Clinical Practice of Palliative Care: Current Concepts and Future Perspectives

Pain

Pain is a very prominent and distressful symptom in patients presenting at the end of life. The effective relief of pain in a palliative patient depends mainly on a comprehensive assessment to identify the different physical, psychological, social, and spiritual aspects that are specific to each patient, and optimally intervene on a multidisciplinary level.

Cancer pain is a greatly feared symptom in all the patients. A recent meta-analysis reported pooled prevalence rates of 55% for cancer-related pain in patients who were receiving disease modifying treatment and 64% in those with advanced metastatic or terminal disease.¹⁴ An accurate, thorough, and systematic assessment of cancer pain is crucial to identify the underlying etiology and decide a treatment plan. For cancer pain management, we need to know the cancer patient's life expectancy and the exact staging of the cancer pathology. In case the survival chances are low and life expectancy is not much, one can have the freedom of taking higher degree of risks for providing optimum pain relief. On the other hand, if chances are bright for recovery or subsiding of cancer pathology, then spiritual, psychological, and cognitive support and steps for enhancement of quality of life should be undertaken.

Metastatic disease most commonly occurs in the bones, lungs, and liver. Therefore these patients would have pain which may be located at multiple areas of the body including the pain due to bone metastasis or of neuropathic origin.^15,16 Ineffective pain relief further worsens the cancer burden.

Palliative care involves assessing and managing pain that is persistent, may have multiple etiologies, one or more of which are incurable, is impairing function, increasing dependency, and invokes fear of further suffering and death. The pain must be assessed in detail to know which component of pain prevails in a particular patient. Pharmacological management is one of the main modality for the treatment of pain. The choice of pharmacological agent depends on the primary pathology of the patient as well as underlying comorbidities as all the medications have different action and potential side effects. Along with it there is variability between patients in terms of response to a particular drug.

A thorough assessment of pain in palliative care helps in the development of strategies to manage the pain and enhance quality of life. These may include: (1) regular analgesic administration according to the WHO analgesic ladder; (2) use of appropriate pharmacological and nonpharmacological adjuvant therapies; (3) a wide range of strategies to improve mood, morale, general health, and resilience; and (4) open discussions about pain and sufferings to assist in appropriate pain interpretation.

WHO Analgesic ladder: The WHO analgesic ladder is a method to guide symptomatic pain relief¹⁷ (►Fig. 1).

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Fig. 1

Three step analgesic ladder (fourth step is interventional pain management).

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Step 1: Nonopioid ± Adjuvant.

Step 2: Weak opioid + nonopioid ± adjuvant.

Step 3: Strong opioid + nonopioid ± adjuvant.

Step 4: Interventional/neurolytic pain procedures.

A nonopioid is used for analgesia in the first step of the ladder. This is usually paracetamol at a dose of 1 gram every 6 hours. If it is not effective at this dose we move to Step 2. For Step 2, a weak opioid such as codeine is added to the analgesic used in Step 1. This usually means adding codeine to the regular paracetamol already being taken. The recommended dose of codeine is 30 to 60 mg every 4 hours up to a maximum of 240 mg daily. In the Step 3, among the strong opioids morphine remains the “gold standard” as it has been the most extensively studied, and is available in a wide range of formulations and routes.

If peroral use of oral opioids is not possible then it can be administered transdermally, for example, transdermal fentanyl patch (25 μg/h, 50 μg/h, etc.) and transdermal buprenorphine patch (5 mg/h, 10 mg/h). Another option is that of subcutaneous infusion of opioids. For the management of breakthrough pain, intranasal fentanyl sprays or buccal fentanyl tablets or sublingual tablets can be utilized.¹⁸ For an adult who has pain on the regular weak opioid used in Step 2, an appropriate starting dose of oral morphine is 5 mg every 4 hours. Later sustained release preparations can also be used. Laxatives are generally prescribed along with morphine to avoid constipation caused mainly through peripheral opioid receptor.¹⁹ Other side effects associated with the use of opioids are nausea, vomiting caused by direct stimulation of the chemoreceptor trigger zone, or the vestibular apparatus and through the inhibition of gut motility.²⁰

Most opioids are metabolized in the liver by glucuronidation and/or demethylation catalyzed by cytochrome P450 isoenzymes. It is administered carefully in patients with renal impairment due to one of its active metabolites, M3G, which is dependent on kidney for excretion and hence may lead to opioid-related toxicity. So in patients with compromised renal function lipophilic opioids that do not have active metabolites (e.g., fentanyl) should be considered. Hydromorphone and oxycodone are also to be used with caution followed by close monitoring of the patient.^21,22

Long-term usage of opioids in cancer pain may produce hypogonadism and hyperprolactinemia which may ultimately lead to fertility problems. Long-term use may also predispose to chronic fatigue and osteoporosis due to hormonal changes.^23-25 In cases where long acting preparations and opioids with immunosuppressive properties (e.g., morphine) were used the incidence of infection and hospitalization was higher.²⁶ Components of ►Fig. 2 can be very well utilized in cancer pain patients while prescribing them on opioid therapy. Few of the screening tools like opioid risk tool, risk efficacy and screener and opioid assessment for patient with pain revised can be brought into practice to elicit some amount of information as monitored in ►Fig. 2.²⁷ The dose of opioids shall be on the higher side if the intensity of cancer pain increases or there is a fresh development including the addition of neuropathic component in cancer pain or if the patient is cachectic (so the bioavailability of the opioid goes down or if there is a possibility of drug interaction).²⁸ Requirement for increased doses of opioids may also reflect opioid tolerance or opioid-induced hyperalgesia. This can be managed by altering the opioid or its route of administration or by adding ketamine.

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Fig. 2

Basic components for monitoring cancer pain patients who are on opioids.29

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Caraceni et al have brought out revised evidence-based recommendation on behalf of the European Association for palliative care for the relevant use of various opioids in the management of cancer pain.³⁰

Opioids have been combined with antidepressants or antiepileptic drug in tumor-related cancer pain. A recent systematic review concluded that these combination did not significantly improve pain relief compared with monotherapy.³¹

Adjuvants

These medications have effects on specific types of pain syndromes, such as neuropathic or inflammatory pain. Examples are antidepressants and antiepileptic drugs. Tricyclic antidepressants for example amitriptyline, duloxetine, and venlafaxine are commonly used. Anticonvulsants such as gabapentin and pregabalin are used for pain control as well. Amitriptyline is effective in the dose range of 10 to 75 mg/d especially for targeting the neuropathic component of cancer pain. Their anticholinergic effects are the main side effects. Recently duloxetine and venlafaxine have also been used for neuropathic component of cancer pain. Duloxetine has no anticholinergic effect but may produce nausea, vomiting, and is especially beneficial for elderly patient.³²

Gabapentin and pregabalin inhibit voltage-gated calcium channels. They have strong affinity for alpha 2 delta 1 receptors located on voltage-gated calcium channels. They are mainly excreted by renal route hence dosage needs to be adjusted according to creatinine clearance rate and they have no known drug interaction and on long-term use they may produce gain in body weight. Oral gabapentin is administered in the dose range of 300 to 3,600 mg/d in three divided doses, though in Indian patients usually the upper limit is 1,800 mg/d. Oral pregabalin is administered in dose range of 75 to 600 mg/d in two divided doses, though in Indian patient population the upper limit is 300 to 450 mg/d.³³

Corticosteroids are prescribed in a variety of clinical conditions where inflammation is causing pain such as neuropathic pain, cerebral edema, spinal cord compression, bone or visceral pain. Long duration therapy should be avoided due to side effects (►Table 1).^34,35

Interventional pain management should be considered as adjunct to comprehensive medical management in intractable cancer pain patients. The neuroablative procedures involve the use of chemical agents (alcohol 50-100% and freshly prepared phenol 6-10%), heat (radiofrequency), cold (cryoablation), compression, and surgery.³⁶ Neurolytic blockade of peripheral nerves produces short-term pain relief. Intercostal neurolysis has a median duration of 3 weeks.³⁷ Other options are percutaneous cervical cordotomy and radiofrequency ablation. It reduces perception of temperature in addition to pain. Its value in mesothelioma is well documented.³⁸ Continuous programmable intrathecal pumps containing preservative-free morphine, with or without clonidine are also used but their cost is highly exorbitant.³⁹

Breathlessness

Breathlessness is common in people with advanced cancer or cardiorespiratory or neurological disease. It generally occurs by complex interaction among chest walls, lungs, upper airways, and central nervous system. Once reversible causes have been addressed, management focuses on non-pharmacological interventions, aimed at increasing comfort. Pharmacological treatment includes low dose morphine, and if appropriate, benzodiazepines (if anxiety) or oxygen treatment (if hypoxemic). The effectiveness of treatments will vary between patients, so a flexible approach to management is required (►Table 2).

Nonpharmacological strategies⁴⁶ targeted to improve the comfort of palliative care patient include the following:

• Altering the position of the patient to the maximum comfortable position, for example, elevating the head and trunk, or lying with the affected lung downward if only one lung is pathological to decrease ventilation perfusion mismatch.

• Chest physiotherapy and deep breathing exercises.

• Cognitive behavioral therapy⁴⁷ in the form of relaxation exercises.

• Using a humidifier.

• Decreasing room temperature.

• Elimination of irritants such as smoke or allergens which further irritate the airway.

• Opening a window for ventilation.

Providing a window to see outside has a positive impact on the patient.

Positive counseling and reassurance.

Systemic opioids (oral morphine) are safe and effective treatment for breathlessness in advanced stages of chronic obstructive pulmonary disease patients. Low dose benzodiazepines can be used as an adjuvant therapy to allay anxiety. Oxygen is not administered universally to all patients with breathlessness; only patients with established hypoxemia (PaO₂ < 55 mm Hg) are likely to benefit by oxygen therapy. Benefits of oxygen therapy in a hypoxic patient are reduction of hypercapnia and polycythemia thus leading to better sleep and comfort for the patient.⁴⁸

In patients who are not significantly hypoxemic, there is currently no evidence that oxygen reduces breathlessness.⁴⁹

A Cochrane review found no overall improvement in breathlessness among patients with cancer using oxygen; however, some individuals felt better breathing oxygen.⁵⁰

Malignant pleural effusion is also a leading cause of breathlessness. For treatment of malignant pleural effusion, recently Bhatnagar et al observed that with an indwelling pleural catheter along with talc administration, there are greater chances of pleurodesis.⁵¹

Fatigue

Fatigue may be defined as “a subjective, unpleasant symptom which incorporates total body feelings from tiredness to exhaustion, creating an unrelenting overall condition which interferes with a person's ability to function to their normal capacity.” It has a major impact on the quality of life of the patient.⁵²

There is no single preferred assessment tool but for clinical purposes a numerical scale can be followed. This can be a numerical 0 to 10 scale or fatigue scoring system based on palliative care assessment tool as described below⁵³:

1 : no fatigue.

2 : fatigue present but not affecting daily life.

3 : fatigue present and having moderate effect on daily life.

4 : fatigue present and having overwhelming effect on daily life.

Treatable cause of fatigue must be managed first, for example, anemia, infection, drug side effect, insomnia, and depression. Drug management of fatigue may include the use of corticosteroid, psycho stimulants, or antidepressants.⁵⁴

Nonpharmacological measures in the form of physiotherapy, psychological support, occupational therapy can always be used.

Psychological Symptoms like Delirium, Confusion, Anxiety, and Depression

Delirium is one of the common and most serious neuropsychiatric symptom seen in terminally ill patients. It is associated with high degree of morbidity and stress both for the patient and the family members. In Cochrane database of systemic review, delirium is described using a variety of terms such as agitation, acute confusional state, encephalopathy, organic mental disorders, and terminal restlessness.⁵⁵

In a recent study by Bush et al, the authors observed the incidence of delirium and associated symptoms from 43% in general cancer population to 85% in the patients in terminal stage of their illness.⁵⁶

According to Cherny et al, three clinical subtypes of delirium described are as follows⁴⁵:

1. Hyperactive subtype—hyperaroused, hyperalert, agitated.

2. Hypoactive subtype—hypoaroused, hypoalert, or lethargic.

3. Mixed with alternating features of both.

Common precipitating events include sepsis, medication side effects, and metabolic aberrations (particularly hypercalcemia, hyponatremia, uremia, dehydration, brain metastases, or cerebrovascular events).

Pain physicians always face the dilemma to intervene in reversing delirium, and according to Yennurajalingam et al following are the components of a possible strategy to be adopted to manage delirium⁵⁷

• Identify the underlying cause (if possible) and assess its impact on the patient's quality of life.

• Rank the distress of delirium in the context of the patient's overall symptom complex.

• Assess the potential problems associated with correcting the underlying causes and consequent impact on the quality of life (e.g., using intravenous line for antibiotics and patient pulling out).

• Consider the advantages and disadvantages of intervention versus no intervention.

• One must discuss the treatment options with the palliative care patient (if mild cognitive impairment) and the family, to allow informed decision-making and ultimately the development of a consensus on the appropriate level of intervention.

Various medications for the management of agitation and delirium in the end stage of the disease include antipsychotics of newer class such as olanzapine 5 mg, quetiapine, and aripiprazole.

They tend to have lesser extrapyramidal side effects than earlier generation antipsychotics such as haloperidol, chlorpromazine, levomepromazine, or risperidone. In addition, benzodiazepines may be needed for faster control of agitation and anxiety.

Spiritual Support

The philosophy and practice of palliative care operate upon an understanding of a person as a whole along with his disease. It is reflected in the multidimensional approach of the biopsychosocial model. One cannot provide whole-person care without giving consideration to the relevant spiritual needs held by the patients with serious illness. Palliative care providers are also called to be advocates for the spiritual and religious rituals of patients and families, especially at the time of death.⁵⁸

As defined by the Hospice and Palliative Nurses Association, “spiritual distress refers to a disruption in one's beliefs of value system, a shaking of one's basic beliefs.”⁵⁹

Anandarajah and Hight observed that “spiritual distress and spiritual crisis” occur when a person is “unable to find sources of meaning, hope, love, peace, comfort, strength, and connection in life or when conflict occurs between their beliefs and what is happening in their life.”⁶⁰