Richard T. Lee and Michael J. Fisch
It is likely that 85% of patients with cancer could be free of significant pain with the techniques we have available today. Most pain from cancer can be adequately controlled with analgesics given by mouth. When this is not possible, various more sophisticated pain management techniques can provide good pain control. Unfortunately, poorly controlled pain and/or analgesic side effects have significant effects on the quality of life of patients and their families. For example, symptoms such as depressed mood, fatigue, anorexia, and sleep disturbance are associated with poor pain control. Likewise, opioid side effects may cause chronic nausea, anorexia, constipation, dehydration, sedation, and confusion. Consequently, overall performance status and adherence to anticancer treatment regimens may deteriorate in the presence of poor pain management. Desperate patients and families may seek relief through unproven therapies or even from physician-assisted suicide. Improving the practice of anticipating, evaluating, and treating pain will benefit most patients.
I. PREVALENCE, SEVERITY, AND RISK FOR PAIN
Most cancer patients with terminal disease need expert pain management. Between 60% and 80% of such patients have significant pain at some point in their trajectory of illness, and nearly 20% of oncology outpatients have moderate to severe pain at any given outpatient visit. Sometimes, chronic pain will be expressed by the patient in confusing terms (“stiffness,” “nagging”) or masquerade as other symptoms (fatigue, apathy, anxiety, anorexia). For this reason, the estimates of the prevalence and impact of chronic pain in this population are probably conservative. Nevertheless, in the United States, 60% of all outpatients with metastatic disease have cancer-related pain, and one-third report pain so severe that it significantly impairs their quality of life. Multicenter studies indicate that about 40% of outpatients with cancer pain do not receive analgesics potent enough to manage their pain, especially among minority patients, female patients, and older patients.
II. ETIOLOGY OF CANCER PAIN
A. Direct tumor involvement
This is the most common cause of pain and is present in about two-thirds of those with pain from metastatic cancer. Tumor invasion of bone is the physical cause of pain in about 50% of these patients. The remaining 50% of patients experience tumor-related pain that is due to nerve compression, tumor infiltration, or involvement of the gastrointestinal tract or soft tissue.
B. Persistent pain after treatment
Persistent pain from long-term effects of surgery, radiotherapy, and chemotherapy accounts for an additional 20% of all who report pain with cancer, with a small residual group experiencing pain from non–cancer-related conditions. Chronic pain is a common problem for cancer survivors with some studies indicating nearly a third reporting active pain symptoms.
C. Complex, chronic pain
Most patients with advanced cancer have pain at multiple sites caused by multiple mechanisms. Pain production occurs either by stimulation of peripheral pain receptors or by damage to afferent nerve fibers. Peripheral pain receptors can be stimulated by pressure, compression, and traction as well as by disease-related chemical changes. Pain due to stimulation of pain receptors is called nociceptive pain. Damage to visceral, somatic, or autonomic nerve trunks produces neurogenic or neuropathic pain. Neuropathic pain is thought to be caused by spontaneous activity in nerves damaged by disease or treatment. Patients with cancer often simultaneously experience nociceptive and neuropathic pain. In addition to evaluating the broad possible causes of pain production, the evaluating clinician should also consider the relevant mechanisms of pain perception and expression. Pain perception refers to the transmission of the nociception to the central nervous system (CNS). Peripheral nerve fibers include myelinated Aδ fibers that are responsible for the transmission of sharp pain and unmyelinated C fibers that carry dull and burning pain. These primary sensory afferents have their cell bodies in the dorsal horn, where the pathways decussate and ascend along the spinothalamic tracts to the thalamus and cortex. Repetitive or continuous stimulation of the peripheral nerves can increase the excitability of the secondary neurons and spread the neurologic region of pain perception and transmission. The N-methyl-D-aspartate (NMDA) receptor is involved in the neurobiology of this “wind-up” phenomenon as well as in the development of tolerance to opioid analgesics. Understanding this biology of pain perception helps account for the observation that some patients experience pain that endures even after the tumor or injury has resolved, and sometimes the pain is more severe than one might expect from the nerve or tissue insult itself. Of course, the clinician can directly observe only pain expression; the production and perception of the pain can be inferred only from indirect clues. Pain expression, that is, how patients report or show their pain, can be influenced by multiple factors (mood, cultural beliefs, etc.). For this reason, effective pain assessment and management necessitates a comprehensive understanding of the patient as a person.
III. ASSESSMENT OF PAIN
Proper pain management requires a clear understanding of the characteristics of pain production, perception, and expression, as described previously. The changing expression of cancer pain demands repeated assessment because new causes of pain can emerge rapidly and pain severity can increase quickly. In patients with advanced disease, pain from multiple causes is the rule and not the exception. A careful history includes asking questions concerning the location, severity, and quality of the pain as well as the aspects of the patient’s daily routine that may be adversely affected by the pain experience.
Health professionals should also consider a comprehensive evaluation of pain that incorporates several dimensions of health including physical, psychospiritual, and sociocultural. Just as pain may affect patients’ moods, anxiety or depression also has been shown to alter patients’ perception of pain. Additionally, sociocultural differences in the meaning of pain will alter how patients experience and express their pain symptoms. Identifying these key factors will assist with successful pain management.
A. Pain severity
Inadequate pain assessment and poor physician–patient communication about pain are major barriers to good pain care. Physicians and nurses tend to underestimate pain intensity, especially when it is severe. Patients whose physicians underestimate their pain are at high risk for poor pain management and compromised function. A small minority of patients with cancer may complain of pain in a dramatic fashion, but many more patients underreport the severity of their pain and the lack of adequate pain relief.
Several studies have confirmed that there are multiple reasons for this hesitancy to report pain, including the following:
Reluctance to acknowledge that the disease is progressing
Reluctance to divert the physician’s attention from treating the disease
Reluctance to tell the physician that pain treatments are not working.
Patients may not want to be put on opioid analgesics because of the following reasons:
Fear of addiction
Concern about possible neurotoxic side effects of opioids (sedation, confusion)
Frustration over gastrointestinal side effects of opioids (nausea, constipation, anorexia)
Fear that using opioids “too early” will endanger pain relief when they have more pain
Fear that opioid use means that death is near
Having accepted religious or societal norms or teachings that pain should be endured.
Presenting information that addresses these concerns in a straightforward manner will allay most of these fears and should be considered as an essential step in providing pain control. It is important that patients understand that they will function better if their pain is controlled and their opioid side effects are prevented or managed effectively. Patient education materials available from state cancer pain initiatives and from the National Cancer Institute (www.cancer.gov), the American Cancer Society (www.cancer.org), the National Comprehensive Cancer Network (NCCN; www.nccn.org), and the American Society of Clinical Oncology (www.cancer.net) can be very useful for both patients and families and should be given to patients when they develop pain.
Communication about pain is greatly aided by having patients use a scale to rate the severity of their pain. A simple rating scale ranges from 0 to 10, with 0 being “no pain” and 10 being pain “as bad as you can imagine.” Used properly, pain severity scales can be invaluable for titrating analgesics and monitoring increases in pain with progressive disease. Mild pain is often well tolerated with minimal impact on a patient’s activities. However, there is a threshold beyond which pain is especially disruptive. This threshold has been reached when patients rate the severity of their pain at 5 or greater on a 0 to 10 scale. When pain is too great (7 or greater on this scale), it becomes the primary focus of attention and compromises most activities that are not directly related to pain. Although it may not be possible to eliminate pain totally, reducing its severity to 4 or less should be a minimum standard of pain therapy.
Often, patients may have difficultly relating to a scale of 0 to 10 or communication may be limited due to neurologic deficits. When initially assessing pain, asking what pain level is tolerable to them may assist with a goal pain score. Other times, patients may indicate only minimal changes in their pain score while showing signs of significant improvement. Rather than using the 0 to 10 scale, others may respond better to mild, moderate, or severe while others may be better able to describe differences in pain by stating by what percentage the pain has changed. When communication is limited, questions may focus on behaviors such as sleep, the provider may ask family members about changes in behavior or irritability, or the provider may consider nonverbal cues such as wrinkling of the forehead. Providing patients with different ways in which to express their pain score as well as the provider’s ability to collect information will assist with assessing treatment interventions.
In some instances, patients may develop chronically high levels of pain expression that do not respond to appropriate initial analgesic dosing and coprescribing of medications to prevent nausea and constipation. The proper care of this subset of patients often requires a multidisciplinary approach; it includes regular administration of pain medication plus counseling and sometimes use of antidepressants or anxiolytic agents. Skillful switching of opioid medications (often called “opioid rotation” or “opioid switching”) can produce a more favorable ratio of analgesia to opioid side effects. Interventional pain procedures may be appropriate in selected cases as well. Such procedures may include nerve blocks (such as a celiac plexus block) or neuraxial delivery of opioids and other adjuvant medications (such as epidural or intrathecal therapies).
B. Diagnostic steps
Those who treat patients with cancer should be familiar with the common pain syndromes associated with the disease:
1. Having the patient show the area of pain on a drawing of a human figure aids identification of the syndrome. This can be particularly helpful in indicating areas of referred pain that commonly coincide with nerve compression.
2. Careful questioning concerning the characteristics of the pain is a key component of diagnosis. For example, pain characterized as “burning” or “shooting” may indicate neuropathic pain.
3. In addition to severity, these characteristics include the temporal pattern of the pain (constant or episodic) and its quality. Episodic or “incident” pain (such as severe pain when standing) requires a different strategy for management than chronic pain.
4. Other important characteristics of pain are its relationship to physical activity and what seems to alleviate the pain.
5. The physical examination includes examination of the painful area as well as neurologic and orthopedic assessment. A brief assessment of mood and cognition is also appropriate. Impaired cognition can confound symptom assessment dramatically.
6. Because bone metastases are a common cause of pain and pain can occur with changes in bone density that is not detectable on radiographs, bone scans can be helpful. Magnetic resonance imaging (MRI) is useful in the evaluation of retroperitoneal, paravertebral, and pelvic areas as well as the base of the skull.
C. The impact of pain on the patient
When pain is of moderate or greater severity, one can assume that it has a negative impact on the patient’s quality of life. That impact, including problems with sleep and depression, must be evaluated and treated when appropriate. A reduced number of hours of sleep compared with the last pain-free interval, difficulties with sleep onset, frequent interruptions of sleep, and early morning awakening suggest the need for appropriate pharmacologic intervention. Just as patients hesitate to report severe pain, they may hesitate to report depression. Family caregivers can often provide important clues regarding the presence or absence of a mood disturbance. Significant depression should be treated. Treatment approaches may include use of antidepressants, counseling, and/or referral to a behavioral health specialist. Sometimes a patient will accept only one of the suggested options, thus requiring some degree of flexibility on the part of the clinician in order to achieve the best results.
It is important to make an attempt to differentiate between physical pain and psychological distress. Accurate pain assessment in patients who are cognitively impaired, particularly those with agitation, may be extremely difficult. A small number of patients in severe psychosocial distress express their concerns as a report of physical pain. These patients present with symptoms that may be attributable to either agitated delirium or pain. Although it is important to recognize severe somatization and to provide psychiatric referral or counseling to these patients, it is equally important to recognize true physical pain. Because of the possible misinterpretation by patients that the medical establishment is atrributing their pain as entirely psychological in nature, a frank discussion with patients regarding the difficulty many patients have distinguishing between physical and emotional pain, which often occur together, may help patients understand your approach and often provide an opportunity to acknowledge different sources of pain they may not have considered. Ultimately, the treatment approach for this difficult situation includes concomitant provision of pain treatment(s) and management of the patient’s underlying psychological distress.
D. Addiction/aberrant drug-taking behaviors
Some patients with alcohol or drug addiction may request analgesics for their psychological effects or may have aberrant drug-taking behaviors. Aberrant drug-taking behaviors may include requests for frequent, early renewals; unauthorized dose escalations; reports of lost or stolen prescriptions; adamant requests for specific medications; and acquisition of similar drugs from other medical sources. Patients with past or current substance use disorders may also be difficult to treat because of fear of exposure to opioid analgesics and their potential vulnerability to addiction. In any case, these behaviors or fears should be discussed openly and in nonjudgmental terms with the patient. Ultimately, an agreement should be reached about the use of opioids for the management of pain (as opposed to mood alterations), and some details about the expectations and responsibilities of both the physician and the patient should be delineated. With this group of patients, long-acting opioids or continuous infusion is often preferable to short-acting opioids or patient-controlled analgesia. Although their care is more complex, patients with drug or alcohol addiction should not be denied appropriate pain medications.
A. General aspects
All healthcare professionals who see patients with cancer should be familiar with standard guidelines for management of cancer pain such as those published by the NCCN or the Agency for Healthcare Research and Quality. An example of a cancer pain practice guideline is shown in Table 31.1. This guideline incorporates basic principles of cancer pain assessment, initial treatment, and routine management of opioid side effects.
The prompt relief of pain from cancer frequently involves the use of simultaneously rather than serially administered combinations of drug and other adjunctive therapies. Identification of a treatable neoplasm as a factor in pain production calls for appropriate radiotherapy (e.g., to bone metastases), chemotherapy, or, in some instances, surgical debulking. Until such treatment can be effective (this may take days to weeks), the patient’s pain must be managed with analgesics with or without other specific interventional pain procedures. In some instances, analgesics are the only effective palliative treatment available because of the patient’s condition, the physical basis of the pain, or limited treatment options. The principles of pharmacologic management of pain are evolving through studies of analgesic effectiveness and research on the use of combinations of palliative medications.
There is a growing consensus concerning the types of drugs to use, their routes of administration, and how best to schedule them. The first step is to assess the severity of the pain. Simple categories such as mild, moderate, and severe are often sufficient. Second is the choice of analgesic drug to be used (nonopioid, opioid, or a combination of both), which is commonly based on the severity level. The next step is the choice of adjuvant drugs, which can increase analgesic effectiveness and can produce other palliative effects to counter the disruptive consequences of pain. Finally, some consideration should be made on follow-up assessment of the interventions to ensure adequate relief is achieved.
B. Nonsteroidal anti-inflammatory drugs (NSAIDs)
1. Mechanism of action and selection of agents. NSAIDs constitute the majority of nonopioid analgesics. Their effect on the inflammatory process is a key to their analgesic property. Tumor growth produces inflammatory and mechanical effects in adjacent tissues that can trigger the release of prostaglandins, bradykinin, and serotonin, which in turn may precipitate or exacerbate pain in the surrounding tissues. Prostaglandins are frequently associated with painful bone metastases because of their involvement in bone reabsorption. NSAIDs appear to exert their analgesic, antipyretic, and anti-inflammatory actions by blocking the synthesis of prostaglandins. Table 31.2 gives the usual starting doses and dose ranges for several commonly used NSAIDs. The concern about NSAIDs are due to reports of cardiac toxicity associated with celecoxib as well as most other agents in this class. It is appropriate to discuss the cardiac toxicity of these agents in the context of the risk/benefit ratio relative to the condition(s) for which they are being prescribed.
By virtue of their different mechanisms of action and toxicity profiles, NSAIDs and opioids are often administered together. Enteric-coated aspirin is one of the first-choice drugs for mild to moderate cancerpain. Other NSAIDs such asibuprofen, diflunisal, naproxen, and choline magnesium trisalicylate have established value in the management of clinical pain. These drugs are better tolerated than aspirin but are usually significantly more expensive. Individual differences in analgesic response to the various NSAIDs clearly occur but are not yet well understood.
Cyclooxygenase (COX)-2 NSAIDs are inhibitors of COX-2, the enzyme expressed in inflamed tissues, and have minimal or no effects on COX-1, the enzyme expressed normally in the stomach and kidney. These NSAIDs are widely used because of their once- or twice-daily dosing schedule and the roughly 50% relative reduction in significant gastrointestinal adverse events compared with those induced by other NSAIDs.
2. Side effects. NSAIDs have a number of potentially serious side effects, including gastritis and gastrointestinal hemorrhage, bleeding due to platelet inhibition, renal failure, and cardiac toxicity. Most of these side effects are related to the prostaglandin inhibitory effect of NSAIDs and are therefore common to all of these drugs. Renal failure due to the inhibition of renal medullary prostaglandins can be of particular concern for patients who are also receiving opioids. Decreased renal elimination of active opioid metabolites can result in somnolence, confusion, hallucinations, or generalized myoclonus. Therefore, kidney function should be monitored in patients receiving a combination of NSAIDs and opioids.
Gastrointestinal complications include gastric pain, nausea, vomiting, hemorrhage, and, in extreme cases, perforation. Gastrointestinal damage is mediated by prostaglandin inhibition. The most common form of nephrotoxicity associated with NSAIDs is renal failure related to prostaglandin inhibition and consequent vasodilation. Hepatic injury has been reported with the use of aspirin, benoxaprofen, and phenylbutazone and, less commonly, with diclofenac, ibuprofen, indomethacin, naproxen, pirprofen, and sulindac. Sulindac, however, appears to be associated with a higher incidence of cholestasis.
NSAID use is also associated with various hypersensitivity reactions involving the skin (rash, eruption, itching), blood vessels (angioneurotic edema, vasomotor disorders), and respiratory system (rhinitis, asthma). In particular, aspirin may cause anaphylactic crisis, a syndrome characterized by dyspnea, sudden weakness, sweating, and collapse. Undesirable hematologic effects of NSAIDs include platelet dysfunction, aplastic anemia, and agranulocytosis. Factors often considered in the empiric selection of an NSAID for a given patient include its relative toxicity, cost, and dosage schedule and the patient’s prior experience. The use of certain aspirin analogs (choline magnesium trisalicylate) has been associated with a low incidence of gastropathy and platelet dysfunction. The effects of NSAIDs used as single agents in the management of cancer pain are characterized by a ceiling effect, beyond which further increases in dose do not enhance analgesia.
C. Opioid analgesics
1. When to start therapy. The choice of using an opioid analgesic as opposed to a nonopioid analgesic follows from an assessment of the severity of pain. The decision is relatively easy when pain is mild (choose nonopioid) or severe (choose opioid, usually in combination with a nonopioid). The choice is more difficult when the patient reports moderate pain, especially when there is reason to suspect that the patient may be underreporting pain severity. Several studies have documented that the pain of many patients with cancer are inadequately managed because of the physician’s reluctance to use opioids in dosages and with schedules known to be sufficient to relieve moderate pain.
Opioid analgesics should be prescribed promptly as soon as there is evidence that pain is not well controlled with nonopioid analgesics. When pain is moderate to severe, it is also appropriate to use a strong opioid as a first-line treatment for cancer pain.
2. Schedule of treatment and selection of dose. Except for a minority of patients whose pain is clearly episodic (often called “incidental pain”), analgesics should be given on an around-the-clock basis, with the time interval based on the duration of effectiveness of the drug and the patient’s report of the duration of effectiveness. There is evidence that the total opioid requirement is lower when opioids are given on a scheduled basis, thereby preventing peaks of pain. Putting patients in the position of having to ask for medication or continually making a judgment about whether their pain is severe enough to take analgesics focuses their attention on pain, reminds them of their need for drugs, and allows pain to reach a severity not readily controlled by the same doses that would be effective with scheduled administration. When writing a scheduled dose of opioids, adding notation that patients may refuse doses will allow the patient to remain in control of pain medication dosing and often avoid unnecessary anxiety and conflict between nursing staff and patients. Nevertheless, there may be large individual differences in the required dose of opioid, depending on such factors as the patient’s opioid use history, activity level, and metabolism. The patient’s report of pain severity and pain relief is the best guideline for opioid titration.
3. The so-called weak opioids, including codeine and hydrocodone, usually formulated in combination with acetaminophen or aspirin, can provide patients with good pain relief for long periods of time. As disease advances, oral administration of the more potent opioids provides most patients with pain relief. There is considerable agreement that propoxyphene is not ideal for chronic use because of its low efficacy at commercially available doses; because of the presence of a toxic metabolite, which is a CNS stimulant, at higher doses; because it has a long serum half-life; and because it has no analgesic properties. Oral administration is preferred, but the physician must remain flexible to changes that are dictated by the patient's ability to use orally administered drugs. This may include the use of opioid and nonopioid suppositories and other alternative routes of administration (transdermal, sublingual, rectal, subcutaneous).
4. Oral morphine, either in an immediate- or sustained-release preparation, is the analgesic of choice for moderate to severe cancer pain. Long-acting formulations of morphine and other strong opioids may be convenient for both the patient and the healthcare staff, but they are usually most expensive. Immediate-release morphine is much cheaper, however, and is as effective for chronic pain relief when administered on a regular schedule. A typical starting dose for immediate-release oral morphine is 15 to 30 mg every 4 hours in patients who are not currently receiving opioids. When a patient is switching from another opioid (usually codeine or oxycodone) to morphine, it is important to calculate the equianalgesic morphine dose as a basis for determining what morphine-equivalent doses are the threshold for pain control (Table 31.3). The starting dose may not be sufficient and relatively rapid upward titration may be needed, especially if pain is severe.
The upward titration of morphine and other oral opioid analgesics can be done by giving a supplemental “boost” using 25% to 50% of the scheduled dose 2 hours after the scheduled dose if there is still mild to moderate pain and the patient is not overly sedated or lethargic. However if severe pain remains, a supplemental dose of 50% to 100% would be indicated. The scheduled dose is then set at 125% to 200% of the initial scheduled dose. Because of the time it takes to achieve a steady state, there may need to be some readjustment downward if the patient is unduly sleepy or is lethargic at the time of the scheduled dose. The supplemental dose may be given after any scheduled dose (even if there was an increase in the scheduled dose) as long as a sufficient time has passed for the drug to be absorbed from the stomach. An alternative way to titrate is simply to add 50% to the next scheduled dose, but staying with the previously determined schedule (usually every 4 hours). When the doses of opioid are higher (e.g., morphine 100 mg every 4 hours), some clinicians use less, for example, 20% to 30% (20 to 30 mg) as the boost, but incrementally add to the dose with each scheduled treatment until adequate pain relief has been achieved. It is often best to have the patient check in with a physician or nurse 1 to 3 days after a significant dose or medication adjustment to be sure the treatment plan is understood, safe, and effective.
5. Long-acting preparations. When an effective dose of short-acting morphine has been established, the required 24-hour dose for a long-acting preparation can be calculated. An additional supply of short-acting morphine, given when necessary, will help the patient manage “breakthrough” pain. Consistent need for this additional short-acting morphine (e.g., three or four doses daily) dictates an upward adjustment of the dose of sustained-release drug. Orders for immediate-release morphine should allow for some upward titration of dose by the patient or by the nurse. Each dose of short-acting morphine for breakthrough pain is usually 5% to 15% of the 24-hour dose of long-acting morphine. If more than this is required, it is usually an indication for increasing the dose of the long-acting preparation or considering some other adjuvant or interventional approaches.
6. Although the opioid agonist–antagonist analgesics have established effectiveness in the control of acute (especially procedurally related) pain, their use in chronic cancer pain is limited by the possibility of precipitous withdrawal in the patient who has been taking morphine-type drugs, by their analgesic ceiling effect (when the drug does not provide more pain relief), and by the lack of an oral form of administration.
7. Methadone is an agonist opioid analgesic that has the advantages of extremely low cost (often 10- to 30-fold less expensive than other strong opioids), efficacy in neuropathic pain, slow development of tolerance, and lack of known active metabolites. Because of its long and unpredictable half-life and relatively unknown equianalgesic dose compared with other opioids, methadone has generally been used by pain specialists with experience in its use. The methadone preparation widely utilized in the United States is a racemic mix of the D-isomer and L-isomer of methadone. The D-isomer has antagonist activity at the NMDA receptor, and this produces clinically relevant benefits in the control of neuropathic pain.
The relative potency of methadone increases with higher morphine-equivalent doses. Thus, when converting from another opioid to methadone, the calculated equianalgesic dose of methadone should be decreased by 75% to 90%. A guideline for choosing an appropriate initial dose of methadone based on the oral morphine-equivalent daily dose of the previous opioid is shown in Table 31.4. For example, a patient who has been using sustained-release morphine at 80 mg every 8 hours (240 mg/day) would be appropriately switched to methadone at a dose of 10 mg every 8 hours (30 mg/day, an 8:1 conversion ratio). In contrast, a patient who is taking sustained-release morphine at a total daily dose of 60 mg/day might be switched to an oral methadone dose of 5 mg every 8 hours (15 mg/day, a 4:1 conversion ratio).
Methadone is available as a pill, an elixir, and for parenteral use. The oral bioavailability of the drug is excellent (50% to 80%). Methadone is roughly twice as potent via intravenous (IV) or intramuscular routes compared with oral administration. Thus, a patient with well-controlled pain on a stable oral methadone dose of 10 mg every 8 hours would be switched to IV methadone at 5 mg every 8 hours if necessary. Subcutaneous (SC) use of methadone may cause skin irritation in some patients.
Methadone is metabolized primarily by the hepatic cytochrome-P450-system isoenzyme CYP3A4, and to a lesser extent by isoenzyme CYP2D6. Drugs that inhibit CYP3A4 cause the methadone levels to drift upward, and drugs that induce the metabolism of CYP3A4 will cause the methadone levels to drift downward. Important drugs to consider when prescribing methadone are summarized in Table 31.5.
Methadone is one of a long list of medications that can cause prolongation of the QT interval and torsades de pointes ventricular tachycardia. This is caused by inhibition of the rapid component of the delayed rectifier potassium ion current. Other common drugs that share this attribute include haloperidol, chlorpromazine, clarithromycin, pentamidine, and others. The level of risk associated with these drugs is low and depends on the dose and the population being treated. Oral methadone can be safely administered in the low doses (100 mg/day) that are generally prescribed for the treatment of cancer pain, and routine electrocardiograms are not performed at our institution when prescribing oral methadone. Caution should be taken when prescribing methadone to certain patients who maybe at higher risk of QT prolongation.
8. Alternative potent opioids include levorphanol, which has a longer half-life than morphine, and single-entity oxycodone and hydromorphone, which have half-lives similar to morphine. Equivalent starting doses can be selected from Table 31.3, but if the patient has been on high doses of morphine, care must be taken to reduce the dose by 25% to 50% of the calculated equianalgesic dose to account for incomplete cross-tolerance that may increase the relative potency of the newly prescribed agent.
9. Alternative routes. About 70% of patients benefit from the use of an alternative route for opioid administration sometime before death. The duration for which patients need these routes varies between hours and months. Although intermittent injections can be effective for a brief period of time, this method is painful for the patient, time-consuming for the nursing staff, and difficult to manage at home.
a. IV infusions of opioids produce stable blood levels of drug that are safe and effective for treating both postoperative and cancer pain. IV infusion using a patient-controlled analgesia pump may be very effective in gaining rapid control over pain that has gotten out of hand. It may also be of value when the patient cannot take medications orally and does not wish to take suppositories. The main problem associated with continuous IV infusions is the prolonged maintenance of an IV line. Patients may need to be subjected to numerous venipunctures when peripheral IV lines are used. Totally implantable IV catheters represent a major improvement, permitting long-term IV access. However, these catheters are expensive and need to be surgically implanted, and their maintenance requires considerable nursing expertise and patient teaching. If such a catheter is already available in a patient with advanced cancer who has pain, it certainly could be used for the administration of opioids. Starting doses of morphine for severe pain are 2 to 3 mg hourly as a continuous infusion, with patient-controlled boosts of 1 mg every 6 to 15 minutes. At the end of 24 hours, 50% of the patient boosts can be added to the total 24-hour dose of the continuous infusion until the patient is requiring less than one boost hourly. At that time, a shift to oral analgesics can be started, if the patient is able to take oral medications. If the doses of IV morphine are high, shifting to appropriate oral doses may take several days. It is usually safe and effective to give a 24-hour dose of long-acting morphine orally that is equal in milligrams (not equianalgesic) to the 24-hour IV requirement and simultaneously to reduce the IV dose (continuous infusion rate) by half. Boosts can be given by mouth, but the patient should have the IV boost option as reassurance. The next day, the 24-hour IV dose required (continuous plus boosts) can be added orally to the previous day’s oral dose (long-acting plus short-acting) and the infusion further reduced. The same process is repeated until the patient is getting adequate pain relief with the oral morphine. The infusion can usually be stopped and needed boosts given orally by the third or fourth day.
b. SC route. This route has been found to be safe and effective for the administration of morphine and hydromorphone. SC opioids can be administered as a continuous infusion using a pump (use as small a volume as possible, e.g., less than 5 mL/h) or as an intermittent injection. A butterfly needle can be left under the skin for about 7 days, making both intermittent injections and continuous infusion painless. The needles are frequently inserted in the subclavicular region, anterior chest, or abdominal wall. This allows patients to have free limbs.
c. Rectal route. Most of the experience reported in the literature is with the short-term use of rectal opioids for the management of acute pain. Both solid and liquid solutions have been used. Although there is considerable interindividual variation in the bioavailability of rectally administered morphine, there is general consensus that this drug is well absorbed after rectal administration. A number of authors have treated terminally ill cancer patients with rectal morphine, with good pain control until death. Advantages of the rectal route include the absence of the need for the insertion of needles and the use of portable pumps. However, rectal administration can be uncomfortable or psychologically distressing for some patients; absorption may be decreased by the presence of stool in the rectum, by diarrhea, or simply by normal bowel movements; and progressive titration may be difficult because of the limited availability of different commercial preparations.
d. Transdermal route. Pharmacokinetic data suggest that transdermal fentanyl is well absorbed, although there is considerable delay in reaching steady-state blood levels and a slowly declining plasma concentration after removal of the skin patch. The 72-hour dosing of the patch makes it convenient to use, and treatment appears to be well tolerated. The transdermal route is generally worth avoiding if the enteral route is readily available. Transdermal preparations are usually more expensive and more difficult to titrate compared with oral opioids. However, this route is quite useful for patients with chronic malignant bowel obstruction or similar chronic problems with the oral route. These skin patches range in doses from 12 mcg/hour to 100 mcg/hour.
e. Transmucosal route. Fentanyl citrate can also be formulated in a candied matrix to allow it to be administered orally as a lozenge on a stick. Oral transmucosal fentanyl citrate (OTFC) appears to be rapidly effective for breakthrough pain or for procedures. Dose-equivalency studies have suggested that OTFC is about 10 times more potent than parenteral morphine. Starting doses for the lozenges are usually 200 μg, with dosing intervals of 4 to 6 hours. Drug dose requires titrating up as with other agents with single doses of up to 600 μg. This transmucosal route has been used sparingly because the lozenges are expensive and require the patient to rub the lozenge against the buccal mucosa to enhance absorption. Another formulation that is available is a transmucosal buccal tablet; it has been developed and approved for breakthrough cancer pain with doses ranging from 100 to 800 mcg. The tablet is placed behind a rear molar tooth between the cheek and gums and adheres to the buccal mucosa and slowly dissolves on its own.
f. Neuraxial route. Some patients suffering from localized pain syndromes might benefit from epidural or intrathecal administration of opioids. The advantage of the neuraxial route is the potential to spare side effects of opioids as a relatively small dose of opioid may be effective for the pain problem. The disadvantage is the need for the insertion of catheters into the epidural or intrathecal space, the need for expensive infusion pumps, and, in some patients, the rapid development of tolerance to the analgesic effect of different opioids. To overcome this rapid development of tolerance, some clinicians have used a combined infusion of opioids and local anesthetic. Another issue that has become recognized is catheter tip granuloma formation. This may present as gradual loss of pain control or new back pain, sometimes associated with neurologic deficits. This complication can be diagnosed by MRI and is most common with high concentrations of intrathecal opioids (such as morphine >25 mg/mL). Because of the complexity associated with this route, it should only be considered for selected patients and after an adequate trial of systemic opioids and adjuvant drugs. The insertion of the catheter and the maintenance of the spinal analgesic regimen should be under the control of an interventional pain specialist.
10. Adverse effects of opioids. Concerns about opioid side effects are one of the main reasons cited by both patients and oncologists for limiting their use of opioids or the upward titration of these agents to achieve optimal pain control. It is important to understand the side-effect spectrum of these analgesics and be prepared to deal with side effects prophylactically or promptly when they do occur, as well as to educate patients and family members about side effects. Most patients develop tolerance for side effects much more rapidly than they develop tolerance for the analgesic effects of the opioids.
The analgesic and side effects of opioid agonists are not identical for all patients. Some patients may require a higher equivalent dose of a certain opioid agonist to achieve adequate analgesia. This higher equivalent dose may result in a higher incidence of side effects such as nausea or sedation. Therefore, when significant toxicity occurs in a patient treated with a certain opioid agonist such as morphine, it may be appropriate to change to another opioid. In addition, after prolonged treatment, high dosages, or renal failure, patients may experience the accumulation of active metabolites of opioid agonists. Active metabolites have been identified for morphine, hydromorphone, oxycodone, and fentanyl. This accumulation results in CNS side effects such as sedation, generalized myoclonus, confusion, and, in some patients, agitated delirium or grand mal seizures. In these patients, it is also useful to change from one opioid to another.
This so-called opioid rotation (or “opioid switching”) can produce improved analgesia and fewer adverse effects. Most often, such a switch occurs from morphine to a more potent opioid such as methadone, hydromorphone, fentanyl, or oxycodone. The dose guidelines for switching to methadone are shown in Table 31.4. When switching from morphine to hydromorphone or oxycodone, the initial calculated equianalgesic dose should be reduced by 25% to 50% to account for incomplete cross-tolerance. When switching from morphine to transdermal fentanyl, dose reduction is not needed because the dosing guidelines already incorporated the safety factor necessary for opioid rotation.
a. Sedation. This occurs in most patients during the beginning of opioid treatment or after a major increase in dose. Most patients develop rapid tolerance to this side effect, and while the sedation disappears within 3 to 5 days, the analgesic effect persists. When sedation occurs in patients with cancer receiving a stable dose of opioid, one should suspect the potential accumulation of active opioid metabolites such as morphine-6-glucuronide. This occurs most frequently in patients who are receiving high doses of opioids or who present with renal failure. It is also important to consider non–opioid-related causes such as hypercalcemia, because these patients are frequently very ill and metabolic problems or comorbidity may contribute to sedation. Opioid-induced sedation can be managed by opioid rotation (some opioids have a higher ratio of analgesic effects to sedation than others) or by the addition of psychostimulants such as methylphenidate or modafinil.
b. Nausea and vomiting. Most patients present with these symptoms after initial administration or a major increase in dose. Some authors propose the use of prophylactic antiemetics on a regular basis during the first days of treatment because in most patients, nausea disappears after that period. These side effects can be well managed with a prokinetic agent such as metoclopramide (10 mg by mouth once a day). Dexamethasone 2 to 4 mg by mouth once a day is also a useful antiemetic that potentiates metoclopramide in these patients, but it is prudent to taper this corticosteroid within 1 or 2 weeks. Another reasonable option is to consider lowdose haloperidol as the antidopaminergic properties often play a key role in opioid-induced nausea. As with sedation, nausea is a syndrome with multiple possible etiologies in patients with cancer who are receiving opioids: severe constipation, cancer-induced autonomic dysfunction, gastritis, increased intracranial pressure, and opioid metabolite accumulation are all possible causes of nausea.
c. Constipation. This is probably the most common adverse effect of opioids, and it is necessary to anticipate constipation when opioid therapy is started. Opioids act at multiple sites in the gastrointestinal tract and spinal cord. The result is decreased intestinal secretions and peristalsis. Although tolerance to both sedation and nausea develops quickly, it develops very slowly to the smooth muscle effects of opioids, so that constipation persists when these drugs are used for chronic pain. At the same time that the use of opioid analgesics is initiated, provision for a regular bowel regimen, including stimulants and stool softeners, should be instituted to diminish this adverse effect (see Chapter 26). Methylnaltrexone has been recently approved for opioid-induced constipation. This agent is a peripheral opioid receptor antagonist, a quaternary derivative of naltrexone that does not cross the blood-brain barrier. In studies, methylnaltrexone is able to reverse constipation without affecting analgesia or precipitating the opioid withdrawal symptoms.
d. Respiratory depression. This is the most serious adverse effect of opioid analgesics. Opioids can cause increasing respiratory depression to the point of apnea. In humans, death due to overdose of opioids is nearly always due to respiratory arrest. At equianalgesic doses, the morphinelike agonists produce an equivalent degree of respiratory depression. When respiratory depression occurs, it is usually in opioid-naive patients after acute administration of an opioid and is associated with other signs of CNS depression including sedation and mental clouding. Tolerance quickly develops to this effect with repeated drug administration, allowing the opioid analgesics to be used in the management of chronic cancer pain without significant risk of respiratory depression.
If respiratory depression occurs, it can be reversed by the administration of the specific opioid antagonist naloxone. In patients chronically receiving opioids who develop respiratory depression, naloxone in a 1:10 dilution should be titrated carefully to prevent the precipitation of severe withdrawal syndromes while reversing the respiratory depression. Long-acting drugs such as methadone, fentanyl patches, or slow-release morphine or hydromorphone carry a greater risk of respiratory depression compared to short-acting opioids.
The simultaneous use of other depressants such as benzodiazepines or alcohol are also risk factors for respiratory depression. Preliminary evidence also indicates a history of obstructive sleep apnea may also increase the risk of respiratory complications. Although this is the most feared side effect of opioid analgesics, it seldom occurs in patients receiving chronic opioid therapy for the treatment of cancer pain.
e. Allergic reactions. These occur infrequently with opioids. However, patients are commonly described as being “allergic” to a number of opioid analgesics. This descriptor generally results from a misinterpretation by the patient or clinician of some of the common side effects of opioids, such as nausea, sedation, vomiting, diaphoresis, or pruritis. In most instances, a simple discussion with the patient is enough to clarify this issue.
f. Urinary retention. The increase in the tone of smooth muscle of the bladder induced by opioids results in increased sphincter tone, leading to urinary retention. This is most common in elderly patients. Attention should be directed to this potential transient side effect, and catheterization may be necessary, transiently, for management. Patients do accommodate this side effect, and it is seldom a barrier to effective pain management.
g. “Newer” side effects. During recent years, as a result of increased education in the assessment and management of cancer pain, patients have been receiving higher doses of opioids for longer periods of time than ever before. This more aggressive use of opioids is associated with additional side effects, usually seen only in patients with late-stage disease receiving high doses of opioids.
(1) Cognitive failure. Patients can experience a transient decrease in concentration and psychomotor coordination after starting opioids or after a sudden increase in the opioid dose. In some patients, opioid-induced cognitive failure can be permanent. Some of the cognitive effects can be reversed by the administration of amphetamine derivatives such as methylphenidate. Cognitive screening tools (such as the Mini-Mental State Examination and other similar bedside assessments) are useful in patients receiving high doses of opioids.
(2) Other central effects. Organic hallucinations, myoclonus, grand mal seizures, and even hyperalgesia have been observed in patients receiving high doses of opioids for long periods. These effects are likely due to the accumulation of active opioid metabolites. Sometimes, the development of these problems in a previously stable patient heralds the onset of renal insufficiency or renal failure. Improvement is frequently seen after renal function improves and/or there is an opioid rotation. Hallucinations may be treated symptomatically with low doses of haloperidol 0.5 to 2 mg twice a day while the underlying problem is being addressed. Myoclonus can be treated with clonazepam 0.5 mg by mouth twice a day to start, with titration every 3 days up to a maximum daily dose of 20 mg.
(3) Severe sedation and coma. When coma occurs in patients receiving a stable dose of opioids for a long period of time, it should be suspected that accumulation of active opioid metabolites has occurred. These patients usually improve quickly after discontinuation of opioids.
(4) Pulmonary edema. Although noncardiogenic pulmonary edema is a well-recognized complication of opioid overdose in addicts, it had not been recognized until recently as a potential complication of cancer pain treatment. Pulmonary edema usually occurs when patients have undergone rapid increases in dose, usually as a result of severe neuropathic pain. Even though the mortality of the syndrome is very low among patients presenting with acute opioid overdoses, because of the conservative nature of the treatment of terminally ill patients with cancer, the mortality of pulmonary edema is much higher within this population.
V. ADJUVANT DRUGS
Opioid analgesics are the most important drugs for the treatment of cancer pain. Although these drugs can, in most patients, control severe pain even when they are used appropriately, they may produce new symptoms or exacerbate pre-existing symptoms, most notably nausea and somnolence. This aspect of treatment with opioid compounds is particularly problematic in patients with advanced cancer. The combination of severe pain, anorexia, chronic nausea, asthenia, and somnolence is a frequent finding in patients with advanced cancer. The term adjuvant drug has been used in a variety of ways, even in the context of cancer pain management. For the purposes of the following paragraphs, an adjuvant drug meets one or more of the following criteria:
Increases the analgesic effect of opioids (adjuvant analgesia)
Decreases the toxicity of opioids
Improves other symptoms associated with terminal cancer.
Most symptomatic patients with cancer receive more than one or two adjuvant drugs. Unfortunately, there is still limited consensus on the type and dose of the most appropriate adjuvant drugs.
Claims have been made for the adjuvant analgesic effect of many drugs, but unfortunately, most of the evidence for these effects is anecdotal. Controlled clinical trials are needed to define more clearly the indications and risk-to-benefit ratios. These agents, some of which have the potential to produce significant toxicity, can aggravate the toxicity of opioids.
A. Acetaminophen is a peripherally acting analgesic that does not inhibit peripheral prostaglandin synthesis. Therefore, it does not have anti-inflammatory effects or the side effects associated with the use of NSAIDs. Acetaminophen may be safely combined with opioids, and there is evidence that adding acetaminophen produces meaningful improvement in analgesic efficacy. Commercial preparations containing codeine or oxycodone and acetaminophen or aspirin are among the most widely prescribed scheduled analgesics and are frequently administered to patients with cancer.
Hepatotoxicity remains the major side effect to be cognizant of as patients are often unaware of this, especially when used in combined products. For patients with normal liver function, 6 to 8 g per day is reasonable, but if individuals have compromised liver function, acetaminophen should be limited to 3 to 4 g per day.
Tricyclic antidepressants have been found to be useful for various neuropathic pain syndromes, especially when pain has a prominent dysesthetic or burning character. Both amitriptyline and desipramine have been found to be effective in the management of postherpetic neuralgia, diabetic neuropathy, and other neurologic conditions.
Amitriptyline or imipramine (25 mg at bedtime) may be started at low doses; if the drug is not overly sedating and the patient does not experience bothersome anticholinergic side effects, the dose may be increased every 3 days to a total daily dose of 150 mg. The toxic effects of these drugs are mainly autonomic (dry mouth, postural hypotension) and centrally mediated (somnolence, confusion). Cardiovascular side effects are also possible at therapeutic dosing levels, including increased heart rate, prolonged PR interval, intraventricular conduction delays, increased corrected QT interval, and flattened T waves. Because their use may contribute to symptoms already present in debilitated patients, they should be administered cautiously in those who are very ill.
Duloxetine is a serotonin/norepinephrine reuptake inhibitor indicated for the treatment of diabetic neuropathy. The appropriate dose for this indication is 60 mg once daily. Adults treated with any antidepressant medication should be watched closely for worsening of depression and/or suicidal behavior or suicidal ideation. Monitoring should be particularly vigilant during initiation of therapy and during any change in dosage. Overall, clinical experience and expert consensus suggest that tricyclic antidepressants or duloxetine may be tried for the management of pain that is of central, deafferentation, or neuropathic origin.
Carbamazepine, phenytoin, valproic acid, lamotrigine, gabapentin, pregabelin, and clonazepam, alone or in combination with the tricyclic antidepressants, have been used successfully to treat neuropathic pain. Based on the well-documented efficacy for the treatment of trigeminal neuralgia, considerable experience and expert consensus suggest these agents may be useful adjuvants for neuropathic cancer pain syndromes, including neural invasion by tumor, radiation fibrosis or surgical scarring, herpes zoster, and deafferentation. Some clinicial improvement can be expected in half to two-thirds of patients whose predominant complaint is pain of a shooting, lancinating, burning, or hyperesthetic nature. Effective doses in the treatment of neuropathic pain in patients with cancer are not well established, and there is no clear-cut standard of care for use of these agents to guide the choice of agent or sequence of agents used in therapeutic trials. A common mistake is reporting that a patient failed to respond to this class of agents without either dose titration or adequate period of time to evaluate for response. For instance, clinical trials indicate a dose of 900 to 1200 mg per day before most patients begin to report relief of neuropathic symptoms. Because many of the side effects such as drowsiness occur when increasing the dose of neurontin, this should be done slowly over several weeks.
Controlled studies suggest that the administration of corticosteroids to selected patients with advanced cancer results in decreased pain and improved appetite and activity. Unfortunately, the duration of the effects is probably short-lasting. The mechanism by which corticosteroids appear to produce beneficial symptom effects in patients with terminal cancer is unclear but may involve their euphoric effects or the inhibition of prostaglandin metabolism. The optimal drug and dosing regimens have not been established. For the treatment of painful conditions, prednisone or dexamethasone is often administered in doses totaling 30 to 60 mg by mouth daily and 8 to 16 mg by mouth daily, respectively. As soon as symptomatic relief is obtained, attempts should be made to decrease the dose progressively to the minimally effective dose. Although long-term side effects are not an important consideration in many patients with advanced cancer, treatment may produce limiting side effects in these patients, particularly immunosuppression (candidiasis occurs in most patients), proximal myopathy, and psychiatric symptoms. The incidence of psychological disturbances ranges from 3% to 50%, with severe symptoms occurring in about 5% of patients. The spectrum of disturbances ranges from mild to severe affective disorders, psychotic reactions, and global cognitive impairment.
E. Clonidine, an α2-adrenergic agonist developed for treatment of hypertension, can be administered orally or as part of an epidural regimen for control of cancer-related pain, especially neuropathic pain.
F. Approaches to metastatic bone pain
1. Radioisotope therapy. Strontium-89 and samarium-153 are isotopes that have been found to be useful in providing systemic radiotherapy for palliation of pain in patients with bony metastases. These agents can be useful in patients with adequate bone marrow reserve who have multiple pain locations that limit the feasibility of external beam radiation therapy. The main limitations of radioisotope therapy are its high cost and the potential for hematologic toxicity (mainly thrombocytopenia).
2. Bisphosphonates. These agents have been found to be significantly better than placebo in patients with bone pain due to a variety of primary tumors. Pamidronate, clodronate, and zoledronate are the agents that have been most frequently studied. Because of their poor oral bioavailability, these drugs are most useful when given intravenously. In addition to pain control, these drugs can significantly reduce a number of other complications of osteolysis, such as hypercalcemia, fractures, and need for radiation therapy. Osteonecrosis of the jaw is a serious but rare complication. Dental evaluation should be done prior to initiation of long-term therapy, and dental work completed as soon as possible, preferably when not actively receiving bisphosphonate therapy.
3. External-beam radiotherapy. Radiation therapy can effectively control bone pain in about 70% of patients within 2 to 4 weeks. This treatment is most useful in patients with a single or small number of painful areas. A single administration may be as effective as multiple smaller fractions, reducing the cost and discomfort of transportation back and forth associated with multiple doses.
VI. ADJUVANT PROCEDURES AND THERAPIES
A. Invasive procedures
Evaluation of the physical basis of the pain may indicate that a neuroablative procedure, in which the pain pathway is destroyed, would be of benefit for pain control. As aggressive opioid analgesia becomes more accepted, most patients with cancer do not require these neuroablative interventions. Destruction of the pain pathway can be accomplished surgically or through destructive nerve blocks using an agent such as phenol. The major barrier to the more widespread application of these techniques is the limited number of practitioners with expertise in their use. The most frequently used neurosurgical procedure is the anterolateral or spinothalamic cordotomy. This is often performed as closed percutaneous cordotomy by placing a radiofrequency needle in the anterolateral quadrant of the cervical spinal cord. Unilateral interventions for pain control can unmask significant pain on the contralateral side of the body. Most often, performance of such interventional pain procedures does not eliminate the need to administer and monitor the effectiveness of systemic analgesics. Because of afferent regeneration, destructive procedures have had their greatest application in patients whose expected life span is only a few months.
Destructive anesthetic block of the celiac plexus has been used for several decades in the management of pain in the abdominal region. This block, which can be preceded by reversible diagnostic block, is a boon to many patients suffering from the severe pain accompanying cancer of the pancreas and may also be helpful for pain from cancers of the liver, gallbladder, or stomach. If success is achieved with the diagnostic block, lasting disruption of the pain pathway can be achieved using alcohol or phenol. Pain from rib metastases or tumors of the chest wall can be relieved with intercostal nerve blocks.
Patients with bone metastases sometimes develop pathologic vertebral compression fractures. Percutaneous vertebroplasty is a surgical procedure that involves use of polymethylmethacrylate as bone cement that is injected at high pressure through a needle into the collapsed vertebral body in order to stabilize it and relieve pain. Another interventional technique with similar goals is called kyphoplasty. This procedure involves percutaneous insertion of a needle with an inflatable balloon placed into the fractured vertebra using fluoroscopic guidance. The balloon is inflated so that the vertebral endplates are elevated and bone height is restored. The resulting bone cavity is then filled with acrylic bone cement.
Finally, patients with painful metastatic lesions involving bone that have failed conventional treatments such as external beam radiation therapy and chemotherapy may benefit from percutaneous radiofrequency ablation as a salvage procedure. This is an image-guided procedure, and a single ablation procedure is effective in most patients and well tolerated.
B. Coping or behavioral skill techniques
Teaching specific skills to manage pain can be helpful to many patients, especially those who face pain for months to years. Evaluation and prescription of the specific skills most beneficial to the individual can often be obtained through consultation with a behavioral psychologist, psychiatrist, or nurse pain specialist. Such techniques should never be used as a substitute for appropriate analgesia. The skills include relaxation, self-hypnosis, and other distraction and cognitive control techniques. These measures can affect the sensation of pain by reducing muscle tension on pain-generating lesions as well as by maximizing the patient’s ability to cope with the pain and remain as active as the disease permits. All patients need education about the nature of their pain, the methods that can be used to relieve it, and how they can cooperate with their healthcare providers to achieve good pain control.
This ancient traditional Chinese medicine technique is based on qi, the body’s vital energy. Needles are placed along qi meridians in order to help treat symptoms such as pain. For some patients, acupressure may be used, which involves applying heat or pressure to meridian points instead of puncturing the skin. Stainless steel or gold (semipermanent) needles, seeds, or “studs” are also sometimes placed at specific points on the ears and left in place for several days. Several acupuncture trials for pain have shown a beneficial effect including among cancer patients. Appropriate training and a strong working relationship are a prerequisite when considering the use of acupuncture for cancer patients. Patients at risk for infection (e.g., neutropenia) or bleeding (e.g., thrombocytopenia or on anticoagulation) may need to avoid acupuncture.
Breivik H, Cherny N, Collett B, et al. Cancer-related pain: a pan-European survey of prevalence, treatment, and patient attitudes. Ann Oncol. 2009;20(8):1420–1433.
Burton AW, Fanciullo GJ, Beasley RD, Fisch MJ. Chronic pain in the cancer survivor: a new frontier. Pain Med. 2007;8(2):189–198.
Bruera E, Palmer JL, Bosnjak S, et al. Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study. J Clin Oncol. 2004;22:185–192.
Bruera E, Kim HN. Cancer pain. JAMA. 2003;290:2476–2479.
Carr DB, Goudas LC, Balk EM, Bloch R, Ioannidis JP, Lau J. Evidence report on the treatment of pain in cancer patients. J Natl Cancer Instit Monogr. 2004;32:23–31.
Cherney N, Ripamonti C, Pereira J, et al. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol. 2001;19:2542–2554.
Cleeland CS, Gonin R, Hatfield AK, et al. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med. 1994;330:592–596.
Davis MP, Weissman DE, Arnold RM. Opioid dose titration for severe cancer pain: a systematic, evidence-based review. J Palliat Med. 2004;7:462–468.
Davis MP. What is new in neuropathic pain? Support Care Cancer. 2007;15(4):363–372.
de Leon-Casasola OA. Interventional procedures for cancer pain management: when are they indicated? Cancer Invest. 2004;22:630–642.
Foley KM. Treatment of cancer-related pain. J Natl Cancer Instit Monogr. 2004;32:103–104.
Fourney DR, Schomer DF, Nader R, et al. Percutaneous vertebroplasty and kyphoplasty for painful vertebral body fractures in cancer patients. J Neurosurg. 2003; 98:21–30.
Goetz MP, Callstrom MR, Charboneau JW, et al. Percutaneous, image-guided radio-frequency ablation of painful metastases involving bone: a multicenter study. J Clin Oncol. 2004;22(2):300–306.
Lawlor PG. The panorama of opioid-related cognitive dysfunction in patients with cancer. Cancer. 2002;94:1836–1853.
Manfredi PL, Houde RW. Prescribing methadone, a unique analgesic. J Support Oncol. 2003;1:216–220.
Mercadante S, Bruera E. Opioid switching: a systematic and critical review. Cancer Treat Rev. 2006;32(4):304–315.
Moryl N, Coyle N, Foley KM. Managing an acute pain crisis in a patient with advanced cancer: “this is as much of a crisis as a code.” JAMA. 2008;299(12):1457–1467.
Pereira J, Lawlor P, Vigano A, Dorgan M, Bruera E. Equianalgesic dose ratios for opioids: a critical review and proposals for long-term dosing. J Pain Symptom Manage. 2001;22:672–677.
Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database Syst Rev. 2004;25:169–178.
Smith HS. Opioid metabolism. Mayo Clin Proc. 2009;84(7):613–624.
Stockler M, Vardy J, Pillai A, Warr D. Acetaminophen (paracetamol) improves pain and well-being in people with advanced cancer already receiving a strong opioid regimen: a randomized, double-blind, placebo-controlled cross-over trial. J Clin Oncol. 2004;22(16):3389–3394.
Strouse TB. Pharmacokinetic drug interactions in palliative care: focus on opioids. J Palliat Med. 2009;12(11):1043–1050.