Adenosine as a Non- Opioid Analgesic in the Perioperative Setting

1. Adenosine as a Non-Opioid Analgesic in the Perioperative Setting 마취통증의학과 민 진기

2. -Ubiquitous metabolic intermediate in the body -Involved in nearly every aspect of cell function, including neuromodulation and neurotransmission -Adenosine A1 and A2 receptor :widely distributed in brain and spinal cord novel non-opiate target for pain management

3. -Compared to placebo or remifentanil, an intraoperative adenosine infusion stabilize core hemodynamics and reduce the requirement for anesthesia during surgery and improve postoperative recovery

4. -The safety profile has been well characterized based on use of currently approved adenosine products -Most common adverse events flushig, chest discomfort, dyspnea, headache, gastrointestinal discomfort, and lightheadedness : generally well tolerated and transient

5. -Opioid remain the mainstay for postoperative analgesia, especially for major surgery  however, pain is a multifactorial phenomenon that may not be adequately controlled with opioid monotherapy alone -Opoid: dose-related adverse effect such as respiratory depression, nausea, vomiting, urinary retention, itching, and sedation

6. -To improve pain relief and reduce the incidence and severity of side effects, a multifactorial approach to postoperative analgesia should be used. -NSAIDs may cause bleeding, renal dysfunction, and cardiovascular adverse events. -Although COX-2 specific inhibitors do not increase perioperative bleeding, their cardiorenal side effects may be similar to that of traditional NSAIDs

7. -Adenosine 1) important neuromodulator and regulates neuronal and non-neuronal cellular function by actions on adenosine receptors 2) signaling molecule in immunity and inflammation acting as an endogenous antiinflammatory agent 3) acts as a neurotransmitter and regulates pain transmission in the spinal cord, and these receptors are a novel, nonopiate target for pain management

8. -Two formulations of adenosine are currently on the market for cardiovascular indications ( Adenocard and Adenoscan) -Adenoscan: 60- and 90-mL vialsperioperative setting -Adenocard: conversion to sinus rhythm of PSVT( WPW syndrome)

9. -Clinical pharmacology of adenosine and its efficacy and safety when used as an adjunct in postoperative pain management

10. Preclinical pharmacology -Studies using adenosine analogues with different efficacy for the A1 and A2 adenosine receptors adenosine A1 receptor are involved in inducing the antinociceptive effects -The role of the A1 adenosine receptor in inhibiting spinal sensory transmission confirmed by the inhibitory effect of A1 analogues on the C-fiber-evoked responses of wind up and post discharge of dorsal horn neuron

11. Preclinical pharmacology - adenosine agonists dose dependently inhibit the slow ventral root potential C-fiber-evoked excitatory response associates with nociceptive information -The rank order of agonist potency adenosine agonist inhibit sensory transmission by acting on A1 receptor

12. Preclinical pharmacology -Four loose ligatures around the sciatic nerve, called the chronic constriction injury model in animal adenosine reduced the scratch behavior in rat after both IV administration and IT injection: dose dependent

13. Preclinical pharmacology -This effect of adenosine was abolished by IT injection of the A1 receptor antagonist cyclopentylxantine -A neurotoxicological evaluation using morphologic measurement showed that chronic IT administration of R-PIA( R-phenyl-isopropyl adenosine) once daily for 14 days induced no neurotoxic changes in the rat spinal cord

14. Preclinical pharmacology -Adenosine also interacts with other analgesics IV adenosine had an additive analgesic effect with morphine and ketamine in experimentally induced ischemic pain in healthy volunteers

15. Efficacy in the perioperative setting -Published reports of randomized, controlled trials investigated perioperative adenosine administration for postoperative pain management were searched

16. Efficacy in the perioperative setting

17. Efficacy in the perioperative setting

18. Safety of adenosinesafety of adenosine as an analgesic in the perioperative setting -In the study invloving females who underwent breast surgery, 3 of 36 evaluable adenosine-treated pts. reported one or more of the following: hematoma; fever; reoperation due to postoperative bleeding; postoperative headache

19. safety of adenosine as an analgesic in the perioperative setting -In the study involving females undergoing abdominal hysterectomy, 2 of 23 adenosine treated pts. experienced an adverse event: transient atrioventricular block II or transient decrease in systolic blood pr. due to accidental overdose -In the study of pts. who underwent shoulder surgery, no adverse events were recorded

20. safety of adenosine as an analgesic in the perioperative setting -In 110 pts. who underwent surgery of the upper extremity with brachial plexus block and received IV adenosine in addition to local anesthetics, 4 pts. Experienced an adverse event.  headache (adenosine), faintness (adenosine), palpitation/tightness (adenosine), and itching (placebo)

21. safety of adenosine as an analgesic in the perioperative setting -In the study that compared IV adenosine to IV remifentanil in pts. who underwent a hysterectomy, 1 of 15 pts. in the adenosine group experienced severe bronchospasm shortly after initiation of infusion

22. safety of adenosine in cardiac indication - events most commonly associated with Adenoscan were flushing(44%), chest discomfort(40%), dyspnea or urge to breath deeply (28%), headache (18%), throat, neck, or jaw discomfort (13%), and lightheadedness/ dizziness (12%)

23. safety of adenosine in cardiac indication -Adenoscan is contraindicated for known or suspected bronchoconstrictive or bronchoplastic lung disease -Warnings for fatal cardiac arrest life threatening ventricular arrhythmias, myocardial infarction, sinoatrial and AV block, hypo and hyperthension, and bronchoconstriction

24. safety of adenosine in cardiac indication -In a multicenter study, information was collected from 9256 pts. side effect were generally mild and well tolerated by most pts.(81%), Severe bronchospasm in 7 pts., no death, only one case each of myocardial infarction and pulmonary edema. -Transient AV block occurred in 8% of the pts.

25. safety of adenosine in cardiac indication -In a controlled study that investigated the safety and feasibility of adenosine adjunct to primary PTCA in pts. with acute MI administration of intracoronary adenosine was well tolerated. adverse cardiac events occurred in 5 0f 27(19%)pts. in adenosine group and 13 of 27(48%)pts. in saline group

26. safety of adenosine in cardiac indication -It is important to emphasize that the safety of adenosine in the nonsurgical practice may not reflect its safety in the perioperative period. -Unlike nonsurgical use, there may be a number of drug-to-drug interactions between adenosine and inhaled anesthetics and opioid

27. safety of adenosine in cardiac indication -With increased bronchotracheal stimulation during the perioperative period, the potential for bronchoconstriction may be higher than in a nonsurgical population need to be investigated further

28. conclusion -Adenosine appears to demonstrate opiod-sparing, anesthetic-sparing, and analgesic properties -Dose finding clinical studies are warranted to establish the optimal dose for achieving a balance between efficacy and side effects profile for adenosine use in the perioperative setting