Cancer occurs in 1.2 million people in the United States each year and nearly one half of cancer patients die as a result of their cancer. Despite all advances in prevention, early detection, and newer treatments, including biologics and target-specific agents, cancer remains one of the most feared, debilitating, and lethal diseases. Cancer is the second leading cause of mortality in the United States.¹ Pain is experienced in more than 50% of these patients, and most of them have pain so severe that it interferes with their normal daily activities.^2,3 Less than half get adequate pain relief. The incidence of pain in advanced cancer is 80%, and 90% of patients with osseous metastases have pain.⁴

There is limited knowledge of the basic neurobiological mechanisms that generate cancer pain. However, empirical strategies for treating cancer pain have been validated and found to be highly successful for relieving pain.^5,6 Guidelines for managing cancer pain, although widely published, have not been universally applied, and as a result, there is considerable variation in the treatment of pain.⁷

Definition

Pain is an unpleasant sensory or emotional experience associated with actual or potential tissue damage or described in terms of such damage.⁸ Pain is a state of discomfort (sensory) and distress (affective). Pain corresponds poorly to the degree of tissue destruction, and pain intensity is not proportional to the type or extent of tissue damage. Classic pain categories are chronic and acute, nociceptive and neuropathic, and, within the nociceptive classification, somatic and visceral.²

The experience of pain is complex. Pain is modulated at several different central nervous system levels (Fig. 1): the dorsal horn of the spinal cord; the descending tracts through the bulbospinal pathways from the periaqueductal gray and rostral ventral medulla; and the cingulate cortex, within the amygdala, medial thalamus, and limbic cortex.⁹ Pain is also influenced by past experience and cognitive function.¹⁰ Psychological factors rarely initiate pain, but they greatly influence intensity.

There is a general tendency to separate malignant from nonmalignant pain and to view cancer pain within a biomedical model and noncancer pain within a biopsychosocial model. However, there is no difference anatomically or physiologically, by biochemical substrate, or through mechanisms of nociception that might be used to justify separating the two.¹¹ Pain for the cancer patient is a subjective experience, because nociceptive stimuli capable of eliciting pain are modified by genetics, past history, mood, expectation, and culture, just as they are for those with nonmalignant pain.

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Prevalence and pain interference

The prevalence of cancer pain directly correlates with the stage of disease. Patients with breast and prostate cancers, both of which have a propensity to spread to bone, more often experience pain than patients with uterine and cervical cancers.¹² Pain as an initial manifesting symptom occurs in 20% to 40% of patients. Severe pain (i.e., >5 on a numeric scale 0 being no pain and 10 severe pain) occurs in 20% to 35% of the cancer population and significantly impairs activities of daily living (ADLs). The impact of pain for a given severity varies, depending on the perceived cause of pain. Patients who believe that the pain is a result of their cancer have more pain interference with ADLs for the same degree of pain severity as patients who believe that their pain has a benign cause.¹³ Interference with enjoyment of life is greatest when pain is caused by cancer, intermediate when caused by unknown factors, and least when regarded as being caused by treatment.¹²

Despite the direct association of pain prevalence with stage, pain corresponds poorly to the observed tumor burden. For example, only a minority of radiographically apparent metastases to bone are painful. Interestingly, high-dose single-fraction radiation produces rapid analgesia, usually within days, at lower than tumorcidal doses and more rapidly than those projected for tumor response. This indicates that radiation therapy significantly alters the reactive “inflammatory soup around a metastasis” as a means of analgesia, independent of antitumor activity.

Most pain experienced by patients is a result of their underlying cancers: 20% are from treatment sequelae, and less than 10% are the result of comorbidities. This is not the case for the pediatric cancer population, in whom a greater percentage of pain is the result of treatment, and also for those who have undergone bone marrow transplantation, for whom significant stomatitis is a major cause. One third have one pain, one third have two separate pain syndromes, and one third have three or more distinct pains.¹³ The most common cause of cancer pain is bone metastases. One third of patients have neuropathic pain, either alone or combined with nociceptive pain. Common causes of pain are listed in Box 1. Pain generally changes little in severity in the last 4 to 6 weeks of life.

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Pathophysiology

Nociceptors are primary sensory neurons activated by stimuli from tissue damage. They are high-threshold receptors that remain silent until significantly stimulated.¹⁴ These nociceptors are polymodal; that is, are capable of responding to physical and chemical stimuli. Various mediators can depolarize these nociceptors (Box 2).

Afferents arise from small- and medium-diameter cell bodies within dorsal root ganglia and trigeminal ganglia and have either unmyelinated (C fibers) or thinly myelinated (Aδ fibers) axons. Interneurons within laminae I and II of the dorsal horn amplify or dampen neurotransmission. Afferent axons terminate on lamina I or II within the dorsal horn, and second-order neurons extend processes to the contralateral spinothalamic tract through the ventral lateral thalamus terminating in the cerebral cortex (see Fig. 1). Sensory fibers associated with affective responses also ascend in the contralateral dorsolateral spinal cord to the medial thalamus or brainstem and then to the cingulate cortex and limbic lobe. Spinothalamics extend axons into the medulla and hypothalamus. Downward modulation occurs through the periaqueductal gray (PAG) and rostral ventral medulla (RVM) with axons that transverse the dorsal lateral funiculus. These modulate pain directly by connections to secondary afferent neurons in the dorsal horn or via connections with interneurons in laminae I and II (see Fig. 1).

Somatic pain is experienced as a fast (Aδ fiber) localizing pain or a slow (C fiber) noxious sensation. Visceral pain is unique because there are no fast or slow components and it is poorly localized compared with somatic pain: ascending second-order neurons cross and ascend in the dorsal lamina fasciculus rather than by lateral spinothalamic.

Peicpheral sensitization results from nerve endings exposed to products of tissue damage and inflammation. Nociceptors also contribute to persistent pathologic pain, in the setting of nerve injury. Central sensitization results from neuroplasticity and lowers nociceptor thresholds. Central sensitization, when nerves are damaged and continuously fire, occur from central algesic receptors, such as N-methyl-d-aspartate (NMDA) receptors, and nerve sprouting from lamina IV into laminae I and II, which previously were occupied by secondary sensory neurons. The gate-control theory involves facilitating and inhibitory interneurons, modulated through multiple descending pathways. Whether the gate is opened or closed influences pain intensity according to inhibitory influences from the PAG and RVM on spinal cord interneurons.¹⁵ Central modulation of pain severity by the PAG and RVM is mediated by monoamine neurotransmitters (e.g., serotonin, norephinephrine) and endogenous opioids (e.g., enkephalin, dynorphin). Interneurons release gamma-amino butyric acid (GABA), analgesic amino acids (glycine), algesic amino acids (aspartate, glutamate), and prostaglandins to modulate pain (Fig. 2). Experimental studies have demonstrated that pain generated by bone cancer, inflammation, or neuropathy produces a unique set of sensations and neurochemical changes within the dorsal horn.¹⁶

Cognition and memory play a large role in the experience of pain.¹⁰ Fear and depression reduce pain thresholds and produce anatomic changes that accentuate pain. Long-term neuroanatomic changes have been discovered in amygdala and hippocampus, sites that affect pain memory. These changes involve calcium-calmodulin–dependent protein kinases.¹⁷

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Signs and symptoms

Pain intensity is pivotal to therapeutic decision making (see Fig. 2). The temporal pattern quality and location of pain suggest its pathophysiology and dictate analgesic dosing strategy.

Somatic pain is well localized, sharp, aching, throbbing, or pressure-like in quality. Visceral pain, on the other hand, is gnawing, crampy, diffuse, and not well localized. Colic occurs with the obstruction of a hollow viscus and with achy, sharp, or throbbing pain, from internal organ capsule invasion or mesenteric infilitration.^2,18

Neuropathic pain is often associated with allodynia, hyperpathia, or dysesthesia, in an area of neurologic deficit. Pain usually courses in the distribution of the motor, sensory, or autonomic nerve, except when pain is funicular. Funicular pain occurs with impending spinal cord compression. Neuropathic pain is associated with spontaneous, transient breakthrough pain, which is lancinating in quality. Pain might involve injury to a single nerve or to the cervical, brachial, celiac, lumbar, or sacral plexus. Pain may be generated from spinal cord damage and is experienced first as radicular pain, then as ascending levels of sensory loss.² Centrally mediated pain may be sympathetic, as in causalgia, or deafferentational, as seen with phantom limb pain.

Cancer pain may be acute and associated with generalized sympathetic hyperactivity, resulting in diaphoresis, hypertension, and tachycardia. Tolerance to sympathetic hyperactivity develops quickly as pain becomes chronic. Overt pain behaviors such as grimacing, moaning, and splinting, as well as sympathetic hyperactivity, are often not present with chronic pain.¹⁹ Acute pain occurring on a background of chronic pain is usually associated with complications related to the cancer or its treatment. Unrelieved chronic pain produces depression, anxiety, anorexia, asthenia, and insomnia. The combination of pain quality, location, and radiation is used to classify pain into recognized cancer pain syndromes.^2,20

Breakthrough pain is episodic pain that is usually a transient worsening of chronic stable background pain. Few patients have only intermittent pain; most patients have continuous pain, and most patients with chronic pain also have transient worsening of their pain. Incident pain may be voluntary or involuntary but is most often with activity, weight-bearing, cough, or bowel movement and is usually predictable and somatic in origin. Spontaneous lightning is characteristic of neuropathic pain. End-of-dose failure (i.e., pain that occurs before the next dose of analgesia) is caused by undertreatment of chronic pain.

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Diagnosis

Accurate assessment is the major step necessary for good pain management. Pain severity can be assessed by unidimensional pain scales, such as the visual analogue, numerical, or category scales.^2,20 Pain-relief scales have the advantage of gauging patient-reported benefits to treatment but do not correlate with unidimensional scales; they tend to be more therapeutically optimistic than unidimensional scales. Patients might have pain relief but still have severe pain that interferes with ADLs.^2,21 Comprehensive multidimensional scales are more burdensome for patients to complete, but they can evaluate the affective component of pain and pain interference with activities. Several general quality-of-life scales include pain-intensity or pain-relief scales. Examples are the QLQ-C30 of the European Organization for Research of Cancer and the Functional Assessment of Cancer Therapy (FACT) Scale.²²

Adequate assessment requires a thorough history and physical examination before radiographic studies or physiologic testing. Bypassing a good history and physical for radiographs may be misleading, because there is no simple one-to-one correspondence between the report of pain and the presence of underlying pathology.^2,20 The location, radiation, quality, and intensity of pain, along with the palliative and worsening factors associated with pain, often maps the pain source and provide clues to a possible cause. The date of onset, associated symptoms, and pain trajectory measures disease course and prognosis indirectly and crudely. Past trials of therapy, including over-the-counter medications and home remedies, should be recorded. Crescendo or altered pain patterns, in addition to the usual chronic pain, indicate cancer progression or recurrence until proven otherwise. For example, crescendo pain along the course of post-thoracotomy pain indicates recurrence of lung cancer.

Physical examination is centered to the area of pain but should not be misguided by radiating patterns of pains. For example, shoulder pain may be referred from hepatic metastases or splenomegaly. Anatomic examination is followed by maneuvers to elicit or ameliorate pain. Bone metastases are common, and spinal cord compression from epidural tumor extension is most feared by physicians. Hence, a neurologic examination, manual muscle testing, percussion tenderness and joint mobility, and inspection for muscle symmetry are important parts of the physical examination.

Radiographic studies are guided by the history and physical examination as well as the stage of disease, patient performance status, therapeutic options, and goals of care. Terminally ill patients, or those for whom little is gained by defining radiographic pathology, should be treated with palliative measures and not be subjected to painful, unnecessary testing. Plain radiographs of painful areas are still valuable sources of information. Before examination, pain should be treated so that patients are comfortable and able to complete their radiographic procedures. Magnetic resonance imaging (MRI) scanning of the spine and brain and computed tomography (CT) scanning of the chest and abdomen should be completed; these provide the greatest amount of information. Ultrasonographic examination for pericardial effusions and biliary and urinary tract obstructions is easily accomplished, portable, and without radiation exposure. Electrophysiologic studies can separate mononeuropathies or entrapment neuropathies from plexopathies and ulnar or peroneal entrapment syndromes from brachial and lumbar plexopathies, respectively. Conduction velocities, specific latencies, amplitudes, duration, and configurations of sensory and motor evoked potentials identify and locate neuropathology. However, electrophysiologic studies are normal, with significantly damaged nonmyelinated fibers.

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Treatment

Cancer pain can be relieved in 80% to 90% of patients using an opioid-based analgesic regimen²³ and the WHO analgesic ladder²⁴ as guidelines (see Fig. 2).^25-27 Opioids, preferably oral, are used with around-the-clock dosing, according to the analgesic ladder, with individualized treatment based on pain patterns and with attention to details.²⁷

Morphine should be the first opioid of choice. Alternatively, oxycodone, hydromorphone, or fentanyl may be used initially depending on patient tolerances and clinical context. Efficacy of these other opioids is not better than morphine, but it is not inferior. There may be fewer side effects with oxycodone and fentanyl. Low doses of morphine can be combined with a nonsteroidal anti-inflammatory drug (NSAID) as a substitute for a weak opioid in the second step of the analgesic ladder (see Fig. 2). Avoid codeine, which has excessive side effects, meperidine because of its neuroactive metabolites, and mixed agonist-antagonists because of a ceiling effect. Use oxycodone, fentanyl, and methadone as second-line opioids for patients intolerant to morphine. Drug interactions are least with morphine and more problematic with methadone.

Use around-the-clock normal-release morphine every 4 hours or sustained-release morphine every 12 hours for continuous pain. Reasonable initial doses of morphine in opioid-naive individuals are 5 mg of normal release every 4 hours or 15 mg of sustained release every 12 hours. Rescue doses of normal-release morphine should be provided for breakthrough or incident pain. Doses are based on pain severity; dosing patterns are according to the pain pattern and diurnal variations in pain severity. Alternate routes of administration, such as sublingual, rectal, subcutaneous, IV, or spinal, need to be identified, particularly in dying patients or those unable to take oral medications (Box 3). Analgesic response is quantified by degree and duration of response; dose adjustments are made based on both. Most patients require rescue opioid doses for breakthrough pain. A dose that is 10% to 20% of the total daily opioid dose is a reasonable starting rescue dose, which is repeated every 1 to 2 hours if necessary. Rescue doses need to be titrated to response if the underlying chronic pain is under control. Individualized dosing needs to take into account age, perhaps sex, and renal, liver, and cognitive function.

Alternative opioids may be chosen with organ failure. Methadone and fentanyl are relatively safe, with few dose adjustments necessary for renal failure, whereas morphine is one of the safest opioids for cirrhosis. Oxycodone pharmacokinetics are significantly altered by hepatic and renal failure. Identify dose-limiting side effects and those at risk for respiratory failure, and titrate doses slowly in this group of patients.

An opioid switch is necessary for opioid toxicity, particularly with neurotoxicity (e.g., myoclonus, hallucinations, and confusion) and poorly controlled pain. Adjuvant analgesics and simultaneous opioid reduction (opioid sparing) can accomplish the same (Table 1). Anticipate constipation, and use laxatives such as docusate and bisacodyl, senna, or osmotic laxatives proactively. It is important to be aware of pain syndromes that are relatively opioid-resistant which require the early use of adjuvants, such as antiseizure medications or tricyclic antidepressants, as in the case of neuropathic pain. Interventions such as surgery, radiation, or kyphoplasty may be required for optimal analgesia for some patients with bone metastases. Tables 2 and 3 delineate equianalgesic dosing, opioid rotation, and opioid conversion.²⁴

Opioid side effects are relatively common. There are several ways of managing the more common dose-limiting symptoms (Table 4). The most feared side effect is respiratory depression, which fortunately is uncommon.^24,25 Respiratory compromise, when accompanied by tachypnea or anxiety, is not primarily caused by opioids. Tolerance to respiratory depression occurs quickly. However, care must be taken in those who are frail or opioid-naïve, who have comorbid conditions that predispose to respiratory failure such as chronic obstructive lung disease, or who are given sedative medications. Respiratory depression from opioids is nearly always associated with sedation and miosis. Naloxone is given only if sedation is accompanied by bradypnea and only in doses that reverse respiratory depression and not analgesia, if possible. A 0.4-mg vial of naloxone is diluted in 10 mL of saline; a 1-mL aliquot is given every 1 minute and titrated to the level of consciousness. Patients on sustained-release opioids or methadone might require a continuous infusion of naloxone at the dose that reversed respiratory depression, because the half-life of naloxone is 30 minutes.

Some patients fail to achieve adequate analgesia despite dose escalation because of dose-limiting side effects. Options in these circumstances include the following^24,25,28:

• Opioid switch, because there is no cross-tolerance between various potent opioids
• Opioid conversion to parenteral or spinal routes
• Opioid sparing with the addition of an adjuvant analgesic
• Neuroblockade, neuroablation, or invasive neurostimulation
• Kyphoplasty, radiation, surgery

Adjuvant analgesics are chosen based on pathophysiology (Fig. 3). The term adjuvant analgesic describes a drug that has a primary indication other than pain but has analgesic properties with certain types of pain. Nonsteroidal anti-inflammatory drugs and acetaminophen are not adjuvants, whereas the antiseizure drug gabapentin is an adjuvant analgesic in the case of neuropathic pain. Additional non-pain–related benefits can influence the choice, because several symptoms may be treated by one medication (e.g., corticosteroids for bone pain, nausea, and headaches from cerebral metastases). A dramatic reduction of pain can occur with adjuvant analgesics, precipitating opioid toxicity, and therefore close observation is necessary when adjuvants are initiated. In general, adjuvant analgesics reduce pain and opioid consumption by 30%. Adjuvant analgesics may be started before opioids (e.g., tricyclic antidepressants, valproic acid, or gabapentin for neuropathic pain), depending on the clinical situation and severity of pain. Most adjuvants improve the therapeutic index of opioids but, unlike opioids, have a ceiling effect. Permanent end-organ damage can occur with certain adjuvant medications, unlike opioids. Adjuvants are less flexible and versatile than opioids. The serum level may be helpful in guiding titration, which is not the case with opioids.

Analgesics for somatic pain include NSAIDs. A preferred NSAID is naproxen, because of its twice-daily dosing schedule and low cost. Acetaminophen is an alternative for those with a history of gastrointestinal bleeding or renal dysfunction, but it should be limited to 4 g daily because of the risk of liver toxicity. Corticosteroids can improve multiple symptoms as well as produce a general sense of well-being, but have accumulative side effects that need to be minimized. Doses are reduced to the lowest effective once maximum response has been achieved. Cyclooxygenase-2 (COX-2) selective NSAIDs have a reduced risk of gastrointestinal toxicity and bleeding, but they might not have the analgesia of nonselective COX inhibitors.²⁹ Pamidronate and calcitonin reduce bone pain, as does a single-fraction radiation therapy.

Neuropathic pain might respond to opioids alone, but it often requires adjuvant analgesics. If pain is limited to a particular area (e.g., a mononeuropathy), a lidocaine 5% patch can be applied for 12 to 24 hours to the affected area without systemic absorption and systemic side effects. The secondary tricyclic antidepressants desipramine and nortriptyline are preferred over the tertiary tricyclics, amitriptyline and imipramine, because of reduced anticholinergic side effects. Of the antiseizure medications, gabapentin, pregabalin, and valproic acid has fewer drug interactions than classic antiseizure medications. Gabapentin has the fewest drug interactions and greatest evidence for benefit, but it is extremely sensitive to renal function and less versatile. Mexiletine is a third-line adjuvant. Electrocardiograms need to be reviewed before starting mexiletine, and some physicians evaluate the therapeutic response to parenteral lidocaine before considering mexiletine. Ketamine, in low doses parenterally or orally, blocks NMDA receptors and can reduce pain without psychotomimetic side effects. Oral doses of 25 mg every 6 hours are reasonable starting doses. Methadone, because of its NMDA receptor blockade, can act the same as ketamine and is also the least expensive of the opioids. Levorphanol has the same receptor-binding profile as methadone but fewer drug interactions.

Celiac plexus blocks are particularly effective for locally extensive pancreatic cancer. Kyphoplasty and vertebroplasty reduce pain associated with unstable vertebral compression fractures. Nonpharmacologic therapies, such as guided imagery, relaxation techniques, hypnosis, and biofeedback, complement pharmacotherapy. Treating depression and delirium with phenothiazines, antidepressants, or atypical antipsychotics, which lower pain thresholds, will reduce pain without the need for opioid titration and might allow opioid dose reduction.

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Outcomes

Relief of pain is generally measured by unidimensional or pain relief scales. Ancillary outcomes include improved activities, relief of insomnia, and improved appetite, even if pain severity is relatively stable. Patient satisfaction with treatment, in addition to pain relief, reflects the relationship of the patient and the physician. With pseudoaddiction, once pain is relieved, there is a resolution of overt pain behavior. It is generally more difficult to see an improvement in overall quality of life because this is influenced to a significant degree by the burden of multiple symptoms.

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Conclusion

Pain is one of the most feared symptoms associated with advanced cancer, but it also can be effectively managed in the great majority of patients. Pain assessment is rate-limiting to effective treatment. Numerous opioids are available, but morphine remains the drug of choice. Adjuvant analgesics improve pain control and prevent or ameliorate opioid toxicity by allowing opioid dose reduction. Finally, nonpharmacotherapeutic modalities, as well as treatment of depression and delirium, are important for the overall management of advanced cancer pain.

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Summary

• Classic pain categories are chronic and acute, nociceptive and neuropathic, and, within the nociceptive classification, somatic and visceral.
• The temporal pattern quality and location of pain suggest its pathophysiology. Somatic pain is well localized, sharp, aching, throbbing, or pressure-like. Visceral pain is gnawing, crampy, diffuse, and not well localized.
• Overt pain behavior, such as grimacing, moaning, and splinting, as well as sympathetic hyperactivity, are often not present with chronic pain and are derived from personality characteristics.
• The location, radiation quality, and intensity of pain, along with palliative and worsening factors associated with pain, often locate the pain source and provide clues to possible causes.
• Cancer pain can be relieved in 80% to 90% of patients using an opioid-based analgesic regimen and the WHO analgesic ladder as guidelines.

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Suggested Readings

• Cherny NL. Cancer pain: Principles of assessment and syndromes. In: Berger A, Portenoy R, Weissman D (eds): Principles and Practice of Supportive Oncology. Philadelphia: Lippincott-Raven, 1998, pp 3-42.
• Dahl JL. Effective pain management in terminal care. Clin Geriatr Med. 1996, 12: 279-300.
• Davis M, Walsh D. Cancer pain syndromes. Eur J Pall Care. 2000, 7: 206-209.
• DeConno F, Caraceni A, Gamba A, Marianai L, et al: Pain measurement in cancer patients: A comparison of six methods. Pain. 1994, 57: 161-166.
• Guay DR. Adjunctive agents in the management of chronic pain. Phamacotherapy. 2001, 21: 1070-1081.
• Jemal A, Siegel R, Ward E, et al: Cancer Statistics, 2008. CA Cancer J Clin. 2008, 58: 71-96.
• Portenoy RK, Lesage P. Management of cancer pain. Lancet. 1999, 353: 1695-1700.
• Turk DC, Monarch ES, Williams AD. Cancer patients in pain: Considerations for assessing the whole person. Hematol Oncol Clin North Am. 2002, 16: 511-525.
• Turk DC, Okifuji A. Assessment of patients’ reporting of pain: An integrated perspective. Lancet. 1999, 353: 1784-1788.
• Ventafridda V, Stjernsward J. Pain control and the World Health Organization analgesic ladder. JAMA. 1996, 275: 835-836.
• Walsh D. Pharmacological management of cancer pain. Semin Oncol. 2000, 27: 45-63.
• Pharo GH, Zhou L. Pharmacologic management of cancer pain. J Am Osteopath Assoc. 2005, 105: (11 Suppl 5): S21-S28.
• Zech DF, Grond S, Lynch J, et al: Validation of World Health Organization Guidelines for cancer pain relief: A 10-year prospective study. Pain. 1995, 63: (1): 65-76.