Issues in the Economic Analysis of Therapies for Cancer Pain

Economic analysis of cancer pain management is hampered by the lack of systematic outcomes research. There is some consensus on the broad structures that should be in place to provide optimal care, but the relative costs and benefits of the many analgesic interventions are not known. Clinical decision making in individual cases, like the consensus itself, is guided mainly by experience and anecdote. Meaningful economic analyses based on empirical information about cost and a range of subjective and objective outcomes are needed to minimize cost without compromising care. At present, potential problems in the reimbursement system that may be increasing the cost of pain management or compromising the quality of this care can be identified, and efforts are needed to address these problems.

Introduction

A burgeoning clinical experience has begun to define the nature of optimal therapies for cancer pain and the outcomes that may be anticipated when these therapies are competently administered. Although the existing data are inadequate for a detailed economic analysis of diverse analgesic approaches, current information is beginning to clarify the issues and concerns that must be addressed as such analyses are attempted.

A Paradigm for Economic Analyses

A paradigm for economic analyses of cancer pain management must include justification for the costs of optimal care, agreement about the elements that constitute this care, and recognition of the link between cancer pain and the broader clinical approach known as palliative care. This paradigm strongly supports a more specific framework for cost analysis that has been developed by the pain panel of the US Agency for Health Care Policy and Research (AHCPR) [1].

Justifying the Costs of Pain Management

Numerous surveys have established that chronic pain is experienced by 30% to 50% of cancer patients who are receiving active antineoplastic therapy and by 75% to 90% of those with advanced disease [2,3]. The extraordinary prevalence of this problem assures that a high aggregate cost will be incurred by the provision of optimal care to all patients. It is useful to explore the justification for these costs as a starting point for economic analyses of management strategies.

There are several compelling reasons to ensure access to qualified caregivers and a system of care that is capable of providing the best possible therapy for cancer pain. First, the costs of unrelieved pain are potentially very high. Pain is strongly associated with morbid effects on mood and other aspects of quality of life [4,5]. Severe pain produces a stress response, encourages immobility, reduces the likelihood of salutary behaviors (such as the maintenance of good nutrition), and complicates the medical evaluation and treatment of the neoplasm. Substantial costs may result from the management of pain-related complications, such as deep venous thrombosis caused by immobility, or from the need to repeat procedures or tests that could not be performed adequately due to pain.

Hospitalizations for pain control are common and extremely expensive. For example, an analysis of unscheduled admissions at the City of Hope Medical Center estimated an annual cost for uncontrolled cancer pain that exceeded $5 million [6]. A recent Canadian survey suggested that good palliative care could lower overall costs by reducing the frequency of hospitalization [7].

Second, the cost of optimal pain management compares very favorably with the costs of other cancer care. Cancer treatment in the United States is strongly oriented to expensive antineoplastic therapies, many of which have never been shown to have more than marginal effects on survival. There is increasing recognition of the need to assess these therapies in terms of a broader range of potential benefits and burdens, including cost [8]. Although comparisons remain speculative in the absence of meaningful economic data, it is likely that optimal pain management and other palliative care interventions are far less expensive than many primary antineoplastic approaches. It is difficult to justify the failure to improve symptom control on economic grounds, given these disparities.

Third, it is a moral imperative of medicine to provide comfort, if this is possible and consistent with the larger goals of care [9]. Indeed, comfort and function may be the most important treatment objectives in a disease, like cancer, that is often incurable.

Elements of Pain Management

There is good evidence that the expert administration of simple pharmacologic approaches can provide satisfactory pain relief to at least 70% of cancer patients [2,3,10]. These simple approaches, which were originally promulgated by the Cancer Unit of the World Health Organization (WHO) [3], have been endorsed by many national organizations [11-13] and were recently refined in a consensus document developed by the AHCPR [14]. Those patients who are unable to attain adequate analgesia through optimal pharmacotherapy have numerous other options, all of which are selected on the basis of clinical experience. Although the proportion of patients who could potentially benefit from the full array of pharmacologic and nonpharmacologic analgesic therapies is unknown, specialists in cancer pain generally believe it to be extremely high, probably more than 90%.

Although conventional practice settings do not routinely achieve success rates of 70% to 90% [15], the clinical approaches that potentially yield these outcomes can be explored to define the nature and costs of optimal cancer pain management. These approaches include a comprehensive assessment, pharmacotherapy, and alternative analgesic approaches for refractory pain (Table 1).

Assessment of Cancer Pain

The management of cancer pain relies strongly on a comprehensive assessment. The goals of this assessment include:

1. Detailed information about pain characteristics (such as onset and duration, course, intensity, location, and quality).

2. Elucidation of the etiology of the pain and its relationship to the cancer.

3. Identification of the pain syndrome and development of inferences about the pathophysiology of the pain.

4. Understanding of the impact of the pain and related symptoms on physical and psychosocial functioning.

5. Evaluation of the extent of disease and concurrent medical, psychological, and social disturbances.

In patients with active cancer, the pain assessment is likely to identify an underlying structural lesion directly related to the neoplasm. A survey of patients referred to a pain service in a major cancer hospital noted that previously unsuspected lesions were identified in 63% of patients who were comprehensively evaluated; this outcome altered the known extent of disease in virtually all patients, changed the prognosis for some, and provided an opportunity for a primary antineoplastic therapy in approximately 15% [16].

These data underscore the potential costs of a comprehensive pain assessment. Pain evaluation is time consuming, requires a physical examination, and commonly leads to imaging procedures that clarify the relationship between the neoplasm and the symptom. The costs of this assessment cannot be eliminated and, indeed, could potentially yield savings related to improved management of both symptoms and the underlying disease.

The need for meaningful cost analyses in this area is illustrated by the evaluation of back pain in patients with metastatic cancer. In a substantial, but ill-defined, proportion of patients, a careful clinical evaluation of this pain syndrome suggests the need for a relatively expensive procedure, magnetic resonance imaging. The purpose of this procedure is to diagnose or exclude one potential cause of back pain, epidural extension of the neoplasm, which can produce devastating neurological impairment if not treated early. Given the dire consequences of untreated epidural disease, clinicians must maintain a low threshold for imaging. Although the overall cost of this imaging is undoubtedly very high, it is likely balanced by the savings inherent in the early discovery of epidural disease in some patients. Indeed, it may be speculated that prevention of one case of paralysis may save the health care system an amount sufficient to justify, on a cost basis, many negative imaging procedures. Economic analyses of this type are lacking and are needed to assess the cost implications of cancer pain evaluation.

The Role of Primary Therapy

The first step in the management of cancer pain involves consideration of primary therapy directed against the etiology of the pain. Radiotherapy can both provide analgesia and reduce the risks associated with morbid structural pathology, such as impending fracture or epidural spinal disease [17]. Some patients are offered chemotherapy specifically for analgesic purposes, and the decision to pursue a surgical treatment is often influenced by the potential for analgesic consequences.

The costs associated with the requirement for expert oncologic care to optimize analgesic outcomes merge with those associated with treatments to prolong life. Economic models that clarify these considerations will be complex. In some situations, it may be possible to distinguish the use of radiotherapy for curative or life-prolonging intent from its use as a primary analgesic modality. In other cases, this distinction will have little meaning. Regardless, it is important to recognize that access to competent oncologic care, particularly radiotherapy, is an element of the costs that must be borne to optimize pain management [1].

Selecting and Implementing a Pharmacologic Approach

Pharmacotherapy is widely considered to be the most important analgesic approach for cancer pain [18]. It is a labor-intensive process that usually requires ongoing clinician involvement over a long period [19]. The costs associated with pharmacotherapy, therefore, are accrued over time and include both repeated assessments and adjustments in therapy as the need arises.

The optimal treatment of chronic cancer pain requires the administration of nonsteroidal anti-inflammatory drugs (NSAIDs), opioid analgesics, and adjuvant analgesics. Adjuvant analgesics are drugs that have primary indications other than pain but are analgesic in specific circumstances. According to the widely accepted WHO approach for the selection of analgesic drugs [3], long-term opioid therapy is appropriate for all patients with moderate or severe cancer-related pain. Access to opioids and the expertise to administer these drugs are absolute prerequisites to optimal cancer pain management.

Drug Selection-The pure agonist opioid drugs are preferred in the management of chronic cancer pain. In the United States, the drugs typically used for moderate pain (second step of the WHO "analgesic ladder") comprise codeine, hydrocodone, dihydrocodeine, oxycodone (Roxicodone), and propoxyphene. The drugs for severe cancer pain (third step of the "analgesic ladder") include morphine, hydromorphone (Dilaudid and others), oxymorphone (Numorphan), fentanyl (Duragesic), oxycodone (Roxicodone), levorphanol (Levo-Dromoran), and methadone (Dolophine and others). Most patients with chronic cancer pain ultimately receive one of the latter drugs, and many patients undergo trials of several in an effort to identify the one with the most favorable balance between analgesia and side effects [20]. At present, the selection of an opioid for chronic therapy is usually based on clinician preference and anecdotal experience.

Although differences in price among the various opioid drugs are appreciated (Table 2), the more subtle cost issues have not been explored [21]. There have been no comparative studies of the relative costs associated with equianalgesic doses administered over time, and no studies have assessed the potential for systematic differences in patient satisfaction that could justify these cost differences.

In some cases, specific patient characteristics suggest the value of a particular drug or formulation. These clinical observations suggest the need to evaluate the cost of optimal therapy in different subgroups of cancer patients. For example, patients with inadequate functioning of the gastrointestinal tract may have a strong indication for a trial of fentanyl because of the availability of a transdermal formulation (Duragesic). Similarly, patients who have problems with compliance might best be offered a controlled-release oral morphine formulation (MS Contin, Oramorph SR), which may be associated with an increased likelihood of adherence to the prescribed regimen [22]. The relative size of these subgroups and the varying costs and benefits of the treatment decisions they impel have not been investigated.

Routes of Administration-Opioid drugs are usually administered by the oral route, which is presumed to be the most economical. Many patients are unable to tolerate oral administration, however, and some are considered for alternative routes because of problems with compliance, the need to provide more rapid onset of analgesia, or other reasons. Many alternative routes are available (Table 3), and the cost implications of the decision to use one or another are potentially great [1].

The most common alternative routes of opioid administration are transdermal, subcutaneous or intravenous infusion, and intraspinal. Although clinical experience has helped to define the indications for each of these approaches [19], and some information about cost has begun to appear, the type of comparative cost-benefit data that could truly inform the decision to select one or another route do not currently exist. The transdermal route may be very useful if a patient cannot swallow or absorb an opioid, particularly if the intensity of the pain is relatively stable. Some clinicians also use this route because of perceived convenience or improved compliance. The incremental expense of the transdermal system over equally effective oral therapy has not been determined empirically and probably varies substantially with differences in local pharmacy charges [21]. The widespread use of the transdermal formulation for convenience or compliance should be justified by data that demonstrate improvement in these outcomes. Studies are needed to clarify these indications.

Some patients who cannot use the oral route are offered continuous subcutaneous or intravenous infusion using an ambulatory pump. The pumps commonly used in the United States are electronically sophisticated and typically include a patient-controlled analgesia (PCA) option, which is used to manage breakthrough pain. The costs associated with home intravenous and subcutaneous infusion, with or without PCA, include pump rental, supplies, pharmacy charges, and nursing charges. This cost, which has been estimated to be as much as $4,000 per month in the United States [1], could be reduced if less expensive pumps were used [23]. The least costly infusers lack the PCA option, but might be adequate for patients without breakthrough pain and those who could supplement an infusion with occasional oral doses. In patients without venous access ports, the use of the subcutaneous route may be more economical than the intravenous route due to savings in nursing costs.

The complexity and expense of home infusion therapy underscores the need for systematic cost analyses of this approach. In the absence of such studies, there is the potential for unjustified use of such a "high tech" intervention [24].

The intraspinal route is typically considered when systemic opioid therapy produces intolerable central nervous system toxicity (such as somnolence). Among those who are candidates for the intraspinal route, any of a variety of specific drug delivery systems may be used, including an implanted pump connected to a subarachnoid catheter, an implanted port connected to an epidural catheter, or a percutaneous epidural catheter. The cost implications of these different systems have received little attention in the medical literature. A small survey documented that the initial costs associated with the implantation of a pump connected to a subarachnoid catheter were high, but that the long-term costs were much less than with epidural systems that required more intensive nursing follow-up [25]. This analysis suggested that the decision to use the subarachnoid system could be justified on a cost basis in patients with life expectancies longer than several months.

At present, a large clinical experience suggests that alternative routes of opioid administration must be available to optimize care for the population with cancer pain, particularly those with advanced cancer [26]. Unfortunately, current information is insufficient to compare either the cumulative costs or the clinical outcomes associated with the many approaches available. In the absence of such a scientific foundation, therapeutic decisions are usually based on anecdotal data, patient and clinician preferences, and logistical factors. The potential for nonmedical influences on these decisions is worrisome [24] and should be assessed.

Dose-Once a drug and route of administration are selected, the optimal use of opioid analgesics is based on a series of well-accepted principles [3,12,14,18]. The most important of these is individualization of the dose. The proper dose must be identified when therapy is initiated and whenever pain changes during the course of the disease. To optimize therapy, the dose of the opioid must be increased until satisfactory analgesia is produced or intolerable and unmanageable side effects supervene. Doses can sometimes become extremely high as dose titration proceeds according to this guideline [26]. The requirement of some patients for high doses over long periods must be recognized as part of the aggregate costs associated with the management of cancer pain.

Side Effects-The management of side effects is essential throughout the course of therapy. Effective treatment of nausea, constipation, somnolence, and other symptoms allows exploration of a higher range of doses and increases the likelihood of a successful outcome. Routine pharmacologic approaches to the management of these side effects [27] are generally effective, but the costs incurred by these approaches have not been investigated.

Treating Refractory Patients

Some patients fail to achieve a favorable balance between analgesia and side effects despite careful titration of the opioid dose and routine treatment of side effects. As noted, the prevalence of this phenomenon is not well defined, but is certainly less than 30% of those who require treatment of pain and is probably no more than 10%. Although this proportion is gratifyingly small, pain is highly prevalent, and the number of patients who fail a simple pharmacologic approach is substantial. Many of these patients currently benefit from one or more of a diverse group of alternative analgesic techniques.

There have been no controlled clinical trials comparing alternative methods for the treatment of refractory cancer pain, and no cost comparisons have been undertaken. Clinical decisions are currently based on patient presentation and preference, clinician experience, and the availability of resources. Although it is evident that future cost analyses of cancer pain management should focus on these techniques, the difficulty inherent in doing so without benefit of prior systematic studies of outcome must be acknowledged.

The most common approaches for refractory cancer pain attempt to reduce the systemic opioid requirement by either pharmacologic or nonpharmacologic means. Pharmacologically, this may be accomplished by administration of an opioid in smaller concentrations closer to its receptors (usually via the intraspinal route) or by coadministration of a non-opioid analgesic, either an NSAID or one of the so-called adjuvant analgesics.

Adjuvant Analgesics-The adjuvant analgesics now comprise a very large number of drugs in many unrelated classes (Table 4) [28]. Like the use of alternative routes of opioid administration, the administration of these drugs is currently based on a few controlled studies and anecdotal experience. Some of these agents are very expensive, and there is a clear need for a systematic assessment of costs to help rationalize their use. Unfortunately, a lack of relevant outcome data often precludes meaningful analysis.

The use of adjuvant analgesics in the treatment of malignant bone pain illustrates the complexities involved. An ill-defined number of patients with multifocal bone pain are refractory to radiotherapy and opioid drugs. The pharmacologic options in this situation include NSAIDs, corticosteroids, calcitonin, a bisphosphonate drug such as pamidronate (Aredia), gallium nitrate (Ganite), and, in some cases, the radiopharmaceutical strontium-89 (Metastron). Although these treatments differ dramatically in cost, the type of detailed cost-benefit analyses that would be helpful in clinical decision making are entirely lacking.

This type of analysis should consider the overall quantity of drug required over time, the technical requirements for drug administration and monitoring during therapy, the relative degree and duration of analgesic benefit, the need for supplemental analgesic therapy in successful cases, the likelihood of serious treatment-related morbidity, and the management that such morbidity would entail if it occurred. A broader cost-utility analysis would also require information about patient satisfaction with the therapy and its larger impact on function and quality of life. Clearly, a meaningful cost analysis will require a foundation that can be acquired only through systematic outcomes research.

Nonpharmacologic Therapies-Some patients with opioid-refractory pain benefit from nonpharmacologic therapies. When successful, these interventions also reduce the opioid requirement. Although a small minority of patients require these approaches, the costs incurred by some of these treatments is high, and, for this reason, their importance in an economic analysis of cancer pain management is disproportionate.

Anesthesiologic approaches to refractory cancer pain include temporary nerve blocks, regional local anesthetic infusions, and more permanent neurolytic blocks [29]. Surgical neuroablation for pain control can be performed at virtually every level of the nervous system [30]; cordotomy is used most frequently. Invasive neurostimulatory approaches, usually dorsal column stimulation, are rarely performed for cancer pain but are an option in highly selected cases. Physiatric techniques that may have analgesic effects in refractory patients include a variety of physical medicine approaches and the occasional use of orthotics or prostheses. Some patients with refractory pain can obtain enhanced analgesia from psychological interventions.

There have been no comparative trials of any of these nonpharmacologic interventions for refractory cancer pain. In practice, the costs, risks, and benefits of an approach are weighed on a case by case basis. Anecdotal experience suggests that some highly expensive therapies can be economical if they effectively mobilize the patient, reduce the need for home nursing, or prevent hospitalization. There are no data relevant to the population overall, however.

Pain Management and Palliative Care

In considering the costs of optimal pain management in the cancer population, it is useful to conceptualize the impact of this symptom within the broader purview of palliative care. The concept of palliative care is gaining acceptance within the field of oncology, although its parameters are not yet well defined. The overriding goal of palliative care is improved quality of life. According to the WHO [3]: "Palliative care is the active total care of patients whose disease is not responsive to curative treatment. Control of pain, of other symptoms, and of psychological, social, and spiritual problems is paramount."

A comprehensive pain assessment frequently elucidates a range of issues that are best approached through a palliative care model. Optimal management usually integrates analgesic treatments with other interventions. The therapeutic strategy is determined by the overriding goals of care, which often change over time and may variably focus on survival, function, or comfort. Thus, the treatment of cancer pain occurs within a dynamic clinical situation, in which pain and other problems must be addressed in a system of continuing care that is consistently dedicated to the improvement of quality of life. The implications of this model for the costs of cancer pain management are epitomized by the patient with advanced cancer whose analgesic therapy is included among the services offered by a hospice program.

Other Issues for a Cost Analysis of Cancer Pain

The pain panel of the AHCPR has described other factors that influence the cost of cancer pain management [1]. These include differences in treatment settings, the need to justify services, reimbursement biases, and the potential for conflict of interest.

Treatment Settings

The costs associated with the provision of optimal analgesic therapies vary enormously with the site of care. A careful study of parenteral analgesic infusions, for example, demonstrated a substantial savings from the delivery of care in the home instead of the hospital [31]. The ability to reduce pain-related hospitalizations might be a valid, and easily measured, indicator of a cost-saving therapy.

The costs of outpatient pain management vary with the need for nursing and the use of technology. With the exception of surveys that have demonstrated savings associated with enrollment in hospice programs [1], there has been little systematic investigation of this variation or its clinical implications. Such studies are difficult because of the heterogeneity of the cancer population, which complicates efforts to compare cohorts that require similar levels of care. For example, the differences in cost that might be demonstrated between a home nursing approach to pain management and a clinic system could be related to selection bias, variation in severity of disease, or the need to combine pain treatments with other palliative care interventions. Economic analyses of pain management approaches in the outpatient setting are needed, but these will require meticulous attention to methodological issues, including assessment of potentially important covariates and careful evaluation of a full range of outcomes.

Need to Justify Services

The pain panel of the AHCPR has noted that expensive pain treatments are sometimes initiated because no other reimbursable means exists to provide a needed service for a patient [1]. For example, a clinician might order home-based parenteral infusion to obtain skilled nursing input, if no other medical indications are sufficient to justify this care. The aggregate costs of cancer pain management could presumably be reduced with reforms in the health care system that eliminated the need for these actions.

Reimbursement Biases

Some pressures exerted by the complex system of health care financing may actually increase costs [32]. For example, some payers, including the Medicare program, reimburse for parenteral but not oral analgesic therapy. Some programs encourage hospitalization by placing most of the cost burden for outpatient care on families while covering most of the treatments provided in the hospital.

In a similar manner, reimbursement contingencies may introduce biases that impede the delivery of optimal care [32]. Some private insurance policies have such severe limitations on coverage for outpatient costs, most notably the costs of prescription drugs, that even routine pain management approaches become difficult. The coverage for drugs and other services provided by health maintenance organizations vary; some require additional premiums or copayments for drug costs that could potentially reduce access to needed treatments. There is also evidence that restrictions in Medicaid coverage for drug costs can adversely affect the quality of care or the ability to maintain patients in the home setting [33,34]. Although the impact of these restrictions on the outcomes of indigent patients with cancer pain has not been specifically studied, the potential for these effects must be recognized, particularly at a time of further reductions in health care coverage for the poor.

The Medicare hospice benefit illustrates the complexity of these reimbursement issues and the potential for unforeseen influences on the quality of care. During the past decade, this federal health care program has encouraged a dramatic expansion of hospice in the United States. Costs appear to be decreased for the subset of patients with advanced cancer who are managed within this system [35], and it is generally accepted that the quality of care is adequate for most of these patients. Nonetheless, the reimbursement method also introduces the potential for negative outcomes. The eligibility requirements for the benefit encourage late referrals for specialized care. Hospice patients may have limited access to expensive pain management approaches, and those who require such treatments may not be accepted into programs. Direct contact with a hospice physician, who may be best qualified to offer recommendations for symptom control, is usually very limited. Studies are needed to evaluate these outcomes for those referred to hospice and those who are not.

One possible result of reimbursement limitations and biases in federal, state, and private health care coverage is cost shifting to families for outpatient care [1]. The need for cancer pain management and palliative care undoubtedly contributes to the extremely high costs that may devolve to families of patients with cancer [36]. This burden may take the form of direct out-of-pocket expenses or lost income from the need to care for the patient.
Research is needed to determine the impact of these costs on access to care, effectiveness of medical treatments, and the quality of life of the patient and family.

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