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Quantitative Sensory Tests Predict Clinical Pain Intensity in Patients with Chronic Musculoskeletal Pain Syndromes

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Title:
Quantitative Sensory Tests Predict Clinical Pain Intensity in Patients with Chronic Musculoskeletal Pain Syndromes
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Mokhtech, Meriem
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English

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Subjects / Keywords:
Arthritis ( jstor )
Chronic pain ( jstor )
Fibromyalgia ( jstor )
Hands ( jstor )
Hyperalgesia ( jstor )
Muscles ( jstor )
Pain ( jstor )
Sensitization ( jstor )
Shoulder ( jstor )
Symptomatology ( jstor )
Chronic pain
Hyperalgesia
Musculoskeletal system
Pain
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Undergraduate Honors Thesis

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Abstract:
Patients with chronic musculoskeletal pain syndromes have a number of abnormalities in pain processing, such as hyperalgesia, allodynia, and central sensitization. These processes all play a crucial role in the generation of clinical pain and thus led us to hypothesize that quantitative sensory testing (QST) of chronic pain patients could be used to predict clinical pain intensity. Using an electronic algometer, mechanical hyperalgesia testing was performed on the shoulders and hands of 23 normal control (NC), and 36 fibromyalgia syndrome (FMS) participants. An electronic visual analogue scale (eVAS) was displayed on a 19-inch monitor in front of the participant and was used by the subjects to rate their experimental pain during the testing. The testing consisted of 10 second mechanical stimuli between 200 - 400 kPa, which were applied to the shoulders and the hands, bilaterally. In addition, a tender point (TP) assessment was conducted on all participants. The clinical pain of FMS patients averaged at 2.9 VAS units. Ratings of mechanical stimuli at the shoulders and hands were significantly greater for FMS than NC subjects. NC participants had an average of 3.4 TPs and FMS participants had an average of 15.8 TPs. Hierarchical regressions of pressure pain ratings, TP counts, and negative affect predicted approximately 50% of the variance in clinical pain intensity. Thus this combination of tests may be used in clinical practice for FMS and numerous other pain syndromes. ( en )
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Awarded Bachelor of Science; Graduated May 8, 2012 summa cum laude. Major: Biology, Emphasis/Concentration: Pre-Professional
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Advisor: Roland Staud
General Note:
College of Liberal Arts and Sciences

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University of Florida
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Copyright Meriem Mokhtech. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.

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1 Quantitative Sensory Tests Predict Clinical Pain Intensity in Patients with Chronic Musculoskeletal Pain Syndromes Keywords: Fibromyalgia, Quantitative Sensory Testing, Chronic Pain, Pain Meriem Mokhtech UFID Meriem@ufl.edu Research Advisor: Roland Staud, MD Department of Medicine

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2 Abstract Patients with chronic musculoskeletal pain syndromes have a number of abnormalities in pain processing, such as hyperalgesia, allodynia, and central sensitization These processes all play a crucial role in the generation of clinical pain and thus led us to hypothesize that quantitative sensory testing (QST) of chronic pain patients could be used to predict clinical pain intensity. Using an electronic algometer, mechanical hyperalgesia te sting was performed on the shoulders and hands of 23 normal control (NC), and 36 fibromyalgia syndrome (FMS) participants. An electronic visual analogue scale (eVAS) was displayed on a 19 -inch monitor in front of the participant and was used by the subjects to rate their experimental pain during the testing. The testing consisted of 10 second mechanical stimuli between 200 400 kPa, which were applied to the shoulders and the hands, bilaterally. In addition, a tender point (TP) assessment was conducted on all participants. The clinical pain of FMS patients averaged at 2.9 VAS units. Ratings of mechanical stimuli at the shoulders and hands were significantly greater for FMS than NC subjects. NC participants had an average of 3.4 TPs and FMS participants had an average of 15.8 TPs. Hierarchical regressions of pressure pain ratings, TP count s, and negative affect predicted approximately 50% of the variance in clinical pain intensity. Thus this combination of tests may be used in clinical practice for FMS and numerous other pain syndromes.

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3 Introduction Fibromyalgia syndrome (FMS) is a condition characterized by chronic widespread musculoskeletal pain that appears to be related to deep tissue structures and is most commonly described as dull and aching. Individuals with FMS also experience fatigue, sleep disturbances, and some psychological symptoms (Henriksson, 1994). Patients that report such symptoms are estimated to comprise approximately 2% of the general population (Wolfe et al., 1995). The classification of FMS previously depended upon the 1990 American College of Rheuma tology (ACR) criteria, which centered primarily on a tender point (TP) assessment (Wolfe et al., 1990). In 2010, the ACR revised this diagnostic criteria to be based on the number of painful body regions, the presence and severity of fatigue, cognitive dif ficulty, and the extent of somatic symptoms (Wolfe et al., 2010). While the cause of FMS is still unclear, it is thought to be a result of abnormal functioning of the central nervous system. In better understanding the underlying mechanisms of chronic pain syndromes, it is hoped that better diagnosis and treatment methods can be developed for FMS and other chronic pain conditions. A number of studies have shown that individuals with FMS have abnormalities in pain processing, including increased central sensitization which results in hyperalgesia and enlargement of receptive fields (Staud et al., 2001; Berglund et al., 2002; Granot et al., 2001; Lorenz et al. 1996; Lautenbacher et al., 1997). This in turn suggests that central sensiti zation of afferent nociceptive pathways is an important contributor to the sensory abnormalities of patients with FMS (Yunus, 1992). Central sensitization is the process by which neurons become more likely to fire in response to a given noxious stimulus. The enhancement in neuronal functioning is a result of increases in membrane excitability and synaptic efficacy, and a reduction in inhibition. This

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4 results in allodynia, pain due to a stimulus that normally does not provoke pain, and hyperalgesia, an increased response to a stimulus that is normally painful (Latremoliere et al., 2007). Since much of the temporal, spatial, and threshold changes in chronic pain patients can be attributed to central sensitization, it is clear that the central nervous system (CNS) plays a key role in the mechanism of pain hypersensitivity. However, peripheral impulse inputs have been shown to contribute to maintaining central sensitization in individuals with FMS (Staud et al., 2009). Somatic hyperalgesia is a common symptom of FMS. The presence of mechanical and heat hyperalgesia in FMS patients has been shown numerous times (Staud et al., 2007; Staud et al., 2008), and there is building evidence to show that both peripheral and central pain mechanisms play a role in the hyperalgesia that FMS patients experience. When the neuronal mechanisms of this hyperalgesia were analyzed, it was suggested that the pain of FMS patients is connected to extensive primary and secondary cutaneous hyperalgesia, which are in turn supported by impulses from deep tissues (Staud, 2010). Physiological and physical stress are both initiating factors that are linked to hyperalgesia in individuals with FMS (Neumann et al., 2003). When the hyperalgesia of FMS patients has been established, it can be mainta ined with relatively few tonic impulses (Staud, 2010). Additionally, the majority of the pain reported by FMS patients appears to stem from deep tissue structures, more specifically from muscles. When the effects of peripheral impulses were studied further to determine their contribution to the chronic pain of FMS patients, it was found that after TP injections of 1% lidocaine, local muscle hyperalgesia and remote heat hyperalgesia were significantly reduced (Staud et al., 2009) This emphasizes the role of peripheral inputs in maintaining central sensitization in FMS patients (Staud, 2010).

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5 Patients with FMS also exhibit tenderness, or increased sensitivity, to mechanical stimulation, most notably in deep tissues (Simms et al., 1988). Pressure algometry is typically employed to measure tenderness in FMS patients and there is evidence to show that FMS patients have lower thresholds for pressure pain than NCs (Lautenschlager et al., 19 88). This muscle tenderness often manifests itself in the form of allodynia and can be measured by a TP assessment. As defined by the ACR, there are 18 TPs in the body (Wolfe et al., 1990). However, TP counts have not been shown to reliably predict clinica l pain, rather they are more strongly linked to specific negative psychological components (Wolfe, 1997). There also appears to be a correlation between TP counts and disability in individuals with FMS (Croft et al., 1994a). Furthermore, clinical pain has been strongly associated with negative affect (Keefe et al., 1986). The various pain processing abnormalities of patients with FMS, including mechanical and thermal hyperalgesia and allodynia, as well as central sensitizatio n led us to hypothesize that sensory testing of hyperalgesia and allodynia would be useful in predicting clinical pain in FMS patients. Alternatively, since chronic widespread musculoskeletal pain appears to be related to deep tissue structures, we decided to test whether muscle stimulation is related to the pain of individuals with FMS.

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6 Methods The University of Florida Institutional Review Board approved the procedures and protocol f or this study. Informed consent was obtained from all subjects and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Study Subjects Subjects were recruited from Gainesville and the surrounding areas. Before testin g, an examination was conducted and subjects were excluded from the study if they had abnormal clinical findings unrelated to FMS or were unable to reliably rate pain. A history of diabetes, radiation therapy, or numbness in the extremities were all exclus ionary criteria. All subjects were required to follow strict medication guidelines. No analgesics, non -steroidal anti-inflammatory drugs (NSAID), benzodiazepines, or antihistamines were allowed, and only low dose SSRI/SNRI/TCAs were permitted. All subjects must have been on acceptable medications for at least 5 half -lives prior to study. Negative Affect Questionnaires The study consists of three parts: questionnaires, a TP assessment, and quantitative sensory testing (QST). Participants first signed an Inf ormed Consent Form and were informed of HIPAA protocol. Next, participants completed a medical history sheet, a revised life orientation test (LOT-R), a fear of pain questionnaire (FPQ-III), a Pittsburgh sleep quality index (PSQI), a pain catastrophizing scale (PCS), a Becks depression inventory (BDI-II), a state-trait anxiety inventory (STAI and STAII), and a medical college of Virginia (MCV) pain questionnaire. Tender Point Assessments After consenting, a TP assessment was performed according to the 1990 ACR criteria. Nine paired TPs and two control points, at the center of the nondominant forearm and thumbnail,

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7 were assessed using an algometer that was increased at a rate of 1kg/sec up to a maximu m of 4kg. The algometer had a rubber tip with a 1 cm diameter. Each subject was instructed to report when the sensation at the examination site changed from pressure to pain, at which point pressure testing was stopped. If pain was reported at <4kg, the result was recorded as positive. Ratings of Clinical and Experimental Pain For the QST, both a mechanical and electronic visual analogue scale (VAS) were employed to measure pain ratings. The mechanical VAS is a 10 cm long slide scale, with a range from 0-10 and was anchored on the left with no pain at all and on the right with the most intense pain sensation imaginable. Before the sensory testing took place, initial clinical pain ratings were recorded using a mechanical VAS, where partic ipants were asked to rate their current pain intensity and pain unpleasantness. The subjects were then asked to rate their clinical pain intensity using an electronic VAS (eVAS) displayed on a monitor in front of them, which ranged from 0-100 and was anchored with the same labels as the mechanical VAS. The eVAS was controlled through an intuitive dial that allows for the recording of continuous ratings. Upon completion of QST, subjects were asked to rate their pain sensation and unpleasantness in their entire body using the VAS and then again on the eVAS. Quantitative Sensory Testing Mechanical testing was performed bilaterally on the trapezius TP as well as the hegu region of the hand. The hegu regions were marked with a pen to ensure precision in all test s. Participants were first asked to rate any pain that they were experiencing, in the specific area being tested, on the eVAS. Once local pain was rated the scale was brought back to a 0 rating, and increasing pressure was applied to that location with an algometer for a duration of 6 seconds. After 6 seconds, the target pressure was held constant for an additional 4 seconds. Two

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8 target pressures were used: 200kPa (33.33kPa/sec), and 400kPa (66.67kPa/sec), for FMS participants and NC subjects. The particip ant was instructed to continuously rate the pain sensation they were feeling in the area being tested for the duration of the pressure testing using the eVAS. The participants were told that if at any point the pain sensation became unbearable, they could withdraw from the stimulus. After the 10 seconds of applied pressure, the algometer was removed and the participant was instructed to keep rating the pain sensation in that area, whether it went up, down, or stayed the same, for a maximum of 60 seconds. Th is sequence was repeated three times on each shoulder and each hand. Data Analysis SPSS 11.0 software (SPSS, Inc., Chicago, IL) was used to perform statistical analyses. A hierarchical regression analysis was employed to analyze the relationship between clinical pain, QST, TP counts, and negative affect.

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9 Results Study Participants A total of eighty-three subjects were recruited from Gainesville and the surrounding areas and enrolled in this study. The study population consisted of 23 NC participants, an d 36 FMS subjects. The mean age (SD) of study participants was 42.3 (13.6) and 47.6 (12.8) for NC and FMS subjects respectively. An independent t-test demonstrated no significant effect of diagnostic group (p > .05). Average number of TPs (SD) was 3.4 (3.5) for NC and 15.8 (3.5) for FM subjects. An independent t-test showed a significant difference between groups (p < .001). Clinical Pain Ratings Overall clinical pain of NC was minimal (2.0 VAS units on 100 point scale), whereas FM subjects rated their average (SD) pain as 47 (25) VAS units. An independent t-test showed a significant difference between groups (p < .001). Ratings of Mechanical Pain Stimuli Shoulder Stimuli All subjects received three 200 kPa pressure stimuli to each shoulder. Mean (SD) peak eVAS ratings of 200 kPa pressure stimuli by NC and FM subjects are listed in Table 1. An independent t-test demonstrated a significantly higher experimental pain ratings of FM subjects than NC (p < .001) (Figure 1). Because 400 kPa stimuli at the shoulders and hands did not provide fundamentally different predictors of clinical pain intensity than 200 kPA stimuli only the analyses of 200 kPA stimuli are reported here. Hand Stimuli The experimental pressure pain protocol was repeated at the hands (dorsa l webspace between 1st and 2nd finger) of all study subjects. The average (SD) peak eVAS ratings of NC and

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10 FMS subjects for 200 kPa at the hand are listed in Table 1. An independent t -test demonstrated significantly higher experimental pain ratings of FM than NC subjects (p < .001) (Figure 1). These findings demonstrate that mechanical hyperalgesia is widespread in FMS subjects and can be used to detect significant group differences between all study subjects, including NC. Predicting Clinical Pain Intensity Using Pressure Stimuli Several hierarchical regression analyses were used to determine whether pressure pain ratings can predict clinical pain intensity in FMS subjects. Because previous work with FMS subjects has demonstrated significant contribution s of TP and negative affect to clinical pain, we decided a-priori to include TP count and BDI-II scores in our model. To decrease the number of comparisons and thus spurious findings, multiple other factors were omitted from this analysis because we had no strong a-priori hypotheses for their inclusion. Using Pressure Pain Ratings at the Shoulders A hierarchical regression analysis was performed using clinical pain intensity VAS ratings as the predicted variable. Shoulder pressure pain sensitivity a t 200 kPa was entered as predictor variable in the first block, followed by TP count and BDI -II scores entered in separate blocks. The results of the regression indicated that 45.3 % of the variance in clinical pain scores was predicted by pressure sensitivity of FMS subjects (Table 2). Besides pressure pain ratings, neither TP count nor BDI-II scores contributed significantly to the pain variance in FM subjects. Overall, 50.0 % of the pain variance of FM subjects was predicted by unique contributions of pressure pain ratings at the shoulders, TP count, and BDI-II scores (Table 2). Using Pressure Pain Ratings at the Hands As before, hierarchical regression analyses were performed using clinical pain intensity VAS ratings as the predicted variable. Hand pressure pain sensitivity at 200 kPa, TP count, and

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11 BDI-II scores were entered as predictor variables. The results of these regressions indicated that 32.9% of the variance in clinical pain scores was predicted by pressure sensitivity in FM subjects (Table 3). Besides pressure pain ratings, neither TP count nor BDI -II scores contributed significantly to the pain variance in FM subjects. Overall, 46.6 % of the pain variance of FM subjects was predicted by unique contributions of pressure pain ratings at the hands, TP count, and BDI-II scores (Table 3).

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12 Discussion Since the chief complaint of individuals with FMS is muscle pain, we set out to investigate whether muscle signaling is involved in chronic pain mechan isms and whether stimulation of these muscles can help us predict the clinical pain of an individual with FMS. The central finding of this study is that when pressure pain ratings are considered alongside a TP count and negative affect, the clinical pain i ntensity of participants with chronic musculoskeletal pain can be predicted with reasonable accuracy. Additionally, these three variables do not contribute equally to the calculation of clinical pain intensity. Furthermore, since testing of muscles can be used to predict clinical pain intensity, muscle signaling does indeed play a role in the mechanism responsible for chronic pain. Contribution of Muscle Impulse Input to Fibromyalgia Syndrome Hyperalgesia in FMS patients can result from the sensitization o f nociceptors in deep tissues (Staud, 2011). It is thought that the specific nociceptors being sensitized include A -delta (!) and C-fibers, both nociceptive afferent fibers that are located in the dense innervations of vascular structures of muscles (Mense, 1991). Muscle fibers themselves do not contain any evident nociceptors, but stimulation of muscles can cause pain (Henriksson, 1993; Henriksson, 2003), thus A-delta and C-fibers are the focus of our investigation because they are the closest nociceptors to muscle fibers. Since sensitization results from repeated stimulation of a nociceptor, inflammatory myopathies, muscle activity, and other factors that cause muscle pain can all lead to sensitization of pain receptors (Staud, 2011). Thus, peripheral sensi tization that leads to irregular inputs from sensitized peripheral tissue receptors may in turn result in the mechanical hyperalgesia experienced by FMS patients (Staud, 2011). Psychophysical testing can be used to evaluate the underlying pain mechanisms a nd from our use of QST, we have shown

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13 that through stimulation of the muscles, a patients clinical pain intensity can be predicted with reasonable accuracy. This in turn provides evidence that suggests that abnormal muscle impulse inputs contribute to the pain experienced by individuals with FMS. QST as a Predictor of Clinical Pain From this study, it can be seen that FMS patients exhibit greater mechanical hyperalgesia than their NC counterparts. When examined together, mechanical pain ratings, TPs, and negative affect were found to predict up to 50% of the clinical pain in FMS participants In comparison with the other factors measured, QST, in the form of pressure pain ratings, predicted the greatest amount of the variance in clinical pain intensity. Thus, mechanical hyperalgesia can be used to predict clinical pain in patients with FMS. Ratings of experimental pain and pain -related negative effect have been previously shown to predict clinical pain in patients with FMS (Staud et al., 2003). However, this current approach offers greater ease in predicting the variability of clinical pain in patients with FMS. In the future, QST may be useful for predicting which patients will respond positively to a given treatment by ide ntifying which mechanisms are the greatest contributors to an individuals clinical pain. Tender Points as Predictors of Clinical Pain TPs were previously used to classify FMS patients (Wolfe et al., 1990). However in 2010, the ACR revised the diagnostic criteria to exclude TPs (Wolfe et al., 2010). This change resulted in part because a high TP count ( > 11) does not necessarily mean that a subject will report pain, despite the fact that the majority of individuals with widespread chronic pain have numerous TPs (Croft et al., 1994a). Furthermore, the measure of TPs has not been found to be a strong predictor of the clinical pain intensity of FMS patients (Quimby et al., 1988). Thus, mechanical allodynia, measured by TPs, seems to be only one of the factors underlying chronic

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14 widespread pain (Staud et al., 2003). Through hierarchical regression analysis, we demonstrated that TP counts represent a small but separate factor from mechanical pain stimuli for the prediction of clinical pain. TP counts are thought to be associated with spatial summation (Staud et al., 2003) and thus, activate a different mechanism than that responsible for mechanical hyperalgesia. These two factors seem to make independent contr ibutions to clinical pain intensity. Negative Affect as a Predictor of Clinical Pain In comparison to the contribution of mechanical hyperalgesia, pain related negative affect accounted for a much less significant amount of the variance in clinical pain of FMS patients Similar contributions of negative affect to clinical pain have been shown in a number of other studies (Keefe et al., 1986; Gaskin et al., 1992; Geisser et al. 1994; Staud et al., 2003). Additionally, several other studies of FMS have displayed a comparable relationship between negative mood and pain (Croft et al., 1994b; Lundberg and Gerdle, 2002; Wolfe, 1997). While negative affect did not play the largest role in the prediction of clinica l pain, it is still an important factor and may serve as a target for comprehensive pain therapy (Staud et al., 2003). Conclusions The model of mechanical hyperalgesia, TP count, and negative affect allows for a strong prediction of FMS clinical pain intensity. These factors each contribute to FMS clinical pain and they represent the influence of central and peripheral pain mechanisms. Thus, some of these factors may represent different mechanisms that interact and contribute to FMS (Staud et al., 2003). Furthermore, the pain that patients with FMS experience is likely influenced by peripheral impulse input from deep tissues. In understanding the contributions of these separate mechanisms for chronic pain syndromes, we can get a better idea for what treatme nts will be

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15 most effective in alleviating not only the pain of FMS patients, but also that of other chronic pain sufferers. Acknowledgements I would first like to express my thanks to Dr. Staud for his ongoing guidance, intellectual contributions, and mental stimulation. Furthermore, I would like to recognize the contributions of Elizabeth Weyl to this project, whose knowledge and insight has proved invaluable. I am also grateful for the endless support and continuing assistance of Viktoria Sisto. Lastly, I would like to thank the kind participants of this study for donating their time.

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16 Literature Cited Berglund B, Harju EL, Kosek E, Lindblom U. Quantitative and qualitative perceptual analysis of cold dysesthesia and hyperalgesia in fibromyalgia. Pain 2002 ;96:17787. Croft P, Schollum J, Silman A. Population study of tender point counts and pain as evidence of fibromyalgia. Br Med J 1994a;309:696-9. Croft P, Schollum J, Silman A. Population study of tender point counts and pain as evidence of fibromyalgia. Br Med J 1994b;309:696-9. Desmeules JA, Cedraschi C, Rapiti E, Baumgartner E, Finckh A, Cohen P, Dayer TL. Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis and Rheumatism 2003;48:14209. Gaskin ME, Greene AF, Robinson ME, Geisser ME. Negative affect and the experience of chronic pain. J Psychosom Res 1992;36:707-13. Geisser ME, Robinson ME, Keefe FJ, Weiner ML. Cattastrophizing, depression and the sensory, affective and evaluative aspects of chronic pain. Pain 1 994;59:79-83. Granot M, Buskila D, Granovsky Y, Sprecher E, Neumann L, Yarnitsky D. Simultaneous recording of late and ultra-late pain evoked potentials in fibromyalgia. Clinical Neurophysiology 2001;112:18817. Henriksson CM. Longterm effects of fibromyalgia on everyday life. A study of 56 patients. Scand J Rheymatol 1994, 23:36-41. Henriksson KG. Is fibromyalgia a distinct clinical entity? Pain mechanisms in fibromyalgia syndrome. A myologists view. Best Practice & Research Clinical Rheumatology 1999;13:45561.

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17 Henriksson KG. Fibromyalgia from syndrome to disease. Overview of pathogenetic mechanisms. Journal of Rehabilitation Medicine 2003;35:89 94. Keefe FJ, Wilkins RH, Cook WA Jr, Crisson JE, Muhlbaier LH. Depression, pain, and pain behavior. J Consult Clin Psychol 1986;54:665-9. Latremoliere A., Woolf CJ. Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity. Pain 2009;10:895-926. Lautenbacher S, Rollman GB. Possible deficiencies of pain modulation in fibromyalgia. Clinical Journal of Pain 1997;13:18996. Lautenschlager J, Bruckle W, Schnorrenberger CC, Muller W. Measuring pressure pain of tendons and muscles in healthy probands and patients with generalized tendomyopathy (fibromyalgia syndrome). Z Rheymatol 1988;47:397-404. Lorenz J, Grasedyck K, Bromm B. Middle and long latency somatosensory evoked potentials after painful laser stimulation in patients with fibromyalgia syndrome. Electroencephalography and Clinical Neurophysiology 1996;100:165 8. Lundberg G, Gerdle B. Tender point scores and their relations to signs of mobility, symptoms, and disability in female home care personnel and the prevalence of fibromyalgia syndrome. J Rhematol 2002;29:603-13. Mense S. Considerations concerning the neurobiological basis of muscle pain. Can J Physiol Pharmacol 1991;69:6106. Neumann L, Zeldets V, Bolotin A, Buskila D. Outcome of posttraumatic fibromyalgia: a 3 -year follow-up of 78 cases of cervical spine injuries. Semin Arthritis Rheum 2003;32:320 325.

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18 Quimby LG, Black SR, Gratwick GM. Fibromyalgia: Generalized pain intolerance and manifold symptom reporting. J Rheumatol 1988;15:1264-70. Russell IJ, Orr MD, Littman B, Vipraio GA, Alboukrek D, Michalek JE, Lopez Y, Mackillip F. Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis and Rheumatism 1994;37:1593601. Simms RW, Goldenberg DL, Felson DT, Mason JH. Tenderness in 75 anatomic sites. Distinguishing fibromyalgia patients from controls. Arthritis Rheum. 1988;31:182 -7. Russell IJ, Orr MD, Littman B, Vipraio GA, Alboukrek D, Michalek JE, Lopez Y, Mackillip F. Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis and Rheumatism 1994;37:1593601. Staud R. Is It All Central Sensitization? Role of Peripheral Tissue Nociception in Chronic Musculoskeletal Pain. Curr Rheumatol Rep. 2010;12(6):448-54. Staud R. Peripheral pain mechanisms in chronic widespread pain. Best Practice & Research Clinical Rheumatology 2011 25:155-164. Stau d R, Nagel S, Robinson ME, Price DD. Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: a randomized, double -blind, placebo controlled trial. Pain 2009, 145:96104. Staud R, Craggs JG, Perlstein WM Robinson ME, Price DD. Brain activity associated with slow temporal summation of C-fiber evoked pain in fibromyalgia patients and healthy controls. Eur J Pain 2008, 12:10781089. Staud R, Robinson ME, Vierck CJ Jr., Cannon RC, Mauderli AP, Price DD. Ratings of experimental pain and pain-related negative affect predict clinical pain in patients with fibromyalgia syndrome. Pain. 2003;105:215-222.

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19 Staud R, Robinson ME, Price DD. Temporal summation of second pain and its maintenance are useful for characterizing widespread central sensitization of fibromyalgia patients. J Pain 2007, 8:893901. Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD. Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 2001;91:16575. Wolfe F. The relation between tender pints and fibromyalgia symptom variables: evidence that fibromyalgia is not a discrete disorder in the clinic. Ann Rheum Dis 1997;56:268 -71. Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, Russell AS, Russell IJ, Winfield JB, Yunus MB. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken). 2010;62(5):600-10. Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of bromyalgia in the general population. Arthritis Rheum. 1995;38:19 -28. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33:160-72. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain.2011;152:S215. Yunus MB. Towards a model of pathophysiology of fibromyalgia: aberrant central pain mechanisms with peripheral modulation. Journal of Rheumatology 1992;19:846 50.

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20 Tables and Figures Table 1. Average (SD) Ratings of Pressure Pain at Shoulders and Hands NC FMS Shoulders 200 kPa (peak) 7.1 (11.8) 43.1 (29.4) Hands 200 kPa (peak) 10.9 (13.6) 34.3 (24.4) FM = fibromyalgia; NC = normal controls. Table 2. Pressure Pain at the Shoulders as Predictor of FM Pain Block Variable !R2 F Change p 1 200 kPa Rating .453 24.83 <.001 2 TP count .022 1.39 > .05 3 BDI-II .025 1.21 >.05 Beta (standardized) t 1 200 kPa Rating .528 3.28 <.003 TP count .177 1.18 > .05 BDI-II .152 1.02 > .05 Final Model: R2 = .500, F= 9.32; p < .001 Table 3. Pressure Pain at the Hands as Predictor of FMS Pain Block Variable !R2 F Change p 1 200 kPa Rating .329 14.72 <.005 2 TP count .074 3.60 > .05 3 BDI-II .062 3.26 >.05 Beta (standardized) t 1 200 kPa Rating 0.429 2.87 <.01 TP count 0.239 1.59 > .05 BDI-II 0.262 1.81 > .05 Final Model: R2 = .466, F= 8.13; p < .001

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21 Figure 1. Shoulder and hand pain ratings of all subjects during pressure stimuli. Experimental pressure stimuli were applied to the middle of the shoulders (trapezius muscle) or to the space between the first two fingers using an electronic algometer. After 10 seconds of 200 kPa pressure, pain ratings of FM subjects were significantly higher than NC. Similar results were found at the hands. FM = fibromyalgia; NC = normal controls.



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1 Quantitative Sensory Tests Predict Clinical Pain Intensity in Patients with Chronic Musculoskeletal Pain Syndromes Keywords : Fibromyalgia, Quantitative Sensory Testing, Chronic Pain, Pain Meriem Mokhtech UFID 2934 9419 Meriem @ ufl edu Research Advisor: Roland Staud, MD Department of Medicine

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2 Abstract Patients with chronic musculoskeletal pain syndromes have a number of abnormalities in pain processing, such as hyperalgesia, allodynia, and central sensitization These processes all play a crucial role in the generation of clinical pain and thus led us to hypothesize that quantitative sensory testing (QST) of chronic pain patients could be used to predict clinical pain intensity. Using an electronic algometer, mechanical hyperalgesia te sting was performed on the shoulders and hands of 23 normal control (NC), and 36 fi bromyalgia syndrome (FMS) participants. An electronic visual analogue scale (eVAS) was displayed on a 19 inch monitor in front of the participant and was used by the subjects to rate their experimental pain during the testing. The testing consisted of 10 s econd mechanical stimuli between 200 400 kPa, which were applied to the shoulders and the hands, bilaterally. In addition, a tender point (TP) assessment was conducted on all participants. The clinical pain of FMS patients averaged at 2.9 VAS units. Rati ngs of mechanical stimuli at the shoulders and hands were significantly greater for FMS than NC subjects. NC participants had an average of 3.4 TPs and FMS participants had an average of 15.8 TPs. Hierarchical regressions of pressure pain ratings, TP count s, and negative affect predicted approximately 50% of the variance in clinical pain intensity. Thus this combination of tests may be used in clinical practice for FMS and numerous other pain syndromes.

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3 Introduction Fibromyalgia syndrome (FMS) is a condi tion characterized by chronic widespread musculoskeletal pain that appears to be related to deep tissue structures and is most commonly described as dull and aching. Individuals with FMS also experience fatigue, sleep disturbances, and some psychological symptoms (Henriksson, 1994). Patients that report such symptoms are estimated to comprise approximately 2% of the general population (Wolfe et al., 1995). The classification of FMS previously depended upon the 1990 American College of Rheuma tology (ACR) criteria, which centered primarily on a tender point (TP) assessment (Wolfe et al., 1990). In 2010, the ACR revised this diagnostic criteria to be based on the number of painful body regions, the presence and severity of fatigue, cognitive dif ficulty, and the extent of somatic symptoms (Wolfe et al., 2010). While t he cause of FMS is still unclear, it is thought to be a result of abnormal functioning of the central nervous system. In better understanding the underlying m echanisms of chronic pain syndromes, it is hoped that better diagnosis and treatment methods can be developed for FMS and other chronic pain conditions. A number of studies have shown that individuals with FMS have abnormalities in pain processing, includi ng increased central sensitization which results in hyperalgesia and enlargement of receptive fields (Staud et al., 2001; Berglund et al., 2002; Granot et al., 2001; Lorenz et al. 1996; Lautenbacher et al., 1997). This in turn suggests that central sensiti zation of afferent nociceptive pathways is an important contributor to the sensory abnormalities of patients with FMS (Yunus, 1992). Central sensitization is the process by which neurons become more likely to fire in response to a given noxious stimulus. T he enhancement in neuronal functioning is a result of increases in membrane excitability and synaptic efficacy, and a reduction in inhibition. This

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4 results in allodynia, pain due to a stimulus that normally does not provoke pain, and hyperalgesia, an incre ased response to a stimulus that is normally painful (Latremoliere et al., 2007). Since much of the temporal, spatial, and threshold changes in chronic pain patients can be attributed to central sensitization, it is clear that the central nervous system (C NS) plays a key role in the mechanism of pain hypersensitivity. However, peripheral impulse inputs have been shown to contribute to maintaining central sensitization in individuals with FMS (Staud et al., 2009). Somatic hyperalgesia is a common symptom of FMS. The presence of mechanical and heat hyperalgesia in FMS patients has been shown numerous times (Staud et al., 2007; Staud et al., 2008), and there is building evidence to show that both peripheral and central pain mechanisms play a role in the hypera lgesia that FMS patients experience. When the neuronal mechanisms of this hyperalgesia were analyzed, it was suggested that the pain of FMS patients is connected to extensive primary and secondary cutaneous hyperalgesia, which are in turn supported by impu lses from deep tissues (Staud, 2010). Physiological and physical stress are both initiating factors that are linked to hyperalgesia in individuals with FMS (Neumann et al., 2003). When the hyperalgesia of FMS patients has been established, it can be mainta ined with relatively few tonic impulses (Staud, 2010). Additionally, the majority of the pain reported by FMS patients appears to stem from deep tissue structures, more specifically from muscles. When the effects of peripheral impulses were studied further to determine their contribution to the chronic pain of FMS patients, it was found that after TP injections of 1% lidocaine, local muscle hyperalgesia and remote heat hyperalgesia were significantly reduced (Staud et al., 2009) This emphasizes the role of peripheral inputs in maintaining central sensitization in FMS patients (Staud, 2010).

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5 Patients with FMS also exhibit tenderness, or increased sensitivity, to mechanical stimulatio n, most notably in deep tissues (Simms et al., 1988). Pressure algometry is typically employed to measure tenderness in FMS patients and there is evidence to show that FMS patients have lower thresholds for pressure pain than NCs (Lautenschlager et al., 19 88). This muscle tenderness often manifests itself in the form of allodynia and can be measured by a TP assessment. As defined by the ACR there are 18 TPs in the body (Wolfe et al., 1990). However, TP counts have not been shown to reliably predict clinica l pain, rather they are more strongly linked to specific negative psychological components (Wolfe, 1997). There also appears to be a correlation between TP counts and disability in individuals with FMS (Croft et al., 1994a). Furthermore, clinical pain has been strong ly associated with negative affect (Keefe et al., 1986). The various pain processing abnormalities of patients with FMS, including mechanical and thermal hyperalgesia and allodynia, as well as central sensitizatio n led us to hypothesize that sensory testing of hyperalgesia and allodynia would be useful in predicting clinical pain in FMS patients. Alternative ly since chronic widespread musculosk eletal pain appears to be related to deep tissue structures, we decided to test whether muscle stimulation is related to the pain of individuals with FMS.

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6 Methods The University of Florida Institutional Review Board approved the procedures and protocol f or this study. Informed consent was obtained from all subjects and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Study Subjects Subjects were recruited from Gainesville and the surrounding areas. Before testin g, an examination was conducted and subjects were excluded from the study if they had abnormal clinical findings unrelated to FMS or were unable to reliably rate pain. A history of diabetes, radiation therapy, or numbness in the extremities were all exclus ionary criteria. All subjects were required to follow strict medication guidelines. No analgesics, non steroidal anti inflammatory drugs (NSAID), benzodiazepines, or antihistamines were allowed, and only low dose SSRI/SNRI/TCA s were permitted. All subjects must have been on acceptable medications for at least 5 half lives prior to study. Negative Affect Questionnaires The study consists of three parts: questionnaires, a TP assessment, and quantitative sensory testing (QST). Participants first signed an Inf ormed Consent Form and were informed of HIPAA protocol. Next, participants completed a medical history sheet, a revised life orientation test (LOT R), a fear of pain questionnaire (FPQ III), a Pittsburgh sleep quality index (PSQI), a pain catastrophizing s cale (PCS), a Beck's depression inventory (BDI II), a state trait anxiety inventory (STAI and STAII), and a medical college of Virginia (MCV) pain questionnaire. Tender Point Assessments After consenting, a TP assessment was performed according to the 1990 ACR criteria. Nine paired TPs and two control po ints, at the center of the nondominant forearm and thumbnail

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7 were assessed using an algometer that was increased at a rate of 1kg/sec up to a maximu m of 4kg. The algometer had a rubber tip with a 1 cm diameter. Each subject was instructed to report when the sensation at the examination site changed from pressure to pain, at which point pressure testing was stopped. If pain was reported at < 4kg, the re sult was recorded as positive. Ratings of Clinical and Experimental Pain For the QST, both a mechanical and electronic visual analogue scale (VAS) were employed to measure pain ratings. The mechanical VAS is a 10 cm long slide scale, with a range from 0 10 and was anchored on the left with "no pain at all" and on the right with "the most intense pain sensation imaginable." Before the sensory testing took place initial clinical pain ratings were recorded using a mechanical VAS, where partic ipants were asked to rate their current pain intensity and pain unpleasantness. The subjects were then asked to rate their clinical pain intensity using an electronic VAS (eVAS) displayed on a monitor in front of them, which ranged from 0 100 and was ancho red with the same labels as the mechanical VAS. The eVAS was controlled through an intuitive dial that allows for the recording of continuous ratings. Upon completion of QST, subjects were asked to rate their pain sensation and unpleasantness in their enti re body using the VAS and then again on the eVAS. Quantitative Sensory Testing Mechanical testing was performed bilaterally on the trapezius TP as well as the hegu region of the hand. The hegu regions were marked with a pen to ensure precision in all test s. Participants were first asked to rate any pain that they were experiencing, in the specific area being tested, on the eVAS. Once local pain was rated the scale was brought back to a 0 rating and increasing pressure was applied to that location with an algometer for a duration of 6 seconds. After 6 seconds, the target pressure was held constant for an additional 4 seconds. Two

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8 target pressures were used: 200kPa (33.33kPa/sec), and 400kPa (66.67kPa/sec), for FMS participants and NC subjects. The particip ant was instructed to continuously rate the pain sensation they were feeling in the area being tested for the duration of the pressure testing using the eVAS. The participants were told that if at any point the pain sensation became unbearable, they could withdraw from the stimulus. After the 10 seconds of applied pressure, the algometer was removed and the participant was instructed to keep rating the pain sensation in that area, whether it went up, down, or stayed the same, for a maximum of 60 seconds. Th is sequence was repeated three times on each shoulder and each hand. Data Analysis SPSS 11.0 software (SPSS, Inc., Chicago, IL) was used to perform statistical analyses. A hierarchical regression analysis was employed to analyze the relationship between clinical pain, QST, TP counts, and negative affect.

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9 Results Study Participants A total of eighty three subjects were recruited from Gainesville and the surrounding areas and enrolled in this study. The study population consisted of 23 NC participants, an d 36 FMS subjects. The mean age (SD) of study participants was 42.3 (13.6) and 47.6 (12.8) for NC and FMS subjects respectively. An independent t test demonstrated no significant effect of diagnostic group (p > .05). Average number of TPs (SD) was 3.4 (3 .5) for NC and 15.8 (3.5) for FM subjects. An independent t test showed a significant difference between groups (p < .001). Clinical Pain Ratings Overall clinical pain of NC was minimal (2.0 VAS units on 100 point scale), whereas FM subjects rated their average (SD) pain as 47 (25) VAS units. An independent t test showed a significant difference between groups (p < .001). Ratings of Mechanical Pain Stimuli Shoulder Stimuli All subjects received three 200 kPa pressure stimuli to each shoulder. Mean (SD) peak eVAS ratings of 200 kPa pressure stimuli by NC and FM subjects are listed in Table 1. An independent t test demonstrated a significantly higher experimental pain ratings of FM subjects than NC (p < .001) (Figure 1). Because 400 kPa stimuli at the shou lders and hands did not provide fundamentally different predictors of clinical pain intensity than 200 kPA stimuli only the analyses of 200 kPA stimuli are reported here. Hand Stimuli The experimental pressure pain protocol was repeated at the hands (dorsa l webspace between 1 st and 2 nd finger) of all study subjects. The average (SD) peak eVAS ratings of NC and

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10 FMS subjects for 200 kPa at the hand are listed in Table 1. An independent t test demonstrated significantly higher experimental pain ratings of FM than NC subjects (p < .001) (Figure 1). These findings demonstrate that mechanical hyperalgesia is widespread in FMS subjects and can be used to detect significant group differences between all study subjects, including NC. Predicting Clinical Pain Inten sity Using Pressure Stimuli Several hierarchical regression analyses were used to determine whether pressure pain ratings can predict clinical pain intensity in FMS subjects. Because previous work with FMS subjects has demonstrated significant contribution s of TP and negative affect to clinical pain, we decided a priori to include TP count and BDI II scores in our model. To decrease the number of comparisons and thus spurious findings, multiple other factors were omitted from this analysis because w e had no strong a priori hypotheses for their inclusion. Using Pressure Pain Ratings at the Shoulders A hierarchical regression analysis was performed using clinical pain intensity VAS ratings as the predicted variable. Shoulder pressure pain sensitivity a t 200 kPa was entered as predictor variable in the first block, followed by TP count and BDI II scores entered in separate blocks. The results of the regression indicated that 45.3 % of the variance in clinical pain scores was predicted by pressure sensiti vity of FMS subjects (Table 2). Besides pressure pain ratings, neither TP count nor BDI II scores contributed significantly to the pain variance in FM subjects. Overall, 50.0 % of the pain variance of FM subjects was predicted by unique contributions of p ressure pain ratings at the shoulders, TP count, and BDI II scores (Table 2). Using Pressure Pain Ratings at the Hands As before, hierarchical regression analyses were performed using clinical pain intensity VAS ratings as the predicted variable. Hand pressure pain sensitivity at 200 kPa, TP count, and

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11 BDI II scores were entered as predictor variables. The results of these regressions indicated that 32.9% of the variance in clinical pain scores was predicted by pressure sensitivity in FM subjects (Table 3). Besides pressure pain ratings, neither TP count nor BDI II scores contributed significantly to the pain variance in FM subjects. Overall, 46.6 % of the pain variance of FM subjects was predicted by unique contributions of pressure pain ratings at the hands, TP count, and BDI II scores (Table 3).

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12 Discussion Since the chief complaint of individuals with FMS is muscle pain, we set out to investigate whether muscle signaling is involved in chronic pain mechan isms and whether stimulation of these muscles can help us predict the clinical pain of an individual with FMS. The central finding of this study is that when pressure pain ratings are considered alongside a TP count and negative affect, the clinical pain i ntensity of participants with chronic musculoskeletal pain can be predicted with reasonable accuracy. Additionally, these three variables do not contribute equally to the calculation of clinical pain intensity. Furthermore, since testing of muscles can be used to predict clinical pain intensity, muscle signaling does indeed play a role in the mechanism responsible for chronic pain. Contribution of Muscle Impulse Input to Fibromyalgia Syndrome Hyperalgesia in FMS patients can result from the sensitization o f nociceptors in deep tissues (Staud, 2011). It is thought that the specific nociceptors being sensitized include A delta ( ) and C fibers, both nociceptive afferent fibers that are located in the dense innervations of vascular structures of muscles (Mense, 1991). Muscle fibers themselves do not contain any evident nociceptors, but stimulation of muscles can cause pain (Henriksson, 1993; Henriksson, 2003), thus A delta and C fibers are the focus of our investigation because they are the closest nociceptors t o muscle fibers. Since sensitization results from repeated stimulation of a nociceptor, inflammatory myopathies, muscle activity, and other factors that cause muscle pain can all lead to sensitization of pain receptors (Staud, 2011). Thus, peripheral sensi tization that leads to irregular inputs from sensitized peripheral tissue receptors may in turn result in the mechanical hyperalgesia experienced by FMS patients (Staud, 2011). Psychophysical testing can be used to evaluate the underlying pain mechanisms a nd from our use of QST, we have shown

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13 that through stimulation of the muscles, a patient's clinical pain intensity can be predicted with reasonable accuracy. This in turn provides evidence that suggests that abnormal muscle impulse inputs contribute to the pain experienced by individuals with FMS. QST as a Predictor of Clinical Pain From this study it can be seen that FMS patients exhibit greater mechanical hyperalgesia than their NC counterparts. When examined together, mechanical pain ratings, TPs, and negative affect were found to predict up to 50% of the clinical pain in FMS participants In comparison with the other factors measured, QST, in the form of pressure pain ratings, predicted the greatest amount of the varia nce in clinical pain intensity. Thus, mechanical hyperalgesia can be used to predict clinical pain in patients with FMS. Ratings of experimental pain and pain related negative effect have been previously shown to predict clinical pain in patients with FMS (Staud et al., 2003). However, this current approach offers greater ease in predicting the variability of clinical pain in patients with FMS. In the future, QST may be useful for predicting which patients will respond positively to a given treatment by ide ntifying which mechanisms are the greatest contributors to an individual's clinical pain. Tender Points as Predictors of Clinical Pain TPs were previously used to classify FMS patients (Wolfe et al., 1990). However in 2010, the ACR revised the diagnostic criteria to exclude TPs (Wolfe et al., 2010). This change resulted in part because a high TP count ( > 11) does not necessarily mean that a subject will report pain, despite the fact that the majority of individuals with widespread chronic pain have numero us TPs (Croft et al., 1994a). Furthermore, the measure of TPs has not been found to be a strong predictor of the clinical pain intensity of FMS patients (Quimby et al., 1988). Thus, mechanical allodynia, measured by TPs, seems to be only one of the factors underlying chronic

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14 widespread pain (Staud et al., 2003). Through hierarchical regression analysis, we demonstrated that TP counts represent a small but separate factor from mechanical pain stimuli for the prediction of clinical pain. TP counts are thought to be associated with spatial summation (Staud et al., 2003) and thus activate a different mechanism than that responsible for mechanical hyperalgesia. T hese two factors seem to make independent contr ibutions to clinical pain intensity. Negative Affect as a Predictor of Clinical Pain I n comparison to the contribution of mechanic al hyperalgesia p ain related negative affect accounted for a much less significant amount of the variance in clinical pain of FMS patients Similar contributions of negative affect to clinical pain have been shown in a number of other studies (Keefe et al., 1986; Gaskin et al., 1992; Geisser et al. 1994; Staud et al., 2003). Ad ditionally, several other studies of FMS have displayed a comparable relationship between negative mood and pain (Croft et al., 1994b; Lundberg and Gerdle, 2002; Wolfe, 1997). While negative affect did not play the largest role in the prediction of clinica l pain, it is still an important factor and may serve as a target for comprehensive pain therapy (Staud et al., 2003). Conclusions The model of mechanical hyperalgesia, TP count, and negative affect allows for a strong prediction of FMS clinical pain inte nsity. These factors each contribute to FMS clinical pain and they represent the influence of central and peripheral pain mechanisms. Thus, some of these factors may represent different mechanisms that interact and contribute to FMS (Staud et al., 2003). F urthermore, the pain that patients with FMS experience is likely influenced by peripheral impulse input from deep tissues. In understanding the contributions of these separate mechanisms for chronic pain syndromes, we can get a better idea for what treatme nts will be

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15 most effective in alleviating not only the pain of FMS patients, but also that of other chronic pain sufferers. Acknowledgements I would first like to express my thanks to Dr. Staud for his ongoing guidance, intellectual contributions, and me ntal stimulation. Furthermore, I would like to recognize the contributions of Elizabeth Weyl to this project, whose knowledge and insight has proved invaluable. I am also grateful for the endless support and continuing assistance of Viktoria Sisto. Lastly, I would like to thank the kind participants of this study for donating their time.

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16 Literature Cited Berglund B, Harju EL, Kosek E, Lindblom U. Quantitative and qualitative perceptual analysis of cold dysesthesia and hyperalgesia in fibromyalgia. Pain 2002 ;96:177 87. Croft P, Schollum J, Silman A. Population study of tender point counts and pain as evidence of fibromyalgia. Br Med J 1994a;309:696 9. Croft P, Schollum J, Silman A. Population study of tender point counts and pain as evidence of fibromyalgia. Br Med J 1994b;309:696 9. Desmeules JA, Cedraschi C, Rapiti E, Baumgartner E, Finckh A, Cohen P, Dayer TL. Neurophysiologic evidence for a central sensitization in patients with fibromyalgia. Arthritis and Rheumatism 2003;48:1420 9. Gaskin ME, Greene AF, R obinson ME, Geisser ME. Negative affect and the experience of chronic pain. J Psychosom Res 1992;36:707 13. Geisser ME, Robinson ME, Keefe FJ, Weiner ML. Cattastrophizing, depression and the sensory, affective and evaluative aspects of chronic pain. Pain 1 994;59:79 83. Granot M, Buskila D, Granovsky Y, Sprecher E, Neumann L, Yarnitsky D. Simultaneous recording of late and ultra late pain evoked potentials in fibromyalgia. Clinical Neurophysiology 2001;112:1881 7. Henriksson CM. Longterm effects of fibromya lgia on everyday life. A study of 56 patients. Scand J Rheymatol 1994, 23:36 41. Henriksson KG. Is fibromyalgia a distinct clinical entity? Pain mechanisms in fibromyalgia syndrome. A myologist's view. Best Practice & Research Clinical Rheumatology 1999;13 :455 61.

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17 Henriksson KG. Fibromyalgia from syndrome to disease. Overview of pathogenetic mechanisms. Journal of Rehabilitation Medicine 2003;35:89 94. Keefe FJ, Wilkins RH, Cook WA Jr, Crisson JE, Muhlbaier LH. Depression, pain, and pain behavior. J Consu lt Clin Psychol 1986;54:665 9. Latremoliere A., Woolf CJ. Central Sensitization: A Generator of Pain Hypersensitivity by Central Neural Plasticity. Pain 2009;10:895 926. Lautenbacher S, Rollman GB. Possible deficiencies of pain modulation in fibromyalgia. Clinical Journal of Pain 1997;13:189 96. Lautenschlager J, Bruckle W, Schnorrenberger CC, Muller W. Measuring pressure pain of tendons and muscles in healthy probands and patients with generalized tendomyopathy (fibromyalgia syndrome). Z Rheymatol 1988;47: 397 404. Lorenz J, Grasedyck K, Bromm B. Middle and long latency somatosensory evoked potentials after painful laser stimulation in patients with fibromyalgia syndrome. Electroencephalography and Clinical Neurophysiology 1996;100:165 8. Lundberg G, Gerdle B. Tender point scores and their relations to signs of mobility, symptoms, and disability in female home care personnel and the prevalence of fibromyalgia syndrome. J Rhematol 2002;29:603 13. Mense S. Considerations concerning the neurobiological basis of muscle pain. Can J Physiol Pharmacol 1991;69:610 6. Neumann L, Zeldets V, Bolotin A, Buskila D. Outcome of posttraumatic fibromyalgia: a 3 year follow up of 78 cases of cervical spine injuries. Semin Arthritis Rheum 2003;32:320 325.

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18 Quimby LG, Black SR, Gr atwick GM. Fibromyalgia: Generalized pain intolerance and manifold symptom reporting. J Rheumatol 1988;15:1264 70. Russell IJ, Orr MD, Littman B, Vipraio GA, Alboukrek D, Michalek JE, Lopez Y, Mackillip F. Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis and Rheumatism 1994;37:1593 601. Simms RW, Goldenberg DL, Felson DT, Mason JH. Tenderness in 75 anatomic sites. Distinguishing fibromyalgia patients from controls. Arthritis Rheum. 1988;31:182 7. Rus sell IJ, Orr MD, Littman B, Vipraio GA, Alboukrek D, Michalek JE, Lopez Y, Mackillip F. Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis and Rheumatism 1994;37:1593 601. Staud R. Is It All Central S ensitization? Role of Peripheral Tissue Nociception in Chronic Musculoskeletal Pain. Curr Rheumatol Rep. 2010;12(6):448 54. Staud R. Peripheral pain mechanisms in chronic widespread pain. Best Practice & Research Clinical Rheumatology 2011 25:155 164. Stau d R, Nagel S, Robinson ME, Price DD. Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: a randomized, double blind, placebo controlled trial. Pain 2009, 145:96 104. Staud R, Craggs JG, Perlstein WM Robinson M E, Price DD. Brain activity associated with slow temporal summation of C fiber evoked pain in fibromyalgia patients and healthy controls. Eur J Pain 2008, 12:1078 1089. Staud R, Robinson ME, Vierck CJ Jr., Cannon RC, Mauderli AP, Price DD. Ratings of exper imental pain and pain related negative affect predict clinical pain in patients with fibromyalgia syndrome. Pain. 2003;105:215 222.

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19 Staud R, Robinson ME, Price DD. Temporal summation of second pain and its maintenance are useful for characterizing widespre ad central sensitization of fibromyalgia patients. J Pain 2007, 8:893 901. Staud R, Vierck CJ, Cannon RL, Mauderli AP, Price DD. Abnormal sensitization and temporal summation of second pain (wind up) in patients with fibromyalgia syndrome. Pain 2001;91:165 75. Wolfe F. The relation between tender pints and fibromyalgia symptom variables: evidence that fibromyalgia is not a discrete disorder in the clinic. Ann Rheum Dis 1997;56:268 71. Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, Russe ll AS, Russell IJ, Winfield JB, Yunus MB. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken). 2010;62(5):600 10. Wolfe F, Ross K, Anderson J, Russell IJ, H ebert L. The prevalence and characteristics of bromyalgia in the general population. Arthritis Rheum. 1995;38:19 28. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33:160 72. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain.2011;152:S2 15. Yun us MB. Towards a model of pathophysiology of fibromyalgia: aberrant central pain mechanisms with peripheral modulation. Journal of Rheumatology 1992;19:846 50.

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20 Tables and Figures Table 1. Average (SD) Ratings of Pressure Pain at Shoulders and Hands NC FM S Shoulders 200 kPa (peak) 7.1 (11.8) 43.1 (29.4) Hands 200 kPa (peak) 10.9 (13.6) 34.3 (24.4) FM = fibromyalgia; NC = normal controls. Table 2. Pressure Pain at the Shoulders as Predictor of FM Pain Block Variable R 2 F Change p 1 200 kPa Rating .453 24.83 <.001 2 TP count .022 1.39 > .05 3 BDI II .025 1.21 >.05 Beta (standardized) t 1 200 kPa Rating .528 3.28 <.003 TP count .177 1.18 > .05 BDI II .152 1.02 > .05 Final Model: R 2 = .500, F= 9.32; p < .001 Table 3. Pressure Pain at the Hands as Predictor of FMS Pain Block Variable R 2 F Change p 1 200 kPa Rating .329 14.72 <.005 2 TP count .074 3.60 > .05 3 BDI II .062 3.26 >.05 Beta (standardized) t 1 200 kPa Rating 0.429 2.87 <.01 TP count 0.239 1.59 > .05 BDI II 0 .262 1.81 > .05 Final Model: R 2 = .466, F= 8.13; p < .001

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21 Figure 1. Shoulder and hand pain ratings of all subjects during pressure stimuli. Experimental pressure stimuli were applied to the middle of the shoulders (trapezius muscle) or to the space betw een the first two fingers using an electronic algometer. After 10 seconds of 200 kPa pressure, pain ratings of FM subjects were significantly higher than NC. Similar results were found at the hands. FM = fibromyalgia; NC = normal controls.


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