Adenosine as a Non-Opioid Analgesic in the Perioperative Setting

Department of Anesthesiology, Duke University, Durham, North Carolina, United States
Anesthesia and analgesia (Impact Factor: 3.47). 09/2007; 105(2):487-94. DOI: 10.1213/01.ane.0000267260.00384.d9
Source: PubMed


Adenosine, a ubiquitous metabolic intermediate in the body, is involved in nearly every aspect of cell function, including neuromodulation and neurotransmission. Adenosine A(1) and A(2) receptors are widely distributed in the brain and spinal cord, and are a novel, non-opiate target for pain management. The potential of adenosine as a non-narcotic analgesic in anesthetized patients has been explored in clinical trials, including double-blind studies versus placebo and remifentanil infusion. These studies suggest that, compared to placebo or remifentanil, an intraoperative adenosine infusion stabilizes core hemodynamics and reduces the requirement for anesthesia during surgery. Further, adenosine improves postoperative recovery, as indicated by lower pain scores and less opioid consumption. The safety profile of adenosine has been well characterized based on use of currently approved adenosine products. The most common adverse events associated with its use include flushing, chest discomfort, dyspnea, headache, gastrointestinal discomfort, and lightheadedness. These effects are generally well tolerated and transient. Further studies are warranted to investigate the full potential of adenosine as a non-opioid analgesic in the perioperative setting.

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    • "Clinical studies Earlier clinical investigations reported analgesic effects of adenosine following i.v. infusion in a perioperative setting, and these actions were attributed to A 1 R activation (Hayashida et al., 2005; Gan and Habib, 2007). In more recent and larger controlled clinical trials, adenosine agents have not produced unambiguous analgesic properties . "
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    ABSTRACT: The main focus for development of adenosine targets as analgesics to date has been A1Rs due to its antinociceptive profile in various preclinical pain models. The usefulness of systemic A1R agonists may be limited by other effects (cardiovascular, motor), but enhanced selectivity for pain might occur with partial agonists, potent and highly selective agonists, or allosteric modulators. A2AR agonists exhibit some peripheral pronociceptive effects, but also act on immune cells to suppress inflammation and on spinal glia to suppress pain signalling and may be useful for inflammatory and neuropathic pain. A2BR agonists exhibit peripheral proinflammatory effects on immune cells, but also spinal antinociceptive effects similar to A2AR agonists. A3Rs are now demonstrated to produce antinociception in several preclinical neuropathic pain models, with mechanistic actions on glial cells, and may be useful for neuropathic pain. Endogenous adenosine levels can be augmented by inhibition of metabolism (via adenosine kinase) or increased generation (via nucleotidases), and these approaches have implications for pain. Endogenous adenosine contributes to antinociception by several pharmacological agents, herbal remedies, acupuncture, transcutaneous electrical nerve stimulation, exercise, joint mobilization, and water immersion via spinal and/or peripheral effects, such that this system appears to constitute a major pain regulatory system. Finally, caffeine inhibits A1-, A2A- and A3Rs with similar potency, and dietary caffeine intake will need attention in trials of: (a) agonists and/or modulators acting at these receptors, (b) some pharmacological and herbal analgesics, and (c) manipulations that enhance endogenous adenosine levels, all of which are inhibited by caffeine and/or A1R antagonists in preclinical studies. All adenosine receptors have effects on spinal glial cells in regulating nociception, and gender differences in the involvement of such cells in chronic neuropathic pain indicate gender may also need attention in preclinical and human trials evaluating efficacy of adenosine-based analgesics.
    Neuroscience 10/2015; DOI:10.1016/j.neuroscience.2015.10.031 · 3.36 Impact Factor
    • "Gan et al.[15] reported that i.v. adenosine perioperatively improves postoperative recovery, as indicated by lower pain scores and less opioid consumption. "
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    ABSTRACT: The infraclavicular brachial plexus block (ICB) is designed to deposit anesthetic high in the plexus, achieving anesthesia of the hand, forearm, elbow, and distal arm. Adenosine is a metabolic intermediate that is involved in nearly all aspects of cell function, including neurotransmission and signal transduction.This study was aimed to show whether addition of adenosine to bupivacaine in ultrasound-guided ICB had an analgesic effect. Sixty adult patients were divided into two equal groups, each group included 30 patients. Group I received infraclavicular bupivacaine 0.325% in a volume of 30 ml. Group II received 30 ml of 0.325% bupivacaine + 12 mg adenosine. The block was maintained with an infusion of 10 ml/h. The following parameters were assessed: Success rate, time of the sensory onset, motor block, visual analog scale (VAS), and amount of i.v. pethidine needed. This study showed an analgesic effect of infraclavicular adenosine as evidenced by a statistically significant shorter mean time of onset of the sensory block (16 vs. 20 min, P < 0.05), lower mean VAS score over 48 h (1.7 vs. 2.7, P < 0.05), longer mean time of first parenteral analgesic requirement (299 vs. 255 min, P < 0.05), and lower mean total dose of pethidine needed over 48 h after surgery (25.5 vs. 56.6 mg, P <0.05). All patients got successful infraclavicular block and recovered uneventfully without any sensory or motor deficit. Adenosine may provide valuable addition to the therapeutic options in anesthesia and pain management. Further research is required to figure out its exact role.
    04/2011; 5(2):132-7. DOI:10.4103/1658-354X.82779
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    • "The nature of the modulation of pain signaling depends very much upon the receptor subtype activated. In the periphery, adenosine A1 receptor activation produces pain suppression, while adenosine A2 and A3 receptor activation produces pain enhancement [1-3]. "
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    ABSTRACT: Adenosine has been shown to have a wide spectrum of unique pain-relieving effects in various clinical situations. The aim of this study was to investigate the effects of intraoperative adenosine infusion on acute opioid tolerance and opioid induced hyperalgesia induced by remifentanil in adult patients undergoing tonsillectomy. For this study, ninety patients were randomly allocated into groups that receive either adenosine (adenosine group) or saline (remifentnail group) intravenously under remifentanil based anesthesia and saline (sevoflurane group) under sevoflurane anesthesia. The patients in adenosine group received adenosine at dose of 80 µg/kg/min, and those in remifentnail group and sevoflurane group received an equal volume of saline 10 minutes after the induction of anesthesia until the end of surgery. Intraoperative evaluation included time weighted mean remifentanil dose, and postoperative evaluations included degree of pain severity at 1, 6, 12, and 24 hours, time to first postoperative requirement, and analgesic dose required during 24 hours after operation. Time weighted mean remifentanil dose during intraoperative period in adenosine group was significantly lower than that of remifentnail group (P = 0.00). The first postoperative analgesic were required earlier in remifentanil group than sevoflurane group or adenosine group (P = 0.00). Pethidine requirement during 24 hours in sevoflurane group and adenosine group was significantly lower than that of remifentnail group (P = 0.00). The visual analog scale scores for pain in sevoflurane group and adenosine group were significantly lower than those of remifentnail group for 12 hours after operation (P = 0.00). Incidence of hypotension (P = 0.024) and number of ephedrine administered (P = 0.011) in adenosine group were significantly higher than those of sevoflurane group. The above results suggest that intraoperative adenosine infusion prevent acute opioid tolerance and opioid induced hyperalgesia induced by remifentanil.
    The Korean journal of pain 03/2011; 24(1):7-12. DOI:10.3344/kjp.2011.24.1.7
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