The National Cancer Institute estimates that 1,660,290 new patients with cancer will be diagnosed and about 580,350 Americans are expected to die from cancer of all sites in 2013.1 Cancer is the second leading cause of mortality in the United States, accounting for nearly 1 in every 4 deaths.2 Patients with cancer suffer from a multitude of symptoms that adversely affect their quality of life. Pain is one of the most dreaded symptoms in cancer, regrettably, it is often under-treated. Even with the greater availability of pain medications, it continues to be moderate to severe in more than 50% of cancer patients.3 Guidelines for managing cancer pain, although widely published, have not been universally applied, and as a result, there are considerable gaps in the treatment of pain.4
Cancer pain is a complex, temporally changing symptom which is the end result of mixed mechanism pain. It involves inflammatory, neuropathic, ischemic, and compression mechanisms at multiple sites.5 It is a subjective, heterogeneous experience that is modified by individual genetics, past history, mood, expectation, and culture.
Cancer pain syndromes are categorized as acute and chronic based on onset and duration. Acute pain syndromes have a sudden, well-defined onset, an identifiable cause (e.g. surgery), subject to sympathetic output (fight or flight response), and are expected to improve with management. Chronic pain on the other hand, has a less distinct onset, has a prolonged and fluctuating course, and is largely driven by central sensitization and neuroplastic responses from acute injury.6,7 It is often characterized by "pain flares" referred to as breakthrough pain.8
In 1986, the World Health Organization (WHO) developed a 3-step analgesic ladder (Figure 1) to guide cancer pain management worldwide.9 A 10-year prospective, validation study of the WHO analgesic ladder showed more than 70% of cancer patients achieved good pain relief using WHO recommendations.4 However, more than 25 years later, cancer pain is still a major problem. Prevalence is high in the range of 60 to 80% in advanced cancer patients. When present, cancer pain is moderate in severity and interferes with activity and enjoyment of life to a great extent.10
Patients with bone metastases are more likely to report severe pain than those with soft tissue metastases.11,12 Despite the direct correlation of pain prevalence with stage of cancer, pain corresponds poorly to the observed tumor burden and severe pain can occur in all cancer stages.13 Patients with cancer of the pancreas, bone, brain, lymphoma, lung, and head and neck have the highest prevalence of pain.14 Most pain is the result of their underlying cancers (85%), secondary to antineoplastic therapies (17%), and comorbidities unrelated to cancer (9%).15 Common causes of pain16 are listed in Table 1.
Table 1. Common Causes of Pain in Cancer Patients
|Malignancy-Related||Antineoplastic therapies||Other comorbidities|
Adapted from Twycross R, Harcourt J, Bergl S: A survey of pain in patients with advanced cancer. J Pain Symptom Manage 1996;12:273-282.
Cancer pain shares the same neurophysiologic pathway as non-cancer pain. This process of nociception involves activation of the sensory afferents by persistent noxious stimuli, transduction, transmission, modulation, and perception.17
Stimuli from tissue injury activate primary afferent neurons called nociceptors, found in skin, muscle, joints, and some visceral organs. Nociceptors are high-threshold receptors that are silent until significantly stimulated.18 Most nociceptors are polymodal, responding to thermal, physical, and chemical stimuli. Neuron cell bodies are located within the superficial laminae of the dorsal root ganglia and trigeminal ganglia. Once depolarized, transmission occurs proximally via thin myelinated A-δ fibers (fast) or unmyelinated C fibers (slow). Interneurons within laminae I and II of the dorsal horn amplify or dampen neurotransmission. Afferent axons terminate in lamina I or II, and second-order afferent neurons cross the midline and ascend all the way to the brainstem and thalamus in the anterolateral quadrant of the contralateral half of the spinal cord. Together with axons from second-order lamina I neurons, these fibers form the spinothalamic tract, the major ascending pathway for information about pain and temperature (Figure 2). Sensory fibers associated with affective responses also ascend in the contralateral dorsolateral spinal cord to the medial thalamus or brainstem and then to the cingulate cortex and limbic lobe. Downward modulation occurs through the periaqueductal gray (PAG) and rostral ventral medulla (RVM) with axons that transverse the dorsal lateral funiculus. These modulate pain directly by connections to secondary afferent neurons in the dorsal horn or via connections with interneurons in laminae I and II (Figure 2).19 The neurochemistry of these processes involve multiple neurotransmitters including endorphins, prostraglandins, gamma-aminobutyric acid (GABA), cannabinoids, and many others, that are targets for analgesic medications.17
Given the complexity of pain neurophysiologic and neurochemical processes, clinicians need to integrate findings from history, physical examination, and tests in order to assess pathophysiologic mechanisms and etiology. Inferred pathophysiologies (Table 2) are nociceptive, neuropathic, or psychogenic. Disorders that cannot be categorized are idiopathic. Cancer pain is oftentimes a mixed disorder.8
Table 2. Inferred Pathophysiologies of Cancer Pain
Nociceptive pain is from an acute or persistent injury to somatic or visceral tissues. Somatic nociceptive pain is described by patients as "aching", "stabbing", or "throbbing" and involves injury to bones, joints or muscles. Visceral nociceptive pain results from injury to viscera. It is poorly localized and characterized as "cramping" or "gnawing" if it involves a hollow viscus (e.g. bowel obstruction). It may be described as "aching", "stabbing", "sharp", similar to somatic nociceptive pain, if it involves other visceral structures (e.g. organ capsules, myocardium). Visceral pain is often referred to somatic sites due to convergence on somatic afferents within the dorsal root ganglia and dorsal horn. Referral correlates with visceral pain severity.20
Neuropathic pain syndromes are varied and suggest injury to the peripheral or central nervous system. It is often associated with referred pain (pain is perceived in a location that is not the source of the pain), allodynia (pain induced by non-painful stimulus), hyperpathia (exaggerated pain response to nociceptive stimuli), or dysesthesia (unpleasant, abnormal sensation in an area of neurologic deficit). Pain courses in the distribution of motor, sensory, or autonomic nerves, except when pain is funicular or central, causing burning or lancinating pain in an area of decreased or absent sensation (e.g. in patients with spinal cord injuries).21
Psychogenic pain refers to pain predominantly sustained by psychological factors. Although psychogenic pain is rare in the cancer population, psychosocial and psychiatric evaluations are important in pain assessments. Psychosocial and psychiatric issues contribute to the pain experience and may worsen pain and pain-related distress.17
Signs and Symptoms
Acute pain syndromes (Table 3) are often iatrogenic (i.e. due to tests or treatments) but may also be disease-related complications. Chronic pain syndromes (Table 4) are mostly due to direct effects of malignancy and some are due to antineoplastic treatments.22 Acute pain is associated with generalized sympathetic hyperactivity, resulting in diaphoresis, hypertension, and tachycardia. Tolerance to sympathetic hyperactivity develops quickly as pain becomes chronic. Overt pain behaviors such as grimacing, moaning, and splinting, as well as sympathetic hyperactivity, are not present with chronic pain.23 Unrelieved chronic pain produces depression, anxiety, anorexia, asthenia, and insomnia.
Table 3. Acute Pain Syndromes
|Antineoplastic therapies (i.e. chemotherapy, hormonal treatments, immunotherapy, radiation therapy)||Mucositis, neuropathies, enteritis, proctitis, cystitis, arthralgia, myalgia, angina, diffuse bone pain, flare syndrome, palmar-plantar erythrodysesthesia (hand-foot syndrome)|
|Procedures||Post lumbar puncture headache, post-biopsy pain, pain due to therapeutic interventions (eg. paracentesis, chest tube placement, stent placements, vascular embolizations)|
|Associated with disease||Hemorrhage into a tumor, pathologic fracture, obstruction or perforation of hollow viscus, venous thromboembolic disease|
Table 4. Chronic Pain Syndromes
|Nociceptive somatic pain due to bone metastases||Multifocal bone pain, vertebral pain syndrome in epidural spinal cord compression, pain syndrome related to pelvis and hip, base of skull|
|Nociceptive somatic pain due to soft tissue involvement||Headache and facial pain, ear and eye pain, pleural pain, muscle cramps|
|Nociceptive visceral pain due to malignancy||Hepatic distention syndrome, chronic bowel obstruction, midline retroperitoneal syndrome, malignant perineal pain, ureteric obstruction|
|Neuropathic pain due to malignancy||Radiculopathies, mononeuropathies, plexopathies, neuralgias, peripheral neuropathy|
|Antineoplastic therapies (i.e. chemotherapy, radiation therapy, hormonal treatments, surgery)||Peripheral neuropathy, chronic post-surgical pain (eg.mastectomy, thoracotomy, neck dissection, pelvic surgeries), phantom limb pain, chronic radiation myelopathy, chronic radiation plexopathy, chronic radiation proctitis and enteritis, lymphedema pain, osteoradionecrosis|
Accurate assessment is the first major step necessary for good pain management. Adequate assessment requires a thorough pain history (Table 5) and physical examination before radiographic studies or physiologic testing. Bypassing a good history and physical examination for radiographs is misleading, since correspondence between the report of pain severity and presence of underlying pathology is poor.24 Location, radiation, quality, intensity and temporal pattern of pain, along with provocative and palliative factors associated with pain, map the pain source and provide clues to a possible cause. The date of onset, associated symptoms, and pain trajectory measures disease course and prognosis indirectly and crudely. Past trials of therapy, including over-the-counter medications and home remedies, should be recorded. Crescendo or altered pain patterns, in addition to the usual chronic pain, indicate cancer progression, treatment or cancer complications, or cancer recurrence, until proven otherwise.
Table 5. Components of the Pain History
|1. Location of pain|
|3. Provocative or Palliative factors|
|5. Radiation and Related symptoms|
|6. Severity (Intensity and effect on function)|
|7. Temporal Pattern
Pain severity is assessed by unidimensional pain scales, such as the visual analogue, numerical, or category scales.24 Pain-relief scales have the advantage of gauging patient-reported benefits to treatment but do not correlate closely with unidimensional scales; they tend to be more optimistic than unidimensional scales. Patients might have pain relief but still have severe pain that interferes with activities of daily living (ADLs).25 Comprehensive multidimensional scales are more burdensome for patients to complete, but they can evaluate the affective component of pain and pain interference with activities. Several general quality-of-life scales include pain-intensity or pain-relief scales. Examples are the QLQ-C30 of the European Organization for Research of Cancer and the Functional Assessment of Cancer Therapy (FACT) Scale.26
Physical examination is centered to the area of pain but should not be misguided by referred patterns of pains. For example, hepatic metastases refer pain to the shoulder. Anatomic examination is followed by maneuvers to elicit or ameliorate pain. Bone metastases are common, local palpation and manipulation elicit pain. Spinal cord compression from epidural tumor extension is most feared by physicians. Hence, a neurologic examination, manual muscle testing, percussion tenderness and joint mobility, and inspection for muscle symmetry are important parts of the physical examination. Assessment of psychiatric and psychosocial comorbidities is important to address factors that may adversely affect pain perception and worsen distress.17
Radiographic studies are guided by the history and physical examination, stage of disease, patient performance status, therapeutic options, and goals of care. Terminally ill patients, or those for whom little is gained by radiographic procedures, should be treated with palliative measures and not be subjected to painful, unnecessary testing. If diagnostic imaging is appropriate, pain is treated first so that patients are comfortable and able to complete their procedure. Plain radiographs of painful areas are still valuable. Magnetic resonance imaging (MRI) of the spine and brain and computed tomography (CT) scanning of the chest and abdomen provide the greatest amount of information. Ultrasonography of pericardial effusions and biliary and urinary tract obstructions is easily accomplished, portable, and without radiation exposure. Electrophysiologic studies separate mononeuropathies or entrapment neuropathies from plexopathies, and ulnar or peroneal entrapment syndromes from brachial and lumbar plexopathies, respectively. Conduction velocities, specific latencies, amplitudes, duration, and configurations of sensory and motor evoked potentials identify and locate neuropathology. However, electrophysiologic studies are normal with significantly damaged nonmyelinated fibers.
Cancer pain is relieved in 80% to 90% of patients using an opioid-based analgesic regimen and the WHO analgesic ladder (Figure 1) as guidelines.27,28 Opioids are preferably given orally, used with around-the-clock (ATC) dosing, according to the analgesic ladder, with individualized treatment based on pain patterns, and with attention to details.29 In countries where strong opioids (Table 6) are readily available and where palliative care is established, Step 2 in the analgesic ladder is bypassed and low doses of potent opioids are used instead.30
For many years, morphine, has been deemed the opioid of choice for moderate to severe cancer pain. Recent recommendations31 have also endorsed the use of oxycodone and hydromorphone as first line opioids for cancer pain. In treating continuous pain, use ATC normal-release opioid such as immediate-release morphine, oxycodone or hydromorphone every 4 hours or sustained-release morphine, oxycodone, or hydromorphone every 12 hours. Reasonable initial doses of strong opioids are listed in Table 6.
Table 6. Strong Opioids and Initial Doses for Opioid Naïve Patients
|Opioid||Oral Formulation||Parenteral Formulation|
|Dose (Immediate release)||Interval||Dose (Intravenous)||Interval (prn dosing)|
|Morphine||5-10 mg||4 hours||0.5 – 1 mg||1 hour|
|Hydromorphone||2 mg||4 hours||0.2 mg||1 hour|
|Oxycodone||5 – 10 mg||4 hours||N/A||N/A|
|Fentanyl||N/A||N/A||25 mcg||1 hour|
|Methadone||5 mg (2.5mg in the elderly)||12 hours||0.2 mg||1 hour|
Rescue doses of normal-release opioids should be provided for intermittent pain. Intermittent or breakthrough pain may be incident (i.e. related to movement or activity), non-incident (spontaneous), or end-of-dose-failure.32 Recommendations for rescue dosing are 25% to 50% of the 4 hourly dose, or the 4 hourly dose given hourly, or 10 to 20% of the total daily opioid dose. End-of-dose failure is due to suboptimal doses of ATC opioids and is improved by titrating the ATC opioid dose rather than shortening the dosing interval.32 Rescue doses need to be titrated to response if the underlying chronic pain is under control.
Individualized dosing needs to take into account age, perhaps gender, drug interactions, and organ system dysfunction. Alternative opioids are chosen based on organ failure. Morphine and hydromorphone are safe in mild to moderate hepatic impairment, dose reduction and/or lengthening of dosing interval should be done in patients with severe hepatic impairment. Methadone, fentanyl, and buprenorphine are relatively safe, with few dose adjustments necessary for renal failure. Oxycodone pharmacokinetics is significantly altered by hepatic and renal failure. Drug interactions should be noted as they are least with glucuronidated opioids like morphine and hydromorphone and more problematic with opioids metabolized through the CYP450 enzyme system (e.g. fentanyl, oxycodone, and methadone).33 Assess for dose-limiting side effects (e.g. nausea, myoclonus, delirium, hallucinations, and respiratory depression), titrate doses slowly or switch opioids if needed.
Some patients develop intolerable side effects before achieving pain relief. A retrospective study34 showed that common reasons for opioid rotation were cognitive failure, hallucinations, myoclonus, nausea and vomiting, local toxicity, and refractory pain. One strategy to obtain a balance of analgesia and side effects is to switch or rotate opioids.32 Opioid rotation results in resolution of side effects and improved pain control in >50% of patients.34 It is important to consider patient and disease related factors, medical comorbidities, concomitant pharmacotherapy, patient’s history of any drug sensitivities, the clinical care setting (outpatient, inpatient, long-term care, and hospice) and financial or insurance related issues when rotating to an alternate opioid.35 Other options in managing patients who fail to achieve pain relief due to dose-limiting side effects are as follows:32
- Reduce the systemic opioid dose by 25 to 50 % and simultaneously add a non-opioid or adjuvant analgesic to maintain pain control
- Change the opioid route (i.e. parenteral or spinal route)
- Symptomatically manage opioid adverse effects (Table 7)
Table 7. Opioid side effects and management
|Nausea and vomiting||
Common initial side effects of opioid therapy are mild nausea and vomiting, drowsiness, lightheadedness, and sedation which usually resolve over several days.30 Nausea may require antiemetics. Constipation is a common side effect that persists and is treated proactively with stool softeners and laxatives. The most feared opioid side effect is respiratory depression, which fortunately is uncommon.28,36 Strong opioids do not cause clinically important respiratory depression in patients having pain.37 However, care must be taken in those who are frail, opioid-naïve, or who have comorbid conditions that predispose to respiratory failure such as chronic obstructive lung disease, or who are on sedative medications. Respiratory depression from opioids is nearly always associated with sedation and miosis. Naloxone is given only if sedation is accompanied by bradypnea and only in doses that reverse respiratory depression and not analgesia. A 0.4 mg vial of naloxone is diluted in 10 mL of saline; a 1 mL aliquot is given every 1 minute and titrated to the level of consciousness. Patients on sustained-release opioids or methadone require a continuous infusion of naloxone at the dose that reversed respiratory depression, because the half-life of naloxone is only 30-90 minutes.
Table 8. Non-opioid Analgesics
Management of cancer-related pain also requires expertise in the use of non-opioid analgesics (Table 8), acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), and adjuvant analgesics (Table 9). Acetaminophen is a centrally-acting non-opioid analgesic, used widely in prescription and over-the-counter (OTC) medications to relieve mild to moderate pain and fever. From 1998 to 2003, acetaminophen was the leading cause of acute liver failure in the United States.38 Patients should be advised not to exceed the maximum total daily dose of 4 grams and should be educated on the importance of reading all medication labels to ensure they are not taking multiple acetaminophen containing products.38 Caution should be observed in patients with severe hepatic impairment especially if associated with alcohol dependence and malnutrition.
Table 9. Adjuvant Analgesics for Cancer Pain Treatment
|Category Based on Clinical Use||Drugs|
|Multi-purpose analgesics||Glucocorticoids, tricyclic antidepressants (TCA), serotonin-norepinephrine reuptake inhibitors (SNRIs), Alpha-2 adrenergic antagonists, cannabinoids, lidocaine, capsaicin|
|For neuropathic pain||TCA, SNRIs, anticonvulsant analgesics (gabapentin, pregabalin, carbamazepine, lamotrigine, oxcarbazepine, valproate, topiramate, levetiracetam, lacosamide, ) mexiletene, lidocaine, ketamine clonazepam, baclofen|
|For bone pain||Bisphosphonates, calcitonin, radiopharmaceuticals (strontium-89, samarium-153)|
|For bowel obstruction||Anticholinergics, somatostatin analogues, glucocorticoids|
NSAIDs are both anti-inflammatory and anti-pyretic and are used in cancer pain management. NSAIDs are effective in inflammatory, visceral, bone, and neuropathic pain.39 Their main mechanism of action is inhibiting prostaglandin synthesis via cyclooxygenase (COX) inhibition. They are classified based on their ability to inhibit either COX-1 or COX-2 enzyme isoform. COX-2 selective NSAIDs were primarily developed to reduce NSAID-induced gastrointestinal toxicity, however, naming the "safest" NSAID is difficult as gastrotoxicity is related to multiple factors. Other adverse effects related to NSAID use are increased thrombotic events, platelet dysfunction, bleeding, bronchospasm, renal toxicity, and delayed bone healing.30
Adjuvant analgesics are drugs primarily marketed for conditions other than pain, but relieve certain types of pain, either alone or when used in combination with a primary analgesic on each step of the WHO analgesic ladder. Most adjuvants improve the therapeutic index of opioids but, unlike opioids, have a ceiling effect, a narrow therapeutic window, and are less versatile in routes of administration.40 Inferring the pathophysiology of the cancer pain syndrome guides adjuvant analgesic choices. Based on their use in conventional practice, adjuvant analgesics are broadly categorized as: 1) multi-purpose analgesics; 2) for neuropathic pain; 3) for bone pain; and 4) for bowel obstruction.41 (Table 9)
Some cancer patients will not have acceptable pain control with systemic analgesic therapy and will need additional approaches to pain control. Radiation therapy and interventional treatments like neurolytic blockades, intrathecal drug therapy, kyphoplasty or vertebroplasty, or image-guided tumor ablation may be useful when systemic medications fail to provide pain control or when adverse effects become intolerable.42 Complementary therapies, such as guided imagery, relaxation techniques, hypnosis, and biofeedback have also been used in the multidisciplinary approach to cancer pain management.
Relief of pain is generally measured by unidimensional or pain relief scales. Ancillary outcomes include improved activities, relief of insomnia, improved mood and appetite. Patient satisfaction with treatment, in addition to pain relief, reflects the relationship of the patient and the physician. It is generally more difficult to see an improvement in overall quality of life because this is influenced to a significant degree by the burden of multiple symptoms.
Pain is one of the most feared symptoms associated with advanced cancer, but it also can be effectively managed in the great majority of patients. A good pain assessment is vital to effective treatment. Opioid therapy is the first-line approach in treating moderate to severe cancer pain. Non-opioid analgesics and adjuvant analgesics improve pain control and should be used along with opioids. In patients who do not get pain relief with systemic analgesic therapy, interventional pain procedures and complementary therapies should be considered as part of a multimodal cancer pain management.
- Cancer pain is broadly categorized as acute and chronic pain syndromes. Acute pain syndromes are often iatrogenic but may also be disease-related. Chronic pain syndromes are mostly due to direct effects of malignancy and some are due to antineoplastic treatments.
- Clinicians should integrate findings from history, physical examination, and tests in order to infer the pathophysiologic mechanisms behind the pain and identify the possible pain etiology.
- Inferred pathophysiologies are nociceptive, neuropathic, or psychogenic. Disorders that cannot be categorized are labeled idiopathic. Cancer pain is oftentimes a mixed disorder.
- Cancer pain can be relieved in 80% to 90% of patients using an opioid-based analgesic regimen and the WHO analgesic ladder as guidelines.
- In patients who do not get pain relief with systemic analgesic therapy, interventional pain procedures should be considered as part of multimodal approach to cancer pain management.
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