[Show abstract][Hide abstract] ABSTRACT: Within the last decade understanding of the mechanistic basis of itch has improved significantly, resulting in the development of several human surrogate models of itch and related dysesthetic states. Well-characterized somatosensory models are useful in basic studies in healthy volunteers, in clinical studies for diagnostic and segmentation purposes, and in pharmacological studies to evaluate the antipruritic efficacy of existing and novel compounds. This review outlines recently introduced histamine-independent human models of itch, their mechanisms, their ability to induce clinically relevant phenomena, such as alloknesis, and the results obtained through their use. The article also introduces recent advances in the understanding of itch and provides an overview of the methods to assess experimentally-induced itch and associated manifestations. Major improvements are warranted in the treatment of chronic pruritus, and reliable human surrogate models are a valuable tool in achieving them, both for basic researchers and for clinicians.
[Show abstract][Hide abstract] ABSTRACT: Cuff pressure stimulation is applicable for assessing deep-tissue pain sensitivity by exciting a variety of deep-tissue nociceptors. In this study, the relative transfer of biomechanical stresses and strains from the cuff via the skin to the muscle and the somatic tissue layers around bones were investigated. Cuff pressure was applied on the lower leg at three different stimulation intensities (mild pressure to pain). Three-dimensional finite element models including bones and three different layers of deep tissues were developed based on magnetic resonance images (MRI). The skin indentation maps at mild pressure, pain threshold, and intense painful stimulations were extracted from MRI and applied to the model. The mean stress under the cuff position around tibia was 4.6, 4.9 and around fibula 14.8, 16.4 times greater than mean stress of muscle surface in the same section at pain threshold and intense painful stimulations, respectively. At the same stimulation intensities, the mean strains around tibia were 36.4, 42.3 % and around fibula 32.9, 35.0 %, respectively, of mean strain on the muscle surface. Assuming strain as the ideal stimulus for nociceptors the results suggest that cuff algometry is less capable to challenge the nociceptors of tissues around bones as compared to more superficially located muscles.
Medical & Biological Engineering 04/2015; DOI:10.1007/s11517-015-1291-x · 1.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We tested the hypothesis that pressure sensitivity of the sternum (PPS) is associated with autonomic nervous system (ANS) function as assessed by tilt table test (TTT). in patients with stable ischemic heart disease.
(1) To evaluate an association between PPS and systolic blood pressure (SBP) and heart rate (HR) responses to TTT; and (2) to test the hypothesis that a reduction of resting PPS raises the PPS, SBP and HR responses to TTT response and lowers risk factors for ANS dysfunction (ANSD).
Cross-sectional study: In 361 patients with stable ischemic heart disease we measured PPS, SBP, and HR during TTT. Intervention study: We reassessed subjects with persistent stress who concluded a stress intervention trial by a second TTT.
Cross-sectional study: Resting PPS and the PPS response to TTT were correlated (r = - 0.37). The PPS response to TTT was correlated with that of SBP (r = 0.44) and HR (r = 0.49), and with the number of risk factors for ANSD (r = - 0.21) (all p < 0.0001). Intervention study: A reduction in resting PPS was associated with an increment in PPS response to TTT (r = - 0.52, p < 0.0001). The greater this increment, the greater was the reduction in ANSD risk factors (r = - 0.23; p = 0.003).
The results are consistent with the hypothesis that PPS at rest and in response to TTT reflects ANS function.
Scandinavian journal of clinical and laboratory investigation 04/2015; 75(5):1-10. DOI:10.3109/00365513.2015.1028095 · 2.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The thermoreceptive transient receptor potential ankyrin 1 (TRPA1) is important in the transmission of itch, and its agonist trans-cinnamaldehyde has occasionally been reported to be a pruritogen in humans. However, no studies have accurately quantified the capabilities of trans-cinnamaldehyde to induce itch and related dysesthetic sensations. The present study examined alterations in somatosensory and vasomotor parameters in response to topical trans-cinnamaldehyde 5% and vehicle (ethanol) in 24 healthy subjects. During the study the following parameters were recorded: itch area and intensity, hyperknesis, alloknesis, neurogenic flare, skin blood flow and temperature. Trans-cinnamaldehyde evoked moderate itch sensation, flare, hyperknesis and alloknesis (p < 0.001). Blood flow and skin temperature were elevated in the area of trans-cinnamaldehyde application (p < 0.001). Significant positive correlations were found between blood flow and skin temperature, itch area and blood flow, and itch area and skin temperature. Topical trans-cinnamaldehyde proved feasible as a human itch model with applicability in studying itch mechanisms or anti-pruritic drug profiling.
[Show abstract][Hide abstract] ABSTRACT: Topical high-concentration L-menthol is the only established human experimental pain model to study mechanisms underlying cold hyperalgesia. We aimed at investigating the combinatorial effect of cold stimuli and topical L-menthol on cold pain and secondary mechanical hyperalgesia. Analogue to the heat-capsaicin model on skin sensitization, we proposed that a cold/menthol enhances or prolong L-menthol-evoked sensitization. Topical 40% L-menthol or vehicle was applied (20 min) on the volar forearms of 20 healthy females and males (28.7±0.6 years). Cold stimulation of 5°C for 5 min was then applied to the treated area 3 times with 40 min intervals. Cold detection threshold and pain, mechanical hyperalgesia (pin prick), static and dynamic mechanical allodynia (von Frey and brush), skin blood flow (laser speckle), and temperature (thermo-camera) were assessed. Cold detection threshold and cold pain threshold increased post L-menthol and remained high following the cold rekindling cycles (P<0.001). L-menthol evoked secondary hyperalgesia to pin prick (P<0.001) particularly in females (P<0.05) and also induced secondary allodynia to von Frey and brush (P<0.001). Application of cold stimuli kept these areas enlarged with higher response in females to brush after the 3rd cold cycle (P<0.05). Skin blood flow increased post L-menthol (P<0.001) and stayed stable after cold cycles. Repeated application of cold on skin treated by L-menthol facilitated and prolonged L-menthol-induced cold pain and hyperalgesia. This model may prove beneficial for testing analgesic compounds when a sufficient duration of time is needed to see drugs' effects on cold pain threshold or mechanical hypersensitivity.
[Show abstract][Hide abstract] ABSTRACT: Background
In a cohort of well-characterized patients with different degrees of knee osteoarthritis (OA) and pain, the aims were to utilize mechanism-based quantitative sensory testing (QST) to (1) characterize subgroups of patients; (2) analyse the associations between clinical characteristics and QST; and (3) develop and apply a QST-based knee OA composite pain sensitivity index for patient classification.Methods
Two hundred seventeen OA pain patients and 64 controls were included. Kellgren and Lawrence (KL) grading scores were obtained, and pressure pain thresholds (PPTs), temporal summation of pain to repeated painful pressure stimulation and conditioning pain modulation (CPM) were assessed. Associations between pain score/area/duration, radiological findings and QST-related parameters were analysed. A pain sensitivity index was developed and applied based on PPT, temporal summation and CPM. z-Score, as statistical tool, was calculated for statistically comparing the pain index of a single patient with a healthy control group.ResultsHigh knee pain associated with low KL grade showed particular signs of pain sensitization. Patients showed significant associations between clinical knee pain intensity/duration and lowering of knee PPTs (p < 0.01), facilitation of temporal summation (p < 0.01), reduction of CPM function (p < 0.01) and high pain sensitivity index (p < 0.01). The index classified 27–38% of the OA patients and 3% of the controls as highly sensitive with no association to KL. The index increased for high knee pain intensities and long pain duration.Conclusions
Radiological scores, contrary to clinical pain intensity/duration, were poorly associated with QST parameters. The pain sensitivity index could classify OA patients with different degrees of OA and pain.
European journal of pain (London, England) 01/2015; DOI:10.1002/ejp.651 · 3.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Biochemical and pain biomarkers can be applied to patients with painful osteoarthritis profiles and may provide more details compared with conventional clinical tools. The aim of this study was to identify an optimal combination of biochemical and pain biomarkers for classification of patients with different degrees of knee pain and joint damage. Such profiling may provide new diagnostic and therapeutic options. A total of 216 patients with different degrees of knee pain (maximal pain during the last 24 hours rated on a visual analog scale [VAS]) (VAS 0-100) and 64 controls (VAS 0-9) were recruited. Patients were separated into 3 groups: VAS 10 to 39 (N = 81), VAS 40 to 69 (N = 70), and VAS 70 to 100 (N = 65). Pressure pain thresholds, temporal summation to pressure stimuli, and conditioning pain modulation were measured from the peripatellar and extrasegmental sites. Biochemical markers indicative for autoinflammation and immunity (VICM, CRP, and CRPM), synovial inflammation (CIIIM), cartilage loss (CIIM), and bone degradation (CIM) were analyzed. WOMAC, Lequesne, and pain catastrophizing scores were collected. Principal component analysis was applied to select the optimal variable subset, and cluster analysis was applied to this subset to create distinctly different knee pain profiles. Four distinct knee pain profiles were identified: profile A (N = 27), profile B (N = 59), profile C (N = 85), and profile D (N = 41). Each knee pain profile had a unique combination of biochemical markers, pain biomarkers, physical impairments, and psychological factors that may provide the basis for mechanism-based diagnosis, individualized treatment, and selection of patients for clinical trials evaluating analgesic compounds. These results introduce a new profiling for knee OA and should be regarded as preliminary.
[Show abstract][Hide abstract] ABSTRACT: It is unknown why an acute pain condition under various circumstances can transition into a chronic pain condition.There has been a shift towards neuroinflammation and hence glial cell activations specifically in the dorsal root ganglion and spinal cord as a mechanism possibly driving the transition to chronic pain. This has led to a focus on non-neuronal cells in the peripheral and central nervous system. Besides infiltrating macrophages, Schwann cells and satellite glial cells release cytokines and therefore important mechanisms in the maintenance of pain. Activated Schwann cells, satellite glial cells, microglia, and astrocytes may contribute to pain sensitivity by releasing cytokines leading to altered neuronal function in the direction of sensitisation.Aims of this perspective paper1) Highlight the complex but important recent achievement in the area of neuroinflammation and pain at spinal cord level and in the dorsal root ganglion.2) Encourage further research which hopefully may provide better understanding of new key elements driving the transition from acute to chronic pain.Recent results in the area of neuroinflammation and painFollowing a sciatic nerve injury, local macrophages, and Schwann cells trigger an immune response immediately followed by recruitment of blood-derived immune cells. Schwann cells, active resident, and infiltrating macrophages release proinflammatory cytokines. Proinflammatory cytokines contribute to axonal damage and also stimulate spontaneous nociceptor activity. This results in activation of satellite glial cells leading to an immune response in the dorsal root ganglia driven by macrophages, lymphocytes and satellite cells. The anterograde signalling progresses centrally to activate spinal microglia with possible upregulation of glial-derived proinflammatory/pronociceptive mediators.An important aspect is extrasegmental spreading sensitisation where bilateral elevations in TNF-α, IL-6, and IL-10 are found in dorsal root ganglion in neuropathic models. Similarly in inflammatory pain models, bilateral up regulation occurs for TNF-α, IL-1β, and p38 MAPK. Bilateral alterations in cytokine levels in the DRG and spinal cord may underlie the spread of pain to the uninjured side.An important aspect is how the opioids may interact with immune cells as opioid receptors are expressed by peripheral immune cells and thus can induce immune signaling changes. Furthermore, opioids may stimulate microglia cells to produce proinflammatory cytokines such as IL-1.Conclusions
The present perspective paper indicates that neuroinflammation and the associated release of pro-inflammatory cytokines in dorsal root ganglion and at the spinal cord contribute to the transition from acute to chronic pain. Neuroinflammatory changes have not only been identified in the spinal cord and brainstem, but more recently, in the sensory ganglia and in the nerves as well. The glial cell activation may be responsible for contralateral spreading and possible widespread sensitisation.ImplicationsCommunication between glia and neurons is proposed to be a critical component of neuroinflammatory changes that may lead to chronic pain. Sensory ganglia neurons are surrounded by satellite glial cells but how communication between the cells contributes to altered pain sensitivity is still unknown. Better understanding may lead to new possibilities for (1) preventing development of chronic pain and (2) better pain management.
Scandinavian Journal of Pain 11/2014; 6. DOI:10.1016/j.sjpain.2014.10.002
[Show abstract][Hide abstract] ABSTRACT: Objectives: This study focused on the biomechanical implications of knee osteoarthritis (OA) and the association with pain. The plantar loading force distribution of the foot was determined and correlated to degenerative knee changes, function, pain intensity, and pain sensitization.
Method: Knee OA patients (n = 34) with moderate and mild knee pain were characterized and compared to matched controls (n = 16). The Plantar Foot Posture Index (FPI) and mean maximum plantar forces were determined by pressure-sensitive insoles. Pain intensity and function were assessed by the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the Brief Pain Inventory (BPI). Local knee pain sensitization was assessed by pressure pain thresholds (PPTs) from eight knee locations. Spreading sensitization was assessed by PPTs from two extra-segmental test sites. Temporal summation to repeated pressure stimulation (knee and extra-segmental stimulation) and conditioning pain modulation (CPM) were assessed, representing central pain mechanisms.
Results: The maximum force (MF) applied by the medial forefoot correlated to knee PPTs (r = 0.524, p < 0.001), CPM potency (r = 0.532, p < 0.001), and BPI (r = –0.325, p < 0.05) and WOMAC scores (pain r = –0.425, p < 0.01; stiffness r = –0.386, p < 0.01; function r = –0.378, p < 0.05). The MF applied by the medial hindfoot correlated negatively to scores on the FPI (r = –0.394, p < 0.01) and the Kellgren–Lawrence (K-L) grading scale (r = –0.330, p < 0.05). The MF applied by the medial forefoot correlated to extra-segmental PPTs (r = 0.554, p < 0.001) and the potency of CPM (r = 0.561, p < 0.0001). The MF applied by the lateral hindfoot correlated negatively to the PPT assessed extra-segmentally (r = –0.367, p < 0.05) and positively to CPM potency (r = 0.322, p < 0.05).
Conclusions: This study shows that mean maximum plantar foot force distribution in patients with painful knee OA is associated with specific pain mechanisms, function, radiological findings, and pain intensity.
[Show abstract][Hide abstract] ABSTRACT: Activation of TRPM8 and TRPA1 receptors generates cold and cold pain sensations, respectively, and is presumably important in clinical pain manifestations, such as cold hyperalgesia. This study investigated the interaction between TRPM8 and TRPA1 receptors through stimulation of glabrous human skin (volar forearm) by topical administration of 40% L-menthol and 10% trans-cinnamaldehyde (CA), individually and in combination.
Sensory manifestations were assessed in 10 healthy volunteers via a platform of 11 quantitative sensory (thermal and mechanical stimuli) and vasomotor tests (skin temperature, perfusion and axon-reflex-flare) in a double-blinded randomized crossover design.
Cold pain threshold was increased (p < 0.01, cold allodynia) by L-menthol alone and L-menthol + CA in combination but unaffected by CA. Mechanical pain threshold was significantly decreased (mechanical hyperalgesia) by all three substances (p < 0.01), with a significant intergroup difference found between CA alone and the less decreased L-menthol + CA (p < 0.05). Application of CA alone and L-menthol + CA in combination showed an increase in skin temperature and perfusion significantly larger than that induced by L-menthol alone (p < 0.05). An axon-reflex-flare was present after CA administration, but was significantly reduced upon addition of L-menthol (p < 0.01).
This study elucidates the potential of L-menthol as a counter-irritant to secondary neurogenic inflammation and provides evidence of an intricate interplay between cold receptors TRPA1 and TRPM8, warranting further investigation of the neural coding of cold pain perception.
European journal of pain (London, England) 10/2014; 18(9). DOI:10.1002/j.1532-2149.2014.494.x · 3.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Osteoarthritis (OA) is the most common degenerative joint disease, of which the pathogenesis is inadequately understood. Hypertrophy-like changes have been observed as part of the progression of OA. The aim of the study was to develop and characterize a novel biomarker of chondrocytes hypertrophy and investigate how this marker was associated with cartilage degradation and inflammation in patients with various degrees of OA.
A competitive ELISA, C-Col10, applying a well-characterized monoclonal antibody was developed as a biomarker of chondrocyte hypertrophy through measurement of type X collagen (ColX). The levels of C-Col10, C2M (matrix metalloproteinase-derived fragments of type II collagen) and hsCRP (high sensitive C-reactive protein) were quantified by ELISAs in serum of 271 OA patients stratified by Kellgren-Lawrence (KL) score 0–4. Associations between serum levels of the three biomarkers (log transformed) were analyzed by Pearson’s correlation and differences in C-Col10 levels between patients with high and low levels of inflammation measured by hsCRP were analyzed by ANOVA.
We developed a C-Col10 assay measuring the C-terminus of ColX. We found significantly higher levels of ColX in patients with KL score 2 compared to patients with no radiographic evidence of OA (KL0) (p = 0.04). Levels of ColX were significantly elevated in OA patients with above normal hsCRP levels (p < 0.0001), as well as significantly correlated with levels of C2M (r = 0.55, p < 0.0001), which suggested that chondrocyte hypertrophy was associated with inflammation and cartilage degradation. There was no correlation between C2M and hsCRP. Age and BMI adjustment didn’t change the results. Immuno-staining revealed that ColX was predominately located around the hypertrophic chondrocytes and the clustered chondrocytes indicating that C-Col10 measures may be linked to cartilage hypertrophic changes.
We developed a novel assay, C-Col10, for measurement of chondrocyte hypertrophy and found its levels significantly elevated in OA patients with KL score of 2, and also in OA patients with above normal hsCRP levels. Concentration of C-Col10 strongly correlated with levels of C2M, a marker of cartilage destruction. The data suggest that chondrocyte hypertrophy and subsequent collagen X fragmentation seem to be increased in a subset of patients with inflammatory OA.
[Show abstract][Hide abstract] ABSTRACT: Chronic itch is an annoying and disabling symptom that severely affects patients' quality of life in several dermatological as well as non-dermatological disorders. Chronic itch may be maintained and even aggravated by sensitization of peripheral and central neuronal structures. The possibilities to effectively relieve chronic itch are often limited and the need of more specific, effective and quick-acting treatment options is huge. This review summarizes the fundamental aspects of itch, the neuronal transmission and modulation of itch, and discusses new treatment opportunities.
[Show abstract][Hide abstract] ABSTRACT: Around 20% of patients with osteoarthritis (OA) have chronic post-operative pain after total knee arthroplasty (TKA) and often undergo revision surgery with unfavourable pain outcome. This study compared sensitization in pain patients with knee OA and after revision TKA (re-TKA).
Median pressure pain thresholds (PPTs) assessed from the most affected knee (localized sensitization) were used to subgroup 53 patients with OA pain and 20 patients with pain after re-TKA: group 1: OA and high-knee PPT; group 2: OA and low-knee PPT; group 3: re-TKA and high-knee PPT; group 4: re-TKA and low-knee PPT. Clinical pain intensity was assessed using a visual analogue scale (VAS). Bilateral PPTs were measured from the lower leg and forearm (spreading sensitization). Furthermore, the pain intensities evoked by 10 repeated pressure pain stimuli (temporal summation) at the knee and lower leg were assessed on an electronic VAS.
The mean clinical pain intensity was not significantly different between groups. The PPTs from both lower leg and forearm were significantly lower in group 4 compared to groups 1, 2, and 3 and in groups 2 and 3 compared to group 1 (p < 0.05). Temporal summations from the knee and lower leg were significantly facilitated in groups 3 and 4 compared to groups 1 and 2 (p < 0.05).
Despite similar pain intensities, facilitated temporal summation is worse in re-TKA than in OA and patients with high local knee hyperalgesia show more prominent spreading sensitization. The study suggests that sensitization should be considered in knee OA especially before re-TKA.
European journal of pain (London, England) 08/2014; 18(7). DOI:10.1002/j.1532-2149.2013.00447.x · 3.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Generalized hyperalgesia, a widespread increased sensitivity to painful stimuli, has been demonstrated in a range of chronic pain conditions including low-back pain. The evidence suggests, that generalized hyperalgesia may be an important factor in the development of chronicity, but it is not commonly assessed in clinical practice. Whereas a range of tools and procedures for the quantitative sensory testing of pain sensitivity is available for laboratory pain research, most experimental pain stimuli are not well suited for clinical practice. In the current study, a simple and inexpensive mechanical spring-clamp was tested as a potential experimental pain stimulus.
Ten seconds of mechanical pressure was applied to the thumb of 242 study participants: Healthy volunteers and low-back-pain patients (hospital and primary care). Pain intensity was measured by visual analogue scale before and after conditioned pain modulation by cold-pressor test (CPT). Correlation to pressure pain threshold (PPT) of the infraspinatus muscle and cold-pressor test pain intensity, time to pain onset and time to non-tolerance, was examined. Test/re-test reliability of clamp pain was also assessed and the stimulus–response relationship was examined with a set of 6 different clamps.
Clamp pain was sensitive to changes in pain sensitivity provoked by conditioned pain modulation (CPM). Test/re-test reliability of the spring-clamp pain was better for healthy volunteers over a period of days, than for hospital patients over a period of weeks. A strong correlation (ρ = 0.73, P > 0.0001) was found between clamp force and evoked pain intensity. Correlation to other pain stimuli varied, with a strong correlation between pre and post-CPM clamp pain intensity (ρ = 0.81, P > 0.0001), moderate correlation between clamp pain and PPT (ρ = −0.43, P > 0.0001), as well as CPT pain intensity (ρ = 0.32, P > 0.0001) and a weak correlation with time to onset of CPT pain (ρ = −0.14, P < 0.05).
The application of mechanical pressure is commonly employed to assess general pain sensitivity, and a simple spring-clamp seems a potentially useful instrument for quantitative sensory testing in a clinical setting.
[Show abstract][Hide abstract] ABSTRACT: The assessment of the dentinal hypersensitivity usually depends on subjective responses to clinically applied stimuli and lack of standardized and quantified testing methods.
Objective: This study is to apply standardized mechanical, thermal, and electrical stimuli on the teeth with dentinal hypersensitivity providing an objective evaluation method of diagnosis and treatment evaluation of dentinal hypersensitivity.
Method: Twenty-three subjects (aged 20-40) with unilateral hypersensitivity in incisor/cuspid/pre-molar (S-Tooth) participated in a three-session experiment. The contralateral tooth was selected as control (C-Tooth). Mechanical Stimuli Sensitivity (MSS), Cold Detection Threshold (CDT), Warm Detection Threshold (WDT), Electrical Detection Threshold (EDT), and Electrical Pain Threshold (EPT) were tested on both S-Tooth and C-Tooth at the first day (Day-1) before and immediately after manual toothbrushing using the commercial Crest Pro-health Clinical Sensitivity Dentifrice. The subjects were instructed to perform standard toothbrushing twice daily for seven days. The testing was repeated on the second day (Day-2) and the seventh day (Day-7) after toothbrushing. Data were analyzed with ANOVAs. The study was approved by the local ethical committee and performed at Peking University School of Stomatology.
Result: The S-Tooth was significantly more sensitive in MSS (P=0.033) compared with the C-Tooth. That e S-Tooth was significantly less sensitive in MSS (P=0.004), CDT (P=0.041), WDT (P=0.010), EPT (P=0.047) on Day-7 compared with Day-1, and significantly less sensitive in EPT on both Day-2 (P=0.041) and Day-7 (P=0.001) compared with Day-1. The sensitivity of the C-Tooth was also significantly changed in MSS (P=0.020) and EPT (P=0.004) on Day-7.
Conclusion: The established quantitative sensory testing methods are suitable for use in clinical trials and provide important information on diagnosis and treatment evaluation of dentinal hypersensitivity. The test dentifrice provided a rapid desensitizing effect. Further study with placebo control is required.
[Show abstract][Hide abstract] ABSTRACT: Cold allodynia and cold hyperalgesia are both elusive features of neuropathic pain, particularly in patients with various polyneuropathies. Numerous studies have suggested that topical application of L-menthol causes temporary cold hypersensitivity and thus acts as a proxy for associated symptoms. This review summarizes studies on L-menthol-induced nociception, cold allodynia and cold hyperalgesia in vitro, in animals and in humans.
A comprehensive literature search was performed using the PubMed and Google Scholar databases until February 2013. Obtained manuscripts were reviewed for relevancy and reference lists of the retrieved articles were cross-checked for additional important studies. Solely the literature regarding topical application of L-menthol in humans was attained systematically. Of the total identified studies (96), 10 met the inclusion criteria being controlled studies applying L-menthol at a concentration of ≥30%.
The extracted data are meticulously compared and presented with emphasis on clarity and transparency. In seven animal studies, cold allodynia or hyperalgesia was successfully established utilizing various methods. Eight studies in healthy volunteers unanimously reported a significant increase in cold pain threshold, representing cold allodynia and increased supra-threshold cold pain sensitivity, thus demonstrating cold hyperalgesia.
Topical high-concentration L-menthol consistently induces cold hypersensitivity in animals and humans, thus constituting a predictable surrogate model of cold allodynia and hyperalgesia. Understanding translational features of this model and its underlying mechanisms could be valuable in preclinical and human phases of drug development and in improving current treatment of patients with polyneuropathy.
European journal of pain (London, England) 03/2014; 18(3). DOI:10.1002/j.1532-2149.2013.00380.x · 3.22 Impact Factor