Pain Management

TABLE OF CONTENTS
Pathophysiology
Elements of management
Medical evaluation
Psychosocial assessment
Subgrouping of patients
Pharmacologic treatment
Bone Metastases: the paradigm for oncologic treatment of pain
Radiation therapy
Management of psychological, sociocultural, and spiritual factors
Ongoing care
Suggested reading

Most patients with advanced cancer, and up to 60% of patients with any stage of the disease, experience significant pain. The WHO estimates that 25% of all cancer patients die with unrelieved pain. Although pain can adequately be relieved in most cancer patients, it is remains undertreated for a multitude of reasons.

The management of cancer- and treatment-related pain is not restricted to cancer patients with a poor prognosis. Significant pain adversely impacts function and affects all domains of quality of life. Tolerance to therapy is the most important determinant to the success of cancer therapy. Pain, which reduces the patients' performance status, reduces potential tolerance of cancer therapy and may cause patients to discontinue their cancer treatments. Recent studies have demonstrated that improved pain management results in improved survival. Based on this, clinical trials should account for pain levels in reporting survival outcomes.

The cause of cancer pain should be treated whenever possible. By doing so, rapid, lasting pain relief frequently is achieved. Also, the need for pain medications may be diminished, thus reducing side effects and drug interactions.

The principles of cancer-related pain management are straightforward. Effective management of cancer-related pain can be accomplished by local health care providers, including oncologists and family physicians. More complex cancer pain syndromes may require the coordination of multidisciplinary professionals, including pain medicine specialists, palliative care and hospice care providers.

Pathophysiology

Pathophysiologic classification of pain forms the basis for therapeutic choices. Cancer-related pain may be broadly divided into pain caused by ongoing tissue damage (nociceptive), or by nervous system dysfunction that is not associated with ongoing tissue damage (non-nociceptive or neuropathic). Often, cancer-related pain is the result of both nociceptive and neuropathic causes.

Damage to the nervous system may result in pain and loss of sensation and function. Such pain is typically described as burning or lancinating. Patients may report bizarre complaints, such as painful numbness, itching, or crawling sensations. The postamputation phenomenon of phantom pain (pain referred to the lost body part) may be disabling.

Psychological factors

Psychological factors, and comorbid psychiatric diagnoses such as depression, may be associated with, and even result from, chronic unrelieved pain. Depressed mood and anxiety often are a consequence of the physiological impact of pain including lack of sleep and declining function and nutrition. "Psychogenic pain" or somatoform pain disorder is extremely rare in cancer patients; psychogenic pain should be considered a diagnosis of exclusion. "Pseudo-addiction" is an iatrogenic physiological syndrome caused by the inadequate treatment of pain resulting in behaviors similar to that of opioid psychological dependence (addiction). Pseudo-addiction immediately resolves with adequate treatment of pain.

Pain syndromes

Cancer pain syndromes vary by tumor type and are related to patterns of tumor growth and metastasis. Pain may also be related to antineoplastic therapy. Many patients have pain caused by other comorbid nonmalignant conditions such as arthritis.

Elements of management

FIGURE 1

Algorithm for the integration of pharmacologic management approaches to cancer pain.

Elements of cancer pain management, first and foremost, include adequate management of symptoms to relieve suffering while undertaking a diagnostic evaluation that determines the etiology of the pain. Once the cause of the pain is determined, patient-specific interventions are selected to provide durable pain relief, and prevent potential cancer-related morbidity, like pathologic fracture and spinal cord compression. Interventions to relieve cancer pain should be chosen according to the (1) cause of the pain; (2) patient prognosis and performance status; (3) prior therapies; and most importantly, (4) the preferences of the patient.

Ongoing care is needed to monitor the efficacy of the pain management plan relative to the evolution of other symptoms during treatment, or to later disease progression. Recurrent pain or new sites of pain often are the first indications of cancer progression.

The steps in medical decision-making are to:

• determine whether primary antineoplastic therapy (systemic therapy, radiotherapy, and surgery) is indicated

• tailor pharmacologic analgesic therapy to individual needs (including analgesics, neural ablation and stimulation, neuraxial infusion),

• consider concurrent nonpharmacologic analgesic methods

• monitor response and modify treatment accordingly (Figure 1).

The patient is the focus of care, although family members and others often participate in treatment decisions and require emotional support.

Medical evaluation

TABLE 1

Features of the pain history—"PQRST"

FIGURE 2

Pain rating scale used to establish a baseline against which treatment results are judged; the numeric scale is also administered verbally.

Pain history

The medical evaluation should begin with a thorough history. There are no objective means with which to verify the presence of pain, so one must begin by eliciting the patient's complaint. Pain represents the most common presenting symptom in medicine, and may reflect an acute condition, for example, appendicitis or a chronic condition such as bone metastases. The physiologic signs of acute pain—elevated blood pressure and pulse rate—are unreliable in subacute or chronic pain. The chronic pain of cancer usually is progressive over several months. The patient diagnosed with cancer usually seeks medical attention when an acute exacerbation of pain occurs, or when chronic pain significantly impacts function or quality of life, such as interfering with sleep. Restriction in function and the impact of pain on fatigue, therefore, represent different physiologic signs of chronic pain.

Most cancer patients report more than one site of pain. A detailed history of each type and site of pain should be elicited (Table 1).

Pain rating scales

Validated and reliable pain scales allow evaluation of response to analgesic therapy (Figure 2). There are standardized tools that can be used for patients who are unable to communicate, such as preverbal children and impaired adults. In noncommunicative agitated patients, it is acceptable to treat pain presumptively.

Physical examination

The assessment should evaluate the putative mechanisms that may underlie the pain. This includes careful neurologic testing, especially if neuropathic pain is suspected. A neuropathic process is likely when pain occurs in an area of reduced sensation, allodynia (ie, when usually nonpainful stimuli are reported as painful), and hyperpathia, or summation of painful stimuli.

Review of disease extent and current conditions

The extent of disease and current medical conditions must be understood.

Diagnostic tests

Diagnostics should be reviewed and supplemented as necessary.

Treatment and drug history

Cancer treatment and prior analgesic interventions, along with their outcomes, should be known. Psychological dependency on any drug, including alcohol(Drug information on alcohol), must be identified.

Psychosocial assessment

To establish trust, the clinician should explore the significance of the pain complaint on function and quality of life with the patient. The impact of pain and other symptoms on functional status must be understood to establish treatment goals. Suffering may be attributable to many factors besides physical complaints. The clinician should ask about such psychological factors as financial worries, loss of independence, family problems, social isolation, and fear of death. Often, cancer patients meet diagnostic criteria for the psychiatric diagnosis of adjustment disorder with anxiety and/or depressed mood.

Subgrouping of patients

To help define therapeutic goals, the patient's age and prognosis may be considered. Pain in children is underreported and should be specifically elicited using age-appropriate assessment scales.

Pharmacologic treatment

In the past, the WHO devised a three-step analgesic ladder outlining the use of non-opioid analgesics, opioid analgesics, and adjuvant medications for progressively severe pain. According to this schema, a nonopioid analgesic, with or without an adjuvant agent, should be tried first (step 1). If pain persists or increases on this regimen, the patient should be switched to an opioid plus a nonopioid agent, with or without an adjuvant medication (step 2). If pain continues or intensifies despite this change in therapy, a more potent dose of opioid analgesic should be prescribed, with or without a nonopioid and/or an adjuvant agent (step 3). This WHO three-step analgesic ladder was especially useful in breaking barriers that impeded the control of cancer-related pain worldwide.

However, it is now accepted practice that the level of pain should determine what level of analgesic should be prescribed. It is now recognized that patients with severe cancer pain should not have to suffer through two known inadequate analgesic courses before receiving relief with an appropriate type and administered analgesic. While concerns exist about opioid side effects, it is also important to recognize the significant potential side effects of nonsteroidal anti-inflammatory agents (NSAIDs).

TABLE 2

Nonopioid analgesics and NSAIDs useful for treating cancer pain

TABLE 3

Guidelines for the use of opioid analgesics

TABLE 4

Opioid-agonist analgesics for mild-to-moderate pain

TABLE 5

Opioid agonist analgesics for severe pain

Nonopioid analgesics

Nonopioid analgesics are associated with ceiling effects, and exceeding the maximum dose ranges can result in organ toxicity. Potential side effects, such as hematologic, renal, and gastrointestinal reactions, may be of clinical concern in cancer patients (Table 2). Cyclooxygenase (COX)-2 inhibitors are many times more potent against COX-2 than COX-1. Clinicians are advised to watch the emerging literature regarding the safety of these agents.

Opioid analgesics

General guidelines for opioid therapy are outlined in Table 3.

Dosage Opioid agonists do not exhibit ceiling effects. Dosing is guided by efficacy. Most opioid side effects can be anticipated and controlled. The nonopioid component limits the dosages of tablets that combine an NSAID or acetaminophen and an opioid (Table 4).

Routes of administration The oral route should be used when possible, although some patients may express a preference for an alternative route. If so, or if the oral route is not feasible or side effects are uncontrollable, alternative routes (eg, transdermal, transmucosal, rectal, and spinal) are indicated. Such alternative routes of administration of certain opioid agonists (see Table 5) may improve patients' quality of life and may be particularly useful for treating certain types of cancer pain.

Side effects of opioids can usually be anticipated and prevented. In particular, with regular opioid dosing, laxatives should be prescribed for constipation.

Physical dependence and tolerance to some effects develop with chronic opioid use. Tolerance to respiratory depression, sedation, and nausea is likely. Tolerance to analgesia is not a major clinical problem and can usually be managed by changing the dose or substituting another analgesic agent.

Most current definitions of addiction imply a behavioral syndrome. An important distinction is that addiction does not require physical dependence or tolerance. Tracked over several decades, aberrant drug-taking rarely occurs in patients without a history of substance abuse. Consistent with current guidelines, compliance should always be monitored when opioid analgesics are prescribed.

Precautions during chronic therapy During chronic opioid therapy, certain precautions should be observed:

• Meperidine is contraindicated in the treatment of cancer pain as normeperidine, a toxic metabolite of meperidine, accumulates and can cause significant side effects like seizures.

• Propoxyphene is also contraindicated due to accumulation of norpropoxyphene. This drug has come off of the market in the United States.

• Placebo use is contraindicated as the patient's report of pain should be accepted as any other medical symptom.

• Physical withdrawal symptoms can be avoided by tapering doses.

• A change in mental status should not be attributed to opioid therapy until medical and neurologic factors have been fully evaluated. Especially important is to exclude potential disease progression including brain metastases.

• The mixed agonist-antagonist and partial opioid agonist drugs are not recommended for cancer pain.

• Methadone(Drug information on methadone) has unique pharmacokinetics. Inexperienced practitioners should consult a pain medicine expert before prescribing methadone. See clinical guidelines and FDA warnings.

TABLE 6

Adjuvant drug therapy for cancer pain

Adjuvant medications Neuropathic pain may be less responsive to standard analgesics alone. Adjuvants, such as antidepressants, anticonvulsants, benzodiazepines, local anesthetics, neuroleptics, psychostimulants, antihistamines, corticosteroids, levodopa(Drug information on levodopa), calcitonin, and bisphosphonates, improve the effectiveness of standard analgesics and are useful for particular indications (Table 6). These agents may be administered via oral and other routes. Administration of topical local anesthetics, NSAIDs and other preparations, and anesthetic and neurosurgical procedures (Table 7, Table 8) should also be considered.

TABLE 7

Anesthetic/neurosurgical approaches for controlling cancer pain

Bone Metastases: the paradigm for oncologic treatment of pain

Surgery for bone metastasis

Surgical intervention is warranted for bone metastases to stabilize a pathologic fracture or preempt an impending fracture. The objectives of surgery are to palliate pain, improve patient mobility and function, and control the disease in the bone to prevent further morbidity when nonsurgical therapies fail. In general, surgery involves excision of all gross tumor followed by stabilization of the bone before or after fracture by means of an internal fixation or prosthetic device.

TABLE 8

Neurolytic procedures that may be considered early in certain pain situations

Indications Clinical parameters, such as the patient's general medical condition, performance status, nature of the primary tumor, effectiveness of other therapies, extent of extraskeletal disease, and degree of osseous involvement, as well as the patient's life expectancy, must be considered before surgery. Surgical restoration of the anatomic integrity of the spinal cord due to bony compression [eg, vertebral collapse] is an absolute indication for surgery with rare exception based on prognosis.

Fracture and long bone pain In general, the presence of a pathologic fracture, an impending fracture, or a painful lesion in a long bone despite radiotherapy should be considered to be indications for surgery. A pathologic fracture can also result from structural insufficiency and can develop in the absence of a viable tumor following treatment with irradiation and/or systemic therapy. Current guidelines derived from retrospective clinical studies include lytic lesions > 2.5 cm in diameter, cortical destruction > 50%, and pain despite local irradiation. In the proximal femur, an avulsion fracture of the lesser trochanter places the hip at high risk for fracture.

Clinical criteria for surgery All surgical interventions should be performed with the intent to provide benefit that will outlast the patient's anticipated survival. All patients should be medically fit for anesthesia and the planned surgical procedure. The surgical goals should be achievable with reasonable certainty, and the potential benefits should outweigh the operative risks. The surgical goal of a stable, painless extremity allows optimal patient function and mobility.

Lesion site Major long bones (femur, tibia, and humerus), the vertebrae, and periacetabular regions demand specific attention. Osseous destruction sufficient to compromise the mechanical integrity of these bones should be addressed surgically. Lesions in the weight-bearing bones of the lower extremity (femur and tibia) are particularly vulnerable to fracture.

Lesions in the humerus should be treated surgically when the upper extremities serve a weight-bearing function (eg, assisted ambulation using a walker, crutches, or cane). Early surgical intervention, aggressive rehabilitation, and vigilant postoperative surveillance may optimize patient outcome.

The treatment of metastatic spine disease is mostly palliative. Surgical techniques are designed to correct pathology with the minimum of anatomical disruption. Minimally invasive techniques, such as kyphoplasty and vertebroplasty for vertebral body augmentation are very promising options for treatment in selected patients.

Radiation therapy

Cancer pain can often be relieved by radiation therapy delivered by localized external-beam irradiation, wide-field external-beam irradiation (eg, hemibody irradiation), or systemic treatment with radioactive isotopes (eg, strontium-89 chloride [Metastron], samarium-153 lexidronam [Quadramet], phosphorus-32, and iridium-131). Other examples of cancer pain due to primary or metastatic cancer that are amenable to irradiation include headache from central nervous system (CNS) involvement, pain due to localized neural involvement (eg, brachial plexus or sciatic nerve), visceral pain (eg, adrenal or pelvic masses), and pain due to obstruction (eg, urethral, esophageal).

Systemic radiotherapy

Like bone scans, systemic radiotherapy localizes in all of the bone metastases, while delivering minimal radiation to uninvolved normal bone; no radiation is delivered to adjacent soft tissues. Based on this, systemic radiotherapy is highly indicated in patients with diffuse metastases localized to bone without a soft tissue component. Systemic radiotherapy is contraindicated in bone metastases with soft tissue extension, as no treatment will be administered to the soft tissue component by the systemic radiotherapy. Given the localization of radiation to the bone, the only known toxicity is mild myelosuppression. The risk of myelosuppression depends on the extent of prior therapies, like chemotherapy, that have previously compromised the bone marrow elements.

Strontium-89 is a systemic radionuclide that has clinical efficacy in the palliation of pain from bone metastases, and its levels in bone are regulated much like calcium. The greatest published experience is with strontium-89 in prostate cancer.

Samarium-153 is a β-emitting radioisotope that is bound to a phosphonate that preferentially localizes in active bone, specifically in sites of metastatic disease. Samarium-153 is associated with a lower incidence and severity of hematologic toxicity than is strontium-89.

Systemic therapy

Systemic therapy is the most common cancer treatment for bone metastases. The type of systemic therapy depends on the tumor type, prior systemic therapies, hematologic status, and performance status.

Physical treatments

Cancer patients may benefit from formal rehabilitation, evaluation, and treatment. Physical modalities, such as massage, ultrasonography, hydrotherapy, transcutaneous electrical nerve stimulation, electroacupuncture, and trigger-point manipulation, are indicated for musculoskeletal pain. Also, any of these techniques may enhance exercise tolerance in a patient undergoing rehabilitation. Electrical stimulation may also be applied to the peripheral nerves, spinal cord, and deep brain structures to relieve pain.

Management of psychological, sociocultural, and spiritual factors

A multimodal approach to pain management recognizes the complexity of the human being, especially one with a terminal illness. Psychological, sociocultural, and spiritual factors significantly affect the patient's quality of life.

Empathic care helps relieve existential suffering integrated throughout the course of illness.

Psychiatric diagnoses

Psychiatric conditions, such as anxiety and depression, and psychological factors must be thoroughly addressed, as revealed by emerging evidence from the disciplines of psycho-oncology and psychoneuroimmunology. Techniques such as guided imagery, hypnosis, relaxation, and biofeedback also assist in pain management.

Sociocultural influences

These factors affect the patient's experience and expression of pain. Unrelieved pain, in addition to its negative physiologic effects, may represent the presence and progression of cancer resulting in fear, anger, frustration, disappointment, and other negative emotions. Fear is particularly important as unrelieved pain, especially early in the course of cancer, results in extreme fear of unrelenting and unbearable suffering as cancer progresses. By relieving pain, health care providers reassure patients that pain will be monitored and controlled throughout the course of cancer.

Existential distress

Achieving relief of psychic suffering allows the patient and family to realize improved quality of life and even find contentment or peace in the face of failing health and imminent death. Prayer, meditation, counseling, clergy visits, and support groups may all be beneficial. Palliative care of the family includes bereavement counseling in anticipation of and after the loss of a loved one.

Ongoing care

The goals of pain management must be frequently reviewed and integrated into the overall management plan. Communication among the professional staff, patient, and family is essential. A sensitive, frank discussion with the patient regarding his or her wishes should guide medical decision-making during all phases of the illness.