Ipsilateral and contralateral sensory changes in healthy subjects after experimentally induced concomitant sensitization and hypoesthesia.

BACKGROUND: In unilateral neuropathic pain. e.g. after peripheral nerve injury, both positive and negative sensory signs occur often, accompanied by minor but equally directed contralateral sensory changes. To mimic this feature, we experimentally aimed to induce concomitant c-fibre sensitization and block in healthy subjects and analyzed the bilateral sensory changes by quantitative sensory testing (QST) using the protocol of the German Research Network on Neuropathic Pain. METHODS: Twenty eight healthy subjects were firstly randomized in 2 groups to receive either topical capsaicin (0.6%, 12 cm2, application duration: 15 min.) or a lidocaine/prilocaine patch (25/25 mg, 10 cm2, application duration: 60 min.) on the right volar forearm. Secondly, 7-14 days later in the same area either at first capsaicin (for 15 min.) and immediately afterwards local anesthetics (for 60 min.) was applied (Cap/LA), or in inversed order with the same application duration (LA/Cap). Before, after each application and 7-14 days later a QST was performed bilaterally. STATISTICS: Wilcoxon-test, ANOVA, p < 0.05. RESULTS: Single application of 0,6% capsaicin induced thermal hypoesthesia, cold hypoalgesia, heat hyperalgesia and tactile allodynia. Lidocaine/prilocaine alone induced thermal and tactile hypoesthesia as well as mechanical and cold hypoalgesia, and a heat hyperalgesia (to a smaller extent). Ipsilaterally both co-applications induced a combination of the above mentioned changes. Significant contralateral sensory changes occurred only after the co-application with concomitant sensitization and hypoesthesia and comprised increased cold (Cap/LA, LA/Cap) and mechanical detection as well as cold pain threshold (LA/Cap). CONCLUSION: The present experimental model using combined application of capsaicin and LA imitates partly the complex sensory changes observed in patients with unilateral neuropathic pain and might be used as an additional surrogate model. Only the concomitant use both agents in the same area induces both positive and negative sensory signs ipsilaterally as well as parallel contralateral sensory changes (to a lesser extent). TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01540877 , registered on 23 February 2012.

Changes of the Sensory Abnormalities and Cortical Excitability in Patients with Complex Regional Pain Syndrome of the Upper Extremity After 6 Months of Multimodal Treatment.

Objective: The most prominent sensory sign of the complex regional pain syndrome (CRPS) is blunt hyperalgesia, but longitudinal studies on its relation to the outcome of long-term multimodal treatment are lacking. Methods: We examined 24 patients with CRPS type I using standardized Quantitative Sensory Testing on the affected hand and the contralateral hand at baseline and 6 months following treatment. Somatosensory evoked potentials after single and paired-pulse stimulation of the median nerve were performed to assess the paired-pulse suppression (n = 19). Treatment response at follow-up was defined as pain relief > 30% and improved hand function. Statistics: Wilcoxon test, Pearson correlation. Results: At baseline, similar to previous studies, the pressure pain threshold (PPT) was significantly decreased and the pain response to repeated pinprick stimuli was significantly increased, while all detection thresholds were within the normal range without any difference between the later treatment responders and non-responders. After 6 months of treatment, the PPT increased significantly in the whole study group. However, the pressure hyperalgesia improved only in treatment responders (n = 17, P < 0.05), whereas there was no improvement in non-responders (n = 7). The rest of the sensory profile remained nearly unchanged. There was a correlation between the paired-pulse suppression and the PPT only at follow-up (r = 0.49, P < 0.05), but not at baseline, where low pressure pain threshold was associated with impaired paired-pulse suppression. Conclusion: Thus, the persistence of blunt hyperalgesia seems to be associated with impaired paired-pulse suppression, both representing maladaptive central nervous changes in CRPS, which may account for the treatment non-response in this subgroup.

Influence of (S)-ketamine on human motor cortex excitability.

Previous studies demonstrated a reduction of motor cortical excitability through pharmacological NMDA receptor blockage. Interestingly, subanesthetic doses of racemic ketamine, a non-competitive NMDA receptor antagonist, had no effects on intracortical excitability evoked by transcranial magnetic stimulation. In this study, we aimed to substantiate these findings by using the more active enantiomer (S)-ketamine. (S)-ketamine has a threefold higher affinity for the NMDA receptor, but relatively little is known about its specific effects on human motor cortex excitability. Eleven healthy subjects (two female) participated in a randomized, double-blind, placebo-controlled cross-over study with four treatment conditions: either placebo or one of three subanesthetic doses of intravenous (S)-ketamine (serum target 10, 30 and 50 ng/ml, respectively). We assessed intracortical inhibition and facilitation using a paired-pulse TMS-paradigm. Resting motor threshold and cortical silent period were assessed as additional parameters. Solely at highest (S)-ketamine concentrations, intracortical inhibition was significantly reduced and intracortical facilitation strongly tended to be enhanced. In addition, we found a tendency to a prolonged silent period, while resting motor threshold was unaffected. We conclude that subanesthetic doses of (S)-ketamine show an enhancement on excitability in human motor cortex. Similar to findings using the racemic mixture of ketamine, the effect may be due to an increase in non-NMDA glutamatergic transmission which outweighs the NMDA receptor blockade.

Neuropathic pain: is quantitative sensory testing helpful?

Neuropathic pain arises as a consequence of a lesion or disease affecting the somatosensory system and is characterised by a combination of positive and negative sensory symptoms. Quantitative sensory testing (QST) examines the sensory perception after application of different mechanical and thermal stimuli of controlled intensity and the function of both large (A-beta) and small (A-delta and C) nerve fibres, including the corresponding central pathways. QST can be used to determine detection, pain thresholds and stimulus-response curves and can thus detect both negative and positive sensory signs, the second ones not being assessed by other methods. Similarly to all other psychophysical tests QST requires standardised examination, instructions and data evaluation to receive valid and reliable results. Since normative data are available, QST can contribute also to the individual diagnosis of neuropathy, especially in the case of isolated small-fibre neuropathy, in contrast to the conventional electrophysiology which assesses only large myelinated fibres. For example, detection of early stages of subclinical neuropathy in symptomatic or asymptomatic patients with diabetes mellitus can be helpful to optimise treatment and identify diabetic foot at risk of ulceration. QST assessed the individual's sensory profile and thus can be valuable to evaluate the underlying pain mechanisms which occur in different frequencies even in the same neuropathic pain syndromes. Furthermore, assessing the exact sensory phenotype by QST might be useful in the future to identify responders to certain treatments in accordance to the underlying pain mechanisms.

The serotonin receptor 2A (HTR2A) rs6313 variant is associated with higher ongoing pain and signs of central sensitization in neuropathic pain patients.

BACKGROUND: The serotonin receptor 2A (HTR2A) has been described as an important facilitation mediator of spinal nociceptive processing leading to central sensitization (CS) in animal models of chronic pain. However, whether HTR2A single nucleotide variants (SNVs) modulate neuropathic pain states in patients has not been investigated so far. The aim of this study was to elucidate the potential association of HTR2A variants with sensory abnormalities or ongoing pain in neuropathic pain patients. METHODS: At total of 240 neuropathic pain patients and 253 healthy volunteers were included. Patients were phenotypically characterized using standardized quantitative sensory testing (QST). Patients and controls were genotyped for HTR2A g.-1438G > A (rs6311) and c.102C > T (rs6313). Genotype-related differences in QST parameters were assessed considering QST profile clusters, principal somatosensory components and sex. RESULTS: There was an equal distribution of rs6313 and linked rs6311 between patients and controls. However, the rs6313 variant was significantly associated with a principal component of pinprick hyperalgesia and dynamic mechanical allodynia, indicating enhanced CS in patients with sensory loss (-0.34 ± 0.15 vs. +0.31 ± 0.11 vs., p < .001). In this cluster, the variant allele was also associated with single QST parameters of pinprick hyperalgesia (MPT, +0.64 ± 0.18 vs. -0.34 ± 0.23 p = .002; MPS, +0.66 ± 0.17 vs. -0.09 ± 0.23, p = .009) and ongoing pain was increased by 30%. CONCLUSIONS: The specific association of the rs6313 variant with pinprick hyperalgesia and increased levels of ongoing pain suggests that the HTR2A receptor might be an important modulator in the development of CS in neuropathic pain. SIGNIFICANCE: This article presents new insights into serotonin receptor 2A-mediating mechanisms of central sensitization in neuropathic pain patients. The rs6313 variant allele was associated with increased mechanical pinprick sensitivity and increased levels of ongoing pain supporting a contribution of central sensitization in the genesis of ongoing pain providing a possible route for mechanism-based therapies.

Perineural injection of botulinum toxin-A in painful peripheral nerve injury - a case series: pain relief, safety, sensory profile and sample size recommendation.

Objectives: Subcutaneous injection of botulinum toxin-A (sBONT-A) is a novel treatment for peripheral neuropathic pain. While its analgesic effects are well documented, this treatment is often not comfortable and fails in patients who show signs of sensory loss but rarely allodynia. There are some case reports about perineural BONT-A injection (pBONT-A) which could be an alternative approach. Here we present a retrospective, open label case series of pBONT-A's efficacy and safety regarding neurological consequences involving changes in somatosensory profiles of both responders and non-responders. Methods: Sixty patients (53 ± 13years, 77% males) with PNI were treated with pBONT-A after a test injection with a local anesthetic, which prompted distinctive pain relief. Quantitative sensory testing (QST; DFNS protocol) and pain intensity were assessed before and ≥7 days post pBONT-A injection. Definition of response: satisfactory pain reduction of ≥30% NRS (numerical rating scale: 0 = no pain, 10 = worst pain) for ≥4 days. Statistics: Paired t-test, Mann-Whitney U-test, χ2 test. Results: A temporary weak paresis in one case was clinically verified. The QST -parameters remained unchanged, but patients with more frequent hyperalgesia signs reported less analgesia (p = .04). The pBONT-A injection prompted pain relief by 24.8% (NRS: 6.0 ± 1.7 vs. 4.5 ± 2.1; p < .0001); 57% (n = 34) were responders (NRS: 6.0 ± 1.6 vs. 3.4 ± 1.6, relief of 43.4%; p < .0001). Based on these results, we suggest that future parallel design trials on pBONT-A need to include at least 84 patients. Discussion: Ultrasound-guided pBONT-A injection seems to be a safe treatment leading to a sufficient pain relief for some months without sensory changes. Surprisingly, pBONT-A showed a pronounced analgesic effect also in patients without signs of hyperalgesia.

Technical and clinical performance of the thermo-test device "Q-Sense" to assess small fibre function: A head-to-head comparison with the "Thermal Sensory Analyzer" TSA in diabetic patients and healthy volunteers.

BACKGROUND: Thermo-test devices are rarely used outside specialized pain centres because of high acquisition costs. Recently, a new, portable device ("Q-Sense") was introduced, which is less expensive but has reduced cooling capacity (20°C). We assessed the reliability/validity of the "Q-Sense" by comparing it with the Thermal Sensory Analyzer (TSA). METHODS: Using a phantom-skin model, the physical characteristics of both devices were compared. The clinical performance was assessed in a multicentre study by performing Quantitative Sensory Testing (QST) in 121 healthy volunteers and 83 diabetic patients (Eudra-Med-No. CIV-12-05-006501). RESULTS: Both device types showed ~40% slower temperature ramps for heating/cooling than nominal data. Cold/warm detection thresholds (CDT, WDT) and heat pain thresholds (HPT) of healthy subjects did not differ between device types. Cold pain thresholds (CPT) were biased for Q-Sense by a floor effect (p < .001). According to intraclass correlation coefficients (ICC), agreement between TSA and Q-Sense was good/excellent for CDT (ICC = 0.894) and WDT (ICC = 0.898), moderate for HPT (ICC = 0.525) and poor for CPT (ICC = 0.305). In diabetic patients, the sensitivity of Q-Sense to detect cold hypoesthesia was reduced in males >60 years. Moderate correlations between thermal detection thresholds and morphological data from skin biopsies (n = 51) were similar for both devices. CONCLUSIONS: Physical characteristics of both thermo-test devices are similarly limited by the poor temperature conduction of the skin. The Q-Sense is useful for thermal detection thresholds but of limited use for pain thresholds. For full clinical use, the lower cut-off temperature should be set to ≤18°C. SIGNIFICANCE: High purchase costs prevent a widespread use of thermo-test devices for diagnosing small fibre neuropathy. The air-cooled "Q-Sense" could be a lower cost alternative, but its technical/clinical performance needs to be assessed because of its restricted cut-off for cooling (20°C). This study provides critical information on the physical characteristics and the clinical validity/reliability of the Q-Sense compared to the "Thermal Sensory Analyzer" (TSA). We recommend lowering the cut-off value of the Q-Sense to ≤18°C for its full clinical use.

[Inventories of the Earth. Mineral resource appraisals and the rise of resource economics]. / Inventuren der Erde. Vorratsschätzungen für mineralische Rohstoffe und die Etablierung der Ressourcenökonomie.

How do the earth sciences mediate between the natural and social world? This paper explores the question by focusing on the history of nonfuel mineral resource appraisal from the late nineteenth to the mid twentieth century. It argues that earth sciences early on embraced social scientific knowledge, i.e. economic knowledge, in particular, when it came to determining or deposits and estimating the magnitude of mineral reserves. After 1900, assessing national and global mineral reserves and their "life span" or years of supply became ever more important, scaling up and complementing traditional appraisal practices on the level of individual mines or mining and trading companies. As a consequence, economic methods gained new weight for mineral resource estimation. Natural resource economics as an own field of research grew out of these efforts. By way of example, the mineral resource appraisal assigned to the U.S. Materials Policy Commission by President Harry S. Truman in 1951 is analyzed in more detail. Natural resource economics and environmental economics might be interpreted as a strategy to bring down the vast and holistically conceived object of geological and ecological research, the earth, to human scale, and assimilate it into social matters.

Comparison of muscle and joint pressure-pain thresholds in patients with complex regional pain syndrome and upper limb pain of other origin.

Pain localized in the deep tissues occurs frequently in complex regional pain syndrome (CRPS). In addition, hyperalgesia to blunt pressure over muscles is common in CRPS, but it often appears in limb pain of other origin as well. Considering that 3-phase bone scintigraphy (TPBS) reveals periarticular enhanced bone metabolism in CRPS, joint-associated hyperalgesia to blunt pressure might be a more specific finding than hyperalgesia over muscles. In 34 patients with upper limb pain (18 CRPS, 16 non-CRPS; diagnosed in accordance to the Budapest criteria) and in 18 healthy controls, pressure-pain thresholds (PPT) were assessed bilaterally over the thenar (PPTThenar), the metacarpophalangeal (PPTMCP), and the proximal interphalangeal (PPTPIP) joints using a pressure algometer (Somedic, Sweden). Beforehand, all patients had received TPBS for diagnostic purposes independently of the study. Region-of-interest (ROI) ratios (mineralization phase) for the MCP and PIP, excluding fracture sites, were correlated with the PPT. In CRPS, all ROI ratios were significantly increased and all PPT of the affected hand were decreased compared to non-CRPS (PPTThenar: 243±150kPa vs 358±197kPa, PPTMCP: 80±67kPa vs 159±93kPa, PPTPIP: 80±56kPa vs 184±110kPa; P<.01) and controls (PPTThenar: 478±106kPa, PPTMCP: 254±50kPa, PPTPIP: 275±76kPa; P<.01). A PPTThenar below 293kPa revealed 77% sensitivity but only 63% specificity, whereas a PPTPIP below 102kPa had 82% sensitivity and 94% specificity to identify CRPS. Only in CRPS were PPTMCP and PPTPIP correlated significantly inversely with the ROI ratio (MCP: r=-0.439, PIP: r=-0.447). PPTPIP shows higher specificity for CRPS type I than PPTThenar without loss of sensitivity. Therefore, measurement of joint PPT could be a noninvasive diagnostic tool reflecting increased bone metabolism assessed by TPBS as a sign of bone pathophysiology.

Lidocaine patch (5%) produces a selective, but incomplete block of Aδ and C fibers.

Topical lidocaine (5%) leads to sufficient pain relief in only 29%-80% of treated patients, presumably by small-fiber block. The reasons for nonresponse are unclear; it may be due to different underlying pain mechanisms or partly insufficient anesthetic effect. Using quantitative sensory testing (QST) following the protocol of the DFNS (German Research Network on Neuropathic Pain), this study aims to assess the type and extent of somatosensory changes after lidocaine application in healthy volunteers. Twenty-six healthy volunteers underwent QST on the volar forearm, including thermal and mechanical detection and pain thresholds, twice before (for baseline retest reliability) and once after 6-hour simultaneous application with lidocaine patch 5% and contralateral placebo in a double-blinded manner. Pre and post differences of QST parameters were analyzed by paired t-test (Bonferroni-corrected alpha 0.0023). QST profiles did not change between the 2 baseline measurements and after the placebo application. Lidocaine application led to a significant change of only the small-fiber-associated thresholds (increase of thermal detection and mechanical pain thresholds, decrease of mechanical pain sensitivity). Tactile detection thresholds representing Aß function remained unchanged. Interindividually, the extent of the small-fiber block varied widely (eg, thermal detection thresholds: in 54% of the subjects there were only minimal changes; in only 8% were there changes of >60% of the maximal achievable value). Topical lidocaine (5%) induces thermal hypoesthesia and pinprick hypoalgesia, suggesting an isolated but only partial block of Aδ and C fibers of unpredictable extent. Further studies must analyze the influencing factors and determine whether patients with poor analgesic effect, in particular, are those with insufficient small-fiber block.

Different underlying pain mechanisms despite identical pain characteristics: a case report of a patient with spinal cord injury.

Pain following spinal cord injury has been classified as nociceptive (musculoskeletal, visceral) or neuropathic (above, at, below level). There is no clear relation between the etiology and reported symptoms. Thus, due to different underlying mechanisms, the treatment is often ineffective. We report on a patient with spinal cord injury with neurological level of injury at T8 suffering from bilateral burning and prickling pain in the T9-11 dermatomes bilaterally (at-level pain), as well as diffusely in both legs from below the torso (below-level pain), accompanied by musculoskeletal low back pain. Bilateral comparison of quantitative sensory testing (QST) and skin biopsy revealed completely different findings in the dermatome T9 despite identical at-level pain characteristics. On the right side, QST revealed a normal sensory profile; the intraepidermal nerve fiber density (IENFD) was reduced, but not as severe as the contralateral side. On the left side there was a severe sensory loss with a stronger reduction of the IENDF, similar to the areas below the neurological level. These findings were significantly related to the treatment results. Pregabalin induced unilateral pain relief only in the area with remaining sensory function, whereas the left-sided at-level pain was unchanged. Thus, 2 different underlying mechanisms leading to bilaterally neuropathic pain with identical symptoms and with different treatment success were demonstrated in a single patient. The at-level pain in areas with remaining sensory function despite IENFD reduction could be relieved by pregabalin. Thus, in an individual case, QST may be helpful to better understand pain-generating mechanisms and to initiate successful treatment.

Sensory signs in complex regional pain syndrome and peripheral nerve injury.

This study determined patterns of sensory signs in complex regional pain syndrome (CRPS) type I and II and peripheral nerve injury (PNI). Patients with upper-limb CRPS-I (n=298), CRPS-II (n=46), and PNI (n=72) were examined with quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain. The majority of patients (66%-69%) exhibited a combination of sensory loss and gain. Patients with CRPS-I had more sensory gain (heat and pressure pain) and less sensory loss than patients with PNI (thermal and mechanical detection, hypoalgesia to heat or pinprick). CRPS-II patients shared features of CRPS-I and PNI. CRPS-I and CRPS-II had almost identical somatosensory profiles, with the exception of a stronger loss of mechanical detection in CRPS-II. In CRPS-I and -II, cold hyperalgesia/allodynia (28%-31%) and dynamic mechanical allodynia (24%-28%) were less frequent than heat or pressure hyperalgesia (36%-44%, 67%-73%), and mechanical hypoesthesia (31%-55%) was more frequent than thermal hypoesthesia (30%-44%). About 82% of PNI patients had at least one type of sensory gain. QST demonstrates more sensory loss in CRPS-I than hitherto considered, suggesting either minimal nerve injury or central inhibition. Sensory profiles suggest that CRPS-I and CRPS-II may represent one disease continuum. However, in contrast to recent suggestions, small fiber deficits were less frequent than large fiber deficits. Sensory gain is highly prevalent in PNI, indicating a better similarity of animal models to human patients than previously thought. These sensory profiles should help prioritize approaches for translation between animal and human research.

Are sympathetic blocks useful for diagnostic purposes?

BACKGROUND: Sympathetically maintained pain (SMP) can occur in patients with neuropathic pain. Sympathetically maintained pain is frequently diagnosed clinically by assessing the analgesic effect of an appropriate sympathetic block (SB). The diagnostic value of such blocks depends on both the degree of sympathetic activity disruption achieved and its duration without unintentional concomitant sensory block. METHODS: This pilot study evaluated the rate of diagnostically valuable SBs performed by experienced anesthesiologists in 19 patients (stellate/thoracic blocks: n = 11, lumbar blocks: n = 12). Monitoring included pain rating before SB; 10 and 30 minutes; and at 1, 3, and 6 hours after SB; bilateral skin temperature 30 minutes before SB through 120 minutes after SB; and detection of bilateral thresholds for cold, warmth, tactile, and vibration stimuli before and after. RESULTS: Ten (43%) of 23 SBs were not eligible for SMP diagnosis (4 had insufficient skin temperature increase; and 6 had cold or tactile detection threshold increases in the painful area). In 11 of the SBs, no significant sensory threshold change was detected; however, 2 individuals demonstrated marked reductions in the cold or tactile sensory thresholds. Sympathetically maintained pain was diagnosed in 3 (25%) of the 12 patients who had at least 1 SB with the required skin temperature increase without concomitant somatosensory block. CONCLUSIONS: Sympathetic blocks are useful in the diagnosis of SMP. However, their value is limited by the potential for false positives (unintentional sensory block) or false negatives (insufficient SB). Adequate monitoring of the sympathetic and somatosensory function for a minimum of 90 minutes after the intervention is essential to ensure that a valid diagnosis of SMP is made.

Pain-associated mild sensory deficits without hyperalgesia in chronic non-neuropathic pain.

OBJECTIVES: A mixture of sensory loss and gain is a hallmark of neuropathic pain. But hypesthesia and hyperalgesia also occur with experimentally induced acute pain. Here, we assessed sensory profiles in chronic non-neuropathic pain (osteoarthritis, OA) using the quantitative sensory testing (QST) protocol of the German Research Network on Neuropathic Pain (DFNS). METHODS: Twenty individuals with OA [mean pain intensity on the numerical rating scale (NRS, 0-10): 5.6±1.5] were tested on the painful and contralateral hand and compared with 20 healthy volunteers matched for age, sex, and handedness. RESULTS: In the OA group, analysis of variance revealed increased detection thresholds to tactile stimuli bilaterally and to thermal stimuli restricted to the more painful hand (all P<0.05). Pin-prick hypoalgesia was present restricted to the patients' more affected hand. Neither hyperalgesia nor allodynia was found. QST parameters were correlated with average pain intensity (r between 0.48 and 0.51). CONCLUSIONS: These results suggest that chronic non-neuropathic pain may induce slight sensory impairment for large fiber function (bilateral) and small fiber function (ipsilateral). However, all changes are within the normal range, in contrast to patients with neuropathy. Inhibition of central pathways by nociceptive input and altered sensory processing due to disuse of the hand are possible mechanisms. These functional sensory alterations do not interfere with the diagnosis of neuropathy.

Association between wind-up ratio and central serotonergic function in healthy subjects and depressed patients.

Temporal summation of C-fiber evoked responses generates an increase in action potential discharge in second-order neurons and in perceived pain intensity (wind-up). This may be related to the central serotonergic system which modulates and partly inhibits sensory input. Aim of the study was to investigate the relationship between wind-up and serotonergic activity using loudness dependence of auditory evoked potentials (LDAEP). 18 healthy subjects were compared to 18 patients with major depression, a disease with a putative serotonin deficit. They were examined with quantitative sensory testing (QST) using the protocol of the German Research Network on Neuropathic Pain (DFNS), including the wind-up ratio (WUR), LDAEP, and psychometric measurements. We found a slight positive correlation between WUR and LDAEP both in healthy controls and depressed patients combined (r=0.340, p=0.043), indicating that WUR may be modulated by serotonergic activity. It can be concluded that inhibitory control to noxious stimuli is partly associated with the central serotonergic function as indicated by LDAEP.