Skip to main content
SpringerLink
Log in
Book cover

Methylxanthines pp 311–329Cite as

Methylxanthines and Pain

  • Chapter
  • First Online:

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 200))

Abstract

Caffeine, an antagonist of adenosine A1, A2A and A2B receptors, is known as an adjuvant analgesic in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen in humans. In preclinical studies, caffeine produces intrinsic antinociceptive effects in several rodent models, and augments the actions of NSAIDs and acetaminophen. Antagonism of adenosine A2A and A2B receptors, as well as inhibition of cyclooxygenase activity at some sites, may explain intrinsic antinociceptive and adjuvant actions. When combined with morphine, caffeine can augment, inhibit or have no effect depending on the dose, route of administration, nociceptive test and species; inhibition reflects spinal inhibition of adenosine A1 receptors, while augmentation may reflect the intrinsic effects noted above. Low doses of caffeine given systemically inhibit antinociception by several analgesics (acetaminophen, amitriptyline, oxcarbazepine, cizolirtine), probably reflecting block of a component of action involving adenosine A1 receptors. Clinical studies have demonstrated adjuvant analgesia, as well as some intrinsic analgesia, in the treatment of headache conditions, but not in the treatment of postoperative pain. Caffeine clearly exhibits complex effects on pain transmission; knowledge of such effects is important for understanding adjuvant analgesia as well as considering situations in which dietary caffeine intake may have an impact on analgesic regimens.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   349.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   449.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   449.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Abo-Salem OM, Hayallah AM, Bilkei-Gorzo A et al (2004) Antinociceptive effects of novel A2B adenosine receptor antagonists. J Pharmacol Exp Ther 308:358–366

    Article  PubMed  CAS  Google Scholar 

  • Aguirre-Banuelos P, Castaneda-Hernández G, López-Munoz FJ et al (1999) Effect of coadministration of caffeine and either adenosine agonists or cyclic nucleotides on ketolorac analgesia. Eur J Pharmacol 377:175–182

    Article  PubMed  CAS  Google Scholar 

  • Ahlijanian MK, Takemori AE (1985) Effects of (-)-N6-(R-phenylisopropyl)-adenosine (PIA) and caffeine on nociception and morphine-induced analgesia, tolerance and dependence in mice. Eur J Pharmacol 112:171–179

    Article  PubMed  CAS  Google Scholar 

  • Alvarez I, Andreu F, Buxens J et al (2000) Pharmacology of cizolirtine: a new analgesic agent. Methods Find Exp Clin Pharmacol 22:211–221

    Article  PubMed  CAS  Google Scholar 

  • Ambrósio AF, Soares-da-Silva P, Carvalho CM et al (2002) Mechanisms of action of carbamazepine and its derivatives, oxcarbazepine, BIA 2-093, and BIA 2-024. Neurochem Res 27:121–130

    Article  PubMed  Google Scholar 

  • Aubel B, Kayser V, Farré A et al (2007) Evidence for adenosine- and serotonin-mediated antihyperalgesic effects of cizolirtine in rats suffering from diabetic neuropathy. Neuropharmacology 52:487–496

    Article  PubMed  CAS  Google Scholar 

  • Bastia E, Varani K, Monopoli A et al (2002) Effects of A(1) and A(2A) adenosine receptor ligands in mouse acute models of pain. Neurosci Lett 328:241–244

    Article  PubMed  CAS  Google Scholar 

  • Camann WR, Murray RS, Mushlin PS et al (1990) Effects of oral caffeine on postdural puncture headache. A double-blind, placebo-controlled trial. Anesth Analg 70:181–184

    Article  PubMed  CAS  Google Scholar 

  • Castenada-Hernández G, Castillo-Méndez MS, López-Munoz FJ et al (1994) Potentiation by caffeine of the analgesic effect of aspirin in the pain-induced functional impairment model in the rat. Can J Physiol Pharmacol 72:1127–1131

    Article  Google Scholar 

  • DeLander GE, Hopkins CJ (1986) Spinal adenosine modulates descending antinociceptive pathways stimulated by morphine. J Pharmacol Exp Ther 239:88–93

    PubMed  CAS  Google Scholar 

  • Diamond S, Balm TK, Freitag FG (2000) Ibuprofen plus caffeine in the treatment of tension-type headache. Clin Pharmacol Ther 68:312–319

    Article  PubMed  CAS  Google Scholar 

  • Díaz-Reval MI, Ventura-Martínez R, Hernández-Delgadillo GP et al (2001) Effect of caffeine on antinociceptive action of ketoprofen in rats. Arch Med Res 32:13–20

    Article  PubMed  Google Scholar 

  • Diener HC, Pfaffenrath V, Pagler L et al (2005) The fixed combination of acetylsalicylic acid, paracetamol and caffeine is more effective than single substances and dual combination for the treatment of headache: a multicentre, randomized, double-blind, single-dose, placebo-controlled parallel group study. Cephalalgia 25:776–787

    Article  PubMed  CAS  Google Scholar 

  • Dworkin RH, O’Conner AB, Backonja M et al (2007) Pharmacological management of neuropathic pain: evidence-based recommendations. Pain 132:237–251

    Article  PubMed  CAS  Google Scholar 

  • Eisenach JC, Hood DD, Curry R et al (2004) Intrathecal but not intravenous opioids release adenosine from the spinal cord. J Pain 5:64–68

    Article  PubMed  CAS  Google Scholar 

  • Engelhardt G, Mauz AB, Pairet M (1997) Role of caffeine in combined analgesic drugs from the point of view of experimental pharmacology. Arzneimittelforschung/Drug Res 47:917–927

    CAS  Google Scholar 

  • Esmaoglu A, Akpinar H, Uğur F (2005) Oral multidose caffeine-paracetamol combination is not effective for the prophylaxis of postdural puncture headache. J Clin Anesth 17:58–61

    Article  PubMed  CAS  Google Scholar 

  • Esser MJ, Sawynok J (2000) Caffeine blockade of the thermal antihyperalgesic effect of acute amitriptyline in a rat model of neuropathic pain. Eur J Pharmacol 399:131–139

    Article  PubMed  CAS  Google Scholar 

  • Fennelly M, Galletly DC, Purdie GI (1991) Is caffeine withdrawal the mechanism of postoperative headache? Anesth Analg 72:449–453

    Article  PubMed  CAS  Google Scholar 

  • Fialip J, Porteix A, Marty H et al (1989) Lack of importance of caffeine as an analgesic adjuvant of dipyrone in mice. Arch Int Pharmacodyn Ther 302:86–95

    PubMed  CAS  Google Scholar 

  • Fiebich BL, Biber K, Lieb K et al (1996) Cyclooxygenase-2 expression in rat microglia is induced by adenosine A2A-receptors. Glia 18:152–160

    Article  PubMed  CAS  Google Scholar 

  • Fiebich BL, Lieb K, Hüll M et al (2000) Effects of caffeine and paracetamol alone or in combination with acetylsalicylic acid on prostaglandin E2 synthesis in rat microglial cells. Neuropharmacology 39:2205–2213

    Article  PubMed  CAS  Google Scholar 

  • Flores-Acevedo DM, Flores-Murrieta FJ, Castenada-Hernández G et al (1995) Potentiation of the analgesic effect of tolmetin, a potent non-steroidal anti-inflammatory drug, by caffeine in the rat. Pharmaceut Sci 1:441–444

    CAS  Google Scholar 

  • Fredholm BB (1980) Are methylxanthine effects due to antagonism of endogenous adenosine? Trends Pharmacol Sci 1:129–132

    Article  CAS  Google Scholar 

  • Fredholm BB, Bättig K, Holmén J et al (1999) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 51:83–133

    PubMed  CAS  Google Scholar 

  • Gayawali K, Pandhi P, Sharma PL (1991) Determination of the optimal analgesia-potentiating dose of caffeine and a study of its effect on the pharmacokinetics of aspirin in mice. Methods Find Clin Pharmacol 13:529–533

    CAS  Google Scholar 

  • Ghelardini C, Gaelotti N, Bartolini A (1997) Caffeine induces central cholinergic analgesia. Naunyn Schmiedebergs Arch Pharmacol 356:590–595

    Article  PubMed  CAS  Google Scholar 

  • Godfrey L, Yan L, Clarke GD et al (2006) Modulation of paracetamol antinociception by caffeine and by selective adenosine A2 receptor antagonists in mice. Eur J Pharmacol 531:80–86

    Article  PubMed  CAS  Google Scholar 

  • Granados-Soto V, Castenada-Hernández G (1999) A review of the pharmacokinetic and pharmacodynamic factors in the potentiation of the antinociceptive effect of nonsteroidal anti-inflammatory drugs by caffeine. J Pharmacol Toxicol 42:67–72

    Article  CAS  Google Scholar 

  • Granados-Soto V, López-Munoz FJ, Casteneda-Hernández G et al (1993) Characterization of the analgesic effects of paracetamol and caffeine combinations in the pain-induced functional impairment model in the rat. J Pharm Pharmacol 45:627–631

    Article  PubMed  CAS  Google Scholar 

  • Hampl KF, Schneider MC, Rüttimann U et al (1995) Perioperative administration of caffeine tablets for prevention of post-operative headaches. Can J Anesth 42:789–792

    Article  PubMed  CAS  Google Scholar 

  • Hering-Hanit R, Gadoth N (2003) Caffeine-induced headache in children and adolescents. Cephalalgia 23:332–335

    Article  PubMed  CAS  Google Scholar 

  • Ho IK, Loh HH, Way EL (1973) Cyclic adenosine monophosphate antagonism of morphine analgesia. J Pharmacol Exp Ther 185:336–346

    PubMed  CAS  Google Scholar 

  • Hussey MJ, Clarke CD, Ledent C et al (2007) Reduced response to the formalin test and lowered spinal NMDA glutamate receptor binding in adenosine A2A receptor knockout mice. Pain 129:287–294

    Article  PubMed  CAS  Google Scholar 

  • Jurna I (1981) Aminophylline differentiates between the depressant effects of morphine on the spinal reflex and on the spinal ascending activity evoked from afferent C fibres. Eur J Pharmacol 71:393–400

    Article  PubMed  CAS  Google Scholar 

  • Jurna I (1984) Cyclic nucleotides and aminophylline produce different effects on nociceptive motor and sensory responses in the rat spinal cord. Naunyn Schmiedebergs Arch Pharmacol 327:23–30

    Article  PubMed  CAS  Google Scholar 

  • Laska EM, Sunshine A, Mueller F et al (1984) Caffeine as an analgesic adjuvant. JAMA 251:1711–1718

    Article  PubMed  CAS  Google Scholar 

  • Ledent C, Vaugeois JM, Schiffman SN et al (1997) Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2A receptor. Nature 388:674–678

    Article  PubMed  CAS  Google Scholar 

  • Lipton RB, Stewart WF, Ryan RE et al (1998) Efficacy and safety of acetaminophen, aspirin, and caffeine in alleviating migraine headache pain. Arch Neurol 55:210–217

    Article  PubMed  CAS  Google Scholar 

  • López JRM, Domínguez-Ramírez AM, Cook HG et al (2006) Enhancement of antinociception by co-administration of ibuprofen and caffeine in arthritic rats. Eur J Pharmacol 544:31–38

    Article  PubMed  Google Scholar 

  • López-Munoz FJ, Castenada-Hernández G, Flores-Mirrieta FJ et al (1996) Effect of caffeine coadministration and nitric oxide synthesis inhibition on the antinociceptive action of ketolorac. Eur J Pharmacol 308:275–277

    Article  PubMed  Google Scholar 

  • Malec D, Michalska E (1988) The effect of methylxanthines on morphine analgesia in mice and rats. Pol J Pharmacol Pharm 40:223–232

    Article  PubMed  CAS  Google Scholar 

  • Mashimoto S, Ushijima I, Suetsugi M et al (1998) Stress-dependent antinociceptive effects of carbamazepine: a study in stressed and non-stressed rats. Prog Neuropsychopharmacol Biol Psychiatry 22:159–168

    Article  PubMed  CAS  Google Scholar 

  • Micó JA, Ardid D, Berrocoso E et al (2006) Antidepressants and pain. Trends Pharmacol Sci 27:348–354

    Article  PubMed  Google Scholar 

  • Migliardi JR, Armellino JJ, Friedman M et al (1994) Caffeine as an analgesic adjuvant in tension headache. Clin Pharmacol Ther 56:576–586

    Article  PubMed  CAS  Google Scholar 

  • Misra AL, Pontani RB, Vadlamani NL (1985) Potentiation of morphine analgesia by caffeine. Br J Pharmacol 84:789–791

    Article  PubMed  CAS  Google Scholar 

  • Nehlig A, Daval JL, Debry G (1992) Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Res Rev 17:39–170

    Article  Google Scholar 

  • Oliverio A, Castellano C, Pavone F et al (1983) Caffeine interferes with morphine-induced hyperactivity but not analgesia. Pol J Pharmacol Pharm 35:445–449

    Article  PubMed  CAS  Google Scholar 

  • Pareek SS, Chopde CT, Thakur Desai PA (1994) Adenosine enhances analgesic effect of tricyclic antidepressants. Indian J Pharmacol 26:159–161

    CAS  Google Scholar 

  • Person DL, Kissin I, Brown PT et al (1985) Morphine-caffeine analgesic interaction in rats. Anesth Analg 64:851–856

    Article  PubMed  CAS  Google Scholar 

  • Pham T, Carrega L, Sauze N et al (2003) Supraspinal antinociceptive effects of μ and δ agonists involve modulation of adenosine uptake. Anesthesiology 98:459–464

    Article  PubMed  CAS  Google Scholar 

  • Po ALW, Zhang WY (1998) Analgesic efficacy of ibuprofen alone and in combination with codeine or caffeine in post-surgical pain: a meta-analysis. Eur J Clin Pharmacol 53:303–311

    Article  PubMed  CAS  Google Scholar 

  • Sawynok J (2006) Adenosine and ATP receptors. In: Stein C (ed) Handbook of experimental pharmacology. Springer, Berlin, pp 301–320

    Google Scholar 

  • Sawynok J, Liu XJ (2003) Adenosine in the spinal cord and periphery: release and regulation of pain. Prog Neurobiol 69:313–340

    Article  PubMed  CAS  Google Scholar 

  • Sawynok J, Reid A (1996a) Caffeine antinociception: role of formalin concentration and adenosine A1 and A2 receptors. Eur J Pharmacol 298:105–111

    Article  PubMed  CAS  Google Scholar 

  • Sawynok J, Reid A (1996b) Neurotoxin-induced lesions to central serotonergic, noradrenergic and dopaminergic systems modify caffeine-induced antinociception in the formalin test and locomotor stimulation in rats. J Pharmacol Exp Ther 277:646–653

    PubMed  CAS  Google Scholar 

  • Sawynok J, Yaksh TL (1993) Caffeine as an analgesic adjuvant: a review of pharmacology and mechanisms of action. Pharmacol Rev 45:43–85

    PubMed  CAS  Google Scholar 

  • Sawynok J, Sweeney MI, White TD (1986) Classification of adenosine receptors mediating antinociception in the rat spinal cord. Br J Pharmacol 88:923–930

    Article  PubMed  CAS  Google Scholar 

  • Sawynok J, Sweeney MI, White TD (1989) Adenosine release may mediate spinal analgesia by morphine. Trends Pharmacol Sci 10:186–189

    Article  PubMed  CAS  Google Scholar 

  • Sawynok J, Reid A, Doak GJ (1995) Caffeine antinociception in the rat hot-plate and formalin tests and locomotor stimulation: involvement of noradrenergic mechanisms. Pain 61:203–213

    Article  PubMed  CAS  Google Scholar 

  • Sawynok J, Reid AR, Esser MJ (1999) Peripheral antinociceptive action of amitriptyline in the rat formalin test: involvement of adenosine. Pain 80:45–55

    Article  PubMed  CAS  Google Scholar 

  • Sawynok J, Reid AR, Liu XJ et al (2005) Amitriptyline enhances extracellular levels of adenosine in the rat hindpaw and inhibits adenosine uptake. Eur J Pharmacol 518:116–122

    Article  PubMed  CAS  Google Scholar 

  • Sawynok J, Reid A, Fredholm BB (2008) Caffeine reverses antinociception by amitriptyline in wild type mice but not in those lacking adenosine A1 receptors. Neurosci Lett 440:181–184

    Article  PubMed  CAS  Google Scholar 

  • Schachtel BP, Thoden WR, Konerman JP et al (1991) Headache pain model for assessing and comparing the efficacy of over-the-counter analgesic agents. Clin Pharmacol Ther 50:322–329

    Article  PubMed  CAS  Google Scholar 

  • Seegers AJM, Jager LP, Zandberg P et al (1981) The anti-inflammatory, analgesic and antipyretic activities of non-narcotic analgesic drug mixtures in rats. Arch Int Pharmacodyn Ther 251:237–254

    PubMed  CAS  Google Scholar 

  • Shapiro RE (2008) Caffeine and headaches. Curr Pain Headache Rep 12:311–315

    Article  PubMed  Google Scholar 

  • Siegers CP (1973) Effects of caffeine on the absorption and analgesic efficacy of paracetamol in rats. Pharmacology 10:19–27

    Article  PubMed  CAS  Google Scholar 

  • Sierralta F, Pinardi G, Mendez M et al (1995) Interaction of opioids with antidepressant antinociception. Psychopharmacology 122:374–378

    Article  PubMed  CAS  Google Scholar 

  • Suh HW, Song DK, Kim YH (1997) Differential effects of adenosine receptor antagonists injected intrathecally on antinociception by morphine and β-endorphin administered intracerebroventricularly in the mouse. Neuropeptides 31:339–344

    Article  PubMed  CAS  Google Scholar 

  • Sweeney MI, White TD, Sawynok J (1987a) Involvement of adenosine in the spinal antinociceptive effects of morphine and noradrenaline. J Pharmacol Exp Ther 243:657–665

    PubMed  CAS  Google Scholar 

  • Sweeney MI, White TD, Sawynok J (1987b) Morphine releases endogenous adenosine from the spinal cord in vivo. Eur J Pharmacol 141:169–170

    Article  PubMed  CAS  Google Scholar 

  • Sweeney MI, White TD, Sawynok J (1991) Intracerebroventricular morphine releases cyclic AMP and adenosine from the spinal cord via a serotonergic mechanism. J Pharmacol Exp Ther 259:1013–1028

    PubMed  CAS  Google Scholar 

  • Tomić MA, Vučković SM, Stepanović-Petrović RM et al (2004) The anti-hyperalgesic effects of carbamazepine and oxcarbazepine are attenuated by treatment with adenosine receptor antagonists. Pain 111:253–260

    Article  PubMed  Google Scholar 

  • Tomić MA, Vučković SM, Stepanović-Petrović RM et al (2006) Peripheral anti-hyperalgesia by oxcarbazepine: involvement of adenosine A1 receptors. Pharmazie 61:566–568

    PubMed  Google Scholar 

  • Ulugol A, Karadag HC, Tamer M et al (2002) Involvement of adenosine in the anti-allodynic effect of amitriptyline in streptozotocin-induced diabetic rats. Neurosci Lett 328:129–132

    Article  PubMed  CAS  Google Scholar 

  • Vinegar R, Traus JF, Selph JL et al (1976) Potentiation of the anti-inflammatory and analgesic activity of aspirin by caffeine in the rat. Proc Soc Exp Biol Med 151:556–560

    PubMed  CAS  Google Scholar 

  • Ward N, Whitney C, Avery D et al (1991) The analgesic effects of caffeine in headache. Pain 44:151–155

    Article  PubMed  CAS  Google Scholar 

  • Weber JG, Klinderworth JT, Arnold JJ et al (1997) Prophylactic intravenous administration of caffeine and recovery after ambulatory surgical procedures. Mayo Clin Proc 72:621–626

    PubMed  CAS  Google Scholar 

  • Wilson SG, Mogil JS (2001) Measuring pain in the (knockout) mouse: big challenges in a small mammal. Behav Brain Res 125:65–73

    Article  PubMed  CAS  Google Scholar 

  • Wu WP, Hao JX, Halldner L et al (2005) Increased nociceptive response in mice lacking the adenosine A1 receptor. Pain 113:395–404

    Article  PubMed  CAS  Google Scholar 

  • Wu WP, Hao JX, Fredholm BB et al (2006) Effect of acute and chronic administration of caffeine on pain-like behaviors in rats with partial sciatic nerve injury. Neurosci Lett 402:164–166

    Article  PubMed  CAS  Google Scholar 

  • Yaba G, Sezer Z, Tekol Y (2006) Interaction between venlafaxine and caffeine on antinociception in mice. Pharmazie 61:60–62

    PubMed  CAS  Google Scholar 

  • Yucel A, Ozyalcin S, Talu GK et al (1999) Intravenous administration of caffeine sodium benzoate for postdural puncture headache. Reg Anesth Pain Med 24:51–54

    PubMed  CAS  Google Scholar 

  • Zhang WY (2001) A benefit-risk assessment of caffeine as an analgesic adjuvant. Drug Saf 24:1127–1142

    Article  PubMed  CAS  Google Scholar 

  • Zhang WY, Po ALW (1996) Analgesic efficacy of paracetamol and its combination with codeine and caffeine in surgical pain – a meta-analysis. J Clin Pharm Ther 21:261–282

    Article  PubMed  CAS  Google Scholar 

  • Zhang WY, Po ALW (1997) Do codeine and caffeine enhance the analgesic effect of aspirin? – a systematic overview. J Clin Pharm Ther 22:79–97

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Conklin DR, Li X et al (2005) Intrathecal morphine reduces allodynia after peripheral nerve injury in rats via activation of a spinal A1 adenosine receptor. Anesthesiology 102:416–420

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgement

I thank Allison Reid for editorial and graphical assistance.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Dalhousie University, Halifax, NS, B3H 1X5, Canada

    Jana Sawynok

Authors
  1. Jana Sawynok
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jana Sawynok .

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Berlin Heidelberg

About this chapter

Cite this chapter

Sawynok, J. (2011). Methylxanthines and Pain. In: Methylxanthines. Handbook of Experimental Pharmacology, vol 200. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-13443-2_11

Download citation

Publish with us

Policies and ethics

Search

Navigation