Anesth Analg 2002;95:393-396
© 2002 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
Oral Tizanidine, an  2-Adrenoceptor Agonist, Reduces the Minimum Alveolar Concentration of Sevoflurane in Human Adults
Zen’ichiro Wajima, MD PhD*,
Tatsusuke Yoshikawa, MD PhD*  ,
Akira Ogura, MD PhD ,
Kazuyuki Imanaga, MD*,
Toshiya Shiga, MD PhD*,
Tetsuo Inoue, MD PhD*, and
Ryo Ogawa, MD PhD||
*Department of Anesthesia, Chiba Hokusoh Hospital, Nippon Medical School, Chiba, Japan; Department of Anesthesia, Hakujikai Memorial Hospital, Tokyo, Japan; Department of Anesthesiology, Tokyo Jikeikai Medical School, Tokyo, Japan; Department of Anesthesiology, Yale University School of Medicine, New Haven, Connecticut; and ||Department of Anesthesiology, Nippon Medical School, Tokyo, Japan
Address correspondence and reprint requests to Zen’ichiro Wajima, MD, PhD, Department of Anesthesia, Chiba Hokusoh Hospital, Nippon Medical School, 1715, Kamagari, Inba-mura, Inba-gun, Chiba 270-1694, Japan. Address e-mail to HFB01245{at}nifty.com
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Abstract
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Tizanidine, an  2-adrenoceptor agonist, has an antinociceptive effect in animals. In humans premedicated with oral tizanidine, the increase in blood pressure associated with laryngoscopy and intubation was attenuated, and the amount of midazolam required for loss of consciousness was significantly reduced. We speculated that the oral administration of tizanidine might reduce the minimum alveolar anesthetic concentration (MAC) of sevoflurane. Fifty-two ASA physical status I–II patients, aged 24–56 yr, were randomly allocated into two groups: a Control group (n = 26) and a Tizanidine group (n = 26). As premedication, the Control group received a placebo, and the Tizanidine group received 4 mg of oral tizanidine 90 min before surgical skin incision. Anesthesia was induced in all patients by using vital capacity rapid inhaled induction with sevoflurane (5%). Loss of consciousness was defined as both the loss of the eyelid reflex and the lack of a response to a verbal command. MAC was determined by a technique adapted from the conventional up-down method for quantal responses. The MAC of sevoflurane was 2.2% ± 0.2% in the Control group and 1.8% ± 0.2% in the Tizanidine group (P = 0.0004). The time to loss of consciousness in the Tizanidine group (60.2 ± 22.5 s) was significantly shorter than that in the Control group (73.7 ± 26.3 s) (P = 0.03). The oral administration of tizanidine 4 mg successfully reduced the MAC of sevoflurane by 18% in human adults.
IMPLICATIONS: Oral tizanidine (4 mg), an 2-adrenoceptor agonist, reduces the minimum alveolar concentration of sevoflurane by 18%.
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Introduction
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Tizanidine is an 2-adrenoceptor agonist that has an antinociceptive effect in animals (1–3). In humans who received oral tizanidine as a premedication, the increase in mean blood pressure that accompanies laryngoscopy and tracheal intubation was attenuated (4), and the amount of midazolam required for loss of consciousness was significantly less in patients who received the tizanidine pretreatment (4). Furthermore, oral premedication with tizanidine prolongs tetracaine spinal anesthesia (5). We speculated that the oral administration of tizanidine, which acts in a similar manner to that of clonidine and dexmedetomidine (6), might reduce the minimum alveolar anesthetic concentration (MAC) of sevoflurane. We therefore tested the hypothesis that oral premedication with tizanidine reduces the MAC of sevoflurane.
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Methods
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After receiving the approval of our local ethics committee, the informed consent of each patient was obtained. Fifty-two ASA physical status I–II male and female patients, aged 24–56 yr, who were scheduled to undergo elective abdominal surgery were included in the study. Patients with a history of cardiac, pulmonary, or renal disease; a history of esophageal reflux or hiatal hernia; drug or alcohol abuse; significant obesity; or with a contraindication for the induction of anesthesia via a mask were excluded from the study. The patients were asked to fast for at least 8 h before the oral premedication.
Sedation before anesthesia induction was scored according to the scale described by Kulka et al. (7): 0, patient is awake; 1, patient is sedated, but awake; 2, patient is asleep but reacts immediately to verbal commands; 3, patient is asleep, and reaction to verbal commands is delayed; and 4, patient is asleep and does not react to verbal commands. The observation of sedation scores was conducted by a blinded observer.
The patients were randomly allocated into two groups by use of computer-generated numbers: a Control group and a Tizanidine group. The anesthesiologist was blinded to the study group. The Control group received a placebo 70 min before the induction of anesthesia, whereas the Tizanidine group received 4 mg of tizanidine in 50 mL of water 70 min before the induction of anesthesia. Anesthesia was induced in all patients by using vital capacity rapid inhaled induction with sevoflurane (8,9). The vital capacity rapid inhaled induction method was performed as follows: first, the patients were preoxygenated with 100% oxygen at a flow rate of 8 L/min for 5 min by using a mask and a Jackson-Rees breathing circuit. Induction was started with a full 4-L reservoir bag to allow for inspiration of a full vital-capacity breath. A mixture of 5% sevoflurane and oxygen was delivered by a vaporizer (Sevotec 5; Ohmeda USA, Madison, WI) into the circle system of an anesthesia machine (Modulus CD; Ohmeda USA). The pop-off valve was kept open at all times. Respiratory gases were sampled with a multigas monitor (BP-508; Kolin Corp., Komaki, Japan). After preoxygenation, the patients were instructed to breathe out to residual volume and hold their breath at residual volume while the circuit was replaced with the preprimed circle system. They were then instructed to take a vital-capacity breath and attempt to hold this breath as long as possible, preferably until loss of consciousness ensued. After the initial vital-capacity breathing, patients were allowed to resume spontaneous respiration. Loss of consciousness was defined as both the loss of the eyelid reflex and a lack of response to the verbal command, "Open your eyes." The time until loss of consciousness was recorded. Succinylcholine (1.5 mg/kg) was given IV to facilitate oral endotracheal intubation. Mechanical ventilation was performed with a tidal volume of 10–12 mL/kg to maintain an end-tidal carbon dioxide concentration of 30 to 39 mm Hg. The end-tidal sevoflurane concentration was held at a predetermined concentration for at least 15 min before the MAC measurement was performed. The end-tidal concentrations of sevoflurane were measured from the distal end of the tracheal tube by using a cannula that had been inserted through the elbow of the circuit so that its tip was within 1 cm of the tip of the tracheal tube. Uncommon reactions, such as a Phase II block or prolonged blockade of succinylcholine, were documented by single-twitch peripheral nerve stimulation with a peripheral nerve stimulator.
MAC was determined by a technique adapted from the conventional up-down method (10). A skin incision was made as a noxious stimulus 90 min after the oral administration of tizanidine. Each patient was observed for gross purposeful movement after the skin incision. One point of sevoflurane concentration measurement was obtained from each patient. A single observer (T.S.), blinded to the sevoflurane concentration, judged all responses. The initial sevoflurane concentration used in both groups was 1.8%, and the sevoflurane concentration was changed on the basis of the patient’s response to the noxious stimulus. If the response of the previous patient was positive, the target concentration for the next patient was 0.2% larger; if the response was negative, the next concentration was 0.2% smaller. A requirement for beginning data collection in a group was an initial paired response of movement/no movement or vice versa. Eight MAC values were obtained by calculating the mid- point concentration of all independent pairs of stimuli involving a crossover, i.e., movement/no movement.
Values are expressed as the mean ± SD, except for the sedation scores. An unpaired Student’s t-test was used to determine whether there was a significant difference (P < 0.05) between the two groups with regard to age, weight, height, MAC, or the time to loss of consciousness. A  2 test was used to compare the sedation scores. P values of <0.05 were required to reject the null hypothesis.
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Results
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To obtain 8 crossover responses, 26 patients were required for both groups. No significant differences in demographic characteristics were observed between the two groups (Table 1). None of the patients were excluded from the study.
Twenty-four patients in the Control group had a sedation score of 0, and two patients had a score of 1. In the Tizanidine group, 15 patients had a sedation score of 0, and 11 patients had a score of 1. The difference between the groups was highly significant (P < 0.001).
The MAC of sevoflurane was 2.2% ± 0.2% in the Control group (Fig. 1) and 1.8% ± 0.2% in the Tizanidine group (Fig. 2). The difference between the two groups was statistically significant (P = 0.0004).
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Figure 1. Consecutive target sevoflurane concentration in the Control group for minimum alveolar anesthetic concentration determination. |b = Sevoflurane concentration of individual patients; • = mean sevoflurane concentration of crossover (movement/no movement) responses. The mean of crossover represents the approximate concentration at which 50% of patients showed a positive (+) response: 2.2% ± 0.2% (mean ± SD).
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Figure 2. Consecutive target sevoflurane concentration in the Tizanidine group for minimum alveolar anesthetic concentration determination. |b = Sevoflurane concentration of individual patients; • = mean sevoflurane concentration of crossover (movement/no movement) responses. The mean of crossover represents the approximate concentration at which 50% of patients showed a positive (+) response: 1.8% ± 0.2% (mean ± SD). This was significantly smaller than that in the Control group (P = 0.0004).
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The time to loss of consciousness for the Tizanidine group was 60.2 ± 22.5 s, whereas that for the Control group was 73.7 ± 26.3 s. The difference between the two groups was statistically significant (P = 0.03). No tizanidine-related adverse effects were observed throughout the study.
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Discussion
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Our results demonstrate that the MAC of sevoflurane is reduced by oral premedication of tizanidine. Clonidine, another 2 agonist, reduces the MAC of sevoflurane in adults (11) and children (12) and reduces the induction time of sevoflurane in adults (11) by 34%–47%. Premedication with dexmedetomidine, a more selective 2 agonist than clonidine, reduces the MAC of isoflurane in adults by 47% (13) and reduces the MAC of sevoflurane in adults between the ages of 55 and 70 years by 17% (14). In our study, the oral administration of tizanidine 4 mg decreased the MAC of sevoflurane by 18% in human adults. The limitation of this study is that we did not perform a dose-response study. However, if the dose of the 2 agonist premedication is increased, the MAC of volatile anesthetics generally decreases (13,14). Therefore, we speculate that larger doses of tizanidine may further decrease the MAC of volatile anesthetics, and single doses of up to 20 mg of tizanidine can be orally administered to human adults (15).
Tizanidine is rapidly absorbed after oral administration, reaching a maximum plasma concentration in 0.75 to 2 hours in most studies (15–20), and the elimination half-life of tizanidine in healthy volunteers and patients with multiple sclerosis or spinal cord injuries ranges from 2.1 to 4.2 hours (15,17,19,20). Therefore, we gave 4 mg of tizanidine to the Tizanidine group 70 minutes before the induction of anesthesia, and a skin incision was given as a noxious stimulus 90 minutes after the oral administration of tizanidine.
The time to loss of consciousness in the Tizanidine group was significantly shorter than in the Control group, suggesting that it has a hypnotic effect. The sedation score was higher in the Tizanidine group than in the Control group, also demonstrating the hypnotic effect of oral tizanidine.
A dose-dependent antinociceptive effect of tizanidine has been observed in various animal models (1–3). This effect seems to be mediated via 2 adrenoceptors, rather than opioid receptors (3,21,22), and may involve inhibition of the release of aspartic and glutamic acids (22) or substance P (21) (a putative transmitter in primary afferent fibers that relays information about noxious stimuli to the central nervous system) (23). The primary site of antinociceptive activity seems to be at the spinal level (2,3).
In summary, the oral administration of 4 mg of tizanidine successfully reduced the MAC of sevoflurane by 18% in human adults. No tizanidine-related adverse effects, such as hypotension (which sometimes occurs when clonidine is used), were observed throughout the study. Therefore, we believe that tizanidine can be a safer and cost-effective alternative anesthesia premedication.
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Accepted for publication April 9, 2002.
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Abstract
Introduction
