JDR Woodhead Publishing
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hall, D.L.
Right arrow Articles by Rezvan, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hall, D.L.
Right arrow Articles by Rezvan, E.
J Dent Res 85(9):854-858, 2006
© 2006 International and American Associations for Dental Research

RESEARCH REPORT
Clinical

Oral Clonidine Pre-treatment and Diazepam/Meperidine Sedation

D.L. Hall1,2,*, D.N. Tatakis2, J.D. Walters2, and E. Rezvan2,3

1 Section of Primary Care,
2 Section of Periodontology, The Ohio State University College of Dentistry, 305 W. 12th Avenue, Columbus, OH 43218-2357, USA; and
3 Private Practice, Gilroy, CA, USA

* corresponding author, hall.611{at}osu.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Clonidine has recently been used as a pre-operative medication and sedative/anxiolytic drug. Its extended duration of action makes it suitable for longer procedures. In this randomized, crossover, placebo-controlled clinical trial, we characterized the effects of oral clonidine pre-treatment on intravenous diazepam/meperidine sedation using the bi-spectral index (BIS) in 13 participants. Clonidine significantly increased the numbers of BIS-depressed readings and percent memory loss during sedation, while reducing total diazepam and post-operative analgesic dosages by 44% and 55%, respectively. Systolic, diastolic, and mean arterial blood pressures, as well as pulse rates, were reduced. Respiratory rate, oxygen saturation, end-tidal CO2, and recovery from sedation were unchanged. Participants, surgeons, and sedationists preferred clonidine over the placebo. Clonidine pre-treatment increased and prolonged sedation and amnesia and stabilized vital signs while significantly decreasing diazepam and post-operative analgesic usage. These results suggest that pre-operative clonidine administration could be a useful supplement to intravenous sedation for dental procedures of long duration.

KEY WORDS: clonidine • BIS • diazepam • meperidine • IV sedation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Clonidine is an alpha-2 agonist that was introduced 38 years ago as a treatment for hypertension (Barnett and Cantor, 1968). It has also been used to prevent and/or treat many conditions, including syncope (Hilz et al., 2002) and chronic pain (Puke and Wiesenfeld-Hallin, 1993). Recently, clonidine has been utilized as a pre-operative medication to provide anxiolysis (Beer et al., 2001), sedation (Karhuvaara et al., 1991; Ramesh et al., 1997; Khan et al., 1999), analgesia (Siiba et al., 1999), hemodynamic stability (Laisalmi et al., 2001), saliva control (Arya et al., 1997), and anti-emetic effects (Frank et al., 1999). It also possesses sedative (Flacke et al., 1987; Murai et al., 1995), anesthetic (Flacke et al., 1987), and analgesic (Flacke et al., 1987; Samso et al., 1996) sparing properties that reduce the dosages of other medications. Clonidine exhibits anxiolytic effects independent of sedation (Handley and Mithani, 1984) and also reduces the peri-operative plasma levels of catecholamines (Flacke et al., 1987; Galeotti et al., 2004) and prolactin (Samso et al., 1996).

Previous studies have demonstrated that pre-treatment with clonidine not only potentiates benzodiazepine (Salonen et al., 1992), narcotic, and other drug effects, but also prolongs and stabilizes their activities (Laisalmi et al., 2001). Oral clonidine pre-treatment prior to surgical extraction of third molars decreases intravenous (IV) midazolam dosage by 45% (Murai et al., 1995). None of these studies utilized objective measures of sedation. The Bispectral Index (BIS), which provides a sensitive and objective measure of sedation, has not been previously used for assessing the effects of oral clonidine pre-treatment on long-term diazepam/meperidine IV sedation. In this clinical trial, we characterized and quantified the effects of oral clonidine pre-treatment on diazepam/meperidine IV sedation during periodontal surgical procedures of long duration. We hypothesized that pre-treatment with clonidine would significantly increase the numbers of BIS-depressed readings, prolong sedation and amnesia, and reduce diazepam and post-operative analgesic usage.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Participants
The study protocol and informed consent form were approved by The Ohio State University Institutional Review Board. All participants provided written informed consent. Inclusion criteria were: (1) adults with American Society of Anesthesiologists ASA1 or ASA2 health status, (2) severe chronic periodontal disease and/or the need for dental implant(s), and (3) treatment plan including at least 2 periodontal surgical procedures requiring IV sedation of at least 2 hrs’ duration. Exclusion criteria were: (1) neurological or psychiatric disease; (2) sleep disorders; (3) severe asthma; (4) uncontrolled hypertension; (5) insulin-dependent diabetes; (6) relative or absolute contraindication to local anesthesia, diazepam, meperidine, or clonidine, including pregnancy; and (7) a history of substance abuse. The number of participants required for this study was determined by power analysis of data from a previous BIS study (Hall et al., 2002) indicating that a ‘least significant number’ greater than 13 should provide statistically and critically significant data ({alpha} = 0.05, ß ~= 0.20 or less). Sixteen (16) participants were enrolled.

Experimental Design
The purpose of this study was to investigate the effects of oral clonidine pre-treatment on diazepam/meperidine IV conscious sedation. The primary outcome was the change in BIS readings. Secondary endpoints included Observer’s Assessment of Alertness/Sedation Scale (OAA/S) values, vital signs, diazepam and post-operative analgesic dosages, and survey responses. Each individual participated in 2 sedation sessions, in randomized order, and acted as his or her own control. One hour prior to the first and second sessions, participants were given either oral clonidine (clonidine sessions) or placebo (control sessions). The order of administration of clonidine and placebo was determined by coin toss.

Study Procedures
All participants were seated in a semi-supine position in a standard dental chair. Baseline vital signs, Frontal Temporal Electromyography (EMG), BIS, and OAA/S scores were recorded. OAA/S measures sedation on a 1 (asleep) to 5 (awake) scale (Chernik et al., 1990). Participants were also shown a photograph of a simple object for 5 sec to remember. Each participant then swallowed 1 capsule of clonidine (Catapres®) (0.1 mg/35 kg of body weight) or 1 placebo capsule. Vital signs were continuously monitored by a Millennia Model 3500 (Invivo Research, Inc., Orlando, FL, USA). End-tidal CO2 samples were collected via a divided nasal cannula (Salter Labs #4707F, Arvin, CA, USA). An Aspect A-1050 BIS monitor (Aspect Medical Systems, Newton, MA, USA) was used with default settings including a 30-second smoothing time. A standard frontal temporal montage was recorded with the use of BIS Standard Sensor electrodes applied to each participant’s left temple after mild cotton gauze sponge abrasion, resulting in contact impedance under 5 kOhm. BIS readings, EMG values, and vital signs were recorded every 5 min. Automatic logging of vital sign data was supplemented as needed with manually recorded data. OAA/S readings were determined and recorded every 15 min by the principal investigator. The periodontal resident (sedationist) administered all sedation medications. The principal investigator and periodontal surgeon were masked to all sedation drugs administered and vital signs, including BIS readings. The sedationist was masked to clonidine usage and BIS readings. Immediate access to the "clonidine codes" was available in case of emergency.

One hour after oral pre-medication, all baseline measurements were repeated, and another object photograph was shown. A 20-gauge IV Jelco catheter (Ethicon Inc., Arlington, TX, USA) was then placed in each person’s arm or hand. IV lines were maintained with 5% dextrose and normal saline at a rate of 100 mL/hr. Talking and background noise were minimized, because persons sedated with clonidine are easy to arouse (Hall et al., 2001). Participants breathed 4 L/min of 100% O2 via nasal cannula during venipuncture, sedation, and recovery.

Participants were given IV meperidine (Demerol®), at a dose of 0.35 mg/kg of body weight. After 10 min, each participant received IV diazepam (Valium®), 2.5 mg/min titrated to reach an OAA/S value between 3 and 4. Lidocaine (Xylocaine®), 2% with 1:100,000 epinephrine, was then administered. Subsequent diazepam doses (2.5 mg/min) were titrated as needed to maintain an OAA/S level of 3–4. At the end of each of 4 30-minute periods per session, participants were shown additional object photographs. At the end of each two-hour session, all original baseline measurements were repeated. Recall and recognition were tested after final recovery via a post-session follow-up questionnaire. The sedationist and surgeon also completed post-session questionnaires. All participants were given analgesic prescriptions (acetaminophen/hydrocodone 500/5 mg; 1–2 tablets q 4–6 hrs) to be taken as needed for pain. Participants were asked to record the number of prescription pain pills taken on the days following surgery. Participants also completed a post-study questionnaire following their second session.

Statistical Analysis
Depression of BIS, OAA/S, and EMG readings was assessed by comparison with pre-treatment baseline control readings based on Friedman’s test, with p ≤ 0.01 considered significant. BIS Area Under the Curve, OAA/S Area Under the Curve, and EMG Area Under the Curve values represent areas under the curves for two-hour sedation sessions. Average % Memory Loss (Recall + Recognition) values were determined for all two-hour sedation sessions. A 20% Memory Loss result indicated that a person failed to recall and/or recognize 20% of the object pictures correctly. Parametric vital sign data were evaluated by Dunnett’s Method with Bonferroni Adjustments, and p < 0.05 was considered as significant. Vital sign standard deviations, numbers of significantly depressed BIS readings (#BIS), numbers of significantly depressed OAA/S readings (#OAA/S), numbers of significantly depressed EMG readings (#EMG), BIS Area Under the Curve, OAA/S Area Under the Curve, and EMG Area Under the Curve values were analyzed by paired two-tailed t tests with |t| < 0.05 considered as significant. Numbers of pain pills and two-hour diazepam dosages were compared by Wilcoxon Signed-rank tests, with |z| < 0.05 considered as significant. Percent Memory Loss amnesia data and survey responses were evaluated by chi-square likelihood ratios, with p ≤ 0.05 considered as significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study Population and Sedation Parameters
Three of the 16 participants did not complete the study, because they missed their second session. Participants completing the study (10/31/2003-12/08/2004) included nine females (42 ± 15 yrs, 64 ± 16 kg) and four males (52 ± 3 yrs, 93 ± 16 kg). No study participants experienced or reported untoward reactions or complications from pre-operative clonidine/placebo administration or intravenous sedation. No participants required emergency treatments. The "clonidine codes" were not revealed until the study was completed.

Clonidine pre-treatment significantly increased the numbers of statistically depressed BIS readings (#BIS) compared with placebo sessions (Table 1Go). Sedation with and without clonidine pre-treatment significantly increased the Average % Memory Loss during 2 hrs of sedation compared with baseline controls (p < 0.05). Percent Memory Loss measurements were greater during IV sedation following clonidine pre-treatment vs. placebo. This difference became statistically significant at the final measurement (p < 0.05). There were no significant differences between BIS Area Under the Curve, OAA/S Area Under the Curve, #OAA/S, EMG Area Under the Curve, and #EMG readings during 2 hrs of sedation with vs. without clonidine pre-treatment.


View this table:
[in this window]
[in a new window]
  		Table 1. Sedation Parameters
 
Vital Signs
Clonidine pre-treatment significantly decreased pulse rate, systolic, diastolic, and mean arterial pressures compared with pre-treatment baseline values (Table 2Go). Vital sign reductions were statistically significant (p < 0.05) at each of 24 readings during 2 hrs of IV sedation. Respiratory rates, pulse oximetry saturations, and end-tidal CO2 readings exhibited no significant differences among experimental clonidine, placebo, and pre-treatment baseline values. All measured vital signs did show smaller standard deviations following clonidine pre-treatment compared with placebo. These reductions in participant vital sign standard deviations were statistically significant (|t| < 0.05) for diastolic blood pressure, mean arterial blood pressure, pulse, and respirations.


View this table:
[in this window]
[in a new window]
  		Table 2. Vital Signs
 
Intra-operative Diazepam & Post-operative Analgesic Dosages, Survey Responses
Clonidine significantly reduced total two-hour diazepam dosage by 44% (|z| < 0.005, Table 3Go). Compared with placebo pre-treatment, the average size of the increments (3.3 mg vs. 2.6 mg) was also significantly reduced by clonidine pre-treatment (|z| < 0.005). The average number of diazepam increments (6.2 vs. 4.2) was also reduced by oral clonidine pre-treatment (|z|< 0.005, Table 3Go). Participants self-administered 55% fewer pain pills (6.0 vs. 2.7) on the day of their surgeries following procedures completed with clonidine pre-treatment vs. control sessions (|z|< 0.0002, Table 4Go).


View this table:
[in this window]
[in a new window]
  		Table 3. Diazepam Usage During Sedation
 

View this table:
[in this window]
[in a new window]
  		Table 4. Questionnaire Responses
 
Participant, surgeon, and sedationist survey responses generally indicated a preference for sedation with oral clonidine pre-treatment (Table 4Go). Sedationists’ post-session and participants’ post-study evaluations of quality of sedation favored clonidine pre-treatment by statistically significant margins compared with placebo (p < 0.05). Sedationists and surgeons also indicated that clonidine pre-treatment produced a more even sedation (p < 0.05). A significant majority of participants (p < 0.05) also believed that sessions with clonidine pre-treatment caused more amnesia.

All measures of recovery with clonidine pre-treatment—including sedationist, surgeon, and participant surveys, BIS and OAA/S results—demonstrated no significant differences compared with placebo values. All event memory differences between sessions with and without clonidine pre-treatment were not statistically significant (Table 4Go).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Current dental treatment includes more complex procedures that require longer (two- to three-hour) appointments to complete. These procedures, including periodontal surgery and implant placement, are often performed under local anesthesia supplemented by IV conscious sedation. Sedation provides greater patient comfort, better patient cooperation, and improved operator control. The most commonly used sedative drug regimens include benzodiazepines, narcotics, and other relatively short-acting drugs. This short duration necessitates frequent and multiple re-dosage, which contributes to uneven sedation (Longnecker, 1987). The present randomized, cross-over, placebo-controlled clinical trial investigated the effects of oral clonidine pre-treatment on diazepam/meperidine IV sedation during periodontal surgical procedures of long duration. The results indicate that oral clonidine pre-treatment has a significant effect on sedation parameters (both objective and subjective), on vital signs, and on IV sedative and post-operative analgesic drug usage.

Clonidine pre-treatment significantly increased the number of depressed BIS readings (#BIS) and final % Memory Loss compared with both baseline and placebo values. Clonidine did not increase the magnitude of BIS, OAA/S, and EMG depression of each individual datapoint compared with depressed datapoints without clonidine pre-treatment. BIS Area Under the Curve, OAA/S Area Under the Curve, #OAA/S, EMG Area Under the Curve, and #EMG values during 2 hrs of sedation with and without clonidine pre-treatment were not significantly different. Amnesia induced by BIS-sensitive agents was initially apparent in individuals with BIS readings under 90 (Hall et al., 2002). Profound amnesia was associated with BIS readings under 80 (Glass et al., 1997). BIS can differentiate sedative vs. vital sign stabilizing effects of clonidine. Increased periods of BIS depression with clonidine pre-treatment indicate potentiation of sedative effects in addition to the observed stabilizing effects on blood pressure and heart rate.

The results of this study and previous investigations (Hall et al., 2002; Matsuzaki and Tanaka, 2004) support the use of BIS to monitor conscious sedation. BIS depression during conscious sedation may not be as uniform as it is during general anesthesia, depending on the sedation agents used, the dosage administered, and the individuals selected. In contrast to general anesthesia, attempting to titrate IV conscious sedation to a pre-determined BIS value (endpoint) and to maintain that BIS reading throughout sedation can result in over-dosage. However, BIS can act as an effective dependable alarm, warning of over-sedation. For conscious sedation monitoring, BIS alarms can be set at 70–75.

Recovery assessments (patient, sedationist, and surgeon survey responses) and parameters (BIS, OAA/S) showed no significant differences between clonidine and placebo groups.

All vital signs exhibited less variation and smaller standard deviations with clonidine pre-treatment. When used as a low-dose oral pre-medication, clonidine rarely caused clinically significant bradycardia and/or hypotension requiring treatment (Mikawa et al., 1993). The decreases in heart rate and blood pressure with oral clonidine pre-treatment had no harmful consequences during this study. These findings are confirmed and reinforced by a large body of literature (Jarvis et al., 1992; Mikawa et al., 1993; Arya et al., 1997; Ramesh et al., 1997; Beer et al., 2001; Laisalmi et al., 2001; Nishina et al., 2002). Clonidine pre-treatment does not cause respiratory depression (Jarvis et al., 1992; Prause et al., 2000). Clonidine may have altered the pharmacokinetics of diazepam, since the average times between consecutive doses were increased by clonidine pre-treatment. Oral clonidine is a relatively inexpensive drug ($0.10–$0.15 per 0.1 mg). The retail cost of IV meperidine and diazepam or midazolam averages $5.00 to $10.00 per person. The 44% overall reduction in total benzodiazepine usage and relatively reduced fixed IV narcotic dosage with clonidine could contribute to a meaningful reduction in adverse sedation events and a decrease in the cost of sedation (Valles et al., 1998). The 55% decrease in patient-administered analgesics could also improve post-operative care. The results of this study indicate that oral clonidine pre-treatment is a useful and valuable supplement to intravenous sedation for dental procedures of long duration.


   ACKNOWLEDGMENTS
 
This study was supported by Aspect Medical Systems, Inc. and the Ohio State University College of Dentistry Sections of Periodontology and Primary Care. Aspect Medical Systems, Inc. provided BIS monitoring equipment and related supplies. This work was based on a thesis submitted to The Ohio State University Graduate School in partial fulfillment of the requirements for the Master of Science degree. A preliminary report was presented as an abstract (#910) at the IADR/AADR/CADR 83rd General Session (March 9-12, 2005) in Baltimore, MD, USA.

Received June 20, 2005; Last revision May 1, 2006; Accepted June 5, 2006


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Arya DK, Langley RW, Szabadi E, Bradshaw CM (1997). Comparison of the effects of high ambient temperature and clonidine on autonomic functions in man. Naunyn Schmiedebergs Arch Pharmacol 355:376–383.[ISI][Medline]

Barnett AJ, Cantor S (1968). Observations on the hypertensive action of "Catapres" (ST 155) in man. Med J Aust 1:87–91.

Beer GM, Spicher I, Seifert B, Emanuel B, Kompatscher P, Meyer VE (2001). Oral premedication for operations on the face under local anesthesia: a placebo-controlled double-blind trial. Plast Reconstr Surg 108:637–643.[ISI][Medline]

Chernik DA, Gillings D, Laine H, Hendler J, Silver JM, Davidson AB, et al. (1990). Validity and reliability of the Observer’s Assessment of Alertness/Sedation Scale: study with intravenous midazolam. J Clin Psychopharmacol 10:244–251.[ISI][Medline]

Flacke JW, Bloor BC, Flacke WE, Wong D, Dazza S, Stead SW, et al. (1987). Reduced narcotic requirement by clonidine with improved hemodynamic and adrenergic stability in patients undergoing coronary bypass surgery. Anesthesiology 67:11–19.[ISI][Medline]

Frank T, Thieme V, Olthoff D (1999). Preoperative clonidine comedication within the scope of balanced inhalation anesthesia with sevoflurane in oral surgery procedures. Anaesthesiol Reanim 24:65–70 [article in German].[Medline]

Galeotti N, Bartolini A, Ghelardini C (2004). Alpha-2 agonist-induced memory impairment is mediated by the alpha-2A-adrenoceptor subtype. Behav Brain Res 153:409–417.[ISI][Medline]

Glass PS, Bloom M, Kearse L, Rosow C, Sebel P, Manberg P (1997). Bispectral analysis measures sedation and memory effects of propofol, midazolam, isoflurane and alfentanil in healthy volunteers. Anesthesiology 86:836–847.[ISI][Medline]

Hall DL, Weaver J, Ganzberg S, Rashid R, Wilson S (2002). Bispectral EEG index monitoring of high-dose nitrous oxide and low-dose sevoflurane sedation. Anesth Prog 49:56–62.[Medline]

Hall JE, Uhrich TD, Ebert TJ (2001). Sedative, analgesic and cognitive effects of clonidine infusions in humans. Br J Anaesth 86:5–11.[Abstract/Free Full Text]

Handley SL, Mithani S (1984). Effects of alpha-adrenoceptor agonists and antagonists in a maze-exploration model of ‘fear’-motivated behavior. Naunyn Schmiedebergs Arch Pharmacol 327:1–5.[ISI][Medline]

Hilz MJ, Marthol H, Neundorfer B (2002). Syncope—a systematic overview of classification, pathogenesis, diagnosis and management. Fortschr Neurol Psychiatr 70:95–107 [article in German].[ISI][Medline]

Jarvis DA, Duncan SR, Segal IS, Maze M (1992). Ventilatory effects of clonidine alone and in the presence of alfentanil, in human volunteers. Anesthesiology 76:899–905.[ISI][Medline]

Karhuvaara S, Kallio A, Salonen M, Tuominen J, Scheinin M (1991). Rapid reversal of alpha2 adrenoceptor agonist effects by atipamezole in human volunteers. Br J Clin Pharmacol 31:160–165.[ISI][Medline]

Khan ZP, Ferguson CN, Jones RM (1999). Alpha-2 and imidazoline receptor agonists. Their pharmacology and therapeutic role. Anaesthesia 54:146–165.[ISI][Medline]

Laisalmi M, Koivusalo AM, Valta P, Tikkanen I, Lindgren L (2001). Clonidine provides opioid-sparing effect, stable hemodynamics, and renal integrity during laparoscopic cholecystectomy. Surg Endosc 15:1331–1335.[ISI][Medline]

Longnecker DE (1987). Alpine anesthesia: can pretreatment with clonidine decrease the peaks and valleys? Anesthesiology 67:1–2.[ISI][Medline]

Matsuzaki S, Tanaka H (2004). The feasibility of bispectral index monitoring for intravenous sedation during dental treatment. Anesth Prog 51:52–55.[Medline]

Mikawa K, Maekawa N, Nishina K, Takao Y, Yaku H, Obara H (1993). Efficacy of oral clonidine premedication in children. Anesthesiology 79:926–931.[ISI][Medline]

Murai T, Kyoda N, Misaki T, Takada K, Sawada S, Machida T (1995). Effects of clonidine on intravenous sedation with midazolam. Anesth Prog 42:135–138.[Medline]

Nishina K, Mikawa K, Uesugi T, Obara H, Maekawa M, Kamae I, et al. (2002). Efficacy of clonidine for prevention of perioperative myocardial ischemia: a critical appraisal and meta-analysis of the literature. Anesthesiology 96:323–329.[ISI][Medline]

Prause A, Wappler F, Scholz J, Bause H, Schulte am Esch J (2000). Respiratory depression under long-term sedation with sufentanil, midazolam and clonidine has no clinical significance. Intensive Care Med 26:1454–1461.[ISI][Medline]

Puke MJ, Wiesenfeld-Hallin Z (1993). The differential effects of morphine and the alpha2-adrenoceptor agonists clonidine and dexmedetomidine on the prevention and treatment of experimental neuropathic pain. Anesth Analg 77:104–109.[Abstract/Free Full Text]

Ramesh VJ, Bhardwaj N, Batra YK (1997). Comparative study of oral clonidine and diazepam as premedicants in children. Int J Clin Pharmacol Ther 35:218–221.[ISI][Medline]

Salonen M, Reid K, Maze M (1992). Synergistic interaction between alpha 2-adrenergic agonists and benzodiazepines in rats. Anesthesiology 76:1004–1011.[ISI][Medline]

Samso E, Valles J, Pol O, Gallart L, Puig MM (1996). Comparative assessment of the anaesthetic and analgesic effects of intramuscular and epidural clonidine in humans. Can J Anaesth 43:1195–1202.[Abstract/Free Full Text]

Siiba S, Nakanishi O, Ishikawa T, Hirakawa T, Kawahara H, Imamura Y (1999). Increase in the threshold of pain and touch sensation in the human face with clonidine plus 30% nitrous oxide. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 87:294–298.[ISI][Medline]

Valles J, Samso E, Vilar X, Gallart L, Puig MM (1998). Pharmacy savings generated by preoperative administration of clonidine. J Clin Anesth 10:36–40.[ISI][Medline]





This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hall, D.L.
Right arrow Articles by Rezvan, E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hall, D.L.
Right arrow Articles by Rezvan, E.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
IADR Journals Advances in Dental Research ®
Journal of Dental Research ® Critical Reviews (1990-2004)