We would like to thank Esther Davidse, Michiel Weber, Rens Batist, Joop van Gerven and all other staff involved in development of these pain tasks.

Ethics statement: Procedures involving human subjects have been approved by the Stichting Beoordeling Ethiek Biomedisch&#160; Onderzoek (Foundation BEBO) and the Leiden University Medical Center.
1. Integrated Pain Assessment Tasks
NOTE: The task administration and interface is based on Spike2 software and an analogue-to-digital converter that performs the conversions needed for stimulus triggering and signal recording. This ensures uniform task&#160;administration, data capture, handling and storage, and standardizing the delivery of tasks&#160;by controlling the stimulus generation equipment while presenting instructions to the subject and feedback on slider position via a second monitor.
NOTE: Perform the tasks in short succession and in the order presented. The duration of performing all the tasks is approximately 30 min.
<ol>
	<li>Pain scoring 
	NOTE: For most tasks, stimuli of progressively increasing intensity are presented.
	<ol>
		<li>Prior to the task, present the subject with an electronic visual analog&#160;scale (eVAS) slider.</li>
		<li>Instruct the subject to indicate the intensity of their pain on a scale from 0 (none) to 100 (intolerable pain) by moving the slider from left to right.</li>
		<li>During training, and when necessary, provide the subjects with standardized definitions (Table 1) and instructions.</li>
		<li>Inform the subject that moving the slider all the way to the left ends the administration of the painful stimulus.</li>
		<li>Record when stimulus becomes&#160;painful (eVAS &#62;0), corresponding to the pain detection threshold. Record when the pain is no longer tolerable to the subject (eVAS = 100), corresponding to the pain tolerance level of the subject&#160;and the area under the stimulus-response curve (AUC). 
		NOTE: During training, it is beneficial to provide subjects with a&#160;context of pain intensity. Following each task assess the maximal pain intensity using a 100 mm eVAS, with 0 and 100 defined as &#39;no pain&#39; and &#39;worst pain imaginable&#39;, respectively (Table 1).</li>
	</ol>
	</li>
</ol>
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Threshold</td>
			<td>Verbal instructions to subject (during training and as a reminder)</td>
			<td>Resulting eVAS scores</td>
		</tr>
		<tr>
			<td>PDT (Pain Detection Threshold)</td>
			<td>&#8220;Start moving the eVAS-slider when first change in sensation from non-painful to painful is felt &#8221;</td>
			<td>&#62;0 ( = 1)</td>
		</tr>
		<tr>
			<td>PTT (Pain Tolerance Threshold)</td>
			<td>&#8220;When pain intensity is no longer tolerable&#8221;</td>
			<td>100 (intolerable pain)</td>
		</tr>
		<tr>
			<td>Post-task VAS</td>
			<td>&#8220;An example of the worst pain imaginable could be a surgical treatment without anesthetic&#8221;*</td>
			<td>max 100 (worst imaginable pain)</td>
		</tr>
	</tbody>
</table>
Table 1.&#160;Standard Definitions of VAS Anchor-points. *Pain is a unique personal experience; this definition is provided only to provide a consistent (nociceptive) frame of reference and is chosen as it somewhat negates experiences of loss, psychological suffering, and vicarious pain3.
2. Electrical Stimulation Task
NOTE: The task&#160;has been shown to primarily assess nociception generated from the A&#948; and C sensory afferent fibers, which pass nociceptive signals from the periphery to the spinal cord. The A&#948; fibers conduct the signal relatively rapidly, causing the sharp localization of pain and the rapid spinal response which is perceived during a transcutaneous electrical stimulus9. The method of electrical stimulation is based on methods described previously15.
<ol>
	<li>Clean an area of skin with skin preparation gel overlying the tibial bone, 100 mm distal from the caudal end of the patella. If required, shave the area beforehand.</li>
	<li>Place two Ag-AgCl electrodes on the skin. Place the middle of the first electrode (anode) 100 mm distal to the caudal end of the patella. Place the middle of the second electrode (cathode) directly (&#177;135 mm) underneath the first.</li>
	<li>Record the resistance of the 2 electrodes using an ohmmeter. Ensure it is &#60;2 k&#937;. Optionally, remove the electrodes and re-cleanse the skin with skin preparation gel. Instruct the subject to sit comfortably with their foot flat on the floor.</li>
	<li>Connect the electrodes to a constant current stimulator and apply a tetanic pulse from 0 mA in steps of 0.5 mA/s (cutoff 50 mA), with a frequency of 10 Hz with a duration of 0.2 ms.</li>
</ol>
3. Pressure Stimulation Task
NOTE: This method of pressure pain induction has been shown to primarily assess nociception generated from the muscle with minimal contribution by cutaneous nociceptors17 and is based on methods described previously16.
<ol>
	<li>Place an 11 cm wide tourniquet cuff over the gastrocnemius muscle. Instruct the subject to sit comfortably with their foot flat on the floor. Inflate with a constant pressure rate increase of 0.5 kPa/s up to 100 kPa. Control the pressure with an electro-pneumatic regulator.</li>
</ol>
4. Cold Pressor Task
NOTE: The cold pressor task&#160;involves the submersion of an extremity (generally a hand) into cold water. It is used in clinical studies to investigate cardiovascular responses and nociception. It is also a method to induce iCPM (formerly known as diffuse noxious inhibitory control (DNIC)-like effect)18. The method of cold pressor pain is based on the methods previously described8,10.
<ol>
	<li>Prepare two thermostat-controlled, circulating water baths set at 35.0 &#177; 0.5 &#176;C and 1.0 &#177; 0.5 &#176;C.</li>
	<li>Place a 35 cm tourniquet on the subject&#39;s non-dominant upper-arm. During hand immersion, either regulate the blood pressure manually using a sphygmomanometer or by using a custom built electro-pneumatic regulator.</li>
	<li>Instruct the subject to sit comfortably with their palm flat, fingers spread wide without touching the bath and rate their pain intensity using the eVAS.</li>
	<li>Instruct the subject to place their non-dominant hand into a warm water bath for 2 min.</li>
	<li>At 1 min&#160;45 sec&#160;inflate the blood pressure cuff on their upper-arm to 20 mmHg below resting diastolic blood pressure.</li>
	<li>At 2 min&#160;instruct the subject to move their hand from the warm water bath, directly placing their hand into the cold water bath to similar depth.</li>
	<li>After reaching pain tolerance, or after reaching a time limit (120 sec), instruct the subject to remove their arm from the water. At this point deflate the blood pressure cuff and give the subject a towel to dry their forearm.</li>
</ol>
5. Conditioned Pain Modulation Paradigm
NOTE: iCPM is the activation of the pain-modulatory mechanism, as part of the descending endogenous analgesia system18. The degree of iCPM is assessed by comparing the electrical pain thresholds for the single stimulus paradigm before and after the cold pressor task.
<ol>
	<li>Repeat the electrical stimulation task (section 2) within 5 min&#160;after the end of the cold pressor task.</li>
</ol>
6. Ultra-violet Inflammation Model
NOTE: The UVB &#34;sun burn&#34; model is a pain model in which erythema is induced on the skin by exposing the skin to UVB light in a well-controlled and reproducible manner. This exposure causes changes to the skin which leads to pain perception being intensified in the affected area (primary hyperalgesia) and is used as biomarker for inflammatory pain. This inflammation model is based on the methods previously described4. Inform subjects that the UVB exposure may leave long-lasting (6 - 12 months) skin marking/tanning and that exposure to UVB in general&#160;has been linked to premature skin aging and skin cancer.
<ol>
	<li>Determining a Subject&#39;s Minimal Erythemic Dose (MED)
	<ol>
		<li>Turn on the UVB lamp and allow it to warm up for at least 10 min&#160;prior to use. Replace the fluorescent tubes once output is &#60;3.0 mW/cm2 (after approximately 50 - 100 working hr).</li>
		<li>Instruct the subject to stand with their right hand holding their left shoulder. Place the UVB lamp on the right upper back / shoulder of the subject, in direct contact with the skin. Only induce the erythema on even-toned healthy skin; moles, tattoos, nevus and acne must be avoided.</li>
		<li>Apply the UVB exposure at the screening visit in ascending doses (see Table 2) to 6 different 1 x 1 cm areas of skin on the back to determine the individual UVB dose that produces the first clearly discernable erythema (minimal erythemic dose (MED).</li>
		<li>Assess the erythemic response 24 hr&#160;(&#177;2 hr) after the exposure of the 6 doses. Determine the MED visually, by means of consensus of two observers with good color vision, by observing which dose produces the first clearly discernable erythema. Choose the 3rd UVB dose to approximate the mean MED for the respective skin type20.</li>
	</ol>
	</li>
</ol>
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Skin type</td>
			<td rowspan="2">I</td>
			<td rowspan="2">II</td>
			<td rowspan="2">III</td>
			<td rowspan="2">IV</td>
		</tr>
		<tr>
			<td>Dose</td>
		</tr>
		<tr>
			<td>#1</td>
			<td>64</td>
			<td>126</td>
			<td>176</td>
			<td>234</td>
		</tr>
		<tr>
			<td>#2</td>
			<td>91</td>
			<td>177</td>
			<td>248</td>
			<td>330</td>
		</tr>
		<tr>
			<td>#3</td>
			<td>128</td>
			<td>251</td>
			<td>351</td>
			<td>467</td>
		</tr>
		<tr>
			<td>#4</td>
			<td>181</td>
			<td>355</td>
			<td>496</td>
			<td>660</td>
		</tr>
		<tr>
			<td>#5</td>
			<td>256</td>
			<td>502</td>
			<td>702</td>
			<td>934</td>
		</tr>
		<tr>
			<td>#6</td>
			<td>362</td>
			<td>710</td>
			<td>993</td>
			<td>1321</td>
		</tr>
	</tbody>
</table>
Table 2.&#160;UVB Dose Regimen&#160;Per Skin Type ( mJ/cm2 )
<ol start="2">
	<li>UVB exposure
	<ol>
		<li>Apply a 3 x 3 cm UVB exposure equivalent to the subject&#39;s 3-fold individual MED. Apply this UVB exposure to the subject&#39;s back 24 hr&#160;prior to the first battery of tasks/dosing. Ensure the UVB exposure produces a homogeneous, well-demarcated area of skin erythema and hyperalgesia.</li>
	</ol>
	</li>
	<li>Assessment of Skin Thermal Detection Threshold
	<ol>
		<li>Using a 3 x 3 cm thermode measure the thermal pain detection threshold on normal skin contralateral to the site of UVB irradiation followed by UVB irradiated skin. Set the temperature initially to 34 &#176;C, then ramp up by 0.5 &#176;C/sec. Record the average pain detection threshold of 3 stimuli.</li>
	</ol>
	</li>
</ol>
7. Subjects
NOTE: In addition to standard selection criteria and to ensure a reasonably homogeneous subject population the following exclusion criteria should be considered. Exclude subjects who meet the following criteria:
<ol>
	<li>Indicate nociceptive tasks&#160;are intolerable at screening.</li>
	<li>Achieve tolerance of &#62;80% of maximum input intensity for cold, pressure and electrical tasks&#160;(to exclude pain tolerant individuals which may obfuscate an analgesic effect).</li>
	<li>Have any current, clinically significant, known medical condition, particularly any existing conditions that would affect sensitivity to cold (such as atherosclerosis, Raynaud&#39;s disease, urticaria, hypothyroidism) or pain (parasthesia,&#160;etc.). Use&#160;healthy subjects only.</li>
	<li>Use prescription or nonprescription drugs (especially analgesics) and dietary/herbal supplements within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study treatment.</li>
	<li>Have dark skin (Fitzpatrick skin type V or VI), widespread acne, tattoos or scarring on back (due to interference with the UVB model).</li>
	<li>Sunbathe or have used sunbeds in the 6 months prior to screening or are unable to not be exposed to excessive sunlight or to sunbathe for the duration of the study. Skin coloration due to sunlight and sunburn affect the UVB study endpoints.</li>
</ol>
NOTE: Unless contraindicated, women should be included and where possible menstrual cycle should be either monitored or controlled for (e.g., testing only during luteal phase).

<ol>
	<li>Arendt-Nielsen, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Central+sensitization+in+humans:+assessment+and+pharmacology.">Central sensitization in humans: assessment and pharmacology.</a> Handb.Exp Pharmacol. 227, 79-102 (2015).</li><li>Arendt-Nielsen, L., Yarnitsky, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Experimental+and+clinical+applications+of+quantitative+sensory+testing+applied+to+skin,+muscles+and.">Experimental and clinical applications of quantitative sensory testing applied to skin, muscles and.</a> J Pain. 10 (6), 556-572 (2009).</li><li>Bergh, I., Jakobsson, E., Sjostrom, B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Worst+experiences+of+pain+and+conceptions+of+worst+pain+imaginable+among+nursing+students.">Worst experiences of pain and conceptions of worst pain imaginable among nursing students.</a> J Adv Nurs. 61 (5), 484-491 (2008).</li><li>Bishop, T., Ballard, A., Holmes, H., Young, A. R., McMahon, S. B. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Ultraviolet-B+induced+inflammation+of+human+skin:+characterisation+and+comparison+with+traditional+models+of+hyperalgesia.">Ultraviolet-B induced inflammation of human skin: characterisation and comparison with traditional models of hyperalgesia.</a> Eur J Pain. 13 (5), 524-532 (2009).</li><li>Bloom, F. E., Kupfer, D. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Psychopharmacology : the fourth generation of progress. , (1995).</li><li>Bloom, F. E., Kupfer, D. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Neuropsychopharmacology : the fifth generation of progress. , (2002).</li><li>Cohen, A. F., Burggraaf, J., van Gerven, J. M., Moerland, M., Groeneveld, G. J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+use+of+biomarkers+in+human+pharmacology+(Phase+I)+studies.">The use of biomarkers in human pharmacology (Phase I) studies.</a> Annu.Rev Pharmacol Toxicol. 55, 55-74 (2015).</li><li>Eckhardt, K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Same+incidence+of+adverse+drug+events+after+codeine+administration+irrespective+of+the+genetically+determined+differences+in+morphine+formation.">Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation.</a> Pain. 76 (1-2), 27-33 (1998).</li><li>Handwerker, H. O., Kobal, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Psychophysiology+of+experimentally+induced+pain.">Psychophysiology of experimentally induced pain.</a> Physiol Rev. 73 (3), 639-671 (1993).</li><li>Jones, S. F., McQuay, H. J., Moore, R. A., Hand, C. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Morphine+and+ibuprofen+compared+using+the+cold+pressor+test.">Morphine and ibuprofen compared using the cold pressor test.</a> Pain. 34 (2), 117-122 (1988).</li><li>Lotsch, J., Oertel, B. G., Ultsch, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Human+models+of+pain+for+the+prediction+of+clinical+analgesia.">Human models of pain for the prediction of clinical analgesia.</a> Pain. 155 (10), 2014-2021 (2014).</li><li>Martini, C., Olofsen, E., Yassen, A., Aarts, L., Dahan, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pharmacokinetic-pharmacodynamic+modeling+in+acute+and+chronic+pain:+an+overview+of+the+recent+literature.">Pharmacokinetic-pharmacodynamic modeling in acute and chronic pain: an overview of the recent literature.</a> Expert Rev Clin Pharmacol. 4 (6), 719-728 (2011).</li><li>Oertel, B. G., Lotsch, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clinical+pharmacology+of+analgesics+assessed+with+human+experimental+pain+models:+bridging+basic+and+clinical+research.">Clinical pharmacology of analgesics assessed with human experimental pain models: bridging basic and clinical research.</a> Br J Pharmacol. 168 (3), 534-553 (2013).</li><li>Olesen, A. E., Andresen, T., Staahl, C., Drewes, A. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Human+experimental+pain+models+for+assessing+the+therapeutic+efficacy+of+analgesic+drugs.">Human experimental pain models for assessing the therapeutic efficacy of analgesic drugs.</a> Pharmacol Rev. 64 (3), 722-779 (2012).</li><li>Olofsen, E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Alfentanil+and+placebo+analgesia:+no+sex+differences+detected+in+models+of+experimental+pain.">Alfentanil and placebo analgesia: no sex differences detected in models of experimental pain.</a> Anesthesiology. 103 (1), 130-139 (2005).</li><li>Polianskis, R., Graven-Nielsen, T., Arendt-Nielsen, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Computer-controlled+pneumatic+pressure+algometry--a+new+technique+for+quantitative+sensory+testing.">Computer-controlled pneumatic pressure algometry--a new technique for quantitative sensory testing.</a> Eur.J Pain. 5 (3), 267-277 (2001).</li><li>Polianskis, R., Graven-Nielsen, T., Arendt-Nielsen, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Pressure-pain+function+in+desensitized+and+hypersensitized+muscle+and+skin+assessed+by+cuff+algometry.">Pressure-pain function in desensitized and hypersensitized muscle and skin assessed by cuff algometry.</a> J Pain. 3 (1), 28-37 (2002).</li><li>Pud, D., Granovsky, Y., Yarnitsky, D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+methodology+of+experimentally+induced+diffuse+noxious+inhibitory+control+(DNIC)-like+effect+in+humans.">The methodology of experimentally induced diffuse noxious inhibitory control (DNIC)-like effect in humans.</a> Pain. 144 (1-2), 16-19 (2009).</li><li>Rolke, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantitative+sensory+testing:+a+comprehensive+protocol+for+clinical+trials.">Quantitative sensory testing: a comprehensive protocol for clinical trials.</a> Eur J Pain. 10 (1), 77-88 (2006).</li><li>Sayre, R. M., Desrochers, D. L., Wilson, C. J., Marlowe, E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Skin+type,+minimal+erythema+dose+(MED),+and+sunlight+acclimatization.">Skin type, minimal erythema dose (MED), and sunlight acclimatization.</a> J Am Acad Dermatol. 5 (4), 439-443 (1981).</li><li>Staahl, C., Olesen, A. E., Andresen, T., Arendt-Nielsen, L., Drewes, A. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assessing+efficacy+of+non-opioid+analgesics+in+experimental+pain+models+in+healthy+volunteers:+an+updated+review.">Assessing efficacy of non-opioid analgesics in experimental pain models in healthy volunteers: an updated review.</a> Br J Clin Pharmacol. 68 (3), 322-341 (2009).</li><li>Staahl, C., Reddy, H., Andersen, S. D., Arendt-Nielsen, L., Drewes, A. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Multi-modal+and+tissue-differentiated+experimental+pain+assessment:+reproducibility+of+a+new+concept+for+assessment+of+analgesics.">Multi-modal and tissue-differentiated experimental pain assessment: reproducibility of a new concept for assessment of analgesics.</a> Basic Clin Pharmacol Toxicol. 98 (2), 201-211 (2006).</li></ol>

The authors have nothing to disclose.

For novel and established analgesics alike, a profiling approach is proposed that utilizes reliable and predictive multi-modal pain models. In contrast to other more onerous pain tasks, such as chemical (e.g., capsaicin, nerve growth factor) hyperalgesia or visceral pain models, the pain tasks mentioned in this protocol can be used repeatedly, quickly, in short succession, with minimum burden for the subject and with a modest quantity of equipment. By using a battery of pain biomarkers such as the one mentioned in this protocol, (plasma) concentration-effect relationships can be established leading to better estimation of a drug&#39;s pharmacological activity. Thereby, more rational choices can be made regarding the therapeutic effect of a drug rather than simply using animal data and the maximum tolerated dose derived from adverse events7.
The design of a clinical study utilizing these pain models needs careful consideration. While the aforementioned pain models provide a suitable basis for screening potentially analgesic drugs, other factors need to be considered, especially taking into account the pharmacological mechanisms of the drug and its pharmacokinetics21. Standard practice for researching analgesics should be applied, including the use of positive controls and designing studies that are randomized (balanced, where applicable), placebo-controlled, and double-blind. Furthermore, it is critical that pain tasks are performed consistently between subjects, with standardized instructions and environmental conditions. While there is risk of an interaction between the tasks e.g., sensitization or additive effects, careful study design and consistent delivery of the tasks minimizes this. In fact, one of these interactions is taken advantage of in this battery by incorporating the iCPM paradigm.
When deciding to include pain tasks in a study, the overall burden of the study should be considered as this may restrict the number of treatment arms or the number of times a task is repeated. If other tasks are used, e.g., measures of sedation or alertness, this may limit the total number of tasks a subject can perform within a study day;&#160;this is especially true if populations other than healthy adult subjects are included e.g., adolescents or chronic pain patients.
A series of validated pain tasks&#160;early in drug development is crucial to bridge findings in the laboratory and those in the clinical situation,&#160;provide valuable information in regard to the mechanism of action of a new drug,&#160;choose the most applicable patient population to be studied&#160;and ascertain the most relevant nociceptive test for more intensive PK/PD modelling. PK/PD modelling can be used to identify responders and non-responders, better estimate the time-course of analgesia or aid in the development of different formulations12. By characterizing analgesics in both healthy subjects and patients, a translational connection between early phase development and the clinic can be established. It may also be used to provide information on the pain physiology and pathophysiology in these populations14. Eventually, the ability to link the efficacy profile of a drug to the pain profile of a patient could help guide individualized treatments in the future1.
Human pain models are valuable tools used to assess the analgesic potential of novel compounds and predict their clinical efficacy. While the implementation of these models can be complex and multifaceted, with proper execution, these pain models can provide predictive and reliable results.

Human pain models are useful in the evaluation of analgesics, providing information about a drug&#39;s pharmacology and identifying potentially suitable therapeutic populations. Yet the field is plagued by studies yielding inconsistent findings. The reason for these differences has been put down to the use of different pain assessment methods and different subject populations22. To correctly predict clinical analgesia, the right pain model is needed.2,13 Nevertheless, mechanism-based pain model selection has led to many failures in predicting clinical efficacy11.
The need to use a comprehensive battery of pain models is highlighted by studies whereby only a single pain model, thought to relate to the clinical situation, demonstrates lack of efficacy. No single experimental model can replicate the complex nature of clinical pain. Therefore, one pain model cannot be used exclusively to screen the pharmacological mechanism of action of a compound intended to treat clinical pain. Furthermore, the use of a panel of pain models allows a drug to be fully characterized and profiled. This is especially useful for drugs that have a novel or untested mechanism of action.
There are various paradigms for assessing validity of animal or human models of disease such as investigating the predictive,&#160;construct,&#160;concurrent or convergent,&#160;discriminant,&#160;etiological,&#160;and face validity of a model5. A pain model can be considered of higher value and more relevant to human disease the more criteria it satisfies. However, a more simple measure of validity is to evaluate a model&#39;s predictive validity and reliability6.
With early phase drug development there are also other considerations that need to be taken into account to assess the value of a pharmacodynamic measurement. The assessment should not be too burdensome, should not take too long, and the results should be quickly evaluable, automated and secure data collection is desirable. Also the ability to test several subjects concurrently requires equipment that is technically standardized and well characterized7.
While other evoked pain batteries exist, their objective is more directed towards the classification of pain and for assessing pathophysiological pain mechanisms19. Yet other batteries aim to represent a broad range of pathophysiology including pain models for muscle and visceral pain4. While suitable for testing in acute situations, their invasive nature do not make them suitable for testing repeatedly for longer periods.
The pain models presented here satisfy many of the above mentioned criteria making them especially useful for clinical studies in both healthy subjects and patients. The multi-modal pain task&#160;battery that is presented here encompasses the electrical stimulation task, pressure stimulation task, cold pressor task, UVB inflammatory model that includes a thermal task and a inhibitory conditioned pain modulation (iCPM) paradigm that takes advantage of interactions between the tasks The human pain models presented here have been tested for predicative validity and reliability both in their own right and in combination.

<table border="0" cellpadding="0" cellspacing="0" width="971">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Analogue&#8211;to-digital converter&#160;</td>
			<td style="width:348px;">Cambridge Electronic Design (CED), Cambridge, UK</td>
			<td style="width:240px;">Power1401mkII</td>
			<td style="width:167px;"></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">eVAS slider</td>
			<td>Cambridge Electronic Design (CED), Cambridge, UK</td>
			<td>custom built</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Ag-AgCl electrodes&#160;</td>
			<td>3M Health Care, St Paul, Canada</td>
			<td>Ag-AgCl Red Dot&#8482; 2560 Electrodes</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Ohmmeter</td>
			<td>Generic device</td>
			<td>Not applicable</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Constant current stimulator</td>
			<td>Cambridge Electronic Design (CED), Cambridge, UK</td>
			<td>DS5</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">11 cm wide tourniquet cuff&#160;</td>
			<td>VBM Medizintechnik GmbH, Sulz, Germany</td>
			<td>REF 20-90-722</td>
			<td>modified with Y-tube connector (REF 88404) so both chambers fill simultaneously</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Electro-pneumatic regulator&#160;</td>
			<td>SMC Corporation, Tokyo, Japan</td>
			<td>ITV1030-31F2N3-Q</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Warm water bath &#38; thermostat</td>
			<td>LAUDA, Germany</td>
			<td>Ecoline E125</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Cold water bath and thermostat</td>
			<td>LAUDA, Germany</td>
			<td>Ecoline E212</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">35 cm tourniquet&#160;&#160;</td>
			<td>VBM Medizintechnik GmbH, Sulz, Germany</td>
			<td>REF 20-54-711</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Florescent tubes&#160;</td>
			<td>Philips, Eindhoven, Netherlands</td>
			<td>36W TL01 Narrow-band</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">30 mm x 30 mm thermode</td>
			<td>Medoc, Israel</td>
			<td colspan="2">TSA-II (2001) Neurosensory Analyzer&#160;</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:216px;">Skin preparation gel</td>
			<td>Weaver and Company</td>
			<td style="width:240px;">Nuprep</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;">Sphygmomanometer</td>
			<td>Generic device</td>
			<td>Not applicable</td>
			<td></td>
		</tr>
	</tbody>
</table>

determining pain detection and tolerance thresholds using an integrated, multi-modal pain task battery

Human pain models are useful in the assessing the analgesic effect of drugs, providing information about a drug&#39;s pharmacology and identify potentially suitable therapeutic populations. The need to use a comprehensive battery of pain models is highlighted by studies whereby only a single pain model, thought to relate to the clinical situation, demonstrates lack of efficacy. No single experimental model can mimic the complex nature of clinical pain. The integrated, multi-modal pain task&#160;battery presented here encompasses the electrical stimulation task, pressure stimulation task, cold pressor task, the UVB inflammatory model which includes a thermal task and a paradigm for inhibitory conditioned pain modulation. These human pain models have been tested for predicative validity and reliability both in their own right and in combination, and can be used repeatedly, quickly, in short succession, with minimum burden for the subject and with a modest quantity of equipment. This allows a drug to be fully characterized and profiled for analgesic effect which is especially useful for drugs with a novel or untested mechanism of action.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>Task</td>
			<td>Endpoints</td>
		</tr>
		<tr>
			<td align="center" colspan="2">Primary Endpoints</td>
		</tr>
		<tr>
			<td>Thermal Task (Normal Skin)</td>
			<td>PDT</td>
		</tr>
		<tr>
			<td>Thermal Task (UVB Skin)</td>
			<td>PDT</td>
		</tr>
		<tr>
			<td>Electrical Task (pre-cold pressor)</td>
			<td>PTT</td>
		</tr>
		<tr>
			<td>Pressure Task</td>
			<td>PTT</td>
		</tr>
		<tr>
			<td>Cold Pressor Task</td>
			<td>PTT</td>
		</tr>
		<tr>
			<td align="center" colspan="2">Secondary Endpoints</td>
		</tr>
		<tr>
			<td>Electrical Task (pre-cold pressor)</td>
			<td>PDT, AUC, and post-task VAS</td>
		</tr>
		<tr>
			<td>Pressure Task</td>
			<td>PDT, AUC, and post-task VAS</td>
		</tr>
		<tr>
			<td>Cold Pressor Task</td>
			<td>PDT, AUC, and post-task VAS</td>
		</tr>
		<tr>
			<td>Conditioned Pain Modulation Response (change from electrical pre- and post-cold pressor)</td>
			<td>PDT, AUC, and post-task VAS</td>
		</tr>
	</tbody>
</table>
Table 3.&#160;The Outcome Variables (Endpoints) Defined for a Study. Pain Detection Threshold (PDT), Pain Tolerance Threshold (PTT), Area Under the Visual Analogue Scale (VAS) pain Curve (AUC), and post-task&#160;VAS.
The primary outcome variable of interest is the PTT for the electrical stimuli, pressure and cold pressor tasks, and the PDT for the thermal (heat) stimuli on normal and UVB-exposed skin (Table 3). Data collected from the pain model assessments should be summarized descriptively (absolute values and change from baseline) by time and treatment. In addition, plots showing the mean (95% confidence interval (CI)) result and the mean change from baseline (95% CI) at each time point by treatment should be presented (see Figures 1 and 2). Results following placebo treatment should be relatively stable throughout the study day (Figures 1 and 2). Analgesic responses i.e., increases in the PDT or PTT, should reflect the pharmacokinetic properties of the drug. For the cold pressor task, the relatively rapid onset of action and short half-life of fentanyl and ketamine are reflected in the increase in PTT times (Figure 1). In contrast, the increase in PTT following pregabalin administration mirrors the pharmacokinetics of this drug which has a longer tmax and half-life (Figure 2). The known insensitivity of the cold pressor task&#160;for other analgesics are shown by there being little change from placebo (Figure 1 and 2). Nonetheless, the other tasks in this battery are sensitive to these drugs e.g., the UVB model captures the analgesic properties of the NSAID ibuprophen (data on file),&#160;allowing for drugs to be fully characterized.
Depending on the ultimate design of the study, analyze the endpoints with a mixed model analysis of variance (ANOVA) with treatment, time, sex, treatment by time and treatment by sex as fixed factors, with subject, subject by treatment and subject by time as random factors and with the average baseline measurement as covariate.
<img alt="Figure 1" src="/files/ftp_upload/53800/53800fig1.jpg" /> 
Figure 1.&#160;Effect of Intravenous Analgesics on Cold Pressor Pain Tolerance Thresholds. Example time course of the mean change from baseline profile in least square means (95% CI error bars) for the pain tolerance threshold for cold pressor task after 30 min&#160;intravenous administration of placebo (grey circle), (S)-ketamine 10 mg (green triangle), fentanyl 3 &#181;g/kg (magenta square), and phenytoin 300 mg (blue diamond). <a href="https://www.jove.com/files/ftp_upload/53800/53800fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" src="/files/ftp_upload/53800/53800fig2.jpg" /> 
Figure 2.&#160;Effect of Oral Analgesics on Cold Pressor Pain Tolerance Thresholds. Example time course of the mean change from baseline profile in least square means (95% CI error bars) for the pain tolerance threshold for cold pressor task after oral administration of placebo (grey circle), imipramine 100 mg (green triangle), ibuprofen 600 mg (magenta square), and pregabalin 300 mg (blue diamond). <a href="https://www.jove.com/files/ftp_upload/53800/53800fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Watch this Scientific Journal Video about Determining Pain Detection and Tolerance Thresholds Using an Integrated, Multi-Modal Pain Task Battery at JoVE.com

Determining Pain Detection and Tolerance Thresholds Using an Integrated, Multi-Modal Pain Task Battery

Human pain models are valuable tools used to assess the analgesic potential of novel compounds and predict their clinical efficacy, especially when used in an integrated manner. Although implementation of these models is complex, with proper execution, the pain models described in this protocol can provide predictive and reliable results.

Human pain models are useful in the assessing the analgesic effect of drugs, providing information about a drug&#39;s pharmacology and identify ...

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Behavior

12.5K Views.  Centre for Human Drug Research (CHDR). Human pain models are valuable tools used to assess the analgesic potential of novel compounds and predict their clinical efficacy, especially when used in an integrated manner. Although implementation of these models is complex, with proper execution, the pain models described in this protocol can provide predictive and reliable results.

Video: Determining Pain Detection and Tolerance Thresholds Using an Integrated, Multi-Modal Pain Task Battery

Use of the Operant Orofacial Pain Assessment Device (OPAD) to Measure Changes in Nociceptive Behavior

We present an operant system for the detection of pain in awake, conscious rodents. The Orofacial Pain Assessment Device (OPAD) assesses pain behaviors in a more clinically relevant way by not relying on reflex-based measures of nociception. Food fasted, hairless (or shaved) rodents are placed into a Plexiglas chamber which has two Peltier-based thermodes that can be programmed to any temperature between 7 &deg;C and 60 &deg;C. The rodent is trained to make contact with these in order to access a reward bottle. During a session, a number of behavioral pain outcomes are automatically recorded and saved. These measures include the number of reward bottle activations (licks) and facial contact stimuli (face contacts), but custom measures like the lick/face ratio (total number of licks per session/total number of contacts) can also be created. The stimulus temperature can be set to a single temperature or multiple temperatures within a session. The OPAD is a high-throughput, easy to use operant assay which will lead to better translation of pain research in the future as it includes cortical input instead of relying on spinal reflex-based nociceptive assays.

Use of the Operant Orofacial Pain Assessment Device OPAD to Measure Changes in Nociceptive Behavior

We present a user-friendly, high-throughput operant system for the evaluation of pain behaviors in awake, conscious rodents. The Orofacial Pain Assessment Device (OPAD) can assess pain through a reward/conflict paradigm thus providing a more humane way of testing. This protocol will yield more clinically relevant and translational data from rodents.

We present an operant  system for the detection of pain in awake, conscious rodents. The Orofacial  Pain Assessment Device (OPAD) assesses pain behaviors ...

Simultaneous Scalp Electroencephalography (EEG), Electromyography (EMG), and Whole-body Segmental Inertial Recording for Multi-modal Neural Decoding

Recent studies support the involvement of supraspinal networks in control of bipedal human walking. Part of this evidence encompasses studies, including our previous work, demonstrating that gait kinematics and limb coordination during treadmill walking can be inferred from the scalp electroencephalogram (EEG) with reasonably high decoding accuracies. These results provide impetus for development of non-invasive brain-machine-interface (BMI) systems for use in restoration and/or augmentation of gait- a primary goal of rehabilitation research. To date, studies examining EEG decoding of activity during gait have been limited to treadmill walking in a controlled environment. However, to be practically viable a BMI system must be applicable for use in everyday locomotor tasks such as over ground walking and turning. Here, we present a novel protocol for non-invasive collection of brain activity (EEG), muscle activity (electromyography (EMG)), and whole-body kinematic data (head, torso, and limb trajectories) during both treadmill and over ground walking tasks. By collecting these data in the uncontrolled environment insight can be gained regarding the feasibility of decoding unconstrained gait and surface EMG from scalp EEG.

Simultaneous Scalp Electroencephalography EEG, Electromyography EMG, and Whole-body Segmental Inertial Recording for Multi-modal Neural Decoding

Development of an effective brain-machine-interface (BMI) system for restoration and rehabilitation of bipedal locomotion requires accurate decoding of user's intent. Here we present a novel experimental protocol and data collection technique for simultaneous non-invasive acquisition of neural activity, muscle activity, and whole-body kinematics during various locomotion tasks and conditions.

Recent  studies support the involvement of supraspinal networks in control of bipedal  human walking. Part of this evidence  encompasses studies, ...

Measuring Delay Discounting in Humans Using an Adjusting Amount Task

Delay discounting refers to a decline in the value of a reward when it is delayed relative to when it is immediately available. Delay discounting tasks are used to identify indifference points, which reflect equal preference for two dichotomous reward alternatives differing in both delay and magnitude. Indifference points are key to assessing the shape of a delay-discounting gradient because they allow us to isolate the effect of delay on value. For example, if at a 1 week delay and a maximum of $1,000, the indifference point is at $700 we know that, for that participant, a 1-week delay corresponds to a 30% reduction in value. This video outlines an adjusting amount delay-discounting task that identifies indifference points relatively quickly and is inexpensive and easy to administer. Once data have been collected, non-linear regression techniques are typically used to generate discounting curves. The steepness of the discounting curve reflects the degree of impulsive choice of a group or individual. These techniques have been used with a wide range of commodities and have identified populations that are relatively impulsive. For example, people with substance abuse problems discount delayed rewards more steeply than control participants. Although degree of discounting varies as a function of the commodity examined, discounting of one commodity correlates with discounting of other commodities, which suggests that discounting may be a persistent pattern of behavior1.

Delay discounting refers to a decline in the value of a reward when it is delayed relative to when it is immediately available. We outline a computer-based delay discounting task that is easy to implement and allows for the quantification of the degree of delay discounting in human participants.

Delay discounting refers to a decline in the value of a reward when it is delayed relative to when it is immediately available. Delay discounting tasks ...

A Protocol of Manual Tests to Measure Sensation and Pain in Humans

Numerous qualitative and quantitative techniques can be used to test sensory nerves and pain in both research and clinical settings. The current study demonstrates a quantitative sensory testing protocol using techniques to measure tactile sensation and pain threshold for pressure and heat using portable and easily accessed equipment. These techniques and equipment are ideal for new laboratories and clinics where cost is a concern or a limiting factor. We demonstrate measurement techniques for the following: cutaneous mechanical sensitivity on the arms and legs (von-Frey filaments), radiant and contact heat sensitivity (with both threshold and qualitative assessments using the Visual Analog Scale (VAS)), and mechanical pressure sensitivity (algometer, with both threshold and the VAS). The techniques and equipment described and demonstrated here can be easily purchased, stored, and transported by most clinics and research laboratories around the world. A limitation of this approach is a lack of automation or computer control. Thus, these processes can be more labor intensive in terms of personnel training and data recording than the more sophisticated equipment. We provide a set of reliability data for the demonstrated techniques. From our description, a new laboratory should be able to set up and run these tests and to develop their own internal reliability data.

The goal of this procedure is to demonstrate a battery of quantitative techniques for sensory and pain measurement in humans. The equipment and techniques described are commonly found in pain clinics or are easy to obtain.

Numerous qualitative and quantitative techniques can be used to test sensory nerves and pain in both research and clinical settings. The current study ...

Psychophysically-anchored, Robust Thresholding in Studying Pain-related Lateralization of Oscillatory Prestimulus Activity

In perceptual studies, it is often important to objectively assess the equality of delivered stimulation across participants or to quantify the intra-individual sensation magnitude that is evoked by stimulation over multiple trials. This requires a robust mapping of stimulus magnitude to perceived intensity and is commonly achieved by psychophysical estimation methods such as the staircase procedure. Newer, more efficient procedures like the QUEST algorithm fit a psychophysical function to the data in real time while at the same time maximizing the efficiency of data collection. A robust estimate of the threshold intensity between painful and nonpainful perceptions can then be used to reduce the influence of variations in sensory input in subsequent analyses of oscillatory brain activity. By stimulating at a constant threshold intensity determined by an adaptive estimation procedure, the variance in the ratings can be directly attributed to perceptual processes. Oscillatory activity can then be contrasted between &#34;pain&#34; and &#34;no-pain&#34; trials directly, yielding activity that closely relates to perceptual classification processes in nociception.

Psychophysical methods such as the QUEST estimation procedure can efficiently yield robust estimates of the stimulation intensity at which nonpainful sensations transition into painful sensations. By stimulating repeatedly at the threshold intensity, the variability in rating responses can directly be attributed to perceptual classifications in subsequent analyses.

In perceptual studies, it is often important to objectively assess the equality of delivered stimulation across participants or to quantify the ...

Treating Low Back Pain in Failed Back Surgery Patients with Multicolumn-lead Spinal Cord Stimulation

Failed back surgery syndrome (FBSS) refers to persistent, chronic pain following spinal surgery. Spinal cord stimulation with dorsal epidural leads can be used to treat back and leg pain in FBSS patients. This paper presents a detailed protocol for using spinal cord stimulation with surgical leads in FBSS patients. In our department, with the patient under general anesthesia, we place the lead in the epidural space by means of a small laminectomy at the 10th thoracic level. Placement of the lead is followed by a 1 month trial period with an externalized lead. If pain relief is greater than 50% at the end of this 1 month stimulation trial (required by Belgian reimbursement criteria), an internal pulse generator is then placed under the skin and connected to the lead in a second surgical procedure. We have demonstrated that using this technique in rigorously selected FBSS patients can significantly improve back pain, leg pain, patient activity, and quality of life for a sustained period of time.

This paper presents a method that uses spinal cord stimulation with a multicolumn lead to treat neuropathic low back pain in failed back surgery patients.

Failed back surgery syndrome (FBSS) refers to persistent, chronic pain following spinal surgery. Spinal cord stimulation with dorsal epidural leads can be ...

Simultaneous Recordings of Cortical Local Field Potentials and Electrocorticograms in Response to Nociceptive Laser Stimuli from Freely Moving Rats

Electrocortical responses, elicited by laser heat pulses that selectively activate nociceptive free nerve endings, are widely used in many animal and human studies to investigate the cortical processing of nociceptive information. These laser-evoked brain potentials (LEPs) consist of several transient responses that are time-locked to the onset of laser stimuli. However, the functional properties of the LEP responses are still largely unknown, due to the lack of a sampling technique that can simultaneously record neural activities at the surface of the cortex (i.e., electrocorticogram [ECoG] and scalp electroencephalogram [scalp EEG]) and inside the brain (i.e., local field potential [LFP]). To address this issue, we present here an animal protocol using freely moving rats. This protocol is composed of three main procedures: (1) animal preparation and surgical procedures, (2) a simultaneous recording of ECoG and LFP in response to nociceptive laser stimuli, and (3) data analysis and feature extraction. Specifically, with the help of a 3D-printed protective shell, both ECoG and LFP electrodes implanted on the rat&#39;s skull were securely held together. During data collection, laser pulses were delivered on the rat&#39;s forepaws through gaps in the bottom of the chamber when the animal was in spontaneous stillness. Ongoing white noise was played to avoid the activation of the auditory system by the laser-generated ultrasounds. As a consequence, only nociceptive responses were selectively recorded. Using the standard analytical procedures (e.g., band-pass filtering, epoch extraction, and baseline correction) to extract stimulus-related brain responses, we obtained results showing that LEPs with a high signal-to-noise ratio were simultaneously recorded from ECoG and LFP electrodes. This methodology makes the simultaneous recording of ECoG and LFP activities possible, which provides a bridge of electrocortical signals at the mesoscopic and macroscopic levels, thereby facilitating the investigation of nociceptive information processing in the brain.

We developed a technique that simultaneously records both electrocorticography and local field potentials in response to nociceptive laser stimuli from freely moving rats. This technique helps establish a direct relationship of electrocortical signals at the mesoscopic and macroscopic levels, which facilitates the investigation of nociceptive information processing in the brain.

Electrocortical responses, elicited by laser heat pulses that selectively activate nociceptive free nerve endings, are widely used in many animal and ...

Multi-Modal Signals for Analyzing Pain Responses to Thermal and Electrical Stimuli

The assessment of pain relies mostly on methods that require a person to communicate. However, for people with cognitive and verbal impairments, existing methods are not sufficient as they lack reliability and validity. To approach this problem, recent research focuses on an objective pain assessment facilitated by parameters of responses derived from physiology, and video and audio signals. To develop reliable automated pain recognition systems, efforts have been made in creating multimodal databases in order to analyze pain and detect valid pain patterns. While the results are promising, they only focus on discriminating pain or pain intensities versus no pain. In order to advance this, research should also consider the quality and duration of pain as they provide additional valuable information for more advanced pain management. To complement existing databases and the analysis of pain regarding quality and length, this paper proposes a psychophysiological experiment to elicit, measure, and collect valid pain reactions. Participants are subjected to painful stimuli that differ in intensity (low, medium, and high), duration (5 s / 1 min), and modality (heat / electric pain) while audio, video (e.g., facial expressions, body gestures, facial skin temperature), and physiological signals (e.g., electrocardiogram [ECG], skin conductance level [SCL], facial electromyography [EMG], and EMG of M. trapezius) are being recorded. The study consists of a calibration phase to determine a subject&#8217;s individual pain range (from low to intolerable pain) and a stimulation phase in which pain stimuli, depending on the calibrated range, are applied. The obtained data may allow refining, improving, and evaluating automated recognition systems in terms of an objective pain assessment. For further development of such systems and to investigate pain reactions in more detail, additional pain modalities such as pressure, chemical, or cold pain should be included in future studies. Recorded data of this study will be released as the &#8220;X-ITE Pain Database&#8221;.

This article focuses on the experimental elicitation of pain through heat (thermal) and electrical stimulation while recording physiological, visual, and paralinguistic responses. It aims at collecting valid multimodal data for analyzing pain based on its intensity, quality, and duration.&#160;

The assessment of pain relies mostly on methods that require a person to communicate. However, for people with cognitive and verbal impairments, existing ...

A Cross-Disciplinary and Multi-Modal Experimental Design for Studying Near-Real-Time Authentic Examination Experiences

Over the past ten years, research into students&#39; emotions in educational environments has increased. Although researchers have called for more studies that rely on objective measures of emotional experience, limitations on utilizing multi-modal data sources exist. Studies of emotion and emotional regulation in classrooms traditionally rely on survey instruments, experience-sampling, artifacts, interviews, or observational procedures. These methods, while valuable, are mainly&#160;dependent on participant or observer subjectivity and is limited in its authentic measurement of students&#39; real-time performance to a classroom activity or task. The latter, in particular, poses a stumbling block to many scholars seeking to objectively measure emotions and other related measures in the classroom, in real-time.
The purpose of this work is to present a protocol to experimentally study students&#39; real-time responses to exam experiences during an authentic assessment situation. For this, a team of educational psychologists, engineers, and engineering education researchers designed an experimental protocol that retained the limits required for accurate physiological sensor measurement, best-practices of salivary collection, and an authentic testing environment. In particular, existing studies that rely on physiological sensors are conducted in experimental environments that are disconnected from educational settings (e.g., Trier Stress Test), detached in time (e.g., before or after a task), or introduce analysis error (e.g., use of sensors in environments where students are likely to move). This limits our understanding of students&#39; real-time responses to classroom activities and tasks. Furthermore, recent research has called for more considerations to be covered around issues of recruitment, replicability, validity, setups, data cleaning, preliminary analysis, and particular&#160;circumstances (e.g., adding a variable in the experimental design) in academic emotions research that relies on multi-modal approaches.

An experimental design was developed to investigate the real-time influences of an examination experience to assess the emotional realities students experience in higher education settings and tasks. This design is the result of a cross-disciplinary (e.g., educational psychology, biology, physiology, engineering) and multi-modal (e.g., salivary markers, surveys, electrodermal sensor) approach.

Over the past ten years, research into students&#39; emotions in educational environments has increased. Although researchers have called for more studies ...

Chronic Post-Ischemia Pain Model for Complex Regional Pain Syndrome Type-I in Rats

Complex regional pain syndrome type-I (CRPS-I) is a neurological disease that causes severe pain among patients and remains an unresolved medical condition. However, the underlying mechanisms of CRPS-I have yet to be revealed. It is known that ischemia/reperfusion is one of the leading factors that causes CRPS-I. By means of prolonged ischemia and reperfusion of the hind limb, the rat chronic post-ischemia pain (CPIP) model has been established to mimic CRPS-I. The CPIP model has become a well-recognized animal model for studying the mechanisms of CRPS-I. This protocol describes the detailed procedures involved in the establishment of the rat model of CPIP, including anesthesia, followed by ischemia/reperfusion of the hind limb. Characteristics of the rat CPIP model are further evaluated by measuring the mechanical and thermal hypersensitivities of the hind limb as well as the nocifensive responses to acute capsaicin injection. The rat CPIP model exhibits several CRPS-I-like manifestations, including hind limb edema and hyperemia in the early stage after establishment, persistent thermal and mechanical hypersensitivities, and increased nocifensive responses to acute capsaicin injection. These characteristics render it a suitable animal model for further investigation of the mechanisms involved in CRPS-I.

Provided here is a protocol that details steps to establish an animal model of chronic post-ischemia pain (CPIP). This is a well-recognized model mimicking human complex regional pain syndrome type-I. Mechanical and thermal hypersensitivities are further evaluated, as well as capsaicin-induced nocifensive behaviors observed in the CPIP rat model.