Cost-effectiveness analysis of tapentadol immediate release for the treatment of acute pain

Clinical Therapeutics/Volume 32, Number 10, 2010

Cost-Effectiveness Analysis of Tapentadol Immediate Release for the Treatment of Acute Pain W. Jacqueline Kwong, PharmD, PhD1*; Ipek Özer-Stillman, MS2†; Jeffrey D. Miller, MS2‡; Noah A. Haber, BA2†; Mason W. Russell, MAPE2‡; and Shane Kavanagh, MSc3 1Johnson

& Johnson Pharmaceutical Services, L.L.C., Raritan, New Jersey; 2Abt Bio-Pharma Solutions, Inc., Lexington, Massachusetts; and 3Johnson & Johnson Pharmaceutical Services, Beerse, Belgium

ABSTRACT Background: Tapentadol immediate-release (IR) tablets are indicated for the treatment of moderate to severe acute pain. In clinical trials, tapentadol IR effectively reduced moderate to severe pain with improved tolerability compared with oxycodone IR at doses providing comparable analgesia. Objective: This analysis compared the costeffectiveness of tapentadol IR with doses of oxycodone IR providing comparable analgesia in the outpatient treatment of acute postsurgical and nonsurgical pain. The perspective was that of a US managed care health plan as third-party payer. Methods: A Markov model was developed to simulate clinical-economic outcomes for tapentadol IR 100 mg compared with oxycodone IR 15 mg in the treatment of acute postsurgical pain (3 days) and for tapentadol IR 50 mg compared with oxycodone IR 10 mg in the treatment of acute nonsurgical pain (10 days). The model simulated changes in pain relief; occurrence of opioid-related adverse events (AEs); opioid switching, discontinuation, and dose change; and number of qualityadjusted life-days (QALDs). Data inputs for the model were obtained from clinical trials, claims databases, surveys, Medicare fee schedules, and other published sources. Only direct costs were included. Drug costs were based on the wholesale acquisition cost. Prescription copayments were set at $5 for oxycodone IR and $25 for tapentadol IR. All costs were in 2008 US dollars. Sensitivity analyses were conducted on key model parameters. Results: The cost of pain medication per patient was higher for tapentadol IR than for oxycodone IR in both the surgical pain setting ($15.23 vs $9.57, respectively) and the nonsurgical pain setting ($57.17 vs $21.31). However, this cost difference was offset by reductions in pharmacy and medical costs associated with the treatment of AEs and opioid switching/discontinuation, 1768

resulting in a lower mean treatment cost per patient for tapentadol IR 100 mg compared with oxycodone IR 15 mg in the treatment of acute surgical pain ($52.90 vs $55.99) and for tapentadol IR 50 mg compared with oxycodone IR 10 mg in the treatment of acute nonsurgical pain ($139.48 vs $144.79). Tapentadol IR also was associated with a greater mean number of treatment days with ≥30% improvement in pain intensity without opioid-related AEs compared with oxycodone IR and a greater mean number of QALDs (surgical pain: 1.73 vs 1.68; nonsurgical pain: 6.03 vs 4.92). Because both doses of tapentadol IR were dominant (ie, lower treatment costs and greater effectiveness) relative to the corresponding doses of oxycodone IR providing comparable analgesia, incremental cost-effectiveness ratios were not calculated. Conclusion: The results of this model suggest that at doses providing comparable analgesia, tapentadol IR is a cost-effective alternative to oxycodone IR for the treatment of acute surgical and nonsurgical pain. (Clin Ther. 2010;32:1768–1781) © 2010 Excerpta Medica Inc. Key words: acute pain, cost-effectiveness, opioids, model, tapentadol IR, oxycodone IR.

INTRODUCTION Pain is one of the most common reasons for physician consultation in the United States, as well as one of the most common complaints after surgery and in the *Current affiliation: Daiichi Sankyo, Inc., Parsippany, New Jersey. † Current affiliation: United BioSource Corporation, Bethesda, Maryland. ‡ Current affiliation: RTI Health Solutions, Research Triangle Park, North Carolina. Accepted for publication August 5, 2010. Express Track online publication September 13, 2010. doi:10.1016/j.clinthera.2010.09.011 0149-2918/$ - see front matter © 2010 Excerpta Medica Inc. All rights reserved.

Volume 32 Number 10

W.J. Kwong et al. emergency department.1–4 More than 25 million Americans experience acute pain each year as a result of injury or surgery.5 Despite their established place in pain treatment, traditional μ-opioid–receptor agonists are associated with gastrointestinal (GI) and other dose-limiting adverse events (AEs).6,7 These factors can compromise the adequacy and quality of pain management and lead to treatment discontinuation.6,8–11 Despite the widespread availability of opioids, inadequate treatment of acute pain is common12; it is estimated that >50% of patients experience severe to intolerable pain after surgery or trauma.13,14 If not adequately treated, acute pain may lead to chronic pain, resulting in further costs for patients and health care payers.15,16 The lifetime economic burden of treating chronic pain developing from acute pain in a 30-year-old individual has been estimated to be as much as $1 million.12,17 Tapentadol is a novel centrally acting analgesic that combines μ-opioid–receptor agonism and norepinephrine reuptake inhibition in a single molecule. An immediaterelease (IR) tablet formulation was approved in the United States in 2009 for the relief of moderate to severe acute pain in patients aged ≥18 years. Clinical trials have consistently found tapentadol IR effective in reducing moderate to severe pain with improved tolerability compared with oxycodone IR at doses providing comparable analgesia.18,19 The objective of the present analysis was to evaluate the cost-effectiveness of tapentadol IR compared with doses of oxycodone IR providing comparable analgesia in outpatients with acute postsurgical and nonsurgical pain. A Markov decision-analytic model was developed to simulate the clinical-economic outcomes and relative cost-effectiveness of tapentadol IR 100 mg and oxycodone IR 15 mg in the treatment of acute postsurgical pain and of tapentadol IR 50 mg and oxycodone IR 10 mg in the treatment of acute nonsurgical pain.

METHODS Markov Model Structure The cost-effectiveness analyses employed a Markov decision-analytic model programmed using Microsoft Excel and Microsoft Visual Basic for Applications (Microsoft Corporation, Redmond, Washington). Markov models assume that a patient is always in one of a finite number of discrete health states (“Markov states”) and that probability-based transitions between health states occur over a given time period.20 Because of the episodic nature of pain, Markov modeling is well suited to September 2010

evaluating the cost-effectiveness and budgetary impact of analgesics. The Markov model described in this paper simulated the costs and outcomes for hypothetical cohorts of patients treated with either tapentadol IR or oxycodone IR. The determining factor in focusing this analysis on tapentadol IR and oxycodone IR, apart from their being approved for the same indications, was the availability of data from pivotal clinical trials involving head-tohead comparisons of these agents. The simulated patient cohorts in the model were assumed to have identical baseline characteristics and were selected to represent pain patients in a typical managed care health plan, reflecting conditions in usual clinical practice as closely as possible.21–23 Patients treated with tapentadol IR or oxycodone IR entered the model in the “uncontrolled pain” state and transitioned along decision pathways among 3 mutually exclusive health states—uncontrolled pain while taking an opioid, controlled pain while taking an opioid, and discontinuation of opioid therapy (Figure). Discontinuation of opioid therapy was an absorbing state. Once a patient enters an absorbing health state, that patient can no longer transition to other health states. The length of a Markov cycle is one day; therefore, health-state transition was simulated from day to day during the modeled course of treatment. Over the modeled course of treatment, the model tracked the proportion of patients in each of the health states on a daily basis while taking into account the occurrence of treatmentemergent AEs (TEAEs), changes in opioid dose, and opioid switching/discontinuation.

Data Sources Pain Relief Estimates of the probability of having controlled and uncontrolled pain on each treatment day were based on pain relief scores from 2 Phase III pivotal clinical trials of the efficacy and tolerability of tapentadol IR and oxycodone IR in the treatment of acute postsurgical (bunionectomy) pain18 and acute nonsurgical pain (endstage joint disease).19 In the morning and evening of each treatment day, study subjects responded to the question “How much relief have you had from your starting pain?” using a 5-point Likert-type pain relief scale (PAR) (0 = none, 1 = a little, 2 = some, 3 = a lot, 4 = complete). Although no significant differences were found between morning and evening ratings in the 2 clinical trials, the present model employed the evening 1769

Clinical Therapeutics

Dose change

AEs Uncontrolled pain (PAR <2)

Controlled pain (PAR ≥2)

Switch to another opioid

Discontinue opioid

Figure. Structure of the Markov model. PAR = 5-point Likert-type pain relief scale score (on a scale from 0 = none to 4 = complete); AEs = adverse events.

rating, which was thought to better reflect overall health status. Based on discussions with a panel of 2 physicians specializing in pain management, patients were categorized into 2 groups: those reporting a PAR score ≥2 (at least some relief) were considered to have controlled pain, and those reporting a PAR score <2 were considered to have uncontrolled pain.

Opioid-Induced Adverse Events Data used to model the daily incidence and prevalence of TEAEs were derived from the 2 Phase III clinical trials of tapentadol IR and oxycodone IR mentioned earlier.18,19 The incidence and duration of the following common opioid-related AEs were evaluated in the model: nausea/ vomiting, constipation, central nervous system (CNS) AEs (somnolence, dizziness, or headache), and pruritus.

Opioid Switching, Discontinuation, and Dose Change Daily rates of study discontinuation in the Phase III clinical trials were used to estimate daily rates of opioid 1770

switching and discontinuation.18,19 In the base-case analyses, it was assumed that 30% of patients who withdrew from the clinical trials on each treatment day would switch to an alternative opioid medication and 70% would discontinue opioid therapy. This assumption was later tested in a sensitivity analysis. Patients who discontinued tapentadol IR or oxycodone IR could switch to an alternative opioid (morphine, hydromorphone, or oxymorphone), as determined by formulary allocation (Table I). Because dose-change data were not available from the clinical trials, the proportion of patients with a dose change was set to 0% in the basecase analyses.

Treatment Effectiveness The cost-effectiveness analysis estimated the cost per effective treatment-day gained. Treatment effectiveness was assessed using a composite measure of pain relief and tolerability, defined as either the mean number of days on which patients continued the initial opioid Volume 32 Number 10

W.J. Kwong et al.

Table I. Unit cost, mean daily consumption, and formulary share of Schedule II short-acting oral opioids in the base-case analysis. Costs are in 2008 US dollars. Wholesale Acquisition Cost per Pill

Mean No. of Doses per Day

% of Formulary Allocation*

Tapentadol IR 50 mg 75 mg 100 mg

1.70 1.99 2.65

4.80† 4.80† 5.06†

4.00 1.00 1.00

Oxycodone IR 5 mg 10 mg 15 mg

0.24‡ 0.46‡ 0.96‡

4.96§ 4.80§ 5.06§

64.83 16.42 3.82

Morphine IR 15 mg 30 mg

0.15‡ 0.25‡

4.69§ 5.15§

1.80 1.15

Hydromorphone IR 2 mg 4 mg 8 mg

0.14‡ 0.44‡ 1.05‡

5.81§ 5.69§ 5.72§

2.75 2.39 0.57

Oxymorphone IR 5 mg 10 mg

1.90‡ 3.44‡

3.94§ 4.50§

0.12 0.15

Product

IR = immediate release. *Formulary share data were derived from IMS Health National Prescription Audit Plus and IMS National Sales Perspectives, under the model assumption that tapentadol IR accounted for 6% of the formulary share among all products in the base-case analysis. †Set equal to doses of oxycodone IR providing comparable analgesia. ‡80% of the lowest average wholesale price. 29 §Data on the mean number of doses per day were derived from IMS Health National Prescription Audit Plus and IMS National Sales Perspectives.30

medication and reported ≥30% improvement from baseline pain intensity on an 11-point numeric rating scale (from 0 = no pain to 10 = pain as bad as it can be) without any TEAEs, or the mean number of days on which patients continued the initial opioid medication and had ≥30% improvement from baseline pain intensity on the 11-point numeric rating scale without GI AEs (ie, nausea/vomiting and constipation).24 Composite end points such as these are meaningful to clinicians, who are often challenged to balance pain relief and tolerability when prescribing opioids for their patients.24 Treatment effectiveness data were derived from post hoc analyses of the Phase III clinical trials. The results of the postsurgical pain analysis are on file with JohnSeptember 2010

son & Johnson, and the results of the nonsurgical pain analysis have been reported by Nelson et al.24 It has previously been suggested that an ~30% reduction on the 11-point numeric pain intensity rating scale represents a clinically important difference in chronic pain.25

Quality-Adjusted Life-Days The cost-effectiveness analysis also estimated costs per quality-adjusted life-days (QALDs) gained. Healthstate utilities for pain relief and disutilities for opioidrelated AEs were obtained from the published literature26–28 and adapted to the model for calculation of the number of QALDs over the course of treatment. 1771

Clinical Therapeutics The utility values associated with PAR scores of 0, 1, 2, 3, and 4 were 0.47, 0.60, 0.73, 0.81, and 0.88, respectively. Disutilities associated with nausea/vomiting, constipation, CNS AEs, and pruritus were 0.32, 0.23, 0.32, and 0.00, respectively. A disutility value of 0.00 was used for pruritus because of a lack of appropriate data for the model; the pruritus disutility value of 0.042 from the pain model developed by Greiner et al28 was tested in the sensitivity analyses. The number of QALDs associated with each treatment alternative was calculated using the following formula: QALDs = Σ (Utility for pain level i × Number of treatment days with PAR level i) – Σ (Disutility j × Number of treatment days with adverse event j)

Costs All analyses were performed from the perspective of a US managed care health plan as third-party payer. Hence, only direct costs were included in the analyses; indirect costs due to work loss (absenteeism and presenteeism) were excluded. Costs evaluated in the model included pharmacy costs and medical costs. Pharmacy costs included costs for the initial opioid prescription, costs of alternative opioid medications for those who switched therapies, and costs of prescription drugs used to treat AEs (eg, antiemetics, laxatives). Medical costs included routine physician office visits and nonroutine use of health care resources, including physician visits related to opioid switching/discontinuation, telephone calls and physician visits due to AEs, and emergency department visits and hospitalizations due to AEs. Drug costs from the perspective of the managed care organization were estimated based on the wholesale acquisition cost, minus any out-of-pocket prescription copayments by patients. The wholesale acquisition costs of oxycodone IR and possible alternative opioids (ie, morphine IR, hydrocodone IR, and oxymorphone IR) were estimated as 80% of the lowest published 2008 average wholesale price,29 without discounts or rebates (Table I). Default values for the mean daily consumption of oxycodone IR, morphine IR, hydrocodone IR, and oxymorphone IR were derived from IMS Health data. It was assumed that the daily consumption of tapentadol IR was the same as that of oxycodone IR at doses providing comparable analgesia. Prescription copayments were set at $5 for oxycodone IR, morphine IR, and hydromorphone IR to reflect 1772

typical copayments for generic drugs; prescription copayments were set at $25 for tapentadol IR and oxymorphone IR to reflect typical copayments for tier-2 branded products. The cost to the consumer of copayments was excluded from costs entered in the model. Rates of resource utilization for the treatment of AEs were derived from an Internet survey of 300 patients with acute pain,30 and the associated unit costs were derived from the 2008 Medicare Physician Fee Schedule,31 an analysis of the PharMetrics Patient-Centric database by Kwong et al,32 a customized search of the Healthcare Cost and Utilization Project,33 and other published literature (Table II).34–36 When necessary, cost estimates were adjusted to 2008 US dollars using the medical care component of the US Consumer Price Index.37 For patients with postsurgical pain, only costs incurred after discharge were included, and patients were assumed to receive the modeled opioid prescription at the time of discharge. The costs of surgery, anesthesia, and initial parenteral or epidural analgesia were excluded from the analyses. Patients with nonsurgical pain were assumed to receive the modeled opioid prescription during an outpatient physician visit. All costs in the model were expressed in 2008 US dollars; because of the short duration of treatment for acute pain, no discounting of costs was required.

Formulary Allocation Formulary allocation was used to calculate a weighted mean daily cost for alternative opioids in patients who switched opioid therapy. The formulary shares of Schedule II short-acting oral opioids other than tapentadol IR were based on prescription share data from IMS Health. In the base-case analysis, tapentadol IR was assumed to represent 6% of the formulary share among existing Schedule II short-acting oral opioids (Table I). Similar to oxycodone IR, the lowest dose strength of tapentadol IR (50 mg) was assumed to have a higher formulary share than tapentadol IR 75 or 100 mg (4%, 1%, and 1%, respectively).

General Model Assumptions The general assumptions in the model were as follows. Patients requiring dose changes could change only to other modeled doses of the same drug. Opioid discontinuation was an absorbing state in which it was assumed that patients no longer experienced pain relief, were no longer at risk for TEAEs, and no longer incurred treatVolume 32 Number 10

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Table II. Unit costs and rates of treatment for opioid-related adverse events (AEs) in the base-case analysis. Costs are in 2008 US dollars. Resource Use*

Nausea/Vomiting

Constipation

CNS-Related AEs

Pruritus

Telephone call to physician % of Patients with AEs seeking treatment for AE Cost per telephone call†

18.00 22.85

9.10 22.85

7.51 22.85

16.70 22.85

Office visit % of Patients with AEs seeking treatment for AE Cost per visit†

5.47 59.42

4.20 59.42

4.35 59.42

7.14 59.42

Emergency department visit % of Patients with AEs seeking treatment for AE Cost per visit‡

2.34 637.00

0 637.00

0.39 637.00

0 637.00

Hospitalization % of Patients with AEs seeking treatment for AE Cost per hospitalization§

0 7884.00

0.61 8913.00

0.39 1714.00

0 5484.00

Prescription drug use % of Patients with AEs seeking treatment for AE Daily prescription drug cost ]

7.88 20.00

17.20 1.38

3.56 2.12

5.95 0

CNS = central nervous system. *Data on the proportions of patients seeking treatment for AEs were obtained from Gregorian et al.30 † Costs were derived from the 2008 Medicare Physician Fee Schedule: Current Procedural Terminology (CPT) 99442 for a telephone call and CPT 99213 for an office visit.31 ‡ Derived from Machlin. 34 § To calculate the cost per hospitalization, the per diem cost from the 2008 Statistical Abstract of the United States 35 was multiplied by the length of stay. Length-of-stay data for nausea/vomiting and constipation were derived from an analysis of PharMetrics data by Kwong et al, 32 data for pruritus were obtained from a customized search of the Healthcare Cost and Utilization Project,33 and the length of stay for CNS-related AEs was assumed to be 1 day. ]


Daily prescription costs for nausea/vomiting were derived from an analysis of PharMetrics data by Kwong et al, 32 and prescription costs for constipation and CNS-related AEs were obtained from Neighbors et al.36

ment costs. Patients could switch opioid therapy once during the modeled duration of treatment. Patients who switched medications transitioned into a general switching state. Mean values for AE, cost, and efficacy data for other drugs in the model were applied to patients in this state for the remainder of the simulation. Prescription costs for patients in this state were based on a mean daily cost calculated from the daily wholesale acquisition cost for other drugs, weighted by formulary allocation. Any switching, discontinuation, or dose change of opioid treatment was assumed to require an additional September 2010

physician office visit. Drug costs and copayments were applied at the time of filling the prescription, whether or not the entire prescription was used. The copayment for the prescription to which a patient was switched was based on a weighted mean of copayments for other drugs in the model.

Base-Case Analysis The base-case analysis compared the cost-effectiveness of tapentadol IR 100 mg and oxycodone IR 15 mg in the treatment of acute postsurgical pain and between 1773

Clinical Therapeutics tapentadol IR 50 mg and oxycodone IR 10 mg in the treatment of acute nonsurgical pain. The modeled duration of treatment for acute postsurgical pain (3 days) and nonsurgical pain (10 days) was consistent with the duration of double-blind treatment in the 2 pivotal Phase III clinical trials of tapentadol IR that compared the efficacy of tapentadol IR and oxycodone IR on a daily basis.18,19 The doses of tapentadol IR and oxycodone IR used in the model have been reported to provide comparable analgesia in published clinical trials.18,19 In the cost-effectiveness analysis, incremental cost-effectiveness ratios (ICERs) were calculated as the total cost per effective treatment-day gained and the cost per QALD gained.

RESULTS Treatment of Acute Postsurgical Pain Over the 3 days of postsurgical pain treatment, the mean number of treatment days per patient in which patients had at least some pain relief was the same for both tapentadol IR 100 mg and oxycodone IR 15 mg

(2.75 days) (Table III). Patients receiving tapentadol IR 100 mg relative to oxycodone IR 15 mg had a lower mean number of treatment days with nausea/vomiting (0.814 vs 1.234, respectively) and constipation (0.198 vs 0.261), but a greater mean number of treatment days with CNS AEs (1.010 vs 0.797) and pruritus (0.470 vs 0.404). Considering efficacy and tolerability together, tapentadol IR 100 mg was associated with a higher mean number of treatment days with ≥30% improvement in pain intensity and no TEAEs compared with oxycodone IR 15 mg (0.92 vs 0.70), as well as a higher mean number of treatment days with ≥30% improvement in pain intensity and no GI AEs (1.59 vs 1.22), and a higher mean number of QALDs (1.73 vs 1.68). Although the mean cost of pain medication per patient was higher for tapentadol IR 100 mg than for oxycodone IR 15 mg ($15.23 vs $9.57, respectively), this cost difference was partially offset by the 33% lower mean cost of prescription drug treatment for AEs with tapentadol IR 100 mg relative to oxycodone IR 15 mg ($2.90 vs $4.33 per patient) (Table IV). The cost

Table III. Pain relief, adverse events (AEs), and treatment effectiveness over 3 days of treatment for acute postsurgical pain and 10 days of treatment for acute nonsurgical pain. Treatment of Acute Postsurgical Pain (3 Days)

Variable

Tapentadol IR 100 mg

Oxycodone IR 15 mg

Treatment of Acute Nonsurgical Pain (10 Days) Tapentadol IR 50 mg

Oxycodone IR 10 mg

Mean no. of treatment days with at least some pain relief (PAR ≥2)

2.75

2.75

5.39

5.12

Mean no. of treatment days with TEAEs Nausea/vomiting Constipation CNS-related AEs Pruritus

0.814 0.198 1.010 0.470

1.234 0.261 0.797 0.404

0.670 0.171 1.023 0.139

2.290 1.576 1.522 0.705

Treatment effectiveness ≥30% Improvement from baseline in pain intensity, with no TEAEs and initial opioid continued ≥30% Improvement from baseline in pain intensity, with no GI AEs and initial opioid continued

0.92

0.70

2.91

1.56

1.59

1.22

3.62

2.19

Quality-adjusted life-days

1.73

1.68

6.03

4.92

IR = immediate release; PAR = 5-point Likert-type pain relief scale score; TEAE = treatment-emergent adverse event; CNS = central nervous system; GI = gastrointestinal.

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Table IV. Summary of cost estimates after 3 days of treatment for acute postsurgical pain and 10 days of treatment for acute nonsurgical pain.* Costs are in 2008 US dollars. Treatment of Acute Postsurgical Pain (3 Days)

Cost Component Mean total pharmacy cost per patient Pain medication AE-related medication Subtotal

Treatment of Acute Nonsurgical Pain (10 Days)

Tapentadol IR 100 mg

Oxycodone IR 15 mg

Tapentadol IR 50 mg

Oxycodone IR 10 mg

15.23 2.90 18.13

9.57 4.33 13.91

57.17 2.40 59.57

21.31 8.16 29.47

Mean total medical cost per patient Routine physician visits Physician visits related to opioid switching/ discontinuation Telephone calls to physician due to AEs Physician visits due to AEs Emergency department visits due to AEs Hospitalization due to AEs Subtotal, medical costs of AEs Subtotal, all medical costs

5.27

7.44

59.42

59.42

0 3.98 4.18 10.10 11.25 29.51 34.78

0 4.41 4.29 14.05 11.91 34.66 42.10

10.59 0.35 0.90 4.66 3.99 9.90 79.91

22.74 0.95 2.47 11.88 17.87 33.17 115.33

Overall total cost per patient

52.90

55.99

139.48

144.79

IR = immediate release; AE = adverse event. *Any apparent discrepancies in subtotals and totals are the result of rounding.

difference was further offset by the 17% lower mean medical costs associated with the treatment of AEs ($29.51 vs $34.66 per patient). Thus, the overall mean total cost per patient was 6% lower for tapentadol IR 100 mg than for oxycodone IR 15 mg ($52.90 vs $55.99). Calculation of incremental cost-effectiveness indicated that because tapentadol IR was associated with better clinical outcomes (in terms of number of effective treatment-days and QALDs) and lower costs relative to oxycodone IR, it was the economically dominant treatment strategy; thus, ICERs were not calculated.

Treatment of Nonsurgical Pain Over the 10 days of nonsurgical pain treatment, the mean number of treatment days per patient on which patients had at least some pain relief was comparable between tapentadol IR 50 mg and oxycodone IR 10 mg (5.39 and 5.12, respectively) (Table III). Patients receivSeptember 2010

ing tapentadol IR 50 mg relative to oxycodone IR had a lower mean number of treatment days with nausea/ vomiting (0.670 vs 2.290), constipation (0.171 vs 1.576), CNS AEs (1.023 vs 1.522), and pruritus (0.139 vs 0.705). Tapentadol IR 50 mg also was associated with a higher mean number of treatment days with ≥30% improvement in pain intensity and no TEAEs compared with oxycodone IR 10 mg (2.91 vs 1.56), as well as a higher mean number of treatment days with ≥30% improvement in pain intensity and no GI AEs (3.62 vs 2.19) and a higher mean number of QALDs (6.03 vs 4.92). The mean cost of pain medication per patient was higher for tapentadol IR 50 mg than for oxycodone IR 10 mg ($57.17 vs $21.31, respectively) (Table IV). However, this cost difference was offset by a 71% lower mean cost of prescriptions for AEs with tapentadol IR 50 mg compared with oxycodone IR 10 mg ($2.40 vs $8.16 per patient) and a 53% lower cost for physician visits related to opioid switching/discontinuation ($10.59 1775

Clinical Therapeutics vs $22.74), as well as 70% lower mean medical costs associated with the treatment of AEs ($9.90 vs $33.17). The overall mean total cost for tapentadol IR 50 mg was 4% lower than for oxycodone IR 10 mg ($139.48 vs $144.79 per patient). As in the analysis of postsurgical pain, incremental cost-effectiveness calculations indicated that tapentadol IR 50 mg was dominant compared with oxycodone IR 10 mg, being associated with both lower total treatment costs and better outcomes. Thus, ICERs were not calculated.

Sensitivity Analyses Because the parameter values used in the model were obtained from a variety of sources and thus had varying levels of uncertainty, sensitivity analyses were conducted to determine the robustness of the model results and to identify the parameters that contributed most to the model results. Overall, the results were not highly sensitive to changes in key model parameters; that is, the changes did not appreciably alter the cost-effectiveness ratios (including economic dominance), nor did they affect conclusions about the relative cost-effectiveness of tapentadol IR observed in the base-case analyses. Because the base-case analysis found that differences in acquisition costs between tapentadol IR and oxycodone IR were offset by the reduced costs associated with opioid switching/discontinuation and treatment of AEs, the sensitivity analyses were particularly focused on the latter parameters. For example, the proportion of patients switching from the initial opioid to an alternative opioid in the base-case analysis was assumed to be equal to 30%, so this assumption was tested by varying the proportion of patients switching to alternative opioids from 20% to 40%. The results generated by the model were relatively unchanged in both the acute postsurgical pain analysis (Table V) and the acute nonsurgical pain analysis (Table VI). Similar variations on other parameters were tested, including the costs of AE treatment (±10%), opioid costs (±10%), prescription copayments (±10%), the utilities of pain relief (+10%), and the disutilities of AEs (–10%, with a value of 0.042 for pruritus). The only variation that resulted in a change in tapentadol’s economic dominance was when opioid costs were increased by 10% in the nonsurgical pain analysis—tapentadol IR 50 mg ceased to be dominant, although the incremental cost per day was minimal (≤$0.13 in all scenarios) (Table VI). 1776

DISCUSSION A model was developed to evaluate the cost-effectiveness of tapentadol IR relative to doses of oxycodone IR providing comparable analgesia in the treatment of acute surgical and nonsurgical pain. The findings of the model suggest that under the base-case assumptions, the incrementally higher drug acquisition cost of tapentadol IR compared with oxycodone IR was offset by reduced pharmacy and medical costs associated with treatment of opioid-related AEs, and lower rates of opioid switching/discontinuation. AE-related emergency department visits and hospitalizations were main drivers underlying the cost differential. As a consequence, use of tapentadol IR was associated with a lower mean cost of pain treatment per patient relative to oxycodone IR. Moreover, use of tapentadol IR was associated with consistently better effectiveness compared with oxycodone IR—specifically, more days with improvement in pain intensity and more QALDs. Insofar as use of tapentadol IR was associated with better clinical outcomes and lower costs relative to oxycodone IR, it can be considered an economically dominant treatment strategy. Although their acquisition cost is generally low, the analgesics used to manage acute pain, as well as the choice of which to use, can have a considerable impact on health care budgets.38 Somewhat surprisingly, few studies to date have addressed the comparative cost of analgesics in the management of acute pain, even though such knowledge might lead to better, more efficient decisions about resource allocation.38,39 Other economic modeling studies have evaluated the pharmacologic treatment of chronic pain with sustained-release oral and transdermal opioids40–44; however, to the authors’ knowledge, this is the first published analysis to compare the economic benefits of treatment with tapentadol IR relative to an alternative Schedule II short-acting oral opioid. Again, this is surprising given that opioids are among the mainstays of treatment for moderate to severe nociceptive pain45–47 and given the growing interest in the economics of pain-management practice.48 Several limitations of this analysis should be mentioned. First, as is true of any economic model, the accuracy and credibility of the model results depend on the accuracy and robustness of the data inputs. This model was designed to provide baseline estimates of clinical and economic outcomes associated with the treatment of acute postsurgical and nonsurgical pain in hypothetical cohorts of patients using clinical inputs Volume 32 Number 10

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Table V. Sensitivity analysis of the cost-effectiveness of tapentadol immediate release (IR) 100 mg compared with oxycodone IR 15 mg in the treatment of acute postsurgical pain.* Mean No. of Days With ≥30% Pain Improvement Without TEAEs

Mean No. of Days With ≥30% Pain Improvement Without GI AEs

Difference

ICER

Difference

ICER

Difference

ICER

Parameter

Total Cost Difference per Patient, 2008 US $

Base case

–3.09

+0.22

Dominant

+0.37

Dominant

+0.05

Dominant

Switch rate Set to 20% Set to 40%

–3.05 –3.12

+0.22 +0.22

Dominant Dominant

+0.37 +0.37

Dominant Dominant

+0.05 +0.05

Dominant Dominant

All AE treatment costs 10% Increase 10% Decrease

–3.74 –2.43

+0.22 +0.22

Dominant Dominant

+0.37 +0.37

Dominant Dominant

+0.05 +0.05

Dominant Dominant

All opioid costs 10% Increase 10% Decrease

–0.56 –5.62

+0.22 +0.22

Dominant Dominant

+0.37 +0.37

Dominant Dominant

+0.05 +0.05

Dominant Dominant

Prescription copayment 10% Increase 10% Decrease

–5.05 –1.12

+0.22 +0.22

Dominant Dominant

+0.37 +0.37

Dominant Dominant

+0.05 +0.05

Dominant Dominant

Utilities of pain relief 10% Increase

–3.09

+0.22

Dominant

+0.37

Dominant

+0.04

Dominant

Disutilities of AEs 10% Decrease for all AEs Pruritus†

–3.09 –3.09

+0.22 +0.22

Dominant Dominant

+0.37 +0.37

Dominant Dominant

+0.04 +0.04

Dominant Dominant

Mean QualityAdjusted Life-Days

TEAEs = treatment-emergent adverse events; GI = gastrointestinal; ICER = incremental cost-effectiveness ratio. *A negative cost difference indicates a lower cost for tapentadol IR 100 mg than for oxycodone IR 15 mg. A positive value for the difference in mean number of days with pain improvement indicates a greater number of days for tapentadol IR 100 mg than for oxycodone IR 15 mg. ICERs were calculated as (Cost1 – Cost2)/(Efficacy1 – Efficacy2). Dominant indicates that tapentadol IR 100 mg was associated with a lower cost and better treatment outcomes compared with oxycodone IR 15 mg. †The disutility value for pruritus was 0.042, derived from the pain model developed by Greiner et al.28

from Phase III trials. Such trials represent efficacy in a controlled clinical environment rather than under realworld conditions. Patients in the clinical trials were limited to those who had undergone bunionectomy18 or who had end-stage joint disease.19 Thus, it is not known how the results might differ among patients who undergo other surgical procedures, have pain caused by injury/trauma, or who have other comorbid condiSeptember 2010

tions (eg, cancer), all of whom may have varying levels of pain and rates of AEs. The analytic approach was strengthened by incorporation in the model of real-world data whenever feasible, including observational data from a US health care claims database and from a patient survey. Of course, these data have their own limitations as a result of being drawn from sources that were neither randomized nor controlled. Nonetheless, the authors 1777

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Table VI. Sensitivity analysis of the cost-effectiveness of tapentadol immediate release (IR) 50 mg compared with oxycodone IR 10 mg in the treatment of acute nonsurgical pain.* Mean No. of Days With ≥30% Pain Improvement Without TEAEs

Mean No. of Days With ≥30% Pain Improvement Without GI AEs

Difference

ICER

Difference

ICER

Difference

ICER

Parameter

Total Cost Difference per Patient, 2008 US $

Base case

–5.31

+1.36

Dominant

+1.43

Dominant

+1.11

Dominant

Switch rate Set to 20% Set to 40%

–3.67 –6.95

+1.36 +1.36

Dominant Dominant

+1.43 +1.43

Dominant Dominant

+1.13 +1.09

Dominant Dominant

All AE treatment costs 10% Increase 10% Decrease

–8.22 –2.44

+1.36 +1.36

Dominant Dominant

+1.43 +1.43

Dominant Dominant

+1.11 +1.11

Dominant Dominant

All opioid costs 10% Increase 10% Decrease

+0.15 –10.77

+1.36 +1.36

$0.11 Dominant

+1.43 +1.43

$0.11 Dominant

+1.11 +1.11

$0.13 Dominant

Prescription copayment 10% Increase 10% Decrease

–7.19 –3.44

+1.36 +1.36

Dominant Dominant

+1.43 +1.43

Dominant Dominant

+1.11 +1.11

Dominant Dominant

Utilities of pain relief 10% Increase

–5.31

+1.36

Dominant

+1.43

Dominant

+1.12

Dominant

Disutilities of AEs 10% Decrease for all AEs Pruritus†

–5.31 –5.31

+1.36 +1.36

Dominant Dominant

+1.43 +1.43

Dominant Dominant

+1.09 +1.14

Dominant Dominant

Mean QualityAdjusted Life-Days

TEAEs = treatment-emergent adverse events; GI = gastrointestinal; ICER = incremental cost-effectiveness ratio. *A negative cost difference indicates a lower cost for tapentadol IR 50 mg than for oxycodone IR 10 mg. A positive value for the difference in mean number of days with pain improvement indicates a greater number of days for tapentadol IR 50 mg than for oxycodone IR 10 mg. ICERs were calculated as (Cost1 – Cost2)/(Efficacy1 – Efficacy2). Dominant indicates that tapentadol IR 50 mg was associated with lower cost and better treatment outcomes compared with oxycodone IR 10 mg. †The disutility value for pruritus was 0.042, derived from the pain model developed by Greiner et al.28

believe an appropriate balance was reached in choosing data for the model. One of the more interesting aspects of this analysis was its emphasis on precise accounting of the clinical and economic implications of TEAEs. Although opioids are widely used and extremely effective for the relief of acute pain, they are often associated with TEAEs—nausea and vomiting being least desirable from the patient’s 1778

perspective.18,49,50 In patients with moderate to severe pain, tapentadol IR has consistently been associated with improved tolerability, particularly GI tolerability (nausea/ vomiting and constipation), relative to conventional opioids.18,19 As expected, the favorable results from clinical trials of tapentadol IR were in agreement with the results generated by the present model, in which patients treated with tapentadol IR generally used fewer health care Volume 32 Number 10

W.J. Kwong et al. resources for the treatment of opioid-related AEs. Gan et al51 conducted a cost-benefit analysis of antiemetic therapy and found that patients highly valued avoiding the postsurgical nausea and vomiting associated with receipt of general anesthesia. These authors reported that patients were willing to pay $56 to $100 (2001 US $) out of pocket for a totally effective antiemetic. Other studies have reported that a desire to avoid opioid-related AEs may contribute to unrelieved pain in patients who refuse or are noncompliant with opioid treatment, although physicians may also be reluctant to prescribe opioids to avoid TEAEs.18,52–54 Although some opioid-related AEs are time limited and others, such as constipation, tend to be persistent, the collective and cumulative impact of these AEs on costs and overall outcomes is of considerable importance to health care payers. The results of an acute pain study indicated that opioids were the predominant class of medications associated with adverse drug events in hospitalized patients, accounting for 59% of all adverse drug events detected during a 10-year surveillance period, along with a half-day increase in the length of stay and $840 in additional hospital costs per patient.55 In a follow-up study, the investigators found that surgical patients experiencing opioid-related AEs had a 7.4% increase in median total hospital costs compared with matched controls, with the additional costs varying according to the surgery ($541 for obstetric/ gynecologic surgery, $677 for general surgery, and $862 for orthopedic surgery).56 There is a clear need for analgesics for acute pain that are highly effective and have improved tolerability profiles compared with opioids available before 2009. It is hoped that this analysis provides formulary and other health care decision-makers with information to better inform their treatment choices in the management of acute pain. The locus of medical care in the United States continues to shift from the inpatient setting to outpatient, office, and home settings, taking the delivery of pain management services in the same direction.57,58 The need for cost containment has changed incentives in health care coverage and reimbursement practices, which in turn affects pain-management practice patterns. In the present model, tapentadol IR was associated with reduced use of medical resources while providing comparable pain relief to oxycodone IR with a reduced frequency of opioid-related AEs, leading to possible improvement in QALDs. Taken together, these properties may contribute to overall cost savings and improved efficiency in health care resource allocation. September 2010

CONCLUSIONS Results from this model suggest that tapentadol IR is a cost-effective alternative to doses of oxycodone IR that provide comparable analgesia for the treatment of acute surgical and nonsurgical pain. These results provide quantitative, predictive evidence regarding the economics of adding this drug to an established therapeutic class.

ACKNOWLEDGMENTS This analysis was sponsored by Johnson & Johnson Pharmaceutical Services (J&J). Dr. Kwong was an employee of J&J at the time of the study. Mr. Kavanagh is an employee of J&J and holds stock in the company, as does Mr. Russell. At the time of the study, Mrs. ÖzerStillman, Mr. Miller, Mr. Haber, and Mr. Russell were employees of Abt Bio-Pharma Solutions, Inc., which received funding from J & J to conduct this research. The authors have indicated that they have no other conflicts of interest regarding the content of this article. All authors contributed to the study concept and design, as well as analysis and interpretation of the data. Mrs. Özer-Stillman, Mr. Miller, and Mr. Haber developed the model. Mr. Miller had primary responsibility for preparing the manuscript, and all authors had a hand in its review and revision. Dr. Kwong and Mr. Kavanagh provided data support. The authors thank Gary E. Ruoff, MD, and Perry G. Fine, MD, for sharing their expertise and providing invaluable assistance during the conduct of the analysis.

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Address correspondence to: Shane Kavanagh, MSc, Vice President, WW Health Economics & Pricing, Johnson & Johnson Pharmaceutical Services, Turnhoutseweg 30, B-2340 Beerse, Belgium. E-mail: skavanag@ its.jnj.com 1781