety and increased distress in patients with previous psychiatric issues [72-74]. Taking MDMA alongside antidepressants can also cause dangerous side effects including serotonin toxicity (syndrome), which can lead to coma or death [75].

A discussion of treatment for PTSD using MDMA-assisted therapy is presented elsewhere. (See "Management of posttraumatic stress disorder in adults", section on 'Medications with limited supporting evidence'.)

Psilocybin — Small trials with psilocybin suggest that it is associated with improvement in patients with refractory mood disorders, refractory obsessive-compulsive disorder, end-of-life anxiety, and tobacco and alcohol use disorders [64-66,76-78].

When taken at high doses (0.3 to 0.6 mg/kg), psilocybin can cause mild to profound changes in sensory perception, including synesthesia, euphoria, sensory illusions, and auditory or visual hallucinations. These effects are typically dose dependent and last roughly three to six hours. Further negative effects include feelings of a seemingly "unending experience," as well as other negative psychological symptoms, nausea, vomiting, and transient headaches [79-82].

Efficacy data are presented below:

In a small (n = 12) randomized trial investigating the safety and efficacy of psilocybin for the treatment of anxiety in patients with advanced-stage cancers, no significant change in the self-reported STAI score was found; however, those treated with psilocybin and six hours of continuous bedside monitoring had greater improvement in anxiety at one and three months and in depression at one and six months when compared with those treated with an active placebo (niacin) plus bedside monitoring [83].

In a larger trial among patients with advanced, life-limiting cancer who also had an anxiety or mood disorder (n = 51), participants received a high dose (22 mg/70 kg) or a low dose (1 or 3 mg/70 kg) of psilocybin, with the low dose serving as an active control [84]. Participants were crossed over to receive the alternative dose in a second session five weeks later. Supportive psychotherapy was given before and during the sessions. Significant decreases were seen in depression and anxiety symptoms after five weeks in the high-dose group but not the low-dose group, and this effect persisted through the six-month follow-up. The six-month response rate was found to be 78 percent for depressive syndromes and 83 percent for anxiety syndromes, with remission rates of 65 and 57 percent, respectively.

Another crossover trial, using niacin as an active control, evaluated the efficacy of a single high dose of psilocybin (0.3 mg/kg) in conjunction with psychotherapy in patients with cancer-related anxiety and depressive symptoms (n = 29). Those treated with psilocybin had greater reductions in depression and anxiety immediately after treatment and at the final timepoint of 26 weeks as compared with the placebo group [85]. At follow-up 6.5 months after the intervention, 60 to 80 percent of participants had a sustained response for both depression and anxiety.

The use of psilocybin for treatment of depression is discussed elsewhere. (See "Assessment and management of depression in palliative care", section on 'Psilocybin-assisted psychotherapy'.)

Indications for referral to a mental health specialist — The aim of consultation is to bring the right resources at the right time to the right patient, to ensure clinical excellence, produce favorable outcomes, and provide patient-centered care focused on symptom management and quality of life.

In general, if psychiatric symptoms complicate management of the primary illness or are a major source of suffering, then immediate referral to a mental health specialist should be undertaken. In complicated cases, or those where a second confirming opinion might be helpful, consultation with mental health professionals can often benefit the team, patients, and families. Triggers for consultation can include preexisting psychopathologies, refractory symptoms, ineffective initial treatments, diagnostic uncertainty, complicated family or interpersonal dynamics, concerns about polypharmacy, off-label use of psychiatric drugs, suicidal thoughts, or a desire for hastened death. Ideally, a psychiatrist with advanced palliative care psychiatry skills, either through experience or formal training, would be available for consultation. Alternatively, psychiatrists with subspecialty training in psychosomatic medicine/consult-liaison psychiatry can frequently facilitate more effective management in seriously ill patients [14,15]. Palliative medicine specialists may also have the knowledge and experience in managing such patients.

Consultation for psychiatric and/or psychological treatment for anxiety is suggested in the following situations [86]:

Significant worsening of symptoms

Anxiety interferes with the patient’s ability to function

Anxiety persists for more than seven days

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Palliative care".)

SUMMARY AND RECOMMENDATIONS

While many patients have worries, fears, and apprehensions, they may not rise to the level of an anxiety disorder. In addition, while symptoms of anxiety may be common in these patients, anxiety disorders themselves should not be assumed to be an inevitable or normal part of serious illness and should be treated seriously. (See 'Introduction' above and 'Generalized anxiety disorder' above and 'Panic disorder' above and 'Posttraumatic stress disorder' above.)

While symptoms of anxiety may occur in more than 70 percent of patients in palliative care, approximately only 8 percent meet criteria for a diagnosable anxiety disorder, which is more common among certain subgroups, such as women, physically impaired patients, or younger patients. (See 'Epidemiology' above.)

In hospice and palliative care settings, anxiety is generally described as a feeling of helplessness or fear, often generated by death-related issues. However, anxiety may be related to other quality of life areas, including the physical, psychological, social, spiritual, and practical domains. (See 'Clinical manifestations' above.)

Many symptoms of anxiety overlap with the symptoms associated with other psychiatric disorders, particularly depression, delirium, and dementia. It is important that the clinician aim to distinguish these other conditions from primary anxiety disorders. (See 'Differential diagnosis' above.)

For patients in palliative care, symptoms of anxiety, anxiety disorders, and trauma-related disorders can manifest in various ways. The primary diagnoses in this population include adjustment disorder with anxious features, panic disorder, posttraumatic stress disorder (PTSD), and generalized anxiety disorder (GAD). (See 'Diagnosis' above.)

Routine screening for anxiety and depression should be carried out in palliative care patients. Initial screening can be accomplished with the Patient Health Questionnaire for Depression and Anxiety (PHQ-4) tool (table 1). If the screen is positive for anxiety or depression, the patient should be assessed for an anxiety or depressive disorder using Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria. The severity of these symptoms can be evaluated using the seven-question GAD scale (GAD-7) (table 2) and the nine-item Patient Health Questionnaire (PHQ-9) (table 3), respectively. (See 'Assessment' above.)

Symptoms of anxiety should be treated when an anxiety disorder is present, or for those with a GAD-7 score ≥10, or when symptoms are interfering with function or quality of life. A personalized and engaged treatment approach that is based on developing a strong supportive relationship with the clinical team should be utilized and augmented, if necessary, by psychotherapy, psychopharmacologic treatments, and complementary treatments, including exercise and modifications of lifestyle factors. (See 'Treatment approach' above.)

For most patients entering palliative care in whom anxiety symptoms warrant the initiation of medication, often benzodiazepines are the first step. If symptoms do not improve or are severe, antidepressants or alternative agents may be used. (See 'Pharmacotherapy' above.)

For patients in whom psychiatric symptoms complicate the management of the primary illness, are a major source of suffering, or are unremitting, immediate referral to a mental health specialist should be undertaken. (See 'Indications for referral to a mental health specialist' above.)

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References