Quantitative Assessment of Subjective Symptoms and Corneal Sensitivity in Chronic Orbital Pain Patients.

PURPOSE: To objectively evaluate the subjective symptoms and characteristics of chronic orbital pain as well as to quantify sensitization of peripheral trigeminal nerves. METHODS: In this prospective cohort study, patients who previously showed a response to peripheral trigeminal nerve blocks for unilateral, idiopathic chronic orbital pain and healthy subjects completed validated questionnaires assessing headaches, neuropathic signs and symptoms, photophobia, and pain qualities. Corneal sensitivity was measured in both eyes for all subjects with a Cochet-Bonnet aesthesiometer. For pain patients, the full assessment protocol was repeated 2-4 weeks after the study injection, and corneal sensitivity was also measured 30 minutes postinjection. Outcomes assessed were headache, neuropathic pain, and photophobia scores; pain qualities; and corneal sensitivity. RESULTS: Six female chronic orbital pain patients (mean age 48.2 years) and 11 female controls (mean age 47.5) were included. The mean headache, neuropathic pain, and photophobia questionnaire scores were significantly higher for pain patients than for controls (p < 0.001). On sensory testing, 5 pain patients (83.3%) endorsed allodynia, and all 6 (100%) had hyperalgesia in the ipsilateral frontal nerve dermatome. No controls had allodynia or hyperalgesia. Corneal sensitivity was similar between eyes in pain patients and between groups. Questionnaire scores and corneal sensitivity did not change significantly after the injection. CONCLUSIONS: Chronic orbital pain patients have a measurable reduction in quality of life due to headaches and photophobia. The supraorbital and supratrochlear nerves are sensitized, resulting in cutaneous hypersensitivity in the corresponding dermatome, but corneal nerves have normal sensitivity.

Reliability of quantitative sensory testing in the assessment of somatosensory function after high-frequency stimulation-induced sensitisation of central nociceptive pathways.

ABSTRACT: The high frequency stimulation (HFS) model can be used alongside quantitative sensory testing (QST) to assess the sensitisation of central nociceptive pathways. However, the validity and between-session reliability of using QST z -score profiles to measure changes in mechanical and thermal afferent pathways in the HFS model are poorly understood. In this study, 32 healthy participants underwent QST before and after HFS (5× 100 Hz trains; 10× electrical detection threshold) in the same heterotopic skin area across 2 repeated sessions. The only mechanical QST z -score profiles that demonstrated a consistent gain of function across repeated test sessions were mechanical pain threshold (MPT) and mechanical pain sensitivity (MPS), which were associated with moderate and good reliability, respectively. There was no relationship between HFS intensity and MPT and MPS z -score profiles. There was no change in low intensity, but a consistent facilitation of high-intensity pin prick stimuli in the mechanical stimulus response function across repeated test sessions. There was no change in cold pain threshold (CPT) and heat pain threshold (HPT) z -score profiles across session 1 and 2, which were associated with moderate and good reliability, respectively. There were inconsistent changes in the sensitivity to innocuous thermal QST parameters, with cool detection threshold (CDT), warm detection threshold (WDT), and thermal sensory limen (TSL) all producing poor reliability. These data suggest that HFS-induced changes in MPS z -score profiles is a reliable way to assess experimentally induced central sensitisation and associated secondary mechanical hyperalgesia in healthy participants.

Translation, cross-cultural adaptation and measurement proprieties of the German version of the Allodynia Symptom Checklist (ASC-12).

BACKGROUND: Cutaneous allodynia is highly prevalent among migraineurs and is associated with a poor prognosis. The Allodynia Symptom Checklist (ASC-12) is a comprehensive questionnaire to identify the presence and severity of allodynia. Our aim was to translate and adapt the ASC-12 to German and evaluate its measurement properties. METHODS: Following the COSMIN guidelines, 80 migraine patients were enrolled in the study to evaluate the stages of translation (n=30) and measurement propriety assessment (n=50), respectively. After reaching a final version, the German ASC-12 was assessed for structural validity, internal consistency, test-retest reliability, construct validity and absolute agreement, using mechanical and thermal pain thresholds as reference method. RESULTS: The German version of the ASC-12 presented an adequate structural validity compatible with the original version of the questionnaire. Its internal consistency ranged from 0.70 to 0.80 considering the total score and the thermic, static and dynamic mechanic subdomains. The total score presented excellent reliability (ICC: 0.85) with a standard error of measurement of 1.15 points and smallest detectable change of 3.40 points. ASC-12 total scores were correlated with headache intensity (r=0.38, p=0.004), headache disability (r=0.37, p=0.004) and cold pain thresholds (r=0.28, p=0.025). The thermic allodynia ASC-12 scores were correlated with cold (r=0.36, p=0.005) and heat (r=-0.30, p=0.010) pain thresholds, while the static mechanical allodynia ASC-12 scores correlated with mechanical pain threshold (r=0.29, p=0.019) and with mechanical pain sensitivity (r=0.24 to 0.28, p< 0.045). Despite no significant bias between methods, quantitative sensory testing (QST) results and ASC-12 scores tend to disagree. CONCLUSION: The German version of the ASC-12 is available for research and clinical settings and presented adequate measurement proprieties, as the original version. Despite the correlation between the ASC-12 and QST, one method cannot be replaced by the other.

Quantitative Dynamic Allodynograph-A Standardized Measure for Testing Dynamic Mechanical Allodynia in Chronic Limb Pain.

BACKGROUND: Dynamic mechanical allodynia (DMA) is both a symptom and a central sensitization sign, yet no standardized method for quantifying the DMA area has been reported. This study aimed to establish psychometric properties for Quantitative Dynamic Allodynography (QDA), a newly developed protocol measuring the DMA area as a percentage of the body surface. METHODS: Seventy-eight patients aged 18-65 diagnosed with chronic complex regional pain syndrome (CRPS) participated in this study. Test-retest reliability was conducted twice, one week apart (N = 20), and inter-rater (N = 3) reliability was conducted on 10 participants. Disease severity (CRPS Severity Score, CSS), pain intensity (VAS), and quality of life (SF-36) measures were utilized to test construct validity. RESULTS: High inter-rater reliability (intraclass correlation coefficient (ICC) = 0.96, p < 0.001) and test-retest reliability (r = 0.98, p < 0.001) were found. Furthermore, the QDA score was found to be correlated with the CSS (r = 0.47, p < 0.001), VAS (r = 0.37, p < 0.001), and the SF-36 physical health total (r = -0.47, p < 0.001) scores. CONCLUSION: The QDA is the first developed reliable and valid protocol for measuring DMA in a clinical setting and may be used as a diagnostic and prognostic measure in clinics and in research, advancing the pain precision medicine approach.

Quantitative Sensory Testing to Characterize Sensory Changes in Hidradenitis Suppurativa Skin Lesions.

Importance: Pain is the most impactful symptom in patients with hidradenitis suppurativa (HS). Characterization of sensory profiles may improve understanding of pain mechanisms in HS and facilitate identification of effective pain management strategies. Objective: To characterize somatosensory profiles in patients with HS at clinically affected and nonaffected sites compared with pain-free reference data. Design, Setting, and Participants: This cross-sectional study was conducted at the Emory University Dermatology Clinic. It was hypothesized (1) that patients with HS would demonstrate hypersensitivity to pain in HS lesions and (2) that some patients would have sensory profiles consistent with complex pain mechanisms. Therefore, adults with dermatologist-diagnosed HS and at least 1 painful HS lesion at the time of testing were enrolled between September 10, 2020, and March 21, 2022. Patients with other diagnoses contributing to pain or neuropathy were excluded. Data analysis was conducted between March and April 2022. Exposure: Quantitative sensory testing was performed on HS lesions and control skin according to a standardized protocol. Main Outcomes and Measures: Quantitative sensory testing outcomes included innocuous thermal and mechanical sensitivity (cold, warmth, and light touch detection thresholds), noxious thermal and mechanical sensitivity (cold, heat, pinprick, and deep pressure pain thresholds and suprathreshold pinprick sensitivity), temporal summation of pinprick, paradoxical thermal sensations, and dynamic mechanical allodynia (pain upon light stroking of the skin). Sensitivity in HS lesions was compared with sensitivity in a control location (the hand) and in pain-free controls using t tests. Results: This study included 20 participants with a median age of 35.5 (IQR, 30.0-46.5) years, the majority of whom were women (15 [75%]). In terms of race and ethnicity, 2 participants (10%) self-identified as Asian, 11 (55%) as Black, 6 (30%) as White, and 1 (5%) as more than 1 race or ethnicity. Compared with site-specific reference values from healthy, pain-free control participants, HS lesions were insensitive to innocuous cold and warmth, noxious heat, and light touch (t = -5.69, -10.20, -3.84, and 4.46, respectively; all P < .001). In contrast, HS lesions also demonstrated significant hypersensitivity to deep pressure pain (t = 8.36; P < .001) and cutaneous pinprick (t = 2.07; P = .046). Hypersensitivity to deep pressure pain was also observed in the control site (t = 5.85; P < .001). A subset of patients with HS displayed changes in pain processing that are often seen in neuropathic and nociplastic pain conditions, including hypersensitivity to repetitive pinprick (5 [26%]), paradoxical thermal sensations (3 [15%]), and pain upon light stroking of the skin (10 [50%]). Conclusions and Relevance: The findings of this cross-sectional study suggest that HS involves local changes in the skin or its free nerve endings, possibly leading to peripheral neuropathy and alterations in the transduction of innocuous and noxious thermal and mechanical stimuli. For some patients, central nervous system changes in somatosensory processing may also occur, but confirmatory evidence is needed. Better understanding of neuropathic and nociplastic mechanisms in HS pain could lead to individually tailored treatments.

The value of inquiring patients about local discomfort during blood pressure measurement for fibromyalgia detection. A cross-sectional study.

BACKGROUND: Fibromyalgia overlaps and/or mimics other rheumatic diseases and may be a confounding factor in the clinimetric assessment of these illnesses. Allodynia is a distinctive fibromyalgia feature that can be elicited during routine blood pressure measurement. For epidemiological purposes fibromyalgia can be diagnosed using the 2016 Wolfe et al. criteria questionnaire. No physical examination is required. OBJECTIVE: To evaluate the role of a straightforward question formulated during routine blood pressure measurement for fibromyalgia detection in a rheumatology outpatient clinic. PATIENTS AND METHODS: All adult patients attending our Rheumatology outpatient clinic were invited to participate. While awaiting their medical consultation, they filled-out the 2016 Wolfe et al. FM diagnostic criteria questionnaire. During the ensuing routine physical examination, the physician advanced the following guideline: "I am going to take your blood pressure; tell me if the cuff's pressure causes pain". Then, blood pressure cuff was inflated to 170 mm/Hg. Sphygmomanometry induced allodynia was defined as any local discomfort caused by blood pressure measurement. If a patient voiced any uneasiness, a follow-up dichotomic question was formulated "did it hurt much or little". Sphygmomanometry-induced allodynia was correlated with the presence of fibromyalgia according to the 2016 Wolfe diagnostic criteria. RESULTS: Four hundred and ninety-one patients were included in the study; most of them (84%) were female. The female cohort displayed the following features: Twenty five percent had fibromyalgia. Twenty seven percent had sphygmomanometry-induced allodynia. In women, sphygmomanometry-evoked allodynia had 63% sensitivity and 84% specificity for fibromyalgia diagnosis. The area under curve was 0.751. Moreover, having "much" local pain elicitation during blood pressure testing had 23% sensitivity and 96% specificity for fibromyalgia diagnosis. Men behaved differently; 15% fulfilled the fibromyalgia diagnostic criteria, but only 2% had sphygmomanometry induced allodynia. CONCLUSIONS: Inquiring female patients about local discomfort during routine blood pressure measurement is a simple and efficient procedure for fibromyalgia detection. This undemanding approach could be implemented in all clinical settings. There is marked sexual dimorphism in the link between sphygmomanometry-induced allodynia and fibromyalgia diagnosis. The presence of fibromyalgia is almost certain in those individuals having substantial pain elicitation during blood pressure measurement.

Preoperative and Postoperative Hyperalgesia in Dental Patients on Chronic Opioid Therapy: A Pilot Study.

OBJECTIVE: Opioid-induced hyperalgesia, a paradoxical increase in pain sensitivity associated with ongoing opioid use, may worsen the postoperative pain experience. This pilot study examined the effect of chronic opioid use on pain responses in patients undergoing a standardized dental surgery. METHODS: Experimental and subjective pain responses were compared prior to and immediately following planned multiple tooth extractions between patients with chronic pain on opioid therapy (≥30 mg morphine equivalents/d) and opioid-naïve patients without chronic pain matched on sex, race, age, and degree of surgical trauma. RESULTS: Preoperatively, chronic opioid users rated experimental pain as more severe and appreciated less central modulation of that pain than did opioid-naïve participants. Postoperatively, chronic opioid-using patients rated their pain as more severe during the first 48 hours and used almost twice as many postoperative analgesic doses during the first 72 hours as the opioid-naïve controls. CONCLUSION: These data suggest that patients with chronic pain taking opioids approach surgical interventions with heightened pain sensitivity and have a more severe postoperative pain experience, providing evidence that their complaints of postoperative pain should be taken seriously and managed appropriately.

Modulation of Melatonin in Pain Behaviors Associated with Oxidative Stress and Neuroinflammation Responses in an Animal Model of Central Post-Stroke Pain.

Central post-stroke pain is a severe persistent pain disease that affects 12% of stroke survivors (CPSP). These patients may have a cognitive impairment, depression, and sleep apnea, which leave them open to misdiagnosis and mistreatment. However, there has been little research on whether the neurohormone melatonin can effectively reduce pain in CPSP conditions. In the present study, we labeled melatonin receptors in various brain regions of rats. Later, we established a CPSP animal model by intra-thalamic collagenase lesions. After a rehabilitation period of three weeks, melatonin was administered using different doses (i.e., 30 mg/kg, 60 mg/kg, 120 mg/kg) for the following three weeks. Mechanical allodynia, thermal hyperalgesia, and cold allodynia behavioral tests were performed. Immediately after behavioral parameters were tested, animals were sacrificed, and the thalamus and cortex were isolated for biochemical (mitochondrial complexes/enzyme assays and LPO, GSH levels) and neuroinflammatory (TNF-α, IL-1ß, IL-6) assessments. The results show that melatonin receptors were abundant in VPM/VPL regions. The thalamic lesion significantly induced pain behaviors in the mechanical, thermal planters, and cold allodynia tests. A significant decrease in mitochondrial chain complexes (C-I, II, III, IV) and enzymes (SOD, CAT, Gpx, SDH) was observed after the thalamic lesion. While there were significant increases in reactive oxygen species levels, including increases in LPO, the levels of reduced GSH were decreased in both the cortex and thalamus. Proinflammatory infiltration was noticed after the thalamic lesion, as there was a significant elevation in levels of TNF-α, IL-1ß, and IL-6. Administration of melatonin has been shown to reverse the injury effect dose-dependently. Moreover, a significant increase in C-I, IV, SOD, CAT, and Gpx levels occurred in the CPSP group. Proinflammatory cytokines were significantly reduced by melatonin treatments. Melatonin seems to mediate its actions through MT1 receptors by preserving mitochondrial homeostasis, reducing free radical generation, enhancing mitochondrial glutathione levels, safeguarding the proton potential in the mitochondrial ETC by stimulating complex I and IV activities, and protecting the neuronal damage. In summary, exogenous melatonin can ameliorate pain behaviors in CPSP. The present findings may provide a novel neuromodulatory treatment in the clinical aspects of CPSP.

Clinical Assessment of Mechanical Allodynia in Youth With Complex Regional Pain Syndrome: Development and Preliminary Validation of the Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense).

Youth with complex regional pain syndrome (CRPS) commonly experience mechanical allodynia and disability. Assessment of mechanical allodynia is typically binary (present or absent), making it difficult to assess the quality and degree of mechanical allodynia before and after treatment. This study developed and validated the Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense) to provide an easy way for rehabilitation clinicians to evaluate mechanical allodynia before and after intensive interdisciplinary pain treatment. The 6 Pedi-Sense items demonstrated adequate internal consistency reliability (CR) at admission (CR = .956) and discharge (CR = .973), reasonably fit the hypothesized linear model of stimulus intensity (P < .0001), and significantly loaded onto a single latent factor, mechanical allodynia (P < .0001), at admission and discharge. Pedi-Sense scores significantly correlated with disability (rs = .40; P = .004) and pain catastrophizing (rs = .33; P = .017) at admission. The Pedi-Sense appeared responsive to intervention as participants' total scores improved by 1.44 points (95% CI: .72, 2.15) after IIPT interventions that included daily tactile desensitization. However, test-retest and interrater reliability and the specific contribution of desensitization treatment to the overall success of multi-modal pain rehabilitation still needs to be evaluated. PERSPECTIVE: This article presents the development and preliminary validation of a novel clinical assessment of static and dynamic mechanical allodynia. The Pediatric Tactile Sensitivity Test of Allodynia (Pedi-Sense) allows rehabilitation clinicians to easily evaluate mechanical allodynia at the bedside with minimal training and simple equipment to guide desensitization treatment in clinical settings.

Pain mechanisms in complex regional pain syndrome: a systematic review and meta-analysis of quantitative sensory testing outcomes.

BACKGROUND: Complex regional pain syndrome (CRPS) is a chronic condition following inciting events such as fractures or surgeries with sensorimotor and autonomic manifestations and poor prognosis. This review aimed to provide conclusive evidence about the sensory phenotype of CRPS based on quantitative sensory testing (QST) to understand the underlying pain mechanisms and guide treatment strategies. DATABASES: Eight databases were searched based on a previously published protocol. Forty studies comparing QST outcomes (thermal, mechanical, vibration, and electric detection thresholds, thermal, mechanical, pressure, and electric pain thresholds, wind-up ratio, mechanical pain sensitivity, allodynia, flare area, area after pinprick hyperalgesia, pleasantness after C-tactile stimulation, and pain ratings) in chronic CRPS (adults and children) versus healthy controls were included. RESULTS: From 37 studies (14 of low quality, 22 of fair quality, and 1 of good quality), adults with CRPS showed: (i) significant loss of thermal, mechanical, and vibration sensations, significant gain of thermal and mechanical pain thresholds, significant elevation of pain ratings, and no difference in wind-up ratio; (ii) significant reduction of pleasantness levels and increased area of pinprick hyperalgesia, in the affected limb. From three fair-quality studies, adolescents and children with CRPS showed loss of cold detection with cold hyperalgesia in the affected limb. There was moderate to substantial overall heterogeneity. CONCLUSION: Diffuse thermal and mechanical hypoesthesia with primary and secondary hyperalgesia, enhanced pain facilitation evidenced by increased area of pinprick hyperalgesia, and elevated pain ratings are dominant in adults with CRPS. Adolescents and children with CRPS showed less severe sensory abnormalities.

A simple, bed-side tool to assess evoked pressure pain intensity.

OBJECTIVES: Existing equipment for quantitative sensory testing is generally expensive and not easily applicable in a clinical setting thus simple bed-side devices are warranted. Pressure hyperalgesia is a common finding in patients with musculoskeletal pain and an experimental model is delayed-onset muscle soreness (DOMS). DOMS is characterised by muscle hyperalgesia and some studies report facilitation of temporal summation of pain. This study aimed to detect DOMS induced muscle hyperalgesia and temporal summation of pain using a newly developed bed-side quantitative sensory testing device to deliver standardised pressure. METHODS: Twenty-two healthy participants participated in two sessions with the second session approximately 48 h after baseline. Pressure pain intensities were assessed from the gastrocnemius muscle with four probes calibrated to apply 2, 4, 6 and 8 kg, respectively. Temporal summation of pain (10 stimuli delivered at 0.5 Hz using the 6 kg probe) intensities were assessed from the same location. DOMS was evoked in the gastrocnemius muscle by an eccentric exercise. Sleepiness and physical activity were measured with the Epworth Sleepiness Scale and the Global Physical Activity Questionnaire to investigate if they were associated with the quantitative sensory testing measures. RESULTS: Pressure pain intensity was significantly increased 48 h after induction of DOMS when compared to baseline for all four probes (p<0.05). Temporal summation of pain was not statistically significant affected by DOMS and sleep quality and physical activity did not associate with any of the measures. CONCLUSIONS: This study introduces a simple, bed-side assessment tool for the assessment of pressure pain intensity and hence hyperalgesia and temporal summation of pain.

Allodynia, Hyperalgesia, (Quantitative) Sensory Testing and Conditioned Pain Modulation in Patients With Complex Regional Pain Syndrome Before and After Spinal Cord Stimulation Therapy.

OBJECTIVES: Complex regional pain syndrome (CRPS) is a chronic debilitating disease characterized by sensory abnormalities. Spinal cord stimulation (SCS) is an effective therapy for CRPS, but few studies have investigated the effects of SCS therapy on sensory characteristics. Therefore, this study investigated the effect of SCS on allodynia, hyperalgesia, electrical quantitative sensory testing (QST) parameters, and conditioned pain modulation (CPM) effect. MATERIALS AND METHODS: This study is part of a multicenter randomized controlled trial (ISRCTN 36655259). Patients with CRPS in one extremity and eligible for SCS were included. The outcome parameters allodynia (symptom and sign), hyperalgesia (symptom), sensory thresholds with QST, CPM effect, and pain scores were tested before and after three months of SCS (40-Hz tonic SCS). Both the CRPS-affected extremity and the contralateral, clinically unaffected extremity were used to test three sensory thresholds with electrical QST: current perception threshold (CPT), pain perception threshold (PPT), and pain tolerance threshold (PTT). The PTT also was used as a test stimulus for the CPM paradigm both before and after the conditioning ice-water test. Nonparametric testing was used for all statistical analyses. RESULTS: In total, 31 patients were included for analysis. Pain, allodynia (sign and symptom), and hyperalgesia (symptom) were all significantly reduced after SCS therapy. On the unaffected side, none of the QST thresholds (CPT, PPT, and PTT) was significantly altered after SCS therapy. However, the CPT on the CRPS-affected side was significantly increased after SCS therapy. A CPM effect was present both before and after SCS. CONCLUSIONS: Standard 40-Hz tonic SCS significantly reduces pain, hyperalgesia, and allodynia in patients with CRPS. These findings suggest that SCS therapy should not be withheld from patients who suffer from allodynia and hyperalgesia, which contradicts previous findings derived from retrospective analysis and animal research. ISRCTN Registry: The ISRCTN registration number for the study is ISRCTN 36655259.

Quantitative sensory test findings in cervical radicular pain and their relationship with the symptoms.

OBJECTIVES: This study aims to define and compare sensory phenotypes in cervical radiculopathy patients exhibiting neuropathic pain (NP) components with healthy volunteers using clinical examination and quantitative sensory test (QST) findings. Another aim of the study is to show whether symptomatic components of the pain detect questionnaire (PDQ) are correlated with the QST findings, which may help clinicians indicate patients with sensory abnormalities without the use of specialized tests. METHODS: Fifty-seven participants were included in the study, including patients with NP (n=20) and healthy volunteers (n=37). After obtaining the sociodemographic and clinical data of the participants, the PDQ was performed in patients with pain followed by QST analysis in all participants. RESULTS: Analyses between painful and non-painful extremities yielded no differences in all groups for QST (p>0.05). Sensory thresholds were found to be higher in the NP group compared to healthy volunteers, and the pain threshold test was found to be lower (p<0.05) in the intergroup analyses. The changes described were found in both painful and non-painful limbs. Pain with slight pressure was found to be correlated with the lower heat pain threshold values (R=-0.602, p=0.005). CONCLUSION: Patients with NP were found to have lower thresholds for pain and higher sensory thresholds when compared to healthy volunteers. Moreover, pain with pressure component in PDQ was found to be associated with hyperalgesia in QST.

Sympathetic skin response as an objective tool to estimate stimulus-associated arousal in a human model of hyperalgesia.

BACKGROUND: Pain is a private experience, whose assessment relies on subjective self-reporting. Inaccurate communication renders pain evaluation unreliable in individuals with alteration of consciousness, lack of verbal interaction, cognitive dysfunction or simple malingering, hence the importance of developing reliable objective assessment tools. OBJECTIVES: Since pain is associated with autonomic arousal, here we used readouts of autonomic activity to assess objectively the arousing effect of somatic stimuli in a human model of hyperalgesia. METHODS: We used topical capsaicin to induce cutaneous hypersensitivity in the right arm of 20 healthy volunteers, and recorded sympathetic skin responses (SSR) and numerical perceptive ratings (NRS) to stimulation of the sensitized region and its homologous contralateral site, using brush (Aß), pinprick (Aδ) and laser (C-Warmth) stimuli. RESULTS: Both subjective ratings and SSRs were significantly enhanced to stimulation of the sensitized region, and their respective ratios of maximal enhancement were positively correlated. At individual level, a significant association was observed between SSR and NRS behavior (χ2(1)= 11.03; p < 0.001), with a positive predictive value of 87% (CI95 [77-97%]) for SSR increase predicting enhancement of subjective reports. A "lie experiment" asking subjects to simulate elevated NRS failed to enhance SSRs. Significant habituation of SSRs appeared when stimuli were repeated at ∼15s intervals, hence decreasing their negative predictive value when several consecutive stimuli were averaged (NPV=46%; CI95 [30-62%]). CONCLUSION: The SSR may represent a rapid and reliable procedure to assess cutaneous hypersensitivity, simple to use in clinical practice and resistant to simulation. Rapid habituation is a drawback that can be countered by using few repetitions and low stimulus rates.

A Closer Look at Localized and Distant Pressure Pain Hypersensitivity in People With Lower Extremity Overuse Soft-Tissue Painful Conditions: A Systematic Review and Meta-Analysis.

OBJECTIVE: The nociceptive pain processing of soft-tissue overuse conditions is under debate because no consensus currently exists. The purpose of this meta-analysis was to compare pressure pain thresholds (PPTs) in symptomatic and distant pain-free areas in 2 groups: participants with symptomatic lower extremity overuse soft-tissue conditions and controls who were pain free. METHODS: Five databases were searched from inception to December 1, 2021, for case-control studies comparing PPTs between individuals presenting with symptomatic lower extremity tendinopathy/overuse injury and controls who were pain free. Data extraction included population, diagnosis, sample size, outcome, type of algometer, and results. The methodological quality (Newcastle-Ottawa Quality Assessment Scale) and evidence level (Grading of Recommendations Assessment, Development, and Evaluation) were assessed. Meta-analyses of symptomatic, segmental related, and distant pain-free areas were compared. RESULTS: After screening 730 titles and abstracts, a total of 19 studies evaluating lower extremity overuse conditions (Achilles or patellar tendinopathy, greater trochanteric pain syndrome, plantar fasciitis, and iliotibial band syndrome) were included. The methodological quality ranged from fair (32%) to good (68%). Participants with lower extremity overuse injury had lower PPTs in both the painful and nonpainful areas, mirrored test-site, compared with controls (affected side: mean difference [MD] = -262.92 kPa, 95% CI = 323.78 to -202.05 kPa; nonaffected side: MD = -216.47 kPa, 95% CI = -304.99 to -127.95 kPa). Furthermore, people with plantar fasciitis showed reduced PPTs in the affected and nonaffected sides at segmental-related (MD = -176.39 kPa, 95% CI = -306.11 to -46.68 kPa) and distant pain-free (MD = -97.27 kPa, 95% CI = 133.21 to -61.33 kPa) areas compared with controls. CONCLUSION: Low- to moderate-quality evidence suggests a reduction of PPTs at the symptomatic area and a contralateral/mirror side in lower extremity tendinopathies and overuse conditions compared with pain-free controls, particularly in plantar fasciitis and greater trochanteric pain syndrome. Participants with plantar fasciitis showed a reduction of PPTs on the affected and non-affected sides at a segmental-related area (very low-quality evidence) and at a remote asymptomatic area (moderate-quality evidence). IMPACT: Some overuse peripheral pain conditions may be more associated with pressure pain sensitivity than others. Accordingly, examination and identification of conditions more peripherally, centrally, or mixed mediated could potentially lead to more specific and different treatment strategies.

Assessment of Nerve Injury-induced Mechanical Hypersensitivity in Rats using an Orofacial Operant Pain Assay.

Pain has sensory and affective components. Unlike traditional, reflex-based pain assays, operant pain assays can produce more clinically relevant results by addressing the cognitive and motivational aspects of pain in rodents. This paper presents a protocol for assessing mechanical hypersensitivity following chronic constriction injury of the infraorbital nerves (CCI-ION) in rats using an orofacial operant pain system. Before CCI-ION surgery, rats were trained in an orofacial pain assessment device (OPAD) to drink sweetened condensed milk while making facial contact with the metal spiked bars and lick-tube. In this assay, rats can choose between receiving milk as a positive reinforcer or escaping an aversive mechanical stimulus that is produced by a vertical row of small pyramid-shaped spikes on each side of the reward access hole. Following 2 weeks of training in the OPAD and before the CCI-ION surgery, baseline mechanical sensitivity data were recorded for 5 days for each rat during a 10 min testing session. During a session, the operant system automatically records the number of reward bottle activations (licks) and facial contacts, contact duration, and latency to the first lick, among other measures. Following baseline measurements, rats underwent either CCI-ION or sham surgery. In this protocol, mechanical hypersensitivity was quantified by measuring the number of licks, latency to the first lick, the number of contacts, and the ratio of licks to facial contacts (L/F). The data showed that CCI-ION resulted in a significant decrease in the number of licks and the L/F ratio and an increase in the latency to the first lick, indicating mechanical hypersensitivity. These data support the use of operant-based pain assays to assess mechanical pain sensitivity in preclinical pain research.

Cutaneous allodynia and thermal thresholds in chronic migraine: The effect of onabotulinumtoxinA.

OBJECTIVE: Cutaneous allodynia (CA) is a common symptom in migraine. Its incidence is more frequent in the chronic migraine (CM). CA usually occurs during pain attacks. However, it can also be interictal and its frequency and severity seem to be correlated with the duration of the disease. Several quantitative sensory testing (QST) studies have revealed variable results about mechanical and thermal allodynia accompanying migraine. This study aimed to investigate the effects of CA and onabotulinumtoxinA (BoNT-A) injection on the thermal thresholds measured by QST in patients with CM. The effects of BoNT-A on headaches, CA, and other accompanying symptoms of migraine were also evaluated. METHODS: Single BoNT-A injections were performed in 22 female cases (mean age: 38.1 ± 7.2 years) with CM. Patients were evaluated at 1-7 days before, 28-35, and 84-91 days after the injection. The 22 healthy women in the control group (mean age: 36.6 ± 7.6 years) were examined once. Headache and its characteristics, medication intake, allodynia, presence of anxiety, and depression symptoms were evaluated through relevant scales. The heat (HDT) and cold (CDT) detection thresholds on the forehead and hand were measured bilaterally with QST. The presence of brush allodynia for patients was examined by applying a 4 × 4 gauze pad over the same areas. RESULTS: The patients in the CM group had migraine for an average of 22.5 ± 6.1 years and CM for 6.1 ± 3.2 years. The average number of painful days per month was 22.1 ± 4.0 days. All the patients had migraine attacks with CA (mean 5.6/month). The average allodynia symptom checklist (ASC-12) score was 7.8 ± 6.2. Thermal thresholds measured in the patients with CM were similar to those of the controls. Thermal thresholds did not show significant differences between the symptomatic and the asymptomatic sides at the last migraine attack. There was also no correlation between the allodynia revealed by the physical examination and the thermal thresholds detected by QST. The ASC-12 score decreased significantly with BoNT-A injection (p = 0.030), but no significant change was observed in thermal thresholds after this treatment. CONCLUSION: There was no significant correlation between CA and thermal thresholds. BoNT-A was successful in relieving headache and other associated symptoms, including CA, but had no significant effect on QST parameters.

61-year-old woman • nausea • paresthesia • cold allodynia • Dx?

► Nausea ►Paresthesia ► Cold allodynia.

Cold allodynia is correlated to paroxysmal and evoked mechanical pain in complex regional pain syndrome (CRPS).

OBJECTIVES: Mechanisms of complex regional pain syndrome (CRPS) are still debated. Identifying subgroups of patients have been attempted in the hope of linking clinical findings to possible mechanisms. The aim of the present study was to investigate whether subgroups of CRPS (based on quantitative sensory testing (QST)-results) differed with respect to different characteristics of pain like spontaneous ongoing or paroxysmal pain and mechanical dynamic allodynia. METHODS: 61 CRPS-patients (type 1 and 2) were examined clinically and with QST, in affected and contralateral extremity, with assessment of thresholds for warmth, cold and heat-and cold pain. RESULTS: 43 patients (20 men, 23 men) were diagnosed with CRPS 1 (70.5%) and 18 patients (8 women and 10 men) with CRPS 2 (29.5%). Three subgroups were defined based on thermal thresholds; A (thermal allodynia 22.9%), B (thermal hyposensitivity 37.3%), C (thermal allodynia and hyposensitivity 39.3%). Paroxysmal pain was more prevalent in patients with thermal allodynia (merging group A + C, 25/38-65.8%) compared to patients without thermal allodynia (group B, 5/23-21.7%) (p-value=0.00085). CONCLUSIONS: We suggest that cold allodynia is based on hyper-excitability of very superficial skin nociceptors. The correlation between paroxysmal pain, allodynia to light touch and cold allodynia suggests that activity in those peripheral nociceptors can drive both, paroxysmal pain and spinal sensitization leading to stroke evoked allodynia. Mechanistically, the physical cold stimulus can unmask disease-related hyperexcitability by closure of temperature-sensitive potassium channels or induction of resurgent currents. Small fiber degeneration alone may not be the crucial mechanism in CRPS, nor explain pain.

Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice.

Efficacy of monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (calcitonin receptor-like receptor/receptor activity modifying protein-1, CLR/RAMP1) implicates peripherally-released CGRP in migraine pain. However, the site and mechanism of CGRP-evoked peripheral pain remain unclear. By cell-selective RAMP1 gene deletion, we reveal that CGRP released from mouse cutaneous trigeminal fibers targets CLR/RAMP1 on surrounding Schwann cells to evoke periorbital mechanical allodynia. CLR/RAMP1 activation in human and mouse Schwann cells generates long-lasting signals from endosomes that evoke cAMP-dependent formation of NO. NO, by gating Schwann cell transient receptor potential ankyrin 1 (TRPA1), releases ROS, which in a feed-forward manner sustain allodynia via nociceptor TRPA1. When encapsulated into nanoparticles that release cargo in acidified endosomes, a CLR/RAMP1 antagonist provides superior inhibition of CGRP signaling and allodynia in mice. Our data suggest that the CGRP-mediated neuronal/Schwann cell pathway mediates allodynia associated with neurogenic inflammation, contributing to the algesic action of CGRP in mice.