Clinical pharmacology of fentanyl buccal tablet for the treatment of breakthrough pain

Fentanyl buccal tablet (FBT) is a new formulation of fentanyl providing rapid-onset analgesia for the treatment of breakthrough pain. FBT has been approved for the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to opioid therapy for underlying persistent pain. FBT has demonstrated a favorable pharmacokinetic profile, which is closely aligned to the rapid onset and duration of an episode of breakthrough pain, and is generally safe and well tolerated.     

Fentanyl buccal tablet: rapid relief from breakthrough pain

Breakthrough pain – a transient increase in pain occurring over a baseline of controlled persistent pain – represents an important clinical challenge in the management of cancer and other chronic pain conditions. The fentanyl buccal tablet is a new sugar-free, easily-administered formulation that uses an effervescent drug delivery system to enhance the rate and extent of fentanyl absorption across the buccal mucosa. Clinical trials indicate that the rapid systemic exposure provided by fentanyl buccal tablets translates into clinically significant improvements in pain intensity. Pain relief is observed within 10 – 15 min of administration. Fentanyl buccal tablets are generally well tolerated, with the most commonly observed adverse events being typical opioid side effects. Fentanyl buccal tablets represent a convenient and effective treatment for the control of breakthrough pain.     

Dosing fentanyl buccal tablet for breakthrough cancer pain: dose titration versus proportional doses

Abstract

Objectives:

The aim of this study was to compare the efficacy and safety of doses of fentanyl buccal tablet (FBT) proportional to doses of opioids used for background analgesia versus dose titration starting with the minimal dose for the management of breakthrough cancer pain (BTcP).     

Efficacy of intranasal fentanyl spray versus other opioids for breakthrough pain in cancer

Abstract

Objective:

To compare the efficacy of intranasal fentanyl spray (INFS), oral transmucosal fentanyl citrate (OTFC), fentanyl buccal tablet (FBT) and oral morphine (OM) for the treatment of breakthrough cancer pain (BTCP).     

HPLC法测定田参正脉含片中二氢杨梅素的含量

目的建立人参含片中二氢杨梅素的含量测定方法。方法采用高效液相色谱法,色谱柱为Lichrospher C18柱（4．6×250mm,5μm）。ODS预柱,流动相为甲醇0．1％磷酸（25：75）;检测波长290nm;流速为1．0mL·min^-1。结果本法精密度高,稳定性好。二氢杨梅素溶液在0．00532～0．1064mg·mL^-1的浓度范围内具有良好的线性关系（r=0．9997）,平均加样回收率为101．62％,RSD为1．55％（n=6）。结论本方法简便,准确,重现性好,可作为该制剂的含量测定方法。     

Bioavailability of morphine after administration of a new bioadhesive buccal tablet

A new bioadhesive buccal morphine tablet was developed for controlled release delivery of drug and improved bioavailability compared with oral controlled release tablet. In order to characterize the pharmacokinetic properties of this bioadhesive buccal formulation, a bioavailability study was performed in 12 healthy volunteers who received: a 30 mg oral controlled release tablet (A); a 20 mg aqueous solution retained in the mouth for 10 min (B); and the 60 mg bioadhesive buccal tablet placed between the lower gum and lip for 6 h (C). The mean amount of morphine absorbed from the solution was very low, only 2 mg of the 20 mg dose. After administration of forms A and C, plasma levels exhibit typical sustained release concentration–time curves. The mean amount of drug recovered from the residual bioadhesive buccal tablet after 6 h indicated that approximately 50% of the dose was released from the bioadhesive buccal tablet. The relative bioavailability of the buccal tablet (corrected for residual unabsorbed dose) compared with the controlled-release tablet was 98% based on the morphine AUC values. Good correlations between the AUC and the C_max of the bioadhesive tablet for the drug and metabolite plotted versus the amount of morphine absorbed were found. © 1998 John Wiley & Sons, Ltd.     

银黄含片中黄芩苷、绿原酸含量测定方法的研究

目的为银黄含片建立含量测定方法.方法采用HPLC-DAD检测器实现了同时测定银黄含片的绿原酸、黄芩苷含量.结果采用HPLC—DAD同时测定银黄含片的两种主成分——绿原酸、黄芩苷的含量,方法准确度、精密度、灵敏度等指标均符合要求.克服了绿原酸、黄芩苷的相互干扰,结果更能反映制剂的真实含量.结论获得一种能同时测定绿原酸、黄芩苷含量的测定方法,为银黄系列产品的检测提供了依据.     

喉咽清含片抗病毒作用的实验研究

目的 :观察喉咽清含片的抗病毒作用。方法 :采用体外抗病毒实验 ,观察喉咽清含片对病毒致细胞病变的作用 ;采用体内抗病毒实验 ,观察喉咽清含片对病毒感染小鼠的肺指数和肺指数抑制率的影响。结果 :喉咽清含片对流感病毒甲 3型 (A3)、副流感病毒 1型 (HVJ)、腺病毒 (AdV3,AdV7)及疱疹病毒 (HSV 1,HSV 2 )所致细胞病变效应有抑制作用 ;喉咽清含片 6 .6 g·kg- 1·d- 1和 13.2 g·kg- 1·d- 1剂量 (生药量 )能降低流感病毒鼠肺适应株FM1感染小鼠的肺指数 ,肺指数抑制率分别为 2 1%和32 %。结论 :喉咽清含片有较强的抗病毒作用     

Pulmonary administration of aerosolised fentanyl: pharmacokinetic analysis of systemic delivery

Aims Pulmonary drug delivery is a promising noninvasive method of systemic administration. Our aim was to determine whether a novel breath-actuated, microprocessor-controlled metered dose oral inhaler (SmartMist^TM, Aradigm Corporation) could deliver fentanyl in a way suitable for control of severe pain.
Methods Aersolised pulmonary fentanyl base 100–300  μg was administered to healthy volunteers using SmartMist^TM and the resultant plasma concentration-time data were compared with those from the same doses administered by intravenous (i.v.) injection in the same subjects.
Results Plasma concentrations from SmartMist^TM were similar to those from i.v. injection. Time-averaged bioavailability based upon nominal doses averaged 100%, and was >50% within 5  min of delivery. Fentanyl systemic pharmacokinetics were similar to those previously reported with no trends to dose-dependence from either route. Side-effects (e.g. sedation, lightheadedness) were the same from both routes.
Conclusions Fentanyl delivery using SmartMist^TM can provide analgetically relevant plasma drug concentrations. This, combined with its ease of noninvasive use and transportability, suggests a strong potential for field and domicilliary use, and for patient controlled analgesia without the need for i.v. cannulae.     

Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain

AIMS: It is estimated that two-thirds of cancer patients will at some point during their illness experience breakthrough pain. In this study, the pharmacokinetics of a novel sublingual dosage form of fentanyl developed for breakthrough pain was evaluated. METHODS: Eleven Caucasian patients (seven male and 4 female, aged 34-75 years, median 60 years) with metastatic malignant disease were recruited initially, but three patients withdrew. Prior to the study all patients were on continuous nonfentanyl opiate medication. The study was a double-blind, cross-over trial, consisting of three 1-day treatment periods. A new rapidly dissolving preparation of fentanyl, was administered sublingually in single doses of 100, 200 and 400 microg, respectively, on three separate occasions. Plasma fentanyl concentrations were determined using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated by noncompartment analysis. Tolerability and the occurrence of adverse events were monitored throughout the study by patient questionnaire. RESULTS: The data from nine subjects who completed at least two periods were used in the analysis of variance. There were no significant differences between doses (100, 200 and 400 microg) for dose adjusted AUC (F = 0.42, P = 0.6660), dose adjusted C(max) (F = 0.08, P = 0.9206) and Tmax (F = 0.94, P = 0.4107). Thus, these parameters showed dose proportionality. The differences (400-100microg) in dose adjusted AUC from the three-period crossover analysis was -0.016 min.ng/ml (t = 0.71, P = 0.8718). Interindividual variability in systemic exposure to fentanyl was fairly small (25-40%), which may be related to a good in vivo biopharmaceutical performance of the sublingual tablet, and a relatively small fraction of the dose being swallowed. The first detectable plasma concentration of fentanyl was observed between 8 and 11 min after administration. t(max) increased from 39.7 +/- 17.4 to 48.7 +/- 26.3 and 56.7 +/- 24.6 min for the 100, 200 and 400 microg doses, respectively. Adverse events were few and did not increase with increasing dose. CONCLUSION: With this rapidly dissolving fentanyl formulation, the first detectable plasma concentration of fentanyl was observed at 8-11 min after administration. The pharmacokinetics of the drug showed dose proportionately. This formulation of fentanyl seemed to be well tolerated by the patients.     

Fentanyl buccal tablet (FBT) for relief of breakthrough pain in opioid-treated patients with chronic low back pain: a randomized,placebo-controlled study

ABSTRACT

Background: Short-acting opioids are commonly used to treat breakthrough pain (BTP) and rapid-onset formulations are being developed to improve the effectiveness of this approach. Fentanyl buccal tablet (FBT) is a new formulation of fentanyl that enhances transbuccal drug delivery via an effervescent reaction and may provide relatively rapid-onset analgesia. FBT was evaluated for BTP in opioid-treated patients with chronic low back pain – the first such study in a population with chronic non-cancer pain.

Design: Randomized, double-blind, placebo-controlled.

Patients and setting: Patients with chronic low back pain receiving long-term opioid therapy at 16 pain treatment centers in the United States.

Procedures: Following open-label titration to identify an effective FBT dose, patients were randomly assigned to one of three double-blind dose sequences (six doses of FBT, three placebo) to treat nine BTP episodes. Pain intensity (PI), measured on an 11-point scale (0 = no pain; 10 = worst pain), and other outcomes were assessed for 2?h after dosing.

Data analysis: The primary efficacy measure was the sum of pain intensity differences (PIDs) for the first 60?min (SPID₆₀); secondary efficacy measures included PIDs at other time points, pain relief (PR), meaningful PR, time to meaningful PR, use of supplementary BTP medication, and self/investigator-reported adverse events.

Results: Of the 124 patients screened, 105 patients were enrolled, 84 identified an effective FBT dose, and 77 entered the double-blind phase. SPID₆₀ significantly favored FBT (?p < 0.0001). All secondary measures also favored FBT, with PIDs and PR showing significant differences versus placebo as early as 10 and 15?min, respectively. An improvement in PI score of ≥ 33% occurred in a significantly larger proportion of FBT-treated episodes versus placebo from 15?min (20% vs. 11%, p < 0.01) through 2?h (65% vs. 28%, p < 0.0001). Patients were approximately four times more likely to require supplemental opioids for BTP episodes following administration of placebo compared with episodes treated with FBT. AEs were typical for opioids, and were mostly reported during dose titration. Limitations of this study may be related to its open-label dose-titration phase (which has the potential to compromise blinding) and the recruitment of patients from pain clinics, which could potentially yield a study population that is not representative of the general population with BTP.

Conclusions: FBT was efficacious and well tolerated in the treatment of BTP in opioid-treated patients with chronic low back pain.     

A review of the pharmacokinetic profile of transmucosal fentanyl formulations

Abstract

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.     

石辛含片治疗智齿冠周炎的临床疗效观察

目的观察石辛含片在治疗智齿冠周炎中的临床效果。方法将72例智齿冠周炎患者随机分为观察组和对照组各36例。观察组采用石辛含片治疗;对照组采用阿莫西林克拉维酸钾片和甲硝唑片治疗。治疗后观察2组临床疗效、药物依从性及不良反应。结果观察组总有效率为94.44%高于对照组的72.22%,差异有统计学意义（P〈0.05）。2组药物依从性比较差异无统计学意义（P〉0.05）,且均未发生严重不良反应。结论石辛含片治疗智齿冠周炎疗效显著,药物依从性高,不良反应轻微,可作为治疗智齿冠周炎的较好选择。     

Efficacy and long-term tolerability of sublingual fentanyl orally disintegrating tablet in the treatment of breakthrough cancer pain

Abstract

Background and objectives:

Breakthrough cancer pain (BTcP) represents an important clinical challenge in the care of patients with cancer. This trial evaluated the efficacy and long-term tolerability of a sublingual formulation of the fast-acting opioid fentanyl, for the treatment of BTcP in opioid-tolerant patients with cancer.     

Comparison of salivary miconazole concentrations after administration of a bioadhesive slow-release buccal tablet and an oral gel

Summary The salivary miconazole concentrations after administration of a bioadhesive slow-release buccal tablet and an oral gel have been compared. The bioadhesive tablet consisted of a mixture of thermally modified starch and 5% polyacrylic acid.Although the amount of drug administered via the bioadhesive tablet was sixfold lower than when the gel was used, the salivary miconazole levels were higher and remained above the MIC value ofCandida albicans for more than 10 hours. The mean adhesion time of the tablet was 586 min.The bioadhesive tablet appears to be a promising drug delivery system for the buccal administration of drugs for local therapy.     

Effect of fentanyl and naloxone on the P300 auditory potential

The effect of fentanyl (opioid agonist) and naloxone (morphine antagonist) on the amplitude, area and latency of the P300 auditory potential was studied in patients undergoing minor surgical procedures. Fentanyl (5.0 micrograms/kg), naloxone (3.0 micrograms/kg) and isotonic saline (for control) were injected intravenously through a catheter just before surgery, and following a single-blind procedure and three different pharmacological paradigms with three consecutive conditions each: (1) initial baseline (C), saline (S) and late baseline (C'); (2) C, fentanyl (F) and C'; (3) C, naloxone (N) and C'. Fentanyl significantly reduced the amplitude and area with no changes in the latency of small (S) and large (L) P300 potentials. Concomitantly, fentanyl increased the number of omitted counts of the target tones of the "odd ball" P300 test and the spatial threshold of the two point discrimination test in patients with small and large P300 potentials. Naloxone significantly increased the amplitude and area and decreased the latency of the small P300 potential and decreased the amplitude and area with no changes in latency of the large P300 potentials. Concomitantly, naloxone decreased the number of omitted counts of the patients with small but not large P300 potentials and decreased the spatial threshold in patients with both small and large P300 potentials. Neither fentanyl nor naloxone produced systematic changes in the evaluation of pain and hearing of patients with small and large P300 potentials. Although dramatic changes in pulse, blood pressure, respiration and EEG were found in some cases immediately after the administration of fentanyl and naloxone, these changes were not consistent and were not present at the time other tests were performed.     

Efficacy,safety, and tolerability of sublingual fentanyl orally disintegrating tablet in the treatment of breakthrough cancer pain: a randomized,double-blind,placebo-controlled study

BackgroundBreakthrough pain (BTP) is an important challenge in treatment and requires a rapid onset of action for pain control. BTP should be adequately controlled with a stable dose of a short-acting oral opioid. So far, no drug is available for the treatment of BTP in cancer patients in Iran, so we designed the first study in Iran to investigate the effect of sublingual fentanyl in relief of pain episodes in these patients.ObjectiveThe purpose of this study was to evaluate the efficacy and safety of sublingual fentanyl in the treatment of breakthrough pain in cancer patients.MethodThis study was a randomized double-blind placebo-controlled clinical trial in cancer patients with breakthrough pain (at least 1–4 episodes of acute pain with moderate to severe pain daily) referred to the pain clinic of Akhtar and Masih Daneshvari hospitals in 2019. The study consisted of two stages: 100 patients were selected by simple, non-random sampling and entered the open-label titration phase. The primary efficacy endpoint was the sum of pain intensity difference over 30 min post-administration. Secondary efficacy endpoints included pain intensity difference (PID) and pain relief (PR) throughout the 60-min post-dose assessment period. In the double-blind study, patients were randomly divided into two groups of placebo (n=50) and intervention (sublingual fentanyl tablet) (n=50). For evaluation of efficacy, 10 episodes were treated in each group and the results were recorded by the patient. (Clinical trial registration: IRCT20131124015515N8).ResultsA total of 100 patients entered the titration phase, primary efficacy of sublingual fentanyl was 3.5±0.6 and secondary efficacy of sublingual fentanyl (60 min, after treatment) was 0.3±0.6 which was statistically significant. In the titration phase, the treatment success rate was 100%. In the double-blind phase of the study, the pain intensity in multiple episodes showed a significant improvement at 15, 30, 45, and 60 min after drug administration (P=0.0001). The intensity of pain in each episode was significantly decreased compared to the next episode (P=0.0001). The mean frequency of pain episodes in the sublingual fentanyl group showed a significant decrease (P=0.0001). The most common adverse drug events in the titration phase were drowsiness (20%), dizziness (7%), and nausea 4%, and in the double-blind phase only drowsiness (12%). (Cancer Research Center, Shahid Beheshti University of Medical Sciences, Survey).ConclusionSublingual fentanyl appears to be effective for patients with rapid-onset analgesia, has short-acting duration, is effective medication, safe, and well tolerated. It is a suitable choice in Iranian patients with chronic cancer-related pain controlled suffering from acute pain episodes related to cancer.     

Effect of fentanyl and naloxone on human somatic and auditory-evoked potential components

The effect offentanyl (a morphine agonist) and naloxone (a morphine antagonist) on early and late components of somatic (SEP)- and auditory (AEP)-evoked potentials was studied in patients undergoing minor surgical procedures, in which these compounds were used in producing and regulating a state of neuroleptanalgesia. Fentanyl (2.5, 5.0 and 10.0 μg/kg), naloxone (1.5 and 3.0 g/kg) and isotonic saline (for comparative purposes) were injected just before surgery, intravenously through a catheter and following a single blind procedure and three different pharmacological paradigms with four consecutive conditions each: (1) Initial baseline (C), first saline (S), second saline (S') and late baseline (C'). (2) C, First fentanyl (F), second naloxone (N') and C. (3) C, First naloxone (N), second fentanyl (F') and C'. Special care was taken in controlling the constancy of the muscular and cochlear receptor activation concomitant to somatic-evoked potentials and auditory-evoked potentials, determined by the amplitude of the muscular response at the tenar muscles (MP) and component I of the brain stem potentials (ABSP). Evaluation by the patients pain, topognoses and hearing and other somatic and autonomic indicators of the level of the analgesic response were also controlled. Fentanyl significantly reduced, while naloxone increased, the amplitude of late components P150 of somatic-evoked potentials and auditory-evoked potentials. Concomitantly, fentanyl increased, while naloxone decreased, the spatial threshold (two point discrimination test) at finger tip and arm. These effects were observed in patients taking various doses, although they were more consistent with larger doses of these compounds. In contrast, no systematic changes were found in the amplitude of the response of tenar muscles and the early P20 component of somatic-evoked potentials and in PI and V components of auditory brain stem potentials. Nor were there any changes evaluation of pain and hearing during different paradigms and conditions by the patients. Although dramatic changes in pulse, blood pressure, respiration and EEG were found in some cases immediately after the administration of fentanyl and naloxone, these changes were not systematic and did not last for the duration of other tests.     

A pharmacodynamic and pharmacokinetic comparison of pindolol 20 mg retard and a conventional tablet

Summary In 10 healthy volunteers the time course of cardiac beta-adrenoceptor blocking activity, plasma levels and cumulative urinary excretion of pindolol were compared during a 4-day course of pindolol 5 mg (Visken^®) t. d. s., and one tablet of pindolol 20 mg retard (Visken^® retard) once a day. After oral administration of the 20 mg retard tablet, plasma concentrations of pindolol higher than half the maximum value (1/2 Cp (t_max)) were maintained about 2.5 times as long as after administration of the conventional 5 mg tablet. This is evidence for an important and marked retardation of drug release. During treatment with pindolol 20 mg retard once daily, cardiac beta-adrenoceptor blockade, measured by the reduction in exercise-induced tachycardia and in the exercise-induced rise in systolic blood pressure, at almost all times throughout the 24 h period was at least as great as during treatment with pindolol 5 mg t. d. s. This suggests that patients successfully treated with pindolol 5 mg t. d. s. can be maintained with the same beta-adrenoceptor blockade by a single tablet of pindolol 20 mg retard once daily.