A Health Economic Model of Breakthrough Pain

Breakthrough pain (BTP) is an abrupt onset, transitory flare of pain occurring in the context of managed, chronic, baseline cancer pain.¹ BTP builds to a moderate or severe intensity, usually peaking within 3 to 5 minutes after onset; episodes last approximately 30 minutes. To distinguish it from inadequate background analgesia, BTP is usually defined as 4 or fewer episodes in a 24-hour period.²

BTP prevalence estimates among cancer patients vary from 24% to 95%, depending on the definition of BTP and the setting from which the study sample was drawn. A 63% prevalence of BTP has been observed in patients admitted to hospice with  onmalignant terminal disease.³ This paper focuses on cancer-related BTP—the most frequently studied BTP scenario with the widest portfolio of US Food and Drug Administration–approved or developing pharmacologic interventions.

Background
Pharmacologic and Nonpharmacologic Management of BTP. A solid body of literature establishes the importance of BTP, as well as detailing strategies for its management; however, despite this available information, undertreatment remains a common phenomenon. In a study of guideline-based pain management versus standard care, DuPen et al demonstrated that a substantial reason for undertreatment of cancer pain in general is underdosing of rescue medication for BTP.⁴ Strategies for managing cancer-related BTP include nonopioid medications (eg, nonsteroidal anti-inflammatory drugs, acetaminophen), short-acting opioids (eg, codeine, hydrocodone, morphine, oxycodone, hydromorphone, fentanyl), and nonpharmacologic strategies (eg, ice, heat, guided imagery). Oral short-acting opioid formulations are most effective for preemptive management of BTP in patients who suffer predictable moderate-to-severe episodes and who do not respond to nonopioid or nonpharmacologic strategies. Rapid-onset transmucosal lipophilic opioids are recommended for patients with unpredictable moderate-to-severe incident or idiopathic BTP.⁵ Other strategies, such as radiotherapy, neurosurgical procedures, acupuncture,^6,7 intrathecal and epidural infusions, neurolytic blocks, and yoga, can factor importantly into the management of cancer pain in general, and improvement in BTP is a corollary outcome in these clinical scenarios.

Impact of BTP
BTP exacts a significant toll on patients, their families, caregivers, and social networks; the healthcare system; and society at large. These consequences are physical, emotional, spiritual, social, and financial in nature. BTP in cancer patients is reported to be associated with decreased functional status, increased levels of anxiety and depression, greater dissatisfaction with opioid treatment, and poorer medical outcomes.^8,9 Studies to date, however, have not yet taken a comprehensive approach to delineating the impact of BTP on patients, providers and institutions, and society. Additional work is needed to describe and enumerate the full aspects of suffering caused by BTP; a critical first step will be the development of instruments that are sensitive and specific to quality-of-life (QOL) domains differentially affected by BTP.⁹

Purpose
The primary purposes of this paper are as follows: (1) to summarize the costs and benefits associated with BTP and its treatment, as described to date in the cancer population; (2) to present a framework that clinicians can use to guide their decision-making for patients with BTP; and (3) to provide a model for health economic analysis, on a population level, of alternate strategies for the management of BTP, and to delineate steps for accomplishing the analysis. We begin by drawing on the pharmacoeconomic approach, which entails systematic quantification of the costs, risks, and benefits of medical interventions.¹⁰

Pharmacoeconomic Analysis: The Foundation for a BTP Health Economic Model. Most pharmacoeconomic analyses employ 1 of 4 methods: costminimization analysis, cost-effectiveness analysis, cost-benefit analysis, and cost-utility analysis. All of these approaches measure costs in monetary units, but they differ in how they value outcomes¹⁰ (Table 1). Pharmacoeconomic analyses typically categorize costs into 3 basic types—direct, indirect, and intangible. Direct costs include fixed and variable medical costs (eg, hospital capital expenses, costs of medical treatment) and nonmedical costs (eg, transportation to the clinic). Indirect costs encompass the costs of morbidity and mortality because of the illness or health event, and include lost income and time spent in the waiting room. Intangible costs comprise the toll of psychosocial states resulting from the illness or health event, such as suffering, pain, or depression.¹¹



Once costs have been defined, pharmacoeconomic analyses proceed to assign values to cost items and outcomes, determine outcome probabilities, and compare costs with benefits. One such process, presented by Jolicoeur et al, delineates a method for conducting pharmacoeconomic analysis in 10 steps: (1) defining the problem, (2) determining the study’s perspective, (3) determining the alternatives and outcomes, (4) selecting the appropriate pharmacoeconomic method, (5) placing monetary values on the outcomes, (6) identifying study resources, (7) establishing the probabilities of the outcomes, (8) applying decision analysis, (9) discounting costs or performing a sensitivity or incremental cost analysis, and (10) presenting the results, along with any limitations of the study.¹⁰ Other structures may prove equally useful, the critical step in any such analysis being the balancing of costs against benefits. The utility of this step will depend fundamentally on the extent to which both sides of the equation thoroughly capture the impacts of the intervention.