Judith A. Paice PhD, RN
Pain is relatively common in persons in whom cancer has been diagnosed, ranging from 14 to 100%. At the time of diagnosis, approximately 20 to 75% of adults have pain, while 23 to 100% of those with advanced disease report pain. Children with cancer have similar pain experiences. Because the risk of cancer-related pain is high, universal screening should be conducted in all patients with cancer when they seek medical attention at a clinic or when they are hospitalized. Any report of pain warrants a comprehensive assessment.
The consequences of inadequate cancer pain relief are significant, including increased physiologic stress, diminished immunocompetence, decreased mobility, increased risk of pneumonia and thromboembolism, and increased work of breathing and myocardial oxygen requirements. Furthermore, pain may lead to impaired quality of life. Several groups, including children, older adults, minorities, individuals from lower socioeconomic groups and the uninsured, women, non-English speaking persons, persons with a history of substance abuse, and cancer survivors, are at increased risk for undertreatment of pain. Inadequate assessment and management lead to reduced function, increased risk of depression and anxiety, and ultimately, impaired quality of life.
Cancer pain can be categorized in several ways, including the duration(acute versus chronic), the intensity(mild, moderate, or severe), the quality of the pain (neuropathic, nociceptive, or mixed), and its temporal pattern (continuous, breakthrough, or both). To determine the pain experience of an individual patient, careful assessment is warranted. The assessment techniques, including a detailed pain history and careful physical assessment, described in Chapter 2are essential. Additional components of pain assessment in those with cancer include the following:
Pain assessment generally begins with screening, using one of the available unidimensional tools, such as the 0 to 10 Numeric Pain Intensity Scale. If patients are unable to use this scale, alternatives include a verbal descriptor scale (no pain, mild, moderate, severe). Any patient who identifies having pain, even mild pain, should undergo a more thorough assessment. The Brief Pain Inventory is a valid, clinically useful pain assessment tool that has been used extensively in people with cancer. It includes a diagram to note the location of pain, questions regarding pain intensity (current, average, worst using a 0 to 10 rating scale), as well as items that gauge impairment due to pain (Figure 8-1). The Brief Pain Inventory has been translated into many languages, including French, Italian, Mandarin, and Spanish.
Because pain does not exist in isolation and symptom clusters are common in those with cancer, a comprehensive assessment should include more than pain. Several instruments have been designed to clinically measure multiple symptoms, including the Edmonton Symptom Assessment Scale, the MD Anderson Symptom Inventory, the Memorial Symptom Assessment Scale, and others. A recently developed tool, termed the “Distress Thermometer” is a vertical visual analogue scale designed to look like a thermometer, with 0 meaning “no distress” and 10 (at the top of the thermometer) indicating “extreme distress.” Accompanying the thermometer scale is a checklist that includes a variety of physical, psychological, practical, family support, and spiritual/religious concerns. These are brief, clinically useful tools that quantify the intensity of a variety of symptoms common in cancer. These instruments foster the systematic assessment of pain and other symptoms, while assisting the clinician in forming a treatment plan.
A complete medication history is critical and includes what has been prescribed for pain, what the patient is actually taking, and why any disparity between the two might exist. Studies suggest that cancer patients have significant barriers to taking pain medication (including adverse effects, lack of efficacy, cost, fears of addiction or tolerance, or other concerns), and as a result, adherence is often limited. Advise patients to bring all pill bottles with them to the clinic or hospital, including over-the-counter and herbal medications. This obviates confusion about which drugs are used for pain relief and which are used for other conditions. Patients should also be asked about past and current use of recreational drugs and alcohol. Persons with a past history of substance abuse may be extremely reluctant to take opioids for pain relief, believing that the drugs may cause them to again lose control. Patients with a current history of addictive disease present more complex challenges, although pain treatment is usually possible. Input from addiction specialists and others with expertise in this area can be useful (see Chapter 7 for more information).
During the pain history, patients and their families may reveal their perceptions regarding the meaning of pain. Pain in cancer may signal progressive disease, loss of independence, or perceived punishment for some past indiscretion. Honest and clear discussions of the disease state are warranted, along with revisiting the patient and family's goals. Reframing may be needed (reinterpreting the meaning of the pain), along with referral to therapists, religious figures, social workers, or other support personnel. Consider cultural influences that may affect pain reporting and treatment. For example, in some cultures, admitting to having pain implies weakness.
The comprehensive physical evaluation of pain in cancer includes particular attention to the neurologic examination, including the sensory, motor, and autonomic systems. Observe sites of pain for evidence of infection, trauma, skin breakdown, changes in bony structures, or cutaneous malignant lesions. Sensory evaluation, particularly in patients receiving chemotherapy, can differentiate large fiber versus small neuronal fiber damage. Reduced sensation to vibration or altered proprioceptive ability suggests the large neuronal fiber damage seen with cisplatin and oxaliplatin therapy. Changes in temperature sensation in the affected region and increased pain response (observed by an exaggerated response to pin prick) are indicators of small fiber dysfunction, relatively common after treatment with paclitaxel, docetaxel, and vincristine. Autonomic nervous system dysfunction can occur, particularly when patients have received vincristine, and can be assessed by comparing blood pressure and pulse rate while lying and sitting or standing. In autonomic nervous system dysfunction, the blood pressure drops when the patient is upright, while the heart rate stays relatively constant (unlike hypotension, which results in reduced blood pressure and elevated heart rate). These findings during active cancer treatment often warrant dose reduction or modification of the chemotherapeutic regimen.
Another component of the neurologic examination is evaluation of cranial nerves, particularly with reports of pain in the head or neck. For example, metastases to the base of the skull (more common in breast, lung, or prostate cancer) can lead to eye pain, headache, hearing loss, and other findings depending on the site of the lesion. Leptomeningeal metastases (more common in breast, lung, and non-Hodgkin lymphoma) present as headache, neck or back pain, consistent with the level of the lesion. Both of these syndromes suggest a poor
prognosis and pain management is crucial to enhance quality of life.
Figure 8.1. Brief Pain Inventory (short form). (Reproduced, with permission, from Charles S. Cleeland, PhD, Pain Research Group, Copyright 1991.)
Allodynia, when normal stimulation is perceived as painful, is a relatively common finding in neuropathy. Examples include tactile allodynia in postherpetic or chemotherapy-induced peripheral neuropathy. The evaluation of tactile allodynia includes lightly stroking the area with a brush or cotton ball. Thermal allodynia is evaluated by holding a cool or warm item lightly against the skin. It is an acute neurotoxicity that is commonly seen during infusion of oxaliplatin; patients describe touching a cold item as burning. Thermal allodynia occurs in 85 to 95% of patients and may also include jaw pain, eye pain, ptosis, and pain in the infusion arm. A small percentage of patients, 1 to 2%, may experience pharyngolaryngeal dysesthesia. To prevent this, patients are advised to avoid drinking cold fluids during and a few days after the infusion.
Reflexes may be reduced or absent in affected areas. Standard motor evaluation should include observation of gait as well as assessment of strength and tone. This also provides baseline safety information to begin planning for assistive devices if the patient is unsteady as well as the need for other safety measures in the home. For example, simple ankle braces can prevent falls in patients with foot drop due to spinal metastases and resultant motor weakness. While conducting the physical examination, observe for possible safety concerns. Is ambulation limited, and is use of a cane or other assistive device warranted? Does the patient have significant paresthesias, placing them at risk for trauma, in much the same way the diabetic patient is at risk for infection after minor injury to the feet or hands? Referral to an occupational therapist can determine functional level and need for assistive devices. Home health nurses can make visits to the home to assess for safety in the living environment; in general, one such visit is reimbursed by most third party payers.
Radiographic studies and laboratory analyses can contribute essential information in the care of patients with cancer pain. For example, back pain that is found on magnetic resonance imaging to be a sign of impending spinal cord compression should be aggressively treated to prevent complete compression with paralysis. Bone scans can identify the presence of metastases causing pain, and tumor markers may provide evidence for the spread of a malignancy.
In addition, laboratory data may reveal other conditions that can complicate pain therapy, such as elevated calcium levels as a potential cause of confusion. The extent of the diagnostic evaluation is based on the course of the patient's illness as well as his or her goals for care. Pain may be managed empirically in patients with cancer who have advanced disease, who are no longer considering curative therapy, and who wish to forgo extensive diagnostic evaluation.
Table 8-1. Examples of Acute Pain Syndromes Seen in Cancer.
Specific Cancer Pain Syndromes
Cancer pain syndromes can be grouped in a variety of categories: acute versus chronic, nociceptive (also called somatic) versus neuropathic, and disease-versus treatment-related. Breakthrough pain is a particularly challenging cancer pain syndrome, and several types of breakthrough pain have been identified.
Acute pain is generally due to invasive procedures, such as diagnostic or surgical interventions, or to the effects of chemotherapy and other treatment, including mucositis or bone pain flair after hormonal therapy. The management is not unlike the techniques used to manage acute pain in patients with nonmalignant disease. Table 8-1 lists examples of treatment-related acute pain unique to persons with cancer.
Chronic pain syndromes often include involvement of bone, soft tissue, the viscera, and the nervous system. Bone metastases, more common sources of pain in patients with breast, lung, or prostate cancers, are chronic in nature. Lymphedema, occurring in approximately 20% of women who undergo axillary node dissection, is an example of soft tissue pain associated with significant physical and psychological morbidity. Visceral pain, described as cramping, poorly localized, and diffuse, may arise from involvement of tumor within the liver, intestine, kidney, peritoneum, bladder, or other organs (see Chapter 11). Neuropathic pains can evolve from numerous causes, may be difficult for patients to describe, and are often complex to treat. Finally, many people with cancer experience syndromes unrelated to the cancer or its treatment, such as osteoarthritis.
Nociceptive pain can be somatic or visceral in nature, is generally described as aching or throbbing, and is frequently due to musculoskeletal complications of cancer. Examples include bone metastases or soft tissue involvement by tumor. Painful flair after hormonal therapy is also nociceptive in nature. Squeezing, gnawing, or cramping pain in the abdomen may be due to pressure on organ capsules or stretching of the mesentery or other visceral structures. Visceral pain may be referred, such as the case of tumor in the liver causing stretching of the capsule surrounding the liver, leading to pain in the right upper quadrant, and often, the right shoulder.
Neuropathic pain, described as tingling, burning, electrical, or shooting, suggests damage to central or peripheral nervous system structures. Examples include peripheral neuropathy due to chemotherapy or radicular pain secondary to spinal metastases with infringement upon nerve roots. Chemotherapeutic agents most closely associated with peripheral neuropathy include the following:
Table 8-2 lists common causes of neuropathic pain seen in persons with cancer. The physician should remember that persons with cancer may have comorbid conditions that lead to neuropathic pain or may place these patients at greater risk for the development of neuropathy. These noncancer causes of neuropathy are listed in Table 8-3. See Chapter 10 for a complete discussion of neuropathic pain.
Tumor burden often leads to pain (Table 8-4). The treatment of cancer, including surgery, chemotherapy, radiation therapy, hormonal, and biological therapies, can also lead to pain (Table 8-4). Careful evaluation is essential, along with consideration of goals of care. Treatment-related pain may lead to interruptions in therapy, changes in the cancer regimen, and in some cases, cessation of therapy.
Table 8-2. Common Causes of Neuropathic Pain in Cancer.
Table 8-3. Common Noncancer Causes of Neuropathic Pain.a
Intermittent episodes of moderate to severe pain that occur in spite of control of baseline continuous pain are very common in patients with cancer pain. Despite the prevalence of breakthrough pain, studies suggest that short-acting analgesics are frequently not provided, and patients do not take as much as are allowed. Patients with cancer experience breakthrough pains a few times a day, which last a few moments to many minutes, often occurring without warning. Three general types of breakthrough pain have been described: incident pain, spontaneous pain, and end-of-dose failure.
Incident pain is associated with specific activities, such as coughing or walking. In one study of patients with cancer who were near the end of life, 93% had breakthrough pain; 72% of the episodes were related to movement or weight bearing. Patients should be encouraged to use a rapid-onset, short-duration analgesic formulation in anticipation of pain-eliciting activities or events. When possible, use the same drug that the patient is taking for baseline pain relief for incident pain (eg, long-acting morphine and immediate-release morphine). Adjust and titrate the breakthrough pain medication dose
to the severity of anticipated pain or the intensity and duration of the pain-producing event.
Table 8-4. Common Pain Syndromes Seen in Patients with Cancer.
Spontaneous pain occurs in an unpredictable fashion and is not temporally associated with any activity or event. These pains are more challenging to control. The use of adjuvant analgesics for neuropathic pains may help diminish the frequency and severity of these types of pain. Otherwise, immediate treatment with a potent, rapid-onset opioid analgesic is indicated.
End-of-dose failure describes pain that occurs toward the end of the usual dosing interval of a regularly scheduled analgesic. In this case, the patient taking an oral long-acting opioid formulation consistently reports pain several hours prior to the next dose (or in the case of the fentanyl patch describes pain the day before patch change). This results from declining blood levels of the long-acting analgesic prior to administration or uptake of the next scheduled dose. Pain diaries and questioning about the onset of pain will assist with rapid diagnosis of end-of-dose failure. Strategies include increasing the dose of around-the-clock medication or shortening the dose interval to match the onset of this type of breakthrough pain. For instance, a patient who is taking continuous-release morphine every 12 hours and whose pain “breaks through” after about 8 to 10 hours is experiencing end-of-dose failure. The dose should be increased by 25 to 50%, if this is tolerated, or the dosing interval should be increased to every 8 hours.
Bosompra K et al. Swelling, numbness, pain, and their relationship to arm function among breast cancer survivors: a disablement process model perspective. Breast J. 2002;8:338 .
Caraceni A et al. Classification of cancer pain syndromes. Oncology (Williston Park). 2001;15:1627 .
Caraceni A et al. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol.2004;22:2909 .
Chang VT et al. Validation of the Edmonton Symptom Assessment Scale. Cancer. 2000;88:2164 .
Cleeland CS et al. Assessing symptom distress in cancer patients: the M.D. Anderson Symptom Inventory. Cancer. 2000;89:1634 .
Clohisy DR et al. Bone cancer pain. Cancer. 2003;97:866 .
Drake PA. Hemorrhage after bone marrow harvest: a case presentation. Clin J Oncol Nurs. 2000;4:29 .
Forcina JM. Re: 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. 2002;95:110 .
Hwang SS et al. Dynamic cancer pain management outcomes: the relationship between pain severity, pain relief, functional interference, satisfaction and global quality of life over time. J Pain Symptom Manage. 2002;23:190 .
Kanner R. Diagnosis and management of neuropathic pain in patients with cancer. Cancer Invest. 2001;19:324 .
Mercadante S et al. Episodic (breakthrough) pain: consensus conference of an expert working group of the European Association for Palliative Care. Cancer.2002;94:832 .
Miaskowski C et al. Guideline for the management of cancer pain in adults and children. Glenview, IL: American Pain Society; 2005.
Paice J. Mechanisms and management of neuropathic pain in cancer. J Support Oncol. 2003;1:107 .
Paice J. Pain. In: Yarbro C, Frogge M, Goodman M, editors. Cancer Symptom Management. 3rd ed. Boston: Jones & Bartlett Publishers; 2004:77-96.
Portenoy RK, Conn M. Cancer pain syndromes. In: Bruera E, Portenoy RK, editors. Cancer Pain: Assessment and Management. Cambridge: Cambridge University Press; 2003. pp. 89-108.
Potter VT et al. Patient barriers to optimal cancer pain control. Psychooncology. 2003;12:153 .
Quasthoff S et al. Chemotherapy-induced peripheral neuropathy. J Neurol. 2002;249:9 .
Soares LG. Poor social conditions, criminality and urban violence: Unmentioned barriers for effective cancer pain control at the end of life. J Pain Symptom Manage. 2003;26:693 .
Thomas RR et al. Hypersensitivity and idiosyncratic reactions to oxaliplatin. Cancer. 2003;97:2301 .
Wilson RH et al. Acute oxaliplatin-induced peripheral nerve hyper-excitability. J Clin Oncol. 2002;20:1767 .
The management of cancer pain includes pharmacologic interventions, cancer therapies, and nonpharmacologic techniques.
Pharmacologic therapies include nonopioids (acetaminophen and nonsteroidal anti-inflammatory drugs [NSAIDs]), opioids, and adjuvant analgesics. These are discussed in depth in Chapter 3. Specific cancer-related applications of each of these agents are addressed below. Because of the complexity of many cancer pain syndromes, multimodal therapies are indicated. This may include the use of nonopioids, opioids, and adjuvants, along with nonpharmacologic techniques. These combinations, such as morphine and gabapentin, have been shown to provide better relief than when given individually.
The mechanism of action of acetaminophen is unknown. Acetaminophen is analgesic and antipyretic but has limited anti-inflammatory effect. Available in oral administration, the maximum recommended dose is 4000 mg/d. Inadvertent overdose is common since acetaminophen is found in many combination over-the-counter products, including cold medications and sleep agents. Dose adjustment should be made for persons with hepatic dysfunction, including those patients with liver metastases.
NSAIDs are analgesic, antipyretic, and anti-inflammatory. This class of compounds includes older nonselective agents and selective cyclooxygenase (COX)-2 inhibitors.
The nonselective NSAIDs, such as ibuprofen and naproxen, inhibit COX enzymes, theoretically leading to analgesia as well as adverse effects. These adverse effects are not trivial and include gastrointestinal bleeding, renal dysfunction, and clotting abnormalities. Given these risks and benefits, NSAIDs are an effective component of the multimodal therapy necessary to treat cancer pain in carefully selected patients.
Currently, NSAIDs are available by the oral route in the United States, except for ketorolac, which can be administered parenterally. Because of its potent effects on renal prostaglandins and the gastrointestinal mucosa, potentially leading to renal failure or gastrointestinal bleeding, ketorolac has a very limited role in cancer pain control outside of short-term use after a surgical or other invasive procedure.
Selective COX-2 inhibitors, introduced in 1999, were believed to provide protection from the gastrointestinal effects commonly associated with NSAIDs, of particular concern in people with cancer. Furthermore, celecoxib was being tested as a chemopreventive agent in colorectal and other cancers. However, concern arose regarding the cardiovascular effects of the COX-2 inhibitors, leading to the withdrawal of rofecoxib and valdecoxib from the US market. This concern was based on data suggesting an increased risk of cardiovascular events, including acute myocardial infarction, associated with the use of higher doses (25 mg) of this drug. And although celecoxib remains available, the National Institutes of Health announced that it suspended the use of celecoxib in a large colorectal cancer prevention clinical trial conducted by the National Cancer Institute. The Adenoma Prevention with Celecoxib (APC) trial incorporated celecoxib at doses of 400 to 800 mg/d versus placebo. The trial was stopped because interim analysis demonstrated a 2.5-fold increased risk of major cardiovascular events for participants taking the drug compared with those receiving placebo (see http://www.nih.gov/news/pr/dec2004/od-17.htm). The underlying mechanism of these cardiovascular events is unclear, although one hypothesis includes the role of prostacyclins and thromboxane. Nonselective COX-2 inhibitors, or traditional NSAIDs, suppress both prostacyclins (which prevents platelet formation and clumping, as well as fosters vasodilation) and thromboxane (which enhances platelet clumping and causes vasoconstriction). Selective COX-2 inhibitors block only prostacyclins, hypothetically leading to increased risk of clots. However, alternate mechanisms have also been postulated. When considering therapy with celecoxib, carefully weigh the risks and benefits, the anticipated duration of therapy, and the goals of care.
The pharmacology of opioids has been thoroughly reviewed in Chapter 3. Pure opioid agonists are the mainstay of cancer pain management. There is no role for partial or mixed agonist-antagonist agents in cancer pain control.
Multiple routes of administration are warranted in cancer care. For example, mucositis or dysphagia due
to irradiation of a tumor in the aerodigestive system can lead to inability to tolerate oral administration of opioids. Alternatives to oral opioid administration include the following:
Long-acting (or sustained-release) formulations are the mainstay of cancer care. First, the dosage is titrated using an immediate-release compound until an effective dose is determined. That dose is then converted to one of the available long-acting formulations. Selection is based on the patient's ability to obtain relief with a particular opioid; the need for an oral, enteral, or transdermal delivery method; support in the home to adhere to a particular regimen; and preference.
Long-acting morphine (MS Contin and generic equivalents) is administered every 12 hours, although some patients require 8-hour dosing. Avinza and Kadian can be administered daily, can be opened and sprinkled in applesauce for patients who can swallow soft items but not pills, and they can also be placed in some enteral feeding tubes.
Long-acting oxycodone (Oxy Contin and generic equivalents) can be administered every 12 hours; 8-hour delivery is rarely necessary.
Transdermal fentanyl (Duragesic and generic equivalents) can be administered every 72 hours, although some patients require more frequent patch changes.
Methadone has a long half-life (approximately 15 to 60 hours), thus allowing administration every 8 hours to provide analgesia. In addition to binding to µ opioid receptors, it is an antagonist at the N-methyl-D-aspartate (NMDA) receptor, which may allow improved neuropathic pain control. These attributes, coupled with its low cost, have led to an increase in the use of methadone for pain control.
The equianalgesic dosing of methadone is complicated. In opiate naïve patients, the conversion with morphine may be 1:1. However, when patients are receiving higher doses of morphine (or other opioids), the ratio increases. Few studies have been conducted, thus conversions are approximations:
<100 mg oral morphine equivalents
101-300 mg oral morphine equivalents
301-600 mg oral morphine equivalents
601-800 mg oral morphine equivalents
800-1000 mg oral morphine equivalents
>1000 mg oral morphine equivalents 20:1 (http://www.eperc.mcw.edu , Fast Fact #75)
Titration should be undertaken slowly in most cases, with increases occurring no more frequently than every 1 to 5 days. Several different conversion schema can be found at http://www.cancer.gov/cancerinfo/pdq/supportivecare/pain.
Intravenous and subcutaneous administration of methadone are alternative routes, although there are reports of irritation with subcutaneous delivery. There have been reports of prolonged Q-Twave interval noted with high-dose intravenous delivery of methadone, with the concern that this may be due to additives in the parenteral formulation. However, more recent information suggests this effect may also occur with high-dose oral administration, although others suggest the effect may be due to prolonged administration rather than a high dose.
Methadone is metabolized primarily by CYP3A4 but also by CYP2D6 and CYP1A2. Therefore, drugs that induce CYP enzymes accelerate the metabolism of methadone, resulting in reduced serum levels of the drug (Table 8-5). The patient may experience shortened duration of analgesia or reduced overall pain relief. Examples of these drugs often used in palliative care include several antiretroviral agents, dexamethasone, carbamazepine, phenytoin, and barbiturates. Drugs that inhibit CYP enzymes slow methadone metabolism,
potentially leading to sedation and respiratory depression. These include ketoconazole; cimetidine; omeprazole; and selective serotonin reuptake inhibitors, such as fluoxetine, paroxetine, and sertraline.
Table 8-5. Agents That Interact with Serum Methadone Levels.
Cross-tolerance to opioids develops in patients who are enrolled in a methadone maintenance program for addictive disease. These patients require higher doses than opioid naïve patients. Prescribing methadone for addictive disease requires a special license in the United States. Therefore, prescriptions provided for methadonetomanage pain in cancer care should include the statement “for pain.”
Along with a long-acting opioid, short-acting opioids are indicated to manage breakthrough pain. Break-through dosing of oral opioids is generally 10 to 20% of the 24-hour oral dose. This can be administered as frequently as every hour.
Side effects of opioids are generally preventable or easily managed. See Chapter 3 for additional information. Constipation occurs in most persons requiring opioids for pain control. Prevention is usually effective using a combination stimulant laxative/softener, such as senna and docusate. As the dose of opioid is titrated upward, the dose of laxative/softener generally needs to be increased. Dietary changes, bulking agents such as methylcellulose, and increased fluid intake are rarely sufficient to counteract the constipating effects of opioid therapy in people with cancer.
Nausea is more commoninopioid-naïve persons. Prescribing an around-the-clock antiemetic for the first 24 to 48 hours in patients who have experienced this adverse effect of opioids in the past can obviate this effect. Some patients may require longer-term antiemetic therapy of 1 week or longer. Since many people with cancer have already been treated with an antiemetic during chemotherapy administration, select an antiemetic that has been well-tolerated by the patient in the past, such as phenothiazines (including prochlorperazine) or prokinetic agents (such as metoclopramide). Serotonin 5-HT3 receptor antagonists, such as ondansetron and others in this class, likely have limited usefulness in the management of prolonged opioid-induced nausea and vomiting.
Sedation related to opioid administration is generally managed by switching to an alternate opioid (opioid “rotation” or “switching”) or adding a psychostimulant, such as methylphenidate. In one study that allowed doses up to 20 mg/d taken at any time (morning, afternoon, or evening), patients were found to have relief of sedation, reduced fatigue, improved appetite, as well as deeper sleep. Others have been described safely and effectively using doses of 60 mg and higher.
Myoclonus is a neurotoxicity of opioid administration, usually seen with higher doses of opioid, with concomitant renal dysfunction, often in cases of advanced malignancy. Adding a benzodiazepine, such as clonazepam 0.5 mg orally twice daily, or switching to an alternate opioid may relieve the myoclonic jerking that can occur. Chapter 9 details the management of opioid-induced myoclonus.
Adjuvant analgesics include antidepressants, anticonvulsants, corticosteroids, and local anesthetics. These are key components of the multimodal therapy necessary to treat cancer pain, generally in combination with opioids.
Tricyclic antidepressants appear to provide analgesia through inhibition of nore-pinephrine and serotonin reuptake. A recent consensus
panel listed this category as one of five first-line therapies for the management of general neuropathic pains. Side effects often limit the use of these agents in cancer care. Cardiac arrhythmias, conduction abnormalities, narrow-angle glaucoma, and clinically significant prostatic hyperplasia are relative contraindications to the tricyclic antidepressants. The delay in onset of pain relief of days to weeks may preclude the use of these agents for pain relief in patients with limited life expectancy. On the other hand, their sleep-enhancing and mood-elevating effects may be of benefit.
Venlafaxine, a newer, atypical antidepressant, has been shown to reduce neuropathy associated with cisplatin-induced neuropathy and has the added advantage of treating hot flashes. Case studies suggest venlafaxine is also useful in reducing oxaliplatin-associated neuropathy.
The older anticonvulsants, such as carbamazepine and clonazepam, relieve pain by blocking sodium channels, and as a result, often are referred to as membrane stabilizers. Anticonvulsants are very useful in the treatment of neuropathic pain and may be effective in reducing neuropathic pain associated with chemotherapy. Gabapentin is believed to have several different mechanisms of action, including acting as an NMDA antagonist among other analgesic activities. The analgesic doses of gabapentin reported to relieve pain in noncancer and cancer pain conditions ranged from 900 mg/d to 3600 mg/d in divided doses. A common reason for inadequate relief is failure to titrate upward after prescribing the usual starting dose of 100 mg orally three times daily. Gradual downward titration from gabapentin is critical to prevent possible seizures. Other anticonvulsants have been used with success in treating neuropathies, including lamotrigine, levetiracetam, tiagabine, topiramate, and zonisamide, yet no randomized controlled clinical trials in cancer are currently available. Table 8-6 lists dosing information and adverse effects.
Corticosteroids inhibit prostaglandin synthesis and reduce edema surrounding neural tissues. This category of drug is particularly useful for neuropathic pain syndromes, including plexopathies and pain associated with stretching of the liver capsule due to metastases. Corticosteroids are also highly effective at treating bone pain due to their anti-inflammatory effects, as well as relieving pain due to malignant intestinal obstruction. Dexamethasone produces the least amount of mineralocorticoid effect, and is available in oral, intravenous, subcutaneous, and epidural formulations. The standard dose is 12 to 24 mg/d and can be administered once daily due to the long half-life of this drug. Intravenous bolus doses should be pushed slowly, to prevent uncomfortable perineal burning and itching.
Local anesthetics work in a manner similar to the older anticonvulsants, by inhibiting the movement of ions across the neural membrane and are useful for relieving neuropathic pain. Local anesthetics can be given orally, topically, intravenously, subcutaneously, or spinally. Local anesthetic gels and patches have been used to prevent the pain associated with needle stick and other minor procedures. Both gel and patch versions of lidocaine have been shown to reduce the pain of postherpetic neuropathy, a syndrome common in malignancy. Intravenous lidocaine at 1 to 2 mg/kg (maximum 500 mg) administered over 1 hour, followed by a continuous infusion of 1 to 2 mg/kg/h has been reported to reduce intractable neuropathic pain in patients who are in inpatient palliative care and home hospice settings. Epidural or intrathecal lidocaine or bupivacaine delivered with an opioid can reduce neuropathic pain.
NMDA antagonists are believed to block the binding of excitatory amino acids, such as glutamate, in the spinal cord and brain. Ketamine, a dissociative anesthetic, is thought to relieve severe neuropathic pain by blocking these NMDA receptors. Routine use often is limited by cognitive changes and other adverse effects and a recent Cochrane review found insufficient trials conducted to determine safety and efficacy in cancer pain. Oral compounds containing dextromethorphan have been tested but have been found to be ineffective in relieving cancer pain.
Bisphosphonates may reduce pain related to metastatic bone disease by inhibiting osteoclast-mediated bone resorption (Table 8-7). These drugs are also used to prevent skeletal complications and to treat hypercalcemia. They should not be used in patients without evidence of bony metastases. Pamidronate disodium reduces pain, hypercalcemia, and skeletal morbidity associated with breast cancer and multiple myeloma, although a recent study of prostate cancer failed to demonstrate any benefit. The drug is administered as an intravenous infusion and dosing is generally repeated every 4 weeks. The analgesic effects occur in 2 to 4 weeks. Zoledronic acid, a newer bisphosphonate, has been shown to relieve pain due to metastatic bone disease and is somewhat more convenient in that it can be infused over a shorter duration of time. Clodronate and sodium etidronate appear to provide little or no analgesia. A recent report suggests osteonecrosis of the jaw may occur in patients who have been given bisphosphonates, then undergo dental extraction or other oral surgery procedures, even at a time distant from the bisphosphonate administration. Patients with poor dentition should undergo dental work prior to bisphosphonate therapy.
Table 8-6. Selected Antidepressants and Anticonvulsants Used in the Management of Malignant Neuropathic Pain.
Radiotherapy can be enormously beneficial in relieving pain due to bone metastases or other lesions. In many cases, single fraction external beam therapy can be used to facilitate treatment. Radiolabeled agents such as strontium-89 and samarium-153 have been shown to be effective at reducing metastatic bone pain. Thrombocytopenia and leukopenia are relative contraindications since strontium-89 causes thrombocytopenia in as many as 33% of those treated and leukopenia in up to 10%. Therapy should be considered only in those patients with a projected lifespan of greater than 3 months since there is
a delay in onset of effect. A transitory pain flare is reported by as many as 10% of persons receiving strontium-89, and additional analgesics should be provided in anticipation, as well as patient education.
Table 8-7. Bisphosphonates and Calcitonin for Malignant Bone Pain.
Palliative chemotherapy is the use of antitumor therapy to relieve symptoms associated with malignancy. Patient goals, performance status, sensitivity of the tumor, and potential toxicities must be carefully weighed. Examples of symptoms that may improve with chemotherapy include hormonal therapy in breast cancer to relieve chest wall pain due to tumor ulceration, or chemotherapy in lung cancer to relieve dyspnea.
In addition to previously mentioned spinal administration of analgesics, interventional therapies to relieve pain at end-of-life can be beneficial; these therapies include nerve blocks, vertebroplasty, radiofrequency ablation of painful metastases, procedures to drain painful effusions, and other techniques. However, few of these procedures have undergone controlled clinical studies, particularly in cancer pain. One technique, the celiac plexus block, has been shown to be superior to morphine in patients with pain due to unresectable pancreatic cancer. A complete review of many of these procedures can be found in Chapter 4. Choosing one of these techniques depends on the availability of experts in this area who understand the special needs of cancer patients, the patient's ability to undergo the procedure, and the patient's and family's goals of care.
Table 8-8. Cognitive-Behavioral Therapies for Cancer-Related Pain.
Nondrug therapies, including cognitive-behavioral techniques and physical measures, can serve as adjuncts to analgesics (Table 8-8). These strategies are particularly useful to address periods of increased pain intensity, while waiting for the onset of the immediate-release analgesic. The patient's and caregivers' abilities to participate must be considered when selecting one of these therapies, including fatigue level, belief in the use of these types of techniques, cognitive ability, and other factors.
Cognitive-behavioral therapy includes strategies that improve coping and enhance relaxation. Examples include guided imagery, music, prayer, and reframing. In a randomized clinical trial of patients undergoing bone marrow transplantation, pain was reduced in those patients who received relaxation and imagery training and in those who received cognitive-behavioral skill development with relaxation and imagery, but not in those patients who received treatment as usual or who were randomized to receive support from a therapist. A recent study of art therapy in an inpatient cancer unit revealed a significant reduction in pain, anxiety, fatigue, and other symptoms.
Physical measures, such as massage, reflexology, heat, chiropractic and other techniques, relieve pain, although the mechanism is unknown. In a study of massage inhospice patients, relaxation resulted as measured by blood pressure, heart rate, and skin temperature. In another study, a 10-minute back massage was found to relieve pain in male cancer patients. These are simple inexpensive procedures that can incorporate family members, who are often seeking strategies to demonstrate support of their loved one.
Complex Cancer Pain Syndromes & Their Management
Several syndromes present unique challenges to the management of cancer-related pain. These include bone pain, malignant bowel obstruction, and pain crisis (Table 8-9).
Pain duetobone metastatesorpathologic fractures can be difficult to manage. Bone pain is generally associated with painful breakthrough pain when the patient tries to move in bed, sit, or stand. Although short-acting opioids may be effective, when the patient stops moving, the opioid is no longer necessary as the pain source diminishes, leaving the patient somnolent when at rest. Patient-controlled analgesia may be of benefit while the patient is awaiting surgical repair or fixation of the fracture. If the patient is opioid naïve, a bolus dose should be initiated, with rapid titration to determine the most effective dose to
relieve pain. If the pain is persistent, a basal rate may be calculated based on the necessary total bolus dose during an established time period. The bolus is continued along with the basal rate. For patients already taking opioids, the oral dose can be converted to the basal infusion, or the long-acting opioid is continued and the bolus dose is used for rapid-onset breakthrough pain.
Table 8-9. Management of Complex Cancer Pain Syndromes.
Long-acting opioids combined with short-acting agents are the foundation of long-term treatment of persistent pain. However, additional nonopioid therapies are usually warranted, including corticosteroids, bisphosphonates if indicated, radiotherapy or radionuclides. Vertebroplasty may stabilize the vertebrae if tumor invasion leads to instability.
Bowel obstruction is common in progressive gynecologic (particularly ovarian cancer) and colorectal malignancies. This is a sign of more advanced disease, as the majority of patients with bowel obstruction will die within 6 months. Prevention is sometimes possible by adding corticosteroids to reduce inflammation, along with the aggressive use of stool softeners, laxatives, and agents that stimulate motility, such as metoclopramide. When obstruction cannot be prevented or delayed, several approaches can reduce pain as well as nausea and vomiting. Palliation can include surgery in selected cases, or more commonly, intravenous or subcutaneous octreotide, nasogastric tube suction, and venting gastrostomy, in addition to analgesics and antiemetics. As with all aspects of cancer pain management, the patient's and family's goals must be considered when devising a plan of care. The family's inability to manage external tubes, pumps, or infusion devices may affect the plan of care or result in placement where more assistance can be provided. Hospice usually can provide the support necessary to allow the patient to remain at home.
Most nociceptive (ie, somatic and visceral) pain is controllable with appropriately titrated analgesic therapy. However, some pain syndromes, such as complicated
neuropathic pain or rapidly escalating pain, may be less responsive to conventional analgesic therapies. The following should be considered in the face of a pain crisis:
Barrueto F Jr et al. Gabapentin withdrawal presenting as status epilepticus. J Toxicol Clin Toxicol. 2002;40:925 .
Bell R et al. Ketamine as an adjuvant to opioids for cancer pain. Cochrane Database System Rev. 2003;(1):CD003351 .
Bruera E et al. Methadone use in cancer patients with pain: a review. J Palliat Med. 2002;5:127 .
Bruera E et al. Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study. J Clin Oncol. 2004;22:185 .
Caraceni A et al. Gabapentin for neuropathic cancer pain: a randomized controlled trial from the Gabapentin Cancer Pain Study Group. J Clin Oncol.2004;22:2909 .
Cherny N et al. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol. 2001;19:2542 .
Doverty M et al. Methadone maintenance patients are cross-tolerant to the antinociceptive effects of morphine. Pain. 2001;93:155 .
Durand JP et al. Clinical activity of venlafaxine and topiramate against oxaliplatin-induced disabling permanent neuropathy. Anticancer Drugs. 2005;16:587 .
Dworkin RH et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol. 2003;60:1524 .
Ferrari A et al. Methadone-metabolism, pharmacokinetics and interactions. Pharmacol Res. 2004;50:551 .
Ferrini R et al. How to initiate and monitor infusional lidocaine for severe and/or neuropathic pain. J Support Oncol. 2004;2:90 .
Gilron I et al. Morphine, gabapentin, or their combination for neuropathic pain. N Engl J Med. 2005;352:1324 .
Grothey A. Clinical management of oxaliplatin-associated neurotoxicity. Clin Colorectal Cancer. 2005;5 Suppl 1:S38 .
Hammack JE et al. Phase III evaluation of nortriptyline for alleviation of symptoms of cisplatinum-induced peripheral neuropathy. Pain. 2002;98:195 .
Hanks GW et al. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer. 2001;84:587 .
Indelicato RA et al. Opioid rotation in the management of refractory cancer pain. J Clin Oncol. 2002;20:348 .
Juni P et al. Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? BMJ. 2002;324:1287 .
Kornick CA et al. QTc interval prolongation associated with intravenous methadone. Pain. 2003;105:499 .
Kraeber-Bodere F et al. Treatment of bone metastases of prostate cancer with strontium-89 chloride: efficacy in relation to the degree of bone involvement. Eur J Nucl Med. 2000;27:1487 .
Krantz MJ et al. Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy. 2003;23:802 .
Lauretti GR et al. Comparison of sustained-release morphine with sustained-release oxycodone in advanced cancer patients. Br J Cancer. 2003;89:2027 .
Lucas LK et al. Recent advances in pharmacotherapy for cancer pain management. Cancer Pract. 2002;10:S14 .
Maremmani I et al. QTc interval prolongation in patients on long-term methadone maintenance therapy. Eur Addict Res. 2005;11:44 .
McNamara P. Opioid switching from morphine to transdermal fentanyl for toxicity reduction in palliative care. Palliat Med. 2002;16:425 .
Mercadante S. The use of anti-inflammatory drugs in cancer pain. Cancer Treat Rev. 2001;27:51 .
Mercadante S et al. Pain mechanisms involved and outcome in advanced cancer patients with possible indications for celiac plexus block and superior hypogastric plexus block. Tumori. 2002;88:243 .
Moryl N et al. Pitfalls of opioid rotation: substituting another opioid for methadone in patients with cancer pain. Pain. 2002;96:325 .
Payne R et al. Long-term safety of oral transmucosal fentanyl citrate for breakthrough cancer pain. J Pain Symptom Manage. 2001;22:575 .
Prommer E. Guidelines for the use of palliative chemotherapy. AAHPM Bulletin. 2004;5:1-4.
Ruggiero SL et al. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 2004;62:527 .
Sarhill N et al. Methadone-induced myoclonus in advanced cancer. Am J Hosp Palliat Care. 2001;18:51 .
Sciuto R et al. Metastatic bone pain palliation with 89-Sr and 186-Re-HEDP in breast cancer patients. Breast Cancer Res Treat. 2001;66:101 .
Small EJ et al. Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol. 2003;21:4277 .
Smith MT. Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol.2000;27:524 .
Solomon DH et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation. 2004;109:2068 .
Tanaka E et al. Update: the clinical importance of acetaminophen hepatotoxicity in non-alcoholic and alcoholic subjects. J Clin Pharm Ther. 2000;25:325 .
Tasmuth T et al. Venlafaxine in neuropathic pain following treatment of breast cancer. Eur J Pain. 2002;6:17 .
Watanabe S et al. Opioid rotation to methadone: proceed with caution. J Clin Oncol. 2002;20:2409 .
Wong GY et al. Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer: a randomized controlled trial. JAMA. 2004;291:1092 .
Wong Retal. Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database System Rev. 2002;(2):CD002068 .
Wooldridge JE et al. Corticosteroids in advanced cancer. Oncology (Williston Park). 2001;15:225 .
Wright AW et al. Hydromorphone-3-glucuronide: a more potent neuroexcitant than its structural analogue, morphine-3-glucuronide. Life Sci. 2001;69:409 .
American Cancer Society http://www.cancer.org/docroot/home/index.asp
American Pain Foundation http://www.painfoundation.org
American Pain Society http://www.ampainsoc.org
Cochrane Pain, Palliative Care and Supportive Care Group http://www.cochrane.org/cochrane/revabstr/SYMPTAbstractIn-dex.htm
End of Life, Palliative Education Resource Center - EPERC (Fast Facts) http://www.eperc.mcw.edu/
Federation of State Medical Boards of the United States (for information regarding prescribing controlled substances) http://www.fsmb.org
International Association for the Study of Pain http://www.iasp-pain.org/index.html
National Cancer Institute, PDQ http://www.cancernet.nci.nih.gov/cancertopics/pdq/supportivecare/pain/
National Comprehensive Cancer Network http://www.nccn.org/