Opioid-free compositions for anesthesia applications and related methods and systems

Abstract

Opioid-free compositions, methods and systems are described.The compositions include magnesium salts, alpha-2 agonists, sodium channel inhibitors, and optionally NMDA antagonists, beta blockers, and / or corticosteroids, together with pharmaceutically acceptable vehicles, carriers, or excipients.The compositions are suitable for pre- and intraoperative methods for patients undergoing medical or surgical procedures.

Description

[Technical field]

[0001] 1. Field This disclosure relates to anesthesiology. [Background technology]

[0002] 2.Background Opioids are typically the drugs of first choice for anesthesia given their known effectiveness and versatility in the practice of anesthesia and pain management.

[0003] However, opioid administration is associated with several side effects that can lead to significant morbidity and mortality, as well as additional costs of postoperative care.

[0004] Despite advances in anesthesiology, identifying drugs that provide effective anesthesia while simultaneously minimizing the side effects and complications associated with opioid administration remains a challenge. Summary of the Invention [Problem to be solved by the invention]

[0005] 3. Disclosure Summary Provided herein are, in some embodiments, opioid-free compositions having anesthetic properties for anesthetic applications, and related methods and systems, that allow for the delivery of effective anesthesia to an individual while simultaneously reducing the side effects and complications associated with opioid administration. [Means for solving the problem]

[0006] According to a first aspect, an opioid-free pre-operative pharmaceutical composition is described. The opioid-free pre-operative pharmaceutical composition comprises: Magnesium (Mg 2+ ) salts, such as magnesium sulfate, alpha-2 agonists, such as dexmedetomidine, and, where appropriate, Sodium channel blockers, such as lidocaine, and / or N-methyl-D-aspartate receptor (NMDA) inhibitors, such as ketamine, and / or Corticosteroids, such as dexamethasone Includes. In some embodiments, the composition further comprises a pharma- ceutically acceptable vehicle, carrier, or excipient. In the opioid-free pre-operative composition, the magnesium salt, alpha-2 agonist, and optionally the sodium channel inhibitor, NMDA antagonist, and / or corticosteroid are present in an amount effective to treat anxiety and / or induce sedation and / or analgesia in an individual during the pre-operative phase of a medical or surgical procedure, particularly when used in conjunction with the pre-operative methods of the present disclosure.

[0007] According to a second aspect, there is provided a method describing opioid-free pre-operative treatment of an individual undergoing a medical or surgical procedure, comprising: An effective amount Magnesium salts, such as magnesium sulfate, in amounts ranging from 5 to 50 mg / kg IBW; an alpha-2 agonist, such as dexmedetomidine, in an amount ranging from 0.1 to 1 mcg / kg IBW, and optionally a sodium channel blocker, such as lidocaine, in an amount ranging from 0.1 to 2 mg / kg IBW, and / or Corticosteroids, such as dexamethasone, in amounts ranging from 0.01 to 0.2 mg / kg IBW, and / or NMDA antagonists other than Mg, such as ketamine, in amounts ranging from 0 to 0.5 mg / kg IBW to the individual, A magnesium salt, an alpha-2 agonist, and optionally a sodium channel inhibitor, a corticosteroid, and an NMDA are administered to an individual in a combination in amounts effective to treat anxiety and / or to induce sedation and / or analgesia in the individual during the pre-operative phase of a medical or surgical procedure. This is the method.

[0008] In various embodiments, the administering step comprises administering to the individual a pre-surgical composition of the present disclosure, hi various embodiments, the administering step comprises the substep of combining a magnesium salt, an alpha-2 agonist, and optionally a sodium channel blocker, an NMDA antagonist other than a magnesium salt, and / or a corticosteroid to prepare a pre-surgical composition.

[0009] According to a third aspect, an opioid-free pre-operative system is described for opioid-free pre-operative treatment of an individual. The opioid-free pre-operative system comprises: In the methods of opioid-free preoperative treatment described herein, there is included an amount effective for simultaneous, combined, or sequential use to induce anesthesia, sedation, and / or analgesia in an individual, Magnesium (Mg 2+ ) salts, for example magnesium sulfate, Alpha-2 agonists, e.g. dexmedetomidine, and, where appropriate, Sodium channel blockers, such as lidocaine, and / or NMDA antagonists other than magnesium salts, such as ketamine, and / or Corticosteroids, such as dexamethasone Includes.

[0010] According to a fourth aspect, an opioid-free intraoperative pharmaceutical composition is described. The opioid-free intraoperative pharmaceutical composition comprises: Magnesium salts, such as magnesium sulfate; alpha-2 agonists, such as dexmedetomidine; sodium channel inhibitors, such as lidocaine; and, where appropriate, N-methyl-D-aspartate receptor inhibitors, such as ketamine, and / or Beta blockers, e.g. esmolol Includes. In various embodiments, the composition further comprises a pharma- ceutically acceptable vehicle, carrier, or excipient. In the intraoperative composition, the magnesium salt, the alpha-2 agonist, the sodium channel inhibitor, and optionally the NMDA antagonist other than the magnesium salt, and the beta blocker are present in the composition in an amount effective to induce and / or maintain analgesia, anesthesia, and / or sedation, and to maintain hemodynamic stability in an individual during the intraoperative phase of a medical or surgical procedure.

[0011] According to a fifth aspect, there is provided a method describing opioid-free perioperative treatment of an individual undergoing a medical or surgical procedure, comprising: An effective amount Magnesium salts, such as magnesium sulfate, in amounts ranging from 1 to 20 mg / kg / hr of standard body weight (IBW); Alpha-2 agonists, such as dexmedetomidine, in amounts ranging from 0.01 to 1 mcg / kg / hr IBW; sodium channel blockers in amounts ranging from 0.1 to 3 mg / kg / hr IBW; and, where appropriate, beta blockers, such as esmolol, in amounts ranging from 3 to 300 mcg / kg / min or 3 to 20 mcg / kg / min IBW; and / or NMDA antagonists other than magnesium salts in doses ranging from 0 to 0.5 mg / kg / hr IBW to the individual.

[0012] The magnesium salts, alpha-2 agonists, and sodium channel inhibitors, and optionally beta blockers, and NMDA antagonists other than magnesium salts, are administered to an individual in amounts effective to induce and / or maintain analgesia, anesthesia and / or sedation, and to maintain hemodynamic stability in the individual during the perioperative phase of a medical or surgical procedure.

[0013] In various embodiments, the administering step comprises administering an opioid-free intraoperative composition of the present disclosure to an individual. In various embodiments, the administering step comprises combining a magnesium salt, an alpha-2 agonist, a sodium channel inhibitor, and optionally an N-methyl-D-aspartate receptor inhibitor, and / or a beta blocker to prepare an intraoperative composition. According to a sixth aspect, an opioid-free intraoperative system is described for opioid-free intraoperative treatment of an individual undergoing a medical or surgical procedure. The opioid-free intraoperative system comprises: Magnesium salts, such as magnesium sulfate, Alpha-2 agonists, such as dexmedetomidine, and Sodium channel blockers, such as lidocaine or procaine, and optionally An N-methyl-D-aspartate receptor inhibitor, such as ketamine, and / or a beta blocker, such as esmolol, are included in amounts effective for simultaneous, combined, or sequential administration to induce and / or maintain analgesia, anesthesia and / or sedation, and to maintain hemodynamic stability in an individual during the perioperative phase of a medical or surgical procedure in accordance with the methods of opioid-free perioperative treatment disclosed herein.

[0014] According to a seventh aspect, a method is described for opioid-free peri-operative treatment of an individual undergoing a medical or surgical procedure. The method comprises: administering to the individual an amount effective for opioid-free preoperative treatment according to any one of the methods described herein; and administering to the individual an amount effective for opioid-free perioperative treatment according to any one of the methods described herein; Includes.

[0015] In various embodiments, administering the opioid-free pre-operative treatment step comprises administering to the individual a pre-operative composition of the present disclosure. In various embodiments, administering the opioid-free pre-operative treatment step comprises the substep of preparing a pre-operative composition by combining a magnesium salt, an alpha-2 agonist, and optionally a sodium channel inhibitor, and / or an NMDA antagonist other than a magnesium salt, and / or a corticosteroid.

[0016] In various embodiments, administering an opioid-free perioperative treatment comprises administering to an individual an intraoperative composition of the present disclosure. In various embodiments, administering an opioid-free perioperative treatment comprises administering to an individual a substep of combining a magnesium salt, an alpha-2 agonist, a sodium channel inhibitor, and optionally an N-methyl-D-aspartate receptor inhibitor, and / or a beta blocker.

[0017] According to an eighth aspect, an opioid-free perioperative system is described for opioid-free perioperative treatment of an individual undergoing a medical or surgical procedure. The opioid-free perioperative system comprises: an opioid-free perioperative system as described herein; and The opioid-free intraoperative system described herein, in an amount effective for simultaneous, combined, or sequential administration to maintain anesthesia, sedation, analgesia, and / or stable vital signs in an individual, as well as to contribute to depth of anesthesia during surgery, in accordance with the methods of opioid-free perioperative treatment disclosed herein.

[0018] In various embodiments of the opioid-free perioperative system, the magnesium salt, alpha-2 agonist, and optionally the sodium channel inhibitor, and / or NMDA antagonist other than the magnesium salt, and / or corticosteroid of the opioid-free preoperative system are comprised in a composition configured to facilitate rapid and accurate dosing.

[0019] In various embodiments of the opioid-free perioperative system, the magnesium salt, alpha-2 agonist, sodium channel inhibitor, and optionally, N-methyl-D-aspartate receptor inhibitor, and / or beta blocker of the opioid-free intraoperative system are included in a composition configured to facilitate rapid and accurate dosing.

[0020] The opioid-free compositions, methods and systems described herein, in some embodiments, make it possible to eliminate or reduce the need for post-operative opioid consumption, thereby reducing exposure and risk of developing opioid use disorder.

[0021] The opioid-free compositions, methods and systems described herein, in some embodiments, allow for the prevention or reduction of pain associated with surgery. The opioid-free compositions, methods and systems described herein, in some embodiments, allow for the minimization of side effects associated with opioid administration, such as respiratory depression, nausea / vomiting, and constipation.

[0022] The opioid-free compositions, methods and systems described herein, in some embodiments, allow for minimizing the immunosuppression associated with opioid administration that impacts surgical outcomes, including increased risk of infection and potentially increased risk of metastasis in cancer populations (ncbi.nlm.nih.gov / pmc / articles / PMC5902248 / on the world wide web).

[0023] The opioid-free compositions, methods and systems described herein, in some embodiments, allow for the elimination of acute opioid-induced tolerance and hyperalgesia, which is further perpetuated by over-prescribing secondary to suboptimal post-operative pain control.

[0024] The opioid-free compositions, methods and systems described herein, in some embodiments, enable a significant reduction in morbidity, mortality and additional post-operative medical costs associated with opioid administration.

[0025] The opioid-free compositions, methods and systems described herein can be used in connection with various applications in which anesthesia or analgesic effects are desired.For example, the opioid-free compositions, methods and systems described herein can be used to treat individuals undergoing medical or surgical procedures.Additional exemplary applications include the use of the compositions described herein in several fields, including basic biology research, applied biology, bioengineering, medical research, therapeutics, and additional fields that can be ascertained by those skilled in the art upon reading this disclosure.

[0026] The details of one or more embodiments of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages will be apparent from the description and drawings, and from the claims.

[0027] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate one or more embodiments of the disclosure and, together with the detailed description and examples, serve to explain the principles and practice of the disclosure. [Brief description of the drawings]

[0028] [Figure 1] Figure 1 shows a schematic diagram illustrating the different stages of a medical or surgical procedure with opioid-free anesthesia, including operative time, anesthesia time and perioperative time. (Source: NM Elkassabany and ER Mariano, Anaesthesia 2019, 74, 560-563). [Diagram 2]Figure 2 shows a schematic diagram of an exemplary model of excitotoxic formation of dark neurons in the dorsal horn of the spinal cord by peripheral nerve injury or repeated morphine administration. (Adapted from Mayer, DJ, Mao, J., Holt, J., Price, DD Proc Natl Acad Sci US A. 1999 Jul 6; 6(14): 7731-7736). [Diagram 3] Figure 3 shows an overview of clinically used pharmacotherapeutic approaches leading to the attenuation of spinal pain amplifiers. These approaches include the use of clonidine and antidepressants, local anesthetics (LA) (e.g., intravenous (IV) lidocaine), ketamine, nonsteroidal anti-inflammatory drugs (NSAIDs), gabapentin and pregabalin. (Source: Deumens, Steyaert, Forget et al., Progress Neurobio. 2012). [Figure 4] FIG. 4 compares PACU opioid consumption and Aldrete scores for surgical patients receiving either opioid-free anesthesia (OFA) or non-opioid-free anesthesia (Non-OFA) of the present disclosure (see Example 16). [Diagram 5] Figure 5 shows the results of a retrospective analysis of 140 patients who underwent total knee replacement surgery at the hospital. Patients who received the OFA of the present disclosure and postoperative opioid-avoidance pain management experienced a 50 percent reduction in hospital length of stay (LOS) after surgery compared to traditional care. These patients were able to go home an average of 1.39 days sooner than patients who received traditional anesthesia services (see Example 17). [Figure 6] FIG. 6 illustrates the cost savings associated with the reduction in postoperative hospital stay described in FIG. [Figure 7]Figure 7 shows the cost of administering a typical "traditional" opioid-based anesthesia when a single vial is used for each patient ($single vial), and the cost when the vial is available for more than one patient ($dosage). Many hospitals only allow individual vials to be split into multiple doses under strict sterile conditions in the pharmacy. [Figure 8] FIG. 8 shows the cost of exemplary components in the opioid-free composition of the present disclosure, as well as additional medications that may be used in conjunction with the opioid-free composition. FIG. 8 shows the cost for the concentration and administration of the opioid-free composition when a single vial is used for each patient ($single vial), and the cost "$dosage" when the vial can be utilized for more than one patient. Many hospitals only allow individual vials to be split into multiple doses under strict sterile conditions in the pharmacy. [Figure 9] FIG. 9 shows "traditionally used" anesthesia medications in terms of unit cost and manufacturing concentration. [Figure 10] FIG. 10 shows an exemplary OFA composition of a Preemptive Analgesia Loading Dose Syringe described herein, where the composition includes lidocaine, Mg2+ salt, dexmedetomidine and dexamethasone. [Figure 11] FIG. 11 shows an alternative combination of an opioid-free anesthetic infusion solution in a 100 mL IV bag, where the composition includes lidocaine, Mg, dexmedetomidine, ketamine and esmolol-HCl. [Figure 12] 12 shows an image of the ankle after ankle fusion surgery. The ankle fusion procedure was performed using the opioid-free composition of the present disclosure. The patient experienced an uneventful postoperative course (see Example 18). [Figure 13] FIG. 13 shows images from anesthesia records showing minimal changes in vital signs (sympathetic response) during the post-operative period shown in FIG. 12 (see Example 18). [Figure 14] Figure 14A shows an image of the patient's severe ankle fracture before surgery. Figure 14B shows an image of the ankle after the fixation procedure. The ankle fixation surgery was performed using the opioid-free composition of the present disclosure and without administering a peripheral nerve block (see Example 19). The patient reported no pain in the recovery ward and did not require rescue opioids during this period. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] 5. Detailed Description The present invention includes the following. (1.) Magnesium salts (Mg 2+ ) salts, such as magnesium sulfate, and Alpha-2 agonists, such as dexmedetomidine, and optionally Sodium channel blockers, such as lidocaine, and / or N-methyl-D-aspartate receptor inhibitors, such as ketamine, and / or corticosteroids, such as dexamethasone together with a pharma- ceutically acceptable vehicle, carrier, or excipient, The magnesium salt, the alpha-2 agonist, and optionally a sodium channel inhibitor, and / or an NMDA antagonist, and / or a corticosteroid are included in an amount effective to treat anxiety and / or to induce sedation and / or analgesia in an individual during the pre-operative phase of a medical or surgical procedure. Opioid-free pre-operative pharmaceutical composition.

[0030] (2.) The opioid-free preoperative pharmaceutical composition described in (1.) above, wherein the alpha-2 agonist is selected from dexmedetomidine, clonidine, fadolmidine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, methyldopa, methylnorepinephrine, norepinephrine, (R)-3-nitrobiphenyline, amitraz, detomidine, lofexidine, and medetomidine, or any combination thereof.

[0031] (3.) The opioid-free preoperative pharmaceutical composition described in (1.) or (2.) above, wherein the alpha-2 agonist comprises dexmedetomidine.

[0032] (4.) The opioid-free preoperative pharmaceutical composition according to any one of (1.) to (3.) above, wherein the sodium channel inhibitor is selected from the group consisting of quinidine, ajmaline, procainamide, disopyramide, lidocaine, procaine, prilocaine, phenytoin, mexiletine, tocainide, encainide, flecainide, propafenone, and moricinzine, or any combination thereof.

[0033] (5.) The opioid-free preoperative pharmaceutical composition according to any one of (1.) to (4.) above, wherein the sodium channel inhibitor comprises lidocaine and / or procaine, or any combination thereof.

[0034] (6.) An opioid-free preoperative pharmaceutical composition according to any one of (1.) to (5.) above, wherein the sodium channel inhibitor comprises lidocaine.

[0035] (7.) The opioid-free preoperative pharmaceutical composition according to any one of (1.) to (6.) above, wherein the NMDA antagonist other than a magnesium salt is selected from the group consisting of ketamine, dextromethorphan (DXM), phencyclidine (PCP), and methoxetamine (MXE), or any combination thereof.

[0036] (8.) The opioid-free preoperative pharmaceutical composition according to any one of (1.) to (7.) above, wherein the NMDA antagonist other than a magnesium salt comprises ketamine.

[0037] (9.) The opioid-free preoperative pharmaceutical composition according to any one of (1.) to (8.) above, wherein the corticosteroid is selected from the group consisting of cortisone, hydrocortisone, fludrocortisone acetate, prednisolone, prednisone, methylprednisolone, triamcinolone, dexamethasone sodium phosphate (dexamethasone), betamethasone, triamcinolone acetonide, and fluorometholone, or any combination thereof.

[0038] (10.) The opioid-free preoperative pharmaceutical composition according to any one of (1.) to (9.) above, wherein the corticosteroid comprises dexamethasone sodium phosphate.

[0039] (11.) The alpha-2 agonist comprises dexmedetomidine; The sodium channel blocker comprises lidocaine or procaine, and the NMDA antagonist comprises ketamine; Beta blockers include esmolol, Corticosteroids include dexamethasone, An opioid-free preoperative pharmaceutical composition according to any one of (1.) to (10.) above.

[0040] (12.) The opioid-free preoperative pharmaceutical composition according to any one of (1.) to (11.) above, wherein the concentration of the magnesium salt is in the range of 1 mg / mL to 500 mg / mL.

[0041] (13.) The opioid-free preoperative pharmaceutical composition according to any one of (1.) to (12.) above, wherein the concentration of the magnesium salt is in the range of 1 mg / mL to 300 mg / mL.

[0042] (14.) An opioid-free preoperative pharmaceutical composition according to any one of (1.) to (13.) above, wherein the concentration of the alpha-2 agonist is in the range of 0.01 to 50 mcg / mL.

[0043] (15.) An opioid-free preoperative pharmaceutical composition according to any one of (1.) to (14.) above, wherein the concentration of the alpha-2 agonist is in the range of 0.1 to 50 mcg / mL.

[0044] (16.) An opioid-free preoperative pharmaceutical composition according to any one of (1.) to (15.) above, wherein the concentration of the alpha-2 agonist is in the range of 0.1 to 30 mcg / mL.

[0045] (17.) An opioid-free preoperative pharmaceutical composition according to any one of (1.) to (16.) above, wherein the concentration of the alpha-2 agonist is in the range of 0.1 to 1 mcg / mL.

[0046] (18.) An opioid-free preoperative pharmaceutical composition according to any one of (1.) to (17.) above, wherein the concentration of the sodium channel inhibitor is in the range of 0.1 mg / mL to 35 mg / mL.

[0047] (19.) An opioid-free preoperative pharmaceutical composition according to any one of (1.) to (18.) above, wherein the concentration of the sodium channel inhibitor is in the range of 1 mg / mL to 20 mg / mL.

[0048] (20.) The opioid-free preoperative pharmaceutical composition according to any one of (1.) to (19.) above, wherein the concentration of the NMDA antagonist other than a magnesium salt ranges from 0.01 mg / mL to 35 mg / mL.

[0049] (21.) The opioid-free pre-operative pharmaceutical composition according to any one of (1.) to (20.) above, wherein the concentration of the NMDA antagonist other than the magnesium salt is in the range of 0.1 mg / mL to 5.0 mg / mL. In some embodiments, the concentration of the NMDA antagonist other than the magnesium salt is in the range of 0.1 mg / mL to 0.5 mg / mL.

[0050] (22.) The opioid-free preoperative pharmaceutical composition according to any one of (1.) to (21.) above, wherein the concentration of the corticosteroid is in the range of 0.01 to 10 mg / mL.

[0051] (23.) The opioid-free perioperative (peri) pharmaceutical composition according to any one of (1.) to (22.) above, wherein the concentration of the corticosteroid is in the range of 1 to 2.0 mg / mL.

[0052] (24.) A method of opioid-free preoperative treatment of an individual undergoing a medical or surgical procedure, comprising: An effective amount Magnesium salts, such as magnesium sulfate, in amounts ranging from 5 to 50 mg / kg IBW; an alpha-2 agonist, such as dexmedetomidine, in an amount ranging from 0.1 to 1 mcg / kg IBW, and optionally Sodium channel blockers, such as lidocaine, in amounts ranging from 0.1 to 2 mg / kg IBW; Corticosteroids, such as dexamethasone, in amounts ranging from 0.01 to 0.2 mg / kg IBW, and / or NMDA antagonists other than Mg, such as ketamine, in amounts ranging from 0 to 0.5 mg / kg IBW to the individual, Effective amounts of a magnesium salt, an alpha-2 agonist, and optionally a sodium channel inhibitor, and / or a corticosteroid, and / or NMDA are administered in combination to an individual to treat anxiety and / or induce sedation and / or analgesia in the individual during the pre-operative phase of a medical or surgical procedure. method.

[0053] (25.) The method according to (24.) above, wherein the administration of the opioid-free preoperative treatment is carried out by administering to an individual a preoperative pharmaceutical composition according to any one of (1.) to (23.) above.

[0054] (26.) An opioid-free preoperative system for opioid-free preoperative treatment of an individual, comprising: Magnesium (Mg 2+ ) salts, such as magnesium sulfate, alpha-2 agonists, such as dexmedetomidine, and, where appropriate, Sodium channel blockers, such as lidocaine and / or procaine, NMDA antagonists other than magnesium salts, such as ketamine, and / or corticosteroids, such as dexamethasone in an amount effective for simultaneous, combined, or sequential use to treat anxiety and / or induce sedation and / or analgesia in an individual in the method of opioid-free preoperative treatment according to 24 or 25 above; Opioid-free preoperative system.

[0055] (27.) The system described in (26.) above, comprising a magnesium salt, an alpha-2 agonist, and optionally a sodium channel inhibitor, an NMDA antagonist other than a magnesium salt, and / or a corticosteroid, in formulations and dosages designed to be combined prior to administration to provide the pre-operative composition described herein.

[0056] (28.) Magnesium (Mg 2+) salts, such as magnesium sulfate, alpha-2 agonists, such as dexmedetomidine, Sodium channel blockers, such as lidocaine, and optionally N-methyl-D-aspartate receptor (NMDA) inhibitors, such as ketamine, and / or beta blockers, such as esmolol together with a pharma- ceutically acceptable vehicle, carrier, or excipient, wherein the magnesium salt, the alpha-2 agonist, the sodium channel inhibitor, and, optionally, an NMDA antagonist other than a magnesium salt, and a beta blocker are included in an amount effective to induce and / or maintain analgesia, anesthesia, and / or sedation, and to maintain hemodynamic stability in an individual during the perioperative phase of a medical or surgical procedure. Opioid-free intraoperative pharmaceutical composition.

[0057] (29.) The opioid-free intraoperative pharmaceutical composition according to (28.) above, wherein the alpha-2 agonist is selected from dexmedetomidine, clonidine, fadolmidine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, methyldopa, methylnorepinephrine, norepinephrine, (R)-3-nitrobiphenyline, amitraz, detomidine, lofexidine, and medetomidine, or any combination thereof.

[0058] (30.) Alpha-2 agonists include dexmedetomidine. An opioid-free intraoperative pharmaceutical composition according to (28.) or (29.) above.

[0059] (31.) The opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (30.) above, wherein the sodium channel inhibitor is selected from the group consisting of quinidine, ajmaline, procainamide, disopyramide, lidocaine, procaine, prilocaine, phenytoin, mexiletine, tocainide, encainide, flecainide, propafenone, and morisindine, or any combination thereof.

[0060] (32.) The opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (31.) above, wherein the sodium channel inhibitor comprises lidocaine, procaine, or any combination thereof.

[0061] (33.) An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (32.) above, wherein the sodium channel inhibitor comprises lidocaine.

[0062] (34.) The opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (33.) above, wherein the NMDA antagonist other than a magnesium salt is selected from the group consisting of ketamine, dextromethorphan (DXM), phencyclidine (PCP), and methoxetamine (MXE), or any combination thereof.

[0063] (35.) An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (34.) above, wherein the NMDA antagonist other than a magnesium salt comprises ketamine.

[0064] (36.) Alpha-2 agonists include dexmedetomidine; The magnesium includes magnesium sulfate, the sodium channel blocker comprises lidocaine or procaine, the NMDA antagonist comprises ketamine; The beta blocker is, for example, esmolol. An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (35.) above.

[0065] (37.) An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (36.) above, wherein the concentration of the magnesium salt is in the range of 1 mg / mL to 500 mg / mL.

[0066] (38.) An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (37.) above, wherein the concentration of the magnesium salt is in the range of 1 mg / mL to 370 mg / mL.

[0067] (39.) An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (38.) above, wherein the concentration of the alpha-2 agonist is in the range of 0.01 to 30 mcg / mL.

[0068] (40.) An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (38.) above, wherein the concentration of the alpha-2 agonist is in the range of 0.1 to 30 mcg / mL.

[0069] (41.) An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (38.) above, wherein the concentration of the alpha-2 agonist is in the range of 0.1 to 1 mcg / mL.

[0070] (42.) An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (41.) above, wherein the concentration of the sodium channel inhibitor is in the range of 0.1 mg / mL to 35 mg / mL.

[0071] (43.) An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (41.) above, wherein the concentration of the sodium channel inhibitor is in the range of 1 mg / mL to 3 mg / mL.

[0072] (44.) The opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (43.) above, wherein the concentration of the NMDA antagonist other than a magnesium salt ranges from 0.01 mg / mL to 20 mg / mL.

[0073] (45.) An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (43.) above, wherein the concentration of the NMDA antagonist other than a magnesium salt is from 0.1 mg / mL to mg / mL.

[0074] (46.) The opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (45.) above, wherein the beta blocker is selected from the group consisting of carvedilol, propranolol, esmolol, timolol, metoprolol, labetalol, atenolol, bisoprolol, and nebivolol, or any combination thereof.

[0075] (47.) An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (46.) above, wherein the beta blocker comprises esmolol.

[0076] (48.) An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (47.) above, wherein the concentration of the beta blocker is in the range of 0.001 mg / mL to 20 mg / mL.

[0077] (49.) An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (47.) above, wherein the concentration of the beta blocker is in the range of 0.01 mg / mL to 1.2 mg / mL.

[0078] (50.) An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (47.) above, wherein the concentration of the beta blocker is in the range of 0.05 mg / mL to 0.18 mg / mL.

[0079] (51.) A method of opioid-free perioperative treatment of an individual undergoing a medical or surgical procedure, comprising: An effective amount Magnesium salts, such as magnesium sulfate, in amounts ranging from 1 mg / kg / hr to 20 mg / kg / hr of standard body weight (IBW); an alpha-2 agonist, such as dexmedetomidine, in an amount ranging from 0.01 to 1 mcg / kg / hr IBW; a sodium channel blocker, such as lidocaine, in an amount ranging from 0.1 to 3 mg / kg / hr IBW; and, where appropriate, beta blockers, such as esmolol, in amounts ranging from 3 to 300 mcg / kg / min or 3 to 20 mcg / kg / min IBW; and / or NMDA antagonists other than magnesium salts, such as ketamine, in amounts ranging from 0 to 0.5 mg / kg / hr IBW to the individual, Effective amounts of a magnesium salt, an alpha-2 agonist, a sodium channel inhibitor, and, optionally, a beta blocker, and / or an NMDA antagonist other than a magnesium salt are administered in combination to an individual to induce and / or maintain analgesia, anesthesia and / or sedation, and to maintain hemodynamic stability in the individual during the perioperative phase of a medical or surgical procedure; method.

[0080] (52.) The method according to (51.) above, wherein the opioid-free intraoperative treatment is carried out by administering to an individual an intraoperative pharmaceutical composition according to any one of (28.) to (50.) above.

[0081] (53.) An opioid-free intraoperative system for opioid-free intraoperative treatment of an individual, comprising: Magnesium (Mg 2+ ) salts, such as magnesium sulfate, alpha-2 agonists, such as dexmedetomidine, Sodium channel blocking anesthetics, such as lidocaine and / or procaine, and optionally N-methyl-D-aspartate receptor (NMDA) inhibitors, such as ketamine, and / or beta blockers, such as esmolol in an amount effective for simultaneous, combined, or sequential administration to induce and / or maintain analgesia, anesthesia, and / or sedation in an individual, and to maintain hemodynamic stability during the perioperative phase of a medical or surgical procedure, according to the method of opioid-free perioperative treatment of claim 51 or 52. Opioid-free intraoperative system.

[0082] (54.) Magnesium (Mg2+ ) salt, an alpha-2 agonist, such as dexmedetomidine, a sodium channel blocking anesthetic, such as lidocaine and / or procaine, and optionally an N-methyl-D-aspartate receptor (NMDA) inhibitor, such as ketamine, and / or a beta blocker, such as esmolol, in formulations and dosages designed to be combined prior to administration to provide the intraoperative composition described herein.

[0083] (55.) A method for providing opioid-free perioperative treatment of an individual undergoing a medical or surgical procedure, comprising: Implementing opioid-free preoperative treatment of an individual undergoing a medical or surgical procedure as described in any one of (24.) or (25.) above; and Implementing opioid-free perioperative treatment of an individual undergoing a medical or surgical procedure as described in any one of (51.) or (52.) above, and, where appropriate, administering a post-operative composition described herein to an individual during the post-operative phase of a medical or surgical procedure at a time and under conditions to treat the individual's pain and / or inflammation; A method comprising:

[0084] (56.) The method according to (55.) above, wherein the opioid-free preoperative treatment is carried out by administering to an individual a preoperative pharmaceutical composition according to any one of (1.) to (23.) above.

[0085] (57.) The method according to (55.) above, wherein the opioid-free intraoperative treatment is carried out by administering to an individual an intraoperative pharmaceutical composition according to any one of (28.) to (50.) above.

[0086] (58.) An opioid-free perioperative system described for opioid-free perioperative treatment of an individual, comprising: The opioid-free preoperative system according to (26.) or (27.) above, and the opioid-free intraoperative system according to (53.) or (54.) above. in an amount effective for simultaneous, combined, or sequential administration to induce anesthesia and maintain stable vital signs in an individual according to the method of opioid-free preoperative treatment described in (55.) or (56.) above; Opioid-free perioperative system.

[0087] (59.) An opioid-free perioperative system as described in (58.) above, comprising a magnesium salt of the opioid-free preoperative system, an alpha-2 agonist, a sodium channel blocking anesthetic, and optionally an NMDA antagonist other than a magnesium salt, and / or a corticosteroid, in formulations and dosages designed to be combined prior to administration to provide a preoperative composition as described herein.

[0088] (60.) Magnesium (Mg) in the opioid-free perioperative system 2+ ) salt, an alpha-2 agonist, such as dexmedetomidine, a sodium channel blocking anesthetic, such as lidocaine and / or procaine, and optionally an N-methyl-D-aspartate receptor (NMDA) inhibitor, such as ketamine, and / or a beta blocker, such as esmolol, in formulations and dosages designed to be combined prior to administration to provide the intraoperative composition described herein.

[0089] (61.) The opioid-free perioperative system according to any one of (55.) to (60.) above, further comprising a calcium channel inhibitor, a Cox inhibitor, a GABA analog, an antidepressant, cannabidiol (CBD), and / or an antiemetic.

[0090] (62.) The opioid-free perioperative system described in (61.) above, wherein the calcium channel inhibitor comprises verapamil or diltiazem.

[0091] (63.) The opioid-free perioperative system according to (61.) or (62.) above, wherein the Cox inhibitor is selected from the group consisting of celecoxib (i.e., celexoxib), rofecoxib (commonly known as Vioxx), etoricoxib, valdecoxib, parecoxib, aspirin, diflunisal, ibuprofen, dexybuprofen, naproxen, fenoprofen, ketoprofen, indomethacin, tolmetin, diclofenac, sulindac, etodolac, ketorolac, piroxicam, meloxicam, tenoxicam, droxicam, mefenamic acid, meclofenamic acid, clonixin, licofelone, and paracetamol (acetaminophen), or any combination thereof.

[0092] (64.) The opioid-free perioperative system according to any one of (61.) to (63.) above, wherein the GABA analog is selected from the group consisting of pregabalin, gabapentin, picamilon, and progabide, or any combination thereof.

[0093] (65.) The opioid-free perioperative system described in any one of (61.) to (64.) above, wherein the antidepressant is selected from the group consisting of (SNRI), selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA), tetracyclic antidepressants (TeCA), monoamine oxidase inhibitors (MAOI), noradrenaline, and specific serotonergic antidepressants (NASSA).

[0094] (66.) The opioid-free perioperative system according to any one of (61.) to (65.) above, wherein the antidepressant comprises a serotonin and noradrenaline reuptake inhibitor (SNRI) selected from the group consisting of venlafaxine, Cymbalta (duloxetine), venlafaxine XR, venlafaxine ER, desvenlafaxine, and venlafaxine.

[0095] (67.) The opioid-free perioperative system according to any one of (61.) to (66.) above, wherein the antiemetic agent is selected from the group consisting of ondansetron, dolasetron, granisetron, palonosetron, promethazine, imenhydrinate, metoclopramide and meclizine, or any combination thereof.

[0096] 4.1 Definition Unless expressly stated otherwise, the following terms have the meanings indicated below when used herein.

[0097] The word "comprise" or variations such as "comprises" or "comprising" are understood to mean the inclusion of a stated integer or group of integers but not the exclusion of any other integers or groups of integers.

[0098] The term "opioid" refers to natural or synthetic compounds that bind to opioid receptors, including agonists and antagonists. Opioid receptors are found primarily in the central and peripheral nervous systems, as well as the gastrointestinal tract (Dhaliwal and Gupta, Physiology, Opioid Receptor. [Updated 2021 Jul 26]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. Available at ncbi.nlm.nih.gov / books / NBK546642 / on the world wide web). Opioids include natural opioids (e.g., morphine, codeine, and thebaine), as well as synthetic opioids (e.g., hydromorphone, oxymorphone, hydrocodone, oxycodone, remifentanil, sufentanil, and fentanyl). Additional opioids include alfentanil, demerol, buprenorphine, and Nubian.

[0099] The term "opioid-free" refers to compositions, methods, and / or systems configured to achieve the described effect without the need for opioids. Thus, the term "opioid-free" as used herein with respect to anesthetic compositions, methods, and / or systems refers to compositions, methods, and / or systems configured to induce and / or maintain analgesia and / or anesthesia without the need to include, administer, or generally use an opioid.

[0100] The term "opioid-free treatment period" refers to a period of opioid-free treatment encompassing home, pre-operative, intra-operative, and post-operative recovery during hospitalization, and / or home recovery.

[0101] The abbreviation "OFA" refers to opioid-free anesthesia, which is synonymous with preemptive nonopioid analgesia.

[0102] The abbreviation "Non-OFA" refers to non-opioid-free anesthesia.

[0103] The term "preemptive non-opioid analgesia" or "preemptive non-opioid anesthesia" refers to compositions or related methods that have an anti-nociceptive effect on a patient, preventing the establishment of altered processes of afferent input that amplify postoperative pain (Gottschalk and Smith, Am. Fam. Physician. 2001 May 15;63(10):1979-1985). Preemptive non-opioid analgesia prevents the establishment of central and peripheral sensitization caused by the incisional and inflammatory injury that occurs during the intraoperative and postoperative phases of a medical or surgical procedure. Preemptive non-opioid analgesia is used interchangeably with OFA.

[0104] The term "central sensitization" refers to the development and maintenance of persistent post-injury chronic pain, e.g., post-surgery changes in the central nervous system that result in pain hypersensitivity (Latremoliere, A., & Woolf, CJ, J. Pain Res., (2009) 10(9), 895-926).

[0105] The term "anesthesia" is defined as the loss of nociceptive sensation with or without loss of consciousness. Anesthesia includes general anesthesia (GA), sedation, and regional and local anesthesia. Anesthesia is used for medical purposes. Anesthesia allows painless performance of medical procedures that would otherwise cause severe or intolerable pain to unanesthetized patients or would otherwise be technically infeasible. Thus, anesthesia is typically induced by blocking nociception, which refers to the response of the sensory nervous system to mechanical (e.g., cut, crush) stimulation of sensory nerve cells called nociceptors, which generate pain signals that travel along chains of nerve fibers from the spinal cord to the brain. Anesthesia may result in full or partial awakening in the patient (MAC (Monitored Anesthesia Care), neuraxial anesthesia (spinal / epidural), and regional anesthesia (Bier block / nerve block)), as understood by those skilled in the art.

[0106] The term "general anesthesia" or "GA" refers to a state in which central nervous system activity is suppressed, resulting in unconsciousness and complete lack of sensation. General anesthesia can be induced by intravenous, inhaled and / or intramuscular administration of a suitable drug, such as ketamine or a combination of ketamine and other drugs, as will be understood by those skilled in the art.

[0107] The term "sedation" refers to the administration of anxiolytics, pain mediators, and a wide range of sedation inducing a minimal to unresponsive state that facilitates medical or diagnostic procedures. Monitored anesthesia care (MAC) is characterized by altered suppression of consciousness to allow the patient to continuously and independently maintain the patient's airway, retain protective reflexes, and remain responsive to verbal cues and / or tactile or physical stimuli. Exemplary sedatives that can be used in human and veterinary applications for MAC or for induction and / or maintenance of general anesthesia (GA) include propofol, etomidate, ketamine, pentobarbital, Bristol (methohexital), lorazepam, midazolam, isoflurane, sevoflurane, desflurane, and dexmedetomidine.

[0108] The terms "regional anesthesia" and "local anesthesia" refer to a condition in which the transmission of nerve impulses is blocked in a particular part of the body. Depending on the situation, local or regional anesthesia can be used either by itself (in which case the patient remains fully conscious) or in combination with general anesthesia or sedation. Local anesthesia nerve block or regional block, as used herein, refers to pain relief by blocking pain signaling from the surgical site via targeted perineural local anesthesia injection / infusion. In local anesthesia, the area of ​​interest is typically infiltrated with local anesthesia and sedation or IV medication is typically not involved (unless required by the patient's condition), as will be understood by those skilled in the art. If sedation is desired or required, local / MAC (monitored anesthesia care) is specified. Not all local anesthetics can be administered intravenously due to cardiotoxic effects associated with local anesthesia systemic toxicity (LAST) leading to cardiac arrest.

[0109] The terms "anesthetic," "anesthetic," and the like, as used herein, refer to compounds, compositions, processes, or procedures that induce insensibility to pain through temporary loss of sensation. A patient under the influence of an anesthetic is said to be anesthetized.

[0110] The term "Aldrete score" refers to a patient's score according to the "Aldrete scoring system," which is a commonly used scale that determines whether a patient can be safely discharged from the postanesthesia care unit (PACU) and admitted to either a postoperative ward or a separate recovery area. Factors that affect a patient's Aldrete score include the patient's activity, respiration, blood pressure, consciousness, and complexion.

[0111] The application "medical or surgical procedure" generally refers to a procedure that requires anesthesia, sedation, or analgesia. In some contexts, medical or surgical procedures encompass the administration of anesthesia, sedation, or analgesia in a setting outside of a hospital or surgical site, such as a hospice. In other contexts, medical or surgical procedures refer to procedures that require anesthesia, sedation, or analgesia, as well as procedures that involve the practice of surgical manual and instrumental procedures on an individual to investigate or treat a pathological condition, such as a disease or injury, to help improve bodily function or appearance, or to repair an unwanted ruptured area. In particular, the term "medical or surgical procedure" includes both surgery and revision surgery, with the term "revision surgery" referring to a second or subsequent surgery after an initial operation to again address an aspect of patient care that is best treated surgically. Reasons for revision surgery include persistent bleeding after surgery, the development or persistence of infection.

[0112] The term "pre-operative" refers to the phase of a medical or surgical procedure that includes establishing a baseline assessment of the patient in a clinical setting or at home, conducting a pre-operative interview, or preparing the patient for anesthesia.

[0113] The term "intraoperative" refers to a phase of a medical or surgical procedure, including from the start of the procedure to the end of the procedure. In particular, the term "intraoperative" refers to the time from when the patient enters the operating room to when the patient leaves the operating room. Included in this term is induction of spinal anesthesia / placement, application of surgical dressings and / or casts, as would be understood by one of ordinary skill in the art. Intraoperative is generally interchangeable with an indication that the patient is "in surgery" or, if surgery is ongoing, that the patient is "having surgery," as would also be understood by one of ordinary skill in the art.

[0114] The term "post-operative" or "post-operative" refers to the phase following a medical or surgical procedure that begins at the end of surgery and ends at the time of discharge from a medical facility. The post-operative phase typically encompasses the time that the patient is transferred to a recovery room, post-anesthesia care unit (PACU) or intensive care unit (ICU) until the patient is discharged from a medical facility or follow-up care is completed. During this phase, the patient can be administered a post-operative composition as part of a post-operative pain management care plan.

[0115] The abbreviation "PACU" refers to post-anesthesia care unit.

[0116] The abbreviation "PHO" stands for Preoperative Waiting.

[0117] The term "induction" or "induce" refers to the achievement of a state of unconsciousness in a patient by administration of a composition as described herein. Exemplary intravenous induction compositions include compositions containing at least one of propofol, thiopental sodium, etomidate, methohexital and ketamine, or a combination thereof.

[0118] The term "maintain" or "maintenance" refers to the continuation of a patient's unconscious state following induction by administration of a pharmaceutical composition or agent. Exemplary maintenance compositions include mixtures of oxygen, sometimes nitrous oxide, and a volatile anesthetic agent, and / or compositions for intravenous (IV) administration as disclosed herein.

[0119] The term "magnesium salt" or "Mg 2+ "Salt" refers to a compound containing a magnesium ion (Mg) with a pharma- ceutically acceptable counterion. 2+ ) as well as solvates and hydrates thereof.

[0120] The term "pharmacologically acceptable counter ion" includes, for example, acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycinate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, lys ... Counterions that may be used include, but are not limited to, methyl phosphate ...

[0121] The term "alpha-2 agonist" refers to a drug that stimulates the action of alpha-2 adrenergic receptors. Alpha-2 adrenergic receptors are located in the prejunctional terminals of the central nervous system, where they inhibit the release of norepinephrine in a form of negative feedback. They are further located post-synaptically on vascular smooth muscle cells of certain blood vessels, as found in cutaneous arterioles or veins. Alpha-2 adrenergic receptors bind both norepinephrine released by sympathetic postganglionic fibers and epinephrine released by the adrenal medulla. The general effects of alpha-2 adrenergic receptors include inhibition of norepinephrine release by negative feedback, a temporary increase in blood pressure after a sustained decrease in blood pressure, a decrease in heart rate, vasoconstriction of certain arteries, venoconstriction of some veins, a decrease in the motility of smooth muscle of the gastrointestinal tract, and sedation and analgesia. Exemplary alpha-2 agonists include dexmedetomidine, clonidine, fadolmidine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, methyldopa, methylnorepinephrine, (R)-3-nitrobiphenyline, amitraz, detomidine, lofexidine, and medetomidine. For human use, exemplary alpha-2 agonists include dexmedetomidine, clonidine, methyldopa, and norepinephrine.

[0122] The term "sodium channel blocker" refers to a blocker that blocks the release of sodium ions (Na +) conduction. As used herein, the term "sodium channel inhibitor" is intended to be synonymous with "sodium channel blocker." Exemplary sodium channel inhibitors include quinidine, ajmaline, procainamide, disopyramide, lidocaine, procaine, prilocaine, phenytoin, mexiletine, tocainide, encainide, flecainide, propafenone, and moricinzine. For human use, exemplary sodium channel inhibitors include procainamide, lidocaine, procaine, prilocaine, and flecainide.

[0123] The term "NMDA antagonist" refers to an agent that blocks or antagonizes the action of N-methyl-D-aspartate receptors.Exemplary NMDA antagonists include ketamine, magnesium salts (e.g., magnesium sulfate), dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), and nitrous oxide (NO).In human applications, exemplary NMDA antagonists include ketamine, magnesium salts (e.g., magnesium sulfate), and nitrous oxide (NO).

[0124] The term "beta blocker" refers to an agent that blocks the receptor sites for the endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) at the beta adrenergic receptors of the sympathetic nervous system.Exemplary beta blockers include carvedilol, propranolol, esmolol, timolol, metoprolol, labetalol, atenolol, bisoprolol, and nebivolol.In human use, exemplary beta blockers include propranolol, esmolol, metoprolol, and labetalol.

[0125] The terms "corticoid" or "corticosteroid" refer to any of the naturally occurring steroid hormones produced in the adrenal cortex of vertebrates, as well as synthetic analogues of these naturally occurring steroid hormones.

[0126] Exemplary corticosteroids include cortisone, hydrocortisone, fludrocortisone acetate, prednisolone, prednisone, methylprednisolone, triamcinolone, dexamethasone sodium phosphate (dexamethasone), betamethasone, triamcinolone acetonide, and fluorometholone. Glucocorticosteroids inhibit the production of prostaglandins, bradykinin, histamine, and leukotrienes, thereby reducing inflammation.

[0127] The term "drug" refers to a component of a pharmaceutical composition that is biologically active. The modifier of the term "drug" indicates the relevant biological activity that is typically carried out by the interaction of the drug with one or more molecular targets in an individual. In contrast to the active ingredient, the inactive ingredient is usually called an excipient in the pharmaceutical context. The main excipient that serves as a vehicle to carry the active ingredient is usually called a vehicle. Saline, sterile water, petrolatum and mineral oil are common vehicles, which are understood by those skilled in the art.

[0128] The term "calcium channel blocker" refers to a blocker that blocks the release of calcium ions (Ca 2+ Calcium channel inhibitors refer to agents that block the conduction of the endothelial cells (the endothelial cells). As used herein, the term "calcium channel inhibitor" is intended to be synonymous with "calcium channel blocker." Exemplary calcium channel inhibitors include verapamil, diltiazem, nifedipine, nimodipine, nicardipine, flunarizine, and cinnarizine.

[0129] The term "Cox inhibitor" refers to a type of nonsteroidal anti-inflammatory drug.Exemplary Cox inhibitors include celecoxib, etodolac, etoricoxib, valdecoxib, parecoxib, aspirin, diflunisal, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, indomethacin, tolmetin, diclofenac, sulindac, ketorolac, piroxicam, meloxicam, tenoxicam, droxicam, mefenamic acid, meclomefenamic acid, clonixin, licofelone, and paracetamol (acetaminophen).In human use, exemplary Cox inhibitors include celecoxib, etodolac, aspirin, ibuprofen, naproxen, ketoprofen, indomethacin, diclofenac, ketorolac, meloxicam, tenoxicam, and paracetamol (acetaminophen).

[0130] The term "nonsteroidal anti-inflammatory drug" or "NSAID" refers to a class of compounds that do not contain any steroid moiety, but can still provide analgesic, antipyretic and / or anti-inflammatory effects. Exemplary NSAIDs include celecoxib, rofecoxib (commonly known as Vioxx), etoricoxib, valdecoxib, parecoxib, aspirin, diflunisal, ibuprofen, dexybuprofen, naproxen, fenoprofen, ketoprofen, indomethacin, tolmetin, diclofenac, sulindac, etodolac, ketorolac, piroxicam, meloxicam, tenoxicam, droxicam, mefenamic acid, meclomefenamic acid, clonixin, and licofelone. NSAIDs that can be used in combination with the opioid-free compositions, methods, and systems of the present disclosure can be ascertained by one of skill in the art in terms of the properties of the NSAID, and the properties of the agent for use in the opioid-free compositions, methods, and systems of the present disclosure, as well as any additional indications, are provided in the present disclosure.

[0131] The term "GABA analog" refers to an agent that binds to the GABA receptor and produces a negative change in the transmembrane potential of a cell, usually causing hyperpolarization. There are two classes of GABA receptors: GABA A and GABA B There is GABA A The receptors are ligand-gated ion channels (also known as ionotropic receptors), whereas GABA B The receptor is a G protein-coupled receptor, also called a metabotropic receptor.Exemplary GABA analogs include pregabalin, gabapentin, picamilon, and progabide.For human use, exemplary GABA analogs include pregabalin and gabapentin.

[0132] The term "antidepressant" refers to a drug that can correct the chemical imbalance of neurotransmitters in the central nervous system and relieve depression, social anxiety, anxiety, seasonal affective disorder and dysthymia, or mild chronic depression.Antidepressant, as used herein, can reduce pain and can be used to prevent and treat chronic or acute pain.

[0133] The term "antiemetic" refers to a drug or medicine that treats, reduces, and / or prevents nausea and / or vomiting. Exemplary antiemetics include ondansetron, dolasetron, granisetron, palonosetron, promethazine, metoclopramide, dimenhydrinate, and droperidol. For human use, exemplary antiemetics include ondansetron, dolasetron, granisetron, promethazine, metoclopramide, and droperidol.

[0134] The term "pharmaceutical composition" refers to a mixture or combination of two or more chemical or biological compounds or substances and a pharma- ceutically acceptable excipient intended for use. The pharmaceutical composition of the present disclosure may be intended for use in anesthesia applications.

[0135] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition that elicits a biological or medical response in a tissue, system, animal or human that is sought by a researcher, health care provider or other clinician. An "effective amount" refers to an amount of a compound, agent, formulation or composition that provides a beneficial effect or favorable outcome in a subject, or an amount of a compound, agent, formulation or composition that exhibits a desired in vivo or in vitro activity. An "effective amount" refers to an amount of a compound, agent, formulation or composition that provides a desired biological outcome. An effective amount can be administered in one or more doses.

[0136] The term "medium" refers to any of a variety of vehicles used as a solvent, carrier, binder or diluent for the delivery of a therapeutically active ingredient in a pharmaceutical composition. Typically, the medium may be an excipient to preferably improve the efficiency of delivery and the effectiveness of the pharmaceutical composition. Preferred media used in the opioid-free compositions of the present disclosure include saline, sterile water, and additional media that can be ascertained by those skilled in the art upon reading this disclosure.

[0137] The term pharma- ceutically acceptable "carrier" refers to a non-toxic carrier that may be administered to a patient together with a therapeutically active ingredient and that does not destroy the pharmacological activity thereof.

[0138] The term pharmaceutically acceptable "excipient" refers to a pharmacologically inactive substance that is combined with a pharmacologically active ingredient of a pharmaceutical composition, including bulking agents, fillers, diluents, and products that are used to promote drug absorption, aid in manufacturing, enhance drug delivery or targeting, improve stability, handling, or solubility, or for other pharmacokinetic considerations.Pharmaceutically acceptable excipients are known in pharmacology and are disclosed in, for example, Gennaro, Ed., Reminington: The Science and Practice of Pharmacy, 20th Ed. (Lippincott, Williams & Wilkins, Baltimore, Md. 2000); Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, DC (eg, 1st, 2nd, and 3rd Eds., 1986, 1994, and 2000, respectively); and Pramanick et al., Pharma Times, 45(3), March 2013, 65-77. Pharmaceutically acceptable excipients include bulking agents, buffers, isotonicity agents, preservatives, antioxidants, antimicrobial agents, chelating agents, solubilizing agents, complexing and dispersing agents, flocculating / suspending agents, wetting agents, and solvent systems.

[0139] The term "treatment" refers to any activity that is part of the medical care of a condition or that deals with a condition medically or surgically.For example, as used herein, treatment includes administering an opioid-free anesthetic composition to an individual to achieve a predetermined state of sedation and analgesia.

[0140] The term "individual" or "patient," as used herein, refers to an animal, particularly a mammal, and more particularly a human. The terms "subject," "individual," and "patient" are used interchangeably herein.

[0141] The term "ideal body weight" or "IBW" refers to an appropriate and healthy weight for height. Typically, the determination of IBW is based on the following equation for a human individual: For men, IBW(kg)=50.0+[2.3×(height(in)-60)], and for women, IBW(kg)=45.5+[2.3×(height(in)-60)]. Additionally, to ascertain an accurate IBW, one of skill in the art can utilize calculators, such as those available on the World Wide Web at calculator.net / ideal-weight-calculator.html. In particular, one of skill in the art will appreciate that there is no "golden rule" for calculating IBW, and that there are multiple charts and calculators that can vary significantly depending on the standards of the country of origin.

[0142] The term "adjusted body weight" or "AdjBW" refers to a calculated adjustment made to a weight measurement and is applicable to subjects with amputation, edema, ascites and chronic renal disease, as well as obesity.

[0143] Unless specifically indicated, the term "patient's body weight" refers to the patient's normal body weight. (Courtney M Peterson et al., "Universal equation for estimating ideal body weight and body weight at any BMI," Am. J. Clin. Nutr. 2016;103:1197-203.)

[0144] The term "infusion" refers to the intravenous administration of a liquid composition into the venous system via a needle or catheter to a patient in need of the composition.

[0145] The term "intramuscular route" refers to administering a composition into a patient's muscle, typically using an injection.

[0146] The term "Numerical Rating Scale" or "NRS" refers to a measure of pain intensity on an 11-point scale (0 to 10), where 0 means no pain, 1 to 3 mean mild pain, 4 to 6 mean moderate pain, and 7 to 10 mean severe pain. (physio-pedia.com / Numeric_Pain_Rating_Scale on the world wide web).

[0147] The term "anesthesia provider" refers to nurse anesthesiologists, physician anesthesiologists, and anesthesiologist assistants under the supervision of anesthesiologists.

[0148] It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used in this disclosure, the singular forms "a," "an," and "the" include plural references unless the content clearly dictates otherwise. The term "plural" includes more than one reference unless the context clearly dictates otherwise.

[0149] Full phrases or words of some abbreviations used herein are shown in parentheses: dex (dexmedetomidine), Lido (lidocaine), sx (surgery), BID (twice a day), HS (bedtime), PO (monthly), Q8H (every 8 hours), Q12H (every 12 hours), D / C (discontinued), IV (intravenous), IVP (IV push), pt. (patient), PONV (postoperative nausea and vomiting), OSA (obstructive sleep apnea), TIVA (total intravenous anesthesia), w / w (weight percent concentration), end tidal CO2 (ETCO2).

[0150] When a Markush group or other grouping is used herein, all individual members of the group, as well as all combinations and possible subcombinations of the group, are intended to be included individually in the disclosure. Unless otherwise stated, any combination of components or materials illustrated or described herein can be used to practice the disclosure. Those skilled in the art can employ methods, device elements, and materials other than those specifically illustrated in the practice of the disclosure without resorting to undue experimentation. All art-known functional equivalents of any of such methods, device elements, and materials are intended to be included in the disclosure. When a range is presented herein, such as a temperature range, frequency range, time range, or composition range, all intermediate ranges and all subranges, as well as all individual values ​​included in the presented range, are intended to be included in the disclosure. Any one or more individual members of the ranges or groups disclosed herein may be excluded from the claims of the disclosure. The disclosure illustratively described herein can be practiced in the absence of any element or limitation not specifically disclosed herein.

[0151] The terms "for example" and "such as," as well as their grammatical equivalents, are understood to be followed by the phrase "without limitation," unless expressly stated otherwise.

[0152] As used herein, the term "about" is intended to account for variations due to experimental error. Unless expressly stated, all measurements reported herein are understood to be modified by the term "about," whether or not this term is explicitly used. As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0153] It should be further understood that features of one embodiment may be generally applied to other embodiments, even if not specifically described or illustrated in such other embodiments, unless expressly prohibited by this disclosure or by the nature of the embodiment concerned. Similarly, the compositions and methods described herein may include any combination of the features and / or steps described herein that is not inconsistent with the objectives of this disclosure. Numerous modifications and / or adaptations to the compositions and methods described herein will be readily apparent to those skilled in the art without departing from the subject matter of the present invention.

[0154] All ranges disclosed herein should be understood to encompass any and all subranges contained therein. For example, a stated range of "1.0 to 10.0" should be considered to include any and all subranges beginning at a minimum value of 1.0 or more and ending at a maximum value of 10.0 or less, such as 1.0 to 5.3, or 4.7 to 10.0, or 3.6 to 7.9. Any one or more individual members of a range or group disclosed herein may be excluded from the claims of this disclosure. The disclosure illustratively described herein can be practiced in the absence of any element or limitation not specifically disclosed herein. Unless expressly stated, all ranges disclosed herein should also be considered to include the endpoints of the range. For example, a range of "between 5 and 10," or "5 to 10," or "5 to 10" should be considered to include the endpoints 5 and 10.

[0155] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure pertains.

[0156] 4.2 Opioid-Free Compositions In one aspect, the present disclosure provides an opioid-free composition with anesthetic properties.In particular, the opioid-free composition of the present disclosure is designed to eliminate or reduce opioids in compositions used to induce and / or maintain anesthesia, and to provide improved postoperative pain control.The opioid-free composition of the present disclosure can be used, in particular, in the preoperative and / or intraoperative phases of medical or surgical procedures to induce or maintain anesthesia in patients.Advantageously, the opioid-free composition of the present disclosure can be administered to patients in opioid-free treatment without or with reduced undesirable side effects associated with opioids, such as hyperalgesia, opioid tolerance, nausea, vomiting, shivering, respiratory depression, urinary retention, bradycardia, hypotension, and additional side effects that can be identified by those skilled in the art.

[0157] In certain embodiments, the opioid-free compositions described herein can be used for sedation cases as well as general anesthesia cases.The use of both results in improved postoperative pain relief compared to opioid-based anesthetics.In some embodiments, the improvement in postoperative pain relief compared to opioid-based anesthetics results in a reduction of at least 1, 2, 3, 4 or 5 pain intensity numerical levels on the Numeric Rating Scale ("NRS") as well as opioid consumption immediately after surgery.

[0158] Reference is made to Figure 1, which provides a schematic diagram of the stages of a medical or surgical procedure. In Figure 1, the intraoperative phase of the medical or surgical procedure is designated as the "operative time" and the combination of the intraoperative and postoperative phases is designated as the "anesthesia time." The anesthesia time begins in the "open operating room" and includes the preoperative holding area and the postanesthesia care unit (PACU) / recovery room. The POH is the location where a patient is typically administered a preoperative loading dose, as will be understood by those skilled in the art.

[0159] In one aspect, the disclosure provides an opioid-free composition comprising a magnesium salt, at least one alpha-2 agonist and at least one sodium channel inhibitor, and optionally at least one NMDA antagonist other than a magnesium salt, at least one beta blocker, and / or at least one corticoid.

[0160] In various embodiments of the opioid-free compositions of the present disclosure, the magnesium salt is selected from the group consisting of acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycinate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobiolate, and the like. and magnesium salts having a pharma- ceutically acceptable counterion selected from the group consisting of phosphate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate, teoclate, threonate, or tosylate, and hydrates and solvates thereof. Selection of a particular magnesium salt, as well as any adjustments in concentration, dosage, composition, and timing of administration, are within the skill of one of ordinary skill in the art, particularly in view of the properties of the particular magnesium salt and the indications provided in this disclosure.

[0161] In certain embodiments, the magnesium salt comprises magnesium sulfate or magnesium chloride, or a magnesium salt functionally equivalent to magnesium sulfate or magnesium chloride. Magnesium salts functionally equivalent to magnesium sulfate or magnesium chloride can be ascertained by one of skill in the art.

[0162] In various embodiments of the opioid-free compositions of the present disclosure, the at least one alpha-2 agonist is selected from the group consisting of dexmedetomidine, clonidine, fadolmidine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, methyldopa, methylnorepinephrine, (R)-3-nitrobiphenyline, amitraz, detomidine, lofexidine, and medetomidine, or any combination thereof, and additional alpha-2 agonists ascertainable by one of skill in the art upon reading this disclosure. The selection of a particular alpha-2 agonist, as well as any adjustments in concentration, dosage, composition, and timing of administration, are within the skill of one of skill in the art, especially in view of the properties of the particular alpha-2 agonist and the indications provided in this disclosure.

[0163] For example, in some embodiments in which the opioid-free composition is administered to a human patient, the at least one alpha-2 agonist is selected from dexmedetomidine, clonidine, methyldopa, and norepinephrine, or any combination thereof. In certain embodiments, the at least one alpha-2 agonist comprises dexmedetomidine. In other embodiments, the at least one alpha-2 agonist comprises clonidine. Those skilled in the art know that dexmedetomidine has a more rapid onset and offset of action than clonidine. Dexmedetomidine has a higher degree of selectivity for alpha-2 receptors (1600:1 compared to 220:1 for clonidine), resulting in more desired effects and fewer undesired effects.

[0164] In certain embodiments, the at least one alpha-2 agonist comprises dexmedetomidine, or an alpha-2 agonist functionally equivalent to dexmedetomidine.

[0165] Generally, those skilled in the art know that alpha-2 agonists have the desired effect of reducing the sympathetic output of norepinephrine. Peripherally, alpha-2 agonists block the conduction of C-fibers, which are unmyelinated fibers that conduct slow but powerful and persistent pain signals. The effect on inhibitory G-coupled proteins produces peripheral analgesia. The activation of alpha-2 adrenergic receptors in the dorsal horn of the spinal cord is responsible for centrally acting analgesia. The inhibition of the release of substance P and norepinephrine is the result of the activation of G-coupled alpha-2 adrenergic receptors. This activation inhibits adenyl cyclase and reduces intracellular cyclic adenosine monophosphate. Supraspinal analgesia and sedation are the result of the activity of alpha-2 adrenergic receptors in the locus coeruleus. Thus, identification of suitable alpha-2 agonists that are functionally equivalent to dexmedetomidine can be performed in light of the general properties of alpha-2 agonists, the properties of dexmedetomidine, and the indications provided in this disclosure, as would be understood by one of skill in the art.

[0166] In various embodiments of the opioid-free composition of the present disclosure, the at least one sodium channel inhibitor is selected from the group consisting of bupivacaine, quinidine, ajmaline, procainamide, disopyramide, lidocaine, procaine, prilocaine, phenytoin, mexiletine, tocainide, encainide, flecainide, propafenone and moricindine, and any combination thereof, and additional sodium channel inhibitors ascertainable by those skilled in the art upon reading this disclosure. The selection of a particular sodium channel inhibitor, and any adjustment of concentration, dosage, composition and timing of administration, are within the skill of those skilled in the art, especially in view of the properties of the particular sodium channel inhibitor and the indications provided in this disclosure. For example, in some embodiments in which the opioid-free composition is administered to a human patient, the at least one sodium channel inhibitor is selected from procainamide, lidocaine, procaine, prilocaine, and flecainide, or any combination thereof. In certain embodiments, the at least one sodium channel inhibitor comprises lidocaine, procaine, or any combination thereof.

[0167] In another embodiment, the sodium channel blocker comprises lidocaine or a sodium channel blocker functionally equivalent to lidocaine. Sodium channel blockers functionally equivalent to lidocaine can be identified by one of skill in the art.

[0168] When present in the opioid-free compositions of the present disclosure, the at least one NMDA antagonist is selected from the group consisting of ketamine, magnesium salts, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE) and nitrous oxide (NO), and any combination thereof, as well as additional NMDA antagonists ascertainable by one of skill in the art upon reading this disclosure. The selection of a particular NMDA antagonist, as well as any adjustments in concentration, dosage, composition and timing of administration, are within the skill of one of skill in the art, particularly in view of the properties of the particular NMDA antagonist and the indications provided in this disclosure.

[0169] For example, in some embodiments where the opioid-free composition is administered to a human patient, the at least one NMDA antagonist is selected from ketamine, magnesium salt (e.g., magnesium sulfate), and nitrous oxide (NO), or any combination thereof.In certain embodiments, the at least one NMDA antagonist comprises ketamine, or a functionally equivalent NMDA antagonist to ketamine.A functionally equivalent NMDA antagonist to ketamine can be identified by a person skilled in the art.In various embodiments, the at least one NMDA antagonist comprises ketamine.

[0170] When present in the opioid-free composition of the present disclosure, the at least one beta blocker is selected from the group consisting of carvedilol, esmolol, propranolol, timolol, metoprolol, labetalol, atenolol, bisoprolol and nebivolol, and any combination thereof, as well as additional beta blockers ascertainable by one of ordinary skill in the art upon reading this disclosure. The selection of a particular beta blocker, as well as any adjustments in concentration, dosage, composition and timing of administration, are within the skill of one of ordinary skill in the art, especially in view of the characteristics of the particular beta blocker and the indications provided in this disclosure.

[0171] For example, in some embodiments in which the opioid-free composition is administered to a human patient, at least one beta blocker is selected from propranolol, esmolol, metoprolol, and labetalol, or any combination thereof.In certain embodiments, at least one beta blocker comprises esmolol, or a beta blocker functionally equivalent to esmolol.A beta blocker functionally equivalent to esmolol can be identified by those skilled in the art.In various embodiments, at least one beta blocker comprises esmolol.

[0172] When present in the opioid-free compositions of the present disclosure, the at least one corticosteroid is selected from the group consisting of dexamethasone sodium phosphate (dexamethasone), cortisone, hydrocortisone, fludrocortisone acetate, prednisolone, prednisone, methylprednisolone, triamcinolone, betamethasone, triamcinolone acetonide, and fluorometholone, and any combination thereof, as well as additional corticosteroids ascertainable by one of skill in the art upon reading this disclosure. Selection of a particular corticosteroid, as well as any adjustments in concentration, dosage, composition, and timing of administration, are within the skill of one of skill in the art, particularly in view of the properties of the particular corticosteroid and the indications provided in this disclosure.

[0173] In certain embodiments, the at least one corticosteroid comprises dexamethasone sodium phosphate (dexamethasone), or a corticosteroid functionally equivalent to dexamethasone. Corticosteroids functionally equivalent to dexamethasone can be identified by those skilled in the art. In some aspects of this embodiment, the corticosteroid comprises dexamethasone sodium phosphate (dexamethasone), which is a corticosteroid belonging to the class of glucocorticosteroids, and can be more broadly classified as steroids, as will be understood by those skilled in the art. In certain embodiments, the at least one corticosteroid comprises dexamethasone.

[0174] In various embodiments, the opioid-free compositions of the present disclosure can also be used in combination with additional agents. Suitable additional agents include sodium channel blockers, calcium channel blockers, Cox-1 or Cox-2 enzyme inhibitors (or Cox inhibitors), acetaminophen, GABA A and GABA B These include GABA receptor agonists, including extrareceptor agonists (GABA mimetics or analogs), antidepressants, antiemetics, cannabinoids (CBD), neurotransmitters, and / or nonsteroidal anti-inflammatory drugs (NSAIDs).

[0175] When used in combination with the opioid-free composition of the present disclosure, the calcium channel inhibitor is selected from the group consisting of verapamil, diltiazem, nifedipine, nimodipine, nicardipine, flunarizine, and cinnarizine, or any combination thereof, and additional calcium channel inhibitors ascertainable by those skilled in the art upon reading this disclosure. In certain embodiments, the calcium channel inhibitor comprises verapamil and / or diltiazem. The selection of a particular calcium channel inhibitor, as well as any adjustments in concentration, dosage, composition, and timing of administration, are within the skill of those skilled in the art, especially in view of the properties of the particular calcium channel inhibitor and the indications provided in this disclosure. For example, in some embodiments in which the opioid-free composition is administered to a human patient, the Cox inhibitor is selected from celecoxib, etodolac, aspirin, ibuprofen, naproxen, ketoprofen, indomethacin, diclofenac, ketorolac, meloxicam, tenoxicam, and paracetamol (acetaminophen), or any combination thereof.

[0176] When used in combination with the opioid-free composition of the present disclosure, the GABA analog is selected from the group consisting of pregabalin, gabapentin, picamilon and progabide, and any combination thereof, and additional GABA analogs that can be ascertained by those skilled in the art by reading this disclosure.The selection of a particular GABA analog, and any adjustment of concentration, dosage, composition and administration time point are within the skill of those skilled in the art, especially in view of the characteristics of the particular GABA analog and the indications provided in this disclosure.In certain embodiments, the GABA analog is Lyrica® (pregabalin) or Neurontin (gabapectin), or a combination thereof.

[0177] When used in combination with the opioid-free composition of the present disclosure, the antidepressant is selected from serotonin and noradrenaline reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), monoamine oxidase inhibitors (MAOIs), and noradrenaline and specific serotonergic antidepressants (NASSAs).Exemplary serotonin and noradrenaline reuptake inhibitors (SNRIs) include venlafaxine, cymbalta (duloxetine), venlafaxine XR, venlafaxine ER, desvenlafaxine, and venlafaxine.Exemplary selective serotonin reuptake inhibitors (SSRIs) include sertraline, citalopram, fluoxetine, escitalopram, paroxetine. Exemplary tricyclic antidepressants (TCAs) include amitriptyline and nortriptyline. Exemplary tetracyclic antidepressants (TeCAs) include mirtazapine. Exemplary monoamine oxidase inhibitors (MAOIs) include phenelzine (Nardil), tranylcypromine (Parnate), isocarboxazid (Marplan), and selegiline (EMSAM, Eldepryl). Exemplary noradrenergic and specific serotonergic antidepressants (NASSAs) include mianserin (Tolvon) and mirtazapine (Remeron, Avanza, Zispin). The selection of a particular antidepressant, and any adjustments of concentration, dosage, composition, and time of administration, are within the skill of the art, especially in view of the characteristics of the particular antidepressant and the indications provided in this disclosure.

[0178] In certain embodiments, the antidepressant comprises a serotonin and noradrenaline reuptake inhibitor (SNRI) selected from the group consisting of venlafaxine, Cymbalta (duloxetine), venlafaxine XR, venlafaxine ER, desvenlafaxine, and venlafaxine.

[0179] When used in combination with the opioid-free compositions of the present disclosure, the antiemetic agent is selected from the group consisting of ondansetron, dolasetron, granisetron, palonosetron, promethazine, dimenhydrinate, metoclopramide, meclizine, droperidol, and haldol, or any combination thereof, and additional antiemetic agents ascertainable by one of ordinary skill in the art upon reading this disclosure. Selection of a particular antiemetic agent, as well as any adjustments in concentration, dosage, composition, and timing of administration, are within the skill of one of ordinary skill in the art, especially in view of the characteristics of the particular antiemetic agent and the indications provided in this disclosure.

[0180] For example, in some embodiments in which the opioid-free composition is administered to a human patient, the antiemetic agent is selected from ondansetron, dolasetron, granisetron, palonosetron, promethazine, metoclopramide, meclizine, and droperidol, or any combination thereof.

[0181] The opioid-free compositions of the present disclosure are typically in the form of a pharmaceutical composition in which the active agent is present in a therapeutically effective amount together with a pharma- ceutically acceptable vehicle, carrier or excipient.

[0182] The opioid-free compositions of the present disclosure include preoperative, intraoperative, perioperative, and postoperative compositions. It is contemplated that the opioid-free compositions can be used in operating rooms, hospices, treatment settings (i.e., settings in which medical procedures are performed outside of an operating room), and other settings known to those skilled in the art.

[0183] 4.2.1 Opioid-Free Pre-Surgical Compositions In one embodiment, the present disclosure provides an opioid-free pre-surgical composition. The opioid-free pre-surgical composition includes magnesium (Mg2 + ) salts, alpha-2 agonists, and, where appropriate, Sodium channel blockers, and / or N-methyl-D-aspartate receptor (NMDA) inhibitors and / or corticosteroids in an amount effective to treat anxiety and / or induce sedation and / or analgesia in an individual during any phase of the pre-operative methods of the present disclosure, together with a pharma- ceutically acceptable vehicle, carrier, or excipient.

[0184] The specific magnesium salt, alpha-2 agonist, sodium channel inhibitor, NDMA inhibitor and corticosteroid present in the opioid-free pre-operative composition are selected from those disclosed above in connection with the opioid-free composition in section 4.2. The amount of each component present in the pre-operative composition of the present disclosure is an amount effective for treating anxiety and / or inducing sedation and / or analgesia in the pre-operative method of the present disclosure. In some embodiments, the opioid-free pre-operative composition further comprises an additional agent selected from the group consisting of a calcium channel inhibitor, CBD, a Cox inhibitor, a GABA analog, an antidepressant, acetaminophen, an antiemetic, or any combination thereof. These additional agents are described above in connection with the opioid-free composition in section 4.2.

[0185] In some embodiments, the magnesium salt is present in the opioid-free pre-surgical composition in an amount ranging from about 1 mg / mL to about 500 mg / mL, from about 2 mg / mL to about 300 mg / mL, from about 3 mg / mL to about 300 mg / mL, from about 4 mg / mL to about 300 mg / mL, from about 5 mg / mL to about 300 mg / mL, from about 50 mg / mL to about 300 mg / mL, or from about 100 mg / mL to about 300 mg / mL. In certain embodiments, the magnesium salt is about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL L, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, about 400 mg / mL, about 410 mg / mL, about 420 mg / mL, about 430 mg / mL, about 440 mg / mL, about 450 mg / mL, about 460 mg / mL, about 470 mg / mL, about 480 mg / mL, about 490 mg / mL, or about 500 mg / mL.

[0186] In various embodiments, the magnesium salt comprises magnesium sulfate or a magnesium salt functionally equivalent to magnesium sulfate.

[0187] In some embodiments, the alpha-2 agonist is present in the opioid-free pre-surgical composition in an amount ranging from about 0.001 mcg / mL to about 50 mcg / mL, 0.01 mcg / mL to about 50 mcg / mL, about 0.1 mcg / mL to about 40 mcg / mL, about 0.2 mcg / mL to about 30 mcg / mL, about 0.3 mcg / mL to about 20 mcg / mL, 0.4 mcg / mL to about 15 mcg / mL, about 0.5 mcg / mL to about 10 mcg / mL, about 1 mcg / mL to about 10 mcg / mL, about 2 mcg / mL to about 10 mcg / mL, or about 3 mcg / mL to about 10 mcg / mL. In certain embodiments, the alpha-2 agonist is about 0.1 mcg / mL, about 0.2 mcg / mL, about 0.3 mcg / mL, about 0.4 mcg / mL, about 0.5 mcg / mL, about 0.6 mcg / mL, about 0.7 mcg / mL, about 0.8 mcg / mL, about 0.9 mcg / mL, about 1 mcg / mL, about 1.5 mcg / mL, about 2 mcg / mL, about 2.5 mcg / mL, about 3 mcg / mL, about 3.5 mcg / mL, about 4 mcg / mL, about 4.5 mcg / mL, about 5 mcg / mL, about 5.5 mcg / mL, The opioid-free pre-surgical composition is present in an amount of about 6mcg / mL, about 6.5mcg / mL, about 7mcg / mL, about 7.5mcg / mL, about 8mcg / mL, about 8.5mcg / mL, about 9mcg / mL, about 9.5mcg / mL, about 10mcg / mL, about 10.5mcg / mL, about 11mcg / mL, about 11.5mcg / mL, about 12mcg / mL, about 12.5mcg / mL, about 13mcg / mL, about 13.5mcg / mL, about 14mcg / mL, about 14.5mcg / mL, or about 15mcg / mL.

[0188] In various embodiments, the alpha-2 agonist comprises dexmedetomidine, or an alpha-2 agonist functionally equivalent to dexmedetomidine.

[0189] In some embodiments, the sodium channel inhibitor is present in the opioid-free pre-surgical composition in an amount ranging from about 0 mg / mL to about 40 mg / mL, from about 0.01 mg / mL to about 36 mg / mL, from about 2.5 mg / mL to about 30 mg / mL, from about 4 mg / mL to about 25 mg / mL, or from about 10 mg / mL to about 20 mg / mL. In various embodiments, the sodium channel inhibitor is present in the opioid-free pre-surgical composition in an amount ranging from about 1 mg / mL to about 10 mg / mL, from about 2 mg / mL to about 8 mg / mL, from about 3 mg / mL to about 7 mg / mL, or from about 4 mg / mL to about 6 mg / mL. In certain embodiments, the sodium channel inhibitor is about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, about 10 mg / mL, 10.5 mg / mL, or about 15 mg / mL. In some embodiments, the opioid-free pre-surgical composition is present in an amount of about 1 mg / mL, about 11 mg / mL, about 11.5 mg / mL, about 12 mg / mL, about 12.5 mg / mL, about 13 mg / mL, about 13.5 mg / mL, about 14 mg / mL, about 14.5 mg / mL, about 15 mg / mL, about 15.5 mg / mL, about 16 mg / mL, about 16.5 mg / mL, about 17 mg / mL, about 17.5 mg / mL, about 18 mg / mL, about 18.5 mg / mL, about 19 mg / mL, about 19.5 mg / mL, or about 20 mg / mL.

[0190] In various embodiments, the sodium channel blocker comprises lidocaine or a sodium channel blocker functionally equivalent to lidocaine.

[0191] In some embodiments, at least one NMDA antagonist other than a magnesium salt is present in the opioid-free pre-surgical composition in an amount ranging from about 0 mg / mL to about 35 mg / mL, from about 0.01 mg / mL to about 30 mg / mL, from about 1 mg / mL to about 25 mg / mL, from about 1.5 mg / mL to about 20 mg / ml, from about 2 mg / mL to about 15 mg / mL, from about 2.5 mg / mL to about 10 mg / mL, or from about 3 mg / mL to about 5 mg / mL. In various embodiments, at least one NMDA antagonist other than a magnesium salt is present in the opioid-free pre-surgical composition in an amount of about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 3.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, or about 10 mg / mL.

[0192] In certain embodiments, the NMDA antagonist, other than a magnesium salt, present in the opioid-free pre-surgical composition comprises ketamine, or an NMDA antagonist functionally equivalent to ketamine.

[0193] In some embodiments, the corticosteroid is present in the opioid-free pre-surgical composition in an amount ranging from about 0 mg / mL to about 10 mg / mL, from about 0.2 mg / mL to about 9 mg / mL, from about 0.4 mg / mL to about 8 mg / mL, from about 0.6 mg / mL to about 7 mg / mL, from about 0.8 mg / mL to about 6 mg / mL, from about 1 mg / mL to about 5 mg / mL, or from about 1.5 mg / mL to about 4 mg / mL. In some embodiments, the corticosteroid is present in the opioid-free pre-surgical composition in an amount ranging from about 0.1 mg / mL to about 5 mg / mL, from about 0.15 mg / mL to about 4 mg / mL, from about 0.2 mg / mL to about 3 mg / mL, from about 0.25 to about 2 mg / mL, from about 0.3 mg / mL to about 1 mg / mL. In various embodiments, the corticosteroid is present in the opioid-free pre-surgical composition in an amount of about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, or about 2 mg / mL.

[0194] In various embodiments, the corticosteroid present in the opioid-free pre-surgical composition comprises dexamethasone, or a corticosteroid functionally equivalent to dexamethasone.

[0195] In one embodiment, the opioid-free pre-operative pharmaceutical composition comprises: a magnesium salt in a concentration ranging from about 1 mg / mL to about 500 mg / mL; an alpha-2 agonist in a concentration ranging from about 0.001 to about 50 mcg / mL; a sodium channel inhibitor at a concentration ranging from about 0 mg / mL to about 40 mg / mL; an NMDA antagonist other than a magnesium salt, at a concentration ranging from about 0 mg / mL to about 35 mg / mL; and It contains a corticosteroid in a concentration ranging from about 0 mg / mL to about 10 mg / mL together with a pharma- ceutically acceptable vehicle, carrier, or excipient.

[0196] In another embodiment, the opioid-free pre-operative pharmaceutical composition comprises a magnesium salt at a concentration ranging from about 50 mg / mL to about 300 mg / mL; an alpha-2 agonist in a concentration ranging from about 1 mcg / mL to about 10 mgc / mL; a sodium channel inhibitor at a concentration ranging from about mg / mL to about 10 mg / mL; It comprises an NMDA antagonist, other than a magnesium salt, in a concentration ranging from about 1.5 mg / mL to about 5 mg / mL, and a corticosteroid in a concentration ranging from about 0.1 mg / mL to about 5 mg / mL, together with a pharma- ceutically acceptable vehicle, carrier, or excipient. In each of the embodiments described in the previous two paragraphs, the magnesium salt comprises magnesium sulfate or a magnesium salt functionally equivalent to magnesium sulfate, the alpha-2 agonist comprises dexmedetomidine or an alpha-2 agonist functionally equivalent to dexmedetomidine, the sodium channel inhibitor, if present, comprises lidocaine or a sodium channel inhibitor functionally equivalent to lidocaine, the NMDA antagonist other than the magnesium salt, if present, comprises ketamine or an NMDA antagonist functionally equivalent to ketamine, and the corticosteroid, if present, comprises dexamethasone or a corticosteroid functionally equivalent to dexamethasone. In various embodiments, the opioid-free pre-operative composition is a bolus formulation.

[0197] 4.2.2 Opioid-free intraoperative compositions In one embodiment, the present disclosure provides an opioid-free intraoperative composition. The opioid-free intraoperative pharmaceutical composition comprises: Magnesium salts, alpha-2 agonists, Sodium channel blockers, as appropriate NMDA antagonists other than magnesium salts and / or beta blockers together with a pharma- ceutically acceptable vehicle, carrier, or excipient.

[0198] The particular magnesium salts, alpha-2 agonists, and sodium channel inhibitors, and optionally NDMA inhibitors and beta blockers present in the opioid-free intraoperative compositions are selected from those disclosed above in connection with the opioid-free compositions in Section 4.2.

[0199] The amount of each component present in the intraoperative compositions of the present disclosure is an amount to induce and / or maintain analgesia, anesthesia, and / or sedation, and to maintain hemodynamic stability in an individual during the intraoperative phase of a medical or surgical procedure of the intraoperative methods of the present disclosure.

[0200] In some embodiments, the magnesium salt is present in the opioid-free intraoperative composition in an amount ranging from about 1 mg / mL to about 370 mg / mL, from about 2 mg / mL to about 300 mg / mL, from about 3 mg / mL to about 200 mg / mL, from about 3.5 mg / mL to about 100 mg / mL, from 4 mg / mL to about 50 mg / mL, or from about 4.5 mg / mL to about 25 mg / mL. In various embodiments, the magnesium salt is present in the opioid-free intraoperative composition in an amount ranging from about 1 mg / mL to about 50 mg / mL, from about 2 mg / mL to about 40 mg / mL, from about 3 mg / mL to about 30 mg / mL, from about 4 mg / mL to about 20 mg / mL, or from about 5 mg / mL to 10 mg / mL. In various embodiments, the magnesium salt is about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, about 10 mg / mL, about 10.5 mg / mL, about 11 mg

[0043] In some embodiments, the opioid-free intraoperative composition is present in an amount of about 10 mg / mL, about 11.5 mg / mL, about 12 mg / mL, about 12.5 mg / mL, about 13 mg / mL, about 13.5 mg / mL, about 14 mg / mL, about 14.5 mg / mL, about 15 mg / mL, about 15.5 mg / mL, about 16 mg / mL, about 16.5 mg / mL, about 17 mg / mL, about 17.5 mg / mL, about 18 mg / mL, about 18.5 mg / mL, about 19 mg / mL, about 19.5 mg / mL, or about 20 mg / mL.

[0201] In various embodiments, the magnesium salt comprises magnesium sulfate or a magnesium salt functionally equivalent to magnesium sulfate.

[0202] In some embodiments, the alpha-2 agonist is present in the opioid-free intraoperative composition in an amount ranging from about 0.001 mcg / mL to about 30 mcg / mL, about 0.005 mcg / mL to about 20 mcg / mL, about 0.01 mcg / mL to about 15 mcg / mL, about 0.025 mcg / mL to about 10 mcg / mL, 0.05 mcg / mL to about 5 mcg / mL, or about 0.1 mcg / mL to about 1 mcg / mL.

[0203] In various embodiments, the alpha-2 agonist is present in the opioid-free intraoperative composition in an amount of about 0.1 mcg / mL, about 0.2 mcg / mL, about 0.3 mcg / mL, about 0.4 mcg / mL, about 0.5 mcg / mL, about 0.6 mcg / mL, about 0.7 mcg / mL, about 0.8 mcg / mL, about 0.9 mcg / mL, or about 1 mcg / mL.

[0204] In various embodiments, the alpha-2 agonist comprises dexmedetomidine, or an alpha-2 agonist functionally equivalent to dexmedetomidine.

[0205] In some embodiments, the sodium channel inhibitor is present in the opioid-free intraoperative composition in an amount ranging from about 0.1 mg / mL to about 35 mg / mL, about 0.2 mg / mL to about 20 mg / mL, about 0.2.5 mg / mL to about 15 mg / mL, about 0.3 mg / mL to about 10 mg / mL, about 0.4 mg / mL to about 5 mg / mL, or about 0.5 mg / mL to 3 mg / mL. In various embodiments, the sodium channel inhibitor is present in an amount ranging from about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2.0 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, about 3.0 mg / mL, about 3.1 mg / mL, about 3.2 mg / mL, about 3.3 mg / mL, about 3.4 mg / mL, about 3.5 mg / mL, about 3.6 mg / mL, about 3.7 mg / mL, about 3.8 mg / mL, about 3.9 mg / mL, about 3.8 mg / mL, about 3.9 mg / mL, about 3.1 mg / mL, about The opioid-free intraoperative composition may be present in an amount of about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, or about 3 mg / mL.

[0206] In various embodiments, the sodium channel blocker comprises lidocaine or a sodium channel blocker functionally equivalent to lidocaine.

[0207] In some embodiments, the NMDA antagonist other than the magnesium salt is present in the opioid-free intraoperative composition in an amount ranging from about 0 mg / mL to about 20 mg / mL, from about 0.001 mg / mL to about 15 mg / mL, from about 0.005 mg / mL to about 10 mg / mL, from about 0.01 mg / mL to about 5 mg / mL, from about 0.05 mg / mL to about 1 mg / mL, or from about 0.1 mg / mL to 0.5 mg / mL. In various embodiments, the NMDA antagonist other than the magnesium salt is present in the opioid-free intraoperative composition in an amount of about 0 mg / mL, about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, or about 1 mg / mL.

[0208] In certain embodiments, the NMDA antagonist, other than a magnesium salt, present in the opioid-free pre-surgical composition comprises ketamine, or an NMDA antagonist functionally equivalent to ketamine.

[0209] In some embodiments, the beta blocker is present in the opioid-free intraoperative composition in an amount ranging from about 0 mg / mL to about 20 mg / mL, from about 0.001 mg / mL to about 15 mg / mL, from about 0.01 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 5 mg / mL, or from about 0.15 mg / mL to about 2.0 mg / mL. In various embodiments, the beta blocker is present in the opioid-free intraoperative composition in an amount of about 0.10 mg / mL, about 0.11 mg / mL, about 0.12 mg / mL, about 0.13 mg / mL, about 0.14 mg / mL, about 0.15 mg / mL, about 0.16 mg / mL, about 0.17 mg / mL, about 0.18 mg / mL, about 0.19 mg / mL, or about 0.20 mg / mL.

[0210] In some embodiments, when the beta blocker comprises esmolol, the beta blocker is present in the opioid-free intraoperative composition in an amount ranging from about 0.001 mg / mL to about 20 mg / mL. In other embodiments, when the beta blocker comprises esmolol, the beta blocker is present in the opioid-free intraoperative composition in an amount ranging from about 0.01 mg / mL to about 10 mg / mL, or from about 0.1 mg / mL to about 5 mg / mL. In various embodiments, esmolol is present in an amount ranging from about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, The opioid-free intraoperative composition is present in an amount of about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL or about 3 mg / mL.

[0211] In one embodiment, the opioid-free intraoperative pharmaceutical composition comprises a magnesium salt at a concentration ranging from about 1 mg / mL to about 370 mg / mL; an alpha-2 agonist in an amount ranging from about 0.001 mcg / mL to about 30 mcg / kg; It comprises a sodium channel inhibitor in an amount ranging from about 0.1 mg / mL to about 35 mg / mL, an NMDA antagonist other than a magnesium salt in a concentration ranging from about 0 mg / mL to about 20 mg / mL, and a beta blocker in a concentration ranging from about 0 mg / mL to about 20 mg / mL, together with a pharma- ceutically acceptable vehicle, carrier, or excipient.

[0212] In another embodiment, the opioid-free intraoperative pharmaceutical composition comprises: a magnesium salt in an amount ranging from about 5 mg / mL to about 10 mg / mL; an alpha-2 agonist in an amount ranging from about 0.1 to about 1 mcg / kg; a sodium channel inhibitor in an amount ranging from about 0.5 mg / mL to about 3 mg / mL; an NMDA antagonist other than a magnesium salt in an amount ranging from about 0 mg / mL to about 0.5 mg / mL; and Beta blockers in amounts ranging from about 0.15 mg / mL to about 2 mg / mL together with a pharma- ceutically acceptable vehicle, carrier, or excipient.

[0213] In each of the embodiments described in the previous two paragraphs, the magnesium salt comprises magnesium sulfate or a magnesium salt functionally equivalent to magnesium sulfate, the alpha-2 agonist comprises dexmedetomidine or an alpha-2 agonist functionally equivalent to dexmedetomidine, the sodium channel inhibitor comprises lidocaine or a sodium channel inhibitor functionally equivalent to lidocaine, the NMDA antagonist other than the magnesium salt, if present, comprises ketamine or an NMDA antagonist functionally equivalent to ketamine, and the beta blocker comprises esmolol or a beta blocker functionally equivalent to esmolol.

[0214] 4.2.3 Opioid-Free Post-Surgery Compositions In one embodiment, the present disclosure provides an opioid-free post-operative composition. The opioid-free post-operative composition comprises: Magnesium salts, alpha-2 agonists, Sodium channel blockers, NMDA antagonists other than magnesium salts, and beta blockers, The post-operative composition comprises one or more of the following, together with a pharma- ceutically acceptable vehicle, carrier, or excipient: The amount of each component present in the post-operative composition is an amount effective to treat pain and / or inflammation during the post-operative phase of a medical or surgical procedure, as will be understood by one of skill in the art upon reading this disclosure.

[0215] The specific magnesium salts, alpha-2 agonists, sodium channel inhibitors, NDMA inhibitors and beta blockers, when present in the opioid-free post-operative composition, are selected from those disclosed above in connection with the opioid-free compositions in Section 4.2.

[0216] In one aspect of this embodiment, the opioid-free post-operative composition comprises an NMDA antagonist other than a magnesium salt. In a second aspect of this embodiment, the opioid-free post-operative composition comprises an NMDA antagonist other than a magnesium salt, and a sodium channel inhibitor. In a third aspect of this embodiment, the opioid-free post-operative composition comprises an NMDA antagonist other than a magnesium salt, a sodium channel inhibitor, and an alpha-2 agonist. In a fourth aspect of this embodiment, the opioid-free post-operative composition comprises an NMDA antagonist other than a magnesium salt, a sodium channel inhibitor, an alpha-2 agonist, and a magnesium salt. In a fifth aspect of this embodiment, the opioid-free post-operative composition comprises an NMDA antagonist other than a magnesium salt, a sodium channel inhibitor, an alpha-2 agonist, and a magnesium salt, and a beta blocker.

[0217] 4.3 Opioid-free treatment methods In one embodiment, the present disclosure provides a method of opioid-free treatment of an individual undergoing a medical or surgical procedure. In one aspect of this embodiment, the present disclosure provides an opioid-free pre-operative treatment of an individual undergoing a medical or surgical procedure. In a second aspect of this embodiment, the present disclosure provides an opioid-free intra-operative treatment of an individual undergoing a medical or surgical procedure. In a third aspect of this embodiment, the present disclosure provides an opioid-free peri-operative treatment of an individual undergoing a medical or surgical procedure. The method described in Section 4.3 can be used for any anesthesia application.

[0218] In some embodiments, an electroencephalogram (EEG) can be used to present EEG data to a patient according to the methods of the present disclosure. EEG can be used to monitor cerebral blood flow during medical or surgical procedures, monitor the patient's depth of anesthesia, and determine the brain's overall electrical activity.

[0219] 4.3.1 Preoperative treatment method The present disclosure provides a method for opioid-free pre-operative treatment of an individual about to undergo a medical or surgical procedure.

[0220] In one embodiment, the present disclosure provides a method of opioid-free pre-operative treatment of an individual undergoing a medical or surgical procedure, comprising: Magnesium salts, Alpha-2 agonists, as well as Sodium channel blockers, and / or corticosteroids, and / or NMDA antagonists other than magnesium salts to the individual.

[0221] The particular magnesium salts, alpha-2 agonists, sodium channel inhibitors, corticosteroids, and NDMA inhibitors used in the pre-operative method are selected from those disclosed above in connection with the opioid-free compositions in Section 4.2.

[0222] The amount of each component used in the pre-operative method is an amount effective to treat anxiety and / or induce sedation and / or analgesia in an individual during the pre-operative phase of a medical or surgical procedure, as will be understood by one of skill in the art upon reading this disclosure.

[0223] In one aspect of this embodiment, the disclosure provides a method of opioid-free pre-operative treatment of an individual undergoing a medical or surgical procedure, comprising: An effective amount Magnesium salts in amounts ranging from 5 to 50 mg / kg IBW; an alpha-2 agonist in an amount ranging from 0.1 to 1 mcg / kg IBW; and, where appropriate, a sodium channel blocker in an amount ranging from 0.1 to 2 mg / kg IBW, and / or Corticosteroids in amounts ranging from 0.01 to 0.2 mg / kg IBW, and / or NMDA antagonists other than magnesium salts in amounts ranging from 0 to 0.5 mg / kg IBW to the individual, A magnesium salt and an alpha-2 agonist, and optionally a sodium channel inhibitor, a corticosteroid and an NMDA, are administered to an individual in a combination in amounts effective to treat anxiety and / or to induce sedation and / or analgesia in the individual during the pre-operative phase of a medical or surgical procedure; A method is provided.

[0224] In one aspect, the present disclosure provides a method of opioid-free pre-operative treatment of an individual undergoing a medical or surgical procedure, comprising: An effective amount a magnesium salt in an amount ranging from 5 to 50 mg / kg IBW; an alpha-2 agonist in an amount ranging from 0.1 to 1 mcg / kg IBW; and, where appropriate, a sodium channel blocker in an amount ranging from 0.1 to 2 mg / kg IBW, and / or a corticosteroid in an amount ranging from 0.01 to 0.2 mg / kg IBW, and / or NMDA antagonists other than magnesium salts in amounts ranging from 0 to 0.5 mg / kg IBW to an individual. The magnesium salt and the alpha-2 agonist, and optionally the sodium channel inhibitor, the corticosteroid, and the NMDA agonist other than the magnesium salt, are administered to the individual in a combination in amounts effective to treat the individual's anxiety and / or to induce sedation and / or analgesia during the pre-operative phase of a medical or surgical procedure.

[0225] In various embodiments of the opioid-free pre-surgical treatment method, the administering step comprises administering an opioid-free pre-surgical composition described herein.

[0226] In various embodiments of the preoperative treatment methods described herein, the method further comprises administering one or more additional agents. In one such embodiment, the method further comprises administering to the individual one or more additional agents selected from the group consisting of calcium channel blockers, Cox inhibitors, GABA analogs, antidepressants, CBD, and / or antiemetics described in Section 4.2. The amount of the one or more additional agents is an amount effective to stop, reduce, or alleviate pain in a patient under anesthesia, sedation, or general anesthesia during surgery.

[0227] In various embodiments of this section, the magnesium salt comprises magnesium sulfate or a magnesium salt functionally equivalent to magnesium sulfate, the alpha-2 agonist comprises dexmedetomidine or an alpha-2 agonist functionally equivalent to dexmedetomidine, the sodium channel inhibitor comprises lidocaine or a sodium channel inhibitor functionally equivalent to lidocaine, the NMDA antagonist other than the magnesium salt, if present, comprises ketamine or an NMDA antagonist functionally equivalent to ketamine, and the corticosteroid comprises dexamethasone.

[0228] 4.3.2 Intraoperative treatment method The present disclosure provides a method for opioid-free perioperative treatment of an individual undergoing a medical or surgical procedure.

[0229] In one embodiment, the present disclosure provides a method of opioid-free perioperative treatment of an individual undergoing a medical or surgical procedure, comprising: An effective amount Magnesium salts, Alpha-2 agonists, Sodium channel blockers, and, where appropriate, Beta blockers, and / or NMDA antagonists other than magnesium salts to an individual.

[0230] The particular magnesium salts, alpha-2 agonists, sodium channel inhibitors, beta blockers, and NDMA inhibitors used in the intraoperative methods are selected from those disclosed above in connection with the opioid-free compositions in Section 4.2.

[0231] The amount of each component used in the intraoperative method is an amount effective to induce and / or maintain analgesia, anesthesia, and / or sedation, and to maintain hemodynamic stability in an individual during the intraoperative phase of a medical or surgical procedure.

[0232] In certain embodiments, a method of opioid-free perioperative treatment comprises administering to a patient an opioid-free perioperative pharmaceutical composition of the present disclosure.

[0233] In some embodiments, the present disclosure provides a method of opioid-free perioperative treatment of an individual undergoing a medical or surgical procedure, comprising: An effective amount Magnesium salts in an amount ranging from about 1 mg / kg / hr to about 20 mg / kg / hr of ideal body weight (IBW); an alpha-2 agonist in an amount ranging from about 0.01 mg / kg / hr to about 1 mcg / k / hr IBW; A sodium channel blocker in an amount ranging from about 0.1 mg / kg / hr to about 3 mg / kg / hr IWB, and optionally a beta blocker in an amount ranging from about 3 mcg / kg / hr to about 300 mcg / kg / hr, and / or NMDA antagonists other than magnesium salts in amounts ranging from about 0 mg / kg / hr to about 0.5 mg / kg / hr IBW to an individual.

[0234] In an alternative embodiment, the present disclosure provides a method of opioid-free perioperative treatment of an individual undergoing a medical or surgical procedure, comprising: Magnesium salts in an amount ranging from about 5 to 20 mg / kg / hr IBW; an alpha-2 agonist in an amount ranging from about 0.1 to about 1 mcg / kg / hr IBW; a sodium channel inhibitor in an amount ranging from about 1 to about 2 mg / kg / hr / IBW; and / or / and as appropriate an NMDA antagonist other than a magnesium salt in an amount ranging from about 0 to about 0.5 mg / kg / hr IBW; Beta blockers in amounts ranging from about 3 to about 20 mcg / kg / min to an individual.

[0235] In some embodiments, a method of opioid-free perioperative treatment of an individual undergoing a medical or surgical procedure, comprising: Magnesium salts in an amount ranging from about 10 to 20 mg / kg / hr IBW; an alpha-2 agonist in an amount ranging from about 0.5 to about 1 mcg / kg / hr IBW; a sodium channel inhibitor in an amount ranging from about 1.5 to about 3 mg / kg / IBW; and, where appropriate, an NMDA antagonist other than a magnesium salt in an amount ranging from about 0.2 to about 0.5 mg / kg / hr IBW; and / or Beta blockers in amounts ranging from about 10 to about 300 mcg / kg / min IBW to the individual.

[0236] In some embodiments, a method of opioid-free perioperative treatment of an individual undergoing a medical or surgical procedure, comprising: Magnesium salts in an amount ranging from about 5 to 10 mg / kg / hr IBW; an alpha-2 agonist in an amount ranging from about 0.1 to about 0.5 mcg / kg / hr IBW; and as appropriate an NMDA antagonist other than a magnesium salt in an amount ranging from about 0 to about 0.2 mg / kg / hr IBW; a sodium channel inhibitor in an amount ranging from about 0.5 to about 1.5 mg / kg / IBW, and / or Beta blockers, such as esmolol, in amounts ranging from about 1 to about 10 mcg / kg / min IBW. to the individual.

[0237] In various embodiments of the perioperative treatment methods described herein, the method further comprises administering one or more additional agents. In one such embodiment, the method further comprises administering to the individual one or more additional agents selected from the group consisting of calcium channel blockers, Cox inhibitors and / or antiemetic agents described in Section 4.2. The amount of the one or more additional agents is an amount effective to stop, reduce or alleviate pain in a patient under anesthesia, sedation or general anesthesia during surgery.

[0238] In various embodiments of the intraoperative treatment methods described in this section, the methods further include administering to the individual an additional anesthetic agent in an amount effective to maintain the individual's anesthesia, sedation and / or analgesia, and vital signs during the intraoperative phase of the medical or surgical procedure. Additional anesthetic agents include, but are not limited to, propofol, nitrous oxide, and other inhalational anesthetic agents.

[0239] 4.3.3 Perioperative treatment methods A combination of opioid-free pre-operative and opioid-free intra-operative treatment methods can be used in the peri-operative treatment of individuals undergoing a medical or surgical procedure.

[0240] In one aspect, the disclosure provides a method of opioid-free peri-operative treatment of an individual undergoing a medical or surgical procedure, comprising: An amount effective to induce and / or maintain analgesia and / or reduce inflammation in an individual, administering to the individual an amount effective for opioid-free preoperative treatment according to any one of the methods described herein; and administering to the individual an amount effective for opioid-free perioperative treatment according to any one of the methods described herein; The present invention provides a method comprising:

[0241] Advantageously, the opioid-free perioperative treatment methods of the present disclosure provide improved post-operative pain relief as compared to non-opioid-free perioperative treatment methods.

[0242] 4.3.4 Postoperative treatment method In one embodiment, the present disclosure provides a method of opioid-free post-operative treatment of an individual following a medical or surgical procedure. The method is: below: Magnesium salts, alpha-2 agonists, Sodium channel blockers, NMDA antagonists other than magnesium salts, and Beta blockers One or more of This includes administering to an individual in an amount effective to treat pain and / or inflammation during the post-operative phase of a medical or surgical procedure.

[0243] The specific magnesium salts, alpha-2 agonists, sodium channel inhibitors, non-magnesium NDMA inhibitors, and beta blockers, when present in the opioid-free post-operative composition, are selected from those disclosed above in connection with the opioid-free compositions in Section 4.2.

[0244] In another embodiment, the present disclosure provides a method of opioid-free post-operative treatment of an individual following a medical or surgical procedure. The method includes: in the post-operative phase of a medical or surgical procedure, in an amount effective to treat pain and / or inflammation; The method includes administering to the individual an effective amount of an opioid-free post-operative composition described herein.

[0245] In certain embodiments, the method of opioid-free perioperative treatment comprises administering to a patient an opioid-free post-operative pharmaceutical composition of the present disclosure selected from those disclosed in Section 4.2.3.

[0246] In various embodiments of the post-operative treatment methods described in this section, the methods further comprise administering to the individual one or more additional post-operative agents.

[0247] In various embodiments of the post-operative treatment methods described in this section, the one or more additional post-operative agents is an antidepressant.

[0248] If administered, the antidepressant is selected from the group consisting of (SNRI), selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants (TCA), tetracyclic antidepressants (TeCA), monoamine oxidase inhibitors (MAOI), noradrenaline and specific serotonergic antidepressants (NASSA).

[0249] In embodiments where the post-operative treatment method includes administration of an antidepressant, the antidepressant comprises a serotonin and noradrenaline reuptake inhibitor (SNRI) selected from the group consisting of venlafaxine, Cymbalta (duloxetine), venlafaxine XR, venlafaxine ER, desvenlafaxine, and venlafaxine. In some embodiments, the antidepressant comprises Cymbalta.

[0250] In various embodiments of the post-operative treatment methods described in this section, the one or more additional post-operative agents are analgesics. In some embodiments, the analgesics are selected from the group consisting of acetaminophen, celecoxib and pregabalin, and combinations thereof.

[0251] In various embodiments of the postoperative treatment methods described in this section, the one or more additional postoperative agents include dexamethasone. When administered, dexamethasone may be administered over a period of time. The amount and time of administration of dexamethasone is within the skill of the art, especially in view of the properties of dexamethasone and the indications provided in this disclosure.

[0252] In some embodiments, the opioid-free post-operative method further comprises administering dexamethasone in an amount of about 5 mg to about 15 mg over about 15 minutes to about 30 minutes to the individual about 1 to 2 days after surgery.

[0253] 4.3.4 Methods for anesthetizing individuals In one embodiment, the present disclosure provides a method of anesthetizing an individual undergoing a medical or surgical procedure. The method includes: administering an opioid-free pre-operative composition of the present disclosure to an individual in an amount effective to treat anxiety and / or induce sedation and / or analgesia in the individual during the pre-operative phase of a medical or surgical procedure; administering an opioid-free intraoperative composition of the present disclosure to an individual in an amount effective to induce and / or maintain analgesia, anesthesia, and / or sedation in the individual during the intraoperative phase of a medical or surgical procedure, and to maintain hemodynamic stability, and optionally administering an opioid-free post-operative composition of the present disclosure to an individual during the post-operative phase of a medical or surgical procedure in an amount effective to treat the individual's pain and / or inflammation; Includes.

[0254] The particular opioid-free pre-operative, opioid-free intra-operative, and opioid-free post-operative compositions used in the methods of anesthetizing an individual are selected from those disclosed above in Sections 4.2.1, 4.2.2, and 4.2.3, respectively.

[0255] 4.4. Dose Levels, Regimens, and Modes of Administration In the methods described in Section 4.3, it is understood that the total dosage of one or more agents and / or compositions of the present disclosure is determined by the patient's anesthesia provider within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including comorbidities and the severity of comorbidities; the activity of the particular agent and / or composition used; the age, weight, general health, age and diet of the patient; the administration time, route of administration and excretion rate of the particular agent used; duration of treatment; drugs used in combination or concomitantly with the particular agent / composition used; and other factors known to those skilled in the medical arts.

[0256] In selecting one or more agents for use in the methods described herein, the anesthesia provider will typically consider the characteristics of a particular agent in the context of the health status of the individual being treated. For example, the anesthesia provider may select an agent that is an alpha-2 agonist, such as guanoxabenz (a metabolite of guanabenz in the human liver, which is an antihypertensive antiadrenergic drug), guanethidine (which acts to selectively inhibit adrenergic postganglionic nerve transmission, similarly suppressing responses mediated by alpha- and beta-adrenergic receptors without producing a parasympathetic block, and is available in oral form), xylazine (an analog of clonidine, which is an agonist of the alpha-2 class of adrenergic receptors typically used for sedation, anesthesia, muscle relaxation, and analgesia in animals, such as horses, cows, and other non-human mammals, and as an emetic, especially in cats), tizanidine (a central muscle relaxant that acts on the synapses of motor neurons), or other agents that act on the synapses of motor neurons, such as guanosine (a serotonin receptor antagonist), ... Consider the selection of: tizanidine, a short-acting agent that can also be used in the management of spasticity by increasing preinhibition; the effect of tizanidine is greatest on polysynaptic pathways; the overall effect of these actions reduces facilitation of spinal motor neurons), medetomidine (a racemic mixture of two stereoisomers, of which dexmedetomidine is the predominant active isomer, a synthetic compound typically used as a surgical anesthetic and analgesic for veterinary use in dogs), (R)-3-nitrobiphenyline, detomidine, lofexidine, and medetomidine, and guanfacine (a centrally acting adrenergic agonist with non-stimulatory and antihypertensive properties that selectively stimulates alpha-2 adrenergic receptors in the CNS, thereby resulting in inhibition of sympathetic nervous system output).

[0257] In addition, anesthesia providers typically select specific dosages and timing of administration by taking into account the different pharmacokinetics of certain drugs. For example, the exemplary beta blockers esmolol, metoprolol, and labetalol have different pharmacokinetic parameters. The pharmacokinetic parameters of esmolol are as follows: onset of action: immediate; peak: 2-6 minutes; duration >20 minutes. The pharmacokinetic parameters of metoprolol are as follows: onset of action: immediate; peak: 20 minutes; duration 5-8 hours. The pharmacokinetic parameters of labetalol are as follows: onset of action: 2-5 minutes; peak: 5-15 minutes; duration up to 4 hours.

[0258] Thus, in some exemplary embodiments, esmolol can be used, preferably as a continuous infusion, for titratability, rapid onset and offset.Metoprolol, a beta blocker, and labetalol, a 7:1 ratio of beta blocker to alpha-1 adrenergic receptor antagonist, and / or other drugs commonly used in anesthesia, can also be administered as an IV bolus to control elevated blood pressure and / or rapid heart rate.Intraoperative beta blockers can be administered as prophylaxis for cardiac events.In general, long-acting beta blockers are less desirable in the context of opioid-free administration, as more titratable beta blockers are preferred.

[0259] When determining dosage and timing of administration in the perioperative treatment methods of the present disclosure, anesthesia providers may take additional considerations into account.

[0260] For example, the timing and dosage of magnesium salts is typically 2+ To keep the "plug" in the NMDA receptor, Mg 2+ The gradient of Mg is chosen to increase outside the cell. 2+When Mg is displaced within the NMDA receptor channel, it counteracts the cascade, ultimately resulting in an increased perception of noxious stimuli (see FIG. 2). In particular, in the pyridoxine-free pre-, intra- or post-operative compositions of the present disclosure, Mg 2+ To keep the "plug" in the NMDA receptor, Mg 2+ Magnesium salts are given to increase the gradient of Mg outside the cell. 2+ Salt infusion should be used with caution or avoided in cases of renal failure and / or advanced heart block, as will be understood by those skilled in the art. In some embodiments, in very long-term cases, the cumulative dose may be greater than 100 mg / kg, resulting in high plasma levels of Mg. 2+ To avoid unwanted salt-related side effects, such as muscle weakness, inability to reverse muscle relaxants, low blood pressure, and extreme cases of bradyarrhythmia, magnesium 2+ Salt infusion can be reduced.

[0261] In some embodiments where the alpha-2 receptor antagonist is dexmedetomidine, the dosage and timing of administration can be selected with the understanding that dexmedetomidine can be given at high loading and injection volume to an individual who is a male aged 18-24 years who is highly agitated, nervous, has a history of post-traumatic stress disorder, and tends to exhibit high sympathetic tone. Dexmedetomidine can also be given in place of other anesthetics due to its neuroprotective effects, especially in the elderly. Dexmedetomidine can be increased in more stimulating surgeries, where this injection is used as a primary pain and stress reduction modality, as will be understood by those skilled in the art. It is worth considering that reducing stress (even existing / non-pain related stress) results in reduced inflammation. Stress, regardless of the origin of the stress, causes the release of pro-inflammatory cytokines. In some embodiments, the dosage of dexmedetomidine can be reduced to reduce unwanted side effects, such as hypotension, bradycardia, and excessive urination.

[0262] In some embodiments, patients receive epidural or spinal nerve blocks in combination with general anesthesia for major surgery. These interventions reduce the transmission of pain signals to the brain, with the result that the patient does not respond to noxious stimuli (in this case, surgery) or has no stress response. When pain is blocked from perception, the amount of anesthesia can remain relatively low even for major surgery. If there is no block and the noxious stimuli are severe, it may be necessary to increase the dose of dexmedetomidine. If the patient is very anxious before surgery, or has a history of chronic anxiety, post-traumatic stress disorder (PTSD), or is a male between 18 and 24 years old, a high dose of dexmedetomidine may be necessary to effectively attenuate sympathetic output at the time of surgery and to aid in gentle emergence from anesthesia.

[0263] In some embodiments, due to the overwhelming anti-inflammatory effect of OFA agent, it is still beneficial to administer OFA agent even in situations where no noxious stimuli are not delivered while the block / spinal cord is in effect. The pain and inflammation reducing properties of OFA last longer than the pain relieving properties of block / spinal cord, which will be understood by those skilled in the art. The block helps to bypass the most painful period immediately after surgery, but the OFA agent helps to reduce pain intensity after the block wears off, compared to individuals who did not receive OFA agent.

[0264] In some embodiments, where the patient has heart block, bradyarrhythmia, severe ventricular dysfunction, poorly controlled hypovolemia or hypertension, or is elderly, the anesthesia provider should be careful in selecting the alpha-2 adrenergic receptor blocker, as well as its dosage and timing of administration.

[0265] In some embodiments, where the patient is diabetic or at high risk for infection, administration of steroids may be reduced or eliminated, as will be appreciated by one of skill in the art.

[0266] In other embodiments where dexamethasone (dexamethasone sodium phosphate) is administered, other relevant timing and dosages can be selected, taking into account that dexamethasone causes insulin resistance 24 hours after its administration, shorter than other short-acting steroids. Dexamethasone can be omitted if other steroids are indicated, such as in cases to prevent adrenal crisis. Adrenal crisis may be a concern when a patient is chronically taking exogenous steroids and is suspected to have some degree of adrenal insufficiency. Examples include conditions such as osteoarthritis, autoimmune disorders, or bronchial reactive airway problems. Therapies that reduce the likelihood of adrenal crisis in such patients include hydrocortisone. Dexamethasone sodium phosphate is within the class of glucocorticosteroids, is more potent and long-acting than hydrocortisone, and can be used as a therapy to prevent adrenal crisis in these patients.

[0267] In some embodiments where basic hygiene, e.g., access to running water, is an issue, the disclosed methods include administering a reduced dose of steroid to minimize the risk of infection. In some embodiments, the disclosed methods include administering an increased dose of dexamethasone for pain control than the dose (about 4 mg) commonly used by anesthesia providers to prevent post-operative nausea and vomiting.

[0268] In certain embodiments, in the preoperative treatment method, the individual components or preoperative composition of the present disclosure can be administered parenterally (e.g., subcutaneously, intramuscularly, or intravenously) or intranasally.In certain embodiments, the individual components or preoperative composition of the present disclosure can be administered by intravenous infusion.In one aspect, the individual components or preoperative composition of the present disclosure can be administered by intravenous infusion in a bolus.

[0269] In some embodiments, in the pre-operative treatment methods, the individual components or pre-operative compositions of the present disclosure are administered as a single bolus dose by intravenous infusion over a period ranging from about 15 minutes to about 60 minutes, about 20 minutes to about 50 minutes, about 15 minutes to about 40 minutes, about 15 minutes to about 30 minutes, or about 20 minutes to about 25 minutes.

[0270] In embodiments in which the opioid-free pre-operative composition is administered by intravenous infusion, what may be contained in the syringe, IV bag, or glass container (vial or bottle) is a liquid composition or a powder that is reconstituted into a liquid composition by a healthcare provider at the time of administration. A pharmaceutically effective amount of the liquid composition may be given by IV over a period of, for example, 15 minutes. Alternatively, a pharmaceutically effective amount of the liquid composition may be drawn in a loading dose and injected into a 25, 50, or 100 cc IV bag of fluid, and then administered to the patient over a period of about 15 minutes, about 30 minutes, about 45 minutes, or about 1 hour or more. In some embodiments, when the opioid-free pre-operative composition is administered by intravenous infusion, what may be contained in the syringe, IV bag, or glass container (vial or bottle) is a liquid composition or a powder that is reconstituted into a liquid composition by a healthcare provider at the time of administration. A pharmaceutically effective amount of the liquid composition may be given by IV over a period of, for example, 15 minutes. Alternatively, a pharma- ceutical effective amount of the liquid composition can be withdrawn in a loading dose and injected into a 25, 50 or 100 cc IV bag of fluid and then administered to the patient over about 15 minutes, about 30 minutes, about 45 minutes, or about an hour or more.

[0271] In embodiments in which the opioid-free intraoperative composition is administered by intravenous infusion, what may be contained in the syringe, IV bag, or glass container (vial or bottle) is a liquid composition, or a powder that is reconstituted into a liquid composition by the healthcare provider at the time of administration.

[0272] In embodiments in which the opioid-free post-operative or peri-operative composition is administered by intravenous infusion, is a liquid composition, or is a powder that is reconstituted into a liquid composition, or in which the peri-operative composition is administered by intravenous infusion, what may be contained in the syringe, IV bag, or glass container (vial or bottle) is a liquid composition, or is a powder that is reconstituted into a liquid composition by the healthcare provider at the time of administration.

[0273] In certain embodiments of the preoperative treatment method, the magnesium salt is administered in an amount ranging from about 1 mg / mL to about 500 mg / mL, about 2 mg / mL to about 300 mg / mL, about 3 mg / mL to about 300 mg / mL, about 4 mg / mL to about 300 mg / mL, about 5 mg / mL to about 300 mg / mL, about 50 mg / mL to about 300 mg / mL, or about 100 mg / mL to about 300 mg / mL. In certain embodiments, the magnesium salt is about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL L, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, about 400 mg / mL, about 410 mg / mL, about 420 mg / mL, about 430 mg / mL, about 440 mg / mL, about 450 mg / mL, about 460 mg / mL, about 470 mg / mL, about 480 mg / mL, about 490 mg / mL, or about 500 mg / mL.

[0274] In certain embodiments of the preoperative treatment method, the alpha-2 agonist is administered in an amount ranging from about 0.001 mcg / mL to about 500 mcg / mL, 0.01 mcg / mL to about 50 mcg / mL, about 0.1 mcg / mL to about 40 mcg / mL, about 0.2 mcg / mL to about 30 mcg / mL, about 0.3 mcg / mL to about 20 mcg / mL, 0.4 mcg / mL to about 15 mcg / mL, about 0.5 mcg / mL to about 10 mcg / mL, about 1 mcg / mL to about 10 mcg / mL, about 2 mcg / mL to about 10 mcg / mL, or about 3 mcg / mL to about 10 mcg / mL. In certain embodiments, one alpha-2 agonist is about 0.1 mcg / mL, about 0.2 mcg / mL, about 0.3 mcg / mL, about 0.4 mcg / mL, about 0.5 mcg / mL, about 0.6 mcg / mL, about 0.7 mcg / mL, about 0.8 mcg / mL, about 0.9 mcg / mL, about 1 mcg / mL, about 1.5 mcg / mL, about 2 mcg / mL, about 2.5 mcg / mL, about 3 mcg / mL, about 3.5 mcg / mL, about 4 mcg / mL, about 4.5 mcg / mL, about 5 mcg / mL, about 6 mcg / mL, about 7 mcg / mL, about 8 mcg / mL, about 9 mcg / mL, about 10 mcg / mL, about 11 mcg / mL, about 12 mcg / mL, about 13 mcg / mL, about 14 mcg / mL, about 15 mcg / mL, about 16 mcg / mL, about 17 mcg / mL, about 18 mcg / mL, about 19 mcg / mL, about 20 mcg / mL, about 21 mcg / mL, about 22 mcg / mL, about 23 mcg / mL, about 24 mcg / mL, about 25 mcg / mL, about 26 mcg / mL, about 27 mcg / mL, about 28 mcg / mL, about 29 mcg / mL, about 30 mcg / mL, about 31 mcg / mL, about 32 mcg / mL, about 33 mcg / mL, about 34 mcg / mL, about 35 mcg / mL, about 36 mcg / mL, about 37 The amount is administered in an amount of about 5mcg / mL, about 6mcg / mL, about 6.5mcg / mL, about 7mcg / mL, about 7.5mcg / mL, about 8mcg / mL, about 8.5mcg / mL, about 9mcg / mL, about 9.5mcg / mL, about 10mcg / mL, about 10.5mcg / mL, about 11mcg / mL, about 11.5mcg / mL, about 12mcg / mL, about 12.5mcg / mL, about 13mcg / mL, about 13.5mcg / mL, about 14mcg / mL, about 14.5mcg / mL, or about 15mcg / mL.

[0275] In certain embodiments of the preoperative treatment method, the sodium channel inhibitor is administered in an amount ranging from about 0 mg / mL to about 40 mg / mL, from about 0.01 mg / mL to about 36 mg / mL, from about 2.5 mg / mL to about 30 mg / mL, from about 4 mg / mL to about 25 mg / mL, or from about 10 mg / mL to about 20 mg / mL. In various embodiments, the sodium channel inhibitor is administered in an amount ranging from about 1 mg / mL to about 10 mg / mL, from about 2 mg / mL to about 8 mg / mL, from about 3 mg / mL to about 7 mg / mL, or from about 4 mg / mL to about 6 mg / mL. In certain embodiments, the sodium channel inhibitor is at about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, about 10 ... It is administered in an amount of 0.5 mg / mL, about 11 mg / mL, about 11.5 mg / mL, about 12 mg / mL, about 12.5 mg / mL, about 13 mg / mL, about 13.5 mg / mL, about 14 mg / mL, about 14.5 mg / mL, about 15 mg / mL, about 15.5 mg / mL, about 16 mg / mL, about 16.5 mg / mL, about 17 mg / mL, about 17.5 mg / mL, about 18 mg / mL, about 18.5 mg / mL, about 19 mg / mL, about 19.5 mg / mL, or about 20 mg / mL.

[0276] In certain embodiments of the preoperative treatment method, at least one NMDA antagonist other than a magnesium salt is administered in an amount ranging from about 0 mg / mL to about 35 mg / mL, from about 0.01 mg / mL to about 30 mg / mL, from about 1 mg / mL to about 25 mg / mL, from about 1.5 mg / mL to about 20 mg / ml, from about 2 mg / mL to about 15 mg / mL, from about 2.5 mg / mL to about 10 mg / mL, or from about 3 mg / mL to about 5 mg / mL. In various embodiments, the at least one NMDA antagonist other than a magnesium salt is administered in an amount of about 0.5 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 3.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, or about 10 mg / mL.

[0277] In certain embodiments of the preoperative treatment method, at least one corticosteroid is administered in an amount ranging from about 0 mg / mL to about 10 mg / mL, from about 0.2 mg / mL to about 9 mg / mL, from about 0.4 mg / mL to about 8 mg / mL, from about 0.6 mg / mL to about 7 mg / mL, from about 0.8 mg / mL to about 6 mg / mL, from about 1 mg / mL to about 5 mg / mL, or from about 1.5 mg / mL to about 4 mg / mL. In some embodiments, the corticosteroid is administered in an amount ranging from about 0.1 mg / mL to about 5 mg / mL, from about 0.15 mg / mL to about 4 mg / mL, from about 0.2 mg / mL to about 3 mg / mL, from about 0.25 to about 2 mg / mL, or from about 0.3 mg / mL to about 1 mg / mL. In various embodiments, the corticosteroid is administered in an amount of about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL, about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, or about 2 mg / mL.

[0278] In certain embodiments, in the intraoperative treatment method, the individual components or intraoperative compositions of the present disclosure can be administered parenterally (e.g., subcutaneously, intramuscularly, or intravenously) or intranasally.In certain embodiments, the individual components or intraoperative compositions of the present disclosure can be administered by intravenous infusion.In one aspect, the individual components or intraoperative compositions of the present disclosure can be administered by continuous intravenous infusion or bolus dose.

[0279] In certain embodiments of the intraoperative treatment method, the magnesium salt is administered in an amount ranging from about 1 mg / mL to about 370 mg / mL, about 2 mg / mL to about 300 mg / mL, about 3 mg / mL to about 200 mg / mL, about 3.5 mg / mL to about 100 mg / mL, 4 mg / mL to about 50 mg / mL, or about 4.5 mg / mL to about 25 mg / mL. In various embodiments, the magnesium salt is administered in an amount ranging from about 1 mg / mL to about 50 mg / mL, about 2 mg / mL to about 40 mg / mL, about 3 mg / mL to about 30 mg / mL, about 4 mg / mL to about 20 mg / mL, or about 5 mg / mL to 10 mg / mL. In various embodiments, the magnesium salt is about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, about 9.5 mg / mL, about 10 mg / mL, about 10.5 mg / mL L, about 11 mg / mL, about 11.5 mg / mL, about 12 mg / mL, about 12.5 mg / mL, about 13 mg / mL, about 13.5 mg / mL, about 14 mg / mL, about 14.5 mg / mL, about 15 mg / mL, about 15.5 mg / mL, about 16 mg / mL, about 16.5 mg / mL, about 17 mg / mL, about 17.5 mg / mL, about 18 mg / mL, about 18.5 mg / mL, about 19 mg / mL, about 19.5 mg / mL, or about 20 mg / mL.

[0280] In certain embodiments of the intraoperative treatment method, at least one alpha-2 agonist is administered in an amount ranging from about 0.001 mcg / mL to about 30 mcg / mL, from about 0.005 mcg / mL to about 20 mcg / mL, from about 0.01 mcg / mL to about 15 mcg / mL, from about 0.025 mcg / mL to about 10 mcg / mL, 0.05 mcg / mL to about 5 mcg / mL, or from about 0.1 mcg / mL to about 1 mcg / mL. In various embodiments, the alpha-2 agonist is administered in an amount of about 0.1 mcg / mL, about 0.2 mcg / mL, about 0.3 mcg / mL, about 0.4 mcg / mL, about 0.5 mcg / mL, about 0.6 mcg / mL, about 0.7 mcg / mL, about 0.8 mcg / mL, about 0.9 mcg / mL, or about 1 mcg / mL.

[0281] In certain embodiments of the intraoperative treatment method, the at least one sodium channel inhibitor is administered in an amount ranging from about 0.1 mg / mL to about 35 mg / mL, about 0.2 mg / mL to about 20 mg / mL, about 0.2.5 mg / mL to about 15 mg / mL, about 0.3 mg / mL to about 10 mg / mL, about 0.4 mg / mL to about 5 mg / mL, or about 0.5 mg / mL to 3 mg / mL. In various embodiments, the sodium channel inhibitor is administered in an amount ranging from about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 mg / mL, about 1.1 mg / mL, about 1.2 mg / mL, about 1.3 mg / mL, about 1.4 mg / mL, about 1.5 mg / mL. , about 1.6 mg / mL, about 1.7 mg / mL, about 1.8 mg / mL, about 1.9 mg / mL, about 2 mg / mL, about 2.1 mg / mL, about 2.2 mg / mL, about 2.3 mg / mL, about 2.4 mg / mL, about 2.5 mg / mL, about 2.6 mg / mL, about 2.7 mg / mL, about 2.8 mg / mL, about 2.9 mg / mL, or about 3 mg / mL of the opioid-free intraoperative composition.

[0282] In certain embodiments of the intraoperative treatment method, at least one NMDA antagonist other than a magnesium salt is administered in an amount ranging from about 0 mg / mL to about 20 mg / mL, from about 0.001 mg / mL to about 15 mg / mL, from about 0.005 mg / mL to about 10 mg / mL, from about 0.01 mg / mL to about 5 mg / mL, from about 0.05 mg / mL to about 1 mg / mL, or from about 0.1 mg / mL to 0.5 mg / mL. In various embodiments, the NMDA antagonist other than a magnesium salt is administered in an amount of about 0 mg / mL, about 0.1 mg / mL, about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, or about 1 mg / mL.

[0283] In certain embodiments of the intraoperative treatment method, at least one beta blocker is administered in an amount ranging from about 0 mg / mL to about 20 mg / mL, from about 0.001 mg / mL to about 15 mg / mL, from about 0.01 mg / mL to about 10 mg / mL, from about 0.1 mg / mL to about 5 mg / mL, or from about 0.15 mg / mL to about 2.0 mg / mL. In various embodiments, the beta blocker is administered in an amount of about 0.10 mg / mL, about 0.11 mg / mL, about 0.12 mg / mL, about 0.13 mg / mL, about 0.14 mg / mL, about 0.15 mg / mL, about 0.16 mg / mL, about 0.17 mg / mL, about 0.18 mg / mL, about 0.19 mg / mL, or about 0.20 mg / mL.

[0284] In certain embodiments, additional beta blockers can be given to supplement the infusion depending on the patient's condition and response to surgery. Alternatively, the dosage / concentration of either the beta blocker or dexmedetomidine can be increased when the patient's physiological response to the surgical stimulus is observed.

[0285] In certain embodiments of the peri-operative treatment method, the opioid-free composition is administered by intramuscular administration, for example, to the individual's mid-lateral thigh and / or arm.

[0286] In some embodiments, the opioid-free composition of the present disclosure can be contained in a 5mL, 10mL, 20mL, 30mL, 50mL, or 60mL vial, syringe, or bottle. The opioid-free composition, particularly the preoperative opioid-free composition, can be reconstituted if applicable and administered undiluted by IV over a period of time, for example, about 15 minutes. Alternatively, a pharmacologic effective amount of the opioid-free composition can be drawn off in a loading dose, diluted with a 50 or 100cc IV bag / bottle of fluid, and infused IV for about 15 minutes, about 30 minutes, about 45 minutes, or about 1 hour or more.

[0287] In some embodiments, the opioid-free intraoperative compositions of the present disclosure can be administered as a continuous infusion for the duration of the surgery, which can last from less than an hour to several hours, depending on the complexity of the medical or surgical procedure.

[0288] In embodiments described herein where the opioid-free composition is used concomitantly with an additional anesthetic agent, such as propofol and / or an inhalant (anesthetic gas), the dosage requirements of the additional anesthetic agent are significantly reduced.

[0289] In certain embodiments, the reduction in the dosage of the at least one anesthetic agent is at least about 1%, about 5%, about 10%, about 25%, about 50%, about 60%, or about 75%. In some embodiments, the reduction in the dosage of the at least one anesthetic agent is at least about 1%, about 5%, about 10%, about 25%, about 50%, about 60%, or about 75%, and the at least one anesthetic agent comprises ketamine.

[0290] The following considerations should be taken into account when selecting dosages and methods of the present disclosure.

[0291] When administering an opioid-free pre-operative composition, one consideration in determining the rate of loading dose administration is how fast it can be administered without exacerbating undesirable side effects. In addition to perineal burning, common side effects from administration of a loading dose include intense generalized heat, described by patients as "hot flashes." There may be discomfort at the IV site, and in some cases, a numbness at the extremities where the IV is placed. In rare cases, there may be a feeling of generalized body weakness. The faster the injection, the more generalized and intense the symptoms. The slower the injection, the less likely the patient will notice any side effects other than sedation experienced approximately 10 minutes after the injection begins. In some embodiments, the rate is 10 mL volume (35 cc / hr) for about 15 minutes.

[0292] The OFA preemptive analgesic loading dose of the present disclosure can include dexamethasone sodium phosphate. Dexamethasone sodium phosphate is usually given after induction of anesthesia because it causes undesirable perineal burning side effects. As a result, the time between administration and mechanical tissue trauma that begins with surgical incision is shortened. However, this practice negates some of the potential benefits.

[0293] Since most OFA agents are given separately, each additional tool is perceived as an increased task by the anesthesia provider. In addition, unlike most agents used in anesthesia, which have an immediate effect upon administration, OFA agents are an exception. Therefore, the timing of administration of the composition of the present disclosure is a factor to consider.

[0294] The combined effect of the drugs in the composition of the present disclosure provides a pain control mechanism with superior analgesia beyond the mere absence of opioids. This type of opioid-free anesthesia virtually eliminates the most common "anesthesia side effects" associated with opioid drugs and provides superior pain control well beyond the intraoperative period. Opioid use two weeks after surgery is strongly correlated with opioid use one year after surgery. This is true given the known risk of postoperative opioid use disorder in opioid naive patients.

[0295] The loading dose of the drug in the perioperative composition can be infused over approximately 15 minutes prior to admitting the patient to the operating room. This allows the dexmedetomidine the time necessary to produce a calming / sedative effect, generally negating the need for administration of an anxiolytic drug prior to induction of anesthesia. The sedative effect lasts approximately 30 minutes after administration, thereby providing a state of efficacy that lasts for 45 minutes after the loading dose. If surgery is delayed for 1-2 hours after the loading dose is administered, only the loading dose of dexmedetomidine and, if used as part of a preoperative loading dose, lidocaine is repeated immediately prior to surgery.

[0296] Either an RN or an anesthesia provider can administer this loading dose composition at a precise volume and rate while assessing vital signs and level of consciousness.

[0297] Although it is not essential that the onset of sedation be established before the patient enters the operating room, it is beneficial in that it allows for the elimination of the anxiolytic Versed (midazolam), another commonly given anesthetic agent. Versed is a benzodiazepine and should be used with caution or avoided in some populations. Postoperative cognitive decline is a known side effect for which elderly patients are particularly vulnerable. It is a controlled substance and therefore there are specific protocols that require careful documentation and witnessing to obtain the medication and to dispose of any remaining medication. The medication is generally given either immediately after the patient leaves the preoperative area to enter the operating room or just before the patient arrives in the operating room. Once in the operating room, a maintenance infusion is started. The anesthetic agent propofol is generally administered as a bolus (a single dose all at once) to induce anesthesia and produce loss of consciousness. After induction, a continuous infusion of intravenous medication (propofol) and / or titration of anesthetic gases via the breathing circuit is used to maintain stage 3 anesthesia (the optimal depth of anesthesia for surgery, between consciousness and medullary depression / death). Towards the end of the procedure, the medication is shut off and the patient is awakened from anesthesia once it has worn off.

[0298] Another reason to give a loading dose agent with sufficient time before incision is to allow the steroid to become effective. The steroid is most commonly used when anesthesia practice is dexamethasone, which takes at least an hour to peak effect. Ideally, the peak effect of the steroid would be before the surgical incision, as surgical trauma will cause local inflammatory changes at the site. Dexamethasone is typically administered after the patient is asleep, because it causes the undesirable effect of intense perineal burning if dexamethasone is given rapidly to an awake patient in an IV bolus. However, this does not leave enough time for the peak effect between induction of anesthesia (and dexamethasone administration) and incision. This time lag, the "prep time," is usually 10-30 minutes, but can be as long as an hour in some cases.

[0299] In very short cases, OFA loading doses are sometimes used pre-op, but instead of performing an infusion of these agents, an incremental bolus of the components of these agents is given, including ketamine, dexmedetomidine, and lidocaine. Some surgical / procedural cases are only 10-15 minutes long. If an infusion is performed, it takes 20+ minutes for the onset of action of the infusion to be observed. Another time-sensitive consideration is that ideally the infusion should be shut off approximately 20 minutes before emergence from anesthesia. If the infusion is continued until the very end of the incision suturing, there will be a long lag time before awakening, which is undesirable in any case. This is especially true if the patient has an advanced airway in place that needs to be removed (extubated from the pt) before leaving the operating room. There are very few cases (major hospitals doing major surgery) where the patient can remain intubated. The majority of cases performed in the US are outpatient. Thus, this type of anesthesia is preferably applicable in the outpatient setting, which is generally a shorter duration case in healthier patients. In the outpatient setting, there is a higher utilization of bolus dosing of some of these drugs, so the peak onset of action is likely to be reached quickly and offset well predictable / timed. In the surgical setting, time equals money, so offset timing is of the utmost importance.

[0300] 4.5 series In one aspect, the present disclosure provides a system for anesthesia applications.

[0301] In the embodiments described herein, magnesium salts, alpha-2 agonists, and optionally sodium channel inhibitors, corticosteroids, beta blockers, and NMDA antagonists other than magnesium may be included in opioid-free pre-operative, opioid-free intra-operative, opioid-free post-operative, and / or opioid-free peri-operative systems in accordance with the present disclosure.

[0302] In the opioid-free systems of the present disclosure, the magnesium salt, alpha-2 agonist, and optionally the sodium channel inhibitor, corticosteroid, beta blocker, and NMDA antagonist other than magnesium may be formulated in separate dosage forms that are provided as part of the system in various combinations with each other according to the present disclosure.

[0303] Thus, in some embodiments, the agents and related compositions of the present disclosure are provided as part of an opioid-free perioperative system for opioid-free perioperative treatment of an individual. The opioid-free pre- and intraoperative system can include magnesium salts, alpha-2 agonists, and optionally NMDA antagonists other than magnesium salts, sodium channel inhibitors, beta blockers, and / or corticosteroids.

[0304] In the opioid-free pre-operative system, the magnesium salt, alpha-2 agonist, and optionally the sodium channel blocker, NMDA antagonist other than magnesium salt, and / or corticosteroid are included in effective amounts for simultaneous, combined, or sequential use as described herein. Optionally, the opioid-free pre-operative system can further include a calcium channel blocker, a Cox inhibitor, a corticosteroid, a GABA analog, an antidepressant, cannabidiol (CBD), and / or an antiemetic for simultaneous, combined, or sequential use as described herein.

[0305] In some embodiments, the system may include one or more agents of the present disclosure in combination with one or more agents for the treatment of conditions associated with surgery. In the system, the components may be included in the composition, if possible, together with a suitable vehicle, carrier or excipient, including carriers or adjuvants as will be understood by those skilled in the art, and may be included in the system independently.

[0306] Typically, in the systems of the present disclosure, one or more agents are provided as separate dosage forms that are combined at an appropriate time during, before or after a medical or surgical procedure to provide an opioid-free composition of the present disclosure and / or to practice any one of the methods described herein.

[0307] In some embodiments, the system can include a magnesium salt composition, an alpha-2 agonist composition, a sodium channel inhibitor composition, and optionally an NMDA antagonist other than a magnesium salt composition, a beta blocker composition, and / or a corticosteroid composition, in any combination, optionally further including a pharma- ceutically acceptable vehicle, carrier, or excipient. In these embodiments, each composition includes the corresponding agent together with a pharma- ceutically acceptable vehicle in a separate dosage form that is combined to provide a pre-operative, intra-operative, or post-operative opioid-free composition of the present disclosure and / or administered by any one of the methods described herein.

[0308] In some embodiments, the system comprises: (1) a magnesium salt composition having a concentration as described in any one of Sections 4.2.1, 4.2.2, or 4.2.3 for opioid-free compositions comprising a magnesium salt; (2) an alpha-2 agonist composition having a concentration as described in any one of Sections 4.2.1, 4.2.2 or 4.2.3 for opioid-free compositions comprising an alpha-2 agonist; (3) a sodium channel blocking composition having a concentration as described in any one of Sections 4.2.1, 4.2.2 or 4.2.3 for opioid-free compositions comprising a sodium channel blocker; and, where appropriate, (4) an NMDA antagonist other than a magnesium salt composition, in a concentration as described in any one of Sections 4.2.1, 4.2.2, or 4.2.3 for opioid-free compositions comprising an NMDA antagonist other than a magnesium salt; and / or (5) a beta blocker composition in a concentration as described in any one of Sections 4.2.1, 4.2.2, or 4.2.3 for opioid-free compositions containing a beta blocker; and / or (6) a corticosteroid composition having a concentration as described in any one of Sections 4.2.1, 4.2.2, or 4.2.3 for opioid-free compositions containing a corticosteroid; and, where appropriate, containers may be included in combination to provide any one of the opioid-free compositions of the present disclosure and / or administered by any one of the methods described herein.

[0309] The particular magnesium salts, alpha-2 agonists, and sodium channel inhibitors, and optionally NMDA antagonists, beta blockers and corticosteroids other than magnesium salts, provided to the system are selected from those disclosed above in connection with the opioid-free compositions in Section 4.2.

[0310] In one embodiment, the disclosure provides a system for opioid-free pre-operative treatment of an individual, the system comprising a magnesium salt, an alpha-2 agonist, and optionally a sodium channel inhibitor, an N-methyl-D-aspartate receptor (NMDA) inhibitor other than a magnesium salt, and / or a corticosteroid.

[0311] In a second embodiment, the disclosure provides a system for opioid-free perioperative treatment of an individual, the system comprising a magnesium salt, an alpha-2 agonist, a sodium channel inhibitor, and optionally an NMDA inhibitor other than a magnesium salt, and / or a beta blocker.

[0312] In a third embodiment, the present disclosure provides a system for opioid-free post-operative treatment of an individual, the system comprising one or more of a magnesium salt, an alpha-2 agonist, a sodium channel inhibitor, an NMDA inhibitor other than a magnesium salt, and a beta blocker.

[0313] In systems for opioid-free pre-surgical treatment of an individual, the magnesium salt, alpha-2 agonist, and optionally a sodium channel blocker, an NMDA inhibitor other than a magnesium salt, and / or a corticosteroid are included in amounts effective for simultaneous, combined, or sequential use to prepare the pre-surgical compositions described herein.

[0314] In systems for opioid-free perioperative treatment of an individual, the magnesium salt, alpha-2 agonist, sodium channel inhibitor, and optionally an NMDA antagonist and / or beta blocker other than a magnesium salt are included in amounts effective for simultaneous, combined, or sequential use to prepare the perioperative compositions described herein.

[0315] In systems for opioid-free post-operative treatment of an individual, one or more of the magnesium salt, alpha-2 agonist, sodium channel inhibitor, NMDA antagonist other than a magnesium salt, and / or beta blocker are included in amounts effective for simultaneous, combined, or sequential use to prepare the post-operative compositions described herein.

[0316] Thus, in some embodiments, the systems of the present disclosure can further comprise a pharma- ceutically acceptable vehicle, carrier, or excipient that is combined with and / or administered by any one of the methods described herein to provide the opioid-free pre-operative, intra-operative, or post-operative compositions of the present disclosure.

[0317] In some embodiments, the compositions described herein can be premixed by a manufacturer, and the donor does not need to mix the agents contained in the composition. Optionally, the donor is provided with instructions on how to administer the composition.

[0318] In each of the above-described embodiments, the containers containing the individual components or opioid-free compositions of the present disclosure can be syringes, IV bags, bottles, or vials of various sizes and shapes.The containers can be glass or plastic (e.g., polyethylene, polypropylene, polyvinyl chloride, or polypropylene-polyethylene blends).

[0319] In embodiments in which the opioid-free pharmaceutical composition of the present disclosure is contained in an IV bag, the size of the IV bag can be 25 mL, 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 300 mL, 400 mL, 500 mL, or 1000 mL.

[0320] In embodiments in which the opioid-free pharmaceutical composition of the present disclosure is contained in a syringe, the syringe may be 1, 3, 5, 10, 12, 20, 25, 30, 50 or 60 mL in size.

[0321] In embodiments in which the opioid-free pharmaceutical composition of the present disclosure is contained in a vial, the vial may be 2, 5, 10, 20, 25, 30, 50, 60, 100 mL in size.

[0322] In embodiments in which the opioid-free pharmaceutical composition of the present disclosure is contained in a bottle, the bottle may be 10, 20, 50, 100, 250, or 500 mL in size.

[0323] 4.6 Kits Containing Opioid-Free Compositions The present disclosure provides a kit of parts for carrying out any of the methods described herein.In one particular embodiment, the kit for opioid-free pre-operative treatment comprises a magnesium salt, an alpha-2 agonist, and optionally a sodium channel inhibitor, an N-methyl-D-aspartate receptor (NMDA) inhibitor other than a magnesium salt, and / or a corticosteroid.In certain embodiments, the kit comprises individual components in separate containers or formulated together in one container as an opioid-free pre-operative composition.

[0324] In another specific embodiment, a kit for an opioid-free intraoperative composition includes a magnesium salt, an alpha-2 agonist, a sodium channel inhibitor, and optionally an NMDA antagonist other than a magnesium salt, and / or a beta blocker. In certain embodiments, the kit includes the individual components in separate containers or formulated together in one container as an opioid-free intraoperative composition.

[0325] In another specific embodiment, a kit for an opioid-free perioperative composition comprises an opioid-free preoperative composition of the present disclosure and an opioid-free intraoperative composition of the present disclosure. In certain embodiments, the kit further comprises a postoperative composition of the present disclosure.

[0326] In various embodiments, the kit-of-parts further comprises one or more additional agents described herein, such as a calcium channel blocker, a Cox inhibitor, a corticosteroid, a GABA analog, an antidepressant, cannabidiol (CBD) and / or an antiemetic agent, as well as additional components ascertainable by one of skill in the art.

[0327] In one embodiment, the kit-of-parts further comprises a standard.

[0328] In each of the above-described embodiments, the containers containing the individual components or opioid-free compositions of the present disclosure can be syringes, IV bags, bottles, or vials of various sizes and shapes.The containers can be glass or plastic (e.g., polyethylene, polypropylene, polyvinyl chloride, or polypropylene-polyethylene blends).

[0329] In embodiments in which the opioid-free pharmaceutical composition of the present disclosure is contained in an IV bag, the size of the IV bag can be 25 mL, 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 300 mL, 400 mL, 500 mL, or 1000 mL.

[0330] In one embodiment, the kit of parts further comprises instructions for use.Instructions, such as written or audio instructions, are usually included in the kit, either on paper or by electronic support such as tape, CD-ROM, flash drive, or by Uniform Resource Locator (URL) instructions, including but not limited to YouTube tutorials that contain pdf copies of instructions for carrying out the methods described herein.The kit can also contain other packaged reagents and materials, depending on the specific method used.Further details regarding the identification of suitable vehicles, carriers or excipients for the composition, as well as the general manufacture and packaging of the kit, can be ascertained by those skilled in the art upon reading this disclosure.

[0331] The present disclosure also provides a computer-based or mobile device-based application ("app") for use in the methods of the present disclosure. The app can be devised to aid an operator (e.g., anesthesia provider) in providing a patient with appropriate pre-operative, intra-operative, post-operative, and / or peri-operative dosages of the drugs described herein, and includes instructions for preparation of the associated composition and / or instructions for associated administration to the patient. The app can devise drug labels to identify the desired mixture contents and / or patient, and / or for the provider to identify preparation information and / or date and time.

[0332] Further features and attributes of the present disclosure will become more apparent from the following detailed disclosure, given by way of example only with reference to the examples. EXAMPLES

[0333] 6. Working Example The compounds, materials, compositions, methods, and systems described herein are further illustrated by the following examples, which are provided by way of illustration and are not intended to limit the scope of the disclosed subject matter.

[0334] In particular, the following examples illustrate exemplary compositions of the present disclosure, and related methods and systems, where the individual is a human patient. Those skilled in the art will recognize the applicability and necessary modifications to adapt the features detailed in the present invention section to additional compositions, methods and systems according to embodiments of the present disclosure. Section 1.01 [Example 1]

[0335] Analgesia Protocol The following materials were used in the examples: -Dexmedetomidine hydrochloride 200mcg / 2mL -Ketamine hydrochloride 500mg / 10mL -Magnesium sulfate 5g / 10m -Esmolol hydrochloride 100mg / 10mL -Lidocaine hydrochloride 2% -Dexamethasone sodium phosphate 10mg / 1mL These materials are available from commercial suppliers such as Hspira, West Ward, Accord, or Fresenius. The pain protocol described below consists of: (1) preoperative at home, (2) preoperative in the hospital ward, (3) preoperative hold IV bolus over 15 minutes, (4) preoperative block, (5) intraoperative, (6) OFA infusion mix instructions, and (7) additional medication regimen. Section 1.02 [Example 1.1]

[0336] Preoperative regimen at home Duloxetine is given to patients 1 to 2 weeks before undergoing surgery that carries a high risk of developing chronic pain, including, but not limited to, amputation, mastectomy, thoracotomy, inguinal hernia repair, coronary artery bypass surgery, cesarean section, scoliosis correction surgery, bimalleolleolar ankle fracture surgery, Achilles tendon repair, thoracotomy, anterior lumbar surgery, abdominal surgery, breast cancer surgery, superficial melanoma excision, dental implants, laparoscopic hernia repair, hip fracture surgery, and arthroplasty. Section 1.03 [Example 1.2]

[0337] Preoperative regimen in the ward The following medications were provided to patients prior to surgery: a) Acetaminophen 1 gm PO or IV acetaminophen 1 gm IVPB before incision. b) Celecoxib 200-400 mg PO (unless allergic to sulfa drugs) or meloxicam 15 mg. c) Pregabalin 50mg to 150mg for neuropathic pain, dose based on: i) 50 mg of pregabalin if the patient is 65 years of age or older, or ii) 75 mg of pregabalin if the patient is under 65 years of age; iii) 150 mg if the patient is routinely taking high doses of pregabalin prior to surgery. Section 1.04 [Example 1]

[0338] Preoperative waiting regimen of the intraoperative composition of the present disclosure A bolus dose of the opioid-free pre-operative composition was administered in a 10 mL syringe as follows: 6 mL of magnesium sulfate (500 mg / mL), 1.5 mL of dexamethasone (10 mg / mL), 0.3 mL of dexmedetomidine (100 mcg / mL), and 2.2 mL of 2% lidocaine was prepared by combining

[0339] The preoperative opioid-free composition was administered to the patient at 1 mL / 10 kg IBW over 15-30 min (30 mg / kg Mg 2+ , which translates to a dosing of 0.3mcg / kg dexmedetomidine, 0.15mg / kg dexamethasone and 0.44mg / kg lidocaine).

[0340] When considering preoperative loading, the following comes to mind: Dexmedetomidine 0.3mcg / kg. IV dexmedetomidine has a peak effect of 15 minutes. If the patient is adequately calmed / sedated after using dexmedetomidine, pre-op benzodiazepines can be eliminated. Magnesium sulfate 30mg / kg. Dexamethasone 0.15 mg / kg. Dexamethasone has an onset of action of 2 hours. The most preferred technique is to inject well before incision when used to reduce inflammation / pain. For the purpose of opioid-free anesthesia, dexamethasone is used at higher dosages than those commonly used for anesthesia for postoperative nausea and vomiting (PONV) prophylaxis. Lidocaine to fill to 10 mL volume. Once excess drug was discarded from the syringe (weight based dose), the remaining volume was refilled with 2% lidocaine to the 10 cc mark and infused at 35 cc / hr resulting in a 17 minute long infusion, thus providing ease of use for the drugs described herein. Section 1.05 [Example 1.4]

[0341] Administration of preoperative block If administering a preoperative block (e.g., nerve block or fascial plane block), dexamethasone and dexmedetomidine can be used as additives. Alternatively, liposomal bupivacaine or a continuous nerve block catheter can be used, if indicated. Section 1.06 [Example 1.5]

[0342] Intraoperative regimen The intraoperative phase can be described as the period during which the patient is admitted to the area where the procedure is to be performed. The intraoperative phase ends when the patient is admitted to the postoperative care unit.

[0343] During the intraoperative phase, prior to induction, patients received: Ketamine 10–15 mg IVP 1–5 min prior to incision and / or intubation. Once the pre-operative infusion was completed and the patient entered the operating room, the patient was given an opioid-free intra-operative composition prepared as described in Example 1.6 below. Nitrous oxide was administered as a low-flow fresh gas nitrous oxide of 50–70%. Section 1.07 [Example 1.6]

[0344] Preparation and Administration of OFA Compositions The following are instructions for preparing the opioid-free intraoperative composition of the present disclosure: Remove 15 mL of fluid from a 100 mL IV bag. Add the following to the IV bag: 10 mL of lidocaine 2%, 2 mL of magnesium sulfate (500 mg / mL) 1.8 mL of esmolol (10 mg / mL) 0.3 mL of dexmedetomidine (100 mcg / mL) (an additional 0.1 mL can be added incrementally to modulate the sympathetic nervous system), 0.25 mL of ketamine (50 mg / mL).

[0345] The following are directions for administering the opioid-free intraoperative compositions of the present disclosure: This should be performed at 1mL / kg / hr IBW. IV infusion dosage: Lido (1% or 2%) at 2mg / kg / hr IBW, Magnesium sulfate at 10mg / kg / hr IBW, Dexmedetomidine at 0.3-1 mcg / kg / hr IBW depending on how the treatment is stimulated in the patient. For OFA medications, esmolol 3-15 mcg / kg / min IWB or up to 300 mcg / kg / min IBW for reduction of hypertension / tachycardia; Preferably prior to incision, if a nerve block is not used, assist the surgeon by infiltrating the surgical site with local anesthesia preferably ketamine at a total dose of 0.5 mg / kg IBW for the duration of the case. Section 1.08 [Example 1.7]

[0346] Additional drug regimens The intraoperative phase can be described as the period during which the patient is admitted to the area where the procedure is to be performed. The intraoperative phase ends when the patient is admitted to the postoperative care unit.

[0347] Below is a regimen of additional medications administered during the intra-operative and post-operative phases of a surgical procedure. The regimen of additional medications is intended to provide improved post-operative pain control to patients undergoing surgery. Acetaminophen 1 gm PO q8 hours routine, discontinue if consuming other acetaminophen-containing medications, e.g., hydrocodone acetaminophen. Celecoxib 100-200 mg PO q12 hours routine. Pregabalin 50-150mg qHS routine.

[0348] In major surgical cases where the patient is admitted to the hospital for postoperative care, on the first postoperative day, 10 mg IV dexamethasone should be given slowly over 10 minutes.

[0349] Continue duloxetine for 2 weeks after surgery in patients at high risk of developing chronic postoperative pain syndrome.

[0350] [Table 1] TIFF2024518865000002.tif103153

[0351] In major surgical cases where the patient is admitted to the hospital for postoperative care, on the first postoperative day, 10 mg IV dexamethasone should be given slowly over 10 minutes.

[0352] Continue duloxetine for 2 weeks after surgery in patients at high risk of developing chronic postoperative pain syndrome. Section 1.09 [Example 2]

[0353] Injection range and loading volume Exemplary infusion ranges (concentrations) and loading amounts selected for the drugs are shown in Table 1 below. Section 1.10 [Example 3]

[0354] Comparison of MuliMix with exemplary OFA compositions MuliMix, described in Mulier, “Is opioid-free general anesthesia for breast and gynecological surgery a viable option?” Vol 32 No. 3, pp. 2567-262, June 2019, is compared to the preemptive analgesic OFA compositions described herein and shown in Table 2 below.

[0355] [Table 2] TIFF2024518865000004.tif180156 TIFF2024518865000005.tif203153 TIFF2024518865000006.tif191153 TIFF2024518865000007.tif187153

[0356] [Table 3] TIFF2024518865000009.tif56152

[0357] The difference between the components of MuliMix composition and the exemplary OFA composition is clear. The OFA preemptive analgesia composition of the present disclosure has a significantly higher dosage than MuliMix and can be used in the preoperative and postoperative periods. There is a dose-response curve for dexmedetomidine, lidocaine and ketamine. The higher the dosage, the greater the sedative effect. The OFA preemptive analgesia composition of the present disclosure with a higher dosage results in a more significant reduction in other anesthetic agents, such as propofol injection, or anesthetic gases, such as sevoflurane, desflurane or isoflurane.

[0358] OFA preemptive analgesia protocol has a preoperative loading dose and an intraoperative infusion. These two formulations have different drugs and concentrations intended for separate and specific purposes. The loading dose is intended to rapidly increase the plasma levels of the OFA agent, so that the therapeutic onset is much more rapid than intraoperative infusion alone. This differs from the MuliMix protocol, which uses the same concentrations in each of the sequential steps, except for the dexmedetomidine loading dose (see Table 2). The loading dose of the protocol described herein is used for outpatient surgery / short-term cases where continuous infusion is excluded. In short-term cases, instead of infusion, we give increasing doses of some of the drugs that typically frontload with a 10mcg bolus of dexmedetomidine, ketamine, and lidocaine, which are commonly mixed with propofol to prevent a burning sensation at the IV site when propofol is administered. Since the loading dose alone is sufficient to cover short-term cases where infusions are not continued, Mg 2+ MuliMix does not include Mg in the mixture. 2+ or dexamethasone sodium phosphate, but suggests that these components be considered for use as part of the anesthetic. Premedication is also on the list to be considered, but unlike the OFA protocol described herein, is not identified as a requirement of the protocol.

[0359] Mg 2+When salts are loaded as an adjunct in the MuliMix protocol, they are instructed to be given as a hand delivered IV push (for a few seconds). When this is done, even if the dose is split into two or more boluses, a substantial drop in blood pressure is observed, especially when under anesthesia / induction. It is not ideal to administer the drug in a way that promotes a drop in blood pressure after induction. There is generally a delay between the induction of anesthesia (putting the patient to sleep) and the stimulation of the surgical incision. This time is often associated with a drop in blood pressure, since the patient is given a large dose of anesthesia to insert the breathing apparatus, but there is no further stimulation until the incision is made. During this time, the surgical team usually positions the patient, sterilizes the area, drapes, prepares instruments, etc. It is an undesirable time to give the drug, as it tends to promote a drop in blood pressure. This is another reason why opioid-free anesthetics are superior to opioid-based anesthesia, where fentanyl, for example, is routinely given for induction of anesthesia before inserting the airway. Fentanyl interacts synergistically with other agents, such as Versed, to promote hypotension during this pause and also to prevent the patient from breathing on their own for several minutes until ETCO2 is increased enough to drive respiration. This requires manual ventilation if the patient is not mechanically ventilated, creating extra work for the provider and potentially a safety concern if the airway is not accessible and patent. Section 1.11

[0360] [Table 4] TIFF2024518865000011.tif234155 TIFF2024518865000012.tif173155 TIFF2024518865000013.tif176153 TIFF2024518865000014.tif75153 McLott Mix, described on the World Wide Web at mclottmix.com, is compared to the preemptive analgesic OFA compositions of the present disclosure and are shown in Table 4 below.

[0361] The difference between McLott Mix and the exemplary OFA composition of the present disclosure is clear. Unlike the opioid-free pre-operative composition of the present disclosure, McLott does not provide any pre-operative oral medication. Rather, McLott Mix is ​​referred to only as an intra-operative composition. McLott's OFA induction is not said to be essential or an integral part of the McLott method. It does not appear to be a similar protocol to the method of the present disclosure.

[0362] In McLott Mix, Mg 2+ The loading dose is not weight-based, which results in under-medication for most adult patients. In contrast, in some embodiments, the opioid-free intraoperative composition and / or method provides a specific weight-based dose of Mg that is known to have clinical efficacy. 2+ Use a load.

[0363] In addition, nalbuphine (Nubain) is listed as part of McLott's OFA derivation. Nalbuphine is a synthetic opioid agonist-antagonist analgesic of the phenanthrene series. It binds to mu, kappa and delta receptors and has analgesic potency equivalent to morphine. Drug abuse and nalbuphine-related addiction have been reported among health care providers, patients and the general public (see drugs.com / pro / nubain.htm & https: / / app.plumbs.com / drug-monograph / UsBzNf0XCMPROD?source=search&searchQuery=Nubain on the World Wide Web). In contrast, the opioid-free composition and associated method of the present disclosure are completely opioid-free.

[0364] Another difference between McLott and the disclosed method is the timing of dexmedetomidine administration. In McLott, dexmedetomidine is administered at induction and not preoperatively. If dexmedetomidine is not given in the preoperative holding area, there is no additional benefit of anxiolysis in the preoperative phase. In addition, giving dexmedetomidine as a bolus at induction is known to cause a temporary increase in blood pressure followed by a decrease in blood pressure, making this timing particularly problematic. Immediately after induction, the airway creation procedure (intubation) can cause a temporary increase in blood pressure and tachycardia. Once the airway is created, it is quite common for a period of significant blood pressure decrease to occur until the start of surgery. If dexmedetomidine is given as a bolus at induction, there is a high probability of these problematic extreme hemodynamics worsening.

[0365] The McLott method does not include a corticosteroid as a pre-operative or induction agent. In contrast, the opioid-free pre-operative compositions and associated methods of the present disclosure include a corticosteroid to help reduce the inflammatory response and post-operative pain.

[0366] The McLott Mix intraoperative infusion is approximately twice as concentrated as the opioid-free intraoperative composition of the present disclosure. McLott's instructions are to give 0.5cc / kg versus 1mL / kg. This adds an additional mathematical step to the administration process. The dosing of dexmedetomidine is higher in the McLott Mix and therefore more likely to cause hypotension and bradycardia side effects compared to the opioid-free intraoperative composition of the present disclosure. Advantageously, the infusion of the opioid-free intraoperative composition of the present disclosure begins at a lower dosing of dexmedetomidine, thus providing the option to increase the dosing of dexmedetomidine if indicated by the patient's response to surgery. The opioid-free intraoperative composition of the present disclosure also uses a low dose of a short-acting beta blocker, which differs from the McLott Mix and adds an additional pathway to block pain. Beta blockers are known to reduce the neuroendocrine stress response, resulting in reduced pro-inflammatory cytokines and NMDA receptor activation. Section 1.12 [Example 5]

[0367] Preparation of an exemplary pre-operative OFA composition of the present disclosure in a loading syringe The pre-operative OFA composition was prepared by mixing the individual component drugs in a syringe, including lidocaine (2% of 44 mg / 2.2 mL), magnesium sulfate (50% of 3 gm / 6 mL), dexmedetomidine (10% of 30 mcg / 0.3 mL) and dexamethasone (1% of 15 mg / 1.5 mL) in a final volume dose of 10 mL in a syringe.

[0368] The individual component drugs used in Example 5 are shown in FIG. Section 1.13 [Example 6]

[0369] Preparation of exemplary intraoperative OFA compositions of the present disclosure Exemplary infusion ranges selected for drug concentrations and doses in a 100 mL IV bag are shown, for example, in the table shown in FIG.

[0370] The intraoperative OFA composition was prepared by mixing the individual component drugs in a 100 mL IV bag. The individual component drugs in the intraoperative OFA composition include lidocaine (200 mg), magnesium sulfate (1 g), dexmedetomidine (0.3 mcg), ketamine (25 mg) and esmolol HCL (18 mg) in a final volume of 100 mL in the IV bag.

[0371] Intraoperative OFA compositions were infused at a rate of 1 cc / kg / hr of patient IBW.

[0372] The individual component drugs used in Example 5 are shown in Figure 11. Example 7: Exemplary Doses and Ranges of Exemplary OFA Compositions of the Disclosure

[0373] A 50 kg patient should be administered the composition described below.

[0374] Lowest preoperative loading dose of most concentrated composition (excluding optional components) 250 mg (0.5 mL of 50%) Magnesium sulfate (5 mg / kg) 5mcg (10% in 0.05mL) dexmedetomidine (0.1mcg / kg) Dexamethasone – as needed Ketamine - as needed Lidocaine - as needed

[0375] Intraoperative infusion - maximum concentrated infusion possible - (excluding the lowest possible dose of all components except the component being tested, except for the appropriate component) 250 mg (0.5 mL of 50%) magnesium sulfate (5 mg / kg / hr) 25 mg (0.65 mL of 4%) lidocaine (0.5 mg / kg / hr) 5mcg 5mcg (10% of 0.05mL) Dexmedetomidine (0.1mcg / kg / hr) Ketamine - as appropriate as described herein Esmolol - as appropriate as described herein

[0376] The following calculations can be performed to ascertain the maximum concentrations of various drugs.

[0377] Calculation for maximum concentration of magnesium sulfate Section 1.14 Preoperative Loading: Minimum: 1mg / mL Maximum: 500 mg / mL. 500 mg / mL is slightly higher than the actual (495 mg / mL), but within reasonable limits, since the only other anhydrous agent is dexmedetomidine, which is nearly eliminated. 50kg pt (maximum concentrated magnesium load) 2500mg (50% of 5mL) Mg+ (50mg / kg) 5mcg (10% in 0.05mL) dexmedetomidine (0.1mcg / kg) Dexamethasone – as needed Ketamine - as needed Lidocaine - as needed = 5.05mL total volume 2500mg / 5.05mL=495mg / mL Section 1.15 Intraoperative Injections: Minimum: 1mg / mL Maximum: approx. 370mg / mL 50kg pt (maximum concentrated Mg++ injected) 1GM (2 mL of 50%) Magnesium Sulfate (20 mg / kg) - Highest dose of magnesium sulfate 25 mg (0.65 mL of 4%) lidocaine (0.5 mg / kg / hr) 5mcg (0.05mL of 10%) dexmedetomidine (0.1mcg / kg / hr) Ketamine - as appropriate as described herein Esmolol - as appropriate as described herein = 2.7mL total volume 1000mg / 2.75mL=370mg / mL

[0378] Calculation for maximum concentration of dexmedetomidine Section 1.16 Preoperative Loading: Minimum: 0.01mcg / mL Maximum: 50mcg / mL 50kg pt (maximum concentrated dexmedetomidine loading dose) 250mg (50% of 5mL) Mg+ (5mg / kg) 50 mcg (10% in 0.5 mL) dexmedetomidine (1 mcg / kg) - maximum loading dose Dexamethasone – as needed Ketamine - as needed Lidocaine - as needed = 1mL total volume 50mcg / 1mL=50mcg / mL Section 1.17 Intraoperative Injections: Minimum: 0.01mcg / mL Maximum: 30mcg / mL 50kg pt (maximum concentrated dexmedetomidine infusion) 250 mg (0.5 mL of 50%) magnesium sulfate (5 mg / kg / hr) 25 mg (0.65 mL of 4%) lidocaine (0.5 mg / kg / hr) 50 mcg (10% in 0.5 mL) dexmedetomidine (1 mcg / kg) - maximum infusion dose Ketamine - as appropriate as described Esmolol - as needed as indicated =1.65mL 50mcg / 1.65mL=30mcg / mL

[0379] Calculations for Maximum Concentration of Lidocaine Section 1.18 Preoperative Loading: Minimum: 0 mg / mL - Loading dose as needed Maximum: 35mg / mL 50kg pt (maximum concentrated lidocaine load) 250mg (50% of 0.5mL) Mg+ (5mg / kg) 5mcg (10% in 0.05mL) dexmedetomidine (0.1mcg / kg) Dexamethasone – as needed Ketamine - as needed 100 mg (4% of 2.5 mL) Lidocaine (2mg / mL) =3.05mL 100mg / 3.05mL=33mg / mL Section 1.19 Intraoperative Injections: Minimum: 0.1 mg / mL OFA composition dosage use 50 kg pt (minimum concentrated lidocaine maximum dose in all other cases - injected) - could have included the smaller concentration from the original vial but did not. Rounded. 1000 mg (2 mL of 50%) magnesium sulfate (20 mg / kg / hr) 25 mg (0.65 mL of 4%) lidocaine (0.5 mg / kg / hr) 50mcg (10% in 0.5mL) dexmedetomidine (1mcg / kg / hr) 25 mg (0.5 mL of 5%) ketamine (0.5 mg / kg / hr) 50mg (6mL of 1%) esmolol (20mcg / kg / hr)-OFA dosing =9.65mL 25mg / 9.65mL=2.6mg / mL Minimum: 0.1 mg / mL - Use maximum esmolol dosing for hypertensive crises 50kg pt (minimum concentrated lidocaine maximum dose in all other cases - injected) - could have included the smaller concentration in the original vial but did not. Rounded. 1000mg (50% of 2mL) Mg+ (20mg / kg / hr) 25 mg (0.65 mL of 4%) lidocaine (0.5 mg / kg / hr) 50mcg (10% in 0.5mL) dexmedetomidine (1mcg / kg / hr) 25 mg (0.5 mL of 5%) ketamine (0.5 mg / kg / hr) Esmolol 900 mg (1% in 90 mL) (300 mcg / kg / hr) - Hypertensive crisis medication =92.65mL 25mg / 92.65mL=0.27mg / mL Maximum: 35mg / mL 50 kg pt (maximum concentrated lidocaine infusion - minimum dose in all other cases) 250 mg (0.5 mL of 50%) magnesium sulfate (5 mg / kg / hr) 150 mg (3.75 mL of 4%) lidocaine (3 mg / kg / hr) 5 mcg (10% in 0.05 mL) Dexmedetomidine (0.1 mcg / kg / hr) Ketamine - as appropriate as described Esmolol - as needed as indicated = 4.3 mL 150mg / 4.3mL=34.88mg / mL

[0380] Calculation for Maximum Concentration of Ketamine Section 1.20 Preoperative Loading: Minimum: 0mg / mL - as appropriate Maximum: 35mg / mL 50kg pt (maximum concentrated ketamine infusion - minimum dose in all other cases) 250 mg (0.5 mL of 50%) Magnesium sulfate (5 mg / kg) 5mcg (10% in 0.05mL) dexmedetomidine (0.1mcg / kg) Dexamethasone – as needed 25 mg (0.25 mL of 10%) ketamine (0.5 mg / kg) Lidocaine - as needed =0.8mL 25mg / 0.8mL=31.25mg / mL Intraoperative injection: Minimum: 0mg / mL - as appropriate Maximum: 20mg / mL 50 kg pt (maximum concentrated lidocaine infusion - minimum dose in all other cases) 250 mg (0.5 mL of 50%) magnesium sulfate (5 mg / kg / hr) 25 mg (0.65 mL of 4%) lidocaine (0.5 mg / kg / hr) 5mcg (0.05mL of 10%) dexmedetomidine (0.1mcg / kg / hr) 25 mg of ketamine (0.25 mL of 10%) ketamine (0.5 mg / kg / hr) Esmolol - as needed as indicated =1.45mL 25mg / 1.45=17.24mg / mL

[0381] Calculation for maximum concentration of esmolol Preoperative loading amount: Intraoperative injection: Minimum: 0mg - as appropriate Maximum: 14.3mg / mL OFA esmolol dosage (for pain relief only) 250mg (50% of 0.5mL) Mg+ (5mg / kg / hr) 25 mg (0.65 mL of 4%) lidocaine (0.5 mg / kg / hr) 5mcg (0.05mL of 10%) dexmedetomidine (0.1mcg / kg / hr) Ketamine - as appropriate as described herein 60 g (2% of 3 mL) esmolol (20 mcg / kg / min) = 4.2 mL 60mg / 4.2mL=14.3mg / mL

[0382] Max: 19.5 mg / mL - Esmolol Dosage for Hypertensive Crises Higher doses of 21-300 mcg / kg / min are for hypertensive emergencies and are outside the scope of this invention (other than for analgesic purposes). This esmolol dosage should be administered as a separate infusion. 250mg (50% of 0.5mL) Mg+ (5mg / kg / hr) 25 mg (0.65 mL of 4%) lidocaine (0.5 mg / kg / hr) 5mcg (0.05mL of 10%) dexmedetomidine (0.1mcg / kg / hr) Ketamine - as appropriate as described herein 900 mg (2% in 45 mL) esmolol (300 mcg / kg / min) =46.2mL 900mg / 46.2mL=19.5mg / mL

[0383] Calculations for maximum concentration of dexamethasone Section 1.21 Preoperative Loading: Minimum: 0mg / mL - as appropriate Maximum: 10mg / mL 50kg pt (maximum concentrated dexamethasone infusion - minimum dose in all other cases) 250 mg (0.5 mL of 50%) Magnesium sulfate (5 mg / kg) 5mcg (10% in 0.05mL) dexmedetomidine (0.1mcg / kg) 10 mg (0.5 mL of 2%) dexamethasone (0.2 mg / kg) Ketamine - as needed Lidocaine - as needed =1.05mL 10 mg / 1.05 mL = 9.52 mg / kg Section 1.22 [Example 9]

[0384] Preparation of an exemplary opioid-free pre-surgical composition of the present disclosure Exemplary pre-surgical compositions according to the present disclosure are reported in Table 5.

[0385] [Table 5] Section 1.23 [Example 10]

[0386] Minimum and Maximum Doses of the Opioid-Free Pre-Surgical Compositions of the Present Disclosure Exemplary minimum and maximum doses of the pre-emptive pre-operative composition in bolus form are provided in Table 6 below.

[0387] [Table 6] Section 1.24 Section 1.25 [Example 11]

[0388] Dosage of opioid-free pre-operative composition Exemplary dosages of the pre-emptive pre-operative composition in bolus form are provided in Table 7 below.

[0389] [Table 7] Additional medications can be administered separately, if needed, either as an infusion or a slow IV bolus, and include dexmedetomidine, and / or magnesium sulfate, and / or dexamethasone, and / or ketamine, and / or lidocaine. Section 1.26 [Example 12]

[0390] Minimum and Maximum Doses of the Opioid-Free Intraoperative Compositions of the Present Disclosure Exemplary weight-based minimum and maximum doses in units / kg / hr of an exemplary opioid-free intraoperative composition of the present disclosure are provided in Table 8. The intraoperative composition is administered as a continuous infusion.

[0391] [Table 8]

[0392] Additional medications may be administered separately, as continuous infusion or as a bolus, if necessary, and include lidocaine 4%, and / or magnesium, and / or dexamethasone, ketamine 100 mg / mL, and / or esmolol, and / or ketamine. Section 1.27 [Example 13]

[0393] Minimum and Maximum Doses of the Opioid-Free Intraoperative Compositions of the Present Disclosure The minimum and maximum doses of exemplary opioid-free intraoperative compositions of the present disclosure are provided in Table 9 in ml / hr (original vial).

[0394] [Table 9] Section 1.28 [Example 14]

[0395] Weight-Based Minimum and Maximum Doses of the Opioid-Free Intraoperative Compositions of the Present Disclosure Weight-based minimum and maximum doses of exemplary opioid-free intraoperative compositions of the present disclosure are provided in Table 10 in unit totals.

[0396] [Table 10] Section 1.29 [Example 15]

[0397] Opioid-free intraoperative treatment methods Exemplary opioid-free intraoperative compositions and methods of the present disclosure are provided in Table 11. Section 1.30

[0398] [Table 11] TIFF2024518865000022.tif183154 [Example 16]

[0399] Opioid consumption and Aldrete scores after OFA and non-OFA administration to patients A study was conducted to evaluate opioid consumption and Aldrete score in patients who received an anesthetic composition during a medical or surgical procedure. The patients were divided into two cohorts. The first cohort (82 patients) received a non-opioid-free anesthetic composition (i.e., containing fentanyl) during a medical or surgical procedure. The second cohort (82 patients) received the opioid-free anesthetic intraoperative composition of the present disclosure during a medical or surgical procedure. The medical or surgical procedure types of the two cohorts were similar and included orthopedic procedures (e.g., ankle arthroscopy, knee arthroscopy, elbow dissection, shoulder arthroscopy, and foot bunionectomy), ENT surgery (e.g., tonsillectomy, functional endoscopic sinus surgery), and GYN surgery (hysterectomy).

[0400] As shown in Figure 4, of 82 patients in the non-OFA cohort, 30 patients received rescue opioids in the PACU (37%). In contrast, only 24 patients in the OFA cohort received opioids (29%). Furthermore, among patients who did not receive rescue opioids, the non-OFA cohort required a significantly higher dose (45 mg vs. 29 mg of Demerol) than the OFA cohort. In addition, the Aldrete Readiness to Discharge score of the OFA cohort was better than the non-OFA cohort at the end of anesthesia recovery time (9.6 vs. 9.4).

[0401] FIG. 4 demonstrates reduced post-operative opioid requirements and improved recovery in patients receiving the OFA composition of the present disclosure compared to patients receiving traditional opioid-based anesthesia. Section 1.31 [Example 17]

[0402] Analysis of hospital stay for patients undergoing OFA A retrospective analysis was conducted on 140 patients who underwent total knee replacement surgery at the hospital. As shown in Figure 5, patients who received the opioid-free composition of the present disclosure and / or postoperative opioid-avoidance pain management experienced a 50% reduction in length of stay (LOS) after surgery compared to traditional care. These patients were able to go home an average of 1.39 days earlier than patients who received traditional anesthesia procedures. This reduction in LOS allows hospitals to save significant amounts of money.

[0403] Many surgeries performed in hospitals require a subsequent hospital stay. The cost of the surgery is paid in a lump sum or "bundled payment" rather than being itemized for each procedure (e.g., the surgery itself, a day of hospitalization, physical therapy, and medications). No other payments are made to the hospital (e.g., complications, extended stay, or discharge to a skilled nursing facility). The bundled payment includes payments for nurses, pharmacists, physical therapy, medications, meals, etc. while the patient is hospitalized. The costs of hospital services are collectively referred to as "adjusted costs" and represent approximately 47% of medical reimbursements to hospitals, with the remaining 53% being profits. Given this payment model, safely discharging a patient early without readmission (e.g., for pain management issues) represents a significant cost savings for the hospital. The daily adjusted cost savings for the hospital resulting from early discharge status are presented in Figure 6. This hospital daily adjusted cost savings, multiplied by the number of days saved by OFA administration and the number of surgeries performed, indicates that administration of opioid-free anesthesia can provide substantial savings. Importantly, the estimated cost savings do not include the additional potential benefits available to hospitals using increased available hospital beds. The estimated cost savings determined here are less than data available in sources such as Becker's Hospital Review and Kaiser foundation. Section 1.32 [Example 18]

[0404] Administration of OFA to patients undergoing ankle repair surgery A patient undergoing a surgical procedure to repair an ankle fracture was administered the opioid-free intraoperative composition of the present disclosure, as well as popliteal and saphenous nerve blocks. Figure 12 shows an x-ray of the ankle fracture fixation after the surgical procedure. The patient's anesthesia record is shown in Figure 13. The anesthesia record shows minimal changes in the patient's vital signs (sympathetic response) during the surgical procedure. Section 1.33 [Example 19]

[0405] Administration of OFA to surgical patients undergoing severe ankle fracture repair A patient undergoing a surgical procedure to repair a severe ankle fracture was administered the opioid-free intraoperative composition of the present disclosure. FIG. 14A shows an x-ray of the ankle fracture before the surgical procedure. FIG. 14B shows an image of the ankle after the surgical procedure. The patient woke up comfortably without the use of a block and did not require opioids while in the PACU. Typically, patients who receive traditional anesthetic compounds have severe postoperative pain after this type of repair. Thus, it is extremely rare that this patient was comfortable and did not require any opioids (pain medication) in the PACU. Importantly, the patient did not develop chronic pain or chronic opioid use and had no sequelae after surgery. All patients and publications described herein are indicative of the skill level of those skilled in the art to which this disclosure pertains.

[0406] The examples set forth above are provided to give one of ordinary skill in the art a complete disclosure and description of how to make and use the disclosed materials, compositions, systems and uses, and are not intended to limit the scope of what the inventors consider to be their disclosure. One of ordinary skill in the art will recognize how to adapt the features and related uses of the exemplary opioid anesthetic compositions to additional opioid anesthetic compositions and / or combinations, and thus to the scope of the various embodiments and claims.

[0407] The entire disclosure of each document cited in the Background, Abstract, Detailed Description and Examples (including patents, patent applications, journal articles, abstracts, laboratory manuals, books or other disclosures) is incorporated herein by reference.All references cited in this disclosure are incorporated by reference to the same extent as if each reference were individually incorporated herein by reference in its entirety.However, in the event of any inconsistency between the cited references and this disclosure, this disclosure shall prevail.

[0408] The terms and expressions used herein are used as terms of description and not as limitations, and such applications and uses of the surface are not intended to exclude any equivalents of the shown and described features or portions thereof, and it is recognized that various modifications are possible within the scope of the disclosure claimed. Thus, although the present disclosure has been specifically disclosed by examples, exemplary embodiments, and appropriate features, it should be understood that modifications and variations of the concepts disclosed herein may be resorted to by those skilled in the art, and such modifications and variations are considered to be within the scope of the present disclosure as defined by the appended claims.

[0409] A number of embodiments of the present disclosure have been described. The specific embodiments provided herein are examples of useful embodiments of the present invention, and it will be apparent to one skilled in the art that the present disclosure can be implemented by using many different devices, device components, and method steps described in the present description. As will be apparent to one skilled in the art, the methods and devices useful in the present methods may include a large number of suitable compositions and processing elements and steps.

[0410] References TIFF2024518865000023.tif240170 TIFF2024518865000024.tif240170 TIFF2024518865000025.tif240170 TIFF2024518865000026.tif240170 TIFF2024518865000027.tif240170 TIFF2024518865000028.tif240170 TIFF2024518865000029.tif240170 TIFF2024518865000030.tif240170 TIFF2024518865000031.tif240170 TIFF2024518865000032.tif240170 TIFF2024518865000033.tif240170 TIFF2024518865000034.tif240170 TIFF2024518865000035.tif240170 TIFF2024518865000036.tif240170 TIFF2024518865000037.tif240170 TIFF2024518865000038.tif240170

Claims

1. Magnesium (Mg2+) salts, Alpha-2 agonists, and, where appropriate, Sodium channel blockers, and / or N-methyl-D-aspartate (NMDA) antagonists other than magnesium salts, and / or Corticosteroids An opioid-free pre-operative pharmaceutical composition comprising, together with a pharma- ceutically acceptable vehicle, carrier, or excipient, said magnesium salt, and alpha-2 agonist, and optionally a sodium channel inhibitor, and / or an NMDA antagonist other than a magnesium salt, and / or a corticosteroid, are included in an amount effective to provide sedation and / or analgesia to an individual in need thereof, and said effective amount of the composition is administered to an individual in need of anesthesia during the pre-operative phase of a medical or surgical procedure while undergoing said medical or surgical procedure; Opioid-free pre-operative pharmaceutical composition.

2. 2. The opioid-free pre-operative pharmaceutical composition of claim 1, wherein the alpha-2 agonist is selected from the group consisting of dexmedetomidine, clonidine, fadolmidine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, methyldopa, methylnorepinephrine, norepinephrine, (R)-3-nitrobiphenyline, amitraz, detomidine, lofexidine, medetomidine, and combinations thereof.

3. 3. The opioid-free pre-operative pharmaceutical composition of any one of claims 1 to 2, wherein the sodium channel inhibitor is selected from the group consisting of quinidine, ajmaline, procainamide, disopyramide, lidocaine, procaine, prilocaine, phenytoin, mexiletine, tocainide, encainide, flecainide, propafenone, moricindine, and combinations thereof.

4. 4. The opioid-free pre-operative pharmaceutical composition of any one of claims 1 to 3, wherein the NMDA antagonist other than a magnesium salt is selected from the group consisting of ketamine, dextromethorphan (DXM), phencyclidine (PCP), and methoxetamine (MXE), or a combination thereof.

5. 5. The opioid-free pre-operative pharmaceutical composition of any one of claims 1 to 4, wherein the corticosteroid is selected from the group consisting of cortisone, hydrocortisone, fludrocortisone acetate, prednisolone, prednisone, methylprednisolone, triamcinolone, dexamethasone sodium phosphate, betamethasone, triamcinolone acetonide, fluorometholone, and combinations thereof.

6. 6. The opioid-free pre-operative pharmaceutical composition of any one of claims 1 to 5, wherein the composition is contained in a container selected from the group consisting of a syringe, an IV bag, a bottle, or a vial, and the container is glass or a plastic selected from the group consisting of polyethylene, polypropylene, polyvinyl chloride, and polypropylene-polyethylene blends.

7. 10. A medicament comprising an opioid-free pre-operative pharmaceutical composition according to any one of claims 1 to 6 for use as an opioid-free pre-operative treatment anesthetic in a medical or surgical procedure, Magnesium salts in an amount ranging from 5 to 50 mg / kg of ideal body weight (IBW); an alpha-2 agonist in an amount ranging from 0.1 to 1 mcg / kg IBW; and, where appropriate, a sodium channel inhibitor in an amount ranging from 0.1 to 2 mg / kg IBW; Corticosteroids in amounts ranging from 0.01 to 0.2 mg / kg IBW, and / or NMDA antagonists other than magnesium salts in amounts ranging from 0 to 0.5 mg / kg IBW Including, effective amounts of said magnesium salt, alpha-2 agonist, and optionally a sodium channel inhibitor, a corticosteroid, and NMDA are administered to said individual in a combination that results in induction of anesthesia, sedation, and / or analgesia in said individual during the pre-operative phase of said medical or surgical procedure; The said medicine.

8. Magnesium (Mg ２＋ )salt, Alpha-2 agonists, and Sodium channel blockers, and, where appropriate, NMDA antagonists other than magnesium salts, and / or Beta blockers together with a pharma- ceutically acceptable vehicle, carrier, or excipient, wherein the magnesium salt, alpha-2 agonist, sodium channel blocker, and, optionally, an NMDA antagonist other than a magnesium salt, a beta blocker, are included in an amount effective to provide anesthesia, sedation, and / or analgesia, and to maintain stable vital signs in an individual in need of anesthesia during the perioperative phase of a medical or surgical procedure while undergoing said medical or surgical procedure. Opioid-free intraoperative pharmaceutical composition.

9. 9. The opioid-free intraoperative pharmaceutical composition of claim 8, wherein the alpha-2 agonist is selected from the group consisting of dexmedetomidine, clonidine, fadolmidine, guanabenz, guanoxabenz, guanethidine, xylazine, tizanidine, medetomidine, methyldopa, methylnorepinephrine, norepinephrine, (R)-3-nitrobiphenyline, amitraz, detomidine, lofexidine, medetomidine, and combinations thereof.

10. 10. The opioid-free intraoperative pharmaceutical composition of any one of claims 8 to 9, wherein the sodium channel inhibitor is selected from the group consisting of quinidine, ajmaline, procainamide, disopyramide, lidocaine, procaine, prilocaine, phenytoin, mexiletine, tocainide, encainide, flecainide, propafenone, moricindine, and combinations thereof.

11. 11. The opioid-free intraoperative pharmaceutical composition of any one of claims 8 to 10, wherein the NMDA antagonist other than a magnesium salt is selected from the group consisting of ketamine, dextromethorphan (DXM), phencyclidine (PCP), methoxetamine (MXE), and combinations thereof.

12. 12. The opioid-free intraoperative pharmaceutical composition of any one of claims 8 to 11, wherein the beta blocker is selected from the group consisting of carvedilol, propranolol, esmolol, timolol, metoprolol, labetalol, atenolol, bisoprolol, nebivolol, and combinations thereof.

13. 13. The opioid-free intraoperative pharmaceutical composition of any one of claims 8 to 12, wherein the alpha-2 agonist comprises dexmedetomidine, the magnesium salt comprises magnesium sulfate or magnesium chloride, the sodium channel inhibitor comprises lidocaine or procaine, the NMDA antagonist comprises ketamine, and the beta blocker comprises esmolol.

14. 14. The opioid-free intraoperative pharmaceutical composition of any one of claims 8 to 13, wherein the composition is contained in a container selected from the group consisting of a syringe, an IV bag, a bottle, and a vial, and the container is glass or a plastic selected from the group consisting of polyethylene, polypropylene, polyvinyl chloride, and polypropylene-polyethylene blends.

15. A medicament comprising an opioid-free intraoperative pharmaceutical composition according to any one of claims 8 to 14 for use as an opioid-free intraoperative therapeutic anesthesia agent in a medical or surgical procedure, Magnesium salts, such as magnesium sulfate, in amounts ranging from 1 to 20 mg / kg / hr of standard body weight (IBW); an alpha-2 agonist, such as dexmedetomidine, in amounts ranging from 0.01 to 1 mcg / kg / hr IBW; and Sodium channel blockers, such as lidocaine, in amounts ranging from 0.1 to 3 mg / kg / hr IBW; and, where appropriate, a beta blocker, such as esmolol, in an amount ranging from 3 to 300 mcg / kg / min or 3 to 20 mcg / kg / min IBW; and / or NMDA antagonists other than magnesium salts in amounts ranging from 0 to 0.5 mg / kg / hr IBW Including, effective amounts of said magnesium salt, alpha-2 agonist, sodium channel inhibitor, and optionally a beta blocker, and / or an NMDA antagonist other than a magnesium salt are administered to said individual in combination during the perioperative phase of said individual's medical or surgical procedure to provide said individual with anesthesia, sedation and / or analgesia, and to maintain stable vital signs, and / or contribute to the depth of anesthesia during surgery; The said medicine.

16. 10. An opioid-free pre-operative system for opioid-free pre-operative treatment of an individual in need of anesthesia while undergoing a medical or surgical procedure, said system comprising the pre-operative pharmaceutical composition of any one of claims 1 to 6 contained in a container, said container being a syringe, an IV bag, a bottle, or a vial, said container being glass or a plastic selected from the group consisting of polyethylene, polypropylene, polyvinyl chloride, or a polypropylene-polyethylene blend.

17. 16. An opioid-free intraoperative system for opioid-free perioperative treatment of an individual requiring anesthesia while undergoing a medical or surgical procedure, said system comprising the intraoperative pharmaceutical composition of any one of claims 9 to 15 contained in a container, said container being glass or a plastic selected from the group consisting of polyethylene, polypropylene, polyvinyl chloride, and polypropylene-polyethylene blends.

18. 1. An opioid-free peri-operative system for opioid-free peri-operative treatment of an individual requiring anesthesia while undergoing a medical or surgical procedure, comprising:

17. The opioid-free pre-operative system of claim 16, and The opioid-free intraoperative system according to claim 17. The opioid-free perioperative system.

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