Original Research Article Assessment of Pressure-Pain Thresholds and Central Sensitization of Pain in Lateral Epicondylalgia

bs_bs_banner Pain Medicine 2013; 14: 297 304 Wiley Periodicals, Inc. MUSCULOSKELETAL SECTION Original Research Article Assessment of Pressure-Pain Thresholds and Central Sensitization of Pain in Lateral Epicondylalgia Anders Jespersen, MD, PhD,* Kirstine Amris, MD,* Thomas Graven-Nielsen, Professor, DMSc., Lars Arendt-Nielsen, Professor, DMSc., Else Marie Bartels, PhD,* Søren Torp-Pedersen, MD,* Henning Bliddal, Professor, DMSc.,* and Bente Danneskiold-Samsoe, Professor, DMSc.* *The Parker Institute, Frederiksberg Hospital, Frederiksberg; Center for Sensory-Motor Interaction (SMI), Aalborg University, Aalborg, Denmark Reprint requests to: Anders Jespersen, MD, PhD, The Parker Institute, Frederiksberg Hospital, Nordre Fasanvej 57, DK-2000 Frederiksberg, Denmark. Tel: +45 3075 3613; Fax: +45 3816 4159; E-mail: anders.j@dadlnet.dk. Abstract Objective. To assess pain sensitivity and spreading hyperalgesia in lateral epicondylalgia (LE). Subjects. Twenty-two women with LE, and 38 controls were included. Outcome Measures. Computerized cuff pressure algometry was used for assessment of pressure-pain threshold and tolerance. The stimulus was applied using a single (stimulation-area: 241 cm 2 ) or doublechambered (stimulation-area: 482 cm 2 ) tourniquet on the arm and leg. Spatial summation was expressed as the ratio between pressure-pain thresholds to single and double cuff-chamber stimulation. During 10-minute constant pressure stimulation at intensity relative to the individual pain threshold, the pain intensity was continuously recorded using an electronic visual analogue scale (VAS), and from this the degree of temporal summation was estimated. For LE, a Doppler ultrasound examination of the elbow was made to identify inflammation. Results. In LE compared with controls the pressure-pain threshold and tolerance were on average reduced by respectively 31% (nonsignificant) and 18% (nonsignificant) on the lower arm and by 32% (P < 0.05) and 22% (P < 0.05) on the lower leg (spreading sensitization). Within the LE group, pressure-pain thresholds were on average reduced by 20% (P < 0.05) and pain tolerance by 10% (nonsignificant) on the painful compared with the asymptomatic side. Spatial summation (P < 0.01) and temporal summation (P < 0.05) was facilitated in LE compared with controls. In LE patients without signs of peripheral inflammation assessed by Doppler ultrasound, temporal summation was significantly stronger than in patients with ongoing inflammation (P < 0.01). Conclusion. Patients with LE may be subgrouped based on pain hypersensitivity and Doppler ultrasound into clinically meaningful subgroups with varying duration of symptoms and different degrees of central sensitization. These groups may require different pain management strategies. Key Words. Cuff Algometry; Hypersensitivity; Hyperalgesia; Spreading Sensitization; Epicondylitis; Central Sensitization; Temporal Summation; Spatial Summation Introduction Lateral epicondylalgia (LE) or tennis elbow is a common disorder affecting approximately 1 3% of the population [1,2]. It is characterized by pain localized to the lateral epicondyle, which in some cases radiates into the dorsal forearm and wrist. The pathophysiology of LE is complex but current evidence suggests that it is caused by an interplay of three different components: Local tendon pathology (angiofibroblastic hyperplasia), changes in the pain system (sensitization), and motor system impairment (dysfunction) [3]. The diagnosis of LE is based upon clinical examination, but some studies have shown a good correlation to power/color Doppler ultrasound 297

Jespersen et al. examination identifying ongoing inflammation in the common extensor region [4]. Pain is the core symptom of LE, and whereas the degree of local tendon changes, and motor system impairment can be assessed by ultrasonography and physical examination, it is more complicated to assess changes in the pain system. Studies have shown that patients with LE have reduced pressure-pain thresholds over the affected epicondyle [5], over the contralateral, unaffected, epicondyle [6], and at other sites of the body such as the neck and the lower leg [7] indicating the presence of spreading sensitization. The increased pain sensitivity in LE may be restricted to pressure pain, since cold and heat pain thresholds are not impaired [6]. However, one study shows that patients with LE exhibit larger areas of referred pain after injections of hypertonic saline both in the affected elbow and on the unaffected side when compared to pain-free controls, which may be a strong indication of central sensitization [8]. Central sensitization of pain is defined as an increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input [9]. Clinically, this results in increased pain sensitivity, spreading of the pain/hyperalgesia to neighboring areas and spontaneous pain [10,11]. A proposed model of central sensitization is that peripheral excitation and sensitization of the nociceptors is induced by a tissue injury. This induces a secondary sensitization of the segmental ipsilateral dorsal horn neurons which again spreads to the segmental contralateral dorsal horn neurons. Finally, an extrasegmental spread of the sensitization occurs. Also, a reorganization of the higher brain areas may take place during the final steps of the sensitization process [12]. Central sensitization have been documented in many musculoskeletal conditions such as fibromyalgia [13,14], chronic low back pain, [15] and osteoarthritis [16,17]. A peripheral nociceptive input caused by local inflammation of the elbow region in LE may induce and maintain central sensitization [8]. Furthermore, central sensitization could explain the lack of sufficient response to treatment in a large number of cases of LE [18] and may suggest that alternative treatment regimes should be applied [19]. Computerized cuff pressure algometry (CPA) is a tool designed for assessment of the pressure-pain sensitivity and central mechanisms related to temporal and spatial summation of pressure pain. CPA primarily assesses sensitivity of muscle and deep tissue and is less influenced by inter- and intra-examiner bias than handheld pressure algometry [20,21]. The method has previously been used to assess deep tissue pain sensitivity in fibromyalgia [22,23] and temporal and spatial summation of pain [17,24] which are associated with central sensitization [12]. The hypotheses of this study are that patients with LE, as compared to pain-free control subjects, in addition to localized pressure hyperalgesia show 1) facilitated temporal summation of pain during continuous cuff pressure stimulation; 2) facilitated spatial summation of pain assessed by cuff pressure stimulations; and 3) spreading hyperalgesia. Moreover, it is hypothesized that subgroups of LE patients may suffer from a primarily centrally mediated pain condition (central sensitization). Materials and Methods Subjects This study included 22 women (median age: 43 years, range 39) with LE recruited from the Department of Rheumatology at Frederiksberg University Hospital in Copenhagen and 38 pain-free female controls (median age: 39 years, range 25) mainly recruited among the participants in the Copenhagen City Heart Study [25]. Mean duration of pain among the patients was 5.6 months (SD: 3.2), mean habitual pain intensity measured on a 100 mm visual analogue scale (VAS) was 26 mm (SD: 25.0), and VAS-pain during activity was 39.2 mm (SD: 28.9). For other demographic data, please see Table 1. Participants were not admitted into the study if any of the following criteria were present: 1) other known rheumatic diseases; 2) past or current history of endocrine, cardiovascular, or pulmonary diseases; 3) psychiatric disorders; and 4) healthy controls who had experienced musculoskeletal pain within the last week. The study was approved by the local ethics committee (KF 01-058/02) and carried out in accordance with the Helsinki Declaration. Signed informed consent was obtained from all the participants. Protocol Computerized cuff pressure algometry was used for the determination of pressure-pain thresholds (lower arm and lower leg) and spatial and temporal summation of pain (lower leg only). In LE, pressure-pain thresholds were assessed on both arms and a Doppler ultrasound examination of the elbow was made on the painful side. In Controls, pressure-pain thresholds were assessed on the dominant arm only and no Doppler ultrasound examination was made. All recordings were made with the subject in supine position. Table 1 Demographic data of the female patients and controls (mean and SD) Demographic Data Lateral Epicondylalgia Controls P-value N = 22 38 Age (years) 43 (10.6) 38 (7.4) 0.03 Height (cm) 1.69 (0.05) 1.68 (0.06) NS Weight (kg) 74.8 (17.7) 67.6 (11.5) NS Body Mass Index 26.2 (5.9) 23.9 (3.6) NS 298

Experimental Setup for Computerized Cuff Pressure Algometry The experimental setup consisted of a tourniquet cuff, a computer controlled air compressor, and an electronic 10-cm visual analogue scale (VAS). The zero and 10 cm extremes on the VAS were defined as no pain and as the worst pain imaginable. The compressor (Condor MDR2, JUN-AIR International A/S, Nørresundby, DK) was connected to an electric-pneumatic converter (ITV2030, SMC Corp., Tokyo, Japan) and controlled by a computer through a data acquisition card (PCI 6024E, National Instruments, Austin, TX, USA). A handheld pressure release button connected to the data acquisition card allowed immediate termination of stimulation. The pain intensity was recorded on the VAS and sampled at 10 Hz. The computer continuously controlled the compression rate. Double-chambered textile tourniquet cuffs (VBM Medizintechnik GmbH, Sulz, Germany) were used for the application of stimulus. For the lower arm, a 35 cm long cuff was placed over the common extensor region. At the lower leg, a 61-cm cuff was placed over the widest part of m. gastrocnemius. Both cuffs were 13-cm wide with chambers along the whole length of the cuffs. In order to ensure reliable pressure readings, it was controlled that the cuff fitted tightly around the limb and that the cuff chambers covered all of the area to be assessed before each measurement [26]. The subjects were blinded to all the thresholds measured. Assessment of Pressure-Pain Thresholds and Summation of Pain Both cuff-chambers were automatically inflated (compression rate: 1.0 kpa/s). The subject was instructed to rate the pain intensity continuously on the VAS from the first sensation of pain and to press the handheld pressure release button at the pain intensity strong enough to make one feel like interrupting or stopping it. Pressure-pain threshold was defined as the moment of transition between strong and painful pressure (the first time the VAS exceeds 0). The pressure value at the termination of pressure inflation was defined as the pressurepain tolerance, and the corresponding VAS score was defined as the pressure-pain limit. The mean of three recordings, with 5-minutes intervals, was used. When determining spatial summation, the described measurements for thresholds were made on the lower leg with the distal cuff-chamber closed (single chamber stimulation), whereby the average stimulation area was reduced from 482 cm 2 to 241 cm 2. Based on the pressure-pain thresholds assessed with single and double chamber, a ratio was calculated to reflect the degree of spatial summation (SS-ratio: Pain Threshold double cuff/pain threshold single cuff). Central Sensitization in Lateral Epicondyalgia For assessment of temporal summation, both cuffchambers were inflated (20 kpa/s) to a pressure based on the average of the pressure-pain threshold and pressure tolerance of the individual subject. This was done to ensure that all the participants reached an equally painful but still tolerable level of cuff stimulation. The subjects were instructed to rate the pain caused by the cuff on the electronic VAS. They were furthermore instructed that the pain intensity could go up, remain stable, or drop, but they were not told that the cuff-pressure stimulation was constant. The stimulation was maintained for 10 minutes. The subjects could terminate the stimulation before if the pain intensity was strong enough to make one feel like interrupting or stopping it. A temporal summation index (TS-index) was extracted to compare the degree of temporal summation between subjects and to account for the subjects terminating stimulation prematurely due to enhanced summation: Main determinant for the degree of temporal summation was the VAS score at the end of the period of constant stimulation (VAS end), as the stimulation intensity was adjusted so that the initial VAS score was relative to the individual pain sensitivity. A possible adaptation or facilitation of pain was assessed and incorporated by a factor multiplied to the index as the final VAS score relative to the maximal VAS score (VAS end/vas max). Severe temporal summation would lead to the participants terminating stimulation prematurely due to intolerable pain. This was accounted for by multiplying the index with a ratio based on effective stimulation time: (10 min/time stimulation). The final temporal summation was hereafter: TS-index = log((vas end/vas max * (10/TIME stimulation) * VAS end). The TS-index increases with increasing degrees of temporal summation. Ultrasonographic Assessment of Inflammation in LE The elbows were examined with a U.S. machine (Siemens Acuson Sequoia; Mountainview, California, USA) equipped with a linear array probe with a center frequency of 14 MHz. The color Doppler settings were the same for all the patients with a gain setting just below the noise level using our setup for low flow: Nyquist limit +/-0.014 m/s, lowest wall filter, and 7 MHz Doppler frequency. With these settings, all color pixels in the image correspond to motion that is, blood flow. We used color rather than power Doppler, because the color Doppler has highest sensitivity on this machine. The patient was examined sitting with the elbow in 90 flexion and the arm resting on the examination couch in front of the examiner. The transducer was aligned with the long axis of the radius over the common extensor origin (CEO). The CEO was examined with color Doppler U.S. in the longitudinal plane by moving the transducer from side to side. Our region of interest (ROI) was limited proximally by the tip of the lateral epicondyle and distally by the humeroradial joint space. The superficial border was the most 299

Jespersen et al. superficial fibers, and the deep border was the bone; thus, we included the lateral collateral ligament in the ROI. The medial and lateral limitations were defined by the borders of the head of the radius thus, the head of the radius had to be present in the image. Based on color Doppler findings, the examiner diagnosed each subject as having or not having ongoing inflammation in the LE. The diagnosis of ongoing inflammation in the LE was defined as the presence of color Doppler activity inside the ROI. Statistics Statistical analyses were calculated using PASW 18.0 statistics (SPSS Inc., Chicago, IL, USA). Analysis of variance (ANOVA) was made with all primary parameters (pressurepain threshold and tolerance, spatial summation, and TS-index) as dependent variables and group (LE, HC) as fixed variables. Furthermore, pressure-pain sensitivity on affected and unaffected arm in LE was assessed in two different analyses against pressure-pain sensitivities on arm in HC. For analysis of temporal summation, an additional repeated measures ANOVA was made with VASpain rating as the dependent variable and group as fixed variable and time as repeated variable. Post hoc tests: Within-group changes in pressure-pain thresholds and spatial summation were assessed using a two-sample t-test. To control for multiple comparisons, Tukey s correction was used. Relationships between parameters were assessed by the Pearson correlation test. Data are presented as mean and standard error of the mean (SEM). Significance was accepted at P < 0.05. Results Pressure-Pain Threshold and Tolerance (Table 2) Pressure-pain threshold and tolerance measured on the lower arm were not significantly different between Table 2 Cuff algometry parameters (mean and SED) Pressure-Pain Thresholds LE and controls although 31% and 18% lower in the LE group. Within the LE group, the pressure-pain thresholds were significantly decreased by 20% on the painful side as compared to the asymptomatic side (P = 0.04). Note: In two LE patients, measurements could not be included from a pain-free side due to bilateral epicondylalgia. Pressure-pain threshold and tolerance measured on the lower leg were reduced by 38% (P = 0.02) and 22% (P = 0.02), respectively, in LE compared to pain-free controls when using single cuff stimulation (stimulation area: 281 cm 2 ). Using double cuff stimulation on the lower leg pressure pain threshold and tolerance were not reduced significantly. In LE, a significant correlation was found between habitual VAS-pain intensity and both pain threshold and tolerance on lower leg and arm (r =-0.45 to r =-0.80, P < 0.05). Similar correlation was also found for VAS-pain intensity during work and pain threshold and tolerance measured on lower leg and arm (r =-0.49 to r =-0.57, P < 0.05) except for pain tolerance 482 cm 2 measured on the lower leg (r =-0.35, NS). No correlation between duration of pain in LE and pain threshold or pain tolerance was observed. Spatial Summation of Pain (Assessed on the Lower Leg) In LE, there was no significant change in pressure-pain threshold when increasing stimulation area, whereas a significant reduction in the pressure-pain threshold was found in controls when increasing stimulation area (P < 0.001). Spatial summation ratio was significantly higher in pain-free controls indicating a higher degree of spatial summation in this group (SS-ratio: LE: Lateral Epicondylalgia Controls P-value Lower arm Affected side Pain-free side Pressure-pain threshold (kpa) 25.3 (4.1) 31.7 (5.2)* 36.8 (4.6) NS Pressure-pain tolerance (kpa) 76.1 (7.3) 84.4 (7.2) 90.5 (5.8) NS Lower leg Single cuff (281 cm 2 ) Pressure-pain threshold (kpa) 22.6 (3.3) 36.2 (3.6) 0.02 Pressure-pain tolerance (kpa) 61.9 (5.5) 79.8 (4.4) 0.02 VAS-pain limit (cm) 8.4 (0.4) 8.2 (0.4) NS Double cuff (482 cm 2 ) Pressure-pain threshold (kpa) 21.1 (2.4) 24.9 (2.0) NS Pressure-pain tolerance (kpa) 51.0 (4.1) 56.0 (3.15) NS VAS-pain limit (cm) 8.2 (0.37) 8.1 (0.37) NS * Pressure-pain threshold was significantly lower on affected side compared to healthy side, P = 0.04. NS = nonsignificant. 300

Central Sensitization in Lateral Epicondyalgia 1.06 0.08, HC: 1.45 0.07, P = 0.001). In patients with LE, the spatial summation ratio correlated significantly to habitual VAS-pain intensity (r =-0.47, P < 0.05). No correlation between spatial summation ratio and duration of pain was observed. Temporal Summation of Pain (Assessed on the Lower Leg) Mean stimulation time was 7.6 0.83 and 9.87 0.09 minutes in LE and pain-free controls, respectively. Seven LE and two pain-free controls discontinued stimulation due to intolerable pain. Two subjects refused to participate in measurements of temporal summation, and one subject was excluded due to a miscalculation of stimulus intensity. Temporal summation, expressed as the temporal summation-index, was 37% higher in LE compared to pain-free controls (TS-index: LE: 0.97 0.16, HC; 0.71 0.04, P < 0.05). A mixed model ANOVA was made on VAS-pain intensity at the different time-points of stimulation. No significant interaction was found between group and time-points (f = 1.68, P = 0.2). A significant correlation was found between duration of clinical pain and TS-index (r = 0.76, P < 0.01) indicating a higher degree of temporal summation in patients with longer lasting pain. No correlation between habitual pain and TS-index was observed. Subgrouping Based on Peripheral Inflammatory Activity (Table 3) Fifty percent of the LE patients (LE+) had ongoing inflammation at the lateral epicondyle on the painful side Table 3 assessed by Doppler ultrasound examinations. Both duration of pain and VAS scores of habitual pain were numerically lower in LE+, although these were not statistically significant (Table 3). Significantly lower pain tolerance measured on arm was observed in LE patients without Doppler signs of inflammation (LE ) compared to pain free controls. Temporal summation expressed as the TS-index was significantly increased in LE compared to both LE+ and controls (P = 0.002 and P = 0.009 respectively). Furthermore, spatial summation was significantly decreased in LE patients both with and without active inflammation (LE+: 1.07, LE : 1.05, Controls: 1.45, P < 0.01). Discussion Summary of Findings Subgrouping based on Doppler ultrasound activity (mean and SEM) Lateral Epicondylalgia + Doppler Activity The current study shows that patients with LE may be subgrouped based on pain sensitivity and Doppler ultrasound suggesting the need for different pain management strategies for the individual groups. Patients without any sign of inflammatory activity in the affected area had facilitated temporal summation as compared to both controls and patients with inflammatory activity. Furthermore, it was shown that LE patients had significantly lower pressure-pain thresholds on the painful arm as compared to the asymptomatic side. Significantly, lower pressurepain threshold and tolerance were found in LE compared to controls when stimulating on the lower leg indicating the existence of spreading sensitization. Spreading Hyperalgesia and Spatial Summation in LE The present study supports the presence of spreading hyperalgesia in the group of LE patients. Fernández-Carnero et al. [7] showed that LE patients had Doppler Activity Controls N = 11 11 38 Duration of pain (months) 4.9 0.9 6.4 1.2 Habitual VAS-pain intensity (mm) 18.5 (3.0) 34.5 (10.6) VAS-pain during activity (mm) 41.5 (6.1) 36.9 (11.0) Lower arm (affected side) Pain threshold (kpa) 31.3 (6.4) 19.4 (4.7) 36.8 (4.6) Pain tolerance (kpa) 89.6 (9.5) 62.7 (9.8)* 90.5 (5.8) Lower leg Pain threshold 241 cm 2 (kpa) 22.1 (3.6) 23.1 (5.7) 36.2 (3.6) Pain tolerance 241 cm 2 (kpa) 59.0 (4.0) 64.9 (10.3) 79.8 (4.4) Pain threshold 482 cm 2 (kpa) 22.2 (3.5) 20.0 (3.5) 24.9 (2.0) Pain tolerance 482 cm 2 (kpa) 50.5 (5.4) 51.5 (6.5) 55.9 (3.1) Spatial summation-ratio 1.07 (0.1)* 1.05 (0.13)* 1.45 (0.07) Temporal summation-index 0.67 (0.17) 1.26 (0.22)*, ** 0.71 (0.04) * Significantly different from Controls (P < 0.05); ** Significantly different from LE+ (P < 0.01). 301

Jespersen et al. pressure-pain hypersensitivity at sites distant from the elbow including the tibialis anterior muscle on the lower leg using manual pressure algometry (stimulation area: 1 cm 2 ). The decrease in pressure-pain threshold on the lower leg in LE reported in the current study was restricted to a stimulation volume of 241 cm 2. To study the role of spatial summation, a ratio between pain threshold determined at stimulation volumes at respectively 281 cm 2 and 482 cm 2 was calculated. The spatial summation ratio was significantly higher in controls indicating a larger increase in pain threshold when decreasing stimulation area by 50% as compared to LE where no change was observed in the pain threshold. To our knowledge, facilitated spatial summation of pain has not been reported previously in LE. However, similar patterns have been observed in fibromyalgia (FM) [27]; and furthermore, a study by Julien et al. suggests that altered spatial summation in FM is caused by a deficit in the descending pain inhibition control system (DNIC) [28]. The latter group showed that in FM no reduction in pain intensity was observed in the ascending phase of painful cold water stimulation (i.e., when decreasing stimulation area), which was in contrast to healthy subjects and patients with low back pain. A similar pattern was observed in LE in this study when decreasing stimulation area. Temporal Summation and Relationship to Ongoing Inflammation of the Elbow This is the first study showing facilitated temporal summation in LE patients indicating involvement of central sensitization [12]. This is in line with other studies reporting generalized hyperalgelsia in LE [7,8]. Although the significant difference in temporal summation was based on the total group of LE patients, a subgroup analysis showed that facilitated temporal summation of pain was most pronounced in the group of patients without Doppler ultrasound verified inflammation of the lateral epicondyle. In addition, this subgroup had significantly lower pressurepain tolerance on the affected arm, a higher habitual pain intensity (ns), and longer duration of symptoms (ns), all indicating a higher degree of central sensitization. This may have an impact on the understanding of LE and the way the condition is managed. We propose that the patients having inflammatory activity on the Doppler examination belongs to an early stage of LE. The ongoing peripheral inflammation may be a consequence of overuse leading to increased nociceptive activity from this tissue. This nociceptive input will induce the process of central sensitization, and if this activity is not inhibited by sufficient treatment the patients will become sensitized leading to increased pain sensitivity, general hyperalgesia, and facilitated temporal summation of pain. In this study, a correlation between temporal summation and duration of pain was found supporting the presence of central sensitization further [29]. The patients showing facilitated temporal summation but not peripheral inflammation on Doppler examination most likely represent a subgroup of patients that are sensitized to a degree where a peripheral input is no longer necessary for the maintaining of pain hypersensitivity due to the central sensitization. This model may impact the way LE is managed and could explain the moderate effect of localized injections [30]. The treatment may have to be tailored depending on whether the pain condition includes central sensitization. Methodological Considerations The study by Fernandez-Carnero et al. indicates that pressure-pain may be the optimal modality for assessing pain sensitivity in LE [6], and in the previous studies, assessing pressure-pain sensitivity in LE handheld algometers with a 1 cm 2 probe have been used. According to the study by Slater et al. [8], the increased pressurepain sensitivity in LE is restricted to the common extensor region, whereas the radial head and the extensor carpi radialis brevis muscle did not have increased pain sensitivity as compared to controls. In this study, pressure-pain sensitivity was assessed using computerized cuff pressure algometry which is an investigator independent method allowing semi-automatic measurements of pressure-pain thresholds and advanced pain mechanisms. During measurements on the lower arm, the tourniquet cuff used did not only stimulate on the lateral epicondyle but also to the distal, adjacent, areas. The cuff makes repeated positioning easier [20] but as the stimulation area is larger, pressure-pain thresholds found in this study are not directly comparable to those found in earlier studies. An advantage of using a cuff for the stimulation instead of a handheld algometer is that the latter may be biased by the sensitivity of skin and examiner interference/feedback [31 33], whereas the cuff used in this study is computer controlled and mainly stimulates muscle tissue [21]. A limitation of the current findings is that the trial population consisted of female subjects only and that pain measurements were not aligned with respect to ovarian cycle and hormone status of the participants. Further studies are needed to clarify the relationship of ovarian cycle and cuff pain measurements in female subjects. In addition, it remains to be clarified whether there are gender differences in cuff pain measurements and central sensitization in subjects with LE. In conclusion, patients with LE may be subgrouped based on pain hypersensitivity and Doppler ultrasound into clinically meaningful subgroups with varying duration of symptoms and different degrees of central sensitization. The patients having a longer duration of symptoms and a higher degree of central sensitization of pain may represent a more severe group of LE patients requiring a different and more intensive pain management strategy. Acknowledgments Each of the authors has read and concurs with the content in the final manuscript. The authors greatly appreciate the participants of the study and acknowledge the assistance of staff members at the Parker Institute. This study was financially supported by grants from The Oak Foundation, The Danish Rheumatism Association, Overlæge Poul 302

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