Anesthesia nerve block and method

Abstract

An improved anesthetic nerve block and method is disclosed, including a dispenser including a reservoir body, a transfer body, and a tip for positioning near a nerve. The local short-acting anesthetic is located within the reservoir. And the physiological carbonate base is positioned in the storage body. The local short-acting anesthetic and the physiological carbonate base are dispensed from a tip portion of a dispenser, wherein the local short-acting anesthetic promotes the physiological carbonate base to penetrate the neural membrane and into the axon. A local long-acting anesthetic is located within the reservoir. The topical long-acting anesthetic is dispensed from the tip of a dispenser and penetrates the neural membrane and into the axon. The topical long-acting anesthetic and the physiological carbonate base cause precipitation and form a crystalline compound that is used to produce a prolonged local nerve block.

Description

Background of the Invention Field of the Invention

[0002] The present invention relates to pain relief, and more particularly, the present invention relates to improved anesthetic nerve blocks and methods.

[0003] Description of Related Technology

[0004] Recognizing that opioid prescriptions are the leading pathway to opioid addiction, with over 350,000 deaths worldwide from opioid overdoses, this invention shows how to replace opioids with nerve blocks that last for days to relieve pain, which could replace the need for opioids after surgery and trauma.

[0005] The recent opioid crisis has focused worldwide attention on the need to provide patients with non-addictive post-operative pain relief following surgery, trauma, and other painful events. The increased use of peripheral nerve blocks (PNB's) by anesthesiologists demonstrates our recognition of the utility and effectiveness of such nerve blocks in treating pain without the need for addictive opioids.

[0006] Pain studies have shown that severe pain (A-delta pain fibers) generally subsides within 48 hours after uncomplicated abdominal surgery. Even inflammatory diffuse pain (C-pain fibers) in such surgeries mostly subsides after 120 hours. Therefore, the goal is to have a postoperative analgesic that lasts 120 hours to eliminate the need for opioid prescriptions.

[0007] Unfortunately, such postoperative analgesia by PNB is usually limited to 24 hours or less, depending on the local anesthetic selected for the block. Including alpha-2 agonists (clonidine, dexmedetomidine, etc.), steroids and even epinephrine have been used to prolong these blocks, although only longer than the time achieved by local anesthetics alone. Even with the longest-acting local anesthetics and the addition of various adjuvants, effective analgesia rarely lasts more than 24 hours in peripheral nerve blocks. The following patents and publications represent attempts made in the prior art to advance triggered pump technology.

[0008] U.S. Patent No. 4,695,576 issued to Ekenstam discloses a local anesthetic LN-n-propylpiperidinic acid-2,6-dimethylaniline, which is prepared by chlorinating L-piperidinic acid to produce an acid chloride (i.e., L-2-piperidinic acid carboxylic acid chloride). The acid chloride is then reacted with 2,6-dimethylaniline to produce L-piperidinic acid-2,6-dimethylaniline. The LN-piperidinic acid-2,6-dimethylaniline is then propylated to produce LN-n-propylpiperidinic acid-2,6-dimethylaniline, which is an effective local anesthetic for humans and has relatively low toxicity.

[0009] US Patent No. 5,192,527 issued to Abrahmsohn discloses a method of controlling the duration of local anesthesia and describes an agent system or kit for inducing and limiting the duration of local anesthesia.

[0010] U.S. Pat. No. 5,777,124 issued to Zavareh et al. discloses a method for preparing levobupivacaine, racemic bupivacaine or another N-alkyl analog thereof, comprising chlorinating pipecolic acid hydrochloride, amidating the obtained pipecolic acid hydrochloride with 2,6-dimethylaniline in a solvent without isolation, and alkylating the obtained pipecolic acid 2,6-dimethylaniline. Alternatively, the amidation may be performed after the alkylation.

[0011] U.S. Patent No. 5,849,763 issued to Bardsley et al. discloses levobupivacaine ((S)-1-butyl-N-(2,6-dimethylphenyl)-2-piperidinamide) useful as an anesthetic, particularly for patients with impaired central nervous system or susceptible to central nervous system side effects. It can also be used as an obstetric anesthetic.

[0012] US Patent 5,919,804 issued to Gennery discloses the use of levobupivacaine for providing anesthesia or analgesia to human patients during and after facial surgery, particularly in dentistry or ophthalmology.

[0013] U.S. Patent 5,945,435 issued to Evetts discloses levobupivacaine particularly suitable for anesthetizing human patients prior to surgery without requiring hospitalization for more than 12 hours after motor block has worn off. Due to its beneficial motor / sensory block characteristics, levobupivacaine can be used in 'day care' surgery.

[0014] U.S. Pat. No. 5,955,479 issued to Bardsley et al. discloses the use of levobupivacaine for treating chronic pain in patients. The levobupivacaine used in the subject method is substantially free of dextrobupivacaine. The methods of the present invention can be used, for example, to treat pain in patients with cardiac damage, patients suffering from central nervous system damage, or cancer.

[0015] US Patent No. 6,019,994 issued to Evetts et al. discloses levobupivacaine or ropivacaine for the treatment of migraine.

[0016] US Patent 6,069,155 issued to Mather et al. discloses a method of anesthetizing a human patient prior to major surgical surgery comprising administering to the patient at least 200 mg of levobupivacaine.

[0017] U.S. Patent 6,156,900 issued to Dyer et al. discloses a process for preparing optically enriched pipecolic acid as a salt with an optically active acid, which comprises asymmetrically converting pipecolic acid, which is a racemic mixture of a mixture of opposite enantiomers enriched in the desired enantiomer, with an optically active acid in the absence of an aldehyde in a solvent containing an acid that causes racemization.

[0018] U.S. Patent No. 8,828,452 issued to Abrahmsohn discloses a method of providing post-operative pain control or relief to a patient. The method comprises, for example, applying bicarbonate to an area of ​​a patient during, immediately following, or immediately following a surgical or dental procedure, to an area previously applied or to an area containing a regional or local anesthetic, in an amount sufficient to provide pain control or relief to the patient for a period of time following the surgical or dental procedure.

[0019] Dyer et al. WO 1996 / 028426 discloses an optically enriched N,O-dialkyl pipecolic acid ester which can be used to prepare levobupivacaine and related analgesics. They can be prepared simply by dialkylating an optically enriched pipecolic acid by reaction with an alkylating agent in the presence of a base and a polar aprotic solvent.

[0020] Despite the contributions of the aforementioned patents to advances in the art, there remains a need for a long-acting local anesthetic that can provide 120 hours or more of post-surgical and post-traumatic analgesia, thereby significantly reducing the need for opioid prescriptions for these conditions.

[0021] It is therefore an object of the present invention to provide an improved anesthetic nerve block which provides a substantial advance in the art.

[0022] It is another object of the present invention to provide an improved anesthetic nerve block that can be rapidly dispensed.

[0023] Another object of the present invention is to provide an improved anesthetic nerve block that can be easily dispensed.

[0024] Another object of the present invention is to provide an improved anesthetic nerve block that can be administered into a living organism with a low risk of injury.

[0025] It is another object of the present invention to provide an improved anesthetic nerve block that can be modified to vary the duration of the nerve block.

[0026] The foregoing has summarized some of the more relevant objects of the present invention. These objects should be construed as merely illustrating some of the more prominent features and applications of the present invention. By modifying the present invention within the scope of the present invention, many other beneficial results can be obtained. Therefore, by referring to the summary of the invention, the detailed description describing the preferred embodiment and the scope of the present invention defined by the claims in conjunction with the accompanying drawings, other objects of the present invention can be fully understood. SUMMARY OF THE INVENTION

[0028] The present invention is defined by the appended claims and the specific embodiments shown in the accompanying drawings. For the purpose of summarizing the present invention, the present invention comprises an improved anesthetic nerve block for interrupting the potential of a nerve and relieving pain in a living organism. A nerve has an axon covered by a nerve membrane. The anesthetic nerve block comprises a dispenser, which includes a storage body, a transfer body and a tip for positioning near the nerve. A local short-acting anesthetic is located in the storage body. A physiological carbonate base is located in the storage body. The local short-acting anesthetic and the physiological carbonate base are dispensed from the tip of the dispenser, wherein the local short-acting anesthetic promotes the physiological carbonate base to penetrate the nerve membrane and enter the axon. A local long-acting anesthetic is located in the storage body. The local long-acting anesthetic is dispensed from the tip of the dispenser and penetrates the nerve membrane and enters the axon. The local long-acting anesthetic and the physiological carbonate base cause precipitation and form a crystalline compound, which is used to produce a prolonged local nerve block.

[0029] In one embodiment of the invention, the local short-acting anesthetic is lidocaine.

[0030] In another embodiment of the present invention, the local long-acting anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, ropivacaine and tetracaine.

[0031] In another embodiment of the present invention, the physiological carbonate base is selected from the group consisting of sodium bicarbonate, sodium carbonate and sodium hydroxide.

[0032] In another embodiment of the present invention, the local short-acting anesthetic is located in the reservoir. The steroid is located in the reservoir. The local short-acting anesthetic and the steroid are dispensed from the tip of the dispenser, wherein the local short-acting anesthetic promotes the steroid to penetrate the nerve membrane and enter the axon. The local long-acting anesthetic is located in the reservoir. The local long-acting anesthetic is dispensed from the tip of the dispenser and penetrates the nerve membrane and enters the axon. The local long-acting anesthetic and the steroid cause precipitation and form a crystalline compound, which is used to produce a prolonged local nerve block.

[0033] In another embodiment of the present invention, the steroid base is selected from the group consisting of dexamethasone, betamethasone and triamcinolone.

[0034] The present invention further comprises a method for producing an anesthetic nerve block. The anesthetic nerve block interrupts the electrical potential of a nerve in a living organism and relieves pain. The nerve has an axon covered by a nerve membrane. The method comprises the following steps: dispensing a local short-acting anesthetic from a dispenser to position the local short-acting anesthetic near the nerve. Dispensing a physiological carbonate base from a dispenser to position the physiological carbonate base near the nerve, wherein the local short-acting anesthetic promotes the physiological carbonate base to penetrate the nerve membrane and enter the axon. Dispensing a local long-acting anesthetic from a dispenser to position the local long-acting anesthetic near the nerve, wherein the local long-acting anesthetic penetrates the nerve membrane and enters the axon, and the local long-acting anesthetic and the physiological carbonate base cause precipitation and form a crystalline compound, which is used to produce a prolonged local nerve block.

[0035] In another embodiment of the present invention, the method comprises the steps of: dispensing a local short-acting anesthetic from a dispenser to position the local short-acting anesthetic near a nerve. Dispensing a local long-acting anesthetic from a dispenser to position the local long-acting anesthetic near a nerve. Dispensing a physiological carbonate base from a dispenser to position the physiological carbonate base near a nerve, wherein the local short-acting anesthetic promotes the physiological carbonate base to penetrate the nerve membrane and enter the axon, and wherein the local long-acting anesthetic penetrates the nerve membrane and enters the axon, and the local long-acting anesthetic and the physiological carbonate base cause precipitation and form a crystalline compound, which is used to produce a prolonged local nerve block.

[0036] The above content has been quite broadly summarized the more relevant and important features of the present invention, so that the subsequent detailed description can be better understood, thereby the contribution of the present invention to the art can be more fully appreciated. Other features of the present invention will be described hereinafter, which form the subject matter of the present invention. It will be appreciated by those skilled in the art that concepts and specific embodiments may be modified to achieve the same purpose of the present invention. It will also be appreciated by those skilled in the art that such equivalent constructions do not depart from the spirit and scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] For a more complete understanding of the nature and purpose of the present invention, reference should be made to the following detailed description taken in conjunction with the accompanying drawings, in which:

[0039] Figure 1 is a side view of a living organism with the sciatic nerve where an anesthetic nerve block solution will be used to relieve pain;

[0040] Figure 2 yes Figure 1 Magnified cross-sectional view of the sciatic nerve;

[0041] Figure 3 yes Figure 2 The enlarged part of

[0042] Figure 4 yes Figure 3 Isometric view of;

[0043] Figure 5 yes Figure 4 A cross-sectional view of

[0044] Figure 6 is with Figure 3 A similar view showing a myelinated neuron (A-delta fiber);

[0045] Figure 7 yes Figure 6 The enlarged part of

[0046] Figure 8 is with Figure 3 A similar view showing unmyelinated neurons (C-fibers);

[0047] Fig. 9 yes Figure 8 The enlarged part of

[0048] Fig.10 is with Figure 4 Similar views showing injections of lidocaine and NaHCO3 / Na2CO3 (plus possible adjuvants);

[0049] Fig.11 yes Fig.10 A cross-sectional view of

[0050] Fig.12 is with Fig.10 A similar view showing bupivacaine carbonate precipitate;

[0051] Fig.13 yes Fig.12 A cross-sectional view of

[0052] Fig.14 is with Fig.12 Similar view showing the nodes of Ranvier and extraaxonal deposits of crystallized bupivacaine carbonate precipitate;

[0053] Fig.15 yes Fig.14 A cross-sectional view of

[0054] Fig.16 yes Fig.15 A magnified view of

[0055] Fig.17 is a side view of a first embodiment of a dispenser for dispensing an anesthetic nerve block solution;

[0056] Fig.18 is a side view of a second embodiment of a dispenser for dispensing an anesthetic nerve block solution;

[0057] Fig.19 yes Fig.18 The enlarged part of

[0058] Fig. 20 is a side view of a third embodiment of a dispenser for dispensing an anesthetic nerve block solution;

[0059] Fig.21 yes Fig. 20 The enlarged part of

[0060] Fig. 22 is a side view of a fourth embodiment of a dispenser for dispensing an anesthetic nerve block solution;

[0061] Fig.23 is a flow chart of a first method of dispensing an anesthetic nerve block solution; and

[0062] Fig.24 is a flow chart of a second method of dispensing anesthetic nerve block solution.

[0063] Like reference characters refer to like parts throughout the several views of the drawings.

[0064] Detailed Description

[0065] Figure 1-24 A modified anesthetic nerve block and method is described. Figure 1-9 , a peripheral stimulus 58 (such as an acupuncture needle to an arm or leg) must be transmitted down its associated nerve to the access spinal cord, where it can then be transmitted to the brain, where the needle needle is sensed. This transmission of nerve electrical impulses from the periphery to the brain is achieved by depolarization of the sodium / potassium potential 56 on the nerve membrane (axonal membrane) 54 in the axon 24. These action potentials 56 in the nerve discharge flow as a result of continuous depolarization along the nerve fiber from the periphery to the spinal cord during nerve impulse conduction.

[0066] Such depolarization can flow from one node of Ranvier 20 to the next in a myelinated nerve fiber, e.g. Figure 6 and 7 These depolarizations are very rapid and site specific in the receptor field, as found in A-delta nerve fibers 50. A-delta nerve fibers propagate toward the spinal cord at 5 to 25 m / sec.

[0067] Alternatively, nerve impulses may propagate along unmyelinated axons, as in A-delta diffuse pain nerve fibers (e.g. Figure 6 and 7 ) and in C-type diffuse pain fibers (as Figure 8 and 9 Here, stimulation causes nerve impulses to propagate in both directions, but the direction toward the spinal cord is more easily propagated and sustained. Impulse propagation in the C-fibers 60 is much slower than in the A-delta fibers, only 0.1 to 2.0 m / s in those C-fibers 60 that conduct pain impulses.

[0068] Local anesthetics produce numbness and pain relief by interrupting the sodium / potassium action potential of the nerve, which in turn conducts the nerve impulse, either in the A-delta sharp pain-sensing fibers at the nodes of Ranvier ( Figure 6 and 7 ), or along the unmyelinated C-diffuse pain fibers ( Figure 8 and 9 ). The interruption of this action potential (at three consecutive nodes of Ranvier in A-delta fibers, or at the equivalent axonal surface of C-fibers) is sufficient to block the nerve impulse as it attempts to pass down the axon of the nerve to the spinal cord. In this way, local anesthetics can block sensory and motor impulses in both A-delta and C-fibers, whether as a central (spinal or epidural) or peripheral nerve block.

[0069] The degree of motor block of different local anesthetics relative to sensory block is highly variable. Although some local anesthetics show equal efficacy (such as etidocaine) to motor block and sensory block, other local anesthetics show a tendency (such as bupivacaine) that sensory block is much larger than motor block. In terms of long-acting local anesthetic block for preventing postoperative pain, amide longer-acting local anesthetics (bupivacaine, ropivacaine and derivatives) have much superior performance, because these amide longer-acting local anesthetics maximize the pain relief period while minimizing motor block. If such long-acting nerve block can be made to last long enough, the demand for opioid analgesics after surgery will be greatly reduced or even completely eliminated. For this purpose, it has been confirmed that bupivacaine and ropivacaine are the most effective local anesthetics currently available.

[0070] In the past, other intellectual property has explored extended sensory nerve blocks, extending analgesia to 72 hours by injecting a physiological base during or after a surgical procedure rather than injecting a local anesthetic nerve block beforehand. However, this prior intellectual property, while very broad in its claims, lacks precision and understanding of the intraneural mechanisms that lead to extended analgesia periods of 120 hours or more. Specifically, Abrahmsohn rejects the simultaneous combination of a local anesthetic with sodium bicarbonate (NaHCO3) or sodium carbonate (Na2CO3), which is an essential step of the present invention.

[0071] like Figure 10-24 The present invention shown includes a long-acting local anesthetic 99, which requires a combination of a physiological base 78 and a shorter-acting amide local anesthetic 76 because it "opens the door" for NaHCO3 / Na2CO3 and the first local anesthetic to penetrate the axonal membrane (axonal nerve membrane) into the axonal body. It is the NaHCO3 / Na2CO3 thus produced that penetrates into the axon itself, which, when subsequently combined with a subsequent amide long-acting local anesthetic (ALALA-bupivacaine, levobupivacaine, ropivacaine), leads to the intra-axonal and extra-axonal precipitation and crystallization of the ALALA-carbonate compound 82. This ALALA carbonate precipitate and crystals 82 are the reason for the 120 hours or more of analgesia. Since Abrahmsohn explicitly prohibited such direct mixing of NaHCO3 and ALALA drugs, the present invention including the precipitation and crystallization of ALALA-carbonate in vivo is directly opposed to Abrahmsohn's intellectual property. Only by forming such precipitates and crystals inside and on the target nerve can a 120-hour block be achieved.

[0072] ALALA - Formation mechanism of carbonate precipitates and crystals

[0073] like Fig.10 and 11As shown, the first step of this new long-acting local anesthetic is to inject a shorter-acting ALA drug that does not precipitate in alkaline solutions at pH 10 or lower, such as lidocaine 76, with a sodium bicarbonate (NaHCO3) / sodium carbonate (Na2CO3) / sodium hydroxide (NaOH) mixture, and in stark contrast to the use of local anesthetics and sodium carbonate / sodium bicarbonate bases simultaneously in the prior art (Abrahmsohn). The addition of the alkaline NaHCO3 / Na2CO3 / NaOH mixture to lidocaine raises the pH of lidocaine, and its protonated (+) 72: unprotonated (-) balance shifts primarily (about 95%) to the unprotonated (-) molecule 70. This unprotonated form 70 of lidocaine 76 will more easily penetrate the nerve membrane (axonal membrane) 54 into the axon 24, but it is uncharged and will not cause nerve impulse block (pain relief and numbness). Due to its small size, NaHCO3 and Na2CO3 easily move into the axon 24 in parallel with the non-protonated lidocaine (-) 70, thereby forming a temporary alkaline intra-axonal environment. Some of the non-ionized lidocaine (-) within the neuron will then begin to equilibrate to form neurologically active ionized lidocaine (+), which is responsible for blocking nerve impulses through the neuron. This protonated lidocaine (+) 72 interferes with the nerve's sodium-potassium pump and inactivates it, thereby causing a block in the transmission of nerve impulses down the nerve and forming a nerve block (numbness). Since the three (3) nodes of Ranvier are thus blocked, no nerve impulses can be transmitted along the axon, resulting in the active block of the nerve by the local anesthetic.

[0074] like Fig.12 and 13 As shown, once the NaHCO3 / Na2CO3 is substantially located within the axon 24 (occurring within seconds of intraneural injection), a second injection of an amide long-acting local anesthetic 80 such as bupivacaine (eg, Fig.12 and 13 , as an example of an ALALA compound). Due to their elevated pKa, ALALA drugs will form crystalline precipitates in alkaline environments82, either intra-axonal or extra-axonal (at nodes of Ranvier 20 in A-delta fibers, and generally peri-axonal in C-fibers). When mixed in equal proportions with 8.4% NaHCO3, a 0.75% bupivacaine solution (225 mg bupivacaine) precipitates 92.53% of the bupivacaine drug mass (only 7.47% remains in solution). Similarly, equal volumes of 8.4% NaHCO3 and 0.75% ropivacaine result in 96.50% of the drug mass being in the form of precipitated ropivacaine, with only 3.50% remaining in solution. It is expected that when levobupivacaine becomes available, the drug will react similarly to levobupivacaine, with 96.5% being converted to precipitate and crystals.

[0075] like Figure 12-16 As shown, the crystalline ALALA-carbonate precipitate 82 ( Figure 12-16 Bupivacaine carbonate (shown) will aggregate and crystallize in and around the axons 24 of the nerve in both A-delta and C-fibers 90. In summary, these alkaline ALALA-precipitates (at pH>7.4) condense into larger crystals to form an inactive reservoir of local anesthetic 90, which only slowly degrades to its non-ionized form (ALALA-) + H2O and CO2 96, and then re-equilibrates to the ionized form (ALALA+), which continues to cause nerve blockade and the resulting pain relief to persist for several days. Therefore, it is the alkaline pH of the ALALA-carbonate precipitate crystals that is responsible for the prolonged nerve block that lasts for several days.

[0076] In vivo formation of crystalline bupivacaine carbonate accumulates as precipitate deposits both intra-axonally and extra-axonally (at the nodes of Ranvier in A-delta fibers and along the entire axon in C-fibers). Although most of the extra-axonal bupivacaine carbonate is eventually cleared by the circulating lymph, a large percentage remains to serve as a reservoir of bupivacaine that contributes to the extended duration of nerve block. The extended duration of nerve block is primarily due to the amount of bupivacaine carbonate precipitates formed intra-axonally in both A-delta and C-fiber neurons.

[0077] ALALA-carbonate that precipitates in vivo will not remain stable, but will decompose into the unprotonated (-) form plus carbon dioxide (CO2), water (H2O), and salt (NaCl) as the alkaline environment within the axon returns to normal pH 7.4. CO2, H2O, and NaCl are reabsorbed into the lymph and blood, with H2O and NaCl ultimately eliminated via the kidneys and CO2 via the lungs. Since the initial decomposition of bupivacaine carbonate in an alkaline environment produces unprotonated (-) bupivacaine, the generation of protonated (+) bupivacaine is limited but sufficient to extend the duration of the established nerve block. As the pH of the alkaline intraaxonal environment gradually returns to pH 7.4, more and more bupivacaine carbonate acquires protons, becomes active in blocking the neuron's sodium-potassium pump, intensifies the nerve block, until finally all of the bupivacaine carbonate has decomposed to bupivacaine (-), protonated to bupivacaine (+), blocks the neuroreceptors, and is metabolized. Only after the last of the bupivacaine (+) has been metabolized does the nerve block effect disappear in individual A-delta and C-fibers.

[0078] Since nerve metabolism in A-delta fibers is faster than C-fibers, A-delta pain fibers will return to normal sensation faster than their C-pain fiber counterparts. This typically results in an A-delta nerve block that lasts 48-72 hours. However, a desirable C-pain fiber block can last 120 hours or longer. A 120-hour sensory nerve block can eliminate the need for opioid-based analgesics after surgery. It is this elimination of the need for postoperative opioid prescriptions that would close the path that currently exists that leads many people into opioid addiction.

[0079] Auxiliary agents

[0080] Other peripheral nerve block adjuncts89 can be added to this ALALA-carbonate block to enhance it. These include adrenaline, α 2 - Agonists such as clonidine, dexmedetomidine, etc. and steroids such as dexamethasone, betamethasone, triamcinolone, etc. Steroid 88 alone can crystallize the amide local anesthetics themselves and enhance the crystallization / precipitation also caused by NaHCO3, Na2CO3, NaOH and other physiological bases by a separate mechanism.

[0081] It has recently been noted that physiological bases 76 (NaHCO3 / Na2CO3 / NaOH) are not the only class of compounds that are capable of precipitating local anesthetics, particularly ALALA compounds. Steroids 88 also have this effect of precipitating ALALA compounds. Whether this results in intraneural or extraneural deposition of ALA local anesthetics is unclear. However, it is known in the literature that supplementing steroids with ropivacaine and bupivacaine in ALALA peripheral nerve blocks can prolong the block, typically lasting 16 to 24 hours, and sometimes up to 30 hours. In the present invention, the inclusion of steroids in the ALALA-compound block does prolong the analgesic effect produced, whether by intraneural (axonal) or extraneural deposition of ALALA-carbonate compounds. However, the elimination of NaHCO3 necessarily results in a block of ~30 hours or less.

[0082] Relevant to the present invention, it is noted that variable combinations of drug masses of Na2CO3, NaHCO3, and various steroids (currently dexamethasone and betamethasone) can produce titratable time ranges of analgesia, depending on how long analgesia is needed after surgery. It is conceivable that various combinations of NaHCO3 (pH = 8-9) and Na2CO3 (pH = 10-11) can produce any desired alkaline environment to control carbonate base absorption into the axons of neurons and the pH of this environment. pH is the controlling factor that determines the amount of precipitate and crystal size during the formation of ALALA-carbonate, and is further altered by corticosteroids. As we have discovered, even higher concentrations of NaHCO3 / Na2CO3 and / or steroids can result in significantly longer analgesic periods of more than 120 hours. Therefore, the generation of predictable and titratable analgesic periods is a result of the drug masses and concentrations of the constituent components in ALALA-carbonate nerve blocks. Thus, a nerve block can be set to last a specific period of time as the mass / concentration of each component in the ALALA-compound block is varied.

[0083] Protocol for generating ALALA-compound nerve blocks

[0084] like Figure 17-23 As shown, the establishment of a 5-day peripheral nerve block involves the injection of two separate and sequential solutions to form ALALA-compound precipitates and crystals in vivo around the nerves where the specific nerve block is to be achieved. These solutions form ALALA-compound precipitates and crystals. Since the two solutions must be kept separate until the injection on the specific nerve is completed, the solutions may then react to form ALALA-compound precipitates and crystals in vivo.

[0085] This separation of solutions is achieved in two different ways:

[0086] 1. Two separate solutions are injected sequentially through a single needle ( Figure 17-19 and 22).

[0087] 2. Simultaneous injection of two solutions through a bifurcated needle, where mixing occurs only at the needle tip opposite the target nerve ( Fig. 20 and 21 ).

[0088] These alkaline solutions are:

[0089] 1. Solution 1 - 4% lidocaine + 1:200,000 epinephrine + 8.4%-10% NaHCO3. 4% lidocaine and 8.4% NaHCO3 / Na2CO3 are in equal proportions. Epinephrine 86 is present at a concentration of ~3 micrograms / ml and serves primarily as a standard vascular marker that will produce mild tachycardia if it leaks into the vascular system. When solution 1 is administered, a pulse oximeter or EKG rhythm strip must be run to confirm the absence of tachycardia within 2 minutes to ensure that solution 1 has not leaked into the vascular system causing a tachycardia greater than 15% above the baseline pulse.

[0090] Such a provision to prevent accidental injection of Solution 1 into the vascular system is mandatory since amide longer acting local anesthetics can be cardiotoxic and cause seizures and even cardiac arrest. Such precautions are crucial for the safety of patients using ALALA-compound blockade.

[0091] This use of epinephrine described in 1. and 2. is exactly the protocol currently followed in all hospitals since the 1980s (test dose) to prevent cardiotoxic reactions to the ALALA drug after epidural catheter placement and before use.

[0092] 2. If tachycardia of 15% or more over baseline pulse occurs during the slow injection of Solution 1, the block is immediately terminated, as tachycardia caused by epinephrine 86 is considered evidence of intravascular leakage of Solution 1. In such a case, if Solution 2 is subsequently injected, local anesthetic systemic toxicity may cause seizures and cardiac arrest in the patient. For this reason, the standard protocol is to wait 2 minutes between the injection of Solution 1 and Solution 2 containing epinephrine. Solution 2 is injected only if no increase in pulse rate greater than 15% over baseline is determined within 2 minutes.

[0093] 3. Injecting cleaning solution 84 through the needle to prevent Solution 1 from mixing with Solution 2 and producing precipitates / crystals that would clog the lumen of the needle before Solution 2 is fully injected. This would prevent complete mixing of Solutions 1 and 2 and thus result in incomplete precipitate / crystal formation. To prevent this, Solution 1 must be flushed out of the single lumen needle before Solution 2 is injected.

[0094] 4. Solution 2 - 0.75% bupivacaine, 0.75% levobupivacaine or 1% ropivacaine is used as the single component of Solution 2, which is usually equal in volume to Solution 1.

[0095] If a higher concentration of the ALALA compound component is utilized, analgesic block can be further prolonged with more and larger crystals formed. Since NaHCO3 is already a saturated solution, it is not possible to attempt to increase the mass of NaHCO3 in solution and thereby increase the pH. However, this can be achieved by increasing the Na2CO3 concentration in the NaHCO3:Na2CO3 mixture and thereby increasing the pH to provide a higher pH in the final mixture, thereby producing more precipitate and crystal formation.

[0096] When physiological 8.4% NaHCO3 (at pH ~ 8) was added to an equal volume of 4% lidocaine in solution 1, the final concentrations of NaHCO3 and lidocaine were reduced to 4.2% and 2%, respectively, and the pH dropped. When an equal volume of solution 2 was added to the perineurial mixture, it was further diluted to form a precipitate containing only 2.1% NaHCO3. This dilution reduced the acid-base balance of the final solution to a point just above pH 7.4 (physiological pH).

[0097] If the pH of the NaHCO3 of Solution 1 is raised by adding Na2CO3 to a point where the pH of the final perineurial solution is ~pH=8, a much greater concentration of ALALA-carbonate precipitate can be formed, resulting in a longer or much longer period of analgesia from the nerve block. This may prove very useful for larger and more complex surgical procedures, and even chronic pain syndromes.

[0098] Since the pH of the physiological base in Solution 1 is raised to prolong analgesia, the same effect can be produced by increasing the ALALA level of drugs, steroids, α 2 - Agonists such as clonidine and dexmedetomidine, NSAIDs or NMDA agonists with any other adjuvants to increase the axonal content of these drugs in the precipitate / crystals. These could functionally extend the analgesia obtained to 14 days or more, helping to suppress the neural feedback that causes chronic regional pain syndrome (CRPS) and allowing the spinal cord to normalize itself. Further animal experiments will demonstrate which drugs and at what concentrations are more useful for this purpose than our current mixture of solutions 1 and 2.

[0099] When these solutions are used for sequential injection through a single needle ( Fig.17 and 22), the material of solution 1 must be cleared from the needle before solution 2 can be injected. The NaHCO3 in solution 1 can cause the bupivacaine or ropivacaine of solution 2 to precipitate in the needle and clog it. Therefore, solution 1 must be flushed out of the single lumen needle before solution 2 can be injected through the needle. The present invention avoids this problem because the delivery device or dispenser uses a co-connected needle or an internally bifurcated needle that can inject these solutions sequentially while always eliminating the possibility of needle clogging due to precipitation ( Figure 18-21 ).

[0100] Once solution 1 is injected around the peripheral nerve, the NaHCO3 and Na2CO3 push the protonated / unbound physicochemical equilibrium of lidocaine toward an unbound fraction of about 95%. Because the unbound fraction of a local anesthetic is essential for its axonal tissue penetration. Lidocaine will then be carried into the axon with a greater mass than usual, and due to this greater mass of lidocaine, NaHCO3 will also be carried into the axon.

[0101] The NaHCO3 in solution 1, when mixed with bupivacaine, levobupivacaine, or ropivacaine in solution 2, will cause these drugs to precipitate immediately as crystals in the alkaline solution. When mixed in equal proportions with 8.4% NaHCO3, a 0.75% bupivacaine solution (225 mg bupivacaine) will precipitate 93.53% of the bupivacaine drug mass (only 7.47% remains in solution). Similarly, equal volumes of 8.4% NaHCO3 and 0.75% ropivacaine will result in 96.50% of the drug mass in the precipitated ropivacaine, with only 3.50% remaining in solution.

[0102] Without removing the ultrasound-placed single-lumen injection needle from its position near the nerve, purge the needle of NaHCO3 (using saline or air) and then inject an equal volume of Solution 2 to Solution 1 by sequential injection. Note that this step is not necessary for commissural or internally bifurcated needles.

[0103] As bupivacaine (or ropivacaine) flows into the NaHCO3 / lidocaine solution 1 around the nerve, bupivacaine begins to precipitate. Most of the drug will precipitate outside the axonal membrane and will therefore be cleared by the normal lymphatic flow around the nerve over time. It has been noted that steroids precipitate local anesthetics in vitro, and it is expected that the same function will be achieved in vivo. A recent paper has pointed out this reaction as a warning for the combination of steroids and bupivacaine in epidural anesthesia. However, drugs that are harmful to epidural blocks can achieve much longer blockade when used instead of opioids for peripheral nerve analgesia. When mixed with NaHCO3 in solution 1, betamethasone and dexamethasone can produce larger precipitation with bupivacaine and ropivacaine, and produce even longer-acting local anesthetic blocks.

[0104] Variable drug masses of NaHCO3 / Na2CO3 / NaOH and other steroids will produce variable lengths of effective analgesia, depending on the concentration / drug mass of NaHCO3 and steroid used in Solution 1. In theory, other steroids not listed here may still demonstrate even greater intra-axonal or nodal deposition of the amide long-acting local anesthetics and correspondingly longer analgesia after surgery.

[0105] Only about 11.9% of the bupivacaine penetrates the axolotl or junction before it precipitates as bupivacaine carbonate. It is this small amount of bupivacaine within the axolotl / junction that is primarily responsible for the sustained nerve block of 120 hours or more.

[0106] However, by changing the final pH of the combination of the ALALA drug with all the adjuvants and base / precipitate, these solutions can be forced to produce far more ALALA precipitate / crystals, thereby achieving a longer and more intensive nerve block. This is the goal of alternative approaches to generating ALALA-precipitate nerve blocks.

[0107] Alternatives to generate ALALA-precipitate nerve blocks

[0108] like Fig.24 As shown, an alternative protocol exists that shows advantages over the original protocol when placing a nerve block that needs to last for more than 120 hours.

[0109] In this alternative, it is first necessary to demonstrate that the block needle placement did not open a connection to the vascular system, e.g. Fig.24 As indicated in Phase 1 of the present invention, a "test dose" is used, with or without adjuvants. However, if the test dose results in a tachycardia ≥ 115% of baseline showing a connection to the vascular system, then the local anesthetic (lidocaine), epinephrine plus any included adjuvants will be the total nerve block the patient receives at that location and time. No ALALA medication will be administered, nor will a physiological base. In this way, intravascular injection of the ALALA medication, which carries the risk of seizures, cardiac arrhythmias, and arrest, will be avoided.

[0110] There is still a mandatory 2 minute wait (shown in stage 2) as a test dose, which reveals whether there is a connection to the body's vascular system. Again, in this way, ALALA drugs that cause cardiotoxic reactions (including seizures, arrhythmias, and cardiac arrest) are avoided by using a test dose. This has been done since the 1980s with obstetric epidural catheters to prevent ALALA cardiotoxic reactions.

[0111] Phase 2 is followed by Phase 3, in which the ALALA drug is injected in the mass of drug necessary to produce the desired duration of analgesia from the nerve block. This phase may contain adjuvants, but not precipitating steroids or physiological bases, which would cause precipitation of the ALALA drug mass when combined outside the body and target nerves.

[0112] In stage 4, the ALALA drug has been deposited around the nerve and the single lumen needle is flushed with a cleansing solution such as saline. This sets up the block needle for stage 5 and injects a physiological base and / or precipitated steroid.

[0113] In phase 5, calculated base and steroid are injected to raise the pH of all drugs injected in phases 1-4 to a pH of ~8.0 (7.4 to 8.4) to form the correct amount of precipitate and crystals (physiologic base and steroid) to produce the desired duration of peripheral nerve block from 3 days to over 30 days.

[0114] Since this alternative approach is to drive the pH to the final in vivo pH, the volumes of the injections no longer have to be equal. Much smaller doses of the higher pH base / steroid can be used to produce the desired final pH in the mixture of the ALALA drug and adjuvants to produce the desired precipitate to achieve the desired duration of analgesia.

[0115] By utilizing this alternative approach to optimize the pH in a nerve block, the amount of precipitation (physiological base and steroid-induced) can be controlled, thereby controlling the density and duration of the block as desired. A simple table will determine the type and quality of each drug, the target pH and duration, and even the density achieved, in order to produce a nerve block of the specific duration and density desired. This is particularly necessary when treating chronic pain patients, especially those with chronic regional pain syndromes.

[0116] Several academic papers recommend not adding too much carbonate base and steroids (especially corticosteroids) because this can cause precipitation of ALALA drugs (bupivacaine, levobupivacaine, ropivacaine). Tetracaine, an ester long-acting local anesthetic (ELALA), has a higher pKA than bupivacaine and also precipitates in carbonate bases and steroids.

[0117] Although academic publications suggest restrictions to avoid the formation of local anesthetic precipitates, our intellectual property intends to form these precipitates within nerve cells and axons as reservoirs of the ALALA or ELALA drug that allow nerve blocks to last well beyond 3 days. The drug quality and composition of these precipitates determines the duration of the nerve block so produced, and therefore the duration of pain relief.

[0118] The formation of ALALA deposits in nerves is the basis for a longer-term disruption of the sodium-potassium ion pump in neurons. When this pump is disabled, the neurotransmission of pain impulses is also disabled, and thus post-surgical and post-traumatic patients receive analgesia when a nerve block is performed.

[0119] There are various carbonate and steroid drugs that when combined with the ALALA (and ELALA) drugs will form local anesthetic precipitates that have varying durations from 3 to 30 days or more.

[0120] Physiological carbonate bases consist primarily of sodium bicarbonate (NaHCO3), sodium carbonate (Na2CO3), and sodium hydroxide (NaOH). Each of these solutions has a different saturation pH, and thus various combinations of these solutions can produce a final common solution with a desired pH. This is critical to obtaining the desired amount of ALALA or ELALA precipitate within the nerve when a specific period of analgesia is desired from a peripheral nerve block.

[0121] As found in our laboratory, 8.4% NaHCO3, when combined in vitro with bupivacaine or ropivacaine, produces a precipitate of 93.5% and 96.5% of the parent ALALA drug, respectively. But when the NaHCO3 is further diluted with lidocaine and adjuvants, and then later diluted with an equal volume of ALALA drug, the percentage of NaHCO3 is diluted from 8.4% to 2.1%, while the pH also drops, and much less ALALA drug is converted to precipitate. Controlling the pH of the final combination of all of these drugs and bases can more effectively control the percentage of ALALA converted to precipitate and crystals, and thereby control the duration of the resulting nerve block.

[0122] Similarly, the combination of ALALA (or ELALA) local anesthetics with steroids, especially corticosteroids, can also cause ALALA-precipitates. Some of these precipitates migrate into the nerve axons to form intraneural ALALA or ELALA steroid precipitates. Corticosteroids known to be used to form these precipitates include dexamethasone, betamethasone and triamcinolone. This combination of steroids and ALALA or ELALA drugs can produce clinically useful precipitates, usually as shown in the following table.

[0123] Summary of possible local anesthetics and precipitating alkalis and steroids 1

[0124]

[0125] Summary of possible local anesthetics and precipitating alkalis and steroids 2

[0126]

[0127] As shown in Summary Table 2, once levobupivacaine and ropivacaine are taken into account, the total conceivable change is 3 x 10 28 Some of these chemical interactions could potentially eliminate PABA from tetracycline decomposition. In this case, the total useful change conceivable from this matrix is ​​4 x 10 28 .

[0128] Summary Table 3 - ALALA-precipitate masses identified so far

[0129]

[0130] Table 3 above lists the components of the ALALA-precipitate mass identified so far:

[0131] 1. ALALA drugs - bupivacaine, levobupivacaine, ropivacaine.

[0132] 2. Physiological base - NaHCO3 at pH ~8.0-8.2 - usually the main physiological base, and Na2CO3 saturated solution at pH ~8-9, but the crystals added directly to the mixture are at pH=11.5.

[0133] The present invention contemplates that these two bases will be added to the solution together to control the pH and thereby precipitate the ALALA compound, bringing the pH of the final mixture to a range of pH 7.5 to pH 8.4. A sufficiently alkaline pH is required to control the extent of ALALA precipitation, which controls the duration of the nerve block of these ALALA-precipitates. If a smaller total volume is desired for the final volume of the injection, even some NaOH crystals may be added to the NaHCO3 / Na2CO3 solution to bring it to the desired pH just prior to the nerve block injection. The present invention aims to have the concentration of NaHCO3 rise as Na2CO3 falls, accounting for only 25-fold changes of physiological bases.

[0134] 3. Precipitating steroids, primarily the corticosteroids dexamethasone and betamethasone. These two corticosteroids are currently used in routine peripheral nerve blocks to extend the ALALA block from 12-16 hours to an effective range of up to 24 hours, after which it tapers off. In light of Hwang's cautionary paper, the likely reason is that the ALALA-precipitate fills the gap between the initial lidocaine + epinephrine taper off and the ALALA-carbonate reverts back to protonated ALALA, allowing the lidocaine nerve block to continue. The useful dosage ranges for these corticosteroids are as given above. It may be necessary to use one or both corticosteroids simultaneously, resulting in 10× and 20× changes in steroid use.

[0135] 4. Auxiliary agents - these are mainly alpha2 - Agonist drugs - dexmedetomidine and clonidine, known to block alpha in the spinal cord 2 - pain receptors and are thought to also work in peripheral nerves. Certainly, dexmedetomidine and clonidine, as well as corticosteroids, have been shown to prolong the standard peripheral nerve block with bupivacaine and ropivacaine by ∼50%. These α 2 -Increased doses of agonist drugs resulted in increased duration of these nerve blocks. Each of these drugs was used at 100x variation.

[0136] Therefore, the possible variations of these blocks for bupivacaine are 25 x 10 x 20 x 100 x 100 = 5,000,000 variations of these drugs with bupivacaine. The same is true for bupivacaine and ropivacaine, for a total of 15,000,000 variations of the available compounds with these ALALA drugs.

[0137] Tetracaine, although it precipitates in physiological bases and corticosteroids, was not considered because it releases toxic PABA when these large peripheral nerve blocking drug masses decompose. Until safer ELALA drug variants or methods to detoxify them are found, this is too dangerous for use in humans.

[0138] Although other variations may show some promise, these are the variations most likely to produce the long-lasting block of 120 hours or more sought by the present invention.

[0139] Both ALALA-carbonate and steroid precipitates can form intraneural deposit reservoirs, which upon degradation form salt, water, carbon dioxide and unprotonated (-) ALALA drug. The unprotonated ALALA form will gain protons and reach equilibrium with its protonated (+) and neutral active form. It is this neutral active protonated form of the ALALA drug that blocks the sodium-potassium ion pumps in neurons and axons, thereby preventing the neurotransmission of pain and causing both numbness and analgesia.

[0140] These potential combinations of drugs and bases constitute a total of 3x 10 28 This initial matrix must then be multiplied by the number of different adjuvants, including all α 2 - adjuvants, NSAIDS, NMDA-antagonists, and even μ 2 -agonists, which are applicable to those blocks that include these adjuvants. Multiply all of these variations by the different percentages of each carbonate base and the drug mass of each of the various steroids that can affect the density and duration of the final nerve block. This will produce a matrix containing thousands to even tens of thousands of entries and variations to control nerve block density and duration.

[0141] Titration of the carbonate or steroid to a specific target pH in the final ALALA compound will control the density and duration of the nerve block; thus, various dilutions of carbonate base and steroid can be used to produce the desired final pH and precipitate as needed for the desired density and duration of nerve block.

[0142] In view of this, some of these combinations will not produce acceptable analgesia, and even other combinations are not suitable for biological tissues. But most will have a certain effect to produce ALALA (or ELALA) precipitates, thereby producing various nerve blocks, and the analgesia lasts for 3 to 30 days or longer. Other compounds may be found in the future to enhance these same intraneural ALALA (or ELALA) precipitates, and thereby produce more effective and titratable nerve blocks and analgesia. These combinations can be used together with peripheral nerve blocks or regional blocks to produce post-surgical and post-traumatic analgesia with specific block density and duration as needed.

[0143] Ester local anesthetics

[0144] It is noted that tetracaine, an ester local anesthetic, has an even higher pKa than bupivacaine and will precipitate in the presence of NaHCO3 and Na2CO3 and will also produce a long-acting local anesthetic block. However, as an ester local anesthetic, tetracaine decomposes to para-aminobenzoic acid (PABA), a known allergen that can cause severe, even fatal, allergic reactions. Given that these allergic reactions are known to occur at doses of 10 mg and lower, the 100 mg to over 200 mg doses required for peripheral nerve blocks will have a greatly increased frequency of occurrence. Even a 200 mg dose may be uniformly lethal in humans. For this reason, unless laboratory experiments can produce an ester or other long-acting local anesthetic that is greater in effect than bupivacaine and without significant toxicity, tetracaine will not be used in volume-dependent peripheral nerve blocks as is currently common. However, it is necessary to include tetracaine in this intellectual property and if and when a non-allergenic variant of this block without prohibitive toxicity becomes possible, it will be utilized and claimed.

[0145] Competitive Intellectual Property

[0146] Exparel is a liposomally encapsulated bupivacaine first released in 2012. Its unique formulation induces peripheral nerve block analgesia that lasts for 3 days and is an improvement over non-opioid analgesia after surgical procedures. However, it has been shown to perform less well in this effect than it claims, with most blocks lasting only 36 to 48 hours.

[0147] Exparel utilizes a liposome shell of varying thickness as a time-limited release mechanism for its encapsulated bupivacaine in a peripheral nerve block after injection. The liposome shell will be digested over time and then release the bupivacaine it encapsulates. The different thicknesses of the shell allow for variable release of local anesthetics. This allows for timed release of bupivacaine to extend peripheral nerve blocks to the advertised 72 hours of analgesia after surgery. Although Exparel has somewhat effective analgesia in a period of less than 48 hours, this mechanism has serious limitations when extending this block to 72 hours, because significant fragility has led to premature delivery of its bupivacaine load under certain conditions, and sometimes even accidental delivery. Therefore, complete prevention of local anesthetic systemic toxicity (LAST) is not achieved using a full bottle dose of 250 mg bupivacaine in Exparel.

[0148] Despite its shortcomings, Exparel has made important progress in achieving increased analgesia after surgical procedures, but has still proven insufficient to provide the required 120 hours of postoperative analgesia to minimize or eliminate the need for opioid-based analgesics.

[0149] Abrahmsohn's IP suffers from multiple deficiencies. Specifically, Abrahmsohn specifies a separation in time and location between the injection of any anion (HCO3) and the injection of any local anesthetic. This has the effect of reducing the reaction between NaHCO3 and the ALALA drug to generate an ALALA-carbonate precipitate. Since this precipitate is the mechanism by which prolonged analgesia for surgical pain is achieved, Abrahmsohn's method is insufficient to provide maximal and reliable analgesia after surgery, nor is it sufficient to achieve an extended analgesic period of more than 72 hours. This is why Abrahmsohn's block times are inconsistent and vary widely (as listed, 0.5 to 72 hours).

[0150] The method of the present invention requires, in most cases, precise placement of a block needle under ultrasound guidance over, but not penetrating, the target nerve prior to in vivo delivery of an ALALA-carbonate / steroid nerve block This provides for the most immediate delivery of the solution to the target nerve, which forms ALALA-carbonate and ALALA-steroid precipitates in and around the target nerve and reliably and reproducibly achieves greater than 120 hours of postoperative analgesia for surgical patients.

[0151] Anesthetic nerve blocks 98 interrupt the electrical potential of nerves 12 in a living organism 10 and relieve pain. Figure 1-16As shown, the nerve 12 includes the perineurium 14, the perineurium 16, the endoneurium 18, the nodes of Ranvier 20, the myelin sheath 22, the axon 24, the neuronal cell body 30, the neuronal nucleus 32, the dendrites 34, the axon terminal 36, the oligodendrocytes (Schwann cells) 38, the myelin sheath 40, the microtubules 42, the microfilaments 44, the myelinated neurons (A-δ fibers) 50, the peripheral terminals 52, the neurolemma (axonal membrane) 54 and the unmyelinated neurons (C-fibers) 60.

[0152] The axon 24 is covered by the neural membrane 54. The anesthetic nerve block 98 includes a dispenser 102, which includes a reservoir 104, a transfer body 106, and a tip 108 for positioning near the nerve 12. A local short-acting anesthetic 76 is located in the reservoir 104. A physiological carbonate base 78 is located in the reservoir 104. The local short-acting anesthetic 76 and the physiological carbonate base 78 are dispensed from the tip 108 of the dispenser 102, wherein the local short-acting anesthetic 76 promotes the physiological carbonate base 78 to penetrate the neural membrane 54 and enter the axon 24. A local long-acting anesthetic 80 is located in the reservoir 104. The local long-acting anesthetic 80 is dispensed from the tip 108 of the dispenser 102 and penetrates the neural membrane 54 and enters the axon 24. The local long-acting anesthetic 80 and the physiological carbonate base 78 cause precipitation and form a crystalline compound 82, which is used to produce a prolonged local nerve block 99.

[0153] like Fig.17 As shown, the dispenser 102 may include a continuous anesthetic injection system 100. The continuous anesthetic injection system 100 includes a syringe 110 having a barrel 112, which slidably accommodates a plunger 114 and dispenses through a needle 116. The dispenser 102 may include a plurality of barrel membranes 118 that maintain the separation of the local short-acting anesthetic 76, the physiological carbonate base 78, and the local long-acting anesthetic 80 within the barrel 112.

[0154] A saline solution 84 may be located within the barrel 112. A plurality of barrel membranes 118 maintain the saline solution 84 between the physiological carbonate base 78 and the local long-acting anesthetic 80 within the barrel 112. After the local short-acting anesthetic 76 and the physiological carbonate base 78 have been dispensed from the needle 116, the saline solution 84 cleans the needle 116. A goring needle 120 may be located within the barrel 112 for sequentially breaking the plurality of barrel membranes 118 and allowing the solution to exit the barrel 112 upon depression of the plunger 114.

[0155] like Fig.18 and 19As shown, the dispenser 102 may alternatively include a first dispenser 134 and a second dispenser 142. The first dispenser 134 has a first reservoir 136, a first transfer body 138, and a first tip 140 for dispensing a local short-acting anesthetic 76 and a physiological carbonate base 78. The second dispenser 142 has a second reservoir 144, a second transfer body 146, and a second tip 148 for dispensing a long-acting local anesthetic or a local long-acting anesthetic 80. The dispenser 102 may include coaxial needles or co-connected needles 130 for parallel injection. The co-connected needles 130 have a common outlet at the tip 132, wherein mixing of the individual cavities occurs at the tip 108 of the needle 116.

[0156] like Fig. 20 and 21 As shown, the dispenser 102 may include a transfer body 106 having a bisecting transfer wall 150. The bisecting transfer wall 150 defines and separates a primary transfer body 152 from a secondary transfer body 154. The primary transfer body 152 dispenses the local short-acting anesthetic 76 and the physiological carbonate base 78. The secondary transfer body 154 dispenses the local long-acting anesthetic 80. The bisecting transfer body 150 prevents mixing of the fluids outside of the tip 108.

[0157] like Fig. 22 As shown, the dispenser 102 may include a first syringe 160, a second syringe 170, and a third syringe 180. The first syringe 160 has a first barrel 162 that slidably accommodates a first plunger 164. The first barrel 162 contains a local short-acting anesthetic 76 and a physiological carbonate base 78. The second syringe 170 has a second barrel 172 that slidably accommodates a second plunger 174. The second barrel 172 contains a physiological saline solution 84. The third syringe 180 has a third barrel 182 that slidably accommodates a third plunger 184. The third barrel 182 contains a local long-acting anesthetic 80. A piston 186 connects the first barrel 162, the second barrel 172, and the third barrel 182 to the needle 116. The piston 186 is positioned sequentially to dispense the local short-acting anesthetic 76 and the physiological carbonate base 78, the physiological saline solution 84, and the local long-acting anesthetic 80. After the local short-acting anesthetic 76 and the physiological carbonate base 78 have been dispensed from the needle 116, the physiological saline solution 84 cleans the needle 116. A tube 188 may be located between the piston 186 and the needle 116. A side barrel 190 may be connected to the first syringe 160, the second syringe 170, and / or the third syringe 180 to dispense an adjuvant 89, such as additional physiological carbonate base 78, steroids 88, epinephrine 86, and the local long-acting anesthetic 80.

[0158] By combining the local short-acting anesthetic 76 with the physiological carbonate base 78, the pH of the local short-acting anesthetic 76 is increased, and the local short-acting anesthetic 76 is changed to an unprotonated (-) molecule, so that the local short-acting anesthetic 76 and the physiological carbonate base 78 are more easily positioned through the nerve membrane 54 and into the axon 24. The pH level of the physiological carbonate base 78 determines the amount and crystal size of the precipitate in the crystalline compound 82. The physiological carbonate base 78 mass / concentration level can be increased to increase the pH, thereby providing a higher pH in the final mixture and resulting in a longer duration of nerve block. Alternatively, the physiological carbonate base 78 mass / concentration level can be reduced to reduce the pH, thereby providing a lower pH in the final mixture and resulting in a shorter duration of nerve block. The physiological carbonate base 78 mass / concentration level adjustment defines a variable nerve block time period. The physiological carbonate base 78 mass / concentration level adjustment further defines a variable nerve block density.

[0159] The local short-acting anesthetic 76 may include lidocaine. The local long-acting anesthetic 80 may include bupivacaine, levobupivacaine, ropivacaine, and tetracaine. The physiological carbonate base 78 may include sodium bicarbonate, sodium carbonate, and sodium hydroxide.

[0160] The anesthetic nerve block 98 may further include, or alternatively include, a steroid 88 in a reservoir 104. The steroid 88 may include dexamethasone, betamethasone, and triamcinolone, as well as other adjuvants. The local short-acting anesthetic 76 and the steroid 88 are dispensed from the tip 108 of the dispenser 102, wherein the local short-acting anesthetic 76 facilitates the steroid 88 to penetrate the neural membrane 54 and enter the axon 24. The local long-acting anesthetic 80 is located in the reservoir 104. The local long-acting anesthetic 80 is dispensed from the tip 108 of the dispenser 102 and penetrates the neural membrane 54 and enters the axon 24. The local long-acting anesthetic 80 and the steroid 88 cause precipitation and form a crystalline compound 82 to produce a prolonged local nerve block 99.

[0161] like Fig.23As shown, a method comprising the present invention includes producing an anesthetic nerve block 98. The anesthetic nerve block 98 interrupts the electrical potential 56 of the nerve 12 in a living organism 10 and relieves pain. The method includes the following steps: dispensing a local short-acting anesthetic 76 from a dispenser 102 to position the local short-acting anesthetic 76 near the nerve 12. Dispensing a physiological carbonate base 78 from the dispenser 102 to position the physiological carbonate base 78 near the nerve 12, wherein the local short-acting anesthetic 76 promotes the physiological carbonate base 78 to penetrate the nerve membrane 54 and enter the axon 24. Dispensing a local long-acting anesthetic 80 from the dispenser 102 to position the local long-acting anesthetic 80 near the nerve 12, wherein the local long-acting anesthetic 80 penetrates the nerve membrane 54 and enters the axon 24, and the local long-acting anesthetic 80 and the physiological carbonate base 78 cause precipitation and form a crystalline compound 82 for producing a prolonged local nerve block 99.

[0162] The method may further include the step of dispensing epinephrine 86 from the dispenser 102 to determine any intravascular leak. The method may further include the step of dispensing saline solution 84 to clean the dispenser 102. The method may further include the step of dispensing steroid 88 from the dispenser 102 to improve precipitation and formation of crystalline compound 82 to produce prolonged local nerve block 99.

[0163] like Fig.24 As shown, the subject invention may alternatively include a method comprising the steps of: dispensing a local short-acting anesthetic 76 from a dispenser 102 to position the local short-acting anesthetic 76 near the nerve 12. Dispensing a local long-acting anesthetic 80 from the dispenser 102 to position the local long-acting anesthetic 80 near the nerve 12. Dispensing a physiological carbonate base 78 from the dispenser 102 to position the physiological carbonate base 78 near the nerve 12, wherein the local short-acting anesthetic 76 promotes the physiological carbonate base 78 to penetrate the nerve membrane 54 and enter the axon 24, and wherein the local long-acting anesthetic 80 penetrates the nerve membrane 54 and enters the axon 24, and the local long-acting anesthetic 80 and the physiological carbonate base 78 cause precipitation and form a crystalline compound 82 for producing a prolonged local nerve block 99.

[0164] The method may further include the step of dispensing epinephrine 14 from the dispenser 102 to determine any intravascular leak. The method may further include the step of dispensing saline solution 84 to clean the dispenser 102. The method may further include the step of dispensing steroid 88 from the dispenser 102 to improve precipitation and formation of crystalline compound 82 to produce prolonged local nerve block 99.

[0165] The subject invention method can be further described below.

[0166] 1. A method of producing a long-acting nerve block in vivo by combining an amide long-acting local anesthetic (ALALA) with a physiological base in the immediate vicinity of the target nerve.

[0167] a. Obtain a long-lasting nerve block #1, where the block needle is precisely placed near but not through the target nerve. Currently, this is achieved through an ultrasound-guided block procedure.

[0168] b. Nerve block #1 with local anesthetics belonging to the ALALA class, including bupivacaine, levobupivacaine, and ropivacaine.

[0169] c. Nerve block of #1, where the ALALA-drug is precipitated by the physiological base NaHCO3, and its pH can be adjusted by including Na2CO3 and / or NaOH to achieve a higher target pH in the injection solution and final compound.

[0170] d. Nerve block of #1, in which the ALALA drug is precipitated by a steroid (particularly a corticosteroid such as dexamethasone and betamethasone) to form an ALALA-steroid precipitate.

[0171] e. Nerve block of #1, in which sequential or simultaneous injection of a physiological base and an ALALA-like drug produces ALALA-carbonate precipitates and crystals.

[0172] f. These ALALA carbonate precipitates and crystals and ALALA steroid precipitates are produced as deposits in and around the axons and cell bodies of neurons.

[0173] The ALALA steroid precipitate of g.1c breaks down over time first into unprotonated ALALA(-) which is able to penetrate the axonal membrane and then into protonated ALALA(+) within the axon, which incapacitates the sodium-potassium pump and thereby blocks the neurotransmission of pain impulses.

[0174] h.1d of ALALA-carbonate precipitates / crystals decompose over time first into unprotonated ALALA(-) which is able to penetrate the axonal membrane and then into protonated ALALA(+) within the axon, which incapacitates the sodium-potassium pump and thereby blocks the neurotransmission of pain impulses.

[0175] i.1c ALALA-steroid precipitate / crystals, wherein such decomposition of the ALALA-steroid precipitate and crystals into active ALALA drug will provide the patient with a duration of analgesia of 120 hours or more.

[0176] j.1d of ALALA-carbonate precipitate / crystals, wherein such decomposition of the ALALA-carbonate precipitate and crystals into active ALALA drug will provide the patient with an analgesic duration of more than 120 hours.

[0177] 2. The blocking method of #1, in which a short-acting amide local anesthetic (ALA, such as lidocaine) is first combined with a physiological base to form unprotonated ALA (-).

[0178] a. ALA drugs used in solution #1 (such as lidocaine) must not precipitate in alkaline solutions with a pH < 10 (lidocaine precipitates at pH ~ 11.5).

[0179] b. The blocking method of #2, when injected through a blocking needle precisely close to the target nerve, easily penetrates the axonal membrane of the target nerve and brings physiological alkali with it into its neurons (cell bodies and axons), thereby causing the internal environment of the axon to become alkaline.

[0180] c. The injection of #2, which may also contain adjuvants to enhance and increase the density and duration of impulse blockade through the target nerve, thereby blocking it to achieve longer-lasting analgesia.

[0181] i. The injection of #2b always includes epinephrine or a similar drug as a marker for significant vascular penetration, which can significantly increase the pulse rate if trace amounts of drug leak into the vascular system. Epinephrine acts as an early warning of unexpected vascular connections that could present a risk of LAST if the ALALA-drug is subsequently injected. This is taken as an indication to terminate the ALALA-carbonate block here and now,

[0182] ii. Injection of #2b, which may include α 2 - agonists such as dexmedetomidine, clonidine, etc., to prolong and enhance the density of the nerve block achieved,

[0183] iii. Injectable solution #2b, which may include steroids, especially corticosteroids, which can cause ALALA-drug precipitation and thereby create a reservoir of ALALA-precipitates distinct from ALALA carbonate precipitates / crystals. These two reservoirs together enhance nerve block density and duration to create the longest lasting sensory nerve block,

[0184] iv. injection of #2b, which may include an appropriate nonsteroidal anti-inflammatory drug (NSAID) to enhance sensory nerve block and aid in sensory nerve block density and duration,

[0185] v. injection of #2b, which may include appropriate N-methyl D-aspartate (NMDA) antagonist drugs, such as ketamine derivatives, dextromethorphan, etc., to enhance sensory nerve blockade and help sensory nerve block density and duration,

[0186] vi. Injection of #2b, which may include an opioid μ 2 -Agonists, such as morphine, hydromorphone, pethidine, fentanyl, and derivatives, if these opioids on specific target nerves μ 2 - if the receptor is identified.

[0187] 3. Clean the single lumen needle of alkaline solution #2 by injecting a cleaning solution prior to subsequent injection of ALALA-drug which could cause immediate precipitation of ALALA-carbonate in this lumen and subsequent lumen obstruction which would prevent complete injection of the desired ALALA dose.

[0188] a. This cleaning solution is only required in single lumen needles and catheters where two injection solutions (Solutions 1 and 2) must pass through the same needle lumen.

[0189] b. The bifurcated lumen needle does not allow these solutions to mix except at the distal tip in close proximity to the target nerve where sediment cannot clog the bifurcated needle. Therefore, the bifurcated needle and bifurcated delivery catheter do not require a cleaning solution.

[0190] 4. A mandatory 2-minute wait (test dose) is required between injections of Solution #1 and Solution #2 to ensure that local anesthetic systemic toxicity (LAST) does not occur. This is accomplished by monitoring the pulse oximeter and / or observing the EKG trace (or similar objective indicator of pulse rate) for tachycardia that exceeds the baseline pulse by at least 15% (115% of baseline), which may indicate leakage of Solution #1 into the blood vessels due to inadvertent penetration of the blood vessels during block needle placement. This is a strong indicator that the block at this site should be terminated. If Solution #2 is then injected after a positive tachycardia result, the patient may experience seizures, cardiac arrhythmias, cardiac arrest, and death.

[0191] 5. Block of #1, wherein, after neutralizing the intraluminal pH of the needle with cleaning solution as needed (from solution #1) of #3 and waiting for 2 minutes to prevent LAST of #4, a second injection of ALALA-drug (solution #2) is deposited around the nerve through the block needle to mix with physiological base in and around the nerve (especially within the axon) to generate ALALA-carbonate precipitate and crystals.

[0192] 6. The adjuvants can be distributed between solutions #1 and 2, depending on their stability in alkaline solutions.

[0193] a. Only epinephrine must be included in solution #1 containing ALA-drugs as a precaution against LAST.

[0194] b. Steroid adjuvants must also be delivered in solution #1 because they react with the ALALA drug to form a precipitate. Due to stability issues between steroids and physiological bases, these adjuvants may be delivered separately from the physiological base.

[0195] c. If necessary, solution #1 can be divided into separate injections of ALA (such as lidocaine) and a physiological base to maintain the integrity of the epinephrine in solution #1.

[0196] d. All other compatible adjuvants may be moved to Solution #2 as needed or desired.

[0197] 7. The duration of nerve block is controlled by the amount of ALALA-carbonate precipitates / crystals formed.

[0198] a. This is controlled by the pH of the physiological base concentration in Solution 1, the higher the pH, the greater the percentage of ALALA drug that is converted to ALALA carbonate precipitate / crystals when mixed with Solution #2.

[0199] b. The final target pH of the mixture of solutions #1 and #2 is pH < 8.4.

[0200] c. Depending on the stability of the adjuvant, a pH > 8.0 in Solution #1 may be necessary in a single lumen block needle to adequately control the formation of ALALA-carbonate precipitates / crystals at the target nerve site.

[0201] d. In bifurcated lumen needles, catheters, and similar delivery devices, much higher non-physiological concentrations of physiological bases can be used in Solution #1 as long as the final mixing of Solutions 1 and 2 still results in a physiological pH < 8.4 of the final deposited ALALA-carbonate precipitate.

[0202] 8. The generation of titratable durations of nerve block can be achieved by varying the pH of solution #1 and the choice and quality of steroid in solution #1 to vary the quality of the ALALA-carbonate precipitate / crystals formed. This results in different durations of nerve block because the two different precipitates (ALALA-carbonate and ALALA steroid) have different decomposition times and different conversion times back into the ALALA(+) axons for nerve block.

[0203] 9. This same approach for amide local anesthetics can also be applied to ester local anesthetics, since tetracaine has an even higher pKA than bupivacaine and precipitation is even easier for tetracaine carbonate and tetracaine-steroid. However, tetracaine is an ester local anesthetic that decomposes to para-aminobenzoic acid (PABA), which is a known irritant and allergen in trace amounts and can cause allergic reactions with the expected larger drug mass in these extended blocks with analgesic durations greater than 72-120 hours. Due to this risk, tetracaine should be avoided in these extended blocks for the time being, but as will be claimed in this IP, safer tetracaine derivatives may be discovered in the future that have no PABA or other allergen formation.

[0204] It is recognized that injecting local anesthetics in and around surgical sites to relieve pain is and has been normal hospital protocol for many years, and the desire for longer lasting local anesthesia has also been a goal pursued at that time. The ALALA compounds of the current invention have been able to achieve this goal by extending the period of local anesthetic effectiveness to 5 days and longer.

[0205] The ALALA compound of the present invention is administered in the same manner as current local anesthetics are administered. Following the current toxicity steps in existing hospital protocols, the ALALA compound is simply substituted in the same steps as currently used local anesthetics are introduced. The only difference from existing hospital protocols is that our ALALA compound is introduced into the equation as a perineural block rather than an epidural block. It should also be noted that all components of our novel ALALA compound are currently approved by the FDA.

[0206] Reference Symbols List

[0207] 10 Living organisms

[0208] 12 Sciatic nerve

[0209] 14 Epineurium

[0210] 16 Perineurium

[0211] 18 Endoneurium

[0212] 20 Ranvier knot

[0213] 22 Myelin

[0214] 24 Axon

[0215] 30 Neuron cell bodies

[0216] 32 Neuronal nuclei

[0217] 34 Dendrites

[0218] 36 Axon terminals

[0219] 38 Oligodendrocytes (Schwann cells)

[0220] 40 Myelin sheath

[0221] 42 Microtubules

[0222] 44 Microwire

[0223] 50 myelinated neurons (A-delta fibers)

[0224] 52 peripheral end (such as skin)

[0225] 54 Neural membrane (axonal membrane)

[0226] 56 Action Potential

[0227] 58 Stimulation

[0228] 60 unmyelinated neurons (C-fibers)

[0229] 70 Unprotonated lidocaine

[0230] 72 Protonated lidocaine

[0231] 74 Bicarbonate HCO3

[0232] 76 Local short-acting anesthetic: lidocaine

[0233] 78 Physiological carbonate bases: sodium bicarbonate, sodium carbonate, sodium hydroxide, dexamethasone, betamethasone and triamcinolone: ​​(plus possible adjuvants)

[0234] 80 Local long-acting anesthetics: bupivacaine, levobupivacaine, ropivacaine, tetracaine (ALALA)

[0235] 82 Formation of precipitate (ALALA) carbonate

[0236] 84 Physiological saline solution

[0237] 86 Adrenaline

[0238] 88 Steroids

[0239] 89 Auxiliary agents

[0240] 90 Nodes of Ranvier, extra-axonal deposits with crystals of bupivacaine carbonate precipitate 92 Bupivacaine HCO3

[0241] 94 Bupivacaine ++ OH- + CO2

[0242] 96 Bupivacaine-+H2O+CO2

[0243] 98 Anesthesia Nerve Block

[0244] 99Prolonged regional nerve block / ALALA-carbonate precipitation / ALALA steroid precipitation

[0245] 100 Continuous Anesthetic Infusion System

[0246] 102 Distributor

[0247] 104 Storage

[0248] 106 Transfer Body

[0249] 108 Tip

[0250] 110 Syringe

[0251] 112 Cylinder

[0252] 114 Plunger

[0253] 116 pins

[0254] 118 Multiple cartridge membranes for separation

[0255] 120 Needle for puncturing membrane

[0256] 130 Coaxial needle for parallel injection

[0257] 132 A co-connected needle with a common outlet at the tip, where mixing of the separate lumens occurs at the tip of the catheter.

[0258] 134 First Distributor

[0259] 136 First Storage

[0260] 138 The First Transfer

[0261] 140 First Tip

[0262] 142 Second Distributor

[0263] 144 Second Storage

[0264] 146 The Second Transformation

[0265] 148 Second tip

[0266] 150 Bisection transfer wall prevents fluid mixing outside the tip

[0267] 152 Main transfer body

[0268] 154 Secondary Transfer

[0269] 160 First Syringe

[0270] 162 First cylinder

[0271] 164 First Plunger

[0272] 170 Second Syringe

[0273] 172 Second cylinder

[0274] 174 Second Plunger

[0275] 180 Third Syringe

[0276] 182 Third cylinder

[0277] 184 Third Plunger

[0278] 186 piston-four-way sequence valve

[0279] 188 tubes

[0280] 190 Auxiliary side cartridges of steroids and / or physiological carbonate bases, which can be used as precipitants for ALALA

[0281] The present disclosure includes the contents contained in the appended claims and the foregoing description. Although the present invention has been described in its preferred form with a certain degree of detail, it should be understood that the present disclosure of the preferred form is made only as an example, and that various changes may be made to the construction details and the combination and arrangement of parts without departing from the spirit and scope of the present invention.

Claims

1. An anesthetic nerve block for interrupting the electrical potential of a nerve having an axon covered by a nerve membrane and relieving pain in a living organism, the anesthetic nerve block comprising: a dispenser comprising a reservoir, a transfer body, and a tip for positioning adjacent to a nerve; a local short-acting anesthetic in said reservoir; physiological carbonate base in said storage bodies; The local short-acting anesthetic and the physiological carbonate base are dispensed from the tip of the dispenser, wherein the local short-acting anesthetic promotes the physiological carbonate base to penetrate the nerve membrane and enter the axon; a long-acting local anesthetic in said reservoir; The local long-acting anesthetic is dispensed from the tip of the dispenser and penetrates the nerve membrane and enters the axon; and The local long-acting anesthetic and the physiological carbonate base cause precipitation and formation of a crystalline compound to produce a prolonged local nerve block.

2. An anesthetic nerve block as claimed in claim 1, wherein the dispenser comprises a syringe having a barrel which slidably receives a plunger and dispenses through a needle.

3. The anesthetic nerve block as described in claim 2, further comprising a plurality of barrel membranes, wherein the barrel membranes are used to maintain the separation of the local short-acting anesthetic, the physiological carbonate base and the local long-acting anesthetic within the barrel.

4. The anesthetic nerve block as claimed in claim 3, further comprising a saline solution in said barrel; The plurality of barrel membranes maintain the physiological saline solution between the physiological carbonate base and the local long-acting anesthetic within the barrel; and After the local short-acting anesthetic and the physiological carbonate base have been dispensed from the needle, the physiological saline solution cleans the needle.

5. An anesthetic nerve block as described in claim 1, wherein the dispenser includes a first dispenser and a second dispenser; The first dispenser has a first storage body, a first transfer body and a first tip for dispensing the local short-acting anesthetic and the physiological carbonate base; and The second dispenser has a second storage body, a second transfer body and a second tip for dispensing the local long-acting anesthetic.

6. The anesthetic nerve block as claimed in claim 1, wherein the storage body comprises a first storage body and a second storage body in communication with the transfer body; The transfer body comprises a transfer body divided into two equal parts; The bisected transfer body defines a primary transfer body and a secondary transfer body; The primary transfer body distributes the local short-acting anesthetic and the physiological carbonate base; and The secondary transfer body distributes the local long-acting anesthetic.

7. An anesthetic nerve block as described in claim 1, wherein the dispenser includes a first syringe, a second syringe, and a third syringe; The first syringe has a first barrel slidably receiving a first plunger; The first cylinder contains the local short-acting anesthetic and the physiological carbonate base; The second syringe has a second barrel slidably receiving a second plunger; The second cylinder contains a physiological saline solution; The third syringe has a third barrel slidably accommodating a third plunger; The third cylinder contains the local long-acting anesthetic; a piston connecting the first cylinder, the second cylinder, and the third cylinder to a needle; The piston is sequentially positioned to dispense the short-acting local anesthetic and the physiological carbonate base, the physiological saline solution, and the long-acting local anesthetic; and After the local short-acting anesthetic and the physiological carbonate base have been dispensed from the needle, the physiological saline solution cleans the needle.

8. An anesthetic nerve block as described in claim 1, wherein said combining said local short-acting anesthetic with said physiological carbonate base causes an increase in the pH of said local short-acting anesthetic and changes said local short-acting anesthetic to a non-protonated (-) molecule so as to more easily localize said local short-acting anesthetic and said physiological carbonate base across said nerve membrane and into said axon; The physiological carbonate base pH level determines the amount of precipitation and crystal size in the crystalline compound; The physiological carbonate base mass / concentration level is increased to raise the pH to provide a higher pH in the final mixture; The physiological carbonate base mass / concentration level adjustment defines a variable nerve block time period; and The physiological carbonate base quality / concentration level adjustment defines a variable nerve block density.

9. An anesthetic nerve block as described in claim 1, wherein the local short-acting anesthetic is lidocaine.

10. An anesthetic nerve block as claimed in claim 1, wherein the local long-acting anesthetic is selected from the group consisting of bupivacaine, levobupivacaine, ropivacaine and tetracaine.

11. An anesthetic nerve block as claimed in claim 1, wherein the physiological carbonate base is selected from the group consisting of sodium bicarbonate, sodium carbonate and sodium hydroxide.

12. The anesthetic nerve block as recited in claim 1, further comprising a steroid in said reservoir; said local long-acting anesthetic and said steroid cause said precipitation and formation of said crystalline compound to produce said prolonged local nerve block; and The steroid is selected from the group consisting of dexamethasone, betamethasone and triamcinolone.

13. An anesthetic nerve block for interrupting the electrical potential of a nerve having an axon covered by a nerve membrane and relieving pain in a living organism, the anesthetic nerve block comprising: a dispenser comprising a reservoir, a dispenser body, and a tip for positioning adjacent a nerve; a local short-acting anesthetic in said reservoir; steroids in said reservoirs; The local short-acting anesthetic and the steroid are dispensed from the tip of the dispenser, wherein the local short-acting anesthetic facilitates the steroid to penetrate the nerve membrane and enter the axon; a long-acting local anesthetic in said reservoir; The local long-acting anesthetic is dispensed from the tip of the dispenser and penetrates the nerve membrane and enters the axon; and The local long-acting anesthetic and the steroid cause precipitation and form a crystalline compound to produce a prolonged local nerve block.

14. An anesthetic nerve block as claimed in claim 13, wherein the steroid is selected from the group consisting of dexamethasone, betamethasone and triamcinolone.

15. A method for producing an anesthetic nerve block that interrupts the electrical potential of a nerve having an axon covered by a nerve membrane and relieves pain in a living organism, the method comprising the steps of: dispensing a local short-acting anesthetic from a dispenser to position the local short-acting anesthetic proximate to a nerve; dispensing a physiological carbonate base from a dispenser to position the physiological carbonate base proximate to a nerve, wherein the local short-acting anesthetic promotes the physiological carbonate base to penetrate the nerve membrane and enter the axon; and The local long-acting anesthetic is dispensed from a dispenser to position the local long-acting anesthetic near a nerve, wherein the local long-acting anesthetic penetrates the nerve membrane and enters the axon, and the local long-acting anesthetic and the physiological carbonate base cause precipitation and form a crystalline compound, which is used to produce a prolonged local nerve block.

16. A method for producing an anesthetic nerve block as claimed in claim 15, further comprising the step of dispensing epinephrine from a dispenser to determine any intravascular leak.

17. A method for producing an anesthetic nerve block as recited in claim 15, further comprising the step of dispensing saline solution to clean the dispenser.

18. A method for producing an anesthetic nerve block as set forth in claim 15, further comprising the step of dispensing a steroid from a dispenser to improve the formation of said precipitate and said crystalline compound to produce a prolonged local nerve block.

19. A method for producing an anesthetic nerve block that interrupts the electrical potential of a nerve having an axon covered by a nerve membrane and relieves pain in a living organism, the method comprising the steps of: dispensing a local short-acting anesthetic from a dispenser to position the local short-acting anesthetic proximate to a nerve; dispensing a local long-acting anesthetic from a dispenser to position the local long-acting anesthetic proximate to the nerve; and A physiological carbonate base is dispensed from a dispenser to position the physiological carbonate base near a nerve, wherein the local short-acting anesthetic promotes the physiological carbonate base to penetrate the nerve membrane and enter the axon, and wherein the local long-acting anesthetic penetrates the nerve membrane and enters the axon, and the local long-acting anesthetic and the physiological carbonate base cause precipitation and form a crystalline compound, which is used to produce a prolonged local nerve block.

20. A method for producing an anesthetic nerve block as claimed in claim 19, further comprising the step of dispensing epinephrine from a dispenser to determine any intravascular leak.

21. A method for producing an anesthetic nerve block as recited in claim 19, further comprising the step of dispensing saline solution to clean said dispenser.

22. A method for producing an anesthetic nerve block as set forth in claim 19, further comprising the step of dispensing a steroid from a dispenser to improve the formation of said precipitate and said crystalline compound to produce a prolonged local nerve block.

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