Caffeine does not attenuate experimentally induced ischemic pain in healthy subjects J. DELLERMALM, M. SEGERDAHL and S. GRASS Department for Clinical Science, Intervention and Technology, Division of Anesthesiology, Karolinska Institutet at Karolinska University Hospital – Huddinge, Stockholm, Sweden Background and aims: Caffeine is likely the most widely used psychoactive substance in the world. It is also an analgesic adjuvant and has individual analgesic proper- ties. The latter effect has been attributed to adenosine receptor antagonism, but the site of action is unknown. The aim of this study was to investigate the analgesic properties of caffeine on experimentally induced ischemic pain and to attempt to elucidate whether the site of action is central or peripheral. Materials and methods: Seventeen healthy subjects re- ceived intravenous (i.v.) regional and systemic infusions of caffeine at 10 mg/kg or placebo in a double-blind, crossover fashion to investigate the site of action for caffeine-induced analgesia. Subjects underwent a sub- maximum effort tourniquet test. Pain scores [visual analo- gue scale (VAS), 0–100] were assessed every minute up to a maximum of 45 min. Results: The sum of pain scores (SPS, accumulation of VAS scores) was attenuated neither by systemic 2405 ( Æ 234) nor by i.v. regional caffeine 2427 (Æ 190) as com- pared with placebo 2442 (Æ 205), P 5 0.99 (mean Æ SEM). Time to maximal VAS score did not differ significantly between treatments, P 5 0.94. There was no correlation between caffeine concentration in plasma and time to maximal pain score, or between SPS and plasma concen- tration. Conclusion: Caffeine does not have an analgesic effect on ischemic pain, either by a peripheral or by a central site of action. Accepted for publication 5 May 2009 r 2009 The Authors Journal compilation r 2009 The Acta Anaesthesiologica Scandinavica Foundation C AFFEINE is likely the most widely used psy- choactive drug in the world. It has effects on numerous physiological functions, including phy- sical endurance, mood, sleep and pain. 1 It has been shown that when administered in combination with analgesics, such as NSAIDs, caffeine has an additive effect on analgesia. This effect is thought to be mediated by a pharmacodynamic interaction, and caffeine is accepted as being an analgesic adjuvant. 2,3 By itself, caffeine also seems to have analgesic properties, mainly described in the treat- ment of various forms of headache, such as non- migrainous and post-dural puncture headache. 4 The mechanism causing the latter is, at least in part, thought to be dilation of cerebral blood vessels. 5 The effect of caffeine on this type of headache may thus be due to its vaso-constrictive properties. 6 However, there are studies showing an analgesic effect of caffeine, e.g. on muscle pain during exercise. 7 To our knowledge, there is only one randomized-controlled trial investigating the effect of caffeine on ischemic pain. This study, however, only included seven subjects and ana- lyzed ischemic muscle pain during 1 min. 8 The mechanisms through which caffeine exerts its analgesic effects can likely be attributed to adenosine receptor antagonism. Caffeine is a non- selective antagonist at all four subtypes of the adenosine receptor: A1, A2a, A2b and A3. The main effect of physiological relevance is thought to be caffeine’s antagonism of A1 and A2a recep- tors. Pre-clinical studies suggest that A1 receptors exert inhibitory effects on pain, while A2a have a pro-nociceptive effect. 9–11 Other effects in the cen- tral nervous system include influence on sleep and arousal, as well as cognition and memory function. Adenosine receptors also appear to be involved in neuronal degeneration and maturation. 12 There are adenosine receptors both centrally in the nervous system and in peripheral tissues. 13 Animal studies have suggested a pro-nociceptive effect when caf- feine is administered peripherally, whereas the 1288 Acta Anaesthesiol Scand 2009; 53: 1288–1292 Printed in Singapore. All rights reserved r 2009 The Authors Journal compilation r 2009 The Acta Anaesthesiologica Scandinavica Foundation ACTA ANAESTHESIOLOGICA SCANDINAVICA doi: 10.1111/j.1399-6576.2009.02038.x