The Efficacy and Safety of Fentanyl Buccal Tablet Compared with Immediate-Release Oxycodone for the Management of Breakthrough Pain in Opioid-Tolerant Patients with Chronic Pain : Anesthesia & Analgesia

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Analgesia: Research Reports

The Efficacy and Safety of Fentanyl Buccal Tablet Compared with Immediate-Release Oxycodone for the Management of Breakthrough Pain in Opioid-Tolerant Patients with Chronic Pain

Ashburn, Michael A. MD, MPH*; Slevin, Kieran A. MD*; Messina, John PharmD; Xie, Fang PhD

Author Information
doi: 10.1213/ANE.0b013e318209d320

Patients with chronic pain frequently experience exacerbations of pain despite treatment with around-the-clock (ATC) opioid regimens.1,2 Breakthrough pain (BTP) is a transitory exacerbation of pain that occurs on a background of otherwise controlled persistent pain.2 The time course of BTP is often brief, reaching peak intensity within 10 minutes.26 In the majority of studies, more than half of patients with controlled persistent pain experience BTP.26 BTP can be associated with substantial functional impairment and psychological distress.3,7

Short-acting oral opioids (e.g., oxycodone or hydrocodone), often in combination with acetaminophen, are frequently prescribed for the management of BTP.1,2,8,9 However, oral opioids have an onset and duration of effect that may not correspond with the time course of the BTP.810 The time to onset of analgesia with orally administered, short-acting opioids (about 30 to 60 minutes)3,8,10,11 occurs after the time of peak intensity for many BTP episodes.

There is limited evidence comparing traditional short-acting opioids with rapid-onset opioids for the treatment of BTP. In the data comparing oral transmucosal fentanyl citrate (OTFC®) to immediate-release oral morphine for the treatment of BTP in patients on a fixed-schedule opioid regimen, measures of outcome such as pain intensity (PI) and pain relief (PR) were significantly better (P < 0.05) with OTFC at all time points measured (15 to 60 minutes).12 Current clinical guidelines have identified the need for additional evidence to guide optimal treatment strategies for BTP, especially from studies of the comparative effect of different short-acting or rapid-onset opioid formulations.1,13

Fentanyl buccal tablet (FBT; FENTORA®, Cephalon, Inc., Frazer, PA) is a rapid-onset formulation indicated for the treatment of BTP in opioid-tolerant patients with cancer.14 FBT delivers fentanyl through the oral mucosa, which achieves a greater rate and extent of fentanyl absorption than does OTFC and allows for rapid absorption and greater bioavailability than with orally delivered opioids that are solely absorbed through the gastrointestinal tract.1517 Several placebo-controlled studies and 2 long-term open-label studies have shown FBT to be effective and generally safe for the management of BTP.1823

We investigated the comparative efficacy and safety of FBT (a rapid-onset opioid) with a traditional short-acting opioid, immediate-release oxycodone, for the management of BTP in opioid-tolerant patients with chronic pain. In this randomized, double-blind study, both BTP medications were titrated to a successful dose for each patient before double-blind treatment.

METHODS

This randomized, double-blind, active-controlled cross-over study evaluated the efficacy and safety of FBT in comparison with oxycodone for the management of BTP in opioid-tolerant patients with chronic pain of both malignant and nonmalignant origin (U.S. National Institutes of Health Clinical Trials Identifier: NCT00463047). The study was conducted at 46 sites in the United States from July 2007 to February 2009. The protocol was approved by the IRBs for all study centers, and study procedures were performed in accordance with good clinical practice.24 Written informed consent was obtained from all patients before study enrollment.

Patients

Men and nonpregnant women between 18 and 80 years of age who had a ≥3-month history of chronic pain were eligible for participation in the study. The chronic pain had to be associated with any of the following conditions: diabetic peripheral neuropathy, postherpetic neuralgia, traumatic injury, complex regional pain syndrome, back pain, neck pain, fibromyalgia, chronic pancreatitis, osteoarthritis, or cancer. Eligible patients were opioid tolerant, i.e., were receiving ≥60 mg/day of oral morphine, ≥25 μg/hr of transdermal fentanyl, ≥30 mg/day of oxycodone, ≥8 mg/day of hydromorphone, or an equivalent, stable daily dose of another opioid for ≥7 days before enrolling in the study. Their chronic pain had to be reasonably well controlled during the 24 hours before screening; well-controlled pain was defined as that having an average PI of ≤6 on an 11-point numeric rating scale (0 = no pain, 10 = worst pain imaginable). Patients had to report experiencing 1 to 4 episodes per day of BTP, each lasting <4 hours, that were at least partially relieved by a supplemental opioid.

Patients were excluded from the study if they had uncontrolled or rapidly escalating pain that was not BTP; a known allergy or another contraindication to any ingredient in the study drug; history of alcohol or other substance abuse during the past 5 years; or presence of cardiopulmonary disease or other medical or psychiatric disorder that, in the investigator's opinion, would have significantly increased the risks associated with opioid treatment or compromised the study data. Patients also were excluded if they were lactating, were expected to have surgery during the study, had participated in a previous FBT study, or had taken part in a study involving an investigational drug in the previous 30 days.

Study Design

This cross-over design study included a screening period, 2 open-label titration periods, and 2 double-blind treatment periods (Fig. 1). Information collected during screening included a medical history, concomitant medication use, and a detailed pain assessment (type of pain, daily frequency of BTP episodes, severity of BTP episodes, details of the ATC opioid medication taken, and supplemental opioid medications taken for BTP). Also, clinical laboratory tests, urine drug screening, a physical examination (including vital sign measurements), and an oral mucosal examination (as a baseline assessment for the emergence of any application site–related adverse events [AEs]) were performed.

F1-36
Figure 1:
Study design. This cross-over design study included a screening period, 2 open-label titration periods, and 2 double-blind treatment periods. Patients were randomized to the order of titrating fentanyl buccal tablet (FBT) (200 to 800 μg) and oxycodone (15 to 60 mg) to a successful dose. Patients were then randomized to treat 10 BTP episodes with 1 of the 2 blinded study drugs during double-blind treatment period 1, and then to manage a subsequent 10 episodes of breakthrough pain with the other blinded study drug during double-blind treatment period 2. OxyIR = immediate-release oxycodone.

The range of doses of FBT (200, 400, 600, or 800 μg) and oxycodone (15, 30, 45, or 60 mg) in this study was selected on the basis of an estimate that FBT 100 μg was approximately equivalent to oxycodone 7.5 mg. This estimate was based on commonly used relative potency calculations.2527

Open-Label Titration Periods

Eligible patients were randomized in a 1:1 ratio to receive either FBT or oxycodone in the first open-label titration period to identify a successful dose of study drug for the treatment of BTP in each patient. A successful dose of study drug was defined as the single dose (of FBT or oxycodone) at which the patient reported adequate PR (i.e., “good” to “excellent” medication performance ratings) for at least 2 of 3 BTP episodes without needing supplemental medication and without experiencing unacceptable AEs. Patients were instructed to continue their prestudy ATC opioid medication throughout the study. The ATC opioid medication could be changed at any time during the titration periods if clinically indicated but could not be adjusted during the double-blind treatment periods.

The titration process continued until patients found a successful dose, reached the maximum dose (FBT 800 μg or oxycodone 60 mg) without achieving adequate PR, or experienced unacceptable AEs. After completion of the first open-label titration period, patients crossed over into the second open-label titration period, in which they identified a successful dose of the other study drug for treatment of BTP. Patients who identified successful doses of both FBT and oxycodone proceeded to the double-blind treatment phase of the study.

Double-Blind Treatment Periods

There were 2 double-blind, double-dummy treatment periods in the study. Patients were randomized to treat 10 BTP episodes with 1 of the 2 blinded study drugs (at the already identified successful dose) during double-blind treatment period 1, and then to manage a subsequent 10 episodes of BTP with the other blinded study drug during double-blind treatment period 2. With this cross-over design, patients served as their own controls, and treatment comparisons were made within patients. To maintain blinding, we used a double-dummy treatment technique: patients took a buccal tablet and an oral capsule for each BTP episode, one treatment being the active study drug and the other a matching placebo.

Patients were instructed not to administer additional study drugs within 4 hours after any study drug administration and were asked to refrain from taking supplemental prestudy medication for at least 60 minutes.

Assessments

Efficacy assessments were recorded in electronic patient diaries (InvivoData, Inc., Pittsburgh, PA). The primary efficacy measure was the difference in PI before and 15 minutes after administration of the study drug (PID15). PI was rated using an 11-point numerical scale (0 = no pain, 10 = worst pain imaginable). Other efficacy measures included PID at 5, 10, 30, 45, and 60 minutes after administration of study drug; summed PID from 5 through 30 minutes (SPID30) and from 5 through 60 minutes (SPID60) after administration of study drug; PR measured on a 5-point scale (0 = none, 4 = complete PR) at 5, 10, 15, 30, 45, and 60 minutes after administration of study drug; time from administration of study drug to time when any PR was achieved; time from administration of study drug to meaningful PR; total PR at 60 minutes (TOTPAR60); percentage of TOTPAR60; and proportion of BTP episodes with an improvement in PI of ≥33% at 5, 10, 15, 30, 45, and 60 minutes after study drug (representing a moderate improvement) and ≥50% at 5 to 60 minutes after study drug (representing a substantial improvement).28,29 Patients were reminded to report time to any PR and meaningful PR at the same time as the scheduled PI and PR assessments. Therefore, in most cases, the time to any or meaningful PR was associated with a scheduled assessment time point and not at the exact time of occurrence. A medication performance assessment was completed at 30 and 60 minutes after each study drug administration and summarized on a 5-point categorical scale (0 = poor, 4 = excellent). Because there is no defined clinically meaningful difference between 2 active treatments for BTP, multiple end points—including PID and PR at multiple time points, relative responder criteria, and global evaluations—were analyzed to characterize the clinical relevance of the effect of each treatment.

After completion of the second double-blind treatment period, patients completed a medication preference questionnaire, which asked them whether they preferred the study drug administered in the first or the second double-blind treatment period.

Safety and tolerability were assessed at all visits. Data were collected on all patient and investigator reports of any AEs, including serious AEs and discontinuations due to AEs. Vital sign evaluations and oral mucosa examinations (assessing the emergence of any application site–related AEs) were performed at each visit; clinical laboratory tests and physical examinations were performed at study entry and at final visit.

Data Analyses

The estimate of sample size was based on data from 2 double-blind, placebo-controlled studies in patients with BTP.20,21 Assuming that 70% of patients identified a successful dose during titration, an estimated enrollment of 260 evaluable patients was needed to achieve 90% power for the primary efficacy analysis using a 2-sided t test with a significance level of 0.05.

A preplanned interim analysis was conducted by an independent consultant after the 160th patient was enrolled and evaluable for efficacy. It was determined that the study was adequately powered at this point because the mean PID15 significantly favored FBT (P < 0.0001). On the basis of this decision rule established a priori for the study, all enrolled patients were allowed to complete the study, but no more patients were enrolled.

The efficacy analysis set, which included all patients who had at least 1 evaluable episode of BTP treated with FBT and at least 1 evaluable episode of BTP treated with oxycodone, was used for the primary and secondary pain assessment analyses. An episode was considered evaluable if a valid PI measurement was obtained immediately before administration of the study drug. Testing based on the secondary variables was performed using α = 0.05. Missing data within an episode were imputed via the last-observation-carried-forward method.

For the primary efficacy measure (PID15), data for FBT and oxycodone were compared using an analysis of variance (ANOVA) model, with treatment, period, and treatment sequence as fixed effects and patients as a random effect (a mixed-effect model for cross-over data as repeated measures). The sequence effect represents the Treatment ×Period interaction in this study design; sequence effect was not statistically significant (P = 0.8495) in the primary efficacy analysis. The same model was used to analyze the PI-based secondary measures (e.g., PID, SPID). Analysis of PR was performed using the Wilcoxon's signed rank test. Analyses of the proportion of episodes with ≥33% and ≥50% reductions in PI, time to any PR, time to meaningful PR, and the medication performance assessment were performed using a generalized estimation equation model. Generalized estimating equations provide a practical method with reasonable statistical efficiency to analyze data when the responses are discrete and correlated.30 Liang and Zeger30 introduced generalized estimating equations as a method of dealing with correlated data when, except for the correlation among responses, the data can be modeled by a generalized linear model (Hanley et al.31). The model used study drug as a fixed effect, patient as a random effect, and the logit link function. Treatment differences and 95% confidence intervals (CIs) were estimated from these models. No adjustments were made for multiple comparisons; P values for secondary measures were descriptive in nature.

All patients who took at least 1 dose of study drug were included in the safety evaluation. AEs were summarized by treatment. Safety comparisons were descriptive, and no formal statistical testing was performed.

RESULTS

Patient Disposition and Characteristics

The patient disposition is illustrated in Figure 2. A total of 486 patients were screened, and 323 patients were enrolled in the study. Of these, 320 received at least 1 dose of study drug (FBT or oxycodone) and were evaluable for safety. A total of 203 (63%) patients found a successful dose of FBT and oxycodone. During the titration periods, 79%–83% of patients identified a successful dose of FBT or oxycodone. There were 191 (60%) patients who completed both titration periods and entered the double-blind treatment phase. Of these, 180 completed both double-blind treatment periods. During titration and double-blind treatment, the reasons for discontinuation were similar between treatments.

F2-36
Figure 2:
Patient disposition. The safety analysis set (n = 320) included all patients treated with at least 1 dose of study drug. The efficacy analysis set (n = 183) included all patients who treated at least 1 breakthrough pain episode with fentanyl buccal tablet or oxycodone during each double-blind treatment period and who recorded the pretreatment pain intensity for each of these episodes. *Three patients were enrolled but not treated.

After completion of the study and during review of the data, it was noted that 56 (17%) patients who had entered the double-blind phase of the study had done so without having met the protocol definition of identifying a successful dose of 1 of the 2 study drugs. The protocol deviations for these patients involved continuing into a subsequent study period without having titrated the study drug to a successful dose, continuing to the subsequent period with a dose that exceeded the successful dose, or not having the successful dose appropriately documented in the electronic diary. A sensitivity analysis that excluded the data from these patients from the primary analysis (PID15) was conducted. There was no substantive effect on the results when the data from these patients were removed (see the Efficacy section); therefore, the results from analyses with all patient data are reported here.

Patient demographics and other baseline characteristics were similar for the enrolled population and efficacy analysis set (Table 1). Table 2 presents the opioid regimens at baseline for treated patients stratified by the randomized titration sequence. Overall, the doses and types of ATC and supplemental medications were similar for the 2 groups. In addition to analgesics, concomitant medications most frequently used by patients in the safety analysis set during the study included psychoanaleptics (i.e., antidepressants and antianxiety drugs) (55%), psycholeptics (i.e., depressants and hypnotic drugs) (49%), antiepileptics (36%), muscle relaxants (34%), drugs for acid-related disorders (29%), serum lipid–reducing drugs (29%), and anti-inflammatory and antirheumatic products (26%).

T1-36
Table 1:
Patient Demographics and Other Baseline Characteristics
T2-36
Table 2:
Around-the-Clock and Supplemental Opioid Regimens at Baseline: Enrolled Patients (N = 323)a

Overall, 71% (227/320) of patients who entered the dose titration phase found a successful dose of FBT (15% identified 200 μg, 16% identified 400 μg, 23% identified 600 μg, 18% identified 800 μg, 29% did not find a successful dose), and 72% (230/320) found a successful dose of oxycodone (15% identified 15 mg, 20% identified 30 mg, 20% identified 45 mg, 17% identified 60 mg, 28% did not find a successful dose). Figure 3 shows the distribution of successful doses of FBT and oxycodone at the end of titration. An ad hoc analysis showed significant concordance between the successful dose of FBT and oxycodone, as is measured by Kendall's τ statistic (τ = 0.62; P < 0.0001). That is, FBT doses of 200, 400, 600, and 800 μg appeared to be approximately equivalent to oxycodone doses of 15, 30, 45, and 60 mg.

F3-36
Figure 3:
Distribution of successful doses of fentanyl buccal tablet (FBT) and oxycodone (n = 320). The number inside each circle indicates the patient count for that node (e.g., 26 patients identified a successful dose of FBT 200 μg and oxycodone 15 mg). The size of the circle correlates with the number of patients achieving a successful dose for a given dose. One hundred seventeen patients failed to identify a successful dose of both study medications. OxyIR = immediate-release oxycodone.

No linear relationship was observed between the successful doses achieved during the titration phase for FBT or oxycodone and the ATC dose or the dose of supplemental opioid medication at baseline. Of the 96 patients who entered the study taking oxycodone as their supplemental opioid and who successfully completed both titration periods, 78 (81%) identified a successful oxycodone dose that was greater than their prestudy oxycodone dose.

Efficacy

The primary efficacy measure, mean PID15, was significantly greater after FBT administration than after oxycodone (mean [SD], 0.82 [1.12] vs. 0.60 [0.88]; 95% CI 0.18–0.29; P < 0.0001; based on an 11-point numerical scale). FBT was shown to be more effective than oxycodone according to several secondary efficacy measures at 15 and 30 minutes after administration of study drug (Table 3).

T3-36
Table 3:
Summary of Efficacy Measures at 15 and 30 Minutes After Administration

Sensitivity analyses were performed, excluding the 56 (17%) patients who had entered into the double-blind phase of the study without having met the protocol definition of successful dose for one of the treatments. It was determined that data from these patients had no meaningful impact on the results of the study as a whole, because mean PID15 was greater after FBT than was that after oxycodone, whether or not these patients were included (P < 0.0001).

The mean PID was greater after FBT administration than after oxycodone beginning at 5 minutes after administration of study drug (P = 0.0081), and differences were maintained through 60 minutes (P < 0.0001; Fig. 4). Differences in favor of FBT between treatments were observed in mean PR beginning at 10 minutes after administration of study drug (P = 0.0275), and differences were maintained through 60 minutes posttreatment (P < 0.05; Fig. 5). Any PR was achieved within the scheduled 10-minute assessment for a higher proportion of BTP episodes after FBT (16%) than after oxycodone (12%; 95% CI 1.0–1.9; P = 0.0268). Meaningful PR was achieved for a higher proportion of BTP episodes after FBT than after oxycodone beginning at ≤15 minutes through 45 minutes after administration of study drug (P < 0.05; Fig. 6). The proportion of BTP episodes for which patients reported a mean improvement of ≥33% in PI was greater with FBT than was that with oxycodone beginning at 15 minutes after study drug treatment (P < 0.05). The proportion of BTP episodes for which patients reported a mean improvement of ≥50% was greater with FBT beginning at 30 minutes posttreatment (P < 0.02); statistical differences were not reported earlier than 30 minutes. On the basis of achievement of meaningful PR, the number of BTP episodes needed to be treated for a differential benefit to be observed was 24 BTP episodes at 15 minutes and 12 BTP episodes at 30 minutes.

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Figure 4:
Pain intensity difference at each time point by treatment. FBT = fentanyl buccal tablet; OxyIR = immediate-release oxycodone.*P < 0.05. †P < 0.0001.
F5-36
Figure 5:
Pain relief at each time point by treatment. FBT = fentanyl buccal tablet; OxyIR = immediate-release oxycodone.*P < 0.05. †P ≤ 0.0001.
F6-36
Figure 6:
Proportion of breakthrough pain episodes for which meaningful pain relief was achieved at each time point by treatment. FBT = fentanyl buccal tablet; OxyIR = immediate-release oxycodone.*P < 0.05.

At 60 minutes postdose, mean (SD) SPID was greater after FBT administration (8.57 [5.27]) than was that after oxycodone (7.68 [4.52]; P < 0.0001), mean (SD) TOTPAR60 was 6.32 (2.51) after FBT administration in comparison with 5.64 (2.28) after oxycodone administration (P < 0.0001), and mean (SD) percentage of maximum TOTPAR60 was 39.5% (15.7%) after FBT administration in comparison with 35.3% (14.3%) after oxycodone administration.

On the medication performance assessment, patients reported “good” to “excellent” ratings of medication performance at 30 minutes postdose for 41% of BTP episodes treated with FBT in comparison with 26% treated with oxycodone (P < 0.0001 for the distribution of responses); “good” to “excellent” ratings were reported at 60 minutes postdose for 79% of the episodes treated with FBT versus 71% treated with oxycodone (P < 0.0001 for the distribution of responses). On the medication preference questionnaire, 99 of 190 patients (52%) preferred FBT and 63 (33%) preferred oxycodone for management of their BTP. Fifteen (8%) patients had no preference and 13 (7%) did not complete the questionnaire.

Safety and Tolerability

Overall, 162 (51%) of the 320 patients who received a study drug reported at least 1 AE during the study, 106 (38%) after receiving FBT and 88 (31%) after receiving oxycodone. The majority of AEs were reported during the titration periods; the most frequently reported AE was nausea (Table 4). Thirty-three (10%) patients (29 during titration periods, 5 during double-blind treatment periods) reported 46 AEs associated with the FBT application site. The majority of these application site AEs (91%) resolved.

T4-36
Table 4:
Summary of Adverse Events (AE)

Thirty-nine (12%) patients discontinued participation in the study because of AEs. The most frequent AEs leading to discontinuation were nausea (10 patients overall; 9 after FBT treatment and 1 after oxycodone treatment), headache (6 patients overall; 2 after FBT treatment and 4 after oxycodone treatment), and dizziness (4 patients overall; 3 after FBT treatment and 1 after oxycodone treatment). Three patients discontinued from the study because of application site AEs (1 patient because of vesicles, 1 because of irritation, and 1 because of ulcer and irritation); all 3 discontinuations occurred during the titration periods.

Two serious AEs (pneumonia) were reported in 1 patient. One episode occurred before the start of study drug treatment and the other occurred on day 36 (during the second titration period after FBT treatment). Both occurrences were considered by the investigator not to be related to the study drug. No other serious AEs were reported.

DISCUSSION

In this study of opioid-tolerant patients with chronic pain, treatment with FBT for BTP was associated with a more rapid onset of analgesia compared with oxycodone. Differences between FBT and oxycodone were observed in PID from 5 minutes through 60 minutes posttreatment (P < 0.05) and in PR from 10 minutes through 60 minutes posttreatment (P < 0.05). Differences were also observed in several other measures, including the proportion of BTP episodes for which PI improved by at least 33%, time to meaningful PR, and patients' medication preference. Although the differences between the treatments were statistically significant, in most cases, they were numerically small. The clinical relevance of the differences in efficacy was illustrated by the results of the global assessment of medication performance and the medication preference questionnaire. Patients reported “good” to “excellent” ratings of medication performance at 30 minutes postdose for 41% of BTP episodes treated with FBT in comparison with 26% treated with oxycodone (P < 0.0001 for the distribution of responses) and more than half of the patients who completed the double-blind part of the study stated a preference for FBT over oxycodone, whereas only one-third indicated a preference for oxycodone.

Overall, FBT and oxycodone were well tolerated in this study. The rates and types of AEs reported were generally similar between treatments, and the safety profile of FBT was consistent with the profile observed in previous studies.1822

There are limited clinical data comparing traditional short-acting opioids with rapid-onset opioids for the treatment of BTP. A previous double-blind, double-dummy, randomized, multiple cross-over study showed OTFC to be more effective than immediate-release oral morphine sulfate for the treatment of BTP.12 However, patients did not titrate immediate-release oral morphine to an effective dose in the same manner as OTFC. Patients continued at the same dose of immediate-release oral morphine that they were taking at study entry. This is probably not an accurate assessment of the dose needed for adequate analgesia, as evidenced by the fact that 81% of patients entering this study taking oxycodone for BTP titrated to a higher dose of oxycodone.

In our study, the percentage of patients who identified a successful dose (63%) was lower than that observed in previous studies of FBT versus placebo (65%–81%).1821 However, patients were required to successfully titrate 2 study drugs (FBT and oxycodone), as opposed to 1 (FBT only) in previous studies. The proportion of patients who established a successful dose of FBT during the first titration period (79%) was within the range of the proportion who achieved successful doses in previous studies.

There was a significant concordance between the successful dose of FBT achieved and the successful dose of oxycodone achieved, such that FBT doses of 200, 400, 600, and 800 μg appeared to be approximately equivalent to oxycodone doses of 15, 30, 45, and 60 mg. This finding was consistent with the estimate that FBT 100 μg is approximately equivalent to oxycodone 7.5 mg on the basis of the calculated relative potency.2527,32 However, no linear relationship was observed between the successful dose of either study drug and the mean baseline dose of ATC opioid medication or baseline dose of supplemental opioid taken before study entry. Although this lack of relationship has been shown in previous studies of OTFC and FBT,1821,3335 it has never been shown with oxycodone. This result suggests that BTP should be assessed and treated independently of persistent pain by titration to a successful dose, regardless of the supplemental opioid.

It is interesting to note that 81% of patients who entered the study taking oxycodone and completed the titration periods titrated to a higher oxycodone dose than to their prestudy dose. More than half of the patients in this study who identified a successful dose (52%) required oxycodone doses ≥45 mg to manage their BTP episodes. Considering that patients may experience as many as 4 BTP episodes per day, we acknowledge that these daily doses of oxycodone may be higher than what many clinicians would be comfortable prescribing (the median supplemental dose was 15 mg/BTP episode of oral morphine equivalents at study entry). However, the study was designed to make a fair comparison between 2 opioids, FBT and oxycodone, each titrated to a successful dose. Because the study titration procedures for oxycodone did not necessarily mimic typical clinical practice, it is unclear whether similar results would be observed outside of a controlled study setting. It is, however, reasonable to expect that administration of lower doses of oxycodone would result in less efficacy than was reported in this study.

The double-blind portion of this study included treatment of up to 20 BTP episodes over an average of 15.9 days for a total of 3522 treated BTP episodes. This study provides rich data regarding the use of opioids for the treatment of BTP in this patient population in a controlled setting. However, because this was not a long-term, parallel-group study, long-term comparative safety and efficacy data regarding the treatment of BTP in this manner are not available, including outcome measures of emotional functioning or physical conditioning and the risk of aberrant drug-related behavior associated with the administration of either study drug.

In conclusion, FBT resulted in a more rapid onset of analgesia than did oxycodone and was generally well tolerated for the treatment of BTP in opioid-tolerant patients.

DISCLOSURES

Name: Michael A. Ashburn, MD, MPH.

Contribution: Conduct of study, data analysis, and manuscript preparation.

Conflict of Interest: Dr. Ashburn is a shareholder and part-time employee of ZARS Pharma (until September 1, 2009); no conflict of interest to report regarding the medications used in this study or the study sponsor.

Name: Kieran A. Slevin, MD.

Contribution: Conduct of study, data analysis, and manuscript preparation.

Conflict of Interest: This author has no conflict of interest to declare.

Name: John Messina, PharmD.

Contribution: Study design, data analysis, and manuscript preparation.

Conflict of Interest: Dr. Messina is an employee of Cephalon, Inc.

Name: Fang Xie, PhD.

Contribution: Study design, data analysis, and manuscript preparation.

Conflict of Interest: Dr. Xie is an employee of Cephalon, Inc.

ACKNOWLEDGMENTS

The authors thank the investigators: Amy Abernathy, MD (Durham, NC); Donald Bacon, MD (San Antonio, TX); Lora L. Brown, MD (Sarasota, FL); Richard E. Blonsky, MD (Chicago, IL); Maia U. Chakerian, MD (Los Gatos, CA); Craig T. Curtis, MD (Orlando, FL); Marc E. Duerden, MD (Indianapolis, IN); Gregory M. Flippo, MD (Birmingham, AL); Michael G. Gibson, MD (Birmingham, AL); Joseph S. Gimbel, MD (Phoenix, AZ); Herbert D. Goodman, MD (Phoenix, AZ); Jeffrey Gudin, MD (Englewood, NJ); David R. Hassman, DO (Berlin, NJ); Michael S. Kaplan, PhD, MD (Baltimore, MD); Adam D. Karns, MD (Beverly Hills, CA); Arifulla Khan, MD (Bellevue, WA); Peter Kroll, MD (Hendersonville, TN); Alexander V. Murray, MD (Greensboro, NC); Shahriar Nabizadeh, MD (Jacksonville, FL); Craig S. Nairn, MD (Albuquerque, NM); Srinivas Nalamachu, MD (Overland Park, KS); Atul T. Patel, MD (Overland Park, KS); Kathleen Gannon, DO (West Des Moines, IA); Steven Siwek, MD (Phoenix, AZ); Neal Slatkin, MD (Duarte, CA); Marvin Tark, MD (Marietta, GA); Donald Taylor, MD (Marietta, GA); Marcia D. Wolf, MD (Pikesville, MD); Pavan K. Yerramsetty, MD (Raleigh, NC); Lloyd Saberski, MD (New Haven, CT); David J. Sandercock, DO (San Antonio, TX); Richard Bowman, MD (Charleston, WV); Randall P. Brewer, MD (Shreveport, LA); Lenin Peters, MD (High Point, NC); William J. Keating, MD (Dawsonville, GA); Frederick T. Murphy, DO (Duncansville, PA); Larry D. Empting, MD (Atlanta, GA); Moges Sisay, MD (Evansville, IN); Mary L. Stedman, MD (Tampa, FL); Michael D. Courtney, MD (Spring Hill, FL); Samir Arora, MD (Columbus, OH); Alex White, MD (Port Orange, FL); Kelby J. Hutcheson, MD (Greenville, SC); Michael J. Drass, MD (Altoona, PA); and Robert Karns, MD (Beverly Hills, CA).

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