Abstract
Despite many advances in the last decades in understanding pain, the development of new analgesic compounds has not followed at the same pace. The development of more targeted analgesic compounds with fewer side effects is therefore essential. With an increased demand to demonstrate pharmacodynamic effects of new analgesic compounds, the importance of human evoked pain models is now higher than ever.
Pharmacodynamic evaluation with human evoked pain models offers the possibility to determine the dose ranges at which new analgesics exert their pharmacological effect. Pain models may also aid in the choice of target population, determine which modality of pain a new drug is expected to be most suitable, help to differentiate between a central or more peripheral mode of action of new drugs, and help determine which other effects contribute to its mode of action, e.g., sedation.
Human evoked pain models are conducted in standardized laboratories where factors like stimulus intensity, frequency, duration, and location can be controlled. Using pain models in healthy volunteers has important advantages over assessing the effects of new drugs in patients with pain; the pain elicited in human pain models is predictable in its intensity while clinical pain will naturally fluctuate. Analgesic properties can be investigated with pain models without the influence of accompanying symptoms that are often seen in patients with pain.
References and Further Reading
Adam F, Alfonsi P, Kern D, Bouhassira D (2014) Relationships between the paradoxical painful and nonpainful sensations induced by a thermal grill. Pain 155:2612–2617
Aguggia M (2003) Neurophysiology of pain. Neurol Sci 24:57–60
Altis K, Schmidtko A, Angioni C, Kuczka K et al (2009) Analgesic efficacy of tramadol, pregabalin and ibuprofen in menthol-evoked cold hyperalgesia. Pain 147:116–121
van Amerongen G, de Boer MW, Groeneveld GJ, Hay JL (2016) A literature review on the pharmacological sensitivity of human evoked hyperalgesia pain models. Br J Clin Pharmacol 82:903–922
Andersen OK, Jensen LM, Brennum J, Arendt-Nielsen L (1994) Evidence for central summation of C and A delta nociceptive activity in man. Pain 59:273–280
Andersen OK, Sonnenborg FA, Arendt-Nielsen L (2001) Reflex receptive fields for human withdrawal reflexes elicited by non-painful and painful electrical stimulation of the foot sole. Clin Neurophysiol 112:641–649
Andersen H, Arendt-Nielsen L, Svensson P, Danneskiold-Samsøe B et al (2008) Spatial and temporal aspects of muscle hyperalgesia induced by nerve growth factor in humans. Exp Brain Res 191:371–382
Andersen HH, Poulsen JN, Uchida Y, Nikbakht A et al (2015) Cold and L-menthol-induced sensitization in healthy volunteers––a cold hypersensitivity analogue to the heat/capsaicin model. Pain 156:880–889
Arendt-Nielsen L, Yarnitsky D (2009) Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and viscera. J Pain 10:556–572
Arendt-Nielsen L, Drewes AM, Hansen JB, Tage-Jensen U (1997) Gut pain reactions in man: an experimental investigation using short and long duration transmucosal electrical stimulation. Pain 69:255–262
Arendt-Nielsen L, Sonnenborg FA, Andersen OK (2000) Facilitation of the withdrawal reflex by repeated transcutaneous electrical stimulation: an experimental study on central integration in humans. Eur J Appl Physiol 81:165–173
Arendt-Nielsen L, Curatolo M, Drewes A (2007a) Human experimental pain models in drug development: translational pain research. Curr Opin Investig Drugs 8:41–53
Arendt-Nielsen L, Frøkjaer JB, Staahl C, Graven-Nielsen T et al (2007b) Effects of gabapentin on experimental somatic pain and temporal summation. Reg Anesth Pain Med 32:382–388
Arendt-Nielsen L, Olesen AE, Staahl C, Menzaghi F et al (2009) Analgesic efficacy of peripheral K-opioid receptor agonist CR665 compared to oxycodone in a multi-modal, multi-tissue experimental human pain model. Anesthesiology 111:616–624
Baron R, Baron Y, Disbrow E, Roberts TP (1999) Brain processing of capsaicin induced secondary hyperalgesia: a functional MRI study. Neurology 53:548–557
Baron R, Maier C, Attal N, Binder A et al (2017) Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles. Pain 158:261–272
Bauer M, Schwameis R, Scherzer T, Lang-Zwosta I et al (2015) A double-blind, randomized clinical study to determine the efficacy of benzocaine 10% on histamine-induced pruritus and UVB-light induced slight sunburn pain. J Dermatolog Treat 26:367–372
Bennett D (2007) Sensitization of nociceptors. In: Schmidt RF, Willis WD (eds) Encyclopedia of pain, 1st edn. Springer-Verlag, Berlin/Heidelberg, pp 1338–1342
Bernstein LM, Baker LA (1958) A clinical test for esophagitis. Gastroenterology 34:60–81
Binder A, Stengel M, Klebe O, Wasner G et al (2011) Topical high-concentration (40%) menthol-somatosensory profile of a human surrogate pain model. J Pain 12:764–773
Bishop T, Hewson DW, Yip PK, Fahey MS et al (2007) Characterisation of ultraviolet-B-induced inflammation as a model of hyperalgesia in the rat. Pain 131:70–82
Bishop T, Ballard A, Holmes H, Young AR et al (2009) Ultraviolet-B induced inflammation of human skin: characterisation and comparison with traditional models of hyperalgesia. Eur J Pain 13:524–532
Bonica JJ (1979) The need of a taxonomy. Pain 6:247–252
Borsook D, Sava S, Becerra L (2010) The pain imaging revolution: advancing pain into the 21st century. Neuroscientist 16:171–185
Bouhassira D, Sabaté JM, Coffin B, Le Bars D et al (1998) Effects of rectal distensions on nociceptive flexion reflexes in humans. Am J Phys 275:410–417
Bouhassira D, Kern D, Rouaud J, Pelle-Lancien E et al (2005) Investigation of the paradoxical painful sensation (‘illusion of pain’) produced by a thermal grill. Pain 114:160–167
Brenner M, Coelho SG, Beer JZ, Miller SA et al (2009) Long-lasting molecular changes in human skin after repetitive in situ UV irradiation. J Invest Dermatol 129:1002–1011
Brennum J, Kjeldsen M, Jensen K, Jensen TS (1989) Measurements of human pressure-pain thresholds on fingers and toes. Pain 38:211–217
van den Broeke EN, Geene N, van Rijn CM, Wilder-Smith OH et al (2014) Negative expectations facilitate mechanical hyperalgesia after high-frequency electrical stimulation of human skin. Eur J Pain 18:86–91
Bromm B, Lorenz J (1984) Neurophysiological evaluation of pain. Electroencephalogr Clin Neurophysiol 107:227–253
Bromm B, Jahnke MT, Treede RD (1984) Responses of human cutaneous afferents to CO2 laser stimuli causing pain. Exp Brain Res 55:158–166
Burke D, Mackenzie RA, Skuse NF, Lethlean AK (1975) Cutaneous afferent activity in median and radial nerve fascicles: a microelectrode study. J Neurol Neurosurg Psychiatry 38:855–864
Casale R, Glynn C, Buonocore M (1992) The role of ischaemia in the analgesia which follows Bier’s block technique. Pain 50:169–175
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA et al (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824
Craig AD, Bushnell MC (1994) The thermal grill illusion: unmasking the burn of cold pain. Science 265:252–255
Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Zbinden AM (1997) Epidural epinephrine and clonidine: segmental analgesia and effects on different pain modalities. Anesthesiology 87:785–794
Curatolo M, Petersen-Felix S, Arendt-Nielsen L (2000) Sensory assessment of regional analgesia in humans: a review of methods and applications. Anesthesiology 93:1517–1530
Daenen L, Nijs J, Cras P, Wouters K et al (2014) Changes in pain modulation occur soon after whiplash trauma but are not related to altered perception of distorted visual feedback. Pain Pract 14:588–598
Demedts I, Tack J (1998) Chest pain of esophageal origin. Curr Opin Gastroenterol 14:340–344
Doll RJ, Buitenweg JR, Meijer HG, Veltink PH (2014) Tracking of nociceptive thresholds using adaptive psychophysical methods. Behav Res Methods 46:55–66
Doll RJ, van Amerongen G, Hay JL, Groeneveld GJ et al (2016) Responsiveness of electrical nociceptive detection thresholds to capsaicin (8%)-induced changes in nociceptive processing. Exp Brain Res 234:2505–2514
Dotson RM (1997) Clinical neurophysiology laboratory tests to assess the nociceptive system in humans. J Clin Neurophysiol 14:32–45
Drewes AM, Schipper KP, Dimcevski G, Petersen P et al (2002) Multimodal assessment of pain in the esophagus: a new experimental model. Am J Physiol Gastrointest Liver Physiol 283:95–103
Drewes AM, Schipper KP, Dimcevski G, Petersen P et al (2003a) Gut pain and hyperalgesia induced by capsaicin: a human experimental model. Pain 104:333–341
Drewes AM, Schipper KP, Dimcevski G, Petersen P et al (2003b) Multi-modal induction and assessment of allodynia and hyperalgesia in the human oesophagus. Eur J Pain 7:539–549
Drewes AM, Reddy H, Staahl C, Pedersen J et al (2005) Sensory-motor responses to mechanical stimulation of the esophagus after sensitization with acid. World J Gastroenterol 11:4367–4374
Dworkin RH, O’Connor AB, Audette J, Baron R et al (2010) Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 85:3–14
Dyck PJ, Peroutka S, Rask C, Burton E et al (1997) Intradermal recombinant human nerve growth factor induces pressure allodynia and lowered heat-pain threshold in humans. Neurology 48:501–505
Eckhardt K, Li S, Ammon S, Schanzle G et al (1998) Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain 76:27–33
Enggaard TP, Poulsen L, Arendt-Nielsen L, Hansen SH et al (2001) The analgesic effect of codeine as compared to imipramine in different human experimental pain models. Pain 92:277–282
Finnerup NB, Sindrup SH, Jensen TS (2010) The evidence for pharmacological treatment of neuropathic pain. Pain 150:573–581
Finnerup NB, Attal N, Haroutounian S, Kamerman P et al (2015) Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 14:162–173
Fitzpatrick TB (1988) The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol 124:869–871
Frølund F, Frølund C (1986) Pain in general practice: pain as a cause of patient-doctor contact. Scand J Prim Health Care 4:97–100
Fruhstorfer H, Gross W, Selbmann O (2001) Von Frey hairs: new materials for a new design. Eur J Pain 5:341–342
Fujii K, Motohashi K, Umino M (2006) Heterotopic ischemic pain attenuates somatosensory evoked potentials induced by electrical tooth stimulation: diffuse noxious inhibitory controls in the trigeminal nerve territory. Eur J Pain 10:495–504
Ge HY, Madeleine P, Cairns BE, Arendt-Nielsen L (2006) Hypoalgesia in the referred pain areas after bilateral injections of hypertonic saline into the trapezius muscles of men and women: a potential experimental model of gender-specific differences. Clin J Pain 22:37–44
Goubert D, Danneels L, Cagnie B, van Oosterwijck J et al (2015) Effect of pain induction or pain reduction on conditioned pain modulation in adults: a systematic review. Pain Pract 8:765–777
Gracely RH (1994) Studies of pain in normal man. In: Wall PD, Melzack R (eds) Textbook of pain, 3rd edn. Churchill Livingstone, Edinburgh, pp 315–336
Gracely RH (2013) Studies of pain in human subjects. In: McMahon SB, Koltzenburg M, Tracey I, Turk DC (eds) Wall and Melzack’s textbook of pain, 6th edn. Elsevier, Philidelphia, pp 283–300
Granot M, Granovsky Y, Sprecher E, Nir RR, Yarnitsky D (2006) Contact heat-evoked temporal summation: tonic versus repetitive-phasic stimulation. Pain 122:295–305
Graven-Nielsen T, Mense S (2001) The peripheral apparatus of muscle pain: evidence from animal and human studies. Clin J Pain 17:2–10
Graven-Nielsen T, Arendt-Nielsen L, Svensson P, Staehelln Jensen T (1997) Quantification of local and referred muscle pain in humans after sequential i.m. injections of hypertonic saline. Pain 69:111–117
Graven-Nielsen T, Babenko V, Svensson P, Arendt-Nielsen L (1998) Experimentally induced muscle pain induces hypoalgesia in heterotopic deep tissues, but not in homotopic deep tissues. Brain Res 787:203–210
Graven-Nielsen T, Arendt-Nielsen L, Mense S (2002) Thermosensitivity of muscle: high-intensity thermal stimulation of muscle tissue induces muscle pain in humans. J Physiol 540:647–656
Grech R, Cassar T, Muscat J, Camilleri KP et al (2008) Review on solving the inverse problem in EEG source analysis. J Neuroeng Rehabil 5:25
Gustorff B, Anzenhofer S, Sycha T, Lehr S et al (2004) The sunburn pain model: the stability of primary and secondary hyperalgesia over 10 hours in a crossover setting. Anesth Analg 98:173–177
Hagenouw RR, Bridenbaugh PO, van Egmond J, Stuebing R (1986) Tourniquet pain: a volunteer study. Anesth Analg 65:1175–1180
Hampson JP, Reed BD, Clauw DJ, Bhavsar R et al (2013) Augmented central pain processing in vulvodynia. J Pain 14:579–589
Handwerker HO, Kobal G (1993) Psychophysiology of experimentally induced pain. Physiol Rev 73:639–671
Hardy JD, Wolff HG, Goodell H (1940) Studies on pain. A new method for measuring pain threshold: observations on spatial summation of pain. J Clin Invest 19:649–657
Hatem S, Attal N, Willer JC, Bouhassira D (2006) Psychophysical study of the effects of topical application of menthol in healthy volunteers. Pain 122:190–196
Hauck M, Domnick C, Lorenz J, Gerloff C et al (2015) Top-down and bottom-up modulation of pain-induced oscillations. Front Hum Neurosci 9:375
Hay JL, Okkerse P, van Amerongen G, Groeneveld GJ (2016) Determining pain detection and tolerance thresholds using an integrated, multi-modal pain task battery. J Vis Exp 14:110
Heinricher MM, Fields L (2013) Central nervous system mechanisms of pain modulation. In: McMahon SB, Koltzenburg M, Tracey I, Turk DC (eds) Wall and Melzack’s textbook of pain, 6th edn. Elsevier, Philidelphia, pp 129–142
Hernández N, Dmitrieva N, Vanegas H (1994) Medullary on-cell activity during tail-flick inhibition produced by heterotopic noxious stimulation. Pain 58:393–401
Hertel HC, Howaldt B, Mense S (1976) Responses of group IV and group III muscle afferents to thermal stimuli. Brain Res 113:201–205
Hu L, Zhang ZG, Mouraux A, Iannetti GD (2015) Multiple linear regression to estimate time-frequency electrophysiological responses in single trials. NeuroImage 111:442–453
Huettel SA, Song AW, McCarthy G (eds) (2014) Functional magnetic resonance ingaging, 2nd edn. Sinauer Associates Inc, Sunderland
Hüllemann P, Watfeh R, Shao YQ, Nerdal A (2015) Peripheral sensitization reduces laser-evoked potential habituation. Neurophysiol Clin 45:457–467
Ikeda H, Heinke B, Ruscheweyh R, Sandkühler J (2003) Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science 299:1237–1240
Ilkjaer S, Petersen KL, Brennum J, Wernberg M et al (1996) Effect of systemic N-methyl-D-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans. Br J Anaesth 76:829–834
Ing Lorenzini K, Besson M, Daali Y, Salomon D et al (2012) Validation of the simplified UVB model to assess the pharmacodynamics of analgesics in healthy human volunteers. Chimia (Aarau) 66:296–299
Ingvar M (1999) Pain and functional imaging. Philos Trans R Soc Lond Ser B Biol Sci 354:1347–1358
Inui K, Kakigi R (2012) Pain perception in humans: use of intraepidermal electrical stimulation: figure 1. J Neurol Neurosurg Psychiatry 83:551–556
Jobert M, Wilson FJ, Roth T, Ruigt GSF (2013) Guidelines for the recording and evaluation of pharmaco-sleep studies in man: the international pharmaco-EEG society (IPEG). Neuropsychobiology 67:127–167
Johnson AC, Greenwood-Van Meerveld B (2016) The pharmacology of visceral pain. Adv Pharmacol 75:273–301
Jones SF, McQuay HJ, Moore RA, Hand CW (1988) Morphine and ibuprofen compared using the cold pressor test. Pain 34:117–122
Kakigi R (1994) Diffuse noxious inhibitory control. Reappraisal by pain-related somatosensory evoked potentials following CO2 laser stimulation. J Neurol Sci 125:198–205
Kakigi R, Inui K, Tamura Y (2005) Electrophysiological studies on human pain perception. Clin Neurophysiol 116:743–763
Kern D, Plantevin F, Bouhassira D (2008) Effects of morphine on the experimental illusion of pain produced by a thermal grill. Pain 139:653–659
Kidd BL, Urban LA (2001) Mechanisms of inflammatory pain. Br J Anaesth 87:3–11
Kilo S, Schmelz M, Koltzenburg M, Handwerker HO (1994) Different patterns of hyperalgesia induced by experimental inflammation in human skin. Brain 117:385–396
Kissin I (2010) The development of new analgesics over the past 50 years: a lack of real breakthrough drugs. Anesth Analg 110:780–789
Klein T, Magerl W, Hopf HC, Sandkühler J (2004) Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans. J Neurosci 24:964–971
Klein T, Stahn S, Magerl W, Treede RD (2008) The role of heterosynaptic facilitation in long-term potentiation (LTP) of human pain sensation. Pain 139:507–519
Kocyigit F, Akalin E, Gezer NS, Orbay O et al (2012) Functional magnetic resonance imaging of the effects of low-frequency transcutaneous electrical nerve stimulation on central pain modulation. A double-blind, placebo-controlled trial. Clin J Pain 28:581–588
Koltzenburg M, Lundberg LE, Torebjörk HE (1992) Dynamic and static components of mechanical hyperalgesia in human hairy skin. Pain 51:207–219
Koppert W, Dern SK, Sittl R, Albrecht S et al (2001) A new model of electrically evoked pain and hyperalgesia in human skin: the effects of intravenous alfentanil, S(+)-ketamine, and lidocaine. Anesthesiology 95:395–402
Korotkov A, Ljubisavljevic M, Thunberg J, Kataeva G et al (2002) Changes in human regional cerebral blood flow following hypertonic saline induced experimental muscle pain: a positron emission tomography study. Neurosci Lett 335:119–123
Krarup AL, Gunnarsson J, Brun J, Poulakis A et al (2013) Exploration of the effects of gender and mild esophagitis on esophageal pain thresholds in the normal and sensitized state of asymptomatic young volunteers. Neurogastroenterol Motil 25:766–e580
Kumar K, Railton C, Tawfic Q (2016) Tourniquet application during anesthesia: “what we need to know?”. J Anaesthesiol Clin Pharmacol 32:424–430
van Laarhoven AI, Kraaimaat FW, Wilder-Smith OH, van Riel PL, van de Kerkhof PC, Evers AW (2013) Sensitivity to itch and pain in patients with psoriasis and rheumatoid arthritis. Exp Dermatol 22:530–534
Laird JM, Bennett GJ (1993) An electrophysiological study of dorsal horn neurons in the spinal cord of rats with an experimental peripheral neuropathy. J Neurophysiol 69:2072–2085
Lapotka M, Ruz M, Salamanca Ballesteros A, Ocon Hernandez O (2017) Cold pressor gel test: a safe alternative to the cold pressor test in fMRI. Magn Reson Med 78:1464–1468
Latremoliere A, Woolf CJ (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 10:895–926
Laursen RJ, Graven-Nielsen T, Jensen TS, Arendt-Nielsen L (1997) Referred pain is dependent on sensory input from the periphery: a psychophysical study. Eur J Pain 1:261–269
Lautenbacher S, Roscher S, Strian F (2002) Inhibitory effects do not depend on the subjective experience of pain during heterotopic noxious conditioning stimulation (HNCS): a contribution to the psychophysics of pain inhibition. Eur J Pain 6:365–374
Le Bars D, Dickenson AH, Besson JM (1979) Diffuse noxious inhibitory controls (DNIC). I. Effects on dorsal horn convergent neurones in the rat. Pain 6:283–304
Lee YS, Kho HS, Kim YK, Chung SC (2007) Influence of topical capsaicin on facial sensitivity in response to experimental pain. J Oral Rehabil 34:9–14
Li H (2017) TRP channel classification. Adv Exp Med Biol 976:1–8
Lötsch J, Angst MS (2003) The μ-opioid agonist remifentanil attenuates hyperalgesia evoked by blunt and punctuated stimuli with different potency: a pharmacological evaluation of the freeze lesion in humans. Pain 102:151–161
Lötsch J, Oertel BG, Ultsch A (2014) Human models of pain for the prediction of clinical analgesia. Pain 155:2014–2021
Louvel D, Delvaux M, Staumont G, Camman F et al (1996) Intracolonic injection of glycerol: a model for abdominal pain in irritable bowel syndrome? Gastroenterology 110:351–361
Macfarlane GJ, McBetch J, Jones GT (2013) Epidemiology of pain. In: McMahon SB, Koltzenburg M, Tracey I, Turk DC (eds) Wall and Melzack’s textbook of pain, 6th edn. Elsevier, Philidelphia, pp 232–247
Maggi CA (1990) The dual function of capsaicin-sensitive sensory nerves in the bladder and urethra. Ciba Found Symp 151:77–90
Mauderli AP, Vierck CJ Jr, Cannon RL, Rodrigues A et al (2003) Relationships between skin temperature and temporal summation of heat and cold pain. J Neurophysiol 90:100–109
McQuay HJ, Moore A (2013) Methods of therapeutic trials. In: McMahon SB, Koltzenburg M, Tracey I, Turk DC (eds) Wall and Melzack’s textbook of pain, 6th edn. Elsevier, Philidelphia, pp 402–412
Melzack R (1975) The McGill pain questionnaire: major properties and scoring methods. Pain 1:277–299
Melzack R (2005) The McGill pain questionnaire: from description to measurement. Anesthesiology 103:199–202
Melzack R, Katz J (2013) Pain measurement in adult patients. In: McMahon SB, Koltzenburg M, Tracey I, Turk DC (eds) Wall and Melzack’s textbook of pain, 6th edn. Elsevier, Philidelphia, pp 301–314
Messeguer A, Plannells-Cases P, Ferrer-Montiel A (2006) Physiology and pharmacology of the vanilloid receptor. Curr Neuropharmacol 4:1–15
Meyer RA, Treede RD (2004) Mechanisms of secondary hyperalgesia: a role for myelinated nociceptors in punctate hyperalgesia. In: Brune K, Handwerker HO (eds) Hyperalgesia: molecular mechanisms and clinical implications, 1st edn. IASP Press, Seatlle, pp 143–155
Mikkelsen S, Ilkjaer S, Brennum J, Borgbjerg FM et al (1999) The effect of naloxone on ketamine-induced effects on hyperalgesia and ketamine-induced side effects in humans. Anesthesiology 90:1539–1545
Mitchell LA, MacDonald RA, Brodie EE (2004) Temperature and the cold pressor test. J Pain 5:233–237
Möller KA, Johansson B, Berge OG (1998) Assessing mechanical allodynia in the rat paw with a new electronic algometer. J Neurosci Methods 84:41–47
Moore DJ, Keogh E, Crombez G, Eccleston C (2013) Methods for studying naturally occurring human pain and their analogues. Pain 154:190–199
Moore RA, Wiffen PJ, Derry S, Maguire T (2015) Non-prescription (OTC) oral analgesics for acute pain – an overview of Cochrane reviews. Cochrane Database Syst Rev 11:CD010794
Morton DL, Sandhu JS, Jones AK (2016) Brain imaging of pain: state of the art. J Pain Res 9:613–624
Mouraux A, Iannetti GD (2008) Across-trial averaging of event-related EEG responses and beyond. Magn Reson Imaging 26:1041–1054
Mouraux A, Guérit JM, Plaghki L (2003) Non-phase locked electroencephalogram (EEG) responses to CO2 laser skin stimulations may reflect central interactions between a partial differential- and C-fibre afferent volleys. Clin Neurophysiol 114:710–722
Mouraux A, Iannetti GD, Plaghki L (2010) Low intensity intra-epidermal electrical stimulation can activate Aδ-nociceptors selectively. Pain 150:199–207
Ness TJ, Gebhart GF (1990) Visceral pain: a review of experimental studies. Pain 41:167–234
Nie H, Arendt-Nielsen L, Madeleine P, Graven-Nielsen T (2006) Enhanced temporal summation of pressure pain in the trapezius muscle after delayed onset muscle soreness. Exp Brain Res 170:182–190
Niesters M, Dahan A, Swartjes M, Noppers I et al (2011) Effect of ketamine on endogenous pain modulation in healthy volunteers. Pain 152:656–663
Nir RR, Yarnitsky D (2015) Conditioned pain modulation. Curr Opin Support Palliat Care 9:131–137
Ochoa J, Mair WG (1969) The normal sural nerve in man. I. Ultrastructure and numbers of fibres and cells. Acta Neuropathol 13:197–216
Oertel BG, Lötsch J (2013) Clinical pharmacology of analgesics assessed with human experimental pain models: bridging basic and clinical research. Br J Pharmacol 168:534–553
Ogawa S, Lee TM, Kay AR, Tank DW (1990) Brain magnetic resonance imaging with contrast dependent on blood oxygenation. Proc Natl Acad Sci U S A 87:9868–9872
Okkerse P, van Amerongen G, de Kam ML, Stevens J et al (2017) The use of a battery of pain models to detect analgesic properties of compounds: a two-part four-way crossover study. Br J Clin Pharmacol 83:976–990
Olesen AE, Staahl C, Arendt-Nielsen L, Drewes AM (2010) Different effects of morphine and oxycodone in experimentally evoked hyperalgesia: a human translational study. Br J Clin Pharmacol 70:189–200
Olesen AE, Andresen T, Staahl C, Drewes AM (2012) Human experimental pain models for assessing the therapeutic efficacy of analgesic drugs. Pharmacol Rev 64:722–779
Olesen AE, Brock C, Sverrisdóttir E, Larsen IM et al (2014) Sensitivity of quantitative sensory models to morphine analgesia in humans. J Pain Res 7:717–726
Olofsen E, Romberg R, Bijl H, Mooren R et al (2005) Alfentanil and placebo analgesia: no sex differences detected in models of experimental pain. Anesthesiology 103:130–139
Page GD, France CR (1997) Objective evidence of decreased pain perception in normotensives at risk for hypertension. Pain 73:173–180
Pedersen JL, Kehlet H (1998) Hyperalgesia in a human model of acute inflammatory pain: a methodological study. Pain 74:139–151
Petty BG, Cornblath DR, Adornato BT, Chaudhry V et al (1994) The effect of systemically administered recombinant human nerve growth factor in healthy human subjects. Ann Neurol 36:244–224
Peyron R, Laurent B, García-Larrea L (2000) Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiol Clin 30:263–288
Pfau DB, Klein T, Putzer D, Pogatzki-Zahn EM et al (2011) Analysis of hyperalgesia time courses in humans after painful electrical high-frequency stimulation identifies a possible transition from early to late LTP-like pain plasticity. Pain 152:1532–1539
Plaghki L, Mouraux A (2003) How do we selectively activate skin nociceptors with a high power infrared laser? Physiology and biophysics of laser stimulation. Neurophysiol Clin 33:269–277
Polianskis R, Graven-Nielsen T, Arendt-Nielsen L (2001) Computer-controlled pneumatic pressure algometry--a new technique for quantitative sensory testing. Eur J Pain 5:267–277
Popescu A, LeResche L, Truelove EL, Drangsholt MT (2010) Gender differences in pain modulation by diffuse noxious inhibitory controls: a systematic review. Pain 150:309–318
Porro CA (2003) Functional imaging and pain: behavior, perception, and modulation. Neuroscientist 9:354–369
Price DD (1996) Selective activation of A-delta and C nociceptive afferents by different parameters of nociceptive heat stimulation: a tool for analysis of central mechanisms of pain. Pain 68:1–3
Price DD (2000) Psychological and neural mechanisms of the affective dimension of pain. Science 288:1769–1772
Pud D, Granovsky Y, Yarnitsky D (2009) The methodology of experimentally induced diffuse noxious inhibitory control (DNIC)-like effect in humans. Pain 144:16–19
Rainville P (2002) Brain mechanisms of pain affect and pain modulation. Curr Opin Neurobiol 12:195–204
Reddy H, Arendt-Nielsen L, Staahl C, Pedersen J et al (2005) Gender differences in pain and biomechanical responses after acid sensitization of the human esophagus. Dig Dis Sci 50:2050–2058
Roberts K, Papadaki A, Goncalves C, Tighe M et al (2008) Contact heat evoked potentials using simultaneous Eeg and Fmri and their correlation with evoked pain. BMC Anesthesiol 8:8
Roberts K, Shenoy R, Anand P (2011) A novel human volunteer pain model using contact heat evoked potentials (CHEP) following topical skin application of transient receptor potential agonists capsaicin, menthol and cinnamaldehyde. J Clin Neurosci 18:926–932
Rosendal L, Larsson B, Kristiansen J, Peolsson M (2004) Increase in muscle nociceptive substances and anaerobic metabolism in patients with trapezius myalgia: microdialysis in rest and during exercise. Pain 112:324–334
Rukwied R, Mayer A, Kluschina O, Obreja O (2010) NGF induces non-inflammatory localized and lasting mechanical and thermal hypersensitivity in human skin. Pain 148:407–413
Ruscheweyh R, Weinges F, Schiffer M, Bäumler M (2015) Control over spinal nociception as quantified by the nociceptive flexor reflex (RIII reflex) can be achieved under feedback of the RIII reflex. Eur J Pain 19:480–489
Sandkühler J (2009) Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 89:707–758
Sandrini G, Alfonsi E, Ruiz L, Livieri C et al (1989) Age-related changes in excitability of nociceptive flexion reflex. An electrophysiological study in school-age children and young adults. Funct Neurol 4:53–58
Sayre RM, Desrochers DL, Wilson CJ, Marlowe E (1981) Skin type, minimal erythema dose (MED), and sunlight acclimatization. J Am Acad Dermatol 5:439–443
Schaffler K, Nicolas LB, Borta A, Brand T et al (2017) Investigation of the predictive validity of laser-EPs in normal, UVB-inflamed and capsaicin-irritated skin with four analgesic compounds in healthy volunteers. Br J Clin Pharmacol 83:1424–1435
Schouenborg J, Weng HR, Kalliomäki J, Holmberg H (1995) A survey of spinal dorsal horn neurones encoding the spatial organization of withdrawal reflexes in the rat. Exp Brain Res 106:19–27
Schulte H, Segerdahl M, Graven-Nielsen T, Grass S (2006) Reduction of human experimental muscle pain by alfentanil and morphine. Eur J Pain 10:733–741
Sengupta J, Gebhart G (1994) Gastrointestinal afferent fibers and sensation. In: Johnson LR (ed.) Physiology of the Gastrointestinal Tract, 3rd edn. Raven, New York, pp 483–519
Serra J, Campero M, Ochoa J (1998) Flare and hyperalgesia after intradermal capsaicin injection in human skin. J Neurophysiol 80:2801–2810
Shukla S, Torossain A, Duann JR, Keung A (2011) The analgesic effect of electroacupunture on acute thermal pain perception – a central neural correlate study with fMRI. Mol Pain 7:45–56
Simone DA, Ngeow JYF, Putterman GJ, LaMotte RH (1987) Hyperalgesia to heat after intradermal injection of capsaicin. Brain Res 418:201–203
Skljarevski V, Ramadan NM (2002) The nociceptive flexion reflex in humans – review article. Pain 96:3–8
Smith GM, Egbert LD, Markowitz RA, Mosteller F (1966) A VAS is used to assess the subject’s pain intensity. J Pharmacol Exp Ther 154:324–332
Song J, Davey C, Poulsen C, Luu P et al (2015) EEG source localization: sensor density and head surface coverage. J Neurosci Methods 256:9–12
Staahl C, Drewes AM (2004) Experimental human pain models: a review of standardised methods for preclinical testing of analgesics. Basic Clin Pharmacol Toxico l95:97–111
Staahl C, Christrup LL, Andersen SD, Arendt-Nielsen L et al (2006) A comparative study of oxycodone and morphine in a multi-modal, tissue-differentiated experimental pain model. Pain 123:28–36
Staahl C, Olesen AE, Andresen T, Arendt-Nielsen L et al (2009a) Assessing analgesic actions of opioids by experimental pain models in healthy volunteers – an updated review. Br J Clin Pharmacol 68:149–168
Staahl C, Olesen AE, Andresen T, Arendt-Nielsen L et al (2009b) Assessing efficacy of non-opioid analgesics in experimental pain models in healthy volunteers: an updated review. Br J Clin Pharmacol 68:322–341
Svendsen O, Edwards CN, Lauritzen B, Rasmussen AD (2005) Intramuscular injection of hypertonic saline: in vitro and in vivo muscle tissue toxicity and spinal neurone c-fos expression. Basic Clin Pharmacol Toxicol 97:52–57
Svenson P, Arendt-Nielsen L (1995) Induction and assessment of experimental muscle pain. J Electromyogr Kinesiol 5:131–140
Svensson P, Cairns BE, Wang K, Arendt-Nielsen L (2003) Injection of nerve growth factor into human masseter muscle evokes long-lasting mechanical allodynia and hyperalgesia. Pain 104:241–247
Svensson P, Wang K, Arendt-Nielsen L, Cairns BE (2008) Effects of NGF-induced muscle sensitization on proprioception and nociception. Exp Brain Res 189:1–10
Thalhammer JG, LaMotte RH (1982) Spatial properties of nociceptor sensitization following heat injury of the skin. Brain Res 231:257–265
Torebjörk HE, Lundberg LE, LaMotte RH (1992) Central changes in processing of mechanoreceptive input in capsaicin-induced secondary hyperalgesia in humans. J Physiol 448:765–780
Tracey I, Mantyh PW (2007) The cerebral signature for pain perception and its modulation. Neuron 55:377–391
Treede RD, Lorenz J, Baumgärtner U (2003) Clinical usefulness of laser-evoked potentials. Neurophysiol Clin 33:303–314
Tuveson B, Leffler AS, Hansson P (2006) Time dependent differences in pain sensitivity during unilateral ischemic pain provocation in healthy volunteers. Eur J Pain 10:225–232
Vo L, Hood S, Drummond PD (2016) Involvement of opioid receptors and α2-adrenoceptors in inhibitory pain modulation processes: a double-blind placebo-controlled crossover study. J Pain 17:1164–1173
Wager TD, Atlas LY, Lindquist MA, Roy M et al (2013) An fMRI-based neurologic signature of physical pain. N Engl J Med 368:1388–1397
Willer JC (1977) Comparative study of perceived pain and nociceptive flexion reflex in man. Pain 3:69–80
Woolf CJ (1983) Evidence for a central component of post-injury pain hypersensitivity. Nature 306:686–688
Woolf CJ (2011) Central sensitization: implications for the diagnosis and treatment of pain. Pain 152:S2–15
Woolf CJ, Max MB (2001) Mechanism-based pain diagnosis: issues for analgesic drug development. Anesthesiology 95:241–249
Yang H, Meijer HGE, Doll RJ, Buitenweg JR (2015) Computational modeling of Adelta-fiber-mediated nociceptive detection of electrocutaneous stimulation. Biol Cybern 109:479–491
Yarnitsky D, Arendt-Nielsen L, Bouhassira D, Edwards RR et al (2010) Recommendations on terminology and practice of psychophysical DNIC testing. Eur J Pain 14:339
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Siebenga, P. et al. (2018). Pharmacodynamic Evaluation: Pain Methodologies. In: Hock, F., Gralinski, M. (eds) Drug Discovery and Evaluation: Methods in Clinical Pharmacology. Springer, Cham. https://doi.org/10.1007/978-3-319-56637-5_56-1
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