Secondary Logo

Journal Logo

The Sedative and Sympatholytic Effects of Oral Tizanidine in Healthy Volunteers

Miettinen, Timo J. MD; Kanto, Jussi H. MD; Salonen, Markku A. MD; Scheinin, Mika MD

General Article
Free
SDC

Tizanidine, an imidazoline derivative with alpha2-receptor-mediated central muscle relaxant activity, is in widespread clinical use for the treatment of spasticity. To evaluate its possible role in anesthesia we assessed the sedative and sympatholytic effects of orally administered tizanidine in a double-blind, placebo controlled, randomized, cross-over study in six healthy male volunteers. Three different doses of tizanidine (4, 8, and 12 mg) were tested and compared to clonidine 150 micro gram. The sedative and sympatholytic effects of tizanidine 12 mg were comparable in magnitude to those of clonidine 150 micro gram, but the effects of clonidine were longer lasting. Similarly, the observed decreases in arterial blood pressure (diastolic, 13% and 19%; systolic, 10% and 8% for tizanidine and clonidine, respectively) and salivation were comparable in magnitude but of shorter duration after tizanidine 12 mg than after clonidine. Clonidine and tizanidine 12 mg had also similar effects on the secretion of growth hormone. Our results indicate that the effects of a single 12-mg oral dose of tizanidine resemble those of 150 micro gram oral clonidine, but are of shorter duration. Tizanidine may thus be a useful alternative to clonidine as an orally active, short-acting alpha2-adrenoceptor agonist in the perioperative period.

(Anesth Analg 1996;82:817-20)

Departments of Anesthesiology and Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland.

This study was supported by the Emil Aaltonen Foundation, Turku University Foundation, and Sandoz Oy, Finland.

Accepted for publication December 5, 1995.

Address correspondence and reprint requests to Timo Miettinen, Department of Anesthesiology, Turku University Hospital, FIN-20520 Turku, Finland.

Several alpha2-adrenoceptor agonists have been evaluated recently as adjuncts to anesthesia [1-5]. The beneficial properties of these drugs include sedative, analgesic, and, possibly, also anxiolytic effects. They also improve sympathoadrenal and hemodynamic stability during and after anesthesia and surgery, and reduce the requirements for volatile anesthetics, opioids, and benzodiazepines [3-9]. In spite of this, they are used relatively rarely in clinical anesthesia because of their hemodynamic side effects. Excessive bradycardia and hypotonia, and even sinus arrest, have been described after the administration of these compounds [1,8,10].

Tizanidine is an orally active alpha2-adrenoceptor agonist and is used clinically mainly as a centrally acting muscle relaxant for painful muscular spasms [11,12]. Its well known side effects include sedation and reduced salivation [13]. Tizanidine has a relatively short duration of action [14]. It may also possess less cardiovascular side effects than other alpha2-adrenoceptor agonists [15]. These features make tizanidine a potentially interesting drug for anesthetic use.

The present study was undertaken to characterize the sedative, hemodynamic, sympatholytic, and other pharmacodynamic effects of tizanidine in healthy volunteers, and to determine an equipotent dose of tizanidine to 150 micro gram of clonidine, to be used in subsequent clinical studies in surgical patients.

Back to Top | Article Outline

Methods

The subjects were six healthy male volunteers, who participated after written, informed consent (mean age 21 yr, range 21-23 yr; mean weight 76 kg, range 68-83 kg; mean height 179 cm, range, 168-187 cm). They had taken no medications during the 2 wk preceding this study. The health of the subjects was ascertained by detailed medical history, physical examination, clinical chemistry tests, and electrocardiogram. The protocol was approved by the Ethics Committee of Turku University Hospital. Alcoholic beverages were not allowed for 24 h prior to each session, and the subjects had fasted since 10:00 PM on the preceding night. The subjects were allowed to drink one glass of water on the morning of the test day. Smoking was prohibited on the test day.

The subjects arrived at the laboratory at 8:00 AM. An intravenous cannula was inserted for blood sampling and it was kept open with a dilute solution of heparin. The experiments were performed in a quiet, dimly lit room. The subjects had a light standard meal and were allowed a lavatory visit at 180 min after drug administration. Otherwise they remained supine throughout the sessions. The subjects were permitted to leave the laboratory 6 h after drug administration.

The study was double-blind and placebo controlled, and followed a randomized, complete block design. Each subject received three different single doses (4, 8, and 12 mg) of tizanidine (Sirdalud Registered Trademark; Sandoz, Basel, Switzerland), one single dose (150 micro gram) of clonidine, and placebo. The doses were given between 8.45 and 9.30 AM and the drugs were ingested with 150 mL of water after a minimum of 30 min supine rest. The interval between each session was at least 5 days.

Arterial blood pressure and heart rate were measured noninvasively with an automated oscillometric device. Impairment of vigilance was assessed objectively with the critical flicker fusion threshold test [16], and with the Maddox Wing test [17], where an increasing degree of exophoria (in diopters) indicates the impairment of extraocular muscle balance.

Visual analog scales, 10 cm long, were used to report subjective sedation (extremes, "fully alert" to "almost asleep") [18]. Nonstimulated saliva secretion was measured by placing three preweighed dental cotton rolls at the orifices of the parotid ducts and under the tongue for 2 min and then recording the weight of the rolls.

Blood samples to determine human growth hormone (GH) and norepinephrine levels were collected into chilled K3 EDTA tubes at 1 min before drug administration and at 30, 60, 90, 120, 180, 240, and 360 min after the administration. Plasma was separated within 30 min of sampling at +4 degrees C, and the samples stored at -70 degrees C until analyzed. Blood samples to determine the drug concentration from serum were collected at the same time points. Human GH concentrations were determined using radioimmunoassay (Spectria Registered Trademark HGH125 I; Orion Diagnostica, Espoo, Finland), and norepinephrine levels by high-performance liquid chromatography with electrochemical detection [19]. Serum tizanidine concentrations were measured using a radioreceptor assay, described earlier [20]. Tritiated clonidine was used as the labeled ligand. Tizanidine displaced clonidine over two log units of concentration, and the Hill slope of the displacement curve was close to unity.

The subjects were asked to report any possible drug-related subjective sensations, and a standardized questionnaire was completed at 1-h intervals during each session.

The data were analyzed using repeated-measures analysis of variance (ANOVA) followed by one-way ANOVA and Fisher's test for individual comparisons. The growth hormone values were converted logarithmically to correct the skewness in distribution. A significance level of less than 0.05 was considered statistically significant. Minitab statistical package (Minitab Inc., State College, PA) was used for computing the tests. All reported results are means +/- SE.

Back to Top | Article Outline

Results

The drugs were well tolerated, with no distinctly unpleasant experiences. The most common side effect was dryness of the mouth, which was usually considered to be "mild." Two of the subjects mentioned dryness of mouth to be "moderate," both after administration of clonidine 150 micro gram. The subjective experience of sedation was rather modest after all drug doses, but tended to be most marked after clonidine 150 micro gram. Neither the visual analog scale nor the Maddox Wing readings revealed any statistically significant differences between the treatments Table 1. Drug-induced impairment of critical flicker fusion ratings was statistically significant Table 1, Figure 1, but further analysis with one-way ANOVA or Fisher's test did not reveal any significant differences between the drug doses.

Table 1

Table 1

Figure 1

Figure 1

Both clonidine and tizanidine decreased arterial blood pressure Table 1. The maximum reductions in diastolic blood pressure for clonidine, tizanidine 12 mg, tizanidine 8 mg, tizanidine 4 mg, and placebo were 19%, 13%, 13%, 7%, and 5%, respectively. For systolic blood pressure (SBP) the maximal reductions were 8%, 10%, 12%, 9%, and 5%, respectively. Drug effects on SBP were largest 90 min after drug administration, when statistically significant differences in SBP (P < 0.05) were observed between placebo and tizanidine 8 mg (108 +/- 3.7 vs 98 +/- 3.0 mm Hg), placebo and tizanidine 12 mg (108 +/- 3.7 vs 98 +/- 3.0 mm Hg), and between placebo and clonidine (108 +/- 3.7 vs 97.1 +/- 3.0 mm Hg). Diastolic blood pressure was most markedly reduced at 2 h after drug administration, when statistically significant differences (P < 0.05) were seen between placebo and clonidine 150 micro gram (62.8 +/- 1.1 vs 56.3 +/- 2.1 mm Hg), placebo and tizanidine 8 mg (62.8 +/- 1.1 vs 56.3 +/- 2.0 mm Hg), and between placebo and tizanidine 12 mg (62.8 +/- 1.1 vs 55.5 +/- 1.4 mm Hg).

Both clonidine and the two larger doses of tizanidine reduced basal salivation. The effect of clonidine lasted clearly longer than the effect of tizanidine Table 1 and Figure 2 (P < 0.05 at 6 h).

Figure 2

Figure 2

The concentration of norepinephrine in plasma was clearly reduced after clonidine and the two higher doses of tizanidine Figure 3. Two hours after drug administration, both tizanidine 12 mg and clonidine 150 micro gram plasma norepinephrine concentrations were statistically significantly different from placebo (0.68 +/- 0.07 nmol/L vs 1.06 +/- 0.08 nmol/L and 0.64 +/- 0.14 nmol/L vs 1.06 +/- 0.08 nmol/L, respectively), but by the end of the session the norepinephrine concentration had returned to the baseline level after tizanidine 12 mg. Clonidine 150 micro gram was still, at 6 h after administration, statistically significantly different (P < 0.05) from all other treatments in terms of plasma norepinephrine levels (0.57 +/- 0.09 nmol/L vs 1.06 +/- 0.1 nmol/L for placebo).

Figure 3

Figure 3

Both clonidine 150 micro gram and tizanidine 12 mg tended to increase plasma, human GH levels, but the changes did not reach statistical significance after logarithmic transformation Table 1, Figure 4.

Figure 4

Figure 4

Tizanidine serum concentrations showed high inter- and intraindividual variability, and did not allow the calculation of exact pharmacokinetic parameters. The peak concentrations were reached in 30-90 min after drug administration.

Back to Top | Article Outline

Discussion

Recently, alpha2-adrenoceptor agonists have gained wide attention as potentially useful pre- or perianesthetic drugs. Tizanidine has not been evaluated in this paradigm. In this study, we sought to determine an equally sedative and sympatholytic dose of tizanidine to 150 micro gram clonidine.

Carabine et al. [21] have reported that oral clonidine in a dose of 200 micro gram had anxiolytic activity with no marked hemodynamic effects. The dose of clonidine used by us, 150 micro gram, is suitable for premedication, since it does not delay recovery from anesthesia [22]. The effects of the largest dose of tizanidine studied by us, 12 mg, closely resembled those of clonidine 150 micro gram in quality and magnitude, but were of shorter duration. Both drugs had relatively modest sedative effects, they reduced arterial blood pressure, salivation, and plasma norepinephrine concentrations to a similar extent, and both tended to stimulate GH secretion. These effects are typical for alpha2-adrenoceptor agonists with relatively rapid penetration into the central nervous system [4-6,23,24]. Plasma norepinephrine concentrations were used here as an indicator of presynaptic sympathetic activity, and growth hormone as a marker for pharmacological effects mediated by alpha2-adrenoceptors in brain.

Our results show that the effects of 12 mg of tizanidine orally resemble those of 150 micro gram of clonidine. This dose of tizanidine is comparable with that normally used in the treatment of spasticity (4-6 mg three times a day). Pharmacokinetic studies performed with tizanidine indicate that serum concentrations increase proportionally to dosage, that peak serum concentrations are usually achieved in 60 minutes, and that the elimination of tizanidine is relatively rapid (t1/2 three hours) [14,15]. Clonidine has a longer duration of action than tizanidine, and the onset of its actions may also be slower. The short duration of action of tizanidine may make it desirable as a drug for premedication.

We want to express our gratitude to Mrs. Tuire Olli-Lahdesmaki, BM, Miss Eija Lehtovirta, and Mrs. Taina Lehti for skillful technical assistance.

Back to Top | Article Outline

REFERENCES

1. Aantaa R, Kanto J, Scheinin M, et al. Dexmedetomidine, an alpha2-adrenoceptor agonist reduces anesthetic requirements for patients undergoing minor gynecological surgery. Anesthesiology 1990;73:230-5.
2. Aho M, Lehtinen A, Laatikainen T, Korttila K. Effects of intramuscular clonidine on hemodynamic and plasma beta-endorphin responses to gynecologic laparoscopy. Anesthesiology 1990;72:797-802.
3. Salonen M, Kanto J, Maze M. Clinical interactions with alpha2-adrenergic agonists in anesthetic practice. J Clin Anesth 1992;4(2):164-72.
4. Aantaa R, Scheinin M. Alpha2-adrenergic agents in anaesthesia. Acta Anaesthesiol Scand 1993;37:433-48.
5. Maze M, Tranquilli W. Alpha2-adrenoceptor agonists: defining the role in clinical anesthesia. Anesthesiology 1991;74:581-605.
6. Maze M, Segal I, Bloor BC. Clonidine and other alpha-adrenergic agonists: strategies for the rational use of these novel anesthetic agents. J Clin Anesth 1988;1:146-57.
7. Woodcock TE, Millard RK, Dixon J, Prys-Roberts C. Clonidine premedication for isoflurane-induced hypotension. Br J Anesth 1988;60:388-4.
8. Quintin L, Bonner F, Macquin I, et al. Aortic surgery: effect of clonidine on intraoperative catecholaminergic and circulatory stability. Acta Anaesthesiol Scand 1990;34:132-7.
9. Longnecker DE. Alpine anesthesia: can pretreatment with clonidine decrease the peaks and valleys? Anesthesiology 1987;67:1-2.
10. Aho MS, Erkola OA, Scheinin H, et al. Effect of intravenously administered dexmedetomidine on pain after laparoscopic tubal ligation. Anesth Analg 1991;73:112-8.
11. Sayers AC, Burki HR, Eichenberger E. The pharmacology of 5-chloro-4-(2-imidazolin2yl-amino9-2,1,3-benzthiazole (DS-103-282), a novel myotonolytic agent. Arzneimittelforschung 1980;30:793-803.
12. Coward DM. Tizanidine: neuropharmacology and mechanism of action. Neurology 1994;44(Suppl 9):S6-11.
13. Bragstad A, Blikra G. Evaluation of a new skeletal muscle relaxant in the treatment of low back pain. Curr Ther Res 1979;26:39-43.
14. Tse FLS, Jaffe JM, Bhuta S. Pharmacokinetics of orally administered tizanidine in healthy volunteers. Fundam Clin Pharmacol 1987;1:479-88.
15. Mathias JC, Luckitt J, Desai P, et al. Pharmacodynamics and pharmacokinetics of the oral antispastic agent tizanidine in patients with spinal cord injury. J Rehabil Res Dev 1989;4:9-16.
16. Smith JM, Misiak H. Critical flicker frequency (CFF) and psychotropic drugs in normal human subjects--a review. Psychopharmacology 1976;47:175-82.
17. Hannington-Kiff GS. Measurement of recovery from outpatient general anesthesia with simple ocular test. BMJ 1970;3:132-5.
18. Bond A, Lader M. The use of analogue scales in rating subjective feelings. Br J Med Psychol 1974;47:211-8.
19. Scheinin M, Koulu M, Laurikainen E, Allonen H. Hypokalaemia and other non-bronchial effects of inhaled fenoterol and salbutamol: a placebo-controlled dose-response study in healthy volunteers. Br J Clin Pharmacol 1987;24:645-53.
20. Salonen M, Maze M. Implementation of radioreceptor assay for dexmedetomidine. Pharmacol Toxicol 1993;73:254-6.
21. Carabine UA, Wright PMC, Moore J. Preanaesthetic medication with clonidine: a dose response study. Br J Anaesth 1991;67:79-83.
22. Bellaiche S, Bonnet F, Sperandio M, et al. Clonidine does not delay recovery from anaesthesia. Br J Anaesth 1991;66:353-7.
23. Tong C, Eisenach JC. Alpha-adrenergic agonists. Anesth Clin North Am 1994;12:49-63.
24. Kallio A, Scheinin M, Koulu M, et al. Effects of dexmedetomidine, a selective alpha2-adrenoceptor agonist, on hemodynamic control mechanisms. Clin Pharmacol Ther 1989;46:33-42.
© 1996 International Anesthesia Research Society