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Canadian Journal of Anesthesia 51:668-671 (2004)
© Canadian Anesthesiologists' Society, 2004
General Anesthesia

Oral tandospirone and clonidine provide similar relief of preoperative anxiety

[L’administration orale de tandospirone ou de clonidine fournit un soulagement similaire de l’anxiété préopératoire]

Aya Iizawa, MD, Tsutomu Oshima, MD, Yoshiko Kasuya, MD and Shuji Dohi, MD

From the Department of Anesthesiology, Gifu University School of Medicine, Gifu, Japan.

Address correspondence to: Dr. Tsutomu Oshima, Department of Anesthesiology, Gifu University School of Medicine, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan. Phone: 81-58-230-6404, Fax: 81-58-230-6405, E-mail: oshimat{at}cc.gifu-u.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Purpose: To compare oral tandospirone with oral clonidine in terms of preoperative anxiolysis.

Methods: Preoperative anxiety was measured using the Spielberger state-trait anxiety inventory (STAI-state). Pretreatment evaluation was performed on the day before surgery and post-treatment examination immediately after entry into the operating room. In a double-blind, randomized design, three groups of 40 patients received one of the following oral medications 90 min before entry into the operating room: 1) tandospirone 10 mg (T group); 2) clonidine 3 µg·kg–1 (C group); or 3) placebo (P group).

Results: Following premedication, the STAI-state decreased in the T group (P < 0.05) while exhibiting no significant changes in the C group. As far as the changes in the STAI-state were concerned, however, the P-group was different from each of the other groups (P < 0.05 vs T group and vs C group).

Conclusion: Oral tandospirone was equivalent to oral clonidine in terms of reduction in preoperative anxiety.


   Introduction
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 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
PREOPERATIVE anxiolysis and sedation are the main objectives of premedication, and both involve a number of possible mechanisms of action implicating central gamma-aminobutyric acid and adrenergic receptors. We have recently demonstrated that oral administration of tandospirone, a partial agonist of the 5-hydroxytryptamine-1A (5-HT1A) receptor, reduces preoperative anxiety to the same extent as oral diazepam1 and exerts antiemetic effects postoperatively.2 On the other hand, clonidine, an {alpha}2-adrenergic receptor agonist, has been used as a premedicant because of its central nervous system (CNS)-mediated responses including anxiolysis, sedation, attenuation of pain perception, and anesthetic sparing effects.3,4 However, there are no data available regarding the anxiolysis of oral tandospirone compared with oral clonidine before surgery.

The present study was designed to compare oral tandospirone with oral clonidine when both are used as preanesthetic drugs in patients scheduled for elective otolaryngologic surgery. Preoperative anxiety was measured using the standard Spielberger state-trait anxiety inventory (STAI). We hypothesized that tandospirone would be equivalent to clonidine for the relief of preoperative anxiety.


   Patients and methods
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 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
The protocol was approved by the Ethics Committee of the Gifu University School of Medicine. Written informed consent was obtained from 120 consecutive inpatients, aged 18 to 64 yr, ASA physical status I or II, scheduled for otolaryngologic surgery. Exclusion criteria were malignancy, coexisting CNS disease, a variety of neurotic disorders, use of centrally acting medications including tandospirone and clonidine, inability to read or speak Japanese, and behavioural impairment.

A randomization list was computer generated, and identical pills containing each drug, according to the list, were prepared by personnel who were not involved in this study. One hundred and twenty patients were divided, using a randomized double-blind design, into three groups of 40 patients each. Together with oral famotidine 20 mg, subjects received oral tandospirone 10 mg (T group), clonidine 3 µg·kg–1 (C group), or placebo (P group) 90 min before entry into the operating room. Pretreatment evaluation was performed on the eve of surgery, a time reported to provide a level representative of the anxiety occurring immediately preoperatively. Post-treatment evaluation was performed upon arrival in the operating room.

Pre- and post-treatment measurements consisted of the state anxiety score measured by the Japanese form of STAI (STAI-state). In addition, the pretreatment evaluation incorporated the trait anxiety score given by the Japanese form of STAI (STAI-trait). The STAI is a standardized psychomotor test composed of 40 questions that subjects answer using a four-point scale. The sum of 20 responses gives STAI-trait, which is directly proportional to baseline tendencies towards anxiety independent of the subject current situation. The remaining 20 questions yield STAI-state, which increases proportionally to situational anxiety level.

To compare data among the T, C, and P groups, categorical data were analyzed using the Pearson Chi-square tests with Yates correction or Fisher exact probability test, as appropriate. Continuous data were analyzed by means of Bonferroni multiple comparison tests after a one-way analysis of variance. In each premedication group, a comparison between post- and pretreatment values was performed using a paired t test. In all tests, a value of P < 0.05 was considered statistically different. Data are presented as the mean ± standard deviation, unless otherwise indicated. Power analysis was performed to determine the number of patients in the study on the basis of the assumptions that 1) the change in STAI-state after premedication in the P-group and in either the T or C group would be 4 ± 10 and –3 ± 10, respectively, as in our recent study;1 2) this difference was considered as clinically significant; and 3) {alpha}= 0.05 and 1–ß = 0.8. On the basis of these assumptions, at least 32 patients per group were required.


   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
There were no significant differences among the T, C, and P groups in terms of age, sex, height, weight, STAI-trait, or planned surgical procedures (TableGo), or in the baseline values obtained prior to premedication for STAI-state (Figure 1Go).


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  		TABLE Demographic characteristics, baseline STAI-trait and surgical procedures
 


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  		FIGURE 1 State anxiety scores measured by the Spielberger state-trait anxiety inventory (STAI-state) in T, C, and P groups. * P < 0.05 compared with pretreatment STAI-state.

 
When post-treatment values were compared with pretreatment values, STAI-state decreased in the T- (P < 0.05), but increased in the P-group (P < 0.05), and remained unchanged in the C-group (Figure 1Go). As far as changes in STAI-state were concerned, the P-group was significantly different from each of the other groups (P < 0.05 vs T-group and vs C-group) with no significant difference between the T and C groups (Figure 2Go).



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  		FIGURE 2 Changes in state anxiety scores measured by the Spielberger state-trait anxiety inventory (STAI-state) in T, C, and P groups. *P < 0.05 compared with the P group.

 

   Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
The principal finding of our study is that the anxiolytic effect of oral tandospirone was equivalent to that of oral clonidine as measured by the STAI-state. The STAI-state was decreased by oral tandospirone, increased in the placebo group and remained unchanged with oral clonidine. Nevertheless, no differences were observed between oral tandospirone and oral clonidine. In terms of preoperative anxiolysis, we were unable to demonstrate the superiority of oral tandospirone to oral clonidine, but at least we could exclude the inferiority of oral tandospirone to oral clonidine.

Oral tandospirone and oral clonidine have different mechanisms of action. Tandospirone is considered to produce its anxiolytic effects by stimulating presynaptic 5-HT1A receptors in the brainstem raphe nuclei. This results in attenuation of postsynaptic cell firing and subsequent inhibition of serotonergic neurotransmission in the limbic system.5–7 On the other hand, the site of action of oral clonidine is probably the locus coeruleus, because infusion of {alpha}2-adrenergic receptor agonists and antagonists into the locus coeruleus of rats can increase or decrease, respectively, activity in the Porsolt forced swim test, a widely accepted predictive model of the efficacy of antidepressant drugs.8,9 The anxiolytic effects of tandospirone have been demonstrated to be separate from its sedative, anticonvulsant and muscle relaxant effects,10,11 while clonidine is an {alpha}2-adrenergic receptor agonist and its sedative properties have been well documented.3 A similar functional duality has been demonstrated to exist in the modulation of depression in patients: serotonergic agents tend to improve mood, whereas noradrenergic agents tend to improve drive or motivation.12 In the present study, however, we did not examine the sedative effects produced by each test drug. Further studies are needed in this area.

In conclusion, oral tandospirone is equivalent to oral clonidine in the relief of preoperative anxiety.


   Footnotes
 
This study was supported in part by Grant-in-Aid 12671460 from the Japan Society for the Promotion of Science.


   References
TOP
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1 Oshima T, Kasuya Y, Terazawa E, Nagase K, Saitoh Y, Dohi S. The anxiolytic effects of 5-hydroxytryptamine-1A agonist tandospirone before otolaryngologic surgery. Anesth Analg 2001; 93: 1214–6.[Abstract/Free Full Text]

2 Oshima T, Kasuya Y, Okumura Y, Terazawa E, Dohi S. Prevention of nausea and vomiting with tandospirone in adults after tympanoplasty. Anesth Analg 2002; 95: 1442–5.[Abstract/Free Full Text]

3 Lakhlani PP, MacMillan LB, Guo TZ, et al. Substitution of a mutant {alpha}2a-adrenergic receptor via "hit and run" gene targeting reveals the role of this subtype in sedative, analgesic, anesthetic sparing-responses in vivo. Proc Natl Acad Sci USA 1997; 94: 9950–5.[Abstract/Free Full Text]

4 Schramm NL, McDonald MP, Limbird LE. The {alpha}2A-adrenergic receptor plays a protective role in mouse behavioral model of depression and anxiety. J Neurosci 2001; 21: 4875–82.[Abstract/Free Full Text]

5 De Vry J. 5-HT1A receptor agonists: recent developments and controversial issues. Psychopharmacology 1995; 121: 1–26.[Medline]

6 Sommermeyer H, Schreiber R, Greuel JM, De Vry J, Glaser T. Anxiolytic effects of the 5-HT1A receptor agonist ipsapirone in the rat: neurobiological correlates. Eur J Pharmacol 1993; 240: 29–37.[Medline]

7 Jolas T, Schreiber R, Laporte AM, et al. Are postsynaptic 5-HT1A receptors involved in the anxiolytic effects of 5-HT1A receptor agonists and in their inhibitory effects on the firing of serotonergic neurons in the rat? J Pharmacol Exp Ther 1995; 272: 920–9.[Abstract/Free Full Text]

8 Simson PG, Weiss JM, Hoffman LJ, Ambrose MJ. Reversal of behavioral depression by infusion of an alpha-2 adrenergic agonist into the locus coeruleus. Neuropharmacology 1986; 25: 385–9.[Medline]

9 Weiss JM, Simson PG, Hoffman LJ, Ambrose MJ, Cooper S, Webster A. Infusion of adrenergic receptor agonists and antagonists into the locus coeruleus and ventricular system of the brain. Effects on swim-motivated and spontaneous motor activity. Neuropharmacology 1986; 25: 367–84.[Medline]

10 Rapoport DM, Greenberg HE, Goldring RM. Differing effects of the anxiolytic agents buspirone and diazepam on control of breathing. Clin Pharmacol Ther 1991; 49: 394–401.[Medline]

11 Unrug-Neervoort A, van Luijtelaar G, Coenen A. Cognition and vigilance: differential effects of diazepam and buspirone on memory and psychomotor performance. Neuropsychobiology 1992; 26: 146–50.[Medline]

12 Healy D, McMonagle T. The enhancement of social functioning as a therapeutic principle in the management of depression. J Psychopharmacol 1997; 11(Suppl.): S25–31.





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