The management of cancer pain is very challenging and, when undertreated, can affect every aspect of physical, emotional, and social function. As cancer treatments continue to advance patients are surviving longer with better outcomes. However, with increased survival time there is a higher likelihood of developing chronic pain; hence, it is important to address this sequela of increased survival.¹

The American Society of Anesthesiologists (ASA) task force defines cancer pain as “pain that is attributable to cancer or its therapy,” and this definition has far-reaching implications for addressing pain.⁴ As with any other kind of pain management, the goals of treatment include optimizing pain control, function, psychological well-being, and quality of life.² Treatments should be geared toward maximizing patient function while minimizing discomfort and side effects and should be discussed in detail with the patient. Palliative care, pain medicine, physical medicine, psychology, and therapy are all important players in the overall management of cancer pain.^2,3 This chapter seeks to address the multifaceted nature of cancer pain and methods of evaluation, and overview some commonly used treatments.

Palliative care focuses on comfort and relief of suffering at the end of life. Cancer-related pain in terminal illness is often at its most acute. At this stage disease burden is advanced and frequently requires multiple approaches to analgesia. Palliative care medicine, an Accreditation Council for Graduate Medical Education (ACGME) recognized subspecialty that consists of physicians trained in multiple primary specialties including internal medicine and physical medicine and rehabilitation, often manages pain in these patients. Palliative care medicine addresses most acute needs related to pain, psychosocial distress, quality of life, and other services such as cancer rehabilitation. The focus of the service is to address issues at the end of life with a goal of optimizing quality of life by improving function, pain management, mobility, and other related factors.⁵

Despite the advantages cancer rehabilitation can provide at the end of life, their services are often underutilized.⁶ The reasons for this are multifactorial. There exists a poor understanding of the role of rehabilitation in advanced cancer, with the perception that rehabilitation requires a long time to accomplish and may inspire false hope to patients who otherwise should be planning for the end of life.^7,8 The decision to refer patients for palliative care and rehabilitation services⁹ is highly dependent on preexisting physician perceptions, with oncologists who are more familiar with end-of-life care more likely to refer to rehabilitation services in the palliative setting.¹⁰

In addition to physician biases, patient attitudes contribute to the underutilization of rehabilitation services at the end of life. Cheville et al found that despite a progressive decline in function, most advanced lung cancer patients did not initially accept rehabilitation services until they were significantly debilitated.¹¹ There are numerous possible explanations for this, including lack of knowledge about rehabilitation medicine and the burden of multiple medical appointments.

The need for cancer rehabilitation in the palliative setting is stark. Rehabilitation interventions at end of life reduce pain, anxiety, and depression and improve quality of life.¹² One randomized controlled trial found that patients at the end of life who had daily rehabilitation had less pain and fewer unmet needs at the time of death, while utilizing fewer resources, than the group who did not receive rehabilitation.¹³ Furthermore, given that there exists a significant amount of musculoskeletal pain at the end of life,¹⁴ cancer rehabilitation medicine practitioners may be able to reduce pain through the use of ultrasound-guided procedures and other modalities.¹⁵ The management of cancer pain requires a multidisciplinary approach, and it is important to be aware of the multitude of resources and specialties available to collaborate as a team.

In addition to pain, cancer patients are at risk for falls, especially at the end of life when the amount of debility is the highest.¹⁶ This is particularly true of geriatric cancer patients who often have modifiable risk factors to prevent falls and injury but are not referred for rehabilitation services when these risk factors are identified.¹⁷ Across all cancer patients, the presence of bone and brain metastases are significant risk factors for functional impairment,^18,19 with rehabilitation care being both safe and effective in ameliorating these impairments.⁵ There is significant research on the value of palliative care and cancer rehabilitation in end-of-life care, and it is important to develop an evidence-based practice in the management of cancer pain.

In summary, although both palliative care medicine and cancer rehabilitation medicine are patient-centered approaches to minimizing symptom burden and optimizing quality of life in advanced cancer, the existence of functional deficits and musculoskeletal pain necessitates expertise in rehabilitation care. Physiatrists must continue to be part of the oncology care structure, and strong evidence through clinical trials would help cement the role of rehabilitation in end-of-life care and cancer pain management. It is essential to establish a comprehensive treatment care team in order to address cancer pain most fully.

When evaluating the patient with cancer-related pain, it is important to take a comprehensive approach to the treatment. Often multiple subspecialties should be involved in collaboration to tailor a regimen to the individual patient. Treatments should also be modified over time to address such things as disease progression as well as symptom improvement. Patients with chronic pain can have multiple causes, which may not be directly related to their disease. It is therefore important to illicit the root cause of any type of pain when possible, as treatments vary based on etiology.²⁰ Effective communication between the treating physicians, the patient, and caregivers is essential.

A full history and physical exam is the first step in evaluating the cancer patient. Cancer can cause impairments due to the disease process itself, and also can cause physical and psychosocial impairments due to the side effects of treatment. A full pain history is necessary, including duration, severity, quality, aggravating and alleviating factors, presence or absence of neuropathic symptoms such as numbness or tingling, and effect on functional status. It is important to evaluate the patient’s current and premorbid functional status, independence in activities of daily living, and the chronicity of the disease, as pain can affect all of these. Evaluation should also include a review of systems; past medical and surgical history; and review of medical records, tests, and imaging. A family history, social history, and environmental factors can also be important and help to establish a basis for which further workup can be done if needed. The physical exam is meant to establish a baseline to gather information and establish treatment goals. Performance status is a metric used to estimate one’s meaningful function and ability to care for oneself and estimates overall health. This is used to gauge global function and a patient’s ability to tolerate treatments such as chemotherapy and radiation for selection in research studies and to estimate prognosis.

Two tools used to measure performance status in cancer patients include the Karnofsky index of performance status (KPS) and the Eastern Cooperative Oncology Group Performance Status Scale (ECOG PS). The Karnofsky index has been in use since the 1940s and assigns a point scale of 0 to 100 based on functional status and the need for assistance, with 100 being fully functional and independent, and 0 being dead. The ECOG performance status scale was introduced in 1960, and uses a simplified 5-point system to measure function, with 5 being dead and 0 being fully functional. These tools have been shown to be very accurate when estimating prognosis, with patients who have higher baseline function faring better through treatment.²¹

For patients who are currently undergoing treatment, side effects from chemotherapy or radiation can be significant. Diarrhea, nausea, and decreased appetite are some common gastrointestinal (GI) complaints that can result from chemotherapy. Other side effects may include decreased energy, hair loss, insomnia, neuropathy, and mood changes. It is important to include questions regarding side effects of chemotherapy and emotional state in the cancer patient evaluation. Up to 25% of cancer patients report depression and sleep disturbances, and this should be part of the evaluation.²²

Another concern unique to the cancer patient is cancer-related fatigue, or CRF. This is a particularly debilitating side effect of profound fatigue, reported by 60% to 100% of patients who survive their treatment, which can be addressed with specialized therapy and exercise, but can be missed on examination if the treating physician is not diligent.

In review, the evaluation of the cancer patient includes a full history and physical exam; review of systems; and review of pertinent medical, surgical, and family history. Additionally, a review of pertinent medical records, studies, and imaging is important. Attention should be paid to any potential side effects of treatment such as sleep, mood, bowel care, appetite, energy, and psychosocial and performance status so as to minimize patient discomfort whenever possible. Pain can be so pervasive and all-encompassing to a patient that other treatments become impossible, and it is essential to address this aspect of patient care comprehensively.

Proper management of pain in cancer patients requires an understanding of the disease process, past treatments, the dynamic process of active cancer, and how it may cause changes in patient symptomology. The types of pain that can result from cancer and its treatment are varied, and therapies should be tailored to the individual. Although the intricacies of cancer pain are beyond the scope of this chapter, the basic principles of cancer pain treatment will be reviewed.

Oncologic care typically involves a combination of chemotherapy, radiation, and/or surgery, with other adjunctive treatments like stem cell transplantation sometimes playing a role. Pain and musculoskeletal dysfunction can result from these therapeutic treatments; pain can be acute, chronic, or both, and inadequate management increases suffering at the end of life. Chemotherapy may cause neuropathic pain, myositis, and other symptoms which contribute to physical decline and deconditioning such as nausea, fatigue, and cognitive dysfunction. Radiation therapy can cause acute nausea and pain, but also more chronic effects such as weakness, pain, and spasms due to radiation fibrosis syndrome.²³ Surgery is more variable than the other major oncology treatment modalities with the potential to cause significant functional impairment through direct damage to nerves, muscles, vasculature, and more.

It is also important to note that tumors can cause pain directly due to compression of surrounding structures. The type and degree of pain typically depend on the location and aggressiveness of the cancerous lesion. For example, tumors in bone cause pain through osteolysis, neuroma formation, and inflammation. Such tumors have the potential to cause significant pain with movement and neurologic deficits, including spinal cord injury or focal weakness when located in the spine (Fig. 46–1).

The pathophysiology and variability of cancer pain are multifaceted, and management is equally complex. Fortunately, the evaluation and treatment of cancer pain are often similar to that of nonmalignant pain. For example, the most common cause of radicular back pain in patients with cancer is exactly the same as for those without malignancy; both populations are equally likely to suffer from herniated intervertebral discs. A full history and examination is necessary to determine appropriate treatment. A prior history of cancer is the most sensitive “red flag” to suggest malignancy as a cause of back pain; however, even with a past medical history of cancer the most common causes of back pain are nonmalignant (even in the context of spine metastases and especially in stable disease).²⁴ Nevertheless, recurrent cancer should be excluded as a potential cause of pain before other treatments are initiated. After malignancy has been excluded, the treatment algorithm would essentially be similar to treating back pain in a patient without cancer.²⁵ In fact, rehabilitation interventions for back pain in the metastatic spine have proven to be safe and effective. One study found that patients who underwent a core-strengthening regimen during radiation to spinal metastases had improved bone density and no incidence of fracture.²⁶

Back pain is merely one example of the many possible pain syndromes found in cancer patients and may require pain interventions in addition to pharmacologic therapy. Interventional pain-relieving procedures for cancer patients may seem daunting at first, but can be safe and helpful. Precautions and proper patient screening should be done in all patients, with special attention paid to conditions that are unique to malignancy. Thrombocytopenia or neutropenia may result from cancer or its treatments, and these conditions can lead to bleeding events or infection, respectively. Patients who are thrombocytopenic are typically those with hematologic malignancies, or those with solid tumors undergoing first-line chemotherapy.²⁷ If a patient’s platelet or absolute neutrophil count fluctuates, checking a complete blood count with differential, in addition to a platelet function assay on the day of the planned procedure, is critical in ensuring patient safety. Other contraindications to interventional procedures specific to the cancer patient include the presence of uncontrolled disease, injecting through a tumor (i.e., performing an epidural steroid injection when there is disease in the epidural space), and use of vascular endothelial growth factor such as bevacizumab, a chemotherapeutic agent that increases the risk of bleeding.

Although interventional procedures are common practice for pain management, pharmacologic treatment of pain can be effective and appropriate. Much of cancer pain has a neuropathic pain component. Adjuvant analgesics such as anticonvulsants (e.g., gabapentin and pregabalin) have been found to be relatively safe in the management of conditions such as chemotherapy-induced peripheral neuropathy, radiation fibrosis syndrome, and bone pain. Despite a low side effect profile, pain providers should “go low and go slow” when starting pain medications in this population. Second-line neuropathic pain agents include serotonin/norepinephrine reuptake inhibitors such as duloxetine or venlafaxine, or tricyclic antidepressants such as amitriptyline or nortriptyline (Table 46–1).

Opioid therapy has become less utilized in chronic, noncancer pain but has a role in malignant pain. In cancer patients with moderate to severe pain, opioid therapy can be effective, and there is a low risk of abuse compared to the general population.²⁸ Opioid analgesics are often compatible with chemotherapeutic drugs, and side effects are often tolerable. Of course, any patient starting opioid therapy should have an informed discussion with their prescribing physician about their goals of care, possible side effects, and proper dosing.²⁹ Screening and responsible opioid prescribing methods should be used as with any other patient on opioid medications, including the use of state prescription monitoring programs and urine drug screens. If pain continues to escalate on opioid analgesics, further investigation of the pain generator(s) is warranted.

Central to the strategy of opioid use is to use only one type of opioid medication at a time so future management can involve opioid rotation as opposed to dose escalation. Commonly used opioid medications include morphine, hydromorphone, fentanyl, oxycodone, and methadone. If a patient presents with multiple opioid pain medications, ideally the provider will calculate an equianalgesic opioid dose (usually in morphine equivalents) and then represcribe a single medication broken into long-acting and short-acting dosages for breakthrough pain (Table 46–2). (Please see Chapter 45 in this textbook for further details.)

Nonsteroidal anti-inflammatory (NSAID) medications are often contraindicated in cancer patients, particularly those with renal compromise or at risk for renal failure, as is seen in multiple myeloma. Other patients are at an increased risk of bleeding due to chemotherapy or the tumor itself, which is also a contraindication for NSAID use. For those cancer patients who do not have contraindications, the use of NSAIDs is indicated and particularly valuable for bony metastasis. Acetaminophen is often acceptable and can potentiate the effects of some opiates.

Finally, cancer pain management must include physical therapy (including physical modalities) whenever indicated by a patient’s condition and ability to safely participate in an exercise program. Because patients are often sarcopenic due to the disease and/or treatment, strengthening weak muscles not only improved mobility and independence but may reduce pain and prevent injury. Modalities such as heat and ice are helpful and should be used except over insensate areas or wounds. Additionally, edema management with a properly trained therapist should be employed whenever edema contributes to pain.

There have been recent advancements and novel treatments for cancer pain, but the concept of using an analgesic ladder, which recommends the use of increasingly potent pain medications to treat more severe pain, was presented in 1986 by the World Health Organization in Geneva, Switzerland, under the title Cancer Pain Relief. This three-step analgesic ladder was created from consensus to establish guidelines for the treatment of cancer pain, using a hierarchical approach to pain medications and pain severity. It was created in response to population studies that indicated cancer pain was being seriously undertreated amidst concerns of opioid dependence and addiction, inadequate education for providers, and lack of availability of opioids in some regions. These guidelines have since been applied to other kinds of pain.

The analgesic ladder approach to pain management is intended to be used in conjunction with a full history, physical examination, and pain assessment including psychiatric evaluation. Treatment of the underlying pathology is recommended whenever possible, including chemotherapy, radiation, and surgery, and the use of splints, cervical collars, and rest is also advocated for orthopedic pain.³⁰ Attention is paid to the importance of psychological health in patients with pain within the guidelines, and cognitive-behavioral treatments are recommended in conjunction with medications when indicated. Pain should be assessed as mild, moderate, or severe, and selection of pain medications is dictated on this rating scale. The type of pain is also important to determine; visceral, somatic, or neuropathic pain requires different medications for optimal treatment.

Visceral pain is a general, poorly localized pain resulting from visceral irritation, such as an infiltrating tumor or external compression from edema or obstruction, and can be treated with anti-inflammatories such as NSAIDs, although damage to gastric mucosa can be a concern in visceral pain. Opioids may also be used.³¹ Somatic pain, on the other hand, is typically sharp in quality and well localized, with irritation occurring in skin, subcutaneous tissue, or muscle, and can be treated with a variety of anesthetics, anti-inflammatories, or opioids. Neuropathic pain, or nerve pain, is often described as burning and tingling and is commonly treated with anticonvulsants, selective serotonin reuptake inhibitors, tricyclic antidepressants, and N-methyl-D-aspartate receptor (NMDA) antagonists. Pain may be caused by the cancer itself in tumor burden, or as a sequela of the cancer or its treatment such as chemotherapy or radiation neuropathy. Patients may have a combination of all three types of pain, and this can complicate treatment (Table 46–3).

Classification of cancer pain can be very helpful in guiding appropriate pain management. The revised Edmonton Classification System for Cancer Pain is utilized for this purpose (Fig. 46–2).

Intensity is routinely characterized using standard visual or numeric analog pain scales (Fig. 46–3).

The step ladder outlines the recommended pain medications, with or without adjuvant treatments, based on the severity of the patient’s pain. Pain that is assessed to be mild should be treated with nonopioid or over-the-counter formulations such as NSAIDs or acetaminophen with or without adjuvant treatments like therapy, neuropathic medications, or antidepressants. For moderate pain, low-dose opioids may be used, and for severe pain higher-dose opioids are advocated. All steps in the ladder also recommend the concurrent use of nonmedication treatments and nonopioid medications, if indicated, for symptom management, but only one drug from each category should be used at a time.

These guidelines were updated in 1996 to address methods of administering pain medications, recommending to use oral formulations whenever possible (designated section “By Mouth”), to administer medications on a timed schedule (“By the Clock”), to tailor a treatment regimen to the individual (“For the Individual”), and to time the medications to the patient’s waking schedule (“Attention to Detail”).³⁰ Data suggested that by the second edition of the World Health Organization (WHO) guidelines, opioid use for severe pain increased, with potentially improved management of cancer pain.³²

The analgesic step ladder advocates for the use of adjuvant or alternative treatments in combination with oral anesthetics. The use of acupuncture in combination with oral pain medications in the WHO step ladder has been shown to be effective in cancer pain management³³ (Fig. 46–4).

The recommended starting dose of opioid medications for moderate to severe pain is 1 to 15 mg oral morphine, with titration up or down from this point to maximize pain control and minimize side effects. Opioid medications are associated with tolerance and physical dependence, and for this reason it is recommended to change medications periodically to maintain analgesic efficacy. Patients may achieve adequate pain control on regularly scheduled doses of analgesics; however, occasionally they may develop episodes of worsened pain. For patients with acutely worsened pain, or “breakthrough” pain, the analgesic ladder advocates additional doses of pain medication, which can be taken as needed in addition to their baseline regimen. Typically breakthrough doses may be anywhere from 50% to 100% of the usual scheduled pain medication dosage; however, this should be tailored individually to the patient.

The analgesic ladder has undergone scrutiny in more recent years. Some suggest that for improved pain control, one can forego step 2 and go directly to step 3 with more potent opioids for more efficient and appropriate pain management rather than slowly advance through all three steps of the ladder.^34,35 Nevertheless, the analgesic ladder established guidelines and served to draw attention to the issue of cancer pain management in a meaningful way.

Opioids remain the mainstay in the treatment of cancer pain. However, once conservative management with medications and therapy is maximized, patients may still have persistent pain. Procedural medicine is a branch of pain management available for more aggressive cancer pain treatments. The last 10 years has demonstrated great advancements in understanding anesthetic approaches to the patient diagnosed with cancer. We have learned that specialized anesthetic techniques cannot only improve pain but also the long-term outcomes of cancer patients. In addition to being potent analgesics, opioids appear to have several detrimental effects. Of particular interest is the effect of opioids on the immune response. Animal studies suggest that opioid therapy may contribute to cancer recurrence and tumor progression.³⁶

Various types of cancer demonstrate increased activity of voltage-gated sodium channels.³⁶ Blockade of these channels by local anesthetics has been described to inhibit tumor progression.³⁶ Opioids have been demonstrated to promote angiogenesis, cancer cell proliferation, and metastasis.³⁶

Several pain procedures have been shown to have added benefit over simple pain control in the cancer population. Regional anesthetics/analgesia may reduce the risk of cancer recurrence after surgery.³⁷ Recurrence of postmastectomy breast cancer has been described to be lower in those patients treated with paravertebral or high-thoracic epidural analgesia when compared to patients treated with volatile anesthetics and opioids.³⁷ Additionally, researchers have shown that specific alterations in analgesic management of cancer patients can reduce the risk of postsurgical cancer recurrence.³⁷ Paravertebral analgesia/anesthesia used for surgical resection of breast cancer is associated with a lower risk of cancer recurrence.^37–40 Epidural analgesia for radical prostatectomy to remove adenocarcinoma is correlated with a 60% risk reduction of recurrent disease.^38–40

The current data for perioperative management of the cancer patient suggest that specific regional anesthetic therapies can not only prevent chronic pain postsurgical resection but also assist in the long-term prognosis of the patient. Subcutaneously tunneled regional catheters that administer local anesthetic provide a more sustainable modality for pain control, albeit with limitations.⁴¹ Dedicated catheter management is required to avoid infection. The percutaneous nature of the tunneled catheter limits the duration of time the catheter can be in place.⁴¹ For example, interscalene and femoral nerve blockade could be beneficial to treat upper extremity– and lower extremity–related pain, respectively.⁴¹ Moreover, tunneled epidural, intrathecal, and paravertebral catheters can offer relief of thoracic-, abdominal-, and pelvic-related cancer pain. Many times regional anesthetic techniques are offered at the end of life and can serve as a sustainable treatment modality.⁴¹

The sympathetic nervous system conveys sensory input from the viscera. For visceral pain, sympathetic nerves can be targeted with chemical procedures such as neurolysis, or with local anesthetic in the form of sympathetic blocks. Typically, a local anesthetic is used as a sympathetic block for temporary pain control, while phenol or alcohol is utilized for neurolysis to degenerate the nerve, which provides longer-lasting relief. The medication is injected at the site of sympathetic nerves to anesthetize the sympathetic chain for the purposes of pain control. Common targets include the stellate ganglion (for head and neck pain), the celiac plexus (for upper abdominal pain), the superior hypogastric plexus (for pelvic pain), the lumbar sympathetic chain (for leg pain), and the ganglion of impar (for perineal pain). These procedures are typically performed under computerized tomography (CT) or fluoroscopic guidance and can afford substantial relief of pain secondary to cancer.^42,43 Blockade and neurolysis can be presented at the time cancer is diagnosed, during active treatment, and at the end of life.