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).

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<li>Polianskis, R., Graven-Nielsen, T., Arendt-Nielsen, L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Pressure-pain+function+in+desensitized+and+hypersensitized+muscle+and+skin+assessed+by+cuff+algometry%5BTitle%5D)+AND+%22J+Pain%22%5BJournal%5D)">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/pubmed?term=((The+methodology+of+experimentally+induced+diffuse+noxious+inhibitory+control+%28DNIC%29-like+effect+in+humans%5BTitle%5D)+AND+%22Pain%22%5BJournal%5D)">The methodology of experimentally induced diffuse noxious inhibitory control (DNIC)-like effect in humans.</a> Pain. 144 (1-2), 16-19 (2009).</li>
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</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><tbody><tr><td>Analogue&amp;ndash;to-digital converter&amp;nbsp;</td><td>Cambridge Electronic Design (CED), Cambridge, UK</td><td>Power1401mkII</td><td></td></tr><tr><td>eVAS slider</td><td>Cambridge Electronic Design (CED), Cambridge, UK</td><td>custom built</td><td></td></tr><tr><td>Ag-AgCl electrodes&amp;nbsp;</td><td>3M Health Care, St Paul, Canada</td><td>Ag-AgCl Red Dot&amp;trade; 2560 Electrodes</td><td></td></tr><tr><td>Ohmmeter</td><td>Generic device</td><td>Not applicable</td><td></td></tr><tr><td>Constant current stimulator</td><td>Cambridge Electronic Design (CED), Cambridge, UK</td><td>DS5</td><td></td></tr><tr><td>11 cm wide tourniquet cuff&amp;nbsp;</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><td>Electro-pneumatic regulator&amp;nbsp;</td><td>SMC Corporation, Tokyo, Japan</td><td>ITV1030-31F2N3-Q</td><td></td></tr><tr><td>Warm water bath &amp;amp; thermostat</td><td>LAUDA, Germany</td><td>Ecoline E125</td><td></td></tr><tr><td>Cold water bath and thermostat</td><td>LAUDA, Germany</td><td>Ecoline E212</td><td></td></tr><tr><td>35 cm tourniquet&amp;nbsp;&amp;nbsp;</td><td>VBM Medizintechnik GmbH, Sulz, Germany</td><td>REF 20-54-711</td><td></td></tr><tr><td>Florescent tubes&amp;nbsp;</td><td>Philips, Eindhoven, Netherlands</td><td>36W TL01 Narrow-band</td><td></td></tr><tr><td>30 mm x 30 mm thermode</td><td>Medoc, Israel</td><td>TSA-II (2001) Neurosensory Analyzer&amp;nbsp;</td><td></td></tr><tr><td>Skin preparation gel</td><td>Weaver and Company</td><td>Nuprep</td><td></td></tr><tr><td>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.remotexs.ntu.edu.sg/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.remotexs.ntu.edu.sg/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 ...

determining-pain-detection-tolerance-thresholds-using-an-integrated

Nanyang Technological University

Research

JoVE Journal

Behavior

12.6K 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

An Experimental Paradigm for the Prediction of Post-Operative Pain (PPOP)

Many women undergo cesarean delivery without problems, however some experience significant pain after cesarean section. Pain is associated with negative short-term and long-term effects on the mother. Prior to women undergoing surgery, can we predict who is at risk for developing significant postoperative pain and potentially prevent or minimize its negative consequences? These are the fundamental questions that a team from the University of Washington, Stanford University, the Catholic University in Brussels, Belgium, Santa Joana Women's Hospital in S&atilde;o Paulo, Brazil, and Rambam Medical Center in Israel is currently evaluating in an international research collaboration. The ultimate goal of this project is to provide optimal pain relief during and after cesarean section by offering individualized anesthetic care to women who appear to be more 'susceptible' to pain after surgery.
A significant number of women experience moderate or severe acute post-partum pain after vaginal and cesarean deliveries. 1 Furthermore, 10-15% of women suffer chronic persistent pain after cesarean section. 2 With constant increase in cesarean rates in the US 3 and the already high rate in Brazil, this is bound to create a significant public health problem. When questioning women's fears and expectations from cesarean section, pain during and after it is their greatest concern. 4 Individual variability in severity of pain after vaginal or operative delivery is influenced by multiple factors including sensitivity to pain, psychological factors, age, and genetics. The unique birth experience leads to unpredictable requirements for analgesics, from 'none at all' to 'very high' doses of pain medication. Pain after cesarean section is an excellent model to study post-operative pain because it is performed on otherwise young and healthy women. Therefore, it is recommended to attenuate the pain during the acute phase because this may lead to chronic pain disorders. The impact of developing persistent pain is immense, since it may impair not only the ability of women to care for their child in the immediate postpartum period, but also their own well being for a long period of time.
In a series of projects, an international research network is currently investigating the effect of pregnancy on pain modulation and ways to predict who will suffer acute severe pain and potentially chronic pain, by using simple pain tests and questionnaires in combination with genetic analysis. A relatively recent approach to investigate pain modulation is via the psychophysical measure of Diffuse Noxious Inhibitory Control (DNIC). This pain-modulating process is the neurophysiological basis for the well-known phenomenon of 'pain inhibits pain' from remote areas of the body. The DNIC paradigm has evolved recently into a clinical tool and simple test and has been shown to be a predictor of post-operative pain.5 Since pregnancy is associated with decreased pain sensitivity and/or enhanced processes of pain modulation, using tests that investigate pain modulation should provide a better understanding of the pathways involved with pregnancy-induced analgesia and may help predict pain outcomes during labor and delivery. For those women delivering by cesarean section, a DNIC test performed prior to surgery along with psychosocial questionnaires and genetic tests should enable one to identify women prone to suffer severe post-cesarean pain and persistent pain. These clinical tests should allow anesthesiologists to offer not only personalized medicine to women with the promise to improve well-being and satisfaction, but also a reduction in the overall cost of perioperative and long term care due to pain and suffering. On a larger scale, these tests that explore pain modulation may become bedside screening tests to predict the development of pain disorders following surgery.

An Experimental Paradigm for the Prediction of Post-Operative Pain PPOP

Diffuse noxious inhibitory control, temporal summation and wound hyperalgesia testing are demonstrated in the obstetric patient. These tests evaluate inhibitory and excitatory mechanisms of pain processing and are here utilized to evaluate endogenous analgesia at different time-points during pregnancy and the peripartum period to help reveal individual s risk for persistent pain.

Many women undergo cesarean delivery without problems, however some experience significant pain after cesarean section. Pain is associated with negative ...

Medicine

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 ...

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 ...

Determining heat and mechanical pain threshold in inflamed skin of human subjects

In a previous article in the Journal of Visualized Experiments we have demonstrated skin microdialysis techniques for the collection of tissue-specific nociceptive and inflammatory biochemicals in humans. In this article we will show pain-testing paradigms that are often used in tandem with microdialysis procedures. Combining pain tests with microdialysis provides the critical link between behavioral and biochemical data that allows identifying key biochemicals responsible for generating and propagating pain.
Two models of evoking pain in inflamed skin of human study participants are shown. The first model evokes pain with aid of heat stimuli. Heat evoked pain as described here is predominantly mediated by small, non-myelinated peripheral nociceptive nerve fibers (C-fibers). The second model evokes pain via punctuated pressure stimuli. Punctuated pressure evoked pain is predominantly mediated by small, myelinated peripheral nociceptive nerve fibers (A-delta fibers). The two models are mechanistically distinct and independently examine nociceptive processing by the two major peripheral nerve fiber populations involved in pain signaling.
Heat pain is evoked with aid of the TSA II, a commercially available thermo-sensory analyzer (Medoc Advanced Medical Systems, Durham, NC). Stimulus configuration and delivery is handled with aid of specific software. Thermodes vary in size and shape but in principle consist of a metal plate that can be heated or cooled at various rates and for different periods of time. Algorithms assessing heat-evoked pain are manifold. In the experiments shown here, study participants are asked to indicate at what point they start experiencing pain while the thermode in contact with skin is heated at a predetermined rate starting at a temperature that does not evoke pain. The thermode temperature at which a subject starts experiencing pain constitutes the heat pain threshold.
Mechanical pain is evoked with punctuated probes. Such probes are commercially available from several manufacturers (von Frey hairs). However, the accuracy of von Frey hairs has been criticized and many investigators use custom made punctuated pressure probes. In the experiments shown here eight custom-made punctuated probes of different weights are applied in consecutive order, a procedure called up-down algorithm, to identify perceptional deflection points, i.e., a change from feeling no pain to feeling pain or vice versa. The average weight causing a perceptional deflection constitutes the mechanical pain threshold.

Algorithms assessing heat and mechanical pain thresholds in experimentally inflamed skin of human study subjects are shown. The two pain testing paradigms independently examine nociceptive processing by the two major peripheral nerve fiber populations transmitting pain, i.e., non-myelinated C fibers and small myelinated A-delta fibers.

In a previous article in the Journal of Visualized Experiments we have demonstrated skin microdialysis techniques for the collection of tissue-specific ...

Biology

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 ...

Investigating Pain-Related Avoidance Behavior using a Robotic Arm-Reaching Paradigm

Avoidance behavior is a key contributor to the transition from acute pain to chronic pain disability. Yet, there has been a lack of ecologically valid paradigms to experimentally investigate pain-related avoidance. To fill this gap, we developed a paradigm (the robotic arm-reaching paradigm) to investigate the mechanisms underlying the development of pain-related avoidance behavior. Existing avoidance paradigms (mostly in the context of anxiety research) have often operationalized avoidance as an experimenter-instructed, low-cost response, superimposed on stimuli associated with threat during a Pavlovian fear conditioning procedure. In contrast, the current method offers increased ecological validity in terms of instrumental learning (acquisition) of avoidance, and by adding a cost to the avoidance response. In the paradigm, participants perform arm-reaching movements from a starting point to a target using a robotic arm, and freely choose between three different movement trajectories to do so. The movement trajectories differ in probability of being paired with a painful electrocutaneous stimulus, and in required effort in terms of deviation and resistance. Specifically, the painful stimulus can be (partly) avoided at the cost of performing movements requiring increased effort. Avoidance behavior is operationalized as the maximal deviation from the shortest trajectory on each trial. In addition to explaining how the new paradigm can help understand the acquisition of avoidance, we describe adaptations of the robotic arm-reaching paradigm for (1) examining the spread of avoidance to other stimuli (generalization), (2) modeling clinical treatment in the lab (extinction of avoidance using response prevention), as well as (3) modeling relapse, and return of avoidance following extinction (spontaneous recovery). Given the increased ecological validity, and numerous possibilities for extensions and/or adaptations, the robotic arm-reaching paradigm offers a promising tool to facilitate the investigation of avoidance behavior and to further our understanding of its underlying processes.

Avoidance is central to chronic pain disability, yet adequate paradigms for examining pain-related avoidance are lacking. Therefore, we developed a paradigm that allows investigating how pain-related avoidance behavior is learned (acquisition), spreads to other stimuli (generalization), can be mitigated (extinction), and how it may subsequently re-emerge (spontaneous recovery).

Avoidance behavior is a key contributor to the transition from acute pain to chronic pain disability. Yet, there has been a lack of ecologically valid ...

Dynamic Quantitative Sensory Testing to Characterize Central Pain Processing

Central facilitation and modulation of incoming nociceptive signals play an important role in the perception of pain. Disruption in central pain processing is present in many chronic pain conditions and can influence responses to specific therapies. Thus, the ability to precisely describe the state of central pain processing has profound clinical significance in both prognosis and prediction. Because it is not practical to record neuronal firings directly in the human spinal cord, surrogate behavior tests become an important tool to assess the state of central pain processing. Dynamic QST is one such test, and can probe both the ascending facilitation and descending modulation of incoming nociceptive signals via TS and CPM, respectively. Due to the large between-individual variability in the sensitivity to noxious signals, standardized TS and CPM tests may not yield any meaningful data in up to 50% of the population due to floor or ceiling effects. We present methodologies to individualize TS and CPM so we can capture these measures in a broader range of individuals than previously possible. We have used these methods successfully in several studies at the lab, and data from one ongoing study will be presented to demonstrate feasibility and potential applications of the methods.

By assessing pain in response to repetitive or different types of standardized stimuli, dynamic quantitative sensory testing (QST) can reveal changes in the central processing of pain. We present methods to optimize and individualize two dynamic QST measures: temporal summation (TS) and conditioned pain modulation (CPM).

Central facilitation and modulation of incoming nociceptive signals play an important role in the perception of pain. Disruption in central pain ...

Neuroscience

A Quantitative Sensory Testing Paradigm to Obtain Measures of Pain Processing in Patients Undergoing Breast Cancer Surgery

Chronic pain following surgery, persistent postsurgical pain, is an important highly prevalent condition contributing to significant symptom burden and lower quality of life. Persistent postsurgical pain is relatively refractory to treatment hence generating a high need for preventive strategies and treatments. Therefore, the identification of patients at risk of developing persistent pain is an area of active ongoing research. Recently it was demonstrated that peri-operative disruptions in central pain processing may be able to predict persistent postsurgical pain at long term follow-up in breast cancer patients. The aim of the current report is to present a short protocol to obtain pain thresholds to different stimuli at multiple sites and a measure of endogenous analgesia in breast cancer patients. We have used this method successfully in a clinical context and detail some representative results from a clinical study.

Persistent postsurgical pain may be related to changes in pain processing. By assessing pain in response to standardized stimuli, changes in pain processing can be elucidated. We present methods to obtain pain thresholds to different stimuli and a measure of endogenous analgesia in patients undergoing breast cancer surgery.

Chronic pain following surgery, persistent postsurgical pain, is an important highly prevalent condition contributing to significant symptom burden and ...

A Novel Approach for Pain Assessment from Pain Body Diagrams

Quantifying Pain Location and Intensity with Multimodal Pain Body Diagrams

To quantify an individual&#39;s subjective pain severity, standardized pain rating scales such as the numeric rating scale (NRS), visual analog scale (VAS), or McGill pain questionnaire (MPQ) are commonly used to assess pain on a numerical scale. However, these scales are often biased and fail to capture the complexity of pain experiences. In contrast, clinical practice often requires patients to report areas of pain by drawing on a body diagram, which is an effective but qualitative tool. The method presented here extracts quantifiable metrics from pain body diagrams (PBDs) which are validated against the NRS, VAS, and MPQ pain scales. By using a novel pressure-hue transformation on a digital tablet, different drawing pressures applied with a digital stylus can be represented as different hues on a PBD. This produces a visually intuitive diagram of hues ranging from green to blue to red, representing mild to moderate to most painful regions, respectively. To quantify each PBD, novel pain metrics were defined: (1) PBD mean intensity, which equals the sum of each pixel&#39;s hue value divided by the number of colored pixels, (2) PBD coverage, which equals the number of colored pixels divided by the total number of pixels on the body, and (3) PBD sum intensity, which equals the sum of all pixels&#39; hue values. Using correlation and information theory analyses, these PBD metrics were shown to have high concordance with standardized pain metrics, including NRS, VAS and MPQ. In conclusion, PBDs can provide novel spatial and quantitative information that can be repeatedly measured and tracked over time to comprehensively characterize a participant&#39;s pain experience.

Author Spotlight: Quantifying Pain Experience &#8211; An Illustrative Approach Using the Pain Body Diagram 

Current pain scales used to quantify pain severity, such as visual analog scales, fail to capture the complexity of subjective pain experiences. Pain body diagrams are qualitative but may be more informative. The goal of this method is to extract quantitative metrics from pain body diagrams using novel pressure-hue transformation.

To quantify an individual&#39;s subjective pain severity, standardized pain rating scales such as the numeric rating scale (NRS), visual analog scale ...

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

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