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Disability and Rehabilitation

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Clinical descriptors for the recognition ofcentral sensitization pain in patients with kneeosteoarthritis

Enrique Lluch, Jo Nijs, Carol A. Courtney, Trudy Rebbeck, Vikki Wylde, IsabelBaert, Timothy H. Wideman, Nick Howells & Søren T. Skou

To cite this article: Enrique Lluch, Jo Nijs, Carol A. Courtney, Trudy Rebbeck, Vikki Wylde,Isabel Baert, Timothy H. Wideman, Nick Howells & Søren T. Skou (2017): Clinical descriptorsfor the recognition of central sensitization pain in patients with knee osteoarthritis, Disability andRehabilitation, DOI: 10.1080/09638288.2017.1358770

To link to this article: http://dx.doi.org/10.1080/09638288.2017.1358770

Published online: 02 Aug 2017.

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PERSPECTIVES IN REHABILITATION

Clinical descriptors for the recognition of central sensitization pain in patientswith knee osteoarthritis

Enrique Llucha,b,c, Jo Nijsb,c, Carol A. Courtneyd, Trudy Rebbecke, Vikki Wyldef, Isabel Baertc,g,Timothy H. Widemanh, Nick Howellsi,j and Søren T. Skouk,l

aDepartment of Physical Therapy, University of Valencia, Valencia, Spain; bDepartment of Physiotherapy, Human Physiology and Anatomy,Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussels, Belgium; cPain in Motion International Research Group,Brussel, Belgium; dDepartment of Physical Therapy, University of Illinois at Chicago, Chicago, IL, USA; eFaculty of Health Sciences, Discipline ofPhysiotherapy, John Walsh Centre for Rehabilitation Research, Royal North Shore Hospital, University of Sydney, Sydney, Australia;fMusculoskeletal Research Unit, University of Bristol, Southmead Hospital, Bristol, UK; gDepartment of Rehabilitation Sciences andPhysiotherapy, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium; hSchool of Physical and Occupational Therapy,McGill University, Montreal, Canada; iAvon Orthopaedic Centre, Southmead Hospital, North Bristol NHS Trust, Bristol, UK; jMusculoskeletalResearch Unit, University of Bristol, Bristol, UK; kDepartment of Sports Science and Clinical Biomechanics, Research Unit for MusculoskeletalFunction and Physiotherapy, University of Southern Denmark, Odense, Denmark; lDepartment of Physiotherapy and Occupational Therapy,Naestved-Slagelse-Ringsted Hospitals, Slagelse, Denmark

ABSTRACTBackground: Despite growing awareness of the contribution of central pain mechanisms to knee osteo-arthritis pain in a subgroup of patients, routine evaluation of central sensitization is yet to be incorporatedinto clinical practice.Aim: The objective of this perspective is to design a set of clinical descriptors for the recognition of cen-tral sensitization in patients with knee osteoarthritis that can be implemented in clinical practice.Methods: A narrative review of original research papers was conducted by nine clinicians and researchersfrom seven different countries to reach agreement on clinically relevant descriptors.Results: It is proposed that identification of a dominance of central sensitization pain is based on descrip-tors derived from the subjective assessment and the physical examination. In the former, clinicians are rec-ommended to inquire about intensity and duration of pain and its association with structural jointchanges, pain distribution, behavior of knee pain, presence of neuropathic-like or centrally mediatedsymptoms and responsiveness to previous treatment. The latter includes assessment of response to clin-ical test, mechanical hyperalgesia and allodynia, thermal hyperalgesia, hypoesthesia and reduced vibrationsense.Conclusions: This article describes a set of clinically relevant descriptors that might indicate the presenceof central sensitization in patients with knee osteoarthritis in clinical practice. Although based on researchdata, the descriptors proposed in this review require experimental testing in future studies.

� IMPLICATIONS FOR REHABILITATION� Laboratory evaluation of central sensitization for people with knee osteoarthritis is yet to be incorpo-

rated into clinical practice.� A set of clinical indicators for the recognition of central sensitization in patients with knee osteoarth-

ritis is proposed.� Although based on research data, the clinical indicators proposed require further experimental testing

of psychometric properties.

ARTICLE HISTORYReceived 3 February 2017Revised 19 July 2017Accepted 19 July 2017

KEYWORDSKnee osteoarthritis; centralsensitization syndromes;clinical descriptors;identification

Introduction

Knee osteoarthritis is a leading cause of chronic pain, disabilityand loss of quality of life affecting over 80% of the elderly popula-tion [1,2]. While several “pain-generating structures” have beenproposed to explain knee osteoarthritis pain [3], the exact etiologyof pain is not well understood [4]. This may be due to the factthat knee osteoarthritis is a whole organ disease with a complexand multifactorial pathophysiology involving structural, psycho-social and neurophysiology factors [5]. Regarding the latter fac-tors, there is strong evidence that central sensitization is a

prominent phenomenon in a subgroup of people with kneeosteoarthritis [6,7], especially in women [8]. Central sensitization isa broad concept encompassing numerous and complex patho-physiological mechanisms and is defined as an “increased respon-siveness of nociceptive neurons in the central nervous system totheir normal or subthreshold afferent input” [9].

Technically, central sensitization is a neuronal response thatcan only be measured in animals [10–12]. Currently, a universallyaccepted term for the phenomenon described as central sensitiza-tion in humans is not available and its use in the scientific litera-ture is still under debate [11–13]. In addition, central sensitization

CONTACT Enrique Lluch Girb�es enrique.lluch@uv.es Department of Physical Therapy, Faculty of Physiotherapy, University of Valencia, C/Gasc�o Oliag, 5, 46010Valencia, Espa~na� 2017 Informa UK Limited, trading as Taylor & Francis Group

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is not a yes/no or present/absent single entity or phenomenonbut it occurs over a continuum, from a little to a lot. While gener-ally higher in certain chronic pain conditions, pain sensitivity isalso along a continuum in these conditions as well [14,15]. Insome patient populations, central sensitization may be the charac-teristic feature of the disorder (e.g., fibromyalgia). In others, suchin knee osteoarthritis, not all patients have central sensitization,but only a subgroup [6]. In addition, central sensitization mayinfluence various regions of the body to varying degreesand manifest clinically either in the form of extended areas ofsymptoms (i.e., widespread pain in fibromyalgia) or as a morestereotypical region of pain (i.e., referred pain).

Despite growing awareness of the important contribution ofcentral pain mechanisms to knee osteoarthritis pain, routine evalu-ation of central sensitization is yet to be incorporated into clinicalpractice. This is likely due in part to the historical laboratory-basedfocus of central sensitization research, where the equipment andprotocols used to identify features of central sensitization (e.g.,quantitative sensory testing [16,17], nociceptive reflex testing [18],brain neuroimaging techniques [19,20]) are relatively sophisti-cated, time-consuming, expensive and not well suited for clinicalsettings.

The development of patient profiles to subgroup individualswith knee osteoarthritis in terms of pain mechanisms, includingthose with “dominant” central sensitization pain, is gaining atten-tion in research as reflected by the increasing number of painphenotyping proposals which have been published in recent years[21–23]. The lack of subgrouping in previous clinical trials hasbeen proposed as an explanation for the modest efficacy of avail-able treatments for knee osteoarthritis [24]. The challenge clini-cians face is to determine, in a given individual with kneeosteoarthritis, the relative contribution of factors influencing kneeosteoarthritis pain [5,23], including the role of centralsensitization.

Currently, there are no widely accepted clinical descriptors toidentify “dominant” central sensitization pain in people with mus-culoskeletal pain including knee osteoarthritis [10,25]. Quantitativesensory testing is a semi-subjective method suggested to be use-ful in detection of altered pain sensitivity [26]. However, labora-tory quantitative sensory testing is not clinically pragmatic andtest modalities and protocols are heterogeneous [26].

The aim of this paper is to provide clinicians with a set of clin-ical descriptors for the recognition of possible central sensitizationin patients with knee osteoarthritis. These descriptors were narra-tively reviewed by nine clinicians and researchers from seven dif-ferent countries by using the current understanding of centralsensitization within the context of knee osteoarthritis pain. Theyare not intended to replace the laboratory-based investigation ofcentral sensitization, but rather to bridge the gap betweenresearch findings and clinical practice by translating the clinicaland laboratory-based studies of central sensitization in kneeosteoarthritis into a broader and more clinically relevant perspec-tive. This is neither a systematic or exhaustive review of the litera-ture on the role of central sensitization in knee osteoarthritis nora definitive clinical guidance on what clinicians should do to iden-tify central sensitization, but a summary of possible factors thatmight indicate the presence of central sensitization in patientswith knee osteoarthritis based on supporting evidence.

Clinical descriptors that may aid in identifying a dominance ofcentral sensitization pain in patients with knee osteoarthritis willbe structured into two categories for a better overview: descrip-tors derived from the subjective assessment (subjective descrip-tors) and descriptors extracted from the physical examination(objective descriptors).

The subjective assessment

Pain intensity and its association with structural joint changesand duration of pain

Individuals with knee osteoarthritis presenting with altered centralprocessing of pain are significantly more likely to report moderateto severe levels of pain [6,21,27–29]. Therefore, a moderate tosevere intensity of self-reported knee pain (e.g., pain on a visualanalog scale >5/10 [30] can be a first indicator of central sensi-tization in knee osteoarthritis. This finding in isolation is, however,insufficient as moderate to severe intensity of self- reported kneepain defined as >5/10 likely encompasses many cases with andwithout central sensitization. Additionally, studies reporting anassociation between higher levels of pain and more pain sensitiza-tion [6,21,27–29] are not clear and consistent regarding whetherpain intensity is related to the “worst pain,” “usual pain,” “currentpain” or “pain with movement.”

Unlike severity of pain, the presence of more severe structuralchanges in the knee joint on imaging is not associated with cen-tral sensitization 0.2 [21,27], An inconsistent correlation betweenthe degree of structural damage and pain and disability could bean indicator of central sensitization [31,32], albeit the discrepancybetween structural and clinical findings is well known in osteo-arthritis in general [31]. Indeed, central sensitization is especiallyapparent among patients with knee osteoarthritis with high levelsof pain but low levels of imaging structural damage [21,32]. Theimaging findings most strongly linked to knee pain and disabilityin people with knee osteoarthritis pain seem to be joint synovitisand bone marrow lesions (identified most readily on MRI imaging)[33–35]. Therefore, if clinicians find insufficient evidence of injuryor pathology at the knee that is likely to contribute to the self-reported pain and disability, it may raise suspicion about the pres-ence of central sensitization pain [36].

Regarding the duration of symptoms, there is controversy inthe literature, with some studies reporting an association betweena long history of symptoms and central sensitization [21] whileothers do not [29]. It is assumed that the lack of associationbetween central sensitization and disease duration indicatesthat some individuals may be predisposed to central sensitizationirrespective of the duration of knee osteoarthritis [29].

Pain distribution

Several methods and instruments have been used to record thepatient’s pain location and to classify the pattern of knee osteo-arthritis pain. The most common method is asking people to drawthe area where they feel pain on a body chart [37–39]. Amongpeople with knee osteoarthritis, the medial knee region is themost frequently reported pain location [38,39], though generalizedor diffuse knee pain is also commonly reported [18,39,40].

In relation to knee osteoarthritis, several studies have specific-ally investigated the association between central pain mechanismsand a widespread distribution of symptom location [40–45].They concluded that a widespread, non-anatomical distribution ofpain seems to be a strong indicator of central sensitization.Accordingly, aggravation and expansion of existing symptoms tosites around and remote to the knee joint may be a clinical signof central sensitization. Therefore, occurrence of contralateralsymptoms, commonly reported by people with knee osteoarthritis,should not be automatically attributed by clinicians to alteredweight bearing or biomechanics due to compensation, as mirrorsymptoms may also been explained through spinal and supraspi-nal mechanisms [46].

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To capture and objectify the presence of widespread pain,clinicians can calculate the total number of bodily pain sites in aregion-divided body chart [23,47] or ask the patient to complete apain drawing (e.g., in a digital tablet) and subsequently computethe total area of pain (e.g., total number of pixels inside the digitalchart) [42] (Figure 1). Visser et al. [44] have recently suggestedthat calculating percentage pain surface area on a body diagramis an optimal “snapshot” screening tool to identify patients withan increased likelihood of pain sensitization. In particular, subjectswith chronic widespread pain defined as a percentage pain sur-face area �20% reported high (�19) painDETECT questionnaire

scores (suggesting pain “sensitization” or neuropathic pain) com-pared to control subjects with a lower percentage pain surfacearea. In additions, significant and independent associations wereobserved between the presence of chronic widespread pain andWidespread Pain Index score �7 and painDETECT score �19 [44].

In summary, clinicians may obtain the area of pain of theirpatients with knee osteoarthritis using pain drawings and if pos-sible quantify that area, as the presence of extended areas of painmay be an indicator of central sensitization. However, althoughthere have been attempts to define widespread pain which servesas an indicator of central sensitization (e.g., Widespread Pain

Figure 1. The area of pain, expressed as the total number of pixels colored inside a body chart perimeter, presented separately for men and women with knee osteo-arthritis pain after superimposing their pain drawings. The color grid indicates both the number and the percentage of individuals that reported pain in that specificarea. Dark red represents the most frequently reported area of pain, while dark blue the least frequently reported area of pain. Reprinted with permission from LluchGirb�es et al. [42].

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Index score) [48], there is no validated cutoff score for inferringwhether pain is widespread or not [49].

Behavior of knee pain

Knee osteoarthritis is commonly associated with pain at rest (orstimulus-independent pain) and pain on movement (mainly dur-ing weight-bearing activities) resulting in difficulties with walkingand climbing stairs [37]. In the context of knee osteoarthritis, painon movement is often more severe than pain at rest in the earlystages of the disease and has an earlier onset in the diseasecourse [50,51]. There is a growing recognition of the importanceof distinguishing between these two types of pain due to differ-ent mechanistic pathways and clinical implications [51,52].

Pain on movement has been linked to central sensitization inpeople with knee osteoarthritis [53]. In particular, increased sensi-tivity to physical activity (measured by evaluating changes inpatient self-reported pain over the course of a 6-min walk test) isassociated with psychophysical indices of central sensitizationsuch as temporal summation of pain [53]. In addition, less exer-cise-induced hypoalgesia/analgesia occurs in different chronicpain populations where central sensitization is a key characteristicas compared to healthy subjects [54]. One could argue thereforethat the same would be applicable to the subgroup of patientswith knee osteoarthritis where central sensitization is dominant.Previous studies reported normal exercise-induced analgesia inpatients with knee osteoarthritis following lower [55] and upperbody exercises [56]. However, in these studies, no attempt wasmade to classify the patients in terms of pain mechanisms. Rather,pressure pain thresholds instead of self-reported pain [53] wereused to quantify sensitivity to physical activity. Clinicians maytherefore look for a disproportionate self-reported increase inknee pain after physical activity tests or activity-based interven-tions to infer the possible presence of central sensitizationmechanisms.

Asking about easing and aggravating factors for knee osteo-arthritis pain may also be helpful to distinguish between thoseindividuals with either a more dominant nociceptive or centralsensitization pain. A clear, proportionate mechanical/anatomicalnature to aggravating and easing factors was associated withnociceptive pain in people with low back (± leg) pain [57]. In thatsame population, a lack of clear proportionate mechanical natureto aggravating and easing factors was considered a predictor signof central sensitization pain [58]. Therefore a “disproportionate,non-mechanical, unpredictable pattern of pain provocation inresponse to multiple/non-specific aggravating/easing factors” [58]may indicate the presence of central sensitization pain in peoplewith knee osteoarthritis.

Presence of neuropathic-like or centrally mediated symptoms

A potential contribution of central sensitization to knee osteoarth-ritis has been suspected on the basis of patients reporting neuro-pathic-like [59] or centrally mediated symptoms (i.e., sleepdisturbance, memory changes, general fatigue) [60,61]. Thesesymptoms are frequently but not exclusively seen in patients withcentral sensitization, so they only offer indirect evidence of centralsensitization in knee osteoarthritis and need to be integrated intothe context of other findings [62]. In particular, two validatedquestionnaires have shown to be useful for measuring characteris-tics that indicate altered central nociceptive processing in patientswith knee osteoarthritis: the Central Sensitization Inventory [63]and the (modified) painDETECT [64].

The Central Sensitization Inventory is a self-reported screeninginstrument that helps to identify key symptoms associated withcentral sensitization [63,65]. It is not a direct measure of the actualneuronal phenomenon of central sensitization as its name mayinfer. The Central Sensitization Inventory evaluates hypersensitivityof senses unrelated to the musculoskeletal system such as noise,heat or cold or bright light and comprises of 25 items eachranged on a 5-point scale with the end points (0) “never” and (4)“always” (range: 0–100). It has high reliability and validity [63] anda cutoff score of 40 out of 100 was able to distinguish betweenindividuals diagnosed with central sensitivity syndromes and anon-patient comparison sample (sensitivity¼ 81%, specific-ity¼ 75%) [66].

Higher scores on the Central Sensitization Inventory are associ-ated with the presence of widespread hyperalgesia in people withknee osteoarthritis [42]. In addition, people with knee osteoarth-ritis scoring more that 40 (out of 100) before surgery, consideredthe cutoff value to affirm that key symptoms associated with cen-tral sensitization are present, reported higher pain intensity, lowersatisfaction and increased analgesic requirements in the earlyphase after total knee replacement surgery [67]. This highlightsthe value of the Central Sensitization Inventory to detect the pos-sible presence of central sensitization and predict poorer out-comes after surgery in people with knee osteoarthritis.

A growing level of evidence suggests that knee osteoarthritispain has a neuropathic component in some individuals [68,69],previously approximated to be 30% [70]. Although thepainDETECT [19,71] and modified painDETECT [72,73] question-naires have been used to screen neuropathic-like symptoms inpeople with knee osteoarthritis, they may also function as meas-ures of characteristics that indicate augmented central nociceptiveprocessing [71,73]. Sensitivity, specificity and positive predictivevalues of the painDETECT for neuropathic pain symptoms in peo-ple with back pain using the cutoff score of 19 were 85%, 80%and 83%, respectively [64]. Like the original painDETECT, themodified painDETECT is comprised of nine items but with somemodifications adapted to people with knee osteoarthritis, such asframing of questions to ask about symptoms “in or around” theworst knee, over a specific time frame. Therefore, clinicians areencouraged to use this modified version of the painDETECT inpatients with knee osteoarthritis. Details on the features of theCentral Sensitization Inventory and (modified) painDETECT ques-tionnaires are presented in Table 1.

Psychosocial factors

Psychosocial factors are known to explain some of the variation inpain reporting among individuals with knee osteoarthritis [74].There is some evidence pointing toward a relationship betweenmaladaptive psychosocial and emotional factors and central sensi-tization in people with knee osteoarthritis, including pain hypervi-gilance, pessimism, catastrophism and poor coping strategies[75–77]. However, as data were obtained from cross-sectionalstudies, firm conclusions regarding causality between cognitive-emotional factors and central sensitization in knee osteoarthritiscannot be drawn. Also maladaptive cognitive-emotional factorsmay also occur in patients with chronic pain but without centralsensitization. At this early stage in this line of research, we feelthat maladaptive psychological factors are best regarded as anoverlapping but ultimately distinct construct from central sensi-tization and therefore they have not been included as clinical indi-cators of central sensitization among patients with kneeosteoarthritis.

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Responsiveness to previous treatment

It has been argued that an inconsistent, unpredictable orunsuccessful response to local, nociception-targeted treatmentsor a strong exacerbation of symptoms severity post-treatmentmay aid in recognition of central sensitization in patients withchronic musculoskeletal pain [78]. There is evidence that thepresence of central sensitization is a prognostic factor for pooroutcomes in response to locally applied physical therapy inter-ventions in some chronic pain conditions such as lateral epicon-dylalgia [79] or whiplash-associated disorders [80]. Although it isconceivable that the presence of central sensitization might alsoaffect physical therapy treatment outcomes negatively in peoplewith knee osteoarthritis, this hypothesis is not yet proven [81].An inability to endogenously modulate nociception (dysfunc-tional endogenous analgesia) may explain the disproportionateincrease in pain often observed in people with knee osteoarth-ritis after locally applied interventions (e.g., knee joint mobiliza-tion) [82].

Less responsiveness to analgesic and non-steroidal anti-inflam-matory pain medications together with better outcomes withadministration of some centrally acting drugs (i.e., duloxetine) isanother factor that can further consolidate the role of central sen-sitization in knee osteoarthritis pain [83]. Therefore, clinicians areadvocated to routinely ask about medications and responsivenessto them.

Persistent post-surgical pain occurs in approximately 20% ofpatients with knee osteoarthritis after total knee replacement [84]and it has been linked to the presence of central sensitization[85,86] as the purported peripheral nociceptive sources arereplaced yet patients still experience persistent pain. An unfavor-able symptom outcome after surgery may thus alert clinicians tothe potential presence of central sensitization among other factors[85,86]. Therefore, assessment of persistent post-surgical pain in aconsistent and standardized way by mean, for instance, of a coreoutcome set [87] is considered essential for alerting the clinicianto the possible presence of central sensitization. Furthermore, therelatively high proportion of patients with persistent pain aftertotal knee replacement highlights the importance of diagnosingcentral sensitization before patients undergo surgery and revisionsurgery [85].

The physical examination

Response to clinical tests

Several types of information obtained from the physical examin-ation can be of value in recognizing dominance of central sensi-tization in individuals with knee osteoarthritis pain [78]. Inparticular, an inconsistent or confusing response to clinical testsapplied to the knee joint during the physical examination (i.e., themajority of assessment techniques provoke symptoms) may besuggestive of the presence of central sensitization. This clinicalfinding has not yet been investigated, but might be plausiblebased on our current understanding of the mechanism and clin-ical expression of central sensitization, where non-painful mechan-ical stimulus can be interpreted as nociceptive [16].

Widespread mechanical hyperalgesia and allodynia

Research has shown evidence in support of generalized or wide-spread hypersensitivity to mechanical stimuli in people with kneeosteoarthritis as compared to healthy controls [6,16,62].Widespread mechanical hyperalgesia is a well-recognized clinicalmanifestation of central sensitization [4,16,17]. Hyper-responsive-ness to mechanical stimuli includes exaggerated responses topressure and touch. To apply this to clinical practice, lower pres-sure pain thresholds as assessed by a pressure algometer at sitesaround (localized pain sensitization) and remote to the knee(widespread pain sensitization) may imply hyperexcitability of cen-tral nociceptive pathways. Pressure pain thresholds have demon-strated a good ability to differentiate between people withosteoarthritis and healthy controls at a general population level[17], but interpretation of pressure pain thresholds within an indi-vidual may be challenging due to broad overlap between normaland OA population values. Normative values are available forhealthy subjects [88] which could potentially serve as a compara-tor when assessing patients with knee osteoarthritis. However,normative values are highly variable and depend on the rate ofapplication as well as anatomical location so it may be challeng-ing to determine “non-normal” values.

In the absence of a pressure algometer, the clinician can alsouse manual palpation (examiner’s thumb) to evaluate widespread

Table 1. Questionnaires used for detecting the presence of neuropathic-like or centrally mediated symptoms in patients with knee osteoarthritis.

Questionnaire Sub scales Items ScoringMeaningfuldifferences Remarks

Central SensitizationInventory

Part A 25 items: (range: 0–100) �40/100: useful to identifypeople with central sensi-tization syndromes(sensitivity¼ 81%, specific-ity¼ 75%) [66]

Severity levels [98]:–subclinical¼ 0–29–mild¼ 30–39–moderate¼ 40–49–severe¼ 50–59–extreme¼ 60–100

Unknown Not validated for kneeosteoarthritis popula-tion: caution whenusing �40/100 to cat-egorically affirm that CSpain is present [67]

Part B 10 items: yes/no Not considered for scoringpainDETECT None 9 items: (range: �1 to 38) Higher scores associated with

widespread reductions inpressure pain thresholds[71]

Unknown

Modified painDETECT None 9 items: (range: �1 to 38) >12/38 associated with signsof CS [72]

Unknown Includes modifications ofthe original painDETECTadapted to people withosteoarthritis (e.g., fram-ing of questions)

CS: central sensitization.

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mechanical hypersensitivity. A moderate correlation between man-ual pressure and pressure algometry was found in people withchronic neck pain [89], albeit the suitability of this to patientswith knee osteoarthritis is unknown. Diffuse non-anatomical ten-derness on manual palpation is a clinical criterion that was shownto be predictive of central sensitization pain in patients with lowback (±leg) pain [58] and chronic neck pain [89]. An expansion ofreceptive fields, which is characteristic of central sensitization [16],may lead to the patient experiencing increased tenderness to pal-pation well outside of the painful knee joint. A novel alternativeto pressure algometry is a spring clamp, as used in a previousstudy in patients with low back pain [90]. By placing the springclamp on the thumbnail for 10 s and asking the patients to assesspain intensity, O’Neill et al. were able to assess the pain responseof the patients [90].

The presence of mechanical (tactile) allodynia (pain due to astimulus that does not normally provoke pain) is associated withknee osteoarthritis [59] and is considered a hallmark sign of cen-tral sensitization [16]. Heightened sensitivity to cutaneous lighttouch can be assessed in the clinical setting using both static anddynamic stimuli by gently touching or brushing/stroking the skinwith a cotton wisp, a cotton wool tip or a brush.

Widespread thermal hyperalgesia

Besides widespread mechanical hyperalgesia, greater pain sensitiv-ity to heat [62] and cold stimuli [91] at remote sites from the kneeare considered clinical indicators of deficient central processing ofnociception in knee osteoarthritis. Hypersensitivity to heat or coldstimuli is normally demonstrated in laboratory conditions by usinga computer-controlled thermotester. However, clinical tests forthermal sensitivity have been developed in other chronic painpopulations (e.g., chronic neck pain) with good correlations withquantitative measures [89,92].

When clinically testing thermal sensitivity, the cold or hot itemis placed on the skin for some seconds (e.g., 10 seconds [92]) andit should be perceived as cold or hot, respectively, but should notelicit pain. If it does trigger pain, then hypersensitivity to cold orheat is established and the individual can be asked to rate thepain experienced during the test on an numerical rating scale[89,92]. Maxwell and Sterling suggested that pain >5/10 on anumeric rating scale after 10 s of ice application may indicate thepresence of cold hyperalgesia in whiplash, thus aiding in progno-sis and treatment decisions [92].

Hypoesthesia and reduced vibration sense

Hypoesthesia (increased perception threshold) to tactile and vibra-tion stimuli has been found in people with knee osteoarthritispain, at both local and remote sites from the knee [59,93]. Clinicalfinding of tactile hypoesthesia adjacent to the injured knee jointhas been considered a clinical indicator of central sensitization[16]. When mapping the region of altered sensation, the patternof sensory deficit in individuals with knee osteoarthritis does notfollow a nerve root or peripheral nerve distribution [16], thus ena-bling differentiation of sensory changes secondary to nerve injury.For assessing tactile hypoesthesia, the mechanical detectionthreshold is calculated using calibrated and standardized von Freyutilizing a series of ascending and descending stimulus intensities[94]. As an alternative, the clinician can use a cotton wool or cot-ton tipped applicator. Typically, assessment is initiated in the areaof most pain and the distribution of hypoesthesia is determinedby repetitively stimulating the skin, moving outward in a wheelspoke pattern.

Like altered mechanical detection threshold, reduced vibrationsense may be indicative of central sensitization in people withknee osteoarthritis [16]. In particular, a reduced vibration detec-tion threshold has been demonstrated in people with knee osteo-arthritis at different sites of the lower extremity [95]. Vibrationdetection threshold is measured using a biothesiometer or vibr-ometer, although neither tool is commonly used in a clinical set-ting. As an alternative, the clinician can use a Rydel–Seiffergraduated tuning fork placed against different bony sites of thelower extremity [95] (i.e., first metatarsophalangeal joint, medialand lateral malleolus, medial and lateral femoral condyle). Thetuning fork can be placed there and record time until the vibra-tion can no longer be perceived by the subject. The presence ofany pain with the vibration stimuli can also be recorded. A painfulresponse with testing (vibration allodynia) has been reported asreflecting central nociceptive changes [16].

Dynamic measures of central sensitization

Temporal summation and conditioned pain modulation are hall-mark dynamic measures of central nociceptive hyperexcitability[4]. While these two measures have been routinely used as labora-tory measures, their utility as clinical measures may be developedin the future. For instance, temporal summation has beenassessed by using von Frey monofilaments [96]. A small springclamp may be an interesting clinically applicable measure toassess conditioned pain modulation with a cold pressor test aspreviously done on patients with back pain [90]. Table 2 providesa checklist with all the descriptors extracted from the subjectiveassessment and physical examination that might indicate the pres-ence of central sensitization in patients with knee osteoarthritis.

Discussion

The awareness is growing that central sensitization is of primeimportance for the management of patients with knee osteoarth-ritis, but its classification is challenging since identification of cen-tral sensitization is not straightforward and quantitative sensorytesting, the most feasible approach for recognizing central sensi-tization, remains primarily a research tool [26]. Expensive labora-tory equipment requiring extensive training make sensory testingmethods used to determine the presence of central sensitizationimpractical for most clinicians. Shorter and less expensive proto-cols and equipments that permit clinical identification of painmechanisms including central sensitization in patients with kneeosteoarthritis pain are thus needed [26].

The purpose of this paper was to present a set of less time-consuming and easily applicable clinical descriptors derived fromsubjective assessment and physical examination that can aid clini-cians to recognize dominance of central sensitization in peoplewith knee osteoarthritis pain. Importantly, these descriptors shouldnot be viewed as unique signs indicating central sensitization, butthey can rather be integrated into the clinical reasoning process,since they indicate a possible contribution of central pain mecha-nisms to knee osteoarthritis, which can affect the appropriatetreatment approach for the individual. What is proposed in thispaper is at this moment not a definitive guidance on what clini-cians should do to identify central sensitization but offer interimguidance only. Central sensitization is not a diagnosis nor an ill-ness and therefore it is not suitable for developing diagnostic cri-teria. The psychometric properties (i.e., inter- and intra-examinerreliability, sensitivity, specificity) of the descriptors proposed inthis paper for identifying central sensitization in knee osteoarth-ritis, either when used alone or in combination, might be the

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subject of future research to allow them to be confidentlyadopted in clinical practice. These descriptors should be viewedas potential candidates that might be tested as future criteria forrecognizing central sensitization in people with knee osteoarthritisand their validity as classification tools is still unsubstantiated.Meanwhile, we hope our proposal will facilitate clinicians theacknowledgment and recognition of central sensitization in kneeosteoarthritis and eventually adaptation/improvement of the pro-posed checklist based on research data.

The presence of central sensitization in knee osteoarthritis hasclinical implications for its management. Early identification ofdominant central sensitization pain in people with knee osteoarth-ritis is crucial as the presence of pain sensitization may predictpoorer outcomes following physiotherapy treatment [81] or sur-gery [85,86]. Individuals with knee osteoarthritis pain, where adominant altered central pain mechanism is demonstrated, mightbenefit from interventions that target central nervous systemmechanisms, such as therapeutic pain neuroscience education orcognitive-behavioral therapy (e.g., graded activity and gradedexposure) [7], but evidence supporting this notion is lacking. Formore in-depth guidelines on the treatment of central sensitizationin patients with knee osteoarthritis pain, the readers are referredto other sources [7,97].

Conclusions

This article presents a set of clinically relevant descriptors usableduring the subjective assessment and physical examination ofpatients with knee osteoarthritis that might lead the clinician tosuspect the presence and severity of central sensitization. Futurestudies are needed to empirically test these descriptors andexplore their suitability as future criteria for recognizing centralsensitization in clinical practice. Clinicians need to be attentive forpatients with signs of central sensitization as they might be at riskfor unfavorable outcome after locally applied interventions to theknee. A broader therapeutic approach aiming to desensitize thecentral nervous system, in contrast to therapeutic modalities that

are only directed to structural knee joint pathology, might bemore beneficial for these patients.

Disclosure statement

The authors report no conflicts of interest.

References

[1] Ma VY, Chan L, Carruthers KJ. The incidence, prevalence,costs and impact on disability of common conditionsrequiring rehabilitation in the US: stroke, spinal cord injury,traumatic brain injury, multiple sclerosis, osteoarthritis,rheumatoid arthritis, limb loss, and back pain. Arch PhysMed Rehabil. 2014;95:986–995.

[2] Neogi T. The epidemiology and impact of pain in osteo-arthritis. Osteoarthr Cartil. 2013;21:1145–1153.

[3] Felson DT. The sources of pain in knee osteoarthritis.Curr Opin Rheumatol. 2005;17:624–628.

[4] Arendt-Nielsen L, Skou ST, Nielsen TA, et al. Altered centralsensitization and pain modulation in the CNS in chronicjoint pain. Curr Osteoporos Rep. 2015;13:225–234.

[5] Kittelson AJ, George SZ, Maluf KS, et al. Future directions inpainful knee osteoarthritis: harnessing complexity in a het-erogeneous population. Phys Ther. 2014;94:422–432.

[6] Fingleton C, Smart K, Moloney N, et al. Pain sensitization inpeople with knee osteoarthritis: a systematic review andmeta-analysis. Osteoarthr Cartil. 2015;23:1043–1056.

[7] Lluch Girb�es E, Nijs J, Torres-Cueco R, et al. Pain treatmentfor patients with osteoarthritis and central sensitization.Phys Ther. 2013;93:842–851.

[8] Bartley EJ, King CD, Sibille KT, et al. Enhanced pain sensitiv-ity among individuals with symptomatic knee osteoarthritis:potential sex differences in central sensitization. ArthritisCare Res (Hoboken). 2016;68:472–480.

Table 2. Summary of clinical descriptors extracted from the subjective assessment and physical examination aiding clinicians to recognize central sensitization inpatients with knee osteoarthritis.

Clinical measure Findings that may indicate CS

Descriptors from subjective assessmentPain intensity

Pain intensity vs. structural damageVAS/NRSVAS/NRS vs. imaging techniques

Moderate to severe pain (>5/10)Disproportion between pain intensity and structural damage

[31,32]Pain distribution Pain drawings Enlarged areas of pain outside the knee [42]; mirror

symptomsBehavior of knee pain History taking Disproportionate pain after physical activity [53]/exerciseNeuropathic-like symptoms painDETECT

Modified painDETECTHigher scores (not specified) [71]

>12/38 [72]Centrally mediated symptoms Central Sensitization Inventory >40/100 [66]Responsiveness to previous treatment History taking Inconsistent, unpredictable or unsuccessful response to local

interventionsPoor results with analgesics/AINES; better results with centrally

acting drugs (i.e., duloxetine) [83]Chronic post-surgical pain [85,86]

Descriptors from physical examinationResponse to clinical tests Clinical orthopedic tests Inconsistent/confusing response to clinical testsMechanical hyperalgesia Algometer

Manual palpationWidespread, non-anatomical lower pressure pain thresholds

[6,16,62]Diffuse non-anatomical tenderness

Allodynia Cotton wisp/cotton wool tip/brush Tactile allodynia [16,59]Thermal hyperalgesia Ice – 10 seconds application [92] NRS >5/10 [92]Hypoesthesia Cotton wool/cotton tipped applicator Local and/or remote tactile hypoesthesia [59,93]Vibration sense Rydel–Seiffer graduated tuning fork Reduced vibration detection threshold at different sites of the

lower extremity [95]Vibration allodynia [16]

CS: central sensitization; NRS: numeric rating scale; VAS: visual analog scale.

DESCRIPTORS FOR SENSITIZATION KNEE OSTEOARTHRITIS 7

Dow

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Cor

nell

Uni

vers

ity L

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ry]

at 0

1:15

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Aug

ust 2

017

[9] IASP Task Force on Taxonomy. Part III: pain terms, a currentlist with definitions and notes on usage. In: Merskey H,Bogduk N, editors. Classification of chronic pain: descrip-tions of chronic pain syndromes and definitions of painterms. 2nd ed. Seattle (WA): IASP Press;1994. p. 209–214.

[10] Woolf CJ. Central sensitization: implications for the diagno-sis and treatment of pain. Pain. 2011;152:S2–S15.

[11] Woolf CJ. What to call the amplification of nociceptive sig-nals in the central nervous system that contribute to wide-spread pain? Pain. 2014;155:1911–1912.

[12] Hansson P. Translational aspects of central sensitizationinduced by primary afferent activity: what it is and what itis not. Pain. 2014;155:1932–1934.

[13] Kosek E, Cohen M, Baron R, et al. Do we need a thirdmechanistic descriptor for chronic pain states? Pain.2016;157:1382–1386.

[14] Schliessbach J, Siegenthaler A, Streitberger K, et al. Theprevalence of widespread central hypersensitivity in chronicpain patients. Eur J Pain. 2013;17:1502–1510.

[15] Wolfe F. Fibromyalgianess. Arthritis Rheum. 2009;61:715–716.

[16] Courtney CA, Kavchak AE, Lowry CD, et al. Interpreting jointpain: quantitative sensory testing in musculoskeletal man-agement. J Orthop Sports Phys Ther. 2010;40:818–825.

[17] Suokas AK, Walsh DA, McWilliams DF, et al. Quantitativesensory testing in painful osteoarthritis: a systematic reviewand meta-analysis. Osteoarthr Cartil. 2012;20:1075–1085.

[18] Courtney CA, Lewek MD, Witte PO, et al. Heightened flexorwithdrawal responses in subjects with knee osteoarthritis.J Pain. 2009;10:1242–1249.

[19] Gwilym SE, Keltner JR, Warnaby CE, et al. Psychophysicaland functional imaging evidence supporting the presenceof central sensitization in a cohort of osteoarthritis patients.Arthritis Rheum. 2009;61:1226–1234.

[20] Parks EL, Geha PY, Baliki MN, et al. Brain activity for chronicknee osteoarthritis: dissociating evoked pain from spontan-eous pain. Eur J Pain. 2011;15:843.e1–814.

[21] Arendt-Nielsen L, Egsgaard LL, Petersen KK, et al. A mech-anism-based pain sensitivity index to characterize kneeosteoarthritis patients with different disease stages andpain levels. Eur J Pain. 2015;19:1406–1417.

[22] Egsgaard LL, Eskehave TN, Bay-Jensen AC, et al. Identifyingspecific profiles in patients with different degrees of painfulknee osteoarthritis based on serological biochemical andmechanistic pain biomarkers: a diagnostic approach basedon cluster analysis. Pain. 2015;156:96–107.

[23] Kittelson AJ, Stevens-Lapsley JE, Schmiege SJ.Determination of pain phenotypes in knee osteoarthritis: alatent class analysis using data from the osteoarthritis initia-tive. Arthritis Care Res (Hoboken). 2016;68:612–620.

[24] Malfait AM, Schnitzer TJ. Towards a mechanism-basedapproach to pain management in osteoarthritis. Nat RevRheumatol. 2013;9:654–664.

[25] Curatolo M. Diagnosis of altered central pain processing.Spine (Phila PA 1976). 2011;36:S200–S204.

[26] Uddin Z, MacDermid JC. Quantitative sensory testing inchronic musculoskeletal pain. Pain Med. 2016;17:1694–1703.

[27] Arendt-Nielsen L, Nie H, Laursen MB, et al. Sensitization inpatients with painful knee osteoarthritis. Pain. 2010;149:573–581.

[28] King CD, Sibille KT, Goodin BR, et al. Experimental pain sen-sitivity differs as a function of clinical pain severity in

symptomatic knee osteoarthritis. Osteoarthr Cartil.2013;21:1243–1252.

[29] Neogi T, Frey-Law L, Scholz J, et al. Sensitivity and sensitisa-tion in relation to pain severity in knee osteoarthritis: traitor state? Ann Rheum Dis. 2015;74:682–688.

[30] Collins SL, Moore RA, McQuay HJ. The visual analogue painintensity scale: what is moderate pain in millimetres? Pain.1997;72:95–97.

[31] Bedson J, Croft PR. The discordance between clinical andradiographic knee osteoarthritis: a systematic search andsummary of the literature. BMC Musculoskelet Disord.2008;9:116.

[32] Finan PH, Buenaver LF, Bounds SC, et al. Discordancebetween pain and radiographic severity in knee osteoarth-ritis: findings from quantitative sensory testing of centralsensitization. Arthritis Rheum. 2013;65:363–372.

[33] Lo GH, McAlindon TE, Niu J, et al. Bone marrow lesions andjoint effusion are strongly and independently associatedwith weight-bearing pain in knee osteoarthritis: data fromthe osteoarthritis initiative. Osteoarthr Cartil.2009;17:1562–1569.

[34] Torres L, Dunlop DD, Peterfy C, et al. The relationshipbetween specific tissue lesions and pain severity in personswith knee osteoarthritis. Osteoarthr Cartil. 2006;14:1033–1040.

[35] Wang X, Jin X, Han W, et al. Cross-sectional and longitu-dinal associations between knee joint effusion synovitisand knee pain in older adults. J Rheumatol. 2016;43:121–130.

[36] Nijs J, Torres-Cueco R, van Wilgen CP, et al. Applying mod-ern pain neuroscience in clinical practice: criteria for theclassification of central sensitization pain. Pain Physician.2014;17:447–457.

[37] Creamer P, Lethbridge-Cejku M, Hochberg MC. Where doesit hurt? Pain localization in osteoarthritis of the knee.Osteoarthr Cartil. 1998;6:318–323.

[38] Thompson LR, Boudreau R, Hannon MJ, et al. The kneepain map: reliability of a method to identify knee pain loca-tion and pattern. Arthritis Rheum. 2009;61:725–731.

[39] Wood LR, Peat G, Thomas E, et al. Knee osteoarthritis incommunity-dwelling older adults: are there characteristicpatterns of pain location? Osteoarthr Cartil. 2007;15:615–623.

[40] Van Ginckel A, Bennell KL, Campbell PK, et al. Location ofknee pain in medial knee osteoarthritis: patterns and asso-ciations with self-reported clinical symptoms. OsteoarthrCartil. 2016;24:1135–1142.

[41] Bajaj P, Bajaj P, Graven-Nielsen T, et al. Osteoarthritis andits association with muscle hyperalgesia: an experimentalcontrolled study. Pain. 2001;93:107–114.

[42] Lluch Girb�es E, Due~nas L, Barbero M, et al. Expanded distri-bution of pain as a sign of central sensitization in individu-als with symptomatic knee osteoarthritis. Phys Ther.2016;96:1196–1207.

[43] Riddle DL, Stratford PW. Knee pain during daily tasks, kneeosteoarthritis severity, and widespread pain. Phys Ther.2014;94:490–498.

[44] Visser EJ, Ramachenderan J, Davies SJ, et al. Chronic wide-spread pain drawn on a body diagram is a screening toolfor increased pain sensitization, psycho-social load, and util-ization of pain management strategies. Pain Pract.2016;16:31–37.

[45] Dave AJ, Selzer F, Losina E, et al. The association of pre-operative body pain diagram scores with pain outcomes

8 E. LLUCH ET AL.

Dow

nloa

ded

by [

Cor

nell

Uni

vers

ity L

ibra

ry]

at 0

1:15

03

Aug

ust 2

017

following total knee arthroplasty. Osteoarthr Cartil. 2016;25:667–675.

[46] Radhakrishnan R, Moore SA, Sluka KA. Unilateral carra-geenan injection into muscle or joint induces chronic bilat-eral hyperalgesia in rats. Pain. 2003;104:567–577.

[47] Skou ST, Graven-Nielsen T, Rasmussen S, et al. Widespreadsensitization in patients with chronic pain after revisiontotal knee arthroplasty. Pain. 2013;154:1588–1594.

[48] Wolfe F, Clauw DJ, Fitzcharles MA, et al. The AmericanCollege of Rheumatology preliminary diagnostic criteria forfibromyalgia and measurement of symptom severity.Arthritis Care Res. 2010;62:600–610.

[49] Amris K, Waehrens EE, Bliddal H, et al. How widespreadshould pain be to be defined as widespread? Pain.2016;157:1831–1832.

[50] Perrot S, Poiraudeau S, Kabir-Ahmadi M, et al. Correlates ofpain intensity in men and women with hip and knee osteo-arthritis. Results of a national survey: the French ARTHRIXstudy. Clin J Pain. 2009;25:767–772.

[51] Sayers A, Wylde V, Lenguerrand E, et al. Rest pain andmovement-evoked pain as unique constructs in hip andknee replacements. Arthritis Care Res (Hoboken). 2016;68:237–245.

[52] Srikandarajah S, Gilron I. Systematic review of movement-evoked pain versus pain at rest in postsurgical clinical trialsand meta-analyses: a fundamental distinction requiringstandardized measurement. Pain. 2011;152:1734–1739.

[53] Wideman TH, Finan PH, Edwards RR, et al. Increased sensi-tivity to physical activity among individuals with kneeosteoarthritis: relation to pain outcomes, psychological fac-tors, and responses to quantitative sensory testing. Pain.2014;155:703–711.

[54] Nijs J, Kosek E, Van Oosterwijck J, et al. Dysfunctionalendogenous analgesia during exercise in patients withchronic pain: to exercise or not to exercise? Pain Physician.2012;15:ES205–ES213.

[55] Kosek E, Roos EM, Ageberg E, et al. Increased pain sensitiv-ity but normal function of exercise induced analgesia in hipand knee osteoarthritis–treatment effects of neuromuscularexercise and total joint replacement. Osteoarthr Cartil.2013;21:1299–1307.

[56] Burrows NJ, Booth J, Sturnieks DL, et al. Acute resistanceexercise and pressure pain sensitivity in knee osteoarthritis:a randomized crossover trial. Osteoarthr Cartil. 2014;22:407–414.

[57] Smart KM, Blake C, Staines A, et al. Mechanisms-based clas-sifications of musculoskeletal pain: part 3 of 3: symptomsand signs of nociceptive pain in patients with low back (±leg) pain. Man Ther. 2012;17:352–357.

[58] Smart KM, Blake C, Staines A, et al. Mechanisms-based clas-sifications of musculoskeletal pain: part 1 of 3: symptomsand signs of central sensitisation in patients with low back(± leg) pain. Man Ther. 2012;17:336–344.

[59] Hochman JR, French MR, Bermingham SL, et al. The nerveof osteoarthritis pain. Arthritis Care Res (Hoboken).2010;62:1019–1023.

[60] Murphy SL, Lyden AK, Phillips K, et al. Association betweenpain, radiographic severity, and centrally-mediated symp-toms in women with knee osteoarthritis. Arthritis Care Res.2011;63:1543–1549.

[61] Murphy SL, Lyden AK, Phillips K, et al. Subgroups of olderadults with osteoarthritis based upon differing comorbidsymptom presentations and potential underlying painmechanisms. Arthritis Res Ther. 2011;13:R135.

[62] Lluch E, Torres R, Nijs J, et al. Evidence for central sensitiza-tion in patients with osteoarthritis pain: a systematic litera-ture review. Eur J Pain. 2014;18:1367–1375.

[63] Mayer TG, Neblett R, Cohen H, et al. The development andpsychometric validation of the central sensitization inven-tory. Pain Pract. 2012;12:276–285.

[64] Freynhagen R, Baron R, Gockel U, et al. painDETECT: a newscreening questionnaire to identify neuropathic compo-nents in patients with back pain. Curr Med Res Opin.2006;22:1911.

[65] Neblett R, Hartzell MM, Cohen H, et al. Ability of the centralsensitization inventory to identify central sensitivity syn-dromes in an outpatient chronic pain sample. Clin J Pain.2015;31:323–332.

[66] Neblett R, Cohen H, Choi Y, et al. The Central SensitizationInventory (CSI): establishing clinically significant values foridentifying central sensitivity syndromes in an outpatientchronic pain sample. J Pain. 2013;14:438–445.

[67] Kim SH, Yoon KB, Yoon DM, et al. Influence of centrallymediated symptoms on postoperative pain in osteoarthritispatients undergoing total knee arthroplasty: a prospectiveobservational evaluation. Pain Pract. 2015;15:E46–E53.

[68] Dimitroulas T, Duarte RV, Behura A, et al. Neuropathic painin osteoarthritis: a review of pathophysiological mecha-nisms and implications for treatment. Semin ArthritisRheum. 2014;44:145–154.

[69] Duarte RV, Raphael JH, Dimitroulas T, et al. Osteoarthritispain has a significant neuropathic component: an explora-tory in vivo patient model. Rheumatol Int. 2014;34:315–320.

[70] Oteo-�Alvaro �A, Ruiz-Ib�an MA, Miguens X, et al. High preva-lence of neuropathic pain features in patients with kneeosteoarthritis: a cross-sectional study. Pain Pract.2015;15:618–626.

[71] Moreton BJ, Tew V, das Nair R, et al. Pain phenotype inpatients with knee osteoarthritis: classification and meas-urement properties of painDETECT and self-report Leedsassessment of neuropathic symptoms and signs scale in across-sectional study. Arthritis Care Res (Hoboken).2015;67:519–528.

[72] Hochman JR, Davis AM, Elkayam J, et al. Neuropathic painsymptoms on the modified painDETECT correlate with signsof central sensitization in knee osteoarthritis. OsteoarthrCartil. 2013;21:1236–1242.

[73] Hochman JR, Gagliese L, Davis AM, et al. Neuropathic painsymptoms in a community knee OA cohort. OsteoarthrCartil. 2011;19:647–654.

[74] Somers TJ, Keefe FJ, Godiwala N, et al. Psychosocial factorsand the pain experience of osteoarthritis patients: newfindings and new directions. Curr Opin Rheumatol.2009;21:501–506.

[75] Baert IA, Lluch E, Mulder T, et al. Does pre-surgical centralmodulation of pain influence outcome after total kneereplacement? A systematic review. Osteoarthr Cartil.2016;24:213–223.

[76] Goodin BR, Glover TL, Sotolongo A, et al. The association ofgreater dispositional optimism with less endogenous painfacilitation is indirectly transmitted through lower levels ofpain catastrophizing. J Pain. 2013;14:126–135.

[77] Herbert MS, Goodin BR, Pero ST IV, et al. Pain hypervigi-lance is associated with greater clinical pain severity andenhanced experimental pain sensitivity among adults withsymptomatic knee osteoarthritis. Ann Behav Med. 2014;48:50–60.

DESCRIPTORS FOR SENSITIZATION KNEE OSTEOARTHRITIS 9

Dow

nloa

ded

by [

Cor

nell

Uni

vers

ity L

ibra

ry]

at 0

1:15

03

Aug

ust 2

017

[78] Nijs J, Van Houdenhove B, Oostendorp RA. Recognition ofcentral sensitization in patients with musculoskeletal pain:application of pain neurophysiology in manual therapypractice. Man Ther. 2010;15:135–141.

[79] Coombes BK, Bisset L, Vicenzino B. Cold hyperalgesia asso-ciated with poorer prognosis in lateral epicondylalgia: a 1-year prognostic study of physical and psychological factors.Clin J Pain. 2015;31:30–35.

[80] Jull G, Sterling M, Kenardy J, et al. Does the presence ofsensory hypersensitivity influence outcomes of physicalrehabilitation for chronic whiplash? A preliminary RCT. Pain.2007;129:28–34.

[81] O'Leary H, Smart KM, Moloney NA, et al. Pain sensitisationand the risk of poor outcome following physiotherapy forpatients with moderate to severe knee osteoarthritis: proto-col for a prospective cohort study. BMJ Open. 2015;5:e007430.

[82] Courtney CA, Steffen AD, Fern�andez-de-Las-Pe~nas C, et al.Joint mobilization enhances mechanisms of conditionedpain modulation in individuals with osteoarthritis of theknee. J Orthop Sports Phys Ther. 2016;46:1–30.

[83] Chappell AS, Ossanna MJ, Liu-Seifert H, et al. Duloxetine, acentrally acting analgesic, in the treatment of patients withosteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial. Pain. 2009; 146:253–260.

[84] Beswick AD, Wylde V, Gooberman-Hill R, et al. What propor-tion of patients report long-term pain after total hip orknee replacement for osteoarthritis? A systematic review ofprospective studies in unselected patients. BMJ Open.2012;2:e000435.

[85] Skou ST, Graven-Nielsen T, Rasmussen S, et al. Facilitationof pain sensitization in knee osteoarthritis and persistentpost-operative pain: a cross-sectional study. Eur J Pain.2014;18:1024–1031.

[86] Wylde V, Palmer S, Learmonth ID, et al. The associationbetween pre-operative pain sensitisation and chronic painafter knee replacement: an exploratory study. OsteoarthrCartil. 2013;21:1253–1256.

[87] Wylde V, MacKichan F, Bruce J, et al. Assessment of chronicpost-surgical pain after knee replacement: development ofa core outcome set. Eur J Pain. 2015;19:611–620.

[88] Neziri AY, Scaramozzino P, Andersen OK, et al. Referencevalues of mechanical and thermal pain tests in a pain-freepopulation. Eur J Pain. 2011;15:376–383.

[89] Rebbeck T, Moloney N, Azoory R, et al. Clinical ratings ofpain sensitivity correlate with quantitative measures in peo-ple with chronic neck pain and healthy controls: cross-sec-tional study. Phys Ther. 2015;95:1536–1546.

[90] O'Neill S, Manniche C, Graven-Nielsen T, et al. Associationbetween a composite score of pain sensitivity andclinical parameters in low-back pain. Clin J Pain.2014;30:831–838.

[91] Moss P, Knight E, Wright A. Subjects with knee osteoarth-ritis exhibit widespread hyperalgesia to pressure and cold.PLoS One. 2016;11:e0147526.

[92] Maxwell S, Sterling M. An investigation of the use of anumeric pain rating scale with ice application to the neckto determine cold hyperalgesia. Man Ther. 2013;18:172–174.

[93] Kavchak AJ, Fern�andez-de-Las-Pe~nas C, Rubin LH, et al.Association between altered somatosensation, pain, andknee stability in patients with severe knee osteoarthrosis.Clin J Pain. 2012;28:589–594.

[94] Rolke R, Baron R, Maier C, et al. Quantitative sensory testingin the German Research Network on Neuropathic Pain(DFNS): standardized protocol and reference values.Pain. 2006;123:231–243.

[95] Shakoor N, Agrawal A, Block JA. Reduced lower extremityvibratory perception in osteoarthritis of the knee. ArthritisRheum. 2008;59:117–121.

[96] Neogi T, Guermazi A, Roemer F, et al. Association of jointinflammation with pain sensitization in knee osteoarthritis:the multicenter osteoarthritis study. Arthritis Rheumatol.2016;68:654–661.

[97] Lluch Girb�es E, Meeus M, Baert I, et al. Balancing “hands-on” with “hands-off” physical therapy interventions for thetreatment of central sensitization pain in osteoarthritis.Man Ther. 2015;20:349–352.

[98] Neblett R, Hartzell MM, Mayer TG, et al. Establishing clinic-ally relevant severity levels for the central sensitizationinventory. Pain Pract. 2016;17:166–175.

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