WO2011074695A1

WO2011074695A1 - Shivering suppressor

Info

Publication number: WO2011074695A1
Application number: PCT/JP2010/072937
Authority: WO
Inventors: 万三鈴木
Original assignee: Suzuki Manzo
Priority date: 2009-12-18
Filing date: 2010-12-20
Publication date: 2011-06-23
Also published as: JPWO2011074695A1

Abstract

A shivering suppressor which is capable of suppressing shivering occurring after dosing with an anesthetic, said anesthetic being remifentanil or a pharmaceutically acceptable salt thereof, and said shivering suppressor comprising naloxone or a pharmaceutically acceptable salt thereof as the active ingredient; and an anesthetic comprising, as the active ingredients, remifentanil or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof.

Description

Shivering inhibitor

The present invention relates to a shivering inhibitor.

Narcotic drugs are widely used for analgesia during surgery, postoperative analgesia, and management of cancer pain. Synthetic narcotics such as fentanyl, in addition to opium alkaloids represented by morphine, have recently been used.

However, when administered in large quantities, respiratory depression over a long period of time has been a problem. Remifentanil (ultiva TM, Janssen Pharma) is a synthetic narcotic that significantly shortens the action time and enables rapid awakening from anesthesia. It was remifentanil that anesthesiologists had been waiting for, but as a problem that I actually used, I found that tremors called shivering occur quite frequently in about 2 hours after waking up from anesthesia. I came.

Shivering is an involuntary shake that is generally performed by the body to raise the body temperature due to a decrease in body temperature (precisely, central temperature). As a technique related to a general shivering inhibitor, for example, in order to suppress shivering that occurs when reducing human body temperature, a shivering inhibitor such as an opioid analgesic such as meperidine or alfentanil, and its effect are enhanced. Therefore, it is known to use an antiemetic together (for example, WO2004 / 041171).

However, Med Sci Monit. 2006 Nov; 12 (11): CR452-6 (Rohm KD, Riechmann J, Boldt J, Suttner SW, Piper SN., "Total intravenous anesthesia with propofol and remifentanil is associated with a nearly twofold higher incidence According to "in postanesthetic shivering than desflurane-fentanyl anesthesia.") After anesthesia with remifentanil, about 50% of patients suffer from shivering even if the body temperature is controlled with a warming device. Therefore, it is considered that shivering after anesthesia with remifentanil is not due to a decrease in body temperature, and the cause of shivering after remifentanil has not yet been elucidated.
Currently, opioid analgesics such as meperidine are used to suppress shivering, but opioid analgesics also have an effect of suppressing airway reflexes. For this reason, when an opioid type analgesic is used after an operation in the oral cavity or the like, there is a concern that the possibility of occurrence of aspiration increases.

Therefore, if the shivering after anesthesia with remifentanil can be reduced, the QOL (quality of life) of the patient can be improved. Therefore, a method and a drug for reducing shivering have been demanded.

The problem to be solved is to provide a shivering inhibitor, an anesthetic and kit, and a shivering suppression method that suppresses the occurrence of strong shivering when waking up from anesthesia with remifentanil or within 2 hours after waking up It is to be.

Each aspect of the present invention provides the following shivering inhibitor, anesthetic agent, kit and shivering inhibitor method, respectively.
[1] A shivering inhibitor that suppresses shivering that occurs after administration of an anesthetic agent, wherein the anesthetic agent is remifentanil or a pharmaceutically acceptable salt thereof, and naloxone or a pharmaceutically acceptable salt thereof is effective. The said shivering inhibitor used as a component.
[2] The shivering inhibitor according to [1], wherein naloxone or a pharmaceutically acceptable salt thereof is administered at a rate of 0.2 μg / kg / hr to 4 μg / kg / hr immediately after administration of the anesthetic agent and from awakening. .
[3] The shivering inhibitor according to [1] or [2], which is administered in combination with remifentanil or a pharmaceutically acceptable salt thereof as the anesthetic agent.
[4] An anesthetic comprising remifentanil or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof as active ingredients.
[5] A kit for anesthesia and suppression of side effects thereof, comprising a compartment containing remifentanil or a pharmaceutically acceptable salt thereof, and a compartment containing naloxone or a pharmaceutically acceptable salt thereof. .
[6] A method for suppressing shivering that occurs after administration of an anesthetic, comprising administering remifentanil or a pharmaceutically acceptable salt thereof as the anesthetic, and administering the shivering inhibitor according to [1]. The said shivering suppression method including doing.
[7] The shivering according to [6], comprising administering naloxone or a pharmaceutically acceptable salt thereof at a rate of 0.2 μg / kg / hr to 4 μg / kg / hr immediately after administration of the anesthetic agent and from awakening. Suppression method.

FIG. 1 is a graph showing suppression of shivering by administration of naloxone according to an example. FIG. 2 is a graph showing a decrease in the degree of shivering by administration of naloxone according to the example.

The shivering inhibitor of the present invention is a shivering inhibitor that suppresses shivering that occurs after administration of an anesthetic, wherein the anesthetic is remifentanil or a pharmaceutically acceptable salt thereof, and naloxone or a pharmaceutically acceptable salt thereof. Salt as an active ingredient.

According to the present invention, the combined use of remifentanil and naloxone significantly suppresses shivering after anesthesia with remifentanil. The suppression effect of naloxone on shivering is not constrained by any specific theory, but shivering is a withdrawal phenomenon when opioids begin to diverge from the narcotic receptors (opioid receptors), and low-concentration opioids act at the last minute. It is assumed that postoperative shivering is suppressed by blocking the receptor that should be present with an opioid antagonist in advance.
Therefore, the need for warming during surgery is reduced, and remifentanil can be used safely in surgery such as neurosurgery and cardiac surgery, where warming during surgery is not recommended. Also, remifentanil can be used safely in oral surgery and the like in order to reduce the frequency of occurrence of shivering.

In this specification, the term “process” is not limited to an independent process, and is included in this term if the intended action of this process is achieved even when it cannot be clearly distinguished from other processes. .
In the present specification, a numerical range indicated by using “to” indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
Further, in this specification, the notation of “/ kg” with respect to the administration rate of the drug means “per kg of body weight of the administration subject”. For example, the notation of “/ kg / hr” is “1” It means “per hour, per kg body weight of administration subject”.
Further, in the present invention, when referring to the amount of each component in the composition, when there are a plurality of substances corresponding to each component in the composition, the plurality present in the composition unless otherwise specified. Means the total amount of substances.
The present invention will be described below.

<1> Shivering inhibitor The shivering inhibitor of the present invention is a shivering inhibitor that suppresses shivering that occurs after anesthetic administration, wherein the anesthetic is remifentanil or a pharmaceutically acceptable salt thereof, and Naloxone or a pharmaceutically acceptable salt thereof is an active ingredient. The present shivering inhibitor can suppress the occurrence of shivering when waking up from anesthesia with remifentanil or within 2 hours after waking up.

The “pharmaceutically acceptable salt” of naloxone means that it reacts with an acid when it has a basic group such as an amino group, and a base when it has an acidic group such as a carboxyl group. Can be converted into a salt by reacting with, so that salt is shown.

The salt based on the basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid. Inorganic acid salts such as salts and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salt, acetate salt, malate salt, fumarate salt, succinate salt, citrate salt, ascorbate salt, tartrate salt, succinate salt, maleate salt, etc .; and glycine salt, lysine salt, arginine Mention may be made of amino acid salts such as salts, ornithine salts, glutamates and aspartates. From the viewpoint of stability and the like, a hydrohalide salt or an inorganic acid salt is preferable, and a hydrochloride is more preferable.

On the other hand, the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, potassium salt or lithium salt, an alkaline earth metal salt such as a calcium salt or magnesium salt, an aluminum salt or an iron salt. Metal salt; inorganic salt such as ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, Triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethylanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) aminomethane Like salt And amine salts such as organic salts; and amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt and aspartate salt.

Examples of administration forms of naloxone include, but are not limited to, injection (intravenous, muscle, topical, etc.), oral administration, oral mucosal administration, intranasal administration, transdermal absorption, and the like. Of these, intravenous injection (including infusion) is particularly preferred. In the case of infusion, for example, naloxone hydrochloride is preferably administered in an amount of 0.2 μg / kg / hr to 4 μg / kg / hr between anesthesia and awakening, and 0.4 μg / kg / hr to 2 μg / hr. It is more preferable to administer in an amount of kg / hr.
“After anesthesia” means after the start of administration of the anesthetic, and “until awake” ends the administration of the anesthetic and stabilizes the patient's breathing or consciousness without the assistance of an anesthesiologist Means up to.

The shivering inhibitor according to the present invention is preferably administered in combination with remifentanil or a pharmaceutically acceptable salt thereof as an anesthetic agent.
As used herein, the term “combination” means administration under conditions that can exist simultaneously in the body of the administration subject, and if the conditions can exist in the body at the same time, they are administered simultaneously or separately at different times. May be. It is preferred that they are administered simultaneously as a mixed solution.

Remifentanil may be used alone or in the form of a pharmaceutically acceptable salt. The “pharmaceutically acceptable salts thereof” of remifentanil can include the same salts as described for naloxone. As a pharmaceutically acceptable salt of remifentanil, hydrochloride is preferable from the viewpoint of stability.
Examples of dosage forms of remifentanil include, but are not limited to, injection (intravenous, muscle, topical, etc.), oral administration, oral mucosal administration, intranasal administration, percutaneous absorption, and the like. Of these, intravenous injection (including infusion) is particularly preferred. In the case of infusion, remifentanil can generally be administered at 0.05 μg / kg / min to 2 μg / kg / min, more preferably 0.05 μg / kg / min to 1 μg / kg / min. Further, the shivering inhibitor and remifentanil may be administered by the same route or by different routes.

When combined with remifentanil or a pharmaceutically acceptable salt thereof, the mixing ratio of remifentanil or a pharmaceutically acceptable salt to naloxone or a pharmaceutically acceptable salt thereof (the ratio at the time of combination) is From the above viewpoint, the mass ratio of remifentanil or a pharmaceutically acceptable salt to naloxone or a pharmaceutically acceptable salt thereof (remifentanil: naloxone) is preferably 500: 1 to 1: 1. Moreover, at the time of combined use, the administration rate of remifentanil may not be constant and may be administered rapidly.

The shivering inhibitor of the present invention may be used in combination with another anesthetic other than remifentanil from the viewpoint of sedation. Examples of the anesthetic agent that can be used in this way include propofol, an inhalation anesthetic sevoflurane (sevoflurane TM, Abbott), and the like. The dosage of these other anesthetic agents that can be used in combination is appropriately selected according to the type of the other anesthetic used.

Each of the shivering inhibitor of the present invention, remifentanil or a pharmaceutically acceptable salt, and other anesthetics used in combination (in the present specification, each drug is collectively referred to as “pharmaceutical formulation”). May also be administered orally as the dosage form.
The pharmaceutical preparation of the present invention can be used as a preparation capable of oral administration such as tablets, capsules, pills, granules or fine granules, but is preferably a tablet.

The pharmaceutical preparation may contain pharmaceutically acceptable additives as appropriate. Such additives include, for example, excipients (eg sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; corn starch, potato starch, pregelatinized starch, dextrin, carboxymethyl starch, carboxymethyl starch sodium Starch derivatives such as: pregelatinized starch; cellulose such as crystalline cellulose, methylcellulose, hydroxypropylcellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carmellose, carmellose calcium, croscarmellose, croscarmellose sodium Derivatives; gum arabic; dextran; pullulan; light anhydrous silicic acid, calcium silicate, silicate hydrate, synthetic aluminum silicate, metasilicate aluminate Silicate derivatives such as gnesium; phosphate derivatives such as dicalcium phosphate; chloride derivatives such as sodium chloride; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate; ), Binders (eg, compounds exemplified in the above excipients; gelatin; polyvinylpyrrolidone; macrogol; or mixtures thereof), disintegrants (eg, compounds exemplified in the above excipients; cross-linked polyvinyl Pyrrolidone; or mixtures thereof), lubricants (eg, stearic acid; metal stearates such as calcium stearate and magnesium stearate; metal benzoates such as sodium benzoate; waxes such as bee gum and gay wax) Boric acid; glycol; carboxylic acids such as fumaric acid and adipic acid; sodium sulfate Metal sulfates such as thorium; leucine; metal lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicate derivatives exemplified by the above excipients; starch derivatives exemplified by the above excipients; hydrogen Carnauba wax; sucrose fatty acid esters; or mixtures thereof), stabilizers (eg, benzoic acid; benzoic acid metal salts such as sodium benzoate; paraoxybenzoic acid esters such as methylparaben and propylparaben; chlorobutanol; Alcohols such as benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid; or a mixture thereof], fluidizing agents (for example, the above-mentioned shaping) Silicate derivatives exemplified by the agent; Or mixtures thereof), surfactants (eg, polysorbates such as polysorbate 80; polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 60; sorbitan fatty acid esters; sucrose fatty acid esters; poly; Oxyethylene polyoxypropylene glycols; polyoxyethylene fatty acid ethers; stearic acid polyoxyls; or mixtures thereof, preferably polysorbate 80, polyoxyethylene hydrogenated castor oil 60 or mixtures thereof), colorants (eg, Yellow iron sesquioxide, iron sesquioxide, black iron oxide), antioxidants, flavoring agents (for example, commonly used sweeteners, acidulants, fragrances, etc.) or diluents. The type and amount of additives used will vary depending on the tablet, capsule or other dosage form drug, but will be selected by well-known techniques in the field of formulation.

For example, in the case of tablets, the content of the binder is generally 1 to 10 parts by weight (preferably 2 to 5 parts by weight) in the whole pharmaceutical preparation, and the content of the disintegrant is usually 1 to 40 parts by mass (preferably 5 to 30 parts by mass), and the content of lubricant is usually 0.1 to 10 parts by mass (preferably 0.5 to 3 parts by mass). The content of the fluidizing agent is 0.1 to 10 parts by mass (preferably 0.5 to 5 parts by mass).

The pharmaceutical preparation of the present invention is easily produced by known methods (for example, a kneading method using water, a wet granulation method, etc.) using pharmaceutically acceptable additives. Examples of such production include, for example, the addition of active ingredients, stabilizers, excipients, binders, disintegrants and other types of auxiliaries as required, and mixing with a high speed agitation granulator. Then, an aqueous solution of a binder is added to the obtained mixture and kneaded to obtain a granulated product. The obtained granulated product is dried using a fluidized bed dryer, and the dried granulated product is forcibly passed through a screen using a crushing granulator and granulating agent. If necessary, other types of auxiliaries and the like may be added and mixed in a V-type mixer, and the resulting mixture may be tableted or filled into capsules to produce tablets or capsules, respectively. it can.

The obtained tablets can be sugar-coated or coated (preferably, coated) as necessary. For example, by spraying the obtained tablet with a coating solution consisting of hydroxypropylmethylcellulose, talc, titanium oxide, lactose, triacetin or polyethylene glycol, yellow iron or iron dioxide, and water in a pan coating machine. Film coating can be applied.

Moreover, after mixing with the above-mentioned high-speed agitation granulator, adding the aqueous solution of the binder and kneading, the kneaded product is granulated using an extrusion granulator, and then with a fence-type dryer Granules can be produced by forcing the dried granules to pass through a screen using a crushing and granulating machine.

The dosage and administration ratio of each pharmaceutical preparation used in the present invention can vary greatly depending on various conditions such as the activity of individual substances, patient symptoms, age, weight and the like.

The amount of naloxone or a pharmaceutically acceptable salt thereof contained in the shivering inhibitor is not particularly limited and is appropriately selected in a wide range, but is usually 1 to 70% by mass, preferably in the total mass of the shivering inhibitor. Is suitably contained in an amount of 1 to 40% by mass.

The dose varies depending on symptoms, age, body weight, dosage form, etc., but is usually 1 day for an adult (weight 50 kg), and the lower limit is 0.001 mg (preferably 0.01 mg, more preferably 0.1 mg). The upper limit of 1.0 mg (preferably 0.5 mg, more preferably 0.4 mg) can be administered.

In the present invention, naloxone or a pharmaceutically acceptable salt thereof, or remifentanil or a pharmaceutically acceptable salt thereof, each of the above doses is divided once or several times as necessary, Each is administered at the same time or separately at different times.

<2> Anesthetic Agent The anesthetic agent of the present invention comprises remifentanil or a pharmaceutically acceptable salt and naloxone or a pharmaceutically acceptable salt thereof as active ingredients. Since this anesthetic contains naloxone or a pharmaceutically acceptable salt thereof together with remifentanil, which is an active ingredient as an anesthetic, or a pharmaceutically acceptable salt, remifentanil and naloxone can be conveniently administered by one administration. Can be used together. Thereby, generation | occurrence | production of shivering can be reduced and the anesthetic effect by remifentanil can be expected without accompanying shivering.

The present anesthetic agent may be in a form in which remifentanil or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof can be administered simultaneously, and one drug is preceded in the body before the other drug. The anesthetic may be configured as an operable form, for example, a sustained release form. Examples of such forms include transdermal drugs.
In this anesthetic, details of remifentanil or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof, a form as a drug, and the like are the same as those described for the above-mentioned shivering inhibitor.
In the present anesthetic agent, the mixing ratio of remifentanil or a pharmaceutically acceptable salt and naloxone or a pharmaceutically acceptable salt thereof is not particularly limited as long as it is within the above dose range. From the viewpoint of pharmacodynamics, the mass ratio of remifentanil or a pharmaceutically acceptable salt to naloxone or a pharmaceutically acceptable salt thereof is preferably 100: 1 to 10: 1 (remifentanil: naloxone). .

<3> Kit The kit of the present invention is a kit for suppressing anesthesia and its side effects, a compartment containing remifentanil or a pharmaceutically acceptable salt thereof, and a compartment containing naloxone or a pharmaceutically acceptable salt thereof. And including.
According to this kit, the shivering resulting from remifentanil can be conveniently suppressed.
The “compartment” in this kit is not particularly limited as long as it is an effective form because each drug exists independently without mixing, and may be, for example, a container or an individual packaging form. It may be in the form of a sheet-like area that is independently divided.
The kit may also contain instructions describing the method of anesthesia with remifentanil or a pharmaceutically acceptable salt, and the method of using naloxone or a pharmaceutically acceptable salt used in combination therewith. .

The dosage, dosage form, and mode of combined use of the shivering inhibitor and remifentanil or a pharmaceutically acceptable salt thereof in the kit of the present invention are the same as those described with respect to the shivering inhibitor.

<4> Shivering suppression method The present invention also includes a shivering suppression method.
The method for inhibiting shivering of the present invention is a method for inhibiting shivering that occurs after administration of an anesthetic agent, wherein remifentanil or a pharmaceutically acceptable salt thereof is administered as the anesthetic agent (hereinafter referred to as “remifentanil administration”). Step)), administration of naloxone or a pharmaceutically acceptable salt thereof (hereinafter referred to as “naloxone administration step”).
Thereby, shivering resulting from remifentanil or a pharmaceutically acceptable salt can be effectively suppressed.
In the method of inhibiting shivering, as described above, naloxone or a pharmaceutically acceptable salt thereof is administered at a rate of 0.2 μg / kg / hr to 4 μg / kg / hr immediately after administration of the anesthetic agent and from awakening. It is preferable to include it in order to surely suppress shivering.

The dosage and administration form of each active ingredient in the method for inhibiting shivering of the present invention, the mode at the time of combined use, and the like are the same as those described for the shivering inhibitor and anesthetic agent.
Note that either the remifentanil administration step and the naloxone administration step may be performed first or simultaneously.

Hereinafter, examples of the present invention will be described, but the present invention is not limited thereto. Further,% in the examples is based on weight (mass) unless otherwise specified.

Obtained approval from the Ethics Committee. Forty-six gynecological laparotomy patients who were approved by the patient were included. Patients were randomly divided into a subject group (n = 25) and a naloxone administration group (n = 21). Saline was administered to the subject group, and naloxone hydrochloride 0.4 μg / kg / hr was administered to the naloxone administration group from immediately after induction of anesthesia to awakening. This dose corresponds to about one-tenth or less of the dose when naloxone hydrochloride is administered for the purpose of antagonism from arousal delay by narcotics.

Anesthesia Method The anesthesia method mainly consisted of total intravenous anesthesia using remifentanil (0.25 μg / kg / min) and propofol (3 μg / ml: predicted blood concentration) (dipribanTM, AstraZeneca). In consideration of postoperative analgesia 2 hours after the operation, epidural anesthesia was used in combination. The administration rate of remifentanil and propofol was adjusted based on the blood pressure or pulse of the patient. In both groups, body temperature was controlled with a warm air heating device with the target of an eardrum temperature of 36 ° C or higher.

Measurement items After the introduction of anesthesia, changes in blood pressure pulse due to tracheal intubation and surgical stimulation, presence or absence of shivering up to 3 hours after awakening from anesthesia, (A) no shivering, (B) minor but with shivering However, it is partial shivering in the muscles and does not require special treatment such as heating. (C) It is severe shivering, for example, treatment such as warming is necessary for shivering close to systemic convulsions. Each level of shivering was evaluated. Statistically, the chi-square test was used.

Results There was no significant difference in the patient's background, and there was no significant difference in changes in blood pressure, pulse, etc. even with intubation and surgical stimulation. Within 30 minutes of awakening, there was no significant difference in the frequency of shivering, but in the subject group, 15 out of 25 patients experienced shivering from 30 minutes to 1 hour, and 21 in the naloxone administration group. Of these, shivering occurred in 6 persons (see FIG. 1). There was also a significant difference in the degree of shivering. For 6 patients with shivering in the naloxone administration group, there are 4 (B) and 2 (C), and among the 15 patients in the target group, (B) 3 and (C) 12 (See FIG. 2).
Therefore, the administration of naloxone significantly reduced the occurrence of shivering by remifentanil.

Remifentanil or a pharmaceutically acceptable salt thereof, a shivering inhibitor containing naloxone or a pharmaceutically acceptable salt thereof as an active ingredient, naloxone or a pharmaceutically acceptable salt thereof, and remifentanil or a pharmaceutically acceptable salt thereof By using an anesthetic containing a salt and a kit, shivering that occurs at the time of waking after anesthesia with remifentanil or within 2 hours after waking up can be suppressed.

The disclosure of Japanese Patent Application No. 2009-288524 filed on Dec. 18, 2009 is incorporated herein by reference in its entirety.
All documents, patent applications, and technical standards mentioned in this specification are to the same extent as if each individual document, patent application, and technical standard were specifically and individually stated to be incorporated by reference, Incorporated herein by reference.

Claims

A shivering inhibitor that suppresses shivering that occurs after anesthetic administration,
The anesthetic is remifentanil or a pharmaceutically acceptable salt thereof; and
The said shivering inhibitor which uses naloxone or its pharmaceutically acceptable salt as an active ingredient.
2. The shivering inhibitor according to claim 1, wherein naloxone or a pharmaceutically acceptable salt thereof is administered at a rate of 0.2 μg / kg / hr to 4 μg / kg / hr immediately after administration of the anesthetic agent and from awakening.
The shivering inhibitor according to claim 1 or 2, which is administered in combination with remifentanil or a pharmaceutically acceptable salt thereof as the anesthetic agent.
An anesthetic comprising remifentanil or a pharmaceutically acceptable salt thereof and naloxone or a pharmaceutically acceptable salt thereof as active ingredients.
A kit for anesthesia and its side effects suppression,
A compartment comprising remifentanil or a pharmaceutically acceptable salt thereof;
A compartment comprising naloxone or a pharmaceutically acceptable salt thereof;
The kit.
A method for suppressing shivering that suppresses shivering that occurs after administration of an anesthetic,
Administering as an anesthetic agent remifentanil or a pharmaceutically acceptable salt thereof;
Administering the shivering inhibitor of claim 1;
The said shivering suppression method containing.
The method of inhibiting shivering according to claim 6, comprising administering naloxone or a pharmaceutically acceptable salt thereof immediately after the administration of the anesthetic agent to awakening at a rate of 0.2 μg / kg / hr to 4 μg / kg / hr.