Doses Of Oral Transmucosal Fentanyl Citrate Research Articles

Association of transdermal fentanyl and oral transmucosal fentanyl citrate in the treatment of opioid naïve patients with severe chronic noncancer pain

Chronic noncancer pain is often undertreated. To assess the efficacy of fentanyl transdermal therapeutic system (TTS) associated with oral transmucosal fentanyl citrate (OTFC) for breakthrough pain in patients with chronic noncancer pain. A total of 215 patients with chronic (> or =6 months), severe (VAS > or = 8) noncancer pain participated in a 6-month prospective study. The starting dose of 12 microg/h fentanyl TTS was titrated in 25 microg/h increments to a visual analog scale (VAS) score < or = 4. OTFC was administered as single-unit doses of 400 microg. The mean (SD) VAS score decreased from 9.86 (0.35) at baseline to 2.05 (0.96) at 6 months. The percentage of patients with poor quality of sleep decreased from 99 percent at baseline to 2.8 percent at the end of the study. The percentage of patients with inadequate pain control decreased from 16.2 percent at month 1 to 2.3 percent at month 6. Pain control was achieved with the 50 microg/h dose in 48 percent of patients, the 75 microg/h dose in 18 percent, and the 100 microg/h dose in 5 percent (only two patients required >100 microg/h). The daily use of single-unit doses of OTFC decreased from 4.64 at month 1 to 2.62 at month 6. Headache, nausea/vomiting, constipation, and somnolence of mild or moderate intensity were the most common side effects. Treatment was discontinued because of nausea/vomiting in seven patients, somnolence in three, and dermatitis in two. Fentanyl TTS associated with OTFC for breakthrough pain is a feasible and effective strategy in opioid naïve patients with severe chronic nonmalignant pain.

Effect of Modulated Electrohyperthermia on the Pharmacokinetics of Oral Transmucosal Fentanyl Citrate in Healthy Volunteers

PurposeThis study aimed to determine whether changes occur in fentanyl absorption and disposition when administered in conjunction with modulated electrohyperthermia (mEHT) treatment. MethodsA randomized, single-dose, crossover, open-label study was used to investigate the effect of mEHT on the pharmacokinetic properties of fentanyl in 12 healthy volunteers. The 12 healthy volunteers were each administered a single dose of oral transmucosal fentanyl citrate (OTFC) or a single dose of OTFC with mEHT. mEHT was performed on the abdomen for 1 hour. Blood samples were collected for 24 hours after dosing. The temperature of the abdominal skin surface was assessed before dosing and at 10, 20, and 60 minutes after dosing. FindingsGeometric mean ratios (ratio of fentanyl with mEHT to fentanyl alone) for the Cmax and AUC0–last were 1.20 (90% CI, 1.09–1.32) and 1.15 (90% CI, 0.99–1.33), respectively. The mean temperature of the abdominal skin surface increased by approximately 4°C. ImplicationsThere was an increase in the overall exposure to the drug without implications of any clinical significance. OTFC can be administered without limitations in combination with mEHT, and it is not necessary to modify the dosing regimen. cris.nih.go,kr Identifier: KCT0001286.

Oral trasmucosal fentanyl citrate for breakthrough pain treatment in cancer patients

Introduction: Breakthrough cancer pain has been defined as a transitory increase in pain intensity that occurs either spontaneously or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain. The availability of supplemental doses of oral opioids, in addition to the continuous analgesic medication, is the main treatment suggested to manage pain flares.Areas covered: Oral transmucosal fentanyl citrate (OTFC) is the first product of a new generation of delivery systems, named rapid-onset opioids (ROOs), characterized by rapidity of effect and the short duration of analgesia. Controlled studies and long-term experience have shown that OTFC is an effective treatment for breakthrough pain management and its use should be considered in any patient experiencing breakthrough pain related to cancer.Expert opinion: The onset of action of OTFC – demonstrated to start within 15 min – and the short time to maximum concentration make it a useful indication for breakthrough pain; dose titration is commonly recommended. However, it is likely that patients receiving high doses of opioids for background analgesia will not be candidates for titration with minimal initial doses of OTFC, as they are opioid tolerant and the process would be time consuming.

Factors in the choice of oral transmucosal fentanyl citrate dose for adult burns dressings

Factors that influenced the choice of dose of oral transmucosal fentanyl at the time of burns dressing change were investigated in a prospective study. After Ethics committee approval, data was analysed from 29 consecutive patients who had been recruited and consented for a study of pain associated with burns dressings. Patients had completed an 11-point verbal pain intensity score (VRS) prior to and after the dressing change. Analgesic use during for this period was documented. Doses of 600 to 1200 mcg of transmucosal fentanyl (Actiq ®) were given based on individual assessment. The pre-dressing VRS (median [range]) in the 15 patients who received 600 mcg was 8 [3–10] and was higher than the VRS of 6 [2–9] in the 800–1200 mcg group. The time since the burn was longer in the low dose group at 7 [1–22] days compared with 5 [0–50] days in the higher dose group. In addition 73% of the low dose group was prescribed opioids regularly prior to the dressing compared with 57% of the high dose group. The choice of a lower transmucosal fentanyl dose was based on prior use of opioids and the age of the burn rather than on the patient's pain intensity.

Oral transmucosal fentanyl citrate in the management of breakthrough pain in cancer: an open, multicentre, dose-titration and long-term use study

Sixty-six patients with cancer-related pain entered an open multicentre study to examine the safety and efficacy of oral transmucosal fentanyl citrate (OTFC) in the treatment of breakthrough pain. Patients were eligible for the study if they were stabilized on a long-acting opioid but were experiencing up to four episodes of breakthrough pain a day and achieving at least partial relief from breakthrough pain using conventional medication (normal release oral morphine in the majority of patients). The efficacy of the conventional medication was documented in a run-in phase and patients then changed to OTFC. All patients were treated initially with a 200 mcg unit of OTFC and the dose was increased if necessary to a level that produced relief of breakthrough pain without troublesome adverse effects. Fifty-eight patients completed the run-in phase using their usual medication and entered the dose titration phase with OTFC and 57 patients received at least one dose of OTFC. Forty-two patients (72%) found a successful dose of OTFC. The primary outcome measures were the Summed Pain Intensity Differences (SPID) and Total Pain Relief (TOTPAR) scores at 60 min. There was a significant difference in both measures in favour of OTFC compared with conventional medication in these patients. Twenty-eight of the 42 patients (67%) preferred OTFC to their usual medication. The most common adverse effects attributed to OTFC were nausea, stomatitis, vomiting and dizziness but there were no unpredicted or severe problems. Thirty-seven patients continued into the long-term study and 12 of these completed six months treatment. Most drop-outs in this phase were associated with progression of the underlying disease. No patient stopped using OTFC because of dissatisfaction with the drug. OTFC appears to be a safe and effective treatment for breakthrough pain in cancer patients and may have advantages over currently available opioid formulations.

The Pharmacokinetics of the Intravenous Formulation of Fentanyl Citrate Administered Orally in Children Undergoing General Anesthesia

The bioavailability of oral transmucosal fentanyl citrate (OTFC) in children is similar to that of fentanyl solution administered orally to adults. We hypothesized that administering an oral fentanyl solution to children would result in similar fentanyl plasma concentrations and pharmacokinetic variables as administering comparable doses of OTFC. In this pilot study, 10 healthy children requiring postoperative analgesia were enrolled. Each received the undiluted IV fentanyl formulation orally (approximately 10-15 microg/kg; maximum, 400 microg). Venous blood samples were collected from 15 to 600 min after administration. Pharmacokinetic variables were determined using noncompartmental analysis and were compared with a previously studied population of children who received a similar dose of OTFC. Pharmacokinetic variables for the orally administered IV fentanyl formulation were as follows: time to reach peak concentration = 1.7 +/- 1.6 h, peak concentration = 1.83 +/- 1.19 ng/mL, half-life = 4.7 +/- 2.8 h, area under the plasma concentration time curve = 6.46 +/- 3.96 h . ng(-1) . mL(-1), apparent oral volume of distribution (V/F) = 17.5 +/- 7.2 L/kg, apparent oral clearance (CL/F) = 3.33 +/- 2.25 L . kg(-1) . h(-1). Although both OTFC and orally administered IV fentanyl resulted in similar pharmacokinetic variables and plasma concentrations for a given dose, there was marked interpatient variability, particularly in the early hours after oral administration of the IV formulation of fentanyl. This suggests that this method of administration be used with caution until further data are available.

A Pharmacokinetic Study to Compare Two Simultaneous 400 μg Doses with a Single 800 μg Dose of Oral Transmucosal Fentanyl Citrate

It is unknown whether two smaller doses of oral transmucosal fentanyl citrate (OTFC) administered simultaneously are pharmacokinetically equivalent to an identical dose administered as a single unit. This issue has important practical implications when patients are attempting to identify the appropriate dosage of OTFC to control their pain. This open-label, randomized, crossover design study compared the pharmacokinetics of two simultaneously consumed 400 μg OTFC doses with one 800 μg OTFC dose in 12 healthy volunteers. The two treatments were pharmacokinetically equivalent. The maximum concentration produced for each dosage group (Cmax) was 1.09 ng/ml for two 400 μg dose and 1.10 ng/ml for one 800 μg dose. Area under the curve (AUC) was 8.2 ng/ml·pChr (SE = 1.1) and 7.2 ng/ml·pChr (SE = 1.0). There were no significant differences between the treatment groups in either the time to peak concentration (Tmax) or the mean residence time (MRT). The results demonstrate the bioequivalence of two 400 μg with one 800 μg OTFC units.

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 μ-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 μg 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 μg 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 μg 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.

A Review of Oral Transmucosal Fentanyl Citrate: Potent, Rapid and Noninvasive Opioid Analgesia

The physiochemical characteristics of the potent synthetic opioid agonist fentanyl make it ideal for noninvasive transmucosal delivery. Studies of oral transmucosal fentanyl citrate (OTFC), a candied matrix formulation administered orally as a palatable lozenge on a stick, have investigated and determined this analgesic's pharmacokinetics and pharmacodynamics in a number of clinical settings, including premedication before surgery, acute analgesia for painful medical procedures, and, most recently, for the control of breakthrough cancer pain. The onset to meaningful pain relief in patients with acute pain from surgery or breakthrough pain from cancer is between 5 and 10 minutes after initiating OTFC use, equivalent to intravenous morphine. Analgesic dose equivalency studies suggest that OTFC is, on average, about 10 times more potent than morphine, although, in randomized, controlled, and blinded studies, many patients who were using relatively high doses of opioid anlagesics on an around the- clock schedule for control of cancer pain reported that even a low dose of OTFC (i.e., 200 microg) provided adequate relief from breakthrough pain. Side effects from OTFC are similar in character and frequency to other opioids, including sedation, nausea, and pruritus. These effects appear to wane rapidly with repeated use of this medication. To date there have been no reported serious adverse events in any of the population groups studied or treated with OTFC.

Oral transmucosal fentanyl citrate for premedication of children undergoing laceration repair

To evaluate the safety and efficacy of two doses of oral transmucosal fentanyl citrate (OTFC) for premedication of children undergoing laceration repair. Prospective, randomized, nonblinded study. Urban pediatric emergency department. Thirty children aged 2 to 8 years requiring laceration repair. Premedication with either 10 to 15 micrograms/kg or 15 to 20 micrograms/kg of OTFC. Activity score, vital signs, oxygen saturation, and pain scores were recorded before and after administration of OTFC. Activity scores decreased significantly 15 to 60 minutes after OTFC. The physician suturing the wound rated the child's sedation/pain control as excellent or good in 83% of patients. Vital signs changes were not clinically remarkable. Oxygen saturations remained at 95% or more except in one child who experienced a transient decrease to 91%. Adverse effects were not serious but included vomiting in 20% of the lower-dose group and 47% of the higher-dose group. There were no significant differences between dose groups for activity or pain score changes, physician assessment, discharge times, or adverse events. Both doses of OTFC reduced activity with comparable efficacy, with no serious vital signs changes. However, the higher-dose group had a greater number (P = NS) of adverse effects.

Oral transmucosal fentanyl citrate for premedication in paediatric outpatients

Two doses (10-15 micrograms.kg-1, Group I, and 15-20 micrograms.kg-1, Group II) of oral transmucosal fentanyl citrate (OTFC) plus a placebo (Group III) were evaluated for premedication in 105 healthy children, aged 2 to 13 yr, undergoing short (less than 1 hr) operations in the hospital short-stay unit. The study was randomized and double-blinded and 91 of the 105 children also received droperidol, 25 micrograms.kg-1 IV, after induction of anaesthesia with halothane and N2O in oxygen. Both doses of OTFC produced significantly greater sedation (first present at 20 min) and anxiolysis (first present in Group I at 40 min) than the placebo. Recovery times were similar in the three groups and analgesic requirements in the recovery room were significantly lower in Group I than Group III. Both OTFC groups took longer to tolerate oral fluids in the postoperative discharge unit than the placebo group and this caused patients in Group I to have a delayed discharge from the hospital compared to Group III. Preoperative pruritus occurred significantly more frequently in Groups I and II (58 and 76 per cent, respectively) than Group III (23 per cent). Although the incidences of nausea and vomiting tended to be slightly higher in the OTFC groups in the preoperative holding and postoperative discharge units, the differences among the groups were not statistically significant. Likewise droperidol did not reduce the incidence of postoperative nausea or vomiting. The data indicate that OTFC may be a safe and effective premedicant in paediatric patients having short operations but delays discharge from the hospital (by 30-50 min) by delaying the time patients tolerate fluids early after operation.

Oral Transmucosal Fentanyl Citrate (Lollipop) Premedication in Human Volunteers

The authors determined whether fentanyl incorporated into a candy lollipop, oral transmucosal fentanyl citrate (OTFC), would cross mucosal tissues of the mouth in sufficient quantities during and after dissolution to produce sedation and/or analgesia. Associated respiratory and circulatory changes, side effects, and plasma concentrations of fentanyl were also measured. The evaluations were done in 28 adult volunteers who received fentanyl citrate in doses of 5, 4, 2, 1, and 0.5 mg in OTFC and rapidly sucked the lollipops (N = 20) or allowed them to passively dissolve (N = 8). Rapid consumption of OTFC resulted in more rapid onset of a pleasant feeling (first subjective sensation) but not more rapid onset of objective sedation or analgesia than passive dissolution. There was a significant correlation between dose of OTFC and magnitude of sedation (P less than 0.001, Spearman rank correlation = -0.82). Higher doses of OTFC produced greater and longer lasting analgesia and respiratory depression and a higher incidence of nausea and vomiting than lower doses, but pruritus (33%-87%) was not related to the dose of OTFC. Heart rate and arterial blood pressures were not changed by any dose of OTFC. The data indicate that low doses of OTFC (0.5 and 1 mg, equivalent to 5-20 micrograms.kg-1 of fentanyl citrate) produce analgesia and sedation with minimal side effects and little respiratory depression in adult volunteers and deserve further evaluation in patients.

Oral Transmucosal Fentanyl Citrate (Lollipop) Premedication in Human Volunteers

The authors determined whether fentanyl incorporated into a candy lollipop, oral transmucosal fentanyl citrate (OTFC), would cross mucosal tissues of the mouth in sufficient quantities during and after dissolution to produce sedation and/or analgesia. Associated respiratory and circulatory changes, side effects, and plasma concentrations of fentanyl were also measured. The evaluations were done in 28 adult volunteers who received fentanyl citrate in doses of 5, 4, 2, 1, and 0.5 mg in OTFC and rapidly sucked the lollipops (N = 20) or allowed them to passively dissolve (N = 8). Rapid consumption of OTFC resulted in more rapid onset of a pleasant feeling (first subjective sensation) but not more rapid onset of objective sedation or analgesia than passive dissolution. There was a significant correlation between dose of OTFC and magnitude of sedation (P < 0.001, Spearman rank correlation = −0.82). Higher doses of OTFC produced greater and longer lasting analgesia and respiratory depression and a higher incidence of nausea and vomiting than lower doses, but pruritus (33%-87%) was not related to the dose of OTFC. Heart rate and arterial blood pressures were not changed by any dose of OTFC. The data indicate that low doses of OTFC (0.5 and 1 mg, equivalent to 5–20 äg·kgminus;1 of fentanyl citrate) produce analgesia and sedation with minimal side effects and little respiratory depression in adult volunteers and deserve further evaluation in patients.

Oral Transmucosal Fentanyl Citrate Premedication in Children

The authors evaluated the safety and efficacy of four doses of oral transmucosal fentanyl citrate (OTFC) as a premedicant in 44 children about to undergo elective operations. The patients received 5-10, 10-15, 15-20, or 20-25 micrograms.kg-1 of OTFC in the holding area and had activity (sedation) scores, vital signs (including systolic and diastolic arterial blood pressures, heart, and respiratory rates), and pulse oximetry determined oxygen saturation measured before and at 15-min intervals after premedication until they were taken to the operating room. Cooperation during anesthetic induction, and quality and speed of recovery room emergence were measured and side effects noted. OTFC was readily accepted and provided significant (dose dependent) reductions in preoperative activity starting after 30 min. Onset of sedation was related to dose of OTFC but time to peak effect was not. Vital signs remained unchanged preoperatively in all groups but patients receiving 20-25 micrograms.kg-1 had oxygen saturations that were significantly lower than patients in the other groups 30 min after beginning OTFC consumption. Three of the 12 patients receiving the highest dose of OTFC experienced transient oxygen saturation less than 90% which, however, was easily treated by commands to take a breath. Anesthetic inductions were rated good or excellent in 80% of the patients and recovery times were similar irrespective of the OTFC dose. OTFC caused dose-independent preoperative pruritus in 90% or more of patients and pruritus (33%-70%), nausea (30%-58%), and vomiting (50%-83%) postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)