Clinical Geriatrics

This article is the third in a continuing series on cancer in older adults. The goal of this series of articles is to highlight the ways in which the diagnosis and management of cancer in older adults differ from the diagnosis and management of cancer in younger patients.

Cancer is a common diagnosis in older adults,¹ yet we lack evidence-based data to guide treatment in the elderly population.² Treatment is further complicated by the heterogeneity of older adults, who vary in their functional status, comorbidities, and polypharmacy; have decreased physiologic reserves; and experience age-related physiologic changes that affect the pharmacokinetics and pharmacodynamics of medications. Due to this complexity, the ability to approach cancer diagnosis and treatment from a “geriatric perspective” is viewed as an essential part of oncologic care.²

Older adults with advanced cancer suffer; pain and other symptoms that negatively affect their quality of life are common and undertreated.^3,4 Clinicians with geriatric expertise have an opportunity to improve care and quality of life for older cancer patients throughout the course of their disease, particularly when the primary goal is palliative.

Providing excellent palliative care begins with assessing the patient’s level of pain and other physical, psychosocial, and spiritual needs. The aim is to preserve quality of life for patients and their families, a central tenet of palliative care, by treating patients appropriately and offering support to them and their families throughout the illness and with bereavement.⁵ In this article, we provide a brief introduction to the steps involved in assessing and managing pain and selected nonpain symptoms in older adults with advanced cancer.

Assessment

Central to palliation is promptly identifying troubling symptoms, implementing the appropriate interventions, and frequently reassessing the patient’s response so that treatment can be adjusted as needed to achieve symptom management goals. Self-report remains the gold standard for symptom assessment, even in patients with cognitive impairment.⁶ Validated symptom assessment scales, such as the Edmonton Symptom Assessment System,⁷ can also be useful.

Some patients with cognitive impairment may have difficulty communicating about their symptoms. Validated scales are available for assessing discomfort in nonverbal patients, and their use is recommended.⁸ If a patient with impaired communication has a condition commonly known to cause discomfort, such as a fracture, wounds, or a history of chronic pain, consider a trial intervention.

Although scales are useful, they are only part of a comprehensive clinical assessment. Symptoms such as pain are multidimensional constructs, in which other domains (eg, psychological state, other physical symptoms, and existential/spiritual and social concerns) interact to form the totality of a person’s experience and expression of symptoms (ie, “total pain”).^9,10 To enhance quality of life, the interdisciplinary approach of hospice and palliative medicine programs requires consideration of all these domains.¹¹

Pain Overview and Management

Pain with cancer is common. It reportedly affects 64% of patients with advanced disease, 59% of patients receiving antineoplastic therapy, and 33% of patients whose cancer has been cured.¹² The undertreatment of cancer pain is also common and has been observed in nursing homes¹³ and in outpatient¹⁴ and inpatient settings.¹⁵ Multiple factors contribute to the undertreatment of cancer pain, including patients’ desires to avoid medications, especially opioids, providers’ difficulty with appropriate pain assessment and a widespread reluctance to prescribe opioids, and system barriers like short office visits leading to time pressures and difficulty scheduling monthly visits for refills of controlled substances.¹⁶ Pain management for geriatric patients is complex. Providers must consider geriatric issues, such as heterogeneity, differing pharmacokinetics, and a high prevalence of comorbidities and polypharmacy, and not allow these to inhibit appropriate pain management.

Nonpharmacologic Therapy

Nonpharmacologic treatment for malignant pain encompasses modalities such as physical therapy, transcutaneous electrical stimulation, administration of heat and cold, psychological and behavioral interventions, complementary and traditional Chinese medicine approaches, mind-body training, and therapeutic massage. Data is conflicted on the effectiveness of nearly all of these modalities, and many are currently being investigated in larger, more scientifically rigorous trials.¹⁷ Strong evidence exists that indicates radiotherapy of skeletal metastases provides pain relief.¹⁸

Pharmacologic Therapy

Since 1986, the basis of pharmacologic treatment has been the World Health Organization’s (WHO) Pain Ladder. Numerous studies have validated this three-step analgesic ladder for treating cancer pain.¹⁹ The conceptual framework of the pain ladder recommends nonopioids for mild pain, lower-dose or “mild” opioids for moderate pain, and higher-dose or “strong” opioids for severe pain, along with adjuvant medications and nonpharmacologic interventions.^20,21 Although the original WHO analgesic ladder—also a three-step approach—suggested different opioids based on pain intensity (eg, codeine for moderate pain), there is no pharmacologic rationale for this approach, and opioids such as morphine or oxycodone can be prescribed at low enough doses to manage moderate pain safely.²¹

Nonopioid Medications. Recommendations for nonopioid pain relief have included the use of acetaminophen, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs) at medium to high doses.²⁰ Due to the renal, cardiovascular, and gastrointestinal adverse events of NSAIDs in older adults, the American Geriatrics Society guidelines recommend acetaminophen as the first-line nonopioid analgesic for these patients.²²

Acetaminophen has a ceiling dose of 4000 mg daily. Exceeding this amount increases the risk of severe liver injury, including liver failure.²³ When calculating the patient’s daily intake of acetaminophen, it is important to include acetaminophen found in any over-the-counter cold and sleep preparations the patient uses and in acetaminophen-opioid preparations, such as hydrocodone plus acetaminophen. To mitigate the risk of acetaminophen overdose, the US Food and Drug Administration (FDA) has asked manufacturers of medications combining acetaminophen and opioids to limit the strength of acetaminophen in these formulations to 325 mg per dosage unit.²³

To reduce the risk of acetaminophen overdose and improve background pain control, it should be prescribed “by the clock” (ie, scheduled administration), rather than on an as-needed basis. Patients should be reminded not to drink alcohol while taking acetaminophen-containing medication.²³ Acetaminophen is contraindicated in patients with hepatic failure and relatively contraindicated in patients with hepatic insufficiency and past or present alcohol abuse.²²

NSAIDs may be more useful than acetaminophen for managing chronic inflammatory pain and in the short-term treatment of osteoarthritis and low back pain²² though studies in elderly cancer patients are minimal. Chronic NSAID use increases the risk of gastrointestinal bleeding, renal failure, hypertension, and cardiovascular adverse events. Older patients have a dose-dependent risk of adverse gastrointestinal effects,²⁴ and even low-dose aspirin or NSAIDs increase the risk for gastrointestinal bleeding two- to sixfold.²⁵ Although cyclooxygenase-2 (COX-2) inhibitors have been shown to decrease the risk of gastrointestinal side effects, they are associated with an increased rate of cardiovascular events.²⁶ Concomitant administration of a gastroprotective agent, such as a histamine-2 (H2) receptor agonist or a proton pump inhibitor, is recommended.²² NSAID use over 2 years in a noncancer population was associated with a 60% increase in the risk of stroke, even in those taking aspirin.²⁷ Because there is limited research in NSAID use in elderly cancer patients and a high rate of frailty in this group, physiologic alterations in the renal, cardiovascular, and gastrointestinal systems related to aging offer a strong relative contraindication to NSAID use.²¹

Opioid Medications. Opioid therapy has been the mainstay of treatment for patients with moderate to severe cancer pain. Patients should be closely monitored during the initiation or titration of opioids.²² As a class, opioids have predictable adverse effects, the most common of which are constipation, sedation, pruritus, nausea, and vomiting. Side effects can often be minimized by decreasing the dose or changing the route of administration (eg, to rectal or intrathecal routes). Opioid rotation (changing opioids when side effects or nonefficacy make continuing current opioid therapy unwise) can minimize intolerance. More commonly, concomitant medications are prescribed to target opiate-induced adverse effects, such as prophylactic laxatives to prevent or lessen constipation.²⁸

Opioids are available in different strengths and preparations. “Weak” opioids—those perched on the second rung of the WHO pain ladder—include codeine, tramadol, and, until recently, propoxyphene. Each carries its own risks when used in elderly patients, and all should be used sparingly. Codeine and tramadol are µ-receptor agonists, and their analgesic effects are negated in patients taking medications that inhibit CYP2D6, such as selective serotonin reuptake inhibitors (SSRIs), H2 blockers, and certain NSAIDs.²⁹ Propoxyphene, which the body converts to a toxic metabolite called norpropoxyphene,²⁹ has been removed from the market in the United States.³⁰

When treating pain in older adults, clinicians should start with nonopioid analgesics and progress, without using the second-rung’s weak opioids, to low-dose “strong” opioids, which are pharmacokinetically more predictable and have better safety profiles than weak opioids.²² Morphine is the prototypical opioid and the one against which the potency of other opioids is compared. It is available in oral, parenteral, and rectal formulations. Morphine is metabolized by the liver into two metabolites that are excreted in the urine. Unless hepatic insufficiency is severe, it does not affect dosing. To prevent opioid toxicity, dose reduction is required for patients with impaired renal function, starting at a creatinine clearance of 50 mL/min.³¹

Hydromorphone, generally thought to be 7.5 times more potent than morphine, is also transformed by the liver into active metabolites that are excreted in the urine. It presents the same risk for toxicity as morphine in patients with impaired renal function.³¹

Oxycodone is only available as an oral preparation, and its efficacy and toxicities are not affected by age, renal function, or serum albumin levels.³¹ The pharmacokinetic profile of oxycodone does not change significantly in the setting of renal insufficiency.

Methadone is increasingly coming into favor as maintenance therapy for chronic cancer pain. Although its excretion is not contingent on renal function, its pharmacokinetic profile varies tremendously among users. This is likely because it is metabolized through the CYP450 pathway in the liver. Methadone has a propensity to accumulate, and patients should be monitored closely. Because methadone can increase QTc intervals and the risk of torsades de pointes (TdP), the patient’s QT interval should be evaluated before methadone is initiated, again at 30 days, and then yearly. If the QTc interval exceeds 500 msec, dose reduction or another agent should be considered. Structural heart disease and a history of arrhythmias are strong relative contraindications for methadone use.³² In retrospective case reports of methadone-induced TdP, most deaths were associated with multiple risk factors, including high daily methadone doses, use of other QTc-prolonging medications or CYP3A4 inhibitors, and electrolyte abnormalities.³³ Consensus guidelines issued in 2008 on the use of methadone in palliative care recommend obtaining an electrocardiogram before initiating therapy, at 24 hours, and at 96 hours, but the guidelines do not advise clinicians on the appropriate response to changes in the QTc interval.³⁴

Fentanyl is a synthetic opioid available as an injection, transdermal patch, lozenge, buccal soluble film or tablet, sublingual film or tablet, and a nasal spray. Fentanyl does not accumulate in patients with renal insufficiency. It is highly protein-bound, however, with an increased risk of accumulation and toxicity in patients with low serum albumin levels. This is of particular concern for patients with cancer, whose lean body mass-to-fat ratio is often low, because it increases the risk of toxicity once fat and muscle stores have been saturated.³¹ Transdermal fentanyl patches should not be used in cachectic³⁵ and opioid-naïve patients. Transdermal fentanyl takes 3 to 5 days to reach a steady state; after patch removal, the drug continues to be released from fat stores and serum drug levels do not decrease significantly for 24 hours.³¹

Adjuvant Medications and Interventional Approaches

Medications with primary uses other than analgesia can have a beneficial effect on pain levels. Although tricyclic antidepressants (TCAs) are considered potentially inappropriate for use in older adults³⁶ with an adverse effects profile that limits administering them at high doses in this population, they have been shown to reduce neuropathic pain.³⁷ SSRIs do not possess analgesic properties, but they can be used to treat coexistent depression that may worsen pain perception. Gabapentin, pregabalin, and other antiepileptic drugs help alleviate neuropathic pain.²² Topical lidocaine patches are commonly used as adjuvant therapy for nociceptive or neuropathic pain, but data demonstrating their safety and effectiveness are limited to post-herpetic neuralgia³⁸ and other neuropathic pain states.³⁹ In a small crossover trial of cancer patients with postsurgical incisional pain, a lidocaine patch was ineffective at reducing pain intensity ratings.⁴⁰ On their own, none of these medications provide sufficient relief of cancer pain, and they should only be used adjuvantly with nonopioid or opioid pain relieving agents.

Bisphosphonates are often helpful in patients with malignancy. They inhibit osteoclastic activity and can decrease metastatic bone pain, which is common in patients with multiple myeloma and breast, prostate, and lung cancers. Intravenous bisphosphonates that are approved for patients with skeletal metastases reduce skeletal morbidity, control malignancy-induced hypercalcemia, and possibly possess antitumor effects.⁴¹ Intravenous administration of bisphosphonates is associated with an increased risk of osteonecrosis of the jaw, a condition that occurs more often in older patients who have coexisting dental or periodontal disease and receive high doses of the therapy over a long period of time.⁴² Bisphosphonates used in conjunction with radiation therapy for those with pain from bony metastases have been found to decrease pain scores and increase quality of life and functional status.⁴³ Bisphosphonates are contraindicated in patients with severe renal insufficiency or uncorrected vitamin D deficiency.⁴² Denosumab, an inhibitor of RANK ligand, was recently found to be noninferior to zoledronic acid at delaying or preventing skeletal-related events in those with advanced cancer, with less acute phase reactions and renal adverse events.⁴⁴

Interventional approaches to managing cancer pain should be considered, particularly when medications are poorly tolerated or pain is refractory.²¹ These include injections, neural blockade, and intraspinal administration of opioids, including implanted delivery systems.^21,45 Celiac plexus neurolysis for intra-abdominal cancer and intercostal nerve blocks for post-thoracotomy intercostal neuralgia⁴⁵ are examples of neurolytic blockades for cancer pain syndromes.