Method of inhibition of pain and inflammation during surgery comprising administration of soluble TNF receptors
View Patent ↗A method and solution for perioperatively inhibiting a variety of pain and inflammation processes at wounds from general surgical procedures including oral/dental procedures. The solution preferably includes at least one tumor necrosis factor (TNF) soluble receptor at dilute concentration in a physiologic carrier, such as saline or lactated Ringer's solution. The solution is applied locally and perioperatively to a surgical site during a surgical procedure for preemptive inhibition of pain and while avoiding undesirable side effects associated with oral, intramuscular, subcutaneous or intravenous application of larger doses of the agents.
1. A method of preemptively inhibiting pain and inflammation at a wound during a surgical procedure, comprising delivering to the wound during a surgical procedure a solution comprising at least one tumor necrosis factor (TNF) soluble receptor, wherein the solution is applied locally and perioperatively to the surgical site.
2. The method of claim 1 , wherein the soluble receptor is selected from the groups of soluble receptors consisting of sTNFR and chimeric rhTNFR:Fc.
3. The method of claim 1 , wherein the solution further comprises at least one additional pain/inflammation inhibitory agent selected to act on a different molecular target than the target upon which the soluble receptor acts.
4. The method of claim 3 , wherein each of the additional agents in the solution is delivered locally at a concentration of no greater than 100,000 nanomolar.
5. The method of claim 3 , wherein each of the plurality of agents in the solution applied is included at a concentration or dosage that is sufficient to provide a level of inhibitory effect at the wound when delivered locally to the wound 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 effect at the wound when delivered systemically.
6. The method of claim 3 , wherein the at least one 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 neurokinin1 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 PLC γ isoform inhibitors; cyclooxygenase inhibitors; lipooxygenase 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 μ-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; and ATP-sensitive potassium channel openers.
7. The method of claim 6 , wherein the selected pain/inflammation inhibitory agents are delivered locally at a concentration of: 0.1 to 1000 nanomolar for soluble receptors; 0.1 to 10,000 nanomolar for serotonin receptor antagonists; 0.1 to 2,000 nanomolar for serotonin receptor agonists; 0.01 to 1,000 nanomolar for histamine receptor antagonists; 0.1 to 10,000 nanomolar for bradykinin receptor antagonists; 0.1 to 1,000 nanomolar for kallikrein inhibitors; 0.1 to 10,000 nanomolar for neurokinin1 receptor subtype antagonists; 1.0 to 10,000 nanomolar for neurokinin 2 receptor subtype antagonists; 1 to 1,000 nanomolar for calcitonin gene-related peptide receptor antagonists; 1 to 1,000 nanomolar for interleukin receptor antagonists; 100 to 100,000 nanomolar for PLA 2 isoform inhibitors; 100 to 10,000 nanomolar for cyclooxygenase inhibitors; 100 to 10,000 nanomolar for lipooxygenase inhibitors; 100 to 10,000 nanomolar for eicosanoid EP-1 receptor subtype antagonists; 100 to 10,000 nanomolar for leukotriene B 4 receptor subtype antagonists; 0.1 to 500 nanomolar for μ-opioid receptor subtype agonists; 0.1 to 500 nanomolar for δ-opioid receptor subtype agonists; 0.1 to 500 nanomolar for κ-opioid receptor subtype agonists; 100 to 100,000 nanomolar for purinoceptor antagonists; and 0.1 to 10,000 nanomolar for ATP-sensitive potassium channel openers.
8. The method of claim 1 , comprising continuously applying the solution to the wound.
9. The method of claim 8 , comprising continuously irrigating the wound with the solution.
10. The method of claim 1 , wherein the solution is applied by irrigation of the wound.
11. The method of claim 1 , wherein the solution is locally applied to the wound in the absence of metabolic transformation.
12. The method of claim 1 , wherein the perioperative application of the solution comprises intraprocedural application together with preprocedural or postprocedural application of the solution.
13. The method of claim 12 , wherein the perioperative application of the solution comprises preprocedural, intraprocedural and postprocedural application of the solution.
14. The method of claim 12 , wherein the solution is continuously applied to the wound.
15. The method of claim 1 , wherein the soluble receptor in the solution is delivered locally at a concentration of no greater than 1,000 nanomolar.
16. The method of claim 1 , wherein the soluble receptor in the solution is included at a concentration or dosage that is sufficient to provide a level of inhibitory effect at the wound when delivered locally to the wound 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 effect at the wound when delivered systemically.