Pain Management and Beyond

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Journal of Pain and Symptom Management

Vol. 24 No. 1S July 2002

Proceedings from the Roundtable on “The Role of Coxibs in Successful Pain Management”

Pain Management and Beyond: Evolving Concepts and Treatments Involving Cyclooxygenase Inhibition Peter S. Staats, MD Department of Anesthesiology and Critical Care Medicine, Division of Pain Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Abstract Chronic uncontrolled pain may be the greatest health care crisis facing the United States. It is the major symptom for which patients seek medical care and is associated with substantial economic and psychosocial costs. For many patients, particularly the elderly and those suffering from cancer, chronic pain is often undertreated. Because pain has an emotional component and is frequently accompanied by depression and/or anxiety, patients benefit from a comprehensive assessment and multidisciplinary approach to treatment. It is likely that coxibs (cyclooxygenase or COX-2-selective inhibitors) will assume an increasingly prominent role in the treatment of chronic pain associated with arthritis, cancer, and other diseases either as monotherapy or in combination with other drugs. In addition, the role of COX-2 inhibition in the prevention and treatment of colon cancer, Alzheimer’s disease (AD), and other chronic health problems is an area currently undergoing intense investigation. J Pain Symptom Manage 2002;24:S4–S9. © U.S. Cancer Pain Relief Committee, 2002. Key Words Pain, cyclooxygenase (COX)-2, coxibs, cancer, rofecoxib, celecoxib, valdecoxib, parecoxib, etoricoxib

Introduction Pain is a major public health problem in the United States, not only because of its wide prevalence and substantial associated costs, but also because it has a negative impact on patients’ functional status and quality of life.1,2 The prevalence of chronic pain in adults is high, with estimates of up to 25% being made. Chronic pain is also the leading cause of disability claims in

Address reprint requests to: Peter S. Staats, MD, The Johns Hopkins University School of Medicine, Department of Anesthesiology and Critical Care Medicine, 550 N. Broadway, Suite 301, Baltimore, MD 21205, USA. Accepted for publication: March 3, 2002. © U.S. Cancer Pain Relief Committee, 2002 Published by Elsevier, New York, New York

the workplace.2 Among the elderly, the prevalence of pain may be as high as 80%.3 Because of the magnitude of this problem, the goal of pain medicine is twofold: to treat the cause of pain or the pain itself, and to shed light on the nature of pain and its mechanism of action.1 Recent pharmacologic advances in the treatment of pain and the use of a multidisciplinary approach can help to optimize pain management.

Defining and Assessing Pain To facilitate pain-related research and improve patient care, the International Association for the Study of Pain has defined pain as “an unpleasant sensory and emotional experi0885-3924/02/$–see front matter PII S0885-3924(02)00413-X

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Evolving Concepts and Treatments Involving COX-2 Inhibition

ence associated with either actual or potential tissue damage, or described in terms of such damage.”4 Diagnosing the source of tissue damage is an important part of pain assessment and requires an extensive evaluation of the patient’s medical, neurologic, and psychological status. The occurrence of psychogenic pain (i.e., pain with no organic cause) is actually very rare, but this label is sometimes misapplied after inadequate diagnoses.5 In order to conduct a comprehensive evaluation, we must differentiate the emotional from the biologic aspects of pain and recognize that the experience of pain depends on the interplay of these factors.6 Biologically, pain can be classified as somatic, visceral, or neuropathic (Table 1). Somatic pain involves activation of peripheral receptors and somatic sensory efferent nerves without damage to the peripheral nerves. Visceral pain, a type of somatic pain, results from activation of visceral nociceptive receptors and efferent nerves and is frequently described as a deep, aching, and cramping sensation. Because the innervation of visceral afferents is arborized with that of somatic afferents in the spinal cord, visceral pain is poorly localized. Neuropathic pain, on the other hand, results from direct injury to the central or peripheral nervous system and is frequently characterized by a burning sensation.1 Patients with chronic pain (defined as pain that has persisted for at least three months) can be classified into three major etiologic groups, although there is some overlap. The first group consists of patients whose chronic pain is associated with structural disease (e.g., metastatic cancer, sickle cell disease, or arthritis). These patients experience prolonged episodes of pain separated by pain-free intervals. The second group is composed of patients whose

pain is caused by psychophysiologic disorders. While structural disease (e.g., a herniated disc, torn ligament, or myofascial disease) may have once been present, psychological factors perpetuate pain long after the physical defect has healed. The third and most rare group of patients is those with psychogenic pain, which has neither a structural nor a physiologic basis.1 It is clear that psychological and emotional factors play an important part in exacerbating, as well as in relieving, pain. Psychiatric syndromes, such as anxiety and depression, frequently coexist in patients with pain and need to be identified and treated. Thus, simultaneous treatment of medical, functional, and psychological impairment is associated with successful management of chronic pain and reduced disability.3 Despite such management goals, most patients are not satisfied with their pain care.7 Furthermore, it has been demonstrated that pain is often undertreated, especially in the elderly3 and in cancer patients (Figure 1).8,9

Impact of Undertreated Pain Inadequately treated pain has adverse consequences in both the clinical and surgical settings. For example, undertreated postoperative pain can produce immune suppression and an increased rate of infection.10 Undertreated pain also has an impact on direct and indirect medical costs (e.g., through lost work days due to disability).2 In fact, the cost impact of chronic pain-associated problems may be greater than that of cancer and heart disease combined.2 Chronic pain can also lead to serious emotional and psychological sequelae, as it alters the patient’s personality, lifestyle, and functional ability.1,11 Thus, it is important to evalu-

Table 1 Biological Classifications of Pain Primary Pain Receptor Type/Damage Involved Somatic Visceral Neuropathic

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Peripheral and somatic sensory efferent nerves/no damage Visceral nociceptive and efferent nerves/no damage Direct injury to peripheral or central nerves

Subjective Description (Symptoms) Usually well localized Poorly localized, deep aching, cramping Burning sensation

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Fig. 1. Pain is undertreated: the physician’s perspective. Approximately half of the physicians in one survey believed that cancer pain management was adequate in their own practice.8 Attitudes and practice may have changed only slightly since this early survey.

ate physical and psychosocial function during pain assessments.3

Approaches to Pain Management A comprehensive assessment of a patient’s detailed medical history, involving thorough medical, neurological, and psychological evaluations, is the first step toward the development of a goal-oriented treatment plan.1 It is important to note that the inadequate assessment of pain frequently creates a barrier to good pain management.8

There are various targets for pain treatment, based on the pathophysiology of pain (Figure 2). Nerve blocks, for example, affect peripheral nociceptors, while prostaglandin synthesis inhibitors (e.g., nonselective, nonsteroidal anti-inflammatory drugs [NSAIDs] and cyclooxygenase-2 [COX-2]-selective inhibitors, or coxibs) function in the periphery as well as in the spinal cord. In the management of acute and chronic pain, individualization of drug treatment is crucial, and the type of pain and its intensity must be considered.1 Combinations of drugs having different mechanisms of action, such as

Fig. 2. Targets for pain treatment. Effective pain control alters pathophysiologic mechanisms involved in pain (e.g., nerve transmission, spinal cord stimulation, prostaglandin synthesis). NMDA  N-methyl-D-aspartate; TCAs  tricyclic antidepressants.

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an NSAID and an opioid analgesic, may result in beneficial additive or even synergistic effects.

Cancer Pain Management Undertreatment of pain is a particularly disturbing trend among cancer patients: an estimated 50% to 80% of those in nonhospice settings do not have adequate pain control.8 While cancer pain varies according to the primary and metastatic sites of disease and disease stage, it is prevalent in one third of patients treated for active metastatic disease and in 60% to 90% of those with advanced disease. Undertreatment of cancer pain clearly has an adverse effect on patients’ quality of life; conversely, there is evidence that effective pain treatment actually prolongs the life of cancer patients.12 Barriers to effective pain management in the oncologic population include poor pain assessment compounded by physician concerns about the side effects of various analgesics and/or potential tolerance to opioids. Patients may also be reluctant to report pain and to take analgesics because of an unfounded fear of addiction.8 Thus, treatment of cancer pain is complicated by psychological and social issues, which must be taken into account.1

Role of Coxibs Treatment of cancer pain with COX-2-selective inhibitors, or coxibs (e.g., rofecoxib and celecoxib) has aroused considerable interest not only because of their analgesic properties but also because these agents have a potential chemopreventive action. Numerous epidemiologic studies have shown a correlation between long-term NSAID use and a reduced risk of colon cancer.13 Furthermore, an early study with sulindac indicated that this NSAID reduced the size and number of polyps in young patients with familial adenomatous polyposis (FAP), a genetic disorder in which large numbers of polyps develop spontaneously and progress eventually to tumors.14 While the precise mechanism of action for the chemoprotective effect of NSAIDs is unknown, it now appears that COX activity is involved.15,16 COX exists as two isoenzymes: generally, COX-2 is the inducible isoform, and COX-1 is the constitutively expressed isoform. In human and rodent colorectal carcinomas and in car-

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cinogen-induced rat colonic tumors, the expression of COX-2 is increased.15,17 The observation that COX-2 may be necessary for efficient tumor growth has led to the speculation that NSAIDs may exert their antineoplastic effects through the inhibition of COX-2.17 More specifically, inhibition of COX-2 may promote apoptosis (cell death) and inhibit angiogenesis.18 Collectively, these, and other, findings suggest that coxibs, through their selective action on COX-2, may have utility in treating, and possibly preventing, colon cancer. In one animal study,19 celecoxib inhibited both the incidence and multiplicity of rat colonic tumors to a greater degree than has previously been reported for nonselective NSAIDs. Preliminary clinical findings appear promising, especially for FAP. Celecoxib is approved for the treatment of FAP. Well-controlled trials of coxibs are underway to evaluate their use in managing malignant pain. Clinicians involved in the care of cancer patients already appreciate being able to prescribe nonselective NSAIDs rather than opioids for pain. Among the potential benefits is that the adverse effect profiles of nonselective NSAIDs are more suited to the malignant pain population because cancer itself can exacerbate certain adverse effects of opioids.20,21 Coxibs either alone or in combination with opioids may be of even greater utility, providing the opioid-sparing benefits of NSAIDs while improving safety.

Emerging Areas of Coxib Use Investigators have also conducted several studies that have demonstrated a link between COX and Alzheimer’s disease (AD). These studies revealed that the relative risk of AD was significantly lower in patients with a history of prior NSAID use but not among those who had been using aspirin or acetaminophen.22,23 This suggests a potential role of inflammatory processes, possibly mediated by COX-2, in the etiology of AD. Some differential expression may exist in the brain between COX-1 and COX-2.24-28 Furthermore, studies have shown that COX-2 expression can be rapidly induced by nerve cell injury, tumor promoters, bacterial endotoxins, neurotoxins, cytokines, and anoxia, as well as

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by other, noninflammatory, triggers.25,27,29 However, lower than normal COX-2 levels in the brain of AD patients have been observed, possibly reflecting extensive neuronal loss. Therefore, COX-2 inhibitors may only have utility in AD before significant neuronal loss has occurred.22,23,30 It is expected that coxibs will assume a broader role in the treatment of a variety of diseases and that newer coxibs may be employed that are even more COX-2 selective. Three such new agents are valdecoxib, parecoxib, and etoricoxib. Valdecoxib (10 mg) was recently approved for osteoarthritis (OA), rheumatoid arthritis (RA), and pain associated with dysmenorrhea. It is a second-generation, oral COX-2 inhibitor and is approximately four times more selective for COX-2 than is celecoxib. The efficacy of valdecoxib in treating OA was demonstrated in a multicenter, double-blind, randomized, placebo-controlled trial involving 642 OA patients.31 The results of this trial indicated that valdecoxib dosages of 5 mg twice daily, 10 mg once daily, and 10 mg twice daily are as effective as treatment with naproxen 500 mg twice daily. In a sample of healthy elderly subjects (n  65), valdecoxib had no effect on platelet function, serum thromboxane levels, or bleeding times. Ibuprofen, on the other hand, significantly affected hemostasis in these subjects.32 Parecoxib is being developed as the only COX-2-selective inhibitor available in a parenteral formulation; it is the prodrug of valdecoxib, converted to its active form once in the body. In clinical trials, parecoxib had a longer duration of action and lower incidence of gastric or duodenal ulcers than did ketorolac.33 It is hoped that parenteral coxibs will replace ketorolac as the first choice nonnarcotic analgesic for severe postsurgical pain. These coxibs have applications in other acutely painful conditions (e.g., fractures) as well. Etoricoxib, the most potent second-generation coxib to date, is three times more selective than rofecoxib, 3.5 times more selective than valdecoxib, and 14 times more selective than celecoxib. Dosing for this agent is expected to range between 90 and 120 mg daily.34 In a clinical trial involving 617 patients with OA of the knee, etoricoxib was proven effective over 52 weeks.35 This agent has also been proven effective in RA (n  581) in dosages of 80 and

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120 mg daily over 8 weeks.36 Replicative Phase III studies are ongoing to further evaluate the efficacy and safety of this agent in OA and RA.

Discussion The undertreatment of chronic pain can have far-reaching consequences, raising healthcare costs and reducing patients’ quality and duration of life. Successful pain treatment reduces disability and increases productivity, alleviating the cost impact and profound suffering associated with chronic pain. Evidence-based guidelines for the evaluation and treatment of chronic pain, particularly in specific patient populations, such as sickle cell patients, will help to improve outcomes and care for patients in pain. Established and ongoing research suggest a broadening role for coxibs in pain management paradigms.

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