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From the Department of Anaesthesiology, Queen Mary Hospital, University of Hong Kong, Hong Kong.
Address correspondence and reprint requests to M. G. Irwin, MBChB, MD, FRCA, Department of Anaesthesiology, University of Hong Kong, Room 424, K Block, Queen Mary Hospital, Pokfulam Road, Hong Kong. Address e-mail to mgirwin{at}hkucc.hku.hk.
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Abstract |
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 Top Abstract IntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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METHODS: Koch's design for crossover trials (three-treatment and two-period design) was adopted. The study was double-blind and there were three treatment groups: A (placebo), B (intranasal dexmedetomidine 1 µg/kg) and C (intranasal dexmedetomidine 1.5 µg/kg). Each of the 18 subjects participated in two study periods. The study drug was administered intranasally after baseline observations of modified Observer Assessment of Alertness/Sedation Scale, visual analog scale of sedation, bispectral index, visual analog scale of anxiety, pain pressure threshold measured by an electronic algometer, systolic blood pressure (SBP) and diastolic blood pressure, heart rate, respiratory rate, and oxygen saturation. These were repeated during the course of the study.
RESULTS: Intranasal dexmedetomidine was well tolerated. Both 1 and 1.5 µg/kg doses equally produced significant sedation and decreases in bispectral index, SBP, diastolic blood pressure, and heart rate when compared with placebo (P < 0.05). The onset of sedation occurred at 45 min with a peak effect at 90–150 min. The maximum reduction in SBP was 6%, 23%, and 21% for Groups A, B, and C respectively. There was no effect on pain pressure threshold, oxygen saturation or respiratory rate. Anxiolysis could not be evaluated as no subjects were anxious at baseline.
CONCLUSION: The intranasal route is effective, well tolerated, and convenient for the administration of dexmedetomidine. Future studies are required to evaluate the possible role of the noninvasive route of administration of dexmedetomidine in various clinical settings, including its role as premedication prior to induction of anesthesia.
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Introduction |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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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%.
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METHODS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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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:
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.
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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.
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RESULTS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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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.
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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.
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DISCUSSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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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.
Analgesic Effects
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.
Hemodynamic Effects
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 -2 agonist, very high blood concentrations of dexmedetomidine will cause -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.
Limitations
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.
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CONCLUSION |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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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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Footnotes |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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This article has been cited by other articles:
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  V. M. Yuen, T. W. Hui, M. G. Irwin, and M. K. Yuen A Comparison of Intranasal Dexmedetomidine and Oral Midazolam for Premedication in Pediatric Anesthesia: A Double-Blinded Randomized Controlled Trial Anesth. Analg., June 1, 2008; 106(6): 1715 - 1721. [Abstract] [Full Text] [PDF]
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indicated Treatment A and Treatment B were significantly different; + indicated Treatment A and Treatment C were significantly different; # indicated Treatment B and Treatment C were significantly different.
