Abstract
This review summarizes clinical application of adenosine and adenosine 5′-triphosphate (ATP) in pain conditions. Investigations have been performed in patients with acute perioperative pain or chronic neuropathic pain treated with intravenous adenosine or ATP, or intrathecal adenosine. Characteristic central adenosine A1 receptor-mediated pain-relieving effects have been observed after intravenous adenosine infusion in human inflammation/sensitization pain models and in patients with chronic neuropathic pain. Adenosine compounds, in low doses, can reduce allodynia/hyperalgesia more consistently than spontaneous pain, suggesting that these compounds affect neuronal pathophysiological mechanisms involved in central sensitization. Such pain-relieving effects, which are mostly mediated via central adenosine A1 receptor activation, have a slow onset and long duration of action, lasting usually for hours or days and occasionally for months. With acute perioperative pain, treatment with a low-dose infusion of adenosine compounds and the A1 receptor-mediated central antisensitization mechanisms may play only a minor part in the total perioperative pain experience. By administering sufficient doses of adenosine compounds during surgery, however, significant and long-lasting perioperative pain relief can be achieved via central A1 receptor-mediated antinociceptive/analgesic actions as well as via peripheral A2a or A3 receptor-mediated antiinflammatory actions. Thus, adenosine compounds have significant potential for alleviating various types of pain.
Similar content being viewed by others
References
J Sawynok (1998) ArticleTitleAdenosine receptor activation and nociception Eur J Pharmacol 317 1–11
R Guieu B Dussol G Halimi G Bechis F Sampier Y Berland J Sampol F Couraud H Rochat (1998) ArticleTitleAdenosine and the nervous system: pharmacological data and therapeutic perspectives Gen Pharmacol 31 553–561
BA Chizh P Illes (2001) ArticleTitleP2X receptors and nociception Pharmacol Rev 53 553–568
JA Ribeiro AM Sebastiao A de Mendonca (2002) ArticleTitleAdenosine receptors in the nervous system: pathophysiological implications Prog Neurobiol 68 377–392
MF Jarvis (2003) ArticleTitleContributions of P2X(3) homometric and heterometric channels to acute and chronic pain Expert Opin Ther Targets 7 513–522
J Sawynok XJ Liu (2003) ArticleTitleAdenosine in the spinal cord and periphery: release and regulation of pain Prog Neurobiol 69 313–340
AF Fukunaga TA Miyamoto Y Kikuta Y Kaneko T Ichinohe (1995) Role of adenosine and adenosine triphosphate as anesthetic adjuvants L Belardinelli A Pelleg (Eds) Adenosine and adenine nucleotides: from molecular biology to integrative physiology Kluwer Academic Boston 511–523
AF Fukunaga (1997) Adenosine compounds PF White (Eds) Textbook of intravenous anesthesia Williams & Wilkins Baltimore 413–432
A Sollevi (1997) ArticleTitleAdenosine for pain control Acta Anaesthesiol Scand Suppl 110 135–136
M Segerdahl A Sollevi (1998) ArticleTitleAdenosine and pain relief: a clinical overview Drug Dev Res 45 151–158
BS Khakh G Burnstock C Kennedy BF King A North P Seguela M Voigh PPA Humphrey (2001) ArticleTitleInternational Union of Pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits Pharmacol Rev 53 107–108
K Sak TE Webb (2002) ArticleTitleA retrospective of recombinant P2Y receptor subtypes and their pharmacology Arch Biochem Biophys 397 131–136
T Sumida MA Smith Y Maehara JG Collins LM Kitahata (1998) ArticleTitleSpinal R-phenyl-isopropyl adenosine inhibits spinal dorsal horn neurons responding to noxious heat stimulation in the absence and presence of sensitization Pain 74 307–313
KF Sjülund M von Heijne JX Hao XJ Xu A Sollevi Z Wiesenfeld-Hallin (1998) ArticleTitleIntrathecal administration of the adenosine A1 receptor agonist R-phenylisopropyl adenosine reduces presumed pain behaviour in a rat model of central pain Neurosci Lett 243 89–92
PM Lavand’homme JC Eisenach (1999) ArticleTitleExogenous and endogenous adenosine enhance the spinal antiallodynic effects of morphine in a rat model of neuropathic pain Pain 80 31–36
M Okada T Nakagawa M Minami M Satoh (2002) ArticleTitleAnalgesic effects of intrathecal administration of P2Y nucleotide receptor agonists UTP and UDP in normal and neuropathic pain model rats Pharmacol Exp Ther 303 66–73
AA Gomaa (1987) ArticleTitleCharacteristics of analgesia induced by adenosine triphosphate Pharmacol Toxicol 61 199–202
JL Gordon (1986) ArticleTitleExtracellular ATP: effects, sources and fate Biochem J 233 309–319
HJ Agteresch PC Dagnelie JW van den Berg JH Wilson (1999) ArticleTitleAdenosine triphosphate: established and potential clinical applications Drugs 58 211–232
R Guieu F Sampieri J Pouget B Guy H Rochat (1994) ArticleTitleAdenosine in painful legs and moving toes syndrome Clin Neuropharmacol 17 460–469
M Hayashida K Sato A Fukunaga K Fukuda H Sekiyama S Sawamura H Arita K Hanaoka (2004) ArticleTitleIntravenous infusion of adenosine 5′-triphosphate alleviated a disabling postherpetic neuralgia J Anesth 18 36–38
I Biaggioni B Olafsson RM Robertson AS Hollister D Robertson (1987) ArticleTitleCardiovascular and respiratory effects of adenosine in conscious man; evidence for chemoreceptor activation Circ Res 61 779–786
A Sollevi (1991) Effect of adenosine infusion in the conscious man JW Phillis (Eds) Adenosine and adenosine nucleotides as regulators of cellular function CRC Press Boca Raton, FL 283–291
A Sollevi M Belfrage T Lundeberg M Segerdahl P Hansson (1995) ArticleTitleSystemic adenosine infusion: a new treatment to alleviate spontaneous and evoked neuropathic pain Pain 61 155–158
M Belfrage A Sollevi M Segerdahl KF Sjölund P Hansson (1995) ArticleTitleSystemic adenosine infusion alleviates spontaneous and stimulus evoked pain in patients with peripheral neuropathic pain Anesth Analg 81 713–717
C Sylvén (1993) ArticleTitleMechanisms of pain in angina pectoris: a critical review of the adenosine hypothesis Cardiovasc Drugs Ther 7 787–791
RB Parker PL McCollam (1990) ArticleTitleAdenosine in the episodic treatment of paroxysmal supraventricular tachycardia Clin Pharm 9 261–271
M Segerdahl A Ekblom K Sandelin M Wickman A Sollevi (1995) ArticleTitlePeroperative adenosine infusion reduces the requirements for isoflurane and postoperative analgesics Anesth Analg 80 1145–1149
M Segerdahl E Persson A Ekblom A Sollevi (1996) ArticleTitlePerioperative adenosine infusion reduces isoflurane requirements during general anesthesia for shoulder surgery Acta Anaesthiol Scand 40 792–797
M Segerdahl L Irestedt A Sollevi (1997) ArticleTitleAntinociceptive effect of perioperative adenosine infusion in hysterectomy Acta Anaesthiol Scand 41 473–479
E Zarate MM Sa Rego PF White L Duffy VE Shearer JD Griffin CW Whitten (1999) ArticleTitleComparison of adenosine and remifentanil infusions as adjuvants to desflurane anesthesia Anesthesiology 90 956–963
AF Fukunaga GE Alexander CW Stark (2003) ArticleTitleCharacterization of the analgesic actions of adenosine: comparison of adenosine and remifentanil infusions in patients undergoing major surgical procedures Pain 101 129–138
A Ekblom M Segerdahl A Sollevi (1995) ArticleTitleAdenosine but not ketamine or morphine increases the cutaneous heat pain threshold in healthy volunteers Acta Anaesthesiol Scand 39 717–722
C Sylvén B Eriksson J Jensen E Geigant RG Hallin (1996) ArticleTitleAnalgesic effects of adenosine during exercise-provoked myocardial ischemia Neuroreport 7 1521–1525
NJ Giffin F Kowacs V Libri P Williams PJ Goadsby H Kaube (2003) ArticleTitleEffect of the adenosine A1 receptor agonist GR79236 on trigeminal nociception with blink reflex recordings in healthy human subjects Cephalalgia 23 287–292
M Segerdahl A Ekblom A Sollevi (1994) ArticleTitleThe influence of adenosine, ketamine and morphine on experimentally induced ischemic pain in healthy volunteers Anesth Analg 79 787–791
CP Rae MD Mansfield C Dryden J Kinsella (1999) ArticleTitleAnalgesic effect of adenosine on ischaemic pain in human volunteers Br J Anaesth 82 427–428
M Segerdahl A Ekblom KF Sjölund M Belfrage C Forsberg A Sollevi (1995) ArticleTitleSystemic adenosine attenuates touch evoked allodynia induced by mustard oil in humans Neuroreport 6 753–756
KF Sjölund M Segerdahl A Sollevi (1999) ArticleTitleAdenosine reduces secondary hyperalgesia in two human models of cutaneous inflammatory pain Anesth Analg 88 605–610
J Dirks KL Petersen MC Rowbotham JB Dahl (2001) ArticleTitleEffect of systemic adenosine on pain and secondary hyperalgesia associated with the heat/capsaicin sensitization model in healthy volunteers Reg Anesth Pain Med 26 414–419
J Dirks KL Petersen JB Dahl (2003) ArticleTitleThe heat/capsaicin sensitization model: a methodologic study J Pain 4 122–128
R Karlsten T Gordh BA Svensson SuffixJr (1993) ArticleTitleA neurotoxicologic evaluation of the spinal cord after chronic intrathecal injection of R-phenylisopropyl adenosine (R-PIA) in the rat Anesth Analg 77 731–736
K Rane R Karlsten A Sollevi T Gordh SuffixJr BA Svensson (1999) ArticleTitleSpinal cord morphology after chronic intrathecal administration of adenosine in the rat Acta Anaesthesiol Scand 43 1035–1040
A Chiari TL Yaksh RR Myers J Provencher L Moore CS Lee JC Eisenach (1999) ArticleTitlePreclinical toxicity screening of intrathecal adenosine in rats and dogs Anesthesiology 91 824–832
K Rane M Segerdahl M Goiny A Sollevi (1998) ArticleTitleIntrathecal adenosine administration: a phase I clinical safety study in healthy volunteers, with additional evaluation of its influence on sensory thresholds and experimental pain Anesthesiology 89 1108–1115
JC Eisenach DD Hood R Curry (2002) ArticleTitlePhase I safety assessment of intrathecal injection of an American formulation of adenosine in humans Anesthesiology 96 24–28
JC Eisenach DD Hood R Curry (2002) ArticleTitlePreliminary efficacy assessment of intrathecal injection of an American formulation of adenosine in humans Anesthesiology 96 29–34
JC Eisenach R Curry DD Hood (2002) ArticleTitleDose response of intrathecal adenosine in experimental pain and allodynia Anesthesiology 97 938–942
R Guieu JC Peragut P Roussel H Hassani F Sampieri G Bechis R Gola H Rochat (1996) ArticleTitleAdenosine and neuropathic pain Pain 68 271–274
KF Sjölund M Belfrage R Karlsten M Segerdahl S Arner T Gordh A Solevi (2001) ArticleTitleSystemic adenosine infusion reduces the area of tactile allodynia in neuropathic pain following peripheral nerve injury: a multi-centre, placebo controlled study. Eur J Pain 5 199–207
E Gyllenhammar LO Nordfors (2001) ArticleTitleSystemic adenosine infusions alleviated neuropathic pain Pain 94 121–122
ME Lynch AJ Clark J Sawynok (2003) ArticleTitleIntravenous adenosine alleviates neuropathic pain: a double blind placebo controlled crossover trial using an enriched enrolment design Pain 103 111–117
R Karlsten T Gordh SuffixJr (1995) ArticleTitleAn A1-selective adenosine agonist abolishes allodynia elicited by vibration and touch after intrathecal injection Anesth Analg 80 844–847
M Belfrage M Segerdahl S Arner A Sollevi (1999) ArticleTitleThe safety and efficacy of intrathecal adenosine in patients with chronic neuropathic pain Anesth Analg 89 136–142
JC Eisenach RL Rauck R Curry (2003) ArticleTitleIntrathecal, but not intravenous adenosine reduces allodynia in patients with neuropathic pain Pain 105 65–70
A Sollevi (1992) ArticleTitleAdenosine infusion during isoflurane-nitrous oxide anaesthesia: indications of perioperative analgesic effect Acta Anaesthesiol Scand 36 595–599
A Apan S Ozcan U Buyukkocak O Anbarci H Basar (2003) ArticleTitlePerioperative intravenous adenosine infusion to extend postoperative analgesia in brachial plexus block Eur J Anaesthesiol 20 916–919
A Apan H Basar S Ozcan U Buyukkocak (2003) ArticleTitleCombination of adenosine with prilocaine and lignocaine for brachial plexus block does not prolong postoperative analgesia Anaesth Intensive Care 31 648–652
K Rane A Sollevi M Segerdahl (2000) ArticleTitleIntrathecal adenosine administration in abdominal hysterectomy lacks analgesic effect Acta Anaesthesiol Scand 44 868–872
K Rane A Sollevi M Segerdahl (2003) ArticleTitleA randomised double-blind evaluation of adenosine as adjunct to sufentanil in spinal labour analgesia Acta Anaesthesiol Scand 47 601–603
BN Cronstein (1994) ArticleTitleAdenosine, an endogenous anti-inflammatory agent J Appl Physiol 76 5–13
MC Montesinos A Desai D Delano JF Chen JS Fink MA Jacobson BN Cronstein (2003) ArticleTitleAdenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68 Arthritis Rheum 48 240–247
RA Seymour JE Hawkesford CM Hill J Frame C Andrews (1999) ArticleTitleThe efficacy of novel adenosine agonist (WAG 994) in postoperative dental surgery Br J Clin Pharmacol 47 675–680
M Hayashida A Fukunaga K Hanaoka (2003) ArticleTitleAn animal model for surgical anesthesia and analgesia: characterization with isoflurane anesthesia and remifentanil analgesia Anesth Analg 97 1340–1346
Hayashida M, Fukunaga A, Fukuda K, Sakurai S, Hanaoka K (2004) Does intravenous infusion of adenosine really exert an anti-nociceptive effect? In: Proceedings of the 11th International Pain Clinic World Society of Pain Clinicians, Monduzzi Editore, Bologna, pp 475–478
M Hayashida K Fukuda A Fukunaga A Meno K Sato K Tarui H Arita Y Kaneko K Hanaoka (2005) ArticleTitleAnalgesic effect of intravenous ATP on postherpetic neuralgia in comparison with responses to intravenous ketamine and lidocaine J Anesth 19 31–35
Fukuda K, Hayashida M, Fukunaga A, Kasahara M, Koukita Y, Ichinohe T, Kaneko Y (2004) Intravenous ATP in chronic intractable orofacial pain. In: Proceedings of the 11th International Pain Clinic World Society of Pain Clinicians, Monduzzi Editore, Bologna, pp 479–482
HJ Agteresch PC Dagnelie T Rietveld JWO van der Berg AHJ Danser JHP Wilson (2000) ArticleTitlePharmacokinetics of intravenous ATP in cancer patients Eur J Clin Pharmacol 56 49–55
CM Haskell M Wong A Williams LY Lee (1996) ArticleTitlePhase I trial of extracellular adenosine 5′-triphosphate in patients with advanced cancer Med Pediatr Oncol 27 165–173
K Komukai K Hashimoto T Shibata K Iwano M Muto J Mogi K Imai T Horie S Mochizuki (2002) ArticleTitleEffect of continuous ATP injection on human hemodynamics Circ J 66 926–929
HL Fields M Rowbotham R Baron (1998) ArticleTitlePostherpetic neuralgia: irritable nociceptors and deafferentation Neurobiol Dis 5 209–227
M Pappagallo AL Oaklander AL Quatrano-Piacentini MR Clark SN Raja (2000) ArticleTitleHeterogenous patterns of sensory dysfunction in postherpetic neuralgia suggest multiple pathophysiologic mechanisms Anesthesiology 92 691–698
M Moriyama A Kitamura H Ikezaki K Nakanishi C Kim A Sakamoto R Ogawa (2004) ArticleTitleSystemic ATP infusion improves spontaneous pain and tactile allodynia, but not tactile hypesthesia, in patients with postherpetic neuralgia J Anesth 18 177–180
Author information
Authors and Affiliations
About this article
Cite this article
Hayashida, M., Fukuda, Ki. & Fukunaga, A. Clinical application of adenosine and ATP for pain control. J Anesth 19, 225–235 (2005). https://doi.org/10.1007/s00540-005-0310-8
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s00540-005-0310-8