The alpha2-adrenoceptor agonist, dexmedetomidine, was originally developed as a sedative and analgesic drug for use in intensive care. However, it has a number of unique pharmacodynamic properties, which also make it useful in anesthesia: decreased MAC, analgesia without respiratory depression and a significant reduction in catecholamine secretion (1).
Sedative drugs are often administered preoperatively to relieve patient anxiety. Dexmedetomidine has been investigated for this purpose in both animals (2) and adult humans (3–5). The dose used in adult patients ranged from 1 to 2.5 μg/kg IM and was shown to be as effective as midazolam at inducing preoperative sedation and anxiolysis (3). Parenteral administration, however, is painful and may not be acceptable, especially to an anxious patient.
A crossover study of 12 adult subjects indicated that the bioavailability of dexmedetomidine via the buccal route is 82%, but it requires patients to attempt to retain the administered medication in the mouth (6). Intranasal administration is relatively easy and convenient, it also reduces first pass metabolism and has been used successfully for fentanyl, ketamine, and midazolam premedication (7–9). Although the pharmacokinetic properties of transmucosally administered dexmedetomidine have been demonstrated by Anttila et al. (6), the clinical effects of nonparenteral administration of dexmedetomidine have only been described in anecdotal case reports (10,11). The aim of this study was to evaluate the sedative, anxiolytic, and analgesic effects of dexmedetomidine when administered via the nasal route in healthy adults. A crossover design was chosen because it reduced the number of volunteers required. In addition, subjects acted as their own controls, which decrease pharmacogenetic variability. The doses of 1 and 1.5 μg/kg were chosen based on previous studies on IM dexmedetomidine in healthy volunteers (12,13) and the pharmacokinetic study by Anttila et al. (6), which demonstrated that the bioavailabilty of transmucosal dexmedetomidine was 82%.
After approval by the local IRB, 18 healthy volunteers between the ages of 18 and 38 yr participated in the study. All subjects gave written informed consent. Exclusion criteria included ASA class II or more, history of drug, tobacco or alcohol abuse, chronic use of any medication, body mass index <18 or greater than 28 kg/m2, and pregnancy. All subjects were asked to abstain from alcohol or any drug ingestion for 24 h prior to the investigation.
Koch's design for crossover trials (three-treatment and two-period design) was adopted (14). Each subject participated in two periods of study and there were three treatment groups:
Group A: Placebo (water) intranasally
Group B: Dexmedetomidine 1 μg/kg intranasally
Group C: Dexmedetomidine 1.5 μg/kg intranasally
Hence there were six possible treatment sequences: AB, AC, BA, BC, CA, CB.
The 18 subjects were randomly assigned to one of these treatment sequences by drawing lots; consequently there were three subjects for each. There was at least 1 wk between the first and second session for each subject. Both subjects and the observer were blinded to the drugs administered. An independent investigator, an anesthesiologist, prepared and administered the drug or placebo. Dexmedetomidine, at a concentration of 100 μg/mL, was used without further dilution. The volume of placebo (water) was equivalent to the volume of undiluted dexmedetomidine at dose 1 μg/kg. The solutions were prepared in 2.5 mL syringes. Equal volumes of the prepared solution were then dripped into both nostrils of the subjects. The drug or placebo was administered with subjects in the supine position, and they were allowed to sit up or assume a more comfortable position 5 min later. Each observation period lasted for 180 min. The investigations were performed in a fully equipped operating room with full resuscitation facilities.
After the subjects arrived for the study, they were allowed to rest for 10–15 min before the study commenced. Subjects were recumbent in a recovery bed when all the noninvasive monitors were applied. A Datex S/5 monitor (Datex-Ohmeda Inc., Madison, WI) was used and consisted of a pulse oximeter, automated sphygmomanometer, three lead electrocardiograph, and bispectral index (BIS). Oxygen saturation and heart rate (HR) were continuously measured, while systolic and diastolic blood pressure (SBP and DBP), and respiratory rate were recorded every 5 min throughout the study period. Baseline vital signs and other data were collected immediately before and repeatedly after intranasal drug or placebo administration.
Sedation status was assessed both objectively and subjectively. Objective sedation status was measured by a blinded observer with a modified Observer's Assessment of Alertness/Sedation scale (OAA/S) (Table 1) and BIS version XP (BIS XP, Aspect Medical, Newton, MA). Sedation status was also assessed by subjects with a visual analog scale (VASsedation). To assess VASsedation, the subject moved a sliding indicator line on a 100 mm ruler, with end-points of very alert (0) and very sedated (100), to identify their level of alertness. A score of 100 was used if the subject was not rousable. OAA/S and BIS were recorded every 5 min and VASsedation was recorded every 15 min.
The anxiety level was assessed by the same blinded observer every 5 min with a 4 point anxiety score (1 = combative, 2 = anxious, 3 = calm, 4 = amiable). Anxiety level was also assessed by subjects with a visual analog scale (VASanxiety) every 15 min, where 100 was “very anxious” and 0 equivalent to “very calm.”
Pain pressure threshold (PPT) was assessed by applying pressure to the forearm with an electronic algometer (Somedic, Somedic Production AB, Sweden). The transducer probe of the algometer was put on the same area of each subject's forearm, and increasing pressure was applied until the subject indicated pain. The PPT was assessed every 15 min after VASsedation was obtained. The average of three measurements was taken as the measurement at each particular timepoint. BIS was recorded just before a subject was aroused to have the VASsedation, VASanxiety, and PPT assessed.
When the 180 min observation period was over, subjects were allowed to rest until they felt that they were ready to leave. Similar precautions were taken as with day-stay surgery; hence when the subjects left, they fulfilled the discharge criteria for day surgery. The subjects were also informed that they should be accompanied by a responsible relative or adult on discharge and should not drive, handle major machinery, make major decisions or go back to work on the day of the investigation.
Demographic data were analyzed by analysis of variance (ANOVA), Fisher's exact test and the Kruskal-Wallis test. Sedation data, pain threshold data, and hemodynamic data were analyzed by mixed model analysis for crossover trials with repeated measurements within visits (periods). (15) Bonferroni t-test was used for post hoc pairwise comparisons where appropriate. Data collected in 5 min epochs were converted to 15 min data by averaging the values during each 15 min period. The SAS System for Windows Release 9.1 (SAS Institute Inc., Cary, NC, USA.) was used. Results throughout the text, tables, and figures are presented as mean ± sd unless otherwise indicated, and statistical significance was defined as P < 0.05.
Intranasal administration of dexmedetomidine was well tolerated. No local irritation or pain occurred with the application of this drug in any of our subjects. No subject complained of a smell or taste with either intranasal drug or placebo administration. There was no severe bradycardia or conduction abnormality on electrocardiogram monitoring. The observed hemodynamic changes did not induce any subjective symptoms. There was no orthostatic hypotension when the subjects were allowed to stand at the end of the session. One of the 18 subjects reported slight dizziness when she was on public transport on a hot day about 60 min after completing the study. She insisted on leaving immediately after the observation period of 3 h was completed. She was asymptomatic when she left and was accompanied by a responsible adult. She had received 1.5 μg/kg of intranasal dexmedetomidine on that day. Her symptoms subsided completely after 2 h of rest. No other major adverse effects were observed or reported. We did not specifically inquire about dry mouth, which is a common side effect of α 2 agonists, but three subjects volunteered this information at the end of the study.
There were no significant differences in the demographic data of subjects in the three different treatment combinations (Table 2). There was no evidence of a visit effect on the sedation scores, BIS, and PPT using a mixed model analysis for crossover trials with repeated measurements within visits (periods). This implies that the order of treatments had no effect on outcome.
Figures 1–3 graphically display the mean ± sd modified OAA/S scores, BIS, and VASsedation in relation to time in different treatment groups. The sedation level of Groups B and C became significantly different from that of Group A 45–60 min after intranasal drug administration, and the differences remained statistically significant for the rest of the study period. The peak sedation effect occurred at 90–105 min. There were no differences in sedation status between Group B and Group C. Although the VASsedation for Group B and Group C was not statistically different, there was a tendency for it to be greater in Group C throughout the study period. The lowest mean modified OAA/S was 3.7 and 3.5 for Group B and Group C subjects respectively. The lowest mean BIS for both Groups B and C was 75. The highest mean VASsedation scores were 74 and 83.2 for Groups B and C respectively.
Figures 4 and 5 show the mean SBP, DBP, and HR in relation to time in each group. The SBP and DBP of Group B and Group C became significantly lower than that of Group A 45–60 min after intranasal dexmedetomidine administration and remained so for the rest of the study. There was no difference in SBP or DBP between Groups B and C. The HR of Groups B and C was lower than that of Group A 60–75 min after drug administration. These differences were modest but remained statistically significant for the rest of the study between Groups A and C. The maximum decreases in SBP were 6, 23, and 21% and in HR were 16, 22, and 26% for Groups A, B, and C respectively.
None of the subjects was anxious at baseline. There were no significant differences in anxiety levels among different treatment groups during the study period. There was no difference in PPT values as assessed by the algometer between the three groups of subjects (Figures 5 and 6). The oxygen saturation and respiratory rate in the three groups were the same throughout the study period.
This is the first clinical trial evaluating the clinical effects of intranasally administered dexmedetomidine in healthy volunteers. We have shown that it produced significant sedation in all modalities of measurement: subjectively with VASsedation, objectively with BIS and by a blinded observer with modified OAA/S scores. Previous studies in healthy volunteers have demonstrated that dexmedetomidine-induced sedation can be monitored with BIS (16) and electroencephalogram-based spectral entropy (17).
The onset and peak sedative effect correlates well with different methods of sedation assessment. Significant sedation occurred 45–60 min after both doses of intranasal dexmedetomidine with a peak sedative effect after approximately 90–105 min. This study was designed to evaluate the potential role of intranasal dexmedetomidine as premedication before induction of anesthesia; hence, 180 min of observation period was selected. Although the subjects' sedation status did not return to baseline at the end of the study period (3 h after administration), they were all easily roused and they left after meeting the criteria for discharge after day surgery.
In a study of buccally administered dexmedetomidine the clinical sedative effect correlated well with the plasma level (6) with a peak plasma concentration attained at 1.5 ± 0.2 h and the bioavailability was 82%. However, a significant proportion was swallowed by the subjects, with the average amount of drug absorbed via the buccal mucosa at about 56% (mean ± sd, 1.12 ± 0.33 μg/kg of the 2 μg/kg of dexmedetomidine administered). It is likely that the bioavailability of intranasally administered dexmedetomidine is similar, as both routes involve absorption via a mucosal membrane. However, we did not measure the plasma concentration and bioavailability in this study. Nevertheless, we have shown that approximately 75% and 92% of subjects attained a sedation level of modified OAA/S of 3 or below after 1 and 1.5 μg/kg of intranasal dexmedetomidine respectively. A study on healthy volunteers has shown that 1 μg/kg of IV dexmedetomidine produces sedation that is equivalent to a modified OAA/S of 3 or below in 67% of subjects (18). Hence, similar pharmacodynamic sedative effects were seen with the same dose of IV and intranasal dexmedetomidine, although the time to the maximal sedative effect and duration of effect was different. This probably reflects the more gradual increase in plasma concentration that would be seen after an indirect route of administration.
The pharmacokinetic profile of transmucosal administration was quite similar to that of IM administration. Scheinin et al. (12) have shown that time to maximal effect after 0.5, 1.0, and 1.5 μg/kg of IM dexmedetomidine occurred between 60 and 150 min. In another study, Dyck et al. (19) reported the bioavailability of 2 μg/kg IM dexmedetomidine to be between 70% and 80%. Anttila et al. (6) reported in their study that the bioavailability of IM dexmedetomidine was 103% and the time to peak plasma concentration was 1.7 ± 1.8 h.
Interestingly, the sedative effect of IM dexmedetomidine was shown to be less than satisfactory when given as 1 μg/kg as premedication 60 min before induction of anesthesia (4,20). In Aho et al.'s study (4) of a comparison of 0.6, 1.2, and 2.4 μg/kg of IM dexmedetomidine, only patients who received 2.4 μg/kg were significantly sedated and became less anxious prior to induction of anesthesia. Scheinin et al. (3) reported that 2.5 μg/kg of IM dexmedetomidine was effective premedication for general anesthesia. On the contrary, Virkkila et al. (5) have suggested that 1 μg/kg of IM dexmedetomidine produced short-acting sedation similar to that of midazolam in elderly patients undergoing cataract surgery under regional anesthesia. On the other hand, in Scheinin et al.'s study on healthy volunteers (12), both 1 and 1.5 μg/kg of IM dexmedetomidine produced significant sedation and impared vigilance. Mattila et al. (13) have also demonstrated that 1.2 μg/kg of IM dexmedetomidine produced subjective sedation comparable to that of 80 μg/kg of IM midazolam in healthy volunteers.
The discrepancy in the sedative effect of similar doses of IM dexmedetomidine can be attributed to different subject groups and different study designs. Healthy volunteers may be more relaxed and nonanxious at baseline. On the contrary, patients participating in premedication clinical trials could be more anxious in anticipation of surgical procedures. Hence larger doses were required to produce an adequate sedative and anxiolytic effect. However, a smaller dose could be adequate in elderly patients as suggested by Virkkila et al. (5). Therefore. although the doses of intranasal dexmedetomidine used in this study produced significant sedation in healthy volunteers in an experimental setting, whether these doses will produce clinical sedation in anxious patients facing surgery or other painful procedures will need to be evaluated. Unfortunately, the anxiolytic effect of intranasal dexmedetomidine could not be properly evaluated in this study on healthy volunteers, as all subjects were not anxious at baseline. Whether it will produce anxiolysis in clinical settings requires further evaluation.
Studies on healthy volunteers have shown that dexmedetomidine produces a significant analgesic effect, and this has rendered it particularly useful in the perioperative setting. Ebert et al. (1) demonstrated a dose-dependent analgesic effect of IV dexmedetomidine to the cold-pressor test with no ceiling effect in the plasma concentrations they evaluated. The VAS pain score was decreased by up to 35% in this study. Moreover, dexmedetomidine infusion decreased norepinephrine release and diminished the arterial blood pressure response to the cold-pressor test. A mild to moderate analgesic effect was also shown in another study using the same experimental pain model (21). An evaluation of the analgesic effect of different doses of IV dexmedetomidine (0.25, 0.5, and 1 μg/kg) on ischemic pain in healthy volunteers demonstrated moderate analgesia with a ceiling effect at 0.5 μg/kg. (22) Opioid sparing of as much as 66% has been confirmed in various clinical trials in a variety of patients and surgical procedures (23–28).
However, other reports have suggested that dexmedetomidine lacks broad analgesic activity in certain experimental pain models, such as heat-pain stimulation (29) and heat and electrical pain threshold and tolerance (30). Neither fentanyl nor dexmedetomidine affected the pain threshold when it was assessed by dental dolorimetry (22). This is consistent with our findings, and can be explained by the fact that pain threshold and subjective assessment of pain sensation are different. Although we did not show any effect of intranasal dexmedetomidine on PPT, this does not preclude an effect on the affective-motivational component of pain. Although a study of the effect of medetomidine on heat pain and electric tooth pulp stimulation failed to detect any analgesic effect in these pain models, the unpleasant sensation of tourniquet-induced ischemic pain was significantly attenuated (31). More studies are needed to clarify the analgesic properties of dexmedetomidine. It would be particularly interesting to elucidate its role in nociceptive and neuropathic pain, and on affective and sensory components of pain.
Rapid IV infusion of dexmedetomidine produces biphasic changes in arterial blood pressure and HR. Bloor et al. (32) showed that 1 and 2 μg/kg of IV dexmedetomidine infused over 2 min caused an initial increase in SBP of 7% and 11% respectively. This was associated with a reflex bradycardia and was soon followed by a decrease in arterial blood pressure with a peak hypotensive effect occurring 60 min after drug infusion. Similar effects have been seen in healthy volunteers to a rapid IV infusion of 75 μg dexmedetomidine (33).
In our study, we did not observe any increase in blood pressure after 1 and 1.5 μg/kg of intranasal dexmedetomidine. A modest reduction in HR and arterial blood pressure became evident about 45 min after drug administration, and the maximum effect occurred at about 90 min. Although a highly selective α-2 agonist, very high blood concentrations of dexmedetomidine will cause α-1-mediated vasoconstriction. Since intranasal administration is likely to lead to a more gradual increase in the plasma drug level, this appears to avoid a hypertensive response. Similar to the sedative effects, the hemodynamic effects did not return to baseline at the end of our observation period.
There are a few limitations to this study. The number of volunteers recruited was small and there was no pre hoc power calculation. Hence, we cannot be sure that the absence of a difference between Groups B and C was not a false negative result. Since the study was designed to evaluate the potential role of intranasal dexmedetomidine for premedication, the observation period was 180 min. However, there was still some sedation and hemodynamic effects at the end of the observation period. Hence, we cannot comment on the duration of the clinical effect of the two doses of intranasal dexmedetomidine in healthy volunteers. Only PPT was tested. Other modalities of pain assessment, such as the cold pressor test, may have demonstrated differences, but were not performed in this study.
The utility of dexmedetomidine in the perioperative setting continues to expand. Its sedative, anxiolytic, analgesic, and hemodynamic effects have rendered it a useful adjunct to anesthesia and sedation. Our study suggests that intranasal administration is effective with a smooth and predictable onset and with high patient acceptability. Onset is delayed compared with IV dosing but this avoids the initial hypertensive response and is relatively simple and noninvasive. When adequate time is allowed, the clinical effect produced is comparable to that of IV and IM administration. Although the relatively delayed and prolonged effects could be a drawback in some clinical settings, it could be potentially advantageous in others, such as when there are surgical delays. This could be particularly helpful in pediatrics. The sedation produced may actually even be sufficient for some local anesthetic procedures, and this will be an interesting area for further study.
Nonparenteral administration of dexmedetomidine is a convenient and safe alternative to parenteral administration. In this study, we have demonstrated that 1 and 1.5 μg/kg of intranasally administered dexmedetomidine produced clinically significant sedation and hemodynamic changes in healthy volunteers. Future studies are warranted to define the optimal dose and the role of this route of administration in clinical settings.
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