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Oral Transmucosal Fentanyl Citrate for Premedication in Adults

Macaluso, Amy D. MD; Connelly, Amy M. MD; Hayes, W. Brendan MD; Holub, Michael C. MD; Ramsay, Michael A. E. MD; Suit, C. Tracy BS; Hein, H. A. Tillmann MD; Swygert, Thomas H. MD

General Article

This study was designed to assess the efficacy of oral transmucosal fentanyl citrate (OTFC) for premedication in an adult population and to determine its effects on anxiety, sedation, gastric volume, and gastric fluid acidity.The fentanyl citrate is incorporated in a lozenge mounted on a handle (oralet). The effects of OTFC, placebo oralet, and no premedication were compared in a prospective, double-blind study on 90 adult ASA physical status I and II patients undergoing same-day admission surgery. Patients were randomly assigned to one of three groups: OTFC group (n = 30), placebo group (n = 30), and control group (n = 30). Arterial blood pressure, heart rate, respiratory frequency, and oxygen saturation determined by pulse oximetry were recorded before any premedication was given, and then every 10 min until the patient was taken to the operating room. Baseline anxiety and sedation levels were assessed to ensure group similarity immediately before premedication was given and at the more anxiety-provoking phase upon entering the operating room. Anxiety levels were rated using the Spielberger State-Trait Anxiety Inventory short form and sedation levels were assessed with the Ramsay scale. Side effects, as reported by the patients, were also recorded. Gastric contents were aspirated via an orogastric tube after induction of anesthesia and were measured for volume and pH. No significant differences were found among the three groups in mean arterial pressure, heart rate, or respiratory frequency. Initial oxygen saturation levels in all groups decreased after 30 min but not less than 96% except for one patient in the OTFC group, who decreased to 88%. On entering the operating room, the OTFC group demonstrated significantly higher levels of anxiolysis than the control group, but no significant differences were seen between the OTFC and the placebo groups or the placebo and control groups. Mean gastric volumes (OTFC, 29 mL; placebo, 26 mL; control, 24 mL) and pH (OTFC, 2.0; placebo, 1.8; control, 2.1) were similar in all groups. There were no significant differences among the groups in levels of sedation achieved. Mild dizziness or light-headedness was the most commonly reported side effect in 23% of the OTFC group. In the OTFC group, 71.4% liked the premedicant effect as compared to 46.4% of the placebo group. Most of the groups found the oralet method of premedicant delivery very acceptable. This study demonstrates that the OTFC oralet is an effective anxiolytic in adults. It has minimal side effects and is prepared in an acceptable format. There was no measurable increase in gastric contents or acidity in the oralet groups, compared to those patients who were given nothing by mouth.

(Anesth Analg 1996;82:158-61)

Departments of Anesthesiology and Pain Management, Baylor University Medical Center, and University of Texas Southwestern Medical Center, Dallas, Texas.

Accepted for publication August 14, 1995.

Address correspondence and reprint requests to Michael A. E. Ramsay, MD, Chief, Department of Anesthesiology and Pain Management, Baylor University Medical Center, 3500 Gaston Ave., Dallas, TX 75246.

Oral transmucosal fentanyl citrate (OTFC) has been used to easily and rapidly deliver sedation to children and volunteers [1-5]. This experience with the fentanyl oralet suggests that it may be useful as a premedicant for adult patients undergoing same-day admission surgery. The 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. The effect of consuming an oralet on gastric volume and pH was also measured and compared to a control group.

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Methods

After institutional review board approval and informed consent, 90 patients presenting for same-day admission surgery were entered into the study. Subjects were eligible for inclusion if they were classified as ASA physical status I or II and between the ages of 21 and 60 yr. Pregnant females were excluded. All subjects had fasted for at least 8 h prior to participation in the study. Patients were randomly assigned by computer program (Pharmasy Registered Trademark; Healthcare Counsulting Assoc., Dallas, TX) to one of three groups upon entering the preoperative anesthetic assessment area: patients in Group I were given a 300-micro gram OTFC oralet if they weighted less than 70 kg or a 400-micro gram OTFC oralet if they weighed 70 kg or more; Group II patients received a placebo oralet; Group III patients were given no premedication. Each group included 30 subjects. All investigators were blinded to the type of oralet patients in Groups I and II consumed; however, patients in the control group could be identified by their not having received an oralet. The fentanyl and placebo oralets were supplied and manufactured by Abbott Laboratories (Abbott Park, IL) and were identical in taste and appearance.

To ensure similarity between the groups, baseline anxiety and sedation levels were assessed when the patients arrived in the preoperative area prior to receiving medication. On entering the operating room the three groups of patients were reassessed. The level of sedation was evaluated using the Ramsay sedation scale [6] and anxiety levels were rated with the Spielberger State-Trait Anxiety Inventory short form [7] (Appendix 1) Table 3. Baseline arterial blood pressure, heart rate, respiratory frequency, and oxygen saturation (SpO2) were measured just prior to any premedication and every 10 min thereafter, while in the preoperative area. The presence of side effects was determined by direct questioning of patients before they left the preoperative area and again before they left the recovery area. After induction of anesthesia, blind gastric aspiration was performed via an orogastric tube utilizing the technique of Soreide et al. [8] and the volume was measured. Gastric pH was assessed using the Altex Registered Trademark 3500 model (Beckman, Irvine, CA) pH meter. Gastric pH was converted to H+ ion concentrations before statistical analysis was performed. In the recovery room, patients were asked to rate the premedicant they were given (Groups I and II only) and the mode of delivery as very good, good, neutral, dislike, or strongly dislike, scored from 5 to 1, respectively.

Statistical analysis of mean arterial pressure, heart rate, respiratory frequency, SpO2, and anxiety data was performed using a repeated-measures analysis of variance. Sedation effects and patient preferences were evaluated with the Mantel-Haenszel chi squared test. All other data points were analyzed with the Student's t-test with a Bonferroni correction. The level of all tests considered significant was P < 0.05.

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Results

The three groups were similar in age and weight distribution with a mean age of 41 +/- 10 yr and a mean weight of 79 +/- 17 kg. No association was found between type of surgical procedure and group assignment.

Mean arterial pressure, heart rate, and respiratory frequency did not change significantly over time, nor did they differ significantly between the fentanyl, placebo, and control groups. SpO2 levels in all groups decreased significantly from baseline to measurements taken 30 min later; however, the mean SpO2 for the three groups never decreased to less than 96% except for one patient in the OTFC group where there was a decrease to a level of 88%.

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 fentanyl were significantly less anxious than those in the control group receiving no premedication. There were no significant differences when the OTFC and placebo groups were compared Figure 1. The patients in the control group, who received no oralet, were the least calm on arrival in the operating room. There was no difference in the mean observation times (37 +/- 12 min) from time of premedicant administration to arrival in the operating room, with ranges of 20-70 min for the oralet groups and 10-70 min for the control group. 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 right arrow 1.8 +/- 0.6, placebo 3.4 +/- 0.6 right arrow 3.3 +/- 0.7). The OTFC group significantly increased its score (3.3 +/- 0.7 right arrow 4.5 +/- 0.7; P < 0.05) indicating an anxiolytic effect. No changes were found in sedation levels among the groups. In all three groups gastric volumes and pH measurements were similar Table 1.

Figure 1

Figure 1

Table 1

Table 1

In the OTFC group, 71% rated the effect of the premedication "good" or "very good" compared to 46% 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 Table 2.

Table 2

Table 2

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Discussion

An ideal premedicant for patients undergoing same-day admission surgeries would relieve preoperative anxiety, provide sedation, facilitate induction of anesthesia, and be dispensed easily by health care personnel and have minimal side effects. In several studies on children, OTFC was an acceptable method of delivering sedatives [1-4]. No studies have focused on the benefits of the oralet as a premedicant in adults.

A concern about the fentanyl or placebo oralet was that it might promote the secretion of gastric acid, leading to an increased risk for aspiration and resulting complications. This study found that gastric volumes and pH were not significantly different among the three groups, which suggests that consuming an oralet does not increase gastric secretion or the risk of aspiration in adults. This study data confirmed the report of Stanley et al. [3], that gastric pH values are similar in OTFC, placebo, and control groups but differed in that it demonstrated no significant increase in gastric volume between patients who received oralets and those who did not. This is in the contrast to the study of Soreide et al. [9] who demonstrated increased gastric volumes in subjects who had chewed sugar-free gum.

There were few adverse effects. In the fentanyl group, 23% (7/30) complained of mild dizziness or light-headedness; nausea, facial or chest flushing, and paresthesia each were reported by 7%. None of the study participants appeared to be particularly distressed by the appearance of such mild adverse reactions. One OTFC patient experienced hypoventilation, evidenced by a transient decrease in SpO2 to 88%. This was corrected by asking the subject to take a deep breath. Although only one patient experienced respiratory depression, there was a decline in SpO2 in all groups. Other studies have reported a higher incidence of respiratory depression and emphasize the use of OTFC only in a monitored setting [2,10]. The overall incidence of adverse reactions in adults was far less than that reported in children [1,3,11].

The test of a premedicant is its anxiolytic effect on the patient entering the operating room. The fentanyl oralet was more effective at reducing anxiety at this stage than no premedication. The patients who received no oralet, the control group, were the least calm set of patients at this time. The placebo oralet group was clinically less anxious than the control group, even though this anxiety did not reach statistical significance. This suggests that the placebo oralet may have some anxiolytic properties (i.e., a pacifier effect).

Sedation scores did not differ among the three groups at either assessment. This may be a result of poor absorption of OTFC due to vehicle pH, additives, or inadequate dosage of the drug [12]. A broader range of fentanyl concentrations would allow for more precise dosing and perhaps a better sedative effect. Adequate time was provided after administration of the fentanyl oralet to observe peak clinical effects which occur within 20-30 min after consumption [13,14]; Abbott Laboratories, Abbott Park, IL: Important clinical considerations in the use of fentanyl oralet [package insert]).

In this study, the use of an oralet as the method of delivery of premedication was widely accepted and approved by adults. The oralet is easy to administer by the nursing staff and causes no measurable increase in gastric volume. However, patients who receive OTFC require continuous monitoring by qualified medical personnel. This may reduce its usefulness as a preoperative medication in a fast-paced, same-day admission or day surgery setting. Possibly, a drug more commonly used as a preoperative medication to reduce anxiety, such as a benzodiazepine, would be a more appropriate and effective drug to incorporate into an oralet as opposed to a narcotic.

The authors thank Abbott Laboratories (Abbott Park, IL) for providing the fentanyl and placebo oralets. We would also like to thank Mario Tanzi, RPh, and Kelly Preecs for their assistance.

Table 3

Table 3

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REFERENCES

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