Definition of Pain and Anatomic Correlates
Management
Conclusions
References

The public fear that cancer is inevitably painful [1] is warranted: The majority of patients with advanced cancer and up to 60% of patients with any stage of disease will experience significant pain. The World Health Organization has estimated that 25% of all cancer patients die with unrelieved pain [2].

Leading oncologic organizations have stated that the relief of pain and other symptoms should be a priority in the care of these patients [3–6]. The benefits of adequate pain control include facilitation of the diagnostic workup and treatment, improved functional status, and better quality of life.

It has been demonstrated that most cancer patients' pain can be relieved adequately with oral analgesics [7,8]. Despite this, cancer pain is undertreated for a multitude of reasons. The problem is not trivial, because unrelieved pain is known to be a risk factor for suicide in cancer patients [9]. The Eastern Collaborative Oncology Group 1991 survey of oncologists revealed that physicians attribute undertreatment to their own lack of education and poor clinical role models [10]. Hill and others have outlined other influences, such as physicians' fear of regulatory agency scrutiny and fear of patient addiction [11,12]. Current efforts are directed at standardizing pain treatment [13] and separating issues of pain treatment from those of substance abuse. It is encouraging to note that a dialogue between addiction specialists and cancer pain specialists has begun to address these issues [14].

The effective management of cancer patients with pain is best accomplished in a multidisciplinary fashion with coordination of the services of oncologists, pain specialists, nurses, social workers, physiatrists, physical therapists, psychologists, psychiatrists, community health-care providers, clergy, and hospice workers [15]. Maintaining communication among members of the care-giving team is essential to providing optimal care.

Definition Of Pain and Anatomic Correlates

Pain has been defined as “a sensory and emotional experience associated with tissue damage or described in terms of such damage [16].” In humans, parallel neural pathways transmit information about painful stimuli from the periphery, through the spinal cord, to multiple areas of the brain. Pain signals (nociceptive inputs) are localized and interpreted and the affective component assigned at the cerebral cortical level. Modulation of nociceptive input by opioid and nonopioid mechanisms occurs in the periphery, at the dorsal horn of the spinal cord, in the brain stem, and possibly in higher centers.

Pathophysiology

The pathophysiologic classification of pain forms the basis for therapeutic choices. Pain states may be broadly divided into those associated with ongoing tissue damage (nociceptive) and those resulting from nervous system dysfunction in the absence of ongoing tissue damage (non-nociceptive or neuropathic). The pathophysiologic schema proposed by Portenoy is shown in Figure 1 [17].

FIGURE 1: Proposed taxonomy of chronic pain, based on presumed pathophysiology distinctions among nociceptive, neuopathic, and psychogenic pain. Adapted from Portenoy RK [17].

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

Care should be taken when considering the diagnosis of “psychogenic pain,” or somatoform pain disorder [18], because this type of pain is rare in cancer patients. More commonly, psychological factors affect the reporting of pain. It is also true that chronic unrelieved pain has psychological consequences, but this does not support a psychiatric basis for the pain complaint.

Pain Syndromes

Common cancer pain syndromes vary by tumor type and are related to patterns of tumor growth and metastasis. Pain may be directly related to antineoplastic therapy and may be indirectly related or unrelated to either the neoplasm or its treatment (Table 1)[2].

Management

Elements of cancer pain management include a proper medical evaluation, psychosocial assessment, formulation of the pain “diagnosis,” and consideration of pharmacologic and nonpharmacologic treatments. Ongoing care is needed to monitor the efficacy of analgesics and the evolution of different symptomatology during treatment or disease progression.

The steps in medical decision making are to: (1) determine whether primary antineoplastic therapy is indicated for palliation, (2) tailor pharmacologic analgesic therapy to individual needs, (3) consider concurrent nonpharmacologic analgesic methods, and (4) monitor the patient for response and modify treatment accordingly (Figure 2) [19]. The patient remains the focus of care, although family members and other concerned individuals often participate in treatment decisions and require emotional support.

FIGURE 2: Algorithm for the integration of management approaches to cancer pain. Adapted from Foley KM, Arbit E [19].

Patient Evaluation

The medical evaluation begins with a thorough history. Because there are no objective means with which to verify the presence of pain, one must believe a patient's complaint. The physiologic signs of acute pain—elevated blood pressure and pulse rate—are not reliable in verifying subacute or chronic pain. Most cancer patients report more than one site of pain [20]. A detailed history of each type of pain should be elicited (Table 2)[21]. As the chief complaint resolves, what was initially considered a secondary problem may require attention.

Pain-rating scales should be used to establish a baseline against which the success of treatment may be judged (Figure 3). Behavioral observations may be used to assess patients who are unable to communicate. Although there are standardized tools for preverbal children [22], they are not available for impaired adults. Therefore, it is sometimes necessary to treat pain presumptively.

FIGURE 3: Pain rating scales used to establish a baseline against which treatment results are judged.

The physical examination includes careful neurologic testing, especially if neuropathic pain is suspected. Pain in an area of reduced sensation, allodynia (ie, when normal stimuli are reported as painful), and hyperpathia or summation of painful stimuli support a neuropathic process.

The extent of disease and current medical conditions must be determined. Diagnostic tests should be reviewed and supplemented as necessary. Cancer treatment and prior analgesic interventions with their outcomes should be recorded. Psychological dependency on licit or illicit drugs, including alcohol(Drug information on alcohol), must be identified.

Psychosocial Assessment

To establish trust, the evaluating clinician should explore the significance of the pain complaint with the patient. The impact of pain and other symptoms on functional status must be understood to establish the goals of treatment. Suffering may be attributable to many factors other than 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 the diagnostic criteria for the psychiatric diagnosis of adjustment disorder, with anxiety and/or depressed mood [23].

Patient Subgroups

It is useful to recognize distinct subgroups of patients (Table 3)[24]. To help define the goals of therapy, age, prognosis, and history of drug or alcohol abuse may be considered. Adjustments in drug dosages are usually needed for elderly patients who are more sensitive to analgesics and their side effects. Children may require relatively larger doses of opioids [25]. The use of chronic opioid analgesics requires special consideration in patients who are in long-term remission. Patients with substance-abuse problems who are receiving opioids for pain demand careful attention.

Pharmacologic Treatment

The World Health Organization's three-step analgesic ladder outlines the use of nonopioid analgesics, opioid analgesics, and adjuvants for progressively severe pain (Figure 4).

FIGURE 4: Analgesic ladder outlining the use of nonopioid analgesics, opioid analgesics, and analgesic adjuvants for progressively severe pain. Adapted from World Health Organization: Cancer Pain Relief and Palliateve Care, Geneva, World Health Organization, 1990.

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, or gastrointestinal reactions, may be of clinical concern in cancer patients (Table 4)[26].

TABLE 4: Nonopioid Analgesics and Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Useful for Treating Cancer Pain

Generic name (Usual dosage range)	Maximum/Day	Adverse effects/Comments
Acetaminophen (325-975 mg q4-6h)	6,000 mg	Hepatic and renal impairment
Acetylsalicyclic acid (aspirin, ASA)(325-975 mg q4-6h)	6,000 mg	Dyspepsia and GI ulceration, antiplatelet effect, bleeding
Choline magnesium trisalicylate (500-1,500 mg q8-12h)	4,500 mg	Dyspepsia, reduced antiplatelet effect, hypermagnesemia in renal failure
Choline salicylate (435-870 mg q3-4h)	5,220 mg	Dyspepsia, reduced antiplatelet effect
Magnesium salicylate (300-600 mg q4h)	4,800 mg	Dyspepsia, reduced antiplatelet effect
Salsalate (1,000-1,500 mg q8-12h)	4,000 mg	Dyspepsia, reduced antiplatelet effect
Sodium salicylate (325-650 mg q3-4h)	5,200 mg
Ibuprofen (200-800 mg q4-6h)	3,200 mg	ªDermatitis +
Ketoprofen (25-75 mg q6-8h)	300 mg	ªHeadache +++
Ketorolac tromethamine (Oral: 10 mg q4-6h; parenteral: 60 mg, then 15-30 mg q6h)	Oral: 40 mg Parenteral: 120 mg	ªLimit duration of therapy, headache +++, GI bleeding ªLimit therapy to 5 days, headache +++, GI bleeding
Meclofenamate sodium (50-100 mg q4-6h)	400 mg	ªHeadache +, dermatitis +
Mefenamic acid (250 mg q6h)	1,000 mg	ªLimit therapy to 7 days
Naproxen sodium (220-550 mg q8-12h)	1,375 mg	ªHeadache +
Naproxen (250-500 mg q8-12h)	1,500 mg	ªHeadache +
ªMinor adverse reactions include dyspepsia, heartburn, nausea, vomiting, anorexia, diarrhea, constipation, flatulence, bloating, epigastric pain, abdominal pain, dizziness, and drowsiness. Major adverse reactions that may appear at any time include renal failure, hepatic dysfunction, bleeding, and gastric ulceration. + Each plus sign represents a 5% incidence of the reported adverse effect. Adapted with permission, from American Pain Society [26].

General guidelines for opioid therapy are outlined in Table 5 [27].

The rules of opioid use are to: (1) individualize the agent, route, dose, and schedule; (2) titrate to efficacy; (3) provide for breakthrough pain; (4) anticipate and treat side effects; and (5) make conversions from one route to another or one agent to another by using known equianalgesic doses. Opioid agonists do not exhibit ceiling effects. Dosing is guided by efficacy and limited by side effects (Table 6)[26]. Dosages of tablets combining a nonsteroidal anti-inflammatory drug (NSAID) and an opioid are limited according to the NSAID.

The oral route of administration should be used when possible. If this is not feasible or systemic side effects are uncontrollable, alternative routes are indicated (Table 7) [26]. Spinal routes [28,29], both epidural and intrathecal, can be employed with internal delivery systems that allow patients to be fully ambulatory. Although in wide use, these methods have not been tested for cost-effectiveness. The spinal route should be considered if oral and other routes are unavailable or systemic therapy produces unacceptable side effects. Another advantage of spinal administration is that local anesthetic agents may be combined with the opioid to enhance analgesia at a lower total opioid dose.

The side effects of opioids can usually be anticipated and treated. In particular, laxatives should be prescribed with regular opioid dosing. Physical dependence and tolerance to some effects develop with chronic opioid use. Tolerance is likely to develop to respiratory depression, sedation, and nausea [27]. Tolerance to analgesia is not a major clinical problem and can usually be managed by changing the dose of an agent or substituting another agent [24]. Most current definitions of addiction imply a behavioral syndrome of compulsive, harmful use but do not require the existence of physical dependence or tolerance [30]. Iatrogenic addiction is not likely to occur in patients without a substance-abuse history [31].

During chronic opioid therapy, certain precautions should be observed. Normeperidine is a toxic metabolite of meperidine that accumulates with repetitive dosing; thus, the use of meperidine for chronic pain is limited. Placebo use is discouraged, because it does not help to distinguish the pathophysiology of pain. Physical withdrawal symptoms can be avoided by tapering doses. A changed mental status should not be attributed to opioid therapy until medical and neurologic factors have been fully evaluated.

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 diphosphonates are useful for particular indications (Table 8)[32,33]. These agents may be administered through oral and other routes [34].

Nonpharmacologic Treatment

Many nonpharmacologic approaches are available for the treatment of cancer pain, but the indications for these forms of therapy have yet to be defined.

Stimulation and Ablation: The loss of normal sensory input, as occurs when a peripheral nerve is severed, may lead to deafferentation pain. Some patients obtain relief from electrical stimulation, which augments non-nociceptive input (Table 9)[19]. Neurostimulation may be applied transcutaneously or via implanted devices to peripheral nerves, the spinal cord, or the brain. Carefully selected patients may benefit from surgical implantation of stimulation devices [35,36].

Neuroablation, or destruction of nerve tissue, may be accomplished by chemical or surgical means. The goal of this technique is to isolate the site of somatic pain from the central nervous system. The efficacy of each procedure must be weighed against the risks. A significant percentage of patients who fail to respond to oral therapy may be helped with appropriate nerve blocks. It is not known which patients might benefit from earlier procedures [37,38]. Somatic nerve blocks may be diagnostic (ie, to determine the indication for permanent neurolysis of somatic nerves), facilitative, prophylactic, or therapeutic. Visceral blocks (such as the celiac plexus block) have been demonstrated to be effective for specific pain syndromes. Sympathetically maintained pain is suggested when signs of marked sympathetic dysfunction accompany typical diffuse burning or deep aching pain. Sympathetic blockade may then be diagnostic and therapeutic. In some cases of refractory generalized pain, pituitary adenolysis has been effective (Table 10)[19].

TABLE 10: Anesthetic Procedures

Type of procedure	Most common indications
Nerve block
Peripheral	Pain in discrete dermatomes in the chest and abdomen
Epidural	Unilateral lumbar or sacral pain; midline perineal pain; bilateral lumbosacral pain
Intrathecal	Midline, perineal pain; bilateral lumbosacral pain
Autonomic
Stellate ganglion	Sympathetic-maintained pain; arm pain
Lumbar sympathetic	Sympathetic-maintained pain; lumbosacral plexopathy; vascular insufficiency of the lower extremities
Celiac plexus	Midabdominal pain
Continuous epidural infusion of local anesthetics	Unilateral and bilateral lumbosacral pain; midline perineal pain
Chemical hyposphectomy	Diffuse bone pain
Inhalation therapy	Generalized pain; incident pain
Trigger-point injection	Focal muscle pain
Adapted from Foley KM and Arbit E [19].

Surgical ablation [39] may be accomplished by rhizotomy (section of nerve root) or dorsal root entry-zone lesions. Spinal anterolateral tractotomy or cordotomy, mesencephalotomy, medullary tractotomy, and cingulotomy should be reserved for carefully selected cases.

Physical Therapy: Physical therapy modalities, such as massage, ultrasonography, hydrotherapy, electroacupuncture, and trigger point injection, are indicated for musculoskeletal pain and may enhance exercise tolerance in a patient undergoing rehabilitation [40]. Skillful soft-tissue manipulation is probably underutilized.

Psychological Techniques: Cancer patients may regain a much needed sense of control by using psychological techniques, such as imagery, hypnosis, relaxation, biofeedback, and other cognitive-behavioral methods [41].

Ongoing Care

The goals of treatment must be frequently reviewed and integrated into the overall management plan [42,43]. Communication among the professional staff, patient, and family or other significant caregivers is essential. A sensitive, frank discussion with the patient regarding his or her wishes should guide medical decision-making during all phases of illness.

Conclusions

Control of cancer pain remains a challenge. A combination of pharmacologic and nonpharmacologic methods will relieve pain for the majority of cancer patients, yet a significant number of patients have pain that defies our best efforts to provide effective therapy. Current investigation into the pathophysiology of some forms of neuropathic pain holds promise for the development of new strategies. Advances in existing ambulatory-care technology may produce better systems for the long-term management of pain.