Pain in patients who are long-term survivors of cancer is an increasingly important topic. Currently more than 3.5% of the population in the United States are cancer survivors, and this rate is rising annually.3,4 Chronic pain syndromes are surprisingly common in this patient population. Currently, about 50% of patients with head and neck cancer will become long-term survivors, and 17% of these persons report substantial chronic pain.⁵ Twenty percent of breast cancer survivors younger than 40 years who are treated with surgery, radiation, and chemotherapy report significant pain years after treatment has been completed, and this pain appears to interfere with quality of life.^6,7 Approximately 30% of long-term survivors of lung cancer report substantial pain related to their illness.⁸ In addition, hip and sacral pain related to prior treatment with radiation is seen in 30% of long-term gynecologic cancer survivors.⁹ Chemotherapy-induced neuropathic pain is also an increasingly important long-term problem for cancer survivors.¹⁰ Of particular importance is emerging information suggesting that inadequately treated acute pain may predispose long-term cancer survivors to chronic pain syndromes.¹¹

Current Status of Cancer Pain Management

Studies from hospices and from World Health Organization demonstration sites suggest that 85% of patients with cancer pain can have their pain palliated with use of oral opioids. A wide array of effective options exists for the remaining 15% of patients. These options include parenteral, transdermal, transmucosal, intranasal, or intraspinal opioids, glucocorticoids, antiinflammatory and adjuvant medications, antineoplastic therapies, and anesthetic and neurosurgical procedures.

Although proper use of available therapeutic approaches should result in excellent pain control in nearly 95% of patients with cancer pain, this pain remains grossly undertreated throughout the world. In most countries, the lack of availability of oral opioids is a major contributing factor.¹² Even in countries such as the United States and the United Kingdom, where a wide range of opioid analgesics and routes of administration are readily available, studies suggest that cancer pain is undertreated. A survey of oncologists highlights their reluctance to assess pain routinely and to prescribe appropriate analgesics. These findings prompted the creation of cancer pain initiatives in most states and the development of cancer pain guidelines and algorithms.^13–18 In addition, to improve the overall management of pain in the United States, The Joint Commission has set new standards for pain management that are required for continued accreditation.¹⁹

Barriers to the Provision of Adequate Analgesia

Many reasons have been cited for the inadequate treatment of patients with cancer pain in developed nations. Some of these reasons relate directly to health care providers, including:

• Failure to appreciate the intensity of the pain their patients are experiencing

• Reluctance to evaluate the etiology of the pain

• Lack of training in pain management

• Excessive concern regarding the regulatory oversight of opioid prescribing

One major barrier to the provision of adequate analgesia in patients with cancer is the failure of health care providers to appreciate the intensity of patients’ pain. This barrier occurs because pain is entirely subjective and can only be experienced and quantified by the patient. There are no pathognomonic findings on physical examination, and results of laboratory studies can be normal. Assessment of pain is further complicated by the complexities surrounding death and dying and the possibility that patients with chronic, severe pain might not appear or act uncomfortable. In one study examining health care provider perceptions of patient pain, pain intensity was quantitatively assessed using a visual analog scale (VAS) in 103 consecutive patients admitted to the solid-tumor service of a large cancer center.²⁰ Each patient’s primary care nurse, house officer, and oncology fellow rated his or her perceptions of their patient’s pain intensity using the same pain rating instrument as the patient. The results (Fig. 40-1) demonstrate a lack of correlation between the patient’s and the health care provider’s perception of patient pain. Furthermore, the concordance between patient and health care provider pain intensity scores was highest when patients had no pain and lowest when the patients were experiencing severe discomfort. Similar results have been obtained in studies of patients with cancer and their next of kin and in patients with burns.

Figure 40-1 Correlation of health care provider and patient perceptions of patient pain. VAS, Visual analog scale, (Data from Grossman SA, Sheidler VR, Swedeen K, et al. Correlation of patient and caregiver ratings of cancer pain. J Pain Symptom Manage 1991;6:53. Copyright U.S. Cancer Pain Relief Committee.)

Health care providers might be unaware of the pain their patients are experiencing for many reasons. Because pain is entirely subjective, its presence and intensity must be communicated to health care providers by patients. Patients, however, might not discuss their pain if they expect cancer to be painful or if they are concerned about opioid addiction, tolerance, or adverse effects or about diverting their physician’s attention from treating the tumor or the intensity with which the oncologist is treating the tumor. In addition, patients might be reluctant to admit to themselves or others that their pain has worsened, knowing that this admission could signify progression of the cancer. Health care providers also contribute to the lack of communication by neglecting to emphasize their interest or abilities in controlling pain and by failing to use validated pain assessment tools. Serial numeric pain ratings in the medical record encourage the necessary dialogue between patients and health care providers about pain management issues.

These issues are greatly magnified in children, the elderly, or persons with a history of drug abuse. Children have special difficulty in communicating pain intensity, and their unique pain management needs have been relatively neglected. Special pain assessment tools are required, and the child’s age and developmental level must be considered when planning assessment or interventions. Many elderly patients also find it difficult to communicate their discomfort to health care professionals, have multisystem disease, and are especially sensitive to the adverse effects of analgesics.21–24 Persons with cancer and a current or prior history of drug abuse often have difficulty finding health care providers who believe their reports of pain and who will provide the high doses of analgesics required by these opioid-tolerant individuals.²⁵

Another barrier to the provision of adequate analgesia relates to the training of medical professionals. The principles of cancer pain management receive little attention in academic centers and relevant scientific societies. Medical school courses and textbooks typically focus on diseases rather than symptoms, and pain management issues are infrequently highlighted at rounds, educational conferences, or in the formal curriculum of those training to care for patients with cancer. These circumstances leave many health care professionals eager to concentrate on medical problems they feel competent to handle. In addition, the scarcity of research abstracts on cancer pain at the scientific meetings of physician oncologic societies reinforces the notion that pain control is a topic of limited importance. The lack of training and emphasis on cancer pain management is evident in many ways, including physicians’ lack of opioid-prescribing skills, failure to evaluate the etiology of cancer pain, and excessive concerns regarding the regulatory oversight of opioid prescribing. These difficulties in calculating equi-analgesic doses have prompted the development of software to facilitate opioid conversions.²⁶

Many physicians and nurses consider “cancer pain” a diagnostic entity that requires opioids without a formal evaluation of the etiology of the pain. Although this approach can provide relief, it is often ineffective and can lead to indefensible medical practices. For example, progressive back pain in a patient with metastatic lung cancer can occur as a result of a postobstructive pneumonia or tumor invasion of the esophagus, liver, spleen, pleura, pericardium, rib, vertebrae, intercostal nerves, brachial plexus, leptomeninges, or epidural space. Each of these diagnostic possibilities can be associated with a different therapeutic approach or sense of urgency. To provide opioids without evaluation would be an error in such a patient with an impending epidural cord compression. Furthermore, many common cancer pain syndromes might be better treated with therapies tailored to a patient’s individual pain problem. These therapies may include local radiation, nerve blocks, glucocorticoids, anticonvulsant agents, or surgery to maximize analgesia, minimize adverse effects, and improve quality of life.

Physicians, pharmacists, and nurses caring for patients with cancer must be willing to prescribe, dispense, and administer the opioids in doses required to alleviate their pain. However, drug enforcement agencies often discourage opioid prescribing in an attempt to reduce the illegal diversion of these drugs. Some health care professionals with limited knowledge and experience react to the perceived threat of investigation by law enforcement agencies with dramatic decreases in opioid prescribing, potentially compromising the appropriate treatment of patients with cancer pain.27,28

Evaluation of the Patient with Pain

A comprehensive assessment of cancer pain is the first important step toward optimal pain relief. This evaluation should provide the clinician with sufficient information to carry out the following tasks:

• Estimate the severity of pain

• Form a clinical impression regarding the etiology of the pain

• Determine the need for further diagnostic studies

• Formulate therapeutic recommendations that take into account the patient’s overall medical and psychosocial status (Box 40-3)

Box 40-3 Components of a Comprehensive Assessment of Cancer Pain

I Detailed History of Current Pain Problem

A Catalogue of pain (number and locations)

B Information for each pain

1. Intensity (0-10)

2. Locations and radiation

3. Onset and changes over time

4. Temporal pattern (e.g., constant or intermittent) and quality (e.g., burning)

5. Exacerbating and relieving factors

6. Associated neurologic or vasomotor abnormalities

7. Other associated factors

8. How the pain interferes with the patient’s life

9. Current therapeutic modalities (e.g., schedule, efficacy, and adverse effects)

10. Prior therapeutic modalities (e.g., schedule, efficacy, and adverse effects)

II Oncologic History

A Histologic

B Presentation: date, stage, and sites of involvement

C Antineoplastic therapies: dates, types, doses, toxicities, and response to each therapy

D Current sites of disease: stable, responding, or progressive

E Patient expectations and goals

III Medical History—May be Affected by Pain Therapies

A Coexisting diseases

B Medications and allergies

C Substance abuse history

D Other constitutional symptoms (e.g., anorexia, fatigue, sedation and other changes in mental status, nausea, vomiting, dysphagia, dyspnea, constipation, urinary and sexual function, depression, dry mouth, ability to take medications by mouth, and presence of a central venous catheter)

IV Personal and Social History

A Background: age, education, employment, marital status, place of residence, religious affiliation, and cultural and ethnic background

B Current status: functional status, caregivers and their health and availability, support system

V Physical Examination

VI Review of Additional Information

A Medical records, radiologic/laboratory studies

B Family members and physicians and/or nurses who know the patient and his or her illness

VII Differential Diagnosis

VIII Recommendations Regarding Workup and Therapy

IX Reassessment

As with any serious medical condition, the assessment of cancer pain requires a detailed history, physical examination, and review of available records, laboratory data, and imaging studies. The special challenges associated with the assessment of cancer pain include the entirely subjective nature of pain, the complex multisystem involvement in patients with advanced malignancies, and the ever-changing clinical situation in this patient population.

A detailed pain history is the cornerstone of the assessment. Obtaining this history can be a complex process, because 75% of patients with advanced cancer have several concurrent painful sites and nearly one third have four or more separate pain problems.¹⁹ Each distinct pain must be identified and characterized. Pertinent information should include its intensity, location, radiation, how and when it began, how it has changed over time, and what makes it better or worse. The quality of each pain, its temporal pattern, whether it is associated with neurologic or vasomotor abnormalities, how it interferes with the patient’s life, and an account of the successes and failures of current and prior therapeutic modalities also provide valuable insight.

Many instruments have been developed to aid in pain assessment. These instruments attempt to characterize and quantify the quality and/or intensity of a patient’s pain and represent the best available means to document the discomfort and to follow the results of therapy serially. Each instrument has its shortcomings, but several have been validated in patients with cancer pain and incorporated into clinical practice. Most instruments contain a variant of the unidimensional visual analog scale and a schematic representation of the body for patients to indicate where their pain is located. The McGill Pain Questionnaire is comprehensive but too awkward and time-consuming for most oncology patients in a clinical setting.²⁹ The Wisconsin Brief Pain Inventory, which can be completed in 15 minutes, provides information on the characteristics, severity, and location of the pain, its interference with normal life functions, and the efficacy of prior therapy. The Memorial Pain Assessment Card can be completed in less than a minute and features scales for the measurement of pain intensity and pain relief.³⁰ It is also designed to provide insight into global suffering or psychological distress. The Hopkins Pain Rating Instrument is a validated plastic version of the visual analog scale that obviates the need for the paper, pencil, ruler, and measurements associated with the standard visual analog scale.³¹ This instrument simplifies repeated pain intensity measurements, making it easier to reassess the efficacy of therapeutic endeavors on a continuing basis.³²

A complete oncologic history is also essential, because 90% of cancer pain is related to the malignancy or cancer treatment. The histology, presentation, stage, sites of involvement, and natural history and the history of surgery, radiation, chemotherapy, and hormonal treatments will help shape a therapeutic approach. In addition, it is important to note whether the malignancy is responding to therapy, stable, or progressing. A general medical history is also helpful, because pain treatments can affect coexisting medical problems, exacerbate constitutional symptoms, interact with other medications, or be contraindicated because of allergies. For example, a patient with painful bone metastases and severe peptic ulcer disease would not be an ideal candidate for potent antiinflammatory agents. Opioids can be problematic in patients with severe benign prostatic hypertrophy or severe obstructive pulmonary disease and carbon dioxide retention. Likewise, knowledge that a patient tolerates food or fluids poorly by mouth, has an indwelling venous access device, or admits to substance abuse might influence decisions about the best way to control that patient’s pain. The patient’s age, functional status, social support, education, residence, health insurance, finances, and religious and cultural background might also figure prominently in planning therapy. A careful neurologic and physical examination also provides important clues as to the etiology of the pain. Added insight can come from a review of available laboratory and imaging data, from medical records, and from discussions with family members and physicians who are familiar with the patient and his or her illness.

The history, physical examination, and review of other available data should provide the clinician with sufficient information to formulate a differential diagnosis for each of the patient’s distinct pains and to make recommendations regarding the workup and therapy for each. Based on this initial impression, analgesic therapy should be initiated. The nature of the treatment prescribed might depend on the clinician’s judgment regarding the origin of the pain. Somatic, visceral, neuropathic, and sympathetically maintained pain are each approached somewhat differently (Table 40-1). Prompt institution of therapy reassures patients that their pain will receive immediate attention, ensures patient comfort for diagnostic studies, and can provide information on the accuracy of the clinician’s assessment. Excellent pain relief suggests an accurate initial diagnosis and appropriate therapy, whereas suboptimal control might prompt a new treatment approach or a search for a different etiology of the pain.

Table 40-1

Classification of Cancer Pain

Type	Characteristics	Examples	Primary Therapies
Somatic	Constant, aching, gnawing, often well localized	Bone metastases	Treatment of tumor, antiinflammatory agents, analgesics
Visceral	Constant, aching, often associated with nausea	Pancreatic cancer	Treatment of tumor, analgesics, nerve blocks
Neuropathic	Paroxysmal shocklike pain on top of a burning, constricting sensation	Plexopathy or postherpetic neuralgia	Treatment of tumor, analgesics, TENS, nerve blocks
Sympathetically maintained	Severe burning, squeezing, or constricting with local edema	Reflex sympathetic dystrophy	Sympathetic blockade, physiotherapy, adjuvant analgesics

TENS, Transcutaneous electrical nerve stimulation.

One of the most difficult aspects of cancer pain management is that the patient’s clinical situation is rarely static. The patient’s underlying malignancy, antineoplastic therapy, and psychosocial status change continually during the course of the illness. As a result, the etiology and intensity of each new or worsening pain must be reassessed. The toxicities of the analgesics should also be evaluated periodically, because they can affect quality of life substantially. If significant toxicities are recognized, alternate approaches with a lower toxicity profile can be attempted.

Management of Cancer Pain

Nearly 85% of patients with cancer pain can achieve good control of their pain with conventional oral medications. More aggressive or invasive therapies should provide pain relief to an additional 10% of patients, leaving only a small fraction of patients with cancer with inadequate relief.

Pharmacologic Therapy

Pharmacologic approaches are the most commonly used treatments for cancer pain, because they are effective, safe, and usually inexpensive. These pharmacologic approaches are classified as nonopioids, opioids, and adjuvant analgesics. The World Health Organization’s analgesic ladder was introduced as a framework for analgesic prescribing. Aspirin, acetaminophen, or nonsteroidal antiinflammatory drugs (NSAIDs) are preferred for mild to moderate pain.³³ If these drugs do not provide adequate analgesia, then codeine, oxycodone, or hydrocodone will frequently provide excellent relief. For persistent or severe pain, codeine (or its congener) is replaced by a potent opioid, such as morphine (Table 40-2). Drug rotation should be considered before an entire class of agents is abandoned, because patients frequently tolerate one NSAID or opioid better than another. In addition, patients with severe pain might need a strong opioid as initial therapy to ensure rapid pain relief.³⁴

Table 40-2

Common Opioids Used for Cancer Pain Management *

Agent	Parenteral (IM/SQ/IV)	Oral	Duration (h)	Half-life (h)	Comments
Morphine	10 mg	30 mg	3-6 (PO) 8-24 (SR) 3-4 (P) 4-5 (R)

2-4 Many oral formulations for individual patient needs Hydromorphone 1.5 mg 7.5 mg 3-4 (PO/P/R) 2-3 Good choice for subcutaneous administration due to potency Fentanyl 0.1 NA

2-4 (TM)

0.5-4 (P)

48-72 (TD)

3-4 TD fentanyl 25 mcg/h approximately equals 45 mg/day morphine (PO); TD has a slow onset and offset (12-24 h); optimal dosing of TM products are found through titration and not through ATC dose of opioid Oxycodone – 20 mg

3-4 (PO)

12 (SR)

4-6 (R)

2-3 No ceiling dose if given without nonopioid analgesics Oxymorphone 1 10 4-6 (PO) 9-11 Levorphanol 2 4 4-8 (PO) 12-16 Accumulates with repeated dosing, especially days 2-5 Methadone 5 10 6-8 (PO/P) 15-150 Despite a long half-life, duration of analgesia is not prolonged; however, drug accumulation can result in toxicities; caution is warranted when converting to methadone in patients with high opioid tolerance Hydrocodone – – 4-6 4 Only available as fixed combination with acetaminophen or aspirin Codeine† 130 mg 200 mg 3-4 (PO/P) 2-4 10% of the population lack the enzyme needed to metabolize codeine to its active component

ATC, Around the clock; h, hour; IM, intramuscular; IV, intravenous; P, parenteral; PO, oral; R, rectal; SQ, subcutaneous; SR, sustained release; TD, transdermal; TM, transmucosal.

^*Refer to www.hopweb.org for opioid conversions.

The site of action of the nonopioids is primarily the peripheral nervous system. These agents are not associated with physical dependence, tolerance, or addiction, and they have a maximum dose associated with analgesia. Many are available in combination with a weak opioid. The antiinflammatory component of aspirin and of the NSAIDs and cyclooxygenase-2 (COX-2) inhibitors is often useful for patients with somatic pain from bone metastasis, inflammation, or mechanical compression of tendons, muscles, pleura, and peritoneum and for nonobstructive visceral pain. Because some of these agents can affect platelet and renal function or act as antipyretics, they should be administered thoughtfully to patients receiving chemotherapy. COX-2 inhibitors allow NSAIDs to be used with less risk of gastrointestinal bleeding and platelet dysfunction. However, the increased risk of myocardial infarction, stroke, heart failure, and hypertension in patients with a prior cardiac history warrants caution with both selective and nonselective NSAIDs.³⁵ In addition, it is important to recognize that sustained high doses of acetaminophen can cause renal and hepatic damage, especially when combined with more than 2 oz of alcohol per day or with other agents that cause liver damage or induce hepatic microsomes. The manufacturer of Tylenol, McNeil Consumer Healthcare, voluntarily decreased the maximum daily dose of acetaminophen to 3 g per day on their product labeling.

Most patients with moderate to severe pain rely primarily on opioid analgesics for the management of their cancer pain. The pain of the vast majority of patients can be managed with oral opioids, which are best given “around the clock” to keep pain under control. Although tolerance to these agents occurs, tumor progression is the most common reason for increasing opioid requirements. Tolerance can easily be overcome by raising opioid doses. Addiction is extremely rare in patients with cancer who are taking opioids for pain relief (Box 40-4). Most opioid adverse effects can be managed without excessive difficulty (Table 40-3). Constipation should be anticipated and treated prophylactically.³⁶

Box 40-4

Important Definitions in the Treatment of Cancer Pain

Physical Dependence

• A normal physiological response to chronic opioid administration characterized by development of the abstinence syndrome on abrupt withdrawal of opioids

• A potential problem in virtually all patients receiving moderate to high doses of opiates

Tolerance

• A normal pharmacologic response to chronic opioid therapy characterized by the development of a relative resistance to analgesic and other effects of the drug

• Overcome by increasing the dose administered

Psychological Dependence (Addiction)

• Abnormal behavior pattern characterized by an all-consuming desire to obtain opioids for reasons other than pain relief; this often occurs at the expense of the patient’s physical, social, and environmental well-being

• Extraordinarily rare in patients with cancer pain

• Not to be confused with “pseudoaddiction,” which is behavior commonly seen in patients who are undertreated and in pain and are attempting to obtain appropriate analgesia

Data from American Pain Society. Definitions related to the use of opioids for the treatment of pain, <http://www.painmed.org/files/definitions-related-to-opioid-treatment-for-pain.pdf/>; 2001 [accessed 28.02.13].

Table 40-3

Management of Common Opioid Adverse Effects

Adverse Effect	Specific Agents
Constipation	Stool softeners
	Irritants
	Bulk laxatives
	Lubricants
	Enemas Peripheral Mu antagonists
Nausea and vomiting	Promethazine
	Prochlorperazine Haloperidol
	Olanzapine
	5HT₃ antagonists Dronabinol
	Scopolamine
Sedation	Dextroamphetamine
	Methylphenidate
	Modafinil
Pruritus	Hydroxyzine
	Diphenhydramine
Myoclonus	Benzodiazepines
	Anxiolytics
Withdrawal symptoms	Clonidine

The opioids have their primary effect centrally, where they interfere with pain perception. They can be classified into three groups:

1. Morphine-like opioid agonists that bind competitively with µ and κ receptors (e.g., codeine, fentanyl, hydromorphone, morphine, oxycodone, and methadone)

2. Opioid antagonists that have no agonist receptor activity (e.g., naloxone)

3. Mixed agonists-antagonists (e.g., pentazocine and butorphanol) or partial agonists (e.g., buprenorphine)

The mixed agonist-antagonist drugs have limited utility in persons with cancer pain because of their adverse effect profiles and their propensity to induce opioid withdrawal in patients who have received opioid agonists. Proper opioid prescribing is critical for patients with cancer (Box 40-5), who often require high doses of opioids for long periods.¹⁴

Box 40-5 Management Approach

Tenets of Opioid Prescribing

• Order opioids on a scheduled “around-the-clock” basis to optimize relief.

• Order an as-needed opioid to treat breakthrough or incidental pain. For example, if a patient is taking morphine elixir, 100 mg orally every 4 hours, order an additional 25 to 50 mg of oral morphine elixir every 2 hours as needed for pain.

• Initiate a prophylactic bowel regimen at the same time opioids are prescribed. Patients usually require a combination of stool softeners and stimulant laxatives to treat opioid-induced constipation.

• Treat opioid-induced nausea and vomiting with aggressive antiemetic management, which includes giving patients antiemetics on an around-the-clock basis. Patients often become tolerant to this adverse effect several days after beginning opioids.

• Once baseline opioid requirements are determined, sustained-release opioid preparations can be used to reduce the number of pills taken each day.

• Teach the patient and family about the purpose and benefits of opioids to allay their fears about adverse effects and addiction. This instruction will improve patient compliance.

• Frequent assessment of pain relief is paramount during the opioid titration period. Titrate doses based on the patient’s report of pain relief and/or the amount of as-needed opioid that has been required for patient comfort.

• Maximize the doses of one opioid before changing to another agent or route. Changes should be made primarily because of toxicities. For example, a patient taking 200 mg of controlled-release morphine every 12 hours and 200 mg of immediate-release morphine daily for breakthrough pain should have the dose of controlled-release morphine increased to 300 mg every 12 hours if he or she is not experiencing significant opioid adverse effects. This approach is more likely to be beneficial than beginning titration with subcutaneous or intravenous morphine or oral hydromorphone.

• Refer to equi-analgesic tables when initiating or changing a patient’s analgesic regimen (see Table 40-2 and Box 40-4).

• Avoid chronic administration of intramuscular or rectal opioids.

• Do not use chronic administration of meperidine, which can be associated with the accumulation of normeperidine, a neurotoxic metabolite.

Several classes of drugs that are used primarily for conditions other than pain have been found to be useful adjuvant analgesics in specific circumstances (Table 40-4).¹⁴ Antidepressants and anticonvulsants can be effective in neuropathic pain. Psychostimulants can decrease opioid-induced sedation. Glucocorticoids are effective antiinflammatory agents and are also used to reduce pain associated with brain edema and epidural metastases. Muscle relaxants and anxiolytic, antispasmodic, and neuroleptic agents also are administered for specific indications. Bisphosphonates reduce the incidence of skeletal complications, particularly in patients with myeloma and breast cancer. Caution must be exercised in the use of adjuvant drugs that have sedative properties because the dose of opioids should not be compromised by the toxicities of these secondary agents.

Table 40-4

Commonly Used Adjuvant Analgesics for Cancer Pain

Drug Category	Indications	Drugs	Common Toxicities	Comments
Antidepressants	Neuropathic pain	Amitriptyline Nortriptyline Desipramine Duloxetine Venlafaxine	Sedation, dry mouth, constipation, postural hypotension, urinary retention	Begin with low doses and increase the dose every few days
Anticonvulsants	Neuropathic pain	Carbamazepine Pregabalin Clonazepam Gabapentin	Drowsiness, dizziness, nausea, rash, bone marrow depression	Monitor platelets with carbamazepine
Psychostimulants	Opioid-induced sedation	Dextroamphetamine Methylphenidate Modafinil	Nervousness, irritability, insomnia, dizziness, dry mouth	Give early in the day to avoid insomnia; do not use if the patient is already delirious or confused
Corticosteroids	Spinal cord compression, increased intracranial pressure, visceral distention	Dexamethasone Methylprednisolone Prednisone	Gastritis, insomnia, fluid retention, hyperglyceroximal myopathy, increased appetite
Muscle relaxants	Muscle spasm	Diazepam Baclofen Methocarbamol Cyclobenzaprine	Sedation, dizziness, nausea, weakness, confusion
Benzodiazepines	Muscle spasm, myoclonus, anxiety, insomnia	Diazepam Lorazepam Alprazolam Midazolam Temazepam	Sedation, delirium, hypotension, headache, respiratory depression	Not analgesics; synergistic effect with opioids can cause respiratory depression
Antispasmodics	Gastrointestinal or bladder spasm	Diphenoxylate and atropine Loperamide Scopolamine patch Dicyclomine	Sedation, dry mouth, constipation
Neuroleptics	Delirium, agitation, nausea and vomiting, hiccoughs	Olanzapine Risperidone Quetiapine Haloperidol Prochlorperazine Chlorpromazine	Sedation, orthostatic hypotension, confusion, extrapyramidal reactions	Useful for symptoms other than pain
Bisphosphonates	Bone pain	Pamidronate	Hypocalcemia, fever, gastrointestinal disturbances, anemia	Delays time to painful skeletal events; also used with analgesics for bone pain
		Zoledronic acid Alendronate Risedronate Ibandronate Etidronate	Hypocalcemia, fever, gastrointestinal disturbances, anemia

Although the pain of the vast majority of outpatients can be managed with oral opioids, alternative routes of analgesic administration are sometimes needed. Subcutaneous, intravenous, transdermal, transmucosal, intranasal, or intraspinal opioids can be delivered by intermittent bolus, continuous infusion, or a combination of both, as is frequently the case with patient-controlled analgesia. These alternative routes of administration should be considered when a patient has one of the following conditions:

• Intractable vomiting or gastrointestinal tract obstructions, making oral therapy impractical

• Ineffective pain relief despite titration to toxicity with several oral opioids

• Unacceptable toxicities to several oral opioids

• Such high opioid requirements that oral administration is impractical

The costs associated with these routes of opioid administration must be considered carefully. In addition, care must be taken not to transform the home unnecessarily into a complex health care setting.

Subcutaneous opioid injections administered through a subcutaneous needle on a fixed schedule are commonly used by hospices as an effective, less expensive alternative to continuous intravenous or subcutaneous infusions. A transdermal system for opioid administration can be beneficial for some patients. Although transdermal fentanyl provides patients with continuous drug delivery, it does not eliminate the need for additional analgesics for breakthrough pain. The slow onset of action of fentanyl and the uncertainties associated in conversion from other opioids have led many practitioners to reserve transdermal fentanyl for patients with stable opioid requirements who do not have significant incidental pain.

Transmucosal immediate-release fentanyl (TIRF) products can be effective for patients with incident or breakthrough pain, for whom rapid onset and short duration of action are desired.³⁷ These fentanyl products are available as a lozenge, a buccal and sublingual tablet, a soluble film, and a sublingual and nasal spray. The onset of analgesia can be as soon as 5 minutes. The optimal dose for these delivery systems is found through titration and is not predicted by the around-the-clock dose of opioids. In 2012, the U.S. Food and Drug Administration enacted a TIRF Risk Evaluation and Mitigation Strategy, which requires providers and pharmacists to enroll and complete training before prescribing or dispensing TIRF products. Patients must sign an agreement before initiating therapy.³⁸

Intraspinal opioids produce analgesia without blocking other sensory, motor, or sympathetic functions. These opioids can be delivered into the epidural space through a tunneled external catheter or to the subarachnoid space or lateral ventricles using a totally implanted pump.³⁹ Because the total daily dose of intraspinal opioid is one tenth to one hundredth that of parenteral opioid, it is associated with fewer systemic toxicities. Chronic administration of opioids via the epidural or intrathecal route is invasive, expensive, and frequently ineffective in patients requiring high doses of systemic opioids. Tolerance, pruritus, urinary retention, and nausea and vomiting occur in as many as 20% of patients receiving opioids via the spine. Respiratory depression is unusual. The addition of low doses of anesthetic agents or agents such as clonidine to opioids delivered via the intrathecal or epidural route could add considerably to pain relief. Ziconotide, a selective N-type calcium channel blocker, is approved for intrathecal analgesia in patients with pain refractory to other treatments.⁴⁰ Intraspinal opioids are generally used after documentation of the failure of maximal doses of opioids delivered through other routes.⁴¹ Consensus guidelines are available to guide the practitioner with proper drug selections for intraspinal analgesia.⁴²

Regional Analgesia

Regional analgesia can be achieved with long-acting local anesthetics that provide pain relief for 3 to 12 hours, neurolytic agents (alcohol or phenol) that produce analgesia for weeks to months, or opioids injected into the epidural or subarachnoid space (Table 40-5). Diagnostic blocks with local anesthetics are usually performed before neurolysis, which permits the anesthesiologist to determine the response to local therapy and allows the patient to decide whether the “numbness” that replaces the pain is tolerable. If the pain can be relieved temporarily with local anesthetics, alcohol or phenol can be injected into the subarachnoid or epidural space to destroy nociceptive fibers in the dorsal rootlets, thus simulating a surgical rhizotomy. Although injections of these neurolytic agents are commonly called “permanent blocks,” pain relief usually lasts several months. Neurolytic blocks can be particularly useful in the thoracic region, where they are associated with few motor complications. In the cervical and lumbar regions, motor and/or sphincter dysfunction that can be permanent develops in nearly 20% of patients. In patients with preexisting lower extremity paralysis, a colostomy, or nephrostomy tubes—cases in which loss of motor or sphincter function might be less critical—lumbar neurolysis might be worthwhile. Other potential adverse effects of these procedures include hypotension, toxic reactions from accidental intravenous or subarachnoid administration, or pneumothorax after needle placement. Neurolysis is usually restricted to patients with a limited life expectancy, because it can produce a painful neuritis that becomes clinically apparent only months after the procedure.

Table 40-5

Regional Anesthetic Techniques

	Types of Blocks	Examples	Indications	Comments
Local anesthetic blocks	Diagnostic	Intercostal nerve block	Determine etiology of pain and the response and adverse effects following local therapies	Analgesic effect will last only hours
	Treatment of sympathetically maintained pain	Stellate ganglion block	Sympathetically maintained pain	Repeated blocks might be needed
	Trigger point injections	Trigger point injection	Myofascial pain syndrome	Repeated blocks might be needed
Neurolytic (alcohol or phenol) blocks	Peripheral	Intercostal nerve blocks	Chest wall tumor	Pain relief usually lasts several months
Neurolytic (alcohol or phenol) blocks	Visceral	Celiac plexus block Superior hypogastric block Ganglionic impar block	Pancreatic cancer Gastrointestinal/genitourinary cancers	Pain relief usually lasts several months
	Neuraxial	Epidural	Pain localized to two or three dermatomes	Pain relief usually lasts several months
		Intrathecal neurolysis

Neurolytic blocks are used in select patients who have localized or regional pain. Percutaneous celiac plexus neurolysis is an outpatient procedure associated with few risks; it alleviates pain originating in the pancreas, stomach, gallbladder, or other upper abdominal viscera in most patients. One randomized, prospective, double-blind trial comparing celiac plexus injections of alcohol or saline solution and systemic analgesic therapy in patients with unresectable pancreatic cancer showed greater pain relief with the block. Opioid consumption and quality of life were not statistically significant, however.⁵⁰ In other settings, it has been shown to decrease opioid requirements. Although pain can recur months after a celiac block, subsequent blocks can provide excellent pain relief. Less commonly used neurolytic procedures include intercostal blocks (chest wall or rib pain), neuraxial blocks (pain in two to three dermatomes), Gasserian ganglion neurolysis (pain in the anterior two thirds of the head), brachial plexus blocks (for patients with preexisting limb paralysis), and ganglion impar and superior hypogastric blocks (for lower abdominal and pelvic pain).

Neuroablative Procedures

Neuroablative procedures are performed infrequently in patients with cancer because of the success of more conservative approaches. The most commonly performed procedures are radiofrequency ablation and the open unilateral anterolateral cordotomy, percutaneous cordotomy, and commissural myelotomy. An open cordotomy is usually performed through a T2 or T3 laminectomy and produces excellent pain relief in the lower part of the body in 80% of patients. A 5% to 10% mortality rate and significant morbidity in an additional 15% of patients are reported for this procedure. Hemiparesis, urinary retention, sexual impotence, unmasking pain on the opposite side of the body, and late sensory abnormalities are not infrequent. Bilateral cordotomies are associated with higher complication rates. Percutaneous cordotomy is safer and provides excellent pain relief; however, pain recurs within 3 months in 50% of patients. A commissural myelotomy can be considered in select patients who experience bilateral pelvic and perineal pain. This procedure involves a laminectomy and surgical division of the crossing fibers of the spinal cord. Although it can result in pain relief with sphincter sparing, few neurosurgeons have extensive expertise with this procedure.

Difficult-to-Manage Pain Problems

Difficult-to-manage pain problems are most common in patients with any of the following conditions:

• Pain of neuropathic origin

• Episodic or incidental pain

• Impaired cognitive or communicative skills

• History of substance abuse

Referral to an experienced multidisciplinary cancer pain team can be helpful if initial attempts to control pain in patients with these underlying problems are unsuccessful.

Patients with Pain of Neuropathic Origin

Any injury to the peripheral or central nervous system can cause neuropathic pain, which is often characterized by paroxysms of shocklike pain on top of a burning or constricting sensation. Neuropathic pain in patients with cancer commonly arises when a tumor invades or compresses a peripheral nerve, nerve plexus, or the spinal cord. It can occur as a result of surgery, radiation, or chemotherapy as exemplified by postmastectomy and postthoracotomy syndromes, radiation-induced plexopathies, and chemotherapy-induced neuropathies.⁵¹ Neuropathic pain also can accompany disorders that are unrelated to the tumor or its treatment, such as diabetes mellitus, nerve entrapment syndromes, and herpes zoster.

Providing adequate relief from neuropathic pain can be difficult even for experienced physicians.⁵² Although this pain may improve upon the administration of opioids, it usually responds less well to these agents than does nociceptive pain. Optimal therapy for neuropathic pain often relies on opioids used in combination with a variety of nonopioid “adjuvant” analgesics (see Table 40-4). Tricyclic antidepressants have been studied most extensively in this situation. Although the most convincing efficacy data is with amitriptyline, this agent is associated with significant anticholinergic effects and sedation. Other drugs in this class with a more favorable toxicity profile include desipramine and nortriptyline. Duloxetine, a serotonin and dual serotonin-norepinephrine reuptake inhibitor, has a substantial effect in neuropathic pain.⁵³

Anticonvulsant agents are also helpful in the management of neuropathic pain, particularly if the pain has lancinating qualities. The doses of these agents are similar to those used for the control of seizures. Care must be taken to avoid abrupt withdrawal, which could induce seizures. Randomized controlled trials have demonstrated the efficacy and tolerability of gabapentin for the treatment of postherpetic neuralgia and painful diabetic neuropathy.⁵⁴ Other studies suggest that it might help in the management of neuropathic pain resulting from cancer or its treatment. This agent is well tolerated, no drug-drug interactions have been identified, and the average effective dose is 1800 to 3600 mg/day. Pregabalin has a mechanism of action and adverse effects similar to gabapentin. Maximum doses are achieved within 1 to 2 weeks, offering a potential advantage over gabapentin. Systemically administered local anesthetics have been used for the treatment of neuropathic pain. Anesthetic creams that produce few systemic adverse effects are also available. Topical lidocaine patches are an effective means to control neuropathic pain that is confined to a small area. In clinically controlled trials, intravenous lidocaine has been demonstrated to be as effective as other analgesics for refractory pain.^55,56 Capsaicin, a neurotoxin that selectively destroys nociceptors, is also manufactured as a topical preparation and provides relief in some patients. If oral agents and topical creams are ineffective, afferent input can be reduced with transcutaneous electrical nerve stimulation or regional anesthetic techniques such as long-term epidural catheters or intrathecal pumps for the delivery of local anesthetics. Neurolytic blocks, more invasive neurostimulatory techniques, or even neurosurgical procedures might be indicated in extreme situations.

In patients experiencing opioid-resistant pain, unique agents such as ketamine can be considered. Ketamine is a rapidly acting dissociative anesthetic agent that in subanesthetic doses can provide relief for patients with cancer. Although no large randomized, controlled trials to evaluate the efficacy of ketamine have been performed, a large body of uncontrolled trials and case reports exists. Ketamine can be administered by several routes of administration including intrathecal, intravenous, topical, and intranasal. The agent is generally well tolerated at the lower doses, with the major concern being psychotomimetic effects. Its analgesic and opioid-sparing effects are postulated to be mediated by blockade of the NMDA receptor. The efficacy of ketamine persists after the medication has been discontinued, which may be beneficial.57,58

Patients with Episodic or Incidental Pain

It is widely recognized that some patients experience transient but severe exacerbations of their pain. These exacerbations can occur for a variety of reasons, one of which is an inadequate analgesic regimen. For example, a patient who receives opioids every 6 hours and has good relief for only 4 hours needs a change in regimen to ensure that opioid levels will not fall below the analgesic threshold after 4 hours. This change is best accomplished by providing the agent more frequently or by administering sufficient doses of a sustained-release preparation. Episodic pain associated with voluntary or involuntary movements poses a more difficult therapeutic problem. Examples of these “incident” pains are seen in patients with pelvic metastases or pathological fractures who have severe pain with walking or sitting, patients with rib metastases who experience stabbing chest pain with movement or coughing, or patients with esophageal, rectal, or bladder lesions with pain on swallowing, defecation, or urination, respectively. Involuntary precipitants can include bowel or ureteral distention. In a study of incident pain, nearly three quarters was directly related to neoplastic lesions, 20% resulted from antineoplastic therapy, and the remainder was unrelated to the tumor or its treatment.61–61

Proper management of these patients requires a comprehensive assessment to determine the origin of the pain. Therapy directed at the underlying etiologic factors is most likely to provide pain relief. Relieving a bowel obstruction, repairing or casting a fracture, treating a local metastatic lesion with radiation therapy, or performing a neurolytic block for a painful rib lesion is likely to provide superior analgesia to that provided by opioids. The frequency and severity of incidental pain might also be reduced significantly by antiinflammatory agents or corticosteroids in bone or nerve compression pain and by anticonvulsants or tricyclic antidepressants in neuropathic pain. In addition, agents that reduce the frequency of precipitating events should be used, including antitussives, laxatives, antiperistaltic drugs, or agents that reduce muscle spasms. Physiotherapy can be useful in persons with musculoskeletal complications, and cognitive and psychological approaches can be helpful to patients with episodic pain. Rarely, patients require invasive anesthetic or neurosurgical approaches for relief of transient but severe pain. Local anesthetic injections might predict whether a patient is likely to respond to chemical neurolysis or a destructive neurosurgical procedure. Continuous epidural anesthetics and opioids might also be helpful in carefully selected patients.

Many of the approaches described in the foregoing discussion might not be effective, or even possible or advisable, in the context of a patient’s illness. In such situations, opioids remain the mainstay of therapy. The baseline dose of opioid can be escalated until pain relief or intolerable adverse effects occur. Although this approach might produce relief, patients are often excessively sedated during the intervals between the severe pain episodes. Alternatively, patients might elect to take supplemental analgesics (usually short-acting opioids) 30 to 60 minutes before they know a precipitating event is likely to occur. If the pain is unpredictable, the additional medications are taken as soon as the pain begins. The optimal timing of opioids for episodic pain is difficult to achieve. Episodic pain is characterized by a quick onset and short duration. Although parenteral opioids have a faster onset of action than oral opioids, using them is not practical in the home setting. Alternatively, transmucosal fentanyl products may provide the best option. The doses of these supplemental opioids must be determined from the patient’s baseline opioid requirements. It is common to begin with 5% to 10% of the total daily opioid dose ordered every 2 to 3 hours as needed. The dosing of transmucosal formulations, as previously mentioned, is determined through titration and is not based on the baseline opioid requirement.⁵⁹

Patients with Impaired Cognitive or Communicative Function

The difficulties that physicians and nurses have in determining the intensity of pain in patients with cancer have been described previously in this chapter. Problems in conveying pain intensity are greatly magnified in patients who cannot communicate with their health care providers or who are cognitively impaired. These deficits complicate the assessment of both pain intensity and pain relief. Some patients are unable to speak the language of the health care provider, whereas others have severe neurologic deficits, such as an expressive aphasia. As previously noted, children and the elderly have special difficulty communicating pain intensity. Patients with severe cognitive deficits present obvious problems in assessing an entirely subjective symptom. Delirious patients with cancer are often restless, moaning, and unable to convey the intensity, nature, or even location of their pain. These patients require a review of correctable factors contributing to the delirium. Neurologic events, infections, trauma, bladder distention, fecal impaction, hypoxia, or metabolic abnormalities are common. The patient’s drug regimen should be simplified, and agents with anticholinergic properties should be discontinued. If the patient is receiving an opioid, reducing the dose, switching agents, or using a continuous infusion or sustained-release preparation to avoid wide fluctuations in drug levels might result in improvement.

Patients with a History of Substance Abuse

The principles of cancer pain assessment and management in patients with a current or prior history of drug abuse are similar to those for any patient with cancer pain.²⁵ These individuals should not remain in pain as a result of this complicating medical problem. Patients with a history of drug abuse, however, often have difficulty finding physicians who believe their reports of pain and who will provide the high doses of analgesics required in these opioid-tolerant individuals. As a result, they can become angry, frustrated, and more persistent in their demands for opioids. This constellation of symptoms is also seen in patients who do not have a history of drug abuse but who have severe, untreated pain. Their preoccupation with obtaining analgesics is referred to as pseudoaddiction and tends to disappear rapidly with appropriate pain therapy.

A frank discussion of major issues relating to the proper use of opioid analgesics for pain management with the patient, the patient’s family, and the drug counselor is important. Pain management agreements often help to ensure that all parties understand and agree to the same principles and plans for therapy. Oral agents are preferred, or regional pain management techniques that could limit the need for opioids can be considered. Opioids such as methadone might be prescribed in lieu of morphine or hydromorphone.