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1.  Single-Point but Not Tonic Cuff Pressure Pain Sensitivity Is Associated with Level of Physical Fitness – A Study of Non-Athletic Healthy Subjects 
PLoS ONE  2015;10(5):e0125432.
Exercise is often used for pain rehabilitation but the link between physical activity level and pain sensitivity is still not fully understood. Pressure pain sensitivity to cuff algometry and conditioned pain modulation (CPM) were evaluated in highly active men (n=22), normally active men (n=26), highly active women (n=27) and normally active women (n=23) based on the Godin Leisure-Time Exercise Questionnaire. Cuff pressure pain sensitivity was assessed at the arm and lower leg. The subjects scored the pain intensity on an electronic Visual Analogue Scale (VAS) during ten minutes with 25 kPa constant cuff pressure and two minutes with zero pressure. The maximal VAS score and area under the VAS-curve were extracted. Pressure pain thresholds (PPT) were recorded by manual pressure algometry on the ipsilateral tibialis anterior muscle before, during and after the tonic arm stimulation. Tonic cuff stimulation of the arm and leg resulted in higher VAS peak scores in women compared with men (p<0.04). In all groups the PPTs were reduced during and after the cuff stimulation compared with baseline (p=0.001). PPT were higher in men compared with women (p=0.03) and higher in highly physical active compared with normal active (p=0.048). Besides the well-known gender difference in pressure pain sensitivity this study demonstrates that a high physical fitness degree in non-athletic subjects is associated with increased pressure pain thresholds but does not affect cuff pressure pain sensitivity in healthy people.
PMCID: PMC4416774  PMID: 25933412
2.  Serum Levels of Proinflammatory Cytokines in Painful Knee Osteoarthritis and Sensitization 
Osteoarthritis (OA) is the most common joint disorder in the world. Among the mechanisms involved in osteoarthritis, biomarkers (cytokines profile) may be related to pain and pain intensity, functional capacity, and pressure pain thresholds (PPT). Thus, the study of these relationships may offer useful information about pathophysiology and associated mechanisms involved in osteoarthritis. Therefore, the objective of this study was to investigate the seric concentration of pro (IL-6, IL-8, and TNF-α) and anti-inflammatory (IL-10) cytokines in patients with painful knee osteoarthritis and to correlate the levels of these biomarkers with the patients' functional capacity and pressure pain threshold (PPT) values.
PMCID: PMC4363921  PMID: 25821631
3.  Dynamic mechanical assessment of muscle hyperalgesia in humans: The dynamic algometer 
Pressure algometry is typically used to assess mechanical hyperalgesia; however, this technique only assesses pain at a single point at a time. In multiple pain conditions, pain varies over a larger area, and multiple measures must be obtained and collated into a pressure sensitivity map. The authors of this article aimed to develop a device to assess hyperalgesia that involves mapping pain evoked by pressure over a larger area.
Musculoskeletal pain is often associated with a nonhomogeneous distribution of mechanical hyperalgesia. Consequently, new methods able to detect this distribution are needed.
To develop and test a new method for assessing muscle hyperalgesia with high temporal and spatial resolution that provides complementary information compared with information obtained by traditional static pressure algometry.
The dynamic pressure algometer was tested bilaterally on the tibialis anterior muscle in 15 healthy subjects and compared with static pressure algometry. The device consisted of a wheel that was rolled over the muscle tissue with a fixed velocity and different predefined forces. The pain threshold force was determined and pain intensity to a fixed-force stimulation was continuously rated on a visual analogue scale while the wheel was rolling over the muscle. The pressure pain sensitivity was evaluated before, during, and after muscle pain and hyperalgesia induced unilaterally by either injection of hypertonic saline (0.5 mL, 6%) into the tibialis anterior or eccentric exercise evoking delayed-onset muscle soreness (DOMS).
The intraclass correlation coefficient was >0.88 for the dynamic thresholds; thus, the method was reliable. Compared with baseline, both techniques detected hyperalgesia at the saline injection site and during DOMS (P<0.05). The dynamic algometer also detected the widespread, patchy distribution of sensitive loci during DOMS, which was difficult to evaluate using static pressure algometry.
The present study showed that dynamic pressure algometry is a reliable tool for evaluating muscle hyperalgesia (threshold and pain rating) with high temporal and spatial resolution. It can be applied as a simple clinical bed-side test and as a quantitative tool in pharmacological profiling studies.
PMCID: PMC4325887  PMID: 25664539
Hyperalgesia; Muscle pain; Pressure assessment
4.  Mechanistic experimental pain assessment in computer users with and without chronic musculoskeletal pain 
Musculoskeletal pain from the upper extremity and shoulder region is commonly reported by computer users. However, the functional status of central pain mechanisms, i.e., central sensitization and conditioned pain modulation (CPM), has not been investigated in this population. The aim was to evaluate sensitization and CPM in computer users with and without chronic musculoskeletal pain.
Pressure pain threshold (PPT) mapping in the neck-shoulder (15 points) and the elbow (12 points) was assessed together with PPT measurement at mid-point in the tibialis anterior (TA) muscle among 47 computer users with chronic pain in the upper extremity and/or neck-shoulder pain (pain group) and 17 pain-free computer users (control group). Induced pain intensities and profiles over time were recorded using a 0-10 cm electronic visual analogue scale (VAS) in response to different levels of pressure stimuli on the forearm with a new technique of dynamic pressure algometry. The efficiency of CPM was assessed using cuff-induced pain as conditioning pain stimulus and PPT at TA as test stimulus.
The demographics, job seniority and number of working hours/week using a computer were similar between groups. The PPTs measured at all 15 points in the neck-shoulder region were not significantly different between groups. There were no significant differences between groups neither in PPTs nor pain intensity induced by dynamic pressure algometry. No significant difference in PPT was observed in TA between groups. During CPM, a significant increase in PPT at TA was observed in both groups (P < 0.05) without significant differences between groups. For the chronic pain group, higher clinical pain intensity, lower PPT values from the neck-shoulder and higher pain intensity evoked by the roller were all correlated with less efficient descending pain modulation (P < 0.05).
This suggests that the excitability of the central pain system is normal in a large group of computer users with low pain intensity chronic upper extremity and/or neck-shoulder pain and that increased excitability of the pain system cannot explain the reported pain. However, computer users with higher pain intensity and lower PPTs were found to have decreased efficiency in descending pain modulation.
PMCID: PMC4265505  PMID: 25481709
Sensitization; Pain mechanisms; Computer work; Conditioned pain modulation; Work-related musculoskeletal disorders; Pressure pain threshold; Experimental pain
5.  Heat-rekindling in UVB-irradiated skin above NGF-sensitized muscle: experimental models of prolonged mechanical hypersensitivity 
Experimental models of prolonged pain hypersensitivity in humans are desirable for screening novel analgesic compounds. In this study, heat stimuli were applied in ultraviolet-B (UVB)-irradiated skin and in the UVB-irradiated skin combined with nerve growth factor (NGF)-injected muscle to investigate 1) whether the evoked mechanical hypersensitivity by UVB irradiation would be prolonged or enhanced following heat rekindling, and 2) whether the combination between cutaneous and muscle hypersensitivity may influence the rekindling effects. Skin sensitization was induced in 25 volunteers by UVB irradiation in areas above the upper-trapezius muscle, low-back or forearm. Muscle sensitization was induced in the low back by bilateral injections of NGF. The area of cutaneous hyperalgesia was evaluated 3 days after the irradiation by mechanical pin-prick stimulation whereas the areas of allodynia were evaluated 1, 2 and 3 days after irradiation by von Frey hair assessments. Cutaneous heat stimulation (40°C for 5 min) was performed on the 3rd day to investigate its effect on the areas of cutaneous allodynia and hyperalgesia. Findings revealed that 1) allodynia and hyperalgesia developed following UVB irradiation, 2) heat stimulation of the UVB-irradiated skin enlarged both hyperalgesic and allodynic areas (P < 0.01), and 3) muscle sensitization did not influence the effect of UVB on allodynia or the response to heat rekindling. These data suggest that heat rekindling applied to an UVB-sensitized skin can maintain or facilitate allodynia and hyperalgesia for a longer period offering a suitable model for testing analgesic compounds when sufficient duration of time is needed for investigation of drug efficacy.
PMCID: PMC4208735  PMID: 25349637
Ultraviolet-B irradiation (UVB); heat rekindling; nerve growth factor (NGF); hyperalgesia; allodynia; muscle; skin
6.  Type X collagen levels are elevated in serum from human osteoarthritis patients and associated with biomarkers of cartilage degradation and inflammation 
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.
PMCID: PMC4179849  PMID: 25245039
Hypertrophic chondrocytes; Osteoarthritis; Type X collagen; Cartilage degradation; Biomarkers; Type II collagen; Inflammation
7.  Is the Conditioned Pain Modulation Paradigm Reliable? A Test-Retest Assessment Using the Nociceptive Withdrawal Reflex 
PLoS ONE  2014;9(6):e100241.
The aim of this study was to determine the reliability of the conditioned pain modulation (CPM) paradigm assessed by an objective electrophysiological method, the nociceptive withdrawal reflex (NWR), and psychophysical measures, using hypothetical sample sizes for future studies as analytical goals. Thirty-four healthy volunteers participated in two identical experimental sessions, separated by 1 to 3 weeks. In each session, the cold pressor test (CPT) was used to induce CPM, and the NWR thresholds, electrical pain detection thresholds and pain intensity ratings after suprathreshold electrical stimulation were assessed before and during CPT. CPM was consistently detected by all methods, and the electrophysiological measures did not introduce additional variation to the assessment. In particular, 99% of the trials resulted in higher NWR thresholds during CPT, with an average increase of 3.4 mA (p<0.001). Similarly, 96% of the trials resulted in higher electrical pain detection thresholds during CPT, with an average increase of 2.2 mA (p<0.001). Pain intensity ratings after suprathreshold electrical stimulation were reduced during CPT in 84% of the trials, displaying an average decrease of 1.5 points in a numeric rating scale (p<0.001). Under these experimental conditions, CPM reliability was acceptable for all assessment methods in terms of sample sizes for potential experiments. The presented results are encouraging with regards to the use of the CPM as an assessment tool in experimental and clinical pain.
Trial Registration:
Clinical NCT01636440
PMCID: PMC4065000  PMID: 24950186
8.  Blockade of glutamate release by botulinum neurotoxin type A in humans: A dermal microdialysis study 
In addition to its well-studied muscle-relaxant effects, botulinum neurotoxin A acts as an analgesic, an effect believed to be due to its suppression of the release of pain mediators, including glutamate. However, the research that led to these conclusions was conducted using animal models. Accordingly, the authors of this article aimed to determine whether the botulinum neurotoxin A has a similar effect on glutamate release in human skin.
The analgesic action of botulinum neurotoxin type A (BoNTA) has been linked to the blockade of peripheral release of neuropeptides and neurotransmitters in animal models; however, there is no direct evidence of this in humans.
To investigate the effect of BoNTA on glutamate release in humans, using an experimental model of pain and sensitization provoked by capsaicin plus mild heat.
Twelve healthy volunteers (six men, six women) were pretreated with BoNTA (10 U) on the volar forearm and with a saline control on the contralateral side. Dermal microdialysis was applied one week later to collect interstitial samples before and after the application of a capsaicin patch (8%) plus mild heat (40°C/60 min) to provoke glutamate release, pain and vasodilation. Samples were collected every hour for 3 h using linear microdialysis probes (10 mm, 100 kD). Dialysate was analyzed for glutamate concentration. Pain intensity and skin vasomotor reactions (temperature and blood flow changes) were also recorded.
BoNTA significantly reduced glutamate release compared with saline (P<0.05). The provoked pain intensity was lower in the BoNTA-pretreated arm (P<0.01). The reduction in pain scores was not correlated with glutamate level. Cutaneous blood flow (P<0.05), but not cutaneous temperature (P≥0.05), was significantly reduced by BoNTA. There was a correlation between glutamate level and skin blood flow (r=0.58/P<0.05) but not skin temperature (P≥0.05). No differences according to sex were observed in any response.
The present study provided the first direct evidence supporting the inhibitory effect of BoNTA on glutamate release in human skin, which is potentially responsible for some of the analgesic action of BoNTA.
PMCID: PMC4158957  PMID: 24851237
Botulinum neurotoxin type A; Capsaicin; Glutamate; Human experimental pain model; Microdialysis; Vasodilation
9.  Blockade of Opioid Receptors in the Medullary Reticularis Nucleus Dorsalis, but not the Rostral Ventromedial Medulla, Prevents Analgesia Produced by Diffuse Noxious Inhibitory Control in Rats With Muscle Inflammation 
Diffuse Noxious Inhibitory Controls (DNIC) involves application of a noxious stimulus outside the testing site to produce analgesia. In human subjects with a variety of chronic pain conditions, DNIC is less effective; however, in animal studies, DNIC is more effective after tissue injury. While opioids are involved in DNIC analgesia, the pathways involved in this opioid-induced analgesia are not clear. The aim of the present study was to test the effectiveness of DNIC in inflammatory muscle pain, and to study which brainstem sites mediate DNIC- analgesia. Rats were injected with 3% carrageenan into their gastrocnemius muscle and responses to cutaneous and muscle stimuli were assessed before and after inflammation, and before and after DNIC induced by noxious heat applied to the tail (45°C and 47°C). Naloxone was administered systemically, into rostral ventromedial medulla (RVM), or bilaterally into the medullary reticularis nucleus dorsalis (MdD) prior to the DNIC-conditioning stimuli. DNIC produced a similar analgesic effect in both acute and the chronic phases of inflammation reducing both cutaneous and muscle sensitivity in a dose-dependent manner. Naloxone systemically or microinjected into the MdD prevented DNIC-analgesia, while naloxone into the RVM had no effect on DNIC analgesia. Thus, DNIC analgesia involves activation of opioid receptors in the MdD.
PMCID: PMC3954524  PMID: 21330219
Pain; muscle; inhibition; DNIC; opioid
10.  Time Course Analysis of the Effects of Botulinum Neurotoxin Type A on Pain and Vasomotor Responses Evoked by Glutamate Injection into Human Temporalis Muscles 
Toxins  2014;6(2):592-607.
The effect of botulinum neurotoxin type A (BoNTA) on glutamate-evoked temporalis muscle pain and vasomotor responses was investigated in healthy men and women over a 60 day time course. Subjects participated in a pre-BoNTA session where their responses to injection of glutamate (1 M, 0.2 mL) and saline (0.2 mL) into the temporalis muscles were assessed. On Day 1, BoNTA (5 U) was injected into one temporalis muscle and saline into the contralateral temporalis muscle, in a randomized order. Subjects then received intramuscular injections of glutamate (1 M, 0.2 mL) into the left and right temporalis muscles at 3 h and subsequently 7, 30 and 60 days post-injection of BoNTA. Pain intensity, pain area, and neurogenic inflammation (skin temperature and skin blood perfusion) were recorded. Prior to BoNTA treatment, glutamate evoked significantly greater pain and vasomotor reactions (P < 0.001) than saline. BoNTA significantly reduced glutamate-evoked pain intensity (P < 0.05), pain area (P < 0.01), skin blood perfusion (P < 0.05), and skin temperature (P < 0.001). The inhibitory effect of BoNTA was present at 3 h after injection, peaked after 7 days and returned to baseline by 60 days. Findings from the present study demonstrated a rapid action of BoNTA on glutamate-evoked pain and neurogenic inflammation, which is in line with animal studies.
PMCID: PMC3942753  PMID: 24517906
botulinum neurotoxin type A; temporalis muscle; glutamate; pain; neurogenic; vasomotor
11.  Assessment of pain response in capsaicin-induced dynamic mechanical allodynia using a novel and fully automated brushing device 
Dynamic mechanical allodynia is traditionally induced by manual brushing of the skin. Brushing force and speed have been shown to influence the intensity of brush-evoked pain. There are still limited data available with respect to the optimal stroke number, length, force, angle and speed. Therefore, an automated brushing device (ABD) was developed, for which brushing angle and speed could be controlled to enable quantitative assessment of dynamic mechanical allodynia.
To compare the ABD with manual brushing using capsaicin-induced allodynia, and to investigate the role of stroke angle and speed on pain intensity.
Experimental dynamic mechanical allodynia was induced by an intradermal injection of capsaicin (100 μg) into the volar forearm of 12 healthy, male volunteers. Dynamic mechanical allodynia was rated on a 10 cm visual analogue scale (VAS) after each set of strokes at angles of 30°, 60° and 90° with speeds of 17 mm/s, 21 mm/s and 25 mm/s for each angle. A two-way ANOVA with repeated measures was performed to assess the influence of brushing parameters. To evaluate test-retest reliability, Bland-Altman 95% limits of agreement, including a coefficient of repeatability and an intraclass correlation coefficient (ICC), were determined.
The angle and speed exhibited a significant impact on pain intensity (P<0.001 and P<0.015, respectively). Post hoc analysis showed that the highest pain intensity was recorded with an angle of 30° regardless of brushing speed. The ABD demonstrated superior test-retest reliability (coefficient of repeatability = 1.9 VAS; ICC=0.91) compared with manual brushing (coefficient of repeatability = 2.8 VAS; ICC=0.80; P<0.05). The most reliable combination of parameters (coefficient of repeatability = 1.3 VAS; ICC=0.97) was an angle of 60° and a speed of 21 mm/s.
A controlled, automatic brushing method can be used for quantitative investigations of allodynic reactions, and is more reliable for quantitative assessment of dynamic mechanical allodynia compared with traditional manual brushing.
PMCID: PMC3665431  PMID: 23457680
Capsaicin; Dynamic mechanical allodynia; Human experimental pain model; Test-retest reliability
12.  Differences between opioids: pharmacological, experimental, clinical and economical perspectives 
Clinical studies comparing the response and side effects of various opioids have not been able to show robust differences between drugs. Hence, recommendations of the regulatory authorities have been driven by costs with a general tendency in many countries to restrict physician's use of opioids to morphine. Although this approach is recognized as cost-effective in most cases there is solid evidence that, on an individual patient basis, opioids are not all equal. Therefore it is important to have an armamentarium of strong analgesics in clinical practice to ensure a personalized approach in patients who do not respond to standard treatment. In this review we highlight differences between opioids in human studies from a pharmacological, experimental, clinical and health economics point of view. We provide evidence that individuals respond differently to opioids, and that general differences between classes of opioids exist. We recommend that this recognition is used to individualize treatment in difficult cases allowing physicians to have a wide range of treatment options. In the end this will reduce pain and side effects, leading to improved quality of life for the patient and reduce the exploding pain related costs.
PMCID: PMC3555047  PMID: 22554450
costs of illness; meta-analysis; opioids; pain; receptors
13.  The UVB cutaneous inflammatory pain model: a reproducibility study in healthy volunteers 
Background: The human ultraviolet-B (UVB) experimental pain model induces cutaneous neurogenic inflammation, involves hyperalgesia, and is widely used as a pharmacological screening pain model. Aim: To estimate the test-retest reliability of the UVB pain model by application of a comprehensive set of vasomotor and quantitative sensory assessment methods and to estimate sample sizes required for parallel or crossover pharmacological screening studies when this model is considered to be applied. Methods: The upper arms of 15 healthy male volunteers were UVB irradiated with three times the minimal erythema dose. Neurogenic inflammation was assessed by measuring erythema index, superficial blood flow and skin temperature at baseline, 1 day, 2 days and 3 days post irradiation. Sensory changes were assessed by brush stroke, von Frey hairs, pressure algometry, heat-evoked pain, stimulus response function to weight calibrated pin-prick stimulation, and the area of secondary hyperalgesia. The experiment was repeated with a two-week interval. Systematic bias, Coefficient of variation (CV), and intra-class correlation (ICC) were calculated within and between UVB irradiations. The sample sizes for parallel and crossover studies were calculated. Results: Neurogenic inflammation (erythema index) and primary hyperalgesia (pin-prick stimulation) remained significant for 3 days, and were highly reproducible within and between the UVB irradiations resulting of low sample sizes (4-26) in both parallel and crossover studies. Conclusion: Based on sample size calculations, it is recommended to use the erythema index to assess neurogenic inflammation, and pin-prick stimulation for primary hyperalgesia for both parallel and crossover pharmacological screening studies.
PMCID: PMC3867698  PMID: 24379905
Ultraviolet-B; quantitative sensory test; reproducibility; sample size; primary hyperalgesia; secondary hyperalgesia
14.  Nitric oxide release from trigeminal satellite glial cells is attenuated by glial modulators and glutamate 
Nitric oxide (NO) is suggested to play an important role in primary headaches. It has been proposed that release of NO from satellite glial cells (SGCs) of the trigeminal ganglion (TG) could contribute to the pathogenesis of these headaches. The principal aim of this study was to investigate if the phosphodiesterase inhibitor Ibudilast (Ibu) and 1α,25-dihydroxyvitamin D3 (Vit D3) could interfere with NO release from trigeminal SGCs. Since glutamate is released from activated TG neurons, the ability of glutamate to alter NO release from SGCs was also investigated. To study this, we isolated SGCs from the TG of adult male Sprague-Dawley rats, provoked NO release from SGCs with forskolin (FSK; 0.1, 1, 10 μM), and examined the effect of graded concentrations of Ibu (1, 10, 100 μM), Vit D3 (5, 50, 500 nM), and glutamate (10, 100, 1000 μM). Our results indicate that both Ibu and Vit D3 are capable of attenuating the FSK-mediated increased NO release from SGCs after 48 hours of incubation. Lower glutamate concentrations (10 and 100 μM) significantly decreased NO release not only under basal conditions after 24 and 48 hours, but also after SGCs were stimulated with FSK for 48 hours. In conclusion, NO release from SGCs harvested from the TG can be attenuated by glial modulators and glutamate. As NO is thought to increase TG neuron excitability, the findings suggest that targeting SGCs may provide a novel therapeutic approach for management of craniofacial pain conditions such as migraine in the future.
PMCID: PMC3867700  PMID: 24379907
Ibudilast; vitamin D3; migraine; headache; satellite glial cells; nitric oxide; glutamate; glial modulation
15.  The effect of topical capsaicin-induced sensitization on heat-evoked cutaneous vasomotor responses 
Brief, localized, cutaneous, non-painful thermal stimuli can evoke a transient vasomotor response, causing increased cutaneous blood flow and elevated skin temperature. The aims of this study were to investigate 1) if cutaneous sensitization by topical application of capsaicin (TRPV1 receptor agonist) can facilitate the size, duration and spatial extent of this vasomotor response and 2) if males and females respond differently. Thermal pulses (43°C for 60 seconds) were applied on left/right volar forearms of 15 age-matched males and females. Skin temperature and cutaneous blood flow were measured 1, 5, 10, 15, and 30 minutes after heat application before and after topical capsaicin (1%, 30 min application) with contralateral arm serving as the control. Recordings were made from the region of interest at distances of 2, 4, 6, 8, and 10 cm from the capsaicin application site. Sensitization significantly enhanced skin temperature for up to 30 min and compared with non-sensitized skin at 10 min. Females showed the strongest response after sensitization, but the response lasted longer and spread more widely in males. The blood flow responses were significantly longer after capsaicin (from 5 to 30 minutes after thermal application). This increased blood flow extended outside the treated area up to 10 min after stimulation. After sensitization, the area under the blood flow response curves showed significantly stronger responses in females, spreading 4 cm outside the stimulation site. Cutaneous sensitizing caused prolonged and spatially expanded vasomotor responses to standardized thermal stimulation with sex specific differences.
PMCID: PMC3773074  PMID: 24044034
Neurogenic inflammation; vasomotor response; thermal stimulation; sensitization; capsaicin; cutaneous
16.  Altered Visual and Feet Proprioceptive Feedbacks during Quiet Standing Increase Postural Sway in Patients with Severe Knee Osteoarthritis 
PLoS ONE  2013;8(8):e71253.
The objective was to investigate how postural control in knee osteoarthritis (KOA) patients, with different structural severities and pain levels, is reorganized under different sensory conditions.
Forty-two obese patients (BMI range from 30.1 to 48.7 kg*m−2, age range from 50 to 74 years) with KOA were evaluated. One minute of quiet standing was assessed on a force platform during 4 different sensory conditions, applied 3 times at random: Eyes open (EO) and eyes closed (EC) standing on firm and soft (foam) surfaces (EO-soft and EC-soft). Centre of pressure (Cop) standard deviation, speed, range and Cop mean position in both directions (anterior-posterior and medial-lateral) were extracted from the force platform data. Structural disease severity was assessed from semiflexed standing radiographs and graded by the Kellgren and Lawrence (KL) score. Pain intensity immediately before the measurements was assessed by numeric rating scale (range: 0–10).
The patients were divided into “less severe” (KL 1 and 2, n = 24) and “severe” (KL>2, n = 18) group. The CoP range in the medial-lateral direction was larger in the severe group when compared with the less severe group during EC-soft condition (P<0.01). Positive correlation between pain intensity and postural sway (range in medial-lateral direction) was found during EC condition, indicating that the higher the pain intensity, the less effective is the postural control applied to restore an equilibrium position while standing without visual information.
The results support that: (i) the postural reorganization under manipulation of the different sensory information is worse in obese KOA patients with severe degeneration and/or high pain intensity when compared with less impaired patients, and (ii) higher pain intensity is related to worse body balance in obese KOA patients.
PMCID: PMC3750025  PMID: 23990940
17.  Transcranial pulsed electromagnetic fields for multiple chemical sensitivity: study protocol for a randomized, double-blind, placebo-controlled trial 
Trials  2013;14:256.
Multiple chemical sensitivity (MCS) is a chronic condition of unknown etiology. MCS is characterized by recurrent nonspecific symptoms from multiple organ systems in response to chemical exposures in concentrations that are normally tolerated by the majority of the population. The symptoms may have severe impact on patients’ lives, but an evidence-based treatment for the condition is nonexisting. The pathophysiology is unclarified, but several indicators point towards abnormal processing of sensory signals in the central nervous system. Pulsed electromagnetic fields (PEMF) offer a promising new treatment for refractory depression and can be targeted at the brain, thereby activating biochemical cell processes.
In a parallel, randomized, double-blind, placebo-controlled trial conducted at the Danish Research Centre for Chemical Sensitivities, the effects of PEMF in MCS patients will be assessed using the Re5 Independent System. Based on sample size estimation, 40 participants will be randomized to either PEMF therapy or placebo. The allocation sequence will be generated by computer. All involved parties (that is, participants, investigators, the research nurse, and the statistician) will be blinded to group allocation. The participants will receive PEMF therapy or placebo applied transcranially 30 minutes twice a day for 7 days a week over 6 consecutive weeks. Outcomes will be measured at baseline, once weekly during treatment, post treatment, and at 2.5-month and 4.5-month follow-up according to a predefined timetable. The primary outcome will be a measurement of the impact of MCS on everyday life. The secondary outcomes will be measurements of MCS symptoms, psychological distress (stress, anxiety or depressive symptoms), capsaicin-induced secondary punctate hyperalgesia, immunological markers in serum, and quality of life.
This trial will assess the effects of PEMF therapy for MCS. Currently, there is no treatment with a documented effect on MCS, and in terms of healthcare there is very little to offer these patients. There is thus a great need for well-conducted randomized trials aimed at assessing possible treatment effects. A positive outcome will pave the way for improved healthcare and understanding of this very disabling and overlooked condition.
Trial registration, NCT01834781
PMCID: PMC3765111  PMID: 23947742
Multiple chemical sensitivity; Pulsed electromagnetic fields; Re5 therapy; Re5 independent system; Randomized controlled trial
18.  Computer work and self-reported variables on anthropometrics, computer usage, work ability, productivity, pain, and physical activity 
Computer users often report musculoskeletal complaints and pain in the upper extremities and the neck-shoulder region. However, recent epidemiological studies do not report a relationship between the extent of computer use and work-related musculoskeletal disorders (WMSD).
The aim of this study was to conduct an explorative analysis on short and long-term pain complaints and work-related variables in a cohort of Danish computer users.
A structured web-based questionnaire including questions related to musculoskeletal pain, anthropometrics, work-related variables, work ability, productivity, health-related parameters, lifestyle variables as well as physical activity during leisure time was designed. Six hundred and ninety office workers completed the questionnaire responding to an announcement posted in a union magazine. The questionnaire outcomes, i.e., pain intensity, duration and locations as well as anthropometrics, work-related variables, work ability, productivity, and level of physical activity, were stratified by gender and correlations were obtained.
Women reported higher pain intensity, longer pain duration as well as more locations with pain than men (P < 0.05). In parallel, women scored poorer work ability and ability to fulfil the requirements on productivity than men (P < 0.05). Strong positive correlations were found between pain intensity and pain duration for the forearm, elbow, neck and shoulder (P < 0.001). Moderate negative correlations were seen between pain intensity and work ability/productivity (P < 0.001).
The present results provide new key information on pain characteristics in office workers. The differences in pain characteristics, i.e., higher intensity, longer duration and more pain locations as well as poorer work ability reported by women workers relate to their higher risk of contracting WMSD. Overall, this investigation confirmed the complex interplay between anthropometrics, work ability, productivity, and pain perception among computer users.
PMCID: PMC3751662  PMID: 23915209
Computer use; Musculoskeletal complaints; Arm-shoulder pain; Gender; Sex
19.  Gender, variation in opioid receptor genes and sensitivity to experimental pain 
Molecular Pain  2013;9:20.
Pain tolerance is subject to considerable inter-individual variation, which may be influenced by a number of genetic and non-genetic factors. The mu, delta and kappa opioid receptors play a role in pain perception and are thought to mediate different pain modalities. The aim of this study was to explore associations between pain thresholds and gender and genetic variants in the three opioid receptor genes (OPRM, OPRD and OPRK). Experimental multi-modal pain data from previously published studies carried out in healthy Caucasian volunteers were used in order to limit the number of confounders to the study outcome. Data on thermal skin pain (n=36), muscle pressure pain (n=31) and mechanical visceral pain (n=50)) tolerance thresholds were included.
Nineteen genetic polymorphisms were included in linear regression modeling. Males were found to tolerate higher thermal and muscle pressure pain than females (p=0.003 and 0.02). Thirty four percent of variability in thermal skin pain was accounted for by a model consisting of OPRK rs6473799 and gender. This finding was just outside significance when correction for multiple testing was applied. Variability in muscle pressure pain tolerance was associated with OPRK rs7016778 and rs7824175. These SNPs accounted for 43% of variability in muscle pressure pain sensitivity and these findings remained significant after adjustment for multiple testing. No association was found with mechanical visceral pain.
This is a preliminary and hypothesis generating study due to the relatively small study size. However, significant association between the opioid receptor genes and experimental pain sensitivity supports the influence of genetic variability in pain perception. These findings may be used to generate hypotheses for testing in larger clinical trials of patients with painful conditions.
PMCID: PMC3635934  PMID: 23570317
OPRM; OPRK; OPRD; Gender; Pain tolerance thresholds; Opioid receptor genes
20.  Evaluation of Anti-Hyperalgesic and Analgesic Effects of Two Benzodiazepines in Human Experimental Pain: A Randomized Placebo-Controlled Study 
PLoS ONE  2013;8(3):e43896.
Background and Aims
Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABAA-receptors (clobazam and clonazepam) were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain.
In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo). The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation), and pain during cuff algometry.
For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p<0.001), but not after clobazam and clonazepam. Results suggestive for an anti-hyperalgesic effect of the benzodiazepines were obtained with all three intramuscular pain models and with cuff algometry. No effect could be detected with the other pain models employed.
Collectively, the results are suggestive for a possible anti-hyperalgesic effect of drugs acting at the GABAA-receptors in humans, particularly in models of secondary hyperalgesia and deep pain. The findings are not conclusive, but support further clinical research on pain modulation by GABAergic drugs. Because of the partial results, future research should focus on compounds acting selectively on subunits of the GABA complex, which may allow the achievement of higher receptor occupancy than unselective drugs. Our data also provide information on the most suitable experimental models for future investigation of GABAergic compounds.
Trial Registration NCT01011036
PMCID: PMC3598812  PMID: 23554851
21.  Low pressure pain thresholds are associated with, but does not predispose for, low back pain 
European Spine Journal  2011;20(12):2120-2125.
Chronic pain is often associated with hyperalgesia in cross-sectional studies. In the present study, a random cohort of 40-year-old individuals (n = 264) from the general population was assessed for low back pain (LBP) status and pressure pain threshold (PPT), with follow-up assessment 4 and 8 years later. Low PPT at baseline as a potential risk factor for the development of LBP was investigated longitudinally and the association between LBP and hyperalgesia was studied cross-sectionally at baseline and 8-year follow-up. Generalized (p  < 0.03) and localized pressure hyperalgesia (p < 0.02) was found in participants with long-lasting LBP, but not with recent LBP (p > 0.08). Of the participants without recent or long-lasting LBP, those with a low PPT at baseline (lower 10% percentile) had no increased risk of developing LBP (p > 0.05). The findings indicate that PPT decreases as a consequence of long-lasting pain, whereas a low PPT seems not to constitute a separate risk factor for the development of LBP.
Electronic supplementary material
The online version of this article (doi:10.1007/s00586-011-1796-4) contains supplementary material, which is available to authorized users.
PMCID: PMC3229747  PMID: 21512842
Low back pain; Generalized hyperalgesia; Quantitative sensory testing; Central sensitization; Pressure pain threshold
22.  Efficacy of multimodal, systematic non-surgical treatment of knee osteoarthritis for patients not eligible for a total knee replacement: a study protocol of a randomised controlled trial 
BMJ Open  2012;2(6):e002168.
It is recommended that non-operative treatment of knee osteoarthritis (KOA) should be individually tailored and include multiple treatment modalities. Despite these recommendations, no one has yet investigated the efficacy of combining several non-surgical treatment modalities in a randomised controlled study. The purpose of this randomised controlled study is to examine if an optimised, combined non-surgical treatment programme results in greater improvements in pain, function and quality of life in comparison with usual care in patients with KOA who are not eligible for total knee arthroplasty (TKA).
Methods and analysis
This study will include 100 consecutive patients from the North Denmark Region not eligible for TKA with radiographic KOA (K-L grade ≥1) and mean pain during the previous week of ≤60 mm (0–100). The participants will be randomised to receive either a 12-week non-surgical treatment programme consisting of patient education, exercise, diet, insoles, paracetamol and/or NSAIDs or usual care (two information leaflets containing information on KOA and advice regarding the above non-surgical treatment). The primary outcome will be the change from baseline to 12 months on the self-report questionnaire Knee Injury and Osteoarthritis Outcome Score (KOOS)4 defined as the average score for the subscale scores for pain, symptoms, activities of daily living and quality of life. Secondary outcomes include the five individual KOOS subscale scores, pain on a 100 mm Visual Analogue Scale, EQ-5D, self-efficacy, pain pressure thresholds, postural control and isometric knee flexion and knee extension strength.
Ethics and dissemination
This study was approved by the local Ethics Committee of The North Denmark Region (N-20110085) and the protocol conforms to the principles of the Declaration of Helsinki. Data collection will be completed by April 2014. Publications will be ready for submission in the summer of 2014.
Trial registration number
This study is registered with (NCT01535001).
PMCID: PMC3533085  PMID: 23151395
Rheumatology; Rehabilitation Medicine
23.  Basic aspects of musculoskeletal pain: from acute to chronic pain 
The transition from acute to chronic musculoskeletal pain is not well understood. To understand this transition, it is important to know how peripheral and central sensitization are manifested and how they can be assessed. A variety of human pain biomarkers have been developed to quantify localized and widespread musculoskeletal pain. In addition, human surrogate models may be used to induce sensitization in otherwise healthy volunteers. Pain can arise from different musculoskeletal structures (e.g. muscles, joints, ligaments, or tendons), and differentiating the origin of pain from those different structures is a challenge. Tissue specific pain biomarkers can be used to tease these different aspects. Chronic musculoskeletal pain patients in general show signs of local/central sensitization and spread of pain to degrees which correlate to pain intensity and duration. From a management perspective, it is therefore highly important to reduce pain intensity and try to minimize the duration of pain.
PMCID: PMC3201649  PMID: 23115471
Sensitization; hyperalgesia; experimental pain; muscle; joint
24.  Total knee replacement plus physical and medical therapy or treatment with physical and medical therapy alone: a randomised controlled trial in patients with knee osteoarthritis (the MEDIC-study) 
There is a lack of high quality evidence concerning the efficacy of total knee arthroplasty (TKA). According to international evidence-based guidelines, treatment of knee osteoarthritis (KOA) should include patient education, exercise and weight loss. Insoles and pharmacological treatment can be included as supplementary treatments. If the combination of these non-surgical treatment modalities is ineffective, TKA may be indicated. The purpose of this randomised controlled trial is to examine whether TKA provides further improvement in pain, function and quality of life in addition to optimised non-surgical treatment in patients with KOA defined as definite radiographic OA and up to moderate pain.
The study will be conducted in The North Denmark Region. 100 participants with radiographic KOA (K-L grade ≥2) and mean pain during the previous week of ≤ 60 mm (0–100, best to worst scale) who are considered eligible for TKA by an orthopaedic surgeon will be included. The treatment will consist of 12 weeks of optimised non-surgical treatment consisting of patient education, exercise, diet, insoles, analgesics and/or NSAIDs. Patients will be randomised to either receiving or not receiving a TKA in addition to the optimised non-surgical treatment. The primary outcome will be the change from baseline to 12 months on the Knee Injury and Osteoarthritis Outcome Score (KOOS)4 defined as the average score for the subscale scores for pain, symptoms, activities of daily living, and quality of life. Secondary outcomes include the five individual KOOS subscale scores, EQ-5D, pain on a 100 mm Visual Analogue Scale, self-efficacy, pain pressure thresholds, and isometric knee flexion and knee extension strength.
This is the first randomised controlled trial to investigate the efficacy of TKA as an adjunct treatment to optimised non-surgical treatment in patients with KOA. The results will significantly contribute to evidence-based recommendations for the treatment of patients with KOA.
Trial registration reference: NCT01410409
PMCID: PMC3461437  PMID: 22571284
25.  Effect of cutaneous blood flow on absorption of insulin: a methodological study in healthy male volunteers 
Absorption of drugs from subcutaneous tissue depends on several factors, including tissue perfusion at the administration site. Tissue perfusion can be manipulated by e.g. application of local heat. This may subsequently alter the rate or amount of absorption of drugs from a subcutaneous depot. The aim of the present study was to investigate if increased tissue perfusion after controlled local heating can change the absorption of subcutaneously administered short-acting insulin (Actrapid®, 100IU/ml). Thirteen healthy Caucasian males participated in two randomized experimental sessions; one session with locally applied controlled heat at the injection site, and a control session without local heat application. Tissue perfusion (blood flow) was monitored with Laser Doppler Imaging, and blood samples were taken to assess the levels of glucose and insulin. Local heat application at the site of insulin injection significantly enhanced tissue perfusion by approximately 145%. However, no correlation was found between insulin absorption and tissue perfusion. Based on our findings, it was concluded that tissue perfusion is not the rate-limiting factor in the absorption of high-concentration short-acting insulin from a subcutaneous depot. It is suggested that dissociation of insulin hexamers into dimers and monomers is a major rate limiting factor to the absorption.
PMCID: PMC3230259  PMID: 22162782
Local heat; skin perfusion; insulin; Actrapid®; subcutaneous depot; absorption

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