Breakthrough Pain In Opioid-tolerant Patients Research Articles

Efficacy and Safety of Sublingual Fentanyl Tablets for the Management of Breakthrough Pain in Patients with Chronic Musculoskeletal Pain with Neuropathic Component: Multicenter Prospective Study

Despite its prevalence and impact, breakthrough pain (BTP) in chronic non-cancer pain with neuropathic component, has not been well studied and is sometimes unrecognized and often undertreated. We evaluated the efficacy of sublingual fentanyl tablet (SLF) for the treatment of BTP in opioid-tolerant patients with chronic musculoskeletal pain with neuropathic component in terms of relief of pain intensity and assessed whether hypothetical pain relief impacts on quality of life (QoL). A multicenter, prospective, open-label study was conducted over a 30-day period. Efficacy was evaluated using a visual analogue scale (VAS) and time to onset of action of SLF. The incidence of dependence was assessed by the Leeds Dependence Questionnaire (LDQ). Changes in QoL were evaluated using the Brief Pain Questionnaire (BPI) and the EuroQol (EQ-5D). Adverse events (AE) were recorded throughout. 106 patients were enrolled and 105 completed the study. The average pain reduction across the study was -3.30 points [95 % confidence interval (CI) 2.9-3.7; P < 0.0001]. Pain intensity improvement from baseline was statistically significant at first assessment and all subsequent assessments (P < 0.0001). The most common AEs included nausea (33.87 %), constipation (33.06 %), somnolence (19.35 %) and vomiting (6.45 %). No significant differences were observed on LDQ (P = 0.71). QoL as measured by BPI showed statistically significant improvement in all four severity items and all interference items (P < 0.0001) and a significant improvement in the percentage of pain relief reported by patients (P < 0.0001). EQ-5D results showed a trend towards improvement. Mean self-rate health status, as measured by the EQ VAS scale increased significantly (P < 0.0001). SLF provides significant reductions in BTP intensity. The results of the BPI and EQ-5D assessments indicate that pain relief is associated with improvement of functioning and enhancement of QoL.

Fentanyl Buccal Tablet Compared with Immediate-Release Oxycodone for the Management of Breakthrough Pain in Opioid-Tolerant Patients with Chronic Cancer and Noncancer Pain: A Randomized, Double-Blind, Crossover Study Followed by a 12-Week Open-Label Phase to Evaluate Patient Outcomes

Evaluate analgesic efficacy, functional benefit, and patient satisfaction with fentanyl buccal tablet vs immediate-release oxycodone for breakthrough pain (BTP). Randomized, double-blind, active-controlled crossover trial and 12-week open-label extension. Forty-two U.S. sites. Opioid-tolerant patients with predominantly chronic noncancer pain experiencing BTP. Patients were randomized to open-label titration periods with fentanyl buccal tablet followed by oxycodone or vice versa for BTP management. After titrating to a successful dose of both medications (single dose providing adequate analgesia without unacceptable adverse events), patients were re-randomized to treat 10 BTP episodes with one medication and 10 with the other. The primary efficacy measure was pain intensity (PI) difference 15 minutes postdose. Secondary measures included PI difference 5, 10, 30, 45, and 60 minutes postdose; sum of PI differences 30 and 60 minutes postdose; ≥33% and ≥50% reduction in PI; and pain relief. Questionnaires assessed functional status/satisfaction. Of 213 patients enrolled, 149 achieved a successful dose of both medications; 131 completed the double-blind phase and 112 the open-label phase. PI difference at 15 minutes (mean [standard deviation]) was greater with fentanyl buccal tablet (0.88 [1.20]) vs oxycodone (0.76 [1.13]; P < 0.001). Patients preferred fentanyl buccal tablet (47%) over oxycodone (35%); 18% had no preference. Patients and clinicians reported consistently better functional improvement and satisfaction with fentanyl buccal tablet vs short-acting opioids (P < 0.05). Fentanyl buccal tablet was associated with rapid onset of analgesia and improvements in functional status and patient satisfaction compared with immediate-release oxycodone.

AB 11. Efficacy and tolerability of intranasal fentanyl spray 50 to 200 microg for breakthrough pain in patients with lung cancer and bone metastases

Background Breakthrough cancer pain (BTcP) represents an important clinical challenge in the care of patients with cancer. Oral opioids have traditionally been the only available drugs for BTcP. However, the onset and duration of action of oral opioids may not be suitable for treating many episodes of BTcP in patients with bone metastases that are of short onset and duration. Aim of this study was to investigate the efficacy and long-term tolerability of intranasal fentanyl spray (INFS) 50 to 200 microg in the treatment of breakthrough pain in opioid-tolerant patients with lung cancer and bone metastases.

A review of the pharmacokinetic profile of transmucosal fentanyl formulations

Background and objectives:Breakthrough pain (BTP) is a transitory flare of moderate-to-severe pain that occurs in patients with stable, controlled persistent pain. Management of BTP episodes is difficult because frequency, time-to-peak intensity, and duration of episodes vary both within and between individuals.Formulations of fentanyl that use a buccal, sublingual, or nasal transmucosal route of administration have been developed for the treatment of BTP in opioid-tolerant patients with cancer. These formulations allow rapid passage into the bloodstream and avoid first-pass metabolism and, therefore, are more likely to match the time-course of BTP episodes than are oral formulations.The purposes of this analysis were to identify and review published data describing the pharmacokinetic properties of rapid-onset fentanyl formulations and to evaluate these properties in view of the temporal dynamic characteristics of BTP in order to help guide medical practice.Methods:Relevant publications were searched in the PubMed database from 1998. The plasma drug concentration–time profile of each formulation obtained from the identified studies was adjusted to a consistent scale for comparison.Results:The data revealed that the various transmucosal formulations resulted in three typical plasma fentanyl concentration profiles: (1) type 1: a very rapid rise and short duration; (2) type 2: a rapid increase and sustained intensity; and (3) type 3: a slower onset and longer duration.Conclusions:Given the substantial variability of BTP episodes experienced by patients, these pharmacokinetic differences may provide useful information for a physician who is selecting a rapid-onset opioid medication for a patient.

Fentanyl nasal spray for the treatment of cancer pain

Introduction: Breakthrough pain, a transitory flare of pain in patients with otherwise controlled chronic pain, has been well characterized in cancer patients but despite medical awareness, sometimes remains underdiagnosed and therefore undertreated.Areas covered: Oral transmucosal fentanyl citrate (OTFC) and fentanyl buccal tablets are the first medications developed specifically for the treatment of breakthrough pain in opioid-tolerant patients. Since oral administration of fentanyl is not an option for many cancer patients, the development of intranasal fentanyl spray (INFS) emerged as a more effective method of administration. Intranasal administration of fentanyl has several advantages over the oral/gastrointestinal route and clinical trials have shown that it is superior to OTFC while being well tolerated and more acceptable by the majority of patients.Expert opinion: The aim of this review is to summarize the pharmacological characteristics and data obtained from clinical studies of INFS in the past few years, and present Fentanyl Pectin Nasal Spray (PecFent), which uses an innovative delivery system and is now approved in the EU. Finally, we discuss the impact that it may have in the future management of breakthrough pain in cancer patients, because an accurate diagnosis followed by the best treatment is crucial for effective pain alleviation.

Functioning/satisfaction with fentanyl buccal tablet compared to traditional short-acting opioids for the management of breakthrough pain in opioid-tolerant patients with chronic pain

There are limited data directly comparing different treatments for breakthrough pain (BTP). After obtaining IRB approval and informed written consent, opioid-tolerant adults with BTP who completed a randomized, double-blind, crossover study were re-randomized to fentanyl buccal tablet (FBT) or any traditional short-acting opioid (SAO) for 12 weeks of open-label treatment. Patients/clinicians completed the following functionality/satisfaction assessments: Patient Assessment of Function (PAF), Clinician Assessment of Patient Function (CAPF), Patient Global Impression of Change (PGIC), and Clinical Global Impression of Change (CGIC). All assessments were rated on a 7-point scale, from very much worsened to very much improved. 130 patients received treatment (65, FBT; 65, SAO). For the PAF, more patients receiving FBT than SAO reported improvement in 11 of 12 areas of functioning (P<0.05 for 7 areas of functioning), including improvement in enjoyment of life (72% vs 43%; P=0.001 for the distribution of responses). For the CAPF, clinicians reported that more patients improved in all 12 areas of functioning (P<0.05 for 6 areas of functioning) with FBT than SAO, including improvement in enjoyment of life (68% vs 38%; P<0.001). Responses to the PGIC and CGIC also favored FBT vs SAO (PGIC: mean [SD] 1.5 [1.02] vs 0.9 [1.09]; CGIC: 1.4 [1.01] vs 0.7 [1.05]; both P<0.001). Adverse events were generally similar between treatments and typical of opioids. In conclusion, following 12 weeks of open-label treatment, patients and clinicians reported consistently better efficacy, including functional improvement, with FBT than with traditional SAOs in opioid-tolerant patients with BTP. Supported by Cephalon, Inc. There are limited data directly comparing different treatments for breakthrough pain (BTP). After obtaining IRB approval and informed written consent, opioid-tolerant adults with BTP who completed a randomized, double-blind, crossover study were re-randomized to fentanyl buccal tablet (FBT) or any traditional short-acting opioid (SAO) for 12 weeks of open-label treatment. Patients/clinicians completed the following functionality/satisfaction assessments: Patient Assessment of Function (PAF), Clinician Assessment of Patient Function (CAPF), Patient Global Impression of Change (PGIC), and Clinical Global Impression of Change (CGIC). All assessments were rated on a 7-point scale, from very much worsened to very much improved. 130 patients received treatment (65, FBT; 65, SAO). For the PAF, more patients receiving FBT than SAO reported improvement in 11 of 12 areas of functioning (P<0.05 for 7 areas of functioning), including improvement in enjoyment of life (72% vs 43%; P=0.001 for the distribution of responses). For the CAPF, clinicians reported that more patients improved in all 12 areas of functioning (P<0.05 for 6 areas of functioning) with FBT than SAO, including improvement in enjoyment of life (68% vs 38%; P<0.001). Responses to the PGIC and CGIC also favored FBT vs SAO (PGIC: mean [SD] 1.5 [1.02] vs 0.9 [1.09]; CGIC: 1.4 [1.01] vs 0.7 [1.05]; both P<0.001). Adverse events were generally similar between treatments and typical of opioids. In conclusion, following 12 weeks of open-label treatment, patients and clinicians reported consistently better efficacy, including functional improvement, with FBT than with traditional SAOs in opioid-tolerant patients with BTP. Supported by Cephalon, Inc.

Long-term dosing, safety, and tolerability of fentanyl buccal tablet in the management of noncancer-related breakthrough pain in opioid-tolerant patients

Objective:To evaluate the long-term dosing, safety, and tolerability of fentanyl buccal tablet (FBT) in a large cohort of opioid-tolerant patients with chronic noncancer pain and breakthrough pain (BTP).Design:Combined analysis of three double-blind, placebo-controlled, and two open-label studies.Results:Of 1160 patients who received ≥1 dose of FBT, 83% achieved a successful dose, ranging from 100 to 800 μg, mostly at 600 or 800 μg. Not all of the patients included in this analysis were enrolled in long-term studies and 156 (13%) patients were still receiving ongoing treatment when their study site closed. Median treatment duration was 106.0 days. The mean FBT dose in the post-titration population (n = 946) increased from 2108 to 3132 μg/day, with ≥1 FBT dose increase in 27% of patients; most dose increases occurred during the first 6 months. The FBT daily dose as a proportion of the daily opioid dose remained fairly stable (59–65%) throughout the treatment period. Overall, 925 (80%) enrolled patients had ≥1 adverse event (AE). The most frequent AEs were nausea (21% of patients), vomiting (11%), dizziness (10%), and headache (10%). Common AEs generally occurred within 7 days of starting treatment and lasted for ≤2 days. Serious AEs occurred in 136 (12%) patients and included six deaths (none related to FBT) and 11 instances of opioid overdose (all with satisfactory resolution). AE-related discontinuations occurred in 163 (14%) patients and were similar to the common AEs.Conclusions:Despite the limitations, including the controlled clinical setting, this pooled analysis of several clinical studies provides valuable information for the long-term management of BTP with FBT. Patients require regular evaluation and, when necessary, adjustment of opioid medications to maintain adequate pain control. FBT was generally safe and well tolerated in this setting.

Pharmacokinetics of 800 mcg of sublingual fentanyl tablets, administered as one 800-mcg tablet, two 400-mcg tablets, or four 200-mcg tablets, in healthy volunteers

Sublingual fentanyl tablet (Abstral®) is a rapid-onset formulation under evaluation in the United States and approved in Europe for management of breakthrough pain in opioid-tolerant patients with cancer. Understanding whether multiple lower-dose tablets yield the same pharmacokinetics as a single tablet containing an equivalent total dose may aid physicians and be more convenient for patients, particularly during dose titration. This open-label, randomized, single-dose, 3-period crossover study compared bioavailability of sublingual fentanyl 800 mcg administered as one 800-mcg tablet, two 400-mcg tablets, or four 200-mcg tablets, administered by placing on the floor of the mouth directly under the tongue until completely dissolved. In total, 36 patients (mean age, 27.3 y; 53% female; 83% white) were randomized into 6 dosing sequences, with 7 days between doses. Naltrexone 50 mg tablets were administered concomitantly to reduce potential for respiratory-related adverse events (AEs). Blood samples for pharmacokinetic assessments were taken predose through 30 hours postdose. Rate and extent of exposure of sublingual fentanyl administered as two 400-mcg tablets and four 200-mcg tablets, measured by mean Cmax, AUC(0-t), and AUC(0-∞), were 98-112% and 97-113%, respectively, of the corresponding measures for one 800-mcg tablet. Tmax and t½ were similar between treatments. These data indicate bioequivalence of sublingual fentanyl administered as one 800-mcg tablet, two 400-mcg tablets, and four 200-mcg tablets. All doses were generally well tolerated. AEs occurred in 21% (7/33), 28% (9/32), and 24% (2/33) of subjects receiving the single 800-mcg tablet, two 400-mcg tablets, and four 200-mcg tablets, respectively. The most common AEs included nausea, vomiting, dizziness, headache, fatigue, and myalgia. Due to dose-proportional pharmacokinetics, multiple lower-dose sublingual fentanyl tablets can be administered to achieve the same effects as a smaller number of larger-dose tablets. Editorial and writing support was provided by Synchrony Medical LLC, funded by ProStrakan Group.

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

Current clinical guidelines have identified the need for studies comparing the effect of different short-acting or rapid-onset opioids for the treatment of breakthrough pain (BTP). In this study we evaluated the efficacy and safety of treatment with fentanyl buccal tablet (FBT) in comparison with immediate-release oxycodone in alleviating BTP in opioid-tolerant patients with chronic pain. In this cross-over design study, opioid-tolerant patients were randomized to open-label titration with FBT (200, 400, 600, 800 μg) followed by oxycodone (15, 30, 45, 60 mg) or vice versa for the management of BTP. After titration to a successful dose of both study drugs, patients were rerandomized to double-blind treatment for 10 BTP episodes with 1 of the already identified successful doses of study drug followed by cross-over to double-blind treatment for 10 BTP episodes with the other study drug. The primary efficacy measure was the difference in pain intensity (based on an 11-point numerical scale) 15 minutes after administration of study drug (PID(15)). Other efficacy measures included PID at other time points postdose (5 through 60 minutes), the sum of pain intensity differences (SPID) at 30 and 60 minutes postdose, pain relief (5 through 60 minutes), proportion of BTP episodes for which patients experienced meaningful reduction in pain intensity, and patient preference for BTP medication. Adverse events were also recorded. Of the 323 patients enrolled, 203 achieved a successful dose of both study drugs, 191 completed the titration phase, and 180 completed the double-blind phase. PID(15) was significantly greater after FBT versus oxycodone (mean [SD], 0.82 [1.12] vs. 0.60 [0.88]; 95% confidence interval [CI] = 0.18, 0.29; P < 0.0001). Secondary efficacy measures favored FBT and showed differences versus oxycodone from 5 minutes postdose for PID and 10 minutes postdose for pain relief. SPID(30) and SPID(60) were greater with FBT than with oxycodone (P < 0.0001 for both measures). A ≥33% improvement in pain intensity occurred in a larger proportion of FBT-treated episodes versus oxycodone beginning 15 through 45 minutes postdose (P < 0.05). FBT was preferred by 52% of patients, oxycodone by 33%. Adverse events with both study drugs were generally typical of opioids, and the majority occurred during titration. Two serious adverse events (pneumonia) were reported in 1 patient; both occurrences were considered unrelated to study drug. FBT resulted in more rapid onset of analgesia and was generally well tolerated in comparison with oxycodone for the treatment of BTP in opioid-tolerant patients.

Efficacy and safety of fentanyl buccal for cancer pain management by administration through a soluble film: an update

More than half of patients receiving prescription medicine for cancer pain have been reported to experience inadequate pain relief or breakthrough pain. Buccal administration can deliver lipophilic opioids rapidly to the systemic circulation through the buccal mucosa, limiting gastrointestinal motility and first-pass metabolism. This review updates the safety and efficacy of fentanyl buccal soluble film (FBSF) in patients with cancer pain. Literature was identified through searches of Medline (PubMed). Search terms included combinations of the following: cancer pain, fentanyl, fentanyl buccal soluble film, pharmacology, kinetics, safety, efficacy and toxicity. FBSF is an oral transmucosal form of fentanyl citrate developed as a treatment of breakthrough pain in opioid-tolerant patients with cancer. Studies have shown that it is well tolerated in the oral cavity, with adequate bioavailability and safety in cancer patients. Further studies are warranted to evaluate, in comparison with other short-acting opioids, its efficacy in the management of breakthrough cancer pain, its addictive potential and its economic impact in cancer patients.

A Novel 12-Week Study, with Three Randomized, Double-Blind Placebo-Controlled Periods to Evaluate Fentanyl Buccal Tablets for the Relief of Breakthrough Pain in Opioid-Tolerant Patients with Noncancer-Related Chronic Pain

To evaluate the time of onset, overall efficacy, and safety of fentanyl buccal tablet (FBT) for noncancer-related breakthrough pain (BTP) in opioid-tolerant adults over 12 weeks. A novel 12-week study that mimicked clinical practice with dose titration to effective dose, open-label treatment, and three randomized, double-blind, placebo-controlled, multiple-crossover periods at weeks 4, 8, and 12. For each double-blind period, study patients received nine doses (FBT = 6, placebo = 3) in a randomized sequence. Twenty-one study centers in the United States. Opioid-tolerant adults with noncancer-related chronic pain and BTP. The primary outcome was the sum of the pain intensity differences (PID) 5-60 minutes post dose (SPID₆₀) during the final double-blind period. Secondary outcomes included pain relief (PR), meaningful PR, and proportion of episodes with a PID of ≥33% and ≥50%. Of 148 patients who entered the titration phase, 105 (71%) achieved a successful dose and 81 (55%) participated in all three assessment periods in the study. The final RCT assessment period results demonstrated continued efficacy of FBT vs placebo (P < 0.05) for SPID₆₀ (mean [SD]: 7.7 [6.2] vs 4.6 [4.7]). The average onset of PR began at 5 minutes, with meaningful PR by ≤10 minutes. The proportion of episodes with ≥33% improvement in PI was 7% with FBT vs 3% with placebo at 5 minutes and with ≥50% was 17% vs 10% at 15 minutes. All periods showed similar results. Adverse events and patient discontinuations were generally typical of clinical opioid use. FBT showed continued clinically important analgesic effects and was generally well tolerated over 12 weeks of treatment.

Evaluation of the Single‐ and Multiple‐Dose Pharmacokinetics of Fentanyl Buccal Soluble Film in Normal Healthy Volunteers

Fentanyl buccal soluble film (FBSF) is a rapidly absorbed transmucosal formulation of fentanyl for the management of breakthrough pain in opioid-tolerant patients with cancer. This open-label, 3-period, sequential dose study evaluated the dose-to-dose reproducibility of the pharmacokinetics of fentanyl following the administration of 600- or 1800-microg doses of FBSF in 12 naltrexone-blocked, healthy adult volunteers. Subjects received 3 study treatments: single doses of 600 microg of FBSF on day 1 and day 4 and three 600-microg doses administered at 1-hour intervals on day 7. Plasma fentanyl concentrations were measured over a 48-hour period after each single dose of FBSF and 72 hours after the 3-dose regimen. Peak plasma concentrations (mean C(max) = 1.08 and 1.01 ng/mL) and overall exposure (mean AUC(0-12) = 6.3 and 6.2 h.ng/mL; mean AUC(inf) = 9.14 and 9.60 h.ng/mL) were nearly identical after the 2 single doses (P >or= .1, all comparisons). C(max) and overall fentanyl exposure (AUC(inf)) increased approximately 3-fold with the 3-dose regimen compared with the single-dose periods. Fentanyl plasma concentrations following single doses of FBSF were reproducible, and 3 doses administered 1 hour apart produced a tripling in exposure and maximal concentration compared with a single dose.

Long-Term Safety and Tolerability of Fentanyl Buccal Tablet for the Treatment of Breakthrough Pain in Opioid-Tolerant Patients with Chronic Pain: An 18-Month Study

Breakthrough pain (BTP) is highly prevalent in patients with chronic cancer and noncancer pain, commonly requiring treatment with short-acting or rapid-onset opioids. This is the first report of an analysis of long-term safety from combined clinical trials of a rapid-onset transmucosal formulation of fentanyl, the fentanyl buccal tablet (FBT). This long-term (18-month), open-label study assessed the safety and tolerability of FBT for the treatment of BTP in a large cohort (n=646) of opioid-tolerant patients receiving around-the-clock (ATC) opioids for persistant noncancer pain. This was a long-term, multicenter, open-label safety study that accepted patients naïve to FBT (new patients) as well as rollover patients from one of two previous short-term, randomized, placebo-controlled studies involving opioid-tolerant adults with chronic noncancer pain. All patients gave written informed consent, and the study was conducted according to Good Clinical Practice and with Independent Ethics Committee or Institutional Review Board approval. During maintenance treatment, 70 of 646 patients (11%) discontinued because of adverse events (AEs), 69 of 646 (11%) because of withdrawn consent, and 57 of 646 (9%) because of noncompliance. A total of 571 of 646 patients (88%) had one or more AEs; most were mild to moderate in intensity and typical of AEs associated with opioid use in a noncancer chronic pain population. Serious AEs were seen in 118 of 646 patients (18%); most were considered by the investigators to be unrelated or unlikely to be related to FBT. There were six deaths (three myocardial infarction, two cardiac arrest, and one pneumonia) that were considered by investigators to be unrelated or unlikely to be related to FBT. There were two reports of accidental overdose contained within nine reports of nonfatal overdose (FBT and/or ATC and/or other medications). Four patients had AEs of abuse or drug dependence, two in association with FBT. Drug withdrawal syndrome occurred in 23 patients after discontinuation of FBT alone or in combination with other opioids. Secondary assessments showed that average pain ratings, as assessed by the Brief Pain Inventory, remained relatively stable throughout the study and that consistent improvements were noted in functional measures. FBT was generally safe and well tolerated, with self-reported functional improvement observed in most of the opioid-tolerant patients with BTP in association with chronic noncancer pain.

Fentanyl buccal soluble film (FBSF) for breakthrough pain in patients with cancer: a randomized, double-blind, placebo-controlled study

BackgroundFentanyl buccal soluble film (FBSF) has been developed as a treatment of breakthrough pain in opioid-tolerant patients with cancer. The objective of this study was to evaluate the efficacy of FBSF at doses of 200–1200 μg in the management of breakthrough pain in patients with cancer receiving ongoing opioid therapy. Patients and methodsThis was a multicenter, randomized, double-blind, placebo-controlled, multiple-crossover study that included opioid-tolerant adult patients with chronic cancer pain who experienced one to four daily episodes of breakthrough pain. The primary efficacy assessment was the sum of pain intensity differences at 30 min (SPID30) postdose. ResultsThe intent-to-treat population consisted of 80 patients with ≥1 post-baseline efficacy assessment. The least-squares mean (LSM ± SEM) of the SPID30 was significantly greater for FBSF-treated episodes of breakthrough pain than for placebo-treated episodes (47.9±3.9 versus 38.1 ± 4.3; P = 0.004). There was statistical separation from placebo starting at 15 min up through 60 min (last time point assessed). There were no unexpected adverse events (AEs) or clinically significant safety findings. ConclusionsFBSF is an effective option for control of breakthrough pain in patients receiving ongoing opioid therapy. In this study, FBSF was well tolerated in the oral cavity, with no reports of treatment-related oral AEs.

Fentanyl buccal tablet vs oxycodone immediate-release for the management of breakthrough pain in opioid-tolerant patients with chronic pain: patient disposition and dose titration

Data show the effective dose of a rapid-onset, transmucosal opioid for breakthrough pain (BTP) is not related to the around-the-clock (ATC) dose of the drug. No data exist, however, on more traditional, short-acting oral opioids. In a head-to-head, 46-center study comparing fentanyl buccal tablet (FBT) with oxycodone immediate-release (OxyIR) for BTP, opioid-tolerant patients titrated FBT and OxyIR to a successful dose that provided adequate analgesia without unacceptable adverse events (AEs) during 2 randomized, open-label periods. The doses of FBT (200, 400, 600, 800 mcg) and OxyIR (15, 30, 45, 60 mg) were selected based on the relative potency estimate that FBT 100 mcg is equivalent to OxyIR 7.5 mg. Efficacy was evaluated during 2 subsequent randomized, crossover, double-blind, double-dummy periods. 320 patients received treatment; 203 found a successful dose of both drugs and 183 were evaluable for efficacy. During the titration periods, 60 patients discontinued while receiving FBT and 69 while receiving OxyIR. Reasons for discontinuation were similar between treatments. 162/320 (51%) patients reported AEs, which were similar between treatments. There was no linear relationship between the successful dose of FBT or OxyIR and the ATC opioid dose. The successful doses of FBT and OxyIR exhibited a strong concordance, as measured by Kendall's tau statistic (tau=0.62; P<0.0001). Of the patients who entered the study taking OxyIR and identified a successful dose of each drug, 78/96 (81%) titrated to a higher dose of OxyIR than was used at study entry. In conclusion, the titrated, successful dose of OxyIR for BTP was not predicted by the ATC opioid dose. However the successful OxyIR dose was concordant with a dose of FBT estimated to be equivalent. The tolerability profiles were similar. (Sponsored by Cephalon, Inc.) Data show the effective dose of a rapid-onset, transmucosal opioid for breakthrough pain (BTP) is not related to the around-the-clock (ATC) dose of the drug. No data exist, however, on more traditional, short-acting oral opioids. In a head-to-head, 46-center study comparing fentanyl buccal tablet (FBT) with oxycodone immediate-release (OxyIR) for BTP, opioid-tolerant patients titrated FBT and OxyIR to a successful dose that provided adequate analgesia without unacceptable adverse events (AEs) during 2 randomized, open-label periods. The doses of FBT (200, 400, 600, 800 mcg) and OxyIR (15, 30, 45, 60 mg) were selected based on the relative potency estimate that FBT 100 mcg is equivalent to OxyIR 7.5 mg. Efficacy was evaluated during 2 subsequent randomized, crossover, double-blind, double-dummy periods. 320 patients received treatment; 203 found a successful dose of both drugs and 183 were evaluable for efficacy. During the titration periods, 60 patients discontinued while receiving FBT and 69 while receiving OxyIR. Reasons for discontinuation were similar between treatments. 162/320 (51%) patients reported AEs, which were similar between treatments. There was no linear relationship between the successful dose of FBT or OxyIR and the ATC opioid dose. The successful doses of FBT and OxyIR exhibited a strong concordance, as measured by Kendall's tau statistic (tau=0.62; P<0.0001). Of the patients who entered the study taking OxyIR and identified a successful dose of each drug, 78/96 (81%) titrated to a higher dose of OxyIR than was used at study entry. In conclusion, the titrated, successful dose of OxyIR for BTP was not predicted by the ATC opioid dose. However the successful OxyIR dose was concordant with a dose of FBT estimated to be equivalent. The tolerability profiles were similar. (Sponsored by Cephalon, Inc.)

Formulation Selection and Pharmacokinetic Comparison of Fentanyl Buccal Soluble Film with Oral Transmucosal Fentanyl Citrate

BioErodible MucoAdhesive (BEMA) is a new transmucosal drug delivery system designed to improve and ease the administration of drugs by this route. The first product that uses this novel delivery system contains fentanyl and is intended for the treatment of breakthrough pain in opioid-tolerant patients with cancer. The generic name is fentanyl buccal soluble film (FBSF). The objectives of this study were to compare the pharmacokinetic profile of FBSF formulations at three different pHs (pH 6, pH 7.25 and pH 8.5) and to understand the differences in the pharmacokinetics of fentanyl from FBSF compared with that of oral transmucosal fentanyl citrate (OTFC). This was a randomized, open-label, single-dose, four-period, Latin-square crossover study consisting of a 9-day inpatient treatment period. The study was conducted at a phase 1 clinical research unit in Austin, TX, USA. Twelve healthy subjects were enrolled, nine males and three females, between the ages of 21 and 44 years. Each subject received four 800 microg doses of fentanyl: single doses of the three FBSF formulations (pH 6, pH 7.25 and pH 8.5) and OTFC, with concurrent naltrexone. Plasma fentanyl concentrations were measured over a 48-hour period after each study dose. Pharmacokinetic parameters were calculated and compared. Peak plasma fentanyl concentrations (Cmax) and overall fentanyl systemic exposure (area under the plasma concentration-time curve from time zero extrapolated to infinity [AUCinfinity]) for each of the three FBSF formulations were greater than for OTFC. The pH 7.25 FBSF formulation provided the earliest time to reach Cmax (tmax), the highest Cmax value and the greatest AUC(infinity) value. Compared with OTFC, peak plasma fentanyl concentrations with pH 7.25 FBSF were significantly higher (mean Cmax 1.67 vs 1.03 ng/mL; p<0.05). Overall exposure was also greater with pH 7.25 FBSF than with OTFC (mean AUCinfinity 14.5 vs 10.3 ng . h/mL). All three FBSF formulations produced greater peak plasma concentrations and overall exposure to fentanyl than OTFC. In particular, the pH 7.25 FBSF formulation showed the most favourable pharmacokinetic profile of the three FBSF formulations. In comparison with OTFC, the pH 7.25 FBSF formulation produced the fastest and most efficient fentanyl delivery and was selected for further clinical development.

Efficacy and tolerability of intranasal fentanyl spray 50 to 200 μg for breakthrough pain in patients with cancer: A phase III, multinational, randomized, double-blind, placebo-controlled, crossover trial with a 10-month, open-label extension treatment period

Objective: This trial investigated the efficacy and long-term tolerability of intranasal fentanyl spray (INFS) 50 to 200 μg in the treatment of breakthrough pain in opioid-tolerant patients with cancer. Methods: This Phase III, double-blind, randomized, placebo-controlled, crossover trial was conducted at pain centers, anesthesiology departments, palliative care units, and oncology clinics in Austria, Denmark, France, Germany, and Poland. Eligible patients were adults with cancer receiving a stable dose of long-term opioid treatment for the control of background pain. Patients were treated at home with their effective dose of INFS (50, 100, or 200 μg) or inactive spray (placebo) in a randomized sequence for 3 weeks, followed by a 10-month, open-label tolerability phase during which they received their effective dose of INFS. Throughout the study, patients were allowed to use their usual rescue medication, which was recorded in patient diaries. The primary efficacy end point was the pain intensity difference at 10 minutes after study drug administration (PID 10), as assessed using an 11-point numeric rating scale (0 = no pain to 10 = worst pain imaginable). An effect size of 0.5 for PID was considered clinically relevant. The rate of response, defined as PID 10 >2, was also assessed. Adverse events (AEs) were recorded in patient diaries during the efficacy period and reported in monthly clinic visits and follow-up weekly telephone contacts during the extension period. Results: In all, 120 patients were enrolled and achieved an effective dose; 113 were randomized and 111 were included in the intent-to-treat analysis set (56 men, 55 women; mean [SD] age, 60.6 [9.45] years; mean weight, 70.3 kg [men] and 65.3 kg [women]; white race, 107 [96.4%]; INFS 50 μg, 18; INFS 100 μg, 48; INFS 200 μg, 45; placebo, 110). PID 10 with INFS was 2-fold that with placebo (adjusted means, 2.36 vs 1.10; adjusted difference, 1.26 [greater than the clinically relevant difference of 0.5]; P < 0.001). Additional analysis revealed that the mean response rate with all 3 doses of INFS was 51.1% versus 20.9% with placebo. The prevalence of AEs was 22/111 (19.8%) during the efficacy period, during which the most frequently reported AEs were nausea (5 [4.5%]) and vertigo (2 [1.8%]). No serious AEs were considered related to the study drugs. In all, 108 patients entered the extension period, with a mean duration of exposure to INFS of 134.9 days. Progression of underlying malignant disease was the most common AE reported during this period (55 [50.9%]); this event was not considered treatment related. Conclusions: In these opioid-tolerant patients with cancer, INFS at doses of 50, 100, and 200 μg was associated with an onset of activity at 10 minutes and effective treatment of breakthrough pain compared with placebo. All doses were generally well tolerated and clinically efficacious.

Fentanyl buccal tablet

Studies of populations with chronic cancer pain have shown a high prevalence of breakthrough pain (BTP), defined as transitory, severe flares of pain that occur on a background of otherwise controlled, persistent pain. High BTP prevalence rates have also been reported in patients with chronic noncancer pain, although data in these patient populations are more limited. The incidence of BTP appears to be associated with progression of chronic disease, with more than 80% of patients reporting BTP with far-advanced, end-stage cancer and noncancer terminal conditions (1). The most widely accepted therapeutic approach for the management of BTP involves use of short-acting opioids taken as needed in addition to the around-the-clock opioid regimen being used for the continuous component of the persistent pain syndrome. For some patients, an optimal treatment outcome for BTP may be unattainable because of a mismatch between the time course of the BTP episode and the onset of analgesia of short-acting opioids. Breakthrough pain typically reaches peak intensity within a few minutes, whereas the onset of analgesia with traditional, orally administered short-acting opioids is between 30 and 60 minutes (2-7). Consequently, treatment outcomes for BTP are likely to be improved with agents that have a more rapid onset of analgesia. Fentanyl buccal tablet (FBT) is a new formulation of fentanyl indicated for the management of BTP in patients with cancer who are already receiving, and who are tolerant to, opioid therapy for their underlying persistent cancer pain. The FBT formulation uses OraVescent (Cephalon, Inc., Frazer, PA, USA) drug delivery technology to provide rapid absorption of fentanyl through the buccal mucosa. In pharmacokinetic studies in healthy volunteers, FBT demonstrated high, early systemic absorption. In addition, FBT delivered a larger proportion of the fentanyl dose transmucosally and produced a greater early systemic exposure than oral transmucosal fentanyl citrate (OTFC), which is also indicated for the management of BTP in opioid-tolerant cancer patients. A number of short-term studies have evaluated the efficacy, safety and tolerability of FBT in the management of BTP in opioid-tolerant patients with chronic pain. All these studies included an open-label dose-titration phase prior to randomized, placebo-controlled, double-blind treatment. Pain Intensity of a BTP episode was measured using an 11-point scale (0 = no pain, 10 = worst pain), and the primary outcome measure was the Summed Pain Intensity Difference (SPID) at a specified time point. Secondary efficacy measures included Pain Relief, Pain Intensity Differences, and the proportion of BTP episodes demonstrating >or=33% and >or=50% improvement in Pain Intensity scores at each time point postdose, and the proportion of BTP episodes requiring supplemental medication. In a pivotal study of opioid-tolerant patients with cancer-related chronic pain and BTP, the primary outcome measure, SPID at 30 minutes (SPID(30)), significantly favored FBT compared with placebo (mean +/- SE: 3.0 +/- 0.12 vs. 1.8 +/- 0.18, p<0.0001). Better efficacy was also observed with FBT compared with placebo for pain relief, Pain Intensity Differences, and the proportion of episodes showing >or=33% and >or=50% improvement in Pain Intensity Scores. Treatment with FBT was generally well tolerated. Most adverse events were mild to moderate in severity and typical of those associated with opioid use (e.g., nausea, dizziness) (8). Similar results have been observed in studies of opioid-tolerant patients with BTP in association with noncancer-related chronic pain. In a study of patients with chronic low back pain, the primary outcome measure, SPID(60), significantly favored FBT over placebo (mean +/- SE: 8.3 +/- 0.66 vs. 3.6 +/- 0.57, p <0.0001). All secondary efficacy measures were similarly improved, with Pain Intensity Differences and Pain Relief scores showing significant differences versus placebo as early as 10 and 15 minutes, respectively. As in the study of cancer patients, treatment with FBT was well tolerated (9). Across all studies, there was no simple linear relationship between the effective dose of FBT and the dose of the around-the-clock opioid regimen or the previous supplemental opioid, indicating that doses of FBT should be individually titrated to effectiveness rather than calculated as a percentage of existing opioid regimens. This monograph summarizes current data on the clinical pharmacology, efficacy, safety and tolerability of FBT relating to the management of opioid-tolerant patients with BTP in association with chronic pain.

Poster 191: Efficacy, Safety, and Tolerability of Fentanyl Buccal Tablet in Opioid-Tolerant Patients With Chronic Cancer Pain and Breakthrough Pain

Objective: To evaluate the efficacy and safety of a fentanyl buccal tablet (FBT) for the management of breakthrough pain in opioid-tolerant patients with chronic cancer pain. Design: Double-blind, randomized, placebo-controlled study. Setting: 30 centers in the United States. Participants: 129 enrolled patients; 70% (87/125) identified an effective FBT dose (100, 200, 400, 600, or 800μg) during initial open-label dose titration. Interventions: Patients self-administered prespecified sequences of 10 tablets (7 FBT, 3 placebo).

A double-blind, randomized, placebo-controlled study of fentanyl buccal tablet (FBT) in opioid-tolerant patients with chronic cancer pain and breakthrough pain

9057 Background: Episodes of cancer-related breakthrough pain (BTP) often peak in intensity in minutes. Pain relief with traditional, short-acting oral opioids is often not achieved for =30 min. Fentanyl buccal tablet (FBT) has a rapid onset of analgesia. This double- blind, randomized, placebo-controlled study evaluated the efficacy and safety of FBT in opioid-tolerant patients with cancer and BTP. Methods: After open-label titration to establish a successful dose of FBT, patients were randomized to prespecified, double-blinded sequences of 10 tablets (7 FBT, 3 placebo). Pain intensity (PI) was assessed from 5 to 120 min post dose. The primary efficacy measure was the sum of PI differences (PIDs) for the first 60 min (SPID60); secondary measures included PIDs, =33% and =50% improvements in PI, and global medication performance (GMP). Use of supplemental BTP medication and adverse events (AEs) were reported. Results: 129 patients were enrolled; 87/125 treated (70%) identified an effective FBT dose and entered the double-blind phase. SPID60 significantly favored FBT vs placebo (mean±SEM, 9.7±0.63 vs 4.9±0.50; p&lt;0.0001). PID differed significantly vs placebo at 10 min (mean±SEM, 0.9±0.09 vs 0.5±0.09; p&lt;0.0001) and at all time points through 2 hr (p&lt;0.0001). Improvements in PI of =33% and =50% from baseline occurred in a larger proportion of episodes following FBT vs placebo from 10 min (16% vs 10% and 7% vs 4%, respectively; p&lt;0.05) through 2 hr (74% vs 38% and 66% vs 28%; p&lt;0.0001). Ratings of GMP were superior for FBT vs placebo at 60 and 120 min (p&lt;0.0001). Supplemental opioids were required for approximately 3 times more BTP episodes following placebo compared with FBT. AEs were typical for opioids, e.g. nausea (13%), dizziness (11%), fatigue (8%), and constipation (6%). Application site-related AEs occurred in 12 patients (10%). A total of 11/125 (9%) patients had =1 serious AE; these were considered not/unlikely to be related to study drug. Conclusions: FBT was effective and well tolerated in the management of BTP in opioid-tolerant patients with cancer-related pain, with an early onset of analgesia and a sustained duration of effect. No significant financial relationships to disclose.