The relative potency of oral transmucosal fentanyl citrate compared with intravenous morphine in the treatment of moderate to severe postoperative pain.

UNLABELLED: Pharmacokinetic studies have shown that oral transmucosal absorption of fentanyl is relatively rapid compared with gastrointestinal absorption, and it results in increased bioavailability. We designed this study to establish the relative potency of oral transmucosal fentanyl citrate (OTFC) compared with i.v. morphine in 133 postoperative patients. The morning after surgery, patients randomly received one dose of either OTFC (200 or 800 microg) and a placebo i.v. injection or i.v. morphine (2 or 10 mg) and an oral transmucosal placebo unit. Pain intensity, pain relief, time to meaningful pain relief, and time to remedication were recorded. Median time to onset of relief was approximately 5 min for all groups. Over the first hour, little difference among treatment groups was seen for pain intensity and pain relief. By 2 h after study drug administration, 800 microg of OTFC and 10 mg of i.v. morphine generally produced similar analgesia, which was better than the smaller doses. Duration of analgesia with the larger doses (800 microg of OTFC and 10 mg of morphine) was similar and longer that produced by the smaller doses. The larger doses of OTFC and morphine produced better and more sustained analgesia than 200 microg of OTFC or 2 mg of morphine. IMPLICATIONS: The relative potency of oral transmucosal fentanyl citrate (OTFC) to i.v. morphine was 8-14:1. In this postoperative setting, OTFC produced rapid pain relief similar to that produced by i.v. morphine. The larger doses of OTFC (800 microg) and morphine (10 mg) produced better and more sustained analgesia than 200 microg of OTFC or 2 mg of morphine.

Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: a controlled dose titration study.

Oral transmucosal fentanyl citrate (OTFC) is a novel opioid formulation in which the potent synthetic mu-agonist fentanyl is embedded in a sweetened matrix that is dissolved in the mouth. It is undergoing investigation as a treatment for cancer-related breakthrough pain, a prevalent phenomenon defined as a transitory flare of moderate to severe pain that interrupts otherwise controlled persistent pain. There have been no controlled trials of other treatments for this condition. To evaluate the safety and efficacy of ascending doses of OTFC, a novel controlled dose titration methodology was developed that applied blinding and randomization procedures to the evaluation of recurrent pains in the home environment. The study was a multicenter, randomized, double-blind dose titration study in ambulatory cancer patients. The sample comprised adult patients receiving a scheduled oral opioid regimen equivalent to 60-1000 mg oral morphine per day, who were experiencing at least one episode per day of breakthrough pain and had achieved at least partial relief of this pain by use of an oral opioid rescue dose. After collection of 2 days of baseline data concerning the efficacy of the usual rescue drug, patients were randomly treated with either 200 or 400 microg OTFC unit doses in double-blind fashion. Up to two breakthrough pains each day could be treated with up to four OTFC unit doses per pain. OTFC in unit doses containing 200, 400, 600, 800, 1200 or 1600 microg of fentanyl citrate were available for the study. The unit dose was titrated upward in steps until the patient had 2 consecutive days on which breakthrough pain could be treated with the single unit dose, titration was ineffective at a 1600 microg unit dose, or 20 days elapsed. To maintain the double-blind, orders to titrate up were ignored one-third of the time according to a pre-defined randomization schedule accessible only to an unblinded study pharmacist. Main outcome measures included, numeric or categorical measures of pain intensity, pain relief, and global assessment of drug performance. Dose response relationships were found suggesting that the methodology was sensitive to opioid effects. Seventy-four percent of patients were successfully titrated. There was no relationship between the total daily dose of the fixed schedule opioid regimen and the dose of OTFC required to manage the breakthrough pain. Although the study was not designed to provide a definitive comparison between OTFC and the usual rescue drug, exploratory analyses found that OTFC provided significantly greater analgesic effect at 15, 30 and 60 min, and a more rapid onset of effect, than the usual rescue drug. Adverse effects of the OTFC were typically opioid-related, specifically somnolence, nausea and dizziness. Very few adverse events were severe or serious. This study demonstrated the feasibility of controlled trial methodology in studies of breakthrough pain. OTFC appears to be a safe and effective therapy for breakthrough pain, and dose titration can usually identify a unit dose capable of providing adequate analgesia. If the lack of a relationship between the effective OTFC dose and fixed schedule opioid regimen is confirmed, dose titration may be needed in the clinical use of this formulation. Further investigation of OTFC as a specific treatment for breakthrough pain is warranted.

Dose-titration, multicenter study of oral transmucosal fentanyl citrate for the treatment of breakthrough pain in cancer patients using transdermal fentanyl for persistent pain.

PURPOSE: Supplemental, "as-needed," administration of an opioid is a common approach to the problem of breakthrough pain in cancer patients. Oral transmucosal fentanyl citrate (OTFC) is undergoing investigation as a new treatment for breakthrough pain. The primary purpose of the study was to demonstrate that a single-unit dose of OTFC can safely and effectively treat breakthrough pain. A secondary goal was to determine appropriate dosing guidelines. PATIENTS AND METHODS: This was a multicenter, randomized, double-blind, dose-titration study in 62 adult cancer patients using transdermal fentanyl for persistent pain. Consenting patients provided 2 days of baseline data to evaluate the performance of their usual breakthrough pain medication. Patients then randomly received 200 microg or 400 microg OTFC in double-blind fashion. (Patients were always assigned, rather than randomized, to 200 microg if 400 microg represented > 20% of around-the-clock medication.) Pain intensity (PI), pain relief (PR), and global satisfaction scores were recorded. OTFC was then titrated until the patient received adequate PR for each episode using one OTFC unit. Orders to titrate up were ignored one third of the time to improve the blind. Two days of baseline data were compared with 2 days of OTFC data after titration identified an effective dose of OTFC. RESULTS: Most patients (76%) found a safe and effective dose of OTFC. There was no meaningful relationship between the around-the-clock opioid regimen and the effective dose of OTFC. In open-label comparisons, OTFC produced a faster onset of relief and a greater degree of PR than patients' usual breakthrough medication. Somnolence, nausea, and dizziness were the most common side effects associated with OTFC. CONCLUSION: Most patients find a single OTFC dosage that adequately treats breakthrough pain. The optimal dose is found by titration and is not predicted by around-the-clock dose of opioids.

Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients.

BACKGROUND: Patients with cancer frequently experience episodes of acute pain, i.e., breakthrough pain, superimposed on their chronic pain. Breakthrough pain is usually treated with short-acting oral opioids, most of which provide some relief after 15-20 minutes, with peak effects after 30-45 minutes. Oral transmucosal fentanyl citrate (OTFC), a unique formulation of the opioid fentanyl, has been shown to provide meaningful pain relief within 5 minutes in patients following surgery. We conducted a multicenter, randomized, double-blinded, placebo-controlled trial of OTFC for cancer-related breakthrough pain. METHODS: Patients who were 18 years of age or older, receiving the equivalent of at least 60 mg oral morphine or at least 50 microg transdermal fentanyl per day for chronic cancer-related pain, and experiencing at least one episode of breakthrough pain per day were studied. After titration to an effective OTFC dose, subjects were given 10 randomly ordered treatment units (seven OTFC units and three placebo units) in the form of identical lozenges. If acceptable pain relief was not achieved within 30 minutes, subjects were instructed to take their previous breakthrough pain medication (i.e., rescue medication). Pain intensity, pain relief, and use of rescue medication were evaluated at 15-minute intervals over a 60-minute period. RESULTS: Eighty-nine of 92 patients who received the randomized treatment were assessable (i.e., treated with at least one unit of OTFC and one unit of placebo). OTFC produced significantly larger changes in pain intensity and better pain relief than placebo at all time points (two-sided P<.0001). Episodes treated with placebo required the use of rescue medication more often than episodes treated with OTFC (34% versus 15%; relative risk = 2.27; 95% confidence interval = 1.51-3.26; two-sided P<.0001). CONCLUSIONS: OTFC appears effective in the treatment of cancer-related breakthrough pain.

Oral transmucosal etomidate in volunteers.

BACKGROUND: The oral transmucosal route of delivery is now used for many drugs, including fentanyl and midazolam. Etomidate's pharmacokinetic profile and physiochemical properties suggest it may be suitable for transmucosal delivery. Transmucosal delivery might extend etomidate's use to sedation and anxiolysis. This is the first study in humans to examine the oral transmucosal administration of a novel etomidate dosage form. METHODS: Ten healthy adult volunteers consumed 12.5-mg, 25-mg, 50-mg, and 100-mg doses of oral transmucosal etomidate (OTET) on four different study days. Serum etomidate concentrations, sedation, respiratory and cardiovascular variables, taste, and side effects were determined. RESULTS: Five minutes after OTET administration, etomidate was detected in the venous blood. Mean peak concentrations occurred 20-30 min later and ranged from 61-174 ng/ml, related to the dose administered. Drowsiness and light sleep occurred in a dose-related manner 10-20 min after administration and lasted for 30-60 min. No episodes of SpO2 <90%, hypotension, or emesis occurred at any dose throughout the study. Nausea was rare. Two volunteers exhibited a brief episode of involuntary tremor after the 100-mg dose. The bitter taste of OTET was judged increasingly unpleasant with escalating doses. CONCLUSIONS: Oral transmucosal etomidate produces dose-related increases in sedation and clinically significant serum concentrations with minimal side effects. The time course of these effects suggests that OTET might be useful when brief mild to moderate sedation with rapid recovery is desirable. Further development of this novel dosage form is warranted.

Population pharmacokinetics of teicoplanin in patients with endocarditis.

Teicoplanin is a new glycopeptide antibiotic, active against aerobic and anaerobic gram-positive bacteria. The drug is intended for the treatment of systemic infections including endocarditis. In two U.S. clinical safety and efficacy trials, loading doses of 6 to 30 mg/kg doses of teicoplanin were administered initially to 197 patients, followed by once-a-day treatment of approximately the same doses over several weeks. Blood samples were collected sporadically during the study to monitor serum teicoplanin concentrations either by FPIA or microbiological assay. Nonlinear mixed-effects modeling was performed on these data to characterize the population pharmacokinetics of teicoplanin that were best described by a two-compartment model. Patient body weight, concomitant gram-positive drug treatment, and serum creatinine had significant influences on systemic clearance (CL) of the glycopeptide. In addition, body weight affected the volume of distribution of the central compartment (Vc). Other demographic factors such as age, gender, etc., had no effects. The FPIA assay method was more precise than the microbiological assay.

Single and multiple oral dose pharmacokinetics of clentiazem in normal volunteers.

This study was designed to determine the pharmacokinetics and dose proportionality of clentiazem (CLZ) after single doses (SD) of 20, 40, and 80 mg and multiple dose administration (SS) of 40, 80, and 160 mg/day for 5 days. The study was an open-label, randomized four-period complete crossover design. Twenty-four healthy male volunteers participated in the study, and blood samples were drawn over 48 hours after both SD and SS. Plasma samples were analyzed for CLZ and three metabolites by high-pressure liquid chromatography. After SD, the area under the plasma concentration-time curve (AUC0-infinity) and maximum concentration (Cmax) increased disproportionately with the increase in dose. At steady-state, a twofold increase in dose (20 to 40 mg twice daily and 40 to 80 mg twice daily) resulted in an increase in AUCss of 2.14- and 2.51-fold, respectively. Oral clearance of CLZ decreased (203.8 L/h at 40 mg/d to 140.2 L/h at 160 mg/d) and bioavailability increased (0.35 at 40 mg/d to 0.50 at 160 mg/d) with increasing doses. The terminal half-life of CLZ remained unchanged with increasing doses (13.7-15.5 hours). The ratios of AUCss to AUC0-infinity at SD ranged from 1.13 to 1.27, indicating no significant accumulation of CLZ (P > .05). The AUC ratio of N-desmethyl CLZ to that of CLZ remained constant after SD. On SS, however, there was a small decrease in this ratio with increasing dose (0.77 at 40 mg/d to 0.61 at 160 mg/d). These results indicate that the degree of nonlinearity observed with CLZ pharmacokinetics may largely be due to saturable first-pass metabolism.

Statistical comparison of stability study designs.

Studies are routinely conducted during development of a new drug to investigate the effect of strength, package, batch, storage condition, and storage time on stability of the dosage form. A typical study will have three batches, several strengths, several packages, and several storage conditions. Thus, if every batch by strength by package combination is tested for every storage condition, i.e., if a complete factorial design is used, a substantial expense is involved. To reduce expense, a matrix design is commonly used; e.g., only the smallest and largest bottles are tested. Fractional factorial-type designs for stability studies are proposed, and the statistical powers of various designs are compared.