Additionally, psychiatrists assist palliative care patients in dealing with somatic complaints such as pain, insomnia, shortness of breath, and nausea, all of which may be exacerbated by psychiatric conditions.3–5
In this article, we review the efficacy and safety of the treatments most commonly used by psychiatrists in palliative care settings.
Pharmacological Concerns in the Terminally Ill
In the absence of large-scale randomized control trials in terminally ill patients, the standard of care is generally based on current best practices. For instance, because most palliative care patients are elderly, well-known pharmacodynamic and pharmacokinetic data from elderly populations, such as the volume of distribution (Vd) of drugs, can guide treatment choices in these settings.3,5,6
Vd is determined by the degree of plasma protein binding and body composition. Elderly patients tend toward increased adipose tissue, leading to a larger Vd for lipophilic drugs. This equates to a longer half-life for many psychoactive drugs, such as barbiturates and benzodiazepines.
Total body water decreases by about 15% in the elderly, resulting in a decreased Vd and increased serum concentrations of water-soluble drugs such as lithium, alcohol, aminoglycosides, and digoxin. Anemia, very common in this population, reduces Vd and increases drug concentrations of water-soluble drugs.6,7
Other pharmacological considerations are drug metabolism and clearance. Since drug metabolism occurs primarily in the liver, decreased liver oxidation in elderly patients increases drug toxicity. Clearance of most drugs and their metabolites occurs via the kidneys and depends on the glomerular filtration rate, which decreases with age.
Serum creatinine is not a reliable indicator of renal function in the elderly, as creatinine is a product of muscle breakdown, and muscle mass decreases with age. Creatinine clearance (CrCl) is a more useful measure of renal function in these patients, but may still lead to dosing errors.6
These facts should lead clinicians to be cautious in administering and dosing medications in elderly palliative care patients.
Effects of Depression
Depression is an under-recognized comorbidity associated with terminal illness.8,9 In the advanced cancer population, depression is not simply a quality-of-life issue, it can impair cognition and contribute to caregiver burnout.8 Besides advising pharmacological management of mood disorders in this population, psychiatrists play a role in helping patients and family members with referrals for grief counseling and stress management.5
Initial studies of depression in advanced cancer and dementia patients suggested that antidepressants such as selective serotonin reuptake inhibitors (SSRIs) were effective and safe. Specifically, sertraline and mirtazapine were superior to placebo for the treatment of depression in Alzheimer’s disease.10,11
However, newer studies show limited efficacy and perhaps even higher adverse drug reactions in older patients taking sertraline or mirtazapine versus placebo.12,13
The potential for drug-drug interactions also must be considered in this population. For instance, antidepressants such as fluoxetine, sertraline, paroxetine, and fluvoxamine inhibit cytochrome P450 (CYP), the major group of liver enzymes involved in drug metabolism and bioactivation; this can decrease chemotherapy efficacy or increase drug toxicity.14,15
Paroxetine shows some benefit in the treatment of cancer-related fatigue, but it inhibits hepatic CYP2D6 isoenzyme and P-glycoprotein, proteins involved in metabolizing drugs such as metoprolol and digoxin. Escitalopram, citalopram, venlafaxine, mirtazapine, and milnacipran are weaker CYP inhibitors.16,17 They therefore have better drug interaction profiles and should be considered first when selecting an antidepressant in this population.
Researchers continue to explore how SSRIs can improve quality of life and lower mortality in palliative care patients. The new frontier of pharmacogenetics may soon shed light on the importance of polymorphisms such as CYP2D6 and CYP2C19 in psychopharmacology and drug efficacy.15,18 For now, current research supports the use of antidepressants in terminally ill patients only when medically indicated for severe depression.13
Relief of Fatigue
Fatigue interferes with clinical function and quality of life and is insufficiently relieved by sleep or rest. When treating fatigue, clinicians must first identify treatable causes of fatigue, including cancer-related fatigue (CRF),19 anemia, chemotherapy side effects, immobilization, depression, and insomnia. For some, CRF can improve after initiation of exercise and treatment of anemia.16,17
Stimulants, particularly methylphenidate, are frequently used for fatigue and depression in patients with advanced cancer, despite limited data regarding the safety of these medications in this patient population.
Currently, there are several clinical trials under way examining stimulants for fatigue and as adjuncts to antidepressants for the treatment of depression and anxiety, but most still await FDA approval based on large-scale randomized control studies.15,16
Stimulants are typically used at low doses in this population, such as methylphenidate at 10 mg/day to 20 mg/day, and are often observed to be effective and well-tolerated.16,17,20
Modafinil, a stimulant developed for the treatment of narcolepsy, also appears safe and well tolerated in the treatment of CRF. However, other trials failed to show the benefit of modafinil over placebo.21
A concern that clinicians often have is the potential for stimulant abuse in both patients and their families. Some strategies to diminish the risk of stimulant abuse include the use of extended release or liquid formulations, along with frequent weekly clinical follow-up visits by hospice nurses or doctors.
Another pharmacotherapeutic concern is the possibility that stimulants may alter hemopoietic growth factors and can increase adverse medical outcomes.16 Further research is clearly necessary to investigate this important potential side effect.
Management of Anxiety
Palliative care patients may experience anxiety related to somatic symptoms, psychological distress, social isolation, uncontrolled pain, spiritual conflict, and fears about the future.3 Somatic complaints include restlessness, insomnia, sweating, tachycardia, hyperventilation, and agitation.5,22
Additionally, medical illness may worsen an existing anxiety disorder. Before initiating treatment, practitioners should look for reversible causes of anxiety. The provider should also ask questions about the ingestion of alcohol or caffeine, as well as evaluate the patient’s medication regimen for drug interactions.3
Practitioners should consider both nonpharmacologic and pharmacologic managements of anxiety in palliative care patients. Empathic exploration can reveal latent causes of worry. Involving members of the interdisciplinary palliative care team — particularly nurses, social workers, or chaplains — helps to address stress related to finances, family conflict, and spirituality. Supportive therapy, both individual and group, can also be helpful in managing multisource stress common to this population.3,5,22
Pharmacologictreatmentsoftendecrease suffering through symptomatic control. SSRIs are first-line treatment for anxiety, although their long latency to action is a disadvantage, particularly in the acutely and terminally ill. Benzodiazepines have the benefit of immediate onset of action, but should be used with caution in both the elderly and medically fragile. Given the accompanying increased risk for delirium, falls, respiratory suppression, and worsened memory, sedatives such as benzodiazepines are best used on a short-term basis only when they are clinically indicated and other measures have failed.
Practitioners should initiate treatment using short-acting medications at a low dose, while slowly titrating based on efficacy and tolerability.5 For the treatment of insomnia, alternatives to the benzodiazepine class include zolpidem 5 mg or trazodone 50 mg.5,22 Ideally, clinicians should try to avoid polypharmacy by using one drug to treat multiple symptoms: For instance, mirtazapine 15 mg is effective in treating depression, weight loss, insomnia, anxiety, and nausea.
Psychosis and Delirium
Delirium can occur in up to 90% of patients with end-stage illness and is not detected in up to 50% of cases.5,16,17 Delirium is characterized by fluctuating consciousness, disorientation, hallucinations, perceptual disturbances, delusions, psychomotor agitation or retardation, mood lability, impaired memory, sleep/wake cycle irregularities, and agitation. Reversible causes, such as dehydration, electrolyte abnormalities, anemia, infections, polypharmacy, and sleep deprivation, must be identified and corrected first.11,16,17
Antipsychotics are first-line agents for the treatment of delirium, psychosis, agitation, and nausea in this end-stage population. The use of haloperidol is widespread, as it can be administered orally (PO), intra-muscularly (IM), or intravenously (IV). IV doses are about twice as potent as PO and IM doses (see Table 1, page 145).
Table 1. Treatment of Comorbidities Associated with Terminal Illness
Careful EPS monitoring, along with baseline and follow-up EKGs, should be routine. If sedation is a goal of treatment, such as in hyperactive delirium and agitation, olanzapine (available PO, IM, or orally dissolving tablets) may be considered over less sedating neuroleptics such as haloperiodol (see Table 2, page 145).
Table 2. Treatment of Delirium/Psychosis
Pain in terminally ill patients is its own topic and beyond the scope of this article. However, pain often interrelates with mood disorders and can be a cause of delirium in palliative care patients. Pain in this setting is most often managed with opioids.2,22–24
Prescribers sometimes withhold necessary opioids because of concerns for respiratory depression. However, recent studies suggest pain medications do not absolutely increase mortality and, in fact, decrease patients’ experience of shortness of breath, or “air hunger,” thus decreasing suffering for both patients and their families.24,25 As a caution, opioids are associated with higher incidences of acute delirium and, due to the previously mentioned considerations of Vd, liver metabolism, and drug clearance, drug levels require frequent adjustments.2,5,22 Patient-controlled analgesia (PCA) pumps, which can cause or exacerbate delirium, should be avoided in this population.25
New Horizons and Potential Strategies
Recent National Cancer Institute (NCI) and National Institutes of Health (NIH) trials have examined several pharmacological interventions for decreasing suffering in advanced cancer patients. Although a comprehensive review is beyond the scope of this article, these studies suggest that patient suffering can be attenuated through the treatment and primary prevention of chemotherapy-induced side effects via the use of antioxidants, radioprotectors, and free-radical scavengers such as tempol.26,27
Another promising treatment is IV vitamin C, which in one trial significantly improved quality of life by reducing fatigue, depression, and sleep disorders in advanced cancer patients.28
Patients with terminal illness often experience psychiatric symptoms, including depression, anxiety, delirium, pain, and fatigue. When deciding on pharmacological interventions for mood, anxiety, and thought disorders in terminal illness, palliative care specialists and psychiatrists should focus on patients’ values, drug risks, and symptom reduction.
An understanding of pharmacokinetics is important not only for predicting therapeutic outcome, but also for explaining the benefits and toxicities of specific drugs to patients.
The potential for drug interactions is relatively high in the terminally ill due to polypharmacy. Therefore, it can be helpful to use one drug to treat multiple symptoms, such as haloperidol for nausea, agitation, and delirium. If there are concerns regarding drug toxicities, a brief medication-free trial can assess whether some medications still provide benefit.
Psychiatrists can offer support for some of the most common stressors affecting palliative care patients, including fear of abandonment, demoralization, and fear of uncontrolled pain. Nonpharmacologic interventions, including cognitive-behavioral therapy (CBT), yoga, tai chi, meditation, massage therapy, pet therapy, and acupuncture can also be helpful.29,30
Psychiatrists should also discuss with patients and families what is known (and perhaps more importantly, what is unknown) about the risks and benefits of pharmacological interventions.
Further research, in the form of symptom-focused, randomized, double blind, placebo-controlled trials, is needed in the terminally ill population.
- WHO definition of palliative care. World Health Organization; 2012. Available at: www.who.int/cancer/palliative/definition. Accessed Feb. 24, 2012.
- Ferris FD, Balfour HM, Bowen K, et al. A model to guide patient and family care: based on nationally accepted principles and norms of practice. J Pain Symptom Manage. 2002;24(2):106–123. doi:10.1016/S0885-3924(02)00468-2 [CrossRef]
- Emanuel LL, von Gunten CF, Ferris FD. The Education for Physicians on End-of-life Care (EPEC) curriculum. Robert Wood Johnson Foundation; 1999. Available at: www.ama-assn.org/ethic/epec/download/plenary_3.pdf. Accessed Feb. 24, 2012.
- Miovic M, Block S. Psychiatric disorders in advanced cancer. Cancer. 2007;110(8):1665–1676. doi:10.1002/cncr.22980 [CrossRef]
- Irwin SA, Ferris FD. The Opportunity for Psychiatry in Palliative Care. Can J Psychiatry. 2008;53(11):713–724.
- Lichtman SM. Guidelines for the Treatment of Elderly Cancer Patients. Cancer Control. 2003;10(6):445–453.
- Baker SD, Grochow LB. Pharmacology of cancer chemotherapy in the older person. Clin Geriatr Med. 1997;13(1):169–183.
- Massie MJ. Prevalence of depression in patients with cancer. J Natl Cancer Inst Monogr. 2004;32:57–71. doi:10.1093/jncimonographs/lgh014 [CrossRef]
- Patrick DL, Ferketich SL, Frame PS, et al. National Institutes of Health State-of-the-Science Conference Statement: Symptom Management in Cancer: Pain, Depression, and Fatigue, July 15–17, 2002. J Natl Cancer Inst Monogr. 2004;(32):9–16.
- Raji MA, Brady SR. Mirtazapine for The Treatment of Depression and Comorbidities in Alzheimer’s disease. Ann Pharmacother. 2001;35(9):1024–1027. doi:10.1345/aph.10371 [CrossRef]
- Lyketsos CG, DelCampo L, Steinberg M, et al. Treating depression in Alzheimer disease: efficacy and safety of sertraline therapy, and the benefits of depression reduction: the DIADS. Arch Gen Psychiatry. 2003;60(7):737–746. doi:10.1001/archpsyc.60.7.737 [CrossRef]
- Banerjee S, Hellier J, Dewey M, et al. Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial. Lancet. 2011;378(9789):403–411. doi:10.1016/S0140-6736(11)60830-1 [CrossRef]
- Stockler MR, O’Connell R, Nowak AK, et al. Effect of sertraline on symptoms and survival in patients with advanced cancer, but without major depression: a placebo-controlled double-blind randomised trial. Lancet Oncol. 2007;8(7):603–612. doi:10.1016/S1470-2045(07)70148-1 [CrossRef]
- Flockhart D. Cytochrome P450 Drug Interaction Table. Available at: www.medicine.iupui.edu/clinpharm/ddis/table.aspx. Accessed Feb. 28, 2012.
- Miguel C, Albuquerque E. Drug interaction in psycho-oncology: antidepressants and antineoplastics. Pharmacology. 2011;88(5–6):333–339. doi:10.1159/000334738 [CrossRef]
- Bush SH, Bruera E. The Assessment and management of delirium in cancer patients. Oncologist. 2009;14(10):1039–1049. doi:10.1634/theoncologist.2009-0122 [CrossRef]
- Centeno C, Sanz A, Bruera E. Delirium in advanced cancer patients. Palliat Med. 2004;18(3):184–194. doi:10.1191/0269216304pm879oa [CrossRef]
- Study of Methylphenidate as Add on Therapy in Depressed Cancer Patients. Clinical Trials (PDQ®). National Cancer Institute at the National Institutes of Health. 2011. Available at: www.cancer.gov/clinicaltrials/search/view?cdrid=721576&version=HealthProfessional&protocolsearchid=10094048. Accessed Feb. 28, 2012.
- Berger AM, Abernethy AP, Atkinson A, et al. Cancer-related fatigue. J Natl Compr Canc Netw. 2010;8(8):904–931.
- Minton O, Richardson A, Sharpe M, Hotopf M, Stone PC. Psychostimulants for the management of cancer-related fatigue: a systematic review and meta-analysis. J Pain Symptom Manage. 2011;41(4):761–767. doi:10.1016/j.jpainsymman.2010.06.020 [CrossRef]
- Blackhall L, Petroni G, Shu J, Baum L, Farace E. A pilot study evaluating the safety and efficacy of modafinal for cancer-related fatigue. J Palliat Med. 2009;12(5):433–439. doi:10.1089/jpm.2008.0230 [CrossRef]
- Sykes N, Thorns A: The use of opioids and sedatives at the end of life. Lancet Oncol. 2003;4(5): 312–318. doi:10.1016/S1470-2045(03)01079-9 [CrossRef]
- Bercovitch M, Adunsky A. Patterns of high-dose morphine use in a home-care hospice service: should we be afraid of it?Cancer. 2004;101(6):1473–1477. doi:10.1002/cncr.20485 [CrossRef]
- Bredin M, Corner J, Krishnasamy M, Plant H, Bailey C, A’Hern R. Multicentre randomised controlled trial of nursing intervention for breathlessness in patients with lung cancer. BMJ. 1999;318(7188):901–904. doi:10.1136/bmj.318.7188.901 [CrossRef]
- Dev R, Del Fabbro E, Bruera E. Patient-controlled analgesia in patients with advanced cancer. Should patients be in control?J Pain Symptom Manage. 2011;42(2):296–300. doi:10.1016/j.jpainsymman.2010.11.020 [CrossRef]
- Cotrim AP, Yoshikawa M, Sunshine AN, et al. Pharmacological Protection from Radiation ± Cisplatin-induced Oral Mucositis. Int J Radiat Oncol Biol Phys. 2011. [Epub ahead of print] doi:10.1016/j.ijrobp.2011.09.026 [CrossRef]
- Vollbracht C, Schneider B, Leendert V, Weiss G, Auerbach L, Beuth J. Intravenous Vitamin C administration improves quality of life in breast cancer patients during chemo-/radiotherapy and aftercare: results of a retrospective, multicentre, epidemiological cohort study in Germany. In Vivo. 2011;25(6):983–990.
- Vig EK, Davenport NA, Pearlman RA. Good deaths, bad deaths, and preferences for the end of life: a qualitative study of geriatric outpatients. J Am Geriatr Soc. 2002;50(9):1541–1548. doi:10.1046/j.1532-5415.2002.50410.x [CrossRef]
- Blaes AH, Kreitzer MJ, Torkelson C, Haddad T. Nonpharmacologic complementary therapies in symptom management for breast cancer survivors. Semin Oncol. 2011: 38(3):394–402. doi:10.1053/j.seminoncol.2011.03.009 [CrossRef]
- Elkins G, Fisher W, Johnson A. Mind-body therapies in integrative oncology. Curr Treat Options Oncol. 2010; 11(3–4):129–140. doi:10.1007/s11864-010-0129-x [CrossRef]