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Oral transmucosal fentanyl citrate (OTFC), a water soluble salt when mixed in saliva is 80% nonionized; making it the only opioid suitable for transmucosal absorption. OTFC has rapid onset of action (3–5 min) with peak effect at 20–40 min and total duration of activity is 2–3 h.
This study aims to determine the efficacy of OTFC as premedicant in patients scheduled for surgery under general anesthesia (GA) and to assess the effects of OTFC on anxiety, sedation.
A prospective randomized study.
Patients between 21 and 60 years of age in American Society of Anesthesiologists physical status Classes I and II scheduled for elective surgery under GA were randomly assigned to three groups of 30 each: OTFC, placebo, and control. Mean arterial blood pressure (MAP), heart rate (HR), respiratory rate (RR), and oxygen saturation (SpO2) along with anxiety and sedation scores were recorded as baseline and upon entering the operation theater. Adverse effects were also recorded.
Statistical analysis was done using Statistical Package for Social Sciences Version 15.0 Statistical Analysis Software.
No significant differences were found in MAP, HR, RR, or SpO2 among the groups. OTFC group demonstrated significantly higher levels of anxiolysis than the control group (P < 0.05). No significant difference in sedation score was found. No remarkable adverse effects were observed.
OTFC is an effective anxiolytic in adult with minimal risks and side effects. It is readily acceptable by the patients in its given form.
Lipid-soluble drugs that can be supplied as water-soluble salts provide the opportunity to explore new routes of administration for premedication.[1,2] The salt fentanyl citrate is soluble in both water and a number of candy matrices.[1,3,4,5] These properties suggest that fentanyl citrate may be incorporated into a newer mode of delivery system – the lollipop (oral transmucosal fentanyl citrate [OTFC]), for use as a premedicant. OTFC is an opioid formulation in which the potent synthetic mu-agonist fentanyl is embedded in a sweetened matrix that is dissolved in the mouth. This lipid-soluble opioid when placed in saliva under normal conditions of the mouth is 80% nonionized, making it the only opioid suitable for transmucosal absorption. However, bioavailability of OTFC depends on the fraction of the dose that is absorbed through the oral mucosa (~25%) and the fraction that is swallowed (~75%, but swallowed dose is only partially bioavailable). OTFC can produce a rapid onset of analgesia, even during unit consumption (fentanyl begins to cross the blood–brain barrier in as little as 3–5 min), with peak effect at 20–40 min after the start of administration. The total duration of activity is 23 h. The amount of fentanyl absorbed from each single dose remains stable over multiple administrations. This fact, combined with fentanyl's short half-life, reduces the risk of a cumulative increase in serum level with repetitive doses. OTFC has been used to easily and rapidly deliver sedation to children and volunteers.[8,9,10,11,12,13] This experience with the fentanyl oralet suggests that it may be useful as a premedicant for adult patients undergoing surgery. This study was designed to test the efficacy of the OTFC oralet to reduce anxiety and cause sedation in an adult population on arrival to the operating room just prior to surgery compared to a placebo oralet and a control group receiving nothing.
Ninety adult patients in the age group of 21–60 years scheduled for elective surgeries under general anesthesia (GA) were studied after obtaining the clearance from Hospital Ethical Committee.
The study was carried out in the department of anesthesiology and critical care of a tertiary care hospital within the time period of 18 months. Inclusion Criteria are elective surgeries under GA, American Society of Anesthesiologists (ASA) physical status Classes I or II, between the ages of 21 and 60 years whereas exclusion criteria are ASA physical status Classes III or IV, pregnant females, chronic obstructive pulmonary disease, psychiatric disorders/patients on antidepressants or antipsychotics, opioid dependent patients, head injury/intracerebral space-occupying lesion, sensitivity to opioids, refusal to enroll for the study.
Patients were randomly assigned by computer program to one of three groups upon entering the preoperative anesthetic assessment area:
Each group included thirty participants.
Patients were kept fasting overnight and no premedication were given. All investigators were blinded to the type of oralet patients consumed in Group F and P; however, patients in the Group C could be identified by their not having received an oralet. After assessing the patient for anesthesia, informed consent of patients about study and anesthesia was obtained. On arrival of patients in the preoperative area, baseline anxiety and sedation levels were assessed immediately before receiving medication, to ensure similarity between the groups; and at the more anxiety-provoking phase upon entering the operating room the three groups of patients were reassessed. The level of sedation was evaluated using the Ramsay Sedation Scale, and anxiety level was rated with the Spielberger State-Trait Anxiety Inventory Short Form.
Baseline recordings of following parameters were noted just before any premeditation and every 10 min thereafter for 60 min.
Fentanyl citrate oralet was placed next to buccal mucosa, between cheek and gum, moving it gently side to side. Fifteen minutes is the ideal amount of time to consume a oralet to achieve the desired onset and peak effect. OTFC units are designed for one-time administration. Patients were instructed to remove the unit from their mouth if excessive opioid-related side effects develop such as nausea, vomiting, respiratory depression, pruritus, and headache. The following factors which can possibly decrease transmucosal absorption of OTFC were kept in mind:
The patients were observed for adverse effects if any, before they left the preoperative area and again after the surgery before they left the recovery area. After shifting the patients to operating room, intravenous line was secured with 18G cannula and monitors were attached. All patients were administered injection glycopyrrolate 0.2 mg intravenously and preoxygenated with 100% oxygen for 3 min. Induction of anesthesia was carried out with injection propofol 1% 2 mg/kg intravenously.
Tracheal intubation was performed after administration of succinylcholine (1.5 mg/kg). Anesthesia was maintained with 33% oxygen in nitrous oxide and continuous infusion of injection propofol 1% (50 μg/kg/min with adjustments in infusion rates depending on the hemodynamics of patients). Thereafter, muscle relaxation was achieved with injection vecuronium 0.1 mg/kg followed by incremental doses of injection vecuronium 0.01 mg/kg when required. Intraoperative analgesia was maintained with injection paracetamol (15 mg/kg) intravenously.
At the conclusion of surgery, residual muscle paralysis was reversed with injection neostigmine 60 μg/kg and injection glycopyrrolate 10 μg/kg intravenously. The patient was extubated following return of regular, rhythmic respiration when reasonably awake.
In the recovery room, patients were asked to rate the premedicant they were given (Groups F and P only) and the mode of delivery as very good, good, neutral, dislike, or strongly dislike, scored from 5 to 1, respectively.
Statistical analysis was performed using a repeated measures analysis of variance (level of test considered significant was P < 0.05).
Scale scored from 1 (least sedated) to 6 (most sedated).
Scoring based on patient response:
Statements 1, 4, and 5 scored from +1 to +4
Statements 2, 3, and 6 scored from −1 to −4
Sum of all scores: −9 (most anxious), 0 (neutral), and +9 (most calm).
The patient demographic characteristics were similar in the three groups. The patients were matched for age and weight distribution with a mean age of 39 ± 11 yrs and a mean weight of 49 ± 9 kg [Figure 1].
No significant differences were found when comparing all three groups initially when they arrived in the preoperative holding area. The second assessment was performed at the time of greatest stress, as the patient was placed on the operating table. Patients given OTFC were significantly less anxious than those in the control group receiving no premeditation. There were no significant differences when the OTFC and placebo groups were compared [Figure 4]. The patients in the control group, who received no oralet, were the least calm on arrival in the operating room. The control and placebo groups did not significantly change their anxiety scores from the initial assessment to the second assessment in the operating room (control 2.0 ± 0.6–1.8 ± 0.6, placebo 3.4 ± 0.6–3.3 ± 0.7). The OTFC group significantly increased its score (3.3 ± 0.7–4.5 ± 0.7; P < 0.05) indicating an anxiolytic effect. No changes were found in sedation levels among the groups [Figure 5].
In the OTFC group, 65% rated the effect of the premeditation “good” or “very good” compared to 36% of the placebo group. A majority in all groups thought that the concept of a premedicant delivered in a lozenge mounted on a handle was good. The incidence of significant side effects in all three groups was minimal. There is no incidence of nausea, vomiting, pruritus, headache, and respiratory depression found in any group.
The graphs computed after statistical analysis are hereby included.
Premedication aims at relieving preoperative anxiety, providing sedation, and facilitating induction of anesthesia with minimal side effects. In several studies on children, a number of research publications have highlighted the role of OTFC for premedication in pediatric population.[9,10,11,12,13,14] A web search brought out only a couple of studies focused on fentanyl oralet as a premedicant in adults. After the patient's trachea was intubated, residual gastric contents were collected through a gastric tube, and stimulation of gastric acid secretion with high risk of aspiration remained a concern with OTFC. However, the lower dose of OTFC (200 μg) used in the present study as compared to the earlier ones (300 and 400 μg) did alley the concern to some extent. There was no significant difference in the gastric volumes and pH among the three groups (OTFC, placebo, and control), suggesting thereby that OTFC does not increase gastric secretion or the risk of aspiration in adults. This study confirmed the findings of Stanley et al. that gastric pH values are similar in the three groups but differed in that they demonstrated no significant increase in gastric volume between patients who received oralets and those who did not. However, it was in contrast to the study of Søreide et al. who demonstrated increased gastric volumes in patients who had chewed sugar-free gum. No noteworthy adverse effect was observed in either of the groups with only one patient in the fentanyl group complaining of light-headedness. This could be explained on the basis of the low dose of OTFC used in the present study compared to the earlier ones where the incidences of dizziness, light-headedness, nausea, and respiratory depression were higher.[10,18] The overall incidence of adverse reactions in adults was far less than that reported in children.[9,11,19] Anxiolysis in patients entering the operating room was more effective with premedication with OTFC than those with no premeditation. The control group (no premedication) patients were the least calm set of patients on entering the operating room. The placebo group was clinically less anxious than the control group (statistically nonsignificant), suggesting that the placebo may have some pacifier effect. There was no difference in sedation scores among the three groups at either assessment. This may be a result of low dosage of the drug used in the study. Adequate time was allowed following the administration of the oralets to observe peak clinical effects.[21,22] A study conducted by Binstock et al. found that OTFC reduced early postoperative agitation and increased side effects, namely postoperative nausea and vomiting and prolonged recovery times, which limits its clinical usefulness.
In this study, the use of an oralet as the method of delivery of premeditation was widely accepted and approved by adults. The oralet is easy to administer by the nursing staff and causes no serious side effects such as nausea, vomiting, and pruritus. However, patients who receive OTFC require continuous monitoring by qualified medical personnel.
Oral Transmucosal Fentanyl Citrate (OTFC) is an effective anxiolytic in adults with minimal risks and side effects. It is readily acceptable by the patients in its given form.
There are no conflicts of interest.