The Pharmacoeconomics of Breakthrough Cancer Pain

Journal of Pain & Palliative Care Pharmacotherapy. 2013;27:167–175. Copyright © 2013 Informa Healthcare USA, Inc. ISSN: 1536-0288 print / 1536-0539 online DOI: 10.3109/15360288.2013.787137

PHARMACOECONOMICS AND OUTCOMES IN PAIN AND PALLIATIVE CARE

J Pain Palliat Care Pharmacother Downloaded from informahealthcare.com by University of Queensland on 08/09/13 For personal use only.

The Pharmacoeconomics of Breakthrough Cancer Pain Kuan-Ling Kuo, Surasak Saokaew, and David D. Stenehjem A B STRA CT Breakthrough cancer pain (BTP) has a significant impact on patients’ activities of daily living, family, and the society; however, the economic ramifications of BTP are largely unknown. This review aims to summarize the available pharmacoeconomics studies of BTP in the context of the availability of several formulations of rapid-onset opioids administered by various routes, which are significantly more expensive than oral opioids. A systematic literature search of PubMed and Tufts registry through August 2012 was conducted using key words including “breakthrough cancer pain” and “cost effectiveness.” After exclusion of irrelevant articles, a total of six articles were included. Studies reviewed include two economic survey studies, two quality improvement projects, and two decision-analytic models. These studies demonstrate BTP causes significant financial burden to patients and society through increased hospitalization and health care utilization. Only one study comparing placebo with intranasal fentanyl spray, oral transmucosal fentanyl citrate, and oral transmucosal fentanyl buccal tablet has demonstrated the cost-effectiveness of these rapid-onset opioids for the treatment of BTP. Overall, there is a lack of pharmacoeconomic studies for BTP management with rapid-onset opioids. Further study is warranted assessing the net benefit of rapid-onset opioids to oral opioids to assist decision-making by patients, clinicians, and payers. KEYWORDS breakthrough pain, cancer, outcomes, pharmacoeconomics, rapid-onset opioids

tion to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain.”1 The pain also typically occurs rapidly and with severe intensity and a relatively short duration.3 The incidence and prevalence of BTP ranges widely, since the definition and diagnosis of BTP has been recognized differently.4 BTP has been defined as a transient increase in pain to greater than moderate intensity, which occurs on a baseline pain of moderate intensity or less; or others state the term BTP should be used only when analgesics are controlling baseline pain.4–6 Still other authors argue that the definition of BTP is any acute transient pain that flares over baseline.4,7 A prospective survey was undertaken in hospice cancer patients and 89% of patients experienced BTP.8 A multicenter, prospective study of 1095 cancer patients experiencing chronic pain and requiring opioid medication reported 65% of patients experiencing BTP.9 And a study of cancer patients in the outpatient setting found only 23% of patients experiencing BTP.10 Advanced disease, poor performance

INTRODUCTION A universally accepted definition of breakthrough cancer pain (BTP) does not exist in clinical practice.1,2 Recently, the Association for Palliative Medicine of Great Britain and Ireland suggested the updated definition: “a transient exacerbation of pain that occurs either spontaneously, or in relaKuan-Ling Kuo, BSPharm, is a research assistant in the Pharmacotherapy Outcomes Research Center and a PhD student in the Department of Pharmacotherapy, University of Utah, Salt Lake City, Utah, USA. Surasak Saokaew, PharmD, is an instructor in the Department of Pharmaceutical Care, School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand; a researcher in the Center of Pharmaceutical Outcomes Research, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand; and a PhD student in clinical epidemiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. David D. Stenehjem, PharmD, is a clinical hematology/oncology pharmacist at the Huntsman Cancer Institute, Research Assistant Professor in the Department of Pharmacotherapy, and an investigator in the Pharmacotherapy Outcomes Research Center, University of Utah, Salt Lake City, Utah, USA. Address correspondence should be: David Stenehjem, PharmD, Pharmacotherapy Outcomes Research Center, L.S. Skaggs Pharmacy Institute, 30 South 2000 East, Room 4834, Salt Lake City, Utah, 84112 (E-mail: [email protected]).

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TABLE 1.

Oral Opioids and Rapid-Onset Opioids for Breakthrough Cancer Pain.31


Generic (brand) name Oral opioids Oxycodone (Roxicodone, Oxecta) Morphine (MSIR, Roxanol) Hydromorphone (Dilaudid) Rapid-onset opioids Fentanyl citrate (Actiq) Fentanyl citrate (Fentora) Fentanyl citrate (Onsolis) Fentanyl citrate (Abstral) Fentanyl citrate (Subsys) Fentanyl citrate (Lazanda)

Common name (abbreviation)

Starting dose

NA

5–10 mg

NA NA

Oral transmucosal fentanyl citrate (OTFC) Fentanyl buccal tablet (FBT) Fentanyl buccal soluble film (FBSF) Sublingual fentanyl (SLF) Fentanyl sublingual spray (FSS) Intranasal fentanyl spray (INFS); fentanyl-pectin nasal spray (FPNS)

Dosage form

Strengths available

AWP/starting dose

Oral

Tablet, capsule, solution

5, 10, 15, 20, 30 mg

$0.48/5 mg tablet

15–30 mg

Oral

Tablet, solution

15, 30 mg

$0.18/15 mg tablet

2–4 mg

Oral

Tablet, solution

2, 4, 8 mg

$0.49/2 mg tablet

200 μg

Oral mucosa

Lozenge

200, 400, 600, 800, 1200, 1600 μg

$54.48/200 μg

100 μg

Buccal mucosa Buccal mucosa

Buccal tablet

100, 200, 400, 600, 800 μg 200, 400, 600, 800, 1200 μg

$26.18/100 μg

100, 200, 300, 400, 600, 800 μg 100, 200, 400, 600, 800, 1200, 1600 μg 100, 400 μg/spray (5 mL, delivering 8 metered sprays)

$16.18/100 μg

200 μg 100 μg

Route

Buccal film

100 μg

Sublingual Sublingual tablet Sublingual Liquid spray

100 μg

Intranasal

Liquid spray

$25.73/200 μg

$23.3/100 μg/spray $42/100 μg/spray

Note. NA = not applicable; AWP = average wholesale price (2012).

status, and severe baseline pain may increase the risk for BTP.3,11 Besides the physical symptoms of pain, BTP is associated with psychological and functional impairment. A qualitative study conducted at a large United Kingdom cancer center found that BTP has a significant impact on activities of daily living, necessitating lifestyle changes from being bed-bound to the inability to work.12 BTP not only influences the patient, but also patients’ family and society. BTP is also associated with decreased functional status, increased anxiety and depression levels, greater dissatisfaction with opioid treatment, and worse medical outcomes than patients without BTP.11 Oral opioids and rapid-onset opioids are the two main treatment categories for outpatient management of BTP (Table 1). Oral opioids, including immediate-release formulations of oxycodone, morphine, and hydromorphone, are widely available, inexpensive, and which most clinicians are comfortable prescribing and dose adjusting. However, due to the slower onset time of these opioids, pain control early in a BTP episode may be suboptimal. Furthermore, the duration of action may extend past the typical length of a BTP episode, resulting in opioid-related adverse effects after the episode

subsides. Rapid-onset opioids were developed to overcome the pharmacokinetic limitations of the oral opioids and the currently available agents include oral transmucosal fentanyl citrate (OTFC); fentanyl buccal tablet (FBT); fentanyl buccal soluble film (FBSF); fentanyl sublingual spray (FSS) and tablet (SLF); and intranasal fentanyl spray (INFS). Current guidelines recommend treating BTP with additional doses of immediate-release oral opioids or with rapid-onset opioids.1,13 However, many consider oral opioids the gold standard for treating BTP.14 The rapid-onset opioids are expensive (Table 1), in comparison with the oral opioids, and require dose titration for maximal effect, which may limit practicality and effectiveness in unmonitored settings without appropriate education for both patients and clinicians. However, the rapid-onset opioids have demonstrated in controlled trials the ability to provide rapid pain relief for the management of BTP, raising a cost-effectiveness question comparing the oral opioids with the different formulations of rapid-onset opioids.15 The aim of this study is to assess the available pharmacoeconomics studies of BTP in light of the availability of several rapid-onset opioid formulations and to discuss the economics impact of cancerrelated pain. Journal of Pain & Palliative Care Pharmacotherapy

Journal of Pain & Palliative Care Pharmacotherapy


METHODS A systematic literature search of PubMed electronic database and Tufts registry16 through August 2012 was performed. The key words included “breakthrough cancer pain” and “cost effectiveness” or “economics” or “pharmacoeconomic,” and MeSH terms included “breakthrough pain” and “neoplasms”, or “economics” or “cost-benefit analysis” (search strategy example is: (“cost-benefit analysis” [MeSH Terms] OR (“cost-benefit” [All Fields] AND “analysis” [All Fields]) OR “cost-benefit analysis” [All Fields] OR (“cost” [All Fields] AND “effectiveness” [All Fields]) OR “cost effectiveness” [All Fields]) AND (breakthrough [All Fields] AND (“neoplasms” [MeSH Terms] OR “neoplasms” [All Fields] OR “cancer” [All Fields]) AND (“breakthrough pain” [MeSH Terms] OR “pain” [All Fields]))). A manual search of the references cited from the identified articles was also performed. There was no language or study design restrictions. A total of nine articles were identified via PubMed, but no articles were identi-

fied in the Tufts registry. After exclusion of irrelevant articles17–19 not pertaining to the treatment of breakthrough cancer pain, six potentially relevant articles (three articles from PubMed plus three additional articles identified through review of the citations) were retrieved for more detailed evaluation. Among the six included studies, two were quality improvement projects,20,21 two were survey studies,10,22 and two were decision-analytic models23,24 (Figure 1). Only one study focusing on the pharmacoeconomics of rapid-onset opioids was identified.16

ECONOMIC IMPACT OF CANCER-RELATED PAIN AND BTP Grant et al.20 was the first to report on the economic impact of unrelieved cancer pain. This study assessed the benefit of implementing a variety of general strategies to improve pain management and decrease unscheduled readmissions for uncontrolled cancer pain at a National Cancer Institute–designated

Search terms: • Keywords: ‘breakthrough cancer pain’ and ‘cost effectiveness’ or ‘economics’ or ‘pharmacoeconomic” • MeSH terms: ‘breakthrough pain’ and ‘neoplasms’, or ‘economics’ or ‘cost-benefit analysis’ Databases searched • PubMed (n=9) • Tufts registry (n=0)

9 full records were screened and assessed for eligibility

3 additional articles were identified through review of the citations

6 articles were included for review FIGURE 1. Study flowchart.

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6 articles were excluded • 3 irrelevant • 3 not pertaining to the treatment or economics of breakthrough cancer pain


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cancer center. The general strategies implemented included increased nursing education to encourage their active role in pain management, making pain management a focus in the institution, and creating a supportive care service. The study compared the hospital readmission rates for uncontrolled cancer pain prior to implementation of these broad strategies (1989–1990) with the readmission rate post-implementation (1992–1993). A total of 4066 admissions (not just readmissions) occurred during the post-implementation period compared with 5772 total admissions pre-implementation. Preimplementation there were 255 (4%) readmissions for uncontrolled pain, with an average length of hospitalization of 12 days. Using the average length of stay and $1666 per day as the average daily cost of hospitalization for pain management, the total cost for readmission for pain management during this time period was $5,097,960 for the 4066 admissions. On the contrary, during the post-implementation period the average length of stay for uncontrolled pain was 11.8 days and a reduction in readmissions (n = 121, 3%) was observed. The total cost for pain management was therefore reduced to $2,378,715 during the study period in the pre-implementation group, using the same cost per day. This study did not provide the method or source of cost estimations. The authors concluded that the general strategies implemented to improve pain management and the associated readmission rate resulted in a $2,719,245 reduction in hospitalization costs, which easily justified the pain management strategies and resources implemented during the time period. This study did not specifically assess BTP, but demonstrates the significant economic impact of unrelieved cancer pain and how general pain management strategies can improve patient care while reducing health care utilization and subsequently costs. In a similar study to Grant et al.,20 Fortner and colleagues21 implemented a multisite quality improvement project aimed at improving the pain management and lives of outpatient cancer patients reporting pain. The study also assessed the economic impact of the quality improvement project. The study recruited nonrandom independent cohorts cancer pain patients pre- and post-implementation of the quality improvement project. The quality improvement project focused on nursing education, pain assessment and management prompts, and documentation tools. They surveyed patients for self-reported measures of pain intensity, pain interferences, quality of life, satisfaction with pain treatment, attitudes toward pain, and pain-related medication costs. Both direct and indirect costs related to pain in the 3 months leading up the survey was assessed, as pre-

viously described.10 Patient characteristics pre- and post-implementation were similar in regards to demographics and cancer types. However, the authors did not control for or assess comorbidities or cancer staging differences in the patient populations. The results demonstrate that during the study period and across multiple institutions, recent pain severity and interference in daily life was reduced, and patients were less concerned with becoming addicted to pain medications. Patients post-implementation also had significantly lower mean direct medical costs ($5070/month/patient pre-implementation vs. $1442/month/patient post-implementation; P < .02), and as previously demonstrated, these differences were driven by reduced pain-related hospitalizations (14% of patients pre-implementation vs. 4% postimplementation; P < .04) and emergency department visits (22% of patients pre-implementation vs. 3% post-implementation; P < .01). No differences in indirect costs were observed with implementation of the quality improvement project. Similar to Grant et al.,20 this study demonstrates that general pain improvement strategies can improve patient satisfaction in pain control and daily activities while significantly reducing the pain-related costs associated with health care encounters, in particular hospitalizations. Fortner et al. in 200222 conducted a telephone survey study to investigate the relationship between BTP and direct medical costs. Participants were identified through a consumer survey from 1997–1998 in which responders denoted an immediate family member had cancer.22 The survey was stopped after 1000 adult patients actively being treated for cancer had completed the survey. Survey respondents were asked about the occurrence of BTP and pain-related medical visits (hospitalizations, office visits, and emergency department encounters). The frequency of medical encounters and the duration of hospitalization were used to generate cost estimates based on literature-defined cost per encounter or cost per day of hospitalization.26–28 The estimated yearly cost data were normalized by the Blom’s method,29 since it was positively skewed due to most patients reporting no costs in each categories. Comparisons were made between patients reporting BTP and those without. Overall, 53% of respondents experienced cancerrelated pain, with 25% receiving around-the-clock pain medication and of patients receiving aroundthe-clock pain medication, 64% (n = 160) reported BTP and 36% (n = 89) did not. The mean age of patients reporting BTP patients was 2 years younger than patients not reporting BTP. Patients with BTP reported more frequent hospitalizations with longer lengths of stay (P < .02) and an increased number of emergency department (P < .08) and office (P < .01) Journal of Pain & Palliative Care Pharmacotherapy



visits compared with those without BTP. Resultantly, the total costs for patients with BTP were more than non-BTP patients and the estimated total annual cost per patient per year was $12,000 for BTP patients compared with $2400 for non-BTP patients, which is statistical significant either in pain-related hospitalizations (P < .04) and for physician office visits (P < .01) after controlling for their scheduled analgesics. The greatest expense for both BTP and non-BTP patients was hospitalization (90% and 88%, respectively), followed by physician office visits and emergency department visits. This study was limited by its nonrandomized design, which may have resulted in selection bias. Other limitations include recall bias that may affect the true number of pain-related medical visits recalled, and lastly the cost estimates used for health care encounters were based on average costs reported in the literature of general medical encounters, whereas pain-related encounters may cost more than non–pain-related encounters.22 A subsequent study by Fortner et al. (2003) was designed to describe not only the direct cancerrelated pain costs but also the indirect costs and the potential predictors of these costs.10 The study surveyed 144 patients from four private oncology practices in California, Colorado, Tennessee, and Washington. Patients were included who were older than 18 years, had pain from cancer or its treatment, and were able to complete questionnaires. Interviewers were trained pain management nurses. A Brief Pain Inventory survey30 was utilized to measure pain severity and patients were asked to describe pain-related costs in the 3 months leading up to the survey. The cost estimation is the same as Fortner et al. (2002) based on the literature,26–28 and the cost of analgesic medications were measured by the average wholesale price in 1999 Drug Topics Red Book. Direct costs were defined by patient-reported pain-related hospitalizations, emergency department visits, and physician office visits over a 3-month period. Prescription or nonprescription pain medications were also included as direct costs. Indirect costs included transportation-related expenses, childcare expenses, household assistance, complementary medicine expenses, over-the-counter medications, educational materials, and psychotherapy counseling. The mean age of this cohort was 54 years. The cohort was predominately Caucasian (85%), female (75%), and had breast cancer (40%). BTP occurred in 23% of patients. Overall, direct medical expenses accounted for 93% of the total costs. The greatest mean cost was associated with hospitalizations ($631.48 per patient per month), followed by medical visits ($89.58 per patient per month) and by analgesic medications ($81.76 per patient per month). Despite the cost of C


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hospitalization, only a minority (7.9%) of patients reported being hospitalized. The greatest indirect cost associated with cancer-related pain was extra household assistance ($24.70 per patient per month). Overall, the mean direct and indirect pain-related cost as reported by these cancer patients was approximately $900 per month or $10,000 per year projected per patient, assuming costs would be incurred proportionally over the year. This study also assessed predictors of direct pain-related costs and found that breakthrough pain (P < .01), higher pain intensity (P < .01), lower household income (P < .01), and younger patients (P < .05) incurred significantly higher costs; for predictors of indirect pain-related costs: breakthrough pain (P = .04) and higher pain intensity (P < .01) incurred significantly higher costs. The limitations of this study include not incorporating lost productivity in the indirect costs, including only outpatient cancer patients, and not quantifying the cost of BTP.10 Abernethy et al.24 performed a cost-effectiveness analysis using a decision-analytic model comparing three different literature-defined strategies for cancer pain management. The first part of the model was constructed to estimate the prevalence of cancer and cancer-related pain in the general population based on the National Cancer Institute published US cancer counts and the prevalence of cancer-related pain was imputed from literature review. The second part of the model assessed the efficacy and cost of cancer pain management by guideline-based care (GBC), oncology-based care (OBC), or usual care (UC) in a baseline population of 100,000 individuals demographically similar to the US population. Guidelinebased care assumed patients were treated in according to the Agency for Healthcare Research and Quality clinical practice guidelines published in 1994.31 Oncology-based care was similar to guideline-based care except long- and short-acting opioids, and nonopioid analgesics were prescribed less frequently and overall this strategy was considered 25% less effective than GBC in treatment of cancer-related pain. Usual care was based on care provided by nonpain or nononcology specialists, which was described as suboptimal and was considered 25% less effective than OBC. The efficacy of the different cancer pain management strategies was determined by literature review. Intervention costs were derived from direct medical costs, including pharmaceutical costs (medications for pain and treatment of adverse events) and nonpharmaceutical costs (anesthesiology or surgical procedures, etc). Direct medical encounters and direct nonmedical, indirect, and intangible costs were not included in the model. Results were modeled over 1 month using a payer perspective. Of the 100,000


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individuals modeled, approximately 0.51% (n = 508) were determined to have cancer and 0.20% (n = 205) suffered from cancer pain. Effective pain management was achieved in 80%, 55%, and 30% of cancer pain patients in the GBC, OBC, and UC groups, respectively. The cost of each strategy per month per cancer pain patient was $579, $466, and $315, respectively. The incremental cost-effectiveness ratio per additional patient relieved of cancer pain was of $452 when comparing GBC with OBC, $601 when comparing OBC with UC, and $527 when comparing GBC with UC. The authors concluded that guideline-based cancer pain management is a costeffective strategy leading to more patients relieved of pain with a modest increase in cost. Limitations of the study include the inclusion of only direct costs associated with pain interventions, since as described by Grant et al.20 and Fortner et al.10,22 costs of untreated pain (hospitalization, lost wages, etc.) are a significant driver in the economics of cancer-related pain. Second, the probabilities used in the model may be considered out of date and as such did not include the rapid-onset opioids, many input parameters were assumed, and the model did not specifically address BTP. However, a recent prospective, observational study of over 3000 outpatient medical oncology patients demonstrated that 33% of patients reporting pain were receiving inadequate analgesic prescribing, which closely approximates the 45% of patients in the model not achieving adequate pain relief by oncology base care in the model.32 Overall, this model demonstrates cancer-related pain is undertreated and the cost to improve care is relatively minimal; however, the utilization and cost of the rapid-onset opioids may alter the model results. BTP and untreated cancer pain results in a significant financial burden to the heath care system resulting from increased hospitalizations, emergency department visits, and physician office visits. These studies utilized either patient-reported direct and indirect costs or hospital records to determine the number of health care encounters and all studies used a fixed price for each encounter to calculate the direct cancer-related costs. In all studies, differentiating the cost of BTP from other cancer care or comorbidities was not performed and even today represents a difficult methodological problem. However, future studies would benefit from using actual health care claims data to more accurately represent the direct costs related to BTP, instead of using literature-defined costs per encounter. Estimation of the patient’s responsibility for direct charges would also provide a unique perspective to pain-related costs at the patient level, which could be used in shared decision-making between the patient and clinician when treating BTP.

Studies comparing the cost of pain-related pharmacotherapy are also warranted, since as demonstrated with general strategies to improve pain management, increased expenditure of around-the-clock and BTP medications may be offset by a reduction in expensive hospitalizations, procedures, and emergency department visits and could further justify use of the more expensive rapid-onset opioids.

PHARMACOECONOMICS OF BTP PHARMACOTHERAPY Abernethy et al. (2008) described a health economic framework to assess BTP management on an individual and the population level.33 The proposed health economic framework overlays three perspectives: patient, provider, and society; three cost domains: direct, indirect, and intangible; and three end points: costs, outcomes, and benefits.33 Benefits attributable to effective BTP management included cost savings, symptom improvement, positive qualitative outcomes, and any improvement in intangible factors. The authors concluded that application of this framework would assist clinicians in decisionmaking for patients with BTP and to provide a framework for health economic analysis for BTP management at the population level to assist institutional and payer decision-making to maximize benefits while reducing costs and the negative effects of BTP. Only one pharmacoeconomic study was identified from our literature review. This study is a Swedish, payer perspective decision-analytic model developed to estimate the cost-effectiveness of the rapid-onset opioids for the treatment of BTP, including INFS, OTFC, and FBT.23 Efficacy data were derived from a mixed treatment comparison meta-analysis of six randomized controlled trials (Table 2).34–39 Costs of general practitioner visits, specialized home care, and hospital stays were based on the study by Fortner et al. (2002).22 Swedish pharmacy selling prices in 2008 were used for drug acquisition costs. The utilities were generated by time trade-off methods, and the time horizon in the model was 1 year. It was assumed patients with BTP would not have additional productivity loss or other nonmedical opportunity costs, and the indirect medical costs were more likely to be attributable to cancer rather than BTP. The results demonstrate that overall costs associated with the treatment of BTP with INFS, OTFC, or FBT were mostly attributable the acquisition of drug (90%). In comparison, the majority (81%) of total costs in the placebo arm was attributable to hospital stays. In the base case analysis, INFS dominates OTFC. INFS compared with OTFC avoided an Journal of Pain & Palliative Care Pharmacotherapy

Journal of Pain & Palliative Care Pharmacotherapy TABLE 2.

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Clinical Trials Included in Vissers et al. Study.17


Responder rate Authors

Year

Patients

Mercadante et al.26

2009

86

Drugs compared OTFC vs. INFS

Type of study Open label, randomized, crossover

10 min

15 min

30 min

50% (INF)

70% (INF)

90% (INF)

20% (OTFC) NA

40% (OTFC) 13% (FBT)

80% (OTFC) 48% (FBT)

Portenoy et al.23

2006

80

FBT vs. placebo

Slatkin et al.24

2007

87

FBT vs. placebo

Kress et al.25

2009

111

INFS vs. placebo

Coluzzi et al.28

2001

93

Farrar et al.27

1998

89

OTFC vs. oral morphine OTFC vs. placebo Double-blind, randomized, multiple crossover

Double-blind, randomized, placebo-controlled Double-blind, 16% (FBT) 30% (FBT) randomized, placebo-controlled 58% (INFS) NA Randomized, placebo-controlled, crossover Double-blind, randomized, multiple crossover

51% (FBT)

80% (INFS)

Note. OTFC = oral transmucosal fentanyl citrate; INFS = intranasal fentanyl spray; FBT = fentanyl buccal tablet; NA = not available.

additional 25% of BTP, saved €174, and gained 0.046 quality adjusted life years (QALYs). INFS compared with FBT avoided an additional 24% of BTP, and gained 0.043 QALYs. The authors concluded that based on the probabilistic sensitivity analysis, there is a 99% probability that INFS is the most cost-effective intervention. The limitations of this study include the 1-year time horizon, which may inadequately assess the utility measures that were assessed over a 10-year period. The data for resource use of BTP were based on the telephone survey by Fortner et al. (2002), which as discussed earlier may contain selection, information, and recall bias and did not specifically address the rapid-onset opioids.22 The Swedish perspective of the model would also need to be adapted to be applicable to the US payer perspective. Inclusion of the other rapid-onset opioids such as FBSF, SLF, and FSS would also add additional insight in the comparative effectiveness of the entire class of rapid-onset opioids. This model also compared INFS, OTFC, and FBT with placebo, which in clinical practice many consider immediaterelease morphine as the gold standard of treatment and therefore including morphine in the model may impact the results.14 Including an oral opioid as the base case in a decision-analytic model would necessitate including only trials studying a rapidonset opioid against an oral opioid. Furthermore, few studies (Coluzzi et al. [2001] and Fallon et al. [2011]) have been conducted comparing a rapidonset opioid with morphine and these studies have shown a slight statistical advantage of the rapid-onset opioids (OTFC and FPNS) in pain relief relative to immediate-release morphine, with debatable clinical C


benefit and at the expense of an increased incidence of treatment-related side effects.39,40 Lastly, safety was not included in this model, since it was primarily assumed that no differences in adverse events would be observed because the active ingredient was the same (fentanyl); however, to fully measure the net benefit of a rapid-onset opioid, inclusion of safety would be preferable.

CONCLUSION Overall, there is lack of pharmacoeconomic studies in BTP, with most studies conducted to date assessing the economic impact of untreated cancer pain. Ferrell et al. (1994) addressed two main factors for the general lack of cost studies on pain management.27 First, pain is subjective and difficult to quantify into dollars. The nature of BTP and its several subtypes also results in treatment that is hard to standardize. Second, until recently, pharmacotherapy for pain management was generally considered inexpensive.27 Additionally, accounting for the direct costs of BTP is difficult, since there are no specific diagnostic or clinical billing codes linked to episodes of BTP, making it hard to differentiate the cost between unrelieved cancer pain and BTP.33 Today, the costs for therapies of both around-the-clock pain management and BTP can be considerable, since several new formulations of rapid-onset opioids administered by various routes are available. Further studies assessing the contemporary management of BTP in observational cohorts would provide unique insight into the utilization, outcomes, and costs of patients treated in a


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real-life context comparing oral opioids and rapidonset opioids. These observational studies are necessary, since most clinical trials conducted to date with the rapid-onset opioids have used enriched patient populations selected through dose response or titration of the study intervention and used placebo as the comparator arm. The results of these observational studies could then be used in pharmacoeconomic models assessing the net relative benefit of the rapid-onset opioids compared with oral opioids to inform BTP decision-making by patients, clinicians, and payers. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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