These multicenter data confirmed principal properties of NB (sensory loss), PH (heat hyperalgesia), and SH (pinprick hyperalgesia) that have been already reported in human and animal experiments.8,35,42,47,55 They also revealed additional sensory alterations in these human surrogate models that had not been previously described, that is, sensory gain in NBs and sensory loss in hyperalgesia models. This probably reflects a selection or reporting bias in previous studies that had not assessed these sensory functions.
In a randomized split-half analysis, a sorting algorithm previously validated for sensory profiles of neuropathic pain patients60 led to reproducible sorting of surrogate model sensory profiles into patterns defined a priori according to known mechanisms. Sorting of 902 neuropathic pain patients into these mechanistic phenotypes led to a similar distribution as the original heuristic clustering,5,60 laying the basis for a mechanism-based treatment approach.64
The sensory profile of human surrogate models for transient functional denervation (ie, A-fiber compression block and topical lidocaine) was characterized by pronounced loss in thermal and mechanical detection combined with PHS. These patterns have been reported in previous single-center studies.34,65 Consistent with its selective effect on myelinated nerve fibers, compression NB had larger effects on MDT and CDT than on warm detection threshold.28,65 Pinprick stimuli are often perceived as less painful in complete A-fiber block,28,65 whereas mild pinprick hyperalgesia has been associated with preserved A-delta fiber function2,29 Topical lidocaine had mild effects compared with complete conduction block by regional anesthesia.22,33 Interestingly, in contrast to the present data, intradermal lidocaine 0.01% and 0.1% was reported to induce also a heat hyperalgesia probably due to sensitization of TRPV1 and TRPA1 receptors.38,39,49,63
Muscle HFS was introduced as a model for plasticity of deep pain, and the overlying skin did not exhibit profiles compatible with SH. Our data were from the lower back; more pronounced effects might occur when other muscles, for example, in the lower limb or face are stimulated.
The sorting according to surrogate model profiles was applied to our previously published patient data, which leads to a similar distribution as the original heuristic clustering. This supports previous mechanistic interpretations of the clinically found phenotypes: the thermal hyperalgesia patient phenotype shows strong overlap with surrogate models of PH. This supports previous interpretations as irritable nociceptor18 and peripheral sensitization.57 Both evoked and ongoing pain is likely to be due to surviving nociceptors in these patients.
The mechanical hyperalgesia patient phenotype shows a strong overlap with surrogate models of SH, which supports an interpretation of this phenotype to be a phenotype of reorganization or central sensitization. Substantial thermal sensory loss suggests that also damaged nociceptors are involved, generating ongoing pain and inducing central sensitization.4
The sensory loss patient phenotype shows a strong overlap with experimental NBs. These blocks were frequently used as tools to identify normal sensory function of fiber classes (A vs C), but not yet widely recognized as mimicking aspects of neuropathic pain.7,33 Both the clinical phenotype and the surrogate models are dominated by loss of small and large fiber functions. This supports an interpretation as denervation or deafferentation, where central neurons may develop denervation super-sensitivity to other inputs.14
Roughly one-third of the patients were assigned a NB phenotype according to the surrogate models vs one of the hyperalgesia phenotypes in the heuristic patient cluster analysis. This systematic shift is consistent with the presence of partial nerve damage in most of the neuropathic pain conditions that may lead to coexistence of denervation and sensitization of the remaining pathways.11 These data cover, however, only peripheral neuropathic pain, and to this point, we cannot make any extrapolations onto, for example, central pain, nociceptive pain, or deep pains.
The validity of the prototypic mechanistic profiles is partly demonstrated by the accuracy of allocation of the training set data to the appropriate a priori profile of roughly 80%. This shows general robustness, but also that the deterministic algorithm is not perfect and should be used with some caution on individual basis. For a better separation of mechanism-specific sensory profiles from idiosyncrasies of individual experimental models, more human surrogate models of PH and SH (eg, burn injury and surgical incision) and of temporary functional denervation (eg, limb ischemia and capsaicin-induced defunctionalization) should be studied using the methods of this article.
The models in this analysis do not explicitly cover the endogenous pain-modulating systems30 nor ectopic activity. Descending modulation may contribute to the SH phenotype, but might also exhibit yet another sensory profile. Ectopic activity may have been present in any of our models, but we have neither positive nor negative evidence about it.
The percentage of sensory profiles compatible with normal variability was higher in the surrogate models than in the patients (29% vs 20%). We think that this is due to the fact that for ethical reasons, all manipulations in humans were relatively minor (as compared to patients and animal models50).
With these prototypical sensory profiles for 3 predefined mechanisms (denervation, peripheral, and central sensitization), we provide a well-studied mechanistic background for our previously described heuristic sensory phenotype clusters. Using the probabilistic sorting according to human surrogate model profiles, patients suffering from neuropathic pain can be tentatively stratified in future studies to presumed underlying mechanisms. The European Medicines Agency encourages such an approach in its new guideline17 as a step towards increasing response rates in clinical trials by a mechanism-based treatment approach towards neuropathic pain.64 It should be noted, however, that the 3 classes of human surrogate models studied here likely represent combined rather than single mechanisms. This, however, is likely true also for studies in awake behaving animals. Therefore, a reverse translation approach may be useful for developing novel analgesic medications: they should initially be tested in animal models of NB, PH, or SH. Medications effective on these phenotypes can easily be validated in human surrogate models and then transferred to subgroups of neuropathic pain patients.
The authors have no financial or other relationships that might lead to a conflict of interest.
The EUROPAIN project is a public-private partnership and has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no 115007, resources for which are composed of financial contribution from the European Union's seventh framework programme (FP7/2007–2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution. The NEUROPAIN project is an investigator-initiated European multicentre study with R. Baron as principal investigator and 10 coinvestigator sites, supported by an independent research grant from Pfizer Ltd.
The authors thank all consortia for building up the basis of this study by patient and subject recruitment and assessment.
. Andersen HH, Lo Vecchio S, Gazerani P, Arendt-Nielsen L. A dose-response study of topical allyl-isothiocyanate (mustard oil) as human surrogate model of pain, hyperalgesia, and neurogenic inflammation. PAIN 2017;158:1723–32.
. Andrew D, Greenspan JD. Peripheral coding of tonic mechanical cutaneous pain: comparison of nociceptor activity in rat and human psychophysics. J Neurophysiol 1999;82:2641–8.
. Backonja MM, Attal N, Baron R, Bouhassira D, Drangholt M, Dyck PJ, Edwards RR, Freeman R, Gracely R, Haanpaa MH, Hansson P, Hatem SM, Krumova EK, Jensen TS, Maier C, Mick G, Rice AS, Rolke R, Treede RD, Serra J, Toelle T, Tugnoli V, Walk D, Walalce MS, Ware M, Yarnitsky D, Ziegler D. Value of quantitative sensory testing
in neurological and pain disorders: NeuPSIG consensus. PAIN 2013;154:1807–19.
. Baron R, Hans G, Dickenson AH. Peripheral input and its importance for central sensitization. Ann Neurol 2013;74:630–6.
. Baron R, Maier C, Attal N, Binder A, Bouhassira D, Cruccu G, Finnerup NB, Haanpaa M, Hansson P, Hullemann P, Jensen TS, Freynhagen R, Kennedy JD, Magerl W, Mainka T, Reimer M, Rice ASC, Segerdahl M, Serra J, Sindrup S, Sommer C, Tolle T, Vollert J, Treede RD. Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles. PAIN 2017;158:261–72.
. Baumann TK, Simone DA, Shain CN, LaMotte RH. Neurogenic hyperalgesia: the search for the primary cutaneous afferent fibers that contribute to capsaicin
-induced pain and hyperalgesia. J Neurophysiol 1991;66:212–27.
. Baumgartner U, Magerl W, Klein T, Hopf HC, Treede RD. Neurogenic hyperalgesia versus painful hypoalgesia: two distinct mechanisms of neuropathic pain. PAIN 2002;96:141–51.
. Binder A. Human surrogate models of neuropathic pain: validity and limitations. PAIN 2016;157(suppl 1):S48–52.
. Binder A, Stengel M, Klebe O, Wasner G, Baron R. Topical high-concentration (40%) menthol
-somatosensory profile of a human surrogate pain model. J Pain 2011;12:764–73.
. Callsen MG, Moller AT, Sorensen K, Jensen TS, Finnerup NB. Cold hyposensitivity after topical application of capsaicin
in humans. Exp Brain Res 2008;191:447–52.
. Campbell JN, Meyer RA. Mechanisms of neuropathic pain. Neuron 2006;52:77–92.
. Cohen J. A power primer. Psychol Bull 1992;112:155–9.
. Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hoboken: Taylor and Francis, 2013.
. Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, Freeman R, Truini A, Attal N, Finnerup NB, Eccleston C, Kalso E, Bennett DL, Dworkin RH, Raja SN. Neuropathic pain. Nat Rev Dis Primers 2017;3:17002.
. Edwards RR, Dworkin RH, Turk DC, Angst MS, Dionne R, Freeman R, Hansson P, Haroutounian S, Arendt-Nielsen L, Attal N, Baron R, Brell J, Bujanover S, Burke LB, Carr D, Chappell AS, Cowan P, Etropolski M, Fillingim RB, Gewandter JS, Katz NP, Kopecky EA, Markman JD, Nomikos G, Porter L, Rappaport BA, Rice ASC, Scavone JM, Scholz J, Simon LS, Smith SM, Tobias J, Tockarshewsky T, Veasley C, Versavel M, Wasan AD, Wen W, Yarnitsky D. Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations. PAIN 2016;157:1851–71.
. Enax-Krumova EK, Pohl S, Westermann A, Maier C. Ipsilateral and contralateral sensory changes in healthy subjects after experimentally induced concomitant sensitization and hypoesthesia. BMC Neurol 2017;17:60.
. Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: irritable nociceptors and deafferentation. Neurobiol Dis 1998;5:209–27.
. Finnerup NB, Haroutounian S, Kamerman P, Baron R, Bennett DLH, Bouhassira D, Cruccu G, Freeman R, Hansson P, Nurmikko T, Raja SN, Rice ASC, Serra J, Smith BH, Treede RD, Jensen TS. Neuropathic pain: an updated grading system for research and clinical practice. PAIN 2016;157:1599–606.
. Fimer I, Klein T, Magerl W, Treede RD, Zahn PK, Pogatzki-Zahn EM. Modality-specific somatosensory changes in a human surrogate model of postoperative pain. Anesthesiology 2011;115:387–97.
. Fleiss JL, Levin B, Paik MC. Statistical methods for rates and proportions. 3rd ed. Hoboken: Wiley-Interscience, 2003.
. Gandevia SC, Phegan CML. Perceptual distortions of the human body image produced by local anaesthesia, pain and cutaneous stimulation. J Physiol 1999;514:609–16.
. Geber C, Magerl W, Fondel R, Fechir M, Rolke R, Vogt T, Treede RD, Birklein F. Numbness in clinical and experimental pain–a cross-sectional study exploring the mechanisms of reduced tactile function. PAIN 2008;139:73–81.
. Gierthmuhlen J, Enax-Krumova EK, Attal N, Bouhassira D, Cruccu G, Finnerup NB, Haanpaa M, Hansson P, Jensen TS, Freynhagen R, Kennedy JD, Mainka T, Rice ASC, Segerdahl M, Sindrup SH, Serra J, Tolle T, Treede RD, Baron R, Maier C. Who is healthy? Aspects to consider when including healthy volunteers in QST–based studies-a consensus statement by the EUROPAIN and NEUROPAIN consortia. PAIN 2015;156:2203–11.
. Gustorff B, Sycha T, Lieba-Samal D, Rolke R, Treede RD, Magerl W. The pattern and time course of somatosensory changes in the human UVB
sunburn model reveal the presence of peripheral and central sensitization. PAIN 2013;154:586–97.
. Hayman M, Kam PCA. Capsaicin
: a review of its pharmacology and clinical applications. Curr Anaesth Crit Care 2008;19:338–43.
. von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron 2012;73:638–52.
. Henrich F, Magerl W, Klein T, Greffrath W, Treede RD. Capsaicin
-sensitive C- and A-fibre nociceptors control long-term potentiation-like pain amplification in humans. Brain 2015;138:2505–20.
. Jørum E, Warncke T, Ziegler EA, Magerl W, Fuchs PN, Meyer R, Treede RD. Secondary hyperalgesia to punctate stimuli is mediated by A-fiber nociceptors. In: Devor M, Rowbotham M, Wiesenfeld-Hallin Z, editors. Proceedings of the 9th World Congress on Pain, Progr Pain Res Management. Seattle: IASP Press, 2000. p. 215–223.
. Kennedy DL, Kemp HI, Ridout D, Yarnitsky D, Rice ASC. Reliability of conditioned pain modulation: a systematic review. PAIN 2016;157:2410–9.
. Kilo S, Schmelz M, Koltzenburg M, Handwerker HO. Different patterns of hyperalgesia induced by experimental inflammation in human skin. Brain 1994;117:385–96.
. Klein T, Magerl W, Hopf HC, Sandkühler J, Treede RD. Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans. J Neurosci 2004;24:964–71.
. Klein T, Magerl W, Rolke R, Treede RD. Human surrogate models of neuropathic pain. PAIN 2005;115:227–33.
. Krumova EK, Zeller M, Westermann A, Maier C. Lidocaine
patch (5%) produces a selective, but incomplete block of Adelta and C fibers. PAIN 2012;153:273–80.
. LaMotte RH, Lundberg LE, Torebjörk HE. Pain, hyperalgesia and activity in nociceptive C units in humans after intradermal injection of capsaicin
. J Physiol 1992;448:749–64.
. LaMotte RH, Shain CN, Simone DA, Tsai EF. Neurogenic hyperalgesia: psychophysical studies of underlying mechanisms. J Neurophysiol 1991;66:190–211.
. Lang S, Klein T, Magerl W, Treede RD. Modality-specific sensory changes in humans after the induction of long-term potentiation (LTP) in cutaneous nociceptive pathways. PAIN 2007;128:254–63.
. Leffler A, Fischer MJ, Rehner D, Kienel S, Kistner K, Sauer SK, Gavva NR, Reeh PW, Nau C. The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons. J Clin Invest 2008;118:763–76.
. Leffler A, Lattrell A, Kronewald S, Niedermirtl F, Nau C. Activation of TRPA1 by membrane permeable local anesthetics. Mol Pain 2011;7:62.
. Lotsch J, Dimova V, Hermens H, Zimmermann M, Geisslinger G, Oertel BG, Ultsch A. Pattern of neuropathic pain induced by topical capsaicin
application in healthy subjects. PAIN 2015;156:405–14.
. Lotsch J, Dimova V, Ultsch A, Lieb I, Zimmermann M, Geisslinger G, Oertel BG. A small yet comprehensive subset of human experimental pain models emerging from correlation analysis with a clinical quantitative sensory testing
protocol in healthy subjects. Eur J Pain 2016;20:777–89.
. Lotsch J, Oertel BG, Ultsch A. Human models of pain for the prediction of clinical analgesia. PAIN 2014;155:2014–21.
. Magerl W, Fuchs PN, Meyer RA, Treede RD. Roles of capsaicin
-insensitive nociceptors in cutaneous pain and secondary hyperalgesia. Brain 2001;124:1754–64.
. Magerl W, Krumova EK, Baron R, Tolle T, Treede RD, Maier C. Reference data for quantitative sensory testing
(QST): refined stratification for age and a novel method for statistical comparison of group data. PAIN 2010;151:598–605.
. Maier C, Baron R, Tolle TR, Binder A, Birbaumer N, Birklein F, Gierthmuhlen J, Flor H, Geber C, Huge V, Krumova EK, Landwehrmeyer GB, Magerl W, Maihofner C, Richter H, Rolke R, Scherens A, Schwarz A, Sommer C, Tronnier V, Uceyler N, Valet M, Wasner G, Treede RD. Quantitative sensory testing
in the German Research Network on Neuropathic Pain
(DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. PAIN 2010;150:439–50.
. Mendell LM. Constructing and deconstructing the gate theory of pain. PAIN 2014;155:210–6.
. Ochoa JL, Campero M, Serra J, Bostock H. Hyperexcitable polymodal and insensitive nociceptors in painful human neuropathy. Muscle Nerve 2005;32:459–72.
. Pfau DB, Krumova EK, Treede RD, Baron R, Toelle T, Birklein F, Eich W, Geber C, Gerhardt A, Weiss T, Magerl W, Maier C. Quantitative sensory testing
in the German Research Network on Neuropathic Pain
(DFNS): reference data for the trunk and application in patients with chronic postherpetic neuralgia. PAIN 2014;155:1002–15.
. Piao LH, Fujita T, Jiang CY, Liu T, Yue HY, Nakatsuka T, Kumamoto E. TRPA1 activation by lidocaine
in nerve terminals results in glutamate release increase. Biochem Biophys Res Commun 2009;379:980–4.
. Reitz MC, Hrncic D, Treede RD, Caspani O. A comparative behavioural study of mechanical hypersensitivity in 2 pain models in rats and humans. PAIN 2016;157:1248–58.
. Rolke R, Baron R, Maier C, Tolle TR, Treede RD, Beyer A, Binder A, Birbaumer N, Birklein F, Botefur IC, Braune S, Flor H, Huge V, Klug R, Landwehrmeyer GB, Magerl W, Maihofner C, Rolko C, Schaub C, Scherens A, Sprenger T, Valet M, Wasserka B. Quantitative sensory testing
in the German Research Network on Neuropathic Pain
(DFNS): standardized protocol and reference values. PAIN 2006;123:231–43.
. Rolke R, Magerl W, Campbell KA, Schalber C, Caspari S, Birklein F, Treede RD. Quantitative sensory testing
: a comprehensive protocol for clinical trials. Eur J Pain 2006;10:77–88.
. Schilder A, Magerl W, Hoheisel U, Klein T, Treede RD. Electrical high-frequency stimulation of the human thoracolumbar fascia evokes long-term potentiation-like pain amplification. PAIN 2016;157:2309–17.
. Simone DA, Sorkin LS, Oh U, Chung JM, Owens C, LaMotte RH, Willis WD. Neurogenic hyperalgesia: central neural correlates in responses of spinothalamic tract neurons. J Neurophysiol 1991;66:228–46.
. Treede RD, Meyer RA, Raja SN, Campbell JN. Peripheral and central mechanisms of cutaneous hyperalgesia. Prog Neurobiol 1992;38:397–421.
. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO, Griffin JW, Hansson P, Hughes R, Nurmikko T, Serra J. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 2008;70:1630–5.
. Truini A, Biasiotta A, Di Stefano G, La Cesa S, Leone C, Cartoni C, Leonetti F, Casato M, Pergolini M, Petrucci MT, Cruccu G. Peripheral nociceptor sensitization mediates allodynia in patients with distal symmetric polyneuropathy. J Neurol 2013;260:761–6.
. Voets T, Droogmans G, Wissenbach U, Janssens A, Flockerzi V, Nilius B. The principle of temperature-dependent gating in cold- and heat-sensitive TRP channels. Nature 2004;430:748–54.
. Vollert J, Attal N, Baron R, Freynhagen R, Haanpaa M, Hansson P, Jensen TS, Rice ASC, Segerdahl M, Serra J, Sindrup SH, Tolle TR, Treede RD, Maier C. Quantitative sensory testing
using DFNS protocol in Europe: an evaluation of heterogeneity across multiple centers in patients with peripheral neuropathic pain and healthy subjects. PAIN 2016;157:750–8.
. Vollert J, Maier C, Attal N, Bennett DLH, Bouhassira D, Enax-Krumova EK, Finnerup NB, Freynhagen R, Gierthmühlen JJ, Haanpää M, Hansson P, Hüllemann P, Jensen TS, Magerl W, Ramirez JD, Rice ASC, Schuh-Hofer S, Segerdahl M, Serra J, Shillo PR, Sindrup S, Tesfaye S, Themistocleous AC, Tölle TRTR, Treede RD, Baron R. Stratifying patients with peripheral neuropathic pain based on sensory profiles. PAIN 2017;158:1446–55.
. Vollert J, Mainka T, Baron R, Enax-Krumova EK, Hullemann P, Maier C, Pfau DB, Tolle T, Treede RD. Quality assurance for Quantitative Sensory Testing
laboratories: development and validation of an automated evaluation tool for the analysis of declared healthy samples. PAIN 2015;156:2423–30.
. Wasner G, Schattschneider J, Binder A, Baron R. Topical menthol
–a human model for cold pain by activation and sensitization of C nociceptors. Brain 2004;127:1159–71.
. Weinkauf B, Obreja O, Schmelz M, Rukwied R. Differential effects of lidocaine
on nerve growth factor (NGF)-evoked heat- and mechanical hyperalgesia in humans. Eur J Pain 2012;16:543–9.
. Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, Lipton R, Loeser JD, Payne R, Torebjork E. Towards a mechanism-based classification of pain? PAIN 1998;77:227–9.
. Ziegler EA. Secondary hyperalgesia to punctate mechanical stimuli: central sensitization to A-fibre nociceptor input. Brain 1999;122:2245–57.
. Zimmermann M. Dorsal root potentials after C-fiber stimulation. Science 1968;160:896–8.