When it comes to living with cancer, there is good news and bad news. Although patient prognoses have improved over the last decade—with the result being longer life expectancy and remission rates—residual pain and functional deficits often accompany these successes.1 In fact, many of our oncology colleagues and other allied cancer care providers have placed the emphasis of treatment on both remission and advances in minimizing the disease activity, with less emphasis on the aftermath.2
In many ways, these advances have resulted in a greater proportion of cancer pain shifting from an acute to a chronic condition, and represent the sequelae of effective treatments.3This shift has required cancer pain management programs to borrow from the chronic pain playbook: using an interdisciplinary approach to rehabilitation and pain management. After all, there is no difference anatomically or physiologically, by biochemical substrate, or through mechanisms of nociception between benign or malignant etiologies of pain.4 These etiologies of cancer pain can be nociceptive (somatic and visceral), neuropathic, or mixed; and temporally may represent acute or active disease, subacute, or chronic with palliative care—or in remission with residual effects.
Although pain is considered the fifth vital sign, it still remains undertreated especially among minorities both in institutions and outpatient settings due to poor assessment, deficiencies in patient and/or provider education, regulatory issues, and fear of opioid treatments.5 This series of articles will review current concepts in the compassionate and multidisciplinary treatment of cancer-related pain.
Goals of Treatment
The goals of a comprehensive interdisciplinary cancer pain management program include improved function to improve quality of life (QoL) with maintenance, or resumption, of activity of daily living (Table 1). In the psychosocial realm, the goals of treatment include lessening the sense of suffering, while fostering an internal locus of control—that is, believing that pain can be controlled by factors such as one’s attitude, preparation, and effort. This can be accomplished by providing patients with the skills to manage pain on a daily basis using the minimal amount of medications needed to achieve maximal pain relief, thereby limiting side effects in a cost-effective manner. In palliative cancer pain, the emphasis of care primarily may be to reduce pain, and to sustain function.
As a specialist in cancer pain supportive treatments, I should emphasize that the patient’s prognosis, and compliance with treatment recommendations, is strongly correlated with his/her satisfaction with pain control. Compliance to the treatment plan can be cost effective in minimizing additional emergency department visits and subsequent hospitalizations due to inadequate pain control. Pain management also improves patient compliance for other recommended treatments.6 In the vast majority of cancer patients (85%), pain can be well palliated using simple, inexpensive, “low technology” oral analgesics. The cancer pain therapy ladder primarily using oral, transdermal, transmucosal, or suppository agents is effective in alleviating cancer-related pain in up to 80% of patients.7
In the remainder of patients, up to 20% will require supplementary interventions to decrease physical pain.8 In a smaller percentage (5% to 10%) of cancer pain patients, invasive anesthetic or neurosurgical interventions may be required.9 These include adjuvant pain medications, alternate routes of opioid administration, antineoplastic therapy, nonpharmacologic approaches, interventional procedures, and surgery. Neurostimulatory techniques, regional analgesia, and neuroablative procedures can provide excellent palliation in selected refractory patients; however, generally, they do not eliminate the need for systemic opioids. Interventional procedures including nerve blocks (peripheral, epidural, selective nerve root, ganglion, plexus, facet, or medial branch blocks) with radiofrequency denervation, and occasionally chemical neurolysis with botulinum toxin,10 have been useful in selected cases of specific pain generators. Sphenopalatine ganglion, for example, is a neurolytic block for pain due to advanced head and neck cancer.11
Other interventions include thoracotomy, intracerebral, and—more commonly—intraspinal12 analgesics. Neuromodulatory procedures include vagal, occipital, or other peripheral nerve stimulation, and spinal cord or brain stimulation. Neuroablative procedures include the creation of lesions in the dorsal root entry zone, cordotomy, myelotomy, tractotomy, hypophysectomy, thalamotomy, and cingulotomy.13
Identifying Pain Generators
The current treatment of cancer has shifted to more conservative care including radiation therapy (RT), chemotherapy (CT), or minimal resection of neoplastic tissue resulting in higher survival rates,13 but with more residual pain in patients (60% of patients).14 Combined CT and RT results in better remission but has a tendency for higher morbidity rates, including acute and chronic toxicity, as well as treatment-related mortality.11 However, even with less reliance on surgery, preserving the organ does not always correlate with preserved function. Minimally invasive surgery improves functional outcomes. Education is required to inform patients that they need to complete the full course of treatment for a complete remission, which involves improving their compliance and satisfaction with care, and minimizing financial barriers.15
A careful evaluation including history, pain description (particularly if it is worsened during sleep), precipitating and alleviating factors, functional deficits, psychological factors, psychosocial history including the patient’s beliefs, physical examination, review of previous records, and a general knowledge of the different characterizations of cancer or nonmalignant pain will optimize a comprehensive assessment. Documentation is crucial, and frequent reassessment is necessary to dynamically evaluate the problem, monitor for any interval changes, and responses to therapy. Even without a specific known pain generator, one must treat pain aggressively during diagnostic evaluation to validate symptoms, provide comfort, and improve compliance.13 Unfortunately, only 0.1% of the cancer literature addresses the diagnosis of pain or its management.16 Determining the etiology of pain is the key to appropriate therapy.17 One must first determine whether the pain generator is coming from peripheral tissue or combined with the central nervous system (at least 33% of cancer pain has a neuropathic etiology as a source, which may be found in combination with somatic pain).18 Table 2 lists some of the common sources of cancer-related pain.13
Somatic Pain Etiologies
There are a number of causes of somatic pain in cancer patients. This section highlights some of the most common.
Diagnostic or therapeutic procedures (ie, bone marrow aspiration or biopsy, lumbar puncture) result in acute somatic pain, and may require premedication as well as analgesics for several days for the postprocedural pain.
Acute postoperative pain or postsurgical syndromes (eg, debulking or radical neck dissection) needs to be treated with a patient-controlled analgesic in appropriate patients, and with considerations for pre-exemptive analgesics. Such analgesics include cyclooxygenase-2 inhibitors (Celebrex), selective non-steroidal anti-inflammatory drugs (NSAIDs), calcium ligand anticonvulsants, and preprocedural local anesthetic nerve blocks.15
Direct tumor involvement can cause somatic pain described as constant, aching, gnawing, and often well localized (vascular obstruction or invasion, mucous membrane ulceration). Bone metastases are a frequent source of cancer-related physical impairment.
Other sources of somatic pain may include pathologic or osteoporotic stress fractures, and osteonecrosis (following steroids, RT, or alcoholism). CT side effects may result in mucositis and RT side effects may present as odontophagia, mucositis, or burns). Lymphedema from RT of the lymphatic tissue, or excision may result in painful swelling near the affected region or extremities, which in turn may lead to painful cellulitis or skin ulceration. A painful scar or keloid may occur following wound healing with an increased risk of a wound neoplasm.
Often, soft tissue and myofascial pain, as well as muscle spasms, occur due to viscerosomatic or somatosomatic spread of pain generators, resulting in patients with a tumor source having a superimposed musculoskeletal component to their pain.19 Antineoplastic, antimicrobial, endocrinologic (including steroids), nutritional, or electrolyte changes can also result in muscle cramps, restless leg syndrome, myopathy, and other myalgias, which is turn may be perpetuated by pre-existing benign musculoskeletal pathologies, insomnia, and psychological distress. Cancer patients may also experience a general increase in pain perception as the result of an amplification of the pain signal in somatic innervated tissues (central or peripheral sensitization as seen with fibromyalgia, complex regional pain syndrome, or strokes), in addition to changes in their perception of pain based on medical conditions (ie, diabetes, dementia, hypoxemia, or the tolerance effect from opioids).20
In visceral pain, there is a constant, deep aching with poor localization and a variable pain presentation (possibly related to the autonomic nervous system dysfunction), and can be associated with referral patterns. It is often associated with nausea (with gastroesophageal reflux disease or gastroesophagitis), cachexia, constipation (related to medications, abdominal pathology, or immobility), rectal or bladder spasm, or obstruction of hollow viscus (bowel obstruction), ductal system (biliary), or solid viscus (liver or pancreas). There also may be visceral metastases (lung).
Phlebitis and hemorrhagic cystitis with bladder spasms are common sequelae from antineoplastic therapies. Immunocompromised patients may present with painful infections with somatic or neuropathic pain generators including pneumonia, urinary tract infection, wound infections, Candida esophagitis, oral or genital herpes, and herpes zoster. The pharmacologic analgesic treatments may include opioids, corticosteroids, anesthetics, cannabinoids, capsaicin, and NSAIDs.20
Neuropathic Pain Etiologies
Neuropathic pain may be related to direct tumor invasion, surgical excision, radiation, or peripheral polyneuropathy due to chemotherapy or nutritional deficiency. Central nervous system (CNS) etiologies include spinal or brain invasions with stretching of the dural membranes, CNS edema, syringomyelia, encephalopathies, myelopathies, central or peripheral sensitization, and strokes with central pain. Cranial neuropathies including facial neuralgias in patients with cancer most commonly indicate the presence of meningeal carcinoma, tumor involvement of the bones of the cranial base with encroachment of neural foramina, or, rarely, brainstem metastasis. These patients may present with headaches associated with cerebral edema.
Peripheral polyneuropathy is common with paraneoplastic syndrome and gammopathies. Other causes include diabetes, thyroid dysfunction, vitamin B12 deficiency, and alcoholic neuropathy. Patients with underlying peripheral neuropathy (eg, Charcot-Marie-Tooth disease or diabetic neuropathy) have been reported to be much more susceptible to development of severe neuropathy, including potentially fatal autonomic neuropathy.21
RT may result in brachial or lumbosacral plexopathies (diagnosed by clinical evaluation and electrodiagnostic testing, which can show myokymia with denervation and segmental demyelination). RT accelerates vascular injury causing obstruction of the subclavian artery, and it opens the blood–brain barrier, thereby increasing exposure of the brain to subsequent CT effects. RT to the spine, affecting the spinal cord, may result in a late-onset myelopathy, as well as injury to the peripheral nerves (including nerve roots and plexus). This results in acute fibrosis in the nerve sheath and angiopathic changes in the small arterioles.
Brachial and lumbar plexopathies due to RT are more likely to be more painful and involve the lower nerve roots compared to the manifestations of plexopathies due to tumor invasion. They can also cause neural fibrosis and contracture, eventually resulting in muscle atrophy. Cranial RT can result in acute encephalopathy, subacute (drowsiness, nausea, headaches, ataxia, and worsening of underlying neurologic dysfunction), and chronic neurotoxicity (9 months to 2 years after completion of RT) with radiation necrosis.22 Cranial RT also has endocrinologic effects on the hypothalamic-pituitary axis including deficiency of gonadotropins, thyroid-stimulating hormone, and corticotropin. RT also causes soft-tissue pathology including burns, wounds, fibrosis, lymphedema, and painful contractures.22
Treatment-related neurotoxicity is a well-documented side effect of chemotherapy, and its frequency is increasing. Improvements in supportive care have allowed dose escalation for many chemotherapy regimens, increasing the survival rate from cancer but resulting in an increasing prevalence of late-onset neurotoxicity. Some of the agents most commonly associated with chronic polyneuropathy include bortezomib (Velcade), cisplatin (Platinol), oxaliplatin (Eloxatin), paclitaxel (Abraxane, Onxol), thalidomide (Thalomid), and vincristine. Oxaliplatin produces an unusual cold-induced peripheral neuropathy. This pain can often worsen over time, despite remission of cancer and discontinuation of the CT regimen.23 Treatments include medical and nonmedical management, including use of nutritional supplementation, anticonvulsants, antidepressants, anesthetics, topical medications, and ketamine. In general, neuropathic pain is considered “resistant” to opioids, but some opioids may be more effective than others at treating neuropathic pain (methadone, tramadol, tapentadol [Nucynta]). One study has shown that combining the tricyclic antidepressant nortriptyline with gabapentin (Neurontin) produced better pain control than either agent alone.24
There are also CNS and muscle side effects from the following CT agents:
Cytosine arabinoside and 5-fluorouracil: acute cerebellar toxicity and encephalopathy, myelopathy
Methotrexate: acute encephalopathy; chronic and subacute leukoencephalopathy, especially in patients who also have received cranial radiation; myelopathy
Vincristine: encephalopathy, coma, seizures, myopathy
Cisplatin: optic neuropathy, seizures, encephalopathy, cortical blindness, ototoxicity, retinal toxicity (if injected through carotid artery)
Paclitaxel: rare myopathy22
Pain perception can affect function, QoL, and the patient’s attitude towards diagnosis—and must be treated appropriately by a pain practitioner. Emotional distress including anger, depression, non-acceptance, hopelessness, fatigue, insomnia, and anxiety are common manifestations following a diagnosis of cancer or following discussions about poor prognosis. Emotional pain is associated with suffering, but involves the same brain regions as physical pain, suggesting the two are inextricably connected. Physical pain often produces psychological distress and depression in patients, which in turn exacerbates the pain and reduces patients’ compliance. Pain may cause the patient to fear disease progression and impending death, and adversely affects prognosis and/or survival. Fear and depression related to cancer can reduce pain thresholds and produce anatomic changes that accentuate pain. Depression is high among cancer patients (ranging from 10% to 25% in survivors),25 with higher levels of impairment, and is associated with poor compliance with medical care, longer hospitalizations, and higher mortality rates. Anxiety (ranging from 10-30% in cancer survivors) is quite common in cancer patients and may be related to poorly controlled pain, uncertain prognosis, abnormal metabolic states, or medication side effects.26 Post-traumatic stress disorder (seen in 35% of cancer survivors) may occur in response to cancer diagnosis and treatment.27 Poor adjustment reactions are often related to the loneliness, social isolation, financial stress, family tension, community supports, and logistical concerns involved in cancer management.6
Lifestyle changes including weight loss, exercise, smoking, or alcohol cessation28 are important parameters to determine the patient’s internal locus of control, motivation for wellness, compliance, and global improvement of quality of life. Studies have shown that smokers have increased dissatisfaction with postoperative pain control compared to non-smokers.29 Smoking is associated with a reduced average life expectancy of 10 years. It also is associated with increased risk of aberrant behaviors (misuse of medications); higher levels of pain, anxiety, and depression; and reduced exercise tolerance with reduced cardiorespiratory function and hypoxemia, which may affect brain functioning including pain perception. Smoking also is associated with poorer response to cancer therapy, with increased risk of cancer recurrences. Nicotine is metabolized through the cytochrome P450 system (CYP2A6 and CYP2B6), which causes a faster metabolism of certain opioids including oxycodone, antidepressants including duloxetine, or other medications by reducing their serum levels. Nicotine itself may stimulate neoplastic cell mitosis.23 Not only does smoking with cancer pain make the pain more severe, but it interferes more with the patients’ activities of daily living.30
The “medicalization” of dying can lead to unnecessary interventions, prolonged dying, unnecessary suffering, and lack of effective palliative care, especially in the elderly. There are significant variations in the medical costs of end-of-life care by geographical regions. Palliative medicine for long-term supportive care requires a multifaceted approach, and communication is the key to success. Frequently, doctors take aggressive approaches with treatment and only talk to patients about hospice when there is little hope of survival. Pain is one of the most common end-stage symptoms for hospitalized patients. The definition of hospice care focuses on treatments that promote comfort to patients with a life expectancy of <6 months. In a study of hospice care, 75% of the clients die in an institution, though a majority of this population would prefer to die at home, if they were terminally ill.31 The study confirmed that the quality of care in the institutional setting is inferior compared with care at home, especially with hospice services.31In 2009, 42% of the terminally ill Medicare patients used a hospice program, compared to 22% one decade ago. In this study, more than one-quarter of hospice use was for 3 days or fewer, and 40% of these patients had moderate to severe pain. People dying of cancer were more likely to utilize this option and hospice programs have increased to more than 3,500 in the United States.31
There needs to be communication and planning for living wills, power of attorney, and advance directives including do not resuscitate orders. Depression often is unrecognized, untreated, and can lead to decreased QoL, more severe pain, and even requests for hastened death. Palliative sedation therapy is described as “the use of specific sedative medications to relieve intolerable suffering from refractory symptoms by a reduction in patient consciousness, using appropriate drugs carefully titrated to the cessation of symptoms.”2
- National Cancer Institute. SEER stat fact sheets. Available at: http://seer.cancer.gov/statfacts/html/all.html. Accessed March 5, 2013.
- Miaskowski C, et al. Guideline for the Management of Cancer Pain in Adults and Children. Glenview, IL: American Pain Society; 2005.
- Burton AW, Fanciullo GJ, Beasley RD, Fisch MJ. Chronic pain in the cancer survivor: a new frontier. Pain Med. 2007;8(2):189-198.
- Webster L. Pain-Topics. What is noncancer vs cancer pain? http://updates.pain-topics.org/2012/08/what-is-noncancer-vs-cancer-pain.html. Accessed March 5, 2013.
- Wallace LS, Keenum AJ, Abdurraqeeb O, Miser WF, Wexler RK. Terminology matters: patient understanding of “opioids” and “narcotics.” Pain Pract. 2012;13(2):104-108.
- Caraceni A, Martini C, Zecca E, et al. Breakthrough pain characteristics and syndromes in patients with cancer pain: an international survey. Palliat Med. 2004;18(3):177-183.
- Nersesyan H, Slavin KV. Current aproach to cancer pain management: Availability and implications of different treatment options. Ther Clin Risk Manag. 2007; 3(3): 381-400.
- Ahmedzai S. New approaches to pain control in patients with cancer. Eur J Can. 1997;33(Suppl 6):S8-14.
- Miguel R. Interventional treatment of cancer pain: the fourth step in the World Health Organization analgesic ladder? Cancer Control. 2000;7:149-56.
- Van Daele DJ, Finnegan EM, Rodnitzky RL, Zhen W, McCulloch TM, Hoffman HT. Head and neck muscle spasm after radiotherapy: management with botulinum toxin A injection. Arch Otolaryngol Head Neck Surg. 2002;128(8):956-959.
- Varghese BT, Koshy RC, Sebastian P, Joseph E. Combined sphenopalatine ganglion and mandibular nerve, neurolytic block for pain due to advanced head and neck cancer. Palliat Med. 2002;16(5):447-448.
- Kayahara H, Hamakawa H, Fukuzumi M, Tanioka H. Indication for epidural morphine for the relief of intractable pain in advanced oral cancer: report of our cases. Br J Oral Maxillofac Surg. 2000;38(5):546-549.
- Grossman S, Nesbit S. Cancer pain. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Abeloff’s Clinical Oncology. 4th ed. Philadelphia, PA: Churchill Livingstone; 2008:565.
- Polomano, RC, Farrar JT. Pain and neuropathy in cancer survivors: surgery, radiation, and chemotherapy can cause pain; research could improve its detection and treatment. Am J Nurs. 2006;106(3 Suppl):39-47.
- Gordon DB, Dahl JL, Miaskowski C, et al. American Pain Society recommendations for improving the quality of acute and cancer pain management: American Pain Society Quality of Care Task Force. Arch Intern Med. 2005;165(14):1574-1580.
- Goudas L, Carr DB, Bloch R, et al. Management of cancer pain. Evidence Report/Technology Assessment No. 35 (Prepared by the New England Medical Center Evidence-based Practice Center under Contract No 290-97-0019). AHRQ Publication No. 02-E002. Rockville, MD: Agency for Healthcare Research and Quality. October 2001. http://archive.ahrq.gov/clinic/epcsums/canpainsum.htm. Accessed March 11, 2013.
- Bruera ED, Portenoy RK. Cancer Pain: Assessment and Management. Cambridge, UK: Cambridge University Press; 2003:89-110.
- Twycross R. Pain Relief in Advanced Cancer. London, UK: Churchill Livingstone; 1994:111-128.
- Simons DG, Travell JG, Simons LS, Cummings BD. Travell and Simon’s Myofascial Pain and Dysfunction: The Trigger Point Manual. 2nd ed. Baltimore, MD: Williams and Wilkins; 1999.
- Urich CE. Pathophysiology of cancer pain. In: Walsh D, Caraceni AT, Fainsinger R, Foley K, eds. Palliative Medicine. 1st ed. Philadelphia, PA: Saunders; 2008.
- Paice JA. Clinical challenges: chemotherapy-induced peripheral neuropathy. Semin Oncol Nurs. 2009;25(2 Suppl 1):S8-S19.
- Gilbert MR. Neurologic complications. In: Abeloff MD, Armitage JO, Niederhuber JE, Kastan MB, McKenna WG, eds. Abeloff’s Clinical Oncology. 4th ed. Philadelphia, PA: Churchill Livingstone; 2008:565.
- Farquhar-Smith P. Chemotherapy-induced neuropathic pain. Curr Opin Support Palliat Care. 2011;5(1):1-7.
- Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomized controlled crossover trial. Lancet. 2009;374(9697):1252-1261.
- Pirl WF, Greer J, Temel JS, Yeap BY, Gilman SE, Major depressive disorder in long-term cancer survivors: analysis of the National Comorbidity Survey. J Clin Oncol. 2009; 27(25): 4130-4134.
- Greer JA, Solis JM, Temel JS, et al. Anxiety disorders in long-term survivors of adult cancers. Psychosomatics. 2011; 52(5): 417-423.
- National Cancer Institute: PDQ Post-traumatic Stress Disorder. Bethesda, MD: National Cancer Institute. http://www.cancer.gov/cancertopics/pdq/supportivecare/post-traumatic-stress/HealthProfessional/page1/AllPages/Print. Accessed March 11, 2013.
- Allison PJ. Alcohol consumption is associated with improved health-related quality of life in head and neck cancer patients. Oral Oncol. 2002;38(1):81-86.
- Shi Y, Shilling A, Turan A, Kovac A, Apfel CC. Smoking as a strong risk factor for severe acute postoperative pain after ambulatory surgery. Presented at the American Society of Anesthesiologists 2010 Annual Meeting. San Diego, CA; October 16-20, 2010:Abstract 788.
- Yu S, Weingarten TN, Mantilla CB, Hooten WM, Warner DO. Smoking and pain: pathophysiology and clinical implications. Anesthesiology. 2010;113(4):977-992.
- Teno JM, Gozalo PL, Bynum JP, et al. Change in end-of-life care for Medicare beneficiaries: site of death, place of care, and health care transitions in 2000, 2005, and 2009. JAMA. 2013;309(5):470-477.
- Benedetti C, Ibinson J, Adolph M. Cancer pain: anesthetic and neurosurgical interventions. In: Walsh D, Caraceni AT, Fainsinger R, Foley K, eds. Palliative Medicine. 1st ed. Philadelphia, PA: Saunders; 2008.