| US20130116215A1 | 2013-05-09 | |||
| US20110293749A1 | 2011-12-01 | |||
| US20130123320A1 | 2013-05-16 |
| CLAI MS What is claimed is: 1. A pharmaceutically acceptable medicament comprising a. two or more long acting aminoamide local anesthetics selected from the group consisting of ropivicaine, etidocaine, bupivicaine, levobupivicaine, lidocaine, mepivacaine, and prilocaine. b. at least one NSAI D selected from the group consisting of ketorolac, ibuprofen, and indomethacin; c. a corticosteroid selected from the group consisting of dexamethasone, and methylprednisone; d. at least one alpha-2 (a2) adrenergic receptor agonist selected from the group consisting of clonidine, dexmedetomidine, xylazine, detomidine, guanfacine, guanabenz, medetomidine, and methyldopa; e. at least one N-methyl-D aspartate receptor antagonist selected from the group consisting of ketamine, tramadol, and methadone; and f. optionally, epinephrine. 2. The medicament of Claim 1 wherein: a. the two or more long acting aminoamide local anesthetics comprise ropivicaine and bupivicaine; b. the at least one NSAID comprises ketorolac; c. the corticosteroid comprises dexamethasone; d. the at least one a2 adrenergic receptor agonist comprises clonidine; and e. the at least one N-methyl-D aspartate receptor antagonist is ketamine. 3. The medicament of Claim 1 or Claim 2, further comprising epinephrine. 4. The medicament of Claim 3 wherein the concentration of the ropivicaine is 1 .125 mg/ml to 2.5 mg/ml: the concentration of bupivicaine 1 .125 mg/ml to 2.5 mg/ml; the concentration of ketorolac is 100 μg/ml to 400 μg/ml; the concentration of dexamethasone is 20 μg/ml to 100 μg/ml; the concentration of clonidine is 0.5 μg/ml to 2 μg/ml; the concentration of ketamine is 50 μg/ml to 500 μg/ml; and optionally, the concentration of epinephrine is 1 μg/ml and 3 μg/ml. 5. The medicament of Claim 3 wherein The concentration of the ropivicaine is 80% to 120% of 1 .8 mg/ml : the concentration of bupivicaine 80% to 120% of 1.8 mg/ml; the concentration of ketorolac is 80% to 120% of 300 μg/ml; the concentration of dexamethasone is 80% to 120% of 40 μg/ml; the concentration of clonidine is 80% to 120% of 1 μg/ml; the concentration of ketamine is 80% to 120% of 100 μg/ml; and the concentration of epinephrine is 80% to 120% of 1 .5 μg/ml. 6. The medicament of Claim 3 wherein: the concentration of the ropivicaine is about 1 .8 mg/ml : the concentration of bupivicaine 1 .8 mg/ml; the concentration of ketorolac is about 300 μg/ml; the concentration of dexamethasone is about 40 μg/ml; the concentration of clonidine is about 1 μg/ml; the concentration of ketamine is about 100 μg/ml; and the concentration of epinephrine is about 1 .5 μg/ml. 7. A pharmaceutically acceptable medicament selected from the group consisting of formulation 001 - formulation 064. 8. A pharmaceutically acceptable medicament comprising: a. ropivicaine or etidocaine; b. bupivicaine or levobupivicaine; c. ketorolac or ibuprofen; d. dexamethasone or methylprednisone; e. clonidine or dexmedetomidine; f. ketamine or tramdol; and g- optionally epinephrine. 9. A method of treatment comprising the step of administering a medicament of any of Claim 1 - Claim 8 to a subject in need thereof. 10. The method of Claim 9 where the administering step comprises an injection into one or more sites in a region where trauma was been created by a surgery. 1 1 . The method of Claim 10 where the method reduces pain. 12. The method of Claim 1 1 wherein pain is postoperative pain. 13. The method of Claim 9 wherein the administering step is performed in a nerve block procedure. 14. The method of Claim 13 wherein the nerve block procedure is one or more members of the group consisting of a peripheral nerve block, an extradural nerve block, a neuraxial nerve block, a retrobulbar nerve block, and a transversus abdominis plane block. 15. The method of Claim 9 where the administering step is performed in an anesthesia procedure. 16. The method of Claim 15 where the anesthesia procedure is one or more of field block anesthesia, regional anesthesia, peripheral nerve block, plexus anesthesia, epidural anesthesia, extradural anesthesia, spinal anesthesia, local anesthesia, or transincission catheter anesthesia. 17. The method of Claim 9 where the administering step is performed in a joint is selected from the group consisting of hip, knee, shoulder, and ankle. 18. A method of treatment comprising the step of administering a medicament of any one of Claims 1 through Claim 8 as infiltration anesthesia for joint arthroscopy or arthroplasty or both. 19. A kits comprising a sterile multi-draw container containing a 30 to 100 ml aliquot of a medicament of any one of Claims 1 through Claim 8, a vial containing 30 to 100 ml of diluents, and optionally one or more sterile syringes suitable for transferring the diluents to the sterile multidraw container, and written instruction to reconstitute the medicament with the diluents, and wherein the aliquot has been lyophilized. 20. A kit comprising a first vial and a second vial, wherein the first vial contains bupivicaine, ropivicaine, clonidine, ketamine, a suitable pharmaceutically acceptable buffer and optionally epinephrine and the second vial contains ketorolac, dexamethasone, and a suitable pharmaceutically acceptable buffer, and wherein the kit further comprises written instructions for how to combine the contents of the first vial and the contents of the second vial and optionally one or more sterile syringes. |
CROSS-REFERENCE TO RELATED APPLICATIONS
001 This application claims priority to U.S. Provisional Application Serial No. 62/108,763 filed 28 January 2015 and U.S. Provisional Application Serial No.
62/267,688 filed 15 December 2015, both of which are hereby incorporated by reference herein in their entirety.
TECHNICAL FIELD
002 The instant invention relates generally to an analgesic and anesthetic composition and use. More specifically, this invention relates to an analgesic and anesthetic composition to localize and numb the nerves of the user while maintaining motor function.
BACKGROUND
003 The management of pain (e.g. postoperative pain associated with surgery or joint replacement surgery) is often the most challenging and troublesome aspects of medical care. Inadequate pain control can be a source of significant anxiety and concern on the part of patients and their families and adversely affect recovery, rehabilitation, and need for homecare.
004 Current protocols for pain management incorporate various combinations of parenteral narcotics, regional anesthesia and nerve blocks. During the first 24-48 hours after surgery, narcotics are often required along with typical side effects such as nausea, itching, vomiting, drowsiness, urinary retention and ileus, respiratory depression, and even death. Regional anesthesia and nerve blocks may be associated with temporary or permanent neurologic dysfunction.
005 Analgesics and anesthetics are used to dull the pain receptors by controlling nerve output to the user's brain. The use of these traditional pain and sensory moderators allows doctors and medical staff to suppress a patient's reactions during surgeries and other invasive procedures to carry out the procedure correctly. The necessary dosage for these chemical compounds varies depending on physical characteristics of the patient, such as metabolism, weight, and body type. These chemical compounds, when used in a proper surgical setting, leave the patient without the ability to control the parts of the body that are numbed for some time after the surgery. This length of time which the patient cannot move various parts of their body requires the patients to remain in the hospital for the day or overnight. Some procedures may allow the patient to move much sooner than than the anesthetics or would normally allow.
006 What is needed in the art are compositions and methods of providing better pain control and allow the patient mobility ( e . g . after su rg ica l procedures), reduced need for narcotics, and that allow the patient to return home the same day with full motor function.
SUMMARY OF THE INVENTION
007 This invention provides pharmaceutical compositions and methods of providing pain control, such compositions comprising: a. two or more long acting aminoamide local anesthetics b. at least one NSAI D; c. at least one corticosteroid; d. at least one alpha-2 (a 2 ) adrenergic receptor agonist, e. at least one N-methyl-D aspartate receptor antagonist, and f. optionally, epinephrine.
008 The compositions of the instant invention are useful for analgesia and, more specifically, for analgesia acting on the peripheral system or acting on a combination of the peripheral system and the central nervous system; e.g. peri- articularly accompanying arthroplasty. Accordingly, the present invention also provides a method of providing analgesia comprising administering a present composition to a subject in need thereof.
DETAILED DESCRIPTION OF THE INVENTION
009 As used here, the following definitions and abbreviations apply.
0010 "Components" means any of the components of the present invention (e.g. long acting aminoamide local anesthetics, NSAIDs, corticosteroids. a 2 adrenergic receptor agonists, N-methyl-D aspartate receptor antagonists, epinephrines, and excipients). Components, according to the present invention, include any of the useful forms of the components such as polymorphs, crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers), enantiomers, salts, solvates and complexes thereof and solvates and complexes of salts thereof.
001 1 "Examplary" (or "e.g." or "by example") means a non-limiting example.
0012 "Instant" refers to the present invention, e.g. instant NSAID means an NSAID as taught in this present specification according to the instant invention.
0013 "Long acting aminoamide local anesthetics" means a local anesthetic that comprises a lipophilic moiety in amide linkage to a hydrophilic moiety, wherein the anesthetic acts by blocking Na+ channels when the channel is open. Typically, the active form of the anesthetic is the charged form and works without loss of consciousness and the duration of anesthesia or analgesia of four hours or more or optionally 6 hours or more or optionally 8 hours or more.
0014 "Percent" (or %), when in reference to a component of the present inventions, means (when not otherwise defined or repugnant to the context) means % wt/% of the total volume of the instant composition.
Formulations
0015 In one embodiment, the composition comprises: a. two or more long acting aminoamide local anesthetics selected from the group consisting of ropivicaine, etidocaine, bupivicaine [e.g. R(+) or racemic RS (-)] or levobupivicaine [S(-) enantiomer], lidocaine, mepivacaine, prilocaine, dibucaine, and articaine. b. at least one NSAI D selected from the group consisting of ketorolac, ibuprofen, and indomethacin; c. a corticosteroid selected from the group consisting of dexamethasone, methylprednisone, triamcinolone, and prednisolone; d. at least one a 2 adrenergic receptor agonist selected from the group consisting of clonidine, dexmedetomidine, xylazine, detomidine, guanfacine, guanabenz, medetomidine, and methyldopa; e. at least one N-methyl-D aspartate receptor antagonist selected from the group consisting of ketamine, tramadol, and methadone; and f. optionally, epinephrine.
0016 In another embodiment, the composition comprises: a. one or more long acting aminoamide local anesthetics selected from the group consisting of ropivicaine and etidocaine; b. one or more long acting aminoamide local anesthetics selected from the group consisting of bupivicaine and levobupivicaine c. at least one NSAI D selected from the group consisting of ketorolac and ibuprofen; d. at least one corticosteroid selected from the group consisting of
dexamethasone and methylprednisone; e. at least one a 2 adrenergic receptor agonist selected from the group consisting of clonidine and dexmedetomidine; f. at least one N-methyl-D aspartate receptor antagonist selected from the group consisting of ketamine and tramadol; and g. optionally, epinephrine.
0017 In another embodiment, the present compositions comprise ropivacaine, bupivacaine, ketorolac, clonidine, dexamethasone, ketamine, and optionally epinephrine. Combined with the teachings herein, the concentrations of these components can be determined by the skilled artisan. In one embodiment, each of the components can be formulated to the concentrations set forth in Table 1 ranging from the low-dose to the high dose. Table 1
0018 In other embodiments (e.g. for parenteral administration), each of the components of Table 1 can be formulated to contain as little as 10% of the low-dose formulation or an amount greater than that up to 500% of the high dose formulation as set forth in Table 1 , depending upon details known to the pharmaceutical scientist or physician.
0019 In other embodiments, each of the components of Table 1 in compositions for parenteral administration can be formulated to contain as little as 30% of the low- dose formulation or an amount greater than that up to 300% of the high dose formulation as set forth in Table 1 , depending upon details known to the
pharmaceutical scientist or physician.
0020 The skilled artisan will recognize specific medical conditions that require a deviation from these general guidelines.
0021 According to another embodiment, the composition of the instant invention comprises ropivicaine, bupivicaine, ketorolac, dexamethasone, clonidine, ketamine, and optionally epinephrine at concentrations set forth in Table 2, or at a range from 20% of the amount in Table 2 to 500% of the amount in Table 2
Table 2
Formula 003 %wt/vol of
composition
Ropivicaine 0.18 (1.8 mg/ml)
Bupivicaine 0.18 (1.8 mg/ml)
Ketorolac 0.03 (300 Mg/ml)
Dexamethasone 0.04 (40 Mg/ml)
Clonidine 0.0001 (1 Mg/ml)
Ketamine 0.01 (100 Mg/ml) Epinephrine 0.00015 (1.5 Mg/ml)
0022 According to another embodiment, the composition of the instant invention comprises ropivicaine, bupivicaine, ketorolac, dexamethasone, clonidine, ketamine, and optionally epinephrine at concentrations set forth in Table 2, or at a range from 50% of the amount in Table 2 to 200% of the amount in Table 2
0023 In another embodiment, a composition of the instant invention comprises at least six components as set forth in the alternative below in Table 3. The concentration of the components in Table 3 are shown in Table 1 or more narrowly, in Table 2 and Table 4.
Table 3
1 Ropivicaine or Etidocaine
2 Bupivicaine or Levobupivicaine
3 Ketorolac or Ibuprofen
4 Dexamethasone or Methylprednisone
5 Clonidine or Dexmedetomidine
6 Ketamine or Tramdol
7 Optionally
Epinephrine
Table 4
0024 Each of the formulations set forth in Table 5 are specifically contemplated, for example, at concentrations set forth in Table 1 (or more narrowly, in Table 2), and Table 4.
Table 5
Formula Ropivi- Bupivi- Ketor- Dexameth- Cloni- Keta-
# caine caine olac asone dine mine
Bido- Levobupi- Ibupro- Methyl- Dexmede- Tramdol caine vicaine fen prednisone tomidine
004 X X X X X X
005 X X X X X X
006 X X X X X X
007 X X X X X X
008 X X X X X X
009 X X X X X X
010 X X X X X X
011 X X X X X X
012 X X X X X X
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014 X X X X X X
015 X X X X X X
016 X X X X X X
017 X X X X X X
018 X X X X X X
019 X X X X X X
020 X X X X X X
021 X X X X X X X X X X X X
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X X X X X X
X X X X X X
X X X X X X
X X X X X X
X X X X X X
X X X X X X
X X X X X X
X X X X X X
X X X X X X
X X X X X X
X X X X X X
X X X X X X
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X X X X X X
X X X X X X X X X X X X
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X X X X X X
X X X X X X
X X X X X X
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X X X X X X
X X X X X X
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X X X X X X
X X X X X X
X X X X X X
X X X X X X
X X X X X X
X X X X X X
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X X X X X X
X X X X X X
X X X X X X
X X X X X X
X X X X X X 066 X X X X X X
067 X X X X X X
'Χ" indicates the presence of the copmponent in the formula (i.e. composition)
Therapeutic compositions and administration of Instant Compositions
Administration Routes
0025 The instant invention provides compositions in a pharmaceutically acceptable dosage and dose form.
0026 Administration of the present compositions to achieve therapeutic effect may be any parenteral route, e.g. periarticular, intra-articular, intrabursal, interscalene, intradiscal, transdermal, intradermal, transmucosal, subcutaneous, intrathecal, epidural, caudal, periodontal, or intramuscular administration. Certain clinical situations may require administration of the present compositions as a single effective dose, or may be administered as multiple doses or multiple locations.
Dosage forms
0027 Instant compositions are pharmaceutically acceptable, moreover, some embodiments are acceptable for parenteral administration, others for intravenous administration, and others for topical administration. The skilled pharmaceutical scientist readily knows how to add excipients, etc. , to make the composition administratable by the intended route. Optionally instant compositions are administered to patients in a pharmaceutically acceptable form containing physiologically acceptable carriers, excipients or diluents. Such diluents and excipients may be comprised of buffers, salts, antioxidants (for example ascorbic acid), low molecular weight polypeptides (for example polypeptides < 10 amino acids) amino acids, carbohydrates (for example, glucose, dextrose, sucrose, or dextrans), chelating agents such as EDTA, stabilizers (such as glutathione).
Additionally, co-substrates for the Instant Compositions, for example, calcium (Ca 2+ ) may be administered at time of dosage for maximal activity of the enzyme. Such carriers and diluents are nontoxic to the patient at recommended dosages and concentrations.
0028 Optionally, instant compositions are administered to patients in a
dermatologically acceptable topical form. Kits
0029 The technology provided herein also includes kits for use in the present methods.
0030 In one embodiment, the kit comprises a sterile multi-draw container containing a 30 to 100 ml aliquot of an instant composition that has been lyophilized, a sterile multi-draw container containing a 30 to 100 ml of sterile water, a 30 to 100 ml sterile syringe with a 18 to 24 gauge needle, one or more 3 to 100 ml sterile syringes, and instruction to reconstitute the instant compositions with the sterile water.
0031 In another embodiment, the kit contains a vial labeled "A", a vial labeled "B" and a 30 to 100 ml sterile syringe with a 18 to 24 gauge needle as well as
instructions for mixing according to Example 3.
Dosing Frequency
0032 In some embodiments, a single dose of a composition according to the technology is administered to a subject. In other embodiments, one or more doses are administered at multiple sites, e.g. 2 to 10, or 3 to 10, or 4 or more, or 5 or more. In some embodiments, one or more doses are administered over two or more time points, separated by minutes, hours, days, weeks, or more.
Dosing
0033 Dosage requirements of the present compositions may vary significantly depending on administration site, nature of pain, age, race, weight, height, gender, duration of treatment, methods of administration, biological activity of the
compositions, and severity of condition or other clinical variables. Effective dosages may be determined by a skilled physician or other skilled medical personnel.
0034 By way of example, for intraarticular injection, volumes may range from 1 ml to 83.3 ml at each site.
0035 By way of example, for nerve block, volumes may range from 5ml to 30ml. Uses of the Instant Compositions
0036 In one embodiment, instant compositions are useful for infiltration anesthesia, field block anesthesia, regional anesthesia, peripheral nerve block, plexus anesthesia (plexus block), epidural (extradural) anesthesia, spinal anesthesia (e.g. subarachnoid block), local anesthesia, and transincision catheter anesthesia.
0037 In one embodiment, instant compositions are useful for nerve blocks, for example, peripheral nerve blocks, extradural nerve blocks, neuraxial nerve block, retrobulbar nerve block, and transversus abdominis plane (TAP) block.
0038 In one embodiment, instant compositions are useful for joint arthroscopy and arthroplasty (e.g., hip, knee, shoulder, and ankle).
0039 In another embodiment, instant compositions are used for infiltration anesthesia for achilles tendon repair.
0040 In one embodiment, instant compositions are useful for surgical treatment of surgical repair of bone, osteomoty, bone osteochondroma malformation, orofacial surgery, tooth extraction and prosthetic implantation, anterior cruciate ligament harvest, allografts, and/or bone tendon bone grafts.
0041 In one embodiment, instant compositions are useful adjunct to repair of incisional hernias, as adjunct to anterior cruciate ligament reconstruction, for bursectomy excision, and/or hip arthroscopy.
0042 Instant compositions are usefully administered by infiltration throughout a wound at the time of surgery.
0043 In another embodiment, analgesic effect duration is prolonged by the placement of a catheter to the surgical site for postoperative administration of present compositions.
Unexpected Findings
0044 Without be bound by theory, the inventor believes that the superior action of the instant compositions are the result of a complex interaction of components and an interaction between metabolic pathways leading to quick onset of total pain control, long duration, and minimal toxicity or side effects. The specific combinations taught here are the result of inventor insight and empirical observations.
0045 Long acting aminoamide local anesthetics of the instant compositions bind to and block voltage gated Na+ channels in sensory nerves. Moreover, they reduce the transmission of the advancing wave of depolarization down the length of the nerve. In part, the duration of action of instant aminoamide local anesthetics is due to their high lipid solubility, which allows them to remain in lipid bilayers at target sites - rather than being removed by the microvasculature. However, greater
hydrophobicity also results in greater toxicity. Through insight of the inventor and empirical observations, certain preferred combinations of the at least two long acting aminoamide local anethtics are taught here.
0046 In the instant compositions, the efficacy and duration of the long acting aminoamide local anesthetics is further increased by the vasoconstrictive action of a corticoid steroid, an NSAID, and optionally epinephrine. Each of these components is vasoconstrictive through a different mechanism. For example, the NSAID(s) of the instant composition blocks prostaglandin synthesis by blocking cyclooxygenase-2. PGE2 is one of such prostaglandins and is a potent vasodilator. Corticosteroids enhance the vasoconstrictor actions of endogenous or pharmaceutical
norepinephrine and angiotensin II. The optional epinephrine of the instant compositions, causes vasoconstriction through the a1 adrenergic receptor- dependant pathway. The interaction of between these multiple pathways results in an especially effective vasoconstriction and efficacy of the analgesic components.
0047 Tissue damage, resulting from surgery, causes an activation of
prostaglandins which, as discussed above, causes vasodilatation. It should also be noted that prostaglandins also have an effect on pain. At higher concentrations, prostaglandins cause pain by direct action on the nerve endings; at lower concentrations, they reducer the pain threshold. Accordingly, the NSAI D(s) of the instant compositions and corticosteroids of the instant compositions, by blocking prostaglandin synthesis, function to block pain and raise the pain threshold.
0048 The inventor believes that at sufficient concentrations, adrenergic receptor agonists as taught here, can partially inhibit voltage-gated Na+ and K currents and shift the steady-state inactivation curve to more negative potentials. In concert with the action of the two (or more) long acting aminoamide local anesthetics , voltage- gated channels are inhibited to a surprising level.
0049 The inventor believes that at sufficient concentrations, the N-methyl-D aspartate receptor antagonist of the instant compositions antagonize
neurotransmitters g!utamate and glycine and prevent hyperpolarization and drive the membrane potential away from the threshold for firing an action potential. Without being bound by theory, the inventor believes that there is a potentiation of duration and efficacy of amide local anesthetics when combined as taught here.
0050 The addition of the instant alpha 2 adrenergic receptor agonist has a surprisingly impact on the total anti-nociceptive effects (efficacy and duration) of the composition, presumably involving other central pathways (i.e. an enkephalin mediated pathway).
0051 The superior properties, as believed through insight of the inventor, can only be understood in part by the above description of the metabolic pathways.
0052 The superior properties of instant compositions include superior analgesia, duration of analgesia (long acting), safety, narcotic sparing, and motor sparing properties.
0053 Through insight of the inventor, the instant compositions are also superior in one or more of the following benefits: reduction in anesthetic requirements, reduction or elimination of need for parenteral narcotics, reduction in post operative nausea and vomiting, more rapid recovery from anesthesia, decrease in motor weakness, increased mobility, reduction of venus thromboembolism, and increased patient overall satisfaction.
EXAMPLES
Example 1. Formulating present compositions by admixing
0054 The following procedure is performed in a sterile manner using methods well- known to the pharmaceutical scientist or appropriate medical professionals. The individual components of the formulation are obtained as commercially available pharmaceutical products and the amounts of each component are delivered in a sterile manner (e.g. by sterile syringe) according to Table 6 and delivered into a sterile multi-draw stoppered vial. The components of the vial are mixed by swirling. At time of administration, sterile aliquots are loaded into an appropriately-sized syringe. This is a representative formulation method and produces Formula 003. Table 6
Example 2. Formulating present compositions by Lyophilization
0055 The following procedure is performed in a sterile manner using methods well- known to the pharmaceutical scientist or appropriate medical professionals. The components of the formulation are obtained as commercially available
pharmaceutical products and the amounts of each component are delivered in a sterile manner (e.g. by sterile syringe) into a sterile lyophilization tube in amounts set forth in Table 6. The composition is frozen to -70 c and are subjected to vacuum (in a typical commercial lyophilizer) for sufficient time for sublimation of all the liquid. Next, the lyophilized material is transferred to a sterile, multidraw stoppered vial and stored at -70 C until needed. The vial is placed in a box with instructions to reconstitute by addition of 30 ml of distilled, sterile water. This is a representative formulation method and produces Formula 003.
Example 3. Formulating present compositions by the two vial method.
0056 "Vials A and B" are filled according to Table 7. Buffer A is a sterile, pharmaceutically acceptable buffer useful at acidic pH (e.g. the pH of 5.0); Buffer B is useful at somewhat alkaline pH (e.g. ph of 7.5). Buffer A and Buffer B are compatible when combined and result in an appropriate final pH. Useful mixed buffer systems are well known in the art.
0057 The vials are stored at 4°C until use.
0058 At the time of surgery, the contents of Vial A is removed by sterile syringe and added to Vial B and the solutions (in Vial B) are mixed. The formulation method results in remarkable stability. This is a representative formulation method and produces Formula 003
Table 7
Example 4. Administration in conjunction with total knee replacement.
0059 The following procedure is useful for pain management by administration of instant compositions for total knee replacement . All patients are given spinal anesthesia. 0060 The instant composition of Example 1 is prepared as set forth above. The first injection is performed at once after femoral and tibial cuts are made. Three to five small subsequent injections are made, using approximately 15 ml total of an instant composition in the popliteal fossa, aspirating as necessary at this injection site to avoid intra-vascular injection. After the prosthetic implants are set, the next injections are administered to the medial and lateral periosteum of both the femur and the tibia, using approximately 20 ml of an instant composition.
0061 Subsequently, the medial and lateral gutters a re injected with 10 ml of an instant composition on each side after patella preparation. Next, the peripatellar area and the skin a re injected prior to closing the incision, using approximately 10 ml of an instant composition. The remaining amount of an instant
com position is administered to the skin incision covering the superior aspect of the incision at the subcutaneous level.
0062 RESULTS. During the study period, narcotic pain requirements,
manipulation rates, and the need for prolonged physical therapy were significantly reduced as compared to historical controls. Recovery of functional milestones and ROM was achieved at an earlier period in 90% of patients. Overall patient satisfaction was greatly improved.
0063 By controlling acute pain in the critical early postoperative period (three days) following total knee replacement, the pain management protocol allowed for improved recovery of functional milestones and improved patient satisfaction. It appears that pain control plays a much larger role in functional recovery than incision length.
Example 5. Experimental Clinical Study of use for Arthroplasty
0064 Over the period of about one year, 45 total hip replacements and 85 total knee replacements were performed with a periarticular injection of Formula 003 prepared as set forth in Example 1 . All patients were given spinal anesthesia and total knee arthroplasty (i.e. a surgical procedure in which parts of the knee joint are replaced with artificial parts ; "TKA") patients received an adductor canal block.
Multimodal oral and intravenous medications were administered and parenteral narcotics were not used during the preoperative course. 0065 Procedure
0066 Intraoperatively, surgical procedures were performed in line with traditional surgical approaches and techniques. The total knee replacements were generally performed according to Example 4. Prior to closure, Formula 003 was injected into the surgical field.
0067 Patients were followed with postoperative pain scales and monitored for narcotic requirements and complications. Additionally, patient assessment was performed by skilled nursing and physical therapy in home to document recovery of functional status, such as unassisted walking, stair-climbing, range-of-motion (ROM), and overall satisfaction.
0068 Results
0069 During the study period, narcotic pain requirements, manipulation rates, and the need for prolonged physical therapy were significantly reduced . Skilled Nursing visits were on average 3 and PT visits appear to being able to be reduced to 7 or less home visits.
0070 Recovery of functional milestones and range of motion was achieved at an earlier period in most of patients. Pain scores were on average 1 .07 upon discharge from the facility using a 0-10 Visual Analog Scale. Pain from postoperative day ("POD") 0 scores were 3.3. POD 1 pain scores were 3.6. POD 2 pain scores were 3.8 on average. Multimodal protocols including the use of Oxycontin 10mg every 12 hours were administered as part of the protocol. Average length of stay was 338 min from admission to discharge from facility to home. Patients ambulated prior to discharge in the surgery center and were not braced due to adequate motor function. Infection rates were reported at less than 1 %. Estimated blood loss was < 100ml in all cases but 1 , in which the estimated blood loss was 200ml. There were no hospital transfers during the study and none yet to date in the program. There have been no blood transfusions to date. Overall patient satisfaction was positive.
0071 Each of these results set forth above were remarkable compared to previously published studies and based upon the experience and judgment of surgeons participating in this study when compared to analgesia of different forms and different formulations representing the current standard of care. The economic impact was also believed to be remarkable.
0072 Utilizing an instant composition to control acute pain in the critical early postoperative period (48-72 hours) following total hip and total knee replacement, has allowed for improved recovery of functional milestones and improved patient satisfaction. It appears that instant compositions play a large role in the recovery of the total joint patient in the ambulatory setting. Instant composition's early and rapid onset yet apparent 48-72 duration appears to be the most important component allowing for early and rapid discharge after total joint replacement.
0073 Example 6. Post Operative Assessments
0074 Post operative assessments that are useful for demonstrating the superiority of instant compositions and set forth in Table 8. Through insight of the inventor, each of these assessment parameters can be used to demonstrate the unexpected superiority of the instant compositions over standard (state of the medical arts) analgesia compositions.
Table 8
Day 1 Day 2 Day goal
achieved
Range of motion record record record
Walk on flat surface In In meters 100 meters
meters
Western Ontario and record record record
MacM aster Universities
Osteoarthitis Index
(WOMAC Pain Score) blood loss record record
Pain meds record record record
Nausea / vomiting record record record itching record record record drowsiness record record record urinary retention. record record record ileus record record record
Days until prosthesus record failure
Hospital for Special record record record
Surgery Knee Score
(HSS)
Knee Society's Clinical record record record
and Functional Scoring
System (KSS)
Harris Hip Score (HHS) record record record time for rescue analgesia record
0075 All publications and patents referenced in this specification are herein incorporated by reference in their entirety for all purposes. Various modifications and variations of the described compositions, methods, and uses of the technology will be apparent to those skilled in the art without departing from the scope and spirit of the technology as described. Although the technology has been described in connection with specific exemplary embodiments, it should be understood that the technology as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the technology that are obvious to those skilled in pharmacology, biochemistry, medical science, or related fields are intended to be within the scope of the following claims.
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