You have full text access to this OnlineOpen article
Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review
Article first published online: 15 MAY 2009
DOI: 10.1111/j.1365-2125.2009.03456.x
© 2009 The Authors. Journal compilation © 2009 The British Pharmacological Society
Additional Information
How to Cite
Staahl, C., Olesen, A. E., Andresen, T., Arendt-Nielsen, L. and Drewes, A. M. (2009), Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review. British Journal of Clinical Pharmacology, 68: 149–168. doi: 10.1111/j.1365-2125.2009.03456.x
Publication History
- Issue published online: 7 AUG 2009
- Article first published online: 15 MAY 2009
- Received 2 October 2008Accepted 27 April 2009
REFERENCES
- 1, , . Health Status of the German Population: results of a Representative Survey Using the euroqol questionnaire. Gesundheitswesen 2005; 67: 173–82.
- 2, , . Experimental pain in gastroenterology: a reappraisal of human studies. Scand J Gastroenterol 2003; 38: 1115–30.
- 3, , . Human experimental pain models in drug development: translational pain research. Curr Opin Investig Drugs 2007; 8: 41–53.
- 4, . The peripheral apparatus of muscle pain: evidence from animal and human studies. Clin J Pain 2001; 17: 2–10.
- 5, , , , . A comparative study of oxycodone and morphine in a multi-modal, tissue-differentiated experimental pain model. Pain 2006; 123: 28–36.
- 6, , , , . Assessing analgesic actions of non-opioid analgesics by experimental pain models in healthy volunteers – an updated review. Br J Clin Pharmacol 2009; (in press).
- 7, , , , . Multi-modal and tissue-differentiated experimental pain assessment: reproducibility of a new concept for assessment of analgesics. Basic Clin Pharmacol Toxicol 2006; 98: 201–11.
- 8, , , , . Comparison of five experimental pain tests to measure analgesic effects of alfentanil. Anesthesiology 2001; 95: 22–9.
- 9, , . Painful and non-painful pressure sensations from human skeletal muscle. Exp Brain Res 2004; 159: 273–83.
- 10, . Psychophysiology of experimentally induced pain. Physiol Rev 1993; 73: 639–71.
- 11, . Experimental human pain models: a review of standardised methods for preclinical testing of analgesics. Basic Clin Pharmacol Toxicol 2004; 95: 97–111.
- 12. Pain measurement. Acta Anaesthesiol Scand 1999; 43: 897–908.
- 13. The neurobiology of pain. Lancet 1999; 353: 1610–5.
- 14, . Mechanism-based pain diagnosis: issues for analgesic drug development. Anesthesiology 2001; 95: 241–9.
- 15, , , . Gabapentin suppresses cutaneous hyperalgesia following heat-capsaicin sensitization. Anesthesiology 2002; 97: 102–7.
- 16, , . The effect of chronic oral desipramine on capsaicin-induced allodynia and hyperalgesia: a double-blinded, placebo-controlled, crossover study. Anesth Analg 2002; 95: 973–8, table.
- 17, , , , , . Preclinical assessment of candidate analgesic drugs: recent advances and future challenges. J Pharmacol Exp.Ther 2006; 319: 507–14.
- 18, , , , . Assessment of the effect of dextromethorphan and ketamine on the acute nociceptive threshold and wind-up of the second pain response in healthy male volunteers. Br J Clin Pharmacol 2002; 53: 604–12.
- 19, . Lasers and other thermal stimulators for activation of skin nociceptors in humans. Neurophysiol Clin 2003; 33: 259–68.
- 20, . Cold-evoked pain varies with skin type and cooling rate: a psychophysical study in humans. Pain 1999; 83: 123–35.
- 21. Cold-induced pain and prickle in the glabrous and hairy skin. Pain 1998; 75: 47–57.
- 22, , , , , . Role of intradental A- and C-type nerve fibres in dental pain mechanisms. Proc Finn Dent Soc 1992; 88 (Suppl. 1): 507–16.
- 23, , , , . Intra- and interrater agreement of pressure pain threshold for masticatory structures in children reporting orofacial pain related to temporomandibular disorders and symptom-free children. J Orofac Pain 2007; 21: 133–42.
- 24, , , , , . Systemic adenosine increase during cold pressor test is dependent on sympathetic activation. Clin Exp Pharmacol Physiol 1999; 26: 774–8.
- 25, , . The cold pressor test: effects on sympathetic nerve activity in human muscle and skin nerve fascicles. Acta Physiol Scand 1989; 137: 325–34.
- 26, , , . Temporal summation in muscles and referred pain areas: an experimental human study. Muscle Nerve 1997; 20: 1311–3.
- 27, , , , , . The effect of N-methyl-D-aspartate antagonist (ketamine) on single and repeated nociceptive stimuli: a placebo-controlled experimental human study. Anesth Analg 1995; 81: 63–8.
- 28, , . Secondary hyperalgesia and presynaptic inhibition: an update. Eur J Pain 2003; 7: 345–51.
- 29. Inflammatory pain in experimental burns in man. Dan Med Bull 2000; 47: 168–95.
- 30, , . Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin. J Physiol 1992; 448: 749–64.
- 31, . The mu-opioid agonist remifentanil attenuates hyperalgesia evoked by blunt and punctuated stimuli with different potency: a pharmacological evaluation of the freeze lesion in humans. Pain 2003; 102: 151–61.
- 32, , , , , . A new model of electrically evoked pain and hyperalgesia in human skin: the effects of intravenous alfentanil, S(+)-ketamine, and lidocaine. Anesthesiology 2001; 95: 395–402.
- 33, , , , , . Differential modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by S-ketamine and clonidine in humans. Anesthesiology 2003; 99: 152–9.
- 34. Multiple dose gabapentin attenuates cutaneous pain and central sensitisation but not muscle pain in healthy volunteers. Pain 2006; 125: 158–64.
- 35, , , . Experimental deep tissue pain in wrist extensors – a model of lateral epicondylalgia. Eur J Pain 2003; 7: 277–88.
- 36, , , , . Contribution of central sensitisation to the development of non-cardiac chest pain. Lancet 2000; 356: 1154–9.
- 37, , , , . Quantitative sensory examination during epidural anaesthesia and analgesia in man: effects of morphine. Pain 1993; 52: 75–83.
- 38, . Laser-evoked cerebral potentials in the assessment of cutaneous pain sensitivity in normal subjects and patients. Rev Neurol (Paris) 1991; 147: 625–43.
- 39, , , . Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 2005; 9: 463–84.
- 40, , , , , . The effect of ketamine on stimulation of primary and secondary hyperalgesic areas induced by capsaicin – a double-blind, placebo-controlled, human experimental study. Pain 1996; 66: 51–62.
- 41, , . Ketamine, an NMDA receptor antagonist, suppresses spatial and temporal properties of burn-induced secondary hyperalgesia in man: a double-blind, cross-over comparison with morphine and placebo. Pain 1997; 72: 99–106.
- 42, , , , , . Peripheral antihyperalgesic effect of morphine to heat, but not mechanical, stimulation in healthy volunteers after ultraviolet-B irradiation. Anesth Analg 1999; 88: 117–22.
- 43, . Topically administered ketamine reduces capsaicin-evoked mechanical hyperalgesia. Clin J Pain 2006; 22: 32–6.
- 44, , , . Comparative analgesic and mental effects of increasing plasma concentrations of dexmedetomidine and alfentanil in humans. Anesthesiology 2004; 101: 744–52.
- 45, , , , , , . Alfentanil and placebo analgesia: no sex differences detected in models of experimental pain. Anesthesiology 2005; 103: 130–9.
- 46, , , , , , . Ondansetron does not inhibit the analgesic effect of alfentanil. Br J Anaesth 1994; 73: 326–30.
- 47, , , , . Psychophysical and electrophysiological responses to experimental pain may be influenced by sedation: comparison of the effects of a hypnotic (propofol) and an analgesic (alfentanil). Br J Anaesth 1996; 77: 165–71.
- 48, , , . Reduction of human experimental muscle pain by alfentanil and morphine. Eur J Pain 2006; 10: 733–41.
- 49, , , , . Concentration-effect relationships for intravenous alfentanil and ketamine infusions in human volunteers: effects on acute thresholds and capsaicin-evoked hyperpathia. J Clin Pharmacol 2002; 42: 70–80.
- 50, , , , , , . Differential opioid action on sensory and affective cerebral pain processing. Clin Pharmacol Ther 2008; 83: 577–88.
- 51, , , . Profiles of opioid analgesia in humans after intravenous bolus administration: alfentanil, fentanyl and morphine compared on experimental pain. Pain 1990; 43: 47–55.
- 52, , . Behavioral and physiological effects of remifentanil and alfentanil in healthy volunteers. Anesthesiology 1999; 90: 718–26.
- 53, , , , , . Pharmacological modulation of experimental phasic and tonic muscle pain by morphine, alfentanil and ketamine in healthy volunteers. Acta Anaesthesiol Scand 2003; 47: 1020–30.
- 54, , , . Alfentanil, but not amitriptyline, reduces pain, hyperalgesia, and allodynia from intradermal injection of capsaicin in humans. Anesthesiology 1997; 86: 1279–87.
- 55, , , , . Analgesic and cognitive effects of intravenous ketamine-alfentanil combinations versus either drug alone after intradermal capsaicin in normal subjects. Anesth Analg 1998; 86: 1250–6.
- 56, , . Postdelivery of alfentanil and ketamine has no effect on intradermal capsaicin-induced pain and hyperalgesia. Clin J Pain 2002; 18: 373–9.
- 57, , . Dose-dependent effects of morphine on experimentally induced cutaneous pain in healthy volunteers. Pain 2005; 116: 366–74.
- 58, , , . Differential sensitivity of three experimental pain models in detecting the analgesic effects of transdermal fentanyl and buprenorphine. Pain 2006; 126: 165–74.
- 59, , , . Investigation of the potentiation of the analgesic effects of fentanyl by ketamine in humans: a double-blinded, randomised, placebo controlled, crossover study of experimental pain [ISRCTN83088383. BMC Anesthesiol 2005; 5: 2.
- 60, , . The site of action of epidural fentanyl in humans: the difference between infusion and bolus administration. Anesth Analg 2003; 97: 1428–38.
- 61, , , , , , . Steady-state infusions of opioids in human. II. Concentration-effect relationships and therapeutic margins. Pain 1990; 43: 69–79.
- 62, , , , , . Enhanced temporal summation of second pain and its central modulation in fibromyalgia patients. Pain 2002; 99: 49–59.
- 63, , , . Remifentanil inhibits muscular more than cutaneous pain in humans. Br J Anaesth 2000; 85: 529–32.
- 64, , , , , , . The effect of remifentanil on the heat pain threshold in volunteers. Anesth Analg 2001; 92: 369–74.
- 65, , , , , . Modulation of remifentanil-induced analgesia, hyperalgesia, and tolerance by small-dose ketamine in humans. Anesth Analg 2003; 96: 726–32.
- 66, , , , . Effect of remifentanil on pain and secondary hyperalgesia associated with the heat – capsaicin sensitization model in healthy volunteers. Anesthesiology 2001; 94: 15–20.
- 67, , , , . A randomized study of the effect of oral lamotrigine and hydromorphone on pain and hyperalgesia following heat/capsaicin sensitization. J Pain 2003; 4: 400–6.
- 68, , , , , . Imaging human cerebral pain modulation by dose-dependent opioid analgesia: a positron emission tomography activation study using remifentanil. Anesthesiology 2007; 106: 548–56.
- 69, , , , , , , , , . Remifentanil and nitrous oxide reduce changes in cerebral blood flow velocity in the middle cerebral artery caused by pain. Br J Anaesth 2003; 90: 296–9.
- 70, , , , , , . Naloxone provokes similar pain facilitation as observed after short-term infusion of remifentanil in humans. Pain 2003; 106: 91–9.
- 71, , , , . Modulation of remifentanil-induced postinfusion hyperalgesia by propofol. Anesth Analg 2007; 104: 1397–403, table.
- 72, , , , , . Modulation of remifentanil-induced analgesia and postinfusion hyperalgesia by parecoxib in humans. Anesthesiology 2006; 105: 1016–23.
- 73, , . Intravenous remifentanil produces withdrawal hyperalgesia in volunteers with capsaicin-induced hyperalgesia. Anesth Analg 2003; 97: 810–5.
- 74, , , , , . Local application of morphine suppresses glutamate-evoked activities of C and Adelta afferent fibers in rat hairy skin. Brain Res 2005; 1059: 28–34.
- 75, , . Nociceptors and warm receptors innervated by C fibres in human skin. J Neurol Neurosurg Psychiatry 1982; 45: 313–9.
- 76, , . Animal models of nociception. Pharmacol Rev 2001; 53: 597–652.
- 77, , . Diffuse noxious inhibitory controls in man: involvement of an opioidergic link. Eur J Pharmacol 1990; 182: 347–55.
- 78. Spinal cord pharmacology of pain. Br J Anaesth 1995; 75: 193–200.
- 79, , , , , , , . The effect of opioid dose and treatment duration on the perception of a painful standardized clinical stimulus. Reg Anesth Pain Med 2008; 33: 199–206.
- 80, , , , , , . Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 2005; 103: 147–55.
- 81, , , , , . The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain 2003; 105: 79–88.
- 82, , , . Differential effects of morphine on responses of dorsal horn lamina V type cells elicited by A and C fibre stimulation in the spinal cat. Brain Res 1976; 115: 518–24.
- 83, , , . Morphine does not affect laser induced warmth and pin prick pain thresholds. Acta Anaesthesiol Scand 1994; 38: 161–4.
- 84, , . A quantitative double-blind evaluation of the antinociceptive effects of perineurally administered morphine compared with lidocaine. Acta Anaesthesiol Scand 1991; 35: 24–9.
- 85, , . Hypoalgesia following epidural morphine: a controlled quantitative experimental study. Acta Anaesthesiol Scand 1991; 35: 430–5.
- 86, , , , . Dissociation of morphine analgesia and sedation evaluated by EEG measures in healthy volunteers. Arzneimittelforschung 2004; 54: 143–51.
- 87, , , , , . Gabapentin enhances the analgesic effect of morphine in healthy volunteers. Anesth Analg 2000; 91: 185–91.
- 88, , , , . Can co-administration of oxycodone and morphine produce analgesic synergy in humans? An experimental cold pain study. Br J Clin Pharmacol 2004; 58: 235–42.
- 89, , . The N-methyl-D-aspartate-receptor antagonist dextromethorphan lacks analgesic effect in a human experimental ischemic pain model. Acta Anaesthesiol Scand 2000; 44: 924–8.
- 90, , , , , . Can personality traits and gender predict the response to morphine? An experimental cold pain study. Eur J Pain 2006; 10: 103–12.
- 91, , . The influence of adenosine, ketamine, and morphine on experimentally induced ischemic pain in healthy volunteers. Anesth Analg 1994; 79: 787–91.
- 92, , , , . An experimental pain method sensitive to morphine in man: the submaximum effort tourniquet technique. J Pharmacol Exp Ther 1966; 154: 324–32.
- 93, , . Peripheral antinociceptive effects of morphine after burn injury. Acta Anaesthesiol Scand 1993; 37: 710–2.
- 94, , . The synergistic effect of combined treatment with systemic ketamine and morphine on experimentally induced windup-like pain in humans. Anesth Analg 2004; 98: 1574–80.
- 95, , , , , . Peripheral opioid analgesia in experimental human pain models. Brain 2003; 126: 1092–102.
- 96, , . Synergistic affective analgesic interaction between delta-9-tetrahydrocannabinol and morphine. Eur J Pharmacol 2006; 530: 54–8.
- 97, , , , . A psychophysical analysis of morphine analgesia. Pain 1985; 22: 261–9.
- 98, , , , . Plasma and cerebrospinal fluid concentrations of morphine and morphine glucuronides after oral morphine. The influence of renal failure. Anesthesiology 1994; 81: 87–93.
- 99. Pharmacokinetic-pharmacodynamic modeling of opioids. J Pain Symptom Manage 2005; 29: S90–103.
- 100, , , , , , . The analgesic effect of codeine as compared to imipramine in different human experimental pain models. Pain 2001; 92: 277–82.
- 101, , , , , . The hypoalgesic effect of imipramine in different human experimental pain models. Pain 1995; 60: 287–93.
- 102, , , , , , . Morphine responses and experimental pain: sex differences in side effects and cardiovascular responses but not analgesia. J. Pain 2005; 6: 116–24.
- 103, , , , , , , , . Opioidergic activation in the medial pain system after heat pain. Pain 2006; 122: 63–7.
- 104, , , . Opioids and the gut: pharmacology and current clinical experience. Neurogastroenterol Motil 2004; 16: 383–394.
- 105, , , , , , , , . A 5-HT antagonist (UP 26-91) versus codeine and placebo in a human experimental pain study. Pain Res Manage 2000; 4, 135–140.
- 106, , , , , . Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur J Clin Pharmacol 1996; 51: 289–95.
- 107, , , , . Effects of a combination of oral naproxen sodium and codeine on experimentally induced pain. Eur J Clin Pharmacol 1982; 21: 485–90.
- 108, . Subjective, psychomotor, and analgesic effects of oral codeine and morphine in healthy volunteers. Psychopharmacology (Berl) 1998; 140: 191–201.
- 109, , , , , , , . Pharmacokinetics of codeine after single- and multiple-oral-dose administration to normal volunteers. J Clin Pharmacol 1987; 27: 983–7.
- 110, , . Analgesic effects of codeine-6-glucuronide after intravenous administration. Eur J Pain 1997; 1: 185–90.
- 111, , , , , . The analgesic effect of tramadol after intravenous injection in healthy volunteers in relation to CYP2D6. Anesth Analg 2006; 102: 146–50.
- 112, , , , . A comparison of the antinociceptive effects of imipramine, tramadol and anpirtoline. Br J Clin Pharmacol 1994; 37: 325–33.
- 113, , , , . Dose dependent time course of the analgesic effect of a sustained-release preparation of tramadol on experimental phasic and tonic pain. Br J Clin Pharmacol 1996; 41: 115–23.
- 114, . Comparison of tilidine/naloxone, tramadol and bromfenac in experimental pain: a double-blind randomized crossover study in healthy human volunteers. Int J Clin Pharmacol Ther 1999; 37: 377–85.
- 115, , , , , . Role of intradental A- and C-type nerve fibres in dental pain mechanisms. Proc Finn Dent Soc 1992; 88 (Suppl. 1): 507–16.
- 116, , . Comparison of the analgesic efficacy of metamizole and tramadol in experimental pain. Pharmacology 1988; 37: 209–17.
- 117, , . Rofecoxib and tramadol do not attenuate delayed-onset muscle soreness or ischaemic pain in human volunteers. Can J Physiol Pharmacol 2005; 83: 1137–45.
- 118, , , , , , . Supra-additive effects of tramadol and acetaminophen in a human pain model. Pain 2008; 136: 262–70.
- 119, , . Pharmacological aspects of the effects of tramadol on G-protein coupled receptors. J Pharmacol Sci 2007; 103: 253–60.
- 120, , , . Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor. Naunyn Schmiedebergs Arch Pharmacol 2000; 362: 116–21.
- 121, , , . The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 1996; 60: 636–44.
- 122, . Comment on Koltzenburg et al.: differential sensitivity of three experimental pain models in detecting the analgesic effects of transdermal fentanyl and buprenorphine. Pain 2006; 126: 165–74. Pain 2007; 128: 292–94.
- 123, , , . Multiple session experimental pain measurement. Pain 1996; 67: 327–33.
- 124, . From pain research to pain treatment: the role of human experimental pain models. Best Pract Res Clin Anaesthesiol 2002; 16: 667–80.
- 125, , , . Predicting therapeutic efficacy – Experimental pain in human subjects. Brain Res Rev 2009; 60: 243–54.
- 126, , , , . Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther 2008; 83: 559–66.
- 127, , , . Efficiency of the cross-over design: an empirical estimation. Stat Med 2004; 23: 3773–80.
- 128, , , . Assessing the relationship between cold pressor pain responses and dimensions of the anxiety sensitivity profile in healthy men and women. Cogn Behav Ther 2006; 35: 198–206.
- 129, , , . A systematic review of psychological factors as predictors of chronicity/disability in prospective cohorts of low back pain. Spine 2002; 27: E109–120.
- 130, , , , . Effect of racemic mixture and the (S+)-isomer of ketamine on temporal and spatial summation of pain. Br J Anaesth 1996; 77: 625–31.
- 131, , , , , . Intravenous morphine and oxycodone for pain after abdominal surgery. Acta Anaesthesiol Scand 1991; 35: 642–6.

1365-2125/asset/olbannerleft.gif?v=1&s=e86b92cac3efbbd2e255b9fa97ece9623eac0b54)
1365-2125/asset/olbannerright.gif?v=1&s=6a7c47d290382bf3bc40c62461bc36a371a081bf)
