Pathophysiology

The key to treating pain effectively is to identify the underlying causes whenever possible. Cancer pain can be aggravated by factors such as infection, trauma, and tumor growth. Therefore, careful assessment and physical examination are essential. Factors such as inflammation and myofascial pain may also contribute to the overall pain perception.

Nociceptive pain is the most common type of pain and is a normal function of the central nervous system. Nociceptors respond to noxious stimuli and transmit a message through the peripheral nerves, to the spinal cord, and then up to the cerebral cortex, where the message can be interpreted. Some motor responses (e.g., withdrawal of an extremity from intense heat) are initiated from the spinal cord, whereas others are initiated by higher brain centers. Nociceptive pain is further differentiated as somatic (i.e., pain from soft tissue and musculoskeletal structures) or visceral (i.e., pain arising from the internal organs). Somatic pain is often described as dull, sharp, aching, crushing, or heavy, whereas visceral pain is often described as crampy.³ There are fewer pain fibers in the viscera, and a convergence of visceral and cutaneous afferent fibers at the dorsal horn of the spinal cord; therefore, visceral pain can be referred to other areas. Cancer pain often exhibits a classic referral pattern, depending on the pathology of the cancer. For example, pain associated with cancer of the pancreas can be experienced as pain in the middle or upper back or as shoulder pain.

Neuropathic pain develops as a result of injury to the peripheral nerves, spinal cord, or brain tissue. Nerves can be injured or damaged by direct trauma (laceration, compression, stretching, crushing, burning, freezing, or exposure to toxic agents such as chemotherapeutic drugs or viruses), repetitive movements (typing), and diseases (polio, diabetes, multiple sclerosis). The result of the injury is a cascade of events that creates both anatomic and neurochemical changes in the neurons. Once the damage has occurred, the regeneration process of the nerve may result in incomplete healing, which can lead to chronic pain or reduced function.³ Common examples of neuropathic pain syndromes that result in chronic pain include postherpetic neuralgia, phantom pain, post-thoracotomy pain, intercostal neuralgia, and peripheral neuropathy. Neuropathic pain is characteristically described as burning, numbness, tingling, shocking, electric, and jolting, and often has a delayed onset from the time of the precipitating injury. For example, postherpetic neuralgia can occur and persist months to years after the skin lesions of a herpes zoster virus (HZV) infection have completely healed. In that time, the perception of normally mild, nonpainful stimuli (e.g., touch or wearing clothing) can change to an exquisitely sensitive or painful sensation (allodynia or hyperesthesia). In moderate to severe cases, neuropathic pain may be accompanied by regional sympathetic dysfunction, whereby an injured nerve may develop an electrical or a chemical interaction with sympathetic nerve fibers, providing continuous painful stimuli to peripheral nerves.^2,3

Many pain syndromes are accompanied by inflammation that either contributes to or is the primary underlying mechanism of the pain. The inflammatory response includes the release of prostaglandins and leukotrienes that sensitize peripheral nerves to painful stimuli. Associated swelling also causes pressure on the nerves or other sensitive structures, which will contribute to the severity of the pain.

Clinical Presentation

The onset of cancer-associated pain can be acute and severe or may gradually progress from an awareness of discomfort to one of increasing intensity. Patients with chronic cancer pain that seems well managed for a long period of time may suddenly report worsening of pain or pain that is completely different in quality or location. Because it is possible for pain to be experienced before tumor detection, it is essential when treating someone with a history of cancer to rule out tumor growth from metastases, even if the patient has been disease free for some time. Patients who experience a sudden worsening of pain or a new pain might also fear relapse or a disease progression and may insist on referral back to the oncologist.

A careful and thorough history includes identification of the pattern, characteristics, severity, and impact of the pain. The provider should always ask the patient where specifically the pain is located, so that it is clear what is actually being treated. Providers should remember that cancer patients often have pain in multiple body areas from several sources; pain relief regimens need to accommodate this characteristic.

Because pain is subjective, a patient’s report is the most reliable means of establishing the degree or intensity of the pain. The most convenient method, and one accessible to most patients, is the numeric rating scale (NRS) for pain. The patient rates his or her pain from 0 to 10, where 0 indicates no pain and 10 indicates the worst pain imaginable. Other scales can be used, such as the visual analog scale (VAS), the McGill Pain Questionnaire (MPQ), and the Wong-Baker Faces Scale. The Wong-Baker Faces Scale uses a series of faces depicting comfort level, which can be useful for children (3 years of age and older) and for patients with communication difficulties (e.g., a language barrier or difficulty with speech), because they can simply point to the face that matches how they feel.⁴ It is important to use one scale consistently with the patient in order to develop a sense of the change in status or impact of interventions over time. While performing the pain assessment, it is also important to review other symptoms that may have an impact on a patient’s pain level and treatment plan. Tools used to assess multiple symptoms include the Edmonton Symptom Assessment Scale (ESAS) and the MD Anderson Symptom Inventory (MDASI).

To interpret the ratings given by patients, providers must remember that these are subjective measures and therefore have no “normal” values. In general, ratings of 1 to 3 are considered to be mild pain; 4 to 6, moderate; and 7 or greater, severe.⁴ A useful data point in a provider’s assessment is to ask the patient what pain level can be tolerated, because this will help to establish the treatment goal. There is considerable individual variation in the way patients use these scales, so comparison among patients should be avoided except for aggregate analysis for research and quality assurance purposes.

Because pain is a subjective complaint, it can be influenced or distorted by delirium, somatization, and chemical coping. It is therefore imperative to assess not only the pain complaint but also the patient’s cognitive status and coping mechanisms. Cognition can be assessed by standardized tools such as the Memorial Delirium Assessment Scale or Revised Delirium Rating Scale.⁵ Somatization and chemical coping can be difficult to detect, but a careful medical history and patient interview can alert the provider to red flags, such as rapid opioid escalation, continuing complaints of severe pain despite aggressive titration, and history of substance abuse.

Objective findings also exist when determining a patient’s level of pain. A nonverbal pain assessment is essential for those who are unable to effectively communicate, may be sedated, or even may be comatose. Some objective findings include facial grimacing (especially with movement), diaphoresis, shaking, restlessness, crying, moaning, fidgeting, hypertension, tachycardia, and tachypnea. Body language is also helpful with a nonverbal pain assessment. Additional nonverbal signs of pain include fists clenched, hitting, biting, kicking, guarding a sore area, and lying with the knees pulled to the chest or in fetal position.⁶

Physical Examination

Oncology patients can experience significant pain without giving the appearance of suffering. Coping abilities vary widely among individuals. With persistent pain, physiologic and psychosocial adaptations usually occur, which can be confusing on examination. The physical examination should focus initially on the reported painful areas to identify any lesions, inflammation, vascular changes, edema, or pain with palpation. Sensory changes in the affected part or new areas should also be carefully assessed. Changes between examinations may be related to new disease pathology or injury from other sources, such as chemotherapy or radiation therapy. Joint range of motion and muscle strength should also be assessed for changes in motor function. Providers should observe the patient during ambulation (whenever possible) to determine the impact of pain on movement and functional ability. Complaints of back pain with or without leg pain warrant a high suspicion of impending cord compression from primary tumor growth or metastases. Assessment questions for possible cord compression include a history of sensory changes (leg weakness, numbness, or tingling), autonomic dysfunction (loss of bladder or bowel control), and presence of severe back and/or leg pain (usually sudden onset).

Diagnostics

There are no specific imaging or laboratory techniques that a provider can order to directly study pain. The diagnostic evaluation should therefore be guided by the location and nature of the oncology patient’s reports of pain, and understanding of the pathophysiology of the underlying disease. Relevant imaging is essential, however, and should be reviewed and repeated periodically. Computed tomography (CT) scans may be indicated to identify masses that involve the vital organs or lymphadenopathy. Bone scans and plain x-ray films should be obtained if bone metastases are suspected. A bone scan is a sensitive test used to image disease before it is visible on x-ray examination, but it is not specific and may be positive for other inflammatory processes. Because magnetic resonance imaging (MRI) can identify nerve root or spinal cord compression, patients with a history of tumors that tend to metastasize to the bone, especially breast, lung, renal, prostate, and unknown primary site, should promptly undergo MRI to exclude cord impingement with symptoms of back pain with or without leg pain. Spinal cord compression is a true medical emergency; the earliest possible intervention (steroids, surgery, and/or radiotherapy) is critical to preserve neurologic function. Electromyography (EMG) can detect nerve conduction problems not identified on a scan. Blood tests, including a complete blood count (CBC), can help evaluate for relapse of disease, particularly with cancers of the blood. Owing to rising health care costs and the limited information gained from some tests, the provider should always be mindful when ordering any test as to whether this will assist in decision making regarding the oncology patient’s treatment.⁷

Differential Diagnosis

Pain is a significant problem for the majority of cancer patients at some point during the course of their disease and treatment. Researchers have found that 24% to 60% of patients undergoing active cancer treatment report pain, and 62% to 86% of patients with advanced cancer report pain.⁸ Although oncology pain can occur at any time during the course of treatment, the incidence and severity of pain will often increase as the disease progresses. Common treatment-related cancer pain syndromes include those associated with surgery, chemotherapy, radiotherapy, and biologic therapy. For example, surgical patients may develop postmastectomy, post-thoracotomy, or phantom pain. Some chemotherapeutic agents can cause peripheral neuropathies, and extravasational agents can cause significant tissue and nerve damage. Radiation effects can be early (e.g., mucositis) or late (e.g., brachial plexopathy or osteoradionecrosis). Biologic agents such as interferon can cause peripheral neuropathy and joint pain, both of which can be transient or chronic in nature. Tumor-related pain can result from the compression of pain-sensitive structures by a mass (e.g., epidural cord compression), or it can be related to direct infiltration, especially of the nervous and musculoskeletal systems. Pain resulting from bone metastasis is one of the most severe and disabling types of oncology pain.

Oncology patients may experience pain that is unrelated to the oncologic problem, which the provider must also address in the treatment plan. Patients may have a documented, preexisting chronic pain problem, such as low back or neck pain, migraine headaches, or diabetic peripheral neuropathy. An infection can cause sudden and severe pain that is easily improved with appropriate antimicrobial medications. HZV can be contracted in immunocompromised oncology patients, manifesting with a localized rash following dermatomal distribution accompanied by sharp, burning, and/or aching pain that can resolve or persist. Obstruction, constipation, ileus, peptic ulcer disease, gallbladder disease, pancreatitis, diverticulitis, and appendicitis are examples of other diseases and conditions that can all cause acute or chronic abdominal pain and require intervention.⁹

Effective pain management, particularly for the patient with advanced cancer, requires a comprehensive approach that often involves the use of multiple modalities (Box 245-1). A thorough assessment, physical examination, and careful review of medical records are important to determine the type of pain and pathology of the pain, so an appropriate treatment plan can be established. Opioid pain medications and adjuvant treatments (e.g., muscle relaxants, NSAIDs, antidepressants, anticonvulsants, thermal modalities, relaxation techniques) are all used to improve the oncology patient’s quality of life.^10,11

Opioids, the preferred term for narcotic analgesics, are effective and well tolerated when used to relieve many forms of cancer pain. The most commonly used opioid medications for the treatment of cancer pain include morphine, oxycodone, oxymorphone, hydrocodone, hydromorphone, methadone, and fentanyl. Opioids are classified as pure agonists, mixed agonist-antagonists, or partial agonists. The pure agonists produce effective analgesia and (with the exception of meperidine [Demerol]) can be titrated to pain relief without having a ceiling effect (Box 245-2). Meperidine is not recommended for routine use in the cancer population. The metabolite normeperidine causes central nervous system excitability, which can lead to delirium, tremors, seizures, and even death. The risk of this side effect is increased in older adults and in those with renal insufficiency and hepatic impairment.^3,12

The mixed agonist-antagonist opioids produce analgesia but can also reverse analgesia. These medications are also associated with a high incidence of psychotomimetic side effects and, like meperidine, are not recommended for routine use in cancer patients. When agonist-antagonists are given to a patient who has been taking a pure agonist opioid, the agonist-antagonist acts as an antagonist by displacing the agonist from the opiate receptors, which precipitates withdrawal and reverses analgesia.¹³ Withdrawal and exacerbation of pain reduce quality of life and pose a considerable risk to critically ill and debilitated patients. For these reasons, the injudicious use of naloxone, a pure opioid antagonist, should be avoided with cancer patients.

Unfortunately, pure agonist opioids remain underused and misunderstood by many providers. To use these opioids effectively, it is important to distinguish among key terms that are often misapplied in practice: addiction (a physical and/or mental need to use a substance), dependence (the use of a substance or thoughts about the substance that are increasingly important to the detriment of once important things), and tolerance (the need for higher doses of a substance to physically achieve the same response or a lesser response).¹⁴ The phenomenon known as pseudoaddiction must also be recognized so patients can be properly educated about their treatment. Pseudoaddiction is a real and complex phenomenon in which patients may exhibit drug-seeking behaviors and appear aggressive when requesting to increase pain medications when, in fact, they are inadequately treated for their actual pain. These patients may be labeled as “difficult,” “drug seeking,” and “clock watchers.” Although these actions may serve as warning signs to alert the practitioner to abuse, the adequacy of treatment must also be assessed before a judgment can be made.¹⁵

Patients may be reluctant to take opioid medications in the early stages of their cancer diagnosis owing to the belief that morphine is for “dying patients only.” They may also report fears of becoming “immune” or that the drug will not work when it is “really needed.” Although there are patients with stable cancer pain who may stay on the same dose of pain medication for years without a decreased efficacy, this is not the norm. Patients may develop tolerance to opioid medication with prolonged use, but dose escalation can counter this. Progression of the patient’s disease is the most common reason for dose escalation, especially when a rapid increase is needed. Other causes of dose escalation can include delirium, somatization, and chemical coping. Opioid medications do not have a ceiling dose; therefore these medications can be continually titrated on the basis of the patient’s need. The development of tolerance is often concerning to both prescribers and patients, especially when solely focusing on the total amount of medications the patient is taking daily.¹

The World Health Organization (WHO) recommends a stepwise approach to managing cancer pain, which begins when the patient first experiences pain. Initially a nonopioid medication such as a nonsteroidal anti-inflammatory (NSAID) can be used for minor pain (1 to 3 on the pain scale of 1 to 10). If pain persists, initiation of a mild opioid is then indicated, followed by a stronger opioid. Titration of opioid medications is done until the patient experiences tolerable pain reduction, with the understanding that patients may never be truly “free” of pain. Throughout the step process, adjuvant medications (e.g., muscle relaxants, antidepressants, antianxiety agents, and anticonvulsant medications) are also used to help with fear and anxiety and to enhance pain reduction.^3,16,17

The key principle for effective pain control with opioids is careful titration of the medication to achieve the desired comfort without adverse effects.^4,18 Considerable variability in dosage exists among patients. Tolerance will be seen with chronic administration of any opioid; however, this does not happen at the same rate for each patient.¹³ Although some opioids (e.g., morphine and hydromorphone) are classified as strong and others (e.g., codeine and hydrocodone) are classified as weak, these opioids are all actually capable of producing equally effective analgesia when given in equianalgesic doses. Some weak opioids are combined with an NSAID or acetaminophen to enhance pain relief. Use of these combined medications is therefore limited by the risk of renal and hepatic problems related to the nonopioid drug.

There are numerous preparations widely available, allowing for different routes of administration of opioid medications. These include oral, sublingual, buccal, intravenous, subcutaneous, transdermal, rectal, and intraspinal (epidural and intrathecal).¹¹ The oral route of administration is the route of choice in most situations because of ease, comfort, and cost-effectiveness. The choice of route and drug depends on a variety of patient-related factors, including the pathology of the pain, functional status of the gastrointestinal (GI) tract, the abilities of the patient and caregiver to manage the regimen (e.g., cognitive function, psychomotor skills), side effects, the dosage forms, availability, and cost. More invasive routes of administration, such as parenteral and intraspinal, increase the risk for complications (e.g., infection and displacement of the needle) and are usually more costly. The subcutaneous, transdermal, and rectal routes can deliver excellent pain control in patients who cannot tolerate oral medications but want to be managed at home.

Short-acting opioids are clinically indicated to treat postoperative pain and for moderate isolated painful incidents. For the cancer patient, short-acting opioids can be especially helpful for breakthrough pain associated with activity, treatments, or other obvious factors. When an event or activity (e.g., ambulation) is known to provoke pain, the as-needed (prn) dose should be taken 30 to 45 minutes before that activity. For moderate to severe pain that is poorly managed, however, long-acting opioids should be administered around the clock, based on their expected duration of action. As-needed opioid administration with these patients can lead to greater peaks and valleys in analgesic blood levels between doses, especially if the patient waits until the pain is severe before taking the short-acting opioid. Moderate to severe cancer pain is best treated with a long-acting, scheduled opioid medication around the clock, and a short-acting opioid for breakthrough pain. The short-acting opioid dose should be 10% to 15% of the total daily dose of the long-acting opioid.¹⁹ If two or three breakthrough doses are required routinely, the case can be made for the long-acting medication to be increased.

Some oncology patients with moderate to severe pain may require short-term or long-term use of parenteral or subcutaneous opioids. Patient-controlled analgesia pumps can be ideal for patients looking at end-of-life comfort care; these pumps provide continuously programmed opioid delivery. Pumps can also be very helpful with patients in an acute pain crisis, with the goal to ultimately wean off the pump and restart oral medications once the pain is more manageable. The on-demand patient-administered dose used as needed with or without a continuous (basal) infusion allows for individualized dosage and sustained analgesia. If the patient shows early evidence of delirium, somatization, or chemical coping, the on-demand patient-administered dose should be avoided because of the possibility of opioid-induced neurotoxicity.

Table 245-1 illustrates the relative equianalgesic doses for the most commonly used opioids. Morphine is often used for comparison with other opioids because it is the most widely used opioid and there is extensive existing research about its pharmacokinetics. The route of administration must be considered when calculating equianalgesic doses. For example, opioids administered through the GI tract are subject to a first-pass effect, whereby a portion of the drug is metabolized to nonanalgesic substances as it is routed through the hepatic circulation before being circulated systemically. If a patient is receiving adequate analgesia from 10 mg of morphine sulfate given parenterally, it takes 30 mg to achieve the same effect if it is given orally because approximately 20 mg is metabolized before reaching the systemic circulation. The parenteral-to-oral ratio also varies from drug to drug. In addition, the longer a patient is taking an opioid, the less accurate these relationships can be, because of cross-tolerance with similar substances. It must be noted that the relationship between different opioids is not absolute, so equianalgesic comparisons like the one in Table 245-1 are only rough guides. With opioid rotation, it is imperative to err on the side of caution because the risk of overdose does not outweigh the risk of transient discomfort.^3,19

TABLE 245-1

Opioid Conversion Table

Drug	Parenteral Dose (mg) Equivalent to 10 mg IV/SC Morphine	Oral Dose (mg) Equivalent to 30 mg Oral Morphine	Dosage Interval
Morphine	10	30	2-4 hr for immediate release; 8-24 hr for sustained release
Codeine	100	200	2-4 hr
Hydromorphone	1.5	7.5	2-4 hr
Oxymorphone	1	10	4-6 hr for immediate release 8-12 hr for sustained release
Methadone	1-10*	2-20*	8-24 hr
Oxycodone	N/A	20-30	2-4 hr for immediate release; 8-12 hr for sustained release
Fentanyl	0.1	N/A	4 hr for buccal administration

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