JP2024518865A - Opioid-free compositions for anesthesia applications and related methods and systems - Google Patents

Abstract

Opioid-free compositions, methods and systems are described. The compositions include a magnesium salt, an alpha-2 agonist, a sodium channel inhibitor, and optionally an NMDA antagonist, a beta blocker, and/or a corticosteroid, together with a pharma- ceutically acceptable vehicle, carrier, or excipient. The compositions are suitable for pre- and intra-operative methods for patients undergoing medical or surgical procedures.

Description

1. Field This disclosure relates to anesthesiology.

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

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.

Despite advances in anesthesiology, identifying drugs that provide effective anesthesia while minimizing the side effects and complications associated with opioid administration remains a challenge.

3. SUMMARY OF THE DISCLOSURE Provided herein are, in some embodiments, opioid-free compositions having anesthetic properties for anesthetic applications, and related methods and systems, that enable an individual to achieve effective anesthesia while simultaneously reducing the side effects and complications associated with opioid administration.

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,
These include sodium channel blockers, such as lidocaine, and/or N-methyl-D-aspartate receptor (NMDA) inhibitors, such as ketamine, and/or corticosteroids, such as dexamethasone.
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, a sodium channel inhibitor, NMDA antagonist, and/or corticosteroid are present in amounts 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.

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 of a magnesium salt, such as magnesium sulfate, in an amount ranging from 5 to 50 mg/kg of standard body weight (IBW);
An alpha-2 agonist, such as dexmedetomidine, in an amount ranging from 0.1 to 1 mcg/kg IBW, and optionally
administering to the individual a sodium channel inhibitor, e.g., lidocaine, in an amount ranging from 0.1 to 2 mg/kg IBW, and/or a corticosteroid, e.g., dexamethasone, in an amount ranging from 0.01 to 0.2 mg/kg IBW, and/or an NMDA antagonist other than Mg, e.g., ketamine, in an amount ranging from 0 to 0.5 mg/kg IBW;
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 the individual's anxiety and/or to induce sedation and/or analgesia during the pre-operative phase of a medical or surgical procedure;
This is the method.

In various embodiments, the administering step includes administering a pre-surgical composition of the present disclosure to an individual. In various embodiments, the administering step includes the substep of preparing a pre-surgical composition by combining 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.

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, such as magnesium sulfate;
Alpha-2 agonists, such as 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.

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, such as esmolol.
In various embodiments, the composition further comprises a pharma- ceutically acceptable vehicle, carrier, or excipient. In the intraoperative composition, the magnesium salt, alpha-2 agonist, sodium channel inhibitor, and optionally, the NMDA antagonist other than a magnesium salt, and 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.

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 of a magnesium salt, such as magnesium sulfate, in an amount 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 inhibitors in amounts ranging from 0.1 to 3 mg/kg/hr IBW;
and, where appropriate,
The method includes administering to the individual a beta blocker, e.g., esmolol, in an amount ranging from 3 to 300 mcg/kg/min or 3 to 20 mcg/kg/min IBW, and/or an NMDA antagonist other than a magnesium salt in an amount ranging from 0 to 0.5 mg/kg/hr IBW.

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.

In various embodiments, the administering step comprises administering an opioid-free intraoperative composition of the present disclosure to the 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 perioperative treatment of an individual undergoing a medical or surgical procedure. The opioid-free intraoperative system comprises:
Magnesium salts, such as magnesium sulfate,
An alpha-2 agonist, such as dexmedetomidine, and a sodium channel inhibitor, 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, 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.

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 an individual an amount effective for opioid-free pre-operative treatment according to any one of the methods described herein; and administering to an individual an amount effective for opioid-free peri-operative treatment according to any one of the methods described herein;
including.

In various embodiments, administering the opioid-free pre-operative treatment step includes administering to the individual a pre-operative composition of the present disclosure. In various embodiments, administering the opioid-free pre-operative treatment step includes 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.

In various embodiments, administering the opioid-free intraoperative treatment step includes administering to an individual an intraoperative composition of the present disclosure. In various embodiments, administering the opioid-free intraoperative treatment step includes the 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.

According to an eighth aspect, an opioid-free peri-operative system is described for opioid-free peri-operative treatment of an individual undergoing a medical or surgical procedure. The opioid-free peri-operative system comprises:
An opioid-free perioperative system as described herein, and an opioid-free intraoperative system as 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.

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

In various embodiments of the opioid-free perioperative system, the magnesium salt, alpha-2 agonist, sodium channel inhibitor, and optionally, the 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.

The opioid-free compositions, methods and systems described herein, in some embodiments, allow for eliminating or reducing the need for post-operative opioid consumption, thereby reducing exposure and risk for the development of opioid use disorder.

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.

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).

The opioid-free compositions, methods and systems described herein, in some embodiments, allow for the elimination of acute opioid-induced tolerance and hyperalgesia that is further perpetuated by overprescribing secondary to suboptimal postoperative pain control.

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

The opioid-free compositions, methods, and systems described herein can be used in connection with a variety of applications in which an anesthetic or analgesic effect is desired. For example, the opioid-free compositions, methods, and systems described herein can be used to treat an individual about to undergo a medical or surgical procedure. 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 ascertainable by one of skill in the art upon reading this disclosure.

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.

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

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: N. M. Elkassabany and E. R. Mariano, Anaesthesia 2019, 74, 560-563). 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, D.J., Mao, J., Holt, J., Price, D.D. Proc Natl Acad Sci U S A. 1999 Jul 6; 6(14): 7731-7736). 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. (Adapted from Deumens, Steyaert, Forget et al., Progress Neurobio. 2012). 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). 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 and postoperative opioid-avoidance pain management of the present disclosure experienced a 50 percent reduction in hospital length of stay (LOS) after surgery compared to traditional care. These patients were able to return home an average of 1.39 days earlier than patients who received traditional anesthesia services (see Example 17). FIG. 6 illustrates the cost savings associated with the reduction in postoperative hospital stay described in FIG. Figure 7 shows the cost of administering a typical "traditional" opioid-based anesthesia when a single vial is used for each patient ($Single Vial), and the cost when the vial is available for more than one patient ($Dose). Many hospitals only allow individual vials to be split into multiple doses under strict sterile conditions in the pharmacy. FIG. 8 shows the cost of exemplary components in the opioid-free compositions of the present disclosure, as well as additional medications that may be used in conjunction with the opioid-free compositions. FIG. 8 shows the cost for the concentration and dosage 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 permit the division of individual vials into multiple doses under strict sterile conditions in the pharmacy. FIG. 9 shows "traditionally used" anesthesia medications in terms of unit cost and manufacturing concentration. FIG. 10 shows an exemplary OFA composition of a Preemptive Analgesia Loading Dose Syringe described herein, where the composition includes lidocaine, Mg ²⁺ salt, dexmedetomidine and dexamethasone. FIG. 11 shows an alternative combination of an opioid-free anesthetic infusion fluid in a 100 mL IV bag, where the composition includes lidocaine, Mg, dexmedetomidine, ketamine and esmolol-HCl. 12 shows an image of the ankle after an ankle fusion surgical procedure. The ankle fusion procedure was performed using an opioid-free composition of the present disclosure. The patient experienced an uneventful postoperative course (see Example 18). 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 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 an 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.

5. Detailed Description The present invention includes the following:
(1.) A magnesium salt (Mg ²⁺ ) salt, such as magnesium sulfate, and an alpha-2 agonist, such as dexmedetomidine, and optionally
a sodium channel inhibitor, e.g., lidocaine, and/or an N-methyl-D-aspartate receptor inhibitor, e.g., ketamine, and/or a corticosteroid, e.g., 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 amounts 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.

(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.

(3.) An opioid-free preoperative pharmaceutical composition according to (1.) or (2.) above, in which the alpha-2 agonist comprises dexmedetomidine.

(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.

(5.) An 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.

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

(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.

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

(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.

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

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

(12.) An 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.

(13.) An 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.

(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.

(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.

(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.

(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.

(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.

(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.

(20.) An opioid-free preoperative pharmaceutical composition according to any one of (1.) to (19.) above, wherein the concentration of the NMDA antagonist other than the magnesium salt is in the range of 0.01 mg/mL to 35 mg/mL.

(21.) The opioid-free preoperative pharmaceutical composition according to any one of (1.) to (20.) above, wherein the concentration of the NMDA antagonist other than the magnesium salt ranges from 0.1 mg/mL to 5.0 mg/mL. In some embodiments, the concentration of the NMDA antagonist other than the magnesium salt ranges from 0.1 mg/mL to 0.5 mg/mL.

(22.) An 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.

(23.) An opioid-free preoperative (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.

(24.) A method of opioid-free pre-operative treatment of an individual undergoing a medical or surgical procedure, comprising:
an effective amount of a magnesium salt, such as magnesium sulfate, in an amount ranging from 5 to 50 mg/kg of standard body weight (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;
administering to the individual a corticosteroid, e.g., dexamethasone, in an amount ranging from 0.01 to 0.2 mg/kg IBW, and/or an NMDA antagonist other than Mg, e.g., ketamine, in an amount ranging from 0 to 0.5 mg/kg IBW;
Effective amounts of a magnesium salt, an alpha-2 agonist, and optionally a sodium channel inhibitor, and/or a corticosteroid, and/or an NMDA are administered in combination to an individual to treat the individual's anxiety and/or to induce sedation and/or analgesia in the pre-operative phase of a medical or surgical procedure.
Method.

(25.) The method according to (24.) above, in which 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.

(26.) An opioid-free pre-operative system for opioid-free pre-operative 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,
26. The method of opioid-free preoperative treatment according to claim 24 or 25, comprising an NMDA antagonist other than a magnesium salt, such as ketamine, and/or a corticosteroid, 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.
Opioid-free preoperative system.

(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.

(28.) Magnesium (Mg ²⁺ ) salts, such as magnesium sulfate; alpha-2 agonists, such as dexmedetomidine;
a sodium channel blocker, such as lidocaine, and optionally an N-methyl-D-aspartate receptor (NMDA) inhibitor, such as ketamine, and/or a beta blocker, such as esmolol, 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, 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;
An opioid-free intraoperative pharmaceutical composition.

(29.) The opioid-free intraoperative pharmaceutical composition described in (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.

(30.) The alpha-2 agonist comprises dexmedetomidine;
An opioid-free intraoperative pharmaceutical composition according to (28.) or (29.) above.

(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 moricindine, or any combination thereof.

(32.) An 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.

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

(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.

(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 includes ketamine.

(36.) The alpha-2 agonist comprises dexmedetomidine;
The magnesium includes magnesium sulfate,
sodium channel blockers include lidocaine or procaine, NMDA antagonists include ketamine;
The beta blocker is, for example, esmolol.
An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (35.) above.

(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.

(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.

(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.

(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.

(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.

(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.

(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.

(44.) An opioid-free intraoperative pharmaceutical composition according to any one of (28.) to (43.) above, wherein the concentration of the NMDA antagonist other than the magnesium salt is in the range of 0.01 mg/mL to 20 mg/mL.

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

(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.

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

(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.

(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.

(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.

(51.) A method of opioid-free perioperative treatment of an individual undergoing a medical or surgical procedure, comprising:
Effective amounts of magnesium salts, such as magnesium sulfate, in amounts ranging from 1 mg/kg/hr to 20 mg/kg/hr of IBW;
an alpha-2 agonist, such as dexmedetomidine, in an amount ranging from 0.01 to 1 mcg/kg/hr IBW; a sodium channel inhibitor, such as lidocaine, in an amount ranging from 0.1 to 3 mg/kg/hr IBW;
and, where appropriate,
administering to the individual a beta blocker, e.g., esmolol, in an amount ranging from 3 to 300 mcg/kg/min or 3 to 20 mcg/kg/min IBW, and/or an NMDA antagonist other than a magnesium salt, e.g., ketamine, in an amount ranging from 0 to 0.5 mg/kg/hr IBW;
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 in the individual, and to maintain hemodynamic stability during the perioperative phase of a medical or surgical procedure;
Method.

(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.

(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;
53. An opioid-free intraoperative system comprising 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 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 intraoperative phase of a medical or surgical procedure according to the method of opioid-free perioperative treatment of claim 51 or 52.

(54.) The system described in (53.) above, comprising a magnesium (Mg 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.

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

(56.) The method according to (55.) above, in which 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.

(57.) The method according to (55.) above, in which the opioid-free intraoperative treatment is performed by administering to an individual an intraoperative pharmaceutical composition according to any one of (28.) to (50.) above.

(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 amounts 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 according to (55.) or (56.) above;
Opioid-free perioperative system.

(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 the preoperative composition described herein.

(60.) An opioid-free perioperative system as described in (58.) or (59.) above, comprising a magnesium (Mg ²⁺ ) salt of the opioid-free perioperative system, 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 set to be combined prior to administration to provide the intraoperative composition described herein.

(61.) An 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.

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

(63) Cox inhibitors include 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, meclomefenamic acid ... paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, paroxetine, valdecoxib, parox The opioid-free perioperative system according to (61) or (62) above, wherein the opioid is selected from the group consisting of acetaminophen, clonixin, licofelone, and paracetamol (acetaminophen), or any combination thereof.

(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.

(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 (NASSAs).

(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.

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

4.1 Definitions Unless expressly indicated, the following terms as used herein have the meanings indicated below.

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.

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.

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 opioids.

The term "opioid-free treatment period" refers to a period of opioid-free treatment that encompasses home, pre-operative, intra-operative, and post-operative recovery during hospitalization, and/or recovery at home.

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

The abbreviation "Non-OFA" stands for non-opioid-free anesthesia.

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 injuries that occur during the intraoperative and postoperative phases of a medical or surgical procedure. Preemptive non-opioid analgesia is used interchangeably with OFA.

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, C. J., J. Pain Res., (2009) 10(9), 895-926).

The term "anesthesia" is defined as the loss of nociceptive sensation with or without loss of consciousness. Anesthesia includes general anesthesia (GA), sedation, and partial and local anesthesia. Anesthesia is used for medical purposes. Anesthesia allows for the painless performance of medical procedures that would otherwise cause severe or intolerable pain to the unanesthetized patient 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 partial anesthesia (Bier block/nerve block)), as will be understood by those skilled in the art.

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

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.

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 anesthetic 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, a local/MAC (monitored anesthesia care) is specified. Not all local anesthetic agents can be administered intravenously due to cardiotoxic effects associated with local anesthesia systemic toxicity (LAST) leading to cardiac arrest.

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.

The term "Aldrete score" refers to a patient's score according to the "Aldrete scoring system." The term "Aldrete scoring system" is a commonly used scale that determines whether a patient can be safely discharged from the post-anesthesia care unit (PACU) and admitted to either a post-operative 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.

The term "medical or surgical procedure" generally refers to procedures that require anesthesia, sedation, or analgesia. In some contexts, medical or surgical procedures encompass the administration of anesthesia, sedation, or analgesia outside of a hospital or surgical setting, such as in a hospice setting. In other contexts, medical or surgical procedures refer to procedures that require anesthesia, sedation, or analgesia, as well as procedures in which surgical manual and instrumental procedures are performed 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 an infection.

The term "preoperative" 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 preoperative interview, or preparing the patient for anesthesia.

The term "intra-operative" 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 "intra-operative" 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. Intra-operative 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.

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

The abbreviation "PACU" stands for post-anesthesia care unit.

The abbreviation "PHO" stands for Preoperative Waiting.

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

The term "maintain" or "maintenance" refers to the continuation of a patient's state of unconsciousness by administration of a pharmaceutical composition or agent following induction. 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.

The term "magnesium salts" or "Mg ²⁺ salts" refers to salts of the magnesium ion (Mg ²⁺ ) having a pharma- ceutically acceptable counterion, as well as solvates and hydrates thereof.

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, phosphorus, etc. Counterions include, for example, gonate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, octanoate, oleate, pamoate, pantothenate, phosphate, polygalacturonate, propionate, salicylate, stearate, succinate, sulfate, tartrate, theoclate, threonate, or tosylate, and hydrates and solvates thereof, as well as additional counterions ascertainable by one of ordinary skill in the art upon reading this disclosure.

The term "alpha-2 agonist" refers to drugs that stimulate 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 postsynaptically on vascular smooth muscle cells of certain blood vessels, such as those 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. Common 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, reduced heart rate, vasoconstriction of certain arteries, venoconstriction of some veins, reduced 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.

The term "sodium channel inhibitor" refers to an agent that blocks the conduction of sodium ions (Na ⁺ ) through sodium channels. 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.

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 (N ₂ O). For human use, exemplary NMDA antagonists include ketamine, magnesium salts (e.g., magnesium sulfate), and nitrous oxide (N ₂ O).

The term "beta blocker" refers to agents that block 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.

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 analogs of these naturally occurring steroid hormones.

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.

The term "agent" refers to an ingredient of a pharmaceutical composition that is biologically active. Modifiers to the term "agent" indicate the relevant biological activity that is typically carried out by the interaction of the agent with one or more molecular targets in an individual. In contrast to active ingredients, inactive ingredients are usually referred to as excipients in the pharmaceutical context. The primary excipient that serves as a vehicle to carry the active ingredient is usually referred to as a vehicle. Saline, sterile water, petrolatum, and mineral oil are common vehicles, as would be understood by one of skill in the art.

The term "calcium channel inhibitor" refers to an agent that blocks the conduction of calcium ions (Ca ²⁺ ) through calcium channels. 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.

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).

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 used in the opioid-free compositions, methods, and systems of the present disclosure, as well as any additional indications, are provided in the present disclosure.

The term "GABA analog" refers to an agent that binds to GABA receptors 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. GABA _A receptors are ligand-gated ion channels (also known as ionotropic receptors), while GABA _B receptors are G-protein-coupled receptors, also called metabotropic receptors. Exemplary GABA analogs include pregabalin, gabapentin, picamilon, and progabide. For human use, exemplary GABA analogs include pregabalin and gabapentin.

The term "antidepressant" refers to a drug that corrects a chemical imbalance of neurotransmitters in the central nervous system and can relieve depression, social anxiety, anxiety disorder, seasonal affective disorder and dysthymia, or mild chronic depression. Antidepressants, as used herein, can reduce pain and can be used in the prevention and treatment of chronic or acute pain.

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

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 for which it is intended to be used. The pharmaceutical compositions of the present disclosure may be intended for use in anesthesia applications.

The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or pharmaceutical composition that elicits the 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.

The term pharma- ceutically acceptable "vehicle" 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 vehicle may be an excipient, preferably to improve the efficiency of delivery and the efficacy of the pharmaceutical composition. Preferred vehicles for use in the opioid-free compositions of the present disclosure include saline, sterile water, and additional vehicles ascertainable by one of skill in the art upon reading this disclosure.

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 its pharmacological activity.

The term pharma- ceutically acceptable "excipient" refers to a pharmacologically inactive substance that is formulated in combination with a pharmacologically active ingredient of a pharmaceutical composition, and includes bulking agents, fillers, diluents, and products 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, for example, in 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, D.C. (e.g., 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.

The term "treatment" refers to any activity that is part of the medical care of a condition or that medically or surgically addresses a condition. 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.

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.

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.

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 kidney disease, and obesity.

Unless specifically indicated, the term "patient's weight" refers to the patient's ideal 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.)

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.

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

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

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

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 two or more references unless the context clearly dictates otherwise.

The full phrase or word of some abbreviations used herein is 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 (discontinuation), 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).

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 may be used to practice the disclosure. Methods, apparatus elements, and materials other than those specifically illustrated may be employed by one of ordinary skill in the art in the practice of the disclosure without resorting to undue experimentation. All art-known functional equivalents of any of such methods, apparatus elements, and materials are intended to be included in the disclosure. When a range is presented herein, e.g., a temperature range, a frequency range, a time range, or a 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 a range or group disclosed herein may be excluded from the claims of the disclosure. The disclosure illustratively described herein may be practiced in the absence of any element or limitation not specifically disclosed herein.

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.

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.

It should be further understood that features of one embodiment may be generally applicable 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 involved. 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 of skill in the art without departing from the subject matter of the present invention.

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 greater 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 scope of 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.

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

4.2 Opioid-Free Compositions In one aspect, the present disclosure provides opioid-free compositions with anesthetic properties. In particular, the opioid-free compositions of the present disclosure are designed to eliminate or reduce opioids in compositions used to induce and/or maintain anesthesia, and to provide improved post-operative pain control. The opioid-free compositions of the present disclosure can be used, in particular, in the pre-operative and/or intra-operative phases of medical or surgical procedures to induce or maintain anesthesia in patients. Advantageously, the opioid-free compositions of the present disclosure can be administered to patients in opioid-free treatments 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 ascertainable by those skilled in the art.

In certain embodiments, the opioid-free compositions described herein can be used for sedation cases, as well as for general anesthesia cases. Use of both results in improved post-operative pain relief compared to opioid-based anesthetics. In some embodiments, the improved post-operative pain relief compared to opioid-based anesthetics results in a reduction in pain intensity numeric levels of at least 1, 2, 3, 4, or 5 on the Numeric Rating Scale ("NRS"), as well as opioid consumption immediately post-operatively.

Reference is made to FIG. 1, which provides a schematic diagram of the stages of a medical or surgical procedure. In FIG. 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.

In one aspect, the present 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.

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 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.

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.

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, particularly in view of the properties of the particular alpha-2 agonist 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 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 includes dexmedetomidine. In other embodiments, the at least one alpha-2 agonist includes clonidine. Those skilled in the art are aware that dexmedetomidine has a more rapid onset and offset of action than clonidine. Dexmedetomidine has a high degree of selectivity for the alpha-2 receptor (1600:1 compared to 220:1 for clonidine), resulting in more desired effects and fewer undesired effects.

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

In general, those skilled in the art know that alpha-2 agonists have the desired effect of decreasing sympathetic output of norepinephrine. Peripherally, alpha-2 agonists block conduction of C-fibers, which are unmyelinated fibers that conduct slow but potent and persistent pain signals. Effects on inhibitory G-coupled proteins produce peripheral analgesia. Activation of alpha-2 adrenergic receptors in the dorsal horn of the spinal cord is responsible for centrally acting analgesia. Inhibition of the release of substance P and norepinephrine is the result of activation of G-coupled alpha-2 adrenergic receptors. This activation inhibits adenyl cyclase and decreases intracellular cyclic adenosine monophosphate. Supraspinal analgesia and sedation are the result of activity of alpha-2 adrenergic receptors in the locus coeruleus. Therefore, identification of suitable alpha-2 agonists that are functionally equivalent to dexmedetomidine can be performed in view of the general properties of alpha-2 agonists, the properties of dexmedetomidine, and the indications provided in this disclosure, as will be understood by those skilled in the art.

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, as well as additional sodium channel inhibitors ascertainable by one of skill in the art upon reading this disclosure. Selection of a particular sodium channel inhibitor, 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 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.

In other embodiments, 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.

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 (N ₂ O), 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.

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 salts (e.g., magnesium sulfate), and nitrous oxide ( _N2O ), or any combination thereof. In certain embodiments, the at least one NMDA antagonist comprises ketamine, or an NMDA antagonist functionally equivalent to ketamine. An NMDA antagonist functionally equivalent to ketamine can be identified by one skilled in the art. In various embodiments, the at least one NMDA antagonist comprises ketamine.

When present in the opioid-free compositions 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 skill in the art upon reading this disclosure. 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 skill in the art, particularly in view of the characteristics of the particular beta blocker 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 beta blocker is selected from propranolol, esmolol, metoprolol, and labetalol, or any combination thereof. In certain embodiments, the at least one beta blocker comprises esmolol, or a beta blocker functionally equivalent to esmolol. Beta blockers functionally equivalent to esmolol can be identified by one of skill in the art. In various embodiments, the at least one beta blocker comprises esmolol.

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. The 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 characteristics of the particular corticosteroid and the indications provided in this disclosure.

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 are identifiable by one of skill in the art. In some aspects of this embodiment, the corticosteroid comprises dexamethasone sodium phosphate (dexamethasone), which is a corticosteroid that belongs to the class of glucocorticosteroids and may be more broadly classified as steroids, as will be understood by those of skill in the art. In certain embodiments, the at least one corticosteroid comprises dexamethasone.

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 receptor agonists including GABA _A and GABA _B extra-receptor agonists (GABA mimetics or analogs), antidepressants, antiemetics, cannabinoids (CBD), neurotransmitters, and/or nonsteroidal anti-inflammatory drugs (NSAIDs).

When used in combination with the opioid-free compositions 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 one of skill 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 one of skill in the art, particularly 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.

When used in combination with the opioid-free compositions of the present disclosure, the GABA analog is selected from the group consisting of pregabalin, gabapentin, picamilon and progabide, and any combination thereof, as well as additional GABA analogs ascertainable to one of skill in the art upon reading this disclosure. Selection of a particular GABA analog, as well as any adjustments in concentration, dosage, composition and time of administration, are within the skill of one of skill in the art, particularly in view of the properties 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.

When used in combination with the opioid-free compositions 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). Selection of a particular antidepressant, as well as any adjustments in concentration, dosage, composition, and time of administration, is within the skill of one of ordinary skill in the art, especially in view of the characteristics of the particular antidepressant and the indications provided in this disclosure.

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.

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 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 skill in the art, particularly in view of the characteristics of the particular antiemetic agent 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 antiemetic agent is selected from ondansetron, dolasetron, granisetron, palonosetron, promethazine, metoclopramide, meclizine, and droperidol, or any combination thereof.

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.

The opioid-free compositions of the present disclosure include pre-operative, intra-operative, peri-operative, and post-operative compositions. It is contemplated that the opioid-free compositions can be used in operating rooms, hospices, procedural settings (i.e., settings in which medical procedures are performed outside of an operating room), and other settings known to those of skill in the art.

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 may include a magnesium (Mg2 ⁺ ) salt, an alpha-2 agonist,
and, where appropriate,
The present invention includes a sodium channel blocker, and/or an N-methyl-D-aspartate receptor (NMDA) inhibitor, and/or a corticosteroid, together with a pharma- ceutically acceptable vehicle, carrier, or excipient, in an amount effective to treat anxiety and/or induce sedation and/or analgesia in an individual during any phase of the pre-operative method of the present disclosure.

The particular magnesium salt, alpha-2 agonist, sodium channel inhibitor, NDMA inhibitor and corticosteroid present in the opioid-free pre-surgical composition are selected from those disclosed above in connection with the opioid-free compositions in Section 4.2. The amount of each component present in the pre-surgical compositions of the present disclosure is an amount effective to treat anxiety and/or induce sedation and/or analgesia in the pre-surgical methods of the present disclosure. In some embodiments, the opioid-free pre-surgical 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 compositions in Section 4.2.

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 at 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 in the opioid-free pre-surgical composition.

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

In some embodiments, the alpha-2 agonist is present in the opioid-free pre-surgical composition in an amount ranging from about 0.001mcg/mL to about 50mcg/mL, 0.01mcg/mL to about 50mcg/mL, about 0.1mcg/mL to about 40mcg/mL, about 0.2mcg/mL to about 30mcg/mL, about 0.3mcg/mL to about 20mcg/mL, 0.4mcg/mL to about 15mcg/mL, about 0.5mcg/mL to about 10mcg/mL, about 1mcg/mL to about 10mcg/mL, about 2mcg/mL to about 10mcg/mL, or about 3mcg/mL to about 10mcg/mL. In certain embodiments, the alpha-2 agonist may be at least about 0.1 mcg/mL, at least about 0.2 mcg/mL, at least about 0.3 mcg/mL, at least about 0.4 mcg/mL, at least about 0.5 mcg/mL, at least about 0.6 mcg/mL, at least about 0.7 mcg/mL, at least about 0.8 mcg/mL, at least about 0.9 mcg/mL, at least about 1 mcg/mL, at least about 1.5 mcg/mL, at least about 2 mcg/mL, at least about 2.5 mcg/mL, at least about 3 mcg/mL, at least about 3.5 mcg/mL, at least about 4 mcg/mL, at least about 4.5 mcg/mL, at least about 5 mcg/mL, at least 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.

In various embodiments, the alpha-2 agonist includes dexmedetomidine or an alpha-2 agonist functionally equivalent to dexmedetomidine.

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 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 in the opioid-free pre-surgical composition.

In various embodiments, the sodium channel blocker includes lidocaine or a sodium channel blocker functionally equivalent to lidocaine.

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, the 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.

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

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.

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

In one embodiment, the opioid-free pre-operative pharmaceutical composition comprises:
a magnesium salt at a concentration ranging from about 1 mg/mL to about 500 mg/mL; an alpha-2 agonist at 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, in a concentration ranging from about 0 mg/mL to about 35 mg/mL, and 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.

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 at 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.

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,
It comprises a sodium channel blocker, and optionally an NMDA antagonist other than a magnesium salt, and/or a beta blocker, together with a pharma- ceutically acceptable vehicle, carrier, or excipient.

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

The amount of each component present in the intraoperative composition 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 method of the present disclosure.

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, 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 present in the opioid-free intraoperative composition 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, 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 in the opioid-free intraoperative composition.

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

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

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.

In various embodiments, the alpha-2 agonist includes dexmedetomidine or an alpha-2 agonist functionally equivalent to dexmedetomidine.

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. L, 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 in the opioid-free intraoperative composition.

In various embodiments, the sodium channel blocker includes lidocaine or a sodium channel blocker functionally equivalent to lidocaine.

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.

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

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.

In some embodiments, when the beta blocker includes 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 includes 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, about It is present in the opioid-free intraoperative composition 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.

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.

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 a beta blocker in an amount ranging from about 0.15 mg/mL to about 2 mg/mL, together with a pharma- ceutically acceptable vehicle, carrier, or excipient.

In each of the embodiments described in the preceding 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.

4.2.3 Opioid-Free Post-Surgical Composition In one embodiment, the present disclosure provides an opioid-free post-surgical composition. The opioid-free post-surgical composition comprises:
Magnesium salts, alpha-2 agonists,
Sodium channel blockers,
NMDA antagonists other than magnesium salts, and beta blockers;
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 would be understood by one of skill in the art upon reading this disclosure.

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.

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

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

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.

4.3.1 Pre-operative Treatment Methods The present disclosure provides methods of opioid-free pre-operative treatment of individuals about to undergo a medical or surgical procedure.

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,
Methods are provided which include administering to an individual an effective amount of an alpha-2 agonist and, optionally, a sodium channel blocker, and/or a corticosteroid, and/or an NMDA antagonist other than a magnesium salt.

The specific 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.

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.

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 of a magnesium salt in an amount ranging from 5 to 50 mg/kg of standard body weight (IBW);
an alpha-2 agonist in an amount ranging from 0.1 to 1 mcg/kg IBW;
and, where appropriate,
administering to the individual an amount of a sodium channel inhibitor in the range of 0.1 to 2 mg/kg IBW, and/or an amount of a corticosteroid in the range of 0.01 to 0.2 mg/kg IBW, and/or an amount of an NMDA antagonist other than a magnesium salt in the range of 0 to 0.5 mg/kg IBW,
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 the individual's anxiety and/or to induce sedation and/or analgesia during the pre-operative phase of a medical or surgical procedure;
A method is provided.

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 of a magnesium salt in an amount ranging from 5 to 50 mg/kg of IBW, an alpha-2 agonist in an amount ranging from 0.1 to 1 mcg/kg of IBW;
and, where appropriate,
The methods include administering to the individual a sodium channel inhibitor 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 an NMDA antagonist other than a magnesium salt in an amount ranging from 0 to 0.5 mg/kg IBW.
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 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.

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

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.

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 a magnesium salt, if present, comprises ketamine or an NMDA antagonist functionally equivalent to ketamine, and the corticosteroid comprises dexamethasone.

4.3.2 Methods of Intra-Operative Treatment The present disclosure provides methods of opioid-free peri-operative treatment of individuals undergoing a medical or surgical procedure.

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 of a magnesium salt;
alpha-2 agonists,
Sodium channel blockers,
and, where appropriate,
The methods include administering to the individual a beta blocker, and/or an NMDA antagonist other than a magnesium salt.

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

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.

In certain embodiments, a method of opioid-free intraoperative treatment includes administering to a patient an opioid-free intraoperative pharmaceutical composition of the present disclosure.

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 of a magnesium salt 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/kg/hr IBW;
The methods include administering to the individual a sodium channel inhibitor 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 an NMDA antagonist other than a magnesium salt in an amount ranging from about 0 mg/kg/hr to about 0.5 mg/kg/hr IBW.

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 optionally an NMDA antagonist other than a magnesium salt in an amount ranging from about 0 to about 0.5 mg/kg/hr IBW;
The method includes administering to the individual an amount of a beta blocker in the range of about 3 to about 20 mcg/kg/min.

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,
The method includes administering to the individual 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 a beta blocker in an amount ranging from about 10 to about 300 mcg/kg/min IBW.

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 optionally an NMDA antagonist other than a magnesium salt in an amount ranging from about 0 to about 0.2 mg/kg/hr IBW.
The method includes administering to the individual a sodium channel inhibitor in an amount ranging from about 0.5 to about 1.5 mg/kg/IBW, and/or a beta blocker, e.g., esmolol, in an amount ranging from about 1 to about 10 mcg/kg/min IBW.

In various embodiments of the intraoperative 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 a calcium channel inhibitor, a Cox inhibitor, and/or an antiemetic agent as 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.

In various embodiments of the intraoperative treatment methods described in this section, the methods further include administering an additional anesthetic agent to the individual 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.

4.3.3 Peri-Operative Treatment Methods Opioid-free pre-operative treatment methods and opioid-free intra-operative treatment methods can be used in combination for the peri-operative treatment of individuals undergoing a medical or surgical procedure.

In one aspect, the disclosure provides a method of opioid-free perioperative 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 an individual an amount effective for opioid-free pre-operative treatment according to any one of the methods described herein; and administering to an individual an amount effective for opioid-free peri-operative treatment according to any one of the methods described herein;
The present invention provides a method comprising:

Advantageously, the opioid-free perioperative treatment methods disclosed herein provide improved postoperative pain relief compared to non-opioid-free perioperative treatment methods.

4.3.4 Post-Surgical Treatment Methods In one embodiment, the present disclosure provides a method of opioid-free post-surgical treatment of an individual following a medical or surgical procedure.
The method is:
below:
Magnesium salts, alpha-2 agonists,
Sodium channel blockers,
one or more of an NMDA antagonist other than a magnesium salt, and a beta blocker,
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.

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.

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.

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

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

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

When 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).

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.

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.

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

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 the surgery.

4.3.4 Methods of Anesthetizing an Individual 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 intra-operative 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 intra-operative phase of a medical or surgical procedure, and to maintain hemodynamic stability in the individual, and optionally administering an opioid-free post-operative composition of the present disclosure to the individual in an amount effective to treat pain and/or inflammation in the individual during the post-operative phase of a medical or surgical procedure;
including.

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

4.4. Dose Levels, Regimen, and Mode 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 will be 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 time of administration, 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.

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 agent), guanethidine (which acts to selectively inhibit adrenergic postganglionic nerve transmission, similarly suppressing alpha- and beta-adrenergic receptor-mediated responses 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, e.g., horses, cattle, and other non-human mammals, and as an emetic, particularly in cats), tizanidine (a central muscle relaxant, which acts presynaptic on motor neurons), or tizanidine (a central muscle relaxant, which acts presynaptic on motor neurons). Consider the selection of: tizanidine, a short-acting agent that can also be used to manage spasticity by increasing inhibition, the effect of tizanidine is greatest on polysynaptic pathways, and the overall effect of these actions reduces facilitation of spinal motor neurons), medetomidine (a racemic mixture of two stereoisomers with dexmedetomidine being 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 hypotensive properties that selectively stimulates alpha-2 adrenergic receptors in the CNS, thereby resulting in inhibition of sympathetic nervous system output).

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

Thus, in some exemplary embodiments, esmolol can be used, preferably as a continuous infusion, for titratability, rapid onset and offset of action. Metoprolol, a beta blocker, and labetalol, a 7:1 ratio of beta blocker to alpha-1 adrenergic receptor antagonist, and/or other agents 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.

Anesthesia providers may take additional considerations into account when determining dosage and timing of administration in the perioperative treatment methods disclosed herein.

For example, the timing and dosage of magnesium salts are typically selected to increase the gradient of Mg ²⁺ extracellularly to keep the "plug" of Mg ²⁺ in the NMDA receptor. When Mg ²⁺ is displaced in the channel of the NMDA receptor, it counteracts the cascade, ultimately resulting in an increase in the perception of noxious stimuli (see FIG. 2). In particular, in the pyroid-free pre-, intra- or post-operative compositions of the present disclosure, magnesium salts are provided to increase the gradient of Mg ^{2+ extracellularly to keep the "plug" of Mg 2+ in} the NMDA receptor. Mg ²⁺ salt infusion should be used with caution or avoided in 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, Mg ²⁺ salt infusion can be reduced so that the cumulative dose does not cause the undesired side effects of high plasma levels of Mg ²⁺ salt, such as muscle weakness, inability to reverse muscle relaxants, reduced blood pressure, and extreme cases of bradyarrhythmia.

In some embodiments where the alpha-2 receptor antagonist is dexmedetomidine, the dosage and timing of administration can be selected to allow for high loading and infusion of dexmedetomidine 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 the infusion 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.

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 react 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. In the absence of a block and if 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 male, 18-24 years of age, a high dose of dexmedetomidine may be necessary to effectively attenuate sympathetic output at the time of surgery and to aid in a gentle emergence from anesthesia.

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

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 the selection of the alpha-2 adrenergic receptor blocker, as well as its dosage and timing of administration.

In some embodiments where the patient is diabetic or at high risk for infection, administration of steroids can be reduced or eliminated, as will be appreciated by those skilled in the art.

In other embodiments where dexamethasone (dexamethasone sodium phosphate) is administered, other relevant timing and dosages can be selected, bearing in mind 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 patients are chronically taking exogenous steroids and are 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 and is more potent and long-acting than hydrocortisone, and can be used as a therapy to prevent adrenal crisis in these patients.

In some embodiments where basic hygiene, e.g., access to running water, is an issue, the disclosed method includes administering a reduced dose of steroid to minimize the risk of infection. In some embodiments, the disclosed method includes administering an increased dose of dexamethasone for pain control beyond the dose (approximately 4 mg) typically used by anesthesia providers to prevent post-operative nausea and vomiting.

In certain embodiments, in the pre-operative treatment method, the individual components or pre-operative compositions of the present disclosure can be administered parenterally (e.g., subcutaneously, intramuscularly, or intravenously) or intranasally. In certain embodiments, the individual components or pre-operative compositions of the present disclosure can be administered by intravenous infusion. In one aspect, the individual components or pre-operative compositions of the present disclosure can be administered by intravenous infusion in a bolus.

In some embodiments, in the pre-operative treatment method, the individual components or pre-operative compositions of the present disclosure are administered as a single bolus dose by intravenous infusion over a time 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.

In embodiments where 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 pharma- ceutically effective amount of the liquid composition may be given IV over a period of, for example, 15 minutes. Alternatively, a pharma- ceutically effective amount of the liquid composition may be withdrawn in a loading dose, 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, where 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 pharma- ceutically effective amount of the liquid composition may be given IV over a period of, for example, 15 minutes. Alternatively, a pharma- tically effective amount of the liquid composition can be withdrawn in a loading dose, 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.

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.

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.

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 at 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 in the opioid-free pre-surgical composition.

In certain embodiments of the preoperative treatment method, the alpha-2 agonist is administered in an amount ranging from about 0.001mcg/mL to about 500mcg/mL, 0.01mcg/mL to about 50mcg/mL, about 0.1mcg/mL to about 40mcg/mL, about 0.2mcg/mL to about 30mcg/mL, about 0.3mcg/mL to about 20mcg/mL, 0.4mcg/mL to about 15mcg/mL, about 0.5mcg/mL to about 10mcg/mL, about 1mcg/mL to about 10mcg/mL, about 2mcg/mL to about 10mcg/mL, or about 3mcg/mL to about 10mcg/mL. In certain embodiments, one alpha-2 agonist may be administered at a concentration of about 0.1mcg/mL, about 0.2mcg/mL, about 0.3mcg/mL, about 0.4mcg/mL, about 0.5mcg/mL, about 0.6mcg/mL, about 0.7mcg/mL, about 0.8mcg/mL, about 0.9mcg/mL, about 1mcg/mL, about 1.5mcg/mL, about 2mcg/mL, about 2.5mcg/mL, about 3mcg/mL, about 3.5mcg/mL, about 4mcg/mL, about 4.5mcg/mL, about 5mcg/mL, about 5. It 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.

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 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.

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.

In certain embodiments of the preoperative treatment method, the 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.

In certain embodiments, in intraoperative treatment methods, 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 in a bolus dose.

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 , 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.

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, 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. 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.

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.

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, about 0.001 mg/mL to about 15 mg/mL, about 0.005 mg/mL to about 10 mg/mL, about 0.01 mg/mL to about 5 mg/mL, about 0.05 mg/mL to about 1 mg/mL, or 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.

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, about 0.001 mg/mL to about 15 mg/mL, about 0.01 mg/mL to about 10 mg/mL, about 0.1 mg/mL to about 5 mg/mL, or 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.

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 if the patient's physiological response to the surgical stimulus is observed.

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

In some embodiments, the opioid-free compositions of the present disclosure may be contained in 5 mL, 10 mL, 20 mL, 30 mL, 50 mL, or 60 mL vials, syringes, or bottles. The opioid-free compositions, particularly pre-operative opioid-free compositions, may be reconstituted if applicable and administered undiluted via IV over a period of time, for example, about 15 minutes. Alternatively, a pharmacologic effective amount of the opioid-free composition may be withdrawn in a loading dose, diluted with a 50 or 100 cc IV bag/bottle of fluid, and infused IV over a period of about 15 minutes, about 30 minutes, about 45 minutes, or about 1 hour or more.

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 may last from less than an hour to several hours, depending on the complexity of the medical or surgical procedure.

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

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.

The following considerations should be taken into account when selecting the dosages and methods of the present disclosure:

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 a "hot flash." There may be discomfort at the IV site and in some cases a numbness in the extremities where the IV is placed. In rare cases, there may be a feeling of generalized body weakness. The faster the infusion, the more generalized and intense the symptoms. The slower the infusion, the less likely the patient is to notice any side effects other than sedation experienced approximately 10 minutes after the infusion begins. In some embodiments, the rate is 10 mL volume (35 cc/hr) for about 15 minutes.

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

Because most OFA agents are given separately, each additional tool is perceived as increased work by the anesthesia provider. In addition, unlike most agents used in anesthesia, which have an immediate effect upon administration, OFA agents are an exception. Thus, the timing of administration of the compositions of the present disclosure is a factor to consider.

The combined effect of the drugs in the disclosed compositions 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.

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.

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

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 tertiary level of anesthesia (between consciousness and medullary depression/death, optimal for surgery) is maintained by continuous infusion of intravenous medication (propofol) and/or titration of anesthetic gas via the breathing circuit. Towards the end of the procedure, the medication is shut off and the patient is awakened from anesthesia once it has worn off.

Another reason to give a loading dose drug enough time before incision is to allow the steroid to take effect. Steroids are 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 causes local inflammatory changes at the site. Dexamethasone is typically administered after the patient is asleep, as it causes the undesirable effect of intense perineal burning if given rapidly as an IV bolus to an awake patient. However, this does not leave enough time for the peak effect between induction of anesthesia (and dexamethasone administration) and incision. This time gap, the "prep time," is usually 10-30 minutes, but can be as long as an hour in some cases.

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 is 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 pt) before leaving the operating room. There are very few cases (large hospitals doing major surgery) where the patient can remain intubated. The majority of cases performed in the United States are outpatient. Thus, this type of anesthesia is preferably applicable in the outpatient setting and generally for shorter cases in healthier patients. In the outpatient setting, there is a higher utilization of bolus dosing of some of these agents, so the peak onset of action is more likely to be reached quickly and offsets are more predictable/timed. In the surgical setting, time equals money, so offset timing is of the utmost importance.

4.5 Systems In one aspect, the present disclosure provides a system for anesthesia applications.

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.

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 provided as part of the system in various combinations with each other according to the present disclosure.

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.

In the opioid-free pre-operative system, the magnesium salt, alpha-2 agonist, and optionally the sodium channel blocker, NMDA antagonist other than the 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, Cox inhibitor, corticosteroid, GABA analog, antidepressant, cannabidiol (CBD), and/or antiemetic for simultaneous, combined, or sequential use as described herein.

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 independently, possibly with a suitable vehicle, carrier or excipient, including carriers or adjuvants as would be understood by one of skill in the art.

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.

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, a beta blocker composition, and/or a corticosteroid composition other than the magnesium salt 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-opioid-free composition, intra-opioid-free composition, or post-opioid-free composition of the present disclosure, and/or administered by any one of the methods described herein.

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 inhibitor composition, the concentration of which is described in any one of Sections 4.2.1, 4.2.2, or 4.2.3 for opioid-free compositions comprising a sodium channel inhibitor;
and, where appropriate,
(4) an NMDA antagonist other than a magnesium salt composition, in a concentration as set forth 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 set forth in any one of Sections 4.2.1, 4.2.2 or 4.2.3 for opioid-free compositions comprising a beta blocker; and/or (6) a corticosteroid composition, in a concentration as set forth in any one of Sections 4.2.1, 4.2.2 or 4.2.3 for opioid-free compositions comprising a corticosteroid;
and optionally, the container can include a container for combining to provide any one of the opioid-free compositions of the present disclosure and/or for administration by any one of the methods described herein.

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

In one embodiment, the present disclosure provides a system for opioid-free pre-operative treatment of an individual, the system including 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 a second embodiment, the present 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.

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.

In a system for opioid-free pre-operative treatment of an individual, the magnesium salt, alpha-2 agonist, and optionally a sodium channel inhibitor, 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 a pre-operative composition as described herein.

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 the magnesium salt are included in amounts effective for simultaneous, combined, or sequential use to prepare the perioperative compositions described herein.

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

Thus, in some embodiments, the systems of the present disclosure may 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.

In some embodiments, the compositions described herein can be premixed by a manufacturer, eliminating the need for the provider to mix the agents contained in the composition. Optionally, the provider is provided with instructions on how to administer the composition.

In each of the embodiments described above, 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).

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 may be 25 mL, 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 300 mL, 400 mL, 500 mL, or 1000 mL.

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

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

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.

4.6 Kits Comprising Opioid-Free Compositions The present disclosure provides kits of parts for carrying out any of the methods described herein. In one particular embodiment, a 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 the individual components in separate containers or formulated together in one container as an opioid-free pre-operative composition.

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.

In another particular embodiment, a kit for an opioid-free perioperative composition includes 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 includes a postoperative composition of the present disclosure.

In various embodiments, the kit of parts further comprises one or more additional agents described herein, such as calcium channel blockers, Cox inhibitors, corticosteroids, GABA analogs, antidepressants, cannabidiol (CBD) and/or antiemetics, as well as additional components ascertainable by one of skill in the art.

In one embodiment, the kit of parts further comprises a standard product.

In each of the embodiments described above, 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).

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 may be 25 mL, 50 mL, 100 mL, 150 mL, 200 mL, 250 mL, 300 mL, 400 mL, 500 mL, or 1000 mL.

In one embodiment, the kit of parts further comprises instructions for use. Instructions, e.g., written or audio instructions, on paper or by electronic aid such as tape, CD-ROM, flash drive, or by uniform resource locator (URL) directions, including but not limited to YouTube tutorials containing pdf copies of instructions for carrying out the methods described herein, are typically included in the kit. The kit may also contain other packaged reagents and materials, depending on the particular method used. Further details regarding the identification of suitable vehicles, carriers or excipients for the compositions, as well as the general manufacture and packaging of kits, may be ascertainable by one of skill in the art upon reading this disclosure.

The present disclosure also provides computer-based or mobile device-based applications ("apps") for use in the methods of the present disclosure. The apps can be designed to aid an operator (e.g., an 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 include instructions for preparation of the associated compositions and/or instructions for associated administration to the patient. The apps can be designed to label the drugs to identify the desired mixture contents and/or patient, and/or to identify preparation information and/or date and time for the provider.

Further characteristics and properties of the present disclosure will become more apparent from the following detailed disclosure, by way of example only, and with reference to the examples.

6. EXAMPLES 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.

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]

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) pre-op at home, (2) pre-op in the hospital ward, (3) pre-op waiting IV bolus infusion over 15 minutes, (4) pre-op block, (5) intra-op, (6) OFA infusion mix instructions, and (7) additional medication regimen.
Section 1.02
[Example 1.1]

Home Pre-Op Regimen Duloxetine is given to patients 1-2 weeks prior to surgery that carries a high risk of developing chronic pain, including, but not limited to, amputation, mastectomy, thoracotomy, inguinal hernia repair, coronary artery bypass grafting, Caesarean 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]

Preoperative regimen in the ward The following medications were offered to patients before surgery:
a) Acetaminophen 1 g PO or IV acetaminophen 1 gm IVPB prior to incision.
b) Celecoxib 200-400 mg PO (unless allergic to sulfa drugs) or meloxicam 15 mg.
c) Pregabalin 50 mg to 150 mg 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 less than 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]

Pre-operative Waiting Regimen for Intra-operative Compositions of the Present Disclosure A bolus dose of the opioid-free pre-operative composition is administered in a 10 mL syringe as follows:
6 mL of magnesium sulfate (500 mg/mL),
1.5 mL of dexamethasone (10 mg/mL),
It was prepared by combining 0.3 mL of dexmedetomidine (100 mcg/mL) and 2.2 mL of 2% lidocaine.

The pre-operative opioid-free composition was administered to the patient at 1 mL/10 kg IBW over 15-30 minutes (translating to a dosage of 30 mg/kg Mg ²⁺ , 0.3 mcg/kg dexmedetomidine, 0.15 mg/kg dexamethasone and 0.44 mg/kg lidocaine).

When considering preoperative loading, the following comes to mind:
Dexmedetomidine 0.3 mcg/kg. IV dexmedetomidine has a peak effect of 15 minutes. If the patient is sufficiently calm/sedated after using dexmedetomidine, pre-op benzodiazepines can be eliminated.
Magnesium sulfate 30 mg/kg.
Dexamethasone 0.15 mg/kg. Dexamethasone has an onset of action of 2 hours. The most preferred procedure 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]

Administration of Preoperative Blocks When 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]

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.

During the intraoperative phase, prior to induction, patients received:
Ketamine 10-15 mg IVP 1-5 minutes 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 rate of 50-70% fresh gas nitrous oxide.
Section 1.07
[Example 1.6]

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 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).

The following are directions for administering the opioid-free intraoperative compositions of the present disclosure:
Implement an IBW of 1 mL/kg/hr.
IV Infusion Dose:
Lido (1% or 2%) at 2 mg/kg/hr IBW, magnesium sulfate at 10 mg/kg/hr IBW;
Dexmedetomidine, 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 relief of hypertension/tachycardia;
Preferably prior to incision, if a nerve block is not used, the surgeon will preferably be aided by infiltrating the surgical site with local anesthesia Ketamine at a total dose of 0.5 mg/kg IBW for the duration of the case.
Section 1.08
[Example 1.7]

Additional Medication 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.

Below is a regimen of additional medications administered during the intraoperative and postoperative phases of a surgical procedure. The regimen of additional medications is intended to provide improved postoperative 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 hour routine.
Pregabalin 50-150 mg qHS routine.

In major surgery cases where the patient is admitted to the hospital for postoperative care, administer 10 mg IV dexamethasone slowly over 10 minutes on the first postoperative day.

Continuing duloxetine for 2 weeks after surgery in patients at high risk of developing chronic postoperative pain syndrome.

In major surgery cases where the patient is admitted to the hospital for postoperative care, administer 10 mg IV dexamethasone slowly over 10 minutes on the first postoperative day.

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

Infusion Ranges and Loading Volumes Exemplary infusion ranges (concentrations) and loading volumes selected for drugs are shown in Table 1 below.
Section 1.10
[Example 3]

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 composition described herein and shown in Table 2 below.

The differences in the components of the MuliMix composition and the exemplary OFA composition are clear. The OFA preemptive analgesia composition of the present disclosure has significantly higher dosing than MuliMix and can be used in the pre- and post-operative periods. There are dose-response curves for dexmedetomidine, lidocaine and ketamine. The higher the dose, the greater the sedative effect. The OFA preemptive analgesia composition of the present disclosure with the higher dosing provides an even more significant reduction in other anesthetic agents, such as propofol infusion, or anesthetic gases, such as sevoflurane, desflurane or isoflurane.

The 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 infusions, we give increasing doses of some of the drugs that typically preload 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. Mg ²⁺ may be omitted since the loading dose alone is sufficient to cover short-term cases where the infusion is not continued. MuliMix does not explicitly include Mg ²⁺ or dexamethasone sodium phosphate in the mixture, 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 specified as a requirement of the protocol.

When Mg ²⁺ 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 machine, 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. In opioid-based anesthesia, for example, fentanyl is routinely given for induction of anesthesia before the airway is inserted. Fentanyl interacts synergistically with other agents, such as Versed, to promote a drop in blood pressure during this pause in activity and also to prevent the patient from breathing on their own for several minutes until ETCO2 is increased enough to drive breathing. This requires manual ventilation if the patient is not mechanically ventilated, creating extra work for the provider and possibly a safety concern if the airway is not accessible and patent.
Section 1.11

ワールドワイドウエブmclottmix.comに記載されているMcLott Mixを、本開示の先制鎮痛OFA組成物と比較し、下記の表4に示す。

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.

The differences between the McLott Mix and the exemplary OFA compositions of the present disclosure are clear. Unlike the opioid-free pre-operative compositions of the present disclosure, the McLott does not provide any pre-operative oral medication. Rather, the McLott Mix is referred to solely as an intra-operative composition. McLott's OFA induction is not said to be required or an integral part of the McLott method. It does not appear to be a similar protocol to the methods of the present disclosure.

In the McLott Mix, the Mg2 ⁺ loading dose is not weight-based, which results in under-dosing for most adult patients. In contrast, in some embodiments, the opioid-free intraoperative compositions and/or methods use a specific weight-based dose of Mg2 ⁺ loading known to have clinical efficacy.

Additionally, 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 compositions and associated methods of the present disclosure are completely opioid-free.

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 added benefit of anxiolysis in the preoperative phase. In addition, giving dexmedetomidine as a bolus at induction is known to cause a transient rise in blood pressure followed by a fall in blood pressure, making this timing particularly problematic. Immediately after induction, the airway creation procedure (intubation) can cause a transient rise in blood pressure and tachycardia. Once the airway is created, it is quite common for a period of marked blood pressure fall 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 hemodynamic conditions worsening.

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

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 0.5 cc/kg versus 1 mL/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 hypotensive and bradycardial 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, unlike the McLott Mix, adds an additional pathway to block pain. Beta blockers are known to decrease the neuroendocrine stress response, resulting in a reduction in pro-inflammatory cytokines and NMDA receptor activation.
Section 1.12
[Example 5]

Preparation of an Exemplary Pre-Op OFA Composition of the Present Disclosure in a Loading Syringe A pre-op 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) to a final volume dose of 10 mL in a syringe.

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

Preparation of an Exemplary Intra-Operative OFA Composition 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.

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.

Intraoperatively, the OFA composition was infused at a rate of 1 cc/kg/hr of patient IBW.

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

For a 50 kg patient, administer the composition described below.

Minimum preoperative loading dose of most concentrated composition (excluding optional components) 250 mg (50% of 0.5 mL) Magnesium sulfate (5 mg/kg)
5mcg (0.05mL of 10%) Dexmedetomidine (0.1mcg/kg)
Dexamethasone – as needed Ketamine – as needed Lidocaine – as needed

Intraoperative infusion - maximum concentrated infusion possible - (excluding the appropriate component and excluding the lowest possible dose of all components except the component being tested)
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 (0.1 mcg/kg/hr)
Ketamine - as appropriate as described herein Esmolol - as appropriate as described herein

The following calculations can be performed to determine the maximum concentrations for various drugs:

Calculations for Maximum Concentration of Magnesium Sulfate Section 1.14 Preoperative Loading Dose:
Minimum: 1 mg/mL
Maximum: 500 mg/mL. 500 mg/mL is slightly higher than the actual (495 mg/mL), but within reason, since the only other anhydrous drug is dexmedetomidine, which is nearly eliminated.
50 kg pt (maximum concentrated magnesium load)
2500mg (5mL of 50%) Mg+ (50mg/kg)
5mcg (0.05mL of 10%) Dexmedetomidine (0.1mcg/kg)
Dexamethasone – as needed Ketamine – as needed Lidocaine – as needed = 5.05 mL total volume 2500 mg/5.05 mL = 495 mg/mL
Section 1.15 Intraoperative Injections:
Minimum: 1 mg/mL
Maximum: about 370 mg/mL
50 kg pt (maximum concentrated Mg++ injection)
1 GM (2 mL of 50%) magnesium sulfate (20 mg/kg) - Maximum 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 needed as described herein Esmolol - as needed as described herein = 2.7 mL total volume 1000 mg/2.75 mL = 370 mg/mL

Calculations for Maximum Concentration of Dexmedetomidine Section 1.16 Preoperative Loading Dose:
Minimum: 0.01 mcg/mL
Maximum: 50 mcg/mL
50 kg pt (maximum concentrated dexmedetomidine loading dose)
250mg (5mL of 50%) Mg+ (5mg/kg)
50mcg (10% of 0.5mL) Dexmedetomidine (1mcg/kg) - Maximum loading dose Dexamethasone - As needed Ketamine - As needed Lidocaine - As needed = Total volume in 1mL 50mcg/1mL = 50mcg/mL
Section 1.17 Intraoperative Injections:
Minimum: 0.01 mcg/mL
Maximum: 30 mcg/mL
50 kg 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)
50mcg (10% in 0.5mL) Dexmedetomidine (1mcg/kg) - Maximum infusion volume Ketamine - As needed as stated Esmolol - As needed as stated = 1.65mL
50mcg/1.65mL = 30mcg/mL

Calculations for Maximum Concentration of Lidocaine Section 1.18 Preoperative Loading Dose:
Min: 0 mg/mL - Drug loading dose as needed Max: 35 mg/mL
50 kg pt (maximum concentrated lidocaine load)
250mg (0.5mL of 50%) Mg+ (5mg/kg)
5mcg (0.05mL of 10%) Dexmedetomidine (0.1mcg/kg)
Dexamethasone – as needed Ketamine – as needed 100 mg (4% of 2.5 mL)
Lidocaine (2 mg/mL)
= 3.05 mL
100mg/3.05mL=33mg/mL
Section 1.19 Intraoperative Injections:
Minimum: 0.1 mg/mL - Use OFA Composition Dosage 50 kg pt (minimum concentrated lidocaine max dose in all other cases - injected) - Could have included lesser concentration from original vial but did not. Rounded.
1000mg (2mL of 50%) Magnesium sulfate (20mg/kg/hr)
25 mg (0.65 mL of 4%) lidocaine (0.5 mg/kg/hr)
50 mcg (0.5 mL of 10%) dexmedetomidine (1 mcg/kg/hr)
25 mg (0.5 mL of 5%) ketamine (0.5 mg/kg/hr)
50 mg (6 mL of 1%) Esmolol (20 mcg/kg/hr) - OFA Dosage = 9.65 mL
25mg/9.65mL=2.6mg/mL
Minimum: 0.1 mg/mL - use maximum esmolol dosing for hypertensive crisis 50 kg pt (minimum concentrated lidocaine max dose in all other cases - infused) - could have included lesser concentration from original vial but did not. Rounded.
1000mg (2mL of 50%) Mg+ (20mg/kg/hr)
25 mg (0.65 mL of 4%) lidocaine (0.5 mg/kg/hr)
50 mcg (0.5 mL of 10%) dexmedetomidine (1 mcg/kg/hr)
25 mg (0.5 mL of 5%) ketamine (0.5 mg/kg/hr)
900 mg (1% of 90 mL) Esmolol (300 mcg/kg/hr) - Hypertensive Crisis Medications = 92.65 mL
25mg/92.65mL=0.27mg/mL
Maximum: 35 mg/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)
5mcg (0.05mL of 10%) Dexmedetomidine (0.1mcg/kg/hr) Ketamine - as needed as stated Esmolol - as needed as stated = 4.3mL
150 mg/4.3 mL = 34.88 mg/mL

Calculations for Maximum Concentration of Ketamine Section 1.20 Pre-Op Loading Dose:
Min: 0 mg/mL - as needed Max: 35 mg/mL
50 kg pt (maximum concentrated ketamine infusion - minimum dose in all other cases)
250 mg (0.5 mL of 50%) Magnesium sulfate (5 mg/kg)
5mcg (0.05mL of 10%) Dexmedetomidine (0.1mcg/kg)
Dexamethasone - as needed 25 mg (0.25 mL of 10%) Ketamine (0.5 mg/kg)
Lidocaine - as needed = 0.8 mL
25 mg/0.8 mL = 31.25 mg/mL
Intraoperative injection:
Min: 0 mg/mL - as needed Max: 20 mg/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)
5 mcg (0.05 mL of 10%) dexmedetomidine (0.1 mcg/kg/hr)
25 mg ketamine (0.25 mL of 10%) ketamine (0.5 mg/kg/hr)
Esmolol - as appropriate as stated = 1.45 mL
25mg/1.45=17.24mg/mL

Calculated preoperative loading dose for maximum concentration of esmolol:
Intraoperative injection:
Min: 0 mg - as needed Max: 14.3 mg/mL - OFA Esmolol Dosage (for pain relief only)
250mg (0.5mL of 50%) Mg+ (5mg/kg/hr)
25 mg (0.65 mL of 4%) lidocaine (0.5 mg/kg/hr)
5 mcg (0.05 mL of 10%) dexmedetomidine (0.1 mcg/kg/hr)
Ketamine - ad libitum as described herein 60 g (3 mL of 2%) Esmolol (20 mcg/kg/min) = 4.2 mL
60 mg/4.2 mL = 14.3 mg/mL

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 (0.5mL of 50%) Mg+ (5mg/kg/hr)
25 mg (0.65 mL of 4%) lidocaine (0.5 mg/kg/hr)
5 mcg (0.05 mL of 10%) dexmedetomidine (0.1 mcg/kg/hr)
Ketamine - as needed as described herein 900 mg (2% in 45 mL) Esmolol (300 mcg/kg/min)
= 46.2 mL
900mg/46.2mL=19.5mg/mL

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

Preparation of Exemplary Opioid-Free Pre-Surgical Compositions of the Present Disclosure Exemplary pre-surgical compositions according to the present disclosure are reported in Table 5.

セクション１．２３
［実施例１０］

Section 1.23
[Example 10]

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-surgical compositions in bolus form are provided in Table 6 below.

セクション１．２４
セクション１．２５
［実施例１１］

Section 1.24
Section 1.25
[Example 11]

Dosage of Opioid-Free Pre-Surgical Composition Exemplary dosages of the pre-emptive pre-surgical composition in bolus form are provided in Table 7 below.

必要であれば追加の薬剤を注入または緩徐IVボーラスとして、別個に投与することができ、デクスメデトミジン、および/または硫酸マグネシウム、および/またはデキサメタゾン、および/またはケタミン、および/またはリドカインを含む。
セクション１．２６
［実施例１２］

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]

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 compositions are administered as a continuous infusion.

Additional medications can be administered separately, as a continuous infusion or as a bolus, if needed, 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]

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

セクション１．２８
［実施例１４］

Section 1.28
[Example 14]

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

セクション１．２９
［実施例１５］

Section 1.29
[Example 15]

Opioid-Free Perioperative Treatment Methods Exemplary opioid-free intraoperative compositions and methods of the present disclosure are provided in Table 11.
Section 1.30

［実施例１６］

[Example 16]

Opioid Consumption and Aldrete Score Following 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).

As shown in Figure 4, of the 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 discharge readiness scores of the OFA cohort were superior to the non-OFA cohort at the end of anesthesia recovery time (9.6 vs. 9.4).

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]

Analysis of Length of Stay for Patients Undergoing OFA A retrospective analysis was performed 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. This reduction in LOS allows hospitals to save significant amounts of money.

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 cost of hospital services is collectively referred to as "adjusted costs" and represents 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 the data available in sources such as Becker's Hospital Review and Kaiser foundation.
Section 1.32
[Example 18]

Administration of OFA to ankle repair surgery patients Patients undergoing a surgical procedure to repair an ankle fracture were 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]

Administration of OFA to a Severe Ankle Fracture Repair Surgery Patient 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 surgery. FIG. 14B shows an image of the ankle after surgery. The patient woke up comfortably without 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 the artisan to whom this disclosure pertains.

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 materials, compositions, systems and uses of the present disclosure, 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.

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 was individually incorporated by reference in its entirety. However, in the event of any inconsistency between a cited reference and this disclosure, this disclosure will control.

The terms and expressions used herein are used as terms of description and not as limitations, and such uses and surface uses 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.

Numerous 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 of ordinary skill in the art that the present disclosure can be practiced using many of the various apparatus, apparatus components, and method steps described herein. As will be apparent to one of ordinary skill in the art, the methods and apparatus useful in the present methods may include a large number of suitable compositions and processing elements and steps.

References

Claims (66)

Magnesium (Mg2+) salts,
alpha-2 agonists,
and, where appropriate,
1. An opioid-free pre-operative pharmaceutical composition comprising a sodium channel blocker, and/or an N-methyl-D-aspartate (NMDA) antagonist other than a magnesium salt, and/or a corticosteroid, 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, said effective amount of composition being administered to an individual in need of anesthesia during the pre-operative phase of a medical or surgical procedure and while undergoing said medical or surgical procedure;
Opioid-free pre-operative pharmaceutical composition. The opioid-free preoperative pharmaceutical composition of claim 1, 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. The opioid-free preoperative pharmaceutical composition of claim 1 or claim 2, wherein the alpha-2 agonist comprises dexmedetomidine. The opioid-free preoperative pharmaceutical composition according to any one of claims 1 to 3, 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 moricindine, or any combination thereof. The opioid-free preoperative pharmaceutical composition according to any one of claims 1 to 4, wherein the sodium channel inhibitor comprises lidocaine and/or procaine, or any combination thereof. The opioid-free preoperative pharmaceutical composition according to any one of claims 1 to 5, wherein the sodium channel inhibitor comprises lidocaine. The opioid-free preoperative pharmaceutical composition according to any one of claims 1 to 6, 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. The opioid-free preoperative pharmaceutical composition according to any one of claims 1 to 7, wherein the NMDA antagonist other than a magnesium salt comprises ketamine. The opioid-free preoperative pharmaceutical composition of any one of claims 1 to 8, wherein the corticosteroid is selected from the group consisting of cortisone, hydrocortisone, fludrocortisone acetate, prednisolone, prednisone, methylprednisolone, triamcinolone, dexamethasone sodium phosphate, betamethasone, triamcinolone acetonide, and fluorometholone, or any combination thereof. The opioid-free preoperative pharmaceutical composition according to any one of claims 1 to 9, wherein the corticosteroid comprises dexamethasone sodium phosphate. the magnesium salt comprises magnesium sulfate or magnesium chloride;
the alpha-2 agonist comprises dexmedetomidine;
the sodium channel blocker comprises lidocaine, prilocaine, or procaine;
the NMDA antagonist comprises ketamine;
the corticosteroid comprises dexamethasone;
2. The opioid-free pre-operative pharmaceutical composition of claim 1. The opioid-free preoperative pharmaceutical composition according to any one of claims 1 to 11, wherein the concentration of the magnesium salt ranges from 1 mg/mL to 500 mg/mL. The opioid-free preoperative pharmaceutical composition of claim 12, wherein the concentration of the magnesium salt ranges from 1 mg/mL to 300 mg/mL. The opioid-free preoperative pharmaceutical composition according to any one of claims 1 to 13, wherein the concentration of the alpha-2 agonist ranges from 0.01 to 50 mcg/mL. The opioid-free preoperative pharmaceutical composition of claim 14, wherein the concentration of the alpha-2 agonist ranges from 0.1 to 30 mcg/mL. The opioid-free preoperative pharmaceutical composition according to any one of claims 14 to 15, wherein the concentration of the alpha-2 agonist ranges from 0.1 to 1 mcg/mL. The opioid-free preoperative pharmaceutical composition according to any one of claims 1 to 16, wherein the concentration of the sodium channel inhibitor ranges from 0.1 mg/mL to 35 mg/mL. The opioid-free preoperative pharmaceutical composition of claim 17, wherein the concentration of the sodium channel inhibitor ranges from 1 mg/mL to 20 mg/mL. The opioid-free preoperative pharmaceutical composition according to any one of claims 1 to 18, wherein the concentration of the NMDA antagonist other than the magnesium salt ranges from 0.01 mg/mL to 35 mg/mL. 20. The opioid-free preoperative pharmaceutical composition of claim 19, wherein the concentration of the NMDA antagonist other than the magnesium salt ranges from 0.1 mg/mL to 0.5 mg/mL. 21. The opioid-free preoperative pharmaceutical composition of any one of claims 1 to 20, wherein the concentration of the corticosteroid ranges from 0.01 to 10 mg/mL. 22. The opioid-free pre-operative pharmaceutical composition of claim 21, wherein the concentration of the corticosteroid ranges from 1 to 2.0 mg/mL. a magnesium salt at a concentration ranging from about 50 mg/mL to about 500 mg/mL;
an alpha-2 agonist at a concentration ranging from about 1 mcg/mL to about 50 mcg/mL;
and, where appropriate,
a sodium channel inhibitor at a concentration ranging from about 1 mg/mL to about 35 mg/mL;
an NMDA antagonist, other than a magnesium salt, in a concentration ranging from about 0.01 mg/mL to about 35 mg/mL, and a corticosteroid in a concentration ranging from about 0.1 mg/mL to about 10 mg/mL, together with a pharma- ceutically acceptable vehicle, carrier, or excipient;
2. The opioid-free pre-operative pharmaceutical composition of claim 1. 1. A method of opioid-free pre-operative treatment of an individual in need of anesthesia while undergoing a medical or surgical procedure, comprising:
an effective amount of a magnesium salt in an amount ranging from 5 to 50 mg/kg of standard 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;
administering to said individual an amount of a corticosteroid ranging from 0.01 to 0.2 mg/kg IBW, and/or an amount of an NMDA antagonist other than a magnesium salt ranging from 0 to 0.5 mg/kg IBW;
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 method. The method of claim 24, wherein the administration of the opioid-free preoperative treatment is carried out by administering to the individual a preoperative pharmaceutical composition according to any one of claims 1 to 23 or claim 65. Magnesium (Mg2 ⁺ ) salts,
alpha-2 agonists, and sodium channel blockers,
and, where appropriate,
an NMDA antagonist other than a magnesium salt, and/or a beta blocker, together with a pharma- ceutically acceptable vehicle, carrier, or excipient, wherein the magnesium salt, alpha-2 agonist, sodium channel blocker, and, optionally, the NMDA antagonist other than a magnesium salt, 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;
An opioid-free intraoperative pharmaceutical composition. The opioid-free intraoperative pharmaceutical composition of claim 26, 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. The opioid-free intraoperative pharmaceutical composition according to claim 26 or 27, wherein the alpha-2 agonist comprises dexmedetomidine. 29. The opioid-free intraoperative pharmaceutical composition of any one of claims 26 to 28, 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 moricindine, or any combination thereof. The opioid-free intraoperative pharmaceutical composition according to any one of claims 26 to 29, wherein the sodium channel inhibitor comprises lidocaine and procaine, or any combination thereof. The opioid-free intraoperative pharmaceutical composition according to any one of claims 26 to 30, wherein the sodium channel inhibitor comprises lidocaine. 32. The opioid-free intraoperative pharmaceutical composition according to any one of claims 26 to 31, 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. The opioid-free intraoperative pharmaceutical composition according to any one of claims 26 to 32, wherein the NMDA antagonist other than a magnesium salt comprises ketamine. 34. The opioid-free intraoperative pharmaceutical composition of any one of claims 26 to 33, 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. The opioid-free intraoperative pharmaceutical composition according to any one of claims 26 to 34, wherein the beta blocker comprises esmolol. The opioid-free intraoperative pharmaceutical composition according to any one of claims 26 to 35, 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. the magnesium comprises magnesium sulfate;
the alpha-2 agonist comprises dexmedetomidine;
the sodium channel blocker comprises lidocaine, prilocaine, or procaine;
the NMDA antagonist comprises ketamine;
The beta blocker comprises esmolol.
27. The opioid-free intraoperative pharmaceutical composition of claim 26. a magnesium salt in an amount ranging from about 5 mg/mL to about 20 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;
and, where appropriate,
an NMDA antagonist, other than a magnesium salt, in an amount ranging from about 0 mg/mL to about 0.5 mg/mL, and a beta blocker in an amount ranging from about 0.15 mg/mL to about 2 mg/mL, together with a pharma- ceutically acceptable vehicle, carrier, or excipient;
27. The opioid-free intraoperative pharmaceutical composition of claim 26. The opioid-free intraoperative pharmaceutical composition according to any one of claims 26 to 38, wherein the concentration of the magnesium salt ranges from 1 mg/mL to 500 mg/mL. The opioid-free intraoperative pharmaceutical composition of claim 39, wherein the concentration of the magnesium salt ranges from 1 mg/mL to 370 mg/mL. The opioid-free intraoperative pharmaceutical composition according to any one of claims 26 to 40, wherein the concentration of the alpha-2 agonist ranges from 0.01 to 30 mcg/mL. The opioid-free intraoperative pharmaceutical composition of claim 41, wherein the concentration of the alpha-2 agonist ranges from 0.1 to 30 mcg/mL. The opioid-free intraoperative pharmaceutical composition according to claim 41 or 42, wherein the concentration of the alpha-2 agonist is in the range of 0.1 to 1 mcg/mL. The opioid-free intraoperative pharmaceutical composition according to any one of claims 26 to 43, wherein the concentration of the sodium channel inhibitor ranges from 1 mg/mL to 3 mg/mL. The opioid-free intraoperative pharmaceutical composition according to any one of claims 26 to 44, wherein the concentration of the NMDA antagonist other than the magnesium salt ranges from 0.01 mg/mL to 20 mg/mL. The opioid-free intraoperative pharmaceutical composition according to claim 45, wherein the concentration of the NMDA antagonist other than the magnesium salt ranges from 0.1 mg/mL to 0.5 mg/mL. The opioid-free intraoperative pharmaceutical composition according to any one of claims 26 to 46, wherein the concentration of the beta blocker ranges from 0.001 mg/mL to 20 mg/mL. The opioid-free intraoperative pharmaceutical composition of claim 47, wherein the concentration of the beta blocker ranges from 0.01 mg/mL to 2 mg/mL. The opioid-free intraoperative pharmaceutical composition according to any one of claims 27 to 48, wherein the concentration of the beta blocker ranges from 0.05 mg/mL to 1 mg/mL. 1. A method of opioid-free perioperative treatment of an individual in need of anesthesia while undergoing a medical or surgical procedure, comprising:
An effective amount of:
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 an amount ranging from 0.01 to 1 mcg/kg/hr IBW, and a sodium channel inhibitor, such as lidocaine, in an amount ranging from 0.1 to 3 mg/kg/hr IBW;
and, where appropriate,
administering to said individual an amount of a beta blocker, e.g., esmolol, in the range of 3 to 300 mcg/kg/min or 3 to 20 mcg/kg/min IBW, and/or an amount of an NMDA antagonist, other than a magnesium salt, in the range of 0 to 0.5 mg/kg/hr IBW;
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 method. The method of claim 50, wherein the administration of the opioid-free intraoperative treatment is performed by administering to the individual an intraoperative pharmaceutical composition according to any one of claims 26 to 49 or claim 66. A method for opioid-free perioperative treatment of an individual undergoing a medical or surgical procedure, comprising administering an opioid-free preoperative treatment of the individual undergoing a medical or surgical procedure according to any one of claims 24-25, and administering an opioid-free intraoperative treatment of the individual undergoing a medical or surgical procedure according to any one of claims 50-51. The administration of the opioid-free preoperative treatment is carried out by administering to the individual a preoperative composition according to any one of claims 1 to 23 or claim 65, and the administration of the opioid-free intraoperative treatment is carried out by administering to the individual an intraoperative composition according to any one of claims 26 to 49 or claim 66.
53. The method of claim 52. 53. The method of claim 52, further comprising administering to an individual an opioid-free post-operative treatment of said individual requiring anesthesia while undergoing a medical or surgical procedure by administering to said individual an opioid-free post-operative pharmaceutical composition comprising any combination of the following: a magnesium salt, and/or an alpha-2 agonist, and/or a sodium channel inhibitor, and/or an NMDA antagonist other than a magnesium salt, and/or a beta blocker, and a pharma- ceutically acceptable vehicle, carrier, or excipient, wherein said post-operative composition is in an amount effective to treat pain and/or inflammation during the post-operative phase of said medical or surgical procedure in said individual. An opioid-free pre-operative system for opioid-free pre-operative treatment of an individual requiring anesthesia while undergoing a medical or surgical procedure, the system comprising a pre-operative pharmaceutical composition according to any one of claims 1 to 23 or claim 65, and one or more containers containing the composition or one or more individual components of the composition, the container being a syringe, an IV bag, a bottle, or a vial, the container being glass or plastic (e.g., polyethylene, polypropylene, polyvinyl chloride, or a polypropylene-polyethylene blend). An opioid-free intraoperative system for opioid-free intraoperative treatment of an individual requiring anesthesia while undergoing a medical or surgical procedure, the system comprising an intraoperative pharmaceutical composition according to any one of claims 26 to 49 or claim 66, and one or more containers containing the composition or one or more individual components of the composition, the container being a syringe, an IV bag, a bottle, or a vial, the container being glass or plastic (e.g., polyethylene, polypropylene, polyvinyl chloride, or a polypropylene-polyethylene blend). 1. An opioid-free peri-operative system for opioid-free peri-operative treatment of an individual in need of anesthesia while undergoing a medical or surgical procedure, comprising:
57. The opioid-free perioperative system comprising: the opioid-free preoperative system of claim 55; and the opioid-free intraoperative system of claim 56. 58. The opioid-free perioperative system of claim 57, further comprising a calcium channel inhibitor, a Cox inhibitor, a GABA analog, an antidepressant, cannabidiol (CBD), and/or an antiemetic. The opioid-free perioperative system of claim 57 or claim 58, wherein the calcium channel inhibitor comprises verapamil or diltiazem. 60. The opioid-free perioperative system of any of claims 57 to 59, 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 (meloxicam), tenoxicam, droxicam, mefenamic acid, meclomefenamic acid, clonixin, licofelone, and paracetamol (acetaminophen), or any combination thereof. The opioid-free perioperative system of any of claims 57 to 60, wherein the GABA analog is selected from the group consisting of pregabalin, gabapentin, picamilon, and progabide, or any combination thereof. The opioid-free perioperative system of any of claims 57 to 61, 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). The opioid-free perioperative system of any of claims 57 to 62, 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. The opioid-free perioperative system of any of claims 57 to 63, wherein the antiemetic agent is selected from the group consisting of ondansetron, dolasetron, granisetron, palonosetron, promethazine, dimenhydrinate, metoclopramide, meclizine, droperidol, haldol, or any combination thereof. 6 mL of magnesium sulfate (500 mg/mL),
1.5 mL of dexamethasone (10 mg/mL),
An opioid-free pre-operative pharmaceutical composition comprising 0.3 mL of dexmedetomidine (100 mcg/mL), and 2.2 mL of 2% lidocaine for a total volume of 10 mL. 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), and 0.25 mL of ketamine (50 mg/mL)
100 mL of a total volume of an opioid-free intraoperative pharmaceutical composition.

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