The Washington Manual of Oncology, 3 Ed.

Pain Management

Robert A. Swarm • Rahul Rastogi • Lesley Rao

 I. INTRODUCTION TO CANCER PAIN MANAGEMENT. Pain remains a common problem in oncology practice largely because standard analgesic therapies are inconsistently applied; the vast majority of patients could receive good cancer pain control from standard pain treatments. In developed countries, up to 30% of people at initial cancer diagnosis, 50% to 70% of those receiving active antitumor therapy, and up to 80% of those with advanced malignant disease suffer inadequately controlled pain. Improving cancer pain management requires: health-care professionals to know and apply pain pathophysiology, epidemiology, and treatment; patients to be more effective self-advocates and better-informed health-care consumers; and a health-care delivery system that requires consistent symptom control as part of individualized, patient-centered goals of therapy for cancer care. Pain control not only improves quality of life for cancer patients but is a major factor in overall symptom control, which may contribute to survival; therefore, optimized pain control is an integral component of comprehensive cancer care. To consistently control cancer pain, each practitioner must insure that every cancer patient under his/her care receives optimized pain control. Factors known to limit optimal cancer pain management must be identified in clinical practice and appropriately managed (Table 40-1).

1. COMPREHENSIVE PAIN ASSESSMENT. The starting point for good pain control is a comprehensive pain assessment, including thorough pain history and physical examination. Consider repeating diagnostic evaluations because tumor progression or metastasis is the most common cause of increasing pain in patients with cancer. When feasible, antitumor therapies to control underlying disease may be the most effective pain management therapy.
2. Pain assessment scales are used to facilitate measurement of pain intensity and establish a baseline from which to judge the success of pain treatments. A numeric pain scale (“0 = no pain” up to “10 = worst pain imaginable”) is easily used by most adults, but the face scale (happy to sad faces) may be more easily used by young children. Measuring pain intensity is only the starting point in understanding the severity and consequence of a patient’s pain.
3. The comprehensive pain evaluation includes “PQRST” factors: P = provocative factors and palliative factors; Q = quality (characteristics) of pain; R = region, radiation, and referred distribution of pain; S = severity of pain intensity; and T = temporal factors including onset, duration, time of maximum intensity, frequency, and daily variation. Patients should be queried about a previous history of pain and what drugs were effective or ineffective in his or her management.

1. Consider comorbid conditions that may greatly influence analgesic therapy, especially in elderly or those with advanced disease. Renal and/or hepatic insufficiency will significantly impact analgesic choice. Intractable coagulopathy may preclude the use of interventional pain therapies. Advanced medical illness may increase the risk of analgesic adverse effects.
2. Assess components of pain. Nociceptive, neuropathic, affective, behavioral, cognitive, and social. Neuropathic pain may respond best to treatments including anticonvulsant and/or antidepressant therapy. Affect, cognition, and social context may markedly influence selection and/or efficacy of analgesic therapies.
3. Believe the patient’s own report of pain. It is the most reliable indicator of pain. Malingering is rare in cancer pain management. If you do not (or conclude that you cannot) trust the patient’ description of pain, pain will not be controlled.

 III. SYSTEMIC ANALGESICS

1. The World Health Organization (WHO) ladder (Figure 40-1), the most widely used and validated protocol for cancer pain management, is a stepwise approach based on pain intensity. Opioids are the cornerstone of pharmacotherapy for moderate-to-severe cancer pain, but nonopioid and adjuvant analgesics (antidepressants, anticonvulsants) are used to enhance pain relief when needed. Analgesics should be given “by the mouth” (the simplest, most effective route of administration); “by the clock” (regular dosing schedule rather than sporadic “as-needed” dosing); “by the ladder”; and “for the individual” (titrate analgesic to effect, monitor for adverse effects). Unrelieved pain can almost always be controlled by reevaluating the patient and reapplying the principles of the WHO ladder. For pain refractory to systemic analgesics, advanced pain therapies (beyond the WHO ladder) should be utilized.

Figure 40-1. Therapy continuum for cancer pain management. The first three steps are based on the World Health Organization (WHO) analgesic ladder and include a wide range of system analgesics (nonopioid, adjuvant, and opioid analgesics). The final step (“Beyond the WHO Ladder”) includes additional therapies for pain refractory to systemic analgesics.

1. Nonopioid analgesics (Table 40-2) are the principal analgesics for mild pain. In more severe pain, nonopioids are used to supplement opioid to improve pain control and reduce opioid dose (to reduce opioid-related adverse effects and the risk of opioid tolerance).
2. Aspirin and the nonacetylated salicylates are modestly potent analgesics and antipyretics. Aspirin is a uniquely potent inhibitor of platelet function, but the nonacetylated salicylates have no impact on platelet function. The risk of gastrointestinal ulceration, somewhat greater with aspirin than other salicylates, significantly limits the analgesic utility of these agents, especially in medically ill or elderly patients. Salicylate is metabolized in the liver with renal excretion of salicylate and inactive metabolites.

2. Acetaminophen is a modestly potent but effective analgesic and antipyretic. Typical doses (650 to 1,000 mg QID, maximum 4,000 mg/day) are well tolerated, but excessive doses may cause severe hepatotoxicity; for added safety margin, consider limiting chronic acetaminophen dosing to 3,000 mg per day. Acetaminophen is available for intravenous, oral, and rectal administration, but intravenous formulation is expensive, and rectal absorption is poor.
3. Nonsteroidal anti-inflammatory drugs (NSAIDs) are useful in pain from inflammatory processes and/or boney metastases. NSAIDs limit facilitation of pain signal transmission by inhibiting prostaglandin synthesis in peripheral tissues and central nervous system (CNS). Renal toxicity, gastrointestinal ulceration, and platelet dysfunction limit NSAID utility, especially in medically ill patients. Selective cyclooxygenase 2 (COX-2) inhibitors (celecoxib 200 mg daily or BID) have lower risk of gastrointestinal ulceration and no platelet dysfunction, but increased risk of thromboembolic events limits use. Although NSAIDs are administered orally, intravenous formulations (ketorolac (15 to 30 mg i.v./i.m., QID, maximum 5 days due to gastric ulceration risk) and ibuprofen (400 to 800 mg i.v. q 6 hours) are options when enteral administration is not feasible.
4. Opioid analgesics
5. General principles for the use of opioid analgesics
6. Use a comprehensive pain assessment to gather information to guide pain therapy. Repeat/review assessment at each patient contact and whenever pain is not controlled.
7. Teach patients and their families to assess pain by using a numeric score to facilitate communication. Documentation of pain intensity rating, the fifth vital sign, is standard for outpatient and inpatient care.
8. Administer analgesics orally or through the least invasive route that provides effective pain control.
9. Document all narcotic prescriptions in the medical record to aid in the monitoring and adjustment of pain therapy (and to comply with federal and state regulations).
10. Individualize opioid dose. The correct dose is that which adequately controls pain while minimizing adverse effects. Depending on pain severity, degree of opioid tolerance, and comorbid factors, the required daily dose of opioid can range over two to three orders of magnitude.
11. Avoid use of combination analgesic preparations, which contain opioid together with an NSAID or acetaminophen, unless that specific combination of medications is indicated for the specific patient; single agent formulations facilitate analgesic dose titration.
12. Anticipate opioid-related adverse effects and treat promptly (Table 40-3). Almost everyone taking opioid daily will need daily laxatives to prevent constipation.
13. Use regularly scheduled, long-acting analgesic preparations (extended-release preparations of morphine, oxycodone, oxymorphone; fentanyl transdermal patch; and methadone) to improve compliance and provide more consistent pain relief than repeated as-needed dosing of short-acting opioid. Extended-release oral tablets should be swallowed whole and not cut or crushed.
14. Prescribe supplemental doses of opioid for “breakthrough pain” not controlled by the regularly scheduled doses. Use short-acting, immediate-release oral preparations of opioid (morphine, oxycodone, and hydromorphone) at doses of 10% to 15% of total daily opioid dose, as often as every 1 hour as needed.
15. Be flexible but aggressive in treating severe, uncontrolled pain. Hospital admission for parenteral opioids and frequent reassessment of analgesic efficacy may be required. In a pain emergency, opioid should be given intravenously (e.g., morphine 1 to 4 mg i.v., every 10 minutes) and titrated to effect. Once pain is improved, a patient-controlled analgesia (PCA) device may facilitate access to, and documentation of, needed opioid for subsequent conversion to oral formulations.

Seizures rarely have been reported with high-dose opioid infusion, typically associated with preservative agents. If using high-dose infusion, use preservative-free opioid preparations.

1. Be aware of equipotent doses of various opioid analgesics to facilitate changes between agents or routes of administration (Table 40-4).
2. Use naloxone to treat severe respiratory depression related to opioid overdose. About 0.1 to 0.2 mg i.v./i.m. every 1 to 5 minutes as needed; however, opioid antagonism with naloxone may cause extreme pain and other opioid withdrawal symptoms.

2. Limitations of opioid use in cancer pain management. Opioids are the principal analgesics for the management of moderate-to-severe cancer pain; however, several factors limit opioid utility, including adverse effects (Table 40-3), limited efficacy, and access-to-care issues (Table 40-1).
3. Common opioid adverse effects, especially constipation and nausea, should be anticipated so that management strategies can be implemented promptly (Table 40-3).

 i. Respiratory depression—increased susceptibility with preexisting lung disease, sleep apnea, and cardiac disease; somewhat decreased susceptibility with chronic opioid exposure (tolerance). If significant respiratory depression or opioid-induced sedation develops, consider naloxone administration (0.1 to 0.2 mg i.v./i.m. every 1 to 5 minutes as needed); abrupt naloxone reversal of opioid effect may lead to acute opioid withdrawal syndrome (severe pain exacerbation, hypertension, tachycardia, dyspnea, pulmonary edema, and delirium).

  ii. Sedation—typically managed with opioid dose titration, but severe or progressive sedation may signal pending respiratory depression/arrest and necessitate at least temporary opioid discontinuation or even reversal with naloxone. New onset sedation, with stable chronic opioid regimen, may suggest other contributing abnormality: decreased opioid clearance (hepatic and renal insufficiency), CNS pathology, and sepsis.

iii. Hypogonadism—common in chronic opioid therapy, especially higher dose morphine >100 mg daily, due to opioid suppression of hypothalamic–pituitary–gonadal axis. Symptoms, in men and women, may include impaired sexual function, decreased libido, infertility, depression, fatigue, and loss of muscle mass and strength. Opioid endocrine impact may be confounded by consequences of underlying malignancy and/or other medical conditions; management may include opioid titration/discontinuation and/or hormonal replacement therapy, if needed.

1. Immunosuppression—opioid-induced immunosuppression is readily demonstrated in experimental animals, yet the clinical significance is confounded by comorbid disease pathophysiology and lack of randomized clinical trials.

 v. Tolerance/hyperalgesia—essentially all patients receiving chronic opioid therapy develop opioid tolerance, sometimes managed with an increase in opioid dose. Increasingly, opioid tolerance is thought to reflect an induced hyperalgesic state in which chronic opioid still inhibits pain signal transmission, but increasingly facilitates pain signal transmission, resulting in more pain that is more resistant to management. Lack of randomized clinical trials limits clear separation of tolerance from other causes of hyperalgesia; however, people taking opioid chronically generally have significant hyperalgesia. Concern for opioid-induced hyperalgesia has resulted in a marked reduction of opioid use for chronic noncancer pain management and raises concern for chronic opioid use in long-term cancer survivors.

1. Opioid analgesic efficacy is best for moderately severe pain that is continuously present. Efficacy may be limited by the following:

 i. Neuropathic pain, especially associated with severe sensitivity to light mechanical stimulation, may be relatively resistant to opioid analgesics, but may benefit from adjuvant analgesics (anticonvulsants and antidepressants).

  ii. Episodically severe pain may represent a timing challenge for analgesic dosing. Pain episodes may be inadequately controlled while waiting for analgesic effect onset. Conversely, analgesics dosed to control very severe pain episodes may result in relative overdose when the pain episode subsides.

iii. Sharp somatic pain (e.g., wound debridement, pathologic bony fracture) is generally not adequately controlled with opioid except at doses associated with marked sedation. Sharp somatic pain may require “anesthetic” rather than “analgesic” management.

1. Intractable pain, especially in advanced cancer, may not be adequately controlled despite optimal adjustment of systemic analgesics, and may require interventional pain therapies or other techniques.
2. Specific opioid analgesics (Table 40-4)
3. Morphine is hepatically metabolized to active metabolites that contribute to analgesic effect and toxicity. Morphine and metabolites undergo combined fecal and renal excretion; morphine should be used with caution in renal insufficiency as metabolites may accumulate and cause toxicity. Although oral administration is preferred for most patients, morphine can be administered through intravenous, intramuscular, subcutaneous, sublingual, rectal, topical (for painful skin ulceration), epidural, and intrathecal routes.
4. Hydromorphone, and its active hepatic metabolites, are renally cleared by the kidneys and can accumulate in renal failure, precipitating opioid toxicity. In some individuals, common opioid adverse effects may be less with hydromorphone than with morphine. Hydromorphone can be administered through intravenous, intramuscular, subcutaneous, sublingual, rectal, epidural, and intrathecal routes, although oral absorption is less reliable than with oxycodone or morphine.
5. Fentanyl has high lipid solubility and is metabolized by the liver to inactive metabolites that are enterally cleared. Fentanyl is given through intravenous, intramuscular, subcutaneous, transdermal, transoral mucosal, epidural, and intrathecal routes. Long-acting fentanyl transdermal patches may be especially useful when enteral opioids are contraindicated. Typically changed every 72 hours, some patients will require patch replacement every 48 hours. Patients who are cachectic or are experiencing night sweats may have poor absorption of transdermal fentanyl. Short-acting fentanyl transmucosal preparations are partially absorbed through the oral mucosa and may be used for breakthrough pain.
6. Oxycodone is hepatically metabolized to active and inactive metabolites. Oxycodone should be used cautiously in patients with renal and hepatic insufficiency. It is only available for oral administration.
7. Methadone has a remarkably long elimination half-life (30 ± 19 hours). Although equianalgesic to morphine with single-dose administration, methadone accumulates with repeated dosing so that, at steady state, it is fully 10 times more potent than morphine. Methadone must be increased slowly (every 5 to 10 days) and supplemented with as-needed doses of short-acting opioid (morphine and oxycodone) to avoid overdose. Metabolized in the liver by cytochrome P-450 enzymes to inactive metabolites, methadone metabolism is markedly affected by medications that induce or impede P-450 activity. Methadone and metabolites are enterally excreted and do not accumulate in renal failure. Methadone should be avoided in hepatic insufficiency because further prolongation of normally long elimination half-life may preclude safe dose titration. Methadone has nonopioid analgesic effects, through N-methyl D-aspartate (NMDA) receptors, that may add to analgesic effect. Methadone, especially at high doses (greater than 100 mg/day), has been associated with prolongation of QT interval and cardiac arrhythmia. Methadone can be given through oral, rectal, or intravenous routes (local tissue reaction may complicate repeated subcutaneous or intramuscular administration) with high bioavailability.
8. Oxymorphone (parenterally) is approximately 10 times more potent than parenteral morphine, but due to modest oral bioavailability, oral oxymorphone is only three times more potent than oral morphine. Elimination half-life of oxymorphone is 1.3 ± 0.7 hours, with active and inactive oxymorphone metabolites excreted in the urine. Hepatic and/or renal insufficiency greatly influences oxymorphone pharmacokinetics. Oxymorphone is available for oral, parenteral, and rectal administration. Alcohol consumption significantly increases peak oxymorphone absorption from the extended-release oral formulation (Opana ER).
9. Codeine, a prodrug, provides almost no pain relief directly; rather, it undergoes cytochrome P450-2D6 metabolism into active metabolites (morphine and morphine-6-glucuronide) to provide codeine-derived analgesic effect. P450-2D6 polymorphism results in variation of codeine analgesic effect. Approximately 8% Caucasians lack sufficient enzyme activity to derive significant codeine analgesic effect. Conversely, 1% to 10% Caucasians and 3% to 28% of African Americans may be ultrarapid metabolizers at risk for relative opioid overdose from overproduction of active metabolites. Codeine may have higher risk of nausea than hydrocodone or oxycodone. Codeine is available for oral, intramuscular, or subcutaneous administration (intravenous administration should be avoided due to the risk of histamine release and subsequent cardiovascular instability).
10. Hydrocodone, a derivative of codeine, is metabolized by cytochrome P-450 into hydromorphone, which may mediate some of the pharmacologic effects of hydrocodone. It is commonly available for oral administration in preparations combined with nonopioid analgesics, but recently plain hydrocodone long-acting preparations were made available. Patients should be cautioned for rare but nonreversible sensorineural hearing loss with higher dosages of hydrocodone, with most cases reported in context of opioid abuse.
11. Buprenorphine, a mixed agonist-antagonist at µ, δ and κ opioid receptors is a semisynthetic opioid available in sublingual, transdermal, and injectable formulations for management of pain and/or opioid addiction. It is predominately metabolized in liver using cytochrome P450-3A4 enzymes and excreted through bile, with little effect from renal impairment; the active metabolite norbuprenorphine is a potent analgesic. Long buprenorphine half-life of 20 to 70 hour, ceiling effect for both analgesic and euphoric effects, and good safety profile make buprenorphine an alternative to conventional long-acting opioids in chronic and cancer pain.

Concomitant use of buprenorphine with other opioids potentially can precipitate withdrawal syndrome. Buprenorphine should be slowly tapered up to reach desired analgesic effect to prevent these side effects.

1. Tramadol (50 to 100 mg p.o. QID, maximum 400 mg/day) has modest analgesic efficacy due to weak affinity for µ-opioid receptors. Dose is limited to a maximum of 400 mg/day, due to increased risk of seizures with higher doses. Tramadol is also a norepinephrine, serotonin reuptake inhibitor, similar to some antidepressant medications: it should not be used in individuals receiving full doses of antidepressants, to avoid toxicity (serotonin syndrome). Tramadol undergoes hepatic metabolism by the cytochrome P-450 system. In the United States, it is only available for oral administration.
2. Tapentadol is a synthetic, centrally acting, opioid with moderate affinity to µ-opioid receptors that also inhibits synaptic norepinephrine reuptake. Dual mechanism provides opioid sparing effects, and potentially fewer opioid-related side effects. Immediate and extended-release dosing is limited to total 600 mg daily. Doses should be reduced in moderate hepatic insufficiency and tapentadol is contraindicated in severe hepatic insufficiency. Tapentadol decreases seizure threshold and raises intracranial pressure, so it is contraindicated in patients with seizures and intracranial pathologies. Caution should be exercised with concomitant use of serotonergic agents due to potential risk of serotonin syndrome.
3. Meperidine has no utility in pain management. It is metabolized to normeperidine, which accumulates due to a long half-life, and is associated with excitatory effects including tremulousness and seizures. Severe reactions, after even a single dose of meperidine, may occur in patients being treated with monoamine oxidase (MAO) inhibitors, including excitation, delirium, hyperpyrexia, convulsions, and death.
4. Opioid rotation involves intentionally switching from one opioid analgesic to another, using appropriate guidelines for equianalgesic dosing, to improve pain control and reduce opioid adverse effects. Although individuals tolerant to one opioid will have cross-tolerance to other opioids, the cross-tolerance may be incomplete, such that the effective analgesic dose of the new opioid may be 50% (or less) of the anticipated equianalgesic dose based on the prior opioid requirement. Opioid rotation must be undertaken with caution to avoid overdosing or underdosing, potentially resulting in excess adverse effects, inadequate pain control, or other problems. Although the data are limited to case reports and case series, opioid rotation is widely utilized in clinical practice. Special caution is required when switching to methadone from another systemic opioid, due to the long elimination half-life of methadone.
5. Adjuvant analgesics (Table 40-5)
6. Anticonvulsants are variably effective analgesics in neuropathic pain. Gabapentin (300 to 1,200 mg p.o. TID) is the most widely used anticonvulsant for pain control, with some analgesic efficacy for acute postoperative pain, as well as for neuropathic pain. Other anticonvulsants (i.e., pregabalin, topiramate, levetiracetam, lamotrigine, and oxcarbazepine) should be considered upon failure/intolerance to gabapentin. Dosing of anticonvulsants must be adjusted in renal and/or hepatic insufficiency. They are only available for oral administration.
7. Antidepressants, especially tricyclic antidepressants (TCAs), have analgesic efficacy in chronic neuropathic pain. Newer antidepressants (e.g., citalopram, duloxetine, milnacipran, venlafaxine, and fluoxetine) may be less effective analgesics than TCAs but are generally better tolerated. If one antidepressant is poorly tolerated or provides ineffective analgesia, a different antidepressant should be tried. Antidepressants are only available for oral administration.

3. Miscellaneous agents
4. Muscle relaxants have not been studied in cancer pain, but are commonly used for musculoskeletal pain. Sedation is a common adverse effect. Baclofen (10 to 20 mg p.o., three times daily) is widely used for control of spasticity, but also has analgesic efficacy in neuropathic pain. To avoid potentially serious withdrawal, chronic baclofen therapy must be slowly tapered over several days, rather than abruptly discontinued. Tizanidine (2 to 8 mg p.o., three to four times daily) is an effective agent for spasticity with limited efficacy in chronic pain. Potential adverse effects include hypotension and hepatotoxicity (periodically monitor liver function, especially during drug initiation). Renally cleared, tizanidine dosing must be reduced in renal insufficiency. Other muscle relaxants (carisoprodol, cyclobenzaprine, metaxalone) have only a limited role in management of cancer-related musculoskeletal pain.
5. Local anesthetics. Lidocaine intravenous infusion (1 to 2 mg i.v./minute, after 25 to 50 mg i.v. loading dose) may be effective for intractable neuropathic pain resistant to systemic opioid. For long-term use, intravenous lidocaine infusion is difficult to maintain and serum level must be checked regularly to avoid toxicity. Oral mexiletine (10 mg/kg/day, divided into three doses daily) has modest analgesic efficacy. Lidocaine 5% patch provides pain relief through topical anesthetic action, and is especially indicated where neuropathic pain is associated with markedly increased skin sensitivity (cutaneous mechano-allodynia). With little systemic absorption, lidocaine patch has negligible systemic effects, but the water-based adhesive may cause dermatitis if left in place for more than 12 hours daily.
6. Systemic corticosteroids are used in cancer patients to provide analgesia, improve appetite, prevent nausea and malaise, and improve quality of life. Corticosteroids may be particularly useful in acute pain due to boney metastases, infiltration or compression of neural structures, increased intracranial pressure (headache), obstruction of a hollow viscus or organ capsule distention, or spinal cord compression. Long-term use of steroids may lead to gastrointestinal ulceration, so the use of gastroprotective agents is advised.
7. Cannabinoids (CBD), the active ingredient of cannabis sativa, that is, marijuana, are increasingly used as medicinal agent, as marijuana has gained legal approval in various states. Studies regarding analgesics effect have yielded mixed results: some reports suggest significant analgesia for neuropathic pain; others fail to show benefit over conventional analgesics.

 IV. SPECIAL TECHNIQUES FOR THE MANAGEMENT OF RESISTANT CANCER PAIN

1. Psychological and behavior medicine techniques. Cancer pain is a complex emotional experience, and emotional distress, anxiety, and depression increase pain and suffering. Pharmacologic and nonpharmacologic therapies for the treatment of psychological and psychiatric comorbidities are essential to cancer pain management. Cognitive behavioral therapies (CBT) are the most frequently used psychological modalities in chronic pain management. Through CBT, patients learn to control the thoughts, emotions, and behaviors that modulate pain experience. CBT includes hypnosis, relaxation techniques (including progressive muscle relaxation, meditation, and guided imagery), biofeedback, coping skills training, music therapy, cognitive restructuring, supportive and group therapy, and stress management techniques.
2. Physical and occupational therapies are essential to optimize functional status after prolonged medical illness or surgical intervention. Therapeutic and conditioning exercise programs are essential to successful chronic pain management. Specific therapies such as orthotic bracing and assistive devices may improve pain control and/or function.
3. Complementary and alternative therapies are widely used, alone or in conjunction with conventional therapies, for pain control by persons with cancer. Patients should be routinely asked about complementary and alternative (CAM) therapies, if only to allow screening for potential adverse interactions between CAM and conventional therapies. Alternative therapies such as acupuncture, massage, healing touch, and many herbal therapies have shown benefits in controlling pain and other symptoms, but comparative trials with other analgesic therapies are lacking.
4. Interventional techniques for severe cancer pain are important components of comprehensive care for severe cancer pain and should not be relegated to treatments of last resort. Interventional pain therapies should be considered if pain is not adequately controlled with systemic analgesics, or if use of such analgesics is associated with adverse effect (e.g., sedation, constipation, and/or nausea). Interventional pain therapies can potentially improve quality of life by (a) providing more effective pain control and (b) allowing reduction in analgesic dose and/or analgesic adverse effects. Improved pain control and reduced adverse effects through appropriate use of interventional pain therapies may improve life expectancy in patients with terminal disease.
5. Spinal analgesic administration delivers medication to the spinal cord to enhance analgesic efficacy and minimize systemic (brain) adverse effects of analgesics, especially sedation. Spinal analgesics (opioids, local anesthetics, clonidine, and/or baclofen) are used alone or in combination for intrathecal or epidural administration. Spinal administration of combined opioid, local anesthetic, and clonidine is an especially potent analgesic therapy. Spinal analgesics may be administered by epidural or intrathecal (subarachnoid) systems, but an implanted pump (for intrathecal infusion) is most commonly used.
6. Spinal opioids (especially morphine and hydromorphone) have significantly increased potency: 100 mg/day parenteral morphine is roughly equivalent to 10 mg/day epidural morphine, which is roughly equivalent to 1 mg/day intrathecal morphine; however, actual doses must be titrated to effect. Fentanyl, because of its high lipid solubility, has rapid systemic absorption after spinal administration; therefore, spinal administration of fentanyl may have little advantage over systemic administration. Spinal opioid adverse effects include sedation, respiratory depression (onset may be delayed for several hours), constipation, nausea, pruritus, peripheral edema, and urinary retention. Exceptionally high doses of spinal opioids may result in myoclonic jerks or even diffuse muscle rigidity.
7. Spinal local anesthetics (bupivacaine, lidocaine) may markedly decrease pain without sedation or some of the other potential adverse effects associated with opioid analgesics. After spinal administration of low doses of local anesthetic, pain relief is sometimes obtained without significant extremity weakness or numbness. Potential adverse effects include hypotension (especially orthostatic hypotension), extremity weakness, and urinary retention.
8. Spinal clonidine has analgesic efficacy after epidural or intrathecal administration, through action at spinal α₂-adrenergic receptors. Potential adverse effects include hypotension (especially orthostatic hypotension), bradycardia, congestive heart failure, and sedation.
9. Electrical stimulation neuromodulation, including spinal cord stimulation (SCS), peripheral nerve stimulation (PNS), and peripheral field stimulation (PFNS), are implanted medical devices that apply electrical current near neural structures to modulate pain signal neural transmission. SCS may be particularly helpful in managing peripheral neuropathic pain in cancer survivors. SCS use was previously limited by device MRI incompatibility; however, MRI-compatible SCS has recently become available, increasing the utility of these devices to include patients who may need periodic MRI imaging.
10. Vertebral augmentation (vertebroplasty, kyphoplasty, and tumor-ablative vertebroplasty) is a procedure for the percutaneous injection of bone cement (polymethyl methacrylate—PMMA) into vertebral bodies affected by compression fractures due to metastatic tumor, destructive vertebral hemangiomas, or osteoporosis. Kyphoplasty differs from vertebroplasty in that bone cement is injected after a balloon has been used to create a cavity in the vertebral body, in an attempt to restore vertebral body height. Vertebroplasty/kyphoplasty can be highly effective in control of pain from vertebral compression fractures due to osteoporosis and/or tumor. Thorough radiographic evaluation is essential before vertebroplasty/kyphoplasty. Potential adverse effects include spread of unhardened cement beyond the vertebral body, through direct spread to the spinal canal or through vascular embolization.

 In tumor-ablative vertebral augmentation, plasma-mediated radiofrequency ablation is used for metastatic painful vertebral disease to create cavitation within the vertebral body prior to injection of PMMA, to potentially decrease tumor burden and decrease risk of PMMA extravasation beyond vertebral boundaries.

 Vertebroplasty/kyphoplasty need not delay treatment of spinal metastases with radiation therapy, but may provide rapid onset of pain relief, which may facilitate the use of appropriate antitumor therapies.

4. Neurolytic neural blockade should be considered for patients with terminal disease in whom pain is poorly controlled with less-invasive therapies and pain is localized to a suitable region of the body. If pain recurs after several months, neurolytic blockade may be repeated, but repeated blockade is generally not necessary.
5. Neurolytic celiac plexus block, the most commonly performed neurolytic technique for cancer pain, is indicated for upper abdominal visceral pain from pancreatic or other upper abdominal malignancy. Up to 85% of appropriately selected patients report good-to-excellent pain relief after neurolytic celiac plexus block. The side effects of orthostatic hypotension and increased frequency of bowel movements (diarrhea) transiently affect most persons after neurolytic celiac plexus block, but only 1% to 2% require long-term medical management of these symptoms. The risk of significant nerve damage or paralysis (0.1% to 0.2%) may cause some cancer patients to decide against celiac plexus block, but to most, the potential for good-to-excellent pain relief (75% to 85%) that may be associated with improvements in constipation, nausea, and a general sense of well-being outweighs procedural risk.
6. Neurolytic hypogastric plexus block may be effective for visceral pain from pelvic malignancy. Its use is not significantly associated with extremity weakness, but ejaculatory failure/inorgasmia is a potential adverse effect. Neurolytic hypogastric plexus block is not likely to provide good pain control if there is tumor invasion of somatic or neural structures.
7. Tumor ablation is a palliative modality using targeted radiofrequency energy, to decrease tumor size to provide analgesia for pain associated with osteolytic bone metastasis, or localized soft tissue solid tumors etc. This can be achieved by image-guided direct application of energy to ablate tissue and/or transarterial embolization to promote cancer devascularization.
8. Neurosurgical techniques for pain control, such as cordotomy or cingulotomy, are rarely used but potentially powerful tools for the management of otherwise intractable pain. Especially for unilateral lower body or lower extremity pain, in the setting of terminal illness, cordotomy (percutaneous or open surgical approach) may provide remarkable control of previously intractable pain.
9. Management of refractory pain and/or other symptoms of terminal illness. In the last hours to days of life, some dying people develop intractable symptoms such as intractable pain, dyspnea, delirium, and/or emesis (e.g., fecal emesis due to distal bowel obstruction beyond surgical intervention). If such symptoms are intolerable to the dying patient, but would be refractory to further palliative therapy, consideration should be given to alleviation of distress through administration of sedatives. Terminal, palliative sedation should be considered only for those who have requested not to be resuscitated (“no code”) in the event of cardiac/respiratory arrest. Midazolam is the most commonly used drug for palliative sedation (1 to 2 mg i.v., i.m., or subcutaneously q1h, p.r.n.; or loading dose of 1 to 2 mg i.v. with infusion 0.5 to 2 mg/hour) but other benzodiazepines (diazepam, 5 to 10 mg p.o., 2 mg i.v. q2h, p.r.n.) can be used instead. Benzodiazepines may worsen agitation in some persons, and they may be better treated with barbiturates (thiopental infusion 0.5 mg/kg i.v. loading dose, followed by 0.25 to 0.5 mg/kg/hour i.v. infusion; pentobarbital infusion 1 to 2 mg/kg/hour), or neuroleptic sedatives (haloperidol, 1 to 4 mg i.v./p.o. q1h, p.r.n.) titrated to effect to ease suffering from otherwise intractable symptoms. These drugs generally have long elimination half-lives and will accumulate to steady-state level over a few days. The use of palliative terminal sedation to provide a dying person relief from intractable, intolerable suffering is firmly within the realm of good, supportive palliative care and should not be confused with euthanasia.
10. SPECIFIC PAIN SYNDROMES
11. Mucositis is one of the most debilitating, refractory adverse effects following chemotherapy and/or radiotherapy damage to tissues of the alimentary canal. Mucositis is associated with pain and increased risk of infection, malnutrition, and dehydration. Traditional management of oral mucositis has involved patient education for avoidance of dehydration, oral rinses (saline, hydrogen peroxide diluted 1:1 with saline), topical lidocaine solution, systemic analgesics, nutritional support, and prevention/management of infection.
12. Bone pain from cancer, often related to bony metastases, is a common problem. Bone pain management may require various modalities including analgesics, corticosteroids, bisphosphonates, radiation therapy, hormonal and/or chemotherapy, and/or orthopedic surgical intervention.
13. Bisphosphonates inhibit osteoclast-mediated bone resorption and have been shown to relieve pain, reduce the number of metastases, prevent osteolysis, and decrease the frequency of fractures. All bisphosphonates can induce gastrointestinal upset, renal damage, and mandibular osteonecrosis. Dose should be adjusted based on renal function.
14. Denosumab, a monoclonal antibody against RANKL (receptor activator of nuclear factor kappa-beta ligand), blocks osteoclast activation and thereby reduces bone resorption and lessens skeletal-related events in osseous metastasis of solid tumors and multiple myeloma.
15. Abiraterone, an androgen biosynthesis inhibitor acting through selective cytochrome P450 17A1 inhibition, improves survival and bone pain in castration-resistant prostate cancer.
16. Radioisotopes, through parenteral administration, provide systemic radiation to diminish multifocal painful skeletal metastasis. ⁸⁹Sr and ¹⁵³Sm have shown selectivity for bone metastasis and have been found to be effective in reducing pain. High cost, delayed pain relief, and hematologic toxicity limit use.
17. External-beam radiation is used in relieving local tumor-related bone pain. Focal lesion can be managed by localized external-beam irradiation (also known as involved-field irradiation). Multiple painful sites can be managed by wide-field external-beam irradiation (e.g., hemibody irradiation). Side effects include bone marrow suppression and radiation tissue damage.
18. Neuropathic pain from tumor invasion of major nerve plexus. Neuropathic pain may be relatively less responsive to opioid analgesics than nociceptive pain, especially when tumor directly invades a major nerve or plexus. Clinical situations such as tumor invasion of brachial plexus (Pancoast tumor), or retroperitoneal sarcoma invading the lumbosacral plexus, require aggressive pain therapies early in the course of disease. Adjuvant, nonopioid analgesics (anticonvulsants, antidepressant) therapies should be optimized. Although rarely needed, severe neuropathic pain not responding to systemic analgesics is a relatively common indication for spinal analgesics.
19. Cancer treatment–related pain syndromes/cancer survivors and pain. Advances in cancer treatment have improved cancer survival, but also increased the prevalence of patients living with chronic, cancer-related pain. It is estimated that chronic posttreatment pain is present in 33% of cancer survivors. The prevalence of pain varies depending on the type and site of cancer, comorbid conditions, treatments used, and pain management techniques employed. Pain in cancer survivors can be the result of tissue damage from the cancer itself or from cancer treatments: chemotherapy, radiation, hormonal therapy, long-term steroid use, and/or surgery. Graft-versus-host disease is another potential source of persistent pain.

 Chronic pain management in cancer survivors is complex and frequently requires a multidisciplinary approach. The goals of treatment should focus on functional improvement and management strategies rather than complete elimination of pain. Multimodal analgesia combines analgesics with different mechanisms to provide improved pain relief with fewer medication-related adverse effects. In patients with chronic posttreatment pain, there is increasing concern for potential adverse effects of chronic opioid use, including tolerance/hyperalgesia, hypogonadism, and immunosuppression, in addition to the well-known adverse effects of sedation, respiratory depression, constipation, nausea, etc. Nonopioid and adjuvant analgesics (antidepressants and anticonvulsants), and interventional pain therapies may be utilized to limit opioid use and improve symptom control. Physical and rehabilitation therapies, especially when combined with psychological/behavioral medicine therapies, potentially play an important role in functional restoration.

1. Chemotherapy-induced peripheral neuropathy (CIPN) is increasingly seen as a treatment-limiting and potentially disabling complication of some chemotherapy protocols. CIPN most commonly affects large sensory neurons, and therefore may present as a purely sensory disturbance; however, pure motor disturbance or as a mixed sensory-motor disturbance presentation is not uncommon. Typically, paresthesias or dysesthetic sensations follow chemotherapy including platinum compounds, taxanes, vinca alkaloids, thalidomide, ifosfamide, antiganglioside-G-D2 monoclonal antibody, bortezomib, and cytarabine. With no specific treatment of CIPN, effort has been focused on prevention—but with limited success. These strategies include selection of less toxic agents, chemotherapy dose modifications, interruption of dosing (i.e., “stop and go” protocols). Neuroprotective agents that have been used in an attempt to prevent CIPN include various antioxidants (α-lipoic acid, folinic acid, acetyl L-carnitine, glutathione, glutamine, pyridoxine, cyanacobalamin, and fish oil) and various neuroprotectants (GM1 monosialoganglioside, riluzole, minocycline, amifostine, leukemia inhibitory factor, lithium, IGF-1, nimodipine, and calcium–magnesium solution). In lack of proven prevention, various antineuropathic pain medications (gabapentin, pregabalin, levetiracetam, and topiramate), and/or opioids may be useful analgesics. Acupuncture, electrocutaneous nerve stimulation (scrambler therapy), and SCS have been used in the management of CIPN with varied success.
2. Radiation neuropathy presents in patients who have undergone radiation therapy. The incidence is variable and appears to be dose dependent. The most common injuries occur to the brachial plexus (after radiation therapy for breast cancer, lung cancer, or Hodgkin’s lymphoma) and the lumbosacral nerves (after radiation for pelvic and abdominal malignancies). Peripheral neuropathy is also seen, but usually is self-limited and less symptomatic. Injury can occur to any nerve in the beam of the radiation therapy device. The common complaints include paresthesias, dysesthesias, allodynia, hyperalgesia, and hyperpathia in the area of nerve injury. Most of these neuropathies present weeks after radiation therapy. Treatment includes anticonvulsants, opioids, NSAIDs, TCAs, and local and topical anesthetics. In very severe cases, SCS or spinal analgesic administration should be considered. Psychological and physical therapy modalities should be utilized as a part of a multidisciplinary pain management program.
3. Postsurgical pain syndromes
4. Postmastectomy pain syndrome, involving persistent pain in the anterior chest, axilla, and medial and posterior portions of the arm, occurs after 4% to 30% surgical procedures involving the breast and occurs 2 weeks to 6 months after surgery. The pain is variable but is usually a combination of somatic and neuropathic pain. Treatment includes opioids, anticonvulsants, topical agents (lidocaine patch), physical therapy, and cognitive behavioral therapy.
5. Postradical neck dissection pain syndrome is a combination neuropathic and myofascial pain condition that occurs in as many as 50% of postsurgical patients, typically involving one or more branches of the superficial cervical plexus (SCP). It is usually described as spontaneous, continuous burning pain, shooting pain, or allodynia. Treatment is similar to other postsurgical neuropathic pain syndromes, but myofascial trigger point injections using local anesthetic and/or botulinum toxin may be of benefit.
6. Postthoracotomy pain syndrome (PTPS) is persistent pain in the area of thoracotomy incision scar reflecting intercostal neuralgia. Typically occurring in a small percentage or patients, PTPS can persist indefinitely. Care must be taken not to confuse PTPS with tumor reoccurrence pain. The pain is described as numbness, tingling, burning, itching, or shooting. There is quite often hyperesthesia in the involved dermatome. Treatments include physical therapy, opioids, anticonvulsants, lidocaine patch, transcutaneous electrical nerve stimulation, and/or SCS.
7. Postherpetic neuralgia
8. Herpes zoster (HZ), resulting from reactivation of varicella zoster (VZ) infection, is characterized by painful, vesicular cutaneous lesions in a dermatomal pattern. Pain may precede visible lesions by 2 to 3 days. HZ is typically self-limited in normal hosts, but in immunocompromised patients may cause cutaneous dissemination or even potentially fatal systemic and/or CNS infection. Acute HZ pain (acute herpetic neuralgia) typically resolves with healing of cutaneous lesions; however, the risk of persistent postherpetic neuralgia (PHN) increases with age. Even with aggressive therapy, up to 30% of individuals older than 60 years presenting with HZ will experience PHN, and up to 50% of persons with PHN may have pain lasting indefinitely.
9. Prevention of postherpetic neuralgia. The incidence and/or duration of PHN is reduced with oral antiviral agents in adults older than 50 years, if therapy is started within 72 hours of onset of rash. Acyclovir (800 mg every 4 hours, five doses daily, for 7 to 10 days) speeds healing of lesions, decreases pain from acute HZ, and may decrease the incidence of PHN. Newer antivirals famciclovir (500 mg every 8 hours for 7 days) and valacyclovir (1,000 mg every 8 hours for 7 days) have been shown to decrease the incidence of PHN with less frequent dosing, which may improve compliance. The addition of systemic corticosteroid to antiviral therapy does not further reduce the risk of PHN, but adding TCA (amitriptyline 25 mg orally at bedtime) may be of benefit. Sympathetic nerve blocks and epidural steroid injections provide excellent pain relief in acute HZ and may reduce PHN. High-potency, live-attenuated VZ vaccine has been shown to decrease the incidence of HZ and the severity of PHN in adults 60 years of age and older and will likely be used to prevent HZ and PHN in high-risk populations.
10. Treatment of established postherpetic neuralgia is based on the use of systemic analgesics and may include TCAs, anticonvulsants, and/or opioid analgesics. Topical lidocaine 5% patch may be of benefit in PHN associated with cutaneous extra sensitivity (mechano-allodynia).
11. Opioid toxicity syndrome (OTS) consists of diffuse hyperalgesia, myoclonus, and altered mental status (agitation/delirium or sedation/confusion). Although rare, it is most often seen when patients are on high doses of opioid (often greater than 100 mg morphine/hour or equivalent), yet inadequate pain control requires further rapid opioid dose escalation. In such settings, increasing opioid dose may not result in improved pain control, but instead worsened pain (hyperalgesia) and deterioration of mental status. In extreme cases, myoclonus may be nearly continuous and resemble seizurelike activity, but patients are generally conscious and conversant (although often delirious). Dehydration and/or renal insufficiency may increase the risk of OTS. OTS has been most frequently described with systemic morphine, but has been reported with other systemic opioids and with spinal opioid. Opioid-induced facilitation of pain signal transmission (opioid-induced hyperalgesia) appears to be one of the principal factors contributing to OTS. Management of OTS requires switching to another opioid (opioid rotation), typically using less than the fully equivalent dose. In extreme cases of OTS, it may be necessary to completely discontinue opioid analgesics temporarily, and rely on nonopioid analgesics (e.g., anticonvulsants or intravenous lidocaine infusion) for pain control. Once OTS symptoms improve, patients may be managed with relatively lower doses of another opioid.

 VI. PAIN MANGEMENT IN SPECIFIC POPULATIONS

1. Cancer pain management in the noncompliant patient. Pain management therapies are less likely to be successful if not used appropriately and consistently. To manage apparent noncompliance, treating health-care professionals must identify and manage contributing factors such as (a) cognitive impairment (due to underlying disease(s), treatments, and other factors); (b) psychological/psychiatric disorders (depression/anxiety and personality disorders); (c) substance abuse or dependence; and (d) physical ability to obtain, store, and access prescribed treatments.

 In chronic illness and/or malignancy, patients often develop tolerance (increasing dose requirement) and physical dependence (withdrawal symptoms with abrupt discontinuation) but rarely develop new substance dependence or addiction. In the context of chronic pain in oncology practice, “drug-seeking” behavior likely reflects inadequate pain control. “Substance dependence” or “addiction” is best characterized by compulsive, continued drug use despite harm, and/or drug craving.

 Substance abuse/dependence is rarely newly diagnosed in patients with terminal disease, but can significantly complicate pain management therapies. It is essential to obtain the patient’s cooperation in order to get a thorough substance abuse history and find optimal management strategies. Patients with cancer pain and active substance abuse/dependence will require very close monitoring and multidisciplinary care.

1. Involve psychiatrist, addictionologist, especially if substance abuse is recent, ongoing. Encourage participation in a 12-step recovery program (alcoholics anonymous, narcotics anonymous) if feasible.
2. Analgesics filled by only one prescriber.
3. Use one opioid analgesic, preferably a long-acting formulation, given on a regular schedule. As far as possible, limit the use of short-acting or “as-needed” doses of opioid.
4. Optimize the use of nonopioid and nonpharmacologic pain therapies.
5. Utilize pill counts and urine toxicology screens, if needed, to help with monitoring of compliance with prescribed therapies and avoidance of other abuse substances.
6. Limit quantity of controlled substances to weekly supply, if compliance is poor. (In extreme cases, it may be necessary for medication to be dispensed daily by home health nurse or even through a substance abuse program.)
7. Utilization of written opioid analgesic guidelines may help patients to understand what is expected regarding appropriate use of analgesic therapies.

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