Methods of local perfusion for treating wound pain

Abstract

Described herein are methods and kits for locally treating pain in a patient in need thereof. The methods may include topically administering multiple doses of at least one pain management agent in a solution to a human patient by perfusing the at least one pain management agent at a wound, wherein the administration provides continuous pain treatment to the patient for at least 24 hours, at least 48 hours, at least 72 hours, or at least 96 hours.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 486,186, filed February 21, 2023, U.S. Provisional Application No. 63 / 493,577, filed March 31, 2023, U.S. Provisional Application No. 63 / 519,923, filed August 16, 2023, U.S. Provisional Application No. 63 / 596,130, filed November 3, 2023, and U.S. Provisional Application No. 63 / 613,533, filed December 21, 2023, the contents of each of which are incorporated by reference in their entirety.

[0002] The present disclosure relates generally to methods, kits, dosages, and concentrations for perfusion of pain management agents to living tissue. In particular, the disclosure relates to methods, kits, dosages, and concentrations for localized perfusion of pain management agents in and at wounds, including surgical wounds, traumatic wounds, wounds caused or exacerbated by infection, and wounds containing infected medical devices. [Background technology]

[0003] Musculoskeletal wounds are common and painful experiences, ranging in severity from minor abrasions and lacerations to major surgical or traumatic wounds with severe damage to the skin, subcutaneous tissue, and bone. While pain and healing of minor wounds may be partially addressed with over-the-counter analgesics or topical treatments, many of these treatments are short-term (<2, 4, 8, 12, 24, and / or 48 hours). However, treatment of severe wounds may involve surgical intervention, repeated debridement, delayed healing, and subsequent wound closure, as well as other painful complications over the long term. Patients with poor pain management in the postoperative period are likely to develop chronic pain, which may impair their functional status and quality of life. Severe or chronic wound pain is debilitating and has been a major contributing factor to widespread and dangerous addiction to systemic opioid analgesics, including serious complications such as cardiac arrhythmias, stroke, brain damage, coma, or death. Common, less severe complications of systemic opioid use include constipation, dizziness, sedation, nausea, vomiting, and / or respiratory depression.

[0004] Common local anesthetics and analgesics are short acting, making it very difficult to administer them over an extended period of time and protect a healing wound.

[0005] In view of the above, there exists a substantial unmet clinical need for localized pain management of wounds (e.g., over an extended period of time). There is also a need for optimal pain control to facilitate rehabilitation and prevent long-term morbidity. There is also an unmet need for novel methods for locally delivering pain management agents, alone or in combination with antimicrobial agents, over an extended period of time without introducing new potential routes of infection. Summary of the Invention

[0006] According to some embodiments of the disclosed subject matter, treatment methods, dosages, and concentrations of local anesthetic or analgesic therapy, including irrigation, are provided for the treatment of various wounds.

[0007] Provided herein are methods for treating pain for a patient in need thereof. The methods may include topically administering multiple doses of at least one pain management agent in solution to a human patient by perfusing the at least one pain management agent in the wound. The administration provides the patient with continuous pain treatment for at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or longer. The administration provides a serum concentration of the at least one pain management agent that is equal to or less than the maximum safe serum concentration level in a human patient. In some embodiments, the administration provides the patient with continuous pain treatment and / or relief for at least a 48-hour period, at least 3 days, 4 days, 5 days, 6 days, at least 7 days, or at least 10 days. In some embodiments, the administration described herein provides the patient with continuous pain relief from local wound pain and / or breakthrough pain for at least a 24-hour period, a 48-hour period, at least 3 days, 4 days, 5 days, 6 days, at least 7 days, or at least 10 days.

[0008] The perfusion may include alternating injection and suction cycles. The injection and suction cycles may be sequential or staggered (e.g., at different times). The perfusion device may be configured to automatically control the perfusion. The perfusion may include soaking the localized pain site with at least one pain management agent during a time interval between each alternating injection and suction cycle. The time interval may be equal to or less than the half-life or duration of activity of the at least one pain management agent. For example, the time interval may be less than 5 minutes, about 5 to about 60 minutes, about 10 to about 180 minutes, or about 30 to about 120 minutes. The suction cycle may be less than 60 minutes, less than 30 minutes, or less than 15 minutes.

[0009] In some embodiments, the perfusion is performed at least twice in 24 hours, at least four times in 24 hours, at least eight times in 24 hours, at least 16 times in 24 hours, or continuously for 24 hours.

[0010] The pain management agent may be an anesthetic or analgesic. In some embodiments, the pain management agent may be administered without epinephrine and / or without any second pain management agent. In some embodiments, the pain management agent may optionally include two or more pain management agents. In some embodiments, at least one anesthetic agent is an aminoamide selected from the group consisting of lidocaine, mepivacaine, prilocaine, bupivacaine, etidocaine, ropivacaine, levobupivacaine, and combinations thereof. In some embodiments, the topically administered dose of lidocaine is at least 250 mg in 24 hours, the topically administered dose of lidocaine is at a concentration of at least 250 mcg / mL, and the administration provides a serum concentration of lidocaine of less than 5 mcg / mL in a human patient. In another embodiment, the topically administered dose of lidocaine is at least 450 mg, 500 mg, 550 mg, or 600 mg in a 24-hour period (e.g., optionally without epinephrine and / or optionally without a second pain management agent), the topically administered dose of lidocaine is at a concentration of at least 500 mcg / mL, and the administration provides a serum concentration of lidocaine of less than 5 mcg / mL in a human patient. In another embodiment, the topically administered dose of lidocaine is at least 900 mg in a 24-hour period, and the topically administered dose of lidocaine in a 24-hour period exceeds the recommended daily dose of intravenously or systemically administered lidocaine in an adult human patient over a 24-hour period, or the topically administered daily dose of lidocaine is 300-3,000 mg in a 24-hour period, and the administration provides a serum concentration of lidocaine of less than 5 mcg / mL in a human patient. In another embodiment, the topically administered dose of lidocaine is at least 500 mg to 1,500 mg in a 24 hour period and the serum concentration of lidocaine is less than 2.5 mcg / mL in a human patient, or the serum concentration of lidocaine is less than 1.25 mcg / mL in a human patient.

[0011] In some embodiments, the anesthetic is an aminoester selected from the group consisting of benzocaine, chloroprocaine, procaine, tetracaine, and combinations thereof. In some embodiments, the anesthetic is an aminoamide selected from the group consisting of lidocaine, ropivacaine, and bupivacaine. In additional embodiments, the analgesic is an NSAID selected from the group consisting of ketorolac, meloxicam, and combinations thereof. For example, the topically administered dose of ketorolac is at least 60 mg per 24 hours. In further embodiments, the analgesic is a corticosteroid selected from the group consisting of prednisone, methylprednisolone (acetate and sodium succinate), dexamethasone, triamcinolone (acetonide), betamethasone, hydrocortisone, and combinations thereof.

[0012] In various embodiments, the wound is a local pain site, a topical wound, a diabetic ulcer, a traumatic wound, a surgical wound, a subcutaneous surgical wound, or a subcutaneous surgical wound containing an implanted medical device. The implanted medical device may be an orthopedic implant such as a joint replacement prosthesis. In some embodiments, continuous pain treatment may be provided up to at least 1 cm, 2 cm, 3 cm, 5 cm, 10 cm, or 15 cm from the wound (e.g., a local radius of pain treatment in centimeters from the center of the wound or the site of local administration). Perfusion and / or continuous pain treatment may occur at the perimeter of a superficial or subcutaneous wound (e.g., within the two-dimensional surface perimeter of the wound or within the three-dimensional perimeter of the wound).

[0013] In some embodiments, the method may further include locally administering at least one additional therapeutic agent for the treatment of a condition other than pain. The at least one additional therapeutic agent may be at least one antibacterial agent. The at least one antibacterial agent may be one or more antibiotics, two or more antibiotics, or two or more antibacterial agents of different classes. In some embodiments, the two or more antibiotics may include vancomycin and tobramycin, vancomycin and gentamicin, daptomycin and tobramycin, or daptomycin and gentamicin. The two or more antibiotics may be administered simultaneously, sequentially, or at different times. In some embodiments, the at least one pain management agent is lidocaine, and the lidocaine and vancomycin are administered simultaneously, and the tobramycin or gentamicin is administered sequentially to the simultaneously administered lidocaine and vancomycin. The serum concentrations of lidocaine, vancomycin, and tobramycin or gentamicin remain below the recommended safe serum concentrations of lidocaine, vancomycin, and tobramycin or gentamicin throughout the entire administration period. In another embodiment, at least one pain management agent is lidocaine, lidocaine and daptomycin are administered simultaneously, and tobramycin or gentamicin is administered sequentially to the simultaneously administered lidocaine and daptomycin. The serum concentrations of lidocaine, daptomycin, and tobramycin or gentamicin remain below the recommended safe serum concentrations of lidocaine, daptomycin, and tobramycin or gentamicin throughout the entire administration period.

[0014] In some embodiments, the at least one pain management agent is administered sequentially with the at least one antibacterial agent. In other embodiments, the at least one pain management agent is administered simultaneously with the at least one antibacterial agent. The local administration may be provided for 1 to 10 days, 2 to 10 days, 3 to 10 days, at least 1 day, at least 2 days, or at least 3 days. In some embodiments, the at least one pain management agent is in a solution comprising saline. The solution may be epinephrine-free.

[0015] In some embodiments, the concentration of the at least one pain management agent exceeds the maximum recommended concentration of the at least one pain management agent. Local administration may include perfusion of the local wound by soaking with the at least one pain management agent, and aspirating the at least one pain management agent after a period of time.

[0016] Also provided herein are kits for managing localized pain in a human patient, which may include at least one pain management agent, a therapeutic delivery system and / or perfusion device configured to locally perfuse a localized pain site with at least one dose of the at least one pain management agent in solution, and instructions for administering the at least one dose of the at least one pain management agent to provide the patient with continuous pain relief for at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, or longer.

[0017] The at least one pain management agent in the kit may be lidocaine. The therapeutic delivery system and / or perfusion device may be configured to locally administer a total dose of 250 mg or more of lidocaine over a 24-hour period. In some embodiments, the at least one pain management agent may be lidocaine, and the kit further includes at least one antibacterial agent. For example, the at least one antibacterial agent may be an antibiotic selected from vancomycin, daptomycin, tobramycin, and / or any antibiotic known in the art. The at least one pain management agent may be in a solution containing saline. The solution may be epinephrine-free.

[0018] The perfusion device may be configured so that it is not removed from the patient until administration is complete. In some embodiments, the perfusion device is configured to be applied to a wound or localized pain site for more than 48 hours, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or at least 10 days. In some embodiments, the perfusion device is not a sponge. In some embodiments, the perfusion device includes a local perfusion component (e.g., an irrigation tube, a fenestrated implant, a dressing, a sponge, a drain, a cannula, or a suction tube).

[0019] Further provided herein is a method for treating local pain in a wound of a human patient.The method may comprise locally administering to a human patient by perfusion repeated doses of at least two therapeutic agents from separate sources without interruption for changing sources.One of the two or more therapeutic agents is at least one pain management agent, and / or one of the two or more therapeutic agents is at least one antibacterial agent.In some embodiments, the two or more therapeutic agents may be administered sequentially, simultaneously, or at different times.

[0020] Further provided herein is a method for treating local pain and infection in a human patient in need of treatment. The method may include locally administering repeated doses of two therapeutic agents from separate sources to a human patient by perfusion without interruption to change sources, wherein one of the two or more therapeutic agents is at least one pain management agent and at least one antibacterial agent. In some embodiments, the at least one antibacterial agent is at least one antibiotic. In other embodiments, the at least one antibacterial agent is at least two antibiotics. For example, the at least one pain management agent may be lidocaine, and the at least two antibiotics may be vancomycin and tobramycin. The lidocaine and vancomycin may be administered simultaneously, or the tobramycin may be administered sequentially to the simultaneously administered lidocaine and vancomycin. In some embodiments, the lidocaine and vancomycin are administered from a common source.

[0021] Also provided herein is a method for treating localized pain and infection in a human patient in need thereof, comprising locally administering to the human patient by perfusion at least one pain management agent and at least two antibacterial agents, hi some embodiments, the at least one pain management agent can be lidocaine, and the at least two antibacterial agents can be vancomycin and tobramycin.

[0022] These and other aspects are described in detail with reference to the following drawings. [Brief explanation of the drawings]

[0023] [Figure 1A] FIG. 1A shows an example of a therapeutic delivery system and kit. [Figure 1B] FIG. 1B shows a detailed view of the therapeutic delivery system and kit of FIG. 1A. DETAILED DESCRIPTION OF THE INVENTION

[0024] The disclosed subject matter relates to locally administered pain management agents (e.g., anesthetics and analgesics) to improve pain management in wounds, including infected wounds. Disclosed herein are dosing regimens and methods for safely administering repeated or cyclical doses and concentrations of anesthetics or analgesics. Also disclosed are methods for administering doses of anesthetics and analgesics at concentrations higher than previously achieved with systemic therapy, while maintaining the patient's systemic exposure at levels below safe systemic concentration limits. The methods described herein fulfill the needs set forth herein above. For example, the methods described herein offer new opportunities for previously unattainable safe and effective local delivery of therapeutic agents, such as anesthetics and analgesics, via the perfusion route of administration, thereby maximizing the effectiveness of local pain management and minimizing the risks associated with exposure of wounds to concentrated therapeutic agents and environments during treatment.

[0025] Successful local pain management depends on the exposure of the wound to the anesthetic or analgesic, including the dose, concentration, and duration of exposure, which are prescribed based on the specific anesthetic or analgesic used, the mechanism of action, and the pharmacodynamic target of the anesthetic or analgesic. The effectiveness of pain management in a clinical setting is determined by the patient's response to the treatment and the patient's confirmation of effective eradication of pain. To address the highly variable efficacy of treatments and patient responses to similar pain sources and pain levels, within safety limits, systemic pain management medications are frequently transferred to the patient. Systemic analgesics are often prescribed for patient use on an as-needed basis, and in acute care settings, patients frequently control the delivery of intravenous analgesics. Anesthetics and analgesics are commonly used topically for a wide range of indications, and local infusion of anesthetics or analgesics in solution is often applied during or upon completion of surgical treatment of open wounds. However, because the infusion is unidirectional (neither the injected anesthetic nor the analgesic is aspirated or washed away from the infection site), and the unidirectional infusion dose is absorbed into the tissues and bloodstream, local and systemic toxicity considerations limit the local dose and concentration that can be safely administered by infusion. Complications of commonly used local anesthetics can be life-threatening. For example, complications of lidocaine toxicity include seizures, loss of consciousness, respiratory collapse, and myocardial dysfunction. Complications of ketorolac include acute toxicity, abnormal bleeding, hepatotoxicity, acute kidney injury (AKI), thrombotic events, myocardial infarction, and stroke.

[0026] The present disclosure represents a significant improvement and departure from previous methods, as it involves one or more safe and effective doses of at least one pain management agent delivered via perfusion (e.g., injection followed by aspiration) to a localized wound (e.g., traumatic wound, surgical wound, ulcer) in a human patient in need of treatment. Serious complications from the use of systemic opioids and other pain management agents may be substantially reduced or eliminated through the use of local pain management agents. Such safe and effective pain management via perfusion is achieved by injecting a sufficiently high concentration of the pain management agent, allowing the wound to soak for a sufficient period of time for the perfusion fluid / pain management agent to be effective, and then aspirating the pain management agent from the wound frequently enough to maintain safe systemic exposure to the perfusion fluid / pain management agent (e.g., avoiding systemic toxicity). This perfusion cycle can then be repeated within a time period before the effects of the pain management agent wear off. Thus, in certain embodiments, the one or more doses of at least one pain management agent at or above the minimum effective dose delivered to the localized wound may be bidirectional or multidirectional, rather than unidirectional. The injection and aspiration cycles may be performed sequentially or staggered.

[0027] In some embodiments, localized periodic administration provides continuous pain treatment to patients over a period of time. Continuous pain treatment may include continuous pain relief reported by the patient, the absence of breakthrough pain, pain relief, or no pain reported by the patient over that period. In various embodiments, localized administration according to any of the disclosed methods may result in a 10% or greater reduction in pain reported using a numerical rating scale (NRS), a 20% or greater reduction in NRS, a 50% or greater reduction in NRS, a 75% or greater reduction in NRS, an 80% or greater reduction in NRS, a 90% or greater reduction in NRS, or 100% (e.g., complete) elimination of pain reported using the NRS. In other words, localized administration according to any of the disclosed methods may result in a 1-point, 2-point, 3-point, 4-point, 5-point, 6-point, 7-point, 8-point, 9-point or greater reduction in pain reported using the NRS. In some embodiments, pain treatment may include reducing or eliminating the need for systemic analgesics, including reducing or completely eliminating systemic analgesics administered by a medical professional, patient-controlled systemic analgesics (including opioid analgesics), one or more days, two or more days, or three or more days after local administration of at least one pain management agent by perfusion. In some instances, local pain may be considered eliminated by treatment with the disclosed methods.

[0028] The period of time with continuous pain treatment and / or relief may be at least 24 hours, at least 48 hours, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, or at least 10 days.

[0029] In another embodiment, the present disclosure provides an improvement over prior methods by providing concentrations and doses of locally administered anesthetic or analgesic agents that exceed recommended safe systemic concentrations and doses, but do not provide unsafe systemic plasma concentration levels in human patients. Perfusion may include bathing the localized pain site with at least one pain management agent during the time interval between each alternating injection and aspiration cycle. For example, the pain management agent may be administered at a bathing time interval that is equal to or less than the half-life or active period of the locally administered pain management agent. The injection portion of the pain management agent perfusion may occur at intervals that are equal to or less than 10%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 150%, or 200% of the half-life or active period of the pain management agent. The therapeutic activity of a pain management agent may differ from the half-life or active period of the pain management agent. In some instances, the active period of the pain management agent may be longer than the half-life. The infusion portion of the perfusion of the pain control agent may occur at intervals that are less than 25%, less than 50%, less than 75%, or less than 100% of the effective duration of activity of the pain control agent.

[0030] In other examples, the soaking time may be a fixed time of 5 minutes or more, 10 minutes or more, 20 minutes or more, 30 minutes or more, 60 minutes or more, 120 minutes or more, 180 minutes or more, or 240 minutes or more. In other examples, the soaking time may be less than 180 minutes, less than 120 minutes, less than 60 minutes, less than 30 minutes, or less than 20 minutes. In other examples, the soaking time interval between each injection and aspiration cycle may be less than 5 minutes, 5 to 60 minutes, about 10 to about 180 minutes, about 30 to about 120 minutes, or about 60 to about 90 minutes. The aspiration cycle may be less than 180 minutes, less than 120 minutes, less than 90 minutes, less than 60 minutes, or less than 30 minutes.

[0031] As the concentration of the at least one pain management agent increases, the time between the injection and aspiration phases of perfusion may be decreased to maintain a safe serum concentration.

[0032] The present disclosure further provides methods for maintaining an effective concentration of at least one pain management agent at or above the minimum effective dose at a localized wound site in a human patient by repeating the perfusion cycle two or more, three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, or twelve or more times per day, hourly, or more frequently. In other examples, the perfusion is performed at least two, at least four, at least eight, at least sixteen times, or continuously in a 24-hour period. Continuous perfusion includes sequential infusion and aspiration cycles with no time between the previous infusion and the next aspiration cycle.

[0033] The effectiveness of unidirectional injection methods is limited by the potential toxicity of sustained concentrations of anesthetic or analgesic agents delivered to achieve a pharmacodynamic target. Local perfusion tailored to the specific pharmacodynamics and pharmacokinetics of each anesthetic or analgesic overcomes this previous limitation. Several classes of anesthetic and analgesic agents may be suitable for local wound perfusion, including, but not limited to, aminoamides (e.g., lidocaine, bupivacaine, ropivacaine, or combinations thereof), aminoesters (e.g., benzocaine, chloroprocaine, procaine, tetracaine, or combinations thereof), NSAIDs (e.g., ketorolac, meloxicam, or combinations thereof), corticosteroids (e.g., prednisone, methylprednisolone (acetate and sodium succinate), dexamethasone, triamcinolone (acetonide), betamethasone, hydrocortisone, or combinations thereof), and combinations thereof. Those skilled in the art will appreciate that the perfusion methods provided herein may be used to administer each of the aforementioned anesthetic and analgesic agents to provide safe and effective pain management of wounds by adjusting the volume, concentration, soak time, time to drain, and cycle frequency to optimally match the pharmacodynamics and pharmacokinetics of the anesthetic or analgesic agent being administered.

[0034] This method allows for the administration of a total daily dose of at least one pain management agent that is greater than that recommended for safe systemic administration.In one example, the dose of the pain management agent administered locally in 24 hours exceeds the recommended daily systemic dose of the pain management agent in an adult human patient in 24 hours.The recommended daily dose may be the dose recommended for administration to an adult human patient intravenously, orally, or by injection.The total daily dose or amount may be the sum of the multiple doses administered during that period. In some embodiments, the daily dose / amount provided by topical administration may be 10 mg or more per day, 50 mg or more per day, 100 mg or more per day, 200 mg or more per day, 300 mg or more per day, 400 mg or more per day, 500 mg or more per day, 600 mg or more per day, 700 mg or more per day, 800 mg or more per day, 900 mg or more per day, 1000 mg or more per day, 1500 mg or more per day, 2000 mg or more per day, 2500 mg or more per day, or 3000 mg or more per day of at least one pain management agent. In some examples, the pain management agent may be topically administered for at least 12 hours, and the daily dose / amount provided by topical administration may be about half of the amount topically administered in 12 hours.

[0035] In some examples, the topically administered dose (total amount) of lidocaine, bupivacaine, or ropivacaine is at least 200 mg, at least 250 mg, at least 270 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 550 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1000 mg, at least 1500 mg, at least 2000 mg, at least 2500 mg, or at least 3000 mg in a 24-hour period. In other examples, the topically administered daily dose of lidocaine is 300-3,000 mg, at least 250 mg-600 mg, or at least 500 mg-1,500 mg in a 24-hour period. In other embodiments, the maximum daily dose provided by topical administration of ketorolac may be greater than 50 mg per day, greater than 100 mg per day, greater than 200 mg per day, greater than 300 mg per day, greater than 400 mg per day, or greater than 500 mg per day. In one example, the topically administered dose of ketorolac is at least 60 mg in 24 hours. In one example, the topically administered dose / amount of toradol is at least 15 mg, at least 50 mg, at least 100 mg, or up to 120 mg in 24 hours.

[0036] Table 1 provides recommended dosages of common anesthetics and analgesics administered systemically. Table 2 provides examples of anesthetic, NSAID, and corticosteroid additions and dosage ranges per 1200 mL. In this example, the "typical" dose is the maximum recommended systemic dose. Table 3 provides an example of an anesthetic concentration. [Table 1] [Table 2] [Table 3]

[0037] The volume of anesthetic or analgesic administered may be sufficient to expose the entire surface of the wound throughout the soaking period. The dose volume administered for each soaking step may be about 5 cc, about 10 cc, about 20 cc, about 30 cc, about 40 cc, about 50 cc, about 60 cc, about 70 cc, about 80 cc, about 90 cc, about 100 cc, or more than 100 cc. In some embodiments, continuous pain treatment may be provided within a subcutaneous wound volume of at least 5 cc, at least 10 cc, 25 cc, 50 cc, 75 cc, or 100 cc, or at a depth of at least 1 cm, 2 cm, 3 cm, 5 cm, 10 cm, or 15 cm below the skin (e.g., small or large anatomical joint cavities, or small or large surgical wounds). In other examples, continuous pain treatment may be delivered superficially / superficially to the local wound bed, down to the superficial layer.

[0038] Perfusion may be performed at least once a day, at least twice a day, at least five times a day, at least 10 times a day, at least 15 times a day, at least 20 times a day, at least 21 times a day, or at least 22 times a day. In one example, an anesthetic or analgesic may be perfused at the wound site every hour for 20 to 22 hours. In some examples, two or more anesthetic or analgesic agents may be perfused at the wound site simultaneously or sequentially. Two or more anesthetic or analgesic agents may be perfused at different frequencies. For example, one may be perfused hourly for 12 to 24 hours, and a second may be perfused once or twice a day.

[0039] The daily dose of the at least one anesthetic or analgesic agent may substantially exceed the maximum recommended daily systemic dose of the at least one anesthetic or analgesic agent. Substantially exceeding the maximum recommended daily systemic dose of the at least one anesthetic or analgesic agent may include a daily dose that exceeds the maximum recommended daily systemic dose by at least 125%, at least 150%, at least 175%, at least 200%, at least 225%, at least 250%, at least 275%, at least 300%, at least 400%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, at least 1,000% or more.

[0040] In some embodiments, the at least one anesthetic agent is lidocaine. The locally administered concentration of lidocaine may be at least 250 mcg / mL, at least 500 mcg / mL, at least 750 mcg / mL, or at least 1,000 mcg / mL. The maximum recommended daily systemic dose of lidocaine is 300 mg / day. The total dose of lidocaine administered over all administration days may range from about 1 g to 2 g, about 2 g to 4 g, about 4 g to 6 g, about 6 g to 8 g, or about 8 g to 10 g.

[0041] Although high concentrations are administered locally, an advantage of the disclosed methods is that the serum concentration of the anesthetic or analgesic is maintained below the maximum safe level. Thus, the patient benefits from a high concentration of the anesthetic or analgesic while maintaining safe serum levels and minimizing side effects to the patient. The maximum safe serum concentration of lidocaine may be approximately 5 mcg / mL. In some examples, the serum concentration of lidocaine when administered according to the disclosed methods is less than 5 mcg / mL, less than 4 mcg / mL, less than 3 mcg / mL, less than 2.5 mcg / mL, less than 2 mcg / mL, or less than 1.25 mcg / mL. The serum concentration is the concentration of the pain management agent in the patient's blood serum obtained from an intravenous sample taken anywhere in the body to determine systemic toxicity.

[0042] In at least one embodiment, the serum level or serum concentration of the pain management agent is undetectable. In some embodiments, administration provides a serum concentration of the pain management agent in a human patient that is less than 5 mcg / mL, less than 2.5 mcg / mL, less than 1.25 mcg / mL, or below the limit of detection. In one example, a locally administered dose of lidocaine has a concentration of at least 250 mcg / mL, and administration provides a serum concentration of lidocaine of less than 5 mcg / mL in a human patient. In another example, a locally administered dose of lidocaine has a concentration of at least 500 mcg / mL, and administration provides a serum concentration of lidocaine of less than 5 mcg / mL in a human patient. In yet another example, a locally administered daily dose of lidocaine is 300 mg to 3,000 mg in a 24-hour period, and administration provides a serum concentration of lidocaine of less than 5 mcg / mL in a human patient.

[0043] The methods described herein may locally treat pain in a wound in a patient in need of treatment. The wound may be the site of localized pain in the patient. The method may alleviate pain throughout the wound or within a radius of the wound. The radius of the wound may be at least 1 cm, at least 5 cm, at least 10 cm, or at least 15 cm from the center of the wound (or the site of topical administration). In some examples, perfusion or pain treatment may occur within the two-dimensional or three-dimensional perimeter of the wound. In some examples, the wound may be a topical wound or a subcutaneous wound. In other examples, the wound may be a chronic wound. Chronic wounds include various wounds that may be classified into several categories, including traumatic wounds, surgical wounds, ulcers of various causes, and burns. Traumatic wounds include abrasions and lacerations, penetrating wounds, compound fractures, and blast wounds. Chronic surgical wounds may occur at any surgical site and include incisional wounds and deep surgical wounds, including fistulas. Chronic ulcers include pressure ulcers, diabetic foot ulcers, vasculitic ulcers, arterial ulcers, and venous stasis ulcers. Chronic burn wounds can occur anywhere on the body and vary greatly in size and severity. Surgical wounds and previously surgically treated traumatic wounds may also contain implanted medical devices within the wound. For example, surgical wounds may be subcutaneous surgical wounds, and subcutaneous surgical wounds may in some cases contain implanted medical devices. In some cases, implanted medical devices may be orthopedic implants such as joint replacement prostheses.

[0044] In some embodiments, the method may further include locally administering at least one additional therapeutic agent for the treatment of conditions other than pain. Chronic wounds are frequently complicated by the presence of infection. Musculoskeletal infections are often polymicrobial and biofilm-forming, and identification of the pathogen(s) is usually achieved using tissue culture 7 to 14 days after the initiation of treatment. In a significant minority of cases, the pathogen is not identified by tissue culture methods, and recent studies using genetic sequencing techniques have identified multiple microorganisms in both culture-negative cases and cases in which a single pathogen was identified by tissue culture. In some instances, the at least one additional therapeutic agent is at least one antibacterial agent. Thus, administering one or more antibacterial agents in addition to an anesthetic or analgesic for pain management may provide additional benefits in local wound management.

[0045] Broad-spectrum systemic antibiotic therapy for localized infections is the standard first-line treatment, especially when the pathogen has not yet been identified or when polymicrobial infection is likely. In cases of infections in the presence of implanted devices, such as periprosthetic joint infections (PJIs), breast implant infections (BIIs), or fracture-related infections (FRIs), broad-spectrum therapy that exceeds the biofilm bactericidal concentration (BBC) or minimum biofilm eradication concentration (MBEC) for all identified or potential pathogens is preferred. Preclinical studies to quantify the BBC and MBEC of antibiotics for pathogens found in localized human infections are not comprehensive. Given the large number of potential antibiotics and known pathogens, the BBC and MBEC values ​​identified to date far exceed the safe systemic doses and concentrations of commonly tested antibiotics, making practical application of such studies unlikely. In many reports where testing to establish MBEC values ​​was limited to clinically recommended doses or concentrations, the concentrations of antibiotics tested were found not to eradicate specific microbial biofilms, leaving the MBEC for the specific antibiotics and microbial strains tested unknown. Therefore, it is desirable to locally perfuse antibiotics at concentrations above the MBEC for common wound infections while maintaining safe serum concentrations.

[0046] Broad-spectrum antibiotic therapy for localized infections typically includes a glycopeptide (e.g., vancomycin hydrochloride) for Gram-positive coverage and an aminoglycoside (e.g., gentamicin sulfate or tobramycin) for Gram-negative coverage. Safe dosages and systemic concentrations of these and other antibiotics are shown in Table 4. [Table 4]

[0047] In polymicrobial infections, the pathogens involved may include Gram-positive and Gram-negative bacteria, fungi, or any combination of these pathogens. In such cases, and in culture-negative infections (i.e., where no pathogen is identified), it is best practice to administer multiple antimicrobial agents to achieve the broadest possible coverage. In addition to adequate local pain management, what is clinically needed is a systemically safe antibiotic therapy that provides local broad-spectrum biofilm eradication under such highly variable clinical conditions.

[0048] The at least one antimicrobial agent may be administered locally by perfusion in a manner similar to the perfusion of the at least one pain management agent. The at least one pain management agent may be administered sequentially and / or simultaneously with the at least one antimicrobial agent. In some embodiments, the at least one antimicrobial agent is two or more antibiotics. The two or more antibiotics may be administered sequentially. In some instances, a first antibiotic may be administered concurrently with the at least one pain management agent, and a second antibiotic may be administered sequentially after the administration of the first antibiotic and the at least one pain management agent.

[0049] In some embodiments, the two or more antibiotics may include vancomycin and tobramycin, and the at least one pain management agent may be lidocaine. In one example, the lidocaine and vancomycin may be administered simultaneously, and the tobramycin may be administered sequentially to the simultaneously administered lidocaine and vancomycin, while the serum concentrations of each of the lidocaine, vancomycin, and tobramycin remain below the recommended safe serum concentrations of each of the lidocaine, vancomycin, and tobramycin throughout the entire administration period.

[0050] As a route of administration, irrigation is defined as administration to bathe or flush an open wound or body cavity. By controlling the irrigation dose, i.e., concentration, volume, and duration of exposure (soaking or irrigation), novel methods have been developed for treating local pain in the presence of local infection in human patients. The irrigation concentration or total irrigation dose of vancomycin and tobramycin may exceed the concentrations recommended by the manufacturer. Furthermore, the dose and concentration required to achieve the biofilm-forming organism's BBC (biofilm bactericidal concentration) or MBEC (minimum biofilm eradication concentration) vary depending on the organism, biofilm maturity, biofilm location, the implant or tissue to which the biofilm is attached, the dilution and absorption rate of the antibiotic at the irrigation site, and other factors. In one embodiment, provided herein is a method for treating a local infection in a wound in a human patient in need of treatment. The novel method described herein involves the simultaneous or sequential continuous administration of one or more anesthetics or analgesics and one or more antimicrobial agents (preferably antibiotics) via the irrigation route of administration. Optimal effectiveness of this novel method is achieved when the dose and concentration of each anesthetic or analgesic and each antimicrobial agent are administered based on the pharmacodynamics and pharmacokinetics of the administered drug. In certain embodiments of the present invention, one or more of the drugs administered by perfusion are administered at a dose and / or concentration that exceeds the previously established safe systemic dose and / or concentration of the drug while still providing a safe systemic (serum) concentration of the drug. Various antibiotics used to treat infections and biofilms can be used with the disclosed method. Non-limiting examples of antibiotics include aminoglycosides, glycopeptides, cyclic lipopeptides, vancomycin, tobramycin, gentamicin, daptomycin, and combinations thereof.

[0051] The daily dose of at least one pain management agent and at least one antibacterial agent may comprise a single administration or multiple administrations per day.For example, the daily dose may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 times per day.In some examples, the daily dose of at least one pain management agent and at least one antibacterial agent may be administered sequentially and / or simultaneously for at least 1, at least 2, at least 5, at least 10, at least 15, at least 20, or at least 24 administrations. Dosing may be every 30 minutes or less, about every hour, about every 2 hours, about every 3 hours, about every 4 hours, about every 5 hours, about every 6 hours, about every 7 hours, about every 8 hours, about every 9 hours, about every 10 hours, about every 12 hours, about every 18 hours, or about every 24 hours.

[0052] The daily dose may include multiple administrations, such as administering at least one pain management agent in series with at least one antimicrobial agent, with at least one dose of the combination therapy for wound pain and infection considered to be the entirety of both sequential administrations. Alternatively, the daily dose may include a single daily administration of at least one therapeutic agent, and the daily dose of the combination therapy may include single or multiple administrations per day. In some embodiments, at least one anesthetic or analgesic agent may be administered simultaneously with at least one antimicrobial agent, followed by sequential administration of at least one additional antimicrobial agent to provide both pain relief and broad-spectrum antimicrobial coverage. Specifically, one embodiment may include simultaneous administration of lidocaine and vancomycin (or daptomycin) and sequential administration of tobramycin (or gentamicin).

[0053] Alternatively, the daily dose may include a single daily administration of at least one therapeutic agent, followed sequentially for the remainder of the day by multiple administrations of at least one additional therapeutic agent. In one embodiment, the single daily administration includes administration of tobramycin, allowing a 2-hour soak followed by a 30-minute suction, and the multiple sequential administrations include co-perfusion of lidocaine and vancomycin, allowing a 30-minute soak followed by a 30-minute suction, repeated for the remainder of the day, at which point the single daily administration of tobramycin is repeated to begin a new day of combination therapy. This particular perfusion regimen is tailored to the pharmacodynamic targets of each administered drug, specifically tobramycin Cmax / MIC, vancomycin AUC / MIC, and lidocaine's anesthetic effect (60-90 minutes).

[0054] Irrigating the wound may involve soaking the biological tissue with the antibiotic for about 10 minutes to about 180 minutes, about 30 minutes to about 180 minutes, about 30 minutes to about 45 minutes, about 30 minutes to about 60 minutes, about 60 minutes to about 90 minutes, about 60 minutes to about 120 minutes, or about 120 minutes to about 180 minutes. In various examples, irrigating the wound may involve soaking with the antibiotic for 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, or 180 minutes. For tobramycin, a 120-minute soak time is optimal. For other agents, such as vancomycin or lidocaine, the optimal soak time depends on the concentration administered, and both variables may be adjusted to administer higher concentrations for effective pain management or bacterial eradication while maintaining safe systemic exposure levels (determined by serum concentrations).

[0055] Administration of local anesthetic or analgesic, with or without additional antimicrobial agents, may be performed for one or more days as needed to provide the necessary pain relief. Perfusion may be performed for 1 or more days, 2 or more days, 3 or more days, 4 or more days, 5 or more days, 6 or more days, 7 or more days, 8 or more days, 9 or more days, 10 or more days, 14 or more days, or 30 or more days. Local administration may be repeated for up to 10 additional days (e.g., with replacement of the perfusion device between repeated administration periods).

[0056] Further provided herein is a method for treating local pain in a wound of a human patient in need of treatment by locally administering repeated doses of at least two therapeutic agents from separate sources to the human patient by perfusion without interruption for changing sources. In one embodiment, one of the two or more therapeutic agents is at least one pain management agent. In another embodiment, one of the two or more therapeutic agents is at least one antibacterial agent. In a further embodiment, one of the two or more therapeutic agents is at least one pain management agent and at least one antibacterial agent. In some examples, the two or more therapeutic agents are administered sequentially, simultaneously, or in combination thereof. The at least one antibacterial agent may be at least one antibiotic or at least two antibiotics. For example, the at least one pain management agent is lidocaine, and the at least two antibiotics are vancomycin and tobramycin. The lidocaine and vancomycin may be administered simultaneously from a first source, and the tobramycin may be administered from a second source sequentially to the simultaneously administered lidocaine and vancomycin. Lidocaine and vancomycin are administered from a common source.

[0057] Further provided herein is a method of treating localized wound pain in a human patient by locally administering to the human patient by perfusion at least one anesthetic or analgesic agent at a concentration that exceeds the recommended concentration or maximum recommended daily dose of the at least one anesthetic or analgesic agent, whereby the local administration by perfusion provides a serum concentration that is less than the maximum safe serum concentration of the at least one anesthetic or analgesic agent.

[0058] In certain embodiments, the method may include locally administering to a human patient a dose substantially exceeding the recommended safe dose of at least one anesthetic or analgesic, or a dose substantially exceeding the recommended safe dose of at least one antibiotic, and providing a serum concentration of the anesthetic, analgesic, and antibiotic that is less than or equal to the maximum safe serum concentration. In some embodiments, the recommended safe dose is the maximum recommended systemic daily dose.

[0059] In one method, 50 cc of lidocaine at a concentration of 250 mcg / mL may be administered hourly for 22 hours for 7 days, sequentially with 50 cc of tobramycin at a concentration of 1,600 mcg / mL administered once daily, simultaneously with vancomycin at a concentration of 2,500 mcg / mL. The daily doses in this method are 275 mg of lidocaine, 80 mg of tobramycin, and 2,750 mg of vancomycin, for a total dose of about 1.925 g of lidocaine, about 0.56 g of tobramycin, and about 19.25 g of vancomycin, with fixed dose ratios of lidocaine to vancomycin and tobramycin of 1:10 and 3.44:1, respectively. The maximum dose and concentration that may be administered are pharmacokinetically calculated based on known values ​​of selected daily exposure and pharmacokinetic parameters, and such doses and concentrations may be empirically adjusted before or during administration for patients with abnormal antibiotic absorption or elimination.

[0060] In one method, one or more anesthetic or analgesic agents may be administered at a previously known safe dose at a concentration that exceeds the previously known safe concentration of the anesthetic or analgesic agent, while still providing a clinically established safe systemic level of the anesthetic or analgesic agent. This may be achieved by irrigating the wound less frequently per day with the higher concentration, thereby administering a daily dose that remains within the previously known safe limits. In another method, one or more anesthetic or analgesic agents may be administered at a daily dose that exceeds the previously known safe daily dose at a concentration within the known safe limits, while still providing a clinically established safe systemic level of the anesthetic or analgesic agent. This may be achieved by irrigating the wound more frequently per day within the previously known safe concentration limits, thereby administering a daily dose that exceeds the previously known safe limits. In either case, safe serum levels may be maintained by adjusting the soak time and drain time of each dosing cycle to limit systemic absorption of each anesthetic or analgesic agent.

[0061] When two or more therapeutic agents are administered in the methods described herein, they may be administered at a fixed dose ratio of less than, greater than, or equal to 1:1. However, it may be beneficial to administer the therapeutic agents at a fixed dose ratio that exceeds previously established maximum dose ratios. For example, based on the 5th and 95th percentiles of patient weight in the United States, the minimum and maximum recommended daily systemic doses of vancomycin are approximately 1,200 g and 7,500 g, respectively, and the minimum and maximum recommended daily systemic doses of tobramycin are approximately 200 g and 1,250 g, respectively. Therefore, the resulting recommended fixed dose ratio of vancomycin to tobramycin is 6:1. The methods disclosed herein describe administering antibiotics that equal or exceed the MBEC (minimum biofilm eradication concentration) for the target organism while maintaining safe systemic levels of the antibiotic. In such cases, the fixed dose ratio may exceed known systemic dose ratios. In one method, the dose ratio of vancomycin to tobramycin is 40:1. In another method, the fixed dose ratio of vancomycin to tobramycin is 125: 1. In yet another method, the fixed dose ratio of vancomycin to tobramycin is 10: 1.

[0062] Not all therapeutic agents may be administered simultaneously. This may be due to incompatibility of certain therapeutic agents or differences in their pharmacodynamic targets. For example, tobramycin is administered for an optimal concentration-dependent target with an optimal exposure of 2 hours at therapeutic concentrations, whereas vancomycin is administered with an optimal pharmacodynamic target of AUC / MIC or total daily exposure. An additional advantage of the methods and perfusion administration routes described herein is that they allow for simultaneous or sequential administration of multiple solutions from multiple sources that equal or exceed the therapeutic target without interruption or input from the patient or user to change the source of incompatible therapeutic agents.

[0063] While the doses, concentrations, and methods described herein may be described in the context of a particular wound, other wounds or conditions are contemplated as well. For example, even if a method is described as being useful for periprosthetic joint infections, the method may also be used for other infected wounds, such as breast implant infections, fracture-related infections, diabetic ulcers, osteomyelitis, surgical site infections, etc. The anesthetic and analgesic agents and methods described herein may be configured for use with a wide variety of topical wounds and treatment sites other than those specifically listed herein.

[0064] The treatment methods described herein may be performed manually (e.g., injection with a syringe and drainage with a gravity drain), semi-automatically (e.g., injection with a syringe pump and aspiration with an active drainage device), or automatically (e.g., via a dedicated perfusion delivery system). The perfusion delivery system may control perfusion (e.g., delivery and removal of a local therapeutic anesthetic or analgesic) according to a set protocol including one or more sequential stages for delivery at one or more times and durations per day.

[0065] Also provided herein is a perfusion device for treating a localized wound in a human patient in need of treatment. The perfusion device may be configured to automatically control perfusion. The perfusion device may be configured to locally administer a daily dose of at least one anesthetic or analgesic agent for up to 24 hours without interruption or input from the patient or user. In certain embodiments, the perfusion device may be configured to include two or more independent sources of therapeutic agent from which the perfusion device draws therapeutic agent according to various cycle times and frequencies described herein. In some embodiments, the perfusion device delivers therapeutic agent sequentially, simultaneously, alternatingly, or cyclically from the independent sources according to various cycle times and frequencies without any human intervention to change sources, connect the perfusion device to each source, or access or control the flow of therapeutic agent.

[0066] In some embodiments, the perfusion device may further include a suction component. The suction component may be configured to apply suction to or around the wound to remove residual drug at the site of infection. For example, the suction component may be configured to apply a negative pressure of at least -50 mmHg to the living tissue.

[0067] Also disclosed herein are kits for treating localized wound pain in a human patient. The kit may include at least one pain management agent, a therapeutic delivery system and / or perfusion device configured to locally perfuse (inject and aspirate) a series of doses of the at least one pain management agent, and instructions for administration. The instructions may include instructions for administering at least one dose of the at least one pain management agent to provide the patient with continuous pain relief for at least a 24-hour period. It is further contemplated that the instructions may include steps for administering at least one pain management agent and / or at least one antibiotic according to any of the methods disclosed herein. In some embodiments, the at least one pain management agent in the kit may include at least one pain management agent and at least one antibacterial agent, and in some embodiments, the at least one antibacterial agent in the kit may include at least one antibiotic.

[0068] In some examples, at least one pain management agent and / or at least one antibiotic may be provided in undiluted form in a vial or other container. The end user may then combine the at least one pain management agent and / or at least one antibiotic with saline or other biocompatible fluid in one or more fluid reservoirs at a desired concentration once they are ready to administer the pain management agent(s) and / or antibiotic(s). In other examples, the pain management agent(s) and / or antibiotic(s) may be provided in saline and stored in a fluid reservoir, such as a bag. In various embodiments, a kit may include at least one pain management agent, one or more antibiotics, a therapy delivery system, a perfusion device, a fluid reservoir, any other components required for the therapy delivery system or perfusion device to function properly, and any combination of instructions for administering the pain management agent(s) and antibiotic(s). In some examples, the kit may be provided separately to the end user, with the individual components of the kit arriving at the end user at different times and then assembled by the end user prior to administration to a patient. The at least one pain management agent and / or the at least one antibiotic may be provided in a solution containing saline. The solution may further include one or more buffering agents. For example, the solution may include sodium bicarbonate. The solution containing the at least one pain management agent may be epinephrine-free. As seen in Table 1, it is recommended that solutions without epinephrine be administered at lower doses than solutions containing epinephrine. The epinephrine-free solution may be used with any of the disclosed methods for administering doses that exceed the maximum recommended systemic dose of at least one pain management agent.

[0069] In some embodiments, the at least one anesthetic agent may be lidocaine, and the at least one antibiotic agent may be vancomycin, daptomycin, and / or tobramycin. The therapy delivery system and / or perfusion device is configured to locally administer a daily dose of at least one anesthetic or analgesic agent and / or at least one antibiotic agent to a wound via perfusion. The therapy delivery system and / or perfusion device does not include a sponge that requires intervention by the user to remove the sponge after a certain period of time. Instead, the therapy delivery system and / or perfusion device may be configured to include multiple control functions to complete the administration of two or more therapeutic agents from a supply source over a day without interruption or input from the patient or another user. In some examples, the multiple control functions include two or more infusion pumps or two or more control valves, each independently operated by the therapy delivery system.

[0070] The therapeutic delivery system and / or perfusion device may further include a local perfusion component applied to or within the wound to be treated. In some examples, the local perfusion component may include a perforated infusion tube, an implantable fenestrated device, a drain, a dressing, a sponge, a cannula, or a suction tube. In some examples, the therapeutic delivery system and / or perfusion device includes a local perfusion component and is configured not to be removed from the patient until administration is complete. The therapeutic delivery system and / or perfusion device includes a local perfusion component that remains in place for up to 10 days. For example, the perfusion device is configured to be applied to the local pain site (wound) for more than 48 hours, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or at least 10 days.

[0071] The therapy delivery system and / or perfusion device may be configured to administer two or more medications (pain management agents and / or other therapeutic agents) from two or more sources without interruption or intervention by the user. In one example, the therapy delivery system and / or perfusion device is configured to locally administer a total dose of lidocaine equal to or greater than 200 mg, a total dose of tobramycin equal to or greater than 50 mg, and a total dose of vancomycin equal to or greater than 2,000 mg in a 24-hour period without interruption or human intervention.

[0072] 1A-1B illustrate an example of a therapy delivery system 100 and perfusion device 107 that can provide controlled delivery of at least one pain management agent to a treatment site 102 (e.g., an infection in a periprosthetic space, a bone segment, or a wound area). All or part of the therapy delivery system 100 and perfusion device 107 can be included in a kit. Generally, the therapy delivery system 100 can include a (portable) disposable device to allow adjustment of the distance between the therapy delivery system 100 and the treatment site 102 of a patient (e.g., a patient suffering from an infection treatable by fluid perfusion). In the example shown in FIG. 1A, the therapy delivery system 100 provides perfusion to a treatment site 102 that includes an perfusable volume (e.g., a joint cavity or a bone segment). The system 100 can include a fluid delivery system 104A, a fluid collection system 104B, and a control system 106. The fluid delivery system 104A can include one or more fluid reservoirs 108A, B. In some examples, one or more fluid reservoirs 108A, B may contain at least one pain management agent and / or one or more antibiotics provided by the kit. For example, fluid reservoir 108A may contain a pain management agent such as lidocaine in a saline solution, and fluid reservoir 108B may contain an antibiotic such as vancomycin, daptomycin, or tobramycin in a saline solution. Fluid collection system 104B may include one or more collection fluid canisters 109.

[0073] In some examples, the control system 106 may control the flow of fluid from the fluid reservoirs 108A, B to the treatment site 102 and / or draw fluid away from the treatment site 102 to the fluid recovery system 104B. For example, the control system 106 may include one or more of a vacuum source, a pump, or any other means for moving fluid through the system 100. In some examples, one means for moving fluid may be used for both infusing and withdrawing fluid from the treatment site 102. In other examples, one means may be used for infusing and another means for withdrawing. The system may be configured to deliver fluid percutaneously to a perfusion device positioned within the treatment area (e.g., infected tissue and / or an infected joint, e.g., hip, knee, shoulder, wrist, ankle). Although not shown, one or more other medical devices may assist, coordinate, and / or function in parallel with the therapy delivery system 100 to provide therapy to the patient (including the treatment site 102).

[0074] 1A. The therapy delivery system 100 may also couple to a syringe or another manual component for delivery and withdrawal of fluid from the treatment site. In some embodiments, the perfusion device 107 may have a porous component 103. The porous component 103 of the perfusion device 107 may be configured to fill spaces and / or openings in the treatment site and allow fluid exiting the tubing to flow through the porous component 103 and into the treatment site 102.

[0075] Treatment system 100 may be configured to fluidly couple to an irrigation device 107 that can provide controlled delivery of fluid (e.g., antibiotics, saline, local anesthetic) to a treatment site 102 (e.g., an infected joint such as a knee or hip) during, for example, I&D, DAIR, Double DAIR, or other procedures described elsewhere herein, or other types of healing, including wound healing and perioperative healing.

[0076] In example contexts, the therapy delivery system 100 may be used to deliver at least one pain management agent and / or one or more antibiotics to an infected joint (e.g., hip, knee, shoulder, wrist, ankle) or any type of biological tissue that can be treated using controlled fluid irrigation. Examples of treatments include treatment protocols for periprosthetic joint infections, such as debridement, antibiotics, and implant retention (DAIR) and exchange prosthetic joint arthroplasty, irrigation of surgical incisions and traumatic wounds, or irrigation for osteomyelitis and septic arthritis. While the present application may be described in the context of a particular treatment site (e.g., an infected joint) and the site involved, it should be understood that other treatment sites are contemplated and that the manner in which the system interfaces with those various sites may vary.

[0077] 1A-1B, the fluid delivery system 104A includes two or more fluid reservoirs 108A, 108B.

[0078] Each of the fluid reservoirs 108A, 108B has a specific volume and may store a specific fluid type to be delivered during each treatment phase. The contents of the fluid reservoirs are switchable, so that a pain management agent may be stored in the first fluid reservoir 108B or the second fluid reservoir 108A, and one or more antibiotics may be stored in the second fluid reservoir 108A or the first fluid reservoir 108B. In some examples, the fluid reservoirs may contain a combination of at least one pain management agent and an antibiotic. The fluid reservoirs may be provided as part of a kit or may be provided separately and combined with one or more pain management agents and one or more antibiotics of the kit prior to use.

[0079] For example, the first fluid reservoir 108A may contain or store a first fluid, which may include at least one pain management agent, such as lidocaine. The first fluid may be delivered from the first fluid reservoir 108A to the treatment site 102 according to a respective fluid delivery protocol. The fluid delivery protocol may be included in the kit's instructions. The protocol may define the concentration of the at least one pain management agent, the volume of pain management agent fluid to be delivered, the duration of pain management agent fluid delivery, and a pre-delivery vacuum that may be applied at a set pressure (e.g., -125 mmHg) for a set vacuum time (e.g., approximately 30 minutes). The total volume of pain management agent fluid delivered may vary depending on the length of time and the total time for first fluid delivery, soaking, and removal. Delivery of the pain management agent fluid is followed by a soaking protocol to allow the treatment site 102 to soak in the delivered fluid. The duration of the pain management agent fluid soaking protocol may be between 15 and 45 minutes, for example, approximately 30 minutes. The pain management agent fluid may be removed from the treatment site 102 by the fluid collection system 104B. The time for the second fluid removal from the treatment site 102 may be about 30 minutes.

[0080] The second fluid reservoir 108B may store a second fluid, which may include an antibiotic, such as tobramycin, vancomycin, or daptomycin. The total volume of antibiotic fluid delivered may vary depending on the length of time and the total time for the first fluid delivery, soaking, and removal. Delivery of the antibiotic fluid is followed by a soaking protocol to allow the treatment site 102 to soak in the delivered fluid. The duration of the antibiotic fluid soaking protocol may be between 15 and 45 minutes, for example, approximately 30 minutes. The antibiotic fluid may be removed from the treatment site 102 by the fluid recovery system 104B. The removal time of the antibiotic fluid from the treatment site 102 may be approximately 30 minutes.

[0081] The fluid recovery system 104B may direct fluid from the treatment site 102 to the recovery fluid canister 109. In some examples, the control system 106 may create a vacuum within the recovery fluid canister 109 to remove fluid from the treatment site 102 to the recovery fluid canister 109. For example, a pump may be activated by the control system 106 to create a vacuum within at least the recovery fluid canister 109. In other examples, a vacuum pressure source, a syringe, gravity, a pump, or any other mechanism for moving fluid into or out of the treatment site 102 is contemplated. The recovery fluid canister 109 may include a single-use canister having a known volume (e.g., 2000 mL). The recovery fluid canister 109 recovers antibiotic solution or other fluids (e.g., wound exudate) that accumulate during vacuum-induced drainage of fluid from the treatment site 102. The material of the canister 109 is preferably translucent or transparent so that during use, a user can assess the level of contents within the canister 109. The material of the canister 109 is also preferably capable of holding a vacuum at maximum vacuum levels without deforming or restricting flow.

[0082] definition In various embodiments, the description will be made with reference to the drawings. However, certain embodiments may be practiced without one or more of these specific details or in combination with other known methods and configurations. In this description, many specific details, such as specific doses, fixed dose combinations, and concentrations, are presented to provide a thorough understanding of the present invention. In other instances, specific doses, fixed dose combinations, and concentrations are not described in detail to avoid unnecessarily obscuring the description. References throughout this specification to "doses," "fixed dose ratios," "concentrations," and the like, mean that a particular method or described feature is included in at least one novel method of treatment. Thus, the appearance of phrases such as "a method of treatment" in various places throughout this specification does not necessarily refer to the same method of treatment. Furthermore, specific antibiotics, doses, fixed dose combinations, ratios, and concentrations may be combined in any suitable manner in one or more novel methods of treatment.

[0083] Where a range of values ​​is provided, each value between the upper and lower limits of that range is specifically contemplated and described herein.

[0084] As used herein, the term "about" refers to a range of values ​​that includes the specified value and that one of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, "about" refers to within a standard deviation using measurements generally accepted in the art. In embodiments, "about" refers to a range that spans + / - 10% of the specified value and may include the specified value. For example, endpoints may be within 10%, 8%, 5%, 3%, 2%, or 1% of the recited value. Furthermore, for convenience and brevity, a numerical range of "about 50 mg / mL to about 80 mg / mL" should also be understood to provide support for the range "50 mg / mL to 80 mg / mL." Endpoints may be based on variability permitted by appropriate regulatory agencies, such as the FDA, USP, etc.

[0085] As used herein, the term "substantially" means a value that one of ordinary skill in the art would consider significantly greater than the specified value. In some embodiments, "substantially" means at least 25% more than the specified value, or at least 125% of the specified value.

[0086] As used herein, the terms "safe" and "recommended" mean recommended by a medical authority, such as a manufacturer, the FDA, or other similar regulatory body. In some instances, the maximum dose or serum level may be based on peer-reviewed medical literature (e.g., Rybak et al., "Therapeutic Monitoring of Vancomycin in Adult Patients: A Consensus Review of the American Society of Health-System Pharmacists, the Infections Diseases Society of America, and the Society of Infectious Diseases Pharmacists," ASHP Therapeutic Position Statements, pp. 685-700, 2009) or recommended by a professional medical organization or association. In additional instances, the maximum recommended daily systemic dose and / or maximum safe serum concentration may be provided on the label or instructions for use of a particular pain management agent or antibiotic.

[0087] As used herein, the terms "maximum recommended daily dose," "maximum recommended daily systemic dose," and "maximum recommended systemic daily dose" may be used interchangeably. In some instances, the systemic daily dose may be a daily dose administered by intravenous injection.

[0088] While this specification contains many specific details, these should not be construed as limitations on the scope of what is or may be claimed, but rather as descriptions of features specific to particular methods. Some methods described herein may be practiced in combination in a single method. Conversely, various features described in the context of a single method may be practiced individually, separately in multiple methods, or in any suitable subcombination of novel methods. Furthermore, while a method may be described herein as including a particular combination of antibiotics, dosages, or concentrations, and even originally claimed as such, one or more features from the claimed combination may, in some cases, be omitted from the combination, and the claimed combination may be intended as a subcombination or a variation of the subcombination. Similarly, although the sequential administration of multiple antibiotics is described herein in a particular order or for a particular duration, this should not be construed as requiring that the method be performed in a particular sequential order or for a particular duration, or that all elements of the sequence be performed, to achieve the desired results. Only a few examples and methods are disclosed. Variations, modifications, and enhancements to the described and other methods may be made based on what is disclosed.

[0089] In the above description and claims, phrases such as "at least one" or "one or more" may be followed by a connected list of one or more elements, antibiotics, combinations, doses, or concentrations. The term "and / or" may also appear in lists of two or more such elements. Unless otherwise implicitly or explicitly contradicted by the context in which it is used, such phrases are intended to mean any of the listed elements individually, or any of the listed elements in combination with any of the other listed elements. For example, the phrases "at least one of A and B," "one or more of A and B," and "A and / or B" are intended to mean "A only, B only, or a combination of A and B," respectively. A similar interpretation is intended for lists containing more than two items. For example, the phrases "at least one of A, B, and C," "one or more of A, B, and C," and "A, B, and / or C" are intended to mean "A only, B only, C only, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C," respectively.

[0090] Use of the term "based on" above and in the claims is intended to mean "based at least in part on," thereby allowing for unrecited features or elements.

[0091] As used herein, the terms "comprises," "comprising," "containing," "having," and the like may have the meanings ascribed to them in U.S. patent law, and may also mean "includes," "including," and the like, and are generally construed as open-ended terms. The terms "consisting of" or "consists of" are closed-ended terms and include only those components, structures, steps, etc. specifically recited in conjunction with the term, and in accordance with U.S. patent law. "Consisting essentially of" or "consists essentially of" have the meanings generally ascribed to them by U.S. patent law. In particular, this term is generally open-ended, except to permit the inclusion of additional items, materials, components, steps, or elements that do not materially affect the basic and novel characteristics or function of the item(s) with which it is used. For example, trace elements that are present in a composition but do not affect the properties or characteristics of the composition are permitted to be present under the expression "consisting essentially of," even if they are not explicitly listed in the list of items following the term "consisting essentially of." When open-ended terms such as "comprising" or "including" are used herein, it is understood that direct support for the phrase "consisting essentially of" as well as the phrase "consisting of" should also be provided, as if explicitly stated, and vice versa.

[0092] As used herein, first, second, third, etc. are used to characterize and distinguish various elements of the present invention. The use of numerical terms may be used to distinguish one agent from another. The use of such numerical terms does not imply a sequence or order unless clearly indicated by context. Such numerical references may be used interchangeably without departing from the teachings of the embodiments and variations herein.

[0093] The inventions disclosed herein may be packaged in a single package of multiple therapeutic agents, or may be packaged together in multiple packages of combinations of therapeutic agents for use individually or together, and such use may be administered simultaneously, sequentially, cyclically, or sequentially (in a particular sequence which may include repeated use of one or more individual or combinations of therapeutic agents) according to specific instructions.

[0094] All methods described herein may be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended merely to better clarify the invention and does not impose a limitation on the scope of any claims. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0095] Implementation Embodiment 1: A method of treating pain comprising topically administering to a human patient multiple doses of at least one pain management agent in solution by perfusing the at least one pain management agent at a wound, wherein said administering provides continuous pain treatment to said patient for at least 24 hours.

[0096] Embodiment 2: The method of embodiment 1, wherein said administering provides a serum concentration that is less than or equal to the maximum safe serum concentration level of said at least one pain management agent in said human patient.

[0097] Embodiment 3: The method of embodiment 1, wherein said administering provides said patient with continuous pain relief for at least 48 hours.

[0098] Embodiment 4: The method of embodiment 3, wherein said administering provides said patient with continuous pain relief for at least 3 days, 4 days, 5 days, 6 days, at least 7 days, or at least 10 days.

[0099] Embodiment 5: A method according to embodiment 1, wherein the perfusion comprises alternating injection and suction cycles.

[0100] Embodiment 6: A method according to embodiment 5, wherein the injection and aspiration cycles are sequential.

[0101] Embodiment 7: A method according to embodiment 5, wherein the injection and aspiration cycles are performed staggered.

[0102] Embodiment 8: A method as described in embodiment 5, wherein the perfusion device is configured to automatically control the perfusion.

[0103] Embodiment 9: A method as described in embodiment 5, wherein the perfusion comprises immersing the localized pain site with the at least one pain management agent in the time interval between each alternating injection and suction cycle.

[0104] Embodiment 10: The method described in embodiment 9, wherein the time interval is equal to or less than the half-life or duration of activity of the at least one pain control agent.

[0105] Embodiment 11: A method according to embodiment 9, wherein the time interval is from about 10 minutes to about 180 minutes.

[0106] Embodiment 12: A method according to embodiment 9, wherein the time interval is from about 30 minutes to about 120 minutes.

[0107] Embodiment 13: A method according to embodiment 9, wherein the suction cycle is less than 60 minutes.

[0108] Embodiment 14: The method according to embodiment 1, wherein the perfusion is carried out at least twice in 24 hours.

[0109] Embodiment 15: The method described in embodiment 1, wherein the perfusion is performed at least four times in 24 hours.

[0110] Embodiment 16: The method described in embodiment 1, wherein the perfusion is performed at least 8 times in 24 hours.

[0111] Embodiment 17: The method described in embodiment 1, wherein the perfusion is performed at least 16 times in 24 hours.

[0112] Embodiment 18: A method according to embodiment 1, wherein the perfusion is carried out continuously for 24 hours.

[0113] Embodiment 19: A method according to embodiment 1, wherein the pain management agent is an anesthetic or analgesic.

[0114] Embodiment 20: A method according to embodiment 19, wherein the at least one anesthetic agent is an aminoamide.

[0115] Embodiment 21: The method according to embodiment 20, wherein the aminoamide is selected from the group consisting of lidocaine, bupivacaine, ropivacaine, and combinations thereof.

[0116] Embodiment 22: The method described in embodiment 21, wherein the amount of lidocaine administered topically over the 24 hours is at least 250 mg.

[0117] Embodiment 23: The method described in embodiment 21, wherein the locally administered dose of lidocaine has a concentration of at least 250 mcg / mL, and wherein said administration provides a serum concentration of lidocaine in the human patient of less than 5 mcg / mL.

[0118] Embodiment 24: The method described in embodiment 21, wherein the amount of lidocaine administered topically over the 24 hours is at least 500 mg, 550 mg, or 600 mg.

[0119] Embodiment 25: The method described in embodiment 21, wherein the locally administered dose of lidocaine is at a concentration of at least 500 mcg / mL, and wherein said administration provides a serum concentration of lidocaine in the human patient of less than 5 mcg / mL.

[0120] Embodiment 26: The method described in embodiment 21, wherein the amount of lidocaine administered topically over the 24 hours is at least 900 mg.

[0121] Embodiment 27: The method described in embodiment 21, wherein the amount of lidocaine administered locally over a 24-hour period exceeds the recommended daily dose of lidocaine administered intravenously or systemically to an adult human patient over a 24-hour period.

[0122] Embodiment 28: The method described in embodiment 21, wherein the amount of lidocaine topically administered is 300 mg to 3,000 mg over a 24-hour period, and wherein said administration provides a serum concentration of lidocaine of less than 5 mcg / mL in the human patient.

[0123] Embodiment 29: The method described in embodiment 21, wherein the amount of lidocaine administered topically over the 24 hours is at least 500 mg to 1,500 mg.

[0124] Embodiment 30: The method described in embodiment 21, wherein the serum concentration of lidocaine in the human patient is less than 2.5 mcg / mL.

[0125] Embodiment 31: The method described in embodiment 30, wherein the serum concentration of lidocaine in the human patient is less than 1.25 mcg / mL.

[0126] Embodiment 32: A method according to embodiment 19, wherein the anesthetic agent is an amino ester.

[0127] Embodiment 33: The method according to embodiment 32, wherein the aminoester is selected from the group consisting of benzocaine, chloroprocaine, procaine, tetracaine, and combinations thereof.

[0128] Embodiment 34: The method according to embodiment 19, wherein the analgesic agent is an NSAID.

[0129] Embodiment 35: A method according to embodiment 34, wherein the NSAID is selected from the group consisting of ketorolac, meloxicam, and combinations thereof.

[0130] Embodiment 36: The method described in embodiment 35, wherein the amount of ketorolac administered locally is at least 60 mg in 24 hours.

[0131] Embodiment 37: The method according to embodiment 19, wherein the analgesic agent is a corticosteroid.

[0132] Embodiment 38: The method according to embodiment 37, wherein said corticosteroid is selected from the group consisting of prednisone, methylprednisolone, dexamethasone, triamcinolone, betamethasone, hydrocortisone, and combinations thereof.

[0133] Embodiment 39: A method according to embodiment 38, wherein the amount of methylprednisolone administered topically in said 24 hours is at least 40 mg.

[0134] Embodiment 40: A method according to embodiment 1, wherein the wound is a topical wound.

[0135] Embodiment 41: A method according to embodiment 40, wherein the superficial wound is a diabetic ulcer.

[0136] Embodiment 42: A method according to embodiment 1, wherein the wound is a traumatic wound.

[0137] Embodiment 43: A method according to embodiment 42, wherein the traumatic wound comprises an implantable medical device.

[0138] Embodiment 44: A method according to embodiment 1, wherein the wound is a surgical wound.

[0139] Embodiment 45: A method according to embodiment 44, wherein the surgical wound is a subcutaneous surgical wound.

[0140] Embodiment 46: A method described in embodiment 45, wherein the subcutaneous surgical wound comprises an implantable medical device.

[0141] Embodiment 47: A method according to embodiment 46, wherein the implantable medical device is an orthopedic implant.

[0142] Embodiment 48: A method according to embodiment 47, wherein the orthopedic implant is a joint replacement prosthesis.

[0143] Embodiment 49: A method according to embodiment 1, wherein the wound is a site of localized pain.

[0144] Embodiment 50: A method according to embodiment 49, wherein the continuous pain treatment is provided up to at least 15 cm from the wound.

[0145] Embodiment 51: A method as described in embodiment 1, wherein the perfusion occurs within the perimeter of a superficial or subcutaneous wound.

[0146] Embodiment 52: The method described in embodiment 1, further comprising locally administering at least one additional therapeutic agent for the treatment of a condition other than pain.

[0147] Embodiment 53: A method according to embodiment 52, wherein the at least one additional therapeutic agent is at least one antibacterial agent.

[0148] Embodiment 54: A method according to embodiment 53, wherein the at least one antibacterial agent is two or more antibiotics.

[0149] Embodiment 55: A method according to embodiment 54, wherein the two or more antibiotics comprise vancomycin and tobramycin.

[0150] Embodiment 56: A method according to embodiment 54, wherein the two or more antibiotics are administered sequentially.

[0151] Embodiment 57: A method according to embodiment 56, wherein the at least one pain control agent is lidocaine.

[0152] Embodiment 58: A method according to embodiment 57, wherein the lidocaine and vancomycin are administered simultaneously and the tobramycin is administered sequentially to the simultaneously administered lidocaine and vancomycin.

[0153] Embodiment 59: The method described in embodiment 57, wherein the serum concentrations of each of the lidocaine, vancomycin, and tobramycin remain below the recommended safe serum concentrations of each of the lidocaine, vancomycin, and tobramycin throughout the administration period.

[0154] Embodiment 60: A method according to embodiment 53, wherein the at least one pain management agent is administered sequentially with the at least one antibacterial agent.

[0155] Embodiment 61: The method described in embodiment 53, wherein the at least one pain management agent is administered simultaneously with the at least one antibacterial agent.

[0156] Embodiment 62: A method according to embodiment 1, wherein the local administration is provided for 1 to 10 days.

[0157] Embodiment 63: A method according to embodiment 1, wherein the at least one pain control agent is in a solution comprising saline.

[0158] Embodiment 64: A method according to embodiment 63, wherein the solution does not contain epinephrine.

[0159] Embodiment 65: A method according to embodiment 1, wherein the concentration of the at least one pain control agent exceeds the maximum recommended concentration of the at least one pain control agent.

[0160] Embodiment 66: A method as described in embodiment 65, wherein the local administration comprises perfusion of the local wound by soaking with the at least one pain management agent, and aspirating the at least one pain management agent after a certain period of time.

[0161] Embodiment 67: A kit for managing local pain in a human patient, comprising: at least one pain management agent; a therapeutic delivery system and / or perfusion device configured to locally perfuse the local pain site with at least one dose of at least one pain management agent in solution; and instructions for administering said at least one dose of said at least one pain management agent to provide continuous pain relief to a patient for at least 24 hours.

[0162] Embodiment 68: A kit described in embodiment 67, wherein the at least one pain control agent is lidocaine.

[0163] Embodiment 69: A kit as described in embodiment 68, wherein the therapeutic delivery system and / or perfusion device is configured to locally administer a total amount of lidocaine equal to or greater than 250 mg in 24 hours.

[0164] Embodiment 70: A kit described in embodiment 67, wherein the at least one pain management agent comprises lidocaine, and the kit further comprises at least one antibacterial agent.

[0165] Embodiment 71: A kit as described in embodiment 67, wherein the perfusion device is configured not to be removed from the patient until administration is complete.

[0166] Embodiment 72: A kit as described in embodiment 71, wherein the perfusion device is configured to be applied to the local pain site for more than 48 hours.

[0167] Embodiment 73: A kit as described in embodiment 71, wherein the perfusion device is configured to be applied to the local pain site for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or at least 10 days.

[0168] Embodiment 74: A kit described in embodiment 67, wherein the at least one pain management agent is in a solution comprising saline.

[0169] Embodiment 75: A kit according to embodiment 74, wherein the solution does not contain epinephrine.

[0170] Embodiment 76: A kit as described in embodiment 67, wherein the therapeutic delivery system and / or perfusion device comprises a local perfusion component that remains in place for up to 10 days.

[0171] Embodiment 77: A method of treating localized pain in a wound of a human patient, comprising locally administering to the human patient by perfusion, without interruption to change sources, repeated doses of at least two therapeutic agents from separate sources, wherein one of the two or more therapeutic agents is at least one pain management agent.

[0172] Embodiment 78: A method according to embodiment 77, wherein the two or more therapeutic agents are administered sequentially.

[0173] Embodiment 79: A method according to embodiment 77, wherein the two or more therapeutic agents are administered simultaneously.

[0174] Embodiment 80: A method of treating a localized infection in a human patient in need thereof, comprising locally administering to the human patient by perfusion, without interruption to change sources, repeated doses of two therapeutic agents from separate sources, wherein one of the two or more therapeutic agents is at least one antibacterial agent.

[0175] Embodiment 81: A method of treating local pain and infection in a human patient in need thereof, comprising locally administering to the human patient by perfusion, without interruption to change sources, repeated doses of two therapeutic agents from separate sources, wherein one of the two or more therapeutic agents is at least one pain management agent and at least one antibacterial agent.

[0176] Embodiment 82: A method according to embodiment 80, wherein the at least one antibacterial agent is at least one antibiotic.

[0177] Embodiment 83: A method according to embodiment 80, wherein the at least one antibacterial agent is at least two antibiotics.

[0178] Embodiment 84: A method according to embodiment 81, wherein the at least one pain control agent is lidocaine and the at least two antibiotics are vancomycin and tobramycin.

[0179] Embodiment 85: The method described in embodiment 82, wherein the lidocaine and vancomycin are administered simultaneously and the tobramycin is administered sequentially with the simultaneously administered lidocaine and vancomycin.

[0180] Embodiment 86: The method described in embodiment 82, wherein the lidocaine and vancomycin are administered from a common source.

[0181] Embodiment 87: A method for treating local pain and infection in a human patient in need thereof, comprising locally administering by perfusion at least one pain management agent and at least two antibacterial agents to the human patient.

[0182] Embodiment 88: A method according to embodiment 87, wherein the at least one pain control agent is lidocaine and the at least two antibacterial agents are vancomycin and tobramycin.

Claims

1. A method for treating pain, comprising locally administering multiple doses of at least one pain management agent in solution to a human patient by perfusing the at least one pain management agent in a wound, wherein said administration provides continuous pain treatment to the patient for at least 24 hours.

2. 10. The method of claim 1, wherein said administering provides a serum concentration that is less than or equal to a maximum safe serum concentration level of said at least one pain management agent in said human patient.

3. 10. The method of claim 1, wherein said administration provides said patient with continuous pain relief for at least 48 hours.

4. 4. The method of claim 3, wherein said administration provides said patient with continuous pain relief for at least 3 days, 4 days, 5 days, 6 days, at least 7 days, or at least 10 days.

5. 10. The method of claim 1, wherein the perfusion comprises alternating injection and aspiration cycles.

6. 6. The method of claim 5, wherein the injection and aspiration cycles are sequential.

7. 6. The method of claim 5, wherein the injection and aspiration cycles are performed in a staggered manner.

8. 6. The method of claim 5, wherein the perfusion device is configured to automatically control the perfusion.

9. 6. The method of claim 5, wherein the irrigation comprises bathing the localized pain site with the at least one pain management agent during the time interval between each alternating injection and aspiration cycle.

10. 10. The method of claim 9, wherein the time interval is equal to or less than the half-life or duration of activity of the at least one pain management agent.

11. 10. The method of claim 9, wherein the time interval is from about 10 minutes to about 180 minutes.

12. 10. The method of claim 9, wherein the time interval is from about 30 minutes to about 120 minutes.

13. 10. The method of claim 9, wherein the suction cycle is less than 60 minutes.

14. 10. The method of claim 1, wherein the perfusion is performed at least twice in a 24-hour period.

15. 10. The method of claim 1, wherein the perfusion is performed at least four times in a 24-hour period.

16. 10. The method of claim 1, wherein the perfusion is performed at least 8 times in a 24-hour period.

17. 10. The method of claim 1, wherein the perfusion is performed at least 16 times in a 24-hour period.

18. 10. The method of claim 1, wherein the perfusion is performed continuously for 24 hours.

19. 10. The method of claim 1, wherein the pain management agent is an anesthetic or an analgesic.

20. 20. The method of claim 19, wherein the at least one anesthetic agent is an aminoamide.

21. 21. The method of claim 20, wherein the aminoamide is selected from the group consisting of lidocaine, bupivacaine, ropivacaine, and combinations thereof.

22. 22. The method of claim 21, wherein the amount of lidocaine administered topically in the 24 hour period is at least 250 mg.

23. 22. The method of claim 21, wherein the locally administered dose of lidocaine is at a concentration of at least 250 mcg / mL, and wherein the administration provides a serum concentration of lidocaine of less than 5 mcg / mL in the human patient.

24. 22. The method of claim 21, wherein the amount of lidocaine administered topically over the 24 hour period is at least 500 mg, 550 mg, or 600 mg.

25. 22. The method of claim 21, wherein the locally administered dose of lidocaine is at a concentration of at least 500 mcg / mL, and the administration provides a serum concentration of lidocaine in the human patient of less than 5 mcg / mL.

26. 22. The method of claim 21, wherein the amount of lidocaine administered topically over a 24-hour period is at least 900 mg.

27. 22. The method of claim 21, wherein the amount of lidocaine administered topically over a 24-hour period exceeds the recommended daily dose of lidocaine administered intravenously or systemically to an adult human patient over a 24-hour period.

28. 22. The method of claim 21, wherein the amount of lidocaine topically administered is between 300 mg and 3,000 mg over a 24 hour period, and wherein the administration provides a serum concentration of lidocaine of less than 5 mcg / mL in the human patient.

29. 22. The method of claim 21, wherein the amount of lidocaine administered topically over a 24-hour period is at least 500 mg to 1,500 mg.

30. 22. The method of claim 21, wherein the serum concentration of the lidocaine in the human patient is less than 2.5 mcg / mL.

31. 31. The method of claim 30, wherein the serum concentration of the lidocaine in the human patient is less than 1.25 mcg / mL.

32. 20. The method of claim 19, wherein the anesthetic agent is an amino ester.

33. 33. The method of claim 32, wherein the aminoester is selected from the group consisting of benzocaine, chloroprocaine, procaine, tetracaine, and combinations thereof.

34. 20. The method of claim 19, wherein the analgesic is an NSAID.

35. 35. The method of claim 34, wherein the NSAID is selected from the group consisting of ketorolac, meloxicam, and combinations thereof.

36. 36. The method of claim 35, wherein the amount of ketorolac administered topically is at least 60 mg in 24 hours.

37. 20. The method of claim 19, wherein the analgesic agent is a corticosteroid.

38. 38. The method of claim 37, wherein the corticosteroid is selected from the group consisting of prednisone, methylprednisolone, dexamethasone, triamcinolone, betamethasone, hydrocortisone, and combinations thereof.

39. 39. The method of claim 38, wherein the amount of methylprednisolone administered topically over a 24-hour period is at least 40 mg.

40. 10. The method of claim 1, wherein the wound is a topical wound.

41. 41. The method of claim 40, wherein the superficial wound is a diabetic ulcer.

42. 10. The method of claim 1, wherein the wound is a traumatic wound.

43. 43. The method of claim 42, wherein the traumatic wound comprises an implantable medical device.

44. 10. The method of claim 1, wherein the wound is a surgical wound.

45. 45. The method of claim 44, wherein the surgical wound is a subcutaneous surgical wound.

46. 46. ​​The method of claim 45, wherein the subcutaneous surgical wound contains an implantable medical device.

47. 47. The method of claim 46, wherein the implantable medical device is an orthopedic implant.

48. 48. The method of claim 47, wherein the orthopedic implant is a joint replacement prosthesis.

49. 10. The method of claim 1, wherein the wound is a site of localized pain.

50. 50. The method of claim 49, wherein the continuous pain treatment is provided up to at least 15 cm from the wound.

51. 10. The method of claim 1, wherein the perfusion occurs within the perimeter of a superficial or subcutaneous wound.

52. 10. The method of claim 1, further comprising topically administering at least one additional therapeutic agent for the treatment of a condition other than pain.

53. 53. The method of claim 52, wherein the at least one additional therapeutic agent is at least one antibacterial agent.

54. 54. The method of claim 53, wherein the at least one antimicrobial agent is two or more antibiotics.

55. 55. The method of claim 54, wherein the two or more antibiotics comprise vancomycin and tobramycin.

56. 55. The method of claim 54, wherein the two or more antibiotics are administered sequentially.

57. 57. The method of claim 56, wherein the at least one pain management agent is lidocaine.

58. 58. The method of claim 57, wherein the lidocaine and vancomycin are administered simultaneously and the tobramycin is administered sequentially to the simultaneously administered lidocaine and vancomycin.

59. 58. The method of claim 57, wherein the serum concentrations of each of the lidocaine, the vancomycin, and the tobramycin remain below the recommended safe serum concentrations of each of the lidocaine, the vancomycin, and the tobramycin throughout the administration period.

60. 54. The method of claim 53, wherein the at least one pain management agent is administered sequentially with the at least one antibacterial agent.

61. 54. The method of claim 53, wherein the at least one pain management agent is administered simultaneously with the at least one antibacterial agent.

62. 10. The method of claim 1, wherein the topical administration is provided for 1 to 10 days.

63. 10. The method of claim 1, wherein the at least one pain management agent is in a solution comprising saline.

64. 64. The method of claim 63, wherein the solution does not contain epinephrine.

65. 10. The method of claim 1, wherein the concentration of the at least one pain management agent exceeds the maximum recommended concentration of the at least one pain management agent.

66. 66. The method of claim 65, wherein the local administration comprises perfusing the local wound by soaking it with the at least one pain management agent and aspirating the at least one pain management agent after a period of time.

67. 1. A kit for managing localized pain in a human patient, comprising: at least one pain management agent; a therapeutic delivery system and / or perfusion device configured to locally perfuse the local pain site with at least one dose of at least one pain management agent in solution; and instructions for administering said at least one dose of said at least one pain management agent to provide a patient with continuous pain relief for at least 24 hours.

68. 68. The kit of claim 67, wherein the at least one pain management agent is lidocaine.

69. 69. The kit of claim 68, wherein the therapeutic delivery system and / or perfusion device is configured to locally administer a total amount of lidocaine equal to or greater than 250 mg in a 24 hour period.

70. 68. The kit of claim 67, wherein the at least one pain management agent comprises lidocaine, and the kit further comprises at least one antibacterial agent.

71. 68. The kit of claim 67, wherein the perfusion device is configured not to be removed from the patient until administration is complete.

72. 72. The kit of claim 71, wherein the perfusion device is configured to be applied to the localized pain site for more than 48 hours.

73. 72. The kit of claim 71, wherein the perfusion device is configured to be applied to the localized pain site for at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, or at least 10 days.

74. 68. The kit of claim 67, wherein the at least one pain management agent is in a solution comprising saline.

75. 75. The kit of claim 74, wherein the solution does not contain epinephrine.

76. 68. The kit of claim 67, wherein the therapeutic delivery system and / or perfusion device includes a local perfusion component that remains in place for up to 10 days.

77. 1. A method for treating localized pain in a wound in a human patient, comprising locally administering to the human patient by perfusion, without interruption for changing sources, repeated doses of at least two therapeutic agents from separate sources, wherein one of the two or more therapeutic agents is at least one pain management agent.

78. 78. The method of claim 77, wherein the two or more therapeutic agents are administered sequentially.

79. 78. The method of claim 77, wherein the two or more therapeutic agents are administered simultaneously.

80. 1. A method for treating a localized infection in a human patient in need thereof, comprising locally administering to the human patient by perfusion, without interruption to change sources, repeated doses of two or more therapeutic agents from separate sources, wherein one of the two or more therapeutic agents is at least one antibacterial agent.

81. 1. A method for treating localized pain and infection in a human patient in need thereof, comprising locally administering to the human patient by perfusion, without interruption to change sources, repeated doses of two therapeutic agents from separate sources, wherein one of the two or more therapeutic agents is at least one pain management agent and at least one antibacterial agent.

82. 81. The method of claim 80, wherein the at least one antimicrobial agent is at least one antibiotic.

83. 81. The method of claim 80, wherein the at least one antimicrobial agent is at least two antibiotics.

84. 82. The method of claim 81, wherein the at least one pain management agent is lidocaine and the at least two antibiotics are vancomycin and tobramycin.

85. 83. The method of claim 82, wherein the lidocaine and vancomycin are administered simultaneously and the tobramycin is administered sequentially with the simultaneously administered lidocaine and vancomycin.

86. 83. The method of claim 82, wherein the lidocaine and vancomycin are administered from a common source.

87. A method for treating localized pain and infection in a human patient in need thereof, comprising locally administering by perfusion to the human patient at least one pain management agent and at least two antimicrobial agents.

88. 88. The method of claim 87, wherein the at least one pain management agent is lidocaine and the at least two antibacterial agents are vancomycin and tobramycin.

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