Type

Cancer pain can be classified as nociceptive, neuropathic, or a combination of the two. Each type typically presents with a number of relatively distinct qualities.

Nociceptive pain results when pain-sensing neuronal pathways are stimulated and function normally. Specialized receptors at the distal end of neuronal axons, termed nociceptors, detect noxious mechanical, chemical, and thermal stimuli, and generate neuronal electrical activity. These signals are transmitted normally along neuronal pathways to the brain.

Nociceptive pain can originate from somatic or visceral sources, or both. Somatic pain originates from skin, muscle, bone, and fascia. It is mediated by the somatic nervous system. As innervation is highly specific, localization of the pain is precise. Somatic pain is often described as sharp, aching, or throbbing. An oncology example would be the well-localized pain experienced from a spinal compression fracture due to bone metastasis. Visceral pain originates from internal structures. It is mediated by the autonomic nervous system. As there is a lack of specificity of innervation, and considerable neuronal crossover, visceral pain is typically difficult for the patient to localize or describe, and may encompass an area that is much larger than might be expected for a single organ. Visceral pain is often characterized as diffuse and intermittent. Examples can include the abdominal pain experienced with malignant bowel obstruction or from liver metastasis.

Neuropathic pain has been defined as a primary lesion or dysfunction of the pain-sensing nervous system. The lesion can be either peripheral in the somatic or visceral nervous system, or central. The nerves themselves may be subject to damage from compression, infiltration, ischemia, metabolic injury, or transection. The myelin sheath that insulates one nerve from another may also be damaged. Alternatively, neuropathic pain may also be caused by dysfunction of the nervous system, as in central facilitation or “wind-up,” where an event that is normally not painful, such as the pressure from a bed sheet or clothing on the chest of a patient with recurrent breast cancer, causes pain. Neuropathic pain is often described as burning, shooting, stabbing, or electriclike, and may be associated with numbness, tingling, and/or sensory deficits. An example can be the peripheral neuropathy experienced with certain chemotherapy agents.

Temporal Profile

The temporal profile of a pain will provide further clues to its etiology. The patient should be asked about the duration of the pain. When did it first start? How long has it been present? Did it come on slowly, or suddenly? One can ask what the baseline or background pain is like. Does it vary over time (e.g., worse at night)? Is the patient ever pain-free? Are there times when the pain gets much worse? What factors exacerbate or relieve the pain (e.g., activity, touch, clothing, cold/heat, or procedures)? As an example, spontaneous pain of short duration could be the paroxysmal firing of a neuroma. Back pain that occurs only with weight bearing could indicate a spinal bony metastasis. Most cancer pain is continuous over time, with some variation in intensity, particularly at night. Without intervention, it rarely disappears completely. Cancer pain is also frequently associated with intermittent paroxysms of pain that occur with activity (e.g., movement, chewing, swallowing, breathing, defecating, urinating, dressing, touch, etc.), or during a procedure.

Severity

Sequential measurement of severity using a validated severity assessment scale will provide an indication of the changing intensity of the pain experienced by a given patient over time. It will also guide analgesic management. In a given patient, the same tool should be used for each assessment.

A numerical analogue scale is the simplest. The patient is asked to indicate the severity of the pain on a 10-point scale, where 0 represents “no pain” and 10 represents the “worst possible pain.”

Alternatively, a visual analogue scale can provide more visual cues and be more reliable. The patient is asked to indicate the severity of the pain by marking a 100-mm line at a point that indicates the intensity of her/his pain (delimited by the descriptors “no pain” at one end [usually the left] and “worst possible pain” at the other end). A few patients will find it easier to understand a vertical line where “no pain” is at the bottom and “worst possible pain” is at the top. For children and adults who do not understand numerical or visual analogue scales, the Wong–Baker or other faces scales are similarly reliable assessment tools.

To understand how the pain varies over time, one can ask about the intensity of the continuous pain now, the worst it has been in the last 24 hours, the best it has been in the last 24 hours, and the intensity of intermittent pain at its peak.

Total Pain

Together with a careful physical examination and select laboratory and imaging studies, it is usually possible to identify the relevant pathophysiology leading to a pain state. However, a particular pain syndrome is part of a whole person’s experience. The concept of “total pain” emphasizes that multiple nonphysical factors can also contribute to pain—that is, psychologic factors (e.g., anxiety, depression), social factors (e.g., familial estrangement), and spiritual or existential factors (e.g., loss of meaning in life, fear of death). It may not be possible to control pain successfully without also addressing each of these other sources of suffering.

World Health Organization Three-Step Ladder

In 1988 the World Health Organization (WHO) first promoted the Canadian three-step ladder for cancer pain management ( Fig. 34.1 ). Recent pain guidelines from the Royal College of Physicians and the European Association for Palliative Care both use the WHO guidelines as a basis. Today it is the cornerstone for the WHO’s public health initiative to treat cancer pain worldwide.

World Health Organization three-step ladder.

The ladder provides a clinically useful strategy for classifying the available analgesics, and guiding initial analgesic selection based on the severity of the patient’s pain. If the pain is mild (1/10 to 3/10), an analgesic can be chosen from step one. If it is moderate (4/10 to 6/10), one can start with an analgesic from step two. If it is severe (7/10 to 10/10), one can start with an opioid from step three. At any step, adjuvant analgesics can be added to optimize pain control.

STEP ONE: Acetaminophen and the nonsteroidal antiinflammatory drugs (NSAIDs) including acetylsalicylic acid (ASA) are the mainstay of step one of the WHO analgesic ladder for the management of mild pain. They obey first-order kinetics and may be dosed up to recommended maximums ( Table 34.1 ). Many are available without prescription. Sustained-release preparations or NSAIDs with longer half-lives (e.g., piroxicam) that require less frequent dosing may encourage adherence. When pain is more than mild, step-one analgesics can be combined with opioids at steps two and three.

STEP TWO: Several opioid analgesics are conventionally available in combination with acetaminophen, ibuprofen, or ASA, and are commonly used to manage moderate pain. They are listed in Fig. 34.1 under step two of the WHO analgesic ladder. With the exceptions of propoxyphene (that truly has weak analgesic activity), tramadol (that has a unique combination of weak opioid activity with other analgesic properties), meperidine, and codeine (methylmorphine, which has one-tenth the potency of morphine), the opioids in this class are close in potency to morphine (mg for mg). However, they have been called “weak” opioids because, in combination, they have a ceiling to their analgesic potential due to the maximum amounts of acetaminophen or ASA that can be administered per 24 hours (e.g., 4 g acetaminophen per 24 hours).

The combination medications of step two all obey first-order kinetics and may be dosed up to recommended maximums ( Table 34.2 ). The potential adverse effects are those of the component drugs.

Frequently, patients are simultaneously given prescriptions for several step-two drugs, even though pain is poorly controlled. This usually occurs when physicians are reluctant to prescribe a step-three opioid. Aside from propoxyphene, there is no evidence that maximal dosing of any “step-two” medication is better than another, and trials of several step-two medications are likely to prolong the patient’s pain. In addition, when a step-two drug inadequately relieves pain, patients may combine two or more medications, or take more than the prescribed amount in an attempt to obtain pain relief. In doing so, they may unknowingly put themselves at increased risk for significant toxicity from either the acetaminophen or ASA component of the medication. If pain persists, or increases, despite a maximum dose of a step-two drug, a step-three drug should be prescribed instead.

STEP THREE: The pure agonist opioid analgesics comprise step three of the WHO analgesic ladder. Morphine is the prototypical drug because of its ease of administration and wide availability. Other widely prescribed opioids are listed in step three of Fig. 34.1 . Many patients with chronic pain are best managed with an appropriately titrated strong opioid that is combined with one or more coanalgesics. In contrast with the step-one and step-two analgesics, there is no ceiling effect or upper limit to the dose of opioids when titrating to relieve pain.

“STEP FOUR”: Several studies of the WHO three-step ladder have demonstrated that its application results in the adequate control of up to 90% of patients with cancer pain. Several authors have informally invoked “step four” to indicate approaches that should be reserved for patients whose pain is not controlled by competent use of the analgesic approaches outlined in the first three steps. In general, “step four” involves invasive approaches for pain relief that can be summarized as follows.

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  Subcutaneous (SC) or intravenous (IV) administration of opioid analgesics and coanalgesics may be required for patients where oral (PO), buccal mucosal, rectal (PR), or transcutaneous approaches are not possible or practical, or where doses of oral opioids lead to undesirable adverse effects. Adverse effects may be minimized as a result of the uniform delivery of the drug parenterally, the change in route of administration, or the reduction in first-pass metabolite production.

  
  
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  Intraspinal administration of opioid analgesics either epidurally or intrathecally may be required in selected patients.

  
  
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  Intraventricular application of opioid analgesics and other drugs has been investigated for selected central pain syndromes.

  
  
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  Neuroablative techniques such as peripheral neurolytic blockade, ganglionic blockade, cordotomy, and cingulotomy may be appropriate in highly selected patients. An example includes celiac plexus block for pain management due to pancreatic cancer.

  
  
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  Alternative therapies such as acupuncture, massage, meditation, and others may also add additional nonpharmacologic benefit at any step of the WHO ladder.

Acetaminophen

Despite its wide use, the precise mechanism of action remains unclear. Although it is analgesic and antipyretic, it is not antiinflammatory, at least systemically. Its analgesic activity is additive to other analgesic agents, including the NSAIDs and opioids.

Acetaminophen is associated with significant liver toxicity. It is generally recommended that the total dose not exceed 4 g per 24 hours for routine dosing of patients with normal liver function.

Nonsteroidal Antiinflammatory Drugs (Including Acetylsalicylic Acid)

Normally the enzyme cyclooxygenase (COX) catalyzes the conversion of arachidonic acid to prostaglandins and thromboxanes. These inflammatory mediators sensitize nerve endings to painful stimuli and stimulate a group of silent nociceptors that only fire in an inflammatory milieu. In the spinal cord, COX plays a role in setting up the dysfunctional signaling pattern involved in neuropathic pain.

NSAIDs are potent antiinflammatory medications that inhibit the activity of COX and decrease the levels of these inflammatory mediators. As a result, there is less sensitization of nerve endings, less recruitment of silent nociceptors, and less risk of central “wind-up.” While primary analgesia may be achieved at low doses, for their antiinflammatory effects, maximum doses should be used. As they act through an alternate mechanism to opioids and other adjuvant analgesics, NSAIDs may be combined with other analgesics to achieve better pain relief than is possible with a single medication.

The morbidity and mortality associated with NSAIDs, including ASA, are significantly higher than for any of the other analgesics. The adverse effects of NSAIDs are related to their mechanism of action. Inhibition of COX leads to inhibition of platelet aggregation and microarteriolar constriction/decreased perfusion, particularly in the stomach and kidneys. In the stomach, the relative ischemia compromises the production of gastric mucus by the chief cells, and significantly increases the risk of gastric erosions and bleeding. In the kidneys, the relative ischemia increases the risk of renal papillary necrosis and renal failure.

COX exists in two forms: a constitutive form, COX-1, and a form that is inducible under conditions of inflammation, COX-2. There are both COX-2-selective and nonselective NSAIDs that target both forms of COX. Whereas renal insufficiency is a risk of both nonselective and COX-2-selective NSAIDs, the risk of gastropathy and platelet inhibition is significantly decreased with COX-2-selective NSAIDs.

Patients (particularly the elderly) who are dehydrated, malnourished, cachectic, or have a history of nausea, gastritis, or gastric ulceration with NSAIDs are at increased risk for adverse effects from NSAIDs. However, the dyspepsia and abdominal pain that limit the use of NSAIDs in some patients do not correlate with significant gastric erosions and gastrointestinal bleeding.

To minimize the risk of ischemia, the patient should be well hydrated. The use of an H ₂ blocking antacid (e.g., cimetidine or ranitidine) to treat NSAID dyspepsia and abdominal pain does not prevent gastric erosions and gastrointestinal bleeding. Only misoprostol, a prostaglandin-E analogue that reverses the effect of NSAIDs on the microarteriolar circulation of the stomach, and the proton pump inhibitors (such as omeprazole, pantoprazole) have been shown to heal gastric erosions and reduce the risk of significant gastric bleeding.

The nonacetylated salicylates (choline magnesium trisalicylate and salsalate), nabumetone, and the COX-2 inhibitors do not significantly affect platelet aggregation. They may be useful in patients who are thrombocytopenic and for whom other NSAIDs are contraindicated. Sulindac is thought to be least likely to induce renal failure because of its minimal effect on prostaglandin synthesis at the level of the proximal renal tubule.

In contrast to the opioids, NSAIDs and acetaminophen have a ceiling effect to their analgesic potential, do not produce pharmacological tolerance, and are not associated with physical or psychological dependence.

Opioids

Opioid analgesics act by binding to opioid receptors of three subtypes (mu, kappa, and delta), both peripherally and centrally. The central receptors in the spinal cord and brain are most important for mediating analgesia. The opioid analgesics in common usage may be divided into those that are full agonists, partial agonists, and mixed agonist–antagonists. The pure agonist drugs are the most useful in chronic cancer pain.

Opioids to Avoid

The mixed agonist–antagonist opioids (such as pentazocine, butorphanol, and nalbuphine) and the partial agonist opioids (such as buprenorphine) are poor choices for patients with severe pain. They have no advantages over the pure agonist opioids. Besides having a ceiling effect to the analgesia they produce, they have the significant disadvantage that, if combined with a pure opioid agonist, may precipitate acute pain and opioid withdrawal symptoms.

Routes of Administration

The oral route of administration is preferred for the management of cancer pain. It provides the simplest, least expensive way to manage most cancer pain. When it is not available, analgesics can be administered buccally and rectally before resorting to more invasive and expensive routes of delivery. In a small number of patients (<5%), subcutaneous, IV, or intraspinal administration may be required. The time to peak serum concentration (C _max ) correlates with time to peak effect, and this occurs in 1 hour for an oral or rectal dose of a short-acting opioid. Subcutaneous doses reach peak effect in 30 minutes, and IV doses reach peak effect in 8 minutes.

Achieving Initial Pain Relief

In a patient with severe pain, opioids should be dosed frequently until the patient achieves pain relief or undesirable side effects. This is accomplished by administering a single dose and reassessing after the dose has reached peak effect (time to C _max : 1 hour for an oral dose, 30 minutes for a subcutaneous dose, and 8 minutes for an IV dose). If the patient remains in severe pain, the dose should be doubled and the patient observed again until peak effect. This should be repeated with careful observation until the pain is no longer severe or the patient experiences side effects. For example, if a patient continues to have severe pain and no unacceptable side effects 8 minutes after a single 4-mg IV dose of morphine, they should receive an additional 8 mg of morphine intravenously. If they remain in severe pain 8 minutes later, they should be given a 16 mg dose.

Routine Dosing for Constant Pain

One should distinguish between constant and intermittent pain. For constant, ongoing cancer pain, analgesics should be prescribed on a regular schedule at doses sufficient to keep the pain controlled. For patients with constant pain, dosing solely on an “as needed” or “prn” basis guarantees that the patient will frequently return to pain and may increase both the patient’s anxiety and the total dose required to control the pain.

Most of the short-acting drugs used for analgesia, particularly acetaminophen, the NSAIDs including ASA, and the opioids, follow first-order kinetics. When prescribing them on a routine schedule, they should be administered once every half-life in order to achieve steady state and maintain constant serum levels—that is, q4h for oral morphine or oxycodone dosing. Methadone, with its longer half-life, is administered every 8–12 hours.

Titration

When initiating, titrating, or changing analgesic therapy, drugs that follow first-order kinetics take five half-lives to reach pharmacological steady state. Changes in dosages should only be made once the serum level has reached steady state—for example, once every 20–24 hours when morphine is given PO, or even SC. Waiting longer will not improve pain control or safety. Increasing scheduled dosages before steady state is reached may lead to unnecessarily high serum levels and undesired adverse effects.

Sustained-Release Products

Sustained-release medications should not be used alone to adjust or titrate a patient’s uncontrolled pain. Using them for titration unduly prolongs the process to bring the pain under control, because they can be titrated only once every five half-lives (∼60 hours). However, once the pain is controlled, changing to a sustained-release product may enhance the patient’s quality of life and improve compliance and adherence due to the decreased frequency of dosing (e.g., q8h, q12h, q24h, etc.).

Sustained-release preparations of morphine and oxycodone are available for PO administration and should be administered in accordance with the instructions of the manufacturer.

Transdermal fentanyl patches are convenient when patients are receiving stable opioid dosing, but should not be used to titrate unrelieved pain. Approximately 12–18 hours are needed for significant serum levels of fentanyl to accumulate, so appropriate doses of opioids need to be maintained during this window of time. Fentanyl patches may be changed every 72 hours, although a small number of patients may need to have their patch(es) changed every 48 hours. Titration may be done every other day. Caution should be exercised in the setting of cancer cachexia, as there may be variable levels of absorption.

Abuse-Deterrent Formulations

With the increase in prescription of opioids for pain relief has come an increase in prescription opioid abuse. Abuse-deterrent formulations are intended to prevent, impede, or discourage physical and chemical tampering (e.g., crushing, chewing, extraction, smoking, snorting, injecting), while still being able to provide safe and accurate delivery of the opioid for therapeutic benefit. The sustained-release formulations have seen the most use of these (e.g., crush-resistant coatings, nonextractable gels, sequestered naloxone released only with crushing). Technologies for the immediate-release formulations have lagged. Widespread adoption is limited by cost.

Breakthrough or Rescue Dosing for Intermittent Pain

Changes in pain severity may occur spontaneously because of activity (e.g., movement) or a procedure (e.g., venipuncture, wound dressing change). If the duration and severity of the change are sufficient, extra short-acting doses of the same or similar medication (breakthrough or rescue doses) on an “as needed” or “prn” basis may be appropriate. If a patient regularly requires more than 2–4 breakthrough doses per 24 hours, then the routine scheduled dose should be increased. For intermittent pain of short duration (seconds to a few minutes), breakthrough dosing, particularly of the opioids, may lead to undesired adverse effects without increased analgesia.

Breakthrough doses of an analgesic can be given safely with a frequency equivalent to the time required to reach C _max . Again, this is 1 hour for an oral dose, 30 minutes for a subcutaneous dose, and 8 minutes for an IV dose. Making the patient wait any longer when the pain is not controlled simply prolongs the time required to establish optimal pain control.

The size of the breakthrough dose should be related to the routine dose. For the strong opioids such as morphine, hydromorphone, and oxycodone, a simple rule of thumb is for the oral route: Administer 10% of the total 24-hour dose per breakthrough dose every 1 hour as needed. For the IV route, administer 50%–100% of the hourly infusion rate every 5–10 minutes as needed. The dose is then adjusted as the routine dose changes or as the intensity of the intermittent pain requires.

Oral transmucosal fentanyl is available in several preparations, including a candy matrix lozenge on an applicator stick that is twirled against the buccal mucosa, as an orally dissolving tablet that is absorbed transmucosally, or as an adherent film. Additionally, other preparations will likely be commercially available soon, including nasal sprays, inhalers, and active transdermal patches. Relatively quick onset and offset make these preparations useful to treat short-lived breakthrough pain. Dosing of fentanyl preparations must be individualized; it cannot be calculated as an equianalgesic dose.

Equianalgesic Dosing

The relative abilities of opioid analgesics to relieve pain have been correlated ( Table 34.3 ). These relationships are not scientifically precise, as there is significant interpatient variability. Further, the data from which these equivalencies are derived are often obtained in clinical settings other than chronic cancer pain. Nevertheless, the equianalgesic tables are useful to approximate the dose of a new analgesic when changes are contemplated. The dose should then be adjusted based on patient response.

TABLE 34.3

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