Characterization of the analgesic actions of adenosine: comparison of adenosine and remifentanil infusions in patients undergoing major surgical procedures

Abstract

Perioperative pain is still a major problem, and new pharmacological means should be explored to mitigate such pain. Adenosine is an ubiquitous endogenous substance; when exogenously administered, it provides a number of salutary effects including neuromodulation, antinociception, and cytoprotective actions. The aim of this study was to characterize the perioperative antinociceptive-analgesic effects of intraoperative adenosine infusion and determine the duration of actions in the postoperative period, and compare them to those of remifentanil in patients undergoing major surgical procedures in a double-blind study.Sixty-two patients were randomly assigned to one of the two treatments. After standard induction of anesthesia, the lungs were mechanically ventilated. Anesthesia was maintained with a constant alveolar concentration of inhaled anesthetics (3% desflurane and 65% nitrous oxide in oxygen). A variable-rate of intravenous infusion of adenosine (50-500 microg kg(-1) x min(-1)) or remifentanil (0.05-0.5 microg kg(-1) x min(-1)) was initiated 5 min before the skin incision and was titrated to maintain systolic blood pressure and heart rate within 20% of baseline values during surgery. Postoperative evaluations included the level of sedation, degree of pain severity, opioid analgesic (fentanyl, morphine) consumption, and cardiorespiratory variables for 48 h. Intraoperative inhibition of the cardiovascular responses to surgical stimulation could be equally achieved by adenosine or remifentanil, and both could maintain excellent hemodynamic stability. Postoperatively, however, there were striking differences: (1). initial pain score was reduced by 60% (P<0.001) in the adenosine group compared to the remifentanil group and it remained lower throughout the 48 h recovery period; (2). postoperative morphine requirements during the first 0.25, 2 and 48 h were consistently lower in the adenosine group as compared to the remifentanil group (78, 71 and 42%, P<0.001, respectively); (3). adenosine patients remained significantly less sedated at all evaluations; (4) the end-tidal and arterial carbon dioxide values in the remifentanil group were significantly higher when patients were admitted to the postanesthesia care unit. No adverse effect of adenosine was observed at any time. Intraoperative adenosine infusion provided a salutary recovery from anesthesia associated with a pronounced and sustained postoperative pain relief. Compared to remifentanil, adenosine significantly reduced the opioid requirements and minimized the side effects including protracted sedation, cardiorespiratory instability, nausea, and vomiting in the postoperative recovery period.

Addicting drugs utilize a synergistic molecular mechanism in common requiring adenosine and Gi-βγ dimers

“…Also, adenosine receptor antagonists attenuate the development of morphine sensitization in mice (47). In humans, adenosine infusions strikingly reduce the requirement for opiates for postoperative pain (48). These behavioral and clinical observations support our hypothesis that ␤␥-mediated synergy produced by low concentrations of exogenous opioid agonists in the presence of endogenous adenosine regulates responses to opiates.…”

Activation of the Adenosine A3Receptor in RAW 264.7 Cells Inhibits Lipopolysaccharide-Stimulated Tumor Necrosis Factor-α Release by Reducing Calcium-Dependent Activation of Nuclear Factor-κB and Extracellular Signal-Regulated Kinase 1/2

“…In animal models of septic shock, adenosine confers an anti-inflammatory action (Firestein et al, 1994), presumably by inhibiting similar pathways described for LPS. Perioperative infusion of adenosine provides effective control of surgical pain in human without producing major side effects (Fukunaga et al, 2003), suggesting that this agent could be similarly administered to treat sepsis.…”

Clinical application of adenosine and ATP for pain control

“…In anesthetized patients, a relatively low dose of adenosine infusion (80 mg·kg -1 ·min -1 ) has been used [28][29][30]. However, much higher doses (up to 290-500 mg·kg -1 ·min -1 ) also have been successfully administered using a variable rate of titration protocol (Table 1) [31,32].…”