Odontology (2002) 90:57–63
ORIGINAL ARTICLE
Tetsuya Ise · Mikiko Yamashiro · Hideki Furuya
Clonidine as a drug for intravenous conscious sedation
Received: October 17, 2000 / Accepted: May 21, 2002
Abstract Clonidine, an a2-adrenoceptor agonist, was intro-
duced to clinical practice in the 1960s because of its anti-
hypertensive effect. It has several beneficial actions during
the perioperative period, particularly for medically com-
promised patients. The objective of this study was to
evaluate the effects of clonidine as a drug for intravenous
conscious sedation. We assessed the effects of intravenous
clonidine on the hemodynamic and sympathoadrenergic
responses to nociceptive stimuli and we evaluated its seda-
tive and analgesic effects. Twenty-five volunteers aged
between 23 and 25 years were included in this study.
They received clonidine intravenously at 2 mg/kg. Constant-
current, square-wave stimuli were delivered as nociceptive
stimuli to the median nerve of the arm. We measured blood
pressure, heart rate, cardiac output, and plasma concentra-
tions of noradrenaline, adrenaline, and cortisol. The seda-
tive and analgesic effects were measured by visual analogue
scales. Changes in heart rate and blood pressure were not
significantly different between the clonidine and control
groups. Cardiac output tended to decrease after clonidine
administration. Clonidine exerted its greatest sedative
effect 30 min after injection. Noradrenaline concentration
reached its nadir 15 min after clonidine administration. The
time course of adrenaline concentrations was similar to
that of noradrenaline. The plasma concentration of cortisol
decreased in both groups. The most common adverse effect
was dry mouth. In conclusion, intravenous clonidine, at a
dose of 2 mg/kg, did not induce significant bradycardia,
hypotension, or severe side effects in the healthy volunteer.
It attenuated the adrenergic response to electrical stimula-
T. Ise · M. Yamashiro (*) · H. Furuya
Department of Anesthesiology, The Nippon Dental University
School of Dentistry at Tokyo, 2-3-16 Fujimi, Chiyoda-ku, Tokyo 102-
8158, Japan
Tel. +81-3-3261-6083; Fax +81-3-3222-0926
e-mail: mikiko1@yahoo.co.jp
© The Society of The Nippon Dental University 2002
tion. The results suggested that clonidine is a useful drug for
intravenous sedation.
Key words Clonidine · Intravenous conscious sedation ·
Hemodynamics · Sympathoadrenal responses · Sedation
Introduction
Clonidine hydrochloride is an a2-adrenoceptor agonist (a2-
agonist) that was introduced into clinical practice as an
antihypertensive drug in the 1960s. a2-Agonists such as
clonidine have various actions and have been used in vet-
erinary anesthesia for many years. In recent years, a2-
agonists have been considered useful by anesthesiologists
for the perioperative management of patients. These drugs
exert a sympatholytic action centrally to increase hemody-
namic stability under surgical stress,1,2 and they have seda-
tive,3 antianxiety,4 and analgesic effects.5
Dental treatment is often associated with mental and
physical stress. Conscious sedation greatly benefits patients
in alleviating such stress and has found wide clinical appli-
cation. In addition, there has been an increase in the
number of dental outpatients with systemic disease, espe-
cially cardiovascular disease. Furthermore, increases in the
numbers of elderly patients and the introduction of new
therapeutic techniques and materials have resulted in more
diverse and often more lengthy dental surgical procedures.
These circumstances have increased the need for more
effective intraoperative management to reduce the mental
and physical stress placed on patients. The pharmacology of
a2-agonists suggests that clonidine would be useful in intra-
venous sedation.
In consideration of the potential use of clonidine in intra-
venous sedation, we examined the effects of intravenously
administered clonidine on hemodynamic and sympath-
oadrenal responses to nociceptive stimuli. In addition, we
evaluated the sedative and analgesic effects of this repre-
sentative a2-agonist.
58
Subjects and methods
After approval was granted by the Institutional Ethics
Committee, the study was conducted. The subjects of this
study consisted of 25 adult male volunteers, of American
Society of Anesthesiologists’ Physical Status System class 1,
aged 23 to 26 years (Table 1). They gave their informed
consent to participate in the study.
The subjects were placed in the supine position in a quiet
air-conditioned room. The venous route was maintained via
a 22-gauge intravenous catheter (Jelco Plus; Johnson and
Johnson, Brussels, Belgium) placed in the right antecubitus.
A patient-monitoring system (Bp-508; Nippon Colin, Aichi,
Japan) was used for the measurement of blood pressure
(BP), heart rate (HR), and cardiac output (CO). A cuff
sphygmomanometer was attached to the right arm for the
calibration of a tonometry blood pressure sensor that was
placed on the skin over the left radial artery. CO was mea-
sured by a thoracic-cage impedance method (CIC-1000;
Sorba, Milwaukee, WS, USA). Lead II ECG was recorded.
After 5 min of supine rest, 20 subjects (clonidine group)
were given 2 mg/kg of clonidine hydrochloride (Catapres;
Boehringer Ingelheim, Ingelheim am Rhein, Germany)
through the venous route. A control group (5 subjects)
received 1 ml of physiological saline intravenously.
As a pain stimulus, an electric pulse (10.5-mA constant
current, square-wave, train 10, 20 ms in duration every
100 ms) was delivered percutaneously via a disc electrode
to the median nerve at the forearm.
We measured BP, HR, and CO as indicators of circula-
tory changes, before (baseline) and immediately after (min
0) drug or saline administration, and for 60 min thereafter
at 10-min intervals (Fig. 1). Electrical stimuli were given
before and 0, 15, 30, and 60 min after the administration
of clonidine or physiological saline. Immediately after the
electrical stimulation, 5 ml of blood was taken via the
venous access line. Concentrations of cortisol, noradrena-
line (NA), and adrenaline in plasma were measured as indi-
cators of mental or adrenergic responses to painful stimuli
(Fig. 1). Cortisol levels were assayed using a validated
commercial radioimmunoassay kit, Gamma-Coat Cortisol
(Baxter, Deerfield, IL, USA). Noradrenaline (NA) and
adrenaline were detected by fluorometry (1,2-diphenyleth-
Table 1. Demographic data of volunteers
Age (years) 24.0 ± 1.2
Sex Male
Weight (kg) 63.7 ± 4.2
Values are means ± SD
Fig. 2. Visual analogue scales (VASs) for pain and sedation. The VASs each consist of a line, 100 mm in length, anchored by the two extremes
of pain or sleepiness. The numbers of centimeters from the left were recorded as the analgesic and sedative scores
ylenediamine [DPE] method) with a fully automated cate-
cholamine analyzer (HLC-725CA; Tohso, Tokyo, Japan).6
In the clonidine group, the degrees of sedative and
analgesic effects were evaluated on visual analogue scales
(VASs) (Fig. 2). Each VAS was a 100 mm line, the ends of
which represented extreme sleepiness and maximum pain,
respectively, and the distances, in centimeters, from com-
plete arousal and painlessness were defined as the scores for
sedation and pain, respectively (Fig. 2).
A series of questions listing the expected side effects
(Table 2) was used to survey the subjects for side effects.
Each measured value was converted to a percentage of
baseline (100%) and subjected to statistical analysis. The
paired t-test was used to test the difference of mean values,
at a significance level of 0.05.
Results
Heart rate (HR)
Baseline HR for the clonidine group was 66.8 ± 5.2 (mean
± SD) bpm. The HR decreased significantly at 0 (immedi-
ately after intravenous administration of clonidine), 20, 30,
50, and 60 min. The HR dropped to a minimum value of 61.2
± 4.7 bpm at 60 min, which was a decrease of 8.4% from
baseline. Baseline HR for the control group was 69.6 ±
5.7 bpm. HR fell after 20 min, reaching a minimum of 65.2
Table 2. Perceived side effects
Dry mouth 19
Fatigue/weariness 13
Sleepiness 10
Orthostatic dizziness 1
Nausea/vomiting 0
Hallucination 0
Diziness 0
Others; slight headache 1
Fig. 1. Study protocol

Fig. 3. Change in heart rate (HR). Each point represents the mean ±
SD. Baseline heart rates were 66.8 ± 5.2 bpm and 69.6 ± 5.7 bpm in the
clonidine group (n = 20) and control group (n = 5), respectively. The
maximal decrease in the clonidine group, at 60 min (61.2 ± 4.7 bpm),
was 8.4% of baseline. The maximal decrease in the control group, at
30 min (62.2 ± 5.0 bpm), was 5.8% of baseline. *P < 0.05 vs baseline
Fig. 4. Change in systolic blood pressure (SP). Each point represents
the mean ± SD. Baseline SP in the clonidine group (n = 20) was 111.5
± 8.9 mm Hg. The maximal decrease was observed at 40 min (100.3 ±
8.5 mm Hg), which was within 10% of baseline. Baseline SP in the
control group (n = 5) was 111.0 ± 5.1 mm Hg. The maximal decrease in
the control group, at 40 min (101.8 ± 8.1 mm Hg), was 6.8% of the base-
line. *P < 0.05 vs baseline
± 5.0 bpm (a 5.8% drop) at 30 min, but the value was not sig-
nificantly different from the baseline (Fig. 3).
Blood pressure (BP)
Systolic pressure (SP). Baseline SP for the clonidine group
was 111.5 ± 8.9 mm Hg. SP showed a significant drop (P <
0.05) 20 to 60 min after clonidine administration, reaching a
minimum of 100.3 ± 5.8 mm Hg at 40 min; however, the drop
was within 10% (11.2 mm Hg) of the baseline. Baseline SP
for the control group was 111.0 ± 5.1 mm Hg. There was a
drop in the values at 10, 40, 50, and 60 min, with a minimum
value of 101.8 ± 8.1 mm Hg at 40 min, but none of the values
showed a significant difference from baseline (Fig. 4).
Diastolic pressure (DP). Baseline DP for the clonidine
group was 61.9 ± 4.6 mm Hg. No significant change was
observed at any point in time. Baseline DP for the control
59
Fig. 5. Change in diastolic blood pressure (DP). Each point represents
the mean ± SD. Baseline DP in the clonidine group (n = 20) was 61.9
± 4.6 mm Hg. Baseline DP in the control group (n = 5) was 67.2 ±
7.7 mm Hg. Significant increases in DP were seen in the control group
at 10 min and 60 min. *P < 0.05 vs baseline
Fig. 6. Change in mean arterial pressure (MAP). Each point represents
the mean ± SD. Baseline MAP in the clonidine group was 79.7 ±
9.1 mm Hg. The minimum MAP in the clonidine group was 69.3 ± 7.9
mm Hg, at 20 min, which was a 13% reduction from baseline. Baseline
MAP in the control group was 79.0 ± 3.1 mm Hg. *P < 0.05 vs baseline
group was 67.2 ± 7.7 mm Hg. The DP in the control group
tended to increase: the DPs were higher than baseline at 10,
20, 30, 50, and 60 min, with significant increases at 10 and
60 min (Fig. 5).
Mean arterial pressure (MAP). Baseline MAP for
the clonidine group was 79.7 ± 9.1 mm Hg. A significant
decrease from baseline was observed 20 to 60 min after
clonidine administration. The minimum value (69.3 ±
7.9 mm Hg), recorded at 20 min, represented a 13% reduc-
tion from baseline. Baseline MAP for the control group was
79.0 ± 3.1 mm Hg. At no point was a significant change from
baseline observed (Fig. 6).
Cardiac output (CO)
CO dropped after clonidine administration, becoming
significantly discernible from baseline at 40 to 60 min (P <
60
Fig. 7. Change in cardiac output (CO). Each point represents the mean
± SD. *P < 0.05 vs baseline
Fig. 8. Change in plasma cortisol concentration. The plasma cortisol
concentration gradually decreased. The values at 15, 30, and 60 min in
both groups significantly differred from the baseline values. Each point
represents the mean ± SD. *P < 0.05 vs baseline
0.05). A maximum drop of 15% was seen at 60 min. The
control group did not show significant changes from base-
line (Fig. 7).
Plasma cortisol concentration
In the clonidine group, the concentration of plasma cortisol
gradually decreased until 60 min after administration, with
a significant difference from baseline at 15, 30, and 60 min
(P < 0.05). The control group also showed a gradual
decrease in cortisol concentration, with significant differ-
ences from baseline at 15 min and later (P < 0.05) (Fig. 8).
Plasma noradrenaline (NA) concentrations
NA concentration was increased at 0 min in the clonidine
group, but had decreased at 15 min and later, with signifi-
cant decreases at 15, 30, and 60 min (P < 0.05). In the control
group, concentrations increased at 0 and 15 min, and
returned to levels comparable to baseline at 30 and 60 min,
but without significant changes in any of the values (Fig. 9).
Fig. 9. Change in plasma noradrenaline (NA) concentrations. The
plasma noradrenaline concentrations at 15, 30, and 60 min in the cloni-
dine group were significantly lower than baseline. No significant dif-
ference was observed at any time point in the control group. Each point
represents the mean ± SD. *P < 0.05 vs baseline
Fig. 10. Change in plasma adrenaline (A) concentration. The plasma
adrenaline concentrations at 15 and 60 min in the clonidine group
were significantly lower than baseline. No significant difference was
observed at any time point in the control group. Each point represents
the mean ± SD. *P < 0.05 vs baseline
Plasma adrenaline (A) concentration
In the clonidine group, plasma concentrations of A were
lower than baseline at all times, with significant decreases
at 15 and 60 min (P < 0.05). In the control group, a value
lower than baseline was noted after 30 min, but with no sig-
nificant difference from the baseline (Fig. 10).
Degree of sedation
Clonidine induced sedation, as revealed in the VAS scores
noted at 15, 30, and 60 min, with significant differences as
compared with the baseline score (P < 0.05) (Fig. 11).
Degree of analgesic effect
A significant decrease in the VAS score for pain was
noted only at 15 min, as compared with the baseline value
(P < 0.05) (Fig. 12).

Fig. 11. Sedative effect of intravenous clonidine, expressed as mil-
limeters from “wide awake” on a visual analogue scale (VAS; mean ±
SD; n = 20). Sedative scores were significantly higher at 15, 30, and
60 min than at baseline. *P < 0.05 vs baseline (cont)
Fig. 12. Analgesic effect of intravenous clonidine, expressed as mil-
limeters from “no pain” on a visual analogue scale (VAS; mean ± SD;
n = 20). The pain score at 15 min was significantly decreased from the
baseline (cont). *P < 0.05 vs baseline
Subjective side effects
Dry mouth was noted most frequently, being recorded in
19 subjects, this was followed by fatigue or weariness (13
subjects), sleepiness (10 subjects), orthostatic dizziness
(1 subject), and slight headache (1 subject) (Table 2).
Discussion
Previous studies of a2-agonists describe a centrally medi-
ated sympatholytic action,7 improvement of hemodynamic
stability under surgical stress,8,9 a decrease in the required
dosage of narcotics9 or anesthetics,9–11 a sedative action,12
and an analgesic action.13 These effects have been con-
sidered to be favorable in the perioperative management
of patients. It has also been reported that a2-agonists are
effective in the prevention and treatment of perioperative
myocardial ischemia.14
Clonidine is an adrenergic drug with a2-selectivity, with
an a2/a1 ratio of 200 : 1. It came into clinical use as a cen-
trally acting antihypertensive agent in the 1960s.15 Cur-
61
rently, in addition to being used as an antihypertensive drug,
clonidine is used to treat conditions as diverse as various
psychiatric diseases and the treatment of growth retarda-
tion in children.16–20 In the field of veterinary anesthesia,
a2-agonists (e.g., xylazine, detomidine and medetomidine)
have been widely used, and an a2-antagonist, yohimbine, has
been used in combination with xylazine for a number of
years. In 1979, Spaulding et al.9 reported that clonidine
exerted an analgesic action in humans and animals. In the
field of anesthesiology, reports on the relationship between
clonidine and anesthesia appeared in the late 1970s. In 1978,
Kaukinen et al.21 reported that the use of clonidine as pre-
medication for neuroleptanalgesia suppressed the elevation
of blood pressure during anesthesia. In recent years, with
the development of the more selective a2-agonists, experi-
mental and clinical studies have been conducted chiefly
on the analgesic, sedative, and anesthetic effects of a2-
agonists.20,21
The actions of clonidine on the cardiovascular system
include a centrally exerted antihypertensive action, result-
ing in bradycardia through the activation of presynaptic
a2-receptors at the peripheral cardiac sympathetic nerve
endings,22 and an action on the coronary arteries that
increases the coronary blood flow by releasing an endothe-
lium-derived relaxing factor (nitric oxide).14 The antihyper-
tensive and coronary blood flow-increasing actions are
considered to be favorable in patients with hypertension
or ischemic heart disease, but excessive bradycardia and
hypotension are not desirable. In fact, the HR-reducing23
and antihypertensive actions of a2-agonists occasionally
pose problems.
In this study, we examined the degree of HR decrease
and BP drop in healthy adults after the intravenous admin-
istration of clonidine hydrochloride at a 2 mg/kg dose. A
maximum HR decrease of 8.4% (61.2 ± 4.7 bpm) was
observed, which indicated that the intravenous administra-
tion of clonidine at this dose did not involve excessive
bradycardia in healthy adults.
Concerning BP, the maximum drop of SP was within 10%
of the value before clonidine administration and there was
no significant drop of DP, that is, excessive hypotension did
not occur. The minimum MAP value (69.3 ± 7.9 mm Hg),
reached at 20 min, represented a 13% drop; however, this
was not considered an excessive drop in BP, defined as
MAP 60 mm Hg or less, or a 30% or greater drop in healthy
adults.24
The administration of clonidine can result in a decrease
in CO by a central (indirect) or a peripheral (direct; increase
of afterload) mechanism.25 In the present study, clonidine
decreased CO, while the control group showed no signifi-
cant changes. We calculated CO by multiplying a single-
stroke volume value; however, with this calculation, the
decreased HR may have been more responsible for the
apparently decreased CO than any change in heart con-
tractility. Thus, we considered it necessary to use a different
method to ascertain whether the intravenous administra-
tion of clonidine at 2 mg/kg actually did affect CO.
In clinical practice, plasma cortisol concentration is cur-
rently used as an indicator of the degree of stress. Pain
62
stress, for instance, induces an increase in the concentration
of blood cortisol. Similarly, mental conditions, such as fear
and anxiety, before surgery or dental treatment, elevate the
blood cortisol concentration.26 On the other hand, premed-
ication with tranquillizers, such as hydroxyzine, diazepam,
and midazolam, lowers the blood cortisol levels.26 Intra-
venous administration of clonidine at 2 mg/kg significantly
lowered cortisol levels at 15, 30, and 60 min, but almost par-
allel falls in cortisol levels were observed in the control
group. The result could not suggest that clonidine would be
effective for the relief of emotional stress.
Sympathoadrenal stimulation is said to be the main
endocrine response to surgical procedures, and this state of
stimulation is characterized by an increase in the concen-
tration of catecholamines and the resulting hemodynamic
and metabolic responses. Under physical stress and emo-
tional stress, respectively, NA and adrenaline secretion pre-
dominate in these responses. In the present study, we
evaluated the sympatholytic effects of clonidine on the
response to pain stimuli by determining plasma NA levels,
reflecting peripheral sympathetic activity. We found that the
concentration of NA decreased significantly at 15–60 min,
and that of adrenaline decreased significantly at 15 and
60 min. These results suggest that the intravenous adminis-
tration of clonidine at this dose suppressed the sympathetic
response to electrical stimuli (pain).
Sedation is one of the most obvious effects that become
manifest after central a2-receptor stimulation.27 Sedation,
however, may be an undesirable side effect of clonidine
when it is used as an antihypertensive drug. a2-Agonists are
said to have an antianxiety action comparable to that of
benzodiazepines.3,4,12 In the present study, sedation scores
were significantly elevated at 15, 30, and 60 min, suggesting
the achievement of a good sedative action. Interestingly,
although the subjects were asleep, they were easily awoken
and performed tests and did not complain of sleepiness
during a conversation initiated by the investigator, appar-
ently indicating that they were not aware that they had been
asleep.
The activation of a2-receptors produces a powerful
analgesic effect supraspinally and at the spinal level.28 It has
been reported that clonidine exerts a stronger analgesic
action than morphine in animals.29 The combined use of an
a2-agonist and an opioid analgesic results in a synergistically
increased analgesic effect.30–33 Intravenous sedation accom-
panied by an analgesic effect would be quite advantageous.
Unfortunately, there has been no report on the intra-
operative analgesic effect of intravenously administered
clonidine; therefore, we evaluated the analgesic effect of
intravenous clonidine in this study. Pain VAS has been con-
sidered a relatively sensitive method of measuring analgesic
effects, in addition to being highly reliable and generally
applicable.34 Using pain VAS in this study, however,
the intravenous administration of clonidine at 2 mg/kg did
not produce the expected analgesic effect to electrical
stimuli.
Dry mouth was the most commonly perceived side
effect. Reduced salivation has been reported as another
effect of clonidine,35 that is considered to be advantageous
in dental treatment. There were no complaints of nausea,
vomiting, or vertigo, which are, presumably, associated with
an excessive drop in BP, or hallucinations. The complaint of
sleepiness, probably due to the drug’s sedative action, was
relatively common, with a frequency of 50%. Clinically,
depending upon the patient, this is considered to be a desir-
able action in terms of postoperative sedation.
We consider that the employment of a2-agonists for
intravenous conscious sedation provides clinical benefit in
that these agents have a good sedative effect and low rate-
pressure product, and they reduce the stress reactions asso-
ciated with local anesthesia, dental treatment, or oral
surgery. With a half-life of 9–12 h, clonidine has a long dura-
tion of action. However, prolonged sedation is considered
an advantage in inpatients. Although sedation itself causes
respiratory depression to some extent, clonidine-induced
respiratory depression is obviously slight compared with
that caused by narcotics or volatile anesthetics.36 Thus, cloni-
dine has the desirable feature of providing a good sedative
effect with little respiratory depression. If the clinical appli-
cation of a2-antagonists for intravenous conscious sedation
becomes feasible, it will also be possible to antagonize the
actions of clonidine, which, then, it is hoped, will be safer to
use than at present.
Conclusion
With the aim of employing a2-agonists for intravenous con-
scious sedation, we evaluated clonidine, at a dose of 2 mg/kg,
in healthy adult volunteers by applying nociceptive stimuli,
and examining hemodynamic changes, adrenergic res-
ponses, sedative and analgesic effects, and subjective side
effects. We found that there was no significant bradycardia
or drop in BP in the healthy volunteers. Adrenergic
responses seemed to be effectively suppressed. A good
sedative effect was observed for 15 to 60 min after clonidine
administration. The intravenous administration of clonidine
did not provide the expected analgesic effect. The most
common side effect was sleepiness, which is considered to
be desirable in terms of postoperative sedation, depending
upon the circumstances.
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