Anesthetic Pharmacology
`Preclinical Pharmacology
`Section Editor: Marcel E. Durieux
`
`Clinical Pharmacology
`Section Editor: Tony Gin
`
`A Double-Blind, Crossover Assessment of the Sedative
`and Analgesic Effects of Intranasal Dexmedetomidine
`
`Vivian M. Yuen, MBBS, FANZCA,
`FHKCA, FHKAM
`
`Michael G. Irwin, MBChB, MD,
`FRCA, FHKCA, FHKAM
`
`Theresa W. Hui, MBBS, FANZCA,
`FHKCA, FHKAM
`
`Man K. Yuen, MBBS, FANZCA,
`FHKCA, FHKAM
`
`Libby H. Y. Lee, MBBS, FANZCA,
`FHKCA, FHKAM
`
`BACKGROUND: The alpha2-receptor agonist, dexmedetomidine, provides sedation
`with facilitated arousal and analgesia with no respiratory depression. These
`properties render it potentially useful for anesthesia premedication, although
`parenteral administration is not practical in this setting. We designed this study to
`evaluate the sedative, anxiolytic, analgesic, and hemodynamic effects of dexme-
`detomidine administered intranasally in healthy volunteers.
`METHODS: Koch’s design for crossover trials (three-treatment and two-period de-
`sign) was adopted. The study was double-blind and there were three treatment
`groups: A (placebo), B (intranasal dexmedetomidine 1 ␮g/kg) and C (intranasal
`dexmedetomidine 1.5 ␮g/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 ␮g/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.
`(Anesth Analg 2007;105:374 –80)
`
`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 reduc-
`tion in catecholamine secretion (1).
`Sedative drugs are often administered preopera-
`tively 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 ␮g/kg IM and was
`shown to be as effective as midazolam at inducing
`
`From the Department of Anaesthesiology, Queen Mary Hospital,
`University of Hong Kong, Hong Kong.
`Accepted for publication April 23, 2007.
`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@hkucc.hku.hk.
`Copyright © 2007 International Anesthesia Research Society
`DOI: 10.1213/01.ane.0000269488.06546.7c
`
`374
`
`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 dexmedeto-
`midine when administered via the nasal route in healthy
`adults. A crossover design was chosen because it re-
`duced the number of volunteers required. In addition,
`subjects acted as their own controls, which decrease
`
`Vol. 105, No. 2, August 2007
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`pharmacogenetic variability. The doses of 1 and 1.5
`␮g/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 dem-
`onstrated that the bioavailabilty of transmucosal dexme-
`detomidine was 82%.
`
`METHODS
`After approval by the local IRB, 18 healthy volun-
`teers 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 sub-
`ject participated in two periods of study and there
`were three treatment groups:
`Group A: Placebo (water) intranasally
`Group B: Dexmedetomidine 1 ␮g/kg intranasally
`Group C: Dexmedetomidine 1.5 ␮g/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; conse-
`quently 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 admin-
`istered the drug or placebo. Dexmedetomidine, at a
`concentration of 100 ␮g/mL, was used without fur-
`ther dilution. The volume of placebo (water) was
`equivalent to the volume of undiluted dexmedetomi-
`dine at dose 1 ␮g/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 com-
`menced. 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, auto-
`mated sphygmomanometer, three lead electrocardio-
`graph, 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
`
`Table 1. Modified Observer’s Assessment of Alertness/
`Sedation Scale
`
`6
`
`5
`
`4
`3
`
`2
`1
`0
`
`Appears alert and awake, responds readily to name
`spoken in normal tone
`Appears asleep but responds readily to name
`spoken in normal tone
`Lethargic response to name spoken in normal tone
`Responds only after name is called loudly or
`repeatedly
`Responds only after mild prodding or shaking
`Does not respond to mild prodding or shaking
`Does not respond to noxious stimulus
`
`signs and other data were collected immediately
`before and repeatedly after intranasal drug or pla-
`cebo 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 indi-
`cator 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 machin-
`ery, make major decisions or go back to work on the
`day of the investigation.
`Demographic data were analyzed by analysis of vari-
`ance (ANOVA), Fisher’s exact test and the Kruskal-
`Wallis test. Sedation data, pain threshold data, and
`
`Vol. 105, No. 2, August 2007
`
`© 2007 International Anesthesia Research Society 375
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`Amneal Pharmaceuticals LLC – Exhibit 1023 – Page 375
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`Table 2. Patient and Study Characteristics
`
`Groups AB
`and BA
`(n ⴝ 6)
`26.8 ⫾ 4.8 关21–32兴
`2:4
`21.0 ⫾ 3.5 关17.1–25.5兴
`
`Groups AC
`and CA
`(n ⴝ 6)
`26.7 ⫾ 7.7 关19–38兴
`2:4
`21.3 ⫾ 2.4 关18.4–25.5兴
`
`Variables
`Age (yr)
`Sex, M:F
`Body mass index
`(kg/m2)
`Time between two
`treatments (d)
`Values in mean ⫾ SD or median 关range兴 or count.
`Treatment A ⫽ Placebo (water) intranasally.
`Treatment B ⫽ Dexmedetomidine 1 ␮g/kg intranasally.
`Treatment C ⫽ Dexmedetomidine 1.5 ␮g/kg intranasally.
`Notes: Patient characteristics in the three combination treatments were not significantly different.
`
`21 关7–134兴
`
`10 关7–66兴
`
`Groups BC
`and CB
`(n ⴝ 6)
`21.8 ⫾ 1.9 关20–25兴
`3:3
`21.2 ⫾ 2.6 关16.8–24.2兴
`
`Overall
`(n ⴝ 18)
`25.1 ⫾ 5.6 关19–38兴
`7:11
`21.1 ⫾ 2.7
`
`50 关8–134兴
`
`18.5 关7–134兴
`
`P
`0.22
`1.0
`0.98
`
`0.71
`
`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 de-
`fined as P ⬍ 0.05.
`
`RESULTS
`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 hemody-
`namic changes did not induce any subjective symp-
`toms. 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 dizzi-
`ness 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 ␮g/kg of intranasal dexmedetomi-
`dine 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
`␣ 2 agonists, but three subjects volunteered this infor-
`mation at the end of the study.
`There were no significant differences in the demo-
`graphic data of subjects in the three different treat-
`ment 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
`
`376
`
`Effect of Intranasal Dexmedetomidine
`
`Figure 1. Mean ⫾ sd modified Observer Assessment of
`Alertness/Sedation scales (modified OAA/S scales) as a
`function of time in the three treatment groups.
`
`implies that the order of treatments had no effect on
`outcome.
`Figures 1–3 graphically display the mean ⫾ sd modi-
`fied 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 administra-
`tion, 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. Al-
`though 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
`ANESTHESIA & ANALGESIA
`
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`Amneal Pharmaceuticals LLC – Exhibit 1023 – Page 376
`
`

`

`Figure 2. Mean ⫾ sd. Bispectral index (BIS) as a function of
`time in the three treatment groups.
`
`Figure 4. Mean ⫾ sd. Systolic blood pressure (SBP) and
`mean ⫾ sd. Diastolic blood pressure (DBP) as a function of
`time in the three treatment groups.
`
`Figure 3. Mean ⫾ sd. Visual Analog Scale (sedation)
`(VASsedation) as a function of time in the three treatment
`groups.
`
`Figure 5. Mean ⫾ sd. Heart rate (HR) as a function of time in
`the three treatment groups.
`
`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 differ-
`ences were modest but remained statistically signifi-
`cant 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 as-
`sessed 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.
`
`DISCUSSION
`Sedative Effect
`This is the first clinical trial evaluating the clinical
`effects of intranasally administered dexmedetomidine
`in healthy volunteers. We have shown that it pro-
`duced significant sedation in all modalities of mea-
`surement: subjectively with VASsedation, objectively
`with BIS and by a blinded observer with modified
`
`Vol. 105, No. 2, August 2007
`
`© 2007 International Anesthesia Research Society 377
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`on healthy volunteers has shown that 1 ␮g/kg of IV
`dexmedetomidine produces sedation that is equiva-
`lent to a modified OAA/S of 3 or below in 67% of
`subjects (18). Hence, similar pharmacodynamic seda-
`tive 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 ad-
`ministration was quite similar to that of IM adminis-
`tration. Scheinin et al. (12) have shown that time to
`maximal effect after 0.5, 1.0, and 1.5 ␮g/kg of IM
`dexmedetomidine occurred between 60 and 150 min.
`In another study, Dyck et al. (19) reported the bio-
`availability of 2 ␮g/kg IM dexmedetomidine to be
`between 70% and 80%. Anttila et al. (6) reported in
`their study that the bioavailability of IM dexmedeto-
`midine was 103% and the time to peak plasma con-
`centration was 1.7 ⫾ 1.8 h.
`Interestingly, the sedative effect of IM dexmedeto-
`midine was shown to be less than satisfactory when
`given as 1 ␮g/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 ␮g/kg of
`IM dexmedetomidine, only patients who received 2.4
`␮g/kg were significantly sedated and became less
`anxious prior to induction of anesthesia. Scheinin et al.
`(3) reported that 2.5 ␮g/kg of IM dexmedetomidine
`was effective premedication for general anesthesia. On
`the contrary, Virkkila et al. (5) have suggested that
`1 ␮g/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 ␮g/kg
`of IM dexmedetomidine produced significant sedation
`and impared vigilance. Mattila et al. (13) have also
`demonstrated that 1.2 ␮g/kg of IM dexmedetomidine
`produced subjective sedation comparable to that of 80
`␮g/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 nonanx-
`ious at baseline. On the contrary, patients participat-
`ing 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 sug-
`gested by Virkkila et al. (5). Therefore. although the
`doses of intranasal dexmedetomidine used in this
`study produced significant sedation in healthy volun-
`teers 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
`ANESTHESIA & ANALGESIA
`
`Figure 6. Mean ⫾ sd. Pain pressure threshold (PPT) (kPa) as
`a function of time in the three treatment groups. Post hoc
`pairwise comparisons for treatment effect (T): 䡺 indicated
`Treatment A and Treatment B were significantly different; ⴙ
`indicated Treatment A and Treatment C were significantly
`different; # indicated Treatment B and Treatment C were
`significantly different.
`
`OAA/S scores. Previous studies in healthy volun-
`teers 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. Sig-
`nificant 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 dexmedetomi-
`dine 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 ab-
`sorbed via the buccal mucosa at about 56% (mean ⫾
`sd, 1.12 ⫾ 0.33 ␮g/kg of the 2 ␮g/kg of dexmedeto-
`midine administered). It is likely that the bioavailabil-
`ity of intranasally administered dexmedetomidine is
`similar, as both routes involve absorption via a muco-
`sal 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 ␮g/kg
`of intranasal dexmedetomidine respectively. A study
`
`378
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`Effect of Intranasal Dexmedetomidine
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`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 dexmedetomi-
`dine 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 nor-
`epinephrine 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 ␮g/kg) on
`ischemic pain in healthy volunteers demonstrated
`moderate analgesia with a ceiling effect at 0.5 ␮g/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 dexme-
`detomidine 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 dolorim-
`etry (22). This is consistent with our findings, and can
`be explained by the fact that pain threshold and subjec-
`tive assessment of pain sensation are different. Although
`we did not show any effect of intranasal dexmedetomi-
`dine 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 sig-
`nificantly 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 ␮g/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 ␮g dexmedetomidine (33).
`In our study, we did not observe any increase in
`blood pressure after 1 and 1.5 ␮g/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 dexme-
`detomidine 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 per-
`formed in this study.
`
`CONCLUSION
`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 advanta-
`geous 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 ␮g/kg of intranasally administered
`
`Vol. 105, No. 2, August 2007
`
`© 2007 International Anesthesia Research Society 379
`
`Petition for Inter Partes Review of US 8,338,470
`Amneal Pharmaceuticals LLC – Exhibit 1023 – Page 379
`
`

`

`dexmedetomidine produced clinically significant se-
`dation and hemodynamic changes in healthy volun-
`teers. Future studies are warranted to define the
`optimal dose and the role of this route of administra-
`tion in clinical settings.
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