Educational Information: Managing Relentless Pain in Cancer Survivors

Surviving Cancer: The Painful Reality
People with cancer are living longer than ever before.

Today, 66% of people diagnosed with cancer are expected to live at least 5 years, and 10-year survival is approaching 60%.[1] The number of cancer survivors in the United States has grown steadily over the past few decades and now stands at 11.7 million individuals.[2] Improved cancer treatments have even extended the survival of patients with advanced cancer, many of whom are living longer than was previously thought possible.[3]

Increased Survival Requires Management of Survivor Symptoms

One of the consequences of living longer is the symptom burden of cancer survivorship, which is having a substantial impact on quality of life for many survivors.[4] Persistent and late effects of cancer treatment include physical limitations, cognitive sequelae, depression, anxiety, sleep problems, fatigue, sexual dysfunction, and, in some patients, a great deal of pain.[5]

"Our cancer treatments are unfortunately leaving people with significant pain syndromes," observed Dr. Paice, adding "although they are not new, these pain syndromes are on our radar screens more now than they were a couple of years ago."

As cancer survivors reduce the frequency of visits with their oncologists in the months and years following completion of their cancer treatments, their ongoing needs are often taken over by their primary care providers. Treatment-related pain is a chronic, long-term issue for many cancer survivors, and their primary care providers must be aware of the possible sources of treatment-related pain, know how to thoroughly assess patients for such pain, and manage these unique pain syndromes according to the best available evidence or make appropriate referrals to pain management specialists.

Chronic Pain Associated With Cancer Treatment

Of all types of pain suffered by patients with cancer, malignancy-related pain and end-of-life pain have received the most attention, and treatment-related pain the least.[6] As survival lengthens, persistent pain is no longer acute but chronic, and chronic pain must, in many cases, be managed differently.[7] Because cancer treatment-related pain is a relatively new phenomenon, or at least a relatively newly recognized one, no accurate data yet exist on the extent of the problem. Green, Hart-Johnson, and Loeffler recently documented that 43% of a diverse population of cancer survivors had experienced pain since their diagnoses, and 20% suffered chronic cancer-related pain.[8] These figures are likely to under represent the problem.

Dr. Paice sees many of these patients in her practice, and she is not surprised that no accurate numbers exist to give us an adequate grasp of the prevalence of chronic treatment-related pain. "The early clinical trials were looking at how effective the cancer drugs and other treatments were; they weren't systematically measuring all of the adverse effects. And patients were hesitant to admit that they were having a side effect such as pain because they were afraid they would be dropped from the trial," she explained.

Chronic pain syndromes in cancer survivors have many sources. The adverse effects of cancer treatments, which can overlap and amplify one another, are increasingly appreciated as contributing to the pain experience of these patients. Dr. Paice typically sees 5 different cancer treatment-related syndromes in her patients:

  • Chemotherapy-induced peripheral neuropathy (CIPN);
  • Radiation-induced pain;
  • Hormone therapy-induced arthralgia;
  • Surgery-related pain.
Chemotherapy-Induced Peripheral Neuropathy

CIPN is a neurotoxic effect of some chemotherapeutic agents, such as paclitaxel, vincristine, cisplatin, oxaliplatin, thalidomide, and bortezomib.[6] Although dose-dependent, the severity of CIPN can also depend on previous chemotherapy, use of multiple neurotoxic agents,[9] or chemotherapy combined with surgery and/or radiation therapy.[6] CIPN has been described as a severe and debilitating condition that can harshly impair the survivor's quality of life.[10] Neuropathic pain associated with these agents typically resolves upon discontinuation of treatment, reduction of dose, or symptomatic treatment.[6] A subset of patients may continue to experience chronic, intensely painful paresthesias, burning, and/or painful numbness of the hands and feet ("glove and stocking" distribution).[9]

The pathophysiologic mechanism of nerve injury leading to neuropathy in CIPN has not been fully explained.[9] However, in an animal model, it has been shown that chemotherapeutic agents cause energy deficiency by interfering with mitochondrial function and impairing the sodium-potassium pump that maintains the cell's normal resting potential.[11] This results in depolarization of nerve fiber axons to a threshold that allows spontaneous discharge; hence, the occurrence of painful nerve sensations. Bennett suggests that this could be the same mechanism that operates in diabetic neuropathy, explaining why patients with diabetes typically have CIPN more often than people who do not have diabetes.[12] "It is a common comorbid condition," stated Dr. Paice. "I have several patients with well-controlled diabetes who have severe CIPN. They don't have to have uncontrolled diabetes or severe diabetic neuropathy to be at risk for CIPN."

Treatment of CIPN. Attempts to use neuroprotective agents to mitigate the neurotoxic effects of chemotherapeutic drugs have not been completely successful.[12] Current treatment, therefore, includes the antineuropathic pain medications.[6] First-line drugs that have been studied for use in the management of peripheral neuropathy include the tricyclic antidepressants (amitriptyline, nortriptyline) anticonvulsants (gabapentin, pregabalin), and serotonin-norepinephrine reuptake inhibitors (duloxetine, venlafaxine).[13] None of these drugs has shown broad effectiveness for CIPN, however, so for severe, refractory CIPN, opioids may be the best option for selected patients,[12] and in some patients may offer the only relief from unrelenting pain.

Dr. Paice emphasized the need for a multifaceted approach to the management of the pain of CIPN, including the maintenance of physical activity. "These patients need to exercise, to keep moving to ensure that they don't lose muscle strength."

However, their symptoms also necessitate new safety precautions, explained Dr. Paice. "They can lose proprioception -- the spatial orientation of their bodies -- so they are at risk for falls and other injuries. They should make sure their walking surfaces are non-skid, eliminate throw rugs, and use a night light. If their hands are affected, they should turn down the temperature of their hot water so they don't burn themselves because, paradoxically, their sensation of what is normal is reduced. They need frequent assessments of their feet and good foot care."

Radiation-Induced Pain

The use of radiation in cancer treatment can have a number of painful effects on cancer survivors.[9] One of the most painful of these, according to Dr. Paice, is plexopathy, which is damage to and impaired function of a network of nerves. "Nerves in the treatment field are activated by radiation therapy, and afterward, the patient has pain affecting the entire chain of nerves from that plexus. The most common is the brachial plexus, which may be affected in breast cancer patients, causing pain to radiate down the arm. Patients with colon cancer or gynecologic cancer who are treated with radiation may suffer from lumbosacral plexopathies, affecting their legs."

How radiation therapy injures the nerves of the plexus is not known but is believed to be related to microvascular injury, causing fibrosis, or direct damage by irradiation of peripheral axons and myelin sheaths.[14] Larger doses of radiation, more courses, larger fields of treatment, or radiation combined with chemotherapy all place patients at higher risk for radiation-induced injury.[14]

The symptoms of plexopathies are often delayed in onset, from months to years, although most patients develop symptoms within 3 years of radiation therapy.[6] Brachial plexopathy begins with numbness and paresthesias of the hands and fingers, followed by weakness and pain. Lumbosacral symptoms typically begin with asymmetric bilateral leg weakness, fasciculations, numbness, paresthesias, and, in some patients, chronic pain radiating the full length of the limb.[14] When these symptoms begin, it is often necessary to differentiate the pain of plexopathy from that of possible tumor recurrence, necessitating imaging procedures.[9]

Treatment of radiation-induced plexopathy: The pain, weakness, and sensory loss of radiation-induced plexopathy can be severe and disabling and greatly undermine quality of life. According to Dr. Paice, few effective treatments for the pain of plexopathies have been evaluated.[9] Medications similar to those used for CIPN (tricyclic antidepressants, anticonvulsants, opioid analgesics) are often prescribed to give relief but have not been systematically tested for this purpose. Dorsal root entry zone lesions have been attempted for intractable cases of chronic severe pain.[15]

Hormone-Induced Arthralgia

The American Society of Clinical Oncology recommends that postmenopausal women with hormone receptor-positive breast cancer receive aromatase inhibitor therapy at some point during treatment of their breast cancer, incorporated either as up-front therapy or as adjuvant therapy after tamoxifen.[16] With data showing that aromatase inhibitors reduce the risk for breast cancer recurrence and prolong survival, many thousands of women have received aromatase inhibitors as part of their breast cancer treatment, and many more will do so in the future.

Aromatase inhibitors are associated with the development of painful arthralgias and myalgias, most commonly joint symptoms that resemble arthritis, but without the inflammatory component. Aromatase inhibitors essentially mimic the symptoms of menopause by inhibiting the peripheral production of estrogen in postmenopausal women, causing an acute drop in estrogen level, leading to backaches, joint pains, and stiffness characteristic of menopause.[17] Recent research has found a link between arthralgia, bone pain, and bone mineral density, suggesting a role for increased bone breakdown and reduced bone formation in this pain syndrome.[9] Risk factors for pain with aromatase inhibitor therapy include obesity and previous hormone replacement therapy or chemotherapy.[9]

A wide range of symptoms is possible, including pain and stiffness in the joints (hands, fingers, knees, hips, lower back, shoulder, feet), early morning stiffness, difficulty sleeping, rings not fitting, difficulty closing hands completely, and inability to perform activities such as dressing, driving, or typing.[17] Some women report improvement of their symptoms with movement.[9] These symptoms can appear from 2 months to as long as 2 years after the start of therapy.

"In patients who already have a chronic pain syndrome, such as rheumatoid arthritis or fibromyalgia, the pain seems to be more active and more severe," observed Dr. Paice. "It might be in part because they have to stop taking other medications, such as immunosuppressive drugs, while they are on treatment." She noted that this is a significant problem because women must take the aromatase inhibitors for 5 years, and many women want to go back to work and live normal, pain-free lives, so they often choose to stop taking the drugs. In one study, 20% of women who had joint pain stopped taking their aromatase inhibitors,[18] and other studies have documented reduced adherence with aromatase inhibitor therapy over time in women who experience this pain syndrome.

Treatment of hormone-induced pain. Dr.Paice emphasizes that therapy for aromatase inhibitor-induced arthralgia is, at present, primarily empiric, and many of the treatments used by patients or prescribed by physicians have not been tested in clinical trials.[9] These treatments include acupuncture, exercise, acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, glucosamine/chondroitin, omega-3 fish oil, and probiotics.[9] No single therapy has yet been shown to be effective for all women, but oral analgesics have been recommended by some experts for treatment of this pain syndrome.[19] Some experts recommend lifestyle modification for selected patients, including weight reduction, regular exercise, and increasing joint mobility, with the goal of alleviating fatigue and improving muscle strength, posture, and flexibility.[17]

Pain Associate with Surgery

Pain associated with cancer surgery is probably the most well understood of the cancer-treatment pain syndromes.[28] Estimates of the rates of chronic pain after cancer surgery are as high as 50%,[7] and such pain is almost certainly multifactorial. Burton identifies the following predisposing factors for chronic pain following oncology surgery[29]:

  • Pre-existing pain;
  • Repeat surgery;
  • Radiation;
  • Chemotherapy;
  • Psychological vulnerability; and
  • Depression and anxiety.

Although any type of surgery can result in chronic pain, some of the most well-described sources of chronic postoperative pain in cancer survivors include post mastectomy pain, post amputation pain, post thoracotomy pain, and pain associated with head and neck surgeries.

Post mastectomy pain. Chronic pain following breast cancer surgery has not been mitigated to a degree proportional to the advancements in surgery of recent years, even with less invasive procedures.[1] Breast-conserving surgery with axillary node dissection does not result in less chronic pain than modified radical mastectomy, as one might intuitively believe.[30] In women who elect reconstructive surgery, tissue expanders used in the time period between initial surgery and reconstructive procedures represent another source of pain.[31] After the surgical healing period is over, most persisting pain in the post mastectomy patient is neuropathic in nature and is related to surgical trauma and, in particular, the extent of axillary dissection.

In a study that documented a 20% prevalence rate of post mastectomy pain syndrome, women described their pain as being a chronic, stable pain of long duration that began shortly after surgery. They described it as "paroxysms of lancinating pain against a background of burning, aching, tight constriction in the axilla, upper arm, and/or chest that significantly interfered" with performance of daily activities.[32] In a classification proposed by Jung, neuropathic pain includes (1) phantom breast pain; (2) intercostobrachial neuralgia and post mastectomy pain syndrome; (3) neuroma and scar pain; and (4) other nerve injury.[33] Younger women seem to have a higher frequency of post mastectomy pain syndrome.[34] The severity of a patient's acute postoperative pain[35] and the adequacy of its management are also strong predictors of chronic pain in breast cancer survivors.

Authors and Disclosures

Judith Paice, PhD, RN, FAAN, is Director of the Cancer Pain Program in the Division of Hematology-Oncology and Research Professor of Medicine at Northwestern University's Feinberg School of Medicine. Dr. Paice served as President of the American Pain Society from 2006 to 2008 and is currently Secretary of the International Association for the Study of Pain. Much of Dr. Paice's clinical work has been in the relief of pain associated with cancer and HIV disease.

Laura A. Stokowski, RN, MS, Staff Nurse, Inova Fairfax Hospital for Children, Falls Church, Virginia; Editor, Medscape Ask the Experts Advanced Practice Nurses
Disclosure: Laura A. Stokowski, RN, MS, has disclosed no relevant financial relationships.

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