Depression in patients with advanced cancer and pain

Abstracts

JUSTIFICATIVA E OBJETIVOS: A observação da importância dos sintomas emocionais no contexto do binômio saúde-doença e os esforços para divulgação da Medicina Paliativa motivaram a realização deste artigo. O objetivo desta revisão da literatura foi propor uma reflexão sobre o diagnóstico de depressão em pacientes com câncer avançado que apresentam quadros de dor com base nos conceitos e definições já existentes. CONTEÚDO: A dor e a depressão são sintomas prevalentes em pacientes com câncer. Considerando os vários pontos de interseção das doenças físicas e mentais, por vezes o diagnóstico de depressão em pacientes com câncer e dor torna-se difícil. Esse dado tem grande importância haja vista que a depressão compromete de forma importante a qualidade de vida dos pacientes, devendo ser diagnosticada e tratada a contento. CONCLUSÕES: Após a revisão da literatura algumas perguntas ficaram sem resposta adequada. Esse fato desperta o interesse para realização de estudos que proponham saídas para diagnóstico preciso e tratamento eficiente desse sintoma em pacientes com câncer avançado.

DOR, Crônica; DOR, Crônica

REVIEW ARTICLE

Jeane Pereira da Silva Juver^I; Núbia Verçosa^II

^IMestre em Medicina pela FM/UFRJ; Pós-Graduanda do Curso de Pós-Graduação em Cirurgia Geral – Setor Anestesiologia – Nível Doutorado; Responsável Técnica pelo Centro de Cuidados Paliativos do Hospital de Jacarepaguá, Rio de Janeiro; Certificado de Área de Atuação em Dor SBA/AMB

^IIProfessora-Associada, Mestre e Doutora em Medicina pela FM/UFRJ; Coordenadora da Graduação da Disciplina de Anestesiologia do Departamento de Cirurgia da FM/UFRJ; Coordenadora da Pós-Graduação em Cirurgia Geral – Área de Concentração: Anestesia e Analgesia; Responsável pelo Ambulatório de Anestesiologia do Hospital Universitário Clementino Fraga Filho (HUCFF/UFRJ); Certificado de Área de Atuação em Dor SBA/AMB

Correspondence to

SUMMARY

BACKGROUND AND OBJECTIVES: The importance of emotional symptoms in the context of the health-disease binomium, and efforts to spread information on Palliative Medicine motivated this article. The objective of this literature review was to propose a reflection on the diagnosis of depression in patients with advanced cancer with pain, based on existing concepts and definitions.

CONTENTS: Pain and depression are prevalent symptoms in cancer patients. Considering the different points of intersection between physical and mental diseases, sometimes the diagnosis of depression in patients with cancer and pain is difficult. This datum is very important because depression decreases considerably the quality of life of patients, and should be diagnosed and treated properly.

CONCLUSIONS: After reviewing the literature, a few questions remained unanswered. This fact awakens the interest to undertake studies that propose precise diagnostic solutions and efficient treatment of this symptom in patients with advanced cancer.

Key Words: PAIN, Chronic: cancer, depression.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La observación de la importancia de los síntomas emocionales en el contexto del binomio salud-enfermedad y los esfuerzos para la divulgación de la Medicina Paliativa, motivaron la realización de este artículo. El objetivo de esta revisión de la literatura fue proponer una reflexión sobre el diagnóstico de depresión en pacientes con cáncer avanzado que presentan cuadros de dolor con base en los conceptos y definiciones ya existentes.

CONTENIDO: El dolor y la depresión son síntomas prevalecientes en pacientes con cáncer. Considerando los diversos puntos de intersección de las enfermedades físicas y mentales, a veces el diagnóstico de depresión en pacientes con cáncer y dolor se hace difícil. Ese dato tiene una gran importancia a causa de que la depresión compromete de forma importante la calidad de vida de los pacientes, debiendo ser diagnosticada y tratada rápidamente.

CONCLUSIONES: Después de la revisión de la literatura algunas preguntas quedaron sin una respuesta adecuada. Ese hecho despierta el interés para la realización de los estudios que propongan salidas para el diagnóstico preciso y el tratamiento eficiente de este síntoma en pacientes con cáncer avanzado.

INTRODUCTION

Health is so valuable to human beings that it has legal guarantees. Article 196 of the Brazilian Constitution state that "Health is a right of everyone and a duty of the State, by guaranteeing social and economic policies aimed at reducing the risk of diseases and factors that aggravate it, and universal and egalitarian access to actions and services for its promotion, protection, and recovery" ¹.

In 1947, the World Health Organization (WHO) defined health as "a state of total physical, mental, and social well-being and not exclusively the absence of disease" ². Recently, another definition proposed by the same institution states that "Health is a biological and social category in dialectical unit with disease, and expresses the level of physical, mental, and social development of the individual and of the collectivity at every historical moment in the development of society" ².

When analyzing the definitions proposed by the WHO, some points should be considered:

a) Health is not only the absence of disease;

b) Physical, emotional, and social well-being is an integral component of the concept of health;

c) The concept of health is subjective because it is considered a state of well-being; and

d) The placement of the concept of health within the historical context of a society.

With passing of time, new concepts with this holistic vision of the human being have been arising. Among them, we should mention the concept of Total Pain proposed by Dr. Cicely Saunders in the decade of 1960. This idea attributed to the symptom pain a connotation that congregates some facets of the human existence: physical, mental, emotional, and spiritual ^3-10.

This concept of Total Pain was developed in England at the St. Cristopher Hospice by Dr. Saunders after evaluating her cancer patients who complained of pain ³. It can also be used in the treatment of patients with other diseases and influenced the development of a new medical modality called Palliative Medicine ⁴.

Initially, Palliative Medicine was used for patients at the final stages of their disease, and its objective was to improve their quality of life and to give them dignity at the time of their death ^3,4.

Currently, Palliative Medicine is defined by the WHO as: "a type of attention that aims at improving the quality of life of patients, and their families, through prevention, diagnosis, and treatment of pain and other physical, psychosocial, and spiritual symptoms." ¹¹, and it can and should be instituted immediately after the diagnosis of the disease and continued until after the death of the patient, i.e., by providing support for the grieving family.

Based on concepts and definitions mentioned previously, acknowledgment of the importance of emotional symptoms, in the context of the health-disease binomium, motivated the review of psychological disturbances in patients with different diseases. The objective of this retrospective study of review of the literature was the diagnosis of depression in cancer patients who also present with pain.

PAIN IN CANCER

It is estimated that more than 50% of cancer patients present pain during the course of their disease. Seventy percent to 90% of patients with advanced disease complain of this symptom, which can be of moderate severity or unbearable in 30% to 50% of the cases¹⁰. Nowadays, with the current scientific development, it is known that more than 90% of those painful cases can be alleviated with medications and procedures available for use in the daily practice ¹⁰.

Cancer pain can be acute or chronic, nociceptive, neuropathic, or mixed, and has several causes ^10,12,13:

• tumor related;

• treatment related;

• related to the development of paraneoplasic syndromes; and

• non-tumor related.

Some painful symptoms can be secondary to a combination of the factors mentioned above and, in some situations it is not possible to identify which ones are involved. However, in order to improve treatment, it is recommended to attempt to identify the cause(s), so it (they) can be removed whenever possible ^10,12.

It is important to evaluate the intensity and location of the pain, as well as the presence of physical and psychological sequelae ^10,12,13.

Treatment of such a prevalent symptom with different causes and behavioral repercussions should be instituted as soon as possible. In the search of treatment options, the World Health Organization (WHO) has developed the analgesic stair (Figure 1) as a treatment guide for cancer pain ^10,12,13.

The classical analgesic stair (with three steps) proposes the pharmacological treatment of pain. Each step presents medications with different pharmacological mechanisms that affect different points of the pathway of the nociceptive stimulus. For this reason, specific groups of drugs are associated in the different steps, being called multimodal analgesia ^10,12,13.

Recently, it has been proposed the addition of a fourth step to the analgesic stair, where invasive procedures, such as analgesic blocks and surgical procedures, would be placed ¹⁰.

However, despite the use of those resources, some patients do not obtain relief for their suffering, which indicates a more complex process than the physical aspect, involving the genesis and maintenance of pain ^3,4,10.

Studies that use the holistic approach to the human being (Total Pain concept) have been presenting more promising results. Treatments aimed at other aspects of pain, besides the physical component, have been developed, which demand a more encompassing decision making that can improve the quality of care, besides allowing more effective relief of pain, with the consequent reduction in human suffering ^3,4.

DEPRESSION

History

The first report on depression was possibly made by Hippocrates, in Greece, who described symptoms of "food aversion, hopelessness, insomnia, irritability, and restlessness " and if they lasted for a prolonged time this would be compatible with melancholy (melan, black, and cholis, bile). This theory is based on the presence of four essential fluids – bile, phlegm, blood, and black bile. Melancholy would result from an imbalance among them, with predominance of the black bile ¹⁴.

During the Middle Ages, Medicine showed little evolution, since diseases and their treatment were conditioned to the theological vision imposed by the Church at the time. Patients with mental disorders were considered witches or possessed. The fate of those who dared to defy the Church was determined by the Inquisition: torture, to exorcise the bad spirits and, in the case of resistance, "witches" were burned alive publicly ¹⁵.

During the Renaissance, the first attempt to separate the origin of mental disorders from the eternal war between God and the devil was made by trying to find an organic, philosophical, and psychological origin. The Anatomy of Melancholy, by Robert Burton, whose major development was the mention of the possibility that disorders in other parts of the body could affect the brain as a cause of melancholy, was the most important work at the time ^15,16.

During the Enlightenment, William Cullen, born in Scotland, suggested that melancholy was secondary to a change in the nervous system and not to humorous imbalance. Parts of the brain would be in an unequal state of "excitation" and "collapse". It was Cullen who made the most detailed description of mental disease of that time ^17,18.

The XIX Century saw a depuration of the concepts of psychiatric disease, which are close to current concepts. The French physician, Dr. Phillipe Pinel, should be mentioned. In 1793, he introduced a more humane treatment of those disorders in Europe. He gave the "mad man" a voice; he listened to the suffering man, humanized him; this became a motto and almost made him a hero. His classification of psychiatric disorders facilitated the distribution of patients in the hospitals ¹⁹.

Only in the decades of 1950 and 1960 the division between unipolar and bipolar depression was adopted by Dr. Karl Krapel ¹⁹.

Dr. Aubrey Lewis was the first to differentiate depression and psychosis, which became a cornerstone to define and orient the treatment of depression ¹⁹.

At last, one cannot speak of psychiatric disorders without mentioning Dr. Sigmund Freud who, in his work "Mourning and melancholy", described the loss of interest for the external world as a similarity between them, but the difference would be the real loss associated with mourning, while in melancholy the object was lost as an object of love (subjective) ¹⁹.

Biological bases

The study of the biological bases of diseases has been developing considerably in the past decades, and that was not different in the field of psychiatric disorders. However, in this area of knowledge, evaluations are difficult due to the complexity and difficulty to access the central nervous system for biochemical measurements ²⁰.

Virtually all known neurotransmitters have been studied in cases of depression, but the most objective results were obtained with noradrenaline and serotonin. Other neurotransmitters and hormones might play a role in the genesis and/or maintenance of this disorder. Some considerations on the role of those substances are presented below ²⁰.

Noradrenaline: The noradrenergic system was the first to be studied. The first hypothesis formulated proposed that depression would be caused by a deficiency in the activity of catecholamines, while depression would be secondary to an increase in their function. The relevance of this correlation was undeniable, and it allowed the development of other hypothesis, besides attributing the character of systemic disease to depression ²⁰.

Another approach to the adrenergic system would be through its receptors, especially pre- and post-synaptic a-2 adrenergic receptors, considered inhibitory noradrenergic receptors, since they prevent the release of the neurotransmitter in the synaptic cleft (negative feedback). This reduces the amount of free adrenaline available to activate the receptors in the post-synaptic membrane, and for the continuity of the chemical transmission of the nervous impulse. Studies have demonstrated an increase in the function and number of those receptors in patients with depression ²⁰.

Dopamine: clinical and experimental studies indicate that dopaminergic neurotransmission is reduced in patients with depression ²⁰.

Serotonin: Similar to the noradrenergic transmission theory, a functional deficit in serotonergic transmission has been postulated. In cases of depression and mania, this neurotransmitter would be reduced. The differential would be the increased noradrenergic activity, in mania, and reduced, in depression. The classical work of Asberg et al. reported a reduction in the levels of the serotonin metabolite in the cephalospinal fluid of suicide victims. The effective therapeutic responses to selective inhibitors of serotonin reuptake corroborate those observations ²⁰.

The most important serotonin receptor in depression is 5HT_1A, found in pre- and post-synaptic membranes, with functions as a negative auto-receptor similar to the a-2 adrenergic receptor ²⁰.

Other neurotransmitters: g-Aminobutiric acid (GABA) is the main inhibitory neurotransmitter. There are strong evidence that the activity of the GABAergic system is reduced in depression, causing changes in the response of catecholamine receptors (adrenaline and noradrenaline) ²⁰.

On the other hand, the activity of the glutamatergic system, mediated by glutamate (the main excitatory neurotransmitter), seems to be increased in patients with depression, which is controversial, since it is an excitatory neurotransmitter. Recent studies have demonstrated that glutamatergic receptor antagonists, especially the NMDA receptor, have an anti-depressant effect ²⁰.

Hormones: It is known that half of the patients with depression have hypercortisolism (increased cortisol production). It is believed that this behavior is related with changes in the activity of the neurotransmitters: noradrenaline, serotonin, acetylcholine, and GABA, which would regulate the release of the corticotrophin releasing hormone (CRH). This hormone stimulates the medulla of the adrenal gland releasing adrenaline, dopamine and cortisol in the blood stream under stress conditions ²⁰.

Nowadays, psychiatric signs and symptoms are also correlated with thyroid disorders. Patients with depression have reduced levels of thyroid-stimulating hormone (TSH) and increased levels of thyroxine (T₄) when compared with controls. However, the importance of those results has yet to be determined ²⁰.

This biochemical approach to depression facilitated the understanding, diagnosis, and treatment of depression, although many mechanisms have not been completely elucidated.

Definition of depression

The colloquial use of the word 'depression' indicates a normal affective state (sadness) and a symptom, syndrome or disease ^21,23.

Sadness is a normal response to situations of loss (a close person, separation, disease), and it has an important adaptive function for the proper processing of information regarding the loss, and its duration varies. In those situations, some type of interest in environmental events is preserved, when the stimulus is adequate, without important psychomotor inhibition ²¹.

Depression, as a symptom, can also be present in several clinical conditions, such as post-traumatic stress disorders, dementia, schizophrenia, alcoholism, hypothyroidism, cancer, and in response to sustained stress. Since it is a symptom of a disease, its approach is linked directly to the treatment of the baseline condition ²¹.

As a syndrome, depression includes, besides mood changes and psychological symptoms, other changes such as: psychomotor (increased latency between questions and answers), cognitive (attention and concentration deficit), of the instinctive and neurovegetative sphere (fatigue, despair), ideation (pessimism, regrets, and guilt), self-depreciation (low self-esteem, feelings of insufficiency), and psychological symptoms (delirium and hallucinations) ²¹.

As a disease, depression has had several classifications ²¹. Currently, two classifications are available: of the European school, present in the ICD-10 (Chapter V of the 10^th edition of the International Classification of Diseases), and the classification of the American Psychiatric Association called DSM-IV (Diagnostic and Statistic Manual of Mental Disorders).

Identification of symptoms for inclusion in the criteria of each classification is, sometimes, a difficult chore; however, ultimately, both classifications reflect the Kraepelin's nosology ²¹.

Specification F32 – Depressive episode, and its subdivisions, of the ICD-10 (Chart I) will be used as basis for our discussion ²². One should mention that this denomination of depressive episode encompasses a heterogenous group of patients, and regarded by the literature as a big "umbrella". However, this is considered the most prevalent form of presentation of the disease in the general population ^21,23.

Discussion

Depressive symptoms in cancer patients do not always constitute classical psychiatric disorders, but psychological disorders that interfere in the quality of life of the individual ⁵.

In depression, psychological and somatic symptoms remain despite the physical improvement, institution of treatment of the disease, and promising laboratorial exams, which is not compatible with the normal sadness in response to losses ⁶. Studies have demonstrated varying results in the incidence of depressive symptoms, but the prevalence in cancer patients is around 50% to 60% ^5-8.

Despite the knowledge of several clinically effective treatments, these patients are not treated properly. This is attributed to the difficult of making a diagnosis of depression in patients with advanced disease, particularly in cancer patients. This difficulty can be a consequence of the intersection between symptoms of depression and those presents in the late stages of the disease (Table I) ²⁴.

To focus the discussion in the correlation between cancer and depressive symptoms, the references mentioned previously will be used: ICD-10 (F32 – Depressive Episodes) and cancer pain syndromes. This choice was based on the fact that uncontrollable pain is the main cause of depression in cancer patients, and its effective control is indispensable for the diagnosis of a psychological disorder ²⁴.

On the anatomical and functional viewpoint, a coincidence between neurotransmitters and receptors involved in the transmission of the nociceptive stimulus and in the genesis and maintenance of depression can be observed. As example, one can mention: serotonin, noradrenaline, dopamine, glutamate, GABA, and their receptors, among others. This correlation could explain some results ²⁵:

1) The fact that pain is a common cause of depression; and

2) The good response to the treatment of a few pain syndromes with anti-depressants.

Still under the biochemical viewpoint, patients with severe pain have increased cortisol secretion, similar to that found in cases of depression. In this case, this increase in adrenal function constitutes a natural mechanism of flight or fight in the face of a stressor. Initially, after the stress factor is corrected, cortisol levels should return to normal. If cortisol levels do not return to normal after organic causes are corrected, one should consider and investigate the diagnosis of depression with specific tools (semi-structured interviews and scales) ²⁵.

Those considerations should be taken into account because studies suggest that the interaction between pain and depression is so important that the first amplifies or triggers the second ²⁵.

As for symptoms in patients with depression, according to ICD-10, the first group mentioned is "depressed mood, loss of interest, reduced joy and energy, leading to constant fatigue and decreased physical activity".

Depressed mood is constantly seen in patients with serious diseases, especially in advanced stages. The fear of suffering (evidenced by pain) and the proximity of death can cause stress. Some degree of sadness should be considered normal and necessary for the psychological restructuring of the individual in face of this condition. Basically, the differentiation between non-disease and disease is characterized by the severity and duration of the symptom. In cases of depression, the symptom is more severe and longer lasting, remaining even after the reduction of the stress. A specific psychological analysis, with interviews and scales, should be done in cases of doubt. The therapeutic test with anti-depressants can and should be instituted ^24,25.

Loss of interest and pleasure are also present in patients facing a diagnosis with a fatal prognosis. However, during mourning for the loss of health, interest and pleasure can return when the individual is properly stimulated. Making plans for the future and maintaining the interest for life and the present are difficult when the patient is in pain, or when death is no longer a distant possibility. In this situation, if pain and suffering are not relieved, associated with the lack of an existential reformulation, it is unlikely that depression will improve. For such, treatment of the physical symptoms (pain), psychological support (support therapy), with a well-defined indication of anti-depressants, are necessary ^24,25.

Reduced energy, with the consequent constant fatigue and reduced activity, are physical symptoms seen in patients with severe pain, especially when involving the bones (bone metastasis). When physical activity is not present, even after the effective treatment of pain, one should consider the diagnosis of depression. This diagnosis should be confirmed through the analysis of the performance scale (if any degree of activity is possible or not) and psychological state (interviews and scales). When depression has been confirmed, it should be treated with antidepressants ^24,27.

Reduced concentration and attention span are frequent in patients with pain difficult to control. The differential diagnosis with depression can only be done after the control of pain. This is corroborated by observing the decrease or increase in pain intensity in patients with chronic pain through an increase or decrease of attention in their activities. Again, there is an anatomical-functional relationship for this correlation, with the participation of the noradrenergic and dopaminergic systems in the locus ceruleus, which are important in pain transmission and in attention systems ¹². Once the diagnosis of depression is established, pharmacological (drugs) and non-pharmacological (support psychotherapy) treatment should be instituted ^24,25.

Reduced self-esteem and self-confidence is common in patients with depression and with severe pain. In cancer patients, pain is frequently related with an important functional loss. Specialized care can evaluate the presence of a normal reaction in face of the difficulties of the advance stage or an associated disorder ^26,27.

Auto-damaging and suicidal ideations are commonly reported as the first possibilities when facing a potentially fatal diagnosis, especially when they result from the fear of physical suffering. In this situation, once more the differentiation is made by the severity and duration of the symptom. Interviews can be used to elucidate whether patients have real suicidal plans, with the structure to accomplish them, or only have vague thought without structure. In both cases, studies in the literature recommend rigorous pharmacological and non-pharmacological treatment to avoid the suicide ²⁴.

Changes in sleep quality are common in patients with advanced cancer. This phenomenon may be related with the occidental view on sleep that existed until the mid-20^th Century, and described by Robert MacNish in his book The Philosophy of Sleep, which states "Sleep is an intermediate state between vigilance and death; vigilance means the active state of all animal and intellectual functions, while death represents is complete suppression". Based on this belief, sometimes patients have sleep disorders related with the fear of impending death ²⁸. Any physical symptom that could justify the change in sleep pattern, such as: pain, nausea, pruritus, constipation, urinary retention, or fever, should be ruled out. There is no doubt that pain is the most common and severe among those symptoms. Once the physical symptom is identified, specific treatment with antidepressants is indicated, as well as non-pharmacological interventions, like relaxation techniques and visualizations ^24-27. Tricyclic antidepressants are a good choice because sedation is one of their side effects, and, therefore, should be administered at night.

The absence of appetite is common in patients with severe pain. The differentiation of the constitutional presentations (advanced disease or pain) of depression is made on basic ground, since appetite is not present in constitutional anorexia, even after the most intense stimuli, may they be verbal, olfactory, or based on taste ^24,25,29. Tricyclic antidepressants, especially amytriptiline, are the drugs of choice because increased appetite is one of their collateral effects, with the consequent increase in weight ²⁹.

CONCLUSIONS

This brief discussion on the data in the literature demonstrated the durable correlation of depression in patients with cancer and pain. However, some questions remain unanswered, such as:

1) Is depression a necessary stage for human restructuring when facing an important loss, such as the loss of health? Should its treatment only be instituted in severe cases like, for example, with risk of suicide?

2) Is concomitant treatment of both conditions indispensable when one considers a total relationship between chronic pain and depression?

3) Are there biochemical measurements with enough sensitivity and specificity that could be useful to differentiate depression from other clinical situations?

4) Are semi-structured scales and interviews used in clinical practice capable of differentiating factors that can be so subtle?

Science is searching the understanding of this fantastic machine, called human being, which is so complex that cannot be understood with the fragmented vision of a particular field of knowledge. The meeting of different knowledge can be achieved through the interdisciplinary and multi-professional approach.

This new modality of care should be the basis for the treatment of patients with any disease, since the first stages, respecting the philosophy of Palliative Care, in order to humanize medical care.

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Depression in patients with advanced cancer and pain

Depresión en pacientes con dolor en el cáncer avanzado

Publication Dates

• Publication in this collection
  15 Sept 2008
• Date of issue
  June 2008

History

• Accepted
  18 Feb 2008
• Received
  23 Feb 2007