Schematic illustration of the ʻinhibitoryʼ test paradigms (ITP, upper panel) and the ʻsensitizingʼ test paradigms (STP, lower panel).

<p>The ITP-studies employed an inhibitory conditioning stimulus with evaluation of the associated change in the applied test-stimulus (△test-stimulus). The objective of the ITP-studies was to examine the effect of mu-opioid-receptor (MOR) antagonist on the magnitude of the △test-stimulus, indicating an activation of the endogenous opioid system (EOS) responsible for the conditioning response leading to antinociception/hypoalgesia (the central rectangle [Opioid-dependent mechanism?] indicates a hypothetical augmentation of the conditioning response by the EOS). The STP-studies (lower panel) employed a pain stimulus leading to quantifiable ʻsensitizingʼ CNS-responses, e.g., changes in behavioral measures (hyperalgesia, pain ratings, thresholds, tolerance), nociceptive reflexes, neuroimaging or neuroendocrine variables. In a number of studies a sensitizing conditioning stimulus was applied, e.g., a burn injury [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref031" target="_blank">31</a>] and application of capsaicin [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref035" target="_blank">35</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref036" target="_blank">36</a>], enhancing the nociceptive responses. The objective of the STP-studies was to examine the effect of MOR-antagonist on the magnitude of elicited responses, indirectly either supporting or contradicting an effect mediated by the EOS (the central rectangle [Opioid-dependent mechanism?] indicates a hypothetical attenuation of the response by the EOS). FM Peripheral Conditioning = non-noxious Frequency Modulated Peripheral Conditioning; rTMS = repetitive Transcranial Magnetic Stimulation.</p

ʻSensitizingʼ Test Paradigms: Testing Methods and Results.

<p>^△ Outcome variable related to specific objectives of the review.</p><p>^# short lasting erythema and heat hyperalgesia.</p><p>* pain produced by a combination of non-noxious warmth and cool.</p><p>For explanation of abbreviations, please refer to legend <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.t005" target="_blank">Table 5</a>.</p><p>ʻSensitizingʼ Test Paradigms: Testing Methods and Results.</p

ʻSensitizingʼ Test Paradigms: Study Design.

<p>^△ Objectives related to the specific perspectives of the review.</p><p>^† ratio of placebo-treated vs. naloxone-treated was 0.5.</p><p>^# study design is for remifentanil-placebo infusions.</p><p>For explanation of abbreviations, please refer to legend <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.t001" target="_blank">Table 1</a>.</p><p>ʻSensitizingʼ Test Paradigms: Study Design.</p

ʻSensitizingʼ Test Paradigms: Demographics and Drugs.

<p>^§ not interfering with the MOR-antagonist assessments (drugs without administration route stated are i.v.).</p><p>^# 1mg: cold water challenge; 2mg: ischemic pain challenge.</p><p>^A study includes fibromyalgia patients (n = 15, data not reported here).</p><p>^B study includes fibromyalgia patients (n = 10, data not reported here).</p><p>^C study included patients with chronic low back pain (n = 37; data not reported here) and 2 healthy subjects on antidepressant medication.</p><p>^D study includes chronic low back pain patients (n = 45, data not reported here).</p><p>^E study includes treatment arms of combinations of tilidine (100 mg) and naloxone (8–32 mg; data not reported here).</p><p>^F study includes treatment arms with codeine (60 mg p.o.) and codeine/naloxone (2 mg i.v.; data not reported here).</p><p>^G study includes subjects with borderline hypertension (n = 21, data not reported here).</p><p>^H study includes treatment arm with codeine (60 mg p.o.; data not reported here).</p><p>^I study includes patients with bulimia nervosa (n = 10) and anorexia nervosa (n = 10; data not reported here).</p><p>^J study includes patients with major depression (n = 20; data not reported here).</p><p>^K study includes placebo-controlled treatment arm with ketamine (0.4 mg/kg; data not reported here).</p><p>^L the total number of subjects were 20 (4 were excluded).</p><p>^M the total number of subjects were 12 (2 were excluded).</p><p>^N study includes treatment arms with paracetamol (1g i.v.) and paracetamol/naloxone (8 mg i.v.; data not reported here).</p><p>^SD standard deviation.</p><p>For explanation of abbreviations, please, refer to legend <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.t003" target="_blank">Table 3</a>.</p><p>ʻSensitizingʼ Test Paradigms: Demographics and Drugs.</p

ʻInhibitoryʼ Test Paradigms: Study Design.

<p>^△ Objectives related to the specific perspectives of the review.</p><p>^¤ HNCS in man, DNIC in animals (the authors’ terminology [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref021" target="_blank">21</a>]).</p><p><b>BI</b> = first-degree burn injury; <b>BOLD</b> = blood-oxygen-level dependent contrast imaging; <b>BTS</b> = brief thermal sensitization; <b>CB</b> = counterbalanced; <b>CPTT</b> = cold pressor test; <b>DB</b> = double-blind; <b>CYP2D6</b> = cytochrome P450 2D6 enzyme; <b>CPM</b> = conditioned pain modulation; <b>DLPFC/PMC</b> = right dorsolateral–prefrontal cortex premotor cortex (see <b>LDPFC</b>); <b>DNIC</b> = diffuse noxious inhibitory controls; <b>EP</b> = [somatosensory] evoked potentials; <b>EPT</b> = electrical pain threshold; <b>EPIS</b> = endogenous pain inhibitory system; <b>fMRI</b> = functional magnetic resonance imaging; <b>HNCS</b> = heterotopic noxious conditioning stimulations; <b>IDES</b> = intradermal electrical stimulation (rectangular, 0.5 ms duration, 2 Hz, high density); <b>LDPFC</b> = left dorsolateral prefrontal cortex; <b>M1</b> = primary motor cortex; <b>NFR</b> = nociceptive flexion reflex; <b>NRR</b> = not relevant for the review; <b>NTx</b> = naltrexone; <b>Nx</b> = naloxone; <b>OIH</b> = opioid-induced hyperalgesia; <b>R</b> = randomized; <b>PC</b> = placebo-controlled; <b>SB</b> = single-blind; <b>SBP</b> = systolic blood pressure; <b>SC</b> = sham-controlled; <b>SHA</b> = secondary hyperalgesia area; <b>SOWS</b> = subjective opioid withdrawal scale; <b>SSEP</b> = EP; <b>TCI</b> = target-controlled infusion; <b>TDES</b> = transdermal electrical stimulation (low density); <b>TENS</b> = transcutaneous electrical nerve stimulation; <b>X</b> = cross-over (side to side); <b>2-D/3-D</b> = two-/two-dose; <b>2-WX /3-WX/4-WC</b> = two-/three-/four-way cross-over; <b>3-SX/4-SX/5-SX/6-SX</b> = three-/four-/five-/six-session cross-over study; <b>8-S</b> = eight session study; <b>2-PG/3-PG/4-PG/6-PG</b> = two/three/four/six parallel-groups; <b>2x2-WX</b> = 2 parallel groups each with a 2 way-cross over design.</p><p>ʻInhibitoryʼ Test Paradigms: Study Design.</p

Intraepidermal Nerve Fiber Density: Diagnostic and Therapeutic Relevance in the Management of Chronic Pruritus: a Review

<p><b>Article full text</b></p> <p><br></p> <p>The full text of this article can be found here<b>. </b><a href="https://link.springer.com/article/10.1007/s13555-016-0146-1">https://link.springer.com/article/10.1007/s13555-016-0146-1</a></p><p></p> <p><br></p> <p><b>Provide enhanced content for this article</b></p> <p><br></p> <p>If you are an author of this publication and would like to provide additional enhanced content for your article then please contact <a href="http://www.medengine.com/Redeem/”mailto:[email protected]”"><b>[email protected]</b></a>.</p> <p><br></p> <p>The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.</p> <p><br></p> <p>Other enhanced features include, but are not limited to:</p> <p><br></p> <p>• Slide decks</p> <p>• Videos and animations</p> <p>• Audio abstracts</p> <p>• Audio slides</p

ʻInhibitoryʼ Test Paradigms: Testing Methods and Results.

<p>^△ Outcome variable related to specific objectives of the review.</p><p>^¤ Sequence I-II: temporal heat summation (forearm); sequence III-IV: HPT (forearm); sequences separated by 2 min.</p><p><b>ABP</b> = arterial blood pressure; <b>ACC</b> = subgenual anterior cortex cinguli; <b>BIA</b> = burn injury A (probe area 0.8 cm², 48°C, 2 min, application force 1N, arms/hands); <b>BDI</b> = Beck Depression Inventory; <b>BIB</b> = burn injury B (12.5 cm², 47°C, 7 min); <b>BOLD</b> = blood-oxygen-level dependent contrast imaging; <b>BTS</b> = brief thermal sensitization (45°C, 3 min); <b>BR-TNS</b> = nociceptive component of blink reflex (supraorbital transcutaneous nerve stimulation, 0.1 ms duration, 0.15 Hz, 9–12 mA) assessed by integrated and rectified m. orbicularis oculi EMG [25–45 ms gated = R2 response]); <b>BS</b> = brush stimulation (1 cm stroke, 1 Hz, duration 25s, ISI 30s); <b>CAS</b> = conditioned aversive stimuli; <b>CASE</b> = cognitive affective side effects; <b>CC</b> = contact cold (30 x 30 mm²/ 25 x 50 mm²; -0.5°C/s or NR); <b>CDT</b> = cool detection threshold; <b>CEVAS</b> = continuous (0.2 Hz) EVAS; <b>CHA</b> = contact heat (30 x 30 mm², 0.5°C/s); <b>CHB</b> = contact heat (2 cm², 0.5°C/s); <b>CHC</b> = contact heat (3 x 3 cm², 1°C/s); <b>CHEP</b> = contact heat evoked potentials (SSEP); <b>COVAS</b> = computerized visual analog scale; <b>CPR</b> = cold pain rating; <b>CPRR</b> = cold pain ratings at 5, 10 and 15°C, applied in a random order for 2 seconds; <b>CPS</b> = categorical pain scale; <b>CPT</b> = cold pain threshold; <b>CPTo</b> = cold pain threshold; <b>CPTT</b> = cold pressor test (ice-water); <b>CWIT</b> = cold-water immersion test (max. duration 2 min, hand); <b>CWITA</b> = cold-water immersion test A (approx. 7 min duration, hand/foot/leg); <b>CWITB</b> = cold-water immersion test B (40s, repeated 5 times, intersession resting period 3 min, fixed temperature level [8–16°C] corresponding to a CPR [“mild-to-moderate pain”: EVAS mean 42 (0–100)], foot); <b>CWITC</b> = cold-water immersion test C (8 consecutive immersions, 2 min duration, inter-stimulus interval 5 min, fingertip to shoulder and vice versa); <b>CWITD</b> = cold-water immersion test D (immersion 5 min duration, 10°C, hand, n = 18)); <b>DEPTA</b> = dental electrical pain threshold A (10 ms stimuli, 5 Hz); <b>DEPTB</b> = dental electrical pain threshold B (100 pulses, single pulse duration 0.1 ms, 0.6 s train, 0–0.5 mA); <b>DEPTC</b> = dental electrical pain threshold C (duration 22 ms, 6.2 Hz, 0–0.1 mA); <b>DLPFC</b> = left dorsolateral prefrontal cortex; <b>DPCS</b> = descending pain control system; <b>EDT</b> = electrical detection threshold; <b>EMG RII-BF</b> = electromyographic reflex responses [RII, latency 50–70 ms] from biceps femoris muscle [BF]; <b>EMG RIII-BF</b> = electromyographic reflex responses [RIII, latency 90–150 ms] from biceps femoris muscle [BF]; <b>EMG H-reflex</b> = electromyographic reflex responses [H] from soleus muscle [S]; <b>EP</b> = [somatosensory] evoked potentials; <b>EPT</b> = electrical pain threshold; <b>EPTo</b> = electrical pain tolerance; <b>EVAS</b> = electronic VAS; <b>FEPT</b> = finger electrical pain threshold (100 Hz, pulse-trains of 100 ms, duration 1s, 0–1.9 mA); <b>FES</b> = finger electrical stimulation (see FEPT); <b>fMRI</b> = functional magnetic resonance imaging; <b>FPP =</b> finger pressure pain (2,000 g applied at dorsal surface of middle phalanx of index finger for 1 min); <b>HF-TENSA =</b> high-frequency transcutaneous nerve stimulation A (bi-phasic stimulus, duration 0.6 ms, 100 Hz, 45 mA, cheeks); <b>HF-TENSB =</b> high-frequency transcutaneous nerve stimulation B (duration 0.06 ms, 100 Hz, segmental, sural nerve); <b>HF-TNS</b> = high-frequency transcutaneous nerve stimulation (duration 0.2 ms, 100 Hz, 2 mA, segmental/heterosegmental cutaneous nerves); <b>HGD80% max</b> = handgrip dynamometer 80% maximum grip strength for 90s; <b>HGSD</b> = handgrip strength measured by dynamometry (isometric, repeated contractions; set to 50% maximum grip strength 20 contractions/ set to 50% maximum grip strength/30% of maximal voluntary contraction/12-kg load 20 times); <b>HPR</b> = heat pain ratings; <b>HPT</b> = heat pain threshold; <b>HPTo</b> = heat pain tolerance; <b>HR</b> = heart rate; <b>HSA</b> = tonic heat stimulus with contact thermode (1 cm², fixed temperature level corresponding to HPR 50 [COVAS 0–100], duration 120 s); <b>HSB</b> = phasic heat stimulus with contact thermode (9 cm², 47.5°C, duration 5 s, repeated 64 times, inter-stimulus interval 45 s); <b>HSC</b> = tonic heat stimulus with contact thermode (5.3 cm², fixed temperature level [46–50°C] corresponding to a HPR [“mild-to-moderate pain”], duration 30 s repeated 5 times, intersession resting period 3 min); <b>HSD</b> = tonic heat stimulus with contact thermode (9 cm², fixed temperature level corresponding to HPR 7 [NRS 0–10], duration 22 s); <b>HSE</b> = phasic and tonic heat stimuli with contact thermode (6 cm²; 0.7°C/s or 35 s at HPT); <b>HSF</b> = tonic heat stimuli with contact thermode (3 x 3 cm², 4 stimuli, 46°C, 25s, ISI 30s); <b>HSG</b> = phasic heat stimuli with contact thermode (3 x 3 cm², 4 randomized stimuli, 43–48°C, duration 5 s, ISI 62 s, 10°C/s, repeated 10 times); <b>HSH</b> = stimulation with short phasic contact stimuli (stimulus area 0.6 cm², peak temperature 51.8°C, 6 stimuli, ISI 15 s); <b>HSI</b> = phasic heat stimulus with RHSHG-technique (45°C, 5 s); <b>HWIT</b> = hot water immersion test (2 min, hand); <b>IDES</b> = intradermal electrical stimulation (rectangular, 0.5 ms duration, 2 Hz, high density); <b>ISI</b> = interstimulus interval; <b>IPT</b> = ischemia pain threshold; <b>IPTo</b> = ischemia pain tolerance; <b>ITC-SS</b> = infra-threshold cold stimulation—single stimuli (2.5 cm², 0.2°C, 0.7 s stimuli, forearm); <b>ITC-TS</b> = infra-threshold cold stimulation—temporal summation (2.5 cm,² 0.2°C, 0.7 s stimuli, train of 15 stimuli, 3 s inter-stimulus interval, hand); <b>LDPFC</b> = left dorsolateral prefrontal cortex; <b>LF-TENS</b> = transcutaneous electrical nerve stimulation (2.5 Hz, 0.2 ms duration, train of 5 impulses, 100 ms interval; stimulation areas 18.0 cm²); <b>LF-TNS</b> = low-frequency transcutaneous electrical nerve stimulation (duration 0.1 ms, 2 Hz, 9–45 V, 30 min stimulation hand/face [infraorbital nerve]); <b>MAC</b> = maximal aerobic capacity; <b>MPQ</b> = McGill Pain Questionnaire; <b>MSNA</b> = microneurographic recordings of sympathetic nerve activity to muscle; <b>MSR</b> = monosynaptic spinal reflex; <b>NFR</b> = nociceptive flexion reflex (same as NPR [RIII]); <b>N.R.</b> = not reported; <b>NRS</b> = pain ratings by numerical pain scale (0–10/100); <b>NS</b> = noxious stimuli; <b>NPR</b> = nociceptive polysynaptic reflex (same as NFR [RIII]); <b>PAA</b> = pressure algometry (1 cm², 30 kPa/s); <b>PAB</b> = see PAA (1 cm², 98 kPa/s); <b>PANAS</b> = Positive and Negative Affect Schedule; <b>PCS</b> = pain catastrophizing scale; <b>PDT</b> = pin-prick detection threshold; <b>PMES</b> = pain magnitude estimation scale; <b>PPR</b> = pin-prick pain rating; <b>PPT</b> = pin-prick pain threshold; <b>PRPT</b> = pressure pain thresholds; <b>PSR</b> = tactile polysynaptic reflexes (RII); <b>RDEPTB</b> = repetitive (1Hz, 3 min stimulation, inter-stimulus interval 7 min, 11 stimulation periods), DEPTB (see above); <b>RESA</b> = repetitive electrical skin stimulation (1–31 mA; other data NR); <b>RESB</b> = see RESA (1–31 mA, 1 mA increment, 93 stimuli, ISI 2.5 s); <b>RESC</b> = see RESA (200 Hz, duration 20 ms, ISI 20–40 s, repeated 40 times); <b>rTMS</b> = repetitive transcranial magnetic stimulation; <b>RHS</b> = radiant heat stimulation; <b>RHSD</b> = radiant heat stimulation by dolorimeter (0, 50, 340 and 390 mcal/s/cm²); <b>RHSHG</b> = radiant heat stimulation by halogen globe (95 mm² [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref014" target="_blank">14</a>] and [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref052" target="_blank">52</a>]/ 28 mm² [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref028" target="_blank">28</a>] apertures, 0.5°C/s, maximum 45/48/49°C); <b>RMS</b> = root mean square; <b>RPS</b> = ratio proportional pain scale; <b>RR</b> = respiratory rate; <b>SBP</b> = systolic blood pressure; <b>SHA</b> = secondary hyperalgesia areas; <b>SETT</b> = modified submaximal effort tourniquet test; <b>SIA</b> = stress-induced analgesia; <b>SOWS</b> = subjective opioid withdrawal scale; <b>SP</b> = skin pinching (two opposed pegs, diameter 6 mm, force 18–25 N, stimulus duration 2 min, ISI 8 min, 5 anatomical sites); <b>SSE</b> = somatic side effects; <b>SSEP</b> = EP; <b>STCR</b> = supra-threshold cold stimulation pain ratings; <b>STAI</b> = State-trait Anxiety Inventory; <b>STHR</b> = supra-threshold heat stimulation pain ratings; <b>STH-SS</b> = supra-threshold heat stimulation—single stimulation (2.5 cm², 52°C, duration 0.7 s/3.0 s, hand); <b>STH-TS</b> = supra-threshold heat stimulation—temporal summation (se <b>STH-SS</b> characteristics; train-of-ten); <b>STPPR</b> = suprathreshold pressure pain ratings (28 mm², 700 kPa, 60 s); <b>Sural noxious/tactile TNS</b> = transdermal electrical sural nerve stimulation (randomized: 3 noxious stimuli [70–80 mA] or 2 tactile stimuli [4–8 mA]); <b>Sural-TNSA</b> = transdermal electrical sural nerve stimulation A (1 ms duration, train of 8–10, 20 ms train-duration [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref001" target="_blank">1</a>]/1 ms duration, train-of-10, internal frequency 300 Hz, train-frequency 0.2 Hz, 10 mA [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref002" target="_blank">2</a>]/ 1 ms duration, train-of-6, internal frequency 200 Hz, train-frequency 0.2 Hz, 10 mA [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref008" target="_blank">8</a>]/ 1 ms duration, train-of-8, train-frequency 0.25 Hz, 0–30 mA [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref010" target="_blank">10</a>]/ 1 ms duration, train-of-5, train-duration 20 ms, train-frequency 0.17 Hz [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref011" target="_blank">11</a>]/ 1 ms duration, long lasting train (50–60 ms), internal frequency 300 Hz, 10 mA [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref048" target="_blank">48</a>]; <b>Sural-TNSB</b> = transdermal electrical sural nerve stimulation B (300 Hz, 1 ms duration, long-lasting train, 5 mA); <b>Sural-TNSC</b> = transdermal electrical sural nerve stimulation C (volley of 5 stimuli, 1 ms duration, interstimulus interval 3 ms, 4–40 mA, 3 stimulation sessions spaced by 5 min); <b>TAM</b> = tibialis anterior muscle; <b>TCS</b> = thermal contact stimulators (3.1 cm²/0.8 cm², 43/46/49°C, 2 x 6 stimuli, stimulus-duration max. 5 s, forearm); <b>TDES</b> = transdermal electrical stimulation (low density); <b>TESA</b> = transcutaneous electrical stimulation (duration 1 ms, 100 Hz, 0–6.4 mA, increments 0.05 mA, train-of-eight, randomized interval 15–25 s); <b>TESB</b> = see TESA (0.2 mA increments, ISI 1.2 s); <b>TG</b> = “thermal grill” is a device applied to the skin composed of six bars with alternating warm and cold temperatures (even- and odd-numbered) controlled by Peltier elements; <b>Tibial-TNS</b> = transdermal posterior tibial nerve stimulation (1 msec duration, 0.2 Hz); <b>TSHSA</b> = Temporal summation of heat stimuli A (49°C, stimulation area 9 cm², stimulus duration 0.5 s, inter-stimulus interval 2.5 s, train of 10 stimuli, left forearm); <b>TSHSB</b> = Temporal summation of heat stimuli B (48°C, stimulation area 9 cm², stimulus duration 6 s, inter-stimulus interval 4 s, train of 6 stimuli, 10 blocks separated by 40–60 s, left forearm); <b>TTA</b> = thermal thresholds (stimulation areas 1.8/9 cm², lip/forearm); <b>TTB</b> = see TTA (6 cm²; 0.7°C/s, baseline either 32°C or 38°C); <b>TTTo</b> = tourniquet test tolerance; <b>VT</b> = vibratory threshold; <b>UCAS</b> = unconditioned aversive stimulus; <b>UV-burn</b> = ultraviolet “solar” stimulator (150W xenon lamp, UV_A [400 nm] and UV_B [290 nm], aperture 2 cm) skin exposure: 2.5 MED (“minimal erythemic dose”, arm); <b>VAS</b> = pain intensity and/or unpleasantness ratings by visual analog scale (0–100); <b>VNS</b> = visual numeric pain scale (0–100); <b>VRS</b> = verbal pain rating scale; <b>VS</b> = vibratory stimulation (0.8 cm², 100 Hz, 0.5 s, displacement 1 mm); <b>VT</b> = vibratory threshold (stimulation area N.R., 3.7 N/cm², 0.2 microm/s); <b>WCT</b> = warming by contact thermode (2 cm², 37°C, > 80 min); <b>WDL</b> = withdrawal latency; <b>WDT</b> = warmth detection threshold.</p><p>ʻInhibitoryʼ Test Paradigms: Testing Methods and Results.</p

ʻInhibitoryʼ Test Paradigms: Demographics and Drugs.

<p>^§ not interfering with the MOR-antagonist assessments (drugs without administration route stated are i.v.).</p><p>^¤ 3 additional volunteers were included due to unintended ʻcarry-overʼ (sequence) effects.</p><p>^# 12 volunteers total (2 volunteers did not participate in the naloxone parts of the study).</p><p>^SD standard deviation.</p><p>^<b>A</b> = age presented separately for each of the 6 groups of volunteers</p><p><b>B</b> = bolus (up to 4 min administration time allowed); <b>F</b> = female; <b>I</b> = infusion; <b>M</b> = male; <b>ITP</b> = iontophoresis; <b>N.R.</b> = not reported; <b>NTx</b> = naltrexone; <b>Nx</b> = naloxone; <b>SD</b> = standard deviation; <b>TCI</b> = target-controlled infusion (total dose indicated).</p><p>ʻInhibitoryʼ Test Paradigms: Demographics and Drugs.</p

The search algorithm according to the PRISMA-requirements [126].

<p>The search algorithm according to the PRISMA-requirements [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0125887#pone.0125887.ref126" target="_blank">126</a>].</p

Endogenous Opioid-Masked Latent Pain Sensitization: Studies from Mouse to Human

<div><p>Following the resolution of a severe inflammatory injury in rodents, administration of mu-opioid receptor inverse agonists leads to reinstatement of pain hypersensitivity. The mechanisms underlying this form of latent pain sensitization (LS) likely contribute to the development of chronic pain, but LS has not yet been demonstrated in humans. Using a C57BL/6 mouse model of cutaneous mild heat injury (MHI) we demonstrated a dose-dependent reinstatement of pain sensitization, assessed as primary (<i>P</i> < 0.001) and secondary hyperalgesia (<i>P</i> < 0.001) by naloxone (0.3–10 mg/kg), 168 hrs after the induction of MHI. Forward-translating the dose data to a human MHI model (n = 12) we could show that LS does indeed occur after naloxone 2 mg/kg, 168 hrs after a MHI. Our previous unsuccessful efforts to demonstrate unmasking of LS in humans are thus likely explained by an insufficient naloxone dose (0.021 mg/kg). However, while LS was consistently demonstrated in 21/24 mice, LS was only seen in 4/12 subjects. This difference is likely due to selection bias since the C57BL/6 mouse strain exhibits markedly enhanced pain sensitivity in assays of acute thermal nociception. Future exploratory studies in humans should prioritize inclusion of “high-sensitizers” prone to develop LS and use post-surgical models to elucidate markers of vulnerability to chronic postsurgical pain.</p><p>Trial Registration</p><p>EudraCT <a href="https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005663-27/DK" target="_blank">2012-005663-27</a></p></div