Arthroscopic irrigation solution and method for peripheral vasoconstriction and inhibition of pain and inflammation

Abstract

A method and solution for perioperatively inhibiting a variety of pain and inflammation processes during arthroscopic procedures. The solution preferably includes a vasoconstrictor that demonstrates substantial agonist activity at alpha adrenergic receptors and that is selected for peripheral (local) vasoconstriction and one or more additional pain and inflammation inhibitory agents at dilute concentration in a physiologic carrier, such as saline or lactated Ringer's solution. The solution is applied by continuous irrigation of a wound during a surgical procedure for peripheral vasoconstriction and inhibition of pain and/or inflammation while avoiding undesirable side effects associated with systemic application of larger doses of the agents.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:  
     
         1 . A method of inhibiting pain and inflammation at a joint during an arthroscopic surgical procedure, comprising delivering to a joint during an arthroscopic procedure a solution comprising: 
 at least one vasoconstrictive agent that is an adrenergic receptor agonist that demonstrates interactions with at least one member of the alpha receptor subfamily and that may also interact with members of the beta receptor subfamily, and that is selected for peripheral vasoconstriction;    at least a first pain/inflammation inhibitory agent selected to act on a different molecular target than the adrenergic receptor agonist; and    a liquid carrier, wherein the solution is applied locally and perioperatively to the joint.    
     
     
         2 . The method of  claim 1 , wherein the adrenergic receptor agonist is a non-selective alpha adrenergic receptor and beta adrenergic receptor agonist.  
     
     
         3 . The method of  claim 2 , wherein the adrenergic receptor agonist is selected from the class consisting of epinephrine and norepinephrine.  
     
     
         4 . The method of  claim 1 , wherein the at least first pain/inflammation inhibitory agent is selected from the group consisting of: serotonin receptor antagonists; serotonin receptor agonists; histamine receptor antagonists; bradykinin receptor antagonists; kallikrein inhibitors; tachykinin receptor antagonists including neurokinin 1  receptor subtype antagonists and neurokinin 2  receptor subtype antagonists; calcitonin gene-related peptide receptor antagonists; interleukin receptor antagonists; phospholipase inhibitors including PLA 2  isoform inhibitors and PLCγ isoform inhibitors; cyclooxygenase inhibitors, including non-selective cyclooxygenase inhibitors and cyclooxygenase-2 selective inhibitors; lipoxygenase inhibitors; prostanoid receptor antagonists including eicosanoid EP-1 receptor subtype antagonists and eicosanoid EP-4 receptor subtype antagonists and thromboxane receptor subtype antagonists; leukotriene receptor antagonists including leukotriene B 4  receptor subtype antagonists and leukotriene D 4  receptor subtype antagonists; opioid receptor agonists including κ-opioid receptor subtype agonists,δ-opioid receptor subtype agonists, and κ-opioid receptor subtype agonists; purinoceptor agonists and antagonists including P 2Y  receptor agonists and P 2X  receptor antagonists; ATP-sensitive potassium channel openers; mitogen-activated protein kinase (MAPK) inhibitors; neuronal nicotinic acetylcholine receptor agonists; and soluble receptors.  
     
     
         5 . The method of  claim 4 , wherein the solution further comprises at least a second pain/inflammation inhibitory agent selected from the classes of  claim 4  to act on a different molecular target than the adrenergic receptor agonist and the first pain/inflammation inhibitory agent.  
     
     
         6 . The method of  claim 1 , wherein the solution further comprises at least a second pain/inflammation inhibitory agent selected to act on a different molecular target than the adrenergic receptor agonist and the first pain/inflammation inhibitory agent.  
     
     
         7 . The method of  claim 1 , wherein the first pain/inflammation inhibitory agent is selected from the group consisting of ketoprofen and amitriptyline.  
     
     
         8 . The method of  claim 7 , wherein the first pain/inflammation inhibitory agent comprises ketoprofen and the solution further comprises amitriptyline as a second pain/inflammation inhibitory agent.  
     
     
         9 . The method of  claim 8 , wherein the adrenergic receptor agonist is selected from the group consisting of epinephrine and norepinephrine.  
     
     
         10 . The method of  claim 7 , wherein the adrenergic receptor agonist is selected from the group consisting of epinephrine and norepinephrine.  
     
     
         11 . The method of  claim 1 , wherein the first pain/inflammation inhibitory agent comprises a cyclooxygenase inhibitor.  
     
     
         12 . The method of  claim 11 , wherein the solution further comprises a second pain/inflammation inhibitory agent selected from the group consisting of serotonin receptor antagonists and histamine receptor antagonists.  
     
     
         13 . The method of  claim 12 , wherein the second pain/inflammation inhibitory agent functions as both a serotonin receptor antagonist and a histamine receptor antagonist.  
     
     
         14 . The method of  claim 1 , wherein the first pain/inflammation inhibitory agent is selected from the group consisting of serotonin receptor antagonists and histamine receptor antagonists.  
     
     
         15 . The method of  claim 14 , wherein the first pain/inflammation inhibitory agent functions as both a serotonin receptor antagonist and a histamine receptor antagonist.  
     
     
         16 . The method of  claim 1 , comprising continuously applying the solution to the joint.  
     
     
         17 . The method of  claim 16 , comprising continuously irrigating the joint with the solution.  
     
     
         18 . The method of  claim 1 , wherein the solution is applied by irrigation of the joint.  
     
     
         19 . The method of  claim 1 , wherein the solution is locally applied to the joint in the absence of metabolic transformation.  
     
     
         20 . The method of  claim 1 , wherein the perioperative application of the solution comprises intraprocedural application together with preprocedural or postprocedural application of the solution.  
     
     
         21 . The method of  claim 20 , wherein the perioperative application of the solution comprises preprocedural, intraprocedural and postprocedural application of the solution.  
     
     
         22 . The method of  claim 1 , wherein the adrenergic receptor agonist in the solution is delivered locally at a concentration of no greater than 300,000 nanomolar.  
     
     
         23 . The method of  claim 22 , wherein the adrenergic receptor agonist in the solution is delivered locally at a concentration of no greater than 75,000 nanomolar.  
     
     
         24 . The method of  claim 22 , wherein the first pain/inflammation inhibitory agent in the solution is delivered locally at a concentration of no greater than 500,000 nanomolar.  
     
     
         25 . The method of  claim 24 , wherein the first pain/inflammation inhibitory agent in the solution is delivered locally at a concentration of no greater than 100,000 nanomolar.  
     
     
         26 . The method of  claim 1 , wherein each of the agents in the solution is included at a concentration or dosage that is sufficient to provide a level of pain/inflammation inhibitory or vasoconstrictive effect at the joint when delivered locally to the joint and that results in a plasma concentration that is less than a plasma concentration that would be required to achieve the same level of inhibitory or therapeutic effect at the joint when delivered systemically.  
     
     
         27 . The method of  claim 1 , comprising intermittently applying the solution to the joint.  
     
     
         28 . A method of inhibiting pain and inflammation at a joint of an extremity during an arthroscopic or open surgical procedure or other extremity procedure, comprising delivering to the surgical site during the procedure a solution comprising: 
 at least one vasoconstrictive agent that is an adrenergic receptor agonist that demonstrates interactions with at least one member of the alpha receptor subfamily and that may also interact with members of the beta receptor subfamily, and that is selected for peripheral vasoconstriction;    at least a first pain/inflammation inhibitory agent selected to act on a different molecular target than the adrenergic receptor agonist; and    a liquid carrier, wherein the solution is applied locally and perioperatively to the surgical site.    
     
     
         29 . The method of  claim 28 , wherein the adrenergic receptor agonist is a non-selective alpha adrenergic receptor and beta adrenergic receptor agonist.  
     
     
         30 . The method of  claim 29 , wherein the adrenergic receptor agonist is selected from the class consisting of epinephrine and norepinephrine.  
     
     
         31 . The method of  claim 28 , wherein the solution further comprises at least a second pain/inflammation inhibitory agent selected to act on a different molecular target than the adrenergic receptor agonist and the first pain/inflammation inhibitory agent.  
     
     
         32 . The method of  claim 28 , comprising continuously applying the solution to the surgical site.  
     
     
         33 . The method of  claim 28 , wherein the solution is applied by irrigation of the surgical site.  
     
     
         34 . The method of  claim 28 , wherein the perioperative application of the solution comprises intraprocedural application together with preprocedural or postprocedural application of the solution.  
     
     
         35 . The method of  claim 34 , wherein the perioperative application of the solution comprises preprocedural, intraprocedural and postprocedural application of the solution.  
     
     
         36 . The method of  claim 28 , wherein each of the agents in the solution is included at a concentration or dosage that is sufficient to provide a level of pain/inflammation inhibitory or vasoconstrictive effect at the surgical site when delivered locally to the surgical site and that results in a plasma concentration that is less than a plasma concentration that would be required to achieve the same level of inhibitory or therapeutic effect at the surgical site when delivered systemically.  
     
     
         37 . The method of  claim 28 , wherein the adrenergic receptor agonist is selected from the group consisting of epinephrine and norepinephrine.  
     
     
         38 . The method of  claim 37 , wherein the first pain/inflammation inhibitory agent is selected from the group consisting of ketoprofen and amitriptyline.  
     
     
         39 . The method of  claim 38 , wherein the first pain/inflammation inhibitory agent comprises ketoprofen and the solution further comprises amitriptyline as a second pain/inflammation inhibitory agent.  
     
     
         40 . The method of  claim 28 , wherein the procedure during which the solution is delivered comprises an open joint procedure.  
     
     
         41 . The method of  claim 40 , wherein the procedure during which the solution is delivered comprises a total joint replacement.  
     
     
         42 . The method of  claim 41 , wherein the solution is applied by intermittent irrigation during the procedure.  
     
     
         43 . The method of  claim 28 , comprising intermittently applying the solution to the joint.  
     
     
         44 . A method of inhibiting pain and inflammation at perioperative local irrigation of surgical or operative/procedural sites during oral/dental surgery, ocular surgery or burn treatment procedures, comprising delivering to a site during an arthroscopic procedure a solution comprising: 
 at least one vasoconstrictive agent that is an adrenergic receptor agonist that demonstrates interactions with at least one member of the alpha receptor subfamily and that may also interact with members of the beta receptor subfamily, and that is selected for peripheral vasoconstriction;    at least a first pain/inflammation inhibitory agent selected to act on a different molecular target than the adrenergic receptor agonist; and    a liquid carrier, wherein the solution is applied locally and perioperatively to the site.    
     
     
         45 . A composition for use in the inhibition of pain and inflammation at a joint of an extremity or at a wound at an extremity, the composition comprising: 
 at least one vasoconstrictive agent that is an adrenergic receptor agonist that demonstrates interactions with at least one member of the alpha receptor subfamily and that may also interact with members of the beta receptor subfamily, and that is selected for peripheral vasoconstriction; and    at least a first pain/inflammation inhibitory agent selected to act on a different molecular target than the a-adrenergic receptor agonist, wherein the first pain/inflammation inhibitory agent is selected from the group consisting of serotonin receptor antagonists and histamine receptor antagonists.    
     
     
         46 . The composition of  claim 45 , further comprising a liquid carrier.  
     
     
         47 . The composition of  claim 45 , wherein the first pain/inflammation inhibitory agent functions as both a serotonin receptor antagonist and a histamine receptor antagonist.  
     
     
         48 . The composition of  claim 47 , wherein the first pain/inflammation inhibitory agent comprises amitriptyline.  
     
     
         49 . The composition of  claim 48 , further comprising a cyclooxygenase inhibitor.  
     
     
         50 . The composition of  claim 49 , wherein the cyclooxygenase inhibitor comprises ketoprofen.  
     
     
         51 . The composition of  claim 48 , wherein the adrenergic receptor agonist is selected from the group consisting of epinephrine and norepinephrine.  
     
     
         52 . The composition of  claim 45 , wherein the adrenergic receptor agonist is selected from the group consisting of epinephrine and norepinephrine.  
     
     
         53 . The composition of  claim 52 , further comprising a cyclooxygenase inhibitor.  
     
     
         54 . The composition of  claim 53 , wherein the cyclooxygenase inhibitor comprises ketoprofen.